Michael Fischbein

All Publications

• Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome. The Journal of thoracic and cardiovascular surgery Pedroza, A. J., Cheng, P., Dalal, A. R., Baeumler, K., Kino, A., Tognozzi, E., Shad, R., Yokoyama, N., Nakamura, K., Mitchel, O., Hiesinger, W., MacFarlane, E. G., Fleischmann, D., Woo, Y. J., Quertermous, T., Fischbein, M. P. 2023

  Abstract

  Loeys-Dietz syndrome (LDS) patients demonstrate heightened risk of distal thoracic aortic events after valve-sparing aortic root replacement (VSARR). This study assesses the clinical risks and hemodynamic consequences of a prophylactic aortic arch replacement strategy in LDS and characterizes smooth muscle cell (SMC) phenotype in LDS aneurysmal and normal-sized downstream aorta.Patients with genetically confirmed LDS (n=8) underwent prophylactic aortic arch replacement during VSARR. 4D flow magnetic resonance imaging (MRI) studies were performed in n=4 LDS patients (VSARR+arch) and compared with both contemporary Marfan syndrome patients (VSARR only, n=5) and control patients (without aortopathy, n=5). Aortic tissues from n=4 LDS patients and n=2 organ donors were processed for anatomically segmented single-cell RNA sequencing (scRNAseq) and histologic assessment.LDS VSARR+arch patients had no deaths, major morbidity, or aortic events in median 2.00 years follow-up. 4D-MRI demonstrated altered flow parameters in post-operative aortopathy patients relative to controls, but no clear deleterious changes attributable to arch replacement. Integrated analysis of aortic scRNAseq data (>49,000 cells) identified a continuum of abnormal SMC phenotypic modulation in LDS defined by reduced contractility and enriched extracellular matrix synthesis, adhesion receptors, and transforming growth factor-beta signaling. These 'modulated SMCs' populated the LDS tunica media with gradually reduced density from the overtly aneurysmal root to the non-dilated arch.LDS patients demonstrated excellent surgical outcomes without overt downstream flow or shear stress disturbances after concomitant VSARR+arch operations. Abnormal SMC-mediated aortic remodeling occurs within the normal diameter, clinically at-risk LDS arch segment. These initial clinical and pathophysiologic findings support concomitant arch replacement in LDS.

  View details for DOI 10.1016/j.jtcvs.2023.07.023

  View details for PubMedID 37500053

• Smooth Muscle Cell Klf4 Expression Is Not Required for Phenotype Modulation or Aneurysm Formation in Marfan Syndrome Mice. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Dalal, A. R., Shad, R., Yokoyama, N., Nakamura, K., Mitchel, O., Gilles, C., Hiesinger, W., Fischbein, M. P. 2023

  Abstract

  BACKGROUND: Smooth muscle cell (SMC) phenotypic reprogramming toward a mixed synthetic-proteolytic state is a central feature of aortic root aneurysm in Marfan syndrome (MFS). Previous work identified Klf4 as a potential mediator of SMC plasticity in MFS.METHODS: MFS (Fbn1C1041G/+) mouse strains with an inducible vascular SMC fluorescent reporter (MFSSMC) with or without SMC-specific deletion of Klf4 exons 2 to 3 (MFSSMC-Klf4Delta) were generated. Simultaneous SMC tracing and Klf4 loss-of-function (Klf4Delta mice) was induced at 6 weeks of age. Aneurysm growth was assessed via serial echocardiography (4-24 weeks). Twenty-four-week-old mice were assessed via histology, RNA in situ hybridization, and aortic single-cell RNA sequencing.RESULTS: MFS mice demonstrated progressive aortic root dilatation compared with control (WTSMC) mice regardless of Klf4 genotype (P<0.001), but there was no difference in aneurysm growth in MFSSMC-Klf4Delta versus MFSSMC (P=0.884). Efficient SMC Klf4 deletion was confirmed via lineage-stratified genotyping, RNA in situ hybridization, and immunohistochemistry. Single-cell RNA sequencing of traced SMCs revealed a highly similar pattern of phenotype modulation marked by loss of contractile markers (eg, Myh11, Cnn1) and heightened expression of matrix genes (eg, Col1a1, Fn1) between Klf4 genotypes. Pseudotemporal quantitation of SMC dedifferentiation confirmed that Klf4 deletion did not alter the global extent of phenotype modulation, but reduced expression of 23 genes during this phenotype transition in MFSSMC-Klf4Deltamice, including multiple chondrogenic genes expressed by only the most severely dedifferentiated SMCs (eg, Cytl1, Tnfrsf11b).CONCLUSIONS: Klf4 is not required to initiate SMC phenotype modulation in MFS aneurysm but may exert regulatory control over chondrogenic genes expressed in highly dedifferentiated SMCs.

  View details for DOI 10.1161/ATVBAHA.122.318509

  View details for PubMedID 37128911

• Lineage-Specific Induced Pluripotent Stem Cell-Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice. Arteriosclerosis, thrombosis, and vascular biology Nakamura, K., Dalal, A. R., Yokoyama, N., Pedroza, A. J., Kusadokoro, S., Mitchel, O., Gilles, C., Masoudian, B., Leipzig, M., Casey, K. M., Hiesinger, W., Uchida, T., Fischbein, M. P. 2023

  Abstract

  To delineate the effects of integrin αv signaling in Marfan syndrome (MFS) and examine the potential efficacy of integrin αv blockade as a therapeutic strategy for MFS aneurysms.Induced pluripotent stem cells were differentiated into aortic smooth muscle cells (SMCs) of the second heart field (SHF) and neural crest lineages, enabling in vitro modeling of thoracic aortic aneurysm in MFS. Fbn1C1039G/+ MFS mice treated with integrin αv antagonist (GLPG0187) confirmed the pathological role of integrin αv on aneurysm formation.Induced pluripotent stem cell-derived MFS SHF SMCs overexpress integrin αv relative to MFS neural crest and healthy control SHF cells. Furthermore, downstream targets of integrin αv (FAK [focal adhesion kinase]/AktThr308/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment GLPG0187 reduced p-FAK/p-AktThr308/mTORC1 activity in MFS SHF back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS neural crest and control SMCs, which was then inhibited by GLPG0187 treatment. In the Fbn1C1039G/+ MFS mouse model, integrin αv, p-AktThr308, and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6-14 weeks) resulted in reduced aneurysm growth, elastin fragmentation, and normalization of the FAK/AktThr308/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing.The integrin αv-FAK-AktThr308 signaling pathway is activated in induced pluripotent stem cell SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-AktThr308 signaling in Fbn1C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.

  View details for DOI 10.1161/ATVBAHA.122.318448

  View details for PubMedID 37078287

• Outcomes of Reoperative Aortic Root Replacement After Previous Acute Type A Dissection Repair. Seminars in thoracic and cardiovascular surgery Pedroza, A. J., Dalal, A. R., Krishnan, A., Yokoyama, N., Nakamura, K., Tognozzi, E., Woo, Y. J., Macarthur, J. W., Fischbein, M. P. 2023

  Abstract

  Limited aortic root repair for acute type A dissection is associated with greater risk of proximal reoperations compared to full aortic root replacement. Surgical outcomes for patients undergoing reoperative root replacement after previous dissection repair are unknown. This study seeks to determine outcomes for these patients to further inform the debate surrounding optimal upfront management of the aortic root in acute dissection. Retrospective record review of all patients who underwent full aortic root replacement after a previous type A dissection repair operation at a tertiary academic referral center from 2004-2020 was performed. Among 57 cases of reoperative root replacement after type A repair, 35 cases included concomitant aortic arch replacements, and 21 cases involved coronary reconstruction (unilateral or bilateral modified Cabrol grafts). There were 3 acute post-operative strokes and 4 operative mortalities (composite 30-day and in-hospital deaths, 7.0%) . Mid-term outcomes were equivalent for patients who required arch replacement compared to isolated proximal repairs (81.8% vs. 80.6% estimated 5-year survival, median follow-up 5.53 years. Reoperative root replacement after index type A dissection repairs, including those with concomitant aortic arch replacement and/or coronary reconstruction is achievable with acceptable outcomes at an experienced aortic center.

  View details for DOI 10.1053/j.semtcvs.2023.02.001

  View details for PubMedID 36758660

• Embryologic Origin Influences Smooth Muscle Cell Phenotypic Modulation Signatures in Murine Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Dalal, A. R., Shad, R., Yokoyama, N., Nakamura, K., Cheng, P., Wirka, R. C., Mitchel, O., Baiocchi, M., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2022: 101161ATVBAHA122317381

  Abstract

  BACKGROUND: Aortic root smooth muscle cells (SMC) develop from both the second heart field (SHF) and neural crest. Disparate responses to disease-causing Fbn1 variants by these lineages are proposed to promote focal aortic root aneurysm formation in Marfan syndrome (MFS), but lineage-stratified SMC analysis in vivo is lacking.METHODS: We generated SHF lineage-traced MFS mice and performed integrated multiomic (single-cell RNA and assay for transposase-accessible chromatin sequencing) analysis stratified by embryological origin. SMC subtypes were spatially identified via RNA in situ hybridization. Response to TWIST1 overexpression was determined via lentiviral transduction in human aortic SMCs.RESULTS: Lineage stratification enabled nuanced characterization of aortic root cells. We identified heightened SHF-derived SMC heterogeneity including a subset of Tnnt2-expressing cells distinguished by altered proteoglycan expression. MFS aneurysm-associated SMC phenotypic modulation was identified in both SHF-traced and nontraced (neural crest-derived) SMCs; however, transcriptomic responses were distinct between lineages. SHF-derived modulated SMCs overexpressed collagen synthetic genes and small leucine-rich proteoglycans while nontraced SMCs activated chondrogenic genes. These modulated SMCs clustered focally in the aneurysmal aortic root at the region of SHF/neural crest lineage overlap. Integrated RNA-assay for transposase-accessible chromatin analysis identified enriched Twist1 and Smad2/3/4 complex binding motifs in SHF-derived modulated SMCs. TWIST1 overexpression promoted collagen and SLRP gene expression in vitro, suggesting TWIST1 may drive SHF-enriched collagen synthesis in MFS aneurysm.CONCLUSIONS: SMCs derived from both SHF and neural crest lineages undergo phenotypic modulation in MFS aneurysm but are defined by subtly distinct transcriptional responses. Enhanced TWIST1 transcription factor activity may contribute to enriched collagen synthetic pathways SHF-derived SMCs in MFS.

  View details for DOI 10.1161/ATVBAHA.122.317381

  View details for PubMedID 35861960

• Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells. Scientific reports Iosef, C., Pedroza, A. J., Cui, J. Z., Dalal, A. R., Arakawa, M., Tashima, Y., Koyano, T. K., Burdon, G., Churovich, S. M., Orrick, J. O., Pariani, M., Fischbein, M. P. 2020; 10 (1): 20392

  Abstract

  Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype-phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may be related to distinct smooth muscle cell (SMC) embryologic lineages. Thus, peripheral blood mononuclear cell (PBMC)-derived induced pluripotent stem cells (iPSC) were differentiated into lateral mesoderm (LM, aortic root) and neural crest (NC, ascending aorta/transverse arch) SMC lineages to model MFS aortic pathology. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomic analysis by tandem mass spectrometry was applied to profile LM and NC iPSC SMCs from four MFS patients and two healthy controls. Analysis revealed 45 proteins with lineage-dependent expression in MFS patients, many of which were specific to diseased samples. Single protein-level data from both iPSC SMCs and primary MFS aortic root aneurysm tissue confirmed elevated integrin alphaV and reduced MRC2 in clinical disease specimens, validating the iPSC iTRAQ findings. Functionally, iPSC SMCs exhibited defective adhesion to a variety of extracellular matrix proteins, especially laminin-1 and fibronectin, suggesting altered cytoskeleton dynamics. This study defines the aortic embryologic origin-specific proteome in a validated iPSC SMC model to identify novel protein markers associated with MFS aneurysm phenotype. Translating iPSC findings into clinical aortic aneurysm tissue samples highlights the potential for iPSC-based methods to model MFS disease for mechanistic studies and therapeutic discovery in vitro.

  View details for DOI 10.1038/s41598-020-77274-w

  View details for PubMedID 33230159

• Androgens Accentuate TGF-beta Dependent Erk/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice. Journal of the American Heart Association Tashima, Y., He, H., Cui, J. Z., Pedroza, A. J., Nakamura, K., Yokoyama, N., Iosef, C., Burdon, G., Koyano, T., Yamaguchi, A., Fischbein, M. P. 2020; 9 (20): e015773

  Abstract

  Background Male patients with Marfan syndrome have a higher risk of aortic events and root dilatation compared with females. The role androgens play during Marfan syndrome aneurysm development in males remains unknown. We hypothesized that androgens potentiate transforming growth factor beta induced Erk (extracellular-signal-regulated kinase)/Smad activation, contributing to aneurysm progression in males. Methods and Results Aortic diameters in Fbn1C1039G/+ and littermate wild-type controls were measured at ages 6, 8, 12, and 16weeks. Fbn1C1039G/+ males were treated with (1) flutamide (androgen receptor blocker) or (2) vehicle control from age 6 to 16weeks and then euthanized. p-Erk1/2, p-Smad2, and matrix metalloproteinase (MMP) activity were measured in ascending/aortic root and descending aorta specimens. Fbn1C1039G/+ male and female ascending/aortic root-derived smooth muscle cells were utilized in vitro to measure Erk/Smad activation and MMP-2 activity following dihydrotestosterone, flutamide or transforming growth factor beta 1 treatment. Fbn1C1039G/+ males have increased aneurysm growth. p-Erk1/2 and p-Smad2 were elevated in ascending/aortic root specimens at age 16weeks. Corresponding with enhanced Erk/Smad signaling, MMP-2 activity was higher in Fbn1C1039G/+ males. In vitro smooth muscle cell studies revealed that dihydrotestosterone potentiates transforming growth factor beta-induced Erk/Smad activation and MMP-2 activity, which is reversed by flutamide treatment. Finally, in vivo flutamide treatment reduced aneurysm growth via p-Erk1/2 and p-Smad2 reduction in Fbn1C1039G/+ males. Conclusions Fbn1C1039G/+ males have enhanced aneurysm growth compared with females associated with enhanced p-Erk1/2 and p-Smad2 activation. Mechanistically, in vitro smooth muscle cell studies suggested that dihydrotestosterone potentiates transforming growth factor beta induced Erk/Smad activation. As biological proof of concept, flutamide treatment attenuated aneurysm growth and p-Erk1/2 and p-Smad2 signaling in Fbn1C1039G/+ males.

  View details for DOI 10.1161/JAHA.119.015773

  View details for PubMedID 33059492

• Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Tashima, Y., Shad, R., Cheng, P., Wirka, R., Churovich, S., Nakamura, K., Yokoyama, N., Cui, J. Z., Iosef, C., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2020: ATVBAHA120314670

  Abstract

  OBJECTIVE: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF (transforming growth factor)-beta-responsive genes correlated with SMC modulation in mouse and human data sets.CONCLUSIONS: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-beta plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-beta signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

  View details for DOI 10.1161/ATVBAHA.120.314670

  View details for PubMedID 32698686

• Time-to-operation does not predict outcome in acute type A aortic dissection complicated by neurologic injury at presentation JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Chiu, P., Rotto, T. J., Goldstone, A. B., Whisenant, J. B., Woo, Y., Fischbein, M. P. 2019; 158 (3): 665–72

  View details for DOI 10.1016/j.jtcvs.2018.12.023

  View details for Web of Science ID 000481621000026

• Time-to-operation does not predict outcome in acute type A aortic dissection complicated by neurologic injury at presentation. The Journal of thoracic and cardiovascular surgery Chiu, P., Rotto, T. J., Goldstone, A. B., Whisenant, J. B., Woo, Y. J., Fischbein, M. P. 2018

  Abstract

  OBJECTIVE: Neurologic injury complicating the presentation of acute type A aortic dissection remains a challenge for cardiac surgeons.METHODS: This was a retrospective review of patients undergoing open repair of acute type A aortic dissection at our institution between January 2005 and December 2015. Evidence of neurologic injury at the time of presentation was abstracted from the medical record. Propensity-score matching was used to account for baseline differences between groups, and outcome analysis was performed using logistic regression and Kaplan-Meier analysis. Among patients with persistent neurologic deficits, a threshold for time-to-operation was evaluated using receiver operating characteristic curves.RESULTS: There were 345 patients who underwent open repair for acute type A aortic dissection; 50 patients presented with neurologic injury. In the matched analysis, in-hospital mortality was greater among patients who presented with neurologic deficits (odds ratio, 4.42; 95% confidence interval, 1.15-16.97; P=.03). Among patients with persistent neurologic deficits at presentation, receiver operating characteristic curve analysis with cross-validation suggested that time-to-operation was a poor predictor of both neurologic outcome (area under the curve, 0.40) and death (area under the curve, 0.49).CONCLUSIONS: Neurologic injury at the time of presentation with acute type A aortic dissection was associated with an increased risk of in-hospital mortality. Among patients with persistent neurological deficits, time-to-operation failed to predict either neurologic outcome or perioperative mortality suggesting that longer time from onset of symptoms of neurologic injury should not act as a contraindication to proceeding to the operating room for expedient repair.

  View details for PubMedID 30712911

• Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras-Induced ERK (Extracellular Signal-Regulated Kinase) Signaling Pathway JOURNAL OF THE AMERICAN HEART ASSOCIATION Sato, T., Arakawa, M., Tashima, Y., Tsuboi, E., Burdon, G., Trojan, J., Koyano, T., Young-Nam Youn, Penov, K., Pedroza, A. J., Shabazzi, M., Palmon, I., Nguyen, M., Connolly, A. J., Yamaguchi, A., Fischbein, M. P. 2018; 7 (21): e008543

  Abstract

  Background Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane-bound G-protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction. Methods and Results Fbn1C1039G/+ mice were treated with (1) pravastatin (HMG-CoA [3-hydroxy-3-methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A ( MA ; FPT inhibitor), (3) perillyl alcohol ( GGPT 1 and -2 inhibitor), or (4) vehicle control from age 4 to 8 weeks and euthanized at 12 weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal-regulated kinase) signaling. In vitro Fbn1C1039G/+ aortic smooth muscle cells were utilized to measure Ras-dependent ERK signaling and MMP (matrix metalloproteinase) activity. Pravastatin and MA significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast, PA did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in MA -treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c-Raf and phosphorylated ERK 1/2 were significantly reduced in MA -treated mice (4-5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cR af and phosphorylated ERK 1/2 signaling was elevated in Fbn1C1039G/+ smooth muscle cells (n=5 per group). Fbn1C1039G/+ smooth muscle cell Ras-dependent ERK signaling and MMP activity were reduced following MA treatment (n=5 per group). Corroborating in vitro findings, MMP activity was also decreased in pravastatin-treated mice. Conclusions Aneurysm reduction in Fbn1C1039G/+ mice following pravastatin and MA treatment was associated with a decrease in Ras-dependent ERK signaling. MMP activity can be reduced by diminishing Ras signaling.

  View details for PubMedID 30571378

• Immediate operation for acute type A aortic dissection complicated by visceral or peripheral malperfusion JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Chiu, P., Tsou, S., Goldstone, A. B., Louie, M., Woo, Y., Fischbein, M. P. 2018; 156 (1): 18-+

  View details for DOI 10.1016/j.jtcvs.2018.01.096

  View details for Web of Science ID 000436592600021

• Enhanced Caspase Activity Contributes to Aortic Wall Remodeling and Early Aneurysm Development in a Murine Model of Marfan Syndrome ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Emrich, F. C., Okamura, H., Dalal, A. R., Penov, K., Merk, D. R., Raaz, U., Hennigs, J. K., Chin, J. T., Miller, M. O., Pedroza, A. J., Craig, J. K., Koyano, T. K., Blankenberg, F. G., Connolly, A. J., Mohr, F. W., Alvira, C. M., Rabinovitch, M., Fischbein, M. P. 2015; 35 (1): 146-154

  Abstract

  Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome.Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs.Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.

  View details for DOI 10.1161/ATVBAHA.114.304364

  View details for PubMedID 25359856

• Assessment of elastin deficit in a marfan mouse aneurysm model using an elastin-specific magnetic resonance imaging contrast agent. Circulation. Cardiovascular imaging Okamura, H., Pisani, L. J., Dalal, A. R., Emrich, F., Dake, B. A., Arakawa, M., Onthank, D. C., Cesati, R. R., Robinson, S. P., Milanesi, M., Kotek, G., Smit, H., Connolly, A. J., Adachi, H., McConnell, M. V., Fischbein, M. P. 2014; 7 (4): 690-696

  Abstract

  -Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome (MFS). The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using magnetic resonance imaging (MRI) with a gadolinium-based elastin-specific contrast agent (ESMA) in Fbn1(C1039G/+) mice.-Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (WT) (n=9 and n=10, respectively) using 7T MRI with a T1-mapping sequence. Significantly lower enhancement (i.e., lower R1 values, where R1=1/T1) was detected post-ESMA in Fbn1(C1039G/+) compared to WT ascending aortas (1.15±0.07 vs. 1.36±0.05, p<0.05). Post-ESMA R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (p=0.006).-Herein, we demonstrate that MRI with ESMA accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared to WT controls. This approach has translational potential for non-invasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions.

  View details for DOI 10.1161/CIRCIMAGING.114.001658

  View details for PubMedID 24814820

• miR-29b Participates in Early Aneurysm Development in Marfan Syndrome CIRCULATION RESEARCH Merk, D. R., Chin, J. T., Dake, B. A., Maegdefessel, L., Miller, M. O., Kimura, N., Tsao, P. S., Iosef, C., Berry, G. J., Mohr, F. W., Spin, J. M., Alvira, C. M., Robbins, R. C., Fischbein, M. P. 2012; 110 (2): 312-?

  Abstract

  Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined.We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

  View details for DOI 10.1161/CIRCRESAHA.111.253740

  View details for PubMedID 22116819

• Initial Outcomes of the Gore TAG Thoracic Branch Endoprosthesis for Endovascular Repair of Blunt Thoracic Aortic Injury. Annals of vascular surgery Chou, E. L., Lu, E., Dake, M. D., Fischbein, M. P., Bavaria, J. E., Oderich, G., Makaroun, M. S., Charlton-Ouw, K. M., Naslund, T., Suckow, B. D., Matsumura, J. S., Patel, H. J., Azizzadeh, A. 2024

  Abstract

  Endovascular repair of blunt thoracic aortic injury (BTAI) has dramatically reduced the morbidity and mortality of intervention. Injuries requiring zone 2 coverage of the aorta traditionally require left subclavian artery (LSA) sacrifice or open revascularization. Furthermore, these injuries are associated with increased risk of in-hospital mortality and long-term morbidity. Here we report 1-year outcomes of total endovascular repair of BTAI with the GORE® TAG® Thoracic Branch Endoprosthesis for LSA preservation.Across 34 investigative sites, 9 patients with BTAI requiring left subclavian artery coverage were enrolled in a nonrandomized, prospective study of a single branched aortic endograft. The thoracic branch endoprosthesis device allows for graft placement proximal to the LSA and incorporates a single side branch for LSA perfusion.This initial cohort included 8 male and 1 female patient with a median age of 43 (22, 76) and 12 months of follow-up. Five total years of follow-up is planned. All participants had grade 3 BTAI. All procedures took place between 2018-2019. The median injury severity score was 2 (0, 66). The median procedure time was 109 minutes (78, 162). All aortic injuries were repaired under general anesthesia and with heparinization. A spinal drain was used in one patient. Post-deployment balloon angioplasty was conducted in one case at the distal landing zone. There was one asymptomatic LSA branch occlusion 6 months after repair. It was attributed to purposeful proximal deployment of the branch stent to accommodate an early vertebral takeoff. The occlusion did not require revascularization. There were no strokes, mortalities, or aortic adverse events (migration, endoleak, native aortic expansion, dissection or thrombosis) through 12 months of follow-up.Initial cohort outcomes suggest that endovascular repair of zone 2 BTAI is feasible and has favorable outcomes using the thoracic branch device with LSA preservation. Additional cases and longer-term follow-up are required for definitive assessment of the device safety and durability in traumatic aortic injuries.

  View details for DOI 10.1016/j.avsg.2023.12.088

  View details for PubMedID 38492730

• Comprehensive Integration of Multiple Single-Cell Transcriptomic Datasets Defines Distinct Cell Populations and Their Phenotypic Changes in Murine Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology Sharma, D., DeForest Worssam, M., Pedroza, A. J., Dalal, A. R., Alemany, H., Kim, H. J., Kundu, R., Fischbein, M., Cheng, P., Wirka, R., Quertermous, T. 2023

  Abstract

  The application of single-cell transcriptomic (single-cell RNA sequencing) analysis to the study of atherosclerosis has provided unique insights into the molecular and genetic mechanisms that mediate disease risk and pathophysiology. However, nonstandardized methodologies and relatively high costs associated with the technique have limited the size and replication of existing data sets and created disparate or contradictory findings that have fostered misunderstanding and controversy.To address these uncertainties, we have performed a conservative integration of multiple published single-cell RNA sequencing data sets into a single meta-analysis, performed extended analysis of native resident vascular cells, and used in situ hybridization to map the disease anatomic location of the identified cluster cells. To investigate the transdifferentiation of smooth muscle cells to macrophage phenotype, we have developed a classifying algorithm based on the quantification of reporter transgene expression.The reporter gene expression tool indicates that within the experimental limits of the examined studies, transdifferentiation of smooth muscle cell to the macrophage lineage is extremely rare. Validated transition smooth muscle cell phenotypes were defined by clustering, and the location of these cells was mapped to lesion anatomy with in situ hybridization. We have also characterized 5 endothelial cell phenotypes and linked these cellular species to different vascular structures and functions. Finally, we have identified a transcriptomically unique cellular phenotype that constitutes the aortic valve.Taken together, these analyses resolve a number of outstanding issues related to differing results reported with vascular disease single-cell RNA sequencing studies, and significantly extend our understanding of the role of resident vascular cells in anatomy and disease.

  View details for DOI 10.1161/ATVBAHA.123.320030

  View details for PubMedID 38152886

• Introduction to the 2023 Cardiovascular Surgery Issue. Circulation Ruel, M., Fischbein, M. P., de Lemos, J. A. 2023; 148 (17): 1287-1288

  View details for DOI 10.1161/CIRCULATIONAHA.123.067002

  View details for PubMedID 37871236

• Augmenting Mitochondrial Respiration in Immature Smooth Muscle Cells with anACTA2Pathogenic Variant Mitigates Moyamoya-like Cerebrovascular Disease. Research square Kaw, A., Wu, T., Starosolski, Z., Zhou, Z., Pedroza, A. J., Majumder, S., Duan, X., Kaw, K., Pinelo, J. E., Fischbein, M. P., Lorenzi, P. L., Tan, L., Martinez, S. A., Mahmud, I., Devkota, L., Taegtmeyer, H., Ghaghada, K. B., Marrelli, S. P., Kwartler, C. S., Milewicz, D. M. 2023

  Abstract

  ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusion of the distal internal carotid arteries. A smooth muscle cell (SMC)-specific knock-in mouse model (Acta2SMC-R179C/+) inserted the mutation into 67% of aortic SMCs, whereas explanted SMCs were uniformly heterozygous. Acta2R179C/+ SMCs fail to fully differentiate and maintain stem cell-like features, including high glycolytic flux, and increasing oxidative respiration (OXPHOS) with nicotinamide riboside (NR) drives the mutant SMCs to differentiate and decreases migration. Acta2SMC-R179C/+ mice have intraluminal MMD-like occlusive lesions and strokes after carotid artery injury, whereas the similarly treated WT mice have no strokes and patent lumens. Treatment with NR prior to the carotid artery injury attenuates the strokes, MMD-like lumen occlusions, and aberrant vascular remodeling in the Acta2SMC-R179C/+ mice. These data highlight the role of immature SMCs in MMD-associated occlusive disease and demonstrate that altering SMC metabolism to drive quiescence of Acta2R179C/+ SMCs attenuates strokes and aberrant vascular remodeling in the Acta2SMC-R179C/+ mice.

  View details for DOI 10.21203/rs.3.rs-3304679/v1

  View details for PubMedID 37886459

• Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation NATURE CARDIOVASCULAR RESEARCH Kwartler, C. S., Pedroza, A. J., Kaw, A., Guan, P., Ma, S., Duan, X., Kernell, C., Wang, C., Pinelo, J., Bowen, M., Chen, J., Zhong, Y., Sinha, S., Shen, X., Fischbein, M. P., Milewicz, D. M. 2023; 2 (10): 937-+

  View details for DOI 10.1038/s44161-023-00337-4

  View details for Web of Science ID 001125047300009

• Blood transfusion in cardiac surgeries - Toward a personalized protocol. American journal of surgery Min, Y., Dalal, A. R., Pedroza, A. J., Pham, T. D., Panigrahi, A. K., Goldstone, A. B., MacArthur, J. W., Woo, Y. J., Baiocchi, M., Fischbein, M. P. 2023

  View details for DOI 10.1016/j.amjsurg.2023.07.035

  View details for PubMedID 37558518

• Reduced Pulmonary Artery Distensibility Predicts Persistent Pulmonary Hypertension and 2-Year Mortality in Patients with Severe Aortic Stenosis Undergoing TAVR. Academic radiology Turner, V., Maret, E., Kim, J. B., Codari, M., Hinostroza, V., Mastrodicasa, D., Watkins, A. C., Fearon, W. F., Fischbein, M. P., Haddad, F., Willemink, M. J., Fleischmann, D. 2023

  Abstract

  RATIONALE AND OBJECTIVES: Post-TAVR persistent pulmonary hypertension (PH) is a better predictor of poor outcome than pre-TAVR PH. In this longitudinal study we sought to evaluate whether pulmonary artery (distensibility (DPA) measured on preprocedural ECG-gated CTA is associated with persistent-PH and 2-year mortality after TAVR.MATERIALS AND METHODS: Three hundred and thirty-six patients undergoing TAVR between July 2012 and March 2016 were retrospectively included and followed for all-cause mortality until November 2017. All patients underwent retrospectively ECG-gated CTA prior to TAVR. Main pulmonary artery (MPA) area was measured in systole and in diastole. DPA was calculated as: [(area-MPAmax-area-MPAmin)/area-MPAmax]%. ROC analysis was performed to assess the AUC for persistent-PH. Youden Index was used to determine the optimal threshold of DPA for persistent-PH. Two groups were compared based on a DPA threshold of 8% (specificity of 70% for persistent-PH). Kaplan-Meier, Cox proportional-hazard, and logistic regression analyses were performed. The primary clinical endpoint was defined as persistent-PH post-TAVR. The secondary endpoint was defined as all-cause mortality 2 years after TAVR.RESULTS: Median follow-up time was 413 (interquartiles 339-757) days. A total of 183 (54%) had persistent-PH and 68 (20%) patients died within 2-years after TAVR. Patients with DPA<8% had significantly more persistent-PH (67% vs 47%, p<0.001) and 2-year deaths (28% vs 15%, p=0.006), compared to patients with DPA>8%. Adjusted multivariable regression analyses showed that DPA<8% was independently associated with persistent-PH (OR 2.10 [95%-CI 1.3-4.5], p=0.007) and 2-year mortality (HR 2.91 [95%-CI 1.5-5.8], p=0.002). Kaplan-Meier analysis showed that 2-year mortality of patients with DPA<8% was significantly higher compared to patients with DPA≥8% (mortality 28% vs 15%; log-rank p=0.003).CONCLUSION: DPA on preprocedural CTA is independently associated with persistent-PH and two-year mortality in patients who undergo TAVR.

  View details for DOI 10.1016/j.acra.2023.03.014

  View details for PubMedID 37147161

• Outcomes after concomitant arch replacement at the time of aortic root surgery. JTCVS open Krishnan, A., Dalal, A. R., Pedroza, A. J., Nakamura, K., Yokoyama, N., Tognozzi, E., Woo, Y. J., Fischbein, M., MacArthur, J. W. 2023; 13: 1-8

  Abstract

  Contemporary series of aortic arch replacement at the time of aortic root surgery are limited in number of patients and mostly address hemiarch replacement. We describe outcomes after aortic root and concomitant arch replacement, including total arch replacement.This single-institution retrospective review studied 1196 consecutive patients from May 2004 to September 2020 who underwent first-time aortic root replacement. Patients undergoing surgery for endocarditis were excluded (n = 68, 5.7%). Patients undergoing concomitant root and arch replacement were propensity matched with patients undergoing isolated root surgery based on indication, clinical and operative characteristics, demographics, medical history including connective tissue disorders, and urgency. Multivariable Cox proportional hazards and logistic regression modeling were used to assess the primary outcome of all-cause mortality and the secondary outcomes of prolonged ventilator use, postoperative blood transfusion, and debilitating stroke, adjusted for patient and operative characteristics.Among the 1128 patients who underwent aortic root intervention during the study period, 471 (41.8%) underwent concomitant aortic arch replacement. Most underwent hemiarch replacement (n = 411, 87.4%); 59 patients (12.6%) underwent total arch replacement (with elephant trunk: n = 23, 4.9%; without elephant trunk: n = 36, 7.7%). The mean follow-up time was 4.6 years postprocedure. Operative mortality was 2.2%, and total mortality over the entire study period was 9.2%. Propensity matching generated 348 matches (295 concomitant hemiarch, 53 concomitant total arch). Concomitant hemiarch (hazard ratio, 1.00; 95% confidence interval, 0.54-1.86, P = .99) and total arch replacement (hazard ratio, 1.60, 95% confidence interval, 0.72-3.57, P = .24) were not significantly associated with increased mortality. Rates of stroke were not significantly different among each group: isolated root (n = 11/348, 3.7%), root + hemiarch (n = 17/295, 5.8%), and root + total arch (n = 3/53, 5.7%) replacement (P = .50), nor was the adjusted risk of stroke. Both concomitant arch interventions were associated with prolonged ventilator use and use of postoperative blood transfusions.Hemiarch and total arch replacement are safe to perform at the time of aortic root intervention, with no significant differences in survival or stroke rates, but increased ventilator and blood product use.

  View details for DOI 10.1016/j.xjon.2022.12.014

  View details for PubMedID 37063158

  View details for PubMedCentralID PMC10091289

• Blood transfusion in aortic root surgery impairs midterm survival. JTCVS open Dalal, A. R., Pedroza, A. J., Krishnan, A., Min, Y., Tognozzi, E., Yokoyama, N., Nakamura, K., Mitchel, O. R., Baiocchi, M., Woo, Y. J., MacArthur, J. W., Fischbein, M. P. 2023; 13: 9-19

  Abstract

  To evaluate the effect of perioperative allogeneic packed red blood cell (RBC) transfusion during aortic root replacement.We reviewed patients undergoing aortic root replacement at our institution between March 2014 and April 2020. In total, 760 patients underwent aortic root replacement, of whom 442 (58%) received a perioperative RBC transfusion. Propensity score matching was used to account for baseline and operative differences resulting in 159 matched pairs. All-cause mortality was assessed with Kaplan-Meier curves. Data were obtained from our institutional Society of Thoracic Surgeons database and chart review.After propensity score matching, the RBC-transfused and -nontransfused groups were similar for all preoperative characteristics. Cardiopulmonary bypass time, crossclamp time, and lowest operative temperature were similar between the transfused and nontransfused groups (standardized mean difference <0.05). RBC transfusion was associated with more frequent postoperative ventilation greater than 24 hours (36/159 [23%] vs 19/159 [12%]; P = .01), postoperative hemodialysis (9/159 [5.7%] vs 0/159 [0%]; P = .003), reoperation for mediastinal hemorrhage (9/159 [5.7%] vs 0/159 [0%]; P = .003), and longer intensive care unit and hospital length of stay (3 vs 2 days and 8 vs 6 days respectively; P < .001). Thirty-day operative mortality after propensity score matching was similar between the cohorts (1.9%; 3/159 vs 0%; P = .2), and 5-year survival was reduced in the RBC transfusion cohort (90.2% [95% confidence interval, 84.1%-96.7%] vs 97.1% [95% confidence interval, 92.3%-100%] P = .035).Aortic root replacement frequently requires RBC transfusion during and after the operation, but even after matching for observed preoperative and operative characteristics, RBC transfusion is associated with more frequent postoperative complications and reduced midterm survival.

  View details for DOI 10.1016/j.xjon.2023.01.006

  View details for PubMedID 37063152

  View details for PubMedCentralID PMC10091283

• Nuclear Smooth Muscle α-actin in Vascular Smooth Muscle Cell Differentiation. Research square Kwartler, C. S., Pedroza, A. J., Kaw, A., Guan, P., Ma, S., Duan, X. Y., Kernell, C., Wang, C., Pinelo, J. E., Borthwick, M. S., Chen, J., Zhong, Y., Sinha, S., Shen, X., Fischbein, M. P., Milewicz, D. M. 2023

  Abstract

  Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), predispose to adult onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by childhood-onset diverse vascular diseases. Our data indicate that αSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors, and the ACTA2 p.R179 variant decreases nuclear localization of αSMA. SMCs explanted from a SMC-specific conditional knockin mouse model, Acta2SMC-R179/+, are less differentiated than WT SMCs, both in vitro and in vivo, and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neural crest cells to SMCs, and single cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue shows increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.

  View details for DOI 10.21203/rs.3.rs-1623114/v1

  View details for PubMedID 36909460

  View details for PubMedCentralID PMC10002808

• Midterm Outcomes in Type A Aortic Dissection Repair with and without Malperfusion in a Hybrid Operating Room. Seminars in thoracic and cardiovascular surgery Dalal, A. R., Dossabhoy, S., Heng, E., Yasin, A., Leipzig, M. M., Bonham, S. A., Fischbein, M. P., Lee, J. T., Woo, Y. J., Watkins, A. C. 2022

  Abstract

  Treatment approach to type A aortic dissection with malperfusion, immediate open aortic repair versus upfront endovascular treatment, remains controversial. From January 2017 to July 2021, 301 consecutive type A repairs were evaluated at our institution. Starting in 2019, all type A aortic dissections were performed in a fixed-fluoroscopy, hybrid operating room. Propensity score matching was used to control baseline patient characteristics between traditional and hybrid operating room approaches. There were 144 patients in the traditional group and 157 in the hybrid group. In the hybrid group, 41% (64/157) underwent intraoperative angiograms, and of those, 58% (37/64) received at least one endovascular intervention. Following propensity matching, 125 patients remained in each the traditional and hybrid groups. Thirty-day survival was significantly improved in the hybrid cohort at 96.7%% (122/125) as compared to the traditional cohort at 87.2% (109/125) (p=0.002). There were no significant differences in perioperative paralysis (1.6% vs. 1.6%, p>0.9), new hemodialysis (12% vs. 9.6%, p=0.5), fasciotomy (2.4% vs. 5.6%, p=0.20, and exploratory laparotomy (1.6% vs. 4.8%, p=0.3). The hybrid operating room approach to type A aortic dissection, provides the ability to immediately assess distal malperfusion and perform endovascular interventions at the time of open aortic repair, and is associated with significantly higher 30-day and 2-year survival when compared to a stepwise repair approach in a traditional operating room.

  View details for DOI 10.1053/j.semtcvs.2022.12.003

  View details for PubMedID 36567047

• Registry of Aortic Diseases to Model Adverse Events and Progression (ROADMAP) in Uncomplicated Type B Aortic Dissection: Study Design and Rationale. Radiology. Cardiothoracic imaging Mastrodicasa, D., Willemink, M. J., Turner, V. L., Hinostroza, V., Codari, M., Hanneman, K., Ouzounian, M., Ocazionez Trujillo, D., Afifi, R. O., Hedgire, S., Burris, N. S., Yang, B., Lacomis, J. M., Gleason, T. G., Pacini, D., Folesani, G., Lovato, L., Hinzpeter, R., Alkadhi, H., Stillman, A. E., Chen, E. P., van Kuijk, S. M., Schurink, G. W., Sailer, A. M., Bäumler, K., Miller, D. C., Fischbein, M. P., Fleischmann, D. 2022; 4 (6): e220039

  Abstract

  To describe the design and methodological approach of a multicenter, retrospective study to externally validate a clinical and imaging-based model for predicting the risk of late adverse events in patients with initially uncomplicated type B aortic dissection (uTBAD).The Registry of Aortic Diseases to Model Adverse Events and Progression (ROADMAP) is a collaboration between 10 academic aortic centers in North America and Europe. Two centers have previously developed and internally validated a recently developed risk prediction model. Clinical and imaging data from eight ROADMAP centers will be used for external validation. Patients with uTBAD who survived the initial hospitalization between January 1, 2001, and December 31, 2013, with follow-up until 2020, will be retrospectively identified. Clinical and imaging data from the index hospitalization and all follow-up encounters will be collected at each center and transferred to the coordinating center for analysis. Baseline and follow-up CT scans will be evaluated by cardiovascular imaging experts using a standardized technique.The primary end point is the occurrence of late adverse events, defined as aneurysm formation (≥6 cm), rapid expansion of the aorta (≥1 cm/y), fatal or nonfatal aortic rupture, new refractory pain, uncontrollable hypertension, and organ or limb malperfusion. The previously derived multivariable model will be externally validated by using Cox proportional hazards regression modeling.This study will show whether a recent clinical and imaging-based risk prediction model for patients with uTBAD can be generalized to a larger population, which is an important step toward individualized risk stratification and therapy.Keywords: CT Angiography, Vascular, Aorta, Dissection, Outcomes Analysis, Aortic Dissection, MRI, TEVAR© RSNA, 2022See also the commentary by Rajiah in this issue.

  View details for DOI 10.1148/ryct.220039

  View details for PubMedID 36601455

  View details for PubMedCentralID PMC9806732

• Angiogenic stem cell delivery platform to augment post-infarction neovasculature and reverse ventricular remodeling. Scientific reports Shin, H. S., Thakore, A., Tada, Y., Pedroza, A. J., Ikeda, G., Chen, I. Y., Chan, D., Jaatinen, K. J., Yajima, S., Pfrender, E. M., Kawamura, M., Yang, P. C., Wu, J. C., Appel, E. A., Fischbein, M. P., Woo, Y., Shudo, Y. 2022; 12 (1): 17605

  Abstract

  Many cell-based therapies are challenged by the poor localization of introduced cells and the use of biomaterial scaffolds with questionable biocompatibility or bio-functionality. Endothelial progenitor cells (EPCs), a popular cell type used in cell-based therapies due to their robust angiogenic potential, are limited in their therapeutic capacity to develop into mature vasculature. Here, we demonstrate a joint delivery of human-derived endothelial progenitor cells (EPC) and smooth muscle cells (SMC) as a scaffold-free, bi-level cell sheet platform to improve ventricular remodeling and function in an athymic rat model of myocardial infarction. The transplanted bi-level cell sheet on the ischemic heart provides a biomimetic microenvironment and improved cell-cell communication, enhancing cell engraftment and angiogenesis, thereby improving ventricular remodeling. Notably, the increased density of vessel-like structures and upregulation of biological adhesion and vasculature developmental genes, such as Cxcl12 and Notch3, particularly in the ischemic border zone myocardium, were observed following cell sheet transplantation. We provide compelling evidence that this SMC-EPC bi-level cell sheet construct can be a promising therapy to repair ischemic cardiomyopathy.

  View details for DOI 10.1038/s41598-022-21510-y

  View details for PubMedID 36266453

  View details for PubMedCentralID PMC9584918

• Total aortic arch replacement using a frozen elephant trunk device: Results of a 1-year US multicenter trial. The Journal of thoracic and cardiovascular surgery Coselli, J. S., Roselli, E. E., Preventza, O., Malaisrie, S. C., Stewart, A., Stelzer, P., Takayama, H., Chen, E. P., Estrera, A. L., Gleason, T. G., Fischbein, M. P., Girardi, L. N., Patel, H. J., Bavaria, J. E., LeMaire, S. A. 2022

  Abstract

  OBJECTIVE: In this prospective US investigational device exemption trial, we assessed the safety and 1-year clinical outcomes of the Thoraflex Hybrid device (Terumo Aortic) for the frozen elephant trunk technique to repair the ascending aorta, aortic arch, and descending thoracic aorta.METHODS: For the trial, which involved 12 US sites, 65 patients without rupture were recruited into the primary study group, and 9 patients were recruited into the rupture group. All patients underwent open surgical repair of the ascending aorta, aortic arch, and descending thoracic aorta in cases of aneurysm and/or dissection. The primary end point was freedom from major adverse events (MAE), defined as permanent stroke, permanent paraplegia/paraparesis, unanticipated aortic-related reoperation (excluding reoperation for bleeding), or all-cause mortality.RESULTS: In the primary study group, 2 patients were lost to follow-up at 1year. Freedom from MAE at 1year was 81% (51/63). Seven patients (11%) died (including 2 before 30days or discharge), 3 patients (5%) suffered permanent stroke, and 3 (5%) developed permanent paraplegia/paraparesis. Twenty-six patients (41%) underwent planned extension procedures, including 22 endovascular procedures within a median of 122 (interquartile range, 64-156) days. In the aortic rupture group, 2 patients were lost to follow-up at 1year. Freedom from MAE at 1year was 71% (5/7). One patient (14%) died, 2 patients (29%) had permanent stroke, and none had permanent paraplegia/paraparesis. No extension procedures were performed in the rupture group.CONCLUSIONS: One-year results with the Thoraflex Hybrid device are acceptable. Long-term data are necessary to assess the durability of these repairs.

  View details for DOI 10.1016/j.jtcvs.2022.08.029

  View details for PubMedID 36253292

• Inter-observer variability of expert-derived morphologic risk predictors in aortic dissection. European radiology Willemink, M. J., Mastrodicasa, D., Madani, M. H., Codari, M., Chepelev, L. L., Mistelbauer, G., Hanneman, K., Ouzounian, M., Ocazionez, D., Afifi, R. O., Lacomis, J. M., Lovato, L., Pacini, D., Folesani, G., Hinzpeter, R., Alkadhi, H., Stillman, A. E., Sailer, A. M., Turner, V. L., Hinostroza, V., Baumler, K., Chin, A. S., Burris, N. S., Miller, D. C., Fischbein, M. P., Fleischmann, D. 2022

  Abstract

  OBJECTIVES: Establishing the reproducibility of expert-derived measurements on CTA exams of aortic dissection is clinically important and paramount for ground-truth determination for machine learning.METHODS: Four independent observers retrospectively evaluated CTA exams of 72 patients with uncomplicated Stanford type B aortic dissection and assessed the reproducibility of a recently proposed combination of four morphologic risk predictors (maximum aortic diameter, false lumen circumferential angle, false lumen outflow, and intercostal arteries). For the first inter-observer variability assessment, 47 CTA scans from one aortic center were evaluated by expert-observer 1 in an unconstrained clinical assessment without a standardized workflow and compared to a composite of three expert-observers (observers 2-4) using a standardized workflow. A second inter-observer variability assessment on 30 out of the 47 CTA scans compared observers 3 and 4 with a constrained, standardized workflow. A third inter-observer variability assessment was done after specialized training and tested between observers 3 and 4 in an external population of 25 CTA scans. Inter-observer agreement was assessed with intraclass correlation coefficients (ICCs) and Bland-Altman plots.RESULTS: Pre-training ICCs of the four morphologic features ranged from 0.04 (-0.05 to 0.13) to 0.68 (0.49-0.81) between observer 1 and observers 2-4 and from 0.50 (0.32-0.69) to 0.89 (0.78-0.95) between observers 3 and 4. ICCs improved after training ranging from 0.69 (0.52-0.87) to 0.97 (0.94-0.99), and Bland-Altman analysis showed decreased bias and limits of agreement.CONCLUSIONS: Manual morphologic feature measurements on CTA images can be optimized resulting in improved inter-observer reliability. This is essential for robust ground-truth determination for machine learning models.KEY POINTS: Clinical fashion manual measurements of aortic CTA imaging features showed poor inter-observer reproducibility. A standardized workflow with standardized training resulted in substantial improvements with excellent inter-observer reproducibility. Robust ground truth labels obtained manually with excellent inter-observer reproducibility are key to develop reliable machine learning models.

  View details for DOI 10.1007/s00330-022-09056-z

  View details for PubMedID 36029344

• Mid-Term Outcomes of Endovascular Repair of Aortic Arch Aneurysms with the Gore Thoracic Branch Endoprosthesis. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery Liang, N. L., Dake, M. D., Fischbein, M. P., Bavaria, J. E., Desai, N. D., Oderich, G. S., Singh, M. J., Fillinger, M., Suckow, B. D., Matsumura, J. S., Patel, H. J., Makaroun, M. S. 2022

  Abstract

  OBJECTIVES: Aortic aneurysms involving aortic arch vessels are anatomically unsuitable for standard thoracic endovascular repair (TEVAR) without cervical debranching of the arch vessels. We report three-year outcomes of a single-branched thoracic endograft, following previous publication of perioperative and one-year outcomes.DESIGN: This is a multicenter feasibility trial of the GORE TAG Thoracic Branch Endoprosthesis (TBE), a thoracic endovascular graft incorporating a single retrograde branch for aortic arch vessel perfusion.METHODS: The first study arm enrolled patients with intact descending thoracic aortic aneurysm extending to the distal arch with left subclavian artery incorporation (LSA, zone 2). The second arm enrolled patients with arch aneurysms requiring incorporation of the left carotid or innominate artery (zone 0/1) and extra-anatomic surgical revascularization of the remaining aortic arch vessels. Outcomes at three years are reported.RESULTS: The cohort comprised forty patients (31 zone 2, 9 zone 0/1). The majority were male (52%). Mean follow up was 1408±552 days in the zone 2 and 1187±766 days in the zone 0/1 cohort. During 3-year follow-up there was no device migration, fracture, or aortic rupture in either arm. In the zone 2 arm, freedom from reintervention was 97% at 1 and 3 years but there were two side branch occlusions. Two patients had aneurysm enlargement >5mm without documented endoleak or reintervention. Freedom from mortality at 1 and 3 years was 90% and 84%. In the zone 0/1 arm there were no reinterventions, loss of branch patency, or aneurysm enlargement at 3 years. Cerebrovascular events occurred in three patients during follow-up, two unrelated to the device or procedure, and one of unknown relationship. Two patients in this arm died during the follow-up period, both unrelated to the procedure or the aneurysm.CONCLUSIONS: Initial 3-year results of the TBE device for endovascular repair of arch aneurysms show favorable patency and durability with low rates of graft-related complications.

  View details for DOI 10.1016/j.ejvs.2022.08.003

  View details for PubMedID 35970335

• Mosaicism for the smooth muscle cell (SMC)-specific knock-in of the Acta2 R179C pathogenic variant: Implications for gene editing therapies. Journal of molecular and cellular cardiology Kaw, A., Pedroza, A. J., Chattopadhyay, A., Pinard, A., Guo, D., Kaw, K., Zhou, Z., Shad, R., Fischbein, M. P., Kwartler, C. S., Milewicz, D. M. 2022; 171: 102-104

  View details for DOI 10.1016/j.yjmcc.2022.07.004

  View details for PubMedID 35878552

• Tetralogy of Fallot and Aortic Dissection: Implications in Management. JACC. Case reports Vaikunth, S. S., Chan, J. L., Woo, J. P., Bykhovsky, M. R., Lui, G. K., Ma, M., Romfh, A. W., Lamberti, J., Mastrodicasa, D., Fleischmann, D., Fischbein, M. P. 2022; 4 (10): 581-586

  Abstract

  We present the case of a 61-year-old man with tetralogy of Fallot postrepair and mechanical aortic valve replacement with an aortic root/ascending/arch aneurysm with chronic type A aortic dissection. He underwent uncomplicated aortic root and total arch replacement. Continued surveillance for aortic aneurysm is necessary in the tetralogy of Fallot population. (Level of Difficulty: Intermediate.).

  View details for DOI 10.1016/j.jaccas.2022.02.021

  View details for PubMedID 35615213

• Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque. Nature cardiovascular research Cheng, P., Wirka, R. C., Kim, J. B., Kim, H. J., Nguyen, T., Kundu, R., Zhao, Q., Sharma, D., Pedroza, A., Nagao, M., Iyer, D., Fischbein, M. P., Quertermous, T. 2022; 1 (4): 322-333

  Abstract

  Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC phenotype can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD and is associated with the expression of SMAD3 in SMC. However, the mechanism by which this gene modifies CAD risk remains poorly understood. Here we show that SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, more outward remodelling and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC transition cell state toward two fates: a SMC phenotype that governs both vascular remodelling and recruitment of inflammatory cells, as well as a chondromyocyte fate. Together, the findings reveal that Smad3 expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including outward remodelling, monocyte recruitment, and vascular calcification.

  View details for DOI 10.1038/s44161-022-00042-8

  View details for PubMedID 36246779

  View details for PubMedCentralID PMC9560061

• Imaging and Surveillance of Chronic Aortic Dissection: A Scientific Statement From the American Heart Association. Circulation. Cardiovascular imaging Fleischmann, D., Afifi, R. O., Casanegra, A. I., Elefteriades, J. A., Gleason, T. G., Hanneman, K., Roselli, E. E., Willemink, M. J., Fischbein, M. P. 2022; 15 (3): e000075

  Abstract

  All patients surviving an acute aortic dissection require continued lifelong surveillance of their diseased aorta. Late complications, driven predominantly by chronic false lumen degeneration and aneurysm formation, often require surgical, endovascular, or hybrid interventions to treat or prevent aortic rupture. Imaging plays a central role in the medical decision-making of patients with chronic aortic dissection. Accurate aortic diameter measurements and rigorous, systematic documentation of diameter changes over time with different imaging equipment and modalities pose a range of practical challenges in these complex patients. Currently, no guidelines or recommendations for imaging surveillance in patients with chronic aortic dissection exist. In this document, we present state-of-the-art imaging and measurement techniques for patients with chronic aortic dissection and clarify the need for standardized measurements and reporting for lifelong surveillance. We also examine the emerging role of imaging and computer simulations to predict aortic false lumen degeneration, remodeling, and biomechanical failure from morphological and hemodynamic features. These insights may improve risk stratification, individualize contemporary treatment options, and potentially aid in the conception of novel treatment strategies in the future.

  View details for DOI 10.1161/HCI.0000000000000075

  View details for PubMedID 35172599

• Acute Induced Pressure Overload Rapidly Incites Thoracic Aortic Aneurysmal Smooth Muscle Cell Phenotype. Hypertension (Dallas, Tex. : 1979) Pedroza, A. J., Shad, R., Dalal, A. R., Yokoyama, N., Nakamura, K., Hiesinger, W., Fischbein, M. P. 2022: HYPERTENSIONAHA12118640

  View details for DOI 10.1161/HYPERTENSIONAHA.121.18640

  View details for PubMedID 35124970

• The Society of Thoracic Surgeons/American Association for Thoracic Surgery clinical practice guidelines on the management of type B aortic dissection. The Journal of thoracic and cardiovascular surgery MacGillivray, T. E., Gleason, T. G., Patel, H. J., Aldea, G. S., Bavaria, J. E., Beaver, T. M., Chen, E. P., Czerny, M., Estrera, A. L., Firestone, S., Fischbein, M. P., Hughes, G. C., Hui, D. S., Kissoon, K., Lawton, J. S., Pacini, D., Reece, T. B., Roselli, E. E., Stulak, J. 1800

  View details for DOI 10.1016/j.jtcvs.2021.11.091

  View details for PubMedID 35090765

• The Society of Thoracic Surgeons/American Association for Thoracic Surgery Clinical Practice Guidelines on the Management of Type B Aortic Dissection. The Annals of thoracic surgery MacGillivray, T. E., Gleason, T. G., Patel, H. J., Aldea, G. S., Bavaria, J. E., Beaver, T. M., Chen, E. P., Czerny, M., Estrera, A. L., Firestone, S., Fischbein, M. P., Hughes, G. C., Hui, D. S., Kissoon, K., Lawton, J. S., Pacini, D., Reece, T. B., Roselli, E. E., Stulak, J. 2022

  View details for DOI 10.1016/j.athoracsur.2021.11.002

  View details for PubMedID 35090687

• Distance between valvular leaflet and coronary ostium predicting risk of coronary obstruction during TAVR. International journal of cardiology. Heart & vasculature Oh, J., Kobayashi, Y., Kang, G., Nishi, T., Willemink, M. J., Fearon, W. F., Fischbein, M., Fleishmann, D., Yeung, A. C., Kim, J. B. 1800; 37: 100917

  Abstract

  Background: The aim of this study was to evaluate the role of the distance between the aortic valve in projected position to the coronary ostium to determine risk of coronary artery obstruction after transcatheter aortic valve replacement (TAVR).Methods: An Expected Leaflet-to-ostium Distance (ELOD) was obtained on pre-TAVR planning computed tomography by subtracting leaflet thickness and the distances from the center to the annular rim at annulus level and from the center to the coronary ostium at mid-ostial level. Variables were compared between patients with and without coronary obstruction and the level of association between variables was assessed using log odds ratio (OR).Results: A total of 177 patients with 353 coronary arteries was analyzed. Mean annulus diameters (22.8±2.8mm and 23.4±1.0mm, p>0.05) and mean sinus of Valsalva (SOV) diameters (31.2±3.6mm and 31.9±3.6mm, p>0.05) were similar between patients with lower and higher coronary heights, respectively. There were three coronary obstruction cases. ELOD≤2mm in combination with leaflet length longer than mid-ostial height allowed for discrimination of cases with and without coronary obstruction. There was a significant association between coronary obstruction event and ELOD≤2mm (log OR=6.180, p<0.001).Conclusions: Our study showed that a combination of ELOD<2mm and a longer leaflet length than mid-ostial height may be associated with increased risk for coronary obstruction during TAVR.

  View details for DOI 10.1016/j.ijcha.2021.100917

  View details for PubMedID 34917750

• Management of arch aneurysms with a single-branch thoracic endograft in zone 0. JTCVS techniques Dake, M. D., Bavaria, J. E., Singh, M. J., Oderich, G., Filinger, M., Fischbein, M. P., Matsumura, J. S., Patel, H. J. 2021; 7: 1-6

  Abstract

  We present preliminary data from a patient cohort undergoing thoracic endovascular aortic repair for Ishimaru zone 0 and 1 using a novel branched arch endograft.This US multicenter early feasibility investigational device exemption clinical trial treated 9 patients with a mean age 72.8 ± 8.0 years (77.8% male). The endograft was designed with a single side branch designed to facilitate aortic coverage proximal to the innominate or left carotid artery while maintaining branch vessel patency. Pathology treated included fusiform (n = 2) or saccular (n = 7) aneurysm, with a maximum aortic diameter of 6.3 ± 0.7 cm. Treatment was into zone 0 in 8 patients, and zone 1 in 1 patient.All patients underwent initial successful first-stage supra-aortic trunk revascularization using a variety of techniques, without the occurrence of stroke. For the second thoracic endovascular aortic repair stage, median total treatment length was 20 cm. The primary end point of device delivery and branch vessel patency was achieved in 100% of patients, without 30-day mortality or spinal cord ischemia. Cerebrovascular events were observed in 2 patients through 30 days. No type I or III endoleaks were reported and all side branches were patent at 12-month imaging follow-up.Endovascular repair of Ishimaru zone 0 or 1 arch aortic aneurysms can be achieved with a novel branched arch endograft. Future studies will evaluate the mid-term outcomes with this device in other pathologies and further define the occurrence of postoperative neurologic events.

  View details for DOI 10.1016/j.xjtc.2021.01.011

  View details for PubMedID 34318189

  View details for PubMedCentralID PMC8311452

• Management of arch aneurysms with a single-branch thoracic endograft in zone 0 JTCVS TECHNIQUES Dake, M. D., Bavaria, J. E., Singh, M. J., Oderich, G., Filinger, M., Fischbein, M. P., Matsumura, J. S., Patel, H. J. 2021; 7: 1-6

  View details for DOI 10.1016/j.xjtc.2021.01.011

  View details for Web of Science ID 000656818000001

• INTRAOPERATIVE INDUCIBILITY OF ATRIAL FIBRILLATION IMPROVES RISK STRATIFICATION AND REDUCES POST-OPERATIVE ATRIAL FIBRILLATION Pong, T., Cyr, K., Carlton, C., Niesen, J., Aparicio-Valenzuela, J., Fischbein, M., Woo, Y., Boyd, J., Lee, A. ELSEVIER SCIENCE INC. 2021: 1592

  View details for Web of Science ID 000647487501599

• Evaluation of the Gore TAG Thoracic Branch Endoprosthesis in the Treatment of Proximal Descending Thoracic Aortic Aneurysms. Journal of vascular surgery Dake, M. D., Fischbein, M. P., Bavaria, J. E., Desai, N. D., Oderich, G., Singh, M. J., Fillinger, M., Suckow, B. D., Matsumura, J. S., Patel, H. J. 2021

  Abstract

  BACKGOUND -: Thoracic endovascular aortic repair (TEVAR) has radically transformed the treatment of descending thoracic aortic aneurysms. However, when aneurysms involve the aortic arch in the region of the left subclavian artery, branch vessel preservation must be considered. Branched aortic endografts provide a new option to maintain branch patency.METHODS: - Six investigative sites enrolled 31 patients in a non-randomized, prospective investigational device exemption (IDE) feasibility trial of a single branched aortic endograft for ; management of aneurysms that include the distal aortic arch. The GORE TAG Thoracic ; Branch Endoprosthesis (TBE; W.L. Gore & Associates, Inc., Flagstaff, AZ) an investigational device, allows graft placement proximal to the left subclavian artery and incorporates a single side branch for left subclavian perfusion.RESULTS: - All 31 (100%) patients had a successful implantation of the investigational device in landing zone 2. Men slightly outnumbered women (51.6%). Average age of 74.1 +/- 10.4 years. Aneurysm morphology was fusiform in 12 and saccular in 19, with a mean maximum aortic diameter of 54.8 +/- 10.9 mm. Mean follow up for the cohort is 25.2 +/- 11.1 months; patient outcomes are reported here at 1 month and 1 year. At one month, side branch patency was 100% and freedom from core lab reported device related endoleak (type I and III) was 96.7% without 30-day death or permanent paraplegia. One patient experienced a procedure-related stroke. Through one year, there have been five patient deaths, none device or procedure-related (CEC adjudicated); one thoracic re-intervention; no conversions; no reported aneurysm growth (Core lab), and one loss of side branch patency diagnosed of the left subclavian artery in an asymptomatic individual by CT imaging at 6 months with no reported subsequent adverse events due to loss of patency. Endoleaks were Core lab reported in five patients at 12 months (two type II and three were indeterminate).CONCLUSIONS: - This IDE feasibility study reports the preliminary study results of a single side branch endograft to treat patients with proximal descending thoracic aortic aneurysms.

  View details for DOI 10.1016/j.jvs.2021.04.025

  View details for PubMedID 33940079

• 2021 The American Association for Thoracic Surgery expert consensus document: Surgical treatment of acute type A aortic dissection. The Journal of thoracic and cardiovascular surgery Malaisrie, S. C., Szeto, W. Y., Halas, M., Girardi, L. N., Coselli, J. S., Sundt, T. M., Chen, E. P., Fischbein, M. P., Gleason, T. G., Okita, Y., Ouzounian, M., Patel, H. J., Roselli, E. E., Shrestha, M. L., Svensson, L. G., Moon, M. R., AATS Clinical Practice Standards Committee: Adult Cardiac Surgery, Bakaeen, F., Malaisrie, S. C., Chikwe, J., Gaudino, M. F., Girardi, L. N., Szeto, W. Y. 2021

  View details for DOI 10.1016/j.jtcvs.2021.04.053

  View details for PubMedID 34112502

• CTA pulmonary artery enlargement in patients with severe aortic stenosis: Prognostic impact after TAVR. Journal of cardiovascular computed tomography Turner, V. L., Jubran, A., Kim, J. B., Maret, E., Moneghetti, K. J., Haddad, F., Amsallem, M., Codari, M., Hinostroza, V., Mastrodicasa, D., Sailer, A. M., Kobayashi, Y., Nishi, T., Yeung, A. C., Watkins, A. C., Lee, A. M., Miller, D. C., Fischbein, M. P., Fearon, W. F., Willemink, M. J., Fleischmann, D. 2021

  Abstract

  BACKGROUND: Identifying high-risk patients who will not derive substantial survival benefit from TAVR remains challenging. Pulmonary hypertension is a known predictor of poor outcome in patients undergoing TAVR and correlates strongly with pulmonary artery (PA) enlargement on CTA. We sought to evaluate whether PA enlargement, measured on pre-procedural computed tomography angiography (CTA), is associated with 1-year mortality in patients undergoing TAVR.METHODS: We retrospectively included 402 patients undergoing TAVR between July 2012 and March 2016. Clinical parameters, including Society of Thoracic Surgeons (STS) score and right ventricular systolic pressure (RVSP) estimated by transthoracic echocardiography were reviewed. PA dimensions were measured on pre-procedural CTAs. Association between PA enlargement and 1-year mortality was analyzed. Kaplan-Meier and Cox proportional hazards regression analyses were performed.RESULTS: The median follow-up time was 433 (interquartiles 339-797) days. A total of 56/402 (14%) patients died within 1 year after TAVR. Main PA area (area-MPA) was independently associated with 1-year mortality (hazard ratio per standard deviation equal to 2.04 [95%-confidence interval (CI) 1.48-2.76], p​<​0.001). Area under the curve (95%-CI) of the clinical multivariable model including STS-score and RVSP increased slightly from 0.67 (0.59-0.75) to 0.72 (0.72-0.89), p​=​0.346 by adding area-MPA. Although the AUC increased, differences were not significant (p​=​0.346). Kaplan-Meier analysis showed that mortality was significantly higher in patients with a pre-procedural non-indexed area-MPA of ≥7.40​cm2 compared to patients with a smaller area-MPA (mortality 23% vs. 9%; p​<​0.001).CONCLUSIONS: Enlargement of MPA on pre-procedural CTA is independently associated with 1-year mortality after TAVR.

  View details for DOI 10.1016/j.jcct.2021.03.004

  View details for PubMedID 33795188

• Generation of Vascular Smooth Muscle Cells From Induced Pluripotent Stem Cells: Methods, Applications, and Considerations. Circulation research Shen, M., Quertermous, T., Fischbein, M. P., Wu, J. C. 2021; 128 (5): 670–86

  Abstract

  The developmental origin of vascular smooth muscle cells (VSMCs) has been increasingly recognized as a major determinant for regional susceptibility or resistance to vascular diseases. As a human material-based complement to animal models and human primary cultures, patient induced pluripotent stem cell iPSC-derived VSMCs have been leveraged to conduct basic research and develop therapeutic applications in vascular diseases. However, iPSC-VSMCs (induced pluripotent stem cell VSMCs) derived by most existing induction protocols are heterogeneous in developmental origins. In this review, we summarize signaling networks that govern in vivo cell fate decisions and in vitro derivation of distinct VSMC progenitors, as well as key regulators that terminally specify lineage-specific VSMCs. We then highlight the significance of leveraging patient-derived iPSC-VSMCs for vascular disease modeling, drug discovery, and vascular tissue engineering and discuss several obstacles that need to be circumvented to fully unleash the potential of induced pluripotent stem cells for precision vascular medicine.

  View details for DOI 10.1161/CIRCRESAHA.120.318049

  View details for PubMedID 33818124

• Relative strain is a novel predictor of aneurysmal degeneration of the thoracic aorta: An ex vivo mechanical study. JVS-vascular science Chiu, P., Lee, H., Dalal, A. R., Koyano, T., Nguyen, M., Connolly, A. J., Chaudhuri, O., Fischbein, M. P. 2021; 2: 235-246

  Abstract

  Objective: Current guidelines for prophylactic replacement of the thoracic aorta, primarily based on size alone, may not be adequate in identifying patients at risk for either progression of disease or aortic catastrophe. We undertook the current study to determine whether the mechanical properties of the aorta might be able to predict aneurysmal dilatation of the aorta using a clinical database and benchtop mechanical testing of human aortic tissue.Methods: Using over 400 samples from 31 patients, mechanical properties were studied in (a) normal aorta and then (b) between normal and diseased aorta using linear mixed-effects models. A machine learning technique was used to predict aortic growth rate over time using mechanical properties and baseline clinical characteristics.Results: Healthy aortic tissue under in vivo loading conditions, after accounting for aortic segment location, had lower longitudinal elastic modulus compared with circumferential elastic modulus: -166.8 kPa (95% confidence interval [CI]: -210.8 to -122.7, P < .001). Fracture toughness was also lower in the longitudinal vs circumferential direction: -201.2 J/m3 (95% CI: -272.9 to -129.5, P < .001). Finally, relative strain was lower in the longitudinal direction compared with the circumferential direction: -0.01 (95% CI: -0.02 to -0.004, P = .002). Patients with diseased aorta, after accounting for segment location and sample direction, had decreased toughness compared with normal aorta, -431.7 J/m3 (95% CI: -628.6 to -234.8, P < .001), and increased relative strain, 0.09 (95% CI: 0.04 to 0.14, P = .003).Conclusions: Increasing relative strain was identified as a novel independent predictor of aneurysmal degeneration. Noninvasive measurement of relative strain may aid in the identification and monitoring of patients at risk for aneurysmal degeneration. (JVS-Vascular Science 2021;2:1-12.).Clinical Relevance: Aortic aneurysm surveillance and prophylactic surgical recommendations are based on computed tomographic angiogram aortic dimensions and growth rate measurements. However, aortic catastrophes may occur at small sizes, confounding current risk stratification models. Herein, we report that increasing aortic relative strain, that is, greater distensibility, is associated with growth over time, thus potentially identifying patients at risk for dissection/rupture.

  View details for DOI 10.1016/j.jvssci.2021.08.003

  View details for PubMedID 34806052

• Introduction to the 2021 Cardiovascular Surgery Themed Issue of Circulation. Circulation Ruel, M., Fischbein, M. 2021; 144 (14): 1087

  View details for DOI 10.1161/CIRCULATIONAHA.121.057284

  View details for PubMedID 34606297

• Deep Learning-Based 3D Segmentation of True Lumen, False Lumen, and False Lumen Thrombosis in Type-B Aortic Dissection. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Wobben, L. D., Codari, M., Mistelbauer, G., Pepe, A., Higashigaito, K., Hahn, L. D., Mastrodicasa, D., Turner, V. L., Hinostroza, V., Baumler, K., Fischbein, M. P., Fleischmann, D., Willemink, M. J. 2021; 2021: 3912-3915

  Abstract

  Patients with initially uncomplicated typeB aortic dissection (uTBAD) remain at high risk for developing late complications. Identification of morphologic features for improving risk stratification of these patients requires automated segmentation of computed tomography angiography (CTA) images. We developed three segmentation models utilizing a 3D residual U-Net for segmentation of the true lumen (TL), false lumen (FL), and false lumen thrombosis (FLT). Model 1 segments all labels at once, whereas model 2 segments them sequentially. Best results for TL and FL segmentation were achieved by model 2, with median (interquartiles) Dice similarity coefficients (DSC) of 0.85 (0.77-0.88) and 0.84 (0.82-0.87), respectively. For FLT segmentation, model 1 was superior to model 2, with median (interquartiles) DSCs of 0.63 (0.40-0.78). To purely test the performance of the network to segment FLT, a third model segmented FLT starting from the manually segmented FL, resulting in median (interquartiles) DSCs of 0.99 (0.98-0.99) and 0.85 (0.73-0.94) for patent FL and FLT, respectively. While the ambiguous appearance of FLT on imaging remains a significant limitation for accurate segmentation, our pipeline has the potential to help in segmentation of aortic lumina and thrombosis in uTBAD patients.Clinical relevance- Most predictors of aortic dissection (AD) degeneration are identified through anatomical modeling, which is currently prohibitive in clinical settings due to the timeintense human interaction. False lumen thrombosis, which often develops in patients with type B AD, has proven to show significant prognostic value for predicting late adverse events. Our automated segmentation algorithm offers the potential of personalized treatment for AD patients, leading to an increase in long-term survival.

  View details for DOI 10.1109/EMBC46164.2021.9631067

  View details for PubMedID 34892087

• Surgical technique for atrial-esophageal fistula repair after catheter ablation: An underrecognized complication JTCVS TECHNIQUES Guenthart, B. A., Sun, B., De Biasi, A., Fischbein, M. P., Liou, D. Z. 2020; 4: 169-172

  View details for DOI 10.1016/j.xjtc.2020.07.022

  View details for Web of Science ID 000655724800059

• Surgical technique for atrial-esophageal fistula repair after catheter ablation: An underrecognized complication. JTCVS techniques Guenthart, B. A., Sun, B., De Biasi, A., Fischbein, M. P., Liou, D. Z. 2020; 4: 169-172

  View details for DOI 10.1016/j.xjtc.2020.07.022

  View details for PubMedID 34318000

  View details for PubMedCentralID PMC8303005

• Introduction to the 2020 Circulation Cardiovascular Surgery-Themed Issue. Circulation Ruel, M., Gardner, T., Fischbein, M., de Lemos, J. 2020; 142 (14): 1313–14

  View details for DOI 10.1161/CIRCULATIONAHA.120.051356

  View details for PubMedID 33017207

• Impact of cognitive behavioral therapy on depression symptoms after transcatheter aortic valve replacement: A randomized controlled trial. International journal of cardiology Edwards, K. S., Chow, E. K., Dao, C., Hossepian, D., Johnson, A. G., Desai, M., Shah, S., Lee, A., Yeung, A. C., Fischbein, M., Fearon, W. F. 2020

  Abstract

  BACKGROUND: Depression is a significant concern after cardiac surgery and has not been studied in patients undergoing transcatheter aortic valve replacement (TAVR). We sought to examine the prevalence of pre-procedure depression and anxiety symptoms and explore whether brief bedside cognitive behavioral therapy (CBT) could prevent post-TAVR psychological distress.METHODS: We prospectively recruited consecutive TAVR patients and randomized them to receive brief CBT or treatment as usual (TAU) during their hospitalization. Multi-level regression techniques were used to evaluate changes by treatment arm in depression, anxiety, and quality of life from baseline to 1 month post-TAVR adjusted for sex, race, DM, CHF, MMSE, and STS score.RESULTS: One hundred and forty six participants were randomized. The mean age was 82 years, and 43% were female. Self-reported depression and anxiety scores meeting cutoffs for clinical level distress were 24.6% and 23.2% respectively. Both TAU and CBT groups had comparable improvements in depressive symptoms at 1-month (31% reduction for TAU and 35% reduction for CBT, p = .83). Similarly, both TAU and CBT groups had comparable improvements in anxiety symptoms at 1-month (8% reduction for TAU and 11% reduction for CBT, p = .1). Quality of life scores also improved and were not significantly different between the two groups.CONCLUSIONS: Pre-procedure depression and anxiety may be common among patients undergoing TAVR. However, TAVR patients show spontaneous improvement in depression and anxiety scores at 1-month follow up, regardless of brief CBT. Further research is needed to determine whether more tailored CBT interventions may improve psychological and medical outcomes.

  View details for DOI 10.1016/j.ijcard.2020.08.007

  View details for PubMedID 32800909

• CT-based True- and False-Lumen Segmentation in Type B Aortic Dissection Using Machine Learning. Radiology. Cardiothoracic imaging Hahn, L. D., Mistelbauer, G., Higashigaito, K., Koci, M., Willemink, M. J., Sailer, A. M., Fischbein, M., Fleischmann, D. 2020; 2 (3): e190179

  Abstract

  Purpose: To develop a segmentation pipeline for segmentation of aortic dissection CT angiograms into true and false lumina on multiplanar reformations (MPRs) perpendicular to the aortic centerline and derive quantitative morphologic features, specifically aortic diameter and true- or false-lumen cross-sectional area.Materials and Methods: An automated segmentation pipeline including two convolutional neural network (CNN) segmentation algorithms was developed. The algorithm derives the aortic centerline, generates MPRs orthogonal to the centerline, and segments the true and false lumina. A total of 153 CT angiograms obtained from 45 retrospectively identified patients (mean age, 50 years; range, 22-79 years) were used to train (n = 103), validate (n = 22), and test (n = 28) the CNN pipeline. Accuracy was evaluated by using the Dice similarity coefficient (DSC). Segmentations were then used to derive the maximal diameter of test-set patients and cross-sectional area profiles of the true and false lumina.Results: The segmentation pipeline yielded a mean DSC of 0.873 ± 0.056 for the true lumina and 0.894 ± 0.040 for the false lumina of test-set cases. Automated maximal diameter measurements correlated well with manual measurements (R 2 = 0.95). Profiles of cross-sectional diameter, true-lumen area, and false-lumen area over several follow-up examinations were derived.Conclusion: A segmentation pipeline was used to accurately identify true and false lumina on CT angiograms of aortic dissection. These segmentations can be used to obtain diameter and other morphologic parameters for surveillance and risk stratification.Supplemental material is available for this article.© RSNA, 2020.

  View details for DOI 10.1148/ryct.2020190179

  View details for PubMedID 33778582

• Screening and Prophylactic Amiodarone Reduces Post-Operative Atrial Fibrillation in At-Risk Patients JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Pong, T., Cyr, K., Niesen, J., Aparicio-Valenzuela, J., Carlton, C., Fischbein, M. P., Woo, Y., Boyd, J. H., Lee, A. M. 2020; 75 (11): 1361–63

  View details for DOI 10.1016/j.jacc.2020.01.016

  View details for Web of Science ID 000520057100016

  View details for PubMedID 32192666

• Fluid-structure interaction simulations of patient-specific aortic dissection. Biomechanics and modeling in mechanobiology Baumler, K., Vedula, V., Sailer, A. M., Seo, J., Chiu, P., Mistelbauer, G., Chan, F. P., Fischbein, M. P., Marsden, A. L., Fleischmann, D. 2020

  Abstract

  Credible computational fluid dynamic (CFD) simulations of aortic dissection are challenging, because the defining parallel flow channels-the true and the false lumen-are separated from each other by a more or less mobile dissection membrane, which is made up of a delaminated portion of the elastic aortic wall. We present a comprehensive numerical framework for CFD simulations of aortic dissection, which captures the complex interplay between physiologic deformation, flow, pressures, and time-averaged wall shear stress (TAWSS) in a patient-specific model. Our numerical model includes (1) two-way fluid-structure interaction (FSI) to describe the dynamic deformation of the vessel wall and dissection flap; (2) prestress and (3) external tissue support of the structural domain to avoid unphysiologic dilation of the aortic wall and stretching of the dissection flap; (4) tethering of the aorta by intercostal and lumbar arteries to restrict translatory motion of the aorta; and a (5) independently defined elastic modulus for the dissection flap and the outer vessel wall to account for their different material properties. The patient-specific aortic geometry is derived from computed tomography angiography (CTA). Three-dimensional phase contrast magnetic resonance imaging (4D flow MRI) and the patient's blood pressure are used to inform physiologically realistic, patient-specific boundary conditions. Our simulations closely capture the cyclical deformation of the dissection membrane, with flow simulations in good agreement with 4D flow MRI. We demonstrate that decreasing flap stiffness from [Formula: see text] to [Formula: see text] kPa (a) increases the displacement of the dissection flap from 1.4 to 13.4 mm, (b) decreases the surface area of TAWSS by a factor of 2.3, (c) decreases the mean pressure difference between true lumen and false lumen by a factor of 0.63, and (d) decreases the true lumen flow rate by up to 20% in the abdominal aorta. We conclude that the mobility of the dissection flap substantially influences local hemodynamics and therefore needs to be accounted for in patient-specific simulations of aortic dissection. Further research to accurately measure flap stiffness and its local variations could help advance future CFD applications.

  View details for DOI 10.1007/s10237-020-01294-8

  View details for PubMedID 31993829

• Type A Aortic Dissection-Experience Over 5 Decades: JACC Historical Breakthroughs in Perspective. Journal of the American College of Cardiology Zhu, Y. n., Lingala, B. n., Baiocchi, M. n., Tao, J. J., Toro Arana, V. n., Khoo, J. W., Williams, K. M., Traboulsi, A. A., Hammond, H. C., Lee, A. M., Hiesinger, W. n., Boyd, J. n., Oyer, P. E., Stinson, E. B., Reitz, B. A., Mitchell, R. S., Miller, D. C., Fischbein, M. P., Woo, Y. J. 2020; 76 (14): 1703–13

  Abstract

  The Stanford classification of aortic dissection was described in 1970. The classification proposed that type A aortic dissection should be surgically repaired immediately, whereas type B aortic dissection can be treated medically. Since then, diagnostic tools and management of acute type A aortic dissection (ATAAD) have undergone substantial evolution. This paper evaluated historical changes of ATAAD repair at Stanford University since the establishment of the aortic dissection classification 50 years ago. The surgical approaches to the proximal and distal extent of the aorta, cerebral perfusion methods, and cannulation strategies were reviewed. Additional analyses using patients who underwent ATAAD repair at Stanford University from 1967 through December 2019 were performed to further illustrate the Stanford experience in the management of ATAAD. While technical complexity increased over time, post-operative survival continued to improve. Further investigation is warranted to delineate factors associated with the improved outcomes observed in this study.

  View details for DOI 10.1016/j.jacc.2020.07.061

  View details for PubMedID 33004136

• Bicuspid Aortic Valve and Ascending Aortic Aneurysm in a Twin Pregnancy. JACC. Case reports Bryant, E., Tsai, S., Levin, E., Fleischman, D., Ansari, J., Fischbein, M., Bianco, K., Khandelwal, A. 2020; 2 (1): 96-100

  Abstract

  Bicuspid aortic valve with ascending aortic aneurysm is a common condition encountered in pregnancy. There are limited data on how to manage these patients. To our knowledge, we report the only case of a bicuspid aortic valve and aortic aneurysm with twin gestations. (Level of Difficulty: Intermediate.).

  View details for DOI 10.1016/j.jaccas.2019.12.012

  View details for PubMedID 34316973

• Off-Pump Mini Thoracotomy Versus Sternotomy for Left Anterior Descending Myocardial Bridge Unroofing. The Annals of thoracic surgery Wang, H. n., Pargaonkar, V. S., Hironaka, C. E., Bajaj, S. S., Abbot, C. J., O'Donnell, C. T., Miller, S. L., Honda, Y. n., Rogers, I. S., Tremmel, J. A., Fischbein, M. P., Mitchell, R. S., Schnittger, I. n., Boyd, J. H. 2020

  Abstract

  Myocardial bridge (MB) of the left anterior descending (LAD) coronary artery occurs in approximately 25% of the population. For patients with a symptomatic, hemodynamically significant MB who fail medical therapy, MB unroofing represents the optimal surgical management. Here, we evaluated minimally invasive MB unroofing in selected patients compared with sternotomy.MB unroofing was performed in 141 adult patients via sternotomy on-pump (ST-on, n=40), sternotomy off-pump (ST-off, n=62), or mini thoracotomy off-pump (MT, n=39). Angina symptoms were assessed preoperatively and 6-months postoperatively using the Seattle Angina Questionnaire. Matching included all MT patients and 31 ST-off patients with similar MB characteristics, no previous cardiac surgery or coronary interventions, and no concomitant procedures.MT patients tended to have a shorter MB length than ST-on and ST-off patients (2.57 vs 2.93 vs 3.09 cm, p=0.166). ST-on patients had a longer hospital stay than ST-off and MT patients (5.0 vs 4.0 vs 3.0 days, p<0.001), and more blood transfusions (15.2% vs 0.0% vs 2.6%, p=0.002). After matching, MT patients had a shorter hospital stay than ST-off patients (3.0 vs 4.0 days, p=0.005). No deaths or major complications occurred in any group. In all groups, MB unroofing yielded significant symptomatic improvement regarding physical limitation, angina stability, angina frequency, treatment satisfaction, and quality of life.We report the largest experience of off-pump minimally invasive MB unroofing, which may be safely performed in carefully selected patients, yielding dramatic improvements in angina symptomatology at 6 months after surgery.

  View details for DOI 10.1016/j.athoracsur.2020.11.023

  View details for PubMedID 33333083

• Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement. The New England journal of medicine Makkar, R. R., Thourani, V. H., Mack, M. J., Kodali, S. K., Kapadia, S., Webb, J. G., Yoon, S., Trento, A., Svensson, L. G., Herrmann, H. C., Szeto, W. Y., Miller, D. C., Satler, L., Cohen, D. J., Dewey, T. M., Babaliaros, V., Williams, M. R., Kereiakes, D. J., Zajarias, A., Greason, K. L., Whisenant, B. K., Hodson, R. W., Brown, D. L., Fearon, W. F., Russo, M. J., Pibarot, P., Hahn, R. T., Jaber, W. A., Rogers, E., Xu, K., Wheeler, J., Alu, M. C., Smith, C. R., Leon, M. B., PARTNER 2 Investigators 2020; 382 (9)

  Abstract

  BACKGROUND: There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk.METHODS: We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke.RESULTS: At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P=0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery.CONCLUSIONS: Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

  View details for DOI 10.1056/NEJMoa1910555

  View details for PubMedID 31995682

• Divergent effects of canonical and non-canonical TGF-beta signalling on mixed contractile-synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms. Journal of cellular and molecular medicine Pedroza, A. J., Koyano, T., Trojan, J., Rubin, A., Palmon, I., Jaatinen, K., Burdon, G., Chang, P., Tashima, Y., Cui, J. Z., Berry, G., Iosef, C., Fischbein, M. P. 2019

  Abstract

  Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF-beta driven via Smad (canonical) and ERK (non-canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF-beta-driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF-beta-dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF-beta-dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a 'mixed' contractile-synthetic phenotype in MFS aortic aneurysm;and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.

  View details for DOI 10.1111/jcmm.14921

  View details for PubMedID 31886938

• Improved midterm outcomes after endovascular repair of nontraumatic descending thoracic aortic rupture compared with open surgery. The Journal of thoracic and cardiovascular surgery Ogawa, Y., Watkins, A. C., Lingala, B., Nathan, I., Chiu, P., Iwakoshi, S., He, H., Lee, J. T., Fischbein, M., Woo, Y. J., Dake, M. D. 2019

  Abstract

  BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has become first-line treatment for descending thoracic aortic rupture (DTAR), but its midterm and long-term outcomes remain undescribed. This study evaluated whether TEVAR would improve midterm outcomes of nontraumatic DTAR relative to open surgical repair (OSR).METHODS: Between December 1999 and October 2018, 118 patients with DTAR were treated with either OSR (n=39) or TEVAR (n=79) at a single center. Primary end points were 30-day and long-term all-cause mortalities. Secondary end points included stroke, permanent spinal cord ischemia (SCI), prolonged ventilation support or tracheostomy, permanent hemodialysis, and aortic reintervention.RESULTS: Thirty-day mortality was significantly lower with TEVAR (OSR, 38.5%; TEVAR, 16.5%; P=.01). Stroke (15.6% vs 3.8%; P=.03), permanent SCI (15.6% vs 2.5%; P=.02), prolonged ventilation (30.8% vs 8.9%; P=.002), and tracheostomy (12.8% vs 2.5%; P=.04) were significantly lower after TEVAR than OSR. Need for hemodialysis trended higher after OSR (12.8% vs 5.1%; P=.2). Mean follow ups were 1048±1591days for OSR group and 828±1258days for TEVAR. All-cause mortality at last follow-up was significantly lower after TEVAR than OSR (35.4% vs 66.7%; P=.001). Aortic reintervention was required more frequently within 30days after TEVAR (15.2% vs 2.6%; P=.06). By multivariate analysis, TAAA was an independent predictor for mortality.CONCLUSIONS: TEVAR improves both early and midterm outcomes of DTAR relative to OSR. TAAA was a predictor of mortality. Endovascular approach to DTAR may provide the greatest chance at survival.

  View details for DOI 10.1016/j.jtcvs.2019.10.156

  View details for PubMedID 31926735

• Utility of High-Sensitivity and Conventional Troponin in Patients Undergoing Transcatheter Aortic Valve Replacement: Incremental Prognostic Value to B-type Natriuretic Peptide. Scientific reports Kobayashi, Y., Kim, J. B., Moneghetti, K. J., Fischbein, M., Lee, A., Watkins, C. A., Yeung, A. C., Liang, D., Ozen, M. O., Demirci, U., Bowen, R., Fearon, W. F., Haddad, F. 2019; 9 (1): 14936

  Abstract

  High-sensitivity Troponin (hs-Tn) has emerged as a useful marker for patients with myocardial injury or heart failure. However, few studies have compared intermediate and hs-Tn in patients undergoing transcatheter aortic valve replacement (TAVR). Moreover, there remains uncertainty of which thresholds are the most useful for discriminating ventricular dysfunction or outcome. In this study we prospectively enrolled 105 patients with severe aortic stenosis (AS) who underwent TAVR as well as blood sampling for high-sensitivity (hs-TnI) and conventional troponin I (EXL-LOCI and RXL) assessment. Patients underwent comprehensive pre-procedure echocardiography. Ventricular dysfunction was defined using left ventricular mass index (LVMI), LV global longitudinal strain (LVGLS) and LV end-diastolic pressure. The mean age was 84.0±8.7 years old and 60% were male sex with mean transaortic pressure gradient of 50.1±16.0mmHg and AVA of 0.63±0.19cm2. When using a threshold of 6ng/L, 77% had positive hs-TnI while 27% had positive hs-TnI using recommended thresholds (16ng/L for female and 34ng/L for male). Troponin levels were higher in the presence of abnormal LV phenotypes. The strongest correlate of troponin was LVMI. During median follow-up of 375 days, 21 patients (20%) died. Lower threshold of hs-TnI and EXL-TnI was more discriminatory for overall mortality (Log-rank P=0.03 for both), while higher threshold of hs-TnI (p=0.75) and RXL-TnI were not (p=0.30). Combining hs-TnI and BNP improved to predict long-term outcome (p=0.004). In conclusion, hs-TnI levels correlated with the degree of LV dysfunction phenotypes. Furthermore, applying a lower threshold for hs-TnI performed better for outcome prediction than a recommended threshold in patients undergoing TAVR. Combining hs-TnI with BNP helped better risk stratification.

  View details for DOI 10.1038/s41598-019-51371-x

  View details for PubMedID 31624275

• "Cheese Wire" Fenestration of Dissection Intimal Flap to Facilitate Thoracic Endovascular Aortic Repair in Chronic Dissection. Journal of vascular and interventional radiology : JVIR Iwakoshi, S., Watkins, C. A., Ogawa, Y., Fischbein, M., Lee, A., Lee, J. T., Hiesinger, W., Dake, M. D. 2019

  Abstract

  Thoracic endovascular aortic repair (TEVAR) for aneurysmal chronic dissection is often complicated by retrograde filling of the false lumen and dissected distal landing zone. A "cheese wire"-style fenestration of the dissection intimal flap can create a landing zone facilitating TEVAR. This technique successfully aided TEVAR in 3 patients with an average age of 57.3 years. Complications included type III endoleak requiring relining and renal artery occlusion requiring stent placement. Average duration of clinical follow-up was 19 ± 4 months. Imaging follow-up was 8 ± 10 months. All patients have survived for more than 1 year without aneurysm enlargement.

  View details for DOI 10.1016/j.jvir.2019.06.004

  View details for PubMedID 31542270

• Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation. Journal of cellular and molecular medicine Emrich, F., Penov, K., Arakawa, M., Dhablania, N., Burdon, G., Pedroza, A. J., Koyano, T. K., Kim, Y. M., Raaz, U., Connolly, A. J., Iosef, C., Fischbein, M. P. 2019

  Abstract

  Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root aneurysm formation. Reactive oxygen species (ROS) seem to play a role in aortic wall remodelling in MFS, although the mechanism remains unknown. MFS Fbn1C1039G/+ mouse root/ascending (AS) and descending (DES) aortic samples were examined using DHE staining, lucigenin-enhanced chemiluminescence (LGCL), Verhoeff's elastin-Van Gieson staining (elastin breakdown) and in situ zymography for protease activity. Fbn1C1039G/+ AS- or DES-derived smooth muscle cells (SMC) were treated with anti-TGF-beta antibody, angiotensin II (AngII), anti-TGF-beta antibody+AngII, or isotype control. ROS were detected during early aneurysm formation in the Fbn1C1039G/+ AS aorta, but absent in normal-sized DES aorta. Fbn1C1039G/+ mice treated with the unspecific NADPH oxidase inhibitor, apocynin reduced AS aneurysm formation, with attenuated elastin fragmentation. In situ zymography revealed apocynin treatment decreased protease activity. In vitro SMC studies showed Fbn1C1039G/+ -derived AS SMC had increased NADPH activity compared to DES-derived SMC. AS SMC NADPH activity increased with AngII treatment and appeared TGF-beta dependent. In conclusion, ROS play a role in MFS aneurysm development and correspond anatomically with aneurysmal aortic segments. ROS inhibition via apocynin treatment attenuates MFS aneurysm progression. AngII enhances ROS production in MFS AS SMCs and is likely TGF-beta dependent.

  View details for DOI 10.1111/jcmm.14587

  View details for PubMedID 31402541

• Endovascular Versus Open Repair of Intact Descending Thoracic Aortic Aneurysms JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Chiu, P., Goldstone, A. B., Schaffer, J. M., Lingala, B., Miller, D., Mitchell, R., Woo, Y., Fischbein, M. P., Dake, M. D. 2019; 73 (6): 643–51

  Abstract

  For the management of descending thoracic aortic aneurysms, recent evidence has suggested that outcomes of open surgical repair may surpass thoracic endovascular aortic repair (TEVAR) in as early as 2 years.The purpose of this study was to evaluate the comparative effectiveness of TEVAR and open surgical repair in the treatment of intact descending thoracic aortic aneurysms.Using the Medicare database, a retrospective study using regression discontinuity design and propensity score matching was performed on patients with intact descending thoracic aortic aneurysms who underwent TEVAR or open surgical repair between 1999 and 2010 with follow-up through 2014. Survival was assessed with restricted mean survival time. Perioperative mortality was assessed with logistic regression. Reintervention was evaluated as a secondary outcome.Matching created comparable groups with 1,235 open surgical repair patients matched to 2,470 TEVAR patients. The odds of perioperative mortality were greater for open surgical repair: high-volume center, odds ratio (OR): 1.97 (95% confidence interval [CI]: 1.53 to 2.61); low-volume center, OR: 3.62 (95% CI: 2.88 to 4.51). The restricted mean survival time difference favored TEVAR at 9 years, -209.2 days (95% CI: -298.7 to -119.7 days; p < 0.001) for open surgical repair. Risk of reintervention was lower for open surgical repair, hazard ratio: 0.40 (95% CI: 0.34 to 0.60; p < 0.001).Open surgical repair was associated with increased odds of early postoperative mortality but reduced late hazard of death. Despite the late advantage of open repair, mean survival was superior for TEVAR. TEVAR should be considered the first line for repair of intact descending thoracic aortic aneurysms in Medicare beneficiaries.

  View details for PubMedID 30765029

• Incremental Value of Aortomitral Continuity Calcification for Risk Assessment after Transcatheter Aortic Valve Replacement. Radiology. Cardiothoracic imaging Willemink, M. J., Maret, E. n., Moneghetti, K. J., Kim, J. B., Haddad, F. n., Kobayashi, Y. n., Nishi, T. n., Nieman, K. n., Cauwenberghs, N. n., Kuznetsova, T. n., Higashigaito, K. n., Sailer, A. M., Yeung, A. C., Lee, A. M., Miller, D. C., Fischbein, M. n., Fearon, W. F., Fleischmann, D. n. 2019; 1 (5): e190067

  Abstract

  To investigate the association of aortomitral continuity calcification (AMCC) with all-cause mortality, postprocedural paravalvular leak (PVL), and prolonged hospital stay in patients undergoing transcatheter aortic valve replacement (TAVR).The authors retrospectively evaluated 329 patients who underwent TAVR between March 2013 and March 2016. AMCC, aortic valve calcification (AVC), and coronary artery calcification (CAC) were quantified by using preprocedural CT. Pre-procedural Society of Thoracic Surgeons (STS) score was recorded. Associations between baseline AMCC, AVC, and CAC and 1-year mortality, PVL, and hospital stay longer than 7 days were analyzed.The median follow-up was 415 days (interquartiles, 344-727 days). After 1 year, 46 of the 329 patients (14%) died and 52 (16%) were hospitalized for more than 7 days. Of the 326 patients who underwent postprocedural echocardiography, 147 (45%) had postprocedural PVL. The CAC score (hazard ratio: 1.11 per 500 points) and AMCC mass (hazard ratio: 1.13 per 500 mg) were associated with 1-year mortality. AVC mass (odds ratio: 1.93 per 100 mg) was associated with postprocedural PVL. Only the STS score was associated with prolonged hospital stay (odds ratio: 1.19 per point).AMCC is associated with mortality within 1 year after TAVR and substantially improves individual risk classification when added to a model consisting of STS score and AVC mass only.Supplemental material is available for this article.© RSNA, 2019See also the commentary by Brown and Leipsic in this issue.

  View details for DOI 10.1148/ryct.2019190067

  View details for PubMedID 33778530

  View details for PubMedCentralID PMC7977784

• Aortic growth and development of partial false lumen thrombosis are associated with late adverse events in type B aortic dissection. The Journal of thoracic and cardiovascular surgery Higashigaito, K. n., Sailer, A. M., van Kuijk, S. M., Willemink, M. J., Hahn, L. D., Hastie, T. J., Miller, D. C., Fischbein, M. P., Fleischmann, D. n. 2019

  Abstract

  Patients with medically treated type B aortic dissection (TBAD) remain at significant risk for late adverse events (LAEs). We hypothesize that not only initial morphological features, but also their change over time at follow-up are associated with LAEs.Baseline and 188 follow-up computed tomography (CT) scans with a median follow-up time of 4 years (range, 10 days to 12.7 years) of 47 patients with acute uncomplicated TBAD were retrospectively reviewed. Morphological features (n = 8) were quantified at baseline and each follow-up. Medical records were reviewed for LAEs, which were defined according to current guidelines. To assess the effects of changes of morphological features over time, the linear mixed effects models were combined with Cox proportional hazards regression for the time-to-event outcome using a joint modeling approach.LAEs occurred in 21 of 47 patients at a median of 6.6 years (95% confidence interval [CI], 5.1-11.2 years). Among the 8 investigated morphological features, the following 3 features showed strong association with LAEs: increase in partial false lumen thrombosis area (hazard ratio [HR], 1.39; 95% CI, 1.18-1.66 per cm2 increase; P < .001), increase of major aortic diameter (HR, 1.24; 95% CI, 1.13-1.37 per mm increase; P < .001), and increase in the circumferential extent of false lumen (HR, 1.05; 95% CI, 1.01-1.10 per degree increase; P < .001).In medically treated TBAD, increases in aortic diameter, new or increased partial false lumen thrombosis area, and increases of circumferential extent of the false lumen are strongly associated with LAEs.

  View details for DOI 10.1016/j.jtcvs.2019.10.074

  View details for PubMedID 31839226

• Interfacility Transfer of Medicare Beneficiaries With Acute Type A Aortic Dissection and Regionalization of Care in the United States. Circulation Goldstone, A. B., Chiu, P. n., Baiocchi, M. n., Lingala, B. n., Lee, J. n., Rigdon, J. n., Fischbein, M. P., Woo, Y. J. 2019; 140 (15): 1239–50

  Abstract

  The feasibility and effectiveness of delaying surgery to transfer patients with acute type A aortic dissection-a catastrophic disease that requires prompt intervention-to higher-volume aortic surgery hospitals is unknown. We investigated the hypothesis that regionalizing care at high-volume hospitals for acute type A aortic dissections will lower mortality. We further decomposed this hypothesis into subparts, investigating the isolated effect of transfer and the isolated effect of receiving care at a high-volume versus a low-volume facility.We compared the operative mortality and long-term survival between 16 886 Medicare beneficiaries diagnosed with an acute type A aortic dissection between 1999 and 2014 who (1) were transferred versus not transferred, (2) underwent surgery at high-volume versus low-volume hospitals, and (3) were rerouted versus not rerouted to a high-volume hospital for treatment. We used a preference-based instrumental variable design to address unmeasured confounding and matching to separate the effect of transfer from volume.Between 1999 and 2014, 40.5% of patients with an acute type A aortic dissection were transferred, and 51.9% received surgery at a high-volume hospital. Interfacility transfer was not associated with a change in operative mortality (risk difference, -0.69%; 95% CI, -2.7% to 1.35%) or long-term mortality. Despite delaying surgery, a regionalization policy that transfers patients to high-volume hospitals was associated with a 7.2% (95% CI, 4.1%-10.3%) absolute risk reduction in operative mortality; this association persisted in the long term (hazard ratio, 0.81; 95% CI, 0.75-0.87). The median distance needed to reroute each patient to a high-volume hospital was 50.1 miles (interquartile range, 12.4-105.4 miles).Operative and long-term mortality were substantially reduced in patients with acute type A aortic dissection who were rerouted to high-volume hospitals. Policy makers should evaluate the feasibility and benefits of regionalizing the surgical treatment of acute type A aortic dissection in the United States.

  View details for DOI 10.1161/CIRCULATIONAHA.118.038867

  View details for PubMedID 31589488

• Current evidence for prosthesis selection: What can we really say? The Journal of thoracic and cardiovascular surgery Chiu, P. n., Goldstone, A. B., Fischbein, M. P., Woo, Y. J. 2019

  View details for DOI 10.1016/j.jtcvs.2019.03.094

  View details for PubMedID 31200938

• Cytokines profile of reverse cardiac remodeling following transcatheter aortic valve replacement. International journal of cardiology Kim, J. B., Kobayashi, Y., Kuznetsova, T., Moneghetti, K. J., Brenner, D. A., O'Malley, R., Dao, C., Wu, J. C., Fischbein, M., Craig Miller, D., Yeung, A. C., Liang, D., Haddad, F., Fearon, W. F. 2018; 270: 83–88

  Abstract

  OBJECTIVE: Previous studies have suggested that cytokines and growth factors may predict ventricular recovery following aortic valve replacement (AVR). The primary objective of this study was to identify cytokines that predict ventricular recovery following transcatheter AVR (TAVR).METHODS: We prospectively enrolled 121 consecutive patients who underwent TAVR. Standard echocardiographic assessment at baseline, 1-month and 1-year after TAVR included left ventricular (LV) mass index (LVMI) and global longitudinal strain (GLS). Blood samples were obtained at the time of the procedure to measure cytokines using a 63-plex Luminex platform. Partial least squares-discriminant analysis was performed to identify cytokines associated with ventricular remodeling and function at baseline as well as 1 year after TAVR.RESULTS: The mean age was 84 ± 9 years, with a majority of male subjects (59%), a mean LVMI of 120.4 ± 45.1 g/m2 and LVGLS of -13.0 ± 3.2%. On average, LV mass decreased by 8.1% and GLS improved by 20.3% at 1 year following TAVR. Among cytokines assayed, elevated hepatocyte growth factor (HGF) emerged as a common factor significantly associated with worse baseline LVMI and GLS as well as reduced ventricular recovery (p < 0.005). Other factors associated with ventricular recovery included a select group of vascular growth factors, inflammatory mediators and tumor necrosis factors, including VEGF-D, ICAM-1, TNFbeta, and IL1beta.CONCLUSION: We identified a network of cytokines, including HGF, that are significantly correlated with baseline LVMI and GLS, and ventricular recovery following TAVR.

  View details for PubMedID 30219541

• PREDICTING MORTALITY WITH AORTOMITRAL CALCIFICATIONS IN 317 TAVR PATIENTS Willemink, M., Maret, E., Moneghetti, K., Kim, J., Haddad, F., Kobayashi, Y., Higashigaito, K., Yeung, A., Lee, A., Miller, D., Fischbein, M., Fearon, W., Fleischmann, D. ELSEVIER SCIENCE INC. 2018: 1591

  View details for DOI 10.1016/S0735-1097(18)32132-6

  View details for Web of Science ID 000429659703241

• Two-stage surgical approach for ruptured Salmonella aortitis JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Brewer, Z. E., Dake, M. D., Fischbein, M. P. 2018; 155 (3): E87–E89

  View details for PubMedID 29089095

• Acute Limited Intimal Tears of the Thoracic Aorta. Journal of the American College of Cardiology Chin, A. S., Willemink, M. J., Kino, A. n., Hinostroza, V. n., Sailer, A. M., Fischbein, M. P., Mitchell, R. S., Berry, G. J., Miller, D. C., Fleischmann, D. n. 2018; 71 (24): 2773–85

  Abstract

  Limited intimal tears (LITs) of the aorta (Class 3 dissection variant) are the least common form of aortic pathology in patients presenting with acute aortic syndrome (AAS). LITs are difficult to detect on imaging and may be underappreciated.This study sought to describe the frequency, pathology, treatment, and outcome of LITs compared with other AAS, and to demonstrate that LITs can be detected pre-operatively by contemporary imaging.The authors retrospectively reviewed 497 patients admitted for 513 AAS events at a single academic aortic center between 2003 and 2012. AAS were classified into classic dissection (AD), intramural hematoma, LIT, penetrating atherosclerotic ulcer, and rupturing thoracic aortic aneurysm. The prevalence, pertinent risk factors, and detailed imaging findings with surgical and pathological correlation of LITs are described. Management, early outcomes, and late mortality are reported.Among 497 patients with AAS, the authors identified 24 LITs (4.8% of AAS) in 16 men and 8 women (17 type A, 7 type B). Patients with LITs were older than those with AD, and type A LITs had similarly dilated ascending aortas as type A AD. Three patients presented with rupture. Eleven patients underwent urgent surgical aortic replacement, and 2 patients underwent endovascular repair. Medial degeneration was present in all surgical specimens. In-hospital mortality was 4% (1 of 24), and in total, 5 patients with LIT died subsequently at 1.5 years (interquartile range [IQR]: 0.3 to 2.5 years). Computed tomography imaging detected all but 1 LIT, best visualized on volume-rendered images.LITs are rare acute aortic lesions within the dissection spectrum, with similar presentation, complications, and outcomes compared with AD and intramural hematoma. Awareness of this lesion allows pre-operative diagnosis using high-quality computed tomography angiography.

  View details for PubMedID 29903350

• Limited root repair in acute type A aortic dissection is safe but results in increased risk of reoperation JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Chiu, P., Trojan, J., Tsou, S., Goldstone, A. B., Woo, Y., Fischbein, M. P. 2018; 155 (1): 1-+

  View details for DOI 10.1016/j.jtcvs.2017.08.137

  View details for Web of Science ID 000422751300024

• Immediate operation for acute type A aortic dissection complicated by visceral or peripheral malperfusion. The Journal of thoracic and cardiovascular surgery Chiu, P. n., Tsou, S. n., Goldstone, A. B., Louie, M. n., Woo, Y. J., Fischbein, M. P. 2018

  Abstract

  To evaluate the effect of visceral, renal, or peripheral malperfusion on the outcome of acute type A aortic dissection.We performed a retrospective review of the acute type A aortic dissection experience at Stanford Hospital between January 2005 and December 2015. Inverse probability weighting was used to account for differences between patients who experienced malperfusion syndromes and those who did not. Weighted logistic regression was used to evaluate in-hospital mortality, and midterm survival was assessed with the restricted mean survival time and weighted Cox regression. Reintervention was assessed with death as a competing risk.There were 305 patients with type A dissection extending beyond the ascending aorta, and 82 (26.9%) presented with a malperfusion syndrome. In-hospital mortality in the malperfusion subgroup was no different compared with patients without malperfusion in weighted logistic regression, odds ratio, 1.50 (95% confidence interval, 0.65-3.47; P = .3). There was no difference in midterm survival using restricted mean survival time, -50.2 days (95% CI, -366.8 to 266.4; P = .8) in patients with malperfusion compared with patients without malperfusion at 8 years. Patients with malperfusion had an increased risk of interventions (12.5%) on aortic branches compared with patients without (5.7%) in weighted analysis at 10-years, hazard ratio, 3.06 (95% CI, 1.24-7.56; P = .02). The median time to reintervention on aortic branches was 2 days for patients with malperfusion compared with 230 days without malperfusion, P = .01.Immediate operation for acute type A aortic dissection complicated by malperfusion is associated with good results.

  View details for PubMedID 29615333

• Novel role of NANOG in smooth muscle cell phenotypic modulation during aortic dissections JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Shahbazi, M., Fischbein, M. 2017; 154 (5): 1522–23

  View details for PubMedID 28826598

• Impact of Discordant Views in the Management of Descending Thoracic Aortic Aneurysm SEMINARS IN THORACIC AND CARDIOVASCULAR SURGERY Chiu, P., Sailer, A., Baiocchi, M., Goldstone, A. B., Schaffer, J. M., Trojan, J., Fleischmann, D., Mitchell, R., Miller, D., Dake, M. D., Woo, Y., Lee, J. T., Fischbein, M. P. 2017; 29 (3): 283–91

  Abstract

  Thoracic endovascular aortic repair has a lower perceived risk than open surgical repair and has become an increasingly popular alternative. Whether general consensus exists regarding candidacy for either operation among open and endovascular specialists is unknown. A retrospective review of isolated descending thoracic aortic aneurysm at our institution between January 2005 and October 2015 was performed, excluding trauma and dissection. Two cardiac surgeons, 2 cardiovascular surgeons, 1 vascular surgeon, and 1 interventional radiologist gave their preference for open vs endovascular repair. Interobserver agreement was assessed with the kappa coefficient. k-means clustering agnostically grouped various patterns of agreement. The mean rating was predicted using least absolute shrinkage and selection operator regression. Negative binomial regression predicted the discrepancy between our panel of raters and the historical operation. Generalized estimating equation modeling was then used to evaluate the association between the extent of discrepancy and the adverse perioperative outcome. There were 77 patients with preoperative imaging studies. Pairwise interobserver agreement was only fair (median weighted kappa 0.270 [interquartile range 0.211-0.404]). Increasing age and proximal neck length predicted an increasing preference for thoracic endovascular aortic repair in our panel; larger proximal neck diameter predicted a general preference for open surgical repair. Increasing proximal neck diameter predicted a larger discrepancy between our panel and the historical operation. Greater discrepancy was associated with adverse outcome. Substantial disagreement existed among our panel, and an exploratory analysis of the effect of increasing discrepancy demonstrated an association with adverse perioperative outcome. An investigation of the effect of a thoracic aortic team with open and endovascular specialists is warranted.

  View details for PubMedID 29195571

• Dynamic changes in aortic impedance after transcatheter aortic valve replacement and its impact on exploratory outcome. international journal of cardiovascular imaging Kobayashi, Y., Kim, J. B., Moneghetti, K. J., Kobayashi, Y., Zhang, R., Brenner, D. A., O'Malley, R., Schnittger, I., Fischbein, M., Miller, D. C., Yeung, A. C., Liang, D., Haddad, F., Fearon, W. F. 2017

  Abstract

  Valvulo-arterial impedance (Zva) has been shown to predict worse outcome in medically managed aortic stenosis (AS) patients. We aimed to investigate the association between Zva and left ventricular (LV) adaptation and to explore the predictive value of Zva for cardiac functional recovery and outcome after transcatheter aortic valve replacement (TAVR). We prospectively enrolled 128 patients with AS who underwent TAVR. Zva was calculated as: (systolic blood pressure + mean transaortic gradient)/stroke volume index). Echocardiographic assessment occurred at baseline, 1-month and 1-year after TAVR. The primary endpoints were to investigate associations between Zva and global longitudinal strain (GLS) at baseline as well as GLS change after TAVR. The secondary was to compare all-cause mortality after TAVR between patients with pre-defined Zva (=5 mmHg m(2)/ml), stroke volume index (=35 ml/m(2)), and GLS (=-15%) cutoffs. The mean GLS was reduced (-13.0 ± 3.2%). The mean Zva was 5.2 ± 1.6 mmHg*m(2)/ml with 55% of values ≥5.0 mmHg*m(2)/ml, considered to be abnormally high. Higher Zva correlated with worse GLS (r = -0.33, p < 0.001). After TAVR, Zva decreased significantly (5.1 ± 1.6 vs. 4.5 ± 1.6 mmHg*m(2)/ml, p = 0.001). A reduction of Zva at 1-month was associated with GLS improvement at 1-month (r = -0.31, p = 0.001) and at 1-year (r = -0.36 and p = 0.001). By Kaplan-Meier analysis, patients with higher Zva at baseline had higher mortality (Log-rank p = 0.046), while stroke volume index and GLS did not differentiate outcome (Log-rank p = 0.09 and 0.25, respectively). As a conclusion, Zva is correlated with GLS in AS as well as GLS improvement after TAVR. Furthermore, a high baseline Zva may have an additional impact to traditional parameters on predicting worse mortality after TAVR.

  View details for DOI 10.1007/s10554-017-1155-6

  View details for PubMedID 28516313

• Gene expression profiling of acute type A aortic dissection combined with in vitroassessment†. European journal of cardio-thoracic surgery Kimura, N., Futamura, K., Arakawa, M., Okada, N., Emrich, F., Okamura, H., Sato, T., Shudo, Y., Koyano, T. K., Yamaguchi, A., Adachi, H., Matsuda, A., Kawahito, K., Matsumoto, K., Fischbein, M. P. 2017

  Abstract

  The mechanisms underlying aortic dissection remain to be fully elucidated. We aimed to identify key molecules driving dissection through gene expression profiling achieved by microarray analysis and subsequent in vitro experiments using human aortic endothelial cells (HAECs) and aortic vascular smooth muscle cells (AoSMCs).Total RNA, including microRNA (miRNA), was isolated from the intima-media layer of dissected ascending aorta obtained intraoperatively from acute type A aortic dissection (ATAAD) patients without familial thoracic aortic disease ( n  = 8) and that of non-dissected ascending aorta obtained from transplant donors ( n  = 9). Gene expression profiling was performed with mRNA and miRNA microarrays, and results were confirmed by quantitative polymerase chain reaction (qPCR). Target genes and miRNA were identified by gene ontology analysis and a literature search. To reproduce the in silico results, HAECs and AoSMCs were stimulated in vitro by upstream cytokines, and expression of target genes was assessed by qPCR.Microarray analysis revealed 1536 genes (3.6%, 1536/42 545 probes) and 41 miRNAs (3.0%, 41/1368 probes) that were differentially expressed in the ATAAD group (versus donor group). The top 15 related pathways included regulation of inflammatory response, growth factor activity and extracellular matrix. Gene ontology analysis identified JAK2 (regulation of inflammatory response), PDGFA, TGFB1, VEGFA (growth factor activity) and TIMP3 , TIMP4, SERPINE1 (extracellular matrix) as the target genes and miR-21-5p, a TIMP3 repressor, as target miRNA that interacts with the target genes. Validation qPCR confirmed the altered expression of all 7 target genes and miR-21-5p in dissected aorta specimens (all genes, P  < 0.05). Ingenuity pathway analysis showed TNF-α and TGF-β to be upstream cytokines for the target genes. In vitro experiments showed these cytokines inhibit TIMP3 expression ( P  < 0.05) and enhance VEGFA expression ( P  < 0.01) in AoSMCs but not HAECs. miR-21-5p expression increases in AoSMCs under TNF-α and TGF-β stimulation (fold change: 1.36; P  = 0.011).Results of our novel approach, integrating in vitro assessment into gene expression profiling, implicated chronic inflammation characterized by MMP-TIMP dysregulation, increased VEGFA expression, and TGF-β signalling in the development of dissection. Further investigation may reveal novel diagnostic biomarkers and uncover the mechanism(s) underlying ATAAD.

  View details for DOI 10.1093/ejcts/ezx095

  View details for PubMedID 28402522

• Long-term miR-29b suppression reduces aneurysm formation in a Marfan mouse model. Physiological reports Okamura, H., Emrich, F., Trojan, J., Chiu, P., Dalal, A. R., Arakawa, M., Sato, T., Penov, K., Koyano, T., Pedroza, A., Connolly, A. J., Rabinovitch, M., Alvira, C., Fischbein, M. P. 2017; 5 (8)

  Abstract

  Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR-29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1(C1039G/+) Marfan mice. Herein, we sought to determine whether miR-29b suppression can reduce aneurysm formation long-term. Fbn1(C1039G/+) Marfan mice were treated with retro-orbital LNA-anti-miR-29b inhibitor or scrambled-control-miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1(C1039G/+) mice at 14.5 days post-coitum) (n = 8-10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks (n = 8-10, each group). To determine if miR-29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed (n = 4-6, each group). miR-29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA-anti-miR-29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR-29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR-29b inhibition significantly reduces aneurysm development long-term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR-29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.

  View details for DOI 10.14814/phy2.13257

  View details for PubMedID 28455451

• Computed Tomography Imaging Features in Acute Uncomplicated Stanford Type-B Aortic Dissection Predict Late Adverse Events CIRCULATION-CARDIOVASCULAR IMAGING Sailer, A. M., Van Kuijk, S. M., Nelemans, P. J., Chin, A. S., Kino, A., Huininga, M., Schmidt, J., Mistelbauer, G., Baeumler, K., Chiu, P., Fischbein, M. P., Dake, M. D., Miller, D. C., Schurink, G. W., Fleischmann, D. 2017; 10 (4)

  Abstract

  Medical treatment of initially uncomplicated acute Stanford type-B aortic dissection is associated with a high rate of late adverse events. Identification of individuals who potentially benefit from preventive endografting is highly desirable.The association of computed tomography imaging features with late adverse events was retrospectively assessed in 83 patients with acute uncomplicated Stanford type-B aortic dissection, followed over a median of 850 (interquartile range 247-1824) days. Adverse events were defined as fatal or nonfatal aortic rupture, rapid aortic growth (>10 mm/y), aneurysm formation (≥6 cm), organ or limb ischemia, or new uncontrollable hypertension or pain. Five significant predictors were identified using multivariable Cox regression analysis: connective tissue disease (hazard ratio [HR] 2.94, 95% confidence interval [CI]: 1.29-6.72; P=0.01), circumferential extent of false lumen in angular degrees (HR 1.03 per degree, 95% CI: 1.01-1.04, P=0.003), maximum aortic diameter (HR 1.10 per mm, 95% CI: 1.02-1.18, P=0.015), false lumen outflow (HR 0.999 per mL/min, 95% CI: 0.998-1.000; P=0.055), and number of intercostal arteries (HR 0.89 per n, 95% CI: 0.80-0.98; P=0.024). A prediction model was constructed to calculate patient specific risk at 1, 2, and 5 years and to stratify patients into high-, intermediate-, and low-risk groups. The model was internally validated by bootstrapping and showed good discriminatory ability with an optimism-corrected C statistic of 70.1%.Computed tomography imaging-based morphological features combined into a prediction model may be able to identify patients at high risk for late adverse events after an initially uncomplicated type-B aortic dissection.

  View details for DOI 10.1161/CIRCIMAGING.116.005709

  View details for PubMedID 28360261

• THE INFLAMMASOME PATHWAY IS ASSOCIATED WITH ADVERSE VENTRICULAR REMODELING FOLLOWING TRANSCATHETER AORTIC VALVE REPLACEMENT Kim, J., Kobayashi, Y., Kouznetsova, T., Moneghetti, K., Brenner, D., O'Malley, R., Dao, C., Schnittger, I., Liang, D., Wu, J., Fischbein, M., Lee, A., Miller, D., Yeung, A., Fearon, W., Haddad, F. ELSEVIER SCIENCE INC. 2017: 1040

  View details for Web of Science ID 000397342301562

• Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement. The New England journal of medicine Goldstone, A. B., Chiu, P. n., Baiocchi, M. n., Lingala, B. n., Patrick, W. L., Fischbein, M. P., Woo, Y. J. 2017; 377 (19): 1847–57

  Abstract

  In patients undergoing aortic-valve or mitral-valve replacement, either a mechanical or biologic prosthesis is used. Biologic prostheses have been increasingly favored despite limited evidence supporting this practice.We compared long-term mortality and rates of reoperation, stroke, and bleeding between inverse-probability-weighted cohorts of patients who underwent primary aortic-valve replacement or mitral-valve replacement with a mechanical or biologic prosthesis in California in the period from 1996 through 2013. Patients were stratified into different age groups on the basis of valve position (aortic vs. mitral valve).From 1996 through 2013, the use of biologic prostheses increased substantially for aortic-valve and mitral-valve replacement, from 11.5% to 51.6% for aortic-valve replacement and from 16.8% to 53.7% for mitral-valve replacement. Among patients who underwent aortic-valve replacement, receipt of a biologic prosthesis was associated with significantly higher 15-year mortality than receipt of a mechanical prosthesis among patients 45 to 54 years of age (30.6% vs. 26.4% at 15 years; hazard ratio, 1.23; 95% confidence interval [CI], 1.02 to 1.48; P=0.03) but not among patients 55 to 64 years of age. Among patients who underwent mitral-valve replacement, receipt of a biologic prosthesis was associated with significantly higher mortality than receipt of a mechanical prosthesis among patients 40 to 49 years of age (44.1% vs. 27.1%; hazard ratio, 1.88; 95% CI, 1.35 to 2.63; P<0.001) and among those 50 to 69 years of age (50.0% vs. 45.3%; hazard ratio, 1.16; 95% CI, 1.04 to 1.30; P=0.01). The incidence of reoperation was significantly higher among recipients of a biologic prosthesis than among recipients of a mechanical prosthesis. Patients who received mechanical valves had a higher cumulative incidence of bleeding and, in some age groups, stroke than did recipients of a biologic prosthesis.The long-term mortality benefit that was associated with a mechanical prosthesis, as compared with a biologic prosthesis, persisted until 70 years of age among patients undergoing mitral-valve replacement and until 55 years of age among those undergoing aortic-valve replacement. (Funded by the National Institutes of Health and the Agency for Healthcare Research and Quality.).

  View details for PubMedID 29117490

• Prognostic significance of early aortic remodeling in acute uncomplicated type B aortic dissection and intramural hematoma. The Journal of thoracic and cardiovascular surgery Sailer, A. M., Nelemans, P. J., Hastie, T. J., Chin, A. S., Huininga, M. n., Chiu, P. n., Fischbein, M. P., Dake, M. D., Miller, D. C., Schurink, G. W., Fleischmann, D. n. 2017; 154 (4): 1192–1200

  Abstract

  Patients with Stanford type B aortic dissections (ADs) are at risk of long-term disease progression and late complications. The aim of this study was to evaluate the natural course and evolution of acute type B AD and intramural hematomas (IMHs) in patients who presented without complications during their initial hospital admission and who were treated with optimal medical management (MM).Databases from 2 aortic centers in Europe and the United States were used to identify 136 patients with acute type B AD (n = 92) and acute type B IMH (n = 44) who presented without complications during their index admission and were treated with MM. Computed tomography angiography scans were available at onset (≤14 days) and during follow-up for those patients. Relevant data, including evidence of adverse events during follow-up (AE; defined according to current guidelines), were retrieved from medical records and by reviewing computed tomography scan images. Aortic diameters were measured with dedicated 3-dimensional software.The 1-, 2-, and 5-year event-free survival rates of patients with type B AD were 84.3% (95% confidence interval [CI], 74.4-90.6), 75.4% (95% CI, 64.0-83.7), and 62.6% (95% CI, 68.9-73.6), respectively. Corresponding estimates for IMH were 76.5% (95% CI, 57.8-87.8), 76.5% (95% CI, 57.8-87.8), and 68.9% (95% CI, 45.2-83.9), respectively. In patients with type B AD, risk of an AE increased with aortic growth within the first 6 months after onset. A diameter increase of 5 mm in the first half year was associated with a relative risk for AE of 2.29 (95% CI, 1.70-3.09) compared with the median 6 months' growth of 2.4 mm. In approximately 60% of patients with IMH, the abnormality resolved within 12 months and in the patients with nonresolving IMH, risk of an adverse event was greatest in the first year after onset and remained stable thereafter.More than one third of patients with initially uncomplicated type B AD suffer an AE under MM within 5 years of initial diagnosis. In patients with nonresolving IMH, most adverse events are observed in the first year after onset. In patients with type B AD an early aortic growth is associated with a greater risk of AE.

  View details for PubMedID 28668458

• Limited root repair in acute type A aortic dissection is safe but results in increased risk of reoperation. The Journal of thoracic and cardiovascular surgery Chiu, P. n., Trojan, J. n., Tsou, S. n., Goldstone, A. B., Woo, Y. J., Fischbein, M. P. 2017

  Abstract

  Management of the aortic root is a challenge for surgeons treating acute type A aortic dissection.We performed a retrospective review of the acute type A aortic dissection experience at Stanford Hospital between 2005 and 2015 and identified patients who underwent either limited root repair or aortic root replacement. Differences in baseline characteristics were balanced with inverse probability weighting to estimate the average treatment effect on the controls. Weighted logistic regression was used to evaluate in-hospital mortality. Weighted Cox proportional hazards regression was used to evaluate differences in the hazard for mid-term death. Reoperation was evaluated with death as a competing risk with the Fine-Gray subdistribution hazard.After we excluded patients managed either nonoperatively or with definitive endovascular repair, there were 293 patients without connective tissue disease who underwent either limited root repair or aortic root replacement. There was no difference in weighted perioperative mortality, odds ratio 0.89 (95% confidence interval [CI], 0.44-1.76, P = .7), and there was no difference in weighted survival, hazard ratio 1.12 (95% CI, 0.54-2.31, P = .8). Risk of reoperation was greater in limited root repair (11.8%, 95% CI, 0.0%-23.8%) than for root replacement (0%), P < .001.Limited root repair was associated with increased risk of late reoperation after repair of acute type A aortic dissection. Surgeons with adequate experience may consider aortic root replacement in well-selected patients. However, given good outcomes after limited root repair, surgeons should not feel compelled to perform this more-complex operation.

  View details for PubMedID 29042100

• GDF-15 (Growth Differentiation Factor 15) Is Associated With Lack of Ventricular Recovery and Mortality After Transcatheter Aortic Valve Replacement. Circulation. Cardiovascular interventions Kim, J. B., Kobayashi, Y. n., Moneghetti, K. J., Brenner, D. A., O'Malley, R. n., Schnittger, I. n., Wu, J. C., Murtagh, G. n., Beshiri, A. n., Fischbein, M. n., Miller, D. C., Liang, D. n., Yeung, A. C., Haddad, F. n., Fearon, W. F. 2017; 10 (12)

  Abstract

  Recent data suggest that circulating biomarkers may predict outcome in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the association between inflammatory, myocardial, and renal biomarkers and their role in ventricular recovery and outcome after TAVR.A total of 112 subjects undergoing TAVR were included in the prospective registry. Plasma levels of B-type natriuretic peptide, hs-TnI (high-sensitivity troponin I), CRP (C-reactive protein), GDF-15 (growth differentiation factor 15), GAL-3 (galectin-3), and Cys-C (cystatin-C) were assessed before TAVR and in 100 sex-matched healthy controls. Among echocardiographic parameters, we measured global longitudinal strain, indexed left ventricular mass, and indexed left atrial volume. The TAVR group included 59% male, with an average age of 84 years, and 1-year mortality of 18%. Among biomarkers, we found GDF-15 and CRP to be strongly associated with all-cause mortality (P<0.001). Inclusion of GDF-15 and CRP to the Society of Thoracic Surgeons score significantly improved C index (0.65-0.79; P<0.05) and provided a category-free net reclassification improvement of 106% at 2 years (P=0.01). Among survivors, functional recovery in global longitudinal strain (>15% improvement) and indexed left ventricular mass (>20% decrease) at 1 year occurred in 48% and 22%, respectively. On multivariate logistic regression, lower baseline GDF-15 was associated with improved global longitudinal strain at 1 year (hazard ratio=0.29; P<0.001). Furthermore, improvement in global longitudinal strain at 1 month correlated with lower overall mortality (hazard ratio=0.45; P=0.03).Elevated GDF-15 correlates with lack of reverse remodeling and increased mortality after TAVR and improves risk prediction of mortality when added to the Society of Thoracic Surgeons score.

  View details for PubMedID 29222133

• Baseline growth differentiation factor 15 (GDF15) is an independent predictor of reverse left atrial remodeling and mortality at 1-year following Transcatheter Aortic Valve Replacement Kim, J., Kobayashi, Y., Brenner, D., Moneghetti, K., O'Malley, R., Dao, C., Vu, T., Schnittger, I., Liang, D., Wu, J., Fischbein, M., Lee, A., Miller, D., Yeung, A., Haddad, F., Fearon, W. ELSEVIER SCIENCE INC. 2016: B298

  View details for DOI 10.1016/j.jacc.2016.09.150

  View details for Web of Science ID 000398590400257

• Surgical Unroofing of Hemodynamically Significant Left Anterior Descending Myocardial Bridges. Annals of thoracic surgery Boyd, J. H., Pargaonkar, V. S., Scoville, D. H., Rogers, I. S., Kimura, T., Tanaka, S., Yamada, R., Fischbein, M. P., Tremmel, J. A., Mitchell, R. S., Schnittger, I. 2016

  Abstract

  Left anterior descending artery myocardial bridges (MBs) range from clinically insignificant incidental angiographic findings to a potential cause of sudden cardiac death. Within this spectrum, a group of patients with isolated, symptomatic, and hemodynamically significant MBs despite maximally tolerated medical therapy exist for whom the optimal treatment is controversial. We evaluated supraarterial myotomy, or surgical unroofing, of the left anterior descending MBs as an isolated procedure in these patients.In 50 adult patients, we prospectively evaluated baseline clinical characteristics, risk factors, and medications for coronary artery disease, relevant diagnostic data (stress echocardiography, computed tomography angiography, stress coronary angiogram with dobutamine challenge for measurement of diastolic fractional flow reserve, and intravascular ultrasonography), and anginal symptoms using the Seattle Angina Questionnaire. These patients then underwent surgical unroofing of their left anterior descending artery MBs followed by readministration of the Seattle Angina Questionnaire at 6.6-month (range, 2 to 13) follow-up after surgery.Dramatic improvements were noted in physical limitation due to angina (52.0 versus 87.1, p < 0.001), anginal stability (29.6 versus 66.4, p < 0.001), anginal frequency (52.1 versus 84.7, p < 0.001), treatment satisfaction (76.1 versus 93.9, p < 0.001), and quality of life (25.0 versus 78.9, p < 0.001), all five dimensions of the Seattle Angina Questionnaire. There were no major complications or deaths.Surgical unroofing of carefully selected patients with MBs can be performed safely as an independent procedure with significant improvement in symptoms postoperatively. It is the optimal treatment for isolated, symptomatic, and hemodynamically significant MBs resistant to maximally tolerated medical therapy.

  View details for DOI 10.1016/j.athoracsur.2016.08.035

  View details for PubMedID 27745841

• Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation JOURNAL OF NUCLEAR MEDICINE Withana, N. P., Saito, T., Ma, X., Garland, M., Liu, C., Kosuge, H., Amsallem, M., Verdoes, M., Ofori, L. O., Fischbein, M., Arakawa, M., Cheng, Z., McConnell, M. V., Bogyo, M. 2016; 57 (10): 1583-1590

  Abstract

  Macrophages are cellular mediators of vascular inflammation and are involved in the formation of atherosclerotic plaques. These immune cells secrete proteases such as matrix metalloproteinases and cathepsins that contribute to disease formation and progression. Here, we demonstrate that activity-based probes (ABPs) targeting cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes can also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations.Macrophage-rich carotid lesions were induced in FVB mice fed on a high-fat diet by streptozotocin injection followed by ligation of the left common carotid artery. Mice with carotid atherosclerotic plaques were injected with the optical or dual-modality probes BMV109 and BMV101, respectively, via the tail vein and noninvasively imaged by optical and small-animal PET/CT at different time points. After noninvasive imaging, the murine carotid arteries were imaged in situ and ex vivo, followed by immunofluorescence staining to confirm target labeling. Additionally, human carotid plaques were topically labeled with the probe and analyzed by both sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunofluorescence staining to confirm the primary targets of the probe.Quantitative analysis of the signal intensity from both optical and PET/CT imaging showed significantly higher levels of accumulation of BMV109 and BMV101 (P < 0.005 and P < 0.05, respectively) in the ligated left carotid arteries than the right carotid or healthy arteries. Immunofluorescence staining for macrophages in cross-sectional slices of the murine artery demonstrated substantial infiltration of macrophages in the neointima and adventitia of the ligated left carotid arteries compared with the right. Analysis of the human plaque tissues by sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the primary targets of the probe were cathepsins X, B, S, and L. Immunofluorescence labeling of the human tissue with the probe demonstrated colocalization of the probe with CD68, elastin, and cathepsin S, similar to that observed in the experimental carotid inflammation murine model.We demonstrate that ABPs targeting the cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes could also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Therefore, ABPs targeting the cysteine cathepsins are potentially valuable new reagents for rapid and noninvasive imaging of atherosclerotic disease progression and plaque vulnerability.

  View details for DOI 10.2967/jnumed.115.171553

  View details for PubMedID 27199363

• Branched Endovascular Therapy of the Distal Aortic Arch: Preliminary Results of the Feasibility Multicenter Trial of the Gore Thoracic Branch Endoprosthesis. Annals of thoracic surgery Patel, H. J., Dake, M. D., Bavaria, J. E., Singh, M. J., Filinger, M., Fischbein, M. P., Williams, D. M., Matsumura, J. S., Oderich, G. 2016; 102 (4): 1190-1198

  Abstract

  Endovascular treatment for aortic arch aneurysms often requires adjunctive use of hybrid debranching procedures to maintain branch vessel perfusion. This study describes early results with a novel branched arch endograft for total endovascular repair of distal arch aneurysms.This US feasibility multicenter clinical trial evaluated 22 patients (mean age, 74.1 ± 10.5 years; 54.5% male) undergoing branched thoracic endovascular aortic repair in Ishimaru zone 2. This endograft was designed with a single side branch designed to facilitate aortic coverage proximal to the left subclavian artery while maintaining branch vessel patency. The pathologic features treated included fusiform (n = 10) and saccular (n = 12) aneurysms, with a mean aortic diameter of 5.7 ± 1.1 cm. The mean preoperative left-to-right brachial index was 1.0 ± 0.1.The mean total treatment length was 17.6 ± 8.9 cm; 8 patients were treated with a single 10-cm graft for isolated arch disease. The primary endpoint of device delivery and branch vessel patency was achieved in 100% of patients, without 30-day death, stroke, or permanent paraplegia. The median duration of hospitalization was 4.0 days. Type I endoleaks at completion angiography were observed in 4 patients, and all resolved by 1 month without reintervention. All side branches were patent at 1 month. The Kaplan-Meier survival rate at 6 months was 94.7%.Total endovascular repair of distal zone 2 arch aortic aneurysms can be achieved with a novel branched arch endograft. Future studies will evaluate the feasibility of this approach for aneurysms encompassing the brachiocephalic trunk and left carotid artery.

  View details for DOI 10.1016/j.athoracsur.2016.03.091

  View details for PubMedID 27262912

• Giant saphenous vein graft aneurysm compressing the lingular bronchus. journal of thoracic and cardiovascular surgery Chiu, P., Palmon, I., Fischbein, M. P. 2016

  View details for DOI 10.1016/j.jtcvs.2016.08.062

  View details for PubMedID 27771028

• Salvage Extracorporeal Membrane Oxygenation Prior to "Bridge" Transcatheter Aortic Valve Replacement. Journal of cardiac surgery Chiu, P., Fearon, W. F., Raleigh, L. A., Burdon, G., Rao, V., Boyd, J. H., Yeung, A. C., Miller, D. C., Fischbein, M. P. 2016; 31 (6): 403-405

  Abstract

  We describe a patient who presented in profound cardiogenic shock due to bioprosthetic aortic valve stenosis requiring salvage Extracorporeal Membrane Oxygenation followed by a "bridge" valve-in-valve transcatheter aortic valve replacement. doi: 10.1111/jocs.12750 (J Card Surg 2016;31:403-405).

  View details for DOI 10.1111/jocs.12750

  View details for PubMedID 27109017

• Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients NEW ENGLAND JOURNAL OF MEDICINE Leon, M. B., Smith, C. R., Mack, M. J., Makkar, R. R., Svensson, L. G., Kodali, S. K., Thourani, V. H., Tuzcu, E. M., Miller, D. C., Herrmann, H. C., Doshi, D., Cohen, D. J., Pichard, A. D., Kapadia, S., Dewey, T., Babaliaros, V., Szeto, W. Y., Williams, M. R., Kereiakes, D., Zajarias, A., Greason, K. L., Whisenant, B. K., Hodson, R. W., Moses, J. W., Trento, A., Brown, D. L., Fearon, W. F., Pibarot, P., Hahn, R. T., Jaber, W. A., Anderson, W. N., Alu, M. C., Webb, J. G. 2016; 374 (17): 1609-1620

  Abstract

  Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients.We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort.The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan-Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation.In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

  View details for DOI 10.1056/NEJMoa1514616

  View details for PubMedID 27040324

• Midterm Outcomes of Open Descending Thoracic Aortic Repair in More Than 5,000 Medicare Patients ANNALS OF THORACIC SURGERY Schaffer, J. M., Lingala, B., Fischbein, M. P., Dake, M. D., Woo, Y. J., Mitchell, R. S., Miller, D. C. 2015; 100 (6): 2087-2094

  Abstract

  Diseases involving the descending thoracic aorta (DTA) represent a heterogeneous substrate with a variety of therapeutic options. Although thoracic endovascular aortic repair has been increasingly applied to DTA disease, open surgical repair is ostensibly more durable.A total of 5,578 patients who underwent open DTA repair (Current Procedural Terminology code 33875) from 1999 to 2010 were identified from the Medicare database; 5,489 patients had complete data. Survival was assessed with Kaplan-Meier analysis. Cox regression determined predictors of death. Hospital and surgeon volume and variability were modeled, and their association with survival assessed.Median survival after open DTA repair was only 4.3 years (95% confidence interval: 4.0 to 4.6). The likelihood of death varied significantly by certain aortic diseases: aortic rupture and acute aortic dissection patients had the highest early mortality. Survival beyond 180 days was best for patients with acute aortic dissection and isolated thoracic aortic aneurysm, and lowest for patients with thoracoabdominal aneurysm and aortic rupture. Hospital and surgeon volume, as well as interhospital and intersurgeon variability, had associations with overall survival.Open DTA repair has treated a spectrum of aortic diseases in Medicare beneficiaries. Overall mortality was high, predominately confined to the initial postoperative hazard phase. Independent hospital and surgeon effects, hospital and surgeon volume, and a more recent date of surgery correlated with improved survival, while increased operative urgency and complexity correlated with worse outcomes. These observations argue for regionalization of DTA treatment for Medicare patients in specialized centers to concentrate expertise, which should translate into better outcomes.

  View details for DOI 10.1016/j.athoracsur.2015.06.068

  View details for PubMedID 26431919

• Poorer Left Ventricular Global Longitudinal Strain and Less Tricuspid Regurgitation Predicts Improvement in Left Ventricular Function Following Transcatheter Aortic Valve Replacement Kim, J. B., Brenner, D., Kobayashi, Y., O'Malley, R., Kobayashi, Y., Dao, C., Thu Vu, Yeung, A., Miller, D., Fischbein, M., Wu, J. C., Haddad, F., Fearon, W. F. ELSEVIER SCIENCE INC. 2015: B263–B264

  View details for DOI 10.1016/j.jacc.2015.08.664

  View details for Web of Science ID 000363329000588

• The relative performance characteristics of the logistic European System for Cardiac Operative Risk Evaluation score and the Society of Thoracic Surgeons score in the Placement of Aortic Transcatheter Valves trial. journal of thoracic and cardiovascular surgery Beohar, N., Whisenant, B., Kirtane, A. J., Leon, M. B., Tuzcu, E. M., Makkar, R., Svensson, L. G., Miller, D. C., Smith, C. R., Pichard, A. D., Herrmann, H. C., Thourani, V. H., Szeto, W. Y., Lim, S., Fischbein, M., Fearon, W. F., O'Neill, W., Xu, K., Dewey, T., Mack, M. 2014; 148 (6): 2830-7 e1

  Abstract

  The logistic European System for Cardiac Operative Risk Evaluation (LES) score and the Society of Thoracic Surgeons (STS) score are validated to predict 30-day outcomes following surgical aortic valve replacement (SAVR) with or without coronary artery bypass grafting. Their performance when applied to patients undergoing transcatheter aortic valve replacement (TAVR) is controversial.We compared predicted and observed 30-day/in-hospital and 1-year mortality of patients undergoing TAVR in the first Placement of Aortic Transcatheter Valves trial and continued access registry (N = 2466). The performance of the LES and STS scores (prospectively calculated) was evaluated using standard assessments of discrimination and calibration. Performance of STS and LES scores among 307 patients undergoing SAVR from the high-risk cohort of the randomized trial were also examined.In patients undergoing TAVR, the observed 30-day/in-hospital mortality was 6.5%, whereas the predicted 30-day mortality was higher by both STS score (11.4% ± 3.9%) and LES score (26.6% ± 16.2%). The discrimination for both scores was poor for 30-day/in-hospital and 1-year mortality. Calibration was better for STS score than for LES at 1 year but poor for both at 30 days among TAVR cohort. These results were consistent among the subgroups of patients undergoing transfemoral and transapical access; however, the STS score had better performance among the high-risk patients who underwent SAVR at 30 days but not 1 year.The STS and LES surgical risk scores overestimated 30-day/in-hospital mortality and were poor discriminators of post-TAVR mortality, but the calibration of the STS score was better in these high-risk patients. These data highlight the need for TAVR-specific risk models to optimize patient selection.

  View details for DOI 10.1016/j.jtcvs.2014.04.006

  View details for PubMedID 24820191

• The relative performance characteristics of the logistic European System for Cardiac Operative Risk Evaluation score and the Society of Thoracic Surgeons score in the Placement of Aortic Transcatheter Valves trial JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Beohar, N., Whisenant, B., Kirtane, A. J., Leon, M. B., Tuzcu, E. M., Makkar, R., Svensson, L. G., Miller, D. C., Smith, C. R., Pichard, A. D., Herrmann, H. C., Thourani, V. H., Szeto, W. Y., Lim, S., Fischbein, M., Fearon, W. F., O'Neill, W., Xu, K., Dewey, T., Mack, M. 2014; 148 (6): 2830-U1495

  Abstract

  The logistic European System for Cardiac Operative Risk Evaluation (LES) score and the Society of Thoracic Surgeons (STS) score are validated to predict 30-day outcomes following surgical aortic valve replacement (SAVR) with or without coronary artery bypass grafting. Their performance when applied to patients undergoing transcatheter aortic valve replacement (TAVR) is controversial.We compared predicted and observed 30-day/in-hospital and 1-year mortality of patients undergoing TAVR in the first Placement of Aortic Transcatheter Valves trial and continued access registry (N = 2466). The performance of the LES and STS scores (prospectively calculated) was evaluated using standard assessments of discrimination and calibration. Performance of STS and LES scores among 307 patients undergoing SAVR from the high-risk cohort of the randomized trial were also examined.In patients undergoing TAVR, the observed 30-day/in-hospital mortality was 6.5%, whereas the predicted 30-day mortality was higher by both STS score (11.4% ± 3.9%) and LES score (26.6% ± 16.2%). The discrimination for both scores was poor for 30-day/in-hospital and 1-year mortality. Calibration was better for STS score than for LES at 1 year but poor for both at 30 days among TAVR cohort. These results were consistent among the subgroups of patients undergoing transfemoral and transapical access; however, the STS score had better performance among the high-risk patients who underwent SAVR at 30 days but not 1 year.The STS and LES surgical risk scores overestimated 30-day/in-hospital mortality and were poor discriminators of post-TAVR mortality, but the calibration of the STS score was better in these high-risk patients. These data highlight the need for TAVR-specific risk models to optimize patient selection.

  View details for DOI 10.1016/j.jtcvs.2014.04.006

  View details for Web of Science ID 000345686100086

  View details for PubMedID 24820191

• Outcomes After Transfemoral Transcatheter Aortic Valve Replacement A Comparison of the Randomized PARTNER (Placement of AoRTic TraNscathetER Valves) Trial With the NRCA (Nonrandomized Continued Access) Registry JACC-CARDIOVASCULAR INTERVENTIONS Fearon, W. F., Kodali, S., Doshi, D., Fischbein, M. P., Yeung, A. C., Tuzcu, E. M., Rihal, C. S., Babaliaros, V., Zajarias, A., Herrmann, H. C., Brown, D. L., Mack, M., Teirstein, P. S., Whisenant, B. K., Makkar, R., Kapadia, S., Leon, M. B. 2014; 7 (11): 1245-1251

  Abstract

  This study sought to determine whether outcomes for transfemoral (TF) transcatheter aortic valve replacement (TAVR) differ between the randomized controlled trial (RCT) and the subsequent NRCA (Nonrandomized Continued Access) registry of the PARTNER (Placement of AoRTic TraNscathetER Valves) trial.The PARTNER RCT demonstrated that TAVR with the Edwards Sapien valve (Edwards Lifesciences, Irvine, California) is noninferior to surgery in high-risk patients and superior to standard therapy for inoperable patients.The inclusion and exclusion criteria, data collection, monitoring, and core laboratories were the same for the RCT and NRCA registry. Baseline characteristics, procedural results, and 1-year outcomes were compared between patients undergoing TF-TAVR as part of the RCT and as part of the NRCA registry.In the RCT, 415 patients underwent TF-TAVR, whereas in the NRCA, 1,023 patients did. At 30 days, death, cardiac death, stroke, and transient ischemic attacks were not different in the NRCA registry than in the RCT. Major vascular complications (8.0% vs. 15.7%, p < 0.0001) and major bleeding (6.8% vs. 15.3%, p < 0.0001) were significantly lower in the NRCA registry. At 1 year, death rates were significantly lower in the NRCA cohort (19.0% vs. 25.3%, p = 0.009) and cardiac death tended to be lower (8.4% vs. 11.1%, p = 0.12). Stroke or transient ischemic attack (6.2% vs. 8.7%, p = 0.10) and stroke alone (5.0% vs. 7.1%, p = 0.13) also tended to be lower.The large NRCA registry demonstrates further improvement in procedural and longer-term outcomes after TF-TAVR when compared with the favorable results from the PARTNER RCT. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894).

  View details for DOI 10.1016/j.jcin.2014.05.033

  View details for Web of Science ID 000345288400013

• Outcomes after transfemoral transcatheter aortic valve replacement: a comparison of the randomized PARTNER (Placement of AoRTic TraNscathetER Valves) trial with the NRCA (Nonrandomized Continued Access) registry. JACC. Cardiovascular interventions Fearon, W. F., Kodali, S., Doshi, D., Fischbein, M. P., Yeung, A. C., Tuzcu, E. M., Rihal, C. S., Babaliaros, V., Zajarias, A., Herrmann, H. C., Brown, D. L., Mack, M., Teirstein, P. S., Whisenant, B. K., Makkar, R., Kapadia, S., Leon, M. B. 2014; 7 (11): 1245-1251

  Abstract

  This study sought to determine whether outcomes for transfemoral (TF) transcatheter aortic valve replacement (TAVR) differ between the randomized controlled trial (RCT) and the subsequent NRCA (Nonrandomized Continued Access) registry of the PARTNER (Placement of AoRTic TraNscathetER Valves) trial.The PARTNER RCT demonstrated that TAVR with the Edwards Sapien valve (Edwards Lifesciences, Irvine, California) is noninferior to surgery in high-risk patients and superior to standard therapy for inoperable patients.The inclusion and exclusion criteria, data collection, monitoring, and core laboratories were the same for the RCT and NRCA registry. Baseline characteristics, procedural results, and 1-year outcomes were compared between patients undergoing TF-TAVR as part of the RCT and as part of the NRCA registry.In the RCT, 415 patients underwent TF-TAVR, whereas in the NRCA, 1,023 patients did. At 30 days, death, cardiac death, stroke, and transient ischemic attacks were not different in the NRCA registry than in the RCT. Major vascular complications (8.0% vs. 15.7%, p < 0.0001) and major bleeding (6.8% vs. 15.3%, p < 0.0001) were significantly lower in the NRCA registry. At 1 year, death rates were significantly lower in the NRCA cohort (19.0% vs. 25.3%, p = 0.009) and cardiac death tended to be lower (8.4% vs. 11.1%, p = 0.12). Stroke or transient ischemic attack (6.2% vs. 8.7%, p = 0.10) and stroke alone (5.0% vs. 7.1%, p = 0.13) also tended to be lower.The large NRCA registry demonstrates further improvement in procedural and longer-term outcomes after TF-TAVR when compared with the favorable results from the PARTNER RCT. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894).

  View details for DOI 10.1016/j.jcin.2014.05.033

  View details for PubMedID 25459036

• Tirone David procedure for bicuspid aortic valve disease: impact of root geometry and valve type on mid-term outcomes†. Interactive cardiovascular and thoracic surgery Kari, F. A., Kvitting, J. E., Stephens, E. H., Liang, D. H., Merk, D. R., Fischbein, M. P., Mitchell, R. S., Miller, D. C. 2014; 19 (3): 375-381

  Abstract

  A 180/180° configuration has been reported to increase repair durability after valve-sparing aortic root replacement (V-SARR) for bicuspid aortic valve (BAV) disease. We studied the impact of commissural angular configuration (CAC) and of BAV type on valve performance after V-SARR.A total of 85 BAV patients (68 males, age 44 ± 11 years) underwent Tirone David-V V-SARR between 1997 and 2013. BAV type was documented intraoperatively, and CAC determined from pre- and postoperative computed tomography scans as the angle subtended by the non-fused cusp. Transthoracic echocardiogram was performed at 6 ± 3 days and at 2.9 ± 2.1 years. Functional end-points included freedom from aortic regurgitation (AR) 1+, AR 2+ and freedom from AR progression (0 to 1+, or 1+ to 2+). Tested variables included preoperative CAC (>160 vs <160°) and changes in CAC after V-SARR (Δ > 30° vs Δ < 30°) and Sievers' BAV type (SØ or S1).CAC in SØ-BAV (n = 26) changed minimally from 164 ± 12 to 171 ± 11° (mean Δ = 7.2 ± 16°, P = 0.044), whereas in S1-BAV (n = 59) CAC changed substantially from 132 ± 19 to 156 ± 18° (mean Δ = 27 ± 21°, P < 0.001). Larger postoperative CAC angles were not linked to better mid-term valve performance, but Sievers' BAV type had a major effect on valve performance: mild AR in S1/i BAV progressed more often (76 vs 32% at 4 years, P = 0.017) and 1+ AR was more frequent (70 vs 36% at 4 years, P = 0.008) compared with SØ-BAV.BAV type, including number of raphes, sinuses and commissures (SØ superior to S1) but not commissure geometry within the neoroot alone, appears to be linked to functional outcomes after V-SARR for BAV.

  View details for DOI 10.1093/icvts/ivu123

  View details for PubMedID 24903440

• SINGLE-CENTER ACUTE AORTIC SYNDROME REGISTRY: A 10-YEAR EXPERIENCE OF "CLASS 3" LIMITED DISSECTION OF THE AORTA Chin, A. S., Kino, A., Berry, G., Rosenberg, J., Fischbein, M., Miller, D., Fleischmann, D. ELSEVIER SCIENCE INC. 2014: A1000

  View details for DOI 10.1016/S0735-1097(14)61000-7

  View details for Web of Science ID 000359579101658

• Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding. Transfusion Sheikh, A. Y., Hill, C. C., Goodnough, L. T., Leung, L. L., Fischbein, M. P. 2014; 54 (2): 300-305

  Abstract

  BACKGROUND: Glanzmann thrombasthenia (GT) is an autosomal recessive disorder in which the platelet (PLT) glycoprotein IIb/IIIa complex is either deficient or dysfunctional. In its most severe form, GT may result in spontaneous bleeding, although most cases are first detected in the setting of an invasive procedure. CASE REPORT: A 59-year-old male with Type I GT and a history of transfusion reactions to PLT infusions developed severe aortic stenosis secondary to bicuspid valve disease. He successfully underwent open aortic valve replacement with cardiopulmonary bypass without perioperative bleeding complications. RESULTS: A multidisciplinary team (anesthesia, hematology, cardiac surgery, and transfusion medicine) was established to optimize perioperative hematologic management. Bleeding risk was assessed given the patient's prior history and a dosing timeline for administration of blood products and recombinant clotting factors was established. Successful management was achieved during the operation by prophylactic administration of HLA-matched PLTs and Factor VIIa. Prophylactic PLT administration was continued through the immediate postoperative period and no bleeding complications occurred. Thromboelastograms (TEGs) were used in conjunction with traditional hematologic laboratory analysis to optimize clinical management. CONCLUSION: Patients with GT requiring cardiac surgical procedures are at high risk for perioperative bleeding complications. This case report illustrates the importance of multidisciplinary planning, TEG analysis, and the judicious use of recombinant factors to minimize operative bleeding risk.

  View details for DOI 10.1111/trf.12275

  View details for PubMedID 23710629

• Incidence and progression of mild aortic regurgitation after Tirone David reimplantation valve-sparing aortic root replacement JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Stephens, E. H., Liang, D. H., Kvitting, J. E., Kari, F. A., Fischbein, M. P., Mitchell, R. S., Miller, D. C. 2014; 147 (1): 169-?

  Abstract

  The study objective was to determine whether recurrent or residual mild aortic regurgitation, which occurs after valve-sparing aortic root replacement, progresses over time.Between 2003 and 2008, 154 patients underwent Tirone David-V valve-sparing aortic root replacement; 96 patients (62%) had both 1-year (median, 12 ± 4 months) and mid-term (62 ± 22 months) transthoracic echocardiograms available for analysis. Age of patients averaged 38 ± 13 years, 71% were male, 31% had a bicuspid aortic valve, 41% had Marfan syndrome, and 51% underwent aortic valve repair, predominantly cusp free margin shortening.Forty-one patients (43%) had mild aortic regurgitation on 1-year echocardiogram. In 85% of patients (n = 35), mild aortic regurgitation remained stable on the most recent echocardiogram (median, 57 ± 20 months); progression to moderate aortic regurgitation occurred in 5 patients (12%) at a median of 28 ± 18 months and remained stable thereafter; severe aortic regurgitation developed in 1 patient, eventually requiring reoperation. Five patients (5%) had moderate aortic regurgitation at 1 year, which did not progress subsequently. Two patients (2%) had more than moderate aortic regurgitation at 1 year, and both ultimately required reoperation.Although mild aortic regurgitation occurs frequently after valve-sparing aortic root replacement, it is unlikely to progress over the next 5 years and should not be interpreted as failure of the valve-preservation concept. Further, we suggest that mild aortic regurgitation should not be considered nonstructural valve dysfunction, as the 2008 valve reporting guidelines would indicate. We need 10- to 15-year follow-up to learn the long-term clinical consequences of mild aortic regurgitation early after valve-sparing aortic root replacement.

  View details for DOI 10.1016/j.jtcvs.2013.09.009

  View details for PubMedID 24176278

• Aortic wall thickness: an independent risk factor for aortic dissection? journal of heart valve disease Shiran, H., Odegaard, J., Berry, G., Miller, D. C., Fischbein, M., Liang, D. 2014; 23 (1): 17-24

  Abstract

  Aortic aneurysm size is known to portend a higher likelihood of aortic complications in patients with connective tissue disorders (CTD), but other objective tools are needed to determine which patients are at greatest risk of dissection, especially those which reflect the structural integrity and strength of the aortic wall.The aortic wall pathology was evaluated in CTD patients with and without acute aortic dissection to identify parameters that affect the risk of dissection. A retrospective review was performed of aneurysm pathology from patients with Marfan syndrome (MFS; n = 53) without dissection undergoing prophylactic aortic root surgery, and acute type A aortic dissection patients (AAAoD; n = 16). Patients without a cardiovascular cause of death (n = 19) served as controls. The minimal aortic medial wall thickness was measured, and medial myxoid degeneration (MMD) and the degree of elastin loss and fragmentation were graded.The mean minimal aortic wall thickness was 1,625 +/- 364 microm in controls, and 703 +/- 256 microm and 438 +/- 322 microm for MFS and AAAoD patients, respectively. Aortic root diameters did not correlate with aortic wall thickness. A comparison of aortic medial thickness showed that the media was significantly thinner among acute dissection patients than either elective surgical patients (p = 0.02) or controls (p < 0.001). Aortic size, degree of MMD, and elastin loss did not vary significantly between CTD patients.A diminished aortic wall medial thickness may be linked to aortic dissection. High-resolution imaging techniques in the future may lead to the morphological assessment of aortic medial wall thickness in vivo becoming a reality which, in theory, could provide a more refined risk prognostication for acute aortic dissection.

  View details for PubMedID 24779324

• Apoptosis Participates in Early Aneurysm Development via ECM Remodeling in Marfan Syndrome Emrich, F. C., Okamura, H., Dalal, A. R., Merk, D. R., Raaz, U., Hennigs, J. K., Chin, J. T., Miller, M. O., Blankenberg, F. G., Connolly, A. J., Alvira, C. M., Mohr, F. W., Robbins, R. C., Fischbein, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000332162904488

• Long-term microRNA-29b Suppression Prevents Aneurysm Development in Marfan Syndrome Model Mouse Okamura, H., Emrich, F., Dalal, A., Connolly, A., Fischbein, M. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000332162907060

• Left Ventricular Ejection Fraction Improves Less after Trans-Apical Transcatheter Aortic Valve Replacement Compared to a Trans-Femoral Approach Fearon, W. F., Elmariah, S., McAndrew, T., Vlahakes, G. J., Fischbein, M., Liang, D., Kodali, S., Leon, M., Svensson, L., Pibarot, P., Douglas, P., Passeri, J. J., Dewey, T., Szeto, W. Y., Babaliaros, V., Thourani, V., Williams, M., Miller, D. ELSEVIER SCIENCE INC. 2013: B36

  View details for DOI 10.1016/j.jacc.2013.08.841

  View details for Web of Science ID 000329845600109

• A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation. journal of experimental medicine Khatri, P., Roedder, S., Kimura, N., De Vusser, K., Morgan, A. A., Gong, Y., Fischbein, M. P., Robbins, R. C., Naesens, M., Butte, A. J., Sarwal, M. M. 2013; 210 (11): 2205-2221

  Abstract

  Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

  View details for DOI 10.1084/jem.20122709

  View details for PubMedID 24127489

  View details for PubMedCentralID PMC3804941

• Tirone David valve-sparing aortic root replacement and cusp repair for bicuspid aortic valve disease JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kari, F. A., Liang, D. H., Kvitting, J. E., Stephens, E. H., Mitchell, R. S., Fischbein, M. P., Miller, D. C. 2013; 145 (3): S35-?

  Abstract

  The durability of valve-sparing aortic root replacement with or without cusp repair in patients with bicuspid aortic valve (BAV) disease is questioned. We analyzed the results of 75 patients with a BAV undergoing Tirone David reimplantation valve-sparing aortic root replacement.Average age was 45 ± 10 years; 80% were male; 31% had 2+ or greater aortic regurgitation (AR); annular diameter averaged 28 ± 3 mm; 32% had a Sievers' type 0 BAV, and 66% underwent concomitant cusp repair (usually cusp free margin shortening) to correct prolapse. Early (6 ± 3 days) and late (2.9 ± 1.7, 1-10 years) postoperative echocardiographic results were compared (cumulative echocardiographic follow-up, 190 patient-years; median late interval, 2 years [interquartile range, 0.68, 4.2]). Seven patients remained at risk beyond 6 years. Clinical outcome and valve function were analyzed using log-rank calculations.Actuarial survival was 99% ± 2%; freedom from reoperation was 90% ± 5%, infection 98% ± 2%, and stroke 100% at 6 years. After initial improvement in degree of AR (P < .001), minor subclinical progression of AR was observed (P > .5); however, freedom from AR of more than 2+ was 100%. Cusp free margin shortening was not associated with valve deterioration, but commissural suspensory polytetrafluoroethylene neochord creation (n = 4) portended a higher probability of recurrent AR (P = .025).After David procedure and cusp repair in patients with a BAV, midterm clinical and valve function outcomes were favorable out to 6 years. More follow-up is required to determine long-term valve durability and the hazard of other clinically important late adverse events, including eventual reoperation, to beyond 10 years.

  View details for DOI 10.1016/j.jtcvs.2012.11.043

  View details for PubMedID 23260433

• David valve-sparing aortic root replacement: Equivalent mid-term outcome for different valve types with or without connective tissue disorder JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kvitting, J. E., Kari, F. A., Fischbein, M. P., Liang, D. H., Beraud, A., Stephens, E. H., Mitchell, R. S., Miller, D. C. 2013; 145 (1): 117-?

  Abstract

  Although implicitly accepted by many that the durability of valve-sparing aortic root replacement in patients with bicuspid aortic valve disease and connective tissue disorders will be inferior, this hypothesis has not been rigorously investigated.From 1993 to 2009, 233 patients (27% bicuspid aortic valve, 40% Marfan syndrome) underwent Tirone David valve-sparing aortic root replacement. Follow-up averaged 4.7 ± 3.3 years (1102 patient-years). Freedom from adverse outcomes was determined using log-rank calculations.Survival at 5 and 10 years was 98.7% ± 0.7% and 93.5% ± 5.1%, respectively. Freedom from reoperation (all causes) on the aortic root was 92.2% ± 3.6% at 10 years; 3 reoperations were aortic valve replacement owing to structural valve deterioration. Freedom from structural valve deterioration at 10 years was 96.1% ± 2.1%. No significant differences were found in survival (P = .805, P = .793, respectively), reoperation (P = .179, P = .973, respectively), structural valve deterioration (P = .639, P = .982, respectively), or any other functional or clinical endpoints when patients were stratified by valve type (tricuspid aortic valve vs bicuspid aortic valve) or associated connective tissue disorder. At the latest echocardiographic follow-up (95% complete), 202 patients (94.8%) had none or trace aortic regurgitation, 10 (4.7%) mild, 0 had moderate to severe, and 1 (0.5%) had severe aortic regurgitation. Freedom from greater than 2+ aortic regurgitation at 10 years was 95.3% ± 2.5%. Six patients sustained acute type B aortic dissection (freedom at 10 years, 90.4% ± 5.0%).Tirone David reimplantation valve-sparing aortic root replacement in carefully selected young patients was associated with excellent clinical and echocardiographic outcome in patients with either a tricuspid aortic valve or bicuspid aortic valve. No demonstrable adverse influence was found for Marfan syndrome or connective tissue disorder on durability, clinical outcome, or echocardiographic results.

  View details for DOI 10.1016/j.jtcvs.2012.09.013

  View details for PubMedID 23083792

• Bicuspid aortic valve configuration and aortopathy pattern might represent different pathophysiologic substrates JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kari, F. A., Fazel, S. S., Mitchell, R. S., Fischbein, M. P., Miller, D. C. 2012; 144 (2): 516-517

  View details for DOI 10.1016/j.jtcvs.2012.05.035

  View details for PubMedID 22698560

• Potential Role of gamma delta T Cell-Derived IL-17 in Acute Cardiac Allograft Rejection ANNALS OF THORACIC SURGERY Kimura, N., Nakae, S., Itoh, S., Merk, D. R., Wang, X., Gong, Y., Okamura, H., Chang, P. A., Adachi, H., Robbins, R. C., Fischbein, M. P. 2012; 94 (2): 542-548

  Abstract

  Although αβ T cells are known to participate in the development of acute cardiac allograft rejection, the role of γδ T cells remains poorly understood. We hypothesized that γδ T cells contribute to acute allograft rejection thru interleukin (IL)-17 production.Donor hearts from FVB mice (H-2q) were heterotopically transplanted into C57BL/6-wild type (WT) and γδ T cell-deficient (TCRδ-/-) recipient mice (H-2b). Overall graft survival was monitored. Graft infiltrating cell profile, including γδ T cell subtype, cytokine expression, and myeloperoxidase activity were measured by flow cytometry, TaqMan (Applied Biosystems, Carlsbad, CA) polymerase chain reaction, and myeloperoxidase assay, respectively, on postoperative days 3 and 6.Graft survival was prolonged in TCRδ-/- recipients compared with WT controls. Graft infiltrating cells, including CD45+, CD4+, CD8+, and Gr1+ cells were significantly decreased in TCRδ-/- recipients compared with WT. Donor hearts transplanted into TCRδ-/- recipients had reduced IL-17 and IL-6 messenger RNA expression. Corroborating the gene expression, intracellular cytokine staining showed decreased IL-17 producing cells in TCRδ-/- recipients. Finally, Vγ1+ and Vγ4+ T cells did not produce IL-17, although both represent 20% to 30% total graft infiltrating γδ T cells.The γδ T cells promote acute cardiac allograft rejection, presumably by producing IL-17. The γδ T cell depletion may prove beneficial in prolonging allograft survival by suppressing IL-17 production.

  View details for DOI 10.1016/j.athoracsur.2012.03.049

  View details for Web of Science ID 000306700100040

  View details for PubMedID 22560321

• Two-Year Outcomes after Transcatheter or Surgical Aortic-Valve Replacement NEW ENGLAND JOURNAL OF MEDICINE Kodali, S. K., Williams, M. R., Smith, C. R., Svensson, L. G., Webb, J. G., Makkar, R. R., Fontana, G. P., Dewey, T. M., Thourani, V. H., Pichard, A. D., Fischbein, M., Szeto, W. Y., Lim, S., Greason, K. L., Teirstein, P. S., Malaisrie, S. C., Douglas, P. S., Hahn, R. T., Whisenant, B., Zajarias, A., Wang, D., Akin, J. J., Anderson, W. N., Leon, M. B. 2012; 366 (18): 1686-1695

  Abstract

  The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among high-risk patients with aortic stenosis, the 1-year survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical replacement. However, longer-term follow-up is necessary to determine whether TAVR has prolonged benefits.At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either surgical aortic-valve replacement or TAVR. All patients were followed for at least 2 years, with assessment of clinical outcomes and echocardiographic evaluation.The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P=0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001).A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.).

  View details for Web of Science ID 000303434300008

  View details for PubMedID 22443479

• ACCURACY AND REPRODUCIBILITY OF CONTRAST ENHANCED AND NON-ENHANCED COMPUTED TOMOGRAPHY FOR PREDICTING THE ANGIOGRAPHIC DEPLOYMENT ANGLE IN TRANSCATHETER AORTIC VALVE REPLACEMENT (TAVR) 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC)/Conference on ACC-i2 with TCT Dao, C. N., Blake, T., Liang, D., Fischbein, M. P., Yeung, A., Fearon, W., Miller, D. C., Fleischmann, D. ELSEVIER SCIENCE INC. 2012: E1195–E1195

  View details for Web of Science ID 000302326701306

• COMPUTED TOMOGRAPHY BASED PREDICTION OF ANGIOGRAPHIC DEPLOYMENT ANGLES MAY REDUCE PROCEDURE TIME AND CONTRAST MEDIUM VOLUME FOR TRANSCATHETER AORTIC VALVE REPLACEMENT 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC)/Conference on ACC-i2 with TCT Fleischmann, D., Dao, C., Blake, T., Boas, F. E., Liang, D., Yeung, A., Fearon, W., Fischbein, M., Miller, D. C. ELSEVIER SCIENCE INC. 2012: E1199–E1199

  View details for Web of Science ID 000302326701310

• AORTIC WALL THICKNESS MAY BE AN INDEPENDENT RISK FACTOR FOR AORTIC DISSECTION 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC)/Conference on ACC-i2 with TCT Shiran, H., Odegaard, J., Berry, G., Miller, D. C., Fischbein, M., Liang, D. ELSEVIER SCIENCE INC. 2012: E831–E831

  View details for Web of Science ID 000302326700834

• Molecular Imaging of Bone Marrow Mononuclear Cell Survival and Homing in Murine Peripheral Artery Disease JACC-CARDIOVASCULAR IMAGING van der Bogt, K. E., Hellingman, A. A., Lijkwan, M. A., Bos, E., de Vries, M. R., van Rappard, J. R., Fischbein, M. P., Quax, P. H., Robbins, R. C., Hamming, J. F., Wu, J. C. 2012; 5 (1): 46-55

  Abstract

  This study aims to provide insight into cellular kinetics using molecular imaging after different transplantation methods of bone marrow-derived mononuclear cells (MNCs) in a mouse model of peripheral artery disease (PAD).MNC therapy is a promising treatment for PAD. Although clinical translation has already been established, there is a lack of knowledge about cell behavior after transplantation and about the mechanism whereby MNC therapy might ameliorate complaints of PAD.MNCs were isolated from F6 transgenic mice (FVB background) that express firefly luciferase (Fluc) and green fluorescence protein (GFP). Male FVB and C57Bl6 mice (n = 50) underwent femoral artery ligation and were randomized into 4 groups receiving the following: 1) single intramuscular (IM) injection of 2 × 10(6) MNCs; 2) 4 weekly IM injections of 5 × 10(5) MNCs; 3) 2 × 10(6) MNCs intravenously; and 4) phosphate-buffered saline as control. Cells were characterized by flow cytometry and in vitro bioluminescence imaging (BLI). Cell survival, proliferation, and migration were monitored by in vivo BLI, which was validated by ex vivo BLI, post-mortem immunohistochemistry, and flow cytometry. Paw perfusion and neovascularization was measured with laser Doppler perfusion imaging (LDPI) and histology, respectively.In vivo BLI revealed near-complete donor cell death 4 weeks after IM transplantation. After intravenous transplantation, BLI revealed that cells migrated to the injured area in the limb, as well as to the liver, spleen, and bone marrow. Ex vivo BLI showed presence of MNCs in the scar tissue and adductor muscle. However, no significant effects on neovascularization were observed, as monitored by LDPI and histology.This is one of the first studies to assess kinetics of transplanted MNCs in PAD using in vivo molecular imaging. MNC survival is short-lived, MNCs do not preferentially home to injured areas, and MNCs do not significantly stimulate perfusion in this particular model.

  View details for DOI 10.1016/j.jcmg.2011.07.011

  View details for Web of Science ID 000299392300007

  View details for PubMedID 22239892

  View details for PubMedCentralID PMC3638034

• In Vivo Functional and Transcriptional Profiling of Bone Marrow Stem Cells After Transplantation Into Ischemic Myocardium ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Sheikh, A. Y., Huber, B. C., Narsinh, K. H., Spin, J. M., van der Bogt, K., de Almeida, P. E., Ransohoff, K. J., Kraft, D. L., Fajardo, G., Ardigo, D., Ransohoff, J., Bernstein, D., Fischbein, M. P., Robbins, R. C., Wu, J. C. 2012; 32 (1): 92-102

  Abstract

  Clinical trials of bone marrow-derived stem cell therapy for the heart have yielded variable results. The basic mechanism(s) that underlies their potential efficacy remains unknown. In the present study, we evaluated the survival kinetics, transcriptional response, and functional outcome of intramyocardial bone marrow mononuclear cell (BMMC) transplantation for cardiac repair in a murine myocardial infarction model.We used bioluminescence imaging and high-throughput transcriptional profiling to evaluate the in vivo survival kinetics and gene expression changes of transplanted BMMCs after their engraftment into ischemic myocardium. Our results demonstrate short-lived survival of cells following transplant, with less than 1% of cells surviving by 6 weeks posttransplantation. Moreover, transcriptomic analysis of BMMCs revealed nonspecific upregulation of various cell regulatory genes, with a marked downregulation of cell differentiation and maturation pathways. BMMC therapy caused limited improvement of heart function as assessed by echocardiography, invasive hemodynamics, and positron emission tomography. Histological evaluation of cell fate further confirmed findings of the in vivo cell tracking and transcriptomic analysis.Collectively, these data suggest that BMMC therapy, in its present iteration, may be less efficacious than once thought. Additional refinement of existing cell delivery protocols should be considered to induce better therapeutic efficacy.

  View details for DOI 10.1161/ATVBAHA.111.238618

  View details for Web of Science ID 000298288700014

  View details for PubMedID 22034515

  View details for PubMedCentralID PMC3241895

• Interleukin-16 deficiency suppresses the development of chronic rejection in murine cardiac transplantation model JOURNAL OF HEART AND LUNG TRANSPLANTATION Kimura, N., Itoh, S., Nakae, S., Axtell, R. C., Velotta, J. B., Bos, E. J., Merk, D. R., Gong, Y., Okamura, H., Nagamine, C. M., Adachi, H., Kornfeld, H., Robbins, R. C., Fischbein, M. P. 2011; 30 (12): 1409-1417

  Abstract

  IL-16 promotes the recruitment of various cells expressing CD4, a receptor for IL-16. The precise role of IL-16 in transplant rejection remains unknown; therefore, the present study investigated the contribution of IL-16 to the development of chronic rejection in heart transplants.C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into (1) IL-16-deficient (IL-16(-/-)) C57BL/6J or (b) wild type (WT) control recipients (MHC class II mismatch). Grafts were harvested at 52 days, parenchymal rejection was assessed by the ISHLT grading system, and CAV was examined morphometrically. Graft infiltrating cells were detected 10 and 52 days after transplantation. Intragraft cytokine and chemokine profiles were assessed. To confirm the role of IL-16 in CAV development, C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into C57BL/6J WT recipients treated with (1) anti-IL-16-neutralization monoclonal antibody or (b) control immunoglobulin G. Grafts were harvested at 52 days, and CAV was quantified morphometrically. Graft-infiltrating cells were examined histologically.Parenchymal rejection and CAV was significantly attenuated in donor hearts transplanted into IL-16(-/-) recipient mice compared with WT controls. Donor hearts transplanted into IL-16(-/-) recipients had a significant reduction in coronary artery luminal occlusion, intima-to-media ratio, and percentage of diseased vessels. CAV was associated with decreased donor organ inflammation, as well as donor organ cytokine (IL-1β and IL-6) and chemokine (MCP-1 and KC) protein expression. Intimal proliferation and inflammatory cell infiltration were significantly reduced in hearts transplanted into recipients treated with an IL-16-neutralization antibody.IL-16-deficiency reduced graft inflammatory cell recruitment, and allograft inflammatory cytokine and chemokine production. Therefore, IL-16 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

  View details for DOI 10.1016/j.healun.2011.08.017

  View details for Web of Science ID 000297385400016

  View details for PubMedID 22055099

• A novel cardioprotective agent in cardiac transplantation: metformin activation of AMP-activated protein kinase decreases acute ischemia-reperfusion injury and chronic rejection. Yale journal of biology and medicine Chin, J. T., Troke, J. J., Kimura, N., Itoh, S., Wang, X., Palmer, O. P., Robbins, R. C., Fischbein, M. P. 2011; 84 (4): 423-432

  Abstract

  The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury.

  View details for PubMedID 22180679

• Interleukin-17 Accelerates Allograft Rejection by Suppressing Regulatory T Cell Expansion Annual Meeting of the American-Heart-Association Itoh, S., Kimura, N., Axtell, R. C., Velotta, J. B., Gong, Y., Wang, X., Kajiwara, N., Nambu, A., Shimura, E., Adachi, H., Iwakura, Y., Saito, H., Okumura, K., Sudo, K., Steinman, L., Robbins, R. C., Nakae, S., Fischbein, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2011: S187–S196

  Abstract

  Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice.Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17(-/-)) or -wild-type mice. Allograft survival was significantly prolonged in IL-17(-/-) recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17(-/-) recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17(-/-) recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4(+) and CD8(+) T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2(-/-) recipient mice engrafted with either wild-type or IL-17(-/-) CD4(+) and CD8(+) T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls.During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4(+) and CD8(+) T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

  View details for DOI 10.1161/CIRCULATIONAHA.110.014852

  View details for Web of Science ID 000294782800025

  View details for PubMedID 21911812

• Prevention of transplant coronary artery disease by prenylation inhibitors JOURNAL OF HEART AND LUNG TRANSPLANTATION Stein, W., Schrepfer, S., Itoh, S., Kimura, N., Velotta, J., Palmer, O., Bartos, J., Wang, X., Robbins, R. C., Fischbein, M. P. 2011; 30 (7): 761-769

  Abstract

  In this study we systematically dissect the prenylation pathway to better define the mechanism behind statin inhibition in chronic allograft rejection in heart transplants, or transplant coronary artery disease (TCAD).Utilizing a murine heterotopic heart transplant model, animals received daily treatments of either statin or selective isoprenoid blockade inhibitors to block the four major downstream branches of the mevalonate pathway. TCAD was assessed by morphometric analysis at Day 52. Graft-infiltrating cells, cytokine production, smooth muscle cell proliferation and migration and endothelial cell MHC II expression were detected on Day 7.Atorvastatin and two prenylation inhibitors, NE-10790 and manumycin A, significantly reduced TCAD lesions compared with untreated animals. Perillyl alcohol treatment resulted in a trend toward decreased luminal narrowing. Finally, zaragozic acid (cholesterol blockade only) did not alter TCAD severity. Statins and prenylation inhibitors reduced inflammatory cell allograft recruitment, but did not always correlate with TCAD reduction. Cytokine production was decreased in recipient spleens in all treatment groups. Both in vitro and in vivo IFN-γ-stimulated MHC II expression was decreased in a dose-dependent manner in the atorvastatin, perillyl alcohol and NE-10790 groups. In vitro smooth muscle cell proliferation was decreased in all treatment groups. Finally, in vitro smooth muscle cell migration was decreased in the atorvastatin, NE-10790 and manumycin A groups only.FPT and GGPT-2 (inhibition) are the key enzymes in the HGM-CoA reductase pathway and most influential in TCAD prevention. TCAD reduction is most closely related to smooth muscle cell migration, but not its anti-inflammatory properties.

  View details for DOI 10.1016/j.healun.2011.01.720

  View details for Web of Science ID 000291898800004

  View details for PubMedID 21458297

• alpha B-Crystallin Improves Murine Cardiac Function and Attenuates Apoptosis in Human Endothelial Cells Exposed to Ischemia-Reperfusion ANNALS OF THORACIC SURGERY Velotta, J. B., Kimura, N., Chang, S. H., Chung, J., Itoh, S., Rothbard, J., Yang, P. C., Steinman, L., Robbins, R. C., Fischbein, M. P. 2011; 91 (6): 1907-1913

  Abstract

  This study investigates the protective effect of exogenous αB-crystallin (CryAB) on myocardial function after ischemia-reperfusion injury.Mice underwent temporary left anterior descending artery occlusion for 30 minutes. Either CryAB (50 μg) or phosphate-buffered saline (100 μL [n=6, each group]) were injected in the intramyocardial medial and lateral perinfarct zone 15 minutes before reperfusion. Intraperitoneal injections were administered every other day. Left ventricular ejection fraction was evaluated on postoperative day 40 with magnetic resonance imaging. To investigate the effect of CryAB on apoptosis after hypoxia/reoxygenation in vitro, murine atrial cardiomyocytes (HL-1 cells) or human microvascular endothelial cells (HMEC-1) were incubated with either 50 μg CryAB (500 μg /10 mL) or phosphate-buffered saline in a hypoxia chamber for 6, 12, and 24 hours, followed by 30 minutes of reoxygenation at room air. Apoptosis was then assessed by western blot (Bcl-2, free bax, cleaved caspases-3, 9, PARP) and enzyme-linked immunosorbent assay analyses (cytoplasmic histone-associated DNA fragments and caspase-3 activity).On postoperative day 40, CryAB-treated mice had a 1.8-fold increase in left ventricular ejection fraction versus control mice (27%±6% versus 15%±4% SD, p<0.005). In vitro, (1) the HL-1 cells showed no significant difference in apoptotic protein expression, cytoplasmic histone-associated DNA fragments, or caspase-3 activity; (2) the HMEC-1 cells had increased but not significant apoptotic protein expression with, however, a significant decrease in cytoplasmic histone-associated DNA fragments (1.5-fold, p<0.01) and caspase-3 activity (2.7-fold, p<0.005).Exogenous CryAB administration significantly improves cardiac function after ischemia-reperfusion injury, in vivo. The protective anti-apoptotic affects of CryAB may target the endothelial cell.

  View details for DOI 10.1016/j.athoracsur.2011.02.072

  View details for Web of Science ID 000291019400043

  View details for PubMedID 21619989

• RevaTen platelet-rich plasma improves cardiac function after myocardial injury. Cardiovascular revascularization medicine : including molecular interventions Mishra, A., Velotta, J., Brinton, T. J., Wang, X., Chang, S., Palmer, O., Sheikh, A., Chung, J., Yang, P. C., Robbins, R., Fischbein, M. 2011; 12 (3): 158-163

  Abstract

  Cell therapy is an exciting area of investigation for repair of injured myocardial tissue. Platelet-rich plasma (PRP) is an autologous fractionation of whole blood containing high concentrations of growth factors including vascular endothelial growth factor and insulin-like growth factor, among many others. PRP has been shown to safely and effectively enhance healing of musculoskeletal tissue primarily by reparative cell signaling. Despite a growing body of evidence on PRP's safety and efficacy, limited studies have been performed using PRP in cardiovascular tissues. Utilizing a murine myocardial permanent ligation and ischemia/reperfusion model, this study sought to determine whether RevaTen PRP (Menlo Park, CA, USA), a proprietary formulation of PRP, improves cardiac function as measured by left ventricular ejection fraction (LVEF).Via thoracotomy, the left anterior descending arteries (LAD) of 28 mice were occluded by suture either permanently or for 45 min to induce ischemic injury and then reperfused. Mice undergoing permanent ligation had intramyocardial injections of either RevaTen PRP (n=5) or phosphate-buffered saline (PBS; n=4). Magnetic resonance (MR) imaging was performed to calculate LVEF at 7 days. Mice undergoing ischemia and reperfusion had intramyocardial injections of either PRP (n=10) or PBS (n=9) and underwent MR imaging to calculate LVEF at 21 days. Hearts were harvested for histologic examination following imaging.Compared with PBS controls, RevaTen PRP-treated animals that underwent LAD ligation had a 38% higher LVEF 7 days after injury (PRP=36.1±6.1%; PBS=26.4±3.6%, P=.027). Compared with PBS controls, PRP-treated animals who underwent ischemia-reperfusion of the LAD had a 28% higher LVEF 21 days after injury (PRP=37.6±4.8%, control=29.3±9.7%, P=.038). Histologic analysis suggested the presence of more scar tissue in the control group compared to the PRP-treated animals.MR imaging demonstrated a positive effect of RevaTen PRP on left ventricular function in both a ligation and ischemia-reperfusion murine model. Our results suggest RevaTen PRP should be investigated further as a potential point-of-care biologic treatment following myocardial injury.

  View details for DOI 10.1016/j.carrev.2010.08.005

  View details for PubMedID 21122486

• Interleukin-17 Accelerates Allograft Rejection by Suppressing Regulatory T Cell Expansion Itoh, S., Kimura, N., Nakae, S., Axtell, R. C., Velotta, J. B., Wang, X., Iwakura, Y., Steinman, L., Robbins, R. C., Fischbein, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231603509

• "Peninsula- Style" Transverse Aortic Arch Replacement in Patients With Bicuspid Aortic Valve ANNALS OF THORACIC SURGERY Itoh, A., Fischbein, M., Arata, K., Miller, D. C. 2010; 90 (4): 1369-1371

  Abstract

  Although the optimal surgical treatment of the dilated aortic arch is controversial in patients with a bicuspid aortic valve, such exists in more than 70% of bicuspid aortic valve patients. Aortic wall histologic abnormalities are present from the aortic root to the distal arch regardless of aortic size. We describe a simple "peninsula-style" technique of transverse arch replacement used in conjunction with valve-sparing aortic root replacement for patients with a bicuspid aortic valve. This provides resection of the entire dilated thoracic aorta, preserving the arch branches in continuity with the proximal descending aorta.

  View details for DOI 10.1016/j.athoracsur.2009.11.029

  View details for PubMedID 20868855

• THE RESUSCITATED NHBD HEART IS FUNCTIONALLY SUPERIOR TO THE BRAINSTEM DEAD DONOR HEART Ali, A., Fajardo, G., Tsuda, S., Budas, G., Ali, Z., Quertermous, T., Bernstein, D., Robbins, R., Fischbein, M., Large, S., Ashley, E. WILEY-BLACKWELL. 2010: 7

  View details for Web of Science ID 000277330800033

• Micro-CT for Characterization of Murine CV Disease Models JACC-CARDIOVASCULAR IMAGING Sheikh, A. Y., van der Bogt, K. E., Doyle, T. C., Sheikh, M. K., Ransohoff, K. J., Ali, Z. A., Palmer, O. P., Robbins, R. C., Fischbein, M. P., Wu, J. C. 2010; 3 (7): 783-785

  View details for DOI 10.1016/j.jcmg.2010.01.012

  View details for Web of Science ID 000281626700015

  View details for PubMedID 20633858

  View details for PubMedCentralID PMC2952324

• The role of recipient mast cells in acute and chronic cardiac allograft rejection in C57BL/6-KitW-sh/W-sh mice JOURNAL OF HEART AND LUNG TRANSPLANTATION Itoh, S., Nakae, S., Velotta, J. B., Kosuge, H., Connolly, A., Tsai, M., Adachi, H., Galli, S. J., Robbins, R. C., Fischbein, M. P. 2010; 29 (4): 401-409

  Abstract

  Mast cells are hypothesized to promote rejection and adverse remodeling in cardiac allografts. In contrast, it has been reported that mast cells may enhance cardiac allograft survival in rats. We used C57BL/6-Kit(W-sh/W-sh) mast cell-deficient and corresponding wild-type mice to investigate possible contributions of recipient mast cells to acute or chronic cardiac allograft rejection.FVB (H-2(q); acute rejection), or C-H-2(bm12)KhEg (H-2(bm12); chronic rejection) donor hearts were heterotopically transplanted into C57BL/6-Kit(W-sh/W-sh) (H-2(b)) or C57BL/6-Kit(+/+) (H-2(b)) mice. The degree of acute rejection was assessed at 5 days and chronic rejection, at 52 days.In the acute rejection model, donor heart vascular cell adhesion molecule-1 (VCAM-1) expression was significantly lower in C57BL/6-Kit(W-sh/W-sh) than in wild-type recipients; however, acute rejection scores, graft survival, inflammatory cells, or cytokine expression did not differ significantly. In the chronic rejection model, the number of mast cells/mm(2) of allograft tissue was significantly increased 52 days after transplantation in allografts transplanted into C57BL/6-Kit(+/+) but not C57BL/6-Kit(W-sh/W-sh) mice; however, no substantial differences were noted in graft coronary artery disease, graft inflammatory cells, or levels of graft tissue expression of cytokines or adhesion molecules.Cardiac allografts undergoing chronic rejection in wild-type C57BL/6-Kit(+/+) mice exhibit increased numbers of mast cells, but acute or chronic cardiac allograft rejection can develop in C57BL/6-Kit(W-sh/W-sh) mice even though these recipients virtually lack mast cells. These findings indicate that recipient mast cells are not required for acute or chronic cardiac allograft rejection in the models examined.

  View details for DOI 10.1016/j.healun.2009.08.019

  View details for Web of Science ID 000276915100003

  View details for PubMedID 19818646

• IL-17 Contributes to the Development of Chronic Rejection in a Murine Heart Transplant Model JOURNAL OF CLINICAL IMMUNOLOGY Itoh, S., Nakae, S., Axtell, R. C., Velotta, J. B., Kimura, N., Kajiwara, N., Iwakura, Y., Saito, H., Adachi, H., Steinman, L., Robbins, R. C., Fischbein, M. P. 2010; 30 (2): 235-240

  Abstract

  Although interleukin-17 (IL-17) has been reported to participate in the pathogenesis of infectious, autoimmune and allergic disorders, the precise role in allograft rejection remains uncertain. This study illustrates that IL-17 contributes to the pathogenesis of chronic allograft rejection.Utilizing a murine heterotopic heart transplant model system, IL-17-deficient recipient mice had decreased allograft inflammatory cell recruitment, decreased IL-6, MCP-1, and KC production, and reduced graft coronary artery disease (GCAD). Intragraft gamma delta (gammadelta) T cells appear to be the predominant source of IL-17 production.Therefore, IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

  View details for DOI 10.1007/s10875-009-9366-9

  View details for Web of Science ID 000275798900007

  View details for PubMedID 20130970

• Molecular Imaging of Bone Marrow Mononuclear Cell Survival and Homing in Murine Peripheral Artery Occlusive Disease Van Der Bogt, K. E., Hellingman, A. A., Lijkwan, M. A., Bos, E. J., de Vries, M. R., Fischbein, M. P., Quax, P. H., Robbins, R. C., Hamming, J. F., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2009: S1131

  View details for Web of Science ID 000271831504164

• Exogenous aB-crystallin Improves Myocardial Function and Attenuates Apoptosis in Ischemia-Reperfusion Injury 82nd National Conference and Exhibitions and Scientific Sessions of the American-Heart-Association Chang, S. H., Velotta, J. B., Chung, J., Itoh, S., Rothbard, J. B., Yang, P. C., Steinman, L., Robbins, R. C., Fischbein, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2009: S998–S998

  View details for Web of Science ID 000271831503397

• Metformin as a Cardioprotective Agent in Heart Transplantation Decreases Ischemia-Reperfusion Injury and Chronic Rejection Troke, J. J., Itoh, S., Kimura, N., Velotta, J. B., Yoshioka, H., Niizuma, K., Chan, P., Robbins, R. C., Fischbein, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2009: S796

  View details for Web of Science ID 000271831502400

• THE RESUSCITATED DECEASED DONOR HEART IS FUNCTIONALLY SUPERIOR TO THE BRAINSTEM DEAD DONOR HEART Ali, A. A., Fajardo, G., Tsuda, S., Budas, G., Ali, Z., Quertermous, T., Bernstein, D., Tsui, S., Robbins, R., Fischbein, M., Large, S., Ashley, E. WILEY-BLACKWELL PUBLISHING, INC. 2009: 138

  View details for Web of Science ID 000269392800514

• Long-Term Durability of Open Thoracic and Thoracoabdominal Aneurysm Repair SEMINARS IN VASCULAR SURGERY Fischbein, M. P., Miller, D. C. 2009; 22 (2): 74-80

  Abstract

  Results of open surgical repair of descending and thoracoabdominal aortic aneurysms have improved dramatically over the years. Nevertheless, while adjunctive protective strategies, such as spinal cord drainage and distal aortic perfusion, have improved outcomes, clinical challenges remain. In the current era, thoracic aortic surgeons must possess both open and endovascular stent-graft capabilities to offer these complex patients the most optimal and individualized treatment approach. Herein we summarize the contemporary outcomes of open surgical repair of patients with either descending thoracic or thoracoabdominal aortic aneurysms, focusing on the risk of complications and means for preventing their occurrence.

  View details for DOI 10.1053/j.semvascsurg.2009.04.001

  View details for PubMedID 19573745

• The Effects of Ischemia-Reperfusion Injury on Bcl-2 Stein, W., Bartos, J., Schrepfer, S., Hoyt, G., Robbins, R. C., Fischbein, M. LIPPINCOTT WILLIAMS & WILKINS. 2008: S707

  View details for Web of Science ID 000262104502302

• Prevention of Dilated Cardiomyopathy with Nitroxides Stein, W., Bartos, J., Carre, A., Yamada, M., Schrepfer, S., Robbins, R., Fischbein, M. LIPPINCOTT WILLIAMS & WILKINS. 2008: S497

  View details for Web of Science ID 000262104501209

• Comparison of different adult stem cell types for treatment of myocardial ischemia 80th Annual Scientific Session of the American-Heart-Association (AHA) van der Bogt, K. E., Sheikh, A. Y., Schrepfer, S., Hoyt, G., Cao, F., Ransohoff, K. J., Swijnenburg, R., Pearl, J., Lee, A., Fischbein, M., Contag, C. H., Robbins, R. C., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2008: S121–U166

  Abstract

  A comparative analysis of the efficacy of different cell candidates for the treatment of heart disease remains to be described. This study is designed to evaluate the therapeutic efficacy of 4 cell types in a murine model of myocardial infarction.Bone marrow mononuclear cells (MN), mesenchymal stem cells (MSC), skeletal myoblasts (SkMb), and fibroblasts (Fibro) expressing firefly luciferase (Fluc) and green fluorescence protein (GFP) were characterized by flow cytometry, bioluminescence imaging (BLI), and luminometry. Female FVB mice (n=70) underwent LAD ligation and intramyocardially received one cell type (5x10(5)) or PBS. Cell survival was measured by BLI and by TaqMan PCR. Cardiac function was assessed by echocardiography and invasive hemodynamic measurements. Fluc expression correlated with cell number in all groups (r(2)>0.93). In vivo BLI revealed acute donor cell death of MSC, SkMb, and Fibro within 3 weeks after transplantation. By contrast, cardiac signals were still present after 6 weeks in the MN group, as confirmed by TaqMan PCR (P<0.01). Echocardiography showed significant preservation of fractional shortening in the MN group compared to controls (P<0.05). Measurements of left ventricular end-systolic/diastolic volumes revealed that the least amount of ventricular dilatation occurred in the MN group (P<0.05). Histology confirmed the presence of MN, although there was no evidence of transdifferentiation by donor MN into cardiomyocytes.This is the first study to show that compared to MSC, SkMB, and Fibro, MN exhibit a more favorable survival pattern, which translates into a more robust preservation of cardiac function.

  View details for DOI 10.1161/CIRCULATIONAHA.107.759480

  View details for Web of Science ID 000259648600018

  View details for PubMedID 18824743

  View details for PubMedCentralID PMC3657517

• Regenerative cellular therapy: How to enrich the mesenchymal stem cell content in the perfinfarction zone after myocardial infarction Schrelpfer, S., Deuse, T., Stein, W., Reichenspurner, H., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2007: 202

  View details for Web of Science ID 000250394300898

• Effect of inhaled tacrolimus on cellular and humoral rejection to prevent posttransplant obliterative airway disease AMERICAN JOURNAL OF TRANSPLANTATION Schrepfer, S., Deuse, T., Reichenspurner, H., Hoffmann, J., Haddad, M., Fink, J., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. 2007; 7 (7): 1733-1742

  Abstract

  This study aimed to investigate the pharmacokinetics after tacrolimus aerosol inhalation and to assess its efficacy to suppress acute and chronic airway allograft rejection. Orthotopic tracheal transplantations were performed and tacrolimus (4 mg/kg) was administered orally (PO) or via aerosol (AER). Tracheal tissue level AUCs(0-12) were similar in both treatment groups, but blood AUCs(0-12) were approximately 5.5-fold lower with AER (p < 0.001). Interestingly, only PO animals showed elevated BUN, cholesterol and triglycerides on POD 60 (p < 0.05). Histology of grafts harvested after 6 and 60 days revealed that both treatment groups were similarly effective in suppressing graft mononuclear infiltration (p < 0.001). Cellular immune activation (assessed by IFN-gamma- and IL-4-ELISPOTS), however, was far more effectively suppressed by tacrolimus PO (p < 0.001). In both treatment groups, the vigorous alloreactive IgM-antibody surge was effectively inhibited (p < 0.001). Due to the insufficient systemic cellular immunosuppression, discontinuation of tacrolimus AER resulted in a far stronger (3.5-fold) graft infiltration on POD 8 compared to PO (p < 0.001). Tacrolimus aerosol reduces systemic side effects and effectively protects the airway graft from early cellular rejection and chronic obliterative airway disease.

  View details for DOI 10.1111/j.1600-6143.2007.01858.x

  View details for Web of Science ID 000247109900009

  View details for PubMedID 17532751

• Techniques for experimental heterotopic and orthotopic tracheal transplantations - When to use which model? TRANSPLANT IMMUNOLOGY Deuse, T., Schrepfer, S., Reichenspurner, H., Hoyt, G., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. 2007; 17 (4): 255-261

  Abstract

  Different animal models have been developed to study the pathogenesis and treatment of obliterative airway disease (OAD). Here we describe the techniques of heterotopic and orthotopic tracheal transplantations in the rat, comparing the kinetics of systemic host immune response and of histopathologic OAD development.Heterotopic and orthotopic tracheal transplantations were performed in both allogeneic (Brown Norway-to-Lewis) and syngeneic (Lewis-to-Lewis) models. Grafts were harvested after 7, 30, and 60 days post-transplant for histologic evaluation and analysis of host cellular and humoral response.Syngeneic tracheal grafts did not develop luminal obliteration and were morphologically indistinguishable from native tracheas. In heterotopic allografts, airway epithelium was rapidly destroyed and OAD progressed with complete luminal occlusion by 30 days. Orthotopic allografts showed enhanced early infiltration (1298+/-45 vs. 674+/-75 cells/high power field, p<0.001) with concomitant greater day 7 luminal narrowing (45+/-6% vs. 14+/-3%, p<0.001). In this model, donor-type BN epithelium (62+/-17%, 21+/-19%, and 1+/-1% on days 7, 30, and 60) was gradually replaced by recipient-type epithelial cells (2+/-4%, 70+/-22%, and 98+/-2%). OAD developed with circular orientation of cells and connective tissue fibers to 45+/-6% obliteration by day 60. Cellular host response, as determined by IFN-gamma-ELISPOT assay (548+/-132 vs. 402+/-197 spots, p=0.046) and anti-donor alloreactive IgM antibody production (2827+/-148 vs. 1565+/-393 mean channel fluorescence, p<0.001) were significantly stronger in rats bearing orthotopic vs. heterotopic allografts.The orthotopic tracheal transplantation model may be more representative of OAD found in human lung transplant recipients and we therefore encourage the wider use of this model.

  View details for DOI 10.1016/j.trim.2007.01.009

  View details for Web of Science ID 000247093000005

  View details for PubMedID 17493528

• Stem cell transplantation: Organ distribution after intravenous injection. Schrepfer, S., Deuse, T., Reichenspurner, H., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. BLACKWELL PUBLISHING. 2007: 516–17

  View details for Web of Science ID 000246370202303

• Stem cell transplantation: The lung barrier 23rd Congress of the Brazilian-Society- Nephrology Schrepfer, S., Deuse, T., Reichenspurner, H., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. ELSEVIER SCIENCE INC. 2007: 573–76

  Abstract

  Mesenchymal stem cells (MSCs) show differentiation capacity along mesenchymal lineages and have the potential to aid tissue regeneration. MSC transplantation strategies are therefore currently being assessed following injury to various organs. However, potential MSC migration to these organs after intravenous (IV) MSC injection continues to be impeded by cell trapping within the lung.Mouse MSCs were isolated, purified, transfected with firefly luciferase, and labeled with CSFE. Their size was assessed in vitro. To estimate the diameter of mouse pulmonary capillaries, fluorescence-labeled microspheres of different sizes were injected with or without sodium nitroprusside (SN) pretreatment. The lungs were harvested after 30 seconds and mean numbers of trapped microspheres per high-power field (HPF) were calculated. After IV injection of MSC suspensions (with or without SN), their dynamic distribution was monitored by in vivo luciferine imaging as well as by histopathology.The diameter of suspended MSCs in vitro was 15 to 19 microm. Whereas nearly no 4-microm microspheres could be detected in lung sections, the numbers of trapped 10- and 15-microm microspheres could be significantly decreased by prior SN injection from 19.3 +/- 11.1 to 6.0 +/- 1.6 cells/HPF (P = .004) and from 34.9 +/- 11.9 to 25.6 +/- 8.1 cells/HPF (P = .028), respectively. Within seconds after MSC IV injection, the vast majority of cells was found in the lungs. However, cell trapping in the pulmonary microvasculature was significantly reduced by pre-treatment with SN.We demonstrate that cell trapping in lungs can be reduced with IV SN pretreatment, increasing MSC passage through the lung capillaries, and potentially facilitating cell access to injured organs.

  View details for DOI 10.1016/j.transproceed.2006.12.019

  View details for Web of Science ID 000245344200067

  View details for PubMedID 17362785

• Is the malononitrilamide FK778 better for the prevention of acute or chronic rejection? 23rd Congress of the Brazilian-Society- Nephrology Deuse, T., Schrepfer, S., Pelletier, M. P., Fischbein, M. P., Robbins, R. C., Reichenspurner, H. ELSEVIER SCIENCE INC. 2007: 569–72

  Abstract

  The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents.Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses.In untreated recipients, cardiac allograft survival was 6.2 +/- 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 +/- 2.8, 18.5 +/- 2.7, 25.0 +/- 2.5, 20.7 +/- 3.8, 14.5 +/- 2.2, and 23.2 +/- 1.5 days, respectively (P < .05). Tracheal grafts in untreated recipients showed intense infiltration and complete luminal obliteration by day 28. FK778 (20 mg/kg), tacrolimus (1 or 4 mg/kg), MMF (10 or 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly inhibited tracheal luminal obliteration (19.5% +/- 16.4%, 44.2% +/- 33.6%, 12.3% +/- 3.3%, 61.7% +/- 18.6%, 18.3% +/- 11.3%, 55.0% +/- 30.9%, and 8.5% +/- 3.5% (P < .05). All 4 high-dose groups showed similar efficacy.When used in therapeutic doses, tacrolimus and sirolimus were more effective than FK778 to prolong cardiac allograft survival. However, with its antiproliferative effects on smooth muscle cells, its good tolerability, and its blockade of cytomegalovirus replication, FK778 proved effective to prevent chronic OAD development. Thus, FK778 may acquire an important role in maintenance therapy for the prevention of long-term fibroproliferative complications.

  View details for DOI 10.1016/j.transproceed.2006.12.020

  View details for Web of Science ID 000245344200066

  View details for PubMedID 17362784