Danielle Maria Mullis

All Publications

• Large Animal Translational Validation of 3 Mitral Valve Repair Operations for Mitral Regurgitation Using a Mitral Valve Prolapse Model: A Comprehensive In Vivo Biomechanical Engineering Analysis. Circulation. Cardiovascular interventions Zhu, Y., Yajima, S., Park, M. H., Venkatesh, A., Stark, C. J., Tran, N. A., Walsh, S. K., Ethiraj, S., Wilkerson, R. J., Lin, L. E., Lee, S. H., Gates, K. Y., Arthur, J. D., Baker, S. W., Mullis, D. M., Wu, C. A., Harima, S., Pokhrel, B., Resuello, D., Bergamasco, H., Wu, M. A., Baccouche, B. M., Pandya, P. K., Elde, S., Wang, H., Woo, Y. J. 2024; 17 (4): e013196

  Abstract

  Various mitral repair techniques have been described. Though these repair techniques can be highly effective when performed correctly in suitable patients, limited quantitative biomechanical data are available. Validation and thorough biomechanical evaluation of these repair techniques from translational large animal in vivo studies in a standardized, translatable fashion are lacking. We sought to evaluate and validate biomechanical differences among different mitral repair techniques and further optimize repair operations using a large animal mitral valve prolapse model.Male Dorset sheep (n=20) had P2 chordae severed to create the mitral valve prolapse model. Fiber Bragg grating force sensors were implanted to measure chordal forces. Ten sheep underwent 3 randomized, paired mitral valve repair operations: neochord repair, nonresectional leaflet remodeling, and triangular resection. The other 10 sheep underwent neochord repair with 2, 4, and 6 neochordae. Data were collected at baseline, mitral valve prolapse, and after each repair.All mitral repair techniques successfully eliminated regurgitation. Compared with mitral valve prolapse (0.54±0.18 N), repair using neochord (0.37±0.20 N; P=0.02) and remodeling techniques (0.30±0.15 N; P=0.001) reduced secondary chordae peak force. Neochord repair further decreased primary chordae peak force (0.21±0.14 N) to baseline levels (0.20±0.17 N; P=0.83), and was associated with lower primary chordae peak force compared with the remodeling (0.34±0.18 N; P=0.02) and triangular resectional techniques (0.36±0.27 N; P=0.03). Specifically, repair using 2 neochordae resulted in higher peak primary chordal forces (0.28±0.21 N) compared with those using 4 (0.22±0.16 N; P=0.02) or 6 neochordae (0.19±0.16 N; P=0.002). No difference in peak primary chordal forces was observed between 4 and 6 neochordae (P=0.05). Peak forces on the neochordae were the lowest using 6 neochordae (0.09±0.11 N) compared with those of 4 neochordae (0.15±0.14 N; P=0.01) and 2 neochordae (0.29±0.18 N; P=0.001).Significant biomechanical differences were observed underlying different mitral repair techniques in a translational large animal model. Neochord repair was associated with the lowest primary chordae peak force compared to the remodeling and triangular resectional techniques. Additionally, neochord repair using at least 4 neochordae was associated with lower chordal forces on the primary chordae and the neochordae. This study provided key insights about mitral valve repair optimization and may further improve repair durability.

  View details for DOI 10.1161/CIRCINTERVENTIONS.123.013196

  View details for PubMedID 38626077

• Stromal cell-derived factor-1 alpha improves cardiac function in a novel diet-induced coronary atherosclerosis model, the SR-B1ΔCT/LDLR KO mouse. Atherosclerosis Mullis, D. M., Padilla-Lopez, A., Wang, H., Zhu, Y., Elde, S., Bonham, S. A., Yajima, S., Kocher, O. N., Krieger, M., Woo, Y. J. 2024: 117518

  Abstract

  There are a limited number of pharmacologic therapies for coronary artery disease, and few rodent models of occlusive coronary atherosclerosis and consequent myocardial infarction with which one can rapidly test new therapeutic approaches. Here, we characterize a novel, fertile, and easy-to-use HDL receptor (SR-B1)-based model of atherogenic diet-inducible, fatal coronary atherosclerosis, the SR-B1ΔCT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1α), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse.SR-B1ΔCT/LDLR KO mice were fed the Paigen diet or standard chow diet, and we determined the effects of the diets on cardiac function, histology, and survival. After two weeks of feeding either the Paigen diet (n = 24) or standard chow diet (n = 20), the mice received an intramyocardial injection of either SDF-1α or phosphate buffered saline (PBS). Cardiac function and angiogenesis were assessed two weeks later.When six-week-old mice were fed the Paigen diet, they began to die as early as 19 days later and 50% had died by 38 days. None of the mice maintained on the standard chow diet died by day 72. Hearts from mice on the Paigen diet showed evidence of cardiomegaly, myocardial infarction, and occlusive coronary artery disease. For the five mice that survived until day 28 that underwent an intramyocardial injection of PBS on day 15, the average ejection fraction (EF) decreased significantly from day 14 (the day before injection, 52.1 ± 4.3%) to day 28 (13 days after the injection, 30.6 ± 6.8%) (paired t-test, n = 5, p = 0.0008). Of the 11 mice fed the Paigen diet and injected with SDF-1α on day 15, 8 (72.7%) survived to day 28. The average EF for these 8 mice increased significantly from 48.2 ± 7.2% on day 14 to63.6 ± 6.9% on day 28 (Paired t-test, n = 8, p = 0.003).This new mouse model and treatment with the promising angiogenic cytokine SDF-1α may lead to new therapeutic approaches for ischemic heart disease.

  View details for DOI 10.1016/j.atherosclerosis.2024.117518

  View details for PubMedID 38627162

• Four Decades of Progress in Heart-Lung Transplantation: 271 Cases at a Single Institution. The Journal of thoracic and cardiovascular surgery Elde, S., Baccouche, B. M., Mullis, D. M., Leipzig, M. M., Deuse, T., Krishnan, A., Fawad, M., Dale, R., Walsh, S., Padilla-Lopez, A., Wesley, B., He, H., Yajima, S., Zhu, Y., Wang, H., Guenthart, B. A., Shudo, Y., Reitz, B. A., Woo, Y. J. 2024

  Abstract

  OBJECTIVE: The objective of this study is to evaluate survival for combined heart-lung transplant (HLTx) recipients across four decades at a single institution. We aim to summarize our contemporary practice based upon more than 271 HLTx over 40 years.METHODS: Data were collected from a departmental database and the United Network for Organ Sharing (UNOS). Recipients <18y, those undergoing redo HLTx , or triple-organ system transplantation were excluded, leaving 271 patients for analysis. The Pioneering Era was defined by date of transplant between 1981-2000 (N=155), and the Modern Era between 2001-2022 (N=116). Survival analysis was performed using cardinality matching of populations based on donor and recipient age, donor and recipient sex, ischemic time, and sex-matching.RESULTS: Between 1981-2022, 271 HLTx were performed at a single institution. Recipients in the Modern Era were older (42 vs 34y, P<0.001) and had shorter waitlist times (78 vs 234d, P<0.001). Allografts from female donors were more common in the Modern Era (59% vs 39%, P=0.002). In the matched survival analysis, 30-day survival (97% vs 84%, P=0.005), 1-year survival (89% vs 77%, P=0.041), and 10-year survival (53% vs 26%, P=0.012) significantly improved in the Modern Era relative to the Pioneering Era, respectively.CONCLUSIONS: Long-term survival in HLTx is achievable with institutional experience and may continue to improve in the coming decades. Advances in mechanical circulatory support, improved maintenance immunosuppression, and early recognition and management of acute complications such as primary graft dysfunction and acute rejection have dramatically improved the prognosis for HLTx recipients in our contemporary institutional experience.

  View details for DOI 10.1016/j.jtcvs.2024.01.042

  View details for PubMedID 38320627

• Successful Treatment of Rapidly Evolving Cutaneous Leishmaniasis With Amphotericin B and Miltefosine in an Immigrant From Venezuela. Open forum infectious diseases Mullis, D. M., Shegog, E., Studemeister, L., Hwang, M. 2024; 11 (2): ofad683

  Abstract

  Leishmaniasis is a vector-borne disease uncommonly encountered in the United States. This case report describes a 54-year-old man presenting with rapidly progressing, pruritic, painful ulcerative lesions after recently immigrating from Venezuela. A punch biopsy confirmed infection with Leishmaniasis braziliensis. He was successfully treated with amphotericin B and miltefosine.

  View details for DOI 10.1093/ofid/ofad683

  View details for PubMedID 38328492

  View details for PubMedCentralID PMC10849113

• Impact of Integrated Vascular Surgery Residency Training Pathway and Professional Development Time on Career Choice and Research Productivity. Journal of surgical education Fereydooni, A., Fisher, A. T., Mullis, D. M., Smith, B. K., Sgroi, M. D. 2023

  Abstract

  The limited availability of academic surgery positions has led to increased competition for these jobs. Integrated vascular surgery residency (IVSR) allows for earlier specialization, with some programs providing professional development time (PDT). We hypothesized that IVSR and PDT lead to academic employment and increased research productivity.This is a retrospective study of vascular surgery fellowship (VSF) and IVSR graduates.Training, number of publications, H-index, NIH funding, and employment history were collected using institutional websites, Doximity, Scopus, PubMed, and NIH Research Portfolio Reporting.After a review of the research protocol, the Association of Program Directors in Vascular Surgery (APDVS) provided a list of vascular surgery fellowship (VSF) and IVSR graduates.After review of the research protocol, the Association of Program Directors in Vascular Surgery (APDVS) provided a list of vascular surgery fellowship (VSF) and IVSR graduates. Training, number of publications, H-index, NIH funding, and employment history were collected using institutional websites, Doximity, Scopus, PubMed, and NIH Research Portfolio Reporting.From 2013-2017, comparison of IVSR (n=131) to VSF (n=603) graduates showed that IVSR graduates were more likely to be women (38.17% vs 28.19%; p = 0.024), be MD graduates (99.24% vs 93.37%; p = 0.008), attended programs in the northeast (41.98% vs 27.5%; p < 0.001), have advanced degrees (13.74% vs 6.97%; p = 0.01) and graduate from larger programs (median 15 vs 14 faculty; p = 0.013). There was no significant difference in number of publications per trainee by the end of training (median 4 vs 3; P=0.61) or annual trend in average number of publications. After training, there was no significant difference in the type of practice, academic affiliation, practice region, publication number, H-index, NIH funding, level of academic appointment, or leadership positions. From 2013-2019, a comparison of IVSR graduates with (n=32) and without PDT (n=190) demonstrated that those with PDT were more likely to be women (53.13% vs 34.74%; p = 0.038), have advanced degrees (28.12% vs 8.95%; p = 0.002), be at larger programs (median 14 vs 9 faculty; p < 0.001), train at a top 10 NIH funded program (65.62% vs 21.58%; p < 0.001) and publish more by the end of IVSR (median 9 vs 3; p < 0.001). Graduates with PDT were more likely to have academic employment and affiliation, a higher yearly publication rate, and greater H-index.IVSR and VSF graduates have comparable academic employment and research productivity. However, PDT during IVSR correlates with an eventual academic career and greater research productivity. This study supports the importance of PDT in developing academic vascular surgeons. It remains necessary to continue both IVSR and VSF training paradigms as healthcare needs of the population are met through both academic and non-academic surgeons.

  View details for DOI 10.1016/j.jsurg.2023.10.009

  View details for PubMedID 38105151

• Reconstruction of the aorta and pulmonary artery during heart-liver transplantation in an adult congenital patient. JTCVS techniques Mullis, D. M., Limbu, L., Bonham, C. A., MacArthur, J. W. 2023; 21: 129-131

  View details for DOI 10.1016/j.xjtc.2023.06.011

  View details for PubMedID 37854833

  View details for PubMedCentralID PMC10580035

• Biomechanics and clinical outcomes of various conduit configurations in valve sparing aortic root replacement. Annals of cardiothoracic surgery Zhu, Y., Park, M. H., Pandya, P. K., Stark, C. J., Mullis, D. M., Walsh, S. K., Kim, J. Y., Wu, C. A., Baccouche, B. M., Lee, S. H., Baraka, A. S., Joo, H., Yajima, S., Elde, S., Woo, Y. J. 2023; 12 (4): 326-337

  Abstract

  Several conduit configurations, such as straight graft (SG), Valsalva graft (VG), anticommissural plication (ACP), and the Stanford modification (SMOD) technique, have been described for the valve-sparing aortic root replacement (VSARR) procedure. Prior ex vivo studies have evaluated the impact of conduit configurations on root biomechanics, but the mock coronary artery circuits used could not replicate the physical properties of native coronary arteries. Moreover, the individual leaflet's biomechanics, including the fluttering phenomenon, were unclear.Porcine aortic roots with coronary arteries were explanted (n=5) and underwent VSARR using SG, VG, ACP, and SMOD for evaluation in an ex vivo left heart flow loop simulator. Additionally, 762 patients who underwent VSARR from 1993 through 2022 at our center were retrospectively reviewed. Analysis of variance was performed to evaluate differences between different conduit configurations, with post hoc Tukey's correction for pairwise testing.SG demonstrated lower rapid leaflet opening velocity compared with VG (P=0.001) and SMOD (P=0.045) in the left coronary cusp (LCC), lower rapid leaflet closing velocity compared with VG (P=0.04) in the right coronary cusp (RCC), and lower relative opening force compared with ACP (P=0.04) in the RCC. The flutter frequency was lower in baseline compared with VG (P=0.02) and in VG compared with ACP (P=0.03) in the LCC. Left coronary artery mean flow was higher in SG compared with SMOD (P=0.02) and ACP (P=0.05). Clinically, operations using SG compared with sinus-containing graft was associated with shorter aortic cross-clamp and cardiopulmonary bypass time (P<0.001, <0.001).SG demonstrated hemodynamics and biomechanics most closely recapitulating those from the native root with significantly shorter intraoperative times compared with repair using sinus-containing graft. Future in vivo validation studies as well as correlation with comprehensive, comparative clinical study outcomes may provide additional invaluable insights regarding strategies to further enhance repair durability.

  View details for DOI 10.21037/acs-2023-avs2-0068

  View details for PubMedID 37554719

  View details for PubMedCentralID PMC10405339

• Individual and program-related predictors of academic vascular surgery practice. Annals of vascular surgery Fisher, A. T., Fereydooni, A., Mullis, D. M., Smith, B. K., Sgroi, M. D. 2023

  Abstract

  Several studies have explored factors affecting academic employment in surgical subspecialties; however, vascular surgery has not yet been investigated. We examined which elements of surgical training predict future academic productivity and studied characteristics of NIH-funded vascular surgery attendings.With approval from the APDVS, the database of recent vascular surgery fellowship (VSF) and integrated vascular surgery residency (IVSR) graduates was obtained, and public resources (Doximity, Scopus, PubMed, NIH, etc.) were queried for research output during and after training, completion of dedicated research years, individual and program NIH funding, current practice setting and academic rank. Adjusted multivariate regression analyses were conducted for postgraduate academic productivity.From 2013-2017, there were 734 graduates. 603 completed VSF and 131 IVSR; 220 (29%) were female. Academic employment was predicted by MD degree, advanced degree, training at a top NIH-funded program, number publications by end of training, and H-index. Dedicated research time before or during vascular training, advanced degree, or graduating from a top NIH-funded program were predictors of publishing >1 paper/year. Number of publications by end of training and years in practice were predictive of H-index ≥5. VSF vs. IVSR pathway did not have an impact on future academic employment, annual publication rate as an attending, or H-index. Characterization of NIH-funded attendings showed that they often completed dedicated research time (72%) and trained at a top NIH-funded program (79%). Mean publications by graduation among this group was 15.82±11.3, and they averaged 4.31±4.2 publications/year as attendings.Research output during training, advanced degrees, and training at a top NIH funded program predict an academic vascular surgery career. VSF and IVSR constitute equally valid paths to productive academic careers.

  View details for DOI 10.1016/j.avsg.2023.06.037

  View details for PubMedID 37454896

• Results following implementation of a cardiac surgery ERAS protocol. PloS one Obafemi, T., Mullis, D., Bajaj, S., Krishna, P., Boyd, J. 2023; 18 (7): e0277868

  Abstract

  Adequate peri-operative care is essential to ensuring a satisfactory outcome in cardiac surgery. In this study, we look at the impact of evidence-based protocols implemented at Stanford Hospital.This study is a single-center, retrospective analysis. Enhanced recovery after surgery (ERAS) protocols were implemented for CABG/Valve and open Aortic operations on 11/1/2017 and 6/1/2018, respectively. Propensity-score matched analysis was used to compare 30-day mortality and morbidity of patients from the pre- and post-implementation cohorts. Secondary endpoints included the following: total hospital length of stay (LOS), ICU LOS, time until extubation, and time until urinary catheter removal.After the implementation of the ERAS protocols for CABG/Valve operations, the median post-op LOS decreased from 7.0 days to 6.1 days (p<0.001), and median ICU LOS decreased from 69.9 hours to 54.0 (p = 0.098). There was no significant decrease in 30-day mortality (4% to 3.3%, p = 0.47). However, the incidence of post-op ventilator associated pneumonia (VAP) decreased from 5.0% to 2.1% (p = 0.003) and post-op urinary tract infections (UTIs) from 8.3% to 3.6% (p<0.001). Patients who underwent open aortic procedures experienced an improvement in 30-day mortality (7% to 3.5%, p = 0.012), decrease in median ICU LOS (91.7 hours to 69.6 hours, p<0.001), and a decrease in duration of mechanical ventilation (79.3 hours to 46.3 hours, p = 0.003). There was a decrease in post-op LOS, post-op VAP, and post-op UTI, although statistical significance was not attained.At Stanford Hospital, ERAS pathways have led to decreased morbidity and LOS while simultaneously improving mortality amongst our critically ill patient population.

  View details for DOI 10.1371/journal.pone.0277868

  View details for PubMedID 37450443

  View details for PubMedCentralID PMC10348550

• Impact of Integrated Vascular Surgery Residency Training Pathway and Professional Development Time on Career Choice and Research Productivity Fereydooni, A., Fisher, A. T., Mullis, D. M., Smith, B. K., Sgroi, M. D. MOSBY-ELSEVIER. 2023: E37-E38

  View details for Web of Science ID 000951340500011

• Trimmed central venous catheters do not increase endothelial injury in an ovine model. The journal of vascular access Wang, H., Williams, K. M., Elde, S., Bulterys, P. L., Thakore, A. D., Lucian, H. J., Farry, J. M., Mullis, D. M., Zhu, Y., Paulsen, M. J., Woo, Y. J. 2023: 11297298231153716

  Abstract

  Central venous catheters (CVCs) are often trimmed during heart transplantation and pediatric cardiac surgery. However, the risk of endothelial injury caused by the cut tip of the CVC has not been evaluated. We hypothesized that there is no difference in the degree of endothelial injury associated with trimmed CVCs versus standard untrimmed CVCs.In four adult male sheep, the left external jugular vein was exposed in three segments, one designated for an untouched control group, one for the trimmed CVC group, and one for the untrimmed CVC group. Trimmed and untrimmed CVC tips were rotated circumferentially within their respective segments to abrade the lumen of the vein. The vein samples were explanted, and two representative sections from each sample were analyzed using hematoxylin and eosin (H&E) staining, as well as with immunohistochemistry against CD31, von Willebrand factor (vWF), endothelial nitric oxide synthase (eNOS), and caveolin. Higher immunohistochemical stain distributions and intensities are associated with normal health and function of the venous endothelium. Data are presented as counts with percentages or as means with standard error.H&E staining revealed no evidence of endothelial injury in 6/8 (75%) samples from the untouched control group, and no injury in 4/8 (50%) samples from both the trimmed and untrimmed CVC groups (p = 0.504). In all remaining samples from each group, only mild endothelial injury was observed. Immunohistochemical analysis comparing trimmed CVCs versus untrimmed CVCs revealed no difference in the percentage of endothelial cells staining positive for CD31 (57.5% ± 7.2% vs 55.0% ± 9.2%, p = 0.982), vWF (73.8% ± 8.0% vs 62.5% ± 9.6%, p = 0.579), eNOS (66.3% ± 4.2% vs 63.8% ± 7.5%, p = 0.962), and caveolin (53.8% ± 5.0% vs 51.3% ± 4.4%, p = 0.922). There were no significant differences between the groups in the distributions of stain intensity for CD31, vWF, eNOS, and caveolin.Trimmed CVCs do not increase endothelial injury compared to standard untrimmed CVCs.

  View details for DOI 10.1177/11297298231153716

  View details for PubMedID 36765464

• Results following implementation of a cardiac surgery ERAS protocol PLoS One Obafemi, T., Mullis, D. M., Bajaj, S., Krishna, P., Boyd, J. 2023

  View details for DOI 10.1371/journal.pone.0277868

• Sustained Natural Heart Regeneration After Myocardial Infarction in One-Week-Old Rats Without Significant Cardiomyocyte Proliferation American Heart Association Wang, H., Shin, H., Elde, S., Mullis, D. M., Walsh, S., Lee, S., Hironaka, C., Lucian, H., Thakore, A., Tran, N., Jung, J., Wu, M., Zhu, Y., Woo, Y. 2023
• Impact of Donor-Recipient Race Matching on Survival of Patients with Congenital Heart Disease After Heart Transplantation Stanford-UPenn-Duke-Weill Cornell Cardiovascular Research Symposium Garrison, A., Mullis, D. M., Krishnan, A., Heng, E., Alnasir, D., Woo, Y., MacArthur, J. W. 2023
• Long-Term Outcomes After Lung Transplantation in Pediatric Patients with Intellectual Disability Stanford-UPenn-Duke-Weill Cornell Cardiovascular Research Symposium Mullis, D. M., Lee, J. Y., Zawadzki, R. S., Nilkant, R., Kuhan, S., Kidambi, S., Sharir, A., Ma, M. 2023
• Mechanisms of Failure for the Systemic Right Ventricle in Patients with Congenital Heart Disease Stanford-UPenn-Duke-Weill Cornell Cardiovascular Research Symposium Nilkant, R., Mullis, D. M., Sharir, A., Choi, P., Ma, M. 2023
• Social Isolation Decreases Survival and Worsens Cardiac Function in a Novel Murine Model of Coronary Atherosclerosis American Heart Association Mullis, D. M., Wang, H., Zhu, Y., Bonham, S., Padilla-Lopez, A., Kocher, O., Krieger, M., Woo, Y. 2023
• Twenty-Year Single-Center Experience of Catheter Ablation of Ventricular Tachycardia and Progression to Heart Transplantation Basic Cardiovascular Sciences Scientific Sessions 2023 Mullis, D. M., Obafemi, O. O., Kumar, S. S., Kang, A. W., Pelissero, O. G., Aparicio-Valenzuela, J., Haddad, F., Lee, A. M. 2023
• Resection of a synovial cell sarcoma by cardiac autotransplantation: A case report. JTCVS techniques Mullis, D. M., Zhu, Y., Guenthart, B. A., Bonham, S. A., Trope, W. L., Berry, G. J., Woo, Y. J., MacArthur, J. W. 2022; 16: 123-127

  View details for DOI 10.1016/j.xjtc.2022.09.009

  View details for PubMedID 36510550

  View details for PubMedCentralID PMC9735421

• The Critical Biomechanics of Aortomitral Angle and Systolic Anterior Motion: Engineering Native Ex Vivo Simulation. Annals of biomedical engineering Park, M. H., Imbrie-Moore, A. M., Zhu, Y., Wilkerson, R. J., Wang, H., Park, G. H., Wu, C. A., Pandya, P. K., Mullis, D. M., Marin-Cuartas, M., Woo, Y. J. 2022

  Abstract

  Systolic anterior motion (SAM) of the mitral valve (MV) is a complex pathological phenomenon often occurring as an iatrogenic effect of surgical and transcatheter intervention. While the aortomitral angle has long been linked to SAM, the mechanistic relationship is not well understood. We developed the first ex vivo heart simulator capable of recreating native aortomitral biomechanics, and to generate models of SAM, we performed anterior leaflet augmentation and sequential undersized annuloplasty procedures on porcine aortomitral junctions (n=6). Hemodynamics and echocardiograms were recorded, and echocardiographic analysis revealed significantly reduced coaptation-septal distances confirming SAM (p=0.003) and effective manipulation of the aortomitral angle (p<0.001). Upon increasing the angle in our pathological models, we recorded significant increases (p<0.05) in both coaptation-septal distance and multiple hemodynamic metrics, such as aortic peak flow and effective orifice area. These results indicate that an increased aortomitral angle is correlated with more efficient hemodynamic performance of the valvular system, presenting a potential, clinically translatable treatment opportunity for reducing the risk and adverse effects of SAM. As the standard of care shifts towards surgical and transcatheter interventions, it is increasingly important to better understand SAM biomechanics, and our advances represent a significant step towards that goal.

  View details for DOI 10.1007/s10439-022-03091-z

  View details for PubMedID 36264407

• A Novel Rheumatic Mitral Valve Disease Model with Ex Vivo Hemodynamic and Biomechanical Validation. Cardiovascular engineering and technology Park, M. H., Pandya, P. K., Zhu, Y., Mullis, D. M., Wang, H., Imbrie-Moore, A. M., Wilkerson, R., Marin-Cuartas, M., Woo, Y. J. 2022

  Abstract

  PURPOSE: Rheumatic heart disease is a major cause of mitral valve (MV) dysfunction, particularly in disadvantaged areas and developing countries. There lacks a critical understanding of the disease biomechanics, and as such, the purpose of this study was to generate the first ex vivo porcine model of rheumatic MV disease by simulating the human pathophysiology and hemodynamics.METHODS: Healthy porcine valves were altered with heat treatment, commissural suturing, and cyanoacrylate tissue coating, all of which approximate the pathology of leaflet stiffening and thickening as well as commissural fusion. Hemodynamic data, echocardiography, and high-speed videography were collected in a paired manner for control and model valves (n=4) in an ex vivo left heart simulator. Valve leaflets were characterized in an Instron tensile testing machine to understand the mechanical changes of the model (n=18).RESULTS: The model showed significant differences indicative of rheumatic disease: increased regurgitant fractions (p<0.001), reduced effective orifice areas (p<0.001), augmented transmitral mean gradients (p<0.001), and increased leaflet stiffness (p=0.025).CONCLUSION: This work represents the creation of the first ex vivo model of rheumatic MV disease, bearing close similarity to the human pathophysiology and hemodynamics, and it will be used to extensively study both established and new treatment techniques, benefitting the millions of affected victims.

  View details for DOI 10.1007/s13239-022-00641-3

  View details for PubMedID 35941509

• Biomechanical Engineering Analysis of Pulmonary Valve Leaflet Hemodynamics and Kinematics in the Ross Procedure. Journal of biomechanical engineering Zhu, Y., Wilkerson, R., Pandya, P., Mullis, D., Wu, C., Madira, S., Marin-Cuartas, M., Park, M. H., Imbrie-Moore, A., Woo, Y. J. 2022

  Abstract

  Objectives The Ross procedure using the inclusion technique with anti-commissural plication (ACP) is associated with excellent valve hemodynamics and leaflet kinematics. The objective was to evaluate pulmonary cusp's biomechanics and fluttering by including coronary flow in the Ross procedure. Methods Ten porcine and five human pulmonary autografts were harvested from a meat abattoir and from heart transplant patients. Five porcine autografts without reinforcement served as controls. The other autografts were prepared using the inclusion technique with and without ACP (NACP). Hemodynamic and high-speed videography data were measured using the ex vivo heart simulator. Results Although porcine autografts showed similar leaflet rapid opening and closing mean velocities, human ACP compared to NACP autografts demonstrated lower leaflet rapid opening mean velocity in the right (p=.02) and left coronary cusps (p=.003). The porcine and human autograft leaflet rapid opening and closing mean velocities were similar in all cusps. Porcine autografts showed similar leaflet flutter frequencies in the left (p=.3) and non-coronary cusps (p=.4), but porcine NACP autografts vs. controls demonstrated higher leaflet flutter frequency in the right coronary cusp (p=.05). The human NACP vs. ACP autografts showed higher flutter frequency in the non-coronary cusp (p=.02). The leaflet flutter amplitudes were similar in all three cusps in both porcine and human autografts. Conclusions The ACP compared to NACP autografts in the Ross procedure was associated with more favorable leaflet kinematics. These results may translate to improved long-term durability of the pulmonary autografts.

  View details for DOI 10.1115/1.4055033

  View details for PubMedID 35864775

• A novel photosynthetic biologic topical gel for enhanced localized hyperoxygenation augments wound healing in peripheral artery disease. Scientific reports Zhu, Y., Jung, J., Anilkumar, S., Ethiraj, S., Madira, S., Tran, N. A., Mullis, D. M., Casey, K. M., Walsh, S. K., Stark, C. J., Venkatesh, A., Boakye, A., Wang, H., Woo, Y. J. 2022; 12 (1): 10028

  Abstract

  Peripheral artery disease and the associated ischemic wounds are substantial causes of global morbidity and mortality, affecting over 200 million people worldwide. Although advancements have been made in preventive, pharmacologic, and surgical strategies to treat this disease, ischemic wounds, a consequence of end-stage peripheral artery disease, remain a significant clinical and economic challenge. Synechococcus elongatus is a cyanobacterium that grows photoautotrophically and converts carbon dioxide and water into oxygen. We present a novel topical biologic gel containing S. elongatus that provides oxygen via photosynthesis to augment wound healing by rescuing ischemic tissues caused by peripheral artery disease. By using light rather than blood as a source of energy, our novel topical therapy significantly accelerated wound healing in two rodent ischemic wound models. This novel topical gel can be directly translated to clinical practice by using a localized, portable light source without interfering with patients' daily activities, demonstrating potential to generate a paradigm shift in treating ischemic wounds from peripheral artery disease. Its novelty, low production cost, and ease of clinical translatability can potentially impact the clinical care for millions of patients suffering from peripheral arterial disease.

  View details for DOI 10.1038/s41598-022-14085-1

  View details for PubMedID 35705660

• Characteristics of Integrated Thoracic Surgery Residency Matriculants: A Survey of Program Directors. The Annals of thoracic surgery Obafemi, O. O., Mullis, D. M., Rogers, A. B., Lee, A. M. 2022

  Abstract

  BACKGROUND: The six-year Integrated Thoracic Surgery (I-6) residency programs have evolved over the past decade. Despite the rising number of programs, there is minimal data published about the criteria utilized by program directors to select candidates. We analyze the characteristics and qualities of successful matriculants using the American Association of Medical College's (AAMC) data reports and survey responses from program directors.METHODS: Using a survey administered via the RedCap service, program directors were asked to rate the importance of a variety of factors in their evaluations of candidates. AAMC data reports from 2018-2020 provided information on the mean matriculant research productivity, United States Medical Licensing Examination (USMLE) Step 1 scores, and Step 2 Clinical Knowledge (CK) scores.RESULTS: Responses were received from 19 of 33 (58%) I-6 programs. Program directors consistently rated interview performance as a very important factor in their evaluation of applicants. Matching into the specialty is becoming more competitive, with mean USMLE Step 1, Step 2 CK, and research productivity increasing over the past few years; matriculants had mean Step 1 and Step 2 CK scores of 247.3 and 254.2, respectively, in the 2020 match.CONCLUSIONS: Thoracic surgery program directors place high value on applicant Interview Performance, Letters of Recommendation, and Professionalism. Program directors agree that a forthcoming pass/fail USMLE Step 1 score report will lead to closer scrutiny of other factors during the decision-making process and may cause future evaluation of applicants to be heavily reliant on letters of recommendation and medical school pedigree.

  View details for DOI 10.1016/j.athoracsur.2022.01.030

  View details for PubMedID 35157846

• Electrophysiologic Conservation of Epicardial Conduction Dynamics After Myocardial Infarction and Natural Heart Regeneration in Newborn Piglets. Frontiers in cardiovascular medicine Wang, H., Pong, T., Obafemi, O. O., Lucian, H. J., Aparicio-Valenzuela, J., Tran, N. A., Mullis, D. M., Elde, S., Tada, Y., Baker, S. W., Wang, C. Y., Cyr, K. J., Paulsen, M. J., Zhu, Y., Lee, A. M., Woo, Y. J. 2022; 9: 829546

  Abstract

  Newborn mammals, including piglets, exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). The electrophysiologic properties of this naturally regenerated myocardium have not been examined. We hypothesized that epicardial conduction is preserved after P1 MI in piglets. Yorkshire-Landrace piglets underwent left anterior descending coronary artery ligation at age P1 (n = 6) or P7 (n = 7), After 7 weeks, cardiac magnetic resonance imaging was performed with late gadolinium enhancement for analysis of fibrosis. Epicardial conduction mapping was performed using custom 3D-printed high-resolution mapping arrays. Age- and weight-matched healthy pigs served as controls (n = 6). At the study endpoint, left ventricular (LV) ejection fraction was similar for controls and P1 pigs (46.4 ± 3.0% vs. 40.3 ± 4.9%, p = 0.132), but significantly depressed for P7 pigs (30.2 ± 6.6%, p < 0.001 vs. control). The percentage of LV myocardial volume consisting of fibrotic scar was 1.0 ± 0.4% in controls, 9.9 ± 4.4% in P1 pigs (p = 0.002 vs. control), and 17.3 ± 4.6% in P7 pigs (p < 0.001 vs. control, p = 0.007 vs. P1). Isochrone activation maps and apex activation time were similar between controls and P1 pigs (9.4 ± 1.6 vs. 7.8 ± 0.9 ms, p = 0.649), but significantly prolonged in P7 pigs (21.3 ± 5.1 ms, p < 0.001 vs. control, p < 0.001 vs. P1). Conduction velocity was similar between controls and P1 pigs (1.0 ± 0.2 vs. 1.1 ± 0.4 mm/ms, p = 0.852), but slower in P7 pigs (0.7 ± 0.2 mm/ms, p = 0.129 vs. control, p = 0.052 vs. P1). Overall, our data suggest that epicardial conduction dynamics are conserved in the setting of natural heart regeneration in piglets after P1 MI.

  View details for DOI 10.3389/fcvm.2022.829546

  View details for PubMedID 35355973

• From hardware store to hospital: a COVID-19-inspired, cost-effective, open-source, in vivo-validated ventilator for use in resource-scarce regions. Bio-design and manufacturing Park, M. H., Zhu, Y., Wang, H., Tran, N. A., Jung, J., Paulsen, M. J., Imbrie-Moore, A. M., Baker, S., Wilkerson, R., Marin-Cuartas, M., Mullis, D. M., Woo, Y. J. 2021: 1-8

  Abstract

  Resource-scarce regions with serious COVID-19 outbreaks do not have enough ventilators to support critically ill patients, and these shortages are especially devastating in developing countries. To help alleviate this strain, we have designed and tested the accessible low-barrier in vivo-validated economical ventilator (ALIVE Vent), a COVID-19-inspired, cost-effective, open-source, in vivo-validated solution made from commercially available components. The ALIVE Vent operates using compressed oxygen and air to drive inspiration, while two solenoid valves ensure one-way flow and precise cycle timing. The device was functionally tested and profiled using a variable resistance and compliance artificial lung and validated in anesthetized large animals. Our functional test results revealed its effective operation under a wide variety of ventilation conditions defined by the American Association of Respiratory Care guidelines for ventilator stockpiling. The large animal test showed that our ventilator performed similarly if not better than a standard ventilator in maintaining optimal ventilation status. The FiO2, respiratory rate, inspiratory to expiratory time ratio, positive-end expiratory pressure, and peak inspiratory pressure were successfully maintained within normal, clinically validated ranges, and the animals were recovered without any complications. In regions with limited access to ventilators, the ALIVE Vent can help alleviate shortages, and we have ensured that all used materials are publicly available. While this pandemic has elucidated enormous global inequalities in healthcare, innovative, cost-effective solutions aimed at reducing socio-economic barriers, such as the ALIVE Vent, can help enable access to prompt healthcare and life saving technology on a global scale and beyond COVID-19.Supplementary Information: The online version contains supplementary material available at 10.1007/s42242-021-00164-1.

  View details for DOI 10.1007/s42242-021-00164-1

  View details for PubMedID 34567825

• Exvivo biomechanical analysis of the Ross procedure using the modified inclusion technique in a 3-dimensionally printed left heart simulator. The Journal of thoracic and cardiovascular surgery Zhu, Y., Marin-Cuartas, M., Park, M. H., Imbrie-Moore, A. M., Wilkerson, R. J., Madira, S., Mullis, D. M., Woo, Y. J. 2021

  Abstract

  OBJECTIVE: The inclusion technique was developed to reinforce the pulmonary autograft to prevent dilation after the Ross procedure. Anticommissural plication (ACP), a modification technique, can reduce graft size and create neosinuses. The objective was to evaluate pulmonary valve biomechanics using the inclusion technique in the Ross procedure with and without ACP.METHODS: Seven porcine and 5 human pulmonary autografts were harvested from hearts obtained from a meat abattoir and from heart transplant recipients and donors, respectively. Five additional porcine autografts without reinforcement were used as controls. The Ross procedure was performed using the inclusion technique with a straight polyethylene terephthalate graft. The same specimens were tested both with and without ACP. Hemodynamic parameter data, echocardiography, and high-speed videography were collected via the exvivo heart simulator.RESULTS: Porcine autograft regurgitation was significantly lower after the use of inclusion technique compared with controls (P<.01). ACP compared with non-ACP in both porcine and human pulmonary autografts was associated with lower leaflet rapid opening velocity (3.9±2.4cm/sec vs 5.9±2.4cm/sec; P=.03; 3.5±0.9cm/sec vs 4.4±1.0cm/sec; P=.01), rapid closing velocity (1.9±1.6cm/sec vs 3.1±2.0cm/sec; P=.01; 1.8±0.7cm/sec vs 2.2±0.3cm/sec; P=.13), relative rapid opening force (4.6±3.0 vs 7.7±5.2; P=.03; 3.0±0.6 vs 4.0±2.1; P=.30), and relative rapid closing force (2.5±3.4 vs 5.9±2.3; P=.17; 1.4±1.3 vs 2.3±0.6; P=.25).CONCLUSIONS: The Ross procedure using the inclusion technique demonstrated excellent hemodynamic parameter results. The ACP technique was associated with more favorable leaflet biomechanics. Invivo validation should be performed to allow direct translation to clinical practice.

  View details for DOI 10.1016/j.jtcvs.2021.06.070

  View details for PubMedID 34625236

• A neonatal leporine model of age-dependent natural heart regeneration after myocardial infarction. The Journal of thoracic and cardiovascular surgery Wang, H., Hironaka, C. E., Mullis, D. M., Lucian, H. J., Shin, H. S., Tran, N. A., Thakore, A. D., Anilkumar, S., Wu, M. A., Paulsen, M. J., Zhu, Y., Baker, S. W., Woo, Y. J. 2021

  Abstract

  OBJECTIVES: Neonatal rodents and piglets naturally regenerate the injured heart after myocardial infarction. We hypothesized that neonatal rabbits also exhibit natural heart regeneration after myocardial infarction.METHODS: New Zealand white rabbit kits underwent sham surgery or left coronary ligation on postnatal day 1 (n=94), postnatal day 4 (n=11), or postnatal day 7 (n=52). Hearts were explanted 1day postsurgery to confirm ischemic injury, at 1week postsurgery to assess cardiomyocyte proliferation, and at 3weeks postsurgery to assess left ventricular ejection fraction and scar size. Data are presented as mean±standard deviation.RESULTS: Size of ischemic injury as a percentage of left ventricular area was similar after myocardial infarction on postnatal day 1 versus on postnatal day 7 (42.3%±5.4% vs 42.3%±4.7%, P=.9984). Echocardiography confirmed severely reduced ejection fraction at 1day after postnatal day 1 myocardial infarction (33.7%±5.3% vs 65.2%±5.5% for postnatal day 1 sham, P=.0001), but no difference at 3weeks after postnatal day 1 myocardial infarction (56.0%±4.0% vs 58.0%±3.3% for postnatal day 1 sham, P=.2198). Ejection fraction failed to recover after postnatal day 4 myocardial infarction (49.2%±1.8% vs 58.5%±5.8% for postnatal day 4 sham, P=.0109) and postnatal day 7 myocardial infarction (39.0%±7.8% vs 60.2%±5.0% for postnatal day 7 sham, P<.0001). At 3weeks after infarction, fibrotic scar represented 5.3%±1.9%, 14.3%±4.9%, and 25.4%±13.3% of the left ventricle area in the postnatal day 1, postnatal day 4, and postnatal day 7 groups, respectively. An increased proportion of peri-infarct cardiomyocytes expressed Ki67 (15.9%±1.8% vs 10.2%±0.8%, P=.0039) and aurora B kinase (4.0%±0.9% vs 1.5%±0.6%, P=.0088) after postnatal day 1 myocardial infarction compared with sham, but no increase was observed after postnatal day 7 myocardial infarction.CONCLUSIONS: A neonatal leporine myocardial infarction model reveals that newborn rabbits are capable of age-dependent natural heart regeneration.

  View details for DOI 10.1016/j.jtcvs.2021.08.013

  View details for PubMedID 34649718

• Reductively Stable Hydrogen-Bonding Ligands Featuring Appended CF2-H Units JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Shanahan, J. P., Mullis, D. M., Zeller, M., Szymczak, N. K. 2020; 142 (19): 8809–17

  Abstract

  We present the development of ligands featuring the unconventional hydrogen bond donor, -CF2H, within a metal's secondary coordination sphere. When metalated with palladium, o-CF2H-functionalized 1,10-phenanthroline provides highly directed H-bonding interactions with Pd-coordinated substrates. Spectroscopic and computational analyses with a series of X-type ligand acceptors (-F, -Cl, -Br, -OR) establish the H-bonding interaction strength for the -CF2H group (∼3 kcal/mol). The synthesis of Pd0/Ni0 complexes and subsequent coupling (Ni) highlight the unique reductive and base compatibility of the -CF2H hydrogen bond donor group.

  View details for DOI 10.1021/jacs.0c01718

  View details for Web of Science ID 000535252100035

  View details for PubMedID 32352797