Adam M. Andruska

All Publications

• Developing Benchmarks in the Diagnosis and Treatment of Pulmonary Arterial Hypertension in a Tertiary, Academic Medical Center. Pulmonary circulation Kholdani, C. A., Lee, J. H., Swenson, K. E., Liu, J., Hsi, A., Kudelko, K. T., Sweatt, A. J., Spiekerkoetter, E. F., De Jesus Perez, V., Rigdon, J., Hedlin, H., Andruska, A. M., Lyn, R. L., Zamanian, R. T., Sung, Y. K. 2025; 15 (1): e70063

  Abstract

  Benchmarks of clinical management are essential for improving the quality of care. However, the lack of established quality metrics for pulmonary arterial hypertension (PAH) contributes to practice heterogeneity. We assessed our center's diagnostic practices, therapeutic practices, and risk-adjusted survival patterns over time for the purpose of establishing quality benchmarks. We analyzed the demographics, clinical characteristics, and diagnostic evaluation of 702 PAH patients enrolled between 1999 and 2019. We examined outcomes in this cohort, including an analysis of risk stratification, therapeutic practice patterns, hospitalizations, organ transplant, and survival. Initial diagnostic workup of incident PAH cases demonstrated excellent completion of echocardiographic (99%) and pulmonary function testing (91%), with improved completion of VQ scanning over the study time period (90% between 2015 and 2019). Right heart catheterization (RHC) was performed in all patients; RHC performed at our center was more likely to include complete hemodynamic data than those performed at referring institutions (55.4% and 30.4% respectively). The average number of PAH-specific medications prescribed increased over time; however, there was no significant increase in the use of parenteral therapy over time, even when stratified by the REVEAL risk score. Survival rates in the cohort were 94% at 1 year, 75% at 5 years, and 60% at 10 years, comparable to those of other PAH cohorts. Analysis of our well-characterized cohort of PAH patients reveals the extent to which guideline-directed diagnostic and therapeutic care is delivered at our specialty center, and the associated outcomes; these data may serve as a benchmark for continued improvements in quality of PAH care.

  View details for DOI 10.1002/pul2.70063

  View details for PubMedID 40034146

  View details for PubMedCentralID PMC11875057

• Increased BMP-Responsive Transcription Factors in Distinct Endothelial and Mesenchymal Cells in PAH. American journal of respiratory and critical care medicine Andruska, A. M., Cantu Valadez, R., Ichimura, K., Chu, P., Zhang, T., Schimmel, K., Wang, L., Cao, A., Aldred, M. A., Spiekerkoetter, E. 2024

  View details for DOI 10.1164/rccm.202405-1039LE

  View details for PubMedID 39499865

• 3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension. Circulation research Ichimura, K., Boehm, M., Andruska, A. M., Zhang, F., Schimmel, K., Bonham, S., Kabiri, A., Kheyfets, V. O., Ichimura, S., Reddy, S., Mao, Y., Zhang, T., Wang, G., Santana, E. J., Tian, X., Essafri, I., Vinh, R., Tian, W., Nicolls, M. R., Yajima, S., Shudo, Y., MacArthur, J. W., Woo, Y. J., Metzger, R. J., Spiekerkoetter, E. 2024

  Abstract

  Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure.Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function.Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments.3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

  View details for DOI 10.1161/CIRCRESAHA.123.323546

  View details for PubMedID 38770652

• Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs. Lab animal Zhao, L., Cunningham, C. M., Andruska, A. M., Schimmel, K., Ali, M. K., Kim, D., Gu, S., Chang, J. L., Spiekerkoetter, E., Nicolls, M. R. 2024; 53 (2): 43-55

  Abstract

  The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1-P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung-immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement.

  View details for DOI 10.1038/s41684-023-01322-x

  View details for PubMedID 38297075

  View details for PubMedCentralID PMC10834367

• Sorting the wheat from the chaff: the innovative case of precision transpulmonary metabolomics. The European respiratory journal Andruska, A. M., Zamanian, R. T. 2023; 62 (4)

  View details for DOI 10.1183/13993003.01547-2023

  View details for PubMedID 37857433

• Repetitive Schistosoma Exposure Causes Perivascular Lung Fibrosis and Persistent Pulmonary Hypertension. Clinical science (London, England : 1979) Kumar, R., Lee, M. H., Kassa, B., Fonseca Balladares, D. C., Mickael, C., Sanders, L., Andruska, A., Kumar, M., Spiekerkoetter, E., Bandeira, A., Stenmark, K. R., Tuder, R. M., Graham, B. B. 2023

  Abstract

  Pulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite anti-helminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition. Methods: Following intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis. Results: Following intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7 to 14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition. Conclusions: Repeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

  View details for DOI 10.1042/CS20220642

  View details for PubMedID 37014925

• Utility Of Cardiopulmonary Exercise Testing In Chronic Unexplained Dyspnea In A 77 Year Old Female Christle, J. W., Andruska, A. M., Moneghetti, K. J., Wheeler, M. T., Ashley, E. A., Myers, J., Ruoss, S. LIPPINCOTT WILLIAMS & WILKINS. 2021: 395

  View details for Web of Science ID 000693955700461

• Advances in Proximity Ligation in situ Hybridization (PLISH) BIO-PROTOCOL Nagendran, M., Andruska, A. M., Harbury, P. B., Desai, T. J. 2020; 10 (21)

  View details for DOI 10.21769/BioProtoc.3808

  View details for Web of Science ID 000588630200008

• A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells is the Cell of Origin for Occlusive Pulmonary Vascular Lesions. Circulation Steffes, L. C., Froistad, A. A., Andruska, A. n., Boehm, M. n., McGlynn, M. n., Zhang, F. n., Zhang, W. n., Hou, D. n., Tian, X. n., Miquerol, L. n., Nadeau, K. n., Metzger, R. J., Spiekerkoetter, E. n., Kumar, M. E. 2020

  Abstract

  Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow due to medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment, however our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited. Methods: We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathologic features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexed in situ hybridization, immunostaining, deep confocal imaging and staged pharmacologic inhibition we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation. Results: Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension. Conclusions: This work describes the first nongenetically driven murine model of PH that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiologic measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.

  View details for DOI 10.1161/CIRCULATIONAHA.120.045750

  View details for PubMedID 32794408

• Targeting BMPR2 Trafficking with Chaperones - An Important Step Towards Precision Medicine in Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology Andruska, A. n., Ali, K. n., Spiekerkoetter, E. n. 2020

  View details for DOI 10.1165/rcmb.2020-0130ED

  View details for PubMedID 32339467

• EXPRESS: Drug Repositioning in Pulmonary Arterial Hypertension: Challenges and Opportunities. Pulmonary circulation Grinnan, D., Trankle, C., Andruska, A., Bloom, B., Spiekerkoetter, E. F. 2019: 2045894019832226

  View details for PubMedID 30729869

• Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension. International journal of molecular sciences Andruska, A., Spiekerkoetter, E. 2018; 19 (9)

  Abstract

  Since its association with familial pulmonary arterial hypertension (PAH) in 2000, Bone Morphogenetic Protein Receptor II (BMPR2) and its related signaling pathway have become recognized as a key regulator of pulmonary vascular homeostasis. Herein, we define BMPR2 deficiency as either an inactivation of the receptor, decreased receptor expression, or an impairment of the receptor's downstream signaling pathway. Although traditionally the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may have consequences in many other organ systems and cellular compartments. Revisiting how BMPR2 functions throughout health and disease in cells and organs beyond the lung vasculature may provide insight into the contribution of these organ systems to PAH pathogenesis as well as the potential systemic manifestation of PAH. Here we review our knowledge of the consequences of BMPR2 deficiency across multiple organ systems.

  View details for PubMedID 30149506

• Fragile Histidine Triad (FHIT), a Novel Modifier Gene in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Dannewitz Prosseda, S., Tian, X., Kuramoto, K., Boehm, M., Sudheendra, D., Miyagawa, K., Zhang, F., Solow-Cordero, D., Saldivar, J. C., Austin, E. D., Loyd, J. E., Wheeler, L., Andruska, A., Donato, M., Wang, L., Huebner, K., Metzger, R. J., Khatri, P., Spiekerkoetter, E. 2018

  Abstract

  RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries resulting in right heart failure and death. Bone Morphogenetic Protein Receptor type-2 (BMPR2) mutations account for most familial PAH (FPAH) forms while reduced BMPR2 is present in many idiopathic PAH (IPAH) forms, suggesting dysfunctional BMPR2 signaling to be a key feature of PAH. Modulating BMPR2 signaling is therapeutically promising, yet how BMPR2 is downregulated in PAH is unclear.OBJECTIVES: We intended to identify and pharmaceutically target BMPR2 modifier genes to improve PAH.METHODS: We combined siRNA High Throughput Screening (HTS) of >20,000 genes with a multi-cohort analysis of publicly available PAH RNA expression data to identify clinically relevant BMPR2-modifiers. After confirming gene dysregulation in PAH patient tissue, we determined the functional roles of BMPR2-modifiers in vitro and tested the repurposed drug Enzastaurin for its propensity to improve experimental PH.MEASUREMENTS AND MAIN RESULTS: We discovered Fragile Histidine Triad (FHIT) as a novel BMPR2-modifier. BMPR2 and FHIT expression were reduced in PAH patients. FHIT reductions were associated with endothelial and smooth muscle cell dysfunction, rescued by Enzastaurin through a dual mechanism: upregulation of FHIT as well as miR17-5 repression. Fhit-/- mice had exaggerated hypoxic PH and failed to recover in normoxia. Enzastaurin reversed PH in the Sugen5416/Hypoxia/Normoxia rat model, by improving Right Ventricular Systolic Pressure (RVSP), RV hypertrophy, cardiac fibrosis and vascular remodeling.CONCLUSIONS: This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug Enzastaurin as a potential novel therapeutic strategy to improve PAH.

  View details for PubMedID 30107138

• Pneumonia Pathogen Characterization Is an Independent Determinant of Hospital Readmission CHEST Andruska, A., Micek, S. T., Shindo, Y., Hampton, N., Colona, B., McCormick, S., Kollef, M. H. 2015; 148 (1): 103–11

  Abstract

  Hospital readmissions for pneumonia occur often and are difficult to predict. For fiscal year 2013, the Centers for Medicare & Medicaid Services readmission penalties have been applied to acute myocardial infarction, heart failure, and pneumonia. However, the overall impact of pneumonia pathogen characterization on hospital readmission is undefined.This was a retrospective 6-year cohort study (August 2007 to September 2013).We evaluated 9,624 patients with a discharge diagnosis of pneumonia. Among these patients, 4,432 (46.1%) were classified as having culture-negative pneumonia, 1,940 (20.2%) as having pneumonia caused by antibiotic-susceptible bacteria, 2,991 (31.1%) as having pneumonia caused by potentially antibiotic-resistant bacteria, and 261 (2.7%) as having viral pneumonia. The 90-day hospital readmission rate for survivors (n = 7,637, 79.4%) was greatest for patients with pneumonia attributed to potentially antibiotic-resistant bacteria (11.4%) followed by viral pneumonia (8.3%), pneumonia attributed to antibiotic-susceptible bacteria (6.6%), and culture-negative pneumonia (5.8%) (P < .001). Multiple logistic regression analysis identified pneumonia attributed to potentially antibiotic-resistant bacteria to be independently associated with 90-day readmission (OR, 1.75; 95% CI, 1.56-1.97; P < .001). Other independent predictors of 90-day readmission were Charlson comorbidity score > 4, cirrhosis, and chronic kidney disease. Culture-negative pneumonia was independently associated with lower risk for 90-day readmission.Readmission after hospitalization for pneumonia is relatively common and is related to pneumonia pathogen characterization. Pneumonia attributed to potentially antibiotic-resistant bacteria is associated with an increased risk for 90-day readmission, whereas culture-negative pneumonia is associated with lower risk for 90-day readmission.

  View details for DOI 10.1378/chest.14-2129

  View details for Web of Science ID 000359003000031

  View details for PubMedID 25429607

• Systolic blood pressure on discharge after left ventricular assist device insertion is associated with subsequent stroke. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Nassif, M. E., Tibrewala, A., Raymer, D. S., Andruska, A., Novak, E., Vader, J. M., Itoh, A., Silvestry, S. C., Ewald, G. A., LaRue, S. J. 2015; 34 (4): 503-8

  Abstract

  Stroke is a significant complication in patients supported with continuous-flow left ventricular assist devices (CF-LVAD) and hypertension is a significant risk factor for stroke, but the association between blood pressure and stroke in LVAD patients is not well characterized.We identified 275 consecutive patients who survived implant hospitalization between January 2005 and April 2013. Patients were grouped according to systolic blood pressure (SBP) as above a median and below a median of 100 mm Hg by their averaged systolic blood pressure during the 48 hours before discharge from implantation hospitalization. The groups were compared for the primary outcome of time to stroke.The above-median SBP group had mean SBP of 110 mm Hg and the below-median SBP group had mean SBP of 95 mm Hg. There were no significant between-group differences in body mass index, smoking, vascular disease, hypertension, atrial fibrillation, or prior stroke. During a mean follow-up of 16 months, stroke occurred in 16% of the above-median SBP group vs in 7% of the below-median SBP group (hazard ratio, 2.38; 95% confidence interval, 1.11-5.11), with a similar proportion of hemorrhagic and ischemic strokes in each group. In Cox proportional hazard models adjusting for age, diabetes, or prior stroke, the hazard ratio remained statistically significant. SBP as a continuous variable predictor of stroke had an area under the curve of 0.64 in a receiver operating characteristic curve analysis.In this large, CF-LVAD cohort, elevated SBP was independently associated with a greater risk of subsequent stroke. These results identify management of hypertension as a potential modifiable risk factor for reducing the incidence of stroke in patients supported by CF-LVAD.

  View details for DOI 10.1016/j.healun.2014.09.042

  View details for PubMedID 25540881

  View details for PubMedCentralID PMC4402112

• Chronic network stimulation enhances evoked action potentials. Journal of neural engineering Ide, A. N., Andruska, A., Boehler, M., Wheeler, B. C., Brewer, G. J. 2010; 7 (1): 16008

  Abstract

  Neurons cultured on multielectrode arrays almost always lack external stimulation except during the acute experimental phase. We have investigated the effects of chronic stimulation during the course of development in cultured hippocampal neural networks by applying paired pulses at half of the electrodes for 0, 1 or 3 r/day for 8 days. Spike latencies increased from 4 to 16 ms as the distance from the stimulus increased from 200 to 1700 microm, suggesting an average of four synapses over this distance. Compared to no chronic stimulation, our results indicate that chronic stimulation increased evoked spike counts per stimulus by 50% at recording sites near the stimulating electrode and increased the instantaneous firing rate. On trials where both pulses elicited responses, spike count was 40-80% higher than when only one of the pulses elicited a response. In attempts to identify spike amplitude plasticity, we found mainly amplitude variation with different latencies suggesting recordings from neurons with different identities. These data suggest plastic network changes induced by chronic stimulation that enhance the reliability of information transmission and the efficiency of multisynaptic network communication.

  View details for DOI 10.1088/1741-2560/7/1/016008

  View details for PubMedID 20083862

  View details for PubMedCentralID PMC3775841