About

Zoltan Pierre Arany, MD, PhD, is a Professor of Physiology at the University of Pennsylvania's Perelman School of Medicine. He serves as Co-Director of the Cardiovascular Metabolism Program within the Institute of Diabetes, Obesity & Metabolism and is a member of the Penn Muscle Institute. Dr. Arany is also the Co-Director of the Cardiovascular Division at the Institute of Regenerative Medicine and a Staff Physician at the Philadelphia VA Medical Center. His research focuses on cardiovascular metabolism, utilizing a wide range of techniques including human genetics, genetically engineered mouse models, cell culture, metabolomics, and in vivo isotope metabolic tracing to explore fundamental questions within this broad field. His lab aims to leverage state-of-the-art approaches to better understand the metabolic processes involved in cardiovascular health and disease.

Research topics

• Internal medicine
• Medicine
• Biology
• Biochemistry
• Endocrinology
• Cell biology
• Cardiology
• Chemistry
• Obstetrics
• Bioinformatics
• Intensive care medicine
• Chromatography
• Cancer research
• Oncology
• Immunology

Selected publications

• Cardiovascular complications of pregnancy

  Journal of Clinical Investigation · 2026-01-01

  articleOpen accessSenior author

  The maternal cardiovascular system undergoes dramatic remodeling in response to the stresses of pregnancy. Although in most cases these changes are temporary and well tolerated, in others they can give rise to complications, including cardiomyopathy, coronary artery disease, and hypertensive cardiovascular disease. Despite an increasing number of preclinical models to study these diseases, specific treatments for any of these pregnancy complications are lacking. As the maternal mortality rate is rising in the United States, it is critical to understand the molecular mechanisms driving cardiovascular changes during pregnancy, and the pathology that can result.

  PublisherDOI

• Friend of GATA2 Variant Ser657Gly Is Associated With Coronary Microvascular Disease

  Circulation Genomic and Precision Medicine · 2026-04-01

  articleOpen access

  BACKGROUND: The coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. FOG2 (friend of GATA 2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice. Little is known about the role of FOG2 in humans or its role in CMVD. Here, we report a genotype-first approach to determine the role of FOG2 in human CMVD. METHODS: We performed phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants. We interrogated MagNET heart tissue data to identify genes and pathways associated with rs28374544. We then overexpressed FOG2S657G in a cardiomyocyte cell line and assessed the effects on cardiac metabolism and paracrine angiogenic signaling. RESULTS: We identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Using phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants, we identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Individuals carrying the S657G variant, almost all of African ancestry, had increased chest pain, a smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic data sets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the HIF (hypoxia-inducible factor) pathway. In vitro functional studies show that compared with the FOG2 wild-type protein, the FOG2 S657G variant protein promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate. CONCLUSIONS: A common functional coding variant in FOG2, S657G, is associated with CMVD in humans. Altered angiogenic gene expression, regulated in part by FOG2, may contribute to CMVD.

  PublisherDOI

• Pregnancy hormones increase cardiac capillary density via the PGC-1α/ERRα/VEGF pathway in cardiomyocytes

  Frontiers in Cardiovascular Medicine · 2025-10-14

  articleOpen access

  Background: Pregnancy significantly affects the maternal cardiovascular system, with physiological adaptations characterized by cardiac hypertrophy and increased capillarization. However, the molecular mechanisms underlying these adaptations remain incompletely understood. Therefore, we analyzed them in mouse hearts at different stages of pregnancy and after hormone treatment. Methods: We analyzed cell proliferation, capillary density, hypertrophy, and gene expression using immunostaining and quantitative RT-PCR to evaluate differential gene expression in mouse hearts at different stages during pregnancy and after treatment with combinations of progesterone and estrogen for up to 14 days. Results: We found that the number of proliferating cells in the hearts of pregnant mice began to increase at gestational day 3 (GD3), peaked at GD14-mainly in fibroblasts and endothelial cells (ECs), but not in cardiomyocytes (CMs)-and decreased immediately after delivery. EC proliferation was indicative of angiogenesis, as evidenced by increased capillary density. After hormone treatment, capillary density increased in the hearts of both female and male mice, without prominent CM hypertrophy and independently of nuclear hormone receptors. The proportion of proliferating cardiac cells and ECs was significantly increased after 14 days of treatment. Mechanistically, we identified activation of the PGC-1α/ERRα signaling pathway and upregulation of its downstream target VEGF-A. Using a CM-specific PGC-1α knockout mouse line, we demonstrated that the pregnancy hormone-induced angiogenesis is induced via PGC-1α signaling in CMs by secretion of VEGF. Conclusions: Our data indicated a direct effect of pregnancy hormones on cardiac capillarization, rather than indirect effects through CM hypertrophy, and demonstrate that capillary expansion is not sufficient to drive physiological hypertrophy. Pregnancy hormones directly act on CMs via the PGC-1α/ERRα signaling pathway and VEGF secretion, positioning CMs as a key source of angiogenic factors that promote endothelial cell proliferation and enhance capillary density in the heart.

  PublisherOA PDFDOI

• Right Ventricular Dysfunction and Adverse Clinical Outcomes in Peripartum Cardiomyopathy

  JACC Advances · 2025-08-05 · 1 citations

  articleOpen access

  BACKGROUND: The prognostic significance of right ventricular (RV) dysfunction in peripartum cardiomyopathy (PPCM) remains inconsistent across studies. OBJECTIVES: This study aimed to evaluate the association between RV dysfunction at diagnosis and likelihood of left ventricular (LV) systolic function recovery and major adverse outcomes in PPCM. METHODS: We conducted a meta-analysis to identify studies with assessment of RV function, major adverse outcomes, and LV systolic function recovery. RV dysfunction was defined using echocardiographic parameters such as tricuspid annular plane systolic excursion <16 mm, fractional area change <35%, S' <10 cm/s, or RV ejection fraction <45% on cardiac magnetic resonance imaging. The primary outcomes were LV systolic function recovery (LV ejection fraction ≥50%) and major adverse clinical outcomes (LV assist device, recurrent heart failure hospitalization, orthotopic heart transplantation, or death). Pooled ORs and 95% CIs were calculated using random-effect models. RESULTS: Five studies (N = 472, n = 117 with RV dysfunction; 1,212 person-years of follow-up) met criteria. Participants had a mean age of 32 ± 7 years. After a median follow-up of 25 months (Q1-Q3: 6.8-36.9), RV dysfunction in PPCM was significantly associated with a decreased likelihood of LV systolic function recovery (OR: 0.39; 95% CI: 0.21-0.71; P < 0.001) compared to those without RV dysfunction. With a median follow-up of 32.9 months (Q1-Q3: 15.3-42.6), those with RV dysfunction were 4 times more likely to experience adverse clinical outcomes (OR: 4.19; 95% CI: 2.23-7.85; P < 0.001). CONCLUSIONS: Our findings suggest that RV dysfunction at diagnosis is associated with a higher risk of major adverse outcomes and a lower likelihood of LV function recovery in PPCM.

  PublisherDOI

• Cellular and Transcriptional Landscape of Human Hypoplastic Left Heart Syndrome

  Research Square · 2025-05-29

  preprintOpen access
  PublisherOA PDFDOI

• Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK

  Molecular Metabolism · 2025-05-08 · 2 citations

  articleOpen accessSenior authorCorresponding

  The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential “off-target” effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in Bckdk -/- animals. As expected, BT2 failed to activate BCAA oxidation in these animals. Surprisingly, however, BT2 strongly reduced plasma tryptophan levels and promoted catabolism of tryptophan to kynurenine in both control and Bckdk -/- mice. Mechanistic studies revealed that none of the principal tryptophan catabolic or kynurenine-producing/consuming enzymes (TDO, IDO1, IDO2, or KATs) were required for BT2-mediated lowering of plasma tryptophan. Instead, using equilibrium dialysis assays and mice lacking albumin, we show that BT2 avidly binds plasma albumin and displaces tryptophan, releasing it for catabolism. These data confirm that BT2 activates BCAA oxidation via inhibition of BCKDK but also reveal a robust off-target effect on tryptophan metabolism via displacement from serum albumin. The data highlight a potential confounding effect for pharmaceutical compounds that compete for binding with albumin-bound tryptophan. • BT2, an inhibitor of BCKDK with analogs currently in clinical development, has off-target metabolic effects • Treating mice with BT2 dramatically lowers plasma levels of tryptophan even in the absence of BCKDK • Most plasma tryptophan is bound to albumin • BT2 avidly binds to albumin and displaces tryptophan, thereby lowering plasma tryptophan levels

  PublisherDOI

• Abstract 4336062: Histone Modifications are Associated with Altered Lipid Metabolism in the Cerebral Cortex of Neonatal Swine Following Uncomplicated Cardiopulmonary Bypass

  Circulation · 2025-11-03

  article

  Introduction: Excess lipolysis and dysregulated fatty acid oxidation can exacerbate neuroglial injury and impair neurodevelopment. Neurodevelopment is also regulated by histone deacetylation and methylation, which often repress gene transcription and can alter cerebral metabolism. It is unknown if fatty acid metabolism and histone modifications are altered in the neonatal brain following cardiopulmonary bypass (CPB). Research Question: This study sought to determine if histone modifications regulating chromatin accessibility and gene transcription are altered in the brain or associated with changes in cerebral metabolism at 12-24hrs post-CPB. Methods: Fifteen neonatal swine underwent 3hrs of CPB prior to decannulation and survival for 12hrs, 18hrs, or 24hrs (N=5 per cohort). Three additional piglets underwent similar sham procedures with 4hr survival. Cortical brain tissue was then analyzed with liquid chromatography-mass spectrometry using an untargeted approach to quantify 129 metabolites and 45 histone modifications in each sample. Histone modifications with a statistically significant fold-change (FC) post-CPB ( P &lt;0.0001) were correlated with metabolites across all timepoints of analysis. Results: In total, 6/45 (13%) histone modifications were significantly altered in cortical brain tissue following CPB. The acetylation of histone H4 on lysine residue 16 (H4K16ac) was reduced at 12-24hrs post-CPB (FC=0.7-0.8, P &lt;0.0001 ), while trimethylation was enriched on histone H4 at lysine residue 20 (H4K20me3: FC=1.5-2.4; Figure ). H4K20me3 enrichment directly correlated with intermediates of fatty acid metabolism, specifically polyunsaturated long-chain acylcarnitines ( Table ). Histone H3 variants had enriched mono-methylation on lysine 36 residues at 12hrs (H33K36me1: FC=6.9, P &lt;0.0001 ) and 18hrs post-CPB (H31K36me1: FC=1.6, P &lt;0.0001 ). Histone H3 mono-methylation was also enriched on lysine residue 23 (H3K23me1) at 18hrs post-CPB (FC=5.1, P &lt;0.0001 ), and phosphorylation on serine residue 10 (H3S10ph) was enriched at 24hrs post-CPB (FC=6.2, P &lt;0.0001 ). Conclusion: Dynamic changes in histone methylation and deacetylation post-CPB may impact metabolic homeostasis in the neonatal brain during critical periods of neurodevelopment. Further investigations are warranted to elucidate how alterations in lipolysis, fatty acid oxidation, chromatin accessibility, and gene transcription may affect myelination, neuroglial injury, and neurodevelopment in neonates requiring cardiac surgery.

  PublisherDOI

• 344-OR: Understanding the Dynamic Roles of Ketone Body Metabolism of Mesenchymal Stromal Cells in the Regulation of Adipose Tissue Inflammation and Insulin Resistance

  Diabetes · 2025-06-13

  article

  Introduction and Objective: Mesenchymal stromal cells (MSCs), including adipocyte progenitor cells and other types of fibroblasts, contribute to adipose tissue remodeling and function through various mechanisms. In addition to providing a source of new adipocytes, MSCs regulate adipose tissue inflammation in response to nutritional and environmental challenges such as cold exposure. Ketone bodies serve as an alternative energy source when glucose is not readily available. Recent studies indicate that ketone bodies influence brown adipogenesis. This study investigates the roles of ketone body metabolism in adipose tissue MSCs in the regulation of adipose tissue remodeling and energy metabolism. Methods: To address the question, we deleted a key enzyme of ketolysis, 3-oxoacid CoA-transferase 1 (Oxct1), selectively in PDGFRα+ MSCs of mice. To assess the role of ketone body metabolism in response to environmental cold, control and knockout (KO) mice were exposed to cold (6°C) or thermoneutral (TN; 30°C) conditions, followed by assessment of adipose tissues and metabolic phenotypes, including metabolomic profiling. Results: Oxct1 KO mice exposed to a cold environment showed increased levels of adipose tissue inflammation and impaired glucose tolerance. Surprisingly, these inflammatory responses were reversed in mice housed under TN conditions. At TN, Oxct1 KO mice showed lower levels of inflammation and improved glucose tolerance. Comprehensive metabolomic analyses of adipose tissue revealed that the levels of methylglyoxal (MG), an inflammatory metabolite, were reciprocally regulated, with KO mice exhibiting higher MG levels in the cold and lower levels at TN, relative to control mice. Conclusion: Collectively, these results indicate that ketone body metabolism in MSCs is critical for controlling adipose inflammation and metabolic homeostasis. Disclosure I. Hwang: None. J. Jung: None. Z. Arany: Consultant; nanophoria, abrax, Biohaven, Pfizer Inc, scipher. P. Seale: Advisory Panel; iTeos. Consultant; Merck &amp; Co., Inc. Funding American Diabetes Association (1-25-PDF-28)

  PublisherDOI

• Abstract 4338158: The metabolome is preserved in failing mouse hearts but shifts under additional stress

  Circulation · 2025-11-03

  article

  The healthy heart is omnivorous as it readily utilizes fatty acids, glucose, lactate, pyruvate, ketone bodies, and amino acids. This adaptation enables the heart to metabolize alternative fuels when the preferred fatty acids for maximal ATP production cannot be utilized due to decreased cardiac efficiency. It is well established that the failing human heart ultimately becomes metabolically insufficient as it gradually shifts to fuels such as ketone bodies and fails to generate enough ATP to compensate for the energy deficit. While mouse HF models are being utilized to elucidate underlying pathomechanisms and explore metabolic therapy targets, the metabolome of the failing mouse heart is not well characterized. Thus, using stable isotope-labeled metabolites, we sought to characterize the global metabolome and fuel utilization in failing mice myocardia. We hypothesize the metabolome and fuel utilization of the failing mice heart will change substantially like failing human hearts. To assess the metabolic phenotype of the failing mice heart, we induced HFrEF in mice with TAC/MI surgeries, followed by echocardiography after 4 weeks to assess systolic functions and morphometrics. Next, cocktails of isotope-labeled metabolites (glucose, lactate, β-OHB, glutamine, and valine) were infused intravenously for 2 hr while arterial blood was collected at different time points. Alternatively, isoproterenol (90 ng/kg/min) was added to the cocktail to mimic ambulatory heart rates while metabolites were being infused. Intriguingly, the metabolome of the TAC/MI with reduced LVEF compared to the Sham showed only 7.2% of myocardial metabolite levels altered; principal component analysis (PCA) showed no overt change in the metabolome. Similarly, isotope tracing data showed no differences in metabolite enrichment and fuel utilization in the myocardia. However, TAC/MI drastically altered the response to additional stress with isoproterenol, with 34.9% of metabolites changed in myocardial metabolomics between TAC/MI and Sham. Also, PCA showed a significantly diverging metabolic profiling between the failing and normal hearts from TAC/MI and Sham mice, respectively – representing similar observations in failing human hearts. We show for the first time that metabolome is preserved in failing mouse hearts but shifts under stress, thus warranting further investigation into the dynamics of the metabolic profile of the failing heart for insights into developing metabolic therapies for HF.

  PublisherDOI

• What Do We Know of Human Fuel Use during Aerobic Exercise, and How Do We Know It?

  Physiology · 2025-08-05 · 1 citations

  reviewOpen accessSenior authorCorresponding

  Aerobic exercise is arguably the most metabolically demanding challenge imposed on the human body. The metabolic adaptations to exercise are complex, involving most tissues and differing substantially depending on the type, severity, and duration of exercise as well as the extent of prior training. Studies of these metabolic responses have been ongoing for decades, including the active National Institutes of Health (NIH)-supported consortium MotrPAC. Most studies have been carried out in model organisms, generally rodents or dogs. However, the metabolism of these model organisms substantially differs from humans. We therefore review here what is known specifically of human metabolism during exercise. For the sake of brevity, we focus on aerobic exercise without extensive prior training. We review methods used to reach conclusions, highlight the many remaining unknowns, and discuss questions requiring future experimental attention.

  PublisherOA PDFDOI

Recent grants

• Branched chain amino acids and pancreatic cancer

  NIH · $2.3M · 2020–2025

• Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance

  NIH · $3.8M · 2018–2027

• Branched chain amino acids in heart failure

  NIH · $3.7M · 2020–2028

• sFlt and Metabolic Mechanisms of Peripartium Cardiomyopathy

  NIH · $1.6M · 2016–2020

• High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes

  NIH · $2.6M · 2021–2023

Frequent coauthors

• Glenn C. Rowe

  University of Alabama at Birmingham

  118 shared

• Cholsoon Jang

  University of California, Irvine

  106 shared

• Shogo Wada

  Nippon Seiki (Japan)

  76 shared

• Sarosh Rana

  University of Chicago Medical Center

  73 shared

• S. Ananth Karumanchi

  Cedars-Sinai Medical Center

  72 shared

• Michael P. Morley

  University of Pennsylvania

  72 shared

• Kenneth B. Margulies

  University of Pennsylvania

  69 shared

• Sajid Shahul

  University of Chicago

  68 shared

Labs

• Arany LabPI

Education

• B.A., Biochemical Sciences (Summa Cum Laude)

  Harvard College

  1989

• Ph.D., Biological and Biomedical Sciences

  Harvard Graduate School

  1995

• M.D.

  Harvard Medical School

  1998