About

Kenneth B. Margulies, M.D., is a Professor of Medicine in Cardiovascular Medicine at the Hospital of the University of Pennsylvania and an Attending Cardiologist within the University of Pennsylvania Health System. He serves as the Director of Penn Heart Failure and Transplant Research and the Director of the Cardiology Clinical Research Unit in the UPenn Division of Cardiology. Dr. Margulies's research focuses on mechanisms of myocardial remodeling to identify targets for therapeutic interventions. His lab examines myocardial adaptations using explanted human heart tissues obtained at transplantation or organ donation, with a particular emphasis on load-dependent myocardial remodeling, mechanical memory, pathological hypertrophy, regulation of contractility by microtubules and cytoskeletal elements, cardiotoxicity related to VEGF-anti-angiogenic tyrosine kinase inhibitors, and disease-associated shifts in cardiac metabolism. His work employs advanced models including primary human cardiomyocytes, iPSC-derived cardiomyocytes, engineered cardiac microtissues, and digital pathology with machine learning techniques, often integrating genomic inquiries to elucidate molecular mechanisms of myocardial pathology. Dr. Margulies's research also involves strategic patient-based proof-of-concept studies and the development of innovative in vitro models to study load-dependent myocardial maturation and hypertrophy. His team investigates novel contractility modulation in heart failure, exploring the role of microtubule networks and enzymatic regulation of tubulin modifications, with the aim of translating these findings into safer therapeutic strategies. Additionally, his work addresses cardiotoxicity of anti-angiogenic therapies, the metabolic shifts in heart failure—including increased ketone utilization—and the mechanisms of inherited cardiomyopathies, leveraging comprehensive models to understand gene-specific impacts and develop targeted interventions. Dr. Margulies's background includes an A.B. in Politics from Princeton University and an M.D. from Jefferson Medical College, with a longstanding commitment to advancing understanding and treatment of cardiac diseases through mechanistic research and innovative modeling approaches.

Research topics

• Biology
• Medicine
• Cell biology
• Internal medicine
• Cardiology
• Genetics
• Chemistry
• Computational biology
• Endocrinology
• Bioinformatics
• Anatomy
• Biochemistry

Selected publications

• Microtubule dynamics control the direction of cardiomyocyte growth

  Science · 2026-04-23

  article

  The adult heart grows by the addition of sarcomeres along the length or width of individual cardiomyocytes, yet how directional growth is spatially coordinated remains unclear. We found that microtubule dynamics could act as a toggle to direct cardiomyocyte growth. Increasing microtubule stability drove cellular widening, concomitant with redirecting messenger RNA (mRNA) export and translation along the width of the cell and reinforcement of the intercalated disc. Conversely, decreasing microtubule stability promoted cellular lengthening, disrupting the intercalated disc and biasing translation and incorporation of new sarcomeric protein toward this structure. Notably, disrupting intercalated disc adhesion was sufficient for cardiomyocyte elongation yet dispensable for cardiomyocyte widening. Thus, the heart coordinates local translation and structural remodeling to orchestrate bidirectional growth.

  PublisherDOI

• Advancing Genetics and Heart Failure: HFSA Steps Forward to Lead

  Journal of Cardiac Failure · 2026-03-01

  article1st authorCorresponding
  PublisherDOI

• Severe obesity in human HFpEF alters contractile protein function and organization

  Science · 2026-04-23

  article

  Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality and has few effective therapies. Its phenotype has changed over time, with morbid obesity and metabolic defects supplanting hypertension and cardiac hypertrophy. We reveal that cardiomyocytes from patients with severe obesity and HFpEF have very depressed contractile reserve, including reduced calcium- and length-stimulated tension, power, and myosin activation compared to less-obese HFpEF and non-failing (NF) controls ±obesity, but similar to advanced HF with reduced EF. Myocyte defects correlate with body mass index and exercise hemodynamics in patients with HFpEF but not NF and appear reversible upon weight loss. Increased troponin-I phosphorylation at Thr181 occurs only in HF+obesity contributing to sarcomere dysfunction. Weight reduction and sarcomere enhancers may offer benefits in HFpEF with obesity.

  PublisherDOI

• Code for: Severe Obesity in Human HFpEF Alters Contractile Protein Function and Organization.

  Open MIND · 2026-02-15

  other

  Code to generate figures for the manuscipt entitled: Severe Obesity in Human HFpEF Alters Contractile Protein Function and Organization. All necessary npy and xlsx data files are present in the directory.

  DOI

• Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure

  Journal of the American College of Cardiology · 2026-04-01

  articleOpen access

  BACKGROUND: Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear. OBJECTIVES: The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup. METHODS: Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data from a genome-wide association study (GWAS) of time-to-event clinical outcomes in patients with HF. A total of 50,636 individuals of European ancestry with established HF from 22 cohorts were included in the genetic analysis: 12 HF trials, 1 prospective case-cohort study, 9 cohorts nested within non-HF cardiovascular trials, and 1 population-based cohort derived from the UK Biobank. The exposure was genetically predicted BMI and the outcome measures were all-cause mortality and a composite of cardiovascular mortality or HF hospitalization. Genetic associations for the outcomes were derived from our GWAS and MR was used to estimate the unbiased association of genetically predicted BMI with these clinical outcomes. RESULTS: ). Associations were consistent across LVEF ≤40% and >40%: for all-cause mortality, HR: 1.16 (95% CI: 0.99-1.37) and 1.20 (95% CI: 0.94-1.53); and for the composite outcome, HR: 1.30 (95% CI: 1.15-1.48) and 1.57 (95% CI: 1.29-1.91), respectively. CONCLUSIONS: Among patients with HF, higher BMI was associated with increased all-cause mortality and cardiovascular death or HF hospitalization, supporting the potential role of weight-management strategies across the ejection fraction spectrum.

  PublisherDOI

• Long noncoding RNA SALTe1, microvascular ageing, and cardiac dysfunction

  European Heart Journal · 2026-05-04

  articleOpen access

  BACKGROUND AND AIMS: Ageing is accompanied by progressive microvascular dysfunction, a key determinant of organ performance and longevity. The molecular drivers of this process remain incompletely defined, and the mechanisms by which exercise counters vascular ageing are unclear. This study investigated whether exercise-regulated long noncoding RNAs (lncRNAs) contribute to microvascular ageing and age-related cardiac dysfunction. METHODS: RNA sequencing was performed in naturally aged mice with and without voluntary exercise. Functional studies of candidate lncRNAs were conducted using AAV-mediated overexpression, antisense oligonucleotides, and CRISPR-based knockdown, both in vivo and in endothelial cells (ECs). RESULTS: A novel set of lncRNAs altered in hearts from exercised aged mice was identified and termed Senescence Associated LncRNA Transcripts in Exercise (SALTes). Among these, SALTe1 is evolutionarily conserved and enriched in ECs. SALTe1 expression is elevated in hearts from aged mice and in patients with various types of heart failure but suppressed by exercise. In 20-month-old mice, SALTe1 inhibition, via antisense GapmeRs or EC-specific deletion, attenuated endothelial senescence, restored microvascular perfusion, and improved diastolic function. Mechanistic studies showed that SALTe1 acts, at least in part, through upregulation of PARP9. CONCLUSIONS: These findings establish SALTe1 as a pivotal regulator of endothelial senescence as well as microvascular and cardiac dysfunction in ageing. Targeted inhibition of SALTe1 recapitulates the vasculoprotective effects of exercise, highlighting a tractable antisense-based therapeutic strategy for combating age-related cardiac decline.

  PublisherDOI

• Label free multimodal optical imaging of metabolic heterogeneity in aging by integrating SRS, MPF, FLIM, and SHG

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-14

  articleOpen access

  ABSTRACT Cellular metabolism is governed by the coordinated organization of macromolecules, including lipids and proteins, together with redox-active cofactors such as NADH and FAD. However, resolving these biochemical features quantitatively and spatially at subcellular resolution remains challenging because no single imaging modality can capture molecular composition, redox state, and tissue architecture simultaneously without labeling. Here, we present MANIFEST ( M ulti-mod A l N onlinear I maging with F luorescence E xcitation and S tatistical T emporal-resolved spectroscopy), a label-free imaging platform that integrates stimulated Raman scattering (SRS), second harmonic generation (SHG), multiphoton fluorescence (MPF), and fluorescence lifetime imaging microscopy (FLIM). The MANIFEST combines chemical imaging of lipids with autofluorescence- and lifetime-based quantification of NADH and FAD metabolism, enabling spatially resolved analysis of metabolic heterogeneity at organelle and tissue-compartment levels. We apply this framework to four distinct aging or disease models: amyloid-beta-treated tri-cultured brain cells, high-fat diet mouse liver, human non-ischemic cardiomyopathy tissue, and aging mouse retina. Across these systems, MANIFEST reveals disease-associated lipid remodeling, redox imbalance, disrupted metabolic zonation, collagen reorganization, and layer-specific metabolic changes. By integrating complementary nonlinear optical modalities into a single label-free platform, MANIFEST provides a generalizable approach for high-resolution metabolic phenotyping in complex biological systems and offers new opportunities for studying disease mechanisms, aging biology, and metabolism-driven tissue pathology.

  PublisherOA PDFDOI

• Code for: Severe Obesity in Human HFpEF Alters Contractile Protein Function and Organization.

  Zenodo (CERN European Organization for Nuclear Research) · 2026-02-15

  otherOpen access

  Code to generate figures for the manuscipt entitled: Severe Obesity in Human HFpEF Alters Contractile Protein Function and Organization. All necessary npy and xlsx data files are present in the directory.

  PublisherDOI

• An Integrated Clinical-Histopathologic Prediction Model for Cardiac Allograft Rejection: Translating Machine Learning into Clinical Risk Frameworks

  The Journal of Heart and Lung Transplantation · 2026-05-01

  articleOpen access

  BACKGROUND: Cardiac allograft rejection (CAR) remains the leading cause of early graft failure after heart transplantation (HT). Current diagnostics, including histologic grading of endomyocardial biopsy (EMB) and blood-based assays, lack accurate predictive power for future CAR risk. We developed a predictive model integrating routine clinical data with EMB-derived quantitative morphologic features to demonstrate the precision-medicine potential of mining existing data sources in post-HT care. METHODS: In a retrospective cohort of 484 HT recipients with 1,188 EMB encounters within 6 months post-transplant, we extracted 370 quantitative pathology features from digitized H&E-stained slides and 268 longitudinal clinical features from routine lab testing. Trained using the XGBoost algorithm, we compared model performance across time (cross-sectional vs longitudinal) and across data domains (clinical vs morphologic). The top predictors of our best-in-class model informed the derivation of a simplified Integrated Rejection Risk Index (IRRI) for patient risk stratification. Model performance was evaluated by AUROC, AUPRC, and time-to-event hazard ratios. RESULTS: The fully integrated longitudinal model, inclusive of clinical and morphologic domains, achieved superior predictive accuracy (AUROC 0.86, AUPRC 0.74) compared to cross-sectional or single-domain models. IRRI stratified patients into risk categories with distinct future CAR hazards: high-risk patients showed a markedly increased CAR risk (HR=6.15, 95% CI: 4.17-9.09), while low-risk patients had significantly reduced risk (HR=0.52, 95% CI: 0.33-0.84). CONCLUSIONS: By integrating longitudinal clinical and biopsy morphologic features, IRRI provides a scalable, interpretable tool for proactive CAR risk assessment. This precision-based approach offers a promising pathway toward risk-adaptive surveillance and immunosuppressive strategies.

  PublisherDOI

• 26-A-14618-ACC METFORMIN MITIGATES EXTRACELLULAR STIFFNESS-INDUCED CONTRACTILE FATIGUE IN CARDIOMYOCYTES

  Journal of the American College of Cardiology · 2026-03-27

  articleSenior author
  PublisherDOI

Recent grants

• NIH Grant R01HL105993

  NIH · $8.9M · 2017

• NIH Grant R01AG017022

  NIH · $3.5M · 2009

• NIH Grant R01HL089847

  NIH · $1.9M · 2014

• NIH Grant R21HL113777

  NIH · $435k · 2016

• Mechanical Stress-Dependent Remodeling of the Cardiac Microtubule Network

  NIH · $3.4M · 2020–2026

Frequent coauthors

• Thomas P. Cappola

  University of Pennsylvania Health System

  260 shared

• Kenneth Bedi

  Cardiovascular Institute of the South

  170 shared

• Margaret M. Redfield

  Mayo Clinic

  112 shared

• Francis D. Pagani

  Michigan Medicine

  104 shared

• Leslie W. Miller

  Arizona State University

  103 shared

• Jeffrey Brandimarto

  University of Pennsylvania

  93 shared

• Michael P. Morley

  University of Pennsylvania

  86 shared

• Patrick T. Ellinor

  84 shared

Labs

• CAMBPI

Education

• B.A., Politics

  Princeton University

  1982

• M.D., Medicine

  Jefferson Medical College

  1986