Thomas P. Cappola

· MD, ScMVerified

University of Pennsylvania · Rehabilitation Medicine

Active 2001–2026

h-index94

Citations33.4k

Papers33095 last 5y

Funding$29.8M1 active

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About

Thomas P. Cappola, MD, ScM, is the William Smilow Professor and Chief of the Division of Cardiovascular Medicine at the University of Pennsylvania Perelman School of Medicine. His research aims to uncover mechanisms of heart failure in human subjects and to use these insights to improve treatment. His approaches include applied genomics, population science, laboratory studies, and clinical trials. He has established and leads a multicenter cohort study of advanced heart failure (Penn Heart Failure Study, PHFS), co-leads a multicenter consortium for human myocardial transcriptomics and systems genetics (Myocardial Applied Genomics Network, MAGNet), and serves as a Principal Investigator on the NHLBI Heart Failure Clinical Research Network. Additionally, he is a contributing member of numerous international genomics consortia. Within the Cardiovascular Division, he has established collaborative leadership to create programs integrating science and clinical care, serving as a platform for research and training. Clinically, he treats patients with advanced heart failure on the inpatient and outpatient heart failure/transplant service.

Research topics

Medicine
Internal medicine
Biology
Genetics
Cardiology
Family medicine
Emergency medicine
Environmental health
Bioinformatics
Medical emergency
Cell biology

Selected publications

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.
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RACGAP1 as a Circulating Biomarker of Atrial Fibrillation in Heart Failure: A Dual-Cohort Proteomic Study
Circulation Arrhythmia and Electrophysiology · 2026-04-14
article
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Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Adverse Outcomes in Heart Failure
Circulation Heart Failure · 2026-01-28
articleOpen access
BACKGROUND: MGP (matrix Gla-protein), a known inhibitor of vascular calcification, becomes biologically active by vitamin K–dependent carboxylation. Circulating levels of dpucMGP (dephospho-uncarboxylated matrix Gla-protein), the inactive form of MGP, have been associated with large artery stiffening and reduced skeletal muscle mass in heart failure (HF). Whether dpucMGP is related to adverse outcomes in patients with HF is unknown. METHODS: In this cohort study, we measured plasma dpucMGP among 2247 PHFS (Penn HF Study) participants. We examined the relationship between dpucMGP and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with dpucMGP. We assessed the association between dpucMGP levels and (1) death or HF-related hospital admission; (2) all-cause death. RESULTS: Participants’ median age was 61 years (interquartile range, 53–70 years), 64% were male, and 71% were White. dpucMGP exhibited prominent proteomic associations with acute phase response, coagulation, complement system, fibrosis, cell signaling, and metabolic pathways. Greater dpucMGP was associated with older age, renal dysfunction, and warfarin use, whereas Black ethnicity was associated with lower dpucMGP. Increased dpucMGP levels were associated with an increased risk of death or HF-related hospital admission (standardized hazard ratio, 1.23 [95% CI, 1.17–1.28]; P <0.0001) and all-cause death (standardized hazard ratio, 1.32 [95% CI, 1.25–1.40]; P <0.0001), particularly among participants with nonischemic HF. Associations between dpucMGP and outcomes were dependent on warfarin use, and higher dpucMGP levels were found to mediate the association between warfarin use and adverse outcomes (death [total effect: P =0.005; indirect effect: P <0.001] and death or HF-related hospital admission [total effect: P <0.001; indirect effect: P =0.002]). CONCLUSIONS: Higher dpucMGP is associated with multiple biological pathways and with an increased risk for adverse outcomes in HF. Greater dpucMGP levels mediated the relationship between warfarin use and adverse outcomes. Further studies are required to determine the role of therapeutic interventions to reduce dpucMGP levels in this patient population.
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Transferrin Saturation, Serum Iron, and Ferritin in Heart Failure: Prognostic Significance and Proteomic Associations
Circulation Heart Failure · 2025-01-20 · 16 citations
articleOpen access
BACKGROUND: Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID. METHODS: We assessed prognostic associations of ferritin, serum iron, and TSAT among 2050 participants with heart failure (HF) with reduced/mid-range (n=1821) or preserved (n=229) left ventricular ejection fraction enrolled in the PHFS (Penn HF Study), a prospective cohort study. We measured 4928 plasma proteins using an aptamer-based assay (SOMAScanv4) and assessed prognostic and proteomic associations of markers of iron metabolism. RESULTS: Ferritin concentrations were not associated with outcomes, whereas low TSAT and serum iron were associated with the risk of all-cause death (TSAT: standardized hazard ratio, 0.84 [95% CI, 0.76–0.93]; P =0.001; serum iron: standardized hazard ratio, 0.87 [95% CI, 0.79–0.96]; P =0.007). Similarly, TSAT was associated with the risk of death or HF-related admission (standardized hazard ratio, 0.89 [95% CI, 0.83–0.95]; P =0.0006). Significant interactions between TSAT and HF with preserved ejection fraction status were found such that TSAT was more strongly associated with the risk of death and death or HF-related admission in HF with preserved ejection fraction. We identified 359 proteins associated with TSAT, including TFRC (transferrin receptor protein; β, −0.455; P <0.0001) and CRP (C-reactive protein; β, −0.355; P <0.0001). Pathway analyses demonstrated associations with lipid metabolism, complement activation, and inflammation. In contrast to the robust associations between TSAT and outcomes, ID and absolute ID defined by current criteria were not associated with death or death or HF-related admission. TSAT was associated with outcomes regardless of the presence of functional versus absolute ID. CONCLUSIONS: Low TSAT, but not ferritin concentrations, is significantly associated with adverse outcomes in HF. Low TSAT is more strongly associated with outcomes in HF with preserved ejection fraction. Pathways related to inflammation and lipid metabolism are associated with low TSAT in HF.
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Abstract 4360601: Body Mass Index, Diastolic Blood Pressure, and Hypertrophic Cardiomyopathy Polygenic Background Differentially Modify Hypertrophic Cardiomyopathy Risk
Circulation · 2025-11-03
article
Background: Hypertrophic cardiomyopathy (HCM) risk is incompletely explained by pathogenic variants and polygenic background. Mendelian randomization studies have implicated body mass index (BMI) as a modifiable risk factor for HCM in individuals with a pathogenic HCM variant (‘genotype-positive’; G+) and in those without (‘genotype-negative’; G-), and diastolic blood pressure (DBP) as a modifiable risk factor for genotype-negative HCM only. Research Questions: How do BMI, DBP, and HCM polygenic risk influence HCM diagnoses and echocardiographic endophenotypes by genotype status? Methods: Penn Medicine BioBank participants with and without HCM were identified using electronic health records. G+ participants carried pathogenic variants in definitive HCM genes. To avoid confounding, BMI and DBP were represented by polygenic scores (PGSs). PGSs for BMI, DBP, and common variant HCM risk were identified from the PGS Catalog (IDs PGS004150, PGS004604, PGS004910). Stratifying by pathogenic variant status (G+/G-), we tested PGS associations with HCM status with logistic regression. We evaluated their associations with interventricular septal thickness and left ventricular ejection fraction (EF) on echocardiogram using linear regression. Models included age and sex as covariates. Formal interaction testing between each PGS and monogenic variant status was performed. Results: Among 32,615 unrelated participants, 363 (1.1%) were diagnosed with HCM. G+ status conferred a 58-fold increased HCM risk (p=2.6x10 -135 ). Estimated associations between BMI and HCM PGSs and HCM were positive regardless of pathogenic variant status (p<0.05 for HCM PGS only); DBP was associated with HCM only among G- individuals (OR 1.63; 95% CI 1.09 to 1.39; p=7.0x10 -4 ; Figure 1A). All PGSs were positively associated with septal thickness, a defining feature of HCM (Figure 1B). A significant (p<0.05) interaction term was observed between monogenic and polygenic HCM risk. DBP and BMI PGSs were negatively associated with EF among G- individuals, discordant with the typical HCM phenotype (Figure 1B). Conclusions: Increased polygenic BMI, DBP, and HCM risk may promote septal thickening. The interaction between HCM PGS and variant carrier status suggests a synergistic role of common- and rare-variation directly related to HCM. In contrast, DBP appears to modify the risk of genotype-negative disease only. These findings suggest distinct roles of modifiable risk factors in G- and G+ HCM.
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Polygenic Background and Penetrance of Pathogenic Variants in Hypertrophic and Dilated Cardiomyopathies
medRxiv · 2025-06-22 · 1 citations
preprintOpen access
Abstract Importance Polygenic background modifies variant penetrance in hypertrophic (HCM) and dilated (DCM) cardiomyopathy, diseases with opposing morphologic characteristics and inversely related genetic pathways. Whether polygenic susceptibility for one disease protects against monogenic risk for the other remains unexplored. Objective To characterize if polygenic background bidirectionally modifies pathogenicity of established rare variants associated with HCM and DCM. Design Cross-sectional study. Setting The Penn Medicine BioBank (PMBB). Participants Volunteers enrolled in PMBB with available electronic health record and genotyping data. Exposures Normalized polygenic scores (PGS) for HCM and DCM, as well as carrier status of pathogenic variants in established HCM or DCM genes. Main Outcomes HCM and DCM defined using electronic health record diagnosis and procedure code, as well as echocardiogram measurements derived from medical records. Results This study included 49,434 PMBB participants. An increased HCM PGS was associated with significantly increased left ventricular ejection fraction (LVEF), decreased left ventricular internal diameter at end-diastole (LVIDd), and increased interventricular septal thickness (IVS) (p<0.001). An increased DCM PGS was significantly (p<0.001) associated with decreased LVEF and increased LVIDd, but was not associated with IVS. A one standard deviation increase in HCM PGS was associated with increased risk of HCM (OR 1.8; 95% CI 1.6-2.0; p=9.6x10 -25 ) and decreased risk of DCM (OR 0.69; 95% CI 0.64-0.74; p=4.3x10 -22 ). A one standard deviation increase in DCM PGS was associated with an increased risk of DCM (OR 1.6; 95% CI 1.5-1.7; p=1.7x10 -40 ) and decreased risk of HCM (OR 0.69; 95% CI 0.63-0.76; p=3.0x10 -13 ). Monogenic and polygenic risk terms had significant, independent effects when combined in models of disease status and echocardiographic measurements; the additional inclusion of either an HCM or DCM PGS improved the discrimination of models of HCM and DCM that included age, sex, and monogenic variant status (>95% probability of difference in AUROC). Conclusions and Relevance HCM and DCM risk are markedly modified by polygenic background which exists on an overlapping spectrum. Consideration of polygenic background may offer clinical value through improving understanding and prediction of these inherited cardiomyopathies. Key Points Question How is risk for hypertrophic and dilated cardiomyopathy modified by polygenic background? Findings Polygenic scores for HCM and DCM associate with clinical and echocardiographic measures relevant to both diseases and inversely modify the penetrance of pathogenic variants. Meaning Polygenic background contributes to HCM and DCM susceptibility, and exists on an overlapping spectrum.
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Precision Medicine and the FDA Modernization Act 2.0: Catalyzing Innovation in Cardiovascular Therapy
Circulation Genomic and Precision Medicine · 2025-11-03
articleOpen accessSenior author
Animal models are an essential part of preclinical research, serving to protect patients through safety and efficacy studies before human trials begin. Prior to the passage of the Food and Drug Administration (FDA) Modernization Act 2.0 in 2022, animal studies were generally required by regulators in preclinical safety evaluations. This Act amended the Federal Food, Drug, and Cosmetic Act to clarify that while animal testing had been the default standard, it is no longer a mandatory requirement for regulatory filings involving drugs and biological products1. Additionally, the Act explicitly specifies in vitro, in silico, and in chemico testing as alternatives to assess pre-clinical safety and efficacy. The FDA and others refer to these alternative platforms as New Approach Methodologies (NAMs) with an emphasis on the 3Rs of replacing, reducing and refining the use of animal testing2. This shift opens new pathways for developing and evaluating precision therapies in cardiovascular disease particularly if human-derived, genetically accurate models can outperform animal studies in predictive power and translatability.
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Epigenome-wide association study for dilated cardiomyopathy in left ventricular heart tissue identifies putative gene sets associated with cardiac pathology and early indicators of cardiac risk
Clinical Epigenetics · 2025-03-08 · 2 citations
articleOpen access
BACKGROUND: Methylation changes linked to dilated cardiomyopathy (DCM) affect cardiac gene expression. We investigate DCM mechanisms regulated by CpG methylation using multi-omics and causal analyses in the largest cohort of left ventricular tissues available. METHODS: We mapped DNA methylation at ~ 850,000 CpG sites, performed array-based genotyping and conducted RNA sequencing on left ventricular tissue samples from failing and non-failing hearts across two independent DCM cohorts (discovery n = 329, replication n = 85). Summary-data-based Mendelian Randomisation (SMR) was applied to explore the causal contribution of sentinel CpGs to DCM. Fine-mapping of regions surrounding sentinel CpGs revealed additional signals for cardiovascular disease risk factors. Coordinated changes across multiple CpG sites were examined using weighted gene co-expression network analysis (WGCNA). RESULTS: We identified 194 epigenome-wide significant CpGs associated with DCM (discovery P < 5.96E-08), enriched in active chromatin states in heart tissue. Amongst these, 32 sentinel CpGs significantly influenced the expression of 30 unique proximal genes (± 1 Mb). SMR suggested the causal contribution of two sentinel CpGs to DCM and two other sentinel CpGs to the expression of two unique proximal genes (P < 0.05). For one sentinel CpG, colocalisation analyses provided suggestive evidence for a single causal variant underlying the methylation-gene expression relationship. Fine-mapping revealed additional signals linked to cardiovascular disease-relevant traits, including creatinine levels and the Framingham Risk Score. Co-methylation modules were enriched in gene sets and transcriptional regulators related to cardiac physiological and pathological processes, as well as in transcriptional regulators whose cardiac relevance has yet to be determined. CONCLUSIONS: Using the largest series of left ventricular tissue to date, this study investigates the causal role of cardiac methylation changes in DCM and suggests targets for experimental studies to probe DCM pathogenesis.
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Author Correction: Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum
Nature Genetics · 2025-11-28
articleOpen access
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Proteome-Wide Genetic Investigation of Kidney Function in Heart Failure With Preserved Ejection Fraction
JACC Heart Failure · 2025-11-20
articleOpen access
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