Sumeet Anand Khetarpal

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Primary Appointment

Assistant Professor of Medicine, Medicine- Cardiovascular Medicine

Research Disciplines

Cardiovascular Biology, Genetics, Metabolism

Research Interests

Cardiovascular Biology

Research Description

My research program at the University of Virginia (UVA) investigates how the heart communicates with other organs to regulate systemic metabolism, and how these pathways can be targeted to treat cardiovascular and metabolic disease. We focus on two intertwined axes of inter-organ crosstalk: (i) lipoprotein physiology and lipid signaling that shape cardiometabolic risk, and (ii) heart-derived secreted proteins (âcardio-myokinesâ) that govern adaptation to exercise and drive maladaptive remodeling in disease. Methodologically, the lab integrates mouse genetics and physiology (exercise and heart-failure models), viral vectorâmediated gene delivery, primary cell culture, quantitative proteomics and lipidomics, and human genetic/proteomic datasets.
At UVAâs Cardiovascular Research Center, my lab will extend this genetics-to-mechanism paradigm across three synergistic thrusts: (1) discover and define heart-derived proteins that control systemic metabolism and cardiac remodeling (leveraging ECF proteomics, gain/loss-of-function, and receptor/ligand mapping); (2) dissect how lipoprotein regulators (e.g., APOC3-centered pathways) influence cardiac and skeletal-muscle bioenergetics and endothelial function in exercise vs. heart failure; and (3) translate these insights using human genetic and proteomic resources to prioritize therapeutic entry points. This integrated program offers trainees rigorous, multi-modal training at the interface of basic metabolism, cardiovascular biology, and human genetics, with a clear path from discovery to translational relevance.

Personal Statement

My PhD work with Dr. Daniel Rader established a genetics-to-mechanism framework in lipoprotein biology that now underpins our translational approach. In Zanoni, Khetarpal, Larach et al., Science (2016) (PMID: 26965621), we discovered that a rare loss-of-function variant in SCARB1 paradoxically raises HDL-C yet increases CAD risk, redefining HDL functionality and implicating SR-BIâmediated reverse cholesterol transport in atherosclerosis. In Khetarpal and Schjoldager et al., 2016 (PMID: 27508872), we mechanistically interrogated the GALNT2 lipid GWAS locus, demonstrating how O-linked glycosylation modulates lipoprotein traitsâan example of physiology guided by human genetics. In Khetarpal et al., Nature Medicine. 2017 (PMID: 28825717), we characterized a protective missense variant in APOC3, linking altered apoC-III function to lower triglycerides and reduced CAD risk. Together, these studies illustrate how human genetic discovery can reveal unexpected biology in lipid transport and set the stage for therapeutic targeting of atherogenic and metabolically maladaptive lipoproteins.
As a postdoctoral fellow with Dr. Bruce Spiegelman (Dana-Farber) and Dr. Anthony Rosenzweig (MGH), I explored the heartâs endocrine function in exercise and disease. Our work (Khetarpal et al. bioRxiv 2024.01.30.578093; in press at Nature Cardiovascular Research) shows that PGC-1α coordinates mitochondrial adaptation to exercise while suppressing secretion of GDF15, a pro-atrophic signalâestablishing a mechanistic link between a core metabolic coactivator and a maladaptive cardio-myokine. In parallel, we developed an extracellular-fluid proteomics platform to catalogue heart-secreted proteins, revealing new candidate mediators of inter-organ communication for targeted follow-up.

Selected Publications

Pubmed: https://pubmed.ncbi.nlm.nih.gov/?term=Khetarpal+SA%5Bauthor+name%5D&sort=pubdate

Google Scholar: https://scholar.google.com/citations?user=J5RasHoAAAAJ&hl=en

1) Khetarpal SA, Li H, Vitale T, Rhee J, Challa S, Castro C, Pabel S, Sun Y, Liu J, Bogoslavski D, Vargas-Castillo A, Smythers AL, Blackmore KA, Grauvogel L, Mittenbühler MJ, Khandekar MJ, Curtin C, Narvaez-Paliza JM, Wang C, Houstis NE, Sprenger H-G, Jurgens SJ, Biddinger KJ, Kuznetsov A, Freeman R, Ellinor PT, Nahrendorf M, Paulo JA, Gygi SP, Dumesic PA, Asnani A, Aragam KG, Puigserver P, Roh JD, Spiegelman BM*, Rosenzweig A*. Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α. Nature Cardiovascular Research. In press. *Denotes equal co-authorship. PMID: 40993371.

2) Khetarpal SA, Li H, Lerchenmüller C, Rhee J, Rosenzweig A. Molecular Mediators of the Cardiac Benefits of Exercise. Circulation Research. 2025 Jul 7;137(2):163-183. Review. PMID: 40608861.

3) Khetarpal SA, Zeng X, Millar JS, Vitali C, Somasundara AV, Zanoni P, Landro JA, Barucci N, Zavadoski WJ, Sun Z, de Haard H, Toth IV, Peloso GM, Natarajan P, Cuchel M, Lund-Katz S, Phillips MC, Tall AR, Kathiresan S, DaSilva-Jardine P, Yates NA, Rader DJ. A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nature Medicine. 2017, Sep; 23(9): 1086-1094. PMCID: 28825717.

4) Khetarpal SA*, Schjoldager KT*, Christoffersen C, Raghavan A, Edmondson AC, Reutter HM, Ahmed B, Ouazzani R, Peloso GM, Vitali C, Zhao W, Somasundara AV, Millar JS, Park Y, Fernando G, Livanov V, Choi S, Noé E, Patel P, Ho SP; Myocardial Infarction Exome Sequencing Study, Kirchgessner TG, Wandall HH, Hansen L, Bennett EP, Vakhrushev SY, Saleheen D, Kathiresan S, Brown CD, Abou Jamra R, LeGuern E, Clausen H, Rader DJ. Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents. Cell Metabolism. 2016 Aug 9;24(2):234-45. * Denotes equal co-authorship. PMCID: 27508872.

5) Zanoni P*, Khetarpal SA*, Larach DB*, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder Aa, Alam DS, Di Angelantonio E, Abecasis G, Chowdhury R, Erdmann J, Nordestgaard BG, Nielsen SF,  Tybjærg-Hansen A, Schmidt RF, Kuulasmaa K, Liu DJ, Perola M, Blankenberg S, Salomaa V, Männistö S, Amouyel P, Arveiler D, Ferrieres J, Müller-Nurasyid M, Ferrario M, Kee F, Willer CJ, Samani N, Schunkert H, Butterworth AS, Howson JM, Peloso GM, Stitziel NO, Danesh J, Kathiresan S, Rader DJ; CHD Exome+ Consortium; CARDIoGRAM Exome Consortium; Global Lipids Genetics Consortium. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science. 2016 Mar 11;351(6278):1166-71. * Denotes equal co-authorship. PMCID: 26965621.