About

Steven Owen Marx, MD, is the Principal Investigator of the Marx Lab at Columbia University Irving Medical Center, within the Division of Cardiology. His research focuses on the regulation of ion channels by macromolecular complexes, with a particular emphasis on understanding the molecular components and functional implications of these complexes in cardiac and vascular physiology. The lab has demonstrated that specific sequences within ion channels, such as leucine zippers, recruit regulatory proteins that modulate ion channel function under both normal and pathological conditions. Current research efforts are centered on the large conductance calcium-activated potassium channel (BKCa, maxi-K) and the L-type voltage gated calcium channel, utilizing molecular biologic and electrophysiologic techniques to elucidate fundamental processes and their links to systems function. The work conducted in the Marx Lab has significantly advanced the understanding of triggers for fatal cardiac arrhythmias and mechanical dysfunction in heart failure, as well as the control of peripheral blood pressure by the sympathetic nervous system. The Marx Lab collaborates with other research groups, including the Wan Lab and the Morrow Lab, to develop new diagnostic and therapeutic methods for arrhythmias. The lab's scientists have made major advances in elucidating the molecular and cellular bases and fundamental mechanisms of complex, life-threatening arrhythmias and sudden cardiac death. The research program is focused on two major areas: cardiac studies of ion channel regulation in normal and pathological heart conditions, where altered ion channel function is linked to heart failure and arrhythmias; and vascular studies aimed at understanding molecular mechanisms that lead to vascular smooth muscle proliferation, migration, and contractility. The overarching mission of the Marx Lab is to promote interdisciplinary cardiovascular research with the goal of developing new and effective approaches for diagnosing, treating, and preventing diseases of the heart and blood vessels, thereby reducing premature death.

Research topics

• Computer Science
• Medicine
• Chemistry
• Artificial Intelligence
• Biology
• Machine Learning
• Surgery
• Bioinformatics
• Internal medicine
• Computational biology
• Composite material
• Engineering
• Psychology
• Aeronautics
• Materials science
• Neuroscience
• Endocrinology
• Cell biology
• Biochemistry

Selected publications

• Left Ventricular Unloading in Anterior ST-Segment Elevation Myocardial Infarction Without Shock

  Journal of the American College of Cardiology · 2026-03-01 · 1 citations

  article
  PublisherDOI

• Characterizing high-risk enrollment criteria and impact on clinical outcomes in a large randomized clinical trial: Insights from the TWILIGHT trial

  American Heart Journal · 2025-01-30

  articleOpen access
  PublisherOA PDFDOI

• FGF13 is not secreted from neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-12

  preprint

  FGF13, a noncanonical fibroblast growth factor (FGF) and member of the fibroblast growth factor homologous factor (FHF) subset, lacks a signal sequence and was previously reported to remain intracellular, where it regulates voltage-gated sodium channels (VGSCs) at least in part through direct interaction with the cytoplasmic C-terminus of VGSCs. Recent reports suggest that FGF13 is secreted and regulates neuronal VGSCs through interactions with extracellular domains of integral plasma membrane proteins, yet supportive data are limited. Using rigorous positive and negative controls, we show that transfected FGF13 is not secreted from cultured cells in a heterologous expression system nor is endogenous FGF13 secreted from cultured neurons. Further, employing multiple unbiased screens including proximity protein proteomics, our results suggest FGF13 remains within membranes and is unavailable to interact directly with extracellular protein domains.

  PublisherDOI

• FGF13 Regulates VGSC-Independent Cardiomyocyte Impulse Propagation via Cx43 Trafficking

  Circulation Research · 2025-11-07

  articleOpen access

  BACKGROUND: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC–related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded. METHODS: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (c Fgf13 KO ) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. RESULTS: FGF13 ablation prolonged the QRS and QT intervals. Carbenoxolone, a Cx43 gap junction uncoupler, markedly prolonged the QRS duration, leading to conduction system block in c Fgf13 KO but not in wild-type mice. Optical mapping revealed markedly decreased conduction velocity during ventricular pacing. Microscopy revealed perturbed trafficking of Cx43, reduced localization in the intercalated disc, and suggested decreased membrane Cx43 but increased Cx43 hemichannels in cardiomyocytes from c Fgf13 KO mice. Resting membrane potential was depolarized, and action potential duration at 50% repolarization was prolonged in c Fgf13 KO cardiomyocytes. Both were restored toward wild-type values with Gap19 (a Cx43 hemichannel inhibitor), expression of FGF13, or expression of a mutant FGF13 incapable of binding to VGSCs, emphasizing VGSC-independent regulation by FGF13. To assess the functional impact of resting membrane potential depolarization, hearts were subjected to hypokalemia, which had no effect in wild-type hearts but fully rescued conduction velocity in c Fgf13 KO hearts. Proteomic analyses revealed candidate roles for FGF13 in the regulation of vesicular-mediated transport. FGF13 ablation destabilized microtubules and reduced the expression of tubulins and MAP4, the major cardiac microtubule regulator. CONCLUSIONS: FGF13 regulates microtubule-dependent trafficking and targeting of Cx43 and impacts cardiac impulse propagation via VGSC-independent mechanisms.

  PublisherOA PDFDOI

• De novo Design of a Peptide Modulator to Reverse Sodium Channel Dysfunction Linked to Cardiac Arrhythmias and Epilepsy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-28

  preprintOpen access

  Summary Ion channels orchestrate electrical signaling in excitable cells. In nature, ion channel function is customized by modulatory proteins that have evolved to fulfill distinct physiological needs. Yet, engineering synthetic modulators that precisely tune ion channel function is challenging. One example involves the voltage-gated sodium (Na V ) channel that initiates the action potential, and whose dysfunction amplifies late/persistent sodium current ( I NaL ), a commonality that underlies various human diseases including cardiac arrhythmias and epilepsy. Here, using a computational protein design platform, we engineered a de novo peptide modulator, ELIXIR, that binds Na V channels with submicromolar affinity. Functional analysis revealed an unexpected selectivity in inhibiting ‘pathogenic’ I NaL and confirmed its effectiveness in reversing Na V dysfunction linked to both cardiac arrhythmias and epilepsy in cellular and murine models. These findings exemplify the efficacy of de novo protein design for engineering synthetic ion channel modulators and sets the stage for rational design of future therapeutic approaches.

  PublisherOA PDFDOI

• BPS2025 - De novo design of a peptide modulator that inhibits arrhythmogenic late sodium current

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• L-Type Ca _v 1.3 and HCN Channels Mediate Heart Rate Acceleration by Catecholamines

  Circulation Research · 2025-12-04 · 3 citations

  articleOpen access

  BACKGROUND: The ionic mechanism by which catecholamines increase the heart rate is incompletely understood. In this study, we have assessed the roles of sinoatrial node L-type Ca v 1.3 (α 1D ) Ca 2+ channels, phosphorylation of L-type channel regulatory partner protein Rad (Ras-related RGK GTP-binding protein), and cAMP-dependent regulation of hyperpolarization-activated HCN (hyperpolarization-activated cyclic nucleotide-gated) channels. METHODS: We studied β-adrenergic regulation of heart rate and sinoatrial pacemaker activity in mice lacking Ca v 1.3 channels and in mice expressing dihydropyridine-insensitive L-type Ca v 1.2 channels alone or concomitantly expressing cAMP-insensitive HCN4 subunits in a heart-specific and time-controlled manner. We also studied the chronotropic response to sympathomimetics of sinoatrial pacemaker myocytes under conditions of specific inhibition of cAMP-dependent regulation of HCN4 by the cyclic dinucleotide cyclic di-(3′,5′)-GMP and ablation of PKA (protein kinase A)–dependent phosphorylation of Rad. RESULTS: Mutant mice with knockout of Ca v 1.3 and cAMP-insensitive HCN4 subunits in the heart lacked diurnal variation in heart rate and failed to increase their heart rate after administration of catecholamines or during physical activity. Selective pharmacological inhibition of Ca v 1.3 prevented the enhancement of pacemaker activity by sympathomimetics or by direct activation of adenylate cyclase, as well as by phosphodiesterase inhibitors, when cAMP-dependent regulation of HCN was simultaneously silenced. Upregulation of Ca v 1.3 and HCN-mediated funny current ( I f ) accounted for the total change in diastolic current on activation of β-adrenoceptors, explaining the loss of chronotropic effect of catecholamines. Preventing PKA phosphorylation of Rad abrogated the chronotropic response to sympathomimetics of intact hearts under HCN blockade, or in pacemaker myocytes on preventing cAMP-dependent regulation of HCN4, respectively. CONCLUSIONS: PKA phosphorylation of Rad, which disinhibits Ca v 1.3 channels and cAMP-dependent activation of HCN channels, are key effectors in β-adrenergic regulation of cardiac pacemaker activity and can sustain positive chronotropic effects independently. These findings on Rad-mediated regulation of Ca v 1.3 and HCN channels unravel the ionic mechanisms underlying the catecholaminergic acceleration of the heart rate.

  PublisherOA PDFDOI

• FGF13 is not secreted from mouse neurons

  JCI Insight · 2025-11-25

  articleOpen access

  FGF13, a noncanonical fibroblast growth factor (FGF) and member of the fibroblast growth factor homologous factor (FHF) subset, lacks a signal sequence and was previously reported to remain intracellular, where it regulates voltage-gated sodium channels (VGSCs) at least in part through direct interaction with the cytoplasmic C-terminus of VGSCs. Recent reports suggest FGF13 is secreted and regulates neuronal VGSCs through interactions with extracellular domains of integral plasma membrane proteins, yet supportive data are limited. Using rigorous positive and negative controls, we show that transfected FGF13 is not secreted from cultured cells in a heterologous expression system, nor is endogenous FGF13 secreted from cultured neurons. Furthermore, using multiple unbiased screens including proximity labeling proteomics, our results suggest FGF13 remains within membranes and is unavailable to interact directly with extracellular protein domains.

  PublisherOA PDFDOI

• PO-05-106 NON-VOLTAGE-GATED SODIUM CHANNEL-RELATED FUNCTIONS OF FGF13 REGULATE CARDIOMYOCYTE IMPULSE PROPAGATION

  Heart Rhythm · 2025-04-01

  articleOpen access
  PublisherOA PDFDOI

• The Na _V 1.5 auxiliary subunit FGF13 modulates channels by regulating membrane cholesterol independent of channel binding

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-19 · 1 citations

  preprintOpen access

  Abstract Fibroblast growth factor homologous factors (FHFs) bind to the cytoplasmic carboxy terminus of voltage-gated sodium channels (VGSCs) and modulate channel function. Variants in FHFs or VGSCs perturbing that bimolecular interaction are associated with arrhythmias. Like some channel auxiliary subunits, FHFs exert additional cellular regulatory roles, but whether these alternative roles affect VGSC regulation is unknown. Using a separation-of-function strategy, we show that a structurally guided, binding incompetent mutant FGF13 (the major FHF in mouse heart), confers complete regulation of VGSC steady-state inactivation (SSI), the canonical effect of FHFs. In cardiomyocytes isolated from Fgf13 knockout mice, expression of the mutant FGF13 completely restores wild-type regulation of SSI. FGF13 regulation of SSI derives from effects on local accessible membrane cholesterol, which is unexpectedly polarized and concentrated in cardiomyocytes at the intercalated disc (ID) where most VGSCs localize. Fgf13 knockout eliminates the polarized cholesterol distribution and causes loss of VGSCs from the ID. Moreover, we show that the previously described FGF13-dependent stabilization of VGSC currents at elevated temperatures depends on the cholesterol mechanism. These results provide new insights into how FHFs affect VGSCs and alter the canonical model by which channel auxiliary exert influence.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL068093

  NIH · $2.4M · 2012

• Investigation of calcium modulation in cardiomyocytes by novel methods

  NIH · $2.2M · 2013–2018

• L-type channel trafficking and modulation in heart

  NIH · $7.6M · 2014–2027

• Calmodulin regulation of Na+ channels in neurons and cardiomyocytes

  NIH · $2.1M · 2014–2019

• Elucidating the Mechanisms of Vascular Dysfunction in Heart Failure

  NIH · $1.6M · 2016–2020

Frequent coauthors

• Gregg W. Stone

  Icahn School of Medicine at Mount Sinai

  67 shared

• Andrew R. Marks

  Columbia University

  53 shared

• S. I. Zakharov

  Columbia University

  33 shared

• Alexander N. Katchman

  Columbia University

  28 shared

• Arthur Karlin

  Columbia University

  27 shared

• Ao Liu

  Zhejiang Cancer Hospital

  27 shared

• Adnan Kastrati

  German Centre for Cardiovascular Research

  25 shared

• Christian W. Hamm

  Kerckhoff Klinik

  25 shared

Labs

• Marx LabPI

Education

• M.D.

  Columbia University

• B.S.

  University of California, San Diego

Awards & honors

• Alpha Omega Alpha (AOA)
• American College of Cardiology, NYS Chapter Young Investigat…
• John C. Sable Memorial Heart Fund Research Award (1994-1995)
• The Denber Prize for Research, Mount Sinai Cardiovascular In…
• Katz Award Finalist, American Heart Association (1996)