About

Drew Nassal, PhD, is an Assistant Professor in the Department of Physiology and Cell Biology at The Ohio State University College of Medicine. His research focuses on the molecular mechanisms contributing to the pathophysiologic remodeling of the heart and their role in promoting heart failure. His laboratory investigates the processes underlying adaptive and maladaptive hypertrophic growth of the heart, aiming to identify critical transcriptional and cytoskeletal regulators involved in these mechanisms. The goal of his research is to develop targeted interventions to maintain or restore the adaptive growth stage, thereby preventing heart failure. Dr. Nassal's work evaluates measures of heart contractility, extracellular matrix remodeling and fibrosis, electrical remodeling, and arrhythmia as markers of heart performance. His background includes a PhD from Case Western Reserve University and postdoctoral training at The Ohio State University. His research addresses the rising global burden of heart failure by exploring novel therapeutic approaches to mitigate disease progression.

Research topics

• Internal medicine
• Medicine
• Chemistry
• Endocrinology
• Cancer research
• Biology
• Bioinformatics
• Neuroscience

Selected publications

• Selectivity Filter Mutation in NaV1.5 Promotes Ventricular Tachycardia

  JACC. Clinical electrophysiology · 2026-02-01

  articleOpen access
  PublisherOA PDFDOI

• The β _IV -Spectrin/STAT3 Complex Regulates the Orientation of Cardiac Hypertrophic Growth

  Circulation Research · 2025-10-15 · 1 citations

  articleOpen access1st authorCorresponding

  BACKGROUND: Cardiac hypertrophy, defined as a stress-induced increase in heart mass/size, is a major risk factor for adverse cardiovascular events, including heart failure and arrhythmia. Within this general definition, the orientation of cell and organ growth varies considerably depending on stress type and duration, with important implications for cardiac function, yet little is known regarding the mechanisms that regulate hypertrophic orientation. Here, we evaluated the role of the cytoskeletal protein β IV -spectrin and associated prohypertrophic STAT3 (signal transducer and activator of transcription 3) to direct the orientation of hypertrophic growth. METHODS: Transgenic mouse models with altered STAT3 signaling through modified interaction with its scaffolding partner β IV -spectrin, or phospho-regulation of STAT3 directly, were evaluated at baseline, and after transaortic constriction, or aortocaval fistula. Unbiased screening of gene expression from these structurally divergent states was evaluated for pathways responsible for directing myocyte length/width. These pathways were tested in vitro using primary mouse myocytes and in vivo to tune growth patterns for therapeutic intervention. RESULTS: Loss of β IV -spectrin or direct STAT3 activation promoted a preferential increase in myocyte length over width, resulting in dilation of the left ventricular chamber (eccentric hypertrophy) and decreased systolic function. Conversely, preservation of β IV -spectrin favored an increase in myocyte width without left ventricular dilation (concentric hypertrophy) and preserved systolic function in response to transaortic constriction or aortocaval fistula. Differential expression of genes associated with microtubules, including the trafficking kinesin motor, KIF20A (kinesin family member 20A), were identified in concentric versus eccentric hypertrophic states. In vitro assays revealed a relationship between β IV -spectrin/STAT3 signaling, KIF20A expression, microtubule density, and spatial distribution of mRNA for the sarcomeric gene actc1 . Finally, intervention with pharmacological STAT3 inhibition after chronic 6-week transaortic constriction successfully recovered concentric growth with improved systolic function. CONCLUSIONS: These data identify a novel and pivotal role for β IV -spectrin/STAT3 to modify microtubule properties and sarcomeric transcript distribution to direct myocyte geometry in response to chronic stress. These studies further illustrate the unique separation of hypertrophic growth and orientation as distinct pathways in cardiac remodeling.

  PublisherOA PDFDOI

• Abstract 4369350: Understanding the spatial and temporal regulation of the β _IV -spectrin/STAT3 complex in ischemic cardiac remodeling with spatial transcriptomics

  Circulation · 2025-11-03

  article

  Adverse fibrotic remodeling contributes to high morbidity and mortality in patients following myocardial infarction (MI). Healing after MI requires necrotic tissue to be cleared and replaced with fibrosis, which is driven by the coordinated effort of several distinct cardiac cell populations, including myocytes, immune cells, and cardiac fibroblasts (CFs). While a myriad of stimuli driving fibrotic remodeling post-MI have been identified, the contribution of specific cell populations to the signaling cascade and how these communication networks are tuned in response to chronic stress remains unclear. The cytoskeletal protein, β IV -spectrin, coordinates a signaling complex with the transcription factor, STAT3 to modulate CF activation and profibrotic signaling. Specifically, stress-induced loss of β IV -spectrin promotes subcellular redistribution and activation of STAT3 in CFs that increases secretion of profibrotic and proinflammatory factors. Mice expressing degradation-resistant β IV -spectrin ( qv 3J ) show increased mortality and incidence of cardiac rupture within the first week after permanent occlusion of the left anterior descending (LAD) artery. Histology at 7 days post-MI shows improper scar formation with incomplete clearance compared to WT. Therefore, we hypothesized that stress-induced loss of β IV -spectrin in CFs coordinates spatial and temporal regulation of multiple cardiac cell populations to ensure proper healing. In this study, we subjected WT and qv 3J mice to MI and assessed cardiac function and survival through 28 days and performed spatial transcriptomics at 7 days. Cell-type deconvolution from spatial transcriptomics analysis revealed dramatic differences in CF populations, with a decrease in the Cthrc1 CF population in qv 3J hearts compared to WT. A STAT3-dependent fibroblast trajectory was identified that originates from vascular smooth muscle cells and progresses to Chtrc1 CF population in WT hearts, while qv 3J fibroblast trajectory diverged into a more senescent-like state. The border zone in qv 3J hearts showed a congregation of immune cells and fibroblasts that could not infiltrate the infarct zone, leading to high concentrations of MMPs at the location where rupture occurs in these mice. Aberrant CXCL12 signaling was observed in qv 3J mice, explaining the lack of infarct zone infiltration. Our work identifies a novel role for spectrin-based STAT3 regulation in facilitating spatial and temporal remodeling in response to ischemic stress.

  PublisherDOI

• The two-pore K⁺ channel TREK-1 regulates pressure overload-induced cardiac remodeling

  American Journal of Physiology-Heart and Circulatory Physiology · 2025-05-19 · 3 citations

  articleOpen access

  A major finding of this study is the involvement of the background K + channel TREK-1 in modulating STAT3 activation, profibrotic gene expression, and fibrosis with implications for the cardiac remodeling response to chronic pressure overload.

  PublisherDOI

• Phosphorylation of cardiac sodium channel at Ser571 anticipates manifestations of the aging myopathy

  American Journal of Physiology-Heart and Circulatory Physiology · 2024-04-19 · 7 citations

  articleOpen access

  We have investigated the impact of the late Na current ( I Na,L ) on cardiac and myocyte function with aging by using genetically engineered animals with enhanced or stabilized I Na,L , due to phosphomimetic or phosphoablated mutations of Nav1.5. Our findings support the notion that phosphorylation of Nav1.5 at Ser571 prolongs myocardial repolarization and impairs diastolic function, contributing to the manifestations of the aging myopathy.

  PublisherOA PDFDOI

• Editorial: Functional modifications of ion channels in arrhythmogenesis

  Frontiers in Physiology · 2024-10-18 · 1 citations

  editorialOpen access1st authorCorresponding

  Arrhythmias are a major public health burden and a major cause of morbidity and mortality (Srinivasan and Schilling, 2018). Pharmacologic anti-arrhythmic agents targeting ion channel activity have often triggered pro-arrhythmic outcomes (Saljic et al., 2023). To address this paradox, we sought to provide a comprehensive overview of the functional modifications targeting cardiac ion channels. We were interested in the molecular interventions and/or therapies aimed at inducing/inhibiting these modifications for the treatment of arrhythmia. Our scope was to highlight some of these modifications, evaluate their functional impact, the regulation of upstream pathways and their interaction with physiologic and pathologic signaling pathways. These insights may facilitate the identification of novel physiological targets and the development of novel therapeutics. Our topic includes connexin-43 (Cx-43) and its role in maintaining the electrical rhythm as the only ion channel that has been reported to be subject to internal translation (Kotini et al., 2018). We include the impact of β-adrenergic receptor (β-AR) desensitization in heart failure (HF), and how this downregulation can serve as an adaptive process rather than a detrimental process. Further, the effects of Remdesivir (RDV) on sinoatrial nodal cells were studied, providing foundational mechanistic insights into its future clinical use. Finally, modeling of arrhythmia is a barrier towards new discoveries and traditional animal and cell culture models do not truly reflect human cardiac electro-pathophysiology (van der Velden et al., 2022). Therefore, our topic discusses how patient-specific induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs) can provide a better personalized platform for arrhythmia monitoring and drug screening.In our topic, Lei et al. reviewed the normal cardiac rhythm propagation and how the breakdown of this process leads to cardiac arrhythmias. They focused on the electrophysiological basis of arrhythmogenesis, highlighting how normal propagation of electrical activation can be disrupted by pro-arrhythmic triggering events. They also described the role of spatial and temporal instability of propagated AP waves in creating an arrhythmic substrate. They reviewed ion channels, the roles of different ion channels in cardiac action potentials, interactions between ion channels, mechanisms of ion channel modifications and ion channel modulation. Finally, they discussed the feedforward and feedback between excitation-contraction coupling and surface membrane processes, including upstream modulatory targets and cardiac remodeling. Further analysis and insight into these physiologic processes enhances understanding of arrhythmic events and identification of novel investigational and immunotherapeutic approaches.Whisenant et al., reviewed the expanding role of Cx-43, focusing on its unique protein modification of internal translation, the only currently identified ion channel to undergo such regulation. The resulting protein, labeled GJA1-20k for its truncated length, was initially identified to promote the trafficking of full-length Cx-43 to the intercalated discs and enhance the canonical role of connexins in supporting cardiac electrical coupling. However, in this review, they emphasized additional roles beyond regulation of electrical coupling by GJA1-20k, which includes promoting cardioprotective effects of ischemic preconditioning in response to ischemia/reperfusion injury. They highlighted studies which attribute the therapeutic action of GJA1-20k and Cx-43 to the regulation of mitochondrial trafficking and fusion/fission balance. Physiologically, they described GJA1-20k expression to be regulated in response to ischemic stress and discussed the detrimental impact of GJA1-20k ablation on both cardiac rhythm and metabolism. They concluded by emphasizing existing and future pursuits to harness GJA1-20k expression for therapeutic opportunities in both cardiac and non-cardiac applications.Mahmood et al. discussed the controversy of β-AR desensitization/downregulation in HF and whether this regulation is a self-preserving or detrimental process. In response to HF, the sympathetic nervous system is activated, and this activation is mediated mainly by the β1-AR. Receptor activation enhances cardiac contractility, relaxation and cardiac output. While short-term sympathetic activation is beneficial, long term sympathetic activation leads to β-AR desensitization and downregulation on the cell membrane. β-AR desensitization has traditionally been considered detrimental in HF progression. Abnormal Ca 2+ handling of cardiac ryanodine receptor (RyR2) and diastolic Ca 2+ leak also occur in HF. The authors discussed how further activation of the β-AR signaling in HF in the presence of RyR2 dysfunction would further aggravate abnormal Ca 2+ handling, cardiac dysfunction, arrhythmogenesis and sudden cardiac death. Therefore, they concluded that β-AR desensitization can be a self-preserving process to protect the failing heart from developing lethal arrhythmic events under sustained sympathetic stimulation in HF.In consideration of therapeutics promoting proarrhythmic behavior, Li et al. described the electrophysiologic effects of remdesivir (RDV), an antiviral drug widely used in COVID-19 treatment. Their study addresses concerns about the potential of RDV to induce clinical symptoms resembling sick sinus syndrome including bradycardia, sinoatrial conduction block, and sinus arrest. To investigate the underlying mechanisms, they employed an in vivo guinea pig model which recapitulated clinical findings of sinus node dysfunction and identified suppression of the pacemaker current, If. Furthermore, the study uncovered the impact of RDV on QT prolongation, which was attributed to inhibition of the hERG channel current (IKr). These findings emphasize the need for more focused monitoring of patients receiving RDV, stratification of RDV use based on patient risk factors, and development of supplemental strategies to counteract the electrophysiologic side effects of RDV.Lastly, Joshi et al. provides an update on opportunities and challenges in the application of iPSC-CMs for modeling cardiac arrhythmias. They highlighted the power of combined technologies such as 3D culture models, CRISPR gene editing, and optical platforms for enhancing iPSC-CM arrhythmia research. They also reviewed approaches for improving cell maturation, which remains one of the more pronounced limitations of this platform. Collectively, their review underlines the continued significance of the iPSC-CM technology as a resource for identifying and developing translational arrhythmia interventions, which may include posttranslational regulatory pathways.

  PublisherOA PDFDOI

• Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults

  JACC. Clinical electrophysiology · 2024-02-28 · 26 citations

  articleOpen access

  Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaVs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of NaV 1.1 functional expression in DS, pathogenic late sodium current (INa,L) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear. In this study the authors sought to provide evidence implicating remodeling of Na+ - and Ca2+ -handling machinery, including NaV 1.6 and Na+/Ca2+exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias. The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca2+ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. DS promotes INa,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased NaV activity in these regions, super-resolution microscopy revealed increased NaV 1.6 density near Ca2+release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting INa,L in these regions promoted aberrant Ca2+ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of NaV 1.6 protects adult DS mice from increased T-tubular late NaV activity and the resulting arrhythmias, as well as sudden death. These data demonstrate that NaV 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca2+ -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.

  PublisherDOI

• Abstract Tu102: The Role of the βIV-spectrin/STAT3 Complex in Regulating Ischemic Cardiac Remodeling

  Circulation Research · 2024-08-02

  article

  Adverse fibrotic remodeling contributes to high morbidity and mortality in patients following myocardial infarction (MI). The healing process after MI requires necrotic tissue to be cleared and replaced with fibrosis, which is driven by the coordinated effort of several distinct cardiac cell populations, including macrophages and cardiac fibroblasts (CFs). While previous studies have focused on identifying the stimuli that drives fibrotic remodeling in the infarcted myocardium, the contribution of specific cell populations to the signaling cascade and the manner of how these communication networks are tuned in response to chronic stress remains unclear. Prior work has identified a role for the cytoskeletal protein, β IV -spectrin, in coordinating the activity of the transcription factor, STAT3, with implications for CF activation and profibrotic signaling. Specifically, it was found that mice expressing truncated β IV -spectrin ( qv3J ) are resistant to cardiac fibrosis in the setting of chronic pressure overload, with maintained β IV -spectrin expression and STAT3 localization/activity in CFs. Further, β IV -spectrin deficiency causes increased secretion of profibrotic and proinflammatory factors, including matrix metallopeptidases (MMPs). Therefore, we hypothesized that stress-induced loss of β IV -spectrin and subsequent dysregulation of STAT3 signaling in CFs proximal to the infarct promotes fibroblast activation, an important first step in repairing the infarct region. In this study, we subjected WT and qv3J mice to permanent ligation of the left anterior descending artery and assessed cardiac function and survival through 28 days. A subset of mice were sacrificed at 7 days for histology, qPCR, and flow cytometry. Compared to WT, qv3J mice showed a significant decrease in 28-day survival with increased mortality in the first week post-MI. Autopsy identified increased incidence of cardiac rupture in qv3J animals. Immunohistochemistry revealed impaired scar formation at 7 days post-MI in qv3J compared to WT. Quantitative PCR showed altered expression of matrix metallopeptidases (MMPs 3, 8, 9, and 14) in the qv3J hearts at day 7. MMP activity was assessed in whole heart lysates using gelatin-zymography. Collagen uptake was assessed in CFs and bone marrow-derived macrophages isolated from WT and qv3J mice. Our work identifies a novel role of the spectrin-based pathway in facilitating fibrotic remodeling in response to ischemic stress.

  PublisherDOI

• Abstract 4139672: 12,13-diHOME Attenuates Pro-Arrhythmic Effect of High-Fat Diet

  Circulation · 2024-11-12

  article

  Introduction: Obesity is a risk factor for atrial fibrillation (AF) and its incidence that has tripled over the past 30 years. Obesity is associated with dramatic changes in atrial structure and electrophysiology through unclear mechanisms. The linoleic acid metabolite 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a signaling lipid released by brown adipose tissue that acts in an endocrine manner on myriad tissues including the heart. 12,13-diHOME enhances cardiac myocyte Ca 2+ cycling and overall function, though the precise mechanisms are undetermined. This study tested the hypothesis that 12,13-diHOME inhibits the pro-arrhythmic molecule Ca 2+ /calmodulin-dependent kinase II (CaMKII). We propose that obesity-induced loss of 12,13-diHOME promotes CaMKII dysfunction, in vitro ectopy and atrial arrhythmia (AA). Methods: Adult male and female mice were fed either high fat diet (HFD, 60% kcal from fat) or normal chow (NFD) (21% kcal from fat) for 8-16 weeks. Atrial myocytes were isolated for action potential (AP) measurements using whole-cell patch clamp ±12,13-diHOME (5 μM). To test the effect of 12,13-diHOME on AA inducibility, a second cohort of mice was fed HFD and subjected to weekly tissue nanotransfection for non-viral delivery of either Ephx1/2 (HFD-TNT), enzymes responsible for production of 12,13-diHOME, or empty plasmid (HFD-con). Following treatment, mice underwent intracardiac pacing studies to determine AA inducibility. The ability of 12,13-diHOME to directly interact with and inhibit CaMKII was tested using purified components with in vitro radioassay and microscale thermophoresis. Results: HFD induced atrial myocyte AP duration prolongation and a higher incidence of spontaneous depolarization compared to NFD, both of which were reversed by 12,13-diHOME (figure). HFD-TNT exhibited decreased phospho-CaMKII compared to HFD-con mice. In parallel, HFD-TNT trended toward reduced inducibility of AA (0/7 mice inducible, 0%) compared to TNT-CON mice (5/7, 58%) (p=0.07). Radioassay revealed that 12,13-diHOME inhibits CaMKII; thermophoresis demonstrated direct binding with K 1/2 = 19 mM. Conclusion: HFD induces dysregulation in 12,13-diHOME and CaMKII signaling together with defects in atrial myocyte excitability and AA in mice. Non-viral overexpression of 12,13-diHOME shows promise in normalizing CaMKII activity and reducing AA burden. 12,13-diHOME represents a novel avenue for direct regulation of CaMKII signaling and downstream pathology in the heart.

  PublisherDOI

• Abstract Tu085: The βIV-spectrin/STAT3 Complex regulates the orientation of cardiac hypertrophic growth

  Circulation Research · 2024-08-02

  article1st authorCorresponding

  Background: Cardiac hypertrophy is a major risk factor for adverse cardiovascular events including heart failure and arrhythmia. However, the precise orientation of cell and organ growth varies considerably depending on stress type and duration with important implications for cardiac function. Despite this, little is known regarding the mechanisms that regulate hypertrophic orientation. Here we evaluate the role of the cytoskeletal protein β IV -spectrin and signal transducer and activator of transcription (STAT3) in directing the orientation of pressure overload-induced hypertrophy. Methods: Transgenic mouse models with altered STAT3 signaling through modified interaction with its scaffolding partner β IV -spectrin, or phospho-regulation of STAT3 directly, were evaluated at baseline and transaortic constriction (TAC) for its role in promoting concentric versus eccentric morphologies and resulting impact on systolic function. Unbiased screening of gene expression from these structurally divergent states were evaluated for pathways responsible for directing myocyte length/width. These pathways were tested in vitro using primary mouse myocytes and in vivo to tune growth patterns for therapeutic intervention. Results: Loss of β IV -spectrin or direct STAT3 activation promoted a preferential increase in myocyte length over width, resulting in dilation of the left ventricular (LV) chamber (eccentric hypertrophy) and decreased systolic function. Conversely, preservation of β IV -spectrin favored an increase in myocyte width without LV dilation (concentric hypertrophy) and preserved systolic function in response to TAC. Differential expression of genes associated with microtubule dynamics were identified in concentric vs. eccentric hypertrophic states. In vitro assays revealed a relationship between β IV -spectrin/STAT3 signaling and microtubule stability which impacted spatial distribution of mRNA for the sarcomeric gene actc1 . Finally, intervention with pharmacologic STAT3 inhibition following chronic 6-week TAC successfully recovered concentric growth with improved systolic function. Conclusions: These data identify a novel and pivotal role for β IV -spectrin/STAT3 to modify microtubule dynamics and sarcomeric transcript distribution to direct myocyte geometry and therapeutically serve in the prevention or recovery from HF. These mechanisms further illustrate the unique separation of hypertrophic drivers from growth orientation as distinct pathways in cardiac remodeling.

  PublisherDOI

Frequent coauthors

• Thomas J. Hund

  The Ohio State University

  62 shared

• Isabelle Deschênes

  The Ohio State University

  38 shared

• Nehal Patel

  36 shared

• Peter J. Mohler

  The Ohio State University

  22 shared

• Xiaoping Wan

  Shanghai First Maternity and Infant Hospital

  20 shared

• Eckhard Ficker

  17 shared

• Amara Greer-Short

  16 shared

• Rebecca Shaheen

  The Ohio State University

  16 shared