About

TingTing Hong is a researcher with a focus on cardiac biology, particularly investigating the molecular and cellular mechanisms underlying heart failure and cardiac remodeling. Her work extensively explores the role of cardiac bridging integrator 1 (cBIN1) and connexin 43 (Cx43) isoforms in cardiac function, including their involvement in T-tubule microanatomy, calcium handling, and arrhythmogenesis. Hong's research includes gene therapy approaches targeting cBIN1 to rescue chronic heart failure in animal models, highlighting the therapeutic potential of modulating cardiac structural proteins. She has contributed to understanding the regulation of ion channels and cytoskeleton interactions in cardiomyocytes, as well as the protective roles of stress response proteins like GJA1-20k in mitochondrial function and cardioprotection against ischemia/reperfusion injury. Her studies also address the diagnostic and prognostic value of cardiac biomarkers in heart failure with preserved ejection fraction and other cardiovascular diseases. Overall, Hong's research advances knowledge of cardiac muscle health, molecular pathways in heart disease, and innovative gene therapy strategies.

Research topics

• Biology
• Cell biology
• Medicine
• Internal medicine
• Biochemistry
• Endocrinology
• Cardiology

Selected publications

• Integrative Clinical–Molecular Modeling Identifies <i>LRRN4CL</i> as a Determinant of Structural and Functional Myocardial Improvement

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-26

  articleOpen access

  ABSTRACT Background Mechanical ventricular unloading and systemic circulatory support with left ventricular assist devices (LVADs) enable myocardial recovery in a subset of advanced heart failure (HF) patients, but predictors and mechanisms of recovery are not well understood. Integrating clinical and molecular data may improve identification of patients most likely to recover and uncover biologically relevant targets in HF. Methods We collected and analyzed left ventricular apical myocardial tissue and clinical data from 208 patients undergoing LVAD implantation across five centers. Pre-implant transcriptomic profiles (22,373 mRNA transcripts) were integrated with 59 clinical variables using supervised machine learning with repeated cross-validation to identify and prioritize features associated with myocardial recovery, defined as a binary outcome based on improvement in left ventricular ejection fraction (LVEF ≥40%) and left ventricular end-diastolic diameter (LVEDD ≤5.9 cm). We also modeled functional (LVEF) and structural (LVEDD) improvement as a continuous outcome without any predefined LVEF and LVEDD pathological thresholds. Feature prioritization was followed by validation in human myocardial tissue and mechanistic interrogation in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Results Integrative models achieved modest discrimination for myocardial recovery as a binary categorical outcome (maximum mean cross-validated area under the curve 0.73±0.15), identifying clinical features such as HF duration, LVEDD, HF pharmacologic therapy, and device configuration. Leucine-rich repeat neuronal 4C-like ( LRRN4CL ), measured in human myocardium, consistently emerged as a top transcriptomic predictor across both binary and continuous metric models (functional and structural). Higher pre-LVAD LRRN4CL expression was associated with reduced likelihood of myocardial recovery and localized primarily to cardiomyocytes. In iPSC-CMs, LRRN4CL overexpression localized to the sarcoplasmic reticulum, induced transcriptional remodeling characterized by suppression of contractile pathways and activation of stress programs, impaired calcium handling, impaired contraction–relaxation kinetics, and diminished mitochondrial respiratory reserve capacity. Conclusions Integration of clinical and myocardial transcriptomic data identifies LRRN4CL as a novel marker associated with impaired myocardial recovery following LVAD-mediated ventricular unloading and systemic circulatory support. These findings move beyond predictive modeling, linking integrative computational discovery to cardiomyocyte dysfunction and providing a translational framework for biologically informed risk stratification and therapeutic targeting for myocardial recovery. CLINICAL PERSPECTIVE What Is New? Integrative clinical and myocardial transcriptomic modeling identifies LRRN4CL as a novel molecular determinant of structural and functional changes after LVAD-mediated ventricular unloading and enhanced systemic circulatory support. Elevated LRRN4CL expression is associated with adverse remodeling signatures, impaired calcium handling, and stress responses in human iPSC-derived cardiomyocytes. Experimental overexpression of LRRN4CL directly disrupts calcium cycling, contractile performance, and mitochondrial respiration linking molecular signature to functional phenotype. What Are the Clinical Implications? Identification of LRRN4CL as a marker associated with impaired myocardial recovery supports future efforts toward biologically informed risk stratification for patients undergoing LVAD therapy. LRRN4CL as a marker of cardiac improvement potential may extend beyond advanced HF to earlier stage disease patients and inform prognosis, risk stratification, and response to medical therapies. These findings highlight LRRN4CL -associated pathways as potential therapeutic targets and demonstrate how integrative clinical–transcriptomic approaches can move beyond clinical prediction toward identification of new biologically precise therapeutic targets in HF following a bedside to bench and back approach.

  PublisherOA PDFDOI

• PO-05-126 CARDIAC BRIDGING INTEGRATOR 1 GENE THERAPY RECOVERS T-TUBULE AREA AND MORPHOLOGY IN A CANINE MODEL OF CHRONIC ISCHEMIC HEART FAILURE

  Heart Rhythm · 2025-04-01

  articleOpen access
  PublisherOA PDFDOI

• AAV9-cBIN1 gene therapy rescues chronic heart failure due to ischemic cardiomyopathy in a canine model

  Communications Medicine · 2025-03-27 · 15 citations

  articleOpen access

  Ischemic cardiomyopathy and resultant heart failure (HF) is a significant cause of morbidity and mortality worldwide. Downregulation of cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein responsible for organizing t-tubules and organizing the calcium handing apparatus, occurs in progressive HF. Therefore, gene therapy upregulating cBIN1 production may rescue failing muscle and clinical HF. Adult mongrel dogs underwent ligation of the left anterior descending artery and developed progressive dilated cardiomyopathy and chronic HF. When left ventricular ejection fraction (LVEF) dropped below 40%, the animals received a one-time series of endocardial injections of either of low dose gene therapy composed of either adeno-associated virus serotype 9 packaged cBIN1 (AAV9-cBIN1, n = 6) or AAV9-GFP (green fluorescent protein, n = 4). Animals were followed up to 7 weeks after therapy delivery with laboratory, echocardiography, and endocardial mapping assessment. Post injection of the negative control, animals develop progressive symptomatic HF requiring early termination of all but one animal prior to the end of the study. In contrast, the AAV9-cBIN1-treated group reveals a significant improvement in LV function, with a noticeable improvement in LVEF (29 ± 3% vs. 42 ± 2%, p = 0.0095) and global longitudinal strain (−7.1 ± 0.9% vs. −12.5 ± 1.6%, p = 0.0095). Compared to the control animals, the AAV9-cBIN1-treated group displays improved T-tubule morphology, left ventricular chamber size, plasma biomarkers, and endocardial voltage, and survives the study period. Chronic HF from ischemic cardiomyopathy can be successfully treated with low dose AAV9-cBIN1 gene therapy. This study indicates that myocardial specific therapy can dramatically reverse HF progression. Blocked heart arteries are known to damage heart muscle by impairing the ability of the heart to pump blood, resulting in progressive muscle damage and eventual heart failure. Medical interventions that recover failing heart muscle are needed to prevent hospitalization or death. Here, we developed a gene therapy to replace an important heart muscle protein, cardiac bridging integrator 1 (cBIN1), and tested it in a canine model of heart failure induced by blocked heart arteries. These findings show improved cardiac muscle function and survival rate following cBIN1 gene therapy, indicating the potential of this gene therapy to reduce the syndrome of heart failure. Khan et al. perform AAV9-cBIN1 gene therapy in a canine model of acquired chronic ischemic cardiomyopathy. They show AAV9-cBIN1 therapy mitigates disease progression and can reverse heart failure in this model.

  PublisherOA PDFDOI

• Editorial commentary: From glucose-lowering to cardioprotection: Unpacking the pleiotropic effects of SGLT2 inhibitors in heart failure

  Trends in Cardiovascular Medicine · 2025-12-06

  reviewSenior author
  PublisherDOI

• Abstract 4372164: cBIN1 Gene Therapy Delivered Intramyocardially in Left Ventricle Attenuates Right Ventricular Structural Remodeling in a Canine Model of Dilated Ischemic Cardiomyopathy

  Circulation · 2025-11-03

  article

  Introduction: Myocardial infarction is a common cause of heart failure (HF), leading to scar tissue formation and increased stress on the cardiac muscle, which affects atrial and ventricular remodeling. We recently showed that gene therapy targeting cardiac bridging integrator 1 (cBIN1) improves left ventricular (LV) function by restoring T-tubule integrity in a canine model of dilated ischemic cardiomyopathy (DICM). However, it is still unclear how this improvement impacts the right ventricular (RV) structural remodeling. Hypothesis: cBIN1 gene therapy delivered intramyocardially in the LV improves RV structural remodeling in a canine model of DICM. Methods: A preclinical canine model of DICM was created by ligating the left anterior descending artery, resulting in a left ventricular ejection fraction &lt; 40% and NT-proBNP level &gt; 900 pmol/L. Ten weeks (±2) post-procedure, dogs were divided into three groups: Group 1 (n=3) received no therapy; Group 2 (n=4) received intramyocardial injections of AAV9 carrying Green Fluorescent Protein (negative control); and Group 3 (n=5) received AAV9-cBIN1. Eight weeks (±2) later, RV mechanical dyssynchrony (septal-free wall peak strain time difference) and RV free wall strain were assessed through echocardiography in awake dogs using a 4-chamber apical view. RV free wall muscle samples were analyzed for T-tubule cross-sectional area using electron microscopy and fibrosis via Masson Trichrome staining. Results: cBIN1-treated animals exhibited significantly improved RV septal-free wall peak strain time difference often refers as septal-to-lateral wall delay - SLWD ( Figure A ) and RV free wall strain - FWS ( Figure B ) compared to the other HF groups that received either the control GFP therapy or no treatment. At both the tissue and subcellular levels, there was a significant improvement in RVFW fibrosis ( Figure C ) and T-tubule cross-sectional area ( Figure D ) in the cBIN1 group compared to the GFP-treated and untreated animals. Furthermore, there were no observable differences between the untreated and GFP-treated HF groups. Conclusions: Reducing mechanical stress across the LV segments through intramyocardial delivery of cBIN1 gene therapy significantly decreased fibrosis in the RVFW muscle by restoring the T-tubule membrane architecture, which in turn improved RV strain and reduced electromechanical dyssynchrony. The study provides preclinical data to mitigate negative remodeling of the RV following ischemic events.

  PublisherDOI

• BS-499652-001 RESTORATION OF VENTRICULAR ELECTRICAL SYNCHRONY VIA CBIN1 GENE THERAPY IN A CANINE MODEL OF ISCHEMIC CARDIOMYOPATHY

  Heart Rhythm · 2025-04-01

  article
  PublisherDOI

• The Role of Sphingolipids in Myocardial Recovery Mediated by Mechanical Unloading and Circulatory Support

  JACC Basic to Translational Science · 2025-12-19

  articleOpen access

  Myocardial recovery after left ventricular assist device (LVAD) support is a critical phenomenon that allows advanced heart failure patients to retain their native heart. We quantified targeted sphingolipids in serum and cardiac tissue of patients who exhibited recovery post-LVAD. Our analysis revealed sustained elevated circulating ceramides levels in nonresponders post-LVAD, whereas responders showed reduced sphingosine-1-phosphate (S1P) levels. In contrast, cardiac tissue from nonresponders displayed increased S1P levels. We suggest that diminished ceramide and S1P may contribute to an increased likelihood of recovery after LVAD support. Collectively, our findings implicate the sphingolipid metabolic pathway as a potential therapeutic target to promote myocardial recovery after mechanical support.

  PublisherDOI

• TREK-1: a Janus-faced and subcellular location-based regulator of cardiac remodeling in heart failure

  American Journal of Physiology-Heart and Circulatory Physiology · 2025-06-26

  articleOpen accessSenior authorCorresponding
  PublisherDOI

• Design of the First in Human Gene Therapy Trial of TLT-101 for Chronic Heart Failure (FIGHT-HF)

  JACC Basic to Translational Science · 2025-02-11 · 4 citations

  articleOpen access
  PublisherDOI

• Abstract 4363326: Rescue of Cellular Trafficking Prevents Cardiac Dysfunction in Arrhythmogenic Cardiomyopathy

  Circulation · 2025-11-03

  article

  Background: Arrhythmogenic cardiomyopathy (ACM) arises from mutations in desmosomal genes, such as desmoglein (DSG) and desmoplakin (DSP), which converge into a common pathophysiological phenotype at the cellular level, whose hallmarks include disruption of Connexin43 (Cx43) trafficking and membrane localization and suppression of the Wnt/β-catenin signaling pathway. These cellular changes in turn contribute to cardiomyocyte loss, fibrofatty infiltration, and decreased cellular coupling, leading to heart failure, arrhythmias, and sudden cardiac death. GJA1-20k, an internally translated isoform of Cx43, has previously shown therapeutic potential in a DSG model of ACM by preserving Cx43 trafficking and cell-cell coupling. Objective: To investigate the role of GJA1-20k in protecting against a DSP model of ACM by evaluating its effect on Cx43 trafficking and Wnt/β-catenin signaling. Methods: A DSP mutant mouse model of ACM ( Dsp -/- ) received retroorbital injections of AAV9 vectors expressing either GJA1-20k-GFP or GST-GFP at 1×10 12 vg/kg. Echocardiographic measurements were recorded at 4-week intervals until the endpoint was reached, wherein hearts were excised and underwent further processing for histological and biochemical assays. Mechanistic pathways identified were validated in vitro using cell lines. Results: Dsp -/- mice that received GST developed heart failure associated with pathological fibrosis and cardiac remodeling. However, GJA1-20k treated Dsp -/- mice had preserved heart function and absent fibrotic infiltration. At the cardiomyocyte level, GST-treated Dsp -/- mice had significantly reduced Cx43 localization to the intercalated discs and reduced intercalated disc and nuclear localization of β-catenin compared to control mice. This was accompanied by an increase in β-catenin phosphorylation and degradation. However, upon GJA1-20k administration, Dsp -/- mice had restored Cx43 trafficking, increased β-catenin nuclear translocation and activity, and reduced β-catenin degradation. Conclusion: GJA1-20k offers therapeutic potential against ACM by preventing pathological changes in Cx43 localization and Wnt/β-catenin signaling. Moreover, this work introduces the novel concept of next generation gene therapy, whereby targeting common pathological cellular phenotypes downstream of the causative mutation serves as a viable low dose therapeutic approach to diseases of different genetic origin such as ACM.

  PublisherDOI

Recent grants

• NIH Grant K99HL109075

  NIH · $176k · 2014

• Regulation of Cav1.2 Trafficking by GJA1-20k and cBIN1

  NIH · $2.2M · 2021–2025

• Regulation of Ion Channels at BIN1-induced T-tubule Microdomains

  NIH · $2.2M · 2016–2022

• Advancing cBIN1 Therapy to Large Preclinical Animals

  NIH · $419k · 2021–2023

• BIN1 is a mediator and marker of cardiac reserve in heart failure.

  NIH · $730k · 2012–2016

Frequent coauthors

• Robin M. Shaw

  University of Utah

  116 shared

• Rachel Baum

  39 shared

• Sosse Agvanian

  Cedars-Sinai Smidt Heart Institute

  35 shared

• Shaohua Xiao

  University of California, Los Angeles

  33 shared

• Wassim A. Basheer

  Cedars-Sinai Smidt Heart Institute

  28 shared

• Ying Fu

  Xiangya Hospital Central South University

  27 shared

• Tara C. Hitzeman

  23 shared

• André G. Kléber

  Beth Israel Deaconess Medical Center

  23 shared

Labs

• Cardiovascular Pharmacology & ToxicologyPI

Education

• Ph.D.

  University of Utah

• M.D.

  University of Utah