Heart failure (HF) is a major cause of morbidity and mortality, contributing signi?cantly to global health expenditure. Sudden death due to arrhythmia is responsible for over 50% of deaths among HF patients; however, the mechanisms linking HF-induced molecular remodeling to increased sudden death risk remain poorly understood. This has resulted in ineffective pharmacologic therapy for preventing sudden arrhythmic death and in inadequate approaches to arrhythmia risk strati?cation of HF patients. The overall objective of the proposed research is to explore a novel set of mechanisms by which HF remodeling, from the sub-cellular microdomain to the whole heart, leads to increased risk of lethal arrhythmias in human HF. Speci?cally, we propose to investigate how the impact of the degradation of myocyte microdomains on L-type Ca channel and cellular function is ampli?ed regionally by the heterogeneities in electrophysiological remodeling and adrenergic innervation as well as by the disease-induced remodeling in ventricular structure to produce i) arrhythmia triggers and ii) their degeneration into ventricular ?brillation (VF). The project presents an integrated experimental/computational approach to arrhythmogenesis in human HF. Super-resolution scanning patch clamp will provide novel insight into how disruption of sub-cellular compartments affects L-type Ca channel functioning in the HF cell. This data will be used as input into an integrative human HF myocyte model, which following validation, will be implemented in organ-level HF models. Protein and microstructure distribution data informing the organ-level models will be gathered in experiments with explanted HF human hearts. Model components will be combined with MRI scans of HF human heart geometry/structure to develop multiscale HF ventricular models which will then be used to determine the mechanisms responsible for the formation of 1) hot spots, from which triggered activity emanates, and 2) arrthythmogenic substrates at heart rates near rest, causing the degradation of triggered activity into VF. Simulation results regarding the arrhythmogenic substrate and VF likelihood at these heart rates will be validated in a clinical study of HF patients. Completion of the studies proposed here will result in a greater understanding of the mechanisms leading to arrhythmias and sudden death in human HF. Such mechanistic understanding is expected to reduce the impact of HF on its victims and on the health-care system 1) by suggesting targeted and effective new molecular therapies, and 2) by leading to new and improved approaches to arrhythmia risk strati?cation of HF patients.

Public Health Relevance

Heart failure is a major cause of morbidity and mortality, contributing signi?cantly to global health expenditure. Currently, there is no quantitative understanding of how the many human heart-failure remodeling changes at the molecular level interact to give rise to emergent behaviors at the organ scale, and particularly, how they result i increased incidence of sudden arrhythmia death. The overall objective of the proposed research is to uncover the mechanisms giving rise to arrhythmia triggers and the arrhythmogenic substrate, and thus leading to increased arrhythmia risk in heart failure patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Biostatistics & Other Math Sci
Biomed Engr/Col Engr/Engr Sta
United States
Zip Code
Surdo, Nicoletta C; Berrera, Marco; Koschinski, Andreas et al. (2017) FRET biosensor uncovers cAMP nano-domains at ?-adrenergic targets that dictate precise tuning of cardiac contractility. Nat Commun 8:15031
Matkovich, Scot J; Al Khiami, Belal; Efimov, Igor R et al. (2017) Widespread Down-Regulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients With Sepsis. Crit Care Med 45:407-414
Hsueh, Brian; Burns, Vanessa M; Pauerstein, Philip et al. (2017) Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease. Sci Rep 7:5899
Pashakhanloo, Farhad; Herzka, Daniel A; Mori, Susumu et al. (2017) Submillimeter diffusion tensor imaging and late gadolinium enhancement cardiovascular magnetic resonance of chronic myocardial infarction. J Cardiovasc Magn Reson 19:9
Trayanova, Natalia A; Pashakhanloo, Farhad; Wu, Katherine C et al. (2017) Imaging-Based Simulations for Predicting Sudden Death and Guiding Ventricular Tachycardia Ablation. Circ Arrhythm Electrophysiol 10:
Zile, Melanie A; Trayanova, Natalia A (2017) Myofilament protein dynamics modulate EAD formation in human hypertrophic cardiomyopathy. Prog Biophys Mol Biol 130:418-428
Kang, C; Badiceanu, A; Brennan, J A et al. (2017) ?-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle. Sci Rep 7:15922
Cerrone, Marina; Montnach, Jerome; Lin, Xianming et al. (2017) Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat Commun 8:106
Arevalo, Hermenegild J; Boyle, Patrick M; Trayanova, Natalia A (2016) Computational rabbit models to investigate the initiation, perpetuation, and termination of ventricular arrhythmia. Prog Biophys Mol Biol 121:185-94
Sanchez-Alonso, Jose L; Bhargava, Anamika; O'Hara, Thomas et al. (2016) Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure. Circ Res 119:944-55

Showing the most recent 10 out of 23 publications