Sudden Cardiac Death (SCD) occurs in more than half a million people every year and arrhythmias, resulting in hemodynamic insufficiency followed by death, account for the majority of SCD cases. Arrhythmias secondary to scar formation are well understood, but mechanisms by which acute ischemia/reperfusion (I/R) injury promotes ventricular tachycardia and fibrillation (VT/VF) are more complex. I/R-related arrhythmias depend on dynamic properties of the tissue, including Ca2+-mediated triggers, functional conduction block, decreased gap junctional conductance, heterogeneous shortening of the action potential (AP) and dispersion of refractoriness. These complex electrophysiological (EP) changes are caused by limitations in ATP supply, changes in reactive oxygen species (ROS), accumulation of detrimental intracellular (Ca2+, Na+, acid) and extracellular (K+, lactate) constituents, all of which can be traced to a common origin, namely impaired mitochondrial function. Our group was the first to recognize the importance of heterogeneous mitochondrial instability, including sustained depolarization or oscillation of the mitochondrial inner membrane potential (??m), across clusters of myocytes or regions within the heart, in setting the stage for VT/VF. However, the mechanisms behind mitochondrial instability during reperfusion are unclear and how they contribute to arrhythmias is not well understood. While inhibition of the mitochondrial permeability transition pore (mPTP) decreases infarct size, cyclosporine A-mediated inhibition of mPTP has little or no effect on arrhythmia incidence after ischemia, suggesting that the early dysfunction and late injury mechanisms may be distinct. In contrast, we found that mitochondrial benzodiazepine receptor (mBzR) ligands are very effective at restoring the action potential and suppressing arrhythmias induced by I/R, in parallel with their ability to prevent or reverse mitochondrial depolarization. Indeed, our exciting preliminary data suggests that mBzR, rather than mPTP, is more important in terms of ??m and electrical stability during the early reperfusion phase. Here, we will use innovative approaches to image the dynamics of ??m, Vm, matrix Ca and ROS during I/R at the cellular and whole 2+ heart scales, combined with powerful genetic models to selectively knockout the key proteins involved in modulating mPTP (cyclophilin D; PPIF), mitochondrial Ca2+ (the mitochondrial Ca2+uniporter; MCU), and the mBzR (translocator protein; TSPO), to define the causal mechanisms underlying mitochondrial instability and arrhythmias on reperfusion. This project will move the field from conclusions based on pharmacological inference to molecular understanding, allowing us to focus our efforts on the correct mitochondrial targets to pursue to prevent I/R-induced arrhythmias with the goal of decreasing the burden of SCD.

Public Health Relevance

Every year, roughly half-a-million people experience a sudden cardiac arrest. This is often caused by an abnormal heart rhythm known as ventricular fibrillation, triggered by a sudden block (ischemia) or restoration (reperfusion) of coronary blood flow to the heart. In this state, the heart cannot effectively pump blood to the rest of the body. This project explores the mechanisms behind the loss of function of the energy-producing organelles of the cell, the mitochondria, during ischemia, and their unstable recovery during reperfusion, and how this behavior sets the stage for fibrillation. Our goal is to identify therapeutic targets for decreasing mortality from a heart attack.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL137259-01
Application #
9326466
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2017-04-01
Project End
2021-02-28
Budget Start
2017-04-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$511,486
Indirect Cost
$175,233
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Dey, Swati; DeMazumder, Deeptankar; Sidor, Agnieszka et al. (2018) Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure. Circ Res 123:356-371
Wang, Sheng-Bing; Venkatraman, Vidya; Crowgey, Erin L et al. (2018) Protein S-Nitrosylation Controls Glycogen Synthase Kinase 3? Function Independent of Its Phosphorylation State. Circ Res 122:1517-1531
Strauss, Benjamin; Akar, Fadi G (2018) Kir2.1 & Nav1.5 in Sickness and in Health: Who Needs a Chaperone When They Have an Alpha Partner? Circ Res 122:1482-1484
Ilkan, Zeki; Akar, Fadi G (2018) The Mitochondrial Translocator Protein and the Emerging Link Between Oxidative Stress and Arrhythmias in the Diabetic Heart. Front Physiol 9:1518
Kurz, Felix T; Aon, Miguel A; O'Rourke, Brian et al. (2018) Assessing Spatiotemporal and Functional Organization of Mitochondrial Networks. Methods Mol Biol 1782:383-402
Kurz, Felix T; Aon, Miguel A; O'Rourke, Brian et al. (2017) Functional Implications of Cardiac Mitochondria Clustering. Adv Exp Med Biol 982:1-24
Haileselassie, Bereketeab; Su, Erik; Pozios, Iraklis et al. (2017) Myocardial oxidative stress correlates with left ventricular dysfunction on strain echocardiography in a rodent model of sepsis. Intensive Care Med Exp 5:21