Heart failure is a disease that is continually increasing in prevalence worldwide. In the United States, nearly 6 million people suffer from heart failure and it is the most common inpatient diagnosis in the elderly. The economic impact for 2009 has been estimated at $37.2 billion. Treatment of this disease with 2-blockers and/or inhibitors of renin-angiotensin signaling has decreased mortality and morbidity over the years, but mortality still approaches 60% within 5 years of diagnosis. Fatal arrhythmias, known as Sudden Cardiac Death (SCD), account for about half of the early deaths in HF, with progressive cardiac decompensation accounting for the remainder. Many factors contribute to the pathology of HF, including changes in the neurohumoral environment, alterations in ion channel and transporter activity, modulation of cell death pathways, and remodeling of the inherent structure of the tissue. Recent evidence indicates that alterations in the reduction- oxidation (redox) potential of the cytoplasm, sarcoplasmic reticulum, and the mitochondria of the heart may be a key factor involved in the progression of cardiac hypertrophy and failure. In heart failure (HF), there is evidence that oxidative stress may contribute to impaired function, and this may arise as a consequence of altered ion homeostasis, energetic deficiencies, and post-translational modification of protein targets. Moreover, a large number of ion channels, transporters, and signaling pathways have been shown to be modulated either directly by reactive oxygen species (ROS), or by changes in the thiol status or redox carrier concentration. Some, or many, of these targets, could contribute to an enhanced susceptibility of the failing heart to arrhythmogenesis and SCD. A comprehensive view of how shifts in metabolism and redox balance influence the electrophysiological substrate requires a systems biology approach to the problem, involving deconstruction of how individual ion channels, transporters and signaling pathways are affected by redox modulators, and how the performance of the integrated system is changed. Specifically, in this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts (pressure-overload model). An iterative, experimental/computational systems biology approach combining both """"""""horizontal"""""""" and """"""""vertical"""""""" integration will be taken. These approaches will be used to build biophysically-detailed cellular and whole-heart models of redox/antioxidant pathways and their downstream effects on ion channels and transporters, with the goal of defining how metabolic and oxidative stress leads to arrhythmias, pump failure, and SCD. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention.
Narrative Heart failure is a disease that is continually increasing in prevalence worldwide. In this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention to treat heart failure.
|Foster, D Brian; Liu, Ting; Kammers, Kai et al. (2016) Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death. J Proteome Res 15:3009-28|
|Dey, Swati; Sidor, Agnieszka; O'Rourke, Brian (2016) Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes. J Biol Chem 291:11185-97|
|Goh, Kah Yong; Qu, Jing; Hong, Huixian et al. (2016) Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes. Cardiovasc Res 109:79-89|
|Bruegmann, Tobias; Boyle, Patrick M; Vogt, Christoph C et al. (2016) Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations. J Clin Invest 126:3894-3904|
|O'Rourke, Brian; Liu, Ting; Foster, D Brian (2016) Seeing the Forest for the Trees. Circ Res 119:1170-1172|
|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|
|Solhjoo, Soroosh; O'Rourke, Brian (2015) Mitochondrial instability during regional ischemia-reperfusion underlies arrhythmias in monolayers of cardiomyocytes. J Mol Cell Cardiol 78:90-9|
|Boyle, Patrick M; Karathanos, Thomas V; Trayanova, Natalia A (2015) ""Beauty is a light in the heart"": the transformative potential of optogenetics for clinical applications in cardiovascular medicine. Trends Cardiovasc Med 25:73-81|
|Li, Qince; Su, Di; O'Rourke, Brian et al. (2015) Mitochondria-derived ROS bursts disturb Ca²? cycling and induce abnormal automaticity in guinea pig cardiomyocytes: a theoretical study. Am J Physiol Heart Circ Physiol 308:H623-36|
|Bhatt, Niraj M; Aon, Miguel A; Tocchetti, Carlo G et al. (2015) Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. Am J Physiol Heart Circ Physiol 308:H291-302|
Showing the most recent 10 out of 47 publications