Heart failure (HF), a leading cause of morbidity and mortality, involves significant dysfunction of the sino-atrial node (SAN). SAN dysfunction (SND) can result from or worsen HF through a vicious cycle leading to HF progression and/or death. However, mechanisms of HF-induced SND due to alterations in expression and distribution of ion channels/receptors and their regulatory factors across the human SAN pacemaker complex have not been studied in human hearts but rather only in animal models that possess significantly different 3D SAN structure and molecular profile. To overcome these major obstacles, our multidisciplinary team has established a vigorous human heart research program to acquire viable explanted hearts with the long-term goal to develop a novel integrative framework to understand how structural and molecular remodeling contribute to SND and arrhythmias in HF and other diseases. We developed an integrated approach of intramural optical mapping, 3D structural imaging, and molecular mapping to examine the human SAN from molecular to organ levels. Our initial results with this approach suggest that the human SAN complex consists of multiple and redundant intranodal pacemakers and conduction pathways (SAN compartments), which allow for the robust regulation of heart rhythm. Our results also suggest that HF-induced impairments of SAN compartments and SND may be orchestrated in part by (1) fibrotic remodeling, (2) molecular remodeling in expression and distribution of adenosine A1 receptors and the G protein-coupled channel IK.Ado (GIRK1/GIRK4)() and/or (3) If pacemaker channels (HCN1/HCN4). Furthermore, our preliminary data suggest that HF-induced downregulation of If pacemaker channels is linked to the upregulation of several microRNAs (or miRs) in animal models, where SAN targeting treatment with antimiRs restored SAN function and alleviated HF. Finally, our preliminary data demonstrates that these miRs are selectively upregulated in human failing SAN and represent promising targets for SND treatment. Based on these recently published and preliminary data, our central hypothesis is that HF- induced heterogeneous structural and molecular remodeling of SAN compartments impairs the robustness of the human SAN complex and leads to SND. The overall objective is to define functional, structural, and molecular features of the human SAN complex altered by HF to reveal novel targets for SND treatment. This translational research will advance our understanding of human SAN function and expression profiles in normal and diseased hearts that is essential for the development of new therapies against SND.
PROJECT NARRATIVRE Heart failure occurs when the heart muscle is too weak to meet the needs of the body. During heart failure the normal human heart pacemaker, the sinoatrial node, which determines heart rhythm, becomes impaired. Most heart failure patients need an electronic pacemaker to maintain their heart rate. Our goal is to understand how changes in the biochemistry of the human sinoatrial node during heart failure lead to abnormal heart rates. Information from this study will be used to develop new therapies to efficiently restore normal sinus rhythm for heart failure patients.
|Guha, Avirup; Xiang, Xiao; Haddad, Devin et al. (2017) Eleven-year trends of inpatient pacemaker implantation in patients diagnosed with sick sinus syndrome. J Cardiovasc Electrophysiol 28:933-943|
|Csepe, Thomas A; Zhao, Jichao; Sul, Lidiya V et al. (2017) Novel application of 3D contrast-enhanced CMR to define fibrotic structure of the human sinoatrial node in vivo. Eur Heart J Cardiovasc Imaging 18:862-869|
|Hansen, Brian J; Zhao, Jichao; Fedorov, Vadim V (2017) Fibrosis and Atrial Fibrillation: Computerized and Optical Mapping; A View into the Human Atria at Submillimeter Resolution. JACC Clin Electrophysiol 3:531-546|
|Li, Ning; Hansen, Brian J; Csepe, Thomas A et al. (2017) Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure. Sci Transl Med 9:|
|Csepe, Thomas A; Hansen, Brian J; Fedorov, Vadim V (2017) Atrial fibrillation driver mechanisms: Insight from the isolated human heart. Trends Cardiovasc Med 27:1-11|
|Milani-Nejad, Nima; Chung, Jae-Hoon; Canan, Benjamin D et al. (2016) Insights into length-dependent regulation of cardiac cross-bridge cycling kinetics in human myocardium. Arch Biochem Biophys 601:48-55|
|Unudurthi, Sathya D; Wu, Xiangqiong; Qian, Lan et al. (2016) Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability. J Am Heart Assoc 5:e002865|
|Canan, Benjamin D; Haizlip, Kaylan M; Xu, Ying et al. (2016) Effect of exercise training and myocardial infarction on force development and contractile kinetics in isolated canine myocardium. J Appl Physiol (1985) 120:817-24|
|Li, Ning; Csepe, Thomas A; Hansen, Brian J et al. (2016) Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart. Circulation 134:486-98|
|Shettigar, Vikram; Zhang, Bo; Little, Sean C et al. (2016) Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease. Nat Commun 7:10794|
Showing the most recent 10 out of 30 publications