Cardiac Fibrosis and Arrhythmogenesis

Abstract

Myocardial injury, mechanical stress, neurohormonal activation, inflammation, and/or aging all lead to cardiac remodeling, which is responsible for cardiac dysfunction and arrhythmogenesis. Of the key histological components of cardiac remodeling, fibrosis either in the form of interstitial, patchy, or dense scars, constitutes a key histological substrate of arrhythmias. Here we discuss current research findings focusing on the role of fibrosis, in arrhythmogenesis. Numerous studies have convincingly shown that patchy or interstitial fibrosis interferes with myocardial electrophysiology by slowing down action potential propagation, initiating reentry, promoting after-depolarizations, and increasing ectopic automaticity. Meanwhile, there has been increasing appreciation of direct involvement of myofibroblasts, the activated form of fibroblasts, in arrhythmogenesis. Myofibroblasts undergo phenotypic changes with expression of gap-junctions and ion channels thereby forming direct electrical coupling with cardiomyocytes, which potentially results in profound disturbances of electrophysiology. There is strong evidence that systemic and regional inflammatory processes contribute to fibrogenesis (i.e., structural remodeling) and dysfunction of ion channels and Ca2+ homeostasis (i.e., electrical remodeling). Recognizing the pivotal role of fibrosis in the arrhythmogenesis has promoted clinical research on characterizing fibrosis by means of cardiac imaging or fibrosis biomarkers for clinical stratification of patients at higher risk of lethal arrhythmia, as well as preclinical research on the development of antifibrotic therapies. At the end of this review, we discuss remaining key questions in this area and propose new research approaches. © 2017 American Physiological Society. Compr Physiol 7:1009-1049, 2017.

Nontuberculous mycobacterium M. avium infection predisposes aged mice to cardiac abnormalities and inflammation

“…The activated endothelium enhances recruitment of circulating leukocytes and impacts cardiac fibroblast activity favoring the production of collagen (Biernacka & Frangogiannis, ; Kong et al, ; Suthahar et al, ). Excess collagen impacts the ability of cardio myocytes to propagate the cardiac action potential generated by the sinoatrial node, ultimately leading to abnormal diastolic function, and cardiac failure (Nguyen, Kiriazis, Gao, & Du, ; Nguyen, Qu, & Weiss, ). Cardiac hypertrophy is typically associated with diastolic dysfunction.…”

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

“…Excessive deposition of collagen, in between or in place of the healthy myocardium, interferes with the cardiac electrophysiology. Collagen deposition in the heart acts as a physical barrier to conduction, facilitating re-entry (Nguyen et al, 2017). Molecular signatures underlying the epicardium-initiated fibrofatty replacement in ACM hearts remain largely unexplored (Corrado et al, 2017b;Sepehrkhouy et al, 2017).…”

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

“…Cardiac fibrosis is involved in pathological remodeling of the heart, causing abnormalities in cardiac conduction, stiffness of the ventricular walls, reduced contractility, and impaired overall heart performance [1]. Thus, cardiac fibrosis is a detrimental factor in various types of heart diseases [2][3][4], including arrhythmia [5][6][7][8][9], hypertrophy [10], and heart failure [10][11][12][13]. There is substantial experimental evidence demonstrating that fibrosis slows down action potential propagation, initiates reentry, and promotes ectopic automaticity, thereby contributing to arrhythmogenesis [5,9,14].…”

“…Thus, cardiac fibrosis is a detrimental factor in various types of heart diseases [2][3][4], including arrhythmia [5][6][7][8][9], hypertrophy [10], and heart failure [10][11][12][13]. There is substantial experimental evidence demonstrating that fibrosis slows down action potential propagation, initiates reentry, and promotes ectopic automaticity, thereby contributing to arrhythmogenesis [5,9,14]. Fibrosis also accelerates the progression of heart failure [15,16] resulting from nearly all etiologies of heart diseases, such as ischemic cardiomyopathy [17], dilated cardiomyopathy [18][19][20][21], hypertensive heart diseases [22,23], and inflammatory heart diseases [24].…”