The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction (original) (raw)
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Cardiac fibrosis and arrhythmogenesis: The road to repair is paved with perils
Journal of Molecular and Cellular Cardiology, 2014
In the healthy heart, cardiac myocytes form an electrical syncytium embedded in a supportive fibroblast-rich extracellular matrix designed to optimize the electromechanical coupling for maximal contractile efficiency of the heart. In the injured heart, however, fibroblasts are activated and differentiate into myofibroblasts that proliferate and generate fibrosis as a component of the wound-healing response. This review discusses how fibroblasts and fibrosis, while essential for maintaining the structural integrity of the heart wall after injury, have undesirable electrophysiological effects by disrupting the normal electrical connectivity of cardiac tissue to increase the vulnerability to arrhythmias. We emphasize the dual contribution of fibrosis in altering source-sink relationships to create a vulnerable substrate while simultaneously facilitating the emergence of triggers such as afterdepolarization-induced premature ventricular complexes-both factors combining synergistically to promote initiation of reentry. We also discuss the potential role of fibroblasts and myofibroblasts in directly altering myocyte electrophysiology in a pro-arrhythmic fashion. Insight into these processes may open up novel therapeutic strategies for preventing and treating arrhythmias in the setting of heart disease as well as avoiding potential arrhythmogenic consequences of cell-based cardiac regeneration therapy. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signaling in Myocardium."
Circulation, 2009
Background-Cardiac hypertrophy, the clinical hallmark of hypertrophic cardiomyopathy (HCM), is a major determinant of morbidity and mortality not only in HCM but also in a number of cardiovascular diseases. There is no effective therapy for HCM and generally for cardiac hypertrophy. Myocardial oxidative stress and thiol-sensitive signaling molecules are implicated in pathogenesis of hypertrophy and fibrosis. We posit that treatment with N-acetylcysteine, a precursor of glutathione, the largest intracellular thiol pool against oxidative stress, could reverse cardiac hypertrophy and fibrosis in HCM. Methods and Results-We treated 2-year-old -myosin heavy-chain Q403 transgenic rabbits with established cardiac hypertrophy and preserved systolic function with N-acetylcysteine or a placebo for 12 months (nϭ10 per group). Transgenic rabbits in the placebo group had cardiac hypertrophy, fibrosis, systolic dysfunction, increased oxidized to total glutathione ratio, higher levels of activated thiol-sensitive active protein kinase G, dephosphorylated nuclear factor of activated T cells (NFATc1) and phospho-p38, and reduced levels of glutathiolated cardiac ␣-actin. Treatment with N-acetylcysteine restored oxidized to total glutathione ratio, normalized levels of glutathiolated cardiac ␣-actin, reversed cardiac and myocyte hypertrophy and interstitial fibrosis, reduced the propensity for ventricular arrhythmias, prevented cardiac dysfunction, restored myocardial levels of active protein kinase G, and dephosphorylated NFATc1 and phospho-p38. Conclusions-Treatment with N-acetylcysteine, a safe prodrug against oxidation, reversed established cardiac phenotype in a transgenic rabbit model of human HCM. Because there is no effective pharmacological therapy for HCM and given that hypertrophy, fibrosis, and cardiac dysfunction are common and major predictors of clinical outcomes, the findings could have implications in various cardiovascular disorders. (Circulation. 2009;119:1398-1407.) Key Words: antioxidants Ⅲ cardiomyopathy Ⅲ fibrosis Ⅲ genetics Ⅲ hypertrophy C ardiac hypertrophy is a common response of the heart to stress, whether internal, such as a genetic mutation, or external, such as an increased load. Cardiac hypertrophy, regardless of the etiology or ethnic background, is associated with increased morbidity and mortality, including sudden cardiac death. 1-3 Cardiac hypertrophy is also a major determinant of diastolic heart failure, a common form of heart failure particularly in the elderly. 4 Elucidation of the molecular pathogenesis of cardiac hypertrophy and its reversal through interventions could impart considerable clinical impact in a diverse array of cardiovascular diseases. 5 Clinical Perspective p 1407 Hypertrophic cardiomyopathy (HCM) is genetic paradigm of cardiac hypertrophic response. HCM is diagnosed clinically by cardiac hypertrophy in the absence of an external cause and pathologically by myocyte hypertrophy, disarray, and interstitial fibrosis. Cardiac hypertrophy and fibrosis are major determinants of clinical outcome, including the risk of sudden cardiac death in HCM. 3,6 The molecular genetic basis of HCM is partially known, and more than a dozen causal genes are identified. 7 Mechanistic studies point to diversity of
The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, 2011
Chronic volume overload leads to cardiac hypertrophy and later to heart failure (HF), which are both associated with increased risk of cardiac arrhythmias. The goal of this study was to describe changes in myocardial morphology and to characterize arrhythmogenic substrate in rat model of developing HF due to volume overload. An arteriovenous fistula (AVF) was created in male Wistar rats between the inferior vena cava and abdominal aorta using needle technique. Myocardial morphology, tissue fibrosis, and connexin43 distribution, localization and phosphorylation were examined using confocal microscopy and Western blotting in the stage of compensated hypertrophy (11 weeks), and decompensated HF (21 weeks). Heart to body weight (BW) ratio was 89% and 133% higher in AVF rats at 11 and 21 weeks, respectively. At 21 weeks but not 11 weeks, AVF rats had pulmonary congestion (increased lung to BW ratio) indicating presence of decompensated HF. The myocytes in left ventricular midmyocardium were significantly thicker (þ8% and þ45%) and longer (þ88% and þ97%). Despite extensive hypertrophy, there was no excessive fibrosis in the AVF ventricles. Distribution and localization of connexin43 were similar between groups, but its phosphorylation was significantly lower in AVF hearts at 21st week, but not 11th week, suggesting that HF,
Circulation Journal, 2014
Background: Ventricular dilation is known as a pivotal predictor in recent-onset cardiomyopathy (ROCM), but its pathophysiology is not fully understood. In the present study we investigated whether single-cell stiffness of right and left ventricular-derived fibroblasts has an effect on cardiac phenotype in patients with ROCM. Methods and Results: Patients with endomyocardial biopsy-proven ROCM were included (n=10). Primary cardiac fibroblasts (CFBs) were cultured from left and right ventricular endomyocardial biopsies and their single-cell stiffness was analyzed by quantification of Young's modulus using colloidal probe atomic force microscopy. Cardiac fibrosis was analyzed by Masson's trichrome staining. CFBs from the left ventricle showed significantly decreased stiffness when compared with CFBs from the right ventricle, indexed by decreased stiffness (Young's modulus 3,374±389 vs. 4,837±690 Pa; P<0.05). Young's modulus of CFBs derived from the left ventricle correlated negatively with the left ventricular end-diastolic dimension derived from 2-dimensional echocardiography (R 2 =0.77; P<0.01). Neither left nor right ventricular fibrosis correlated with the respective ventricular dimensions. Conclusions: Our data suggest that a decrease in single-cell stiffness of left ventricular fibroblasts could trigger left ventricular dilation in patients with ROCM. This implies a new potential mechanism for the ventricular dilation with this disease.
Journal of Molecular and Cellular Cardiology, 2004
We investigated the cellular and molecular mechanisms of systolic and diastolic dysfunction in a furazolidone (Fz)-induced model of dilated cardiomyopathy (DCM) in turkey poults. Serial echocardiograms disclosed marked systolic dysfunction in the Fz-treated poults, and ventricular weight and left ventricular (LV)/body weight ratio were significantly increased. Isolated heart experiments were performed to determine LV pressure-volume (P-V) relationships. In addition, LV sarcomere lengths (SLs) were measured after hearts had been fixed, and wall stress (r)-SL relationships were determined. When compared to control hearts, LV chamber volume in DCM hearts was~3-fold increased, the active or developed LV P-V relationship was markedly depressed, the passive or diastolic P-V relationship was steeper, and SLs were significantly shorter. However, the developed r-SL relationships of DCM and control hearts were not different indicating that intrinsic myocardial capacity to generate active force is unaffected in this model of DCM. In contrast, passive r, and passive tension in trabecular muscle preparations increased much more steeply with SL in DCM than normal hearts. Trabecular muscle experiments disclosed that the increase in passive myocardial stiffness was primarily collagen based. Titin, the giant sarcomeric molecule, which is an important determinant of passive myocyte properties in normal myocardium, did not contribute significantly to increased passive myocardial stiffness in DCM. We conclude that increased collagen-based passive myocardial stiffness is the major cause of the steeper passive or diastolic P-V relationship in DCM. Further, altered passive myocardial properties and ventricular geometry in DCM play a critical role to reduce ventricular systolic function by limiting SL extension during diastole, thereby limiting the use of the myocardial length-tension relationship.
Pathogenesis of hypertrophic cardiomyopathy: Hypotheses and speculations
American Heart Journal, 1981
Background-In cardiomyocytes from patients with hypertrophic cardiomyopathy, mechanical dysfunction and arrhythmogenicity are caused by mutation-driven changes in myofilament function combined with excitation-contraction (E-C) coupling abnormalities related to adverse remodeling. Whether myofilament or E-C coupling alterations are more relevant in disease development is unknown. Here, we aim to investigate whether the relative roles of myofilament dysfunction and E-C coupling remodeling in determining the hypertrophic cardiomyopathy phenotype are mutation specific. Methods and Results-Two hypertrophic cardiomyopathy mouse models carrying the R92Q and the E163R TNNT2 mutations were investigated. Echocardiography showed left ventricular hypertrophy, enhanced contractility, and diastolic dysfunction in both models; however, these phenotypes were more pronounced in the R92Q mice. Both E163R and R92Q trabeculae showed prolonged twitch relaxation and increased occurrence of premature beats. In E163R ventricular myofibrils or skinned trabeculae, relaxation following Ca 2+ removal was prolonged; resting tension and resting ATPase were higher; and isometric ATPase at maximal Ca 2+ activation, the energy cost of tension generation, and myofilament Ca 2+ sensitivity were increased compared with that in wildtype mice. No sarcomeric changes were observed in R92Q versus wild-type mice, except for a large increase in myofilament Ca 2+ sensitivity. In R92Q myocardium, we found a blunted response to inotropic interventions, slower decay of Ca 2+ transients, reduced SERCA function, and increased Ca 2+ /calmodulin kinase II activity. Contrarily, secondary alterations of E-C coupling and signaling were minimal in E163R myocardium. Conclusions-In E163R models, mutation-driven myofilament abnormalities directly cause myocardial dysfunction. In R92Q, diastolic dysfunction and arrhythmogenicity are mediated by profound cardiomyocyte signaling and E-C coupling changes. Similar hypertrophic cardiomyopathy phenotypes can be generated through different pathways, implying different strategies for a precision medicine approach to treatment.
Cellular and molecular pathways to myocardial necrosis and replacement fibrosis
Heart Failure Reviews, 2011
Fibrosis is a fundamental component of the adverse structural remodeling of myocardium present in the failing heart. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but not without adverse functional consequences. The extensive nature of this microscopic scarring suggests cardiomyocyte necrosis is widespread and the loss of these contractile elements, combined with fibrous tissue deposition in the form of a stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump. Cellular and molecular studies into the signaltransducer-effector pathway involved in cardiomyocyte necrosis have identified the crucial pathogenic role of intracellular Ca 2+ overloading and subsequent induction of oxidative stress,
Cardiomyocyte Stiffness in Diastolic Heart Failure
Circulation, 2005
Background— Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance. Methods and Results— DHF patients (n=12) had an LVEF of 71±11%, an LV end-diastolic pressure (LVEDP) of 28±4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5±4.0%, P <0.05) than did controls (n=8, 3.8±2.0%), and no conspicuous changes in sarcomeric protein composition were detected. Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to...
AJP: Heart and Circulatory Physiology, 2014
Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca2+ cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats ( n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca2+ transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in respons...
Myocardial Titin and Collagen in Cardiac Diastolic Dysfunction: Partners in Crime
Circulation, 2013
H igh myocardial diastolic stiffness has usually been attributed to excessive myocardial collagen deposition. Over the last decennium, stiff cardiomyocytes were also identified as important contributors to high myocardial diastolic stiffness, especially in heart failure (HF) with preserved ejection fraction (HFPEF). 1-3 Cardiomyocyte stiffness relates to elasticity of the giant cytoskeletal protein titin, which spans the sarcomere from the Z disk to the M line and functions as a bidirectional spring responsible for early diastolic recoil and late diastolic distensibility of cardiomyocytes. 4 In HFPEF patients and in HFPEF animal models, 5 the observed increase in cardiomyocyte stiffness was always accompanied by increased deposition of collagen; therefore, it remained unclear whether impaired elasticity of titin could be solely responsible for high myocardial diastolic stiffness and HFPEF. In this issue of Circulation, however, Chung et al 6 provide compelling evidence for titin being the sole perpetrator in the diastolic left ventricular (LV) dysfunction of an HFPEF mouse model. They generated mice with a deletion of nine immunoglobulin (Ig)-like domains from the proximal tandem Ig segment of the titin spring region (IG KO). This deletion extended the remaining titin spring segments and increased overall titin stiffness. Despite unaltered myocardial collagen content or composition, the IG KO mice developed HFPEF, evident from a reduced exercise tolerance, an enlarged left atrium, and a steeper LV end-diastolic pressure-volume relationship. The elegant study by Chung et al therefore clearly establishes myocardial titin to be able to sufficiently compromise diastolic LV function to induce HFPEF.