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  • br Contemporary understanding for alcoholic cardiomyopathy

    2024-04-02


    Contemporary understanding for alcoholic cardiomyopathy Up-to-date, a number of theories are postulated for alcoholic cardiomyopathy including generation of mitochondrial reactive oxygen species (ROS), oxidative stress, neurohormonal overactivation (catecholamines and angiotensin II), apoptosis and direct toxicity of ethanol or its metabolites [12]. It becomes apparent that cardiac toxins such as ethanol and ethanol metabolite acetaldehyde impose cardiac damage directly or indirectly through catecholamines and ROS [[26], [27], [28]]. Alcohol challenge also triggers changes in mitochondrial oxidative phosphorylation system (OXPHOS) [21,29], formation and accumulation of protein-aldehyde adducts [30], fatty ro3 ethyl esters [31], modified lipoprotein and apolipoprotein particles [32], all of which compromise functionality of these essential proteins. These pathological factors may work independently or synergistically to promote hypertrophy, interstitial fibrosis, necrosis, and contractile dysfunction in the heart upon sustained alcohol intake. Using a forced alcoholism model (rats received 10% ethanol as the only fluid source, equivalent to ~5.0–6.5 g/kg/d, for 24 weeks), decreased inotropic capacity and dilated ventricles were noted, along with myocardial fatty degeneration (classical sign of alcoholic cardiomyopathy) and compromised electrical stability of cardiomyocytes, similar to the clinical setting of alcoholic cardiomyopathy [33]. Moreover, alcohol intake ro3 alters membrane composition and permeability, interferes with receptors and ion channels, and decreases myocyte protective and repair machineries. Accumulation of free radicals, modified protein adducts or apoptotic cell death in the face of alcoholism promotes altered intracellular Ca2+ homeostasis, en route to mechanical dysfunction in alcoholism. Ample findings from our lab and others have depicted the essential role of intracellular Ca2+ cycling proteins including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), Na+-Ca2+ exchanger and phospholamban as potential contributing factors for intracellular Ca2+ mishandling in alcoholism [[34], [35], [36]]. A scheme is provided to summarize the current knowledge of the contributing factors for the pathogenesis of alcoholic cardiomyopathy (Fig. 1). It is noteworthy that some of the effects elicited by alcohol may be beneficial such as inhibition of pericardial adhesion and improved postoperative healing process via regulation on matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase expression [37]. At this point, several strategies are available to alleviate alcohol-induced heart damage, although they tend to be employed more as supportive medications in a multidisciplinary approach. For example, alcohol abstinence, correction of micronutrient, and vitamin deficiencies and treatment of alcoholic organ damage offer beneficial effects in managing alcohol complications. In addition, alternate therapies to manage oxidative damage, apoptosis, cardiomyocyte hypertrophy, interstitial fibrosis and cardiomyocyte regeneration (such as stem cell therapy) may be promising although none of these approaches has been approved for current clinical practice [38]. Recent work also suggested that alcohol or its metabolite-induced changes in mitochondrial proteome may accentuate cardiac dysfunction, denoting the importance of mitochondria in alcoholic cardiomyopathy [39]. Findings from our laboratory have brought up the theory of “acetaldehyde toxicity” in the onset and development of alcoholic cardiomyopathy [20,21,40,41]. Our data have revealed that facilitated acetaldehyde production and removal accentuated and attenuated, respectively, the severity of alcoholic cardiomyopathy [41,42]. The likely role of acetaldehyde in the etiology of alcoholic cardiomyopathy was consolidated by the finding that inhibition of the acetaldehyde detoxifying enzyme mitochondrial aldehyde dehydrogenase (ALDH2) using cyanamide exacerbated the elevation of plasma levels of troponin-T, a key myocardial cell death marker, within 6 h of alcohol intake [43]. In addition, alcohol-stimulated cardiac sympathetic tone and tachycardia as well as suppressed parasympathetic activity, are believed to be mediated by acetaldehyde-induced elevation in circulating norepinephrine levels and subsequently activation of autonomic nervous activity [44]. Acetaldehyde may also exert its detrimental effect through reaction with OXPHOS proteins, mitochondrial DNA and membrane phospholipids, leading to mitochondrial respiration chain defect, genotoxicity, epigenetic toxicity and carcinogenicity [27,45]. Recent evidence has suggested that acetaldehyde is responsible for chronic alcohol-induced increases in inducible nitric oxide synthase (iNOS) and mitochondrial ROS production, interleukin-1β (IL-1β) hypersecretion, and activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome in macrophages [46]. Ethanol may be metabolized into acetaldehyde, which is further converted to acetate and NADH by ALDH2 in the presence of NAD+ as a cofactor. NADH generated from ethanol metabolism by ADH may also impair mitochondrial respiratory chain reaction and hepatic function in alcoholism although to a much lesser extent compared with acetaldehyde [47]. However, the precise cellular regulatory machinery for acetaldehyde-induced cardiac damage remains elusive. Recent data favored a role for microRNA in alcoholic cardiomyopathy such as involvement of miR-378a-5p in cardiomyocyte apoptosis and development of alcoholic cardiomyopathy through ALDH2 gene suppression [48]. More recent findings have suggested an important role of altered protein quality control mechanism through autophagy in alcohol- or acetaldehyde-induced changes in myocardial structure and function [[49], [50], [51]]. Derangement in the protein metabolism, including synthesis, catabolism and recycling through autophagy, may be responsible for alcohol-induced myocardial contractile defect [13]. Here we will summarize the recent reports with respect to the role of autophagy and the underlying regulatory mechanisms in the onset and pathogenesis of alcoholic cardiomyopathy.