Pathogenic Mechanisms Underlying Cirrhotic Cardiomyopathy

Abstract

Cardiac dysfunction associated with cirrhosis in the absence of preexisting heart disease is a condition known as cirrhotic cardiomyopathy (CCM). Cardiac abnormalities consist of enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM may contribute to cardiovascular morbidity and mortality after liver transplantation and other major surgeries, and also to the pathogenesis of hepatorenal syndrome. The underlying mechanisms of CCM are poorly understood and as such medical therapy is an area of unmet medical need. The present review focuses on the pathogenic mechanisms responsible for development of CCM. The two major concurrent mechanistic pathways are the inflammatory phenotype due to portal hypertension, and protein/lipid synthetic/metabolic defects due to cirrhosis and liver insufficiency. The inflammatory phenotype arises from intestinal congestion due to portal hypertension, resulting in bacteria/endotoxin translocation into the systemic circulation. The cytokine storm associated with inflammation, particularly TNFα acting via NFκB depresses cardiac function. They also stimulate two evanescent gases, nitric oxide and carbon monoxide which produce cardiodepression by cGMP. Inflammation also stimulates the endocannabinoid CB-1 pathway. These systems inhibit the stimulatory beta-adrenergic contractile pathway. The liver insufficiency of cirrhosis is associated with defective synthesis or metabolism of several substances including proteins and lipids/lipoproteins. The protein defects including titin and collagen contribute to diastolic dysfunction. Other protein abnormalities such as a switch of myosin heavy chain isoforms result in systolic dysfunction. Lipid biochemical changes at the cardiac sarcolemmal plasma membrane result in increased cholesterol:phospholipid ratio and decreased membrane fluidity. Final common pathway changes involve abnormal cardiomyocyte intracellular ion kinetics, particularly calcium. In conclusion, cirrhotic cardiomyopathy is caused by two pathways of cellular and molecular dysfunction/damage due to hepatic insufficiency and portal hypertension.

Cardiomiopatía cirrótica – ¿Realidad clínica o simple curiosidad académica? Revisión.

“… 24-26 Además, los ácidos biliares en exceso estimulan los receptores muscarínicos M2, lo que reduce la producción de AMPc intracelular y disminuyen la contractilidad cardíaca y pueden provocar arritmias. 25 Por otro lado, la disfunción contráctil ocurre por una inversión en el consumo metabólico de ácidos grasos y glucosa por el miocardio y los ácidos biliares en exceso alteran esta relación de la oxidación de sustratos: mayor oxidación de glucosa y menos de ácidos grasos (la inversa es lo normal). En las membranas de los cardiomiocitos, hay una alteración de la relación colesterol:fosfolípidos, lo que produce rigidez de la membrana y alteración del funcionamiento de los receptores β-adrenérgicos y disminución de la producción intracelular de AMPc.…”

The mechanistic and prognostic implications of heart rate variability analysis in patients with cirrhosis

“…An area of controversy remains as to whether decreased HRV is as a result of defective cardiomyocyte responsiveness, this is since cytokines have been found to diminish beta‐ adrenergic signaling, resulting in pronounced adrenergic hypo‐responsiveness (Gaskari et al, 2006 ; Prabhu, 2004 ), known as cirrhotic cardiomyopathy. Cirrhotic cardiomyopathy is indeed a frequent complication exhibited in cirrhosis, resulting in defective contractile activity of the myocardium in response to physiological stress and stimulation (Myers & Lee, 2000 ), however, is nonetheless difficult to diagnose due to the profound systemic vasodilation exhibited in cirrhosis, concealing the presence of cardiomyopathy (Liu et al, 2017 , 2022 ). Several mechanistic theories have indeed been proposed such as abnormalities in the cardiomyocyte membrane, as well as an increased biosynthesis of nitric oxide (NO), and other mediators such as carbon monoxide and endocannabinoids eliciting a role in its pathogenesis (Gaskari et al, 2005 ; Yoon et al, 2020 ), Thus, given that NO has been found to be pivotal in the pathogenesis of the impaired cardiac adrenergic response exhibited in cirrhosis, whether this manifestation contributes to the reduction of HRV in patients, is yet to be more accurately ascertained.…”

Association of left ventricular diastolic dysfunction with inflammatory activity, renal dysfunction, and liver-related mortality in patients with cirrhosis and ascites

“…The background for LVDD in the setting of cirrhosis is increased stiffness of the myocardial wall owing to myocardial hypertrophy, fibrosis, and subendothelial edema [6]. Among the potential pathogenetic mechanisms of cirrhosis-related LVDD, the role of inflammatory activity has attracted growing interest [7]; however, supporting evidence of this association remains limited [8,9]. The presence of LVDD in patients with cirrhosis has been suggested to predispose to development of acute renal dysfunction [10] and HRS [11,12].…”