Cirrhotic Cardiomyopathy

Etiology

CCM is caused by cirrhosis, regardless of its etiology. However, patients with alcohol use disorder and hemochromatosis have additional contributing factors for cardiac dysfunction. A direct correlation is present between the severity of the liver disease, as indicated by the Model For End-Stage Liver Disease score, and the degree of cardiomyopathy. No genetic predisposition for CCM has been identified.[5][6]

Epidemiology

As patients with CCM are generally asymptomatic with near-normal cardiac function, except during periods of stress, the exact prevalence of this disease is difficult to determine. Myocardial compromise is estimated to be present in up to 50% of patients with cirrhosis. Most patients with moderate-to-advanced cirrhosis (ie, Child-Pugh Class B or C) will present with at least 1 feature of CCM (such as QT prolongation or diastolic dysfunction).

Among patients with cirrhosis undergoing liver transplantation, almost 50% have been observed to develop signs of cardiac dysfunction within the perioperative period, with 7% to 21% mortality from heart failure in the months following transplant. Limited studies have indicated that CCM is more common in males, individuals older than 50, and patients with cirrhosis secondary to alcohol abuse.[7][8]

Pathophysiology

Cirrhosis is characterized by hepatic architectural damage, including nodular regeneration and diffuse fibrosis, leading to liver dysfunction and portal hypertension. Recent reviews have detailed the mechanisms underlying CCM and portal hypertension. Liver dysfunction affects cardiac molecules, as evidenced by reduced β-adrenergic receptor density, an increased cholesterol-to-phospholipid ratio in the cardiomyocyte sarcolemmal plasma membrane, and abnormal contractile filaments, such as a shift from the stronger α-myosin heavy chain (MHC) to the weaker β-MHC isoform.

Portal hypertension causes intestinal vascular congestion, leading to bacterial translocation and endotoxemia. Lipopolysaccharides stimulate the release of pro-inflammatory cytokines such as tumor necrosis factor (TNFα) and interleukin (IL)-1β, which increase nitric oxide and carbon monoxide levels, thereby inhibiting cardiac contractility. Other inhibitors of cardiac contractility include oxidative stress, apoptosis, and bile acids.[9]

Patients with cirrhosis also exhibit elevations in cell membrane cholesterol content, which alter membrane fluidity and disrupt the number and function of receptors. This results in a decrease in L-type calcium and potassium channels, increased action potential duration, and prolonged QT interval. Additionally, the dysregulation of Na/Ca channels leads to massive calcium influx into cells and stimulates cardiomyocyte apoptosis. The combination of prolonged action potentials, impaired myocyte relaxation, and alterations in titin and collagen configurations produces eccentric left ventricular hypertrophy and diastolic dysfunction. Eventually, systolic dysfunction develops due to impaired energy metabolism and reduced myocardial reserve.[10]

Histopathology

Histological changes in myocardial cells in CCM include fibrosis, subendocardial edema, and vacuolation of the nucleus and cytoplasm. However, these findings are nonspecific and are similar to cellular changes observed in alcoholic cardiomyopathy. Abnormalities in titin are linked to dilated cardiomyopathy. Notably, titin has 3 isoforms—N2A, N2B, and N2BA. Among these, N2B and N2BA are expressed in adult cardiomyocytes. N2B, shorter and less elastic with greater passive stiffness than N2BA, is highlighted in a study by Tharp et al. An increased ratio of N2BA:N2B isoforms is thought to significantly contribute to dilated cardiomyopathy development.

MHC is the "molecular motor" of the heart and is another crucial myofilament involved in cardiac contraction. A recent study by Honar et al observed significant alterations in MHC's α- and β-isoforms in a rat model of CCM. Specifically, the more robust, faster-contracting α-MHC was replaced by the weaker, slower-contracting β-MHC. This switch from α-MHC to β-MHC, known to contribute to cardiac dysfunction, may also play a critical role in CCM.[9]

History and Physical

CCM is clinically asymptomatic in most patients due to peripheral vasodilation, which reduces afterload and compensates for abnormal cardiac function. However, during periods of stress, rapid hemodynamic changes and impaired cardiac response can lead to acute heart failure symptoms. CCM should be suspected in patients with moderate-to-advanced cirrhosis (Child-Pugh Class B or C) who present with exercise intolerance, worsening fatigue, and peripheral edema, especially in the absence of known cardiac disease. These nonspecific symptoms often overlap with those of advancing cirrhosis, contributing to frequent under-recognition and misdiagnosis of CCM.

Physical examination findings are typically unremarkable for cardiopulmonary disease. However, in the setting of physiological, pharmacological, or pathological stress, signs of congestive heart failure may become apparent. Classical physical exam findings, including peripheral edema, jugular venous distention, and third or fourth heart sounds, will likely be present. During the examination, it is important to observe for classical signs of liver disease, including jaundice, scleral icterus, ascites, and hepatomegaly.[11]

Evaluation

The 2005 World Congress of Gastroenterology in Montreal introduced the first and most widely accepted diagnostic criteria for CCM. These criteria include evidence of systolic dysfunction (eg, blunted increase in cardiac output with physiological or pharmacological stimuli and left ventricular ejection fraction <55%), diastolic dysfunction (eg, the ratio of early to atrial flow velocities <1, mitral deceleration time >200 ms, and isovolumetric relaxation time >80 ms), and various supportive criteria, including electrophysiological abnormalities, enlarged left atrium, increased left ventricular wall thickness, increased brain-type natriuretic peptide, and increased troponins.

Initial lab work should confirm cardiac involvement and include atrial natriuretic peptide, brain natriuretic peptide, or its prohormone N-terminal pro-brain natriuretic peptide, and troponin I. If available, a galectin-3 level can be obtained as a marker of cardiac fibrosis. QT prolongation on electrocardiogram is often the first sign of CCM. This varies between daytime and nighttime due to diurnal variations in the autonomic nervous and circulatory systems. The chest radiograph is typically normal but may show cardiomegaly and pulmonary edema. Echocardiography showing diastolic or systolic dysfunction is essential for diagnosis. Speckle tracking can be used to analyze the ventricular function further. As CCM manifests under stress conditions, a chemical or exercise stress test demonstrating a blunted cardiac response can be useful in confirming this diagnosis.[12][13]

Patients with advanced cirrhosis often exhibit hypercontractile left ventricular function at rest, which can lead to reduced contractile reserve. According to the World Congress of Gastroenterology, the criteria for CCM is less than a 5% increase in left ventricular ejection fraction during stress testing, which suggests decreased contractile reserve and potential subclinical left ventricular systolic dysfunction. Despite this, due to the absence of standardized criteria, the 2019 diagnostic criteria for CCM did not include stress echocardiography for detecting impaired contractile reserve. However, stress echocardiography is well-recognized for identifying diastolic dysfunction and may still be valuable in diagnosing CCM.[14]

Treatment / Management

Currently, a standardized protocol or specific medications are unavailable for the treatment of CCM. Patients should receive standard medical therapy for the management of heart failure and undergo evaluation for liver transplantation.

Medical therapy generally includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, loop and thiazide diuretics, aldosterone receptor antagonists, and β-blockers. ACE inhibitors are known to reduce morbidity and mortality in patients with heart failure but are not recommended in patients with Child-Pugh classes B or C due to the potential of exacerbating systemic vasodilation and increasing the likelihood of hepatorenal syndrome. Loop and thiazide diuretics manage hypervolemia and are critical elements of treatment. Aldosterone receptor antagonists improve hemodynamics in patients with CCM by curtailing the continuous activation of the renin-angiotensin-aldosterone system. Patients with cirrhosis are likely already taking β-blockers to reduce portal hypertension and prevent variceal bleeding. Nonspecific β-blockers, particularly carvedilol, have been suggested to be more effective in reducing portal hypertension and have been shown to reduce QT prolongation.[15]

Transjugular intrahepatic portosystemic shunt placement is used to reduce portal hypertension in patients with cirrhosis, but this procedure is not expected to improve cardiomyopathy. As CCM develops due to cirrhosis, liver transplantation is the cornerstone of treatment. Transplantation has been shown to significantly improve systolic and diastolic dysfunction and reverse QT prolongation in 50% of patients. Cardiac benefits are observed within 3 to 12 months following surgery. The extent of cardiac normalization following liver transplantation is currently unknown.[16][17][18](B3)

Differential Diagnosis

Other differential diagnoses to consider when treating patients with CCM include:

• Alcoholic cardiomyopathy
• Other forms of dilated cardiomyopathy
• Hypertrophic cardiomyopathy
• Restrictive cardiomyopathy

Prognosis

Overall, cirrhosis is associated with an unfavorable prognosis, which is further compounded by the development of CCM. The presence of left ventricular diastolic dysfunction (LVDD) and a Child-Pugh score above 8 is associated with a poorer prognosis. In a study, 1-year survival in patients with cirrhosis without LVDD was 95%, which decreased to 79% and 39% with grade I and grade II LVDD, respectively. While liver transplantation is the definitive treatment for CCM, up to a quarter of cirrhotic patients may experience postoperative cardiovascular complications, contributing to 7% to 21% mortality attributable to cardiovascular causes following liver transplantation.[19]

The impact of CCM on overall survival remains uncertain; however, due to its clinical significance, screening for CCM in cirrhotic patients is advisable. Given the interconnected progression of CCM and cirrhosis, distinguishing morbidity and mortality specifically attributable to CCM is challenging. CCM significantly influences outcomes following liver transplantation. A single-center retrospective matched cohort study by Izzy et al,[18] involving 141 patients who underwent liver transplantation, examined the impact of CCM on posttransplant cardiovascular outcomes. The study revealed that patients without CCM had a higher 5-year cardiovascular disease-free survival rate (85.2% versus 60.7%), with the most pronounced effect observed within the first 90 days posttransplant. These findings underscore the importance of intensifying posttransplant surveillance and management for patients with CCM.[20]

Complications

Complications associated with CCM include:

• Congestive heart failure
• Arrhythmias
• Pulmonary hypertension
• Hepatorenal syndrome
• Sudden cardiac death