Cirrhotic Cardiomyopathy: Moving From Description to Intervention

Prevalent cardiovascular disease in liver transplant (LT) candidates is estimated at 15%–30% and is a leading cause of morbidity and mortality after transplant.1 Cardiac-specific mortality is the most common cause of death in patients with metabolic dysfunction-associated steatotic liver disease2 and the second most common indication for adult LT.3 Cirrhotic cardiomyopathy (CCM) is present in 30%–80% of LT candidates4 and is defined as subclinical myocardial dysfunction in the absence of primary heart disease in patients with cirrhosis.5 CCM is associated with hyperdynamic circulation, low systemic vascular resistance, and metabolic and inflammatory derangements seen in progressive liver cirrhosis. Post-LT manifestations of CCM range from early cardiogenic shock to late-onset congestive heart failure (HF) across a broad range of left ventricular ejection fractions (LVEFs). Extensive literature describes alterations in the renin-angiotensin-aldosterone and sympathetic pathways, with associated structural changes in the myocardium including monocyte/macrophage infiltration and decreased contractility and fibrosis. Clinical evidence for development of CCM can be found in subtle electrocardiogram changes, including prolonged QTc interval, and a blunted response to dobutamine used in cardiac stress testing. Cardiologists asked to risk-stratify these patients preoperatively or assist in the management of post-LT cardiogenic/mixed shock or less severe congestive HF, we review the preoperative prolonged QTc and the advanced echo images and then get to the business of deploying HF therapies, which sometimes includes temporary mechanical circulatory support. In 2020, the International Cirrhotic Cardiomyopathy Consortium (CCC-2020) updated its consensus diagnostic guidelines for CCM, which were originally established in 2005 by the Montreal World Congress of Gastroenterology. CCM by echocardiographic criteria is defined as systolic dysfunction; LVEF <50% or global longitudinal strain (GLS) absolute value by speckle tracking <18%; or evidence of diastolic dysfunction (DD) including: early diastolic transmitral flow velocity by early diastolic mitral annular velocity ≥ 15, left atrial volume index >34 mL/m2, septal tissue Doppler e′ <7 cm/s, or tricuspid regurgitation velocity >2.8 m/s.5 These advanced measurements reflect congestion, elevated intracardiac pressures, and abnormalities in myocardial tissue. These criteria have not yet been validated in large studies, as tissue Doppler and speckle tracking parameters are often missing. We read with interest the article by Gill et al6 published in this issue of Transplantation, who describe report their single-center retrospective observational cohort study evaluating the association between CCM by CCC-2020 criteria with major adverse cardiovascular events (MACEs) within 12 mo of LT. The authors used the earlier criteria transmitral Doppler filling pattern (peak early diastolic velocity to peak late diastolic velocity ratio) to stratify the severity of DD in patients. No tissue Doppler or speckle tracking for GLS was obtained in this historical cohort. The authors identified 57 of 362 LT candidates with CCM (16%) with baseline differences in age (P = 0.002), prior atrial fibrillation (P = 0.003), hepatic encephalopathy (P = 0.006), and hepatorenal syndrome (P = 0.007), but no difference in pre-LT Model for End-stage Liver Disease score (22 versus 20; P = 0.13). MACEs after LT occurred in 13% patients, mostly driven by HF, prespecified as congestive symptoms, physical examination findings, and echo evidence of systolic dysfunction or DD. MACE event odds in patients with pre-LT CCM was 4.5 (confidence interval, 2.3-9.0; P < 0.001), with the odds of HF 22.8 (confidence interval, 6.0-86.0; P < 0.001). There was no mortality associated with CCM in this cohort. Gill et al6 add to a series of cohort studies linking evidence of CCM with worse LT outcomes. Previous studies have varied: Spann et al4 found that the modified CCC-2020 criteria better predicted MACE than the prior 2005 Montreal criteria, when including septal tissue Doppler e′ <7 cm/s. Cesari et al7 found that the 2020 guidelines did not predict MACE and proposed adding a stress test to identify patients with blunted contractile reserve with dobutamine challenge. Similarly, Cailes et al8 demonstrated that combining blunted contractile reserve with the CCC-2020 criteria enhanced the prediction of MACE, HF events, and 30-d mortality. In Gill et al,6 the increase in post-LT MACE among patients with pre-LT CCM was primarily because of a higher incidence of HF cases (21% versus 1%; P < 0.001). Most HF events occurred within 30 d post-LT (60%), with the rest occurring later (40%). The authors do not specify the cause of cirrhosis in HF patients or the exact timing of HF episodes within 30 d post-LT. Likely, the pathophysiology differs between early and late HF events. Takotsubo cardiomyopathy, defined as acute and reversible LV dysfunction not caused by major coronary artery disease, is recognized in the immediate post-LT phase in up to 1% of patients. In 1 report, 55 early post-LT HF cases because of Takotsubo cardiomyopathy (median 4 d post-LT) were mostly associated with alcohol-related cirrhosis (49.1%).9 These patients improved with diuretics, afterload reduction, and vasopressors; most recovered LVEF >50% within 3 mo (81.8%). As case series continue, more lessons are learned: (1) complete echocardiographic data, as recommended by the CCC-2020 criteria, will improve clinical care and the validation capabilities of the new guidelines; (2) pre-LT echocardiography should occur in the context progressive liver disease; Model for End-stage Liver Disease score, development of hepatorenal syndrome, whether the patient is taking or discontinuing beta-blocker and/or mineralocorticoid receptor antagonist medications; and (3) emerging data on the association of elevated N-terminal pro-brain natriuretic peptide levels with the development of acute on chronic liver failure and increased waitlist mortality indicate inclusion of serial cardiac biomarker testing. While advanced cardiac imaging can make a diagnosis of CCM, if there is no intervention pre-LT, then we are left with the business of postoperative management. Opportunities abound to test pre-LT interventions, such as sodium-glucose cotransporter 2 and the use of implantable pulmonary artery pressure monitors to survey for developing congestion, but most importantly, early and meaningful engagement from HF specialists is critically important. Given that heart transplant cardiologists are trained in organ transplant, structured partnerships hold the greatest promise to minimize the morbidity and mortality associated with CCM. Despite the high number of LTs performed every year around the globe, clinical trials testing drugs or devices to mitigate post-LT MACE outcomes associated with pre-LT CCM remain surprisingly sparse. As a Transplant Community, together we can do better.