Current concepts of Cirrhotic Cardiomyopathy

Introduction

Cirrhosis accounts for 1.16 million deaths worldwide, making it the 11^th most common cause of death globally.¹ Cirrhosis deaths are expected to increase over the next decade due to the ongoing epidemics of obesity and alcohol-related liver disease.¹ The primary physiologic complication in patients with cirrhosis is elevated pressure in the portal venous system (i.e., portal hypertension). This can manifest as ascites, hepatic hydrothorax, hepatorenal syndrome, or portal hypertensive gastropathy and gastro-esophageal varices with bleeding. These complications are markers of hepatic decompensation and are associated with 50% mortality at 1 year especially in child C patients.²

The cardiovascular effects of portal hypertension result in hyperdynamic circulation characterized by low systemic vascular resistance and high cardiac output. Cirrhotic cardiomyopathy (CCM) is characterized by intrinsic subclinical alterations in myocardial structure and function in the absence of overt structural abnormalities due to other causes (e.g., ischemia).³ CCM is usually latent, but it can become unmasked under stress, such as an acute change in hemodynamic loading conditions, leading to clinical heart failure.⁴ CCM is related to both portal hypertension and cirrhosis, irrespective of the underlying etiology of end-stage liver disease, though some diseases (e.g., alcohol, NASH, iron overload) may have further impact on cardiac function.⁵

In the following review, we discuss the epidemiology, pathophysiology, diagnostic criteria and clinical implications of CCM. We will focus particularly on aspects of clinical care for screening, surveillance and management of CCM in the context of liver transplantation and transjugular intrahepatic portosystemic (TIPS) placement. Finally, we will address the major unmet needs and research priorities surrounding CCM.

Epidemiology

There is limited information on the epidemiology of CCM, as its diagnosis is difficult because of near normal cardiac function at rest. Typically, the syndrome is not recognized until clinical decompensation occurs in which patients often present with features of high output heart failure or diastolic heart failure.⁶ With regard to heart failure, there are four stages for its development; stage A: the presence of risk factors (e.g., hypertension diabetes mellitus), stage B: presence of structural changes (e.g., remodeling) without clinical features, stage C: clinical presentation, and stage D: refractory clinical presentation⁷ (Table 1). Though, accurate identification and staging of heart failure due to CCM is challenging. Echocardiography, which is used clinically to identify cardiac correlates of early-stage heart failure (stage A or B), is operator-dependent and accuracy and reproducibility can be limited by the acoustic window. In late-stage heart failure (stage C or D), clinical heart failure symptoms may be masked or confounded by those of advanced cirrhosis (e.g., low functional capacity, shortness of breath and fluid overload). Therefore, accurate staging of heart failure due to CCM may require sophisticated investigation beyond standard echocardiography to identify changes in myocardial tissue structure, function and flow prior to the onset of cardiac decompensation (see Diagnosis).

Table 1.

Cirrhotic Cardiomyopathy in the Spectrum of Heart Failure³

	ACCF/AHA HF Stage7	CCM correlate	Therapeutic target
Early Stage	Stage A	Patients with cirrhosis or metabolic syndrome and its components without structural heart disease	Risk factor modification (e.g., control blood pressure, weight loss as needed)
	Stage B	LV remodeling and/or systolic or diastolic dysfunction on imaging without HF symptoms	Treat structural heart disease to prevent progression to symptomatic HF (Stage C)
Late Stage	Stage C	LV remodeling and/or systolic or diastolic dysfunction + prior or current HF symptoms	GDMT to prevent progression to Stage D HF
	Stage D	Refractory HF requiring specialized interventions	GDMT to reduce mortality

Abbreviations: ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CCM, cirrhotic cardiomyopathy; GDMT, guideline-directed medical therapy; HF, heart failure; LV, left ventricle

Due to the latent nature of the disease, the actual prevalence, incidence and natural history of CCM is largely unknown. Attempts have been made to extrapolate the prevalence of CCM by looking at the prevalence of QT interval prolongation in patients with cirrhosis, which previously was touted as the most common manifestation of CCM.^3,6 The prevalence of QT interval prolongation increases with severity of portal hypertension from 25% in Child A cirrhosis to up to 60% in Child C cirrhosis.⁵ However, QT can be prolonged due to a variety of causes (e.g., thyroid disease, obesity, medications⁸), which limits its use as an accurate surrogate for CCM. In patients undergoing liver transplantation, up to 50% of waitlist candidates show signs of cardiac dysfunction, and 7% to 24% of early deaths after liver transplantation result from overt heart failure.^5,9–11 Similarly, the leading cause of death after TIPS in patients with cirrhosis is cardiac decompensation and 20% of patients will have a heart failure hospitalization within 1 year of TIPS.¹²

Pathophysiology

The long recognized characteristic cardiovascular finding in ESLD is the hyperdynamic circulation. This is a low systemic vascular resistance and high cardiac output state (Figure 1).¹³ With portal hypertension and cirrhosis, a constellation of changes in vasoactive mediator levels occurs the result of which is a vasodilatory state; there is also an increased vascular response to vasodilators and a decrease in responsiveness to vasoconstrictors. These changes occur in the systemic circulation and splanchnic circulation but not in the hepatic microcirulation.¹⁴ The vasodilation and associated hypotension lead to activation of vasoconstrictor systems including the renin-angiotensin system (RAAS) and the sympathetic nervous system resulting in renal vasoconstriction and sodium and fluid retention. This in turn expands circulating volume further exacerbating the hyperdynamic circulation. With this, structural and functional changes occur in the heart, including left ventricular remodeling.¹⁵ Diastolic dysfunction develops, as does systolic dysfunction; blunted responses to stress are seen as is chronotropic incompetence.^5,16 At a structural level, changes consistent with diffuse myocardial fibrosis have been described.¹⁷

Figure 1.

Overview of the role of cirrhosis physiology in the development of cirrhotic cardiomyopathy

Although patients with cirrhosis often exhibit total body volume overload, increased arterial compliance leads to a functional hypovolemia and therefore a decrease in cardiac pre-load. In CCM, the heart fails to increase cardiac output in response to the decrease in effective circulating volume which may in part be attributed to high peripheral arterial vasodilation. This cardiac insufficiency may also be masked by splanchnic arterial vasodilation which further unloads the ventricle by increasing splanchnic blood flow. Other contributors to the blunted cardiac response in CCM include autonomic dysfunction and impaired volume and baroreceptor reflexes. In animal models, the cardiac alterations that characterize CCM have been attributed to a variety of molecular causes including biophysical changes in the cardiomyocyte-membrane through altered K⁺ channels, altered L-type Ca²⁺ channels, and altered Na⁺/Ca²⁺ exchanger, attenuation of the stimulatory β-adrenergic system, and overactivity of negative inotropic systems mediated via increases in cyclic GMP.¹⁸

Diagnostic criteria (Figure 2)

Figure 2.

The Revised Criteria for Cirrhotic Cardiomyopathy

Abbreviations: LVEF, left ventricular ejection fraction; GLS, global longitudinal strain; E/A, early to late diastolic transmitral flow velocity; e, early diastolic mitral annular tissue velocity; LAVI, left atrial volume index, TR, tricuspid regurgitation.

* GLS is a negative value reflecting myocardial fiber shortening during systole. To avoid confusion, using the absolute value is recommended to describe changes in GLS.

**Presence of only 2 abnormalities suggests diastolic dysfunction of indeterminate grade. Further evaluation is needed using E/A ratio change during Valsalva, pulmonary vein velocity, GLS, left atrial strain, and isovolumetric relaxation time.

*** This criterion is only applicable in the absence of primary pulmonary hypertension or portopulmonary hypertension.

2005 Criteria

The first attempt to devise diagnostic criteria for cirrhotic cardiomyopathy was in 2005 during the World Congress of Gastroenterology. The proposed criteria at that time described the systolic component of CCM (i.e., systolic dysfunction) as having reduced left ventricular ejection fraction less than 55% or having suboptimal contractile response to pharmacologically or physiologically induced stress. The 2005 criteria described the diastolic component of CCM (i.e., diastolic dysfunction) as low early to late diastolic transmitral flow velocity (E/A) <1, isovolumetric relaxation time >200 millisecond, or deceleration time >80 millisecond.⁴ While that attempt to characterize CCM was an important first step in the right direction, applying 2005 criteria to clinical practice can be challenging for multiple reasons. The remarkable vasodilatory state for patients with end-stage liver disease (ESLD) significantly decreases afterload which can result in an exaggerated, hard to interpret LVEF. Therefore, LVEF may not be reliably used as a sole surrogate for detection of systolic dysfunction in these patients. Applying depressed contractile response to stress to daily practice is limited by lack of unanimous definition or characterization of what depressed contractile response to stress entails. Furthermore, the frequent use of non-selective beta blockers, which lower cardiac output by reducing heart rate, for variceal bleeding prophylaxis in patients with ESLD is another limitation for applying the 2005 CCM criterion. The aforementioned diastolic dysfunction criteria have shortcomings, as well. They tend to exhibit U-shape phenomenon where measurements on both ends of the spectrum (i.e., in normal diastolic dysfunction and in advanced diastolic dysfunction) can look alike.¹⁹ Additionally, volume overload and its effect on preload impedes the utility of E/A ratio since it is relatively preload-dependent.³ It is noteworthy that the 2005 criteria included set of cardiac surrogates to support the diagnosis of CCM such as prolonged QT interval, which has been the most studied supportive criterion of CCM. However, as mentioned above QT can be prolonged due to a variety of causes, which limits its diagnostic potential for CCM.

2020 Criteria

The challenges in applying 2005 criteria to clinical practice triggered interest in revising them and the evolution in echocardiography technology paved the path for the revision. This evolution was most remarkable for clinical implementation of speckle tracking strain imaging and advancing Tissue Doppler imaging (TDI). In 2015, the American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) recommended considering myocardial strain, specifically global longitudinal strain (GLS), assessment in addition to ejection fraction in the evaluation of left ventricular contractile function.²⁰ GLS reflects the myocardial fiber strain defined by proportional shortening in fiber length during systole in relation to diastole and hence it is a negative value (Video 1). In 2016, ASE and EACVI revised the diastolic dysfunction (DD) evaluation criteria some of which are only obtainable via TDI, which has become a routinely applied technology in clinical practice.¹⁹ In early 2020, the Cirrhotic Cardiomyopathy Consortium (CCMC), an international multidisciplinary consortium, published the revised CCM criteria.³ The systolic component of CCM was characterized as reduced LVEF (<50%) or decline in GLS (absolute value < 18). The diastolic component was defined by having at least three of the following: early diastolic transmitral flow to early diastolic mitral annular tissue velocity (E/e’) ≥15, left atrial volume index > 34 ml/m2, septal e’ <7 cm/second, or tricuspid regurgitation maximum velocity >2.8 m/second in the absence of pulmonary hypertension. When diastolic dysfunction is diagnosed, the severity can be determined using E/A ratio (0.8-2 = grade II and >2 = grade III). Patients with only two out of the four aforementioned criteria need further echocardiographic evaluation to define DD and its grade. This additional evaluation entails assessing E/A ratio change during Valsalva, pulmonary vein velocity, GLS, left atrial strain, and isovolumetric relaxation time (IVRT). While 2020 criteria did not include supportive criteria like those of 2005, the CCMC suggested studying the diagnostic utility of a group of variables (e.g., abnormal chronotropic or inotropic response, myocardial mass change, and serum biomarkers) that may have future potential in the management of CCM.³

Pre-transplant implications

The data are scarce regarding impact of CCM in its new definition on pre-transplant outcomes or outcomes in patients with ESLD. However, the individual components of the new CCM criteria have been studied in relation to these outcomes. Lee and colleagues described in 44 patients with decompensated cirrhosis who were prospectively followed for a median of 22 months that E/e’ > 10 was associated with reduced survival (28 vs. 37 months).²¹ Another prospective study evaluated cardiac decompensation within 1 year after TIPS in 100 patients and showed that elevated E/e’ (11 in cardiac decompensation group vs 7 in others) or LAVI (40 vs. 29 mL/m²) pre-TIPS were associated with higher risk of cardiac decompensation post-TIPS.¹² Jansen et al. retrospectively reviewed the 2-year clinical course of 114 patients who underwent TIPS and found that decreased left ventricular contractility detected as depressed GLS absolute value < 16.6% was associated with development of acute on chronic liver failure and impaired survival.²² These studies demonstrate the prognostic value for the new CCM individual criteria. It is important to note that since these studies predate the new CCM criteria, evaluation of CCM as a whole entity was not possible and only some of the CCM criteria (e.g., LAVI, E/e’, and GLS) were evaluated. It is possible that some of the patients with elevated LAVI or E/e’ in these studies had normal values for the other 3 variables of diastolic dysfunction which, in the presence of normal systolic function, rules out CCM. Therefore, future studies are needed to evaluate the prevalence of the recently re-defined CCM and its impact on the clinical course of patients with decompensated cirrhosis including those undergoing TIPS placement.

Data about utility of other cardiac imaging modalities relating to CCM in pre-transplant care are even more limited. Weise et al. showed in 52 patients with cirrhosis that increased myocardial extracellular volume on cardiac magnetic resonance imaging (MRI), reflecting myocardial fibrosis possibly due to CCM, is associated with increased risk of death or receiving liver transplant during two years of observation.¹⁷ Interestingly, the study showed that increased myocardial extracellular volume corresponds with higher Child Pugh scores in the cohort which suggests that CCM can worsen as liver disease progresses.

Post-transplant implications

There have been emerging data about the impact of CCM, diastolic dysfunction or their individual echocardiographic surrogates on post-transplant outcomes. A recently presented retrospective study at the American Transplant Congress (May 2020) showed in 141 patients who were followed for a median of 4.5 years post-transplant that meeting 2020 criteria for a diagnosis of CCM increases the risk of major cardiovascular outcomes (coronary artery disease, congestive heart failure, arrhythmia, and stroke) by more than two-fold.²³ There was a trend toward association between CCM and heart failure occurring more than 90 days post-transplant. It is notable that CCM affected one third of the study cohort in whom diastolic dysfunction was the predominant feature for CCM.²³ Other studies have evaluated the individual criteria of CCM in relation to post-transplant outcomes. Dowsley and colleagues showed that increased LAVI (>40) and increased E/e’ (>10) are associated with post-transplant early heart failure (within 2.6 months). The study also showed that abnormal LAVI predicts poor survival at 1- and 5-years post-transplant.²⁴ While CCM was initially thought to reverse after transplant,²⁵ subsequent studies, using contemporary echocardiographic criteria, did not validate this finding.^9,24

Proposed Management

CCM typically indicates subclinical structural and functional cardiac changes in patients with ESLD which places these patients in stage B on the path towards heart failure, which can become evident as the burden on the heart increases after TIPS placement or after liver transplant. TIPS placement results in increased preload which in the setting of CCM may lead to overt heart failure (i.e., cardiac decompensation). Therefore, if TIPS is performed in a patient with CCM, it may be beneficial to obtain a surveillance echocardiography within the first few months to ensure that there is no subclinical worsening in cardiac function that may warrant initiation of anti-remodeling therapy.

This risk for heart failure can be further augmented after liver transplant when increasing number of patients develop metabolic syndrome or at least some of its components.²⁶ At that point, effective management of hypertension, diabetes mellitus, dyslipidemia, and obesity will be critical in mitigating the risk of developing heart failure as well as other major cardiovascular outcomes. To this end, a recent study showed that arterial hypertension was adequately managed in less than one-third of liver transplant recipients and that adequate control was associated with improved survival and decreased incidence of cardiovascular events.²⁷

Echocardiographic surveillance of transplant candidates with CCM was recently recommended by the CCMC.³ The recommended surveillance interval for comprehensive echocardiography is every 6 months amongst liver transplant candidates on the waitlist. Among liver transplant recipients, surveillance is recommended every 6 months for 2 years following liver transplantation. This surveillance can potentially detect asymptomatic further decline in cardiac function which can affect candidacy to remain on the waitlist. Conversely, in patients with ESLD without transplant potential, surveillance is unlikely to be of benefit given the poor expected survival and high rate of liver-related decompensation relative to cardiac events.^28,29 In the post-transplant setting, surveillance can detect subclinical significant decline in systolic or diastolic function that can trigger therapeutic interventions (e.g., angiotensin converting enzymes inhibitors, beta blockade) that may improve survival.

Future Directions

While our knowledge of CCM has been advancing over the past few years, multiple unanswered questions remain with multiple opportunities for future investigations (Figure 3). The true prevalence of CCM in all comers with decompensated cirrhosis remains unknown as studies have focused predominantly on liver transplant candidates. CCM has been historically associated with hepatorenal syndrome;³⁰ however, this association needs to be re-evaluated according to the new criteria. The evolution of CCM after liver transplant and factors predicting reversal versus persistence of CCM need to be explored to potentially identify patients who can benefit from early intervention.

Figure 3.

Topics and questions for future research about Cirrhotic Cardiomyopathy

Abbreviations: CCM, cirrhotic cardiomyopathy; HRS, hepatorenal syndrome; TIPS, transjugular intrahepatic portosystemic shunt.

*Examples: abnormal chronotropic or inotropic response, electrocardiographic changes, electromechanical uncoupling, myocardial mass change, changes on cardiac magnetic resonance imaging, and serum biomarkers.

Summary

There are new criteria for CCM for which assessment needs to be incorporated in the standard echocardiographic exams performed in patients with ESLD. CCM and its components appear to negatively impact outcomes in patients while awaiting liver transplant, after TIPS, or after liver transplant. Therefore, close follow up is warranted in these patients. Prospective studies are critically needed to further evaluate pre- and post-transplant outcomes in CCM patients.

Supplementary Material

Video

Video 1. Left ventricular longitudinal strain measurement using speckle tracking echocardiography. As the yellow dots become closer, this represents shortening of myocardial fibers during systole. (Curtesy of Dr. Kinno, Loyola University, IL)

Key Points.

• The criteria for diagnosis of cirrhotic cardiomyopathy were recently revised in 2020 to reflect the improved performance of echocardiography for diagnosis of abnormal cardiac structure and function.

• Cirrhotic cardiomyopathy may increase the risk for major cardiac events after transjugular intrahepatic portosystemic shunt (TIPS) placement and after liver transplant.

• Echocardiographic follow up of patients with cirrhotic cardiomyopathy is warranted.

Synopsis:

Cirrhotic cardiomyopathy (CCM) connotes systolic and/or diastolic dysfunction in patients with end-stage liver disease in the absence of prior overt heart disease. Its prevalence is variable across different studies but recent data suggest that CCM may affect up to one third of liver transplant candidates. The etiology of CCM is multifactorial relating to hyperdynamic circulation, myocardial inflammation, myocardial fibrosis, and subendocardial edema. CCM defining features were recently revised, incorporating myocardial deformation imaging and Tissue Doppler echocardiography to improve the diagnostic and prognostic yield of CCM criteria and inform the candidate selection process for liver transplantation. CCM appears to increase the risk for unfavorable outcomes pre- and post-transplant. Close clinical and echocardiographic follow up of patients with CCM may help mitigate adverse cardiac outcomes.

Clinical Care Points:

• The true prevalence, incidence and natural history of CCM is unknown

• Detection of CCM requires a high index of clinical suspicion

• CCM develops over time in response to chronic exposure to hyperdynamic circulation.

• Global longitudinal strain (GLS) needs to be incorporated in systolic function assessment, in addition to left ventricular ejection fraction in patients with ESLD.

• E/e’, septal e’, left atrial volume index (LAVI), and tricuspid regurgitant (TR) velocity should be evaluated to determine diastolic function in patients with ESLD.

• E/e’ >10 can be associated with poor outcomes post-TIPS and post-transplant.

• Reduced GLS may negatively impact TIPS outcomes.

• If TIPS is performed in a patient with CCM, post TIPS echocardiography may be of benefit.

• Once CCM is diagnosed in a liver transplant candidate, echocardiographic surveillance should be considered every 6 months while on the waitlist and continue until 24 months post-transplant.