Assessment of systolic function in the evaluation of patients with cirrhosis
Authors: Søren Møller, Jens D. Hove
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article On page 2019 In patients with cirrhosis and portal hypertension, it is largely the development of complications that determines the course of the disease.1 Patients with cirrhosis typically present with a splanchnic arterial vasodilatation in particular owing to increased expression of nitric oxide (NO) in vascular endothelial cells.2 According to the peripheral arterial vasodilatation hypothesis, central hypovolemia and arterial hypotension lead to baroreceptor activation of the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone systems. The circulatory outcome is a systemic hyperdynamic circulation that affects a variety of organ systems, including that of the heart.1 Recently, Bernardi et al.3 proposed an adjusted systemic inflammation hypothesis that takes into account the concept of bacterial translocation of pathogen‐associated molecular patterns. From this point of view, advanced cirrhosis could be a combined inflammatory and hyperdynamic syndrome leading to general multiorgan failure (Fig. 1).Figure 1: Possible mechanisms of development of multiorgan failure in advanced cirrhosis and portal hypertension. Portal hypertension may lead to increased bacterial translocation with release of pathogen‐associated molecular patterns and cytokines (tumor necrosis factor α [TNF‐α], interleukin‐1β [IL‐1B], and others). A preferential splanchnic vasodilatation leads to activation of vasoconstrictive systems such as the sympathetic nervous system and others, central hypovolemia, cardiovascular dysfunction, and gradual development of multiorgan syndrome.With respect to the heart in cirrhosis, there is now substantial experimental and clinical evidence of structural changes and impaired function in the cirrhotic heart.4 This has led to the crystallization of the clinical entity known as cirrhotic cardiomyopathy, which designates a cardiac dysfunction that includes impaired contractility (chronotropic incompetence) with systolic and diastolic dysfunction and electromechanical abnormalities in the absence of unknown cause of cardiac disease.4 In addition, decreased baroreflex sensitivity and decreased heart rate variability result in a chronotropic incompetence with a defective capacity to increase heart rate in response to activation of SNS.5 This feature is frequently observed in patients with cirrhosis and has been related to disease severity (including portal hypertension and renal failure) and poor prognosis.4 Cirrhotic cardiomyopathy is often latent, but it can be unmasked by physical or pharmacological stress, which in particular reveals the systolic dysfunction.4 In cirrhosis, the systolic dysfunction seems to contribute to augmentation of complications, such as fluid retention, development of refractory ascites, and hepatic nephropathy.5 The use of beta‐blockers in cirrhosis may have potential harmful effects on fluid retention, renal function, and survival.6 Contemporary echocardiography includes classical 2D Doppler echocardiography and is primarily used for measuring cardiac volumes, heart dimensions, and function of the cardiac valves, as well as for assessing diastolic function by measuring E and A waves and E/A wave ratio. Application of pulse‐wave tissue Doppler imaging (TDI) with measurement of the mitral annular E wave (E′) has been suggested to be superior to 2D echocardiography for evaluation of diastolic dysfunction due to the independency of loading conditions.4 In addition, a special application of TDI or speckle tracking is the assessment of strain and strain rate based on movements of the myocardium and thereby myocardial deformation. Finally, the color Doppler M‐mode technique can be used to assess the pressure difference between the apex of the heart and the left ventricular outflow tract. The ejection intraventricular pressure difference (EIVPD) is considered a reliable index of systolic function because it is less dependent on loading condition.4 In the article by Yotti et al.8 in this issue of Hepatology, the authors aimed to assess systolic function in patients with cirrhosis by new sensitive measures (EIVPD), effects of interventions on systolic function, and associations to SNS drive and systemic inflammation. Yotti et al. investigated left ventricular systolic function in two subsets of patients: 1) an observational cross‐sectional study of 59 patients who underwent echocardiography examinations and 2) an interventional cohort in which 11 patients were studied at baseline and after intervention to analyze the acute effects of phenylephrine and albumin on cardiac afterload and preload, respectively. The results of the observational study revealed a higher EIVPD and systolic strain rate in patients with cirrhosis compared with controls and also revealed that systolic function was related to disease severity expressed as Model for End‐Stage Liver Disease score and presence of ascites, SNS activity, heart rate variability, and treatment with beta‐blockers. In the interventional study, an increase in cardiac preload increased cardiac filling pressures, leaving systolic function unaltered. In contrast, an increase in cardiac afterload after phenylephrine infusion resulted in a decrease in systolic function and cardiac output and the changes correlated with circulating NO and interleukin‐1β. The present results lead the authors to important conclusions—namely, that left ventricular systolic function is enhanced in cirrhosis and is related to severity of liver disease and SNS‐activation and that treatment with beta‐blockers significantly affects cardiac systolic function. These results emphasize important key points of cardiovascular dysfunction in cirrhosis. One of the striking outcomes of the study is the finding of enhanced systolic function in cirrhosis at baseline combined with a higher decrease in systolic function after afterload increase. This means that those patients with the most enhanced systolic function are also those with the most activated SNS and, hence, the most sensitive to increases in left ventricular afterload. Although the systolic function did not seem to be impaired at baseline, the decrease after vasoconstrictor‐induced stress may indicate a higher risk for development of complications in this subset of patients who appear more fragile from a hemodynamic point of view. Another important key point is the usage of EIVPD for the determination of the systolic function.7 It is noteworthy that in this patient population, determination of the ejection fraction and strain rate measured by TDI did not correlate with Model for End‐Stage Liver Disease score and SNS. EIVPD may therefore be a more sensitive index than TDI measurements for the identification of patients with cardiac dysfunction. Moreover, it is noteworthy that EIVPD correlated with creatinine concentrations, supporting the assumption of a cardiorenal syndrome in some patients with advanced cirrhosis.5 One important aspect of this study, therefore, is that application of EIVPD may be a useful measure in future assessment, limitation, and definition of cirrhotic cardiomyopathy. It should, however, be noted that so far the color M‐mode–derived EIVPD values depend on customized software, and have only been applied in a very few centers. Hopefully, the article by Yotti et al. will encourage more researchers and vendors of echocardiographic equipment to apply and develop this promising technique. The observation of the impact of beta‐blockers on the circulatory function is an important contribution to the ongoing discussion regarding the risk of beta‐blockers in decompensated cirrhosis. Interestingly, patients treated with beta‐blockers showed a lower systolic function, as evaluated by EIVPD. On the contrary, patients with ascites had a more enhanced systolic function, although the number of patients was limited. This indicates that application of EIVPD could be used to identify patients at risk before commencing treatment with beta‐blockers. Increased circulating concentrations of NO and interleukin‐1β in the Yotti et al. study indicate that bacterial translocation and systemic inflammation may be involved.3 Experimental studies have shown that infusion of albumin in animals also have positive cardiac inotropic effects,10 but this was not confirmed in the Yotti et al. study. The results of the study by Yotti et al. should stimulate further research in this area. In particular, the more sensitive nature of using EIVPD for the assessment of systolic dysfunction in cirrhosis should be further analyzed in relation to the assessment of risk of beta‐blockers in patients with ascites and renal failure. Future larger prospective follow‐up studies are warranted to finally determine the impact of systolic dysfunction on the development of circulatory and renal complications of cirrhosis and in the risk assessment of patients who are treated with beta‐blockers. Author names in bold designate shared co‐first authorship.