Coronary artery disease which makes ischemic heart disease or cardiac dysfunction is rare in cirrhosis.1,2 However, most patients with cirrhosis have hemodynamic alterations characterized by increased cardiac output and decreased systemic vascular resistance and arterial pressure.3,4 Despite the increased resting cardiac output, the ventricular contractile response to stimuli is attenuated, a condition termed cirrhotic cardiomyopathy (CCM).5-7 In the absence of consensus definitions, the term 'cirrhotic cardiomyopathy' is defined at present as: 1) baseline increased cardiac output but blunted ventricular response to stimuli; 2) systolic and/or diastolic dysfunction; 3) absence of overt left ventricular failure at rest; 4) electrophysiological abnormalities including prolonged Q-T interval on electrocardiography and chronotropic incompetence, and not all features are required for the diagnosis. Other causes leading blunted ventricular contractile response to stimuli should be ruled out before defining CCM. CCM is generally latent but unmasked when the patient is subjected to stress in the form of infection, exercise, drugs, hemorrhage, and surgery, such as liver transplantation or insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS). Clinical features include structural, histological, electrophysiological, systolic, and diastolic functional abnormalities. Although CCM is clinically important, the screening methods and the prevalence of CCM are not clear yet. Many factors are suggested as a mechanism of CCM and impaired β-adrenergic receptor signal transduction is one of them.8,9 Hence, we assumed that ventricular systolic and diastolic function in a CCM patient would be blunted by norepinephrine or other catecholamines stimulation such as dobutamine (Fig. 1). Therefore, in this study, we aimed to evaluate whether cardiac responses to stimulation by catecholamine are blunted in patients with cirrhosis through dobutamine stress echocardiography (DSE).

There was no difference in general characteristics between the control group (M:F=7:1, mean age±S.D.; 47.0±10.9 years) and the cirrhosis group (M:F=61:10, mean age±S.D.; 52.0±8.1 years). In patients with liver cirrhosis, no difference in baseline characteristics according to DSE response was observed (Table 1). No complication or adverse event such as arrhythmia or hemodynamic instability related with DSE was observed except a sense of palpitation along with increase of heart rate in eleven patients, however, this symptom was resolved within several minutes after finish of DSE and discontinuation of dobutamine infusion and there was no relationship between the development of palpitation and the results of DSE.

Cardiac output increases whereas systemic vascular resistance and arterial pressure decrease in cirrhosis. Despite the increased basal cardiac output, the cardiac response to physiologic or pharmacologic stimuli is known to be subnormal, a phenomenon called 'cirrhotic cardiomyopathy (CCM)'.3-7 Without firm diagnostic criteria and a screening test, the exact prevalence of CCM remains unknown. In general, CCM does not show overt heart failure at rest due to an 'auto-treating' effect reducing afterload related to peripheral vasodilatation of cirrhosis and compensatory diminution of inhibitory influences such as the cardiac muscarinic system.5,13 Therefore, in general, CCM is clinically not so problematic in a resting state. However, stresses such as liver transplantation, infection, and procedures like the insertion of TIPS, can convert latent to overt heart failure. Indeed, with increasing liver transplantation, CCM-related heart failure is the third-leading cause of death after rejection and infection.7,14 Therefore, the development of a precise screening test and assessment of CCM severity is necessary in the management of cirrhosis.

Diastolic dysfunction is believed to be present in virtually all CCM patients, and a few reports have suggested that CCM could be diagnosed with simple echocardiographic diastolic dysfunction indices such as the E/A ratio even at rest.15 Additionally, the E/A ratio has been suggested recently as predictive marker for survival after TIPS.16 Our study also showed a significant difference in E/A ratio between controls and the total cirrhotic patients group. In addition, baseline and peak E/A ratio increased significantly according to Child-Pugh class as in previous studies, i.e., cirrhotic patients group showed definitive diastolic dysfunction compared with the normal control group.17 However, in the present study, no significant difference in the severity of diastolic dysfunction was seen between subgroups of cirrhosis according to the DSE response. Many previous studies about diastolic dysfunction of CCM have a limitation because they only compared cirrhosis with normal controls. Diastolic dysfunction could be seen almost old ages. Indeed, some authorities contend that some degree of diastolic dysfunction is present in virtually every patient with cirrhosis.18-21 Therefore, estimation of diastolic dysfunction with simple echocardiography is not enough to differentiate true CCM patients from general cirrhotic patients. The most prominent feature of CCM is systolic dysfunction of LV compared with general cirrhotic patients. Hence, a provocative test for cardiac systolic dysfunction in liver cirrhosis patients based on CCM pathophysiology is needed as a screening test. Until now, many attempts to stress the ventricle by a physiological or pharmacological method have been made. In the case of the exercise test, reduced exercise capacity of cirrhotic patients related with aging process or other causes unrelated with cardiac function made it difficult to use as a provocation test.15,22 While some previous studies used dobutamine on cirrhotic patients, it was just used to assess the risk of ischemic heart disease prior to a major operation; it was not proposed to estimate CCM.23,24

Heart cell contractility is mainly determined by the stimulatory β-adrenergic receptor system. When stimulated by norepinephrine or other catecholamines, the β-adrenergic receptor-ligand complex couples with G-protein to stimulate membrane-bound adenylate cyclase, generating cAMP which phosphorylates several proteins leading to intracellular calcium fluxes. The calcium then causes actin-myosin cross-linking, and thus cellular contraction.8,9 The impairment of such stimulatory β-adrenergic receptor signalling pathways is the main pathogenesis of CCM; hence we assumed that ventricular systolic and diastolic function in a CCM patient would be blunted by norepinephrine or other catecholamines stimulation such as dobutamine. Cardiac responses to environmental changes are probably even more important than how heart function at rest. Dobutamine is the most commonly used sympathomimetic agent for pharmacologic stress testing through having its effect of direct inotropic stimulation. This study is the first to apply DSE for differentiating CCM from general cirrhosis. We analyzed blunted and normal response cirrhosis patients according to left ventricular volume response after dobutamine infusion (Fig. 1, 2, 3). The criteria of abnormal LV volume response used in this study has already been proven as an independent prognostic value for cardiac event during major vascular surgery in the department of cardiology.10 In this study, according to these criteria, definitive blunted or inversed responses of LV during DSE were observed in 18 (25%) among 71 cirrhotic patients. Based on action mechanism of dobutamine, impaired cardiac response to dobutamine stimulation may arise from defects in β-adrenergic receptor signalling pathways, implicated in CCM. It suggests that patients with blunted cardiac response to dobutamine may potentially have higher risk of sudden cardiac events, such as heart failure after major operation than those without impaired response. In fact, no characteristic difference in diastolic indices and liver profiles between normal and blunted DSE response group was observed in either the rest or stressed state. In other words, the latent risk of cardiac event cannot be detected with previously established liver profiles such as Child-Pugh score, MELD, or diastolic cardiac indices. Hence, detecting patients with impaired β-adrenergic receptor signal transduction through DSE prior to a major operation could be helpful to prevent unexpected cardiac events.

In conclusion, blunted cardiac response to dobutamine stimulation were frequently observed in cirrhotic patients, which may be attributed to defects in β-adrenergic receptor signalling pathways, which is one of major pathogenesis of CCM.