**Cirrhotic Cardiomyopathy Provisional chapterCirrhotic Cardiomyopathy**

Coskun Celtik, Nelgin Gerenli, Coskun Celtik, Nelgin Gerenli,

Halil Haldun Emiroglu and Nimet Cındık Halil Haldun Emiroglu and Nimet Cındık

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65318

#### **Abstract**

Cirrhotic cardiomyopathy (CCMP) is a functional disorder characterized by electro‐ physiologic disturbances and diastolic and/or systolic dysfunction in patients with chronic liver disease, especially those with ascites and portal hypertension. This disorder is a well‐defined entity in adults, but pediatric data are limited. Clinical and laboratory findings are generally latent. The diagnostic criteria are prolonged QT on electrocardiography due to metabolic and extrahepatic causes, in addition to some abnormal echocardiography findings. If echocardiographic findings are normal and only specific prolonged QT is present, this disorder is named as "latent CCMP"; otherwise, it is "manifest CCMP." This disorder is important because it may lead to problems such as cardiac failure and dysrhythmia before or after liver transplantation. Moreover, it may worsen the prognosis.

**Keywords:** cirrhosis, portal hypertension, cardiomyopathy, prolonged QT, liver

### **1. Introduction**

Portal hypertension (PHT) is an important disorder that increases morbidity and mortality rates. Many hemodynamic changes related to PHT occur in the human body. The majority of these changes are associated with hyperdynamic circulation, which is characterized by elevated heart rate and cardiac output accompanied by vasodilatation in the splanchnic area and systemic circulation and decreased systemic vascular resistance [1–9]. Moreover, disturbances of the autonomic nerve system and baroreceptors and the increased arterial

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

compliance in patients with cirrhosis aggravate the condition [10–12]. Hemodynamic changes that occur in portal hypertension are shown in **Table 1**.

Cardiovascular disorders associated with cirrhosis were first defined in alcoholic cirrhotic patients, in 1953 by Kowalski and Abelmann, but for many years, it was thought that these disorders were associated with chronic alcohol intake [10–12]. Similar disturbances were described in patients with cirrhosis who had hemochromatosis in some later research, but this time the changes were associated with hemochromatosis [13]. Consequently, cirrhotic cardio‐ myopathy was not known in those years.


**Table 1.** The hemodynamic changes due to cirrhotic portal hypertension [6].

Caremelo et al. first described cirrhotic cardiomyopathy in 1986. The authors demonstrated cardiac function disturbances due to cirrhosis in an experimental rat model and suggested the cirrhotic cardiomyopathyhypothesis.Theirhypothesis was supportedby subsequentresearch, and cardiac disorders due to cirrhosis and portal hypertension were named "cirrhotic cardio‐ myopathy" in 1989 [1–12, 14]. Although the name "hepatocardiac syndrome" was proposed by some authors instead of "cirrhotic cardiomyopathy," this term was not accepted [14].

### **2. Definition**

Cirrhotic cardiomyopathy (CCMP) is defined as a functional disorder characterized by electrophysiologic disturbances and diastolic and/or systolic dysfunction in patients with cirrhotic PHT. Even though similar hemodynamic changes have been defined in long‐term non‐cirrhotic PHT, the development of CCMP in such patients has not been reported. There‐ fore, this term is usually used for patients with cirrhosis [10, 15–18].

### **3. Pathogenesis**

compliance in patients with cirrhosis aggravate the condition [10–12]. Hemodynamic changes

Cardiovascular disorders associated with cirrhosis were first defined in alcoholic cirrhotic patients, in 1953 by Kowalski and Abelmann, but for many years, it was thought that these disorders were associated with chronic alcohol intake [10–12]. Similar disturbances were described in patients with cirrhosis who had hemochromatosis in some later research, but this time the changes were associated with hemochromatosis [13]. Consequently, cirrhotic cardio‐

> Cardiac flow (→) ↑ Arterial blood tension → ↓

Systemic vascular resistance ↓

Right ventricle end‐diastole tension → Pulmonary arterial tension → ↑ Pulmonary capillary wedge tension → Left ventricle end‐diastole tension →

Right atrial tension → ↑

Heart rate ↑

Pulmonary blood flow ↑ Pulmonary vascular resistance ↓ (↑)

Skin blood flow → ↑ Muscular and skeletal circulation → ↑ ↓

Caremelo et al. first described cirrhotic cardiomyopathy in 1986. The authors demonstrated cardiac function disturbances due to cirrhosis in an experimental rat model and suggested the cirrhotic cardiomyopathyhypothesis.Theirhypothesis was supportedby subsequentresearch, and cardiac disorders due to cirrhosis and portal hypertension were named "cirrhotic cardio‐ myopathy" in 1989 [1–12, 14]. Although the name "hepatocardiac syndrome" was proposed by

Cirrhotic cardiomyopathy (CCMP) is defined as a functional disorder characterized by electrophysiologic disturbances and diastolic and/or systolic dysfunction in patients with

some authors instead of "cirrhotic cardiomyopathy," this term was not accepted [14].

Renal blood flow ↓ Renal vascular resistance ↑

**Table 1.** The hemodynamic changes due to cirrhotic portal hypertension [6].

that occur in portal hypertension are shown in **Table 1**.

myopathy was not known in those years.

260 Cardiomyopathies - Types and Treatments

**Systemic circulation** Plasma volume ↑ Total blood volume ↑ Noncentral blood volume ↑ Central arterial blood volume → ↓ (↑)

Left atrial volume ↑ Left ventricle volume → (↓) Right atrial volume → ↑ ↓ Right ventricle volume → ↑ ↓

**Pulmonary circulation**

**Renal circulation**

**Cerebral circulation** Cerebral blood flow ↓ →

**2. Definition**

**Skin, muscular, and skeletal circulation**

↑, increased; ↓, decreased; →, not changed

**Heart**

In general, arterial vasodilatation, central hypovolemia, and hyperdynamic circulation which occur as a result of cirrhosis and portal hypertension lead to the development of CCMP together with hepatorenal syndrome and hepatopulmonary syndrome (**Figure 1**) [11, 19–23]. Effects of vasoactive agents are very important in pathogenesis of CCMP. Experimentally, some changes were defined in CCMP, such as downregulation of the density of β receptors, impaired β‐adrenergic signaling, alternations of calcium‐ion channels, and alternations in plasma membrane fluidity in cardiomyocytes. In addition, the increased serum bile acids, cytokines, and endotoxins have been shown to create negative effects on cardiomyocytes [9–12, 14, 22].

**Figure 1.** Cirrhotic cardiomyopathy pathogenesis.

Vasoconstrictor substances are high in the early stages of PHT, and vasodilator substances gradually increase in advanced stages; the balance tips in favor of vasodilators and a receptor insensitivity develops against vasoconstrictors [10–12, 19, 23–30]. As a result of these events, arterial vasodilatation results and the severity of PHT increases [19, 23–30].

The splanchnic vasodilatation that develops in PHT is combined with a hyperkinetic systemic circulation, low arterial tension, decreased peripheral resistance, and increased cardiac flow. Although total plasma volume increases, as a result of collection of blood in the splanchnic area, effective blood capacity cannot be achieved, and central hypovolemia develops. After these changes, activation of the sympathetic nervous system and renin‐aldosterone system occurs; vasopressin release from the hypothalamus increases, which results in fluid and salt retention [30–33].

The vasoconstrictor and vasodilator substances in the pathogenesis PHT become effective together. The most important vasoconstrictor substances are norepinephrine, angiotensin II, vasopressin, thromboxane (TX), and leukotrienes. The effects of these substances are related with activation of the sympathetic nervous system and renin‐angiotensin‐aldosterone system. Researches have shown that portal venous tension can be decreased using alpha‐adrenergic antagonists (prazosin), beta‐adrenergic antagonists (propranolol), angiotensin‐II antagonists, cyclooxygenase isoenzyme blockers, and TX antagonists. Results of these researches support the pathogenesis [22, 29–34].

Endothelin (ET) can show vasoconstrictor or vasodilator effects according to the type. Endo‐ thelins are classified as ET‐1, ET‐2, and ET‐3 according to their region in the body. ET‐1 is mainly found in endothelial cells, the kidney, and the brain and ET‐2 in the small intestine and kidney, and ET‐3 is found in the blood. ET‐1 and ET‐2 create a vasoconstrictor effect, whereas ET‐3 has a vasodilator effect. These two opposite effects are associated with the induction of nitric oxide and prostacyclin release. The most potent vasoconstrictor substance in the body is ET‐1, and it is reported that this substance is very effective in the development of PHT complications [22, 29–34].

Nitric oxide (NO) is another very potent substance in the pathogenesis of PHT. NO is synthe‐ sized from arginine by nitric oxide synthetase (NOS) and causes vasodilatation by increasing cyclic guanosine monophosphate. NO initially increases to compensate against the elevated vasoconstrictor agents in the early stage of PHT, but secondary systemic and splanchnic vasodilatation develops because of excessive NO production. This event is a result of stimu‐ lation of NOS by cytokines such as TNF‐alpha, which increases in cirrhosis [22, 30–36].

The other important vasodilator substances in the pathogenesis of PHT are carbon monoxide (CO), hydrogen sulfide (H2S), prostaglandins, glucagon, and endocannabinoids. CO formed through the heme‐oxygenase system is a weaker vasodilator agent than NO, but it is important for regulation of intrahepatic vascular tone. H2S is formed by intestinal microbiota and increases the effects of other vasodilator substances and PHT severity [22, 30–36].

Prostaglandins are endogen vasodilators produced in the endothelium and are important for hyperdynamic circulation. Prostacyclin is produced from the vascular endothelium. It leads to vasodilatation, which increases the level of intracellular cyclic adenosine monophosphate (c‐AMP) through the activation of adenylate cyclase. In recent studies, it was shown that indomethacin, a prostacyclin inhibitor, decreased the hyperdynamic circulation and balanced the vasoconstrictor effect [22, 30–36].

Glucagon is a hormone released from the pancreas. Glucagon levels increase as a result of low hepatic clearance and stimulation of pancreatic alpha cells in patients with cirrhosis. Glucagon also has the effect of reducing endogenous vasoconstrictor activity in addition to having a vasodilator effect. The use of somatostatin and synthetic glucagon analogs for PHT therapy has been proposed in some studies; however, these agents may constitute a risk because they can aggravate the splanchnic vasodilatation in advanced stages [22, 30–36].

Endocannabinoids such as anandamide are vasodilator substances that increase in PHT, worsen hepatic microcirculation, and accelerate apoptosis. These substances act by stimulating CB1 and CB2 receptors in the vascular endothelium. It has been reported that endogen cannabinoids show a negative inotropic effect on myocardial contractions, and therefore these substances are very important for the development of cirrhotic cardiomyopathy [39–41]. These negative effects can be blocked by CB‐1 receptor antagonists (AM251) [22, 30–40].
