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Historical Aspects and Definition

  1. Top of page
  2. Abstract
  3. Historical Aspects and Definition
  4. Main Features of Cirrhotic Cardiomyopathy
  5. Pathophysiology of Cirrhotic Cardiomyopathy
  6. Clinical Relevance of Cirrhotic Cardiomyopathy
  7. References

The occurrence of systemic hemodynamic abnormalities in cirrhosis has been recognized for more than half a century. These hemodynamic changes consist of a reduced peripheral vascular resistance and a compensatory increase in cardiac output leading to the hyperdynamic circulatory syndrome. By contrast, evidence of cardiac abnormalities associated with cirrhosis is relatively new and still awaits full characterization. The cluster of cardiac abnormalities has been termed cirrhotic cardiomyopathy, defined as a chronic cardiac dysfunction in patients with cirrhosis, characterized by blunted contractile responsiveness to stress, and/or altered diastolic relaxation with electrophysiological abnormalities, in the absence of known cardiac disease1 (Table 1). Initially thought to be a consequence of a latent alcoholic cardiomyopathy in patients with alcoholic cirrhosis, it has become clear that cardiac abnormalities leave aside the etiology of the underlying liver disease.

Table 1. Main Features of Cirrhotic Cardiomyopathy
Systolic dysfunction
 Generally subclinical; can be unveiled by increasing the cardiac afterload, physical exercise, stressful event
Diastolic dysfunction
 Revealed by the echocardiographic study of the diastolic transmitral flow pattern; can be unveiled by sudden increases in cardiac preload (e.g., TIPS)
Electrophysiological abnormalities
 Chronotropic incompetence
  Incapacity of increasing heart rate under physiological or pharmacological adrenergic stimulation
 Electromechanical uncoupling
  Disruption of the process leading to cardiomyocyte contraction following electrical excitation
 Electrocardiographic QT interval prolongation
  Due to altered repolarization, needs to be corrected by heart rate; Fredericia's formula (QTc = QT/3RR) should be used in cirrhosis
Pathological features
 Hypertrophy of left ventricle (mainly interventricular septum and and posterior wall)
 Left atrium atrium dilatation

Main Features of Cirrhotic Cardiomyopathy

  1. Top of page
  2. Abstract
  3. Historical Aspects and Definition
  4. Main Features of Cirrhotic Cardiomyopathy
  5. Pathophysiology of Cirrhotic Cardiomyopathy
  6. Clinical Relevance of Cirrhotic Cardiomyopathy
  7. References

Systolic Dysfunction

A blunted responsiveness to physiological and pharmacological stresses has been documented in several experimental settings. One of the first studies showed that the rise in peripheral vascular resistance induced by angiotensin II infusion was followed by a striking increase in pulmonary arterial wedge pressure without changes in cardiac output. This suggests that the left ventricle is unable to cope with a sudden increase in afterload.2 Since then, many other studies have directly or indirectly confirmed these findings. Similar results have been obtained studying the effects of the exercise challenge, which led the ejection fraction in cirrhotic patients to increase by only 6% compared with a 14% increase in healthy subjects, despite similar values at baseline.3

Diastolic Dysfunction

This is a prominent and frequent feature of cirrhotic cardiomyopathy, which can be disclosed by echocardiographic study of the diastolic transmitral flow pattern.4 An increased atrial contribution to late ventricular filling, leading to a reduced E wave to A wave ratio suggests diastolic dysfunction. Other features include prolonged isovolumetric relaxation time and deceleration time due to increased resistance to ventricular inflow. However, the different methods used to assess diastolic function may have led to different results. An ongoing large multinational study will likely establish the definitive picture of this abnormality.

Diastolic dysfunction is often linked to cardiac structure abnormalities, such as increased interventricular septal and posterior wall thickness, and increased diameter of the left atrium. However, a functional component cannot be excluded, as improvements in diastolic dysfunction have been reported after paracentesis in patients with tense ascites and transjugular intrahepatic portosystemic shunt (TIPS) insertion in patients with reduced effective volemia.5

Electrophysiological Abnormalities

These changes consist of chronotropic incompetence—that is, the inability to increase heart rate under physiological and pharmacological stimuli—electromechanical uncoupling, and prolongation of the electrocardiographic QT interval. The prolonged QT interval has received the greatest attention, as it represents the substrate of severe ventricular arrhythmias in other settings of congenital and acquired QT prolongation.6

The prevalence of QT prolongation in cirrhosis is exceedingly high and increases in parallel with the severity of cirrhosis, so that up to 60% or more of patients with end-stage liver disease show this abnormality.7

Pathophysiology of Cirrhotic Cardiomyopathy

  1. Top of page
  2. Abstract
  3. Historical Aspects and Definition
  4. Main Features of Cirrhotic Cardiomyopathy
  5. Pathophysiology of Cirrhotic Cardiomyopathy
  6. Clinical Relevance of Cirrhotic Cardiomyopathy
  7. References

The pathogenesis of this syndrome is multifactorial and still incompletely defined. It includes diminished β-adrenergic receptor signal transduction, cardiomyocyte cellular plasma membrane dysfunction, and ion channel defects (Fig. 1). These abnormalities result from increased activity or levels of cardiodepressant substances such as cytokines, endogenous cannabinoids, and nitric oxide.1, 4, 8 Increased sympathetic nervous system activity in the presence of potassium channel defects, as occurs in congenital long QT syndromes, likely plays a pathogenetic role also in cirrhosis (Fig. 2). Interestingly, both acute and chronic β-blockade shorten the QT interval in those patients showing a long QT.6

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Figure 1. Schematic representation of the molecular events following β1-adrenergic stimulation in the cardiac myocyte. β1-Adrenergic receptor stimulation leads to interaction with G protein; then, a cascade of events from adenylcyclase activation leads to the phosphorylation of ion channels. Phosphorilation of the Ca channels ultimately leads to cross-bridging of myosin and actin and, therefore, myocyte contraction. Phosphorylation of Na channels favors depolarization of phase 4 of the action potential, ultimately leading to heart rate acceleration. A number of receptor and postreceptor abnormalities have been described in cirrhosis, as reported in the red flags. These defects account for reduced contractility, chronotropic incompetence, and electromechanical uncoupling. β, β1-adrenergic receptor; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; G, G protein; ICa-L, slowly decaying inward Ca2+ current; INa-B, inward Na+ background leak current. Modified with permission from Journal of Hepatology.6 Copyright 2006, Elsevier.

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Figure 2. Schematic representation of the cardiac action potential and the ionic flows leading to depolarization and repolarization. The abrupt depolarization in phase 0 is provoked by the inflow of Na+ and Ca2+ ions. The outflow of K+ initiates the repolarization in phase 1; then a plateau phase follows during phase 2, due to the opposite effects of K+ outflow and Na+ and Ca2+ inflows. The resting potential of phase 4 is reached through the K+ outflow occurring during phase 3. During repolarization, β1-Adrenergic stimulation favors both K+ outflow and Na+ and Ca2+ inflows. This can explain its dual effects—that is, either shortening or prolongation of the repolarization. In the presence of K channel defects, as it occurs in most congenital long QT syndrome, hypokalemia, and many drug-induced QT prolongations, adrenergic stimulation actually lengthens QT interval. In experimental cirrhosis, K channel defects have been described. ICa-T, inward T-type Ca2+ current; INa, inward fast Na+ current; INaCa, electrogenic Na+ - Ca2+ exchange current; ITO-K, transient outward K+ current; ICa-L, slowly decaying inward Ca2+ current; IK, delayed rectifier K+ current. Modified with permission from Journal of Hepatology.6 Copyright 2006, Elsevier.

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Clinical Relevance of Cirrhotic Cardiomyopathy

  1. Top of page
  2. Abstract
  3. Historical Aspects and Definition
  4. Main Features of Cirrhotic Cardiomyopathy
  5. Pathophysiology of Cirrhotic Cardiomyopathy
  6. Clinical Relevance of Cirrhotic Cardiomyopathy
  7. References

In recent years, it has become apparent that cirrhotic cardiomyopathy may be responsible for several complications of cirrhosis. Unexpected cardiac failure with pulmonary edema following liver transplantation may be explained by underlying systolic and diastolic dysfunctions not clearly detected before surgery.1 In addition, patients with a long QT interval undergoing liver transplantation tend to have a worse outcome.6

Systolic dysfunction and chronotropic incompetence are also involved in the pathogenesis of hepatorenal syndrome and probably the circulatory failure induced by severe sepsis. The inability to sustain an increase in cardiac output sufficient to cope with the hemodynamic requirements imposed by the extreme vasodilation characterizing these conditions is of crucial pathogenetic importance.9

Heart failure and acute pulmonary edema have been reported after TIPS, likely due to the acute preload increase following the sudden translocation of portal venous blood into the systemic veins.1 Diastolic dysfunction appears to influence the outcome of TIPS, as patients in whom this abnormality does not improve within 28 days have an increased mortality.5 Thus, careful assessment of cardiac function before TIPS is warranted.

Despite reports of sudden death associated with QT interval prolongation, the common perception is that sudden death is rare in cirrhosis. However, the occurrence of arrhythmic complications is likely to be underestimated, because patients with cirrhosis do not usually undergo electrocardiographic monitoring even when complications arise. Indeed, it is likely that under stressful conditions, such as gastrointestinal bleeding and bacterial infections, which lead to a further and abrupt increase in sympathetic nervous system activity and cytokine release, an altered ventricular repolarization fully displays its threatening potential. At present, it has been demonstrated that gastrointestinal bleeding in cirrhosis actually lengthens the QT interval, and QT prolongation is associated with a 6-week mortality in this setting.10 Whether QT abnormality not only predicts but also contributes to mortality owing to its arrhythmogenic potential, remains to be established. In any case, we should be aware that drugs (Table 2) such as macrolides, some quinolones (moxifloxacin, sparfloxacin), and domperidone that prolong the QT interval and favor ventricular arrhythmias are often used in patients with cirrhosis without monitoring the QT length, thereby underestimating their arrhythmogenic potential.

Table 2. Drugs Known to Prolong QT Interval and Favor Ventricular Arrhythmias
High-risk drugs
 Bepridil
 Disopyramide
 Dofetilide
 Ibutilide
 Procainamide
 Quinidine
 Sotalol
Other drugs
 Amiodarone
 Antibiotics
  Macrolides (clarithromycin and erythromycin)
  Quinolones (moxifloxacin and sparfloxacin)
  Pentamidine
 Antipsychotic agents
  Chlorpromazine
  Haloperidol
  Mesoridazine
  Thioridazine
  Pimozide
 Arsenic trioxide
 Calcium channel blockers
  Lidoflazine
  Verapamil
 Drugs acting on gastrointestinal motility
  Domperidone
  Droperidol
  Cisapride
 Methadone

References

  1. Top of page
  2. Abstract
  3. Historical Aspects and Definition
  4. Main Features of Cirrhotic Cardiomyopathy
  5. Pathophysiology of Cirrhotic Cardiomyopathy
  6. Clinical Relevance of Cirrhotic Cardiomyopathy
  7. References