Cardiopulmonary Complications of Cirrhosis

Abbreviations

BNP

brain natriuretic peptide

CBDL

common bile duct ligation

CCM

cirrhotic cardiomyopathy

HO-1

heme oxygenase-1

HPS

hepatopulmonary syndrome

iNOS

inducible nitric oxide synthase

mPAP

mean pulmonary artery pressure

PAH

pulmonary arterial hypertension

POPH

portopulmonary hypertension

TDI

tissue Doppler imaging

TIPS

transjugular intrahepatic portosystemic shunt

TNF-α

tumor necrosis factor α

Introduction

The impact of cirrhosis on cardiac function was largely ignored until the 1960s because the enhanced basal cardiac output characteristic of the hyperdynamic circulation appeared to reflect normal contractile function. However, in 1969 two pioneering studies contradicted this common belief and found an attenuated cardiac responsiveness to both physiologic and pharmacologic challenges, a phenomenon initially ascribed to the presence of mild or latent alcoholic cardiomyopathy. During the following 2 decades a number of other studies confirmed these findings of impaired cardiac function, but it was not until the late 1980s that the blunted cardiac responses were attributed to cirrhosis itself rather than to alcohol-related injury The term cirrhotic cardiomyopathy (CCM) was coined to describe the phenomenon in which baseline ventricular contractility is normal or increased yet there is a decreased cardiac response to stress. Stress may include pharmacologic agents, exercise, sudden intravascular volume shifts, and procedures such as transjugular intrahepatic portosystemic shunts (TIPSs) and liver transplant.

Definition and Diagnosis of Cirrhotic Cardiomyopathy

There are no specific, widely accepted diagnostic criteria for CCM. The 2005 working group at the World Congress of Gastroenterology in Montreal established criteria for CCM including (1) systolic dysfunction—blunted cardiac response to stress or stimulus (exercise, drugs, infections, or procedures) despite increased baseline cardiac output and cardiac contractility; (2) diastolic dysfunction—age corrected E / A ratio (ratio between early [ E ] and late [ A ] ventricular filling velocities) less than 1.0, prolonged isovolumetric relaxation time (>80 msec), or prolonged deceleration time (>200 msec); (3) supportive criteria—electrophysiologic abnormalities, abnormal chronotropic response, prolonged corrected QT interval (QTc interval), increased myocardial mass, electromechanical dyssynchrony, and/or abnormal levels of cardiac serologic markers (brain natriuretic peptide [BNP] and/or troponin I). However, not all investigators and studies have used the same combination of criteria to make the diagnosis. Therefore clinicians must rely on a combination of tests to assess the features described previously.

The most common tests include electrocardiography, echocardiography with or without tissue Doppler imaging (TDI), and serologic markers.

Electrocardiography

Twelve-lead electrocardiography will detect QTc interval prolongation, which is the most common conduction abnormality observed in patients with CCM. QTc interval prolongation has been reported in 30% to 60% of cirrhotic patients. The wide variability in the percentage of patients with QTc interval prolongations reflects in part the multiple differing methods available to correct the QT interval for heart rate.

Echocardiography

Echocardiography evaluates real-time cardiac function and can detect both systolic and diastolic dysfunction. Baseline ejection fraction in patients with cirrhosis is similar to that in controls, although studies have revealed that there may be reduced ventricular wall compliance and enlarged atrial dimensions. In noncirrhotic patients with heart failure, diastolic dysfunction usually precedes systolic dysfunction. This finding and concept seems to hold true in cirrhotic patients as well. Most of the studies evaluating diastolic function in cirrhosis reveal a stiff, hypertrophic left ventricle at rest. The E / A ratio, a maker of left ventricular function, is invariably reduced in patients with cirrhosis with diastolic dysfunction. Whether diastolic function is a precursor to systolic dysfunction under stress is yet unknown.

Tissue Doppler Imaging

TDI measures the velocity of the myocardium through the phases of one or more heartbeats by the Doppler effect. It is evolving as a useful echocardiographic tool for quantitative assessment of left ventricular systolic and diastolic function and may enhance the detection of diastolic dysfunctions. Cirrhotic patients with abnormal TDI have more ascites, lower albumin levels, higher BNP levels, and a longer QTc interval than cirrhotic patients with normal tissue Doppler imaging.

Stress Testing

Echocardiographic and radionuclide perfusion stress testing may detect cardiac systolic dysfunction in response to a stimulus. Impaired response to stress has been appreciated in cirrhotic patients, particularly in cirrhosis with ascites and more advanced liver disease. However, these tests have not been standardized for diagnosis of CCM.

Serologic Markers

BNP and pro-BNP levels have been found to be elevated in patients with cirrhosis and appear to correlate with the severity of liver disease, diastolic dysfunction, and QTc interval prolongation. Whether these biomarkers specifically reflect cardiac dysfunction or could result from cardiac chamber dilatation associated with volume overload related to end-stage liver disease is not yet established. Nonetheless, reports suggest that elevated BNP levels may be associated with pre–liver transplant and post–liver transplant outcomes. Further studies are needed to verify these findings.

Natural History and Epidemiology

The actual prevalence of CCM is difficult to discern because of the frequent lack of symptoms in the absence of stress and uncertainty regarding diagnostic testing. As many as 50% of patients who undergo liver transplant develop signs of cardiac dysfunction after liver transplant, and one early report found that as many as 7% of patients die of heart failure in the postoperative period. However, a direct relationship between CCM and these outcomes has not been established. Data support that the degree of left ventricular dysfunction correlates with the severity of portal hypertension and synthetic dysfunction. This relationship appears to be similar to that for other end organs, including brain, kidneys, and gut, as well as the overall hyperdynamic circulation. In individuals with CCM, the ventricular contractile response to exercise or other stress progressively diminishes and QT interval prolongation is accentuated as liver function deteriorates. Moreover, the relationship between circulatory changes and liver failure also holds when liver function improves. In patients with alcoholic liver disease, alcohol abstinence improves liver function and also hyperdynamic circulatory indices, as does liver transplant in patients with pretransplant evidence of CCM.

Pathogenesis of Cirrhotic Cardiomyopathy

Most of the data regarding mechanisms of CCM come from evaluation of the common bile duct ligation (CBDL) model. Studies have focused on cardiomyocyte membrane alterations, altered nitric oxide and carbon monoxide signaling, and inflammatory mediators ( Fig. 18-1 ).

Fig. 18-1, Pathogenetic changes of cirrhotic cardiomyopathy.

Cardiomyocyte Membrane Alterations

Alterations in the membrane β-adrenergic receptor system, the primary regulator of myocardial contractility and membrane Ca ²⁺ and K ⁺ channel function, have been found after CBDL. β-Adrenergic receptor density and downstream signaling pathways are decreased and are further inhibited by altered membrane fluidity due to increased cholesterol levels in cirrhosis. These events decrease contractility. In addition, membrane L-type calcium channel protein expression is also decreased, which impairs influx of Ca ²⁺ into the cell and lowers intracellular levels, thereby further reducing contractility. Finally, reduction of two types of membrane K ⁺ currents, the Ca ²⁺ -independent transient outward K ⁺ current and the sustained delayed rectifier current, is found after CBDL. Reduction of these K ⁺ currents may prolong the action potential and thus the QT interval. These events could explain the prolonged QT interval in CCM.

Nitric Oxide and Carbon Monoxide Alterations

Systemic or local cardiac overproduction of nitric oxide, from any of the three isoforms of nitric oxide synthase (NOS), may also play a role in cardiac contractile dysfunction. In CBDL animals, overexpression of inducible NOS but not other isoforms (endothelial or neuronal NOS) occurs in cardiomyocytes. Further, NOS inhibition in isolated left ventricular papillary muscles improved cardiac function.

In addition to alterations in nitric oxide production, cardiac expression of heme oxygenase 1, the enzyme responsible for carbon monoxide generation, is also increased after CBDL. Further, treatment with a heme oxygenase inhibitor (zinc protoporphyrin IX) restored the blunted contractile response in left ventricular papillary muscles. The precise mechanisms and roles of altered nitric oxide and carbon monoxide production in CCM require further investigation.

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