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Prolonged Q-Tc interval in mild portal hypertensive cirrhosis: QTc Prolongation in HIV- is it due to HAART, PIs or just liver dysfunction
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Note from Jules Levin: perhaps QT-c prolongation found in HIV is due to liver dysfuncyion & not HAART.
Journal of Hepatology
Oct 2005
Henriette Yttingab, Jens H. Henriksena, Stefan Fuglsanga, Flemming Bendtsenb, Soren Mollera
ABSTRACT
Background/Aims
The Q-Tc interval is prolonged in a substantial fraction of patients with cirrhosis, thus indicating delayed repolarisation. However, no information is available in mild portal hypertensive patients. We therefore determined the Q-Tc interval in cirrhotic patients with hepatic venous pressure gradient (HVPG)<12mmHg.
Methods
Forty-four patients with cirrhosis and HVPG<12mmHg underwent a haemodynamic study. They were compared with 36 cirrhotic patients with clinically significant portal hypertension (HVPG≥12mmHg) and controls without liver disease.
Results
The fraction with prolonged Q-Tc interval (>0.440s1/2) was similar in the two cirrhotic groups (49 vs 50%, ns) and significantly above that of the controls (5%, P<0.005). Q-Tc was normal in patients with normal HVPG. Likewise, mean Q-Tc was 0.449 and 0.447s1/2 in the two cirrhotic groups (ns), values which are significantly above that of the controls (0.410s1/2, P<0.01). In the mild portal hypertensive group, the Q-Tc interval was inversely related to indicators of liver function, such as indocyanine green clearance (r=-0.34, P<0.02).
Conclusions
Delayed repolarisation of the myocardium already occurs in a substantial fraction of patients with cirrhosis with only a mild increase in portal pressure. The prolonged Q-Tc interval may be related to liver dysfunction and to the presence of portal hypertension.
Study population
Normal portal pressure and mild portal hypertensive cirrhosis. This group consists of 44 consecutive patients with cirrhosis, who were referred for haemodynamic investigation, whose HVPG was<12mmHg. Forty-three patients had biopsy-verified cirrhosis. In the remaining patient, the diagnosis was established on clinical findings, ultrasonography, and laboratory tests. The age range was 23-68 years, with an average age of 51 years. The aetiology was alcoholic in 39 patients. None of the patients had experienced recent gastrointestinal bleeding or had encephalopathy above grade I. All were abstaining from alcohol for at least 3 weeks and had no signs of withdrawal symptoms at the time of the study. None had signs of heart failure, organic renal disease, diabetes, cancer, or any other major disease. All were given a cardiac physical examination and the results were normal. None of the patients were being treated with beta-adrenergic blocking agents, calcium channel blockers, digoxin, antiarrhythmic agents, or vasoactive substances. ECG showed normal configurations, apart from sporadic extrasystoles in a few patients. Twenty-nine patients belonged in Child-Turcotte class A, 12 in class B, and 3 in class C. The patients were divided into three groups: group I (n=7) normal portal pressure (HVPG<5mmHg); group II (n=20) mild portal hypertension (HVPG≥5 and <10mmHg) and never being decompensated (i.e. never fluid retention or treated with diuretics); group III (n=17) mild portal hypertension (HVPG≥5mmHg and <12mmHg) and treated with diuretics. These patients were put on a 50mmol/day sodium intake.
Discussion
The present study shows that: 1° cirrhotic patients with normal portal pressure and well-preserved liver function have normal Q-Tc intervals; 2° cirrhotic patients with mild portal hypertension have a high frequency of prolonged Q-Tc intervals, as have those with clinically significant portal hypertension; 3° the prolonged Q-Tc interval is related to indicators of reduced liver function.
This is the first study to address the length of the Q-T interval in patients with cirrhosis with mild portal hypertension (i.e. a HVPG between 5 and 12mmHg). In these mild portal hypertensive patients, the fraction of patients with prolonged Q-Tc intervals was surprisingly high and equal to a group of patients with clinically significant portal hypertension (HVPG above 12mmHg). However, in cirrhotic patients with normal portal pressure and well-preserved liver function, the Q-Tc values were in the normal range. The patients with HVPG below 12mmHg were consecutively recruited from patients referred for haemodynamic investigation without any knowledge of the ECG, and the Q-T interval was determined blind. A selection bias in favour of patients with high Q-Tc intervals, therefore, seems unlikely. Moreover, the Q-T and Q-Tc intervals were closely similar in the groups with mild and clinically significant portal hypertension with more than 10mmHg difference in the average portal pressure, which indicates that portal hypertension above a certain level is not the most important determinant of prolonged Q-Tc intervals in patients with cirrhosis.
The mechanisms by which cirrhosis affects ventricular repolarisation and thereby the Q-Tc are not known. Several interferences related to liver dysfunction, alcoholic intake, portal hypertension, systemic circulatory disturbances, autonomic dysfunction, and, recently, portosystemic shunting have been suggested [12-16,19]. The suggestion of a role of portosystemic shunting was based on findings of a prolonged Q-Tc in non-cirrhotic portal hypertensive patients and a further prolongation of the Q-Tc interval in some cirrhotic patients after insertion of TIPS [19]. Both patient groups have a common potential pathogenetic factor in their portosystemic shunts. However, the present finding of substantially prolonged Q-Tc intervals in mild portal hypertensive cirrhotic patients, who are likely to present only minor portosystemic shunting, shows that other elements may be important in the long Q-Tc syndrome in cirrhosis.
Increased circulatory concentrations of bile acids and insulin have been proposed as candidates of prolonged Q-Tc in patients with cirrhosis, as bile salts are cardiotoxic and their plasma levels have been reported to be directly related to the length of the Q-T interval [12,19]. ICG clearance may to some extent reflect the cholestatic status of the liver, and the present finding of an inverse relation between the Q-Tc interval and ICG clearance may support this view.
Liver function is complex and multiform. In the present study, it was estimated by the galactose elimination capacity and the indocyanine green clearance [10,21,24]. The significant relation to indocyanine green clearance in the mild portal hypertensive patients and the significant relation to galactose elimination capacity in untreated patients suggest that liver dysfunction is a determinant of a prolonged Q-Tc interval. This point of view is supported by the finding of a normal Q-Tc interval in early cirrhotic patients with normal HVPG and well-preserved liver function.
The lack of an overall relation of the Q-Tc interval and portal hypertension between groups of patients does not preclude a relation to portal pressure. Thus, we have recently found that reduction of portal pressure by beta-adrenergic blockade in the individual cirrhotic patient was related to a reduction in the prolonged Q-Tc interval [20]. However, beta-blocking agents may also have an impact on ventricular repolarisation independent of their effect on portal pressure. Moreover, several previous studies have indicated that there may be a relation between reduced liver function and portal hypertension in unselected patients with cirrhosis [19,28,29]. Orthotopic liver transplantation improves the prolonged Q-Tc interval in patients with cirrhosis. This may be because of improved liver function, reduced portal venous pressure, or both [19,28,29]. However, the relative role of liver dysfunction and elevated portal pressure in the origin of prolonged Q-Tc cannot be established from these studies, as orthotopic liver transplantation most often corrects both abnormalities.
The Q-T interval is an indicator of the electrical systole and may be influenced by several factors, including serum electrolytes and diuretic treatment [30-32]. Our patients had serum potassium concentrations within the normal range and no relation of the Q-Tc interval was observed to serum electrolytes. Diuretic intake was not different in patients with a normal Q-Tc interval and those with a prolonged Q-Tc interval. Neither was there any difference between groups II and III. Ionised calcium has been considered in a previous publication [18]. Hence, it is not likely that changed serum electrolytes or diuretic treatment contributes significantly to the present results.
Delayed repolarisation, as reflected by a prolonged Q-Tc interval, may indicate a decrease in the conduction of one or more types of potassium channels [31,33]. The molecular basis of potassium channel dysfunction in cirrhosis is not known, but the present results indicate a relation to both hepatic dysfunction and portal hypertension. This is in keeping with 1° animal experiments: portal vein stenotic, portal hypertensive rats with normal liver function may have electro-mechanical cardiac dysfunction, but not major prolongation of the Q-Tc interval [34], and 2° a relation of cirrhotic cardiomyopathy to reduced liver function rather than haemodynamic dysfunction in patients with cirrhosis has recently been reported [35].
In conclusion, a prolonged Q-Tc interval, indicating delayed cardiac repolarisation, is present in a substantial fraction of patients with mild portal hypertensive cirrhosis. The prolonged Q-Tc interval may be related to liver dysfunction and to the presence of portal hypertension.
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