Cardiac electrophysiological abnormalities in patients with cirrhosis Andrea Zambruni, Franco Trevisani, Paolo Caraceni, Mauro Bernardi  Journal of Hepatology  Volume 44, Issue 5, Pages 994-1002 (May 2006) DOI: 10.1016/j.jhep.2005.10.034 Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Events associated with the occurrence of paracentesis-induced circulatory dysfunction (panel A) and renal failure induced by spontaneaous bacterial peritonitis (panel B). Both conditions are characterized by a worsening in effective volemia, as witnessed by the striking increases in plasma renin activity (PRA) and plasma norepinephrine concentration (NorE) and the reduction in mean arterial pressure (MAP). A drop in systemic vascular resistance (SVR) only occurred with paracentesis-induced circulatory dysfunction (panel A). In both conditions, an inadequate increase (panel A) or even a reduction (panel B) in cardiac index (CI) or output (CO) was seen. This can be attributed to several causes, such as impaired heart contractility and/or reduced cardiac pre-load. However, the failure of heart rate (HR) to increase (chronotropic incompetence) certainly played an important role. *= statistically significant change. Data derived from Ref. 14 (panel A) and 15 (panel B). In panel A, the value of the increase in PRA has to be multiplied by 10. Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Panel A. Systolic time intervals (STI) are derived from the simultaneous tracings of ECG, carotid artery pulse and phonocardiogram (PCG). The length of the total electromechanical systole is represented by QS2 interval, which begins at the onset of QRS complex and ends at the first high frequency vibrations of the aortic component of the second heart sound (S2). QS2 includes intervals identifying the mechanical systole, such as left ventricular ejection time (LVET; from the beginning upstroke to the though of the incisura of the carotid artery pulse) and mechanical systole (S1S2; from the first heart sound [S1] to the beginning of the aortic component of S2), and those influenced by electromechanical coupling (see Fig. 7), which are derived from the former intervals. These include electromechanical delay (QS1), isometric contraction time (ICT) and pre-ejection period (PEP). Alterations in LVET and S1S2 typically occur in the presence of impaired cardiac contractility, as in patients with heart failure. Isolated changes in PEP, QS1 and ICT suggest electromechanical uncoupling. Panel B. The duration of electrical and mechanical events associated with cardiac systole can be evaluated by the simultaneous reading of ECG tracing and aortic pressure curve. The measurement of QT interval gives an estimate of the duration of electrical systole. The mechanical components of the cardiac cycle (time to peak pressure [tP]; systolic time [tS]; diastolic time [tD]) can be measured on the aortic pressure curve. (TRR: time of one heart cycle). The assessment of the aortic pressure curve through catheterisation allows a more direct estimate of left ventricular pressure than the evaluation of the carotid artery pulse by pressure transducer. Hence, a better estimate of the duration of the mechanical components of the cardiac cycle can be achieved. Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 3 Systolic time intervals in resting healthy controls and patients with cirrhosis. The total electromechanical systole (QS2) was prolonged in cirrhotic patients. However, this was not due to the prolongation of the mechanical components (mechanical systole: S1S2; left ventricular ejection time: LVET) as it happens with impaired contractility, but to the lengthening of systolic time intervals influenced by electromechanical coupling such as electromechanical delay (QS1) and pre-ejection period (PEP). This defect could be related to a reduced response to the adrenergic drive, which is known to shorten all systolic time intervals except mechanical systole and left ventricular ejection time. ICT: isometric contraction time. Data derived from Ref. 4. Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 4 Normal ECG tracing. The various intervals are illustrated. The QT interval is measured from the onset of the QRS complex to the end of the T wave, defined as the return to T–P baseline. If a U wave is present, the QT interval is measured from the onset of the QRS complex to the nadir of the curve between the T and U wave. The duration of QT is calculated by measuring three consecutive intervals in each of the 12 ECG leads and averaged; alternatively, the maximal averaged value of the QT interval in any of the 12 leads is recognized (QTmax). The QT interval varies with heart rate, and its direct measurement should be corrected to avoid such an influence. The most frequently used formula was proposed by Bazzett [22]: QTc (QT corrected for heart rate) =QT/square root RR. In order to overcome possible pitfalls of Bazzett's formula, other ways to correct QT for heart rate have been suggested, such as: QTcub =QT/cubic root RR [25]; QTquadratic = QT/quadratic root RR [24]. Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 5 Prevalence of prolonged (above 440ms) QTc interval in patients with cirrhosis belonging to Child–Pugh classes A, B and C, and in healthy controls. Such a prevalence is exceedingly high in patients, and increases in parallel with the severity of cirrhosis. Data derived from Ref. 26. Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 6 Effect of chronic β-blockade on the duration of QTc interval in patients with cirrhosis. A substantial shortening was seen in most subjects, the most striking reductions generally occurring in patients showing the highest baseline value of QT interval (correlation between baseline QTc interval duration and degree of shortening: r=0.70; P<0.001). QTcmax = frequency adjusted QT interval (Bernardi, M. Unpublished data). Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 7 Receptor and post-receptor pathways following β1-adrenergic stimulation in the cardiomyocyte. Norepinephrine binding with β1-receptors leads to receptor-stimulatory G protein interaction, consequent adenylcyclase stimulation, activation of cAMP-dependent phosphokinase A, and channel phosphorylation. Phosphorylation of L-type Ca2+ channels and ryanodine receptors located in the sarcoplasmic reticulum favours calcium entry from the extracellular compartment (ICa-L: slowly decaying inward Ca2+ current) and Ca2+ release from the sarcoplasmic reticulum, respectively. The resultant troponin C–Ca2+ complex initiates cross-bridge cycling between actin and myosin, which represent the molecular background for contraction (electromechanical coupling). Phosphorylation of Na+ channels (INa-B: inward Na+ background leak current) favours the inward pacemaker current, thus enhancing depolarisation of action potential phase 4; as a result heart rate accelerates. Several receptor and post-receptor defects have been described in cirrhosis, such as β-adrenoceptor density reduction, altered G protein and adenylcyclase functions, altered physical properties of myocyte plasma membrane, which may lead to receptor and ion flux abnormalities, and reduced density and functional depression of L-type Ca2+ channels. These defects can account for chronotropic incompetence and abnormalities in electromechanical coupling. Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions

Fig. 8 The cardiac action potential is primed by the inflow of Na+ and Ca2+ ions (INa: inward fast Na+ current; ICa-T: inward T-type Ca2+ current) leading to the abrupt depolarisation in phase 0. Thereafter, the outflow of K+ (ITO-K: transient outward K+ current) initiates repolarisation (phases 1 and 2), a process which is counterbalanced by Ca2+ and Na+ influx (INaCa: electrogenic Na+- Ca2+ exchange current; ICa-L: slowly decaying inward Ca2+ current). K+ extrusion continues during phase 3 (IK: delayed rectifier K+ current), which restores the resting potential of phase 4. Several conditions, known to prolong the QT interval and listed in the figure, counteract K+ efflux. The sympathoadrenergic drive leads to events which favour both repolarisation, by enhancing K+ efflux, and depolarisation, enhancing Ca2+ entry in phase 2. In the presence of altered K+ fluxes, adrenergic stimulation leads to the prolongation of the repolarisation phases, and, hence QT interval. Ward and co-workers [46] have demonstrated altered K+ currents in ventricular myocytes of cirrhotic rats. Journal of Hepatology 2006 44, 994-1002DOI: (10.1016/j.jhep.2005.10.034) Copyright © 2006 European Association for the Study of the Liver Terms and Conditions