Amedeo Ligabue

Reduced cardiovascular responsiveness to exercise-induced sympathoadrenergic stimulation in patients with cirrhosis

Cardiovascular responsiveness to sympathoadrenergic activation obtained by muscle exercise in the supine position was evaluated in 22 patients with cirrhosis (11 alcoholic, 11 postnecrotic/cryptogenic; 14 with ascites) and 10 controls of comparable age. Plasma norepinephrine, heart rate, diastolic arterial pressure and cardiac function, as evaluated by systolic time intervals, were monitored. At rest, cirrhotics had higher norepinephrine (154 +/- 19 S.E.M. ng/l) and heart rate (79 +/- 2 beats per min) than controls (71 +/- 3 ng/l, p less than 0.01; 67 +/- 2 beats per min, p less than 0.001), whereas diastolic arterial pressure was similar. Among systolic time intervals, electromechanical systole, pre-ejection period, electromechanical delay and pre-ejection period to left ventricular ejection time ratios were prolonged (p less than 0.05 or less). Exercise led to significant increases in plasma norepinephrine, heart rate and diastolic arterial pressure in both controls and patients. In the latter, however, whereas the increase in norepinephrine was greater (p less than 0.001), those in heart rate and diastolic arterial pressure were less (p less than 0.005). As expected, most systolic time intervals shortened, but the decrease in pre-ejection period (p less than 0.05), isometric contraction time (p less than 0.02) and pre-ejection period to left ventricular ejection time ratio (p = 0.06) was less in patients than in controls. Direct correlations between exercise-induced changes in norepinephrine and both diastolic arterial pressure (r = 0.81; p less than 0.005) and heart rate (r = 0.85; p less than 0.002) were observed in controls, while inverse correlations (r = -0.67, p less than 0.001 and r = -0.44; p less than 0.05) were found in cirrhotics. These results suggest that cardiovascular reactivity to the sympathetic drive is impaired in cirrhotics. The impairment of cardiac contractility may be due to altered electromechanical coupling.

Hyperdynamic circulation of advanced cirrhosis: a re-appraisal based on posture-induced changes in hemodynamics

Little is known about the effect of posture on the circulatory abnormalities of advanced cirrhosis. We evaluated the systemic hemodynamics, measured by Doppler-echocardiography, atrial natriuretic factor, plasma renin activity and plasma norepinephrine, in 10 patients with cirrhosis and ascites and 10 healthy controls, after 2 h of standing and during lying down for a further 2 h. Standing hemodynamic patterns of controls and patients with cirrhosis did not differ significantly. The latter, however, showed higher plasma renin activity, norepinephrine and atrial natriuretic factor. The assumption of the supine position led to greater increases in cardiac index and atrial natriuretic factor, and reduction in systemic vascular resistance in patients with cirrhosis. Norepinephrine and plasma renin activity declined in both groups to a similar extent, while heart rate only slowed in controls. Thus, after 2 h in the supine position, patients with cirrhosis showed hyperdynamic circulation with increased cardiac index and heart rate and reduced systemic vascular resistance. Norepinephrine, plasma renin activity and atrial natriuretic factor were also elevated. The hyperdynamic circulation in advanced cirrhosis appears during or is enhanced by lying down. This finding suggests that this syndrome is, at least in part, attributable to excessive blood volume translocation towards the central area. However, the persistent activation of renin-angiotensin and sympathoadrenergic systems suggests that a concomitant reduced vascular sensitivity to vasoconstrictors concurs in its development.

Renal function impairment induced by change in posture in patients with cirrhosis and ascites.

The assumption of upright posture by patients with liver cirrhosis leads to striking activation of adrenergic and renin-angiotensin systems. The tilting-induced modifications in renal function of eight healthy controls and 14 untreated patients with liver cirrhosis and ascites were related to plasma concentrations of noradrenaline, renin activity and aldosterone. All patients had preserved renal blood perfusion. All parameters were evaluated during bed rest for two hours and in the sitting posture for one hour. Basal plasma renin activity (0.1 greater than p greater than 0.05), aldosterone and noradrenaline concentrations (p less than or equal to 0.01) were raised in cirrhotics. The renal function tests (creatinine clearance, filtered sodium, tubular rejection fraction, urinary sodium excretion) were significantly reduced in cirrhosis. Under basal conditions, in cirrhotic patients tubular rejection fraction and urinary sodium excretion were inversely related to both noradrenaline and aldosterone concentrations. After tilting, the noradrenaline and aldosterone integrated outputs (sigma delta) were significantly greater in cirrhosis. All renal function tests significantly decreased in cirrhotics, whereas creatinine clearance only significantly decreased in controls. Patients tubular rejection fraction of sodium and sodium excretion were related to sigma delta aldosteronaemia (r = -0.72; p less than 0.01), but no longer to sigma delta plasma noradrenaline.

Bed-rest-induced hypernatriuresis in cirrhotic patients without ascites: does it contribute to maintain 'compensation'?

Renal function, plasma renin activity, plasma aldosterone concentration and urine excretion of free norepinephrine were evaluated in 13 cirrhotics without previous or ongoing ascites and in 13 healthy subjects, after 6 days of controlled electrolyte intake (40 mmol of Na and 70 mmol of K per day) and during 24 h of recumbency. Plasma concentrations of the atrial natriuretic peptide (ANP) were also measured in 8 patients and 8 controls. Despite a low-normal filtered load of sodium (14.6 +/- 1.2 vs. 17.1 +/- 1.2 mmol/min), cirrhotic patients showed supernormal natriuresis (141.5 +/- 14.1 vs. 78.8 +/- 8.6 mmol/day; p < 0.001). Whereas the fractional excretion of sodium in these patients was twice that of controls (0.70 +/- 0.05 vs. 0.36 +/- 0.04%; p < 0.001), potassium excretion (42.5 +/- 2.7 vs. 43.1 +/- 2.7 mmol/day) and urine volume (1270 +/- 98 vs. 1452 +/- 148 ml/day) did not differ. In cirrhotics, plasma renin activity was reduced (0.50 +/- 0.12 vs. 1.39 +/- 0.33 ng/ml/h; p < 0.02), and plasma aldosterone concentration tended to be lower (66 +/- 10 vs. 86 +/- 9 pg/ml; p = 0.09), while urine norepinephrine excretion did not significantly differ from controls (961 +/- 120 vs. 782 +/- 43 ng/h). ANP was higher in patients than in controls (92 +/- 17 vs. 48 +/- 9 pg/ml; p < 0.05). Natriuresis was directly correlated with ANP (r = 0.69, p < 0.005) and ANP/plasma aldosterone ratio (r = 0.63; p < 0.01) in patients and healthy subjects taken together.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronobiological Evaluation of Sympathoadrenergic Function in Cirrhosis

Intraday activity of the adrenergic system was investigated in 7 healthy controls and in cirrhotic patients without ascites (group 1, 7 cases) and with ascites (group 2, 9 cases) by determining the urinary norepinephrine and vanillylmandelic acid excretions at 4-h intervals for 24 h. Mean arterial pressure and heart rate were also recorded. In controls, the statistical evaluation by the cosinor method showed a circadian rhythm of such variables, with zenith in the morning and nadir at night. Intraday changes of urinary excretion of norepinephrine were closely related to arterial pressure and heart rate in most subjects. The most important change in cirrhotic patients was the achronia [no detection of a statistically significant (p greater than 0.05) rhythm] in urinary excretion of norepinephrine and arterial pressure. This occurred not only in group 2 patients, who had lower arterial pressure and higher NE mesors than controls (p less than 0.05), but also in group 1 patients, whose mesors were comparable to controls. The statistical significance of heart rate rhythmicity was preserved in patients, but its zenith was progressively displaced toward evening (group 1) and night hours (group 2, whose mesor was increased). Changes in urinary excretion of vanillylmandelic acid roughly paralleled those of norepinephrine both in controls and patients, but they did not significantly increase even in the group with ascites. In both groups of cirrhotic patients, the correlation between urinary excretion of norepinephrine, arterial pressure, and heart rate within the same subject was lost in most cases. This chronobiological study showed that the sympathoadrenergic activity can be deranged also in the early stages of cirrhosis, and suggested that an altered control of cardiovascular homeostasis is present even under steady state conditions. This alteration might blunt adrenergic responses to stress conditions.

Impairment of Blood Pressure Control in Patients with Liver Cirrhosis during Tilting: Study on Adrenergic and Renin-Angiotensin Systems

Mean arterial pressure, phenylalanine, tyrosine, norepinephrine and plasma renin activity (PRA) were determined in the plasma of 6 healthy controls and 8 patients with liver cirrhosis receiving a controlled sodium intake (40 mEq/day), after 1 h of bed rest and 10 min after being tilted up at 90 degrees. After resting, patients showed lower arterial pressure (p less than 0.025) and higher plasma levels of phenylalanine (p less than 0.005), tyrosine (p less than 0.05), norepinephrine (n.s.) and PRA (n.s.) than controls. In spite of a prolonged and marked stimulation of the adrenergic system induced by tilting, arterial pressure of cirrhotics, after an initial increase, decreased significantly. A significant PRA increase was observed in both groups but in patients it was greater and lasted longer, up to 30 min, when PRA and arterial pressure were inversely and significantly correlated. The adrenergic system of cirrhosis then appeared unable to maintain adequate levels of arterial pressure, even though hyperstimulated. The renin-angiotensin system played an important compensatory role in this contest.

Hemodynamic and renal effects of ascites apheresis, concentration and reinfusion in advanced cirrhosis

BACKGROUND/AIMS We studied the effects of ascites apheresis, concentration and reinfusion, a new form of treatment for tense or refractory ascites, on systemic hemodynamics and renal function. METHODS Twelve patients with advanced cirrhosis (two belonging to Child-Pughs class B and the remainder to class C) were monitored. They were evaluated under baseline conditions, just after the treatment, and 24 and 48 h after baseline assessment. In addition to systemic hemodynamics--as evaluated by Doppler echocardiography--and renal function, indirect markers of effective volemia, such as atrial natriuretic factor, plasma renin activity and aldosterone concentration, and plasma norepinephrine were also measured. RESULTS The technique led to significant changes in systemic hemodynamics, such as an increase in stroke volume and cardiac output. However, due to a striking reduction in peripheral vascular resistance, mean arterial pressure also declined. The hemodynamic changes were associated with a parallel increase in atrial natriuretic factor. Despite the reduction in arterial pressure, plasma renin activity also significantly declined, while plasma norepinephrine did not undergo significant changes. Although an improvement in glomerular filtration rate and renal sodium excretion occurred, neither change reached statistical significance. All the hemodynamic, renal and neuro-humoral changes described above subsided almost entirely after 48 h, when no significant changes with respect to baseline values were any longer detectable with the exception of a slight reduction in mean arterial pressure. CONCLUSIONS In advanced cirrhosis ascites apheresis, concentration and reinfusion enhance central volemia, but an exaggerated peripheral vasodilation largely wastes the potential favourable effect on arterial volemia. As a result, no significant improvement in renal perfusion and sodium excretion can ensue.

Daily profile of plasma endothelial-1 and -3 in pre-ascitic cirrhosis: relationships with the arterial pressure and renal functin

BACKGROUND/AIMS Measurements of plasma endothelin-1 and -3 in pre-ascitic cirrhosis have provided controversial results. Similarly, the role of the endothelin system in the pathogenesis of volume and hemodynamic disturbances of cirrhosis is still debated. To provide a further insight into this issue, we assessed the daily fluctuations of plasma endothelins and their relationship with arterial pressure and renal function in pre-ascitic cirrhosis. METHODS Endothelin-1 and -3, plasma renin activity, atrial natriuretic peptide, noradrenaline and mean arterial pressure were measured at 11 pm, 7 am, 9 am and 6 pm in 10 patients with pre-ascitic cirrhosis and in 10 healthy subjects on normal sodium diet and carrying on their usual activities (supine from 10 pm to 7 am, standing and mobile after 7 am). Glomerular filtration rate and daily renal sodium excretion were assessed during the supine period, and from 7 am to 12 am and from 12 am to 10 pm during the standing period. RESULTS Endothelin-1 was higher in patients than in control subjects (p=0.000) and did not change during the study. Endothelin-3 was also higher in patients (p=0.002) and showed slight fluctuation in control subjects. The mean daily level of plasma renin activity was lower (p=0.016) and that of atrial natriuretic peptide higher (p=0.000) in patients with cirrhosis. Norepinephrine and mean arterial pressure did not differ significantly between the two groups. No correlations were found between endothelins and either hemodynamic or neuro-hormonal and renal function parameters in the two groups. CONCLUSIONS Despite the presence of increased effective volemia (as suggested by the reduced plasma renin activity and elevated atrial natriuretic peptide) and normal adrenergic tone, patients with pre-ascitic cirrhosis show elevated levels of endothelin-1 and endothelin-3 throughout the day. In early cirrhosis circulating endothelins, although elevated, do not appear to play a more prominent role in setting arterial pressure than in normal subjects, and endothelin elevation is not detrimental to renal function.

Renal sodium handling in cirrhosis with ascites: mechanisms of impaired natriuretic response to reclining

We recently showed that patients with compensated cirrhosis can dispose of their fluid overload while reclining. In contrast, patients with ascites fail to develop supine-induced natriuresis. To assess the effect of reclining on renal sodium handling in patients with advanced cirrhosis and the mechanisms blunting natriuresis in this situation, renal function and plasma concentrations of atrial natriuretic factor, aldosterone and norepinephrine were evaluated in 10 nonazotemic patients with cirrhosis and ascites and 10 healthy controls standing for 2 h and reclining for 2 h. While standing, all patients showed marked sodium retention and significantly elevated plasma atrial natriuretic factor levels, aldosterone and norepinephrine. Glomerular filtration rate did not differ from healthy controls. The reclining increased renal sodium excretion in both groups, but this change was far less marked in patients; natriuresis only rose to the control range in two of them. An increase in atrial natriuretic factor and a depression of plasma aldosterone and norepinephrine was seen in both controls and patients. In the latter, despite the greater change in atrial natriuretic factor and aldosterone, the aldosterone to atrial natriuretic factor ratio, which was inversely correlated with natriuresis during both standing and reclining remained significantly elevated. In the two patients who achieved normal natriuresis during reclining, reclining was associated with both the normalization of the aldosterone/atrial natriuretic factor ratio, and with an increase in glomerular filtration rate. The supine-induced increase in atrial natriuretic factor was not only preserved but was even enhanced in cirrhosis with ascites.(ABSTRACT TRUNCATED AT 250 WORDS)