G. La Villa

Altered cardiovascular responsiveness to active tilting in nonalcoholic cirrhosis

BACKGROUND & AIMS The hyperdynamic circulation of cirrhosis has been related either to plasma volume expansion (increased preload) or peripheral arterial vasodilation (reduced afterload). The aim of this study was to evaluate cardiovascular function in patients with nonalcoholic cirrhosis by echocardiography. METHODS Nineteen patients with abnormal sodium handling (11 sodium excretors and 8 sodium retainers) and 15 healthy volunteers underwent echocardiographic evaluation of left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-systolic volume index (LVESVI), left ventricular ejection fraction (LVEF), cardiac index (CI), mean arterial pressure, and systemic vascular resistance (SVR) during supine resting and after 5 minutes of standing. RESULTS Supine patients had increased LVEF and CI and reduced LVESVI and SVR. LVEDVI was increased only in sodium excretors. Standing induced a decrease in LVEDVI in all subjects. Healthy volunteers maintained cardiovascular homeostasis by increasing LVEF and heart rate, whereas cirrhotic patients experienced a decrease in SVI and CI despite marked increments in heart rate, plasma renin activity, and plasma norepinephrine level. CONCLUSIONS In patients with cirrhosis, the increased LVEF and reduced LVESVI while in a supine position point at reduced afterload as an important determinant of the hyperdynamic circulation. Evidence of an increased preload secondary to increased blood volume, indicated by a high LVEDVI and increased plasma atrial natriuretic peptide levels, was found only in sodium excretors. The altered response to active tilt in cirrhotic patients suggests an impaired myocardial contractility.

Impaired cardiovascular autonomic response to passive tilting in cirrhosis with ascites

The autonomic regulation of cardiovascular function was evaluated in 15 cirrhotic patients with ascites and in 13 healthy subjects by the autoregressive power spectral analysis (PSA) of the intervals between adjacent R waves of the electrocardiogram (RR) interval and arterial pressure variability. Total power, low frequency (LF; index of the sympathetic activity of the heart and circulation), and high frequency (HF; index of vagal tone to the heart) components of the RR interval, systolic, and diastolic arterial pressure were evaluated in the supine position and during passive tilting, together with plasma norepinephrine levels. In the supine position, no significant differences in the PSA data were observed between the control subjects and cirrhotic patients, who had higher plasma norepinephrine levels. In healthy subjects, tilting was associated with an increase in the LF of the RR interval and arterial pressure and a decrease in the HF of the RR interval. In contrast, patients with cirrhosis showed a decrease of both LF and HF. Consequently, the LF/HF ratio significantly increased in healthy subjects, whereas it was unchanged in cirrhotic patients. The LF component of the diastolic pressure also decreased during tilting in cirrhotic patients. Plasma norepinephrine increased after tilting in both groups. These results indicate that the autonomic response to passive tilting is impaired in cirrhotic patients with ascites at both the cardiac and vascular levels, as a result of an altered sympatho‐vagal balance, with reduced sympathetic predominance. These alterations occurred despite an appropriate response to the tilting of plasma norepinephrine, pointing to a receptorial or postreceptorial site of the autonomic impairment.

Dopamine and Sympathoadrenal Activity in Man

The sympathetic adrenal (SA) activity can be modulated by dopamine (DA) through D2 receptors. In man, using D2 antagonists, it has been demonstrated that endogenous DA plays an inhibitory modulation of the SA system during high degree of SA activation. D2 agonists are able to induce a decrease in norepinephrine (NE) release either in vitro or in vivo. This effect leads, in vivo, to a decrease in blood pressure (BP) and to an activation of arterial baroreceptors. Therefore, in vivo, the D2 mediated inhibition of epinephrine (E) release, which is clearly demonstrated in vitro, is overwhelmed by the baroreceptor-mediated activation of the splachnic nerve. As a consequence, the in vivo administration of D2 agonists can induce a different effect on the net peripheral sympathetic tone of an organ, depending on the balance between the degree of the baroreceptor-mediated sympathetic activation and the inhibitory D2-mediated inhibition of NE release at the tissue level. In the present paper we investigated the in vivo effect of placebo (PL) or acute oral bromocriptine (BC) administration on plasma CA and on the cardiac sympatho-vagal balance of 7 normal volunteers, as assessed by power spectral analysis of heart rate (HR) variability (autoregressive method), either in resting or sitting position. Low frequency (LF) and high frequency (HF) components, both expressed in normalized units (nU), and LF/HF ratio were calculated. BC caused a decrease in BP, plasma NE and no change in HR in resting and sitting position. Plasma E increased in sitting position. At the heart level, after BC, we observed, during rest, an increase in LF and LF/HF ratio and a decrease in HF while in sitting position LF did not increase further. These data show that BC, while reducing BP through a decrease of plasma NE, increases LF/HF ratio (sympathetic tone) without any change in heart rate. These data seem to confirm that BC causes an inhibitory modulation of the SA system acting predominantly at the periphery through D2 presynaptic receptors.

Effects of rhein on renal arachidonic acid metabolism and renal function in patients with congestive heart failure

SummaryIn a randomized double-blind cross-over study the effects of rhein (administered as diacetylrhein 50 mg b.d. for 5 days) and placebo on renal arachidonic acid metabolism and renal function have been compared in 12 elderly patients (mean age 75.2 years) with congestive heart failure, whose renal function was known to be dependent on the integrity of the renal prostaglandin system.Rhein like placebo, did not induce any change in the urinary excretion of prostaglandin (PG) E2, 6-keto-PGF1α and thromboxane (TX) B2, nor did it affect creatinine clearance, blood urea, urine output, natriuresis, body weight, plasma renin activity or plasma aldosterone concentration. Separate analysis of the results obtained in the 5 patients receiving diuretic treatment did not show any significant effect of rhein as compared with placebo on the parameters investigated. Serum TXB2 concentration during whole blood clotting, as an index of platelet arachidonic acid metabolism, also showed no significant difference when DAR and placebo were compared.It is concluded that in patients with congestive heart failure rhein does not inhibit renal or platelet eicosanoid metabolism, nor does it modify renal function, sodium excretion or the renal response to diuretics.

Functional Renal Alterations in Chronic Liver Diseases

83 patients with chronic active hepatitis (CAH), 38 of them with cirrhosis, were studied and compared with 10 control subjects suffering from chronic persistent hepatitis (CPH). Tubular acidosis frequently was found in our cases. Renal plasma flow and glomerular filtration rate were significantly decreased in CAH when compared with CPH. Selective renal arteriography showed evident decrease of arterial flow in the outer cortex. Selective renal scan with 99mTc microspheres of human albumin showed a frequent escape of the tracer from the kidney to the lung. PGE1 and PGE2 levels appeared higher in the renal artery than in the vein and were significantly more elevated in 9 cases with cirrhosis vs. 13 controls. These results suggest the frequent functional impairment of the kidney also in the early stages of CAH, with an increase of PGE levels and an opening of intrarenal shunts.

Is the use of albumin of value in the treatment of ascites in cirrhosis? The case in favour

In patients with cirrhosis, ascites accumulates because of sodium retention, triggered by a reduction of the effective arterial blood volume, and imbalanced Starling forces in the splanchnic area due to portal hypertension and hypoalbuminemia. Albumin is the ideal plasma expander in this setting, since it ameliorates systemic and reneal haemodynamics, so reducing sodium retention, and increases oncotic pressure in the splanchnic compartment. In particular, albumin proved useful in patients treated with diuretics, as demonstrated by a randomised study performed at our Instituition in which 126 ascitic inpatients were treated according to a stepped-care diuretic regimen. In fact, patients receiving diuretics plus albumin (n = 63) had a higher cummulative rate of response (p < 0.05) and a shorter hospital stay (20 +/- 1 versus 24 +/- 2 days, p < 0.05) than those given diuretics alone. Treatment with albumin on an outpatient basis (25 g/week) resulted in a lower probability of developing ascites (p < 0.02 vs. patients not given albumin) and a lower probability of readmission (p < 0.02). Patients given albumin also had a better quality of life. As discussed in another article, evidence also supports the use of albumin in patients treated for paracentesis, as well as in patients with spontaneous peritonitis or hepatorenal syndrome.

Loop diuretic therapy in liver cirrhosis with ascites.

Medical treatment of ascites is aimed at reverting sodium retention, that is, at creating a negative sodium balance to relieve ascites. Bed rest and low-sodium diet induce the disappearance of ascites in about 10% of patients. Loop diuretics and aldosterone antagonists must be administered to the patients not responding to the previous regimen. Available evidence indicates that aldosterone antagonists are the first-choice drugs, as these substances are more effective than furosemide. Nevertheless, loop diuretics potentiate the effects of aldosterone antagonists. The reduced efficacy of furosemide in these patients, when compared with that of spironolactone, may be related to an impairment of both pharmacodynamics and pharmacokinetics. In fact, most sodium not reabsorbed in Henles loop, due to the action of furosemide, is subsequently taken up in the distal nephron because of hyperaldosteronism. A further mechanism of resistance may be related to an impaired excretion of furosemide into the tubular lumen. The use of diuretics in the treatment of ascites is associated with several side effects, including prerenal azotemia, hepatic encephalopathy, and electrolyte and acid-base disorders. A stepped-care approach, together with careful monitoring of patients, is the best way to reduce the incidence of these complications. Ethacrynic acid has been shown to be highly effective in the treatment of ascites, even in patients refractory to other diuretics, but its use is associated with a high incidence of hypokalemia and hypochloremic alkalosis. Bumetanide and piretanide are comparable to furosemide, in terms of both efficacy and side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis and Treatment of Ascites in Hepatic Cirrhosis

In cirrhosis of the liver structural distortion of the sinusoidal vessels is the major factor responsible for the increase in portal venous pressure and the development of abdominal ascites. The mechanisms by which advanced cirrhosis of the liver leads to widespread changes in the systemic circulation including vasodilatation, increased cardiac output and expanded plasma volume, together with activation of a range of antinatriuretic and natriuretic factors, are unclear. Several hypotheses have been proposed to explain these pathophysiological consequences, including underfilling of the systemic arterial system, overflow and peripheral vasodilatation, with a decrease in effective arterial blood volume. The evidence for and against these hypotheses is critically examined. In patients with hepatic cirrhosis complicated by ascites, increased intrarenal release of vasodilating prostaglandins may assist in sustaining renal blood flow and glomerular filtration rate by counteracting the vasoconstrictor effects of noradrenaline and angiotensin II. In advanced stages of the syndrome, cirrhotic ascites may become refractory to medical treatment. In this situation renal function becomes progressively impaired and eventually acute renal failure, so-called hepatorenal syndrome, supervenes due to intense renal vasoconstriction and opening of intrarenal arteriovenous shunts. The progressive renal vasoconstriction may also be accentuated by the reduced synthesis of renal vasodilating prostaglandins. The medical treatment of ascites is based on bed-rest, a low-sodium diet and administration of aldosterone antagonists and loop diuretics. Patients who are refractory to such therapy may be further treated by paracentesis or by the LeVeen shunt, though the long-term results of these physical therapies are unsatisfactory.

Liver-kidney pathophysiological interrelationships in liver diseases

On the basis of several clinical and experimental researches, it is possible today to deepen the different mechanisms regarding kidney and liver relationships. However, the most studied field remains the renal function during liver disease. These alterations can be divided into: 1. Renal functional impairment is mainly considered due to hemodynamic derangement with a progressive decrease in peripheral vascular resistance (PVR) and an increase in cardiac output and rate, characteristic of hyperdynamic circulation, and outer cortex renal ischemia. Two principal forms of RFI characterize the hepatorenal syndrome (HRS) while in the first stage is based on the simple decrease in renal clearances with avid sodium retention. 2. Metabolic renal damage is principally due to abnormal serum levels of bile acids, bilirubin and perhaps toxic hepatic molecules which induce tubular dysfunction leading to RTA, of which type I, in the incomplete form, is the most common, varying between 30% and 50% of cases. It is mainly studied during cholestatic disease. 3. Organic renal impairment is principally based on immunological response to viral antigens and abnormal hepatic products which lead to the presence of immunocomplexes and cryoglobulins on the blood which tend to be deposited in the subendothelial and subepithelial glomerular areas, inducing complement activation, mesangial cell proliferation and monocyte-macrophage cell infiltration.

Parallel increase in carotid, brachial and left ventricular cross-sectional areas in arterial hypertension

Few data have been published about the relation between the vessels geometry and development of left ventricular (LV) hypertrophy in patients with arterial hypertension. The aim of this study is to describe arterial and LV geometry changes due to mild-to-moderate arterial hypertension in an untreated hypertensive population. In 95 untreated patients with mild-to-moderate hypertension and 23 age- and sex-matched healthy normotensives, we measured the end-diastolic diameter and wall thickness of the left ventricle and the internal diameter and intimal-medial thickness (IMT) of carotid and brachial arteries. From these data, the cross-sectional areas (CSAs) of arterial and myocardial walls were calculated. Hypertensive patients were further subdivided on the basis of the presence of LV hypertrophy defined according to Devereux et al as anatomical LV mass >125 g/m. In hypertensive patients with hypertrophy, carotid and brachial CSAs increased, without significant changes in thickness/diameter ratio (arterial ‘enlargement’), while the left ventricle developed ‘concentric’ hypertrophy. Arterial and LV CSAs showed a significant direct correlation with systolic blood pressure (BP). However, when data were corrected for BP, the correlation between the increase in arterial and LV CSAs became much improved than for the raw data. In conclusion patients with untreated mild-to-moderate hypertension, both carotid and brachial arterial walls showed an enlargement that was proportional to the development of LV hypertrophy. These results suggest that the effects of arterial hypertension on carotid, brachial and LV wall geometry have a common modulation.