Atrial natriuretic peptide, plasma renin activity, plasma volume, systemic vascular resistance and cardiac output in patients with cirrhosis

The present study aimed to assess relationships between plasma levels of atrial natriuretic peptide (ANP) and plasma volume, systemic vascular resistances, cardiac output and plasma renin activity in patients with cirrhosis. Thirty patients were included: eight with no history of liver disease were used as controls; 22 patients had biopsy-proven alcoholic cirrhosis without ascites (n = 11) and with ascites (n = 11). Mean ANP plasma level was significantly higher in both groups of cirrhotic patients than in controls (P less than 0.05). In the control group, ANP and plasma renin activity were inversely correlated (P less than 0.05) but no correlation was found in cirrhotic patients. In the group of patients with ascites, ANP plasma levels were inversely correlated to plasma volume (P less than 0.05) and to cardiac output (P less than 0.01) and directly correlated to systemic vascular resistances (P less than 0.01). Using multiple regression analysis, ANP remained correlated only with systemic vascular resistances (P less than 0.05). These results suggest that cirrhotic patients have high plasma levels of ANP whether or not they have ascites. In the light of current knowledge of ANP actions, the relationships between ANP plasma levels and plasma volume, cardiac output, and systemic vascular resistances are paradoxical in cirrhotic patients with ascites. ANP does not seem to play a critical role in the pathogenesis of sodium and water retention observed in these patients.     

Effects of long-term propranolol and octreotide on postprandial hemodynamics in cirrhosis: a randomized, controlled trial

BACKGROUND & AIMS: Postprandial increases in portal pressure may influence esophageal variceal rupture. The effects of chronic propranolol and octreotide (100 and 200 microg subcutaneously in a single dose) on postprandial hemodynamics were evaluated. METHODS: FIRST STUDY: 36 cirrhotic patients were studied at baseline and 30 and 60 minutes after a standard meal and then treated with propranolol (139 +/- 9 mg/d during 39 +/- 2 days). SECOND STUDY: After baseline measurements, patients were randomized into 3 groups: (1) placebo, (2) octreotide (100 microg), or (3) octreotide (200 microg) (n = 12 for each group). Thirty minutes postinjection a new baseline was established and measurements were repeated 30 and 60 minutes after the meal. RESULTS: First study: Baseline portal pressure was 18.1 +/- 1.2 mm Hg, 30 and 60 minutes after the meal it was 21.5 +/- 0.8 mm Hg and 20.5 +/- 0.8 mm Hg, respectively (both P < 0.01 vs. baseline). Cardiac index (CI) was 4.5 +/- 0.2, 4.8 +/- 0.2, and 4.9 +/- 0.2 L x min(-1) x m(-2), respectively (both P < 0.05 vs. baseline). Peripheral vascular resistance was 1012 +/- 56, 902 +/- 51 (P = NS), and 884 +/- 49 dynes x sec x cm(-5) (P< 0.05 vs. baseline), respectively. Second study: Propranolol and placebo did not blunt postprandial increase in portal pressure. Octreotide (100 microg) partially ameliorated postprandial increase in portal pressure. Octreotide (200 microg) significantly enhanced the portal hypotensive effect of propranolol and blunted the postprandial increase in portal pressure. CONCLUSIONS: Octreotide blunts postprandial increase in portal pressure not prevented by long-term propranolol administration.     

Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis

BACKGROUND & AIMS: In cirrhosis, an insufficient release of nitric oxide contributes to increased hepatic resistance and portal pressure and enhances the postprandial increase in portal pressure. We hypothesized that simvastatin, which enhances Akt-dependent endothelial nitric oxide synthase phosphorylation, may increase hepatic nitric oxide release and decrease hepatic resistance in patients with cirrhosis and portal hypertension. METHODS: In protocol 1, 13 patients had measurements of the hepatic venous pressure gradient, hepatic blood flow, mean arterial pressure, cardiac output, and nitric oxide products before and 30 and 60 minutes after 40 mg of simvastatin. In protocol 2, 17 patients were randomized to receive placebo or simvastatin (40 mg) 12 hours and 1 hour before the study. After baseline measurements of the hepatic venous pressure gradient, hepatic blood flow, and nitric oxide products, a standard liquid meal was given, and measurements were repeated at 15, 30, and 45 minutes. RESULTS: In protocol 1, acute simvastatin did not modify the hepatic venous pressure gradient but increased the hepatic blood flow (21% +/- 13% at 30 minutes; P = 0.01) and decreased hepatic sinusoidal resistance by 14% +/- 11% (P = 0.04). Nitric oxide product levels significantly increased in hepatic venous blood (from 31.4 +/- 12.3 nmol. mL(-1) to 35.8 +/- 10.7 nmol. mL(-1); P = 0.04), but not in peripheral blood. Systemic hemodynamics were not modified. In protocol 2, simvastatin pretreatment significantly attenuated the postprandial increase in hepatic venous pressure gradient (mean peak increase, 10% +/- 9% vs. 21% +/- 6% in placebo; P = 0.01). Hepatic blood flow increased similarly in the 2 groups. Hepatic nitric oxide products increased in the simvastatin group but not in the placebo group. CONCLUSIONS: Simvastatin administration increases the hepatosplanchnic output of nitric oxide products and decreases hepatic resistance in patients with cirrhosis.     

Echocardiography for Hemodynamic Assessment of Patients With Advanced Heart Failure and Potential Heart Transplant Recipients

Objectives. This study sought to assess the accuracy of Doppler echocardiographic techniques for the determination of right heart catheterization hemodynamic variables in patients with advanced heart failure and in potential heart transplant recipients.

Background. Doppler echocardiographic techniques permit the noninvasive acquisition of hemodynamic variables traditionally used for the assessment of patients with advanced heart failure and potential heart transplant candidates. However, the accuracy of these techniques has not been sufficiently well documented for clinical application in individual patients.

Methods. Echocardiographic data required for estimation of mean right atrial, pulmonary artery and mean left atrial pressures and cardiac output were obtained. Right heart catheterization was performed immediately after Doppler echocardiographic data were acquired, before any intervention that might have altered the subject’s hemodynamic status.

Results. A complete Doppler echocardiographic hemodynamic data set was acquired in 21 (84%) of 25 subjects. For all variables, invasive and noninvasive hemodynamic values were highly correlated (p < 0.001), with minimal bias and narrow 95% confidence limits. An algorithm constructed from the noninvasive hemodynamic variable values identified all patients with adverse pulmonary vascular hemodynamic variables (i.e., transpulmonary gradient ≥12 mm Hg, pulmonary vascular resistance ≥3 Wood units or pulmonary vascular resistance index ≥6 Wood units × m²). This algorithm identified 12 (71%) of 19 patients for whom right heart catheterization was unnecessary.

Conclusions. Doppler echocardiographic estimates of hemodynamic variables in patients with advanced heart failure are accurate and reproducible. This noninvasive methodology may assist with monitoring and optimization of medical therapy in patients with advanced heart failure and may obviate the need for routine right heart catheterization in potential heart transplant candidates.     

Endothelin 1 does not play a major role in the homeostasis of arterial pressure in cirrhotic rats with ascites

Patients with cirrhosis and ascites have increased plasma levels of endothelin, a powerful vasoconstrictor peptide. This study assessed the mechanisms underlying this phenomenon. Plasma endothelin was measured in control rats and cirrhotic rats with and without ascites. In addition, the tissue concentration of endothelin and endothelin 1 messenger RNA (mRNA) and the effect of an endothelin A receptor antagonist on arterial and portal pressure were assessed in cirrhotic rats with ascites and control rats. Plasma endothelin levels were significantly higher in cirrhotic rats with ascites (24.5 ± 2.8 pg/mL; P < 0.001) than in cirrhotic rats without ascites and control rats (7.9 ± 2.0 and 5.8 ± 0.9 pg/mL, respectively). In animals with ascites, endothelin and endothelin 1 mRNA content in the lung, kidney, and aorta was similar to that of the controls. In contrast, higher endothelin content (0.567 ± 0.217 vs. 0.045 ± 0.002 pg/mg protein; P < 0.05) and endothelin 1 mRNA was observed in hepatic tissue of rats with cirrhosis and ascites. Endothelin A receptor blockade was not associated with significant changes in arterial and portal pressure in any group of animals. Increased endothelin 1 mRNA and endothelin production occurs in the livers of cirrhotic rats with ascites. In addition, our findings suggest that endothelin is not involved with the homeostasis of arterial or portal pressure in cirrhosis with ascites.     

Determinants of metastatic rate and survival in patients with zollinger-ellison syndrome: A prospective long-term study

It is unclear whether tumor location, size, or the presence of multiple endocrine neoplasia type 1 (MEN-1) alters metastatic rate and survival in patients with pancreatic endocrine tumors. The purpose of this study was to determine the prognostic factors of survival and metastatic rate in patients with Zollinger-Ellison syndrome (ZES). Data were analyzed from 185 consecutive patients with ZES who were followed up prospectively. Liver metastases were present in 24% of patients and correlated with the size of the primary tumor. Duodenal tumors were smaller than pancreatic tumors. Liver metastases occurred more often (P < 0.00001) with pancreatic than duodenal tumors, whereas the metastatic rate to lymph nodes was not different. Survival of patients with liver but not lymph node metastases was shortened. In patients with sporadic ZES, liver metastases were more common during the initial evaluation and survival was decreased compared with patients with MEN-1; however, during follow-up, an equal percentage of patients with and without MEN-1 developed liver metastases. Survival was primarily determined by the presence of liver metastases. The frequency of liver metastases depends on the size and location of the primary tumor and on the presence of MEN-1 at the initial presentation. Metastases to the lymph nodes do not depend on these factors. A benign and malignant form of ZES exists.     

Arterial hypertension and thyroid disorders: what is important to know in clinical practice?

This review describes the pathogenic mechanisms of blood pressure (BP) regulation and long-term control in thyroid disorders. Variations from the euthyroid status affect virtually all physiological systems but the effects on the cardiovascular system are particularly pronounced. Thyroid disorders induce several hemodynamic changes leading to elevated BP as a consequence of their interaction with endothelial function, vascular reactivity, renal hemodynamic and renin-angiotensin system. However, in thyroid disorders, the regulation of BP and the development and maintenance of variable forms of arterial hypertension (HT) are different. Hyperthyroidism results in an increased endothelium-dependent responsiveness secondary to the shear stress induced by the hyperdynamic circulation, and contributes to reduce vascular resistance. Conversely, hypothyroidism is accompanied by a marked decrease in sensitivity to sympathetic agonists with an increase of peripheral vascular resistance and arterial stiffness. Furthermore in animal models, hypothyroidism reduces the endothelium-dependent and nitric oxide-dependent vasodilatation. HT due to thyroid disorders is usually reversible with achievement of euthyroidism, but in some cases pharmacological treatment for BP control is required. In hyperthyroidism, β-blockers are the first-choice treatment to control BP but when they are contraindicated or not tolerated, ACE-inhibitors or calcium-channel blockers (CCB) are recommended. Hypothyroidism is a typical low rennin HT form showing a better antihypertensive response to CCB and diuretics; indeed in hypothyroidism a low-sodium diet seems further to improve BP control. Randomized clinical trials to compare the efficacy on BP control of the antihypertensive treatment in thyroid disorders are needed.     

Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.

BACKGROUND & AIMS: Recent studies have described the existence of endogenous cannabinoids with vasodilator activity because of their interaction with peripheral CB1 receptors, anandamide being the most extensively investigated. The study investigated whether endogenous cannabinoids are involved in the pathogenesis of the cardiovascular disturbances in experimental cirrhosis. METHODS: Arterial pressure, cardiac output, and total peripheral resistance were measured before and after the administration of a cannabinoid CB1 receptor antagonist to cirrhotic rats with ascites and to control rats. Blood pressure was also assessed in normotensive recipient rats after the intravenous administration of blood cells or isolated monocytes obtained from cirrhotic and control rats. Moreover, the endogenous content of anandamide was measured in circulating monocytes of cirrhotic and control rats by gas chromatography/mass spectrometry. RESULTS: CB1 receptor blockade did not modify systemic hemodynamics in control rats, but significantly increased arterial pressure and peripheral resistance in cirrhotic animals. Blood cell suspension or monocytes from cirrhotic animals, but not from controls, induced arterial hypotension in recipient rats. Finally, anandamide was solely detected in monocytes of cirrhotic animals. CONCLUSIONS: Monocytes of cirrhotic rats with ascites are activated to produce anandamide and this substance contributes to arterial hypotension in experimental cirrhosis.     

Impact of Obesity and Weight Loss on Cardiac Performance and Morphology in Adults

Obesity, particularly severe obesity is capable of producing hemodynamic alterations that predispose to changes in cardiac morphology and ventricular function. These include increased cardiac output, left ventricular hypertrophy and diastolic and systolic dysfunction of both ventricles. Facilitated by co-morbidities such as hypertension, the sleep apnea/obesity hypoventilation syndrome, and possibly certain neurohormonal and metabolic alterations, these abnormalities may predispose to left and right heart failure, a disorder known as obesity cardiomyopathy.     

Adrenergic nervous activity in patients after surgical correction of tetralogy of Fallot

OBJECTIVES

The study was done to define the role of the autonomic nervous system in postoperative tetralogy of Fallot.

BACKGROUND

Subsequent to surgical correction of tetralogy of Fallot, patients are at long-term risk of sudden death owing to ventricular electrical instability. The status of the sympathetic nervous system in these patients, known to play an important role in other patients at risk, remains unknown.

METHODS

We used ¹²³I metaiodobenzylguanidine (MIBG) with tomographic imaging, combined with assessment of heart rate variability (HRV), to evaluate the activity of the sympathetic nervous system. We analyzed 22 patients who had undergone total correction of tetralogy of Fallot: 13 with either no or minor ventricular arrhythmias, and 9 with sustained ventricular tachycardia or ventricular fibrillation.

RESULTS

Analysis of HRV revealed a reduction in vagal control and sympathetic dominance in all patients compared with a healthy control group of 20 subjects. A significant difference was found in the standard deviation of all the adjacent intervals between normal beats (SDNN) in patients with or without severe ventricular arrhythmias. A significant reduction in uptake of ¹²³I MIBG was demonstrated 30 min after IV injection, and a trend toward reduction after 5 h, associated with reduced washout indices. These data reflect a decrease in the number of nerve endings in the right and left ventricular walls, and an inhomogeneous distribution of the adrenergic nervous system. The uptake of MIBG was significantly reduced in the patients at risk of ventricular tachycardia or fibrillation.

CONCLUSIONS

Subsequent to surgical correction of tetralogy of Fallot, the positive correlation between myocardial uptake of MIBG, SDNN and the QRS dispersion confirmed the usefulness of analysis of the adrenergic nervous system to stratify patients at risk of life-threatening arrhythmias.     

Acute effects of fructose consumption on uric acid and plasma lipids in patients with impaired renal function

Objective

Metabolic disturbances are common in patients with renal function impairment and are related to high rates of cardiovascular incidents and mortality. Kidney transplantation leads to improved survival but may lead to additional metabolic alterations caused by immunosuppressive drugs and improved nutrition.

Materials and methods

The short-term effect of oral fructose load on serum uric acid (UA), plasma lipids, and blood pressure (BP) was studied in 85 patients with chronic kidney disease (CKD) and impairment of renal function (glomerular filtration rate 50–65 ml/min per 1.73 m²), comprising 55 renal transplant recipients (RTR) treated with standard triple immunosuppressive therapy including a calcineurin inhibitor (CNI) cyclosporine A (CsA) or tacrolimus (Tac) and 30 non-transplanted patients with CKD. Both non-transplanted CKD patients and RTR had stable renal function and a comparable degree of kidney dysfunction. All subjects received orally 70 g of fructose dissolved in 200 ml of water. Serum UA, lipids, and blood pressure were measured at baseline and 60, 120, 180, and 240 minutes after fructose administration.

Results

There was a significant increase of serum UA concentration (p < 0.001) in both CKD patients and RTR – CsA- or Tac-treated patients comparable in the latter. Total cholesterol (TC), LDL, and HDL cholesterol significantly decreased and serum triglycerides (TG) markedly increased in RTR, whereas in CKD patients all serum lipid fractions increased. Blood pressure was unaffected by fructose intake.

Conclusion

Both non-transplanted and transplanted patients with mild renal function impairment show similar acute purine metabolic disturbances following oral administration of fructose but in the latter dietary fructose may induce a smaller hyperlipidemic response.     

Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice

Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD⁺-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.