Massimo Pozzi

Sympathetic Activation and Loss of Reflex Sympathetic Control in Mild Congestive Heart Failure

BACKGROUND Baroreflex control of sympathetic activity is impaired in severe congestive heart failure (CHF), probably causing the marked sympathetic activation typical of this condition. Little information exists, however, as to whether baroreflex impairment and related sympathetic activation also occur in mild CHF. METHODS AND RESULTS We studied 19 patients (age, 57.5 +/- 2.2 years, mean +/- SEM) with CHF in New York Heart Association (NYHA) class III or IV and with a marked reduction in left ventricular ejection fraction (LVEF, 30.1 +/- 1.5% from echocardiography) and 17 age-matched patients with CHF in NYHA class I or II and with an only slightly reduced LVEF (44.9 +/- 3.3%) that never was < 40%. Seventeen age-matched healthy subjects served as control subjects. Primary measurements included beat-to-beat arterial blood pressure (with the Finapres technique), heart rate (from ECG), and postganglionic muscle sympathetic nerve activity (MSNA, from microneurography at the peroneal nerve). Measurements were performed at baseline and during baroreceptor stimulation (intravenous phenylephrine infusion), baroreceptor deactivation (intravenous nitroprusside infusion), and cold-pressor test. Baseline blood pressure was similar in the three groups, whereas heart rate was progressively greater from control subjects to patients with mild and severe CHF, MSNA (bursts per 100 heart beats) increased significantly and markedly from control subjects to patients with mild and severe CHF (47.1 +/- 2.9 versus 64.4 +/- 6.2 and 82.1 +/- 3.4, P < .05 and P < .01, respectively). Heart rate and MSNA were progressively reduced by phenylephrine infusion and progressively increased by nitroprusside infusion. Compared with control subjects, the responses were strikingly impaired in severe CHF patients, but a marked impairment also was seen in mild CHF patients. On average, baroreflex sensitivity in mild CHF patients was reduced by 59.1 +/- 5.5% (MSNA) and 64.8 +/- 4.8% (heart rate). In contrast, reflex responses to the cold-pressor test were similar in the three groups. CONCLUSIONS These results demonstrate that in mild CHF patients the baroreceptor inhibitor influence on heart rate and MSNA is already markedly impaired. This impairment may be responsible for the early sympathetic activation that occurs in the course of CHF.

Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites

The transjugular intrahepatic portosystemic shunt (TIPS) has been shown to be effective in the control of refractory or recidivant ascites. However, the effect of TIPS on survival as compared with that of large‐volume paracentesis plus albumin is uncertain. A multicenter, prospective, clinical trial was performed in 66 patients with cirrhosis and refractory or recidivant ascites (16 Child‐Turcotte‐Pugh class B and 50 Child‐Turcotte‐Pugh class C) randomly assigned to treatment with TIPS (n = 33) or with large‐volume paracentesis plus human albumin (n = 33). The primary endpoint was survival without liver transplantation. Secondary endpoints were treatment failure, rehospitalization, and occurrence of complications. Thirteen patients treated with TIPS and 20 patients treated with paracentesis died during the study period, 4 patients in each group underwent liver transplantation. The probability of survival without transplantation was 77% at 1 year and 59% at 2 years in the TIPS group as compared with 52% and 29% in the paracentesis group (P = .021). In a multivariate analysis, treatment with paracentesis and higher MELD score showed to independently predict death. Treatment failure was more frequent in patients assigned to paracentesis, whereas severe episodes of hepatic encephalopathy occurred more frequently in patients assigned to TIPS. The number and duration of rehospitalizations were similar in the two groups. In conclusion, compared to large‐volume paracentesis plus albumin, TIPS improves survival without liver transplantation in patients with refractory or recidivant ascites. (HEPATOLOGY 2004;40:629–635.)

Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure

BACKGROUND In congestive heart failure ACE inhibitors chronically reduce plasma norepinephrine. No information exists, however, on whether and to what extent this reduction reflects a true chronic inhibition of sympathetic outflow and which mechanisms may be responsible. METHODS AND RESULTS In 24 patients aged 60.3+/-2.0 years (mean+/-SEM) affected by congestive heart failure (New York Heart Association class II) and treated with diuretics and digitalis, we measured mean arterial pressure (Finapres), plasma renin activity and angiotensin II levels (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography), and muscle sympathetic nerve activity (microneurography at a peroneal nerve) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. In 12 patients measurements were repeated after a 2-month addition of the ACE inhibitor benazepril (10 mg/d P.O.), while in the remaining 12 patients they were performed again after 2 months without any treatment modifications. Benazepril did not alter mean arterial pressure, markedly increased plasma renin activity, reduced plasma angiotensin II, and caused a nonsignificant reduction in plasma norepinephrine. In contrast, muscle sympathetic nerve traffic was significantly reduced (-30.5+/-5.3%, P<.01). This reduction was accompanied by no change in the sympathoexcitatory responses to baroreceptor deactivation but by a marked enhancement of the sympathoinhibitory responses to baroreceptor stimulation (103.5+/-3.4%). CONCLUSIONS These results provide the first direct evidence that in congestive heart failure chronic ACE inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow. This reduction may depend on a persistent restoration of baroreflex restraint on the sympathetic neural drive.

Time course of circulatory and humoral effects of rapid total paracentesis in cirrhotic patients with tense, refractory ascites

BACKGROUND/AIMS Tense ascites of cirrhosis can be treated with total paracentesis; however, the short-term effects of this procedure are poorly defined. METHODS The circulatory and humoral changes induced by total paracentesis (250 mL/min) were studied in 12 cirrhotics with tense, refractory ascites. Data were collected before, during, and after paracentesis and 24 hours later (after albumin infusion). Hormonal parameters were recorded again 48 hours and 6 days thereafter. RESULTS Paracentesis (10.7 +/- 4.4 L; 64 +/- 20 minutes) caused marked reduction of intra-abdominal, intrathoracic, right atrial, and pulmonary pressures. Heart rate did not change. Cardiac output and heart volumes increased. Systemic vascular resistances and mean arterial pressure slightly decreased. Baseline plasma renin and aldosterone levels were markedly increased; a reduction was already evident during paracentesis with the lowest values at the end of the procedure. All changes were maintained 24 hours later. Hormones regained baseline levels 6 days later. CONCLUSIONS Rapid total paracentesis is accompanied by marked cardiovascular and humoral changes. Some of these changes can be explained by mechanical factors that are directly or indirectly related to the relief of abdominal pressure. However, other changes (systemic vasodilatation, humoral deactivation) have a non-mechanical nature and may depend on reflexes originating from cardiac volume receptor stimulation. Most changes may beneficially (albeit transiently) influence the cardiovascular system of cirrhotic patients with tense ascites.

Breakthrough during recombinant interferon alfa therapy in patients with chronic hepatitis C virus infection : prevalence, etiology, and management

Recombinant interferon alfa (r-IFN alpha 2) has been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV). Few patients experience a relapse during the treatment, in spite of a complete initial response (breakthrough). We studied 191 HCV Ab-positive patients with histologically proven chronic hepatitis. All of them were treated with r-IFN alpha 2 (3 MU three times a week). A complete response was seen in 54.4%. However, 12 of 104 responders experienced a breakthrough. At the time of breakthrough, neutralizing IFN antibodies were positive in 6 of 12 patients. Binding IFN antibodies were positive in all of these 12 patients. Continued treatment with r-IFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients.

HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients

BACKGROUND/AIMS Hepatitis C virus (HCV) easily undergoes genomic changes, thus accounting for the presence of different genotypes, with different geographic distributions and different outcomes of chronic hepatitis. Type 1b is frequently found in advanced diseases; however, since this genotype is the most prevalent in older patients, the association with advanced age and severity of the disease is confounding. The aim of this study was to assess changes in the prevalence of HCV genotypes by surveying a large population of chronic hepatitis C patients in Northern Italy, and to assess if the high prevalence of genotype 1b in older patients with advanced diseases simply reflects the duration of HCV infection, rather than intrinsic biological properties of HCV. METHODS We studied 1368 HCV-RNA positive patients, with histologically proven chronic hepatitis. Drug addiction, blood transfusions and sporadically acquired infections represented the risk factors. RESULTS Genotype 1b, the most prevalent isolate, and genotype 2a were associated with older age, cirrhosis, sporadically-acquired infections and blood transfusion, while types 1a, 3a, and 4 were associated with younger age, chronic persistent hepatitis and drug addiction. Patients with a history of transfusions were divided into four groups depending on the period of transfusion. The prevalence of genotype 1b decreased with time. Type 3a appeared only after 1979. CONCLUSION The severity of chronic hepatitis C could be related more to the duration of the infection rather than to the intrinsic pathogenicity of HCV genotypes.

Hepatocellular carcinoma in cirrhotic liver disease: functional computed tomography with perfusion imaging in the assessment of tumor vascularization

RATIONALE AND OBJECTIVES Our goal was to prospectively determine the value of perfusion computed tomography (CT) in the quantitative assessment of tumor-related angiogenesis in cirrhotic patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS Forty-seven patients met all the following inclusion criteria: 1) Child-Pugh class A or B liver cirrhosis; 2) presence of a single lesion suspected as HCC at screening ultrasound examination; and 3) lesion diameter between 1 and 3 cm. All patients underwent contrast-enhanced ultrasound, pre- and post-contrast triple-phase CT, and perfusion computed tomographic study using multidetector 16-slice CT. Six parameters related to the blood microcirculation and tissue perfusion were measured for the focal liver lesion and cirrhotic parenchyma: perfusion (P), tissue blood volume (BV), hepatic perfusion index (HPI), arterial perfusion (AP), portal perfusion (PP), and time to peak (TTP). Perfusion parameters were described with quartile values of their distribution; univariate paired and unpaired Wilcoxon signed rank tests were used for statistical analysis. RESULTS HCC was diagnosed in 21 of the 47 patients; in the remaining 26, HCC was not found at contrast-enhanced ultrasound and multidetector 16-slice computed tomographic study. The values of perfusion parameters measured within tumor tissue were: P (ml/s/100 g): median = 47.0 (first quartile = 36.0, third quartile = 61.4); BV (ml/100 mg): median = 24.0 (first quartile = 18.7, third quartile = 29.3); HPI (%): median = 78.4 (first quartile = 62.9, third quartile = 100); AP (ml/min): median = 45.9 (first quartile = 39.0, third quartile = 60.1); PP (ml/min): median = 9.0 (first quartile = 0.0, third quartile = 24.5); and TTP (seconds): median = 18.7 (first quartile = 16.3, third quartile = 26.5). The corresponding values calculated in cirrhotic surrounding parenchyma were P (ml/s/100 g): median = 11.5 (first quartile = 9.4, third quartile = 13.9); BV (ml/100 mg): median = 10.7 (first quartile = 7.1, third quartile = 14.2); HPI (%): median = 10.6 (first quartile = 8.7, third quartile = 11.9); AP (ml/min): median = 13.2 (first quartile = 10.1, third quartile = 15.5); PP (ml/min) median = 55.2 (first quartile = 40.1, third quartile = 79.5); and TTP (seconds): median = 41.7 (first quartile = 38.9, third quartile = 44.6). P, BV, HPI, and AP values were higher (P < .001), whereas PP and TTP were lower (P < .001) in HCC relative to the surrounding liver. Values of perfusion parameters in the cirrhotic liver of patients with and without HCC were not significantly different (P > .001). CONCLUSION In cirrhotic patients with HCC, perfusion computed tomographic technique can provide quantitative information about tumor-related angiogenesis.

Alterations of radial artery compliance in patients with congestive heart failure

Congestive heart failure is accompanied by several hemodynamic alterations. To investigate whether these alterations include reduced arterial compliance, we studied 25 patients (age 57 +/- 2 years, mean +/- SE) with a mild or severe congestive heart failure based on clinical symptoms (New York Heart Association class II vs III or IV) and on echocardiographic alterations of left ventricular diastolic diameter and ejection fraction. Radial artery diameter and blood pressure were continuously measured by Doppler ultrasonography and a finger pressure device, respectively. Compliance was calculated by the Langewouters formula, and compliance values were derived throughout the systolic-diastolic pressure range. The area under the compliance-pressure curve normalized for pulse pressure was used to compare compliance values in the various groups. Data were obtained both in baseline condition and at the release from a 12-minute brachial artery occlusion. Fourteen healthy, age-matched subjects served as controls. Compared with the control group, patients with severe congestive heart failure showed a reduction of baseline compliance index (-48%, p < 0.01). Furthermore, while in control subjects compliance markedly increased after brachial artery occlusion (+43%, p < 0.01), in patients with severe congestive heart failure no increase occurred. No baseline compliance alteration was seen in patients with mild congestive heart failure in whom, however, the postischemic increase in compliance was also significantly blunted (-50% vs controls, p < 0.05). Thus, arterial compliance and arterial compliance modulation are impaired in congestive heart failure. Although more marked in severe congestive heart failure, the impairment is manifest in mild congestive heart failure as well.

Perfusion CT in cirrhotic patients with early stage hepatocellular carcinoma: Assessment of tumor-related vascularization

PURPOSE To assess the value of CT-perfusion in determining the quantitative vascularization features of early hepatocellular carcinoma (HCC) in cirrhotic patients. MATERIALS AND METHODS A total of 35 cirrhotic patients with single histologically proven HCC not exceeding 3cm in diameter underwent conventional triple-phase multidetector computed tomography (MDCT) examination. All patients were also examined with CT-perfusion (CTp) technique after i.v. injection of 50mL of iodinated contrast. Data were analyzed using a dedicated software which generated a quantitative map of liver parenchyma perfusion. The following parameters were assessed: hepatic perfusion (HP); blood volume (BV); arterial perfusion (AP); time to peak (TTP) and hepatic perfusion index (HPI). Univariate Wilcoxon signed rank test was used for statistical analysis. RESULTS In the 35 HCCs evaluated, the following quantitative data were obtained: HP (mL/s/100g): median=47.0 (1(st)qt=35.5; 3(st)qt=61.2); BV (mL/100mg): median=22.5 (1(st)qt=18.4; 3(st)qt=27.7); AP (mL/min): median=42.9 (1(st)qt=35.8; 3(st)qt=55.6); HPI(%): median=75.3 (1(st)qt=63.1; 3(st)qt=100); TTP(s): median=18.7 (1(st)qt=16.8; 3(st)qt=24.5). Perfusion values calculated in cirrhotic liver parenchyma were HP: median=10.3 (1(st)qt=9.1; 3(st)qt=13.2); BV: median=11.7 (1(st)qt=9.6; 3(st)qt=15.5); AP: median=10.4 (1(st)qt=8.6; 3(st)qt=11.3); HPI: median=17.5 (1(st)qt=14.3; 3(st)qt=19.7); TTP: median=44.6 (1(st)qt=40.3; 3(st)qt=50.1). HP, BV, HPI and AP were found to be significantly higher in HCC lesion than in liver parenchyma (p<0.001), while TTP was significantly lower (p<0.001). CONCLUSION CT-perfusion technique allows obtaining quantitative information about tumor-related vascularization of early HCC, in patients with liver cirrhosis.

Cardiac, Neuroadrenergic, and Portal Hemodynamic Effects of Prolonged Aldosterone Blockade in Postviral Child A Cirrhosis

OBJECTIVES:The present study was designed to determine the effects of long-term antialdosterone treatment on cardiac structural and functional alterations, portal and systemic hemodynamic as well as adrenergic dysfunction characterizing Child A cirrhotic patients with F1 esophageal varices.METHODS:Twenty-two Child A postviral preascitic cirrhotic patients were randomly allocated to 200 mg/day K-Canrenoate (13 patients, age 59.6 ± 2.2 yr, mean + SEM) or no-drug treatment (9 patients, age 61.8 ± 2.3) for a 6-month-period. Measurements, which included hepatic venous pressure gradient (HVPG), left ventricular wall thickness, left ventricular end-diastolic volume and diastolic function (LVWT, LVEDV, and E/A ratio, echocardiography), and muscle sympathetic nerve activity (MSNA, microneurography, peroneal nerve), were obtained at baseline and following 6 months of drug or no-drug treatment. Ten healthy age-matched subjects served as controls.RESULTS:Cirrhotic patients were characterized by increased HVPG, LVWT, and MSNA values and by a depressed E/A ratio. K-Canrenoate treatment significantly reduced HVPG (from 15.3 ± 1.0 to 13.8 ± 0.8 mmHg, p < 0.05), LVWT (from 21.8 ± 0.5 to 20.7 ± 0.6 mm, p < 0.02), and LVEDV (from 99.2 ± 7 to 86.4 ± 6 ml, p < 0.01), leaving E/A ratio and MSNA almost unaltered. No significant change was observed in the untreated group of cirrhotic patients followed for 6 months without intervention.CONCLUSIONS:These data provide evidence that aldosterone blockade by long-term K-Canrenoate administration improves hepatic hemodynamics by lowering HVPG and ameliorates cardiac structure and function by favoring a reduction in LVWT and LVEDV as well. They also show, however, that this therapeutic intervention neither improves left ventricular diastolic dysfunction nor exerts sympathoinhibitory effects.