Benvenuto Grisorio

INCIDENCE OF DILATED CARDIOMYOPATHY AND DETECTION OF HIV IN MYOCARDIAL CELLS OF HIV-POSITIVE PATIENTS

BACKGROUND Human immunodeficiency virus (HIV) infection is increasingly recognized as an important cause of dilated cardiomyopathy. However, the pathogenesis of the heart-muscle disease in the acquired immunodeficiency syndrome is unclear. METHODS We performed a prospective, long-term clinical and echocardiographic follow-up study of 952 asymptomatic HIV-positive patients to assess the incidence of dilated cardiomyopathy and to analyze the clinical variables associated with the development of cardiomyopathy. All patients with an echocardiographic diagnosis of dilated cardiomyopathy underwent endomyocardial biopsy for histologic, immunohistologic, and virologic assessment. RESULTS During a mean (+/-SD) follow-up period of 60+/-5.3 months, an echocardiographic diagnosis of dilated cardiomyopathy was made in 76 patients (8 percent), with a mean annual incidence rate of 15.9 cases per 1000 patients. The incidence of dilated cardiomyopathy was higher in patients with a CD4 count of less than 400 cells per cubic millimeter (as compared with a CD4 count of > or =400 cells per cubic millimeter) and in those who received therapy with zidovudine. A histologic diagnosis of myocarditis was made in 63 of the patients with dilated cardiomyopathy (83 percent). Inflammatory infiltrates were predominantly composed of CD3 and CD8 lymphocytes, with staining for major histocompatibility complex class I antigens in 71 percent of the patients. In the myocytes of 58 patients, HIV nucleic acid sequences were detected by in situ hybridization, and active myocarditis was documented in 36 of the 58. Among these 36 patients, 6 were also infected with coxsackievirus group B (17 percent), 2 with cytomegalovirus (6 percent), and 1 with Epstein-Barr virus (3 percent). CONCLUSIONS Dilated cardiomyopathy may be related either to a direct action of HIV on the myocardial tissue or to an autoimmune process induced by HIV, possibly in association with other cardiotropic viruses.

Hepatocellular Mitochondrial Alterations in Patients With Chronic Hepatitis C: Ultrastructural and Biochemical Findings

OBJECTIVE:Hepatitis C virus (HCV) infection is associated with increased lipoperoxidation, which may lead to interference with mitochondrial function with possible depletion of mitochondrial DNA (mtDNA). We correlated the ultrastructural findings of liver biopsy specimens with the lipoperoxidation markers and contents of mtDNA in chronic hepatitis C (CHC) patients with a different HCV genotype.METHODS:Liver biopsy samples obtained from 75 CHC patients were processed for histological and electron microscopic examination. Twenty-two subjects without known liver disease served as controls. Hepatic glutathione in its reduced (H-GSH) and oxidized (H-GSSG) forms were determined from biopsy specimens by high-performance liquid chromatography. Plasmatic and lymphocytic GSH and erythrocytic malonyldialdehyde (MDA) were also determined, along with the ratio between mtDNA and nuclear DNA (nDNA).RESULTS:Ultrastructural alterations of the mitochondria were documented in 23 patients with genotype 1b, compared with 15 patients with genotype 2a/2c (p= 0.020) and seven patients with genotype 3a (p < 0.001). A significant depletion of H-GSH and lymphocytic GSH, an increase of H-GSSG and MDA, and a reduction of the mtDNA/nDNA ratio were documented in patients with genotype 1b, compared with patients with genotype 2a/2c and 3a and with controls.CONCLUSIONS:In patients with genotype 1b frequent ultrastructural alterations of the mitochondria may be observed, and the depletion of mtDNA in these patients may represent the expression of a greater impairment of the process of oxidative phosphorylation. An increased production of free radicals in patients with genotype 1b may influence the evolution of the liver disease by enhancement of the cytopathic effect of HCV.

Serum ferritin and hepatic glutathione concentrations in chronic hepatitis C patients related to the hepatitis C virus genotype

BACKGROUND/AIMS Increased serum ferritin is thought to be responsible for activation of glutathione turnover in patients with chronic hepatitis C. The aim of the study was to evaluate a possible correlation between levels of serum ferritin and concentrations of hepatic, plasmatic and lymphocytic glutathione in a selected cohort of chronic hepatitis C patients in relation to the hepatitis C virus genotype. METHODS The study considered 130 chronic hepatitis C patients and 23 control subjects. Hepatic glutathione was determined from biopsy liver specimens by high performance liquid chromatography. Total Iron Score was assessed by scoring iron separately within hepatocytes, sinusoidal cells and portal tracts. Blood samples were tested for determination of serum ferritin, and plasmatic and lymphocytic glutathione levels. Hepatic and erythocyte malonyldialdehyde were also determined along with peripheral blood mononuclear cell cytotoxic assay. RESULTS Patients with genotype 1b showed higher levels of serum ferritin compared to patients with genotype 2a/2c and 3a and to controls, along with a significant reduction of the concentrations of hepatic, plasmatic and lymphocytic glutathione and peripheral blood mononuclear cell cytotoxic activity. The levels of serum ferritin correlated significantly to Total Iron Score, to hepatic, plasmatic and lymphocytic glutathione, to hepatic and erythrocyte malonyldialdehyde and to peripheral blood mononuclear cell cytotoxic activity. CONCLUSIONS The levels of serum ferritin correlate significantly to lipoperoxidation markers in chronic hepatitis C patients. The increased production of free radicals with a reduced peripheral blood mononuclear cell cytotoxic activity may represent, especially in patients with genotype 1b, a factor underlying the resistance to interferon therapy and may influence the evolution of the liver disease by enhancement of the cytopathic effect of hepatitis C virus.

Intensity of Myocardial Expression of Inducible Nitric Oxide Synthase Influences the Clinical Course of Human Immunodeficiency Virus-Associated Cardiomyopathy

BACKGROUND Increased levels of tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) have been reported in patients with dilated cardiomyopathy. We investigated the myocardial expression of TNF-alpha and iNOS in patients with HIV-associated cardiomyopathy (HIV-DCM) compared with patients with idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS Endomyocardial biopsy specimens from 82 HIV-DCM and 80 IDCM patients were processed for determination of the immunostaining intensity of TNF-alpha and iNOS and for virological examination. Negative controls were derived from autopsy myocardium specimens from 32 HIV-negative patients without known heart disease. The mortality rate for congestive heart failure between groups according to the intensity of iNOS staining was also evaluated. The mean intensity of both TNF-alpha and iNOS staining was greater in patients with HIV-DCM (0.81 and 1.007, respectively) than in patients with IDCM (0.44 and 0.49, respectively) and controls (0.025 and 0.027, respectively). The staining intensity of both TNF-alpha and iNOS was inversely correlated with CD4 count. The staining intensity of iNOS was greater in HIV-DCM patients with HIV/coxsackievirus B3 (CVB3) or with HIV/cytomegalovirus coinfection than in IDCM patients showing infection with CVB3 and adenovirus alone. The staining intensity of iNOS correlated to mortality rate, because it was higher in HIV-DCM patients and, in particular, in those with an optical density unit >1. CONCLUSIONS Cytokine activation seems to play a significant pathogenetic role in both HIV-DCM and IDCM. In HIV-DCM patients, the state of immunodeficiency may favor the selection of viral variants of increased pathogenicity, influencing the clinical course of cardiomyopathy by enhancement of the inflammatory process.

An open-label, prospective, observational study of the incidence of coronary artery disease in patients with hiv infection receiving highly active antiretroviral therapy☆

BACKGROUND The association of highly active antiretroviral therapy (HAART) regimens that include protease inhibitors (PIs) with metabolic and somatic disorders has raised concerns about the possibility of an increased risk of coronary artery disease (CAD) in patients with HIV infection. OBJECTIVE The aim of this study was to assess the incidence of CAD in previously untreated HIV infected outpatients who received reverse transcriptase inhibitors with or without PIs. METHODS In this open-label, multicenter, prospective, observational trial, previously untreated and asymptomatic HIV-infected Italian patients were followed to assess the incidence of CAD (primary end point) according to the HAART regimen they received: 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) in combination with PIs (group PI+) or 1 non-nucleoside reverse transcriptase inhibitor in combination with 2 NRTIs (group PI-). Patients underwent clinical examination and laboratory testing every 4 months. RESULTS A total of 1551 HIV-infected patients (994 [64%] men; median age, 35 years; range, 22-50 years) were followed for a median 36 months (range, 34-42 months). The cumulative annual incidence of CAD-related events was 9.8/1000 in group PI+ and 0.8/1000 in group PI- (P < 0.001). The annual incidence of myocardial infarction was 5.1/1000 in group PI+ and 0.4/1000 in group PI- (P < 0.001). Independent of patient age, the incidence of CAD was greater among men (P < 0.001) and patients who smoked >20 cigarettes per day (P < 0.001). Lipodystrophy and metabolic alterations were observed in 62% of patients in group PI+ and in 4% of patients in group PI- (P < 0.001). Of 23 patients receiving PIs who developed CAD, 17 (73.9%) had lipodystrophy and all 23 had hypertriglyceridemia and hypercholesterolemia. CONCLUSIONS According to our findings, HAART that includes PIs may accelerate the onset of CAD-related events in young, male, heavy smokers who develop metabolic disorders and lipodystrophy during therapy. Patients with increased coronary risk should receive careful cardiac monitoring if treated with PIs.

Interferon alpha-2b and ribavirin in combination for patients with chronic hepatitis C who failed to respond to, or relapsed after, interferon alpha therapy: a randomized trial

PURPOSE To assess the efficacy of interferon alpha-2b and ribavirin in combination in the treatment of patients with chronic hepatitis C who had either failed to respond to therapy with interferon alpha (nonresponders), or who had relapsed after interferon therapy (relapsers). SUBJECTS AND METHODS Four hundred patients with chronic hepatitis C (200 nonresponders and 200 relapsers) were randomly assigned in equal numbers to receive either subcutaneous administration of recombinant interferon alpha-2b (3 million units three times per week) and ribavirin (1,000 to 1,200 mg/daily orally) or interferon alpha-2b alone (6 million units three times per week). Both ribavirin and interferon alpha-2b were given for 24 weeks. The patients were then followed for an additional 24 weeks. RESULTS At the end of the treatment period, normalization of serum alanine aminotransferase levels and absence of hepatitis C virus RNA were seen in 21% of nonresponders and in 39% of relapsers who were treated with interferon alpha-2b and ribavirin, compared with 5% of nonresponders (P = 0.001) and 9% of relapsers treated with interferon alpha-2b alone (P <0.001). At the end of follow-up, 14% of nonresponders and 30% of relapsers treated with the combination therapy had a sustained response, compared with 1% of nonresponders (P = 0.001) and 5% of relapsers treated with interferon alpha alone (P <0.001). CONCLUSIONS A 24-week course of treatment with interferon alpha-2b and ribavirin offers a chance of sustained response, whereas retreatment with interferon alpha-2b alone does not give satisfactory results. The role of long-term therapy in inducing prolonged remission remains to be explored.

Interferon-α-2B and ribavirin in combination for chronic hepatitis C patients not responding to interferon-α alone: an italian multicenter, randomized, controlled, clinical study

Objective:The aim of the study was to assess the efficacy of interferon (IFN)-α-2b and ribavirin in combination in the treatment of chronic hepatitis C (CHC) patients unresponsive to a previous treatment with IFN-α−2b alone.Methods:We conducted a randomized study in 303 CHC patients. One hundred fifty-two patients received subcutaneous administration of recombinant IFN-α−2b (3 MU thrice weekly) and ribavirin (1000–1200 mg/daily per os), whereas 151 received IFN-α−2b alone (6 MU thrice weekly). Both ribavirin and IFN-α-2b were given for 24 wk, regardless of treatment response. Alanine aminotransferase (ALT) levels and HCV RNA titer were checked during the treatment period and for a further 24 wk.Results:Normal ALT levels were observed in 64.5% of the patients treated with IFN-α and ribavirin and in 22.6% of the patients treated with IFN-α alone. In the group of patients receiving IFN-α and ribavirin HCV RNA was not detectable in 40% of patients responders and remained undetectable in 44.2% of sustained responders. In the group of patients receiving IFN-α alone HCV RNA was not detectable in 24.2% of patients responders and remained not detectable in 33.3% of sustained responders.Conclusion:A 24-wk treatment course with IFN-α and ribavirin given to patients with a previous lack of response to IFN-α alone offers a chance of a sustained biochemical and virological response, at least in a subset of such patients. The role of long-term therapy in inducing prolonged remission still remains to be explored.

Epicardial Adipose Tissue is Related to Carotid Intima-Media Thickness and Visceral Adiposity in HIV-Infected Patients with Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome

BACKGROUND High cardiovascular risk and accelerated atherosclerosis are associated with human immunodeficiency virus (HIV). Recently, the use of highly active antiretroviral therapy (HAART) for the treatment of HIV infection is correlated with the development of HAART-associated metabolic syndrome and lipodystrophy (LDS). Detection of epicardial fat thickness, new index of visceral adiposity in non HIV-infected patients, might be important as diagnostic tool in HIV-infected patients on HAART. OBJECTIVE Primary objective of this study was to evaluate whether echocardiographic epicardial adipose tissue is related to visceral adipose tissue (VAT) and Carotid Intima-Media Thickness (IMT), index of atherosclerosis in HIV-infected patients on HAART with LDS. DESIGN We studied 60 consecutive HIV-infected subjects with HAART-associated metabolic syndrome and LDS and 45 HIV-infected subjects on HAART without LDS. MAIN OUTCOMES MEASURES Epicardial fat thickness and IMT were measured by ultrasonography in both study and control groups. Magnetic resonance imaging (MRI) was used to calculate VAT in HIV-infected subjects on HAART with LDS. RESULTS Epicardial adipose tissue thickness showed an excellent correlation with MRI-VAT (r=0.85; P<0.001) and IMT (r=0.78;P<0.001) in HIV-infected patients on HAART-with LDS. Multiple regression analysis showed that epicardial fat thickness was best predicted by MRI-VAT and IMT (R2=0.57, p<0.001 and p<0.01, respectively). HIV-infected patients with HAART-associated metabolic syndrome and LDS showed higher epicardial fat thickness and IMT (8 vs 6.5 mm; 0.71 vs 0.66 mm, respectively, p<0.01 for both) than HIV-infected subjects on HAART without LDS. CONCLUSION Echocardiographic assessment of epicardial fat may have the potential to be a simple and reliable marker of visceral adiposity and increased cardiovascular risk in HIV-infected patients with HAART-associated metabolic syndrome and LDS.

Relation of Epicardial Fat and Alanine Aminotransferase in Subjects With Increased Visceral Fat

Background: Increased visceral adipose tissue (VAT) is a risk factor for an unfavorable cardio‐metabolic profile and fatty liver. Individuals with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) can be associated with metabolic syndrome (MS) and higher visceral fat. However, the potential link between cardiac adiposity, emerging index of visceral adiposity, and fatty liver is still unexplored.

The pavia consensus statement

The intersection of cardiovascular disease and HIV infection is common and complex, yet inadequately understood. Considering and managing actual or potential cardiovascular illness in patients with HIV infection are important aspects of HIV care. As the diagnosis and management of cardiovascular disease is itself complex, specialists in this area of medicine may need to be consulted. They, in turn, need to be aware of the complex manifestations of HIV infection and the cardiovascular implications of HIV therapy. The bilateral nature of these interactions is an important issue considered in the present report.