Giuseppe Barbaro

Takotsubo Cardiomyopathy A New Form of Acute, Reversible Heart Failure

Several relatively recent case reports and series have described a condition featuring symptoms and signs of acute myocardial infarction without demonstrable coronary artery stenosis or spasm in which the heart takes on the appearance of a Japanese octopus fishing pot called a takotsubo (Figure 1). In takotsubo cardiomyopathy (also called transient apical ballooning and stress cardiomyopathy), left ventricular dysfunction, which can be remarkably depressed, recovers within a few weeks.1–4 Figure 1 Left ventriculogram (A, end-diastolic phase; B, end-systolic phase) in the right anterior oblique projection. The extensive area around the apex shows akinesis, and the basal segments display hypercontraction, especially in the end-diastolic phase. C, ... Takotsubo cardiomyopathy occurs predominantly in post-menopausal women soon after exposure to sudden, unexpected emotional or physical stress. For instance, the incidence of takotsubo cardiomyopathy increased substantially in elderly women living near the epicenter of the Niigata earthquake.4 Although the left ventricular dysfunction is transient and there is no evidence of obstructive epicardial coronary disease, an increasing number of angioplasty procedures have been performed for presumed acute coronary syndromes. Concepts about the demographics, clinical features, prognosis, and management of this reversible form of left ventricular failure are still evolving. In this brief review, we summarize recent clinical reports and discuss an animal model that may clarify the pathogenesis of this condition.

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.

Cardiovascular Manifestations of HIV Infection

Studies published over the past 3 years have tracked the incidence and course of human immunodeficiency virus (HIV) infection in relation to cardiac illness in both children and adults.1 These studies show that subclinical echocardiographic abnormalities independently predict adverse outcomes and identify high-risk groups to target for early intervention and therapy. The Joint United Nations Program on HIV/AIDS estimates that 36.1 million people were living with HIV infection at the end of the year 2000.2 If 8% to 10% of patients develop symptomatic heart failure over a 2- to 5-year period,3 then 3 million cases of HIV-related heart failure will present during that period.1 Cardiovascular manifestations of HIV have been altered by the introduction of highly active antiretroviral therapy (HAART) regimens. On one hand, HAART has significantly modified the course of HIV disease, lengthened survival, and improved the quality of life of HIV-infected patients. On the other hand, the early data have raised concerns that HAART is associated with an increase in both peripheral and coronary arterial diseases.1 The HAART-associated changes are relevant only to the minority of HIV-infected individuals worldwide who have access to HAART. Thus, studies conducted before HAART became available remain globally applicable. In this review article, the principal HIV-associated cardiovascular manifestations will be discussed, with an emphasis on new knowledge about prevalence, pathogenesis, and treatment. HIV disease is recognized as an important cause of dilated cardiomyopathy, with an estimated annual incidence of 15.9 in 1000 before the introduction of HAART3 (Table 1). The importance of cardiac dysfunction is demonstrated by its effect on survival in acquired immunodeficiency syndrome (AIDS). Median survival to AIDS-related death is 101 days in patients with left ventricular dysfunction and 472 days in patients with a normal heart as shown by echocardiography at a similar infection …

Highly Active Antiretroviral Therapy: Current State of the Art, New Agents and Their Pharmacological Interactions Useful for Improving Therapeutic Outcome

Highly active antiretroviral therapy (HAART) dramatically changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor (FI). Several pharmacological agents are available form these classes of antivirals, NRTIs, NNRTIs, PIs and FIs, which will be briefly reviewed here. Some more agents are in advanced clinical evaluation or have recently been approved (such as tenofovir, a NtRTI; atazanavir, a PI; tipranavir, another PI), mainly against drug-resistant viruses. Compounds inhibiting HIV integrase, the third enzyme of HIV, are also available ultimately, with several such derivatives in clinical trials (L-731, 988 and S-1360). Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. All steps in the process of HIV entry into the cell may be targeted by specific compounds that might be developed as novel types of antiretrovirals. Thus, inhibitors of the gp120-CD4 interaction have been detected (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Compounds interacting with Tat/Tar have also been detected which inhibit HIV replication in low micromolar range (EM2487, tamacrazine, CGP 64222 or CGA 137053 among others). Unexploited viral and cellular targets (such as the maturation process-with a first potent compound available, PA-457; the cellular proteins Tsg101, APOBEC3G, or the viral ones Vif, Rev or RNase H) are also presented, together with recently emerged approaches for eradication of HIV reservoirs. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to these drugs may be managed better by taking them into account.

Threshold Values of High-risk Echocardiographic Epicardial Fat Thickness

Objective: Echocardiographic epicardial adipose tissue is a new index of cardiac and visceral adiposity with great potential as a diagnostic tool and therapeutic target. In this study, we sought to provide threshold values of echocardiographic epicardial fat thickness associated with metabolic and anthropometric risk factors.

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.

Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial

BACKGROUND/AIMS To evaluate the therapeutic efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. METHODS One hundred and fifty-one patients were randomly assigned to receive either recombinant interferon alpha-2b (nine million units three times per week) and lamivudine (100 mg/daily per os) for 24 weeks or lamivudine alone (100 mg/daily per os) for 52 weeks. Patients were followed up for a further 48 weeks. RESULTS Sustained HBeAg seroconversion with undetectable serum levels of HBV DNA was observed in 25 of 76 patients (33%) treated with the combination therapy and in 11 of 75 patients (15%) treated with monotherapy (P=0.014). Histological improvement defined as a reduction of at least two points in the inflammation score as compared with pretreatment score was observed in 35 of 76 patients (46%) treated with combination therapy and in 20 of 75 patients (27%) treated with monotherapy (P=0.021). Both therapeutic regimens were well tolerated. CONCLUSIONS Six-month treatment with interferon alpha-2b and lamivudine in combination appeared to increase the rate of sustained HBeAg seroconversion compared to 1-year lamivudine monotherapy. However, the potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Primary Pulmonary Hypertension in HIV Patients: A Systematic Review

The relationship between grade of pulmonary hypertension and factors associated with human immunodeficiency virus among patients with HIV infection is poorly documented. This report documents the most extensive attempt made thus far to determine whether a relationship exists between degree of pulmonary hypertension and the following conditions: HIV risk factor, degree of immunosuppression, presence or absence of AIDS, and presence or absence of liver cirrhosis. A retrospective study involving a search of the published literature on primary pulmonary hypertension among HIV cases from 1987 to 1998, using the Medline and Aidsline databases was conducted. Patients for whom secondary causes of pulmonary hypertension could be excluded were selected, and the following information for each was recorded: age, gender, risk factors for HIV infection, HIV disease stage according to the Centers for Disease Control, previous oppor tunistic and neoplastic diseases, CD4+ cell count (cells/L), presence or absence of liver cirrhosis, pulmonary systolic artery pressure level, and lung pathology specimens. Information about the patients survival time was also recorded. Seventy-six patients were judged to have primary pulmonary hypertension and were included in the study. While no correlation was found between pulmonary systolic artery pressure level and CD4+ cell counts, a statistically significant difference was found between HIV-positive patients with and without AIDS as determined by the Centers for Disease Control criteria with regard to the degree of pulmonary hypertension, expressed as pulmonary systolic artery pressure level (85.4 ± 17 mm Hg vs 71.8 ± 15 mm Hg, p < 0.013). Although a higher PAPS was present in HIV cirrhotic patients, a statistically significant difference was not found between degree of pulmonary hyper tension and evidence of hepatic cirrhosis (85 ±21 mm Hg vs 73.1 ± 15 mm Hg, p < 0.062). Patients with AIDS and primary pulmonary hypertension present a higher degree of pulmonary hypertension than non-AIDS patients. Pulmonary hypertension associated with HIV seems to be related to a cytokine-related stimulation and proliferation of endothelium. High levels of cytokines present in AIDS patients can favor pulmonary hypertension, but the role of a host response to HIV—determined by one or more HLA subtypes—is suspected to enhance high cytokine production levels.

Pathogenesis of HIV-associated cardiovascular complications

Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults. The introduction of HAART regimens has significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV-infected people expected. However, early data raised concerns about HAART being associated with an increase in both peripheral and coronary arterial diseases. In this review we discuss HIV-associated cardiovascular complications focusing on pathogenetic mechanisms that could have a role in diagnosis, management, and therapy of these complications in the HAART era.

Inhibitors of HIV-1 protease: current state of the art 10 years after their introduction. From antiretroviral drugs to antifungal, antibacterial and antitumor agents based on aspartic protease inhibitors.

The introduction of highly active antiretroviral therapy (HAART) in 1996 dramatically changed the course of HIV infection. This therapy involves the use of at least three agents from two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Nine drugs containing PIs are clinically available: the first generation ones, saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir, and the second generation ones, fosamprenavir (the amprenavir prodrug), lopinavir, atazanavir, and tipranavir. Many other compounds are in advanced clinical evaluation, such as among others TMC-114, whereas a lot of different other effective HIV protease inhibitors were reported, mainly by using amprenavir and TMC-114 as lead molecules. The main goals of research in this field are: (i) the design of better pharmacological agents, devoid of severe side effects, resistance problems and with simple administration schedules (preferably once daily), and (ii) achieving eradication of the virus, and possibly, a definitive cure of the disease. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to PI drugs may be managed better by taking them into account (such as for example ritonavir boosting of other PIs which reduces dosages and administration schedules of these drugs). Except for being highly effective in the treatment of HIV infection, recent reports showed this class of drugs to be effective as antitumor agents, as antibacterials (for example against Mycobacterium tuberculosis infection), antifungals (against Candida albicans), antimalarials, antiSARS and anti-influenza agents.