Abstract: Objective: Atherosclerosis is characterized by endothelial inflammation and dysfunction. Adipose tissue has increasingly been recognized as an active endocrine organ secreting so-called adipokines. Among these, resistin - recently described, but not yet extensively studied - has been defined as a novel inflammatory marker in atherosclerosis. The pathophysiology underlying this interplay, however, remains to be fully characterized. The aim of the study is to determine whether resistin might affect prothrombotic characteristics of human coronary artery endothelial cells (HCAECs). Methods and Results: Incubation of HCAECs with resistin caused upregulation of tissue factor (TF) expression as demonstrated by FACS analysis. Moreover, TF activity was induced in a dose-dependent manner, as shown by real-time PCR and colorimetric assay. Resistin-induced TF expression was mediated by oxygen free radicals through the activation of the transcription factor nuclear factor-kappaB (NF-kappaB), as demonstrated by electrophoretic mobility shift assay and by suppression of TF expression by superoxide dismutase, catalase, and the NF-kappaB inhibitors PDTC and BAY 11-7082. Conclusions: These data confirm the hypothesis that resistin may contribute to atherothrombosis, exerting direct effects on HCAECs by promoting TF expression; thus, it represents an effector molecule able to induce a prothrombotic phenotype in cells present in the vessel wall.
Abstract: BACKGROUND: There is a growing body of evidence that physical training exerts its potential benefits on the individual health status by modulating the immune system and the whole body metabolism. A better knowledge of the physiologic immune response to exercise may help to understand the benefits of physical exercise in healthy individuals and elite athletes. Aims: This study aims to analyse cardiotrophin-1 (CT-1) and Tumor Necrosis Factor-alpha (TNF-alpha) plasma levels at rest and during exercise in elite athletes and healthy controls. METHODS: We studied 20 triathletes (TA) and 20 matched controls (CG). Chambers dimensions, left ventricular mass and left ventricular mass index were analysed by echocardiography. VO2 peak and VE/VCO2 were calculated by metabolic stress test. Blood samples were collected before the exercise session, at the exercise peak, and after the end of exercise. ELISA assays were used to measure CT-1 and TNF-alpha plasma levels. RESULTS: Among TA and CG, no significant differences were found for CT-1 (0.25+/-0.14 vs 0.20+/-0.14 fm/l; p=0.29) and TNF-alpha (10.8+/-2.7 vs 9.7+/-4.0 pm/l; p=0.29) basal levels. In the TA, plasma levels of CT-1 were significantly different at rest and during exercise (basal 0.25+/-0.13 pm/l; peak 1.07+/-1.5 pm/l; post-exercise 0.67+/-0.77 pm/l; p=0.04). Conversely, no significant differences were found between basal, peak and post-exercise plasma values of TNF-alpha (basal 10.8+/-2.7 pm/l; peak 11.7+/-2.1 pm/l; post-exercise 11.4+/-2.5 pm/l; p=0.78) in TA. CONCLUSIONS: This study gives novel insights on the behavior of inflammatory cytokines during physical exercise in athletes and healthy individuals.
Abstract: Hypertrophic cardiomyopathy (HCM) is the most frequent genetic cardiovascular disorder worldwide. It is the leading cause of sudden cardiac-related death in young people and a major cause of cardiac failure and death in elderly people. However, HCM frequently goes undiagnosed until the appearance of overt signs and symptoms, thereby delaying prophylactic and therapeutic measures. We screened patients for sarcomeric genes associated with HCM to obtain information that could be useful for an early diagnosis and so limit the severe consequences of silent HCM. We recruited 39 families with HCM from southern Italy and found mutations in 41% of families (12 with familial HCM and 4 with sporadic HCM). The remaining 23 families (59%) were negative for myofilament gene mutations. Of the 12 mutations identified, 8 were novel. Screening of the other family members available revealed that 27 had mutations; 11 of these individuals had no signs or symptoms suggestive of HCM. This study, besides characterizing the spectrum of mutations in another childhood population, and revealing an even greater genetic heterogeneity than formerly recognized, may increase genotype-phenotype correlations, and thus may help to identify asymptomatic candidates for early preventive or therapeutic measures.
Abstract: Until relatively recently, the role of adipose tissue in the development of obesity and its consequences was considered to be a passive one. Mounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that contributes to obesity-associated vasculopathy and cardiovascular risk. It is now clear that, in addition to storing calories as triglycerides, adipocytes secrete a large variety of cytokines, chemokines and hormone-like factors, such as leptin, resistin, and acute-phase proteins. In addition, insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly with an excess of intraabdominal fat. This production of pro-atherogenic substances is of particular interest since an increase in the plasma levels of these mediators may provide a novel mechanistic link between obesity and its vascular complications.
Abstract: Cardiotrophin-1 (CT-1), a member of interleukin (IL)-6 family, was originally isolated for its ability to induce a hypertrophic response in neonatal cardiac myocytes. This cytokine mediates a pleiotropic set of growth and differentiation activities through a unique receptor system, consisting of IL-6 receptor (IL-6R) and a common signal transducer, the glycoprotein 130 (gp130). Both in humans and in mice, CT-1 mRNA has been detected in several tissues, such as liver tissue, adipose tissue, and tissues in the respiratory and nervous systems; in each of these tissues it performs different functions. Predominant actions of CT-1 are on the heart, where it is synthesized and where it provides first myocardial protection by promoting cell survival and proliferation, it carries on its haemodynamic effects and endocrine properties, and finally, it predisposes the heart to pathological conditions. The aim of this review is to describe the pathophysiological mechanisms through which CT-1 carries out its activities, especially on the heart, and its potential contribution as a disease marker in clinical cardiology. Recent studies have confirmed its active role in promoting structural changes typical of most common cardiovascular disease, such as hypertension, valve diseases, congestive heart failure, and coronary artery disease. In fact, CT-1 induces myocyte hypertrophy and collagen synthesis, thereby participating in the progression of ventricular remodelling, which results in cardiac muscle failure at the latest stage. CT-1 plasma levels are elevated in patients with hypertension and coronary artery diseases, and they are also correlated with the severity of valve diseases and heart failure. Therefore, CT-1 may represent a diagnostic, staging, and prognostic biomarker of cardiovascular diseases.
Abstract: Because it is unclear whether the genotype may influence the clinical course in patients with LEOPARD syndrome (LS), we analyzed clinical and molecular predictors of adverse cardiac events in patients with left ventricular hypertrophy (LVH). A comprehensive cardiovascular evaluation, including baseline electrocardiogram, echocardiography, exercise test and 24 hr Holter monitoring at the time of clinical diagnosis and during follow-up was conducted on 24 patients referred to our departments. Phenotypical examination and diagnosis were performed by expert clinical geneticists. The entire PTPN11 and RAF1 coding regions were screened for mutations by DHPLC analysis, followed by sequencing. Patients without PTPN11 mutations (34%) showed a higher frequency of family history of sudden death (P = 0.007), increased left atrial dimensions (P = 0.05), bradyarrhythmias (P = 0.04), episodes of supraventricular tachycardias (P = 0.06), atrial fibrillation (P = 0.009), and nonsustained ventricular tachycardias (P = 0.05) during Holter monitoring. Six patients (25%) had adverse cardiac events during follow-up (including sudden deaths, resuscitated cardiac arrest, septal myectomy, and heart failure). LVH, New York Heart Association Class, left ventricular outflow tract obstruction, and nonsustained ventricular tachycardias were associated to adverse cardiac events. Of note, three patients with mutations in exon 13 showed a severe obstructive cardiomyopathy, with serious cardiac complications during follow-up (heart failure, septal myectomy, and sudden death). In conclusion, patients with LVH associated with LS seem to carry a relatively high risk of adverse (arrhythmic and nonarrhythmic) events. Further genotype-phenotype studies are warranted to fully elucidate the impact of the genotype on the natural history of patients with LS and LVH.
