Valeria Maddaloni

Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target

Atherosclerosis represents the most common pathological substrate of coronary heart disease (CHD), and the characterization of the disease as a chronic low-grade inflammatory condition is now largely accepted. A number of mediators of inflammation have been widely studied, both as surrogate biomarkers and as causal agents, in the pathophysiological network of atherogenesis and plaque vulnerability. The epidemiological observation that biomarkers of inflammation are associated with clinical cardiovascular risk supports the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk on the background of traditional medical therapy. A large number of randomized controlled trials have shown that drugs commonly used in cardiovascular disease (CVD), such as statins, may be effective in the primary and secondary prevention of cardiovascular events through an anti-inflammatory effect. Moreover, several anti-inflammatory drugs are being tested for their potential to reduce residual cardiovascular risk on the background of validated medical therapy for atherosclerotic disease. In this paper, we review relevant evidence with regard to the relationship between inflammation and CVD, from pathogenesis to therapeutic strategies.

Adipose tissue-mediated inflammation: the missing link between obesity and cardiovascular disease?

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.

Novel insights into the role of cardiotrophin-1 in cardiovascular diseases

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.

Tissue factor is induced by resistin in human coronary artery endothelial cells by the NF-ĸB-dependent pathway.

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-ĸB (NF-ĸB), as demonstrated by electrophoretic mobility shift assay and by suppression of TF expression by superoxide dismutase, catalase, and the NF-ĸB 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.

Search of somatic GATA4 and NKX2.5 gene mutations in sporadic septal heart defects

High prevalence of somatic mutations in the cardiac transcription factor genes NKX2.5 and GATA4 have been reported in the affected cardiovascular tissue of patients with isolated cardiac septal defects, suggesting a role of somatic mutations in the pathogenesis of these congenital heart defects (CHDs). However, all somatic mutations have been identified in DNA extracted from an archive of formalin-fixed cardiac tissues. In the present study, to address the hypothesis that somatic mutations are important in isolated CHDs, we analyzed the GATA4 and NKX2.5 genes in the fresh-frozen pathologic cardiac tissue specimen and corresponding non-diseased tissue obtained from a series of 62 CHD patients, including 35 patients with cardiac septal defects and 27 with other cardiac anomalies. We identified one variant and two common polymorphisms in the NKX2.5 gene, and six variants and two common polymorphisms in the GATA4 gene. All identified variants were seen in both the fresh-frozen pathologic cardiac tissue and the corresponding non-diseased tissue, which indicates that they all were constitutional variants. The present study has identified NKX2.5 and GATA4 constitutional variants in our CHD cohort, but was unable to replicate the previously published findings of high prevalence of somatically derived sequence mutations in patients with cardiac septal defects using fresh-frozen cardiac tissues rather than formalin-fixed tissues.

Genotype–phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome†

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.

Hypertrophic Cardiomyopathy in a Girl With Cornelia de Lange Syndrome Due to Mutation in SMC1A

Hypertrophic Cardiomyopathy in a Girl With Cornelia de Lange Syndrome Due to Mutation in SMC1A Giuseppe Limongelli,* Silvia Russo, Maria Cristina Digilio, Maura Masciadri, Giuseppe Pacileo, Fiorella Fratta, Francesca Martone, Valeria Maddaloni, Raffaella D’Alessandro, Paolo Calabro, Maria Giovanna Russo, Raffaele Calabro, and Lidia Larizza Department of Cardiology, Monaldi Hospital, Second University of Naples, Naples, Italy Istituto Auxologico, Milan, Italy Medical Genetics, Bambin Gesu’ Hospital, Rome, Italy Department of Medicine, Surgery and Dentistry, University of Milan, Milan, Italy

Takotsubo Cardiomyopathy Do the Genetics Matter

Takotsubo cardiomyopathy (TTC) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. Recent experimental and clinical observation has suggested a role for genetics in the pathogenesis of TTC. Ethnic as well as seasonal variation in the prevalence of TTC is well described, but it is only recently that familial cases of TTC have been reported. In recent years technological advances in exome capture and DNA sequencing have offered clinicians a new opportunity to discover genetics-related disease. This article explores the role of genetic mechanisms that might explain or modulate the pathogenesis of TTC.

Cardiotrophin-1 and TNF-α circulating levels at rest and during cardiopulmonary exercise test in athletes and healthy individuals

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.

Trisomy 18 and hypertrophy cardiomyopathy in an 18‐year‐old woman

Giuseppe Limongelli,* Giuseppe Pacileo, Daniela Melis, Paolo Calabro’, Maria Cristina Digilio, Anna Sarkozy, Valeria Maddaloni, Giovanni Capozzi, Gianfranco Sebastio, Generoso Andria, and Raffaele Calabro’ Department of Cardiology, Monaldi Hospital, Second University of Naples, Naples, Italy Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy Medical Genetics, Bambin Gesu’ Hospital, Rome, Italy IRCCS-CSS, San Giovanni Rotondo & CSS, Mendel Institute, Rome, Italy