Metabolic syndrome, diabetes and atherosclerosis: Influence of gene-environment interaction

Despite remarkable progress in diagnosis and understanding of risk factors, cardiovascular disease (CVD) remains still the leading cause of morbidity and mortality in the world\u27s developed countries. The metabolic syndrome, a cluster of risk factors (visceral obesity, insulin resistance, dyslipidaemia, and hypertension), is increasingly being recognized as a new risk factor for type 2 diabetes and atherosclerotic cardiovascular disease. Nevertheless, there is wide variation in both the occurrence of disease and age of onset, even in individuals who display very similar risk profiles. There is now compelling evidence that a complex interplay between genetic determinants and environmental factors (still largely unknown) is the reason for this large inter-individual variation in disease susceptibility. The purpose of the present review is to describe the current status of our knowledge concerning the gene-environment interactions potentially implicated in the pathogenesis of metabolic syndrome, diabetes and cardiovascular disease. It focuses predominantly on studies of genes (peroxisome proliferator-activated receptor-gamma, alcohol dehydrogenase type 1C, apolipoprotein E, glutathione S-transferases T1 and M1) that are known to be modified by dietary and lifestyle habits (fat diet, intake of alcohol and smoking habit). It also describes the limited current understanding of the role of genetic variants of xenobiotic metabolizing enzymes and their interactions with environmental toxicants. Additional studies are needed in order to clarify whether inter-individual differences in detoxification of environmental toxicants may have an essential role in the development of CVD and contribute to the emerging field of "environmental cardiology". Such knowledge may be particularly relevant for improving cardiovascular risk stratification and conceiving the development of "personalized intervention program"

Genetic Polymorphisms of the Natriuretic Peptide System in the Pathogenesis of Cardiovascular Disease: What Lies on the Horizon?

BACKGROUND: The natriuretic peptide hormone family includes various proteins characterized by similar chemical structure and shared biological functions, with important effects on the cardiovascular system. Accordingly, these molecules are widely recognized as key clinical biomarkers in the diagnosis and monitoring of heart failure, hypertension, and coronary heart disease. CONTENT: Several single-nucleotide polymorphisms have been recently identified in genes associated with the natriuretic system. This review provides an overview of new insights into the functional role of these genetic variants, as well as their impact on cardiovascular physiopathology and drug response. CONCLUSIONS: Noteworthy relationships between some specific polymorphisms and clinical correlates of cardiovascular disease have emerged. Nevertheless, future confirming studies are needed to substantiate the clinical relevance of such variants

The Role of Human Semen as an Early and Reliable Tool of Environmental Impact Assessment on Human Health

Several studies have shown a dramatic reduction of semen quality in many industrialized countries and infertility is becoming a public health top priority, whose incidence is associated to late-onset adult diseases, especially cancer, shorter life expectancy and trans-generational effects. The male reproductive system is particularly sensitive to a broad variety of reproductive and developmental toxicants, including many environmental pollutants and recent studies suggest that human semen is an early and sensitive environmental and health marker. A set of semen biomarkers is described for reproductive health effects in relation to environmental exposure, where human semen seems to be an early and sensitive source of biomarkers than blood to monitor high environmental pressure on human health. Environmental health should consider reproductive health and development, from intrauterine life to childhood and puberty: these are both vulnerable targets and high-value protection goals, inasmuch as they represent the future of our societies. Hence, biomarkers of reproductive health should be exploited as early signals of environmental pressure and increased risk of adverse chronic health effects so that the use of “human seminal model” might be the main objective to be considered in the agenda of public prevention policies for early detection and innovative programs of health surveillance in environmental risk areas

The association of micronucleus frequency with obesity, diabetes and cardiovascular disease

Obesity and metabolic syndrome (MetS) are serious and growing health care problems worldwide, leading an increased risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). Over the past decade, emerging evidence has shown that an increased chromosomal 20 damage, as determined by the cytokinesis-block micronucleus (CBMN) assay, is correlated to the pathogenesis of metabolic and CVD. An increased micronuclei (MN) frequency has been demonstrated in peripheral blood lymphocytes of patients with polycystic ovary syndrome, 25 a common condition in reproductive-aged women associated with impaired glucose tolerance, T2D mellitus and the MetS. High levels of MN have been detected to be significantly correlated with T2D as well as with the occurrence and the severity of coronary artery disease 30 (CAD). Long-term follow-up studies have shown that an increased MN frequency is a predictive biomarker of cardiovascular mortality within a population of healthy subjects as well as of major adverse cardiovascular events in patients with known CAD. Overall, these findings 35 support the hypothesis that CBMN assay may provide an useful tool for screening of the MetS and its progression to diabetes and CVD in adults as well in children. Large population-based cohorts are needed in order to compare the MN frequencies as well as to better define whether MN 40 is a biomarker or a mediator of cardiometabolic diseases

Imaging and Laboratory Biomarkers in Cardiovascular Disease

Imaging and laboratory biomarkers are an essential support to modern practice of medicine, allowing a better identification, severity titration, staging and follow-up of atherosclerosis and heart failure disease. This review provides an overview of imaging, biochemical and genetic biomarkers used in clinical practice and for research purposes in order to evaluate the 4 different aspect of patient vulnerability to cardiovascular disease: arterial; blood; myocardial; metabolic vulnerability. Yet, no single perfect biomarker exists and there is wide room for optimization and integration between clinical evaluation and biomarker evaluation. In general, a targeted approach tailored on the individual patient should be preferred to a carpet diagnostic bombing, which will lead to an exorbitant multiplier of costs, risks and inappropriate testing

Prothrombotic mutations, family history and the risk of thrombosis in postmenopausal women: implications for hormone replacement therapy

Objective Hormone replacement therapy (HRT) is acknowledged as the gold standard for the alleviation of climacteric vasomotor symptoms. Prothrombotic genetic variants have been suggested to increase thrombotic risk among HRT users. The aim of the study was to determine whether a positive family history may identify a genetic predisposition for thrombosis in women before prescribing HRT. Methods From January 2005 to May 2009, we consecutively enrolled 145 asymptomatic women (mean age 51.2+5.4 years) without previous episodes of venous and/or arterial thrombosis referred to our Genetics Research Unit before starting HRT. A detailed family history was reconstructed and we identified 48 women (33.1%) with a positive family history, defined as venous thromboembolism and/or stroke or heart attack, in first-degree relatives before 60 years for men and 65 years for women. A group of 121 women (mean age 54.0+9.1 years) with an episode of venous and/or arterial thrombosis was also included. Genetic screening for factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase C677T polymorphisms was performed. Results The frequency of factor V Leiden or prothrombin G20210A mutations was significantly higher both in asymptomatic women with a positive family history (16.7% vs. 2.1%, p?0.001) and in patients with thrombosis (12.4% vs. 2.1%; p?0.005) compared with asymptomatic women without a family history. Multivariate regression analysis showed a synergic effect between the presence of one prothrombotic mutation and family history on the risk of thrombosis (odds ratio 3.7, 95% confidence interval 1.9-7.2). Conclusions A positive family history of thrombosis is a sensitive indicator for selected genetic testing in high-risk women before starting HRT

Cumulative patient effective dose and acute radiation-induced chromosomal DNA damage in children with congenital heart disease

Background The seventh Committee on "Biological Effects of Ionizing Radiation" (BEIR VII, 2006) underlines "the need of studies of infants who are exposed to diagnostic radiation because catheters have been placed in their hearts". Objective To determine the lifetime attributable risk (LAR) of cancer associated with the estimated cumulative radiological dose in 59 children (42 male, age 2.863.2 years) with complex congenital heart disease, and to assess chromosomal DNA damage after cardiac catheterisation procedures. Methods In all patients, the cumulative exposure was estimated as effective dose in milliSievert (mSv), and LAR cancer was determined from the BEIR VII report. In a subset of 18 patients (13 male, age 5.265.7 years) micronucleus as a biomarker of DNA damage and longterm risk predictor of cancer was assayed before and 2 h after catheterisation procedures. Doseearea product (Gy cm2) was assessed as a measure of patient dose. Results The median life time cumulative effective dose was 7.7 mSv per patient (range 4.6e41.2). Cardiac catheterisation procedures and CT were responsible for 95% of the total effective dose. For a 1-year-old child, the LAR cancer was 1 in 382 (25th to 75th centiles: 1 in 531 to 1 in 187) and 1 in 156 (25th to 75th centiles: 1 in 239 to 1 in 83) for male and female patients, respectively. Median micronucleus values increased significantly after the procedure in comparison with baseline (before 6&vs after 9&, p?0.02). The median doseearea product value was 20 Gy cm2 (range 1e277). Conclusion Children with congenital heart disease are exposed to a significant cumulative dose. Indirect cancer risk estimations and direct DNA data both emphasise the need for strict radiation dose optimisation in children

Health Risk and Biological Effects of Cardiac Ionising Imaging: From Epidemiology to Genes

Cardiac diagnostic or therapeutic testing is an essential tool for diagnosis and treatment of cardiovascular disease, but it also involves considerable exposure to ionizing radiation. Every exposure produces a corresponding increase in cancer risk, and risks are highest for radiation exposure during infancy and adolescence. Recent studies on chromosomal biomarkers corroborate the current radioprotection assumption showing that even modest radiation load due to cardiac catheter-based fluoroscopic procedures can damage the DNA of the cell. In this article, we review the biological and clinical risks of cardiac imaging employing ionizing radiation. We also discuss the perspectives offered by the use of molecular biomarkers in order to better assess the long-term development of health effects

Identification of platelet hyper-reactivity measured with a portable device immediately after percutaneous coronary intervention predicts in stent thrombosis

Introduction: Platelet hyper-reactivity, despite a standard anti-thrombotic therapy, is a recognized risk factor for recurrent myocardial ischemia and in-stent thrombosis following PCI. We have investigated whether this detrimental condition, measured by collagen-epinephrine closure times (CEPI-CT) with the Platelet Function Analyzer (PFA-100) device could predict IST defined as the composite of cardiovascular death or myocardial infarction. Materials and methods: CEPI-CT was measured in 256 consecutive patients with stable angina (n=103) or ACS (n=153) 30?8 h after PCI (T0) and 1 month later (T1). All patients were followed up for a mean period of 9 months. Platelet hyperactivity was defined as a CEPI-CTb190 s. Results: Baseline CEPI-CTb190 s was associated with a higher rate of death or MI (LogRank χ2 =4.23, p=0.039) as compared with CEPI-CTN190 s (4.6% vs. 0.7%). Multivariable analysis after adjustment for other risk factors confirmed that baseline CEPI-CTb190 s was an independent correlate for death or MI (Hazard ratio 6.981, p=0.008). At T1 there was a significant prolongati