Metabolic syndrome alters inflammatory and membrane markers expression in human atrium cardiomyocytes

Metabolic syndrome (MetS) is a cluster of various clinical cardiovascular risk factor and causes metabolic and structural cardiomyocytes damage. Our previous study showed that MetS increases cardiomyocytes stress chaperones (1). In this work we aimed to investigate if patients with MetS showed alteration of surface, mitochondria and inflammatory markers in atrium cardiomyocytes. Atrium samples from MetS patients with stable angina, undergoing coronary artery bypass graft surgery were used. Samples from matched age subjects without MetS and no smokers, undergoing cardiac surgery for other reasons, were used as controls. The samples, obtained before cardioplegia, were fixed and processed for Caveolin 1 (Cav1), MURC, Citrate Synthase (CS), SIRT3, SOD1, IL6-10, iNOS and eNOS by immunohistochemistry. Compared to controls, in cardiomyocytes from MetS patients decreased the expression of Cav1, MURC, SIRT3, IL10 and eNOS, whereas increased the expression of CS, SOD1, IL6, iNOS. Cardiomyocytes from MetS patients present an evident inflammatory chronic state, that alters the Cav1-MURC expression. These alterations could reduce the exchange functions of sarcolemma so impairing the contractile capacity associated with mitochondrial impairment. We speculate that these damages could induce antioxidant SOD1 over-expression to rescue the cells. All these results, first from human heart, suggest that MetS induces severe enzymatic disregulation in atrium cardiomyocytes that may predispose to cardiac surgery complications

T-wave axis deviation, metabolic syndrome and cardiovascular risk: results from the MOLI-SANI study

Early recognition of patients at increased cardiovascular risk is a major challenge. The surface electrocardiogram provides a useful platform and it has been used to propose several indexes. T wave axis abnormality is associated with an increased risk of cardiovascular mortality, independently of other risk factors and can be associated with the presence of the metabolic syndrome (MetS). We assessed the prevalence of T axis abnormalities and its relationship with MetS and its components in a large population of Italian adults. Data concerning 11,143 women (54±11years) and 9742 men (55±11years) randomly recruited from a general population (Moli-sani cohort) were analyzed. After excluding subjects with incomplete data and with history of cardiac disease or left ventricular hypertrophy, T-wave axis was normal in 74.5% of men and 80.9% of women, borderline in 23.6% and 17.3% and abnormal in 1.9% and 1.8%. In subjects with MetS, the prevalence of borderline or abnormal T-wave axis deviation was higher than in subjects without MetS (in men: 26.6% vs. 22.1% and 2.5% vs. 1.7%; in women: 25% vs. 15% and 2.4% vs. 1.6%, respectively for borderline and abnormal levels, pb0.0001). Each component of MetS increased the odds of having borderline or abnormal T-wave axis deviation by 1.21 in men and 1.31 in women. T wave axis deviation is associated with MetS and its individual components. These findings confirm previous reported results, expanding them to a large and representative sample of European population of Caucasian ethnicity

Intracellular molecular effects of insulin resistance in patients with metabolic syndrome

<p>Abstract</p> <p>Aim of the study</p> <p>Patients with metabolic syndrome (MetS) have an increased risk of cardiovascular disease. Data obtained from muscle biopsies have demonstrated altered insulin signaling (IS) in patients with MetS. The IS regulates critical cell functions including molecular-regulated cellular metabolite fluxes, protein and energetic metabolism, cell proliferation and apoptosis with consequent regulation of cell life including endothelial homeostasis and blood coagulation. However, little is known about blood cell IS in MetS patients. The aim of this study was to develop a method to evaluate IS in peripheral lymphocytes to identify altered intracellular molecules in patients with MetS to use as risk biomarkers of vascular thrombosis.</p> <p>Patients and Methods</p> <p>We investigated 40 patients with MetS and 20 controls. MetS was defined according to guidelines from the US National Cholesterol Education Program Adult Treatment Panel III. Blood samples were taken from all participants. Total mononuclear cells were isolated from peripheral blood using density gradient centrifugation. IS molecules were evaluated using Western blot analysis followed by computer-assisted densitometer evaluation.</p> <p>Results</p> <p>Lymphocytes of MetS patients showed a reduced mTOR expression (the mammalian target of rapamycin) which is a fundamental molecule of IS. Major impairment of IS was confirmed by reduced upstream and downstream mTOR molecules which regulate fundamental cells metabolic functions.</p> <p>Conclusions</p> <p>In patients with MetS, we found a reduction of mTOR and other mTOR-related molecules involved in insulin resistance, cell repair, coagulation and vasculogenesis. A reduced expression of mTOR may reflect an increased risk of vascular thrombosis.</p

T-wave axis deviation, metabolic syndrome and estimated cardiovascular risk in men and women of the MOLI-SANI Study

Aim: We aimed at investigating the association between T-wave axis deviation, metabolic syndrome (MetS), its components and estimated risk of cardiovascular disease (CVD) at 10 years in a adult Italian population. Methods: 11,143 women (54±11 years) and 9,742 men (55±11 years) were analysed from the Molisani cohort, randomly recruited from the general population. MetS was defined using the ATPIII criteria. T-wave axis deviation was measured from the standard 12-lead resting electrocardiogram. CVD risk in ten years was estimated by the CUORE score. Results: 29% of men and 27% of women with MetS showed borderline or abnormal T-wave as compared to 24% and 17% without MetS (p<0.0001 for both genders). Among components of MetS, elevated waist and blood pressure were strongly associated with Twave axis deviation, whereas glucose, HDL and triglycerides were only marginally. The odds of having borderline or abnormal T-wave axis deviation in multivariable regression analysis, was 1.38 (95% CI:1.25-1.53) in MetS men and 1.68 (95% CI:1.51-1.87) in MetS women compared to those without. Further adjustment for MetS components completely abolished the associations. Abnormal T-wave axis deviation was associated with an increased risk of CVD in 10 years in men (OR=4.4; 95% CI:1.10-17.9). Conclusion: T-wave axis deviation is strongly associated with components of the MetS, in particular high waist circumference and blood pressure and with an increased CVD risk, particularly in men. ECG monitoring to identify T-wave axis deviation in obese, hypertensive or MetS subjects can be an early indicator of vascular disease and help in reducing cardiac events

Klotho expression in cardiomyocytes in patients at a higher atherosclerotic cardiovascular disease risk

Klotho proteins (α- and β-Klotho) are transmembrane proteins whose extracellular domain is secreted into blood and urine by ectodomain shedding. As such they behave as circulating proteins that regulate cell metabolism, endothelial function and calcium homeostasis, as well as modulating the lifespan connected activity of Fibroblast Growth Factors (FGFs, mainly 21 and 23) and other molecules (1). Recent data have shown that highest levels of plasma circulating Klotho are associated with a lower cardiovascular risk, thereby suggesting a possible role for Klotho in cardiovascular diseases (2). However, although Klotho has been identified in various organs, including kidney, brain, adipose tissue and intestine, it is unknown whether cardiomyocytes express Klotho and FGFs and, if so, whether high cardiovascular risk can be associated with cardiac expression of Klotho, FGFs and other related molecules. We examined myocardial biopsies from 20 patients with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk in the range of 5% to 7.5% and 10 age-matched control subjects with an estimated 10-year ASCVD risk of &lt;5% (3) undergoing cardiac surgery other than coronary artery by-pass. Both groups of patients were statin naive, had normal hemoglobin A1c, normal coronary arteries on left heart catheterization, and had LDL cholesterol levels between 70 and 189 mg/ DL. Using immunohistochemistry methods, we evaluated Klotho and FGFs expression in human cardiomyocytes, and whether higher ASCVD risk influenced the expression of other molecules involved in endoplasmic reticulum stress (GRP78), oxidative stress (SOD1, NFkB) and inflammation (iNOS, eNOS). Cardiomyocytes of patients with a higher ASCVD risk exhibited lower expression of Klotho, but also higher expression of FGFs, as compared to cardiomyocytes of patients with a reduced ASCVD risk. Furthermore, higher ASCVD risk was associated with significantly increased expression of GRP78, SOD1, NFkB and iNOS (all p&lt;0.05). This study shows for the first time that Klotho proteins are inherently expressed in human cardiomyocytes and also that cardiac expression of Klotho is down regulated in higher ASCVD risk patients, while the expression of FGFs and other stress-related molecules involved in myocyte damage, such as GRP78, SOD1, NFkB and iNOS, is significantly increased. Further studies are warranted to investigate the association of klotho, FGFs and related molecules expression with cardiovascular risk

Decreased expression of Klotho in cardiac atria biopsy samples from patients at higher risk of atherosclerotic cardiovascular disease

Background. Klotho proteins (α- and β) are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors. Recent data has shown that higher plasma circulating Klotho levels reduce cardiovascular risk, suggesting Klotho has a protective role in cardiovascular diseases. However, although so far it has been identified in various organs, it is unknown whether cardiomyocytes express Klotho and Fibroblast Growth Factors(FGFs), and whether high cardiovascular risk could affect cardiac expression of Klotho, FGFs and other molecules. Methods. We selected 20 patients with an estimated 10-year high atherosclerotic cardiovascular disease and 10 age-matched control subjects with an estimated 10-year low risk undergone cardiac surgery for reasons other than coronary artery by-pass. In myocardial biopsies, we evaluated by immuno-histochemistry whether Klotho and FGFs were expressed in cardiomyocytes, and whether higher cardiovascular risk influenced the expression of other molecules involved in endoplasmic reticulum stress, oxidative stress, inflammation and fibrosis. Results. Only cardiomyocytes of patients with a higher cardiovascular risk showed lower expression of Klotho, but higher expressions of FGFs. Furthermore, higher cardiovascular risk was associated with increased expression of oxidative and endoplasmic reticular stress, inflammation and fibrosis. Conclusions. This study showed for the first time that Klotho proteins are expressed in human cardiomyocytes and that cardiac expression of Klotho is down-regulated in higher cardiovascular risk patients, while expression of stress-related molecules were significantly increased