Correction of QRS voltage for body mass index does not improve the prediction of fatal and nonfatal cardiovascular events. The Moli-sani study.

BACKGROUND AND AIMS: The diagnosis of LVH by ECG may particularly difficult in obese individuals. The aim of this study was to prospectively investigate whether the correction for body mass index (BMI) might improve the prognostic significance for cerebro and cardiovascular events of two electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH) in a large cohort of Italian adults. METHODS AND RESULTS: In 18,330 adults (54 ± 11 years, 55% women) from the Moli-sani cohort, obesity was defined using the ATPIII criteria. The Sokolow-Lyon (SL) and Cornell Voltage (CV) criteria were used for ECG-LVH. In overweight and obese subjects, as compared with normal weight, the prevalence of ECG-LVH by the SL index was lower. During follow-up (median 4.3 yrs), 503 cerebro and cardiovascular events occurred. One standard deviation (1-SD) increment in uncorrected and in BMI-corrected SL index and CV was associated with an increased risk of events (HR 1.12, 95% CI 1.02-1.22 and HR 1.16, 95% CI 1.06-1.26 and HR 1.12, 95% CI 1.03-1.23 and HR 1.17, 95% CI 1.07-1.27, respectively for SL and CV). In obese subjects, 1-SD increment in uncorrected CV and in BMI-corrected CV was not associated to a significant risk of events (HR 1.05, 95% CI 0.910-1.22 and HR 1.08, 95% CI 0.95-1.23 respectively). Uncorrected SL index showed a significant association with events, which was marginally stronger with BMI-corrected SL voltage (HR 1.18, 95% CI 1.02-1.37 and HR 1.17, 95% CI 1.04-1.33 respectively, Akaike information criterion change from 3220 to 3218). CONCLUSIONS: BMI correction of ECG LVH voltage criteria does not significantly improve the prediction of cerebro and cardiovascular events in obese patients in a large cohort at low cardiovascular risk.

T-wave axis deviation and left ventricular hypertrophy interaction in diabetes and hypertension.

Electrocardiographic signs of left ventricular hypertrophy (ECG-LVH) and T-wave axis (TA) deviation are independent predictors of fatal and non fatal events. We assessed the prevalence of ECG-LVH, TA abnormalities and their combination according to the presence or absence of diabetes and/or hypertension in a large sample of the adult general Italian population. Data from 10,184 women (54 ± 11 years) and 8775 men (54 ± 11 years) were analyzed from the Moli-sani cohort, a database of randomly recruited adults (age >35) from the general population of Molise, a central region of Italy that includes collection of standard 12-lead resting ECG. Subjects with previous myocardial infarction, angina, cerebrovascular disease or left bundle brunch block or missing values for TA or ECG-LVH have been excluded. TA was measured from the standard 12-lead ECG and it was defined as the rotation of the T wave in the frontal plane as computed by a proprietary algorithm (CalECG/Bravo, AMPS-LLC, NY). ECG-LVH was defined as Sokolow Lyon voltage (SLv) >35 mm or Cornell voltage duration Product (CP) >= 2440 mm*ms. Among subjects with ECG-LVH, prevalence of hypertension was 59.0% and 49.7%, respectively for men and women, whereas that of diabetes was 10.7% and 5.7%. In hypertensives, TA was normal in 72.3% of subjects, borderline in 24.8% and abnormal in 2.9%. In diabetics, TA was normal in 70.4% of subjects, borderline in 26.5% and abnormal in 3.1%. In both hypertensive and diabetic subjects, the prevalence of ECG-LVH, was significantly greater in subjects with borderline or abnormal TA. Hypertension was an independent predictor of abnormal TA (odd ratio: 1.38, P = .025). These results suggest that hypertension might play a relevant role in the pathogenesis of TA deviation.

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 ± 11 years) and 9742 men (55 ± 11 years) 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, p<0.0001). 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.

The Moli-sani project: computerized ECG database in a population-based cohort study.

Computerized electrocardiogram (ECG) acquisition and interpretation may be extremely useful in handling analysis of data from large cohort studies and exploit research on the use of ECG data as prognostic markers for cardiovascular disease. The Moli-sani project (http://www.moli-sani.org) is a population-based cohort study aiming at evaluating the risk factors linked to chronic-degenerative disease with particular regard to cardiovascular disease and cancer and intermediate metabolic phenotypes such as hypertension, diabetes, dyslipidemia, obesity, and metabolic syndrome. Between March 2005 and April 2010, 24 325 people aged 35 years or older, living in the Molise region (Italy), were randomly recruited. A follow-up based on linkage with hospital discharge records and mortality regional registry and reexamination of the cohort is ongoing and will be repeated at prefixed times. Each subject was administered questionnaires on personal and medical history, food consumption, quality of life (FS36), and psychometry. Plasma serum, cellular pellet, and urinary spots were stored in liquid nitrogen. Subjects were measured blood pressure, weight, height, and waist and hip circumferences, and underwent spirometry to evaluate pulmonary diffusion capacity, gas diffusion, and pulmonary volumes. Standard 12-lead resting ECG was performed by a Cardiette ar2100-view electrocardiograph and tracings stored in digital standard communication protocol format for subsequent analysis. The digital ECG database of the Moli-sani project is currently being used to assess the association between physiologic variables and pathophyiosiologic conditions and parameters derived from the ECG signal. This computerized ECG database represents a unique opportunity to identify and assess prognostic factors associated with cardiovascular and metabolic diseases.

Intracellular molecular effects of insulin resistance in patients with metabolic syndrome.

AIM OF THE STUDY: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Evidence of major genes effects on serum homocysteine and fibrinogen levels, and premature ischemic heart disease in Italian extended families.

OBJECTIVES: The purpose of the present study was to investigate the effect of novel genetic factors on plasma levels of total homocysteine (tHcy) and fibrinogen (FIB). As tHcy and FIB have been consistently associated to increased risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) also genes-trait-MI mediational effects were tested. METHODS: A complex segregation analysis, and a mediation analysis of a highly selected group of 44 extended families (302 subjects), each including at least one member with fatal premature (<50 years) IHD were carried out. RESULTS: tHcy and FIB levels turned out to be influenced by at least two major genes. A significant tHcy latent class-MI association (OR = 3.24; 95% CI, 1.37 to 7.68), and a non-significant tHcy plasma level-MI association (OR = 1.65 per 1 = log 10 mumol/l, 95% CI, 0.56 to 4.81) were estimated, suggesting a direct influence of the homocysteine major gene as suppressor of plasma tHcy levels effect. In contrast, FIB latent class-MI association (OR = 0.97; 95% CI, 0.31 to 3.05) and FIB level-MI association (OR = 1.32 per 1 = 70 g/l; 95% CI, 0.88 to 2.00) were not statistically significant. CONCLUSION: These data provide evidence for a major latent gene effect influencing variation in tHcy plasma levels, which is independent on C677T MTHFR polymorphism, and significantly affecting the risk of MI.

Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.

BACKGROUND: Intestinal dysbiosis has been proposed as a possible contributor of the development of type 2 diabetes (T2D). Indeed, commensal fungi and opportunistic bacteria stimulate the local immune system, altering intestinal permeability with consequent leaky gut, which in turn activates systemic inflammation responsible for insulin resistance. It is also well known that chronic exercise improves glucose control and diabetes-induced damage. The aim of this study was to evaluate the role of chronic exercise on gut flora composition and leaky gut in T2D stable patients. METHODS: Thirty clinically stable patients with T2D were studied before and after a six months program of endurance, resistance and flexibility training. Metabolic and anthropometric evaluations were carried out. Gut flora and intestinal permeability were measured in stools by selective agar culture medium and molecular biology measurements of zonulin, which is the protein that modulates enterocyte tight junctions. RESULTS: Diabetes causes significant intestinal mycetes overgrowth, increased intestinal permeability and systemic low-grade inflammation. However, exercise improved glycemia, functional and anthropometric variables. Moreover, chronic exercise reduced intestinal mycetes overgrowth, leaky gut, and systemic inflammation. Interestingly, these variables are closely correlated. CONCLUSIONS: Exercise controls diabetes by also modifying intestinal microbiota composition and gut barrier function. This data shows an additional mechanism of chronic exercise and suggests that improving gut flora could be an important step in tailored therapies of T2D.

Angiotensin receptor blockers improve insulin signaling and prevent microvascular rarefaction in the skeletal muscle of spontaneously hypertensive rats.

OBJECTIVE: Spontaneously hypertensive rats are an example of an animal model of genetic hypertension with insulin resistance. The aim of this study was to investigate insulin signaling in the heart and in the skeletal muscle of spontaneously hypertensive rats, as well as to evaluate the effects of renin-angiotensin system blockade. DESIGN AND METHODS: We investigated eight untreated spontaneously hypertensive rats of 12 weeks of age and eight age-matched normotensive Wistar-Kyoto controls. In addition, eight spontaneously hypertensive rats were treated for 8 weeks with the angiotensin receptor blocker olmesartan, and eight spontaneously hypertensive rats with the angiotensin-converting enzyme inhibitor enalapril. The heart and a skeletal muscle (quadriceps femoris) were promptly dissected and frozen. Insulin signaling was evaluated by Western blot analysis of involved proteins; in addition, microvessel density was indirectly evaluated by immunohistochemistry. RESULTS: Blood pressure values were normalized by both olmesartan and enalapril. In the heart, no statistically significant difference in the expression of proteins involved in insulin signaling was observed between untreated spontaneously hypertensive rats and Wistar-Kyoto controls. On the contrary, in the skeletal muscle of untreated spontaneously hypertensive rats, we noted a significant reduction of insulin receptors, of insulin-receptor substrate-1, and of phosphorylated-mammalian target of rapamycin. The treatment with olmesartan normalized insulin signaling, including expression of glucose transporter-4, whereas the treatment with enalapril was ineffective for the insulin receptor and less effective than olmesartan on the insulin-receptor substrate-1, phosphorylated-mammalian target of rapamycin and glucose transporter-4. There was a significant reduction in microvessel density in the skeletal muscle of spontaneously hypertensive rats compared with Wistar-Kyoto controls, and this was completely prevented by both olmesartan and enalapril. CONCLUSION: These results suggest that changes in insulin signaling occur in the skeletal muscle but not in the heart of untreated spontaneously hypertensive rats. In the skeletal muscle, insulin signaling was restored by olmesartan, whereas enalapril was less effective. Effective antihypertensive treatment with olmesartan or enalapril was associated with prevention of microvascular rarefaction.

Morphometric changes induced by amino acid supplementation in skeletal and cardiac muscles of old mice.

Aging is associated with progressive structural disorganization of muscular and cardiac fibers, decreasing functional capacity, and increased rates of disease and death. Aging is also characterized by disturbances in protein synthesis with impaired cellular organelle functions, particularly in the mitochondria. The availability of amino acids is a key factor for the overall metabolism of mammals and exogenous supplements of amino acid mixtures (AAm) could be a valid therapeutic strategy to improve quality of life, avoiding malnutrition and muscle wasting in the elderly. We investigated the morphoquantitative effects of long-term AAm supplementation on the mitochondria and sarcomeres (by electron microscope) and on collagen matrix deposition (by histologic techniques) in both skeletal and cardiac muscles of young and aged mice. Our data showed that old animals have fewer mitochondria and massive fibrosis in both muscles. Long-term AAm supplementation increased the number and volume of mitochondria and sarcomeres and decreased fibrosis in both skeletal muscle and hearts in old rats. These findings indicate that AAm restored muscular morphologic parameters and probably improved the mechanical performance of these organs.

Direct, reverse or reciprocal causation in the relation between homocysteine and ischemic heart disease.

BACKGROUND: Whether mild hyperhomocysteinemia is a risk factor for ischemic heart disease (IHD) or it is a secondary epiphenomenon remains unknown. We tested the alternative hypotheses that the Hcy-IHD relation is due to direct, reversal or reciprocal causality. METHODS: Ninety-four families from 32 pedigrees (296 members) including subjects who died for a premature (<50 years) IHD and with at least one family member with also a premature IHD were selected. Three Structural Equation Models were created, in which causal (Model 1), reversal (Model 2), and reciprocal (Model 3) tHcy-IHD relation were tested. Results were confirmed by testing "Pearl's instrumental inequalities". RESULTS: A significant tHcy-IHD association was found in Model 1 (OR=1.38, 95% CI: 1.01 to 1.88, for any increase of +10 micromol/l in tHcy), as opposed to a non-significant association in the other models (Model 2: MD=+1.63 micromol/l, 95% CI: -1.72 to +4.99 micromol/l; Model 3: OR=0.69, 95% CI: 0.17 to 2.78 for tHcy predictor of IHD; MD=-0.46 micromol/l, 95% CI: -2.41 to 1.48 micromol/l, for IHD predictor of tHcy). "Pearl's instrumental inequalities" qualify MTHFR as an instrument relative to the tHcy-IHD relation. A suppression effect may explain the non-significant total MTHFR-IHD relation (OR=1.275, 95% CI: 1.02 to 1.71 for the indirect MTHFR-tHcy-IHD path; OR=0.52, 95% CI: 0.17 to 1.64 for the direct MTHFR-IHD path). CONCLUSION: Our findings support the assumption of a triangular genotype-phenotype-disease mediation process in the Hcy-IHD relation, and indirectly, of a causal relationship between moderately elevated plasma tHcy levels and IHD.

Frontal plane T-wave axis orientation predicts coronary events: Findings from the Moli-sani study.

BACKGROUND AND AIMS: The orientation of the frontal plane T-wave axis (T axis) is a reliable measure of ventricular repolarisation. We investigated the association between T-axis and the risk of coronary heart disease (CHD), heart failure (HF), atrial fibrillation (AF), stroke and cardiovascular (CVD) mortality. METHODS: A sample of 21,287 Moli-sani participants randomly recruited from the general adult (≥35 y) Italian population, free of CVD disease, were followed for a median of 4.4 years. T-axis was measured from a standard 12-lead resting ECG. RESULTS: After adjusting for CVD risk factors, subjects with abnormal T-axis showed an increase in the risk of both CHD (Hazard Ratio (HR) = 2.65; 95% CI = 1.67-4.21), HF (HR = 2.56; 1.80-3.63), AF (HR = 2.48; 1.56-3.94) and CVD mortality (HR = 2.83; 1.50-5.32). The association with CHD and HF, but not with AF or CVD death, remained significant after further adjustment for ECG abnormalities. Subjects with abnormal T-axis showed higher levels of subclinical inflammation, hs-troponin I and hs-NT-proBNP (p < 0.001 for all). However, further adjustment for troponin I and/or NT-proBNP determined a reduction of HRs ranging from 12.1 to 24.0% for CHD, while additional adjustment for inflammation markers did not change any association. CONCLUSIONS: An abnormal T-axis orientation is associated with an increased risk of both CHD and HF, independently of common CVD risk factors and other ECG abnormalities. This association was partially explained by increased hs-troponin I and hs-NT-proBNP levels.

Obesity and ECG left ventricular hypertrophy.

AIM: Our aim was to investigate the prevalence and the prognostic significance for fatal and nonfatal cerebrovascular and cardiovascular events of different ECG criteria for left ventricular hypertrophy (LVH) in normal weight, overweight and obese patients in an adult Italian population. METHODS: A total of 18 330 adults (mean age 54 ±â€Š11 years, 55% women, 53% hypertensive patients) were analyzed from the Moli-sani cohort. Obesity was defined using the ATPIII criteria. ECG-LVH was defined according to 2013 ESC-ESH guidelines. RESULTS: The age and sex adjusted prevalence of ECG-LVH did not differ from normal weight patients to class 1-3 obesity patients, when Cornell-voltage criterion was used. In overweight and obese patients, as compared with normal weight patients, a progressively lower prevalence of ECG-LVH was observed when the Sokolow-Lyon index was used, whereas a higher prevalence was shown by using the aVL R-wave voltage (>11 and >5.7 mm) and the Cornell-voltage-QRS duration product. The incidence of cardiovascular events was significantly greater in patients with ECG LVH diagnosis by the Cornell voltage [hazard ratio 1.89, 95% confidence interval (CI) 1.05-3.39] and the Cornell product (hazard ratio 1.87, 95% CI 1.31-2.67). After adjusting for different confounders (age, sex, cigarette, hypertension, hypercholesterolemia, diabetes, income, education, occupational class and physical activity) and for BMI categories, only the Cornell product remained significantly associated with a higher incidence of cardiovascular events (hazard ratio 1.66; 95% CI 1.16-2.38). The predictive significance of different LVH criteria was assessed across BMI categories; after adjusting for confounders, no LVH criteria were significantly associated with an increased risk of cardiovascular events in obese patients; Cornell-product LVH remained an independent predictor of events in normal weight and overweight individuals (hazard ratio 2.63; 95% CI 1.10-6.28 and hazard ratio 2.72; 95% CI 1.52-4.25, respectively). CONCLUSION: Our results confirm that ECG LVH prevalence may differ according to the criteria used across BMI categories in a low cardiovascular risk cohort. The use of different LVH criteria according to BMI categories may improve cardiovascular risk stratification in a general population independently of several confounding factors.

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

BACKGROUND: Klotho proteins (α- and ß) are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors (FGFs). 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 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.

Cumulative effect of predisposing genotypes and their interaction with modifiable factors on the risk of ischemic stroke in young adults.

BACKGROUND AND PURPOSE: Combinations of multiple predisposing polymorphisms and their interactions with modifiable factors may result in synergistic effects on the risk of ischemic stroke. These mechanisms are more likely to play a relevant role in younger individuals. METHODS: The cumulative effect of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene, and the epsilon4-carriership of the apolipoprotein (APOE) gene, as well as their interactions with modifiable predisposing factors, were determined in a series of 163 stroke patients aged younger than 45 years and 158 controls. RESULTS: Odds ratios (ORs) for stroke were 1.73 (95% confidence interval [CI], 1.20 to 2.51) in subjects with 1 polymorphism and 3.00 (95% CI, 1.43 to 6.30) in those with > or =2. Compared with nonsmokers with none of the studied polymorphisms, ORs for stroke were 1.88 (95% CI, 1.18 to 3.00) and 3.55 (95% CI, 1.40 to 8.98) for nonsmokers with 1 and 2 polymorphisms, respectively, and 3.99 (95% CI, 2.00 to 7.96) and 15.99 (95% CI, 4.01 to 63.3) for smokers. Compared with nonhypertensive subjects bearing no polymorphisms, ORs were 1.91 (95% CI, 1.28 to 2.87) and 3.68 (95% CI, 1.64 to 8.26) for nonhypertensive subjects with 1 and 2 polymorphisms, 3.28 (95% CI, 1.01 to 10.7) and 10.79 (95% CI, 1.01 to 115.4) for hypertensive. CONCLUSIONS: These data suggest a gene-dose effect of the examined prothrombotic and proatherogenic gene variants and a synergistic effect of these polymorphisms and modifiable risk factors in the pathogenesis of cerebral ischemia in young adults.

Cost-effectiveness of pre-participation screening of athletes with ECG in Europe and Algeria.

The aim of this study is to evaluate the cost-effectiveness of ECG in combination with family and personal history and physical examination in order to detect cardiovascular diseases that might cause sudden death in athletes. The study was conducted on a cohort of 6,634, mainly young professional and recreational athletes, 1,071 from Algeria and 5,563 from Europe (France, Germany and Greece). Each athlete underwent medical history, physical examination, and resting 12-lead ECG. 293 athletes (4.4 %), 149 in Europe (2.7 %) and 144 in Algeria (13.4 %) required further tests, and 56 were diagnosed with cardiovascular disease and thus disqualified. The cost-effectiveness ratio (CER) was calculated as the ratio between the cost of screening and the number of statistical life-years saved by the intervention. The estimated reduced risk of death deriving from treatment or disqualification resulted in the saving of 79.1 statistical life-years in Europe and 136.3 in Algeria. CER of screening was 4,071 purchasing-power-parity-adjusted US dollars ($PPP) in Europe and 582 $PPP in Algeria. The results of this study strongly support the utilisation of 12-lead ECG in the pre-participation screening of young athletes, especially in countries where secondary preventive care is not highly developed.

Supervised exercise training reduces oxidative stress and cardiometabolic risk in adults with type 2 diabetes: a randomized controlled trial.

To evaluate the effects of supervised exercise training (SET) on cardiometabolic risk, cardiorespiratory fitness and oxidative stress status in 2 diabetes mellitus (T2DM), twenty male subjects with T2DM were randomly assigned to an intervention group, which performed SET in a hospital-based setting, and to a control group. SET consisted of a 12-month supervised aerobic, resistance and flexibility training. A reference group of ten healthy male subjects was also recruited for baseline evaluation only. Participants underwent medical examination, biochemical analyses and cardiopulmonary exercise testing. Oxidative stress markers (1-palmitoyl-2-[5-oxovaleroyl]-sn-glycero-3-phosphorylcholine [POVPC]; 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine [PGPC]) were measured in plasma and in peripheral blood mononuclear cells. All investigations were carried out at baseline and after 12 months. SET yielded a significant modification (p < 0.05) in the following parameters: V'O2max (+14.4%), gas exchange threshold (+23.4%), waist circumference (-1.4%), total cholesterol (-14.6%), LDL cholesterol (-20.2%), fasting insulinemia (-48.5%), HOMA-IR (-52.5%), plasma POVPC (-27.9%) and PGPC (-31.6%). After 12 months, the control group presented a V'O2max and a gas exchange threshold significantly lower than the intervention group. Plasma POVC and PGPC were significantly different from healthy subjects before the intervention, but not after. In conclusion, SET was effective in improving cardiorespiratory fitness, cardiometabolic risk and oxidative stress status in T2DM.

T-wave axis deviation is associated with biomarkers of low-grade inflammation. Findings from the MOLI-SANI study.

T-wave axis deviation (TDev) may help identifying subjects at risk for major cardiac events and mortality, but the pathogenesis of TDev is not well established; in particular, the possible association between TDev and inflammation is unexplored and unknown. We aimed at investigating the association between low-grade inflammation and TDev abnormalities by conducting a cross-sectional analysis on 17,507 subjects apparently free from coronary heart and haematological diseases enrolled in the MOLI-SANI study. TDev was measured from a standard 12-lead resting electrocardiogram. High sensitivity (Hs) C-reactive protein (CRP), leukocyte (WBC) and platelet counts, neutrophil or granulocyte to lymphocyte ratios were used as markers of inflammation. In multivariable model subjects reporting high CRP levels had higher odds of having borderline and abnormal TDev (OR=1.70; 95 %CI: 1.53-1.90 and OR=1.72; 95 %CI: 1.23-2.41, respectively); the association was still significant, although reduced, after controlling for body mass index (OR=1.17; 95 %CI: 1.05-1.32, for borderline and OR=1.46; 95 %CI: 1.03-2.08, for abnormal). Similarly, higher neutrophil or granulocyte to lymphocyte ratios were associated with increased odds of having abnormal TDev. Neither platelet nor leukocyte counts were associated with abnormal TDev. The relationship between CRP with TDev abnormalities was significantly stronger in men, in non- obese or normotensive individuals, and in those without metabolic syndrome. In conclusion, C-reactive protein and some cellular biomarkers of inflammation such as granulocyte or neutrophil to lymphocyte ratios were independently associated with abnormal TDev, especially in subjects at low CVD risk. These results suggest that a low-grade inflammation likely contributes to the pathogenesis of T- wave axis deviation.

Synergistic effect of apolipoprotein E polymorphisms and cigarette smoking on risk of ischemic stroke in young adults.

BACKGROUND AND PURPOSE: The effect of apolipoprotein E (APOE) polymorphisms on stroke risk may be influenced by the coexistence of modifiable predisposing conditions. We explored the interactions of APOE genotypes and conventional risk factors in a case-control study of young adults with cerebral infarct. METHODS: We analyzed 124 consecutive patients (age, 34.7+/-7.3 years) and 147 age- and sex-matched controls. APOE genotypes were determined by restriction fragment-length polymorphism analysis. RESULTS: The prevalence of the epsilon4 allele and epsilon34 genotype was slightly higher in cases than in controls (0.125 versus 0.071 and 0.242 versus 0.136, respectively). Carriers of the epsilon34 genotype and epsilon4 allele were associated with an increased risk of stroke on multivariate analysis compared with the epsilon33 genotype and non-epsilon4 carriers, respectively (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.10 to 4.76; and OR, 2.27; 95% CI, 1.13 to 4.56). ORs for stroke were 2.99 (95% CI, 1.64 to 5.45), 2.69 (95% CI, 1.25 to 5.77), and 5.39 (95% CI, 1.59 to 18.30) for smokers with the epsilon33 genotype, nonsmokers with the epsilon34 genotype, and smokers with the epsilon34 genotype, respectively, compared with nonsmokers with the epsilon33 genotype. Similar results were obtained when epsilon4 carriers and non-epsilon4 carriers were compared in the same interaction model. No significant interaction between APOE and hypertension was found. CONCLUSIONS: In young adults, the APOE epsilon4 allele and cigarette smoking act synergistically, increasing an individual's propensity to have a cerebral ischemic event. This finding may help in determining an individual's predisposition to stroke and more targeted preventive interventions.

Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.

BACKGROUND AND PURPOSE: The role of mild hyperhomocysteinemia as a risk factor for cerebral ischemia may depend on stroke subtype. To test this hypothesis, we undertook a prospective case-control study of a group of patients with spontaneous cervical artery dissection (sCAD), a group of patients with atherothrombotic stroke (non-CAD), and a group of control subjects. METHODS: Fasting total plasma homocysteine (tHcy) concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype were determined in 25 patients with sCAD, 31 patients <45 years of age with non-CAD ischemic stroke, and 36 control subjects. Biochemical data in the patient groups were obtained within the first 72 hours of stroke onset. RESULTS: Median tHcy levels were significantly higher in patients with sCAD (13.2 micromol/L; range, 7 to 32.8 micromol/L) compared with control subjects (8.9 micromol/L; range, 5 to 17.3 micromol/L; 95% CI, 1.05 to 1.52; P=0.006). Cases with tHcy concentration above the cutoff level of 12 micromol/L were significantly more represented in the group of patients with sCAD compared with control subjects (64% versus 13.9%; 95% CI, 2.25 to 44.23; P=0.003); a significant association between the MTHFR TT genotype and sCAD was also observed (36% versus 11.1%; 95% CI, 1.10 to 19.23; P=0.045). No significant difference in tHcy levels and in the prevalence of thermolabile MTHFR was found between patients with non-CAD ischemic stroke and control subjects and between patients with sCAD and non-CAD ischemic stroke. The distribution of the 844ins68bp CBS genotype and the prevalence of subjects carrying both the TT MTHFR and 844ins68bp CBS genotypes were not significantly different among the 3 groups. CONCLUSIONS: Our results are consistent with the hypothesis that increased plasma homocysteine levels and the TT MTHFR genotype may represent risk factors for sCAD. In contrast, their role in atherothrombotic strokes remains a contentious issue.

Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale.

BACKGROUND AND PURPOSE: The pathogenic link between patent foramen ovale (PFO) and stroke remains unknown in most cases. We investigated the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study. METHODS: We investigated 125 consecutive subjects (age, 34.7+/-7.3 years) with ischemic stroke and 149 age- and sex-matched control subjects. PFO was assessed in all patients with transcranial Doppler sonography with intravenous injection of agitated saline according to a standardized protocol. Genetic analyses for the factor V (FV)(G1691A) mutation, the prothrombin (PT)(G20210A) variant, and the TT677 genotype of methylenetetrahydrofolate reductase (MTHFR) were performed in all subjects. RESULTS: A pathogenic role of PFO was presumed in 36 patients (PFO+). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFO-). The PT(G20210A) variant was more frequent in the PFO+ group compared with control subjects and the PFO- group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO-, 11% versus 1.1%; 95% CI, 1.09 to 109; P=0.047). A similar distribution was observed for subjects carrying either the PT(G20210A) variant or the FV(G1691A) mutation (PFO+ versus control subjects, 19.4% versus 5.3%; 95% CI, 0.08 to 0.75; PFO+ versus PFO-, 19.4% versus 3.3%; 95% CI, 1.45 to 26.1; P=0.021). Combined thrombophilic defects were observed in 3 subjects of the PFO+ group, in 2 control subjects (8.3% versus 1.3%; 95% CI, 0.01 to 0.66; P=0.015), and in 0 subjects in the PFO- group. A trend toward a difference in the frequency of the FV(G1691A) mutation between PFO+ and control subjects was found after bivariate analysis (11% versus 3.3%; P=0.068) but not after multinomial logistic regression analysis. No significant association was found in the distribution of the TT MTHFR genotype in the 3 groups. CONCLUSIONS: In young adults, the PT(G20210A) variant and, to a lesser extent, the FV(G1691A) mutation may represent risk factors for PFO-related cerebral infarcts. A role of systemic thrombophilic disorders in the pathogenesis of this specific subtype of stroke may be hypothesized.