Metabolic syndrome and chronic simvastatin therapy enhanced human cardiomyocyte stress before and after ischemia-reperfusion in cardio-pulmonary bypass patients.

Metabolic syndrome (MetS) is a set of metabolic alterations including high levels of low-density lipoprotein (LDL), which increase the risk of cardiomyopathy often leading to surgery. Despite inducing myopathy, statins are widely used to lower LDL. Cardiopulmonary bypass (Cpb) causes oxidative stress and metabolic injury, altering mitochondrial expression (Grp75) and endoplasmic reticulum (Grp78) chaperones, apoptotic enzymes (Bcl2 family) and increasing cardiomyocyte lipid/lipofuscin storage. We believe that cardiomyocytes from patients with MetS may be more sensitive to surgical stress, in particular after simvastatin therapy (MetS+Stat). The study group included ten patients with MetS, ten patients with Mets+Stat and ten healthy subjects. Myocardial biopsies were obtained both before and after-Cpb. Grp75, Grp78, Bax, Bcl2, lipids, lipofuscin and fibrosis were evaluated by immuno/histochemistry. MetS cardiomyocytes had higher Grp75, Bax, fibrosis and lipofuscin. MetS+Stat had lower Grp75 and higher Grp78 expressions, high Bax, fewer fibrosis and higher lipofuscin content. Cpb did not vary the fibrosis and lipids/lipofuscin content, although it influenced the chaperones and Bax expression in all groups. These changes were more profound in patients with MetS and even more so in patients with MetS+Stat. The results suggest that MetS and MetS+Stat cardiomyocytes were more highly stressed after-Cpb. Interestingly, simvastatin caused high stress even before-Cpb.

Interaction of homocysteine and conventional predisposing factors on risk of ischaemic stroke in young people: consistency in phenotype-disease analysis and genotype-disease analysis.

BACKGROUND AND OBJECTIVES: Whether the association between mild hyperhomocysteinaemia and ischaemic stroke is the consequence of a predisposing genetic background or is due to the confounding influence of established predisposing factors remains to be determined. METHODS: Plasma total homocysteine (tHcy) concentration and the distribution of the C677T genotypes of the methylenetetrahydrofolate reductase gene (MTHFR) were compared in 174 consecutive patients with stroke aged <45 years and 155 age and sex-matched controls. The effect of conventional risk factors on the relationship between phenotype-disease and genotype-disease was analysed by two-way and three-way interaction analysis and by the classification and regression trees (CART) model. RESULTS: tHcy concentrations were markedly higher in patients with ischaemic stroke (median 11.9 micromol/l, range 2.0-94.0) than in controls (median 9.8 micromol/l, range 4.7-49.6). An increased risk was also associated with the TT677 genotype (odds ratio (OR) 1.98; 95% confidence interval (CI) 1.04 to 3.78) and with the T allele (1.40; 95% 1.03 to 1.92) of the MTHFR gene. A differential effect of Hcy levels on risk of stroke was observed according to the distribution of environmental-behavioural risk factors, with a stronger influence in the subcategory of people with hypertension and smokers (OR 24.8; 95% CI 3.15 to 196). A comparable environmental-dependent TT677 MTHFR genotype-stroke association was observed in the genotype-disease analysis. CONCLUSIONS: A consistency of phenotype-disease analysis and genotype-disease analysis is indicated by analysing specific subcategories of patients, defined by the distribution of established risk factors. The assumption that the Hcy-stroke relationship is unlikely due to a reverse-causality bias is indirectly supported by our data.

Modeling premature occurrence of acute coronary syndrome with atherogenic and thrombogenic risk factors and gene markers in extended families.

BACKGROUND: The interaction between genetic and environmental risk factors in determining premature cardiovascular events has been largely investigated in case-control association studies. By contrast, few family based analyses have been performed so far. PATIENTS/METHODS: From a series of 2936 subjects aged 45-64, we selected probands who died for a premature (<50 years) ischemic heart disease (IHD) and with at least one family member with a history of IHD also occurring under the age of 50. Ninety-four families from 32 pedigrees including 296 subjects were identified. In this population, we analyzed the relationship between background risk factors [age, gender, the G1691A polymorphisms of factor V gene, the C677T polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, the 844ins68bp polymorphisms of the cystathionine-beta-synthase (CBS) gene, and the apolipoprotein E (APOE) polymorphisms] and environmental risk factors, both atherogenic (smoke, hypertension, diabetes, dyslipidemia, obesity) and thrombogenic (smoke, homocysteine, fibrinogen) by a Markov block-recursive modeling approach. RESULTS: None of the studied polymorphisms had an independent direct effect on the risk of IHD. As opposed to atherogenic factors, thrombogenic factors (homocysteine and fibrinogen) turned out to be possible mediators of the indirect effect of the MTHFR gene on IHD risk (OR: 1.30; 95% CI: 1.01-1.69, for every 8 mm increase in plasma levels of homocysteine in TT-carriers compared with CT/CC-carriers (OR: 1.11; 95% CI: 1.01-1.22), for every 20 g L(-1) increase in plasma levels of fibrinogen in TT-carriers compared with CT/CC-carriers). CONCLUSION: Plasma levels of homocysteine and fibrinogen may be interpreted as intermediate factors mediating the effect of predisposing genes on the risk premature cardiovascular disease.

Polymorphisms of the interleukin-1beta gene affect the risk of myocardial infarction and ischemic stroke at young age and the response of mononuclear cells to stimulation in vitro.

OBJECTIVE: To investigate the role of interleukin-1beta (IL-1beta) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age. METHODS AND RESULTS: A total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the -511C/T IL-1beta polymorphism showed a decreased risk of MI (odds ratio [OR], 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (P=0.0020 in MI; P=0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1beta and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1beta during cell stimulation resulted in a marked reduction of tissue factor activity expression. CONCLUSIONS: -511C/T IL-1beta gene polymorphism affects the risk of MI and ischemic stroke at young age and the response of mononuclear cells to inflammatory stimulation.

[Work, cardiopathy, and sports]. / Lavoro, cardiopatie e sport.

BACKGROUND: Heart disease is the main cause of early disability and premature death in Europe. Regular physical activity may prevent heart disease, diabetes, ictus, and obesity. Nevertheless, a certain resistance to a dynamic lifestyle, lack of free time, lack of motivation and other factors are frequently encountered. OBJECTIVES: To stress the importance of physical activity in the prevention of cardiovascular disease. METHODS: A literature review of the main risk factors for cardiovascular disease was carried out. RESULTS AND CONCLUSION: It has been shown that physical exercise is beneficial to the cardiovascular apparatus and to the bones and joints, by improving some metabolic parameters. Recent studies have shown that a personalized, moderate physical activity should be suggested for primary and secondary prevention, in particular for subjects with coronary artery disease and left ventricular dysfunction. An increase in sports activity and physical exercise at work and at school is recommended so as to improve quality of life and promote home rehabilitation. Some promising experience has already been made among workers and their families with excellent results, as shown by a follow-up period of three years.

Homocysteine levels are associated with the severity of peripheral arterial disease in Type 2 diabetic patients.

BACKGROUND: Homocysteine levels are positively associated with the risk of cardiovascular disease. They might be determined by both MTHFR677C-->T polymorphisms and folate or B-vitamin status. OBJECTIVES: To investigate the possible association between plasma homocysteine levels and its genetic or environmental determinants and either the presence or the severity of peripheral arterial disease (PAD), in Type 2 diabetic patients. METHODS: From a cohort of 944 patients with Type 2 diabetes, 135 patients with PAD were selected, and frequency-matched for age and sex with 219 Type 2 diabetic control patients without macrovascular complications. According to the increasing severity of the disease, patients were divided into PAD1 (only diffuse calcifications of the arteries without any stenosis or occlusion), PAD2 (one or two stenosis or occlusions) and PAD3 (three or more). RESULTS: Homocysteine levels were similar in control and case patients (10.3 micromol L-1 vs. 10.7 micromol L-1, P = 0.53); however, a significant increase was found in PAD3 patients: odds ratio = 2.77 (95% confidence interval 1.14, 6.72) for patients with homocysteine levels above the median vs. those under the median in multivariate analysis. Although all significantly associated with homocysteine levels, neither MTHFR genotype nor folic acid or vitamin B12 levels were associated with severity of PAD. A significant interaction (P < 0.05) was found between folic acid and MTHFR polymorphism in determining the levels of homocysteine. CONCLUSIONS: In Type 2 diabetes, homocysteine was associated with the angiographic severity of PAD, but neither the genotypes nor vitamin levels contributed to this association.

[A hyperhomocysteinemia study in a population with a familial factor for acute myocardial infarct and sudden cardiac death at a young age]. / Studio dell'iperomocisteinemia in una popolazione con pesante familiarità per infarto miocardico acuto e morte improvvisa cardiaca in giovane età.

The alterations of the metabolism of methionine determining an accumulation of homocysteine in blood (hyperhomocysteinemia) recognize a multifactorial etiology, hereditary as well as acquired. To date several case-control studies have documented that the condition of hyperhomocysteinemia can be considered an independent risk factor of coronary disease and its noxious effects are dose-dependent. It exerts its effect by different mechanisms both prothrombotic and endothelial. In our study we started from an initial cohort of 2227 subjects (1210 males, 1017 females) aged between 45 and 64 years among which we selected 22 persons with at least 2 first-degree relatives below age 50 who had had either a major cardiovascular event (acute myocardial infarction or sudden death) or angiographically documented cardiac disease. We reconstructed the proper pedigrees obtaining 22 families in whom we identified four main subgroups to carry out analyses and comparisons: case-control, composed respectively of all the subjects who survived a major cardiovascular event or a coronary disease documented angiographically and clinically healthy subjects; affected line and non affected line, composed respectively of members belonging to the family line of the proband and members of collateral family line. Each of the subjects involved in the study underwent a complete history regarding job and sports activities, a standardized physical examination, 12-lead digital ECG according to the European Standard Communication Protocol. A blood sample was taken in fasting conditions to determine total cholesterol, HDL and LDL cholesterol, triglycerides, glycemia, fibrinogen, plasma homocysteine. The results indicate how among the cases there were more subjects with homocysteine higher than the 95 degrees percentile in males alone (p = 0.03), the estimated odds ratio calculated from Fisher's test was 8.34 (95% confidence interval 1.32-52.7). Despite the fact that mean age was significantly lower (p = 0.01) in males of the affected line compared to those of the non affected line, the results show much higher homocysteine values in the affected family line in both males and females: a difference quite evident in the distribution especially as regards the 95 degrees percentile. These results obtained in the subjects belonging to the same families emphasize that familial aggregation, which influences the sharing of the genetic patrimony, socio-cultural environment and food habits can induce a differential risk for homocysteinemia. The study of mutations of genes coding for the key enzymes of the metabolism of homocysteine, methylenetetrahydrofolate reductase and cystathionine beta-synthase, which we prepared, will enable use to evaluate the relative influence feeding habits and genetic factors have in the development of hyperhomocysteinemia.

Effect of leisure time and working activity on principal risk factors and relative interactions in active middle-aged men.

DESIGN: This study was designed to evaluate, in a cohort of 1039 middle-aged men, the interaction between the duration and intensity of physical activity performed either during leisure time (competitive sports, walking, cycling) or work, and principal coronary disease risk factors. METHOD: A cohort of subjects aged 45-64 years were recruited in 1993. Subjects included both individuals who were physically active and those who were sedentary, and were age-matched. RESULTS: Leisure time physical activity was inversely related to levels of total cholesterol, triglycerides, and fibrinogen, and to diastolic and systolic blood pressure. High-density lipoprotein cholesterol level was directly related to leisure time activity. Working activity, even if strenuous, was not related to risk profile. Leisure time activity did not favorably influence lipid levels in smokers, obese subjects or those with known dyslipidemia. CONCLUSIONS: This study further reinforces the use of continuous diet and drug treatment in dyslipidemic subjects and in smokers, who have to refrain from smoking if they are to benefit fully from the effects of physical activity.

Integration and communication for the continuity of cardiac care (I4C).

The project I4C (Integration and Communication for the Continuity of Cardiac Care) is carried out for the advancement of cardiac care, from prevention to follow-up. The goals of I4C are: (1) integrated access to patient data, wherever they are stored; (2) support of evidence-based care; (3) consistent recording of patient data (eg, patient history, electrocardiograms IECGs] or cine-angios) in a multimedia patient record; and (4) a documented reference data set for research. In several clinics, workstations are being installed to serve the four goals. Integration with other information systems in clinical care is realized by encapsulation. A computer-based patient record (ORCA) has been developed to support the collection, consultation, and sharing of patient data. In I4C, ORCA is intended for use in a research setting as well as routine patient care. The functionality of ORCA covers the collection of patient history data in a highly structured manner, the recording of drug prescriptions, an overview of laboratory test results, and viewers for ECGs and angiographic images. At present, structured data entry and consultation is supported in six European languages.

Cigarette smoking and sports participation in adolescents: a cross-sectional survey among high school students in Italy.

All the male students in a high school in Brescia, North Italy (about 195,000 inhabitants) in Grades 9 through 13 were given a self-administered anonymous questionnaire during school time. Among the 1,462 students who filled in a valid questionnaire, 29.1% claimed to practice one or more sports regularly (at least 4 hours/week for 9 months/year or more), 30.2% practice sports occasionally, and 40.7% no sports at all. The percentage of current smokers (at least one cigarette a month) increased from 9th grade (11.1%) to 10th (13.2%), 11th (15.2%), 12th (27.7%), and 13th (23.7%) grade. The percentage of smokers showed a steady linear increase from the lowest to the highest grade in students practicing no or occasional activity but no increase in those who regularly practice sports. Students' smoking was negatively associated with the regular practice of sports among 12th-13th grade students.

[Circadian variation of sudden cardiac death in young people with and without coronary disease]. / Variazione circadiana della morte cardiaca improvvisa in una popolazione giovanile con e senza malattia coronarica.

Sudden cardiac death is not well known and provoking factors are yet mainly unknown. To clarify whether sudden cardiac death has a circadian rhythm in young people we have studied 40 patients < 45 years who died in Brescia between 1984 and 1993 of sudden cardiac death showing at autopsy features of coronary artery disease (CAD) and 12 patients aged < 30 years who died of sudden cardiac death without autoptic features of CAD. We observed a circadian rhythm in the hours of the morning in the two groups, more evident in patients without CAD. In patients with autoptic features of CAD, we also observed a higher rate of events during the winter months. We would like to stress the importance of the adrenergic system as a trigger able to produce the event. We believe that the role of the sympathetic nervous system is more important than other risk factors (for example platelet aggregability and blood viscosity) to precipitate sudden cardiac death, mainly because the circadian rhythm was more evident in patients without CAD. An increase of the data-base and a more detailed analysis of subgroups is necessary if we concretely want to prevent sudden cardiac death fitting antiarrhythmic therapy with circadian distribution of major events. We underline the practical impact of "chronorisk" together with the other cardiovascular risk factors.

[Ischemic cardiopathy in the young: coronarographic and autopsy picture in 100 subjects]. / La cardiopatia ischemica nel giovane: quadro coronarografico ed autoptico in 100 soggetti.

Many aspects of coronary artery disease in young people are not completely understood. Our study concerns a series of 100 patients < 45 years with acute coronary artery disease. Sixty patients survived and 40 died suddenly. All subjects have been divided into four groups: Group I includes 20 deceased patients with anatomic features of acute myocardial infarction. Group II includes 20 subjects dead without features of acute myocardial infarction. Group III includes 30 patients surviving the first acute myocardial infarction. Group IV includes 30 patients surviving unstable angina. The coronary arteries have been studied by anatomic dissection in Group I and II and with coronarography in Groups III and IV. The left main was only involved in Group I and II patients. Multivessel disease was more frequent in Group I and II, but the difference was not significant. These results underline that coronary artery disease with multivessel involvement is not rare in young patients. The rare occurrence of left main disease at coronary angiography could be the consequence of the natural preselection determined by sudden death.

Comparison of 12-lead repolarization parameters during follow-up study in middle-aged sportsmen and in patients during acute myocardial infarction.

Consecutive electrocardiographic (ECG) analysis is very useful in acute coronary ischemia, but it is known that ECG patterns can be misleading in subjects with left ventricular hypertrophy, mainly during the repolarization phase. An automated system was developed to collect, store, and follow-up all heterogeneous data concerning a cohort of 1,898 subjects (1,039 men), 45-65 years old, 50% of whom were physically active. The reliability of several ECG markers of ischemia was tested during chronic follow-up study (1993-1995) in 23 healthy sedentary men without hypertension (group 1) recorded in our database, as well as in 9 subjects performing regular sporting activity (SA) (group 2). The same parameters were evaluated in the intensive care unit in nine patients affected by coronary artery disease, during either successful or unsuccessful thrombolytic therapy of acute myocardial infarction (AMI) (group 3). Twelve-lead ECGs were recorded, analyzed by the Hannover ECG system program, compressed, and stored according to the Standard Communication Protocol in each of the three groups. The changes in ST amplitude 20, 60, and 80 ms alter the J point were very small in each subject of groups 1 and 2, while upsloping from 1 to 10 mm in several leads was observed slowly, rapidly, or intermittently in group 3 patients during ischemia. The ST slope and the concordance of the T wave and ST amplitude were helpful in differentiating normal and SA subjects from AMI patients. These results, obtained in resting conditions, underline that the difference among ST-T abnormalities in subjects with left ventricular hypertrophy due to SA are consistently different from those observed in patients with AMI. The serial digital ECG can be helpful to underline these differences.

Alcohol consumption among high school students and young athletes in north Italy.

Alcohol consumption was assessed among 366 male high school students and 330 young men playing in sports teams. On the average, the athletes drank less wine, beer and spirits than the students and reported fewer drunkenness episodes. The association of alcohol drinking with sporting activity and with some independent variables was estimated by logistic regression techniques, fitting models for ordinal or nominal response variables. Point estimates of the odds ratios and their confidence limits showed: 1) an inverse relationship between alcohol drinking and sporting activity, especially as regards the consumption of spirits; 2) a strong positive relationship of alcohol drinking with both experimental and regular smoking; 3) peer alcohol drinking (best friend's and girlfriend's drinking) was the strongest predictor of the participant's alcohol consumption.

Invasive and echocardiographic evaluation of non-Q myocardial infarction with isolated stenosis of descending anterior coronary artery.

Prognostic and clinical characteristics of acute myocardial infarction (AMI) can usually justify surgical and/or angioplastic approach if the residual ventricular function is still good. Multivessel disease frequently complicates results interpretation. We studied with 2D echocardiography and coronary angiography two groups of patients with one vessel stenosis located on anterior descending (AD) and previous AMI (means 19 days): 23 patients with spontaneous non-Q infarction (group 1), and 23 patients with Q infarction. Left ventricular function was better in group 1. Percent occlusion of AD was lower in group 1 and angiographic AD caliber was significantly higher. Differences between groups were much more evident in subgroups with proximal stenosis of AD: patients of non-Q subgroups had very good left ventricular function but frequently had post-AMI instable angina (88%). Our results underline the usefulness of aggressive diagnostic and therapeutic approach in non-Q AMI, because of higher amount of myocardium at risk.