High prevalence and diminished awareness of overweight and obesity in a mediterranean population. An alarming call for action.

INTRODUCTION: The epidemic proportions of overweight, obesity and diabetes in most European countries stress the need for the implementation of an effective action plan for the prevention of cardiovascular (CV) disease. This ques-tionnaire study was designed to evaluate the viewpoint of the general population regarding the relative significance of CV risk factors in the cumulative risk of CV disease. METHODS: All participants answered a questionnaire regarding the self-reported presence of CV disease risk factors and the perceived notion of having excess weight. They were also asked to list CV disease risk factors, ranking them in order of perceived relative significance. Participants were also subjected to total cholesterol measurement using a portable total cholesterol testing meter. RESULTS: The survey population consisted of 32,736 individuals (49.1% males). According to participant self reporting, 32.9% were smokers, 24.7% had hypertension, 9.8% had diabetes, 74.8% reported having stress, 41.9% had insufficient physical activity and 43.3% had hyperlipidemia. The prevalence of overweight was 43.9% and the prevalence of obesity (BMI ≥30 kg/m(2)) was 18.6%. Only 24.4% of participants reported that they had excess weight. The 45.2% of the ques-tioned individuals considered that stress was the most important CV risk factor. CONCLUSIONS: Despite the high prevalence of overweight and obesity, the majority of participants were unaware of the contribution of these well-established risk factors to the occurrence of CV disease. Improving public awareness is impor-tant in order to control the epidemic proportions of these modifiable risk factors.

Depression in patients with hypertrophic cardiomyopathy: is there any relation with the risk factors for sudden death?

OBJECTIVES: The aim of this study was to investigate whether depressive symptoms are related to the risk factors for sudden death in patients with hypertrophic cardiomyopathy (HCM). DESIGN: 121 patients diagnosed as having HCM were assessed for depressive symptomatology using the Beck Depression Inventory and the Center for Epidemiological Studies Depression Scale (CES-D) and followed up for a period of 2 years. For the interview, the authors used the Structured Clinical Interview for DSM-III/DSM-III-R. A multidimensional longitudinal study was carried out with both somatic and psychological symptoms and signs taken into consideration. SPSS was used for the statistical analysis. RESULTS: (1) Patients with HCM are more depressed than the general population. (2) There is no positive correlation between the occurrence of depressive symptoms and the risk factors for sudden death in patients with HCM. (3) Patients at high risk for sudden death are not more depressed than the others. (4) Time from diagnosis of the cardiac disease is not related to the presence and severity of depressive symptoms. CONCLUSIONS: Patients with HCM are more depressed than the general population. The authors suggest that depressive symptoms and risk factors for sudden death in these patients are not related. It is important to screen for mood disorders in this patient population in order to provide an early diagnosis and treatment of the psychiatric disease.

Eleven-year prevalence trends of obesity in Greek children: first evidence that prevalence of obesity is leveling off.

We examined 11-year (1997-2007) trends in underweight, overweight, and obesity in Greek children. Population data derived from a yearly, school-based health survey carried out between 1997 and 2007 in >80% of all Greek schools. Height and weight measurements from 651,582 children, aged 8-9 years (boys: 51.2%) were analyzed. The gender- and age-specific BMI cutoff points by the International Obesity Task Force (IOTF) were used in order to define underweight, normal weight, overweight, and obesity. Trend analysis showed an increase in the prevalence of obesity from 7.2 +/- 0.2% in 1997 to 11.3 +/- 0.2% in 2004 for girls (P < 0.001) and from 8.1 +/- 0.2% in 1997 to 12.3 +/- 0.2% in 2004 for boys (P < 0.001). An apparent leveling off in obesity rates was observed during 2004-2007 for both boys and girls. The prevalence of overweight rose between 1997 and 2007 from 20.2 +/- 0.2% to 26.7 +/- 0.2% for girls (P < 0.001) and from 19.6 +/- 0.2% to 26.5 +/- 0.2% for boys (P < 0.001). The overall prevalence of thinness in the same period remained constant in both sexes. The presented population-based data revealed that the prevalence of overweight and obesity among 8- to 9-year-old Greek children is alarmingly elevated, with the overweight rates rising continuously. However, an apparent leveling off in obesity rates for the past 4 consecutive years was documented for the first time in both genders.

Estrogen-induced improvement in coronary flow responses during atrial pacing in relation to endothelin-1 levels in postmenopausal women without coronary disease.

BACKGROUND: The cardioprotective role of hormonal replacement therapy remains in doubt, but interest is increasing in the vascular effects of estrogens especially in coronary circulation. METHODS: Coronary blood flow (CBF) was measured in 24 postmenopausal women (age 55+/-3 years), whose coronary arteries appeared angiographically normal, during incremental atrial pacing (AP) before and 20 minutes after intracoronary administration of either 75 ng/mL 17-beta estradiol (treated group, n=18) or 0.9% saline (controls, n=6). RESULTS: Before estrogen, no differences in the coronary vasomotor responses at AP between the two groups (p=NS) could be detected. After estrogen, in the treated group, at the peak of the second AP, the coronary artery diameter decreased by 0.17 mm (p<0.005) while the CBF increased by 61 mL/min (p<0.05). These changes differed significantly from those observed at the peak of first AP (p<0.001 for both cases). In contrast, in the control group no such changes were observed. The endothelin-1 (ET-1) levels in the coronary sinus were significantly reduced after estrogen infusion, which was negatively correlated with the degree of coronary artery constriction (r= -0.40, p=0.03) and positively correlated with the increase in CBF (r=0.54, p=0.01). CONCLUSIONS: In postmenopausal women without coronary artery disease, the intracoronary estrogen infusion mediates a greater increase in CBF and is positively correlated with the reduction of the coronary sinus ET-1 levels at the peak of AP.

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction.

BACKGROUND: This study was designed to investigate the association of the 894G>T polymorphism in the eNOS gene with risk of acute myocardial infarction (AMI), extent of coronary artery disease (CAD) on coronary angiography, and in-hospital mortality after AMI. METHODS: We studied 1602 consecutive patients who were enrolled in the GEMIG study. The control group was comprised by 727 individuals, who were randomly selected from the general adult population. RESULTS: The prevalence of the Asp298 variant of eNOS was not found to be significantly and independently associated with risk of AMI (RR = 1.08, 95%CI = 0.77-1.51, P = 0.663), extent of CAD on angiography (OR = 1.18, 95%CI = 0.63-2.23, P = 0.605) and in-hospital mortality (RR = 1.08, 95%CI = 0.29-4.04, P = 0.908). CONCLUSION: In contrast to previous reports, homozygosity for the Asp298 variant of the 894G>T polymorphism in the eNOS gene was not found to be associated with risk of AMI, extent of CAD and in-hospital mortality after AMI.

Depressive symptomatology and the prevalence of cardiovascular risk factors among older men and women from Cyprus; the MEDIS (Mediterranean Islands Elderly) epidemiological study.

AIMS: The purpose of this paper is to explore the link between symptoms of depression and the prevalence of cardiovascular risk factors in older adults. METHODS: During 2005, 136 older men and 164 women from various parts of Cyprus agreed to participate in the study. The sampling was random and multistage (according to age-sex distribution of the referent population). All participants were living in the community and not in institutions. Among several socio-demographic, bioclinical, lifestyle and dietary characteristics, depressive symptoms were assessed using the short version of the Geriatric Depression Scale (GDS). RESULTS: Participants without signs of depression, typically, have fewer cardiovascular risk factors (i.e. hypertension, hypercholesterolemia, diabetes and obesity) than those with moderate or severe symptoms. Even when behavioural variables (e.g. diet, smoking, exercise) are statistically controlled, participants that are higher than others on depression are more likely to have hypertension and/or hypercholesterolemia than those with lower scores. Every one-unit increase in GDS score (range 0-15) is associated with a 12% higher likelihood of having an additional cardiovascular disease risk factor. CONCLUSIONS: Symptoms of depression are positively associated with the number of cardiovascular risk factors in 'healthy' older adults, irrespective of lifestyle behaviours (e.g. smoking, dietary intake and physical activity). RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should consider the implications of both the presence and nature of this relationship in their continuing care of older adults.

Long-term primary cultures of human adult atrial cardiac myocytes: cell viability, structural properties and BNP secretion in vitro.

BACKGROUND: Human adult cardiomyocytes (CM) have been used in short-term cultures for in vitro studies of the adult myocardium. However, little information is available regarding human adult CMs cultured for long term (>2 weeks). METHODS: Human adult CMs were isolated from atrial specimens of 43 patients undergoing cardiopulmonary bypass surgery. Cell viability, cytoskeletal properties, intercellular junctional mediators and responsiveness to extracellular stimuli were monitored in CM cultures for 8 weeks. RESULTS: Absolute numbers of CMs decreased through the first 2 weeks, with substantially lower rates of cell loss thereafter. Apoptosis predominated over necrosis as the principal mode of cell death, affecting 4.1+/-1.6% of freshly dissociated cells, that declined in culture (3.6+/-1.0% week 1, 1.3+/-0.5% week 2). CMs maintained rod-shaped morphology and cross-striated expression pattern of sarcomeric proteins desmin and beta-myosin heavy chain for the first 4 weeks. Levels of desmin remained stable on first 3 weeks, but declined thereafter. CMs expressed cardiac-specific adherence molecule N-cadherin throughout the culture duration, indicating conserved contractile potential. CMs remained functional early in culture, as indicated by BNP secretion, with maximal levels on 1st week that declined gradually by week 4. Cell responsiveness to metabolic stresses (serum deprivation) was detected, inducing an early (6 h) 1.8-fold increase in levels of BNP. CONCLUSION: Long-term cultured human adult CMs maintain morphological integrity, adult-type cytoskeletal protein expression, cell-cell communication potential and functionality for 3-4 weeks in vitro.

Severe mitral regurgitation due to perforation of the mitral anterior leaflet.

We present a case of a 75-year-old male with a worsening dyspnea during the last month. Transthoracic echocardiography revealed a severe mitral regurgitation. Transesophageal echocardiography was evident of a 6 mm defect of the mitral anterior leaflet at the region of the anteromedial A1 and medial A2 scallops probably due to perforation, which caused a significant regurgitant jet as documented by the presence of a convergence flow over the 'hole'. As the patient had a prolonged fever of undetermined origin one and a half months ago, perforation of the mitral anterior leaflet must at least be considered to be of an infective origin.

Long-term fish intake is associated with better lipid profile, arterial blood pressure, and blood glucose levels in elderly people from Mediterranean islands (MEDIS epidemiological study).

BACKGROUND: A study to evaluate the link between long-term fish intake and health status in a sample of elderly adults was undertaken. MATERIAL/METHODS: Three hundred men and women from Cyprus, 142 from Mitilini, and 100 from Samothraki islands (aged 65 to 100 years) were enrolled in this study during 2005-2006. Dietary habits (including fish consumption) were assessed through a food frequency questionnaire. Among various factors, fasting blood glucose, arterial blood pressures, and blood lipids were measured. RESULTS: Sixty-one percent of the participants reported that they had consumed fish approximately once a week (mean intake: 1.9+/-1.2 servings/week) for a mean period of 30 years. After adjusting for various confounders, fish intake was inversely associated with systolic blood pressure (p=0.026), fasting glucose (p<0.001), total serum cholesterol (p=0.012), and triglyceride levels (p=0.024). Multinomial logistic regression revealed that a decrease of 100 g per week in fish intake was associated with a 19% (95%CI: 1-41) higher likelihood of having one additional cardiovascular risk factor (i.e. hypertension, hypercholesterolemia, diabetes, obesity). CONCLUSIONS: The results indicate that long-term fish intake is associated with reduced levels of the most common cardiovascular disease risk markers in a cohort of elderly people.

Acute improvement of aortic mechanics following hemodialysis in patients with chronic renal failure.

BACKGROUND: Evidence suggests that distensibility of the aorta is decreased in patients with end-stage renal failure, while the underlying mechanisms are unclear. HYPOTHESIS: The purpose of the study was to evaluate the distensibility of the aorta in patients at the end stage of chronic renal failure before and after hemodialysis (HD). METHODS: The diameter of the ascending aorta and distensibility were assessed in 48 patients on HD (31 men, 17 women, aged 45+/-14 years) and in 27 normal subjects (17 men, 10 women, aged 44+/-14 years). The diameter of the aorta was evaluated by M-mode in the parasternal long-axis view. RESULTS: Aortic distensibility was significantly lower in patients on HD before HD (1.9+/-0.7 cm(2) x dyn(-1) x 10(-6)) than in normal control subjects (3.8+/-1.0 cm(2) x dyn(-1) X 10(-6), p< 0.0001). After dialysis, it increased to 2.6+/-1.2 (p < 0.05 compared with baseline, p < 0.001 compared with controls). The change of aortic distensibility correlated with age (R(2) = 0.629 p < 0.001) and ultrafiltration volume (R(2) = 0.168, p < 0.01). CONCLUSIONS: Aortic distensibility in patients with end-stage renal disease is significantly lower than in normal subjects, and it is significantly improved after HD.

Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study.

BACKGROUND: It is not clear if long-term antithrombotic treatment has a beneficial effect on the incidence of thromboembolism in chronic heart failure (CHF). The HELAS study (Heart failure Long-term Antithrombotic Study) is a multicentre, randomised, double-blind, placebo-controlled trial to evaluate antithrombotic treatment in patients with CHF. METHODS: 197HF patients (EF <35%) were enrolled. Patients with Ischaemic Heart Disease were randomised to receive either aspirin 325mg or warfarin. Patients with Dilated Cardiomyopathy (DCM) were randomised to receive either warfarin or placebo. RESULTS: Analysis of the data from 312 patient years showed an incidence of 2.2 embolic events per 100 patient years, with no significant difference between groups. The incidence of myocardial infarction, hospitalisation, exacerbation of heart failure, death and haemorrhage were not different between the groups. No peripheral or pulmonary emboli were reported. Echocardiographic follow-up for 2years showed an overall increase in left ventricular ejection fraction from 28.2+/-6 to 30.3+/-7 p<0.05, which was most obvious in patients with DCM taking warfarin (EF 26.8+/-5.3 at baseline, 30.7+/-10 at 2 years, p<0.05). CONCLUSIONS: (1) Overall embolic events are rare in heart failure regardless of treatment. (2) Treatment does not seem to affect outcome.

Younger age potentiates post myocardial infarction survival disadvantage of women.

BACKGROUND: Female patients with acute myocardial infarction (MI) exhibit higher unadjusted in-hospital mortality rates compared to male patients. However, contradictory evidence exists on whether this survival disadvantage disappears after adjustment for age and other prognostic factors. This study, based on a countrywide survey of consecutive unselected patients with acute MI, examined whether female gender is an independent predictor of poor short-term outcome and less intensive in-hospital treatment. METHODS: Data on a total of 7433 patients were analyzed. RESULTS: The mean age was 64+/-13 years and the proportion of females in this population was 23%. Univariate and multivariate predictors of in-hospital mortality in female patients were estimated. Unadjusted in-hospital mortality rates of women were significantly higher compared to men (17.7 vs. 8.6, p<0.001). In multivariate analysis, female gender was an independent predictor of in-hospital mortality in the total population [relative risk (RR)=1.29, 95% confidence interval (CI)=1.02-1.64, p=0.036]. The RR of women for in-hospital death was exaggerated among younger patients, aged <55 years (RR=3.84, 95% CI=1.07-13.74, p=0.039). Female gender was also independently and inversely associated with administration of thrombolytic treatment (RR=0.724, 95% CI=0.630-0.831, p=<0.001). CONCLUSION: Although female gender is an independent predictor of higher post-MI in-hospital mortality with a pronounced effect among younger patients, women are less likely to receive thrombolysis than men. Based on the results from this countrywide study, we should consider women, especially of younger age, as patients at particular high risk, who contrary to common practice, deserve more intensive and aggressive in-hospital treatment.

Relation of microalbuminuria to adiponectin and augmented C-reactive protein levels in men with essential hypertension.

Microalbuminuria, and recently, hypoadiponectinemia, have been associated with progression of atherosclerotic disease and increased cardiovascular risk. We examined the possible associations of urinary albumin excretion, expressed as the ratio of albumin to creatinine (ACR), with plasma adiponectin and high-sensitivity C-reactive protein (hs-CRP) levels in men who had essential hypertension. The study population consisted of 108 men who did not have diabetes and were newly diagnosed with stage I to II essential hypertension (age 44.6 years, office blood pressure 148/95 mm Hg) and 110 men matched according to age and body mass index as controls. According to ACR values, which were determined as the average of 2 nonconsecutive overnight spot urine samples, subjects who had hypertension were categorized into 2 groups: those who had microalbuminuria (n = 28; mean ACR 30 to 300 mg/g) and those who had normal albuminuria (n = 80; mean ACR <30 mg/g). Subjects who had hypertension compared with controls exhibited higher ACR and log hs-CRP levels and a trend toward lower log adiponectin values (p = 0.062), whereas those who had normal albuminuria compared with controls had similar log adiponectin levels but significantly higher levels of ACR and log hs-CRP. Moreover, subjects who had hypertension and microalbuminuria compared with those who had hypertension and normal albuminuria had higher log hs-CRP and lower log adiponectin concentrations independently of confounding factors. Among those who had hypertension, ACR exhibited an independent positive correlation with log hs-CRP and a negative correlation with log adiponectin. Multiple linear regression analysis showed that age, body mass index, systolic blood pressure, log hs-CRP, and log adiponectin were significant independent predictors of the ACR. In conclusion, microalbuminuria is accompanied by decreased adiponectin and increased hs-CRP levels in the setting of essential hypertension, reflecting a rather diffuse atherosclerotic process.

Fish consumption and the risk of developing acute coronary syndromes: the CARDIO2000 study.

OBJECTIVE: The aim of this work was to investigate the association between fish consumption and the development of non-fatal acute coronary syndromes (ACS), in a Mediterranean population. METHODS: During 2000-2001, we randomly and stratified selected, from all Greek regions, 848 hospitalised patients (695 males, 58+/-10 years old and 153 females, 65+/-9 years old) who had a first event of ACS and 1078 paired, by region-sex-age, controls without any clinical symptoms or signs of coronary heart disease. RESULTS: On multivariate logistic regression analysis and, after controlling for several potential confounders, we found that fish consumption less than 150 g/week was associated with 38% lower odds of developing ACS as compared to no consumption (odds ratio=0.62, P-value<0.05). In contrast, moderate (150-300 g/week) and high (>300 g/week) fish consumption was not associated with the developing of the disease (odds ratios=1.10 and 1.01, respectively, P-value>0.1). The benefits from low fish consumption were also significant even amongst current smokers and diabetics. CONCLUSION: Moderate fish consumption was independently associated with a significant reduction in the odds of developing ACS. The strength and consistency of this finding has implications for public health and should be explored further.

Nondipping status does not attenuate the conjugated estrogen-induced improvement in aortic stiffness in postmenopausal women with untreated hypertension.

BACKGROUND: Whether the blunted nocturnal blood pressure (BP) fall alters the potential beneficial effects of estrogen replacement therapy (ERT) on arterial elastic properties in hypertensive postmenopausal women has not been clarified. The aim of this study was to determine the potential beneficial effects of ERT on arterial elastic properties and to investigate whether a blunted nocturnal BP fall could unfavorably modify the estrogen-induced alterations of large-artery stiffness in postmenopausal women with untreated essential hypertension. METHODS: A total of 66 postmenopausal women with untreated essential hypertension underwent carotid-femoral pulse wave velocity (PWV) measurements at baseline and after 12 weeks of ERT with 0.625 mg conjugated estrogen. By 24-h ambulatory BP monitoring, women were classified according to dipping status (nondippers, n = 21; dippers, n = 45). RESULTS: The two groups were similar regarding age, body mass index, time since menopause, and lipidemic profile. Initially, nondippers compared to dippers, although they had significantly greater office systolic BP (SBP), 24-h SBP, daytime SBP and night-time SBP (by 5, 2, 3, and 19 mm Hg, respectively, P < .05 for all cases), did not differ regarding left ventricular (LV) mass index and aortic PWV (116 v 114 g/m2 and 8.40 v 7.95 cm/sec, respectively, P = NS for both cases). Use of ERT, without affecting the office SBP and DBP, reduced significantly the aortic PWV in both nondippers and dippers (by 1.28 and 1.50 cm/sec, respectively, P < .05 for both cases). However, these PWV reductions were not different between the two groups (P = NS). A multivariate analysis identified patient age and 24-h SBP as significant determinants of estrogen-induced aortic PWV reduction (P < .05). CONCLUSIONS: A blunted nocturnal BP fall does not attenuate the estrogen-induced favorable modifications of large artery elastic properties in hypertensive postmenopausal women. Whether these findings suggest that hypertensive women with ERT-induced attenuation of PWV represent a specific clinical subgroup of patients with possible ERT-associated cardiovascular benefit remains to be determined by properly randomized trials.

Comparison of the effects of ramipril versus telmisartan in reducing serum levels of high-sensitivity C-reactive protein and oxidized low-density lipoprotein cholesterol in patients with type 2 diabetes mellitus.

The effect of ramipril (an angiotensin [AT]-converting enzyme inhibitor), telmisartan (an AT-II type 1 receptor blocker), or their combination on inflammation and lipid peroxidation was assessed in 37 patients with type 2 diabetes who were free of coronary artery disease. All regimens were associated with a significant reduction of C-reactive protein and oxidized low-density lipoprotein cholesterol serum levels (p <0.001). These results further enlighten the mechanisms underlying the cardiovascular beneficial effect of renin-AT system inhibition.

Lack of association between common polymorphisms in genes of the renin-angiotensin system and mortality after myocardial infarction.

The insertion/deletion (I/D) polymorphism in the ACE gene and the A1166C polymorphism in the AT1R gene have been associated with left ventricular remodelling and prognosis after acute myocardial infarction (AMI). We investigated whether these genetic variants associate with impaired left ventricular ejection fraction (LVEF) and increased risk for in-hospital mortality after AMI. Consecutive AMI patients were recruited on admission and were genotyped for the above-mentioned polymorphisms. The frequency of the studied genotypes did not differ significantly between deceased patients and those who survived. The LVEF did not differ among patients with or without the DD genotype (45 +/- 10 vs. 45 +/- 10%, p = 0.892) or the CC genotype (45 +/- 10 vs. 46 +/- 10%, p = 0.859). These data question the role of the studied genotypes in the pathogenesis of AMI and do not support the previously supported hypothesis that these genotypes influence prognosis after AMI.

Perforated aneurysm on the posterior leaflet of the mitral valve.

We present a case of a 71-year-old homeless diabetic man who was hospitalized due to bilateral cellulitis of the lower limbs. Because of severe calcific aortic stenosis, he had undergone valve replacement by a bioprosthesis 3 years earlier. Except from the two preadmission days, he reported no fever, malaise, or weight loss at any time after surgery. On examination, no specific signs or symptoms suggesting infective endocarditis were noted. After six blood cultures were taken, the patient was put on cloxacillin, clindamycin and gentamicin. All the six blood cultures were finally proven to be negative.

The paradoxical association of common polymorphisms of the renin-angiotensin system genes with risk of myocardial infarction.

BACKGROUND: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) and the A1166C polymorphism of the angiotensin-II AT1 receptor (AT1R) have been extensively investigated as possible risk factors for myocardial infarction (MI). DESIGN AND METHODS: Genetic association, case-control study, specifically designed to investigate the association of the above-mentioned polymorphisms with risk of MI in a homogeneous, low coronary risk, Caucasian population. The study population consisted of 1603 consecutive patients with acute MI who were recruited from nine clinics, located in three cities, and 699 unrelated adults who were randomly selected from the city catalogues. RESULTS: In univariate analysis, the DD genotype was found to be more prevalent among controls (40.8 vs. 35.2%, P=0.011). In multivariate analysis adjusted for age, gender, smoking status, diabetes mellitus, hypercholesterolaemia, hypertension and family history of coronary artery disease, the presence of the DD genotype was independently and negatively associated with risk of AMI (RR=0.743, 95% CI=0.595-0.927, P=0.008). The CC genotype was not found to be significantly associated with risk of MI, either in univariate (6.2 vs. 6.4%, P=0.856), or in multivariate analysis adjusted for the same confounders (RR=0.743, 95% CI=0.473-1.167, P=0.197). CONCLUSIONS: Contrary to previous reports, in this study the DD genotype of the ACE gene, but not the CC genotype of the AT1R gene, was associated with a lower risk of MI. Our results emphasize the complexity of genotype-phenotype interactions in the pathogenesis of ischaemic heart disease and question the previously hypothesized role of the DD genotype on risk of acute myocardial infarction.