Traditional Cardiac Risk Factors Research Articles

Rheumatoid Arthritis: A Significant but Often Underestimated Risk Factor for Perioperative Cardiac Morbidity

Rheumatoid Arthritis: A Significant but Often Underestimated Risk Factor for Perioperative Cardiac Morbidity

The role of vitamin D in left ventricular hypertrophy and cardiac function

The role of vitamin D in left ventricular hypertrophy and cardiac function. Cardiovascular disease is the leading cause of death among patients with end-stage renal disease (ESRD). Traditional cardiac risk factors, as well as other factors specific to the ESRD population such as hyperphosphatemia, elevated calcium and phosphate product, abnormal lipid metabolism, hyperhomocysteinemia, and chronic inflammation play a role in the excessive risk of cardiovascular death in this population. Left ventricular disorders are proven risk factors for cardiac mortality in hemodialysis patients. These disorders are present in incident ESRD patients at rates far above the general population. There is an accumulating body of evidence that suggests that vitamin D plays a role in cardiovascular disease. Abnormal vitamin metabolism, through deficiency of the active form of 1,25-dihydroxyvitamin D(3), and acquired vitamin D resistance through the uremic state, have been shown to be important in ESRD. Vitamin D deficiency has long been known to affect cardiac contractility, vascular tone, cardiac collagen content, and cardiac tissue maturation. Recent studies using vitamin D receptor deficient mice as a model demonstrate a crucial role of vitamin D in regulation of the renin-angiotensin system. Additionally, there is emerging evidence linking treatment with vitamin D to improved survival on hemodialysis and improvement in cardiac function. The emergence of this data is focusing attention on the previously underappreciated nonmineral homeostatic effects of vitamin D that very likely play an important role in the pathogenesis of cardiac disease in ESRD.

Statin Therapy in Rheumatoid Arthritis

Rheumatoid arthritis, a chronic inflammatory polyarthritis that destroys synovial joints, is associated with systemic as well as local inflammation and with an increased risk of cardiovascular disease and death not fully explained by traditional cardiac risk factors. Statins (HMG-coA reductase inhibitors), medications originally designed to lower cholesterol, have been shown to have powerful effects on decreasing cardiovascular mortality rates in the general and high-risk populations. Not all of this protective benefit appears to be mediated by lowered cholesterol levels. Statins also influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide bioavailability, generation of free radicals, and angiogenesis. Recent studies show that statins may provide mild anti-inflammatory benefit in rheumatoid arthritis, in addition to reducing cardiovascular risk.

Stressful Life Events, Depression and Demoralization as Risk Factors for Acute Coronary Heart Disease

Background: While the effect of psychological stress and depression on the course of heart disease is commonly recognized, the relationship between recent life events, major depression, depressive symptomatology and the onset of acute coronary heart disease (CHD) has been less considered. The aim of this study was to investigate the presence of stressful life events, major and minor depression, recurrent depression and demoralization in the year preceding the occurrence of a first acute myocardial infarction (AMI) and/or a first episode of instable angina and to compare stressful life events, also related with mood disorders, in patients and healthy controls. Methods: 97 consecutive patients with a first episode of CHD (91 with AMI and 6 with instable angina) and 97 healthy subjects matched for sociodemographic variables were included. All patients were interviewed with Paykel’s Interview for Recent Life Events, a semistructured interview for determining the psychiatric diagnosis of mood disorders (DSM-IV), a semistructured interview for demoralization (DCPR). Patients were assessed while on remission from the acute phase. The time period considered was the year preceding the first episode of CHD and the year before the interview for controls. Results: Patients with acute CHD reported significantly more life events than control subjects (p < 0.001). All categories of events (except entrance events) were significantly more frequent. 30% of patients were identified as suffering from a major depressive disorder; 9% of patients were suffering from minor depression, 20% from demoralization. Even though there was an overlap between major depression and demoralization (12%), 17% of patients with major depression were not classified as demoralized and 7% of patients with demoralization did not satisfy the criteria for major depression. Independently of mood disorders, patients had a higher (p < 0.001) mean number of life events than controls. With regard to life events, the same significant difference (p < 0.001) compared to controls applied to patients with and without mood disorders. Conclusions: Our findings emphasize, by means of reliable methodology, the relationship between life events and AMI. These data, together with those regarding traditional cardiac risk factors, may have clinical and prognostic implications to be verified in longitudinal studies.

Novel serologic markers of cardiovascular risk

New serologic markers of cardiovascular risk continue to be amassed. Among the new markers, C-reactive protein, fibrinogen, and homocysteine have enjoyed the most acceptance, but newer concepts such as inflammatory cytokines, aspirin resistance, and antioxidant deficiency continue to emerge. Traditional cardiac risk factors are able to predict less than half of cardiovascular events, and the new array of markers have added little to clinical practice, with their use and significance remaining unclear. This article analyzes the new serologic markers of risk in light of the mechanistic, epidemiologic, and clinical data collected over the past decade, and in so doing provides a comprehensive understanding of their role.

Traditional Cardiac Risk Factors: The Gun Is Still Smoking

Traditional Cardiac Risk Factors: The Gun Is Still Smoking

Cardiac risk factor awareness and management in patients with systemic lupus erythematosus

To assess awareness and management of traditional cardiac risk factors (CRFs) in patients with systemic lupus erythematosus (SLE) and physicians. SLE patients (n=110) completed a questionnaire concerning CRFs. Medical records were reviewed blinded to questionnaire results for the presence and management of 6 CRFs: hypertension, hypercholesterolemia, smoking, obesity, diabetes mellitus, and physical inactivity. Subjects were predominantly female (97%), mean (+/-SD) age was 43.4 years (+/-11.8), mean SLE duration was 15.3 years (+/-7.2), and 51% had > or =2 CRFs by self report. Twenty-three percent had never had their cholesterol levels checked. Hypercholesterolemia was more frequently documented in the medical records than reported by the patient (33% versus 24%). Physical inactivity was more frequently self reported than documented (59% versus 23%). Rheumatologists and patients had low interrater reliability for the presence of hypercholesterolemia (kappa=0.26) and physical inactivity (kappa=-0.02). More than half (58%) of CRFs were treated, and 21% of subjects with elevated cholesterol received a medication. Recognition, recording, and management of CRFs falls short given the significance of the problem.

Toll–like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes

Background Coronary artery disease (CAD) and, increasingly, diabetes are recognized as having an inflammatory basis. Membrane toll-like receptors (TLRs) activate signaling pathways that up-regulate inflammation. We evaluated whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory responses, is associated with reduced vascular inflammation (assessed by C-reactive protein [CRP]) and a decreased risk for CAD and diabetes. Methods 1894 patients without acute myocardial infarction undergoing coronary angiography were studied. Genotyping was performed by real-time polymerase chain reaction. CAD was defined as ≥70% stenosis. Diabetes was diagnosed by patients' referring physicians. CRP was measured by fluorescence polarization immunoassay. Regression analyses adjusted for traditional cardiac risk factors. Results Patients averaged 64 ± 11 years of age, and 69% were male. Asp299Gly genotype frequencies were: AA = 0.911 (n = 1725), AG = 0.086 (n = 164), and GG = 0.003 (n = 5), in keeping with Hardy-Weinberg equilibrium. CRP was lower among G-allele carriers (median = 1.11 mg/dL) than wild-type (AA) subjects (1.23 mg/dL, adjusted P = .044). G-allele carriers also had a lower prevalence of CAD (65% vs. 73%, OR = 0.67, CI = 0.46–0.99, adjusted P = .048) and diabetes (11% vs. 18%, OR = 0.63, CI = 0.42–0.95, adjusted P = .029), which persisted in multivariate logistic regression analyses. 299Gly carriage did not affect clinical outcomes nor interact with statin therapy. Conclusions The TLR4 299Gly allele was associated with reduced CRP levels and, in parallel, a decreased risk of angiographic CAD and clinical diabetes. These findings suggest that down-regulation of innate immune responsiveness could beneficially modify CAD and diabetes risk and might provide a novel basis for genetic risk stratification and therapeutic targeting.

Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis

Various etiologic mechanisms have been implicated in the observed increase in cardiovascular mortality in rheumatoid arthritis (RA). Body mass index (BMI) is associated with cardiovascular mortality in the general population. This study compared the effect of BMI on cardiovascular mortality in a population-based cohort of subjects with RA with that in a cohort of individuals without RA from the same population. The RA cohort comprised all members of an incidence cohort of Rochester, Minnesota residents ages > or =18 years who were first diagnosed with RA (by the American College of Rheumatology 1987 criteria) from 1955 through 1994. An age- and sex-matched comparison cohort of subjects without RA was assembled. Both cohorts were followed up longitudinally through their complete (inpatient, outpatient) medical records beginning at age 18 years and continuing until death, migration, or January 1, 2001, and the details of weight and height changes during this period were recorded. High BMI was defined as a BMI >30 kg/m(2) and low BMI as <20 kg/m(2). Cox regression models were used to estimate the effect of BMI on cardiovascular mortality after accounting for traditional cardiac risk factors and malignancies. RA subjects with low BMI at incidence had a significantly higher risk of cardiovascular death (hazard ratio [HR] 3.34, 95% confidence interval [95% CI] 2.23-4.99) compared with non-RA subjects with normal BMI, after adjusting for age, sex, personal cardiac history, smoking status, and presence of diabetes, hypertension, and malignancies. RA subjects with normal BMI at incidence who experienced low BMI during followup also had a higher risk of cardiovascular death (HR 2.09, 95% CI 1.50-2.92) when compared with non-RA subjects who maintained normal BMI throughout followup. Among patients with RA, low BMI is associated with a significantly increased risk of cardiovascular death.

Knowledge of heart disease among women in an urban emergency setting

Study objectives: We examine the hypothesis that a lack of knowledge about heart disease may contribute to the higher prevalence of heart disease–related illnesses in women in urban areas by decreasing their likelihood to make appropriate lifestyle changes. Methods: This was a prospective survey of 224 women presenting to an urban emergency department. All study patients were surveyed about their knowledge of heart disease and associated risk factors. Results: Two hundred patients correctly completed the surveys. Only 25 (13%) women correctly identified heart disease as the leading cause of death in women. Similarly, only 12 (6%) women surveyed thought that heart disease was the greatest health issue facing women today. The majority of women believed that breast cancer was the most important health issue and responsible for the greatest mortality in women. Only 3 of the traditional cardiac risk factors were correctly identified by half of the women surveyed: hypercholesteremia (56%); hypertension (54%); and tobacco use (52%). Family history was correctly identified by 44%, and only 20% of women thought that diabetes was a risk factor for cardiovascular disease. Conclusion: Despite increased medical education and media time spent on women's health issues, up to 87% of women in this urban population did not know the leading cause of death for their sex and therefore are less likely to make important lifestyle modifications to decrease their risk of cardiovascular disease.

Pulmonary hypertension in rheumatoid arthritis

Using Doppler echocardiography (DE), we measured pulmonary arterial systolic pressure (PASP) in rheumatoid arthritis (RA) patients without coexisting cardiopulmonary diseases. Accepting the normal upper limit of PASP as 30 mmHg, we found elevated PASP in 11 out of 40 (27.5%) RA patients, values being mostly 30–40 mmHg, indicating mild pulmonary hypertension (PHT). Although estimation of PASP by DE is not as reliable as cardiac catheterisation, it is possible that mild elevations in PASP may contribute to the high incidence of cardiovascular events not explained by traditional cardiac risk factors in patients with RA. Long‐term follow‐up will be obviously necessary to ascertain the impact of mild PHT on the prognosis and mortality rate of RA patients.

Risk factors and outcomes in patients with coronary artery aneurysms

Previous small series have provided conflicting data on the association between coronary artery aneurysms and traditional cardiac risk factors, as well as limited information on patient outcomes. This investigation sought to determine whether the presence of coronary artery aneurysms has an adverse affect on patient outcomes. The results show that coronary aneurysms were an independent predictor of mortality, and overall 5-year survival in patients with aneurysms was only 71%. We believe that clinicians should aggressively monitor and modify coronary risk factors in patients with coronary aneurysms.

Association of total and central obesity with mortality in postmenopausal women with coronary heart disease.

Overweight and abdominal obesity increase mortality risk, although the risk may be mediated by traditional cardiac risk factors. The authors assessed the association of baseline measures, change in overall body weight and abdominal obesity (waist circumference), and weight and waist circumference cycling with total mortality among postmenopausal women with known heart disease. They used data from 2,739 US women who participated in the Heart and Estrogen/progestin Replacement Study between 1993 and 2001. Over 6.8 years of follow-up, 498 women died. In adjusted Cox models that included either baseline waist circumference or body mass index (BMI), each was associated with mortality. However, after further adjustment for diabetes, hypertension, and lipoproteins, these associations disappeared. In models including both waist circumference and BMI, larger waist circumference (hazard ratio=1.40 per standard deviation, 95% confidence interval: 1.16, 1.68) was associated with increased risk and higher BMI (hazard ratio=0.81 per standard deviation, 95% confidence interval: 0.67, 0.97) was associated with decreased risk of total mortality, independent of cardiac risk factors. Weight and waist circumference cycling were not associated with mortality. Results show that both BMI and waist circumference are associated with mortality among postmenopausal women with established heart disease, but waist circumference may be more important than BMI, and their effects may be largely mediated by other cardiac risk factors.

Long-term follow-up of coronary artery disease presenting in young adults

ObjectivesThis study evaluated long-term survival and predictors of elevated risk for young adults diagnosed with coronary artery disease (CAD). BackgroundCoronary artery disease is rarely seen in young adults. Traditional cardiac risk factors have been studied in small series; however, many questions exist. MethodsWe identified 843 patients under age 40 with CAD diagnosed by coronary angiography from 1975 to 1985. Death, hypertension, gender, family history, prior myocardial infarction (MI), diabetes, heart failure, angina class, number of diseased vessels, ejection fraction (EF), Q-wave infarction, in-hospital death, and initial therapy were studied. Patients were followed for 15 years. ResultsThe mean age was 35 for women (n = 94) and 36 for men (n = 729). The average EF was 55%. Fifty-eight percent of the subjects had single-vessel disease, and 10% were diabetic. The strongest predictors of long-term mortality were a prior MI (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.00 to 1.73), New York Heart Association class II heart failure (HR 1.75, 95% CI 1.03 to 2.97), and active tobacco use (HR 1.59, 95% CI 1.14 to 2.21). Revascularization, rather than medical therapy, was associated with lower mortality (coronary angioplasty: HR 0.51, 95% CI 0.32 to 0.81; coronary artery bypass graft: HR 0.68, 95% CI 0.50 to 0.94). Overall mortality was 30% at 15 years. Patients with diabetes had 15-year mortality of 65%. Those with prior MI had 15-year mortality of 45%, and patients with an EF <30% a mortality of 83% at 15 years. ConclusionsCoronary disease in young adults can carry a poor long-term prognosis. A prior MI, diabetes, active tobacco abuse, and lower EF predict a significantly higher mortality.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors.

To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors. Two hundred thirty-six consecutive patients with RA were assessed for the 1-year occurrence of 1) CV-related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8-year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25-65 years at study entry. We calculated the age- and sex-stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index. Of the 236 RA patients, 234 were observed for 252 patient-years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient-years contributed by patients ages 25-65 years, for an incidence of 3.43 per 100 patient-years. In the comparison cohort, 4,635 community-dwelling persons were followed up for 33,881 person-years, during which 200 new events occurred, for an incidence of 0.59 per 100 person-years. The age- and sex-adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86-8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33-6.36). The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors

To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors.Two hundred thirty-six consecutive patients with RA were assessed for the 1-year occurrence of 1) CV-related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8-year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25-65 years at study entry. We calculated the age- and sex-stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index.Of the 236 RA patients, 234 were observed for 252 patient-years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient-years contributed by patients ages 25-65 years, for an incidence of 3.43 per 100 patient-years. In the comparison cohort, 4,635 community-dwelling persons were followed up for 33,881 person-years, during which 200 new events occurred, for an incidence of 0.59 per 100 person-years. The age- and sex-adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86-8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33-6.36).The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors

USING THE FRAMINGHAM DATABASE TO PREDICT CORONARY HEART DISEASE (CHD) EVENTS IN RENAL TRANSPLANT PATIENTS

853 Cardiovascular disease is the single most significant cause of death in end-stage renal disease (ESRD). The utilization of cardiac risk factors in the general population as predictors for coronary heart disease (CHD) events in a patient undergoing renal transplantation has not been described. Andersen et al. developed a Framingham heart study equation to predict the probability of CHD events using the traditional cardiac risk factors (age, gender, systolic BP (SBP), total cholesterol (Chol), HDL, tobacco use, diabetes [DM], and LVH). Our goal was to examine the applicability of the Framingham CHD risk profile in ESRD patients at the time of renal transplantation. 249 patients (pts) from a single-center renal transplant (Tx) program were analyzed. All pts underwent renal Tx in the calendar year 1995. 214 (86%) underwent 1° renal Tx (49% cadaveric, 26% living-donor, and 22% kidney-pancreas). Average f/u was 3.4 years. The population, with a mean age of 40.7±13 yrs, was 60% male. Average SBP was 139±18.3 mmHg, total Chol 229±55.3 mg/dl, and HDL was 58.4±22.5 mg/dl. 23% of the pts were smokers, 21% had LVH on baseline electrocardiogram and 41% of pts had DM. 10% of the cohort had pre-Tx CHD. 29 pts (11.6%) experienced a post-Tx CHD event defined as angina, CHF, acute MI, cardiac arrest, or sudden death. This was significantly greater than the expected CHD event rate computed for the general population without preexisting heart disease (7.02/249;2.7%), reflecting a 3.8-fold increase in CHD risk in our Tx pt population (p<0.001). The risk of a CHD event was highest in the early post-Tx period. Univariate analyses showed that age (p=0.01), creatinine at discharge (p=0.04), and pretransplant CHD (p=0.004) were associated with post-Tx CHD events. Multivariate analysis demonstrated that pre-Tx CHD (p=0.04) was the only variable predictive of a post-Tx CHD event. Other variables including gender, SBP, diabetes, smoking, LVH, Chol, or HDL were not independently predictive of post-Tx CHD events. Despite underestimating the incidence, the Framingham equation predicted 4-yr risk was highly associated with the hazard of CHD in Tx pts (p=0.0028, Cox prop. hazards). This analysis confirms the increased incidence of CHD events in renal Tx patients. The Framingham risk model appears to be a useful tool in identifying Tx pts at risk for CHD events. For assessing short-term (<5 years) risk however, the calculated result should be multiplied by a factor of 3.8 to obtain a more accurate prediction of a post-Tx CHD event.

Educational Attainment, Anger, and the Risk of Triggering Myocardial Infarction Onset

<h3>Background:</h3> While it has recently been shown that anger may trigger the onset of acute myocardial infarction, there has been no study of the role of socioeconomic factors in such triggering. Socioeconomic factors, such as educational attainment, may modulate the risk of triggering because of their influence on individual reactivity to external stressors and on the prevalence of traditional cardiac risk factors. <h3>Objective:</h3> To evaluate the influence of educational attainment on the relative risk of myocardial infarction onset following episodes of anger. <h3>Methods:</h3> We interviewed 1623 patients (501 women) an average of 4 days following a myocardial infarction. Data were collected on standard demographic variables as well as risk factors for coronary artery disease. Educational attainment was categorized into 3 levels: less than high school, completed high school, and at least some college. Anger was assessed by the Onset Anger Scale, a single-item, 7-level, self-report scale. Occurrence of anger in the 2 hours preceding the onset of myocardial infarction was compared with its expected frequency using self-matched control data based on the casecrossover study design. <h3>Results:</h3> The risk of having a myocardial infarction triggered by isolated episodes of anger declined consistently and significantly with increasing levels of educational attainment (P=.03). The relative risk was twice as high among those with less than high school education (relative risk, 3.3; 95% confidence interval, 2.0-5.4) compared with patients with at least some college education (relative risk, 1.6; 95% confidence interval, 0.9-2.9). <h3>Conclusions:</h3> These findings indicate that socioeconomic factors are potent modulators of the risk of triggering acute cardiovascular disease onset. A better understanding of the physiological mechanisms underlying this association may lead to novel approaches to prevent acute cardiovascular events. Arch Intern Med. 1997;157:769-775

Educational attainment, anger, and the risk of triggering myocardial infarction onset. The Determinants of Myocardial Infarction Onset Study Investigators

While it has recently been shown that anger may trigger the onset of acute myocardial infarction, there has been no study of the role of socioeconomic factors in such triggering. Socioeconomic factors, such as educational attainment, may modulate the risk of triggering because of their influence on individual reactivity to external stressors and on the prevalence of traditional cardiac risk factors. To evaluate the influence of educational attainment on the relative risk of myocardial infarction onset following episodes of anger. We interviewed 1623 patients (501 women) an average of 4 days following a myocardial infarction. Data were collected on standard demographic variables as well as risk factors for coronary artery disease. Educational attainment was categorized into 3 levels: less than high school, completed high school, and at least some college. Anger was assessed by the Onset Anger Scale, a single-item, 7-level, self-report scale. Occurrence of anger in the 2 hours preceding the onset of myocardial infarction was compared with its expected frequency using self-matched control data based on the case-crossover study design. The risk of having a myocardial infarction triggered by isolated episodes of anger declined consistently and significantly with increasing levels of educational attainment (P = .03). The relative risk was twice as high among those with less than high school education (relative risk, 3.3; 95% confidence interval, 2.0-5.4) compared with patients with at least some college education (relative risk, 1.6; 95% confidence interval, 0.9-2.9). These findings indicate that socioeconomic factors are potent modulators of the risk of triggering acute cardiovascular disease onset. A better understanding of the physiological mechanisms underlying this association may lead to novel approaches to prevent acute cardiovascular events.