Major Coronary Heart Disease Events Research Articles

Causal association of TSH with ischemic heart diseases and heart failure: A 2-sample Mendelian randomization study.

Thyroid dysfunction is associated with the risk of cardiovascular disease; however, whether plasma thyroid-stimulating hormone (TSH) levels in subjects with euthyroidism affect the risk of cardiovascular disease remains unclear. This study aimed to investigate the causal association between plasma TSH levels and cardiovascular diseases, particularly ischemic heart disease and heart failure (HF). Summary statistics from the Integrative Epidemiology Unit Open genome-wide association studies Project and FinnGen consortium were used to investigate the causal relationship between plasma TSH levels and the risk of cardiovascular diseases. Two-sample Mendelian randomization analysis using inverse-variance weighting as the primary method was performed. The MR Pleiotropy RESidual Sum and Outlier and leave-one-out methods were used to ensure the robustness of our findings. Genetically determined plasma TSH levels were associated with major coronary heart disease events (OR 1.0557, 95% CI 1.0141-1.0991), all-cause HF (OR 0.9587, 95% CI 0.9231-0.9956), and HF + non-ischemic cardiomyopathy (OR 0.9318, 95% CI 0.8786-0.9882). After the Bonferroni correction, the causation described above disappeared. In the secondary analysis, genetically determined higher TSH levels were associated with a higher risk for unstable angina pectoris (OR 1.0913, 95% CI 1.0350-1.1507), but were associated with a lower risk for HF + overweight (OR 0.9265, 95% CI 0.8821-0.9731). These results were further validated using sensitivity analysis. Our findings show that increased plasma TSH levels in patients with euthyroidism may increase the risk of unstable angina pectoris but reduce the risk of HF in overweight patients. This evidence indicates that plasma TSH levels may need to be carefully controlled in specific patients.

Heart rate variability and cardiovascular diseases: A Mendelian randomization study.

The causal relationship between heart rate variability and cardiovascular diseases and the associated events is still unclear, and the conclusions of current studies are inconsistent. We aimed to explore the relationship between heart rate variability and cardiovascular diseases and the associated events with the Mendelian randomization study. We selected normal-to-normal inter-beat intervals (SDNN), root mean square of the successive differences of inter-beat intervals (RMSSD) and peak-valley respiratory sinus arrhythmia or high-frequency power (pvRSA/HF) as the three sets of instrumental variables for heart rate variability. The outcome for cardiovascular diseases included essential hypertension, heart failure, angina pectoris, myocardial infarction, nonischemic cardiomyopathy and arrhythmia. Cardiac arrest, cardiac death and major coronary heart disease event were defined as the related events of cardiovascular diseases. The data for exposures and outcomes were derived from publicly available genome-wide association studies. Inverse variance weighted was used for the main causal estimation. Analyses of heterogeneity and pleiotropy were conducted using the Cochran Q test of Inverse variance weighted and MR-Egger, leave-one-out analysis, and MR-Pleiotropy Residual Sum and Outlier methods. The Inverse variance weighted method indicated that genetically predicted pvRSA/HF was associated with the increased risk of cardiac arrest (odds ratio 2.02, 95% confidence interval 1.25-3.28, p = .004). The results were free of heterogeneity and pleiotropy. There were no outliers and the leave-one-out analysis proved that the results were reliable. This study provides genetic evidence that pvRSA/HF is causally related to cardiac arrest.

Relationship between Calcium Score and Conventional Risk Factors in the Diagnosis of Atherosclerosis.

Background: The coronary artery calcium score has been established as a highly specific feature of coronary atherosclerosis. The present study aimed to assess the possible association of coronary artery risk factors involving atherosclerosis with the coronary artery calcification (CAC) scores using coronary computed tomographic angiography (CCTA). Methods: The present cross-sectional study, performed on 252 patients in need of CCTA during April 2019 and September 2019 at Farshchian hospital in Hamadan, Iran. The demographic information and risk factors were acquired from the files of patients. Furthermore, the CACs of patients were calculated and expressed as the Agatston score. Based on the Agatston scale, participants were divided into 4 CAC scores: zero (CAC = 0), mild (CAC = 1-99), moderate (CAC = 100-399), and severe (CAC ≥400). The association between possible coronary artery disease (CAD) risk variables and the CAC score was investigated using multinomial logistic regression. Results: Of 252 participants, approximately 40% of studied patients had a positive CAC score (CAC > 0). CAC significantly shifts toward higher scores in smokers, patients with diabetes, hypertension, and older patients. Mild (CAC = 1-99) and moderate CAC (100-399) were significantly associated with diabetes (odds ratio [OR], 3.26; 95% CI, 1.48-7.17) and (OR, 12; 95% CI, 4.40-32.71) for mild and moderate CAC, respectively. However, the strongest predictor for severe CAC was diabetes (OR, 7.72; 95% CI, 2.10-28.35). Conclusion: Coronary artery calcium scoring is a marker for risk factors associated with atherosclerosis. In this study, more than half of patients in CAC screening had CAC = 0. The strongest predictor of severe CAC>0 was smoking and diabetes. Regarding this association between health condition and CAC, determining the CAC can prevent major coronary heart disease events in these patients.

Genetic Predisposition to Coronavirus Disease 2019 in Relation to Ten Cardiovascular Conditions: A Two-Sample Mendelian Randomization Study.

BackgroundThe long-term health consequences of coronavirus disease 2019 (COVID-19) remain largely unclear. This study aimed to apply the Mendelian randomization (MR) design to estimate the causal associations between COVID-19 and ten cardiovascular conditions.MethodsSingle-nucleotide polymorphisms (SNPs) associated with COVID-19 were used as instrumental variables to estimate the causal effect of COVID-19 on ten cardiovascular conditions. The random-effects inverse-variance weighted (IVW) method was conducted for the main analyses with a complementary analysis of the weighted median and MR-Egger approaches.ResultsIn the IVW analysis, genetically predicted COVID-19 was suggestively associated with major coronary heart disease events (OR 1.081; 95% CI 1.007–1.16; P = 0.045) and heart failure (OR 1.049; 95% CI 1.001–1.1; P = 0.045) with similar estimates in weighted median regressions. No directional pleiotropic effects were observed in both funnel plots and MR-Egger intercepts.ConclusionsOur findings provide direct evidence that patients infected with COVID-19 are causally associated with increased risk of cardiovascular disease, especially for major coronary heart disease events and heart failure.

Coronary Artery Calcium Distribution Is an Independent Predictor of Incident Major Coronary Heart Disease Events: Results From the Framingham Heart Study.

The presence and extent of coronary artery calcium (CAC) are associated with increased risk for cardiovascular events. We determined whether information on the distribution of CAC and coronary dominance as detected by cardiac computed tomography were incremental to traditional Agatston score (AS) in predicting incident major coronary heart disease (CHD). We assessed total AS and the presence of CAC per coronary artery, per segment, and coronary dominance by computed tomography in participants from the offspring and third-generation cohorts of the Framingham Heart Study. The primary outcome was major CHD (myocardial infarction or CHD death). We performed multivariable Cox proportional hazards analysis and calculated relative integrated discrimination improvement. In 1268 subjects (mean age, 56.2±10.3 years, 63.2% men) with AS >0 and no history of major CHD, a total of 42 major CHD events occurred during median follow-up of 7.4 years. The number of coronary arteries with CAC (hazard ratio, 1.68 per artery; 95% confidence interval, 1.10-2.57; P=0.02) and the presence of CAC in the proximal dominant coronary artery (hazard ratio, 2.59; 95% confidence interval, 1.15-5.83; P=0.02) were associated with major CHD events after multivariable adjustment for Framingham risk score and categories of AS. In addition, measures of CAC distribution improved discriminatory capacity for major CHD events (relative integrated discrimination improvement, 0.14). Distribution of coronary atherosclerosis, especially CAC in the proximal dominant coronary artery and an increased number of coronary arteries with CAC, predict major CHD events independently of the traditional AS in community-dwelling men and women.

Significance of Comorbid Psychological Stress and Depression on Outcomes After Cardiac Rehabilitation

BackgroundDepression is associated with increased mortality in stable coronary heart disease. Cardiac rehabilitation and exercise training has been shown to decrease depression, psychological stress, and mortality after a coronary heart disease event. The presence of depression at completion of cardiac rehabilitation and exercise training is associated with increased mortality. However, it is unknown if depression with comorbid psychological risk factors such as anxiety or hostility confers an additional mortality disadvantage. We evaluated the mortality effect of anxiety and hostility on depression after cardiac rehabilitation and exercise training. Patients and MethodsWe studied 1150 patients with coronary heart disease following major coronary heart disease events who had completed formal cardiac rehabilitation and exercise training. Using Kellner questionnaires, stress levels were measured in 1 of 3 domains: anxiety, hostility, and depression (with an aggregated overall psychological stress score) and divided into 3 groups: nondepressed (n = 1072), depression alone (n = 18), and depression with anxiety or hostility (n = 60). Subjects were analyzed for all-cause mortality over 161 months of follow-up (mean 6.4 years) by National Death Index. ResultsDepression after cardiac rehabilitation was not common (6.8%; mortality 20.8%) but when present, frequently associated with either anxiety or hostility (77% of depressed patients; mortality 22.0%). After adjustment for age, sex, ejection fraction, and baseline peak oxygen consumption, depression alone (hazard ratio [HR] 1.73, P = .04), as well as depression with comorbid psychological stress, was associated with higher mortality (HR 1.98, P = .03). Furthermore, our data showed an increased mortality when both anxiety and hostility were present in addition to depression after cardiac rehabilitation (HR 2.41, P = .04). ConclusionsAfter cardiac rehabilitation, depression, when present, is usually associated with other forms of psychological stress, which confers additional mortality. More measures are needed to address psychological stress after cardiac rehabilitation.

Competing risk analysis of factors related to long-term incidence of CHD

BackgroundThe 5-year follow-up results for the 1202 middle-aged men prospective study of coronary heart disease (CHD) incidence were published in 1980. This paper extends the follow-up, relating the development of...

Dehydroepiandrosterone and its Sulfate Predict the 5-Year Risk of Coronary Heart Disease Events in Elderly Men

BackgroundThe adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory. ObjectivesThis study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men. MethodsWe used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers. ResultsDuring the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality. ConclusionsLow serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

Midregional proadrenomedullin and its change predicts recurrent major coronary events and heart failure in stable coronary heart disease patients: The LIPID study

BackgroundBiomarkers may contribute to risk stratification in coronary heart disease (CHD). We examined whether plasma midregional proadrenomedullin (MR-proADM) concentration at baseline and its change over one year predicts long-term outcomes in stable CHD patients. MethodsThe LIPID study randomised patients 3–36months after an acute coronary syndrome with total cholesterol 4.0–7.0mmol/L (155–271mg/dL), to placebo or pravastatin 40mg. Follow-up was 6.0years. MR-proADM plasma concentrations at baseline and one year later were determined in 7863 and 6658 patients, respectively. These were categorised into quartiles to perform Cox regression analysis, adjusting for baseline parameters. ResultsBaseline MR-proADM concentrations predicted major CHD events (non-fatal myocardial infarction or CHD death; hazard ratio (HR) 1.52, 1.26–1.84 for Q4–Q1), CHD death (HR 2.21, 1.67–2.92), heart failure (HR 2.30, 1.78–2.97) and all-cause mortality (HR 1.82, 1.49–2.23). Associations were still significant after adjustment for baseline B-type natriuretic peptide (BNP) concentration. Increase in MR-proADM after one year was associated with increased risk of subsequent CHD events (HR 1.34, 1.08–1.66), non-fatal myocardial infarction (HR 1.50, 1.12–2.03), heart failure (HR 1.78, 1.37–2.30) and all-cause mortality (HR 1.31, 1.04–1.64). Associations with heart failure and all-cause mortality remained significant after adjusting for baseline and change in BNP concentration. Change in MR-proADM moderately improved risk reclassification for major CHD events (net reclassification improvement (NRI) 3.48%) but strongly improved risk reclassification for heart failure (NRI 5.60%). ConclusionsBaseline and change in MR-proADM concentrations over one year are associated with risk of major clinical events, even after adjustment for BNP concentrations.

Abstract 18536: Performance of Framingham Risk Function With Coronary Artery Calcium in Predicting Major Coronary Events in an Asian Cohort

Background: In non-White populations, the original Framingham risk functions (FRF) overestimates coronary heart disease (CHD) risk and requires recalibration. We tested whether the inclusion of coronary artery calcium (CAC) can improve the performance of the FRF in CHD prediction in an asymptomatic Asian cohort. Methods: We determined risk factors, CAC burden and CV outcomes in a sample of 4502 asymptomatic South Koreans (from the registry-based ESCORT Study) and in 3141 asymptomatic Caucasian participants from the Framingham Heart Study (FHS). Primary endpoint was a composite of cardiovascular death, myocardial infarction, and unstable angina with revascularization. We assessed both the discriminatory value of the original FRF before and after the addition of CAC using area under the receiver operator characteristic (AUC) and the calibration/predictive ability using the D’Agostino-Nam Chi squared test for survival data, where a chi-square statistic > 20 indicates poor calibration. Results: There were 95 hard CHD events (45 ESCORT, 50 FHS) over a 55 month (ESCORT) and 60 month (FHS) follow-up period. For the FRF, the AUROC was 0.82, and the D’Agostino-Nam chi-squared statistic was 22.59 (p = 0.007) for predicting MACE in the ESCORT cohort. After the addition of CAC, the AUC improved to 0.85 and the D’Agostino-Nam chi-squared statistic improved to 16.14 (p = 0.064). The Caucasian-derived FRF model had poor predictive ability/calibration and consistently overestimated event rates in the Asian ESCORT cohort over all risk categories. For instance, in the 10th decile of risk, the predicted event rate using the FRF was 6% compared to an actual rate of 3.5% in the ESCORT cohort (Figure 1a) Conclusion: Addition of CAC to the classic Framingham risk functions significantly improves its performance in terms of discrimination and calibration in the prediction of major adverse CHD events in an Asian (South Korean) population.

Coronary heart disease differences across Europe

In the Seven Countries Study of Cardiovascular Diseases, 16 cohorts of middle-aged men were enrolled in eight nations of seven countries in three continents in the late 1950s and early 1960s for a total of 12 763 individuals. Thirteen cohorts were located in Europe, two in Finland, one in the Netherlands, three in Italy, two in Croatia - former Yugoslavia, three in Serbia - former Yugoslavia, and two in Greece. Another cohort was enrolled in the USA and two cohorts in Japan. Baseline prevalence of coronary heart disease (CHD) was largely different across areas, as well as 10-year incidence of major CHD events and CHD mortality for periods ranging from 25 to 40 years of follow-up. Higher rates were found in Northern Europe, lower rates in Southern Europe and intermediate rates in Eastern Europe, represented by Serbia. Differences across countries were partly explained by different entry mean levels of serum cholesterol, blood pressure, consumption of saturated fatty acids and adherence to traditional dietary patterns. Forty-year trends of CHD mortality were largely explained by early changes in serum cholesterol and blood pressure levels, with large risk increases in Serbia and Greece, and the tendency to declines in Finland and the Netherlands. These trends in Seven Countries' experience are in line with those manifests in official mortality data. An attempt of interpretation is presented pointing to socio-economic evolution in the involved countries, which heavily modifies health and dietary habits and contributes to explaining these differences at population level.

Nicotinic Acid

Nicotinic acid is back in the spotlight of controversy, and it therefore appears appropriate to consider its benefits and possible problems. Jackevicius et al have just published their concerns that per capita use of nicotinic acid in the United States far exceeds that in Canada, almost 6-fold by their calculation, with Niaspan as the main prescription product in both the countries. Apparently, their economic comparison and implied excess use in the United States were stimulated by 2 recent studies considered to cause uncertainty regarding nicotinic acid, the Atherothrombosis Intervention in Metabolic Syndrome with low HDL/ High Triglycerides: Impact on Global Health Outcomes (AIMHIGH) trial and the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2THRIVE) study. The AIM-HIGH trial reported that in patients with atherosclerotic cardiovascular (CV) disease already treated for a low-density lipoprotein cholesterol (LDL-C) level of 71 mg/dL (1.84 mmol/L), no incremental benefit occurred with the addition of nicotinic acid to statin therapy over 36 months, although significant improvements resulted in high-density lipoprotein cholesterol (HDL-C) and triglycerides. In HPS2THRIVE, nicotinic acid, combined with the antiflushing agent laropiprant, did not decrease CV risk further in the presence of statin therapy, and there was a question of increased risk of nonfatal but serious side effects. In the case of HPS2-THRIVE, the starting overall LDL-C was 1.64 mmol/L (63 mg/dL). Both of these studies involved patients on a statin with proven CV disease and essentially at the target for the high-CV risk patient of LDL-C <70 mg/dL. Showing significant benefit in this situation appears problematic, and possibly, the deck was stacked against nicotinic acid for showing more benefit due to the guideline LDL-C levels being already achieved on a statin. Nevertheless, such results must be put in context, analyzed, and debated. A National Lipid Association statement supports continued use of nicotinic acid as a statin adjunct, especially in patients with low HDL-C and high triglycerides, and points out that in the case of laropiprant in HPS2-THRIVE, the laropiprant may be a problematic factor. It is also appropriate to review that nicotinic acid has supportive evidence-based medicine, despite the current concerns. As can be summarized, there is ample evidence from multiple varied-approach studies of the benefit of a targeted reduction in LDL-C for CV disease prevention. Nicotinic acid can contribute to this LDL-C reduction in many situations. The Coronary Drug Project (CDP) was conducted between 1966 and 1975 and assessed the long-term efficacy and safety of 5 medications in men aged 30 to 64 years, with electrocardiogram-documented previous myocardial infarction (MI). At the end of the trial, nicotinic acid showed a modest benefit in decreasing definite nonfatal recurrent MI, but total mortality was not decreased. Nicotinic acid was discontinued at the end of the CDP. However, with a mean follow-up of 15 years, almost 9 years after the end of the CDP trial (the patients were not taking nicotinic acid during these 9 years after the CDP), the mortality in the nicotinic acid group was 11% lower than in the placebo group (52.0% vs 58.2%; P 1⁄4 .0004). In the Cholesterol Lowering Atherosclerosis Study using colestipol plus nicotinic acid, it was demonstrated by quantitative coronary angiography that coronary artery plaque regression is achievable with statistical significance. In a meta-analysis involving 11 clinical trials of nicotinic acid, including 9959 patients with nicotinic acid either used alone or combined with other lipid-lowering therapy, Lavigne and Karas calculated the odds ratio (OR) for CV disease events. Nicotinic acid use was associated with a significant decrease in combined end points of any CV disease event (OR: 0.66; 95% confidence interval [CI]: 0.49-0.89; P 1⁄4 .007) and major coronary heart disease (CHD) events (OR: 0.75; 95% CI: 0.59-0.96; P 1⁄4 .02). Nicotinic acid did not significantly alter the incidence of stroke, and the difference in HDL-C between treatment arms did not have a significant association with the extent of nicotinic acid effect on outcomes. In a combined analysis of 4 major studies that evaluated the effect of nicotinic acid on glucose levels, on coronary artery stenosis progression utilizing quantitative coronary angiography, and on various clinical events in a combined total of 407 patients, Phan et al found that nicotinic acid over 3 years was associated with increased blood glucose levels and an increased risk of an impaired fasting glucose but not actual diabetes mellitus.

Neutralizing the Adverse Prognosis of Coronary Artery Calcium

ObjectivesTo report and compare the outcomes and survival of patients with abnormal computed tomography–derived coronary artery calcium (CT-CAC) scores undergoing aggressive medical treatment at a cardiac prevention clinic. Patients and MethodsWe conducted a retrospective analysis of 849 patients with intermediate risk based on the Framingham risk score and an abnormal CT-CAC score who were aggressively treated in a preventive cardiology risk factor modification program from June 23, 2000, to September 1, 2012. The primary outcome was a composite end point of myocardial infarction, resuscitated cardiac arrest, revascularization, and cardiovascular death. The effect of the CT-CAC subgroup on major adverse coronary heart disease events (MACEs) was evaluated by calculating hazard ratios with Cox proportional hazards regression modeling. The Centers for Disease Control and Prevention Wonder database was used to identify age- and sex-matched controls from the general population of Kansas and Missouri. ResultsThe mean age of the study patients was 65.4 years (58.4% men [496]). The median follow-up was 58 months, and the mean CT-CAC score was 336 Agatston units. Thirty-four patients (4.0%) reached the primary end point, including 4 deaths. The adjusted 10-year mortality rates were similar in the study group and control group (9.3 vs 10.6; P=.80). After adjustment, a CT-CAC score greater than 400 Agatston units correlated with a higher risk of MACEs (hazard ratio, 3.55; P=.01). ConclusionThese results suggest that intermediate-risk patients with abnormal CT-CAC scores when treated with intensive risk factor reduction have lower rates of MACEs than predicted by the Framingham risk score and the presence of coronary artery calcium.

Correlation and Discrepancies Between Obesity by Body Mass Index and Body Fat in Patients With Coronary Heart Disease

Despite its many shortcomings, body mass index (BMI) is the most widely used screening tool for obesity, in part, because of its practicality. Other more physiologic measurements of obesity are based on body fat (BF). However, the correlation between BMI and BF has not been well-characterized, especially in patients with coronary heart disease (CHD). We retrospectively studied 581 patients with CHD following major CHD events, who were divided according to BMI (calculated as weight divided by height squared), based on the World Health Organization standard cutoff points (underweight [<18.5 kg/m], normal [≥18.5 and <25 kg/m], overweight [≥25 and <30 kg/m], and obese [≥30 kg/m]). Second, the population was divided according to BF, on the basis of the age- and gender-adjusted Gallagher BF classification into underweight, normal, overweight, and obese categories. Body mass index and percent BF correlated significantly (r = 0.60; P < .0001) and classified patients in the same category in about 59% of patients. In approximately 27% of the sample, BMI underestimated BF, while in about 14% of cases BMI overestimated BF. The relationship between BMI and BF was influenced by age, gender, and BMI itself. Even though a correlation exists between BMI and BF, they frequently classify individuals differently in a population of CHD patients. When defining overweight/obesity, care must be taken when using a crude screening tool such as BMI. While it is not expected for all clinicians to add BF assessments within routine patient assessments, the results of this study may be helpful to guide clinicians and researchers who are considering different aspects of body composition.

Physical Activity, Cardiorespiratory Fitness, and Exercise Training in Primary and Secondary Coronary Prevention

Substantial data have established that higher levels of physical activity (PA), participating in exercise training (ET), and higher overall cardiorespiratory fitness (CRF) provide considerable protection in the primary and secondary prevention of coronary heart disease (CHD). This review surveys data from epidemiological and prospective ET studies supporting the favorable impact of PA, ET, and CRF in primary CHD prevention. Clearly, cardiac rehabilitation and ET (CRET) programs have been underutilized for patients with CHD, particularly considering the effect of CRET on CHD risk factors, including CRF, obesity indices, fat distribution, plasma lipids, inflammation, and psychological distress, as well as overall morbidity and mortality. These data strongly support the routine referral of patients with CHD to CRET programs and that patients should be vigorously encouraged to attend CRET following major CHD events.

Most Important Outcomes Research Papers on Cardiovascular Disease in Women

Cardiovascular disease (CVD) in women has been historically understudied. For many years, heart disease had been thought to be primarily a “man’s disease.” Consequently, women have been significantly under-represented in longitudinal studies of disease history and in clinical trials. High-quality data from women at the extremes of age, with multiple co-morbidities, and from racial and ethnic minorities have been particularly rare. In order to increase awareness of cardiovascular prevention among women, in 1999 the American Heart Association (AHA) published its first women-specific clinical recommendations for the prevention of CVD.1 In 2004, the AHA and multiple other collaborating organizations subsequently sponsored “Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women,” which underwent updates in 2007 and 2011. As a result of these and other related initiatives, the rate of public awareness of CVD as the leading cause of death among US women has increased from 30% in 1997 to 54% in 2009.2 CVD-associated death among US women has declined significantly over this time period.3,4 Yet substantial work still needs to be done to improve women’s cardiovascular health. CVD remains the number one killer among women.4 As the obesity epidemic continues, we are actually finding increases in coronary heart disease (CHD) death among young women 35 to 54 years of age.2 Morbidity and mortality from stroke and hypertension remain high.4 In addition, substantial outcomes disparities continue for women from racial and ethnic minorities.4 We have therefore dedicated our topic summaries in this issue of Circulation: Cardiovascular Quality and Outcomes to CVD in women. We have included only those studies where authors provided a convincing a priori reason to study a particular disease process or clinical intervention in women and reported primary endpoints that were sex-specific. We have included articles on the representation of women …

The Current State of Niacin in Cardiovascular Disease Prevention

This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial. Previously available randomized clinical trial data assessing the clinical efficacy of niacin has been challenged by results from AIM-HIGH, which failed to demonstrate a reduction in CVD event incidence in patients with established CVD treated with niacin as an adjunct to intensive simvastatin therapy. Clinical trials of niacin, alone or combined with other lipid-altering therapy, were identified via MEDLINE. Odds ratios (ORs) for CVD endpoints were calculated with a random-effects meta-analyses. Meta-regression modeled the relationship of differences in on-treatment high-density lipoprotein cholesterol with the magnitude of effect of niacin on CVD events. Eleven eligible trials including 9,959 subjects were identified. Niacin use was associated with a significant reduction in the composite endpoints of any CVD event (OR: 0.66; 95% confidence interval [CI]: 0.49 to 0.89; p = 0.007) and major coronary heart disease event (OR: 0.75; 95% CI: 0.59 to 0.96; p = 0.02). No significant association was observed between niacin therapy and stroke incidence (OR: 0.88; 95% CI: 0.5 to 1.54; p = 0.65). The magnitude of on-treatment high-density lipoprotein cholesterol difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes. The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.

Abstract 2646: Haptoglobin 2 Allele Associates with Symptomatic Carotid Stenosis and Major Cardiovascular Events

Objectives: Haptoglobin (Hp) is a plasma protein which binds free hemoglobin (Hb) protecting tissues from iron-induced oxidative damage and promoting Hb clearance via macrophage CD163 receptor. There are two common alleles for Hp (Hp 1 and Hp 2), which influence it’s capacity to bind Hb and induce downstream signaling via CD163+ macrophages. We have previously shown that the CD163-heme oxygenase-1 (HO1) pathway is upregulated in symptomatic carotid stenosis (CS) and other groups have associated the Hp 2-2 genotype with cardiovascular complications in diabetics. Here, our objective was to study whether Hp polymorphism influences the risk of symptomatic CS and major cardiovascular events in the general population. Methods: We genotyped Hp polymorphism in 90 patients with a high-grade CS (≥ 70%) from Helsinki Carotid Endarterectomy Study (HeCES) and in 1426 individuals with carotid ultrasound examination data from the Health 2000 Survey, an epidemiological cross-sectional health survey carried out in Finland in the year 2000. Results: In the Health 2000 population, the Hp genotype frequencies were 0.170 (Hp 1-1), 0.445 (Hp 1-2) and 0.386 (Hp 2-2) consistent with Hardy-Weinberg equilibrium and with those reported from caucasian populations. In the CS patients, the genotype frequencies were skewed towards the Hp 2-2 genotype but not significantly. However, among the patients with symptomatic CS (ipsilateral TIA or stroke), the frequency of Hp 2-2 genotype was significantly higher than in the control population (0.528 vs 0.386, P =0.044). Hp genotypes correlated with HO1 protein expression in the plaque (r=0.46, P = 0.038) but not with iron. In the Health 2000 population, Hp 2 allele was associated with an increased risk of major cardiovascular events (major coronary heart disease event, ischemic stroke or TIA; 13.3% vs 8.3, P =0.032) and the increased risk was present regardless of diabetes. Hp 2 allele was not associated with carotid IMT or presence of plaques. Conclusions: Hp 2 allele associates with the risk of symptomatic CS and major ischemic cardiovascular events. This is likely due to the defective ability of Hp 2 to block oxidative reactions mediated by iron/heme, to clear free Hb present in intraplaque hemorrhages as well as the effects of the Hb-Hp 2 complex on intracellular signaling cascades via the CD163 receptor.

Cardiac Rehabilitation and Exercise Training in Secondary Coronary Heart Disease Prevention

Substantial evidence indicates that increased levels of physical activity, exercise training, and overall cardiorespiratory fitness provide protection in primary and secondary coronary heart disease (CHD) prevention. Clearly, cardiac rehabilitation and exercise training (CRET) programs have been greatly underused in patients with CHD. We review the benefits of formal CRET programs on CHD risk factors including exercise capacity, obesity indices, plasma lipids, inflammation, and psychosocial stress as well as overall morbidity and mortality. These data support the fact that patients with CHD, especially after major CHD events, need routine referral to CRET programs; and patients should be vigorously encouraged to attend these valuable programs.

Impact of Diabetes on Cardiovascular Disease Risk and All-Cause Mortality in Older Men

We have examined the influence of age at onset and duration on the impact of diabetes mellitus on cardiovascular disease risk and all cause-mortality among men aged 60 to 79 years. A prospective study of 4045 men aged 60 to 79 years followed up for a mean of 9 years, during which there were 372 major coronary heart disease (CHD) events (fatal and nonfatal myocardial infarction [MI]), 455 deaths from cardiovascular disease, and 1112 deaths from all causes. Men were classified as having (1) no history of MI and diabetes, (2) late-onset diabetes (diagnosed at ≥60 years or undiagnosed diabetes [fasting blood glucose level, >126.1 mg/dL]), (3) early-onset diabetes (diagnosed before age 60 years), or (4) prior MI. Men who had both MI and diabetes were excluded. Both early and late onset of diabetes were associated with a significantly increased risk of major CHD events and all-cause mortality compared with nondiabetic men who had no CHD, even after adjustment for conventional risk factors and novel risk markers (levels of C-reactive protein and von Willebrand factor and renal dysfunction). Only men with early-onset diabetes (associated with a duration of 16.7 years) showed risk similar to those with previous MI and no diabetes. The adjusted relative risks (95% confidence intervals) for major CHD events were 1.00 (reference), 1.54 (1.07-2.21), 2.39 (1.41-4.05), and 2.51 (1.88-3.36) for groups 1 through 4, respectively. Both early and late onset of diabetes are associated with increased risk of major CHD events and mortality, but only early onset of diabetes (associated with >10 years' duration) appears to be a CHD equivalent.