Sonia S. Anand

Obesity and the risk of myocardial infarction in 27 000 participants from 52 countries: a case-control study

BACKGROUNDnObesity is a major risk factor for cardiovascular disease, but the most predictive measure for different ethnic populations is not clear. We aimed to assess whether markers of obesity, especially waist-to-hip ratio, would be stronger indicators of myocardial infarction than body-mass index (BMI), the conventional measure.nnnMETHODSnWe did a standardised case-control study of acute myocardial infarction with 27 098 participants in 52 countries (12,461 cases and 14,637 controls) representing several major ethnic groups. We assessed the relation between BMI, waist and hip circumferences, and waist-to-hip ratio to myocardial infarction overall and for each group.nnnFINDINGSnBMI showed a modest and graded association with myocardial infarction (OR 1.44, 95% CI 1.32-1.57 top quintile vs bottom quintile before adjustment), which was substantially reduced after adjustment for waist-to-hip ratio (1.12, 1.03-1.22), and non-significant after adjustment for other risk factors (0.98, 0.88-1.09). For waist-to-hip ratio, the odds ratios for every successive quintile were significantly greater than that of the previous one (2nd quintile: 1.15, 1.05-1.26; 3rd quintile: 1.39; 1.28-1.52; 4th quintile: 1.90, 1.74-2.07; and 5th quintiles: 2.52, 2.31-2.74 [adjusted for age, sex, region, and smoking]). Waist (adjusted OR 1.77; 1.59-1.97) and hip (0.73; 0.66-0.80) circumferences were both highly significant after adjustment for BMI (p<0.0001 top vs bottom quintiles). Waist-to-hip ratio and waist and hip circumferences were closely (p<0.0001) associated with risk of myocardial infarction even after adjustment for other risk factors (ORs for top quintile vs lowest quintiles were 1.75, 1.33, and 0.76, respectively). The population-attributable risks of myocardial infarction for increased waist-to-hip ratio in the top two quintiles was 24.3% (95% CI 22.5-26.2) compared with only 7.7% (6.0-10.0) for the top two quintiles of BMI.nnnINTERPRETATIONnWaist-to-hip ratio shows a graded and highly significant association with myocardial infarction risk worldwide. Redefinition of obesity based on waist-to-hip ratio instead of BMI increases the estimate of myocardial infarction attributable to obesity in most ethnic groups.

Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

CONTEXTnPlasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.nnnOBJECTIVEnTo investigate association of genetic loci with CRP levels and risk of coronary heart disease.nnnDESIGN, SETTING, AND PARTICIPANTSnWe first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.nnnMAIN OUTCOME MEASUREnRisk of coronary heart disease.nnnRESULTSnPolymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.nnnCONCLUSIONnThe lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

Cardiovascular Risk and Events in 17 Low-, Middle-, and High-Income Countries

BACKGROUNDnMore than 80% of deaths from cardiovascular disease are estimated to occur in low-income and middle-income countries, but the reasons are unknown.nnnMETHODSnWe enrolled 156,424 persons from 628 urban and rural communities in 17 countries (3 high-income, 10 middle-income, and 4 low-income countries) and assessed their cardiovascular risk using the INTERHEART Risk Score, a validated score for quantifying risk-factor burden without the use of laboratory testing (with higher scores indicating greater risk-factor burden). Participants were followed for incident cardiovascular disease and death for a mean of 4.1 years.nnnRESULTSnThe mean INTERHEART Risk Score was highest in high-income countries, intermediate in middle-income countries, and lowest in low-income countries (P<0.001). However, the rates of major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) were lower in high-income countries than in middle- and low-income countries (3.99 events per 1000 person-years vs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Case fatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3% in high-, middle-, and low-income countries, respectively; P=0.01). Urban communities had a higher risk-factor burden than rural communities but lower rates of cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) and case fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medications and revascularization procedures was significantly more common in high-income countries than in middle- or low-income countries (P<0.001).nnnCONCLUSIONSnAlthough the risk-factor burden was lowest in low-income countries, the rates of major cardiovascular disease and death were substantially higher in low-income countries than in high-income countries. The high burden of risk factors in high-income countries may have been mitigated by better control of risk factors and more frequent use of proven pharmacologic therapies and revascularization. (Funded by the Population Health Research Institute and others.).

Sensitivity and Specificity of the Ankle–Brachial Index to Predict Future Cardiovascular Outcomes: A Systematic Review

Objective—The ankle–brachial index is the ratio of the ankle and the brachial systolic blood pressure and is used to assess individuals with peripheral arterial disease. An ankle–brachial index <0.90 suggests the presence of peripheral arterial disease and is a marker of cardiovascular risk. The objective of this review is to determine the sensitivity and specificity of an ankle–brachial index <0.90 to predict future cardiovascular events, including coronary heart disease, stroke, and death. Methods and Results—We conducted a systematic review of the literature and included studies that used an ankle–brachial index cutoff between 0.80 and 0.90 to classify patients with or without peripheral arterial disease, followed patients prospectively, and recorded cardiovascular outcomes (ie, myocardial infarction, stroke, or mortality). Data were combined using a random-effects model meta-analysis to determine the sensitivity, specificity, relative risks, and likelihood ratios of a low ankle–brachial index to predict future cardiovascular disease. A total of 22 studies were identified, 13 were excluded, and 9 studies were included in the meta-analysis. The sensitivity and specificity of a low ankle–brachial index to predict incident coronary heart diseases were 16.5% and 92.7%, for incident stroke were 16.0% and 92.2%, and for cardiovascular mortality were 41.0% and 87.9%, respectively. The corresponding positive likelihood ratios were 2.53 (95% CI, 1.45 to 4.40) for coronary heart disease, 2.45 (95% CI, 1.76 to 3.41) for stroke, and 5.61 (95% CI, 3.45 to 9.13) for cardiovascular death. Conclusion—The specificity of a low ankle–brachial index to predict future cardiovascular outcomes is high, but its sensitivity is low. The ankle–brachial index should become part of the vascular risk assessment among selected individuals.

Ethnic differences in the relationships between obesity and glucose-metabolic abnormalities: a cross-sectional population-based study.

OBJECTIVES:To evaluate whether body mass index (BMI) and other anthropometric indices of visceral obesity vary by ethnic group in their distribution and their relationship to metabolic abnormalities.DESIGN:Cross-sectional study.PARTICIPANTS:Canadian men and women, aged 35–75 years, of South Asian (n=342), Chinese (n=317), European (n=326) and Aboriginal (n=301) descent were recruited using stratified random sampling.PRIMARY MEASURES:Anthropometric indices (BMI, waist to hip ratio (WHR) and waist circumference (WC)), metabolic markers (fasting glucose, HbA1c, the ratio of total cholesterol/HDL) and clinical markers (systolic blood pressure) were assessed.RESULTS:In subjects with BMI<30u2009kg/m2, the mean marker levels in people with elevated WC (>88u2009cm in women, >102u2009cm in men) vs people with normal WC were 6.16 vs 5.34u2009mmol/l for fasting glucose, 6.05 vs 5.66% for HbA1c and 5.46 vs 4.68 for the ratio of total cholesterol to HDL (P<0.001 in each case). At nearly every given level of BMI, non-European ethnic groups displayed significantly higher marker levels than Europeans. For example, for a given BMI, age and sex, the difference between European and non-European groups in HbA1c levels was 0.53% (95% confidence interval (CI): 0.37–0.69) for South Asians, 0.37% (95% CI: 0.2–0.54) for Chinese and 0.95% (95% CI: 0.78–1.12) for Aboriginal People.CONCLUSIONS:Uniform cut-points for the classification of obesity using BMI, WHR or WC result in marked variation in the levels of glucose-metabolic abnormalities between ethnic groups. Existing action thresholds for these anthropometric indices do not apply to non-European ethnic groups and warrant revision.

Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease.

Estimating modifiable coronary heart disease risk in multiple regions of the world: the INTERHEART Modifiable Risk Score

AIMSnSummating risk factor burden is a useful approach in the assessment of cardiovascular risk among apparently healthy individuals. We aimed to derive and validate a new score for myocardial infarction (MI) risk using modifiable risk factors, derived from the INTERHEART case-control study (n = 19 470).nnnMETHODS AND RESULTSnMultiple logistic regression was used to create the INTERHEART Modifiable Risk Score (IHMRS). Internal validation was performed using split-sample methods. External validation was performed in an international prospective cohort study. A risk model including apolipoproteins, smoking, second-hand smoke exposure, hypertension, and diabetes was developed. Addition of further modifiable risk factors did not improve score discrimination in an external cohort. Split-sample validation studies showed an area under the receiver-operating characteristic (ROC) curve c-statistic of 0.71 [95% confidence interval (CI): 0.70, 0.72]. The IHMRS was positively associated with incident MI in a large cohort of people at low risk for cardiovascular disease [12% increase in MI risk (95% CI: 8, 16%) with a 1-point increase in score] and showed appropriate discrimination in this cohort (ROC c-statistic 0.69, 95% CI: 0.64, 0.74). Results were consistent across ethnic groups and geographic regions. A non-laboratory-based score is also supplied.nnnCONCLUSIONSnUsing multiple modifiable risk factors from the INTERHEART case-control study, we have developed and validated a simple score for MI risk which is applicable to an international population.

Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies

BACKGROUNDnSeveral studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status.nnnMETHODSnIn this pooled analysis, we studied 133,118 individuals (63,559 with hypertension and 69,559 without hypertension), median age of 55 years (IQR 45-63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4.2 years (IQR 3.0-5.0) and blood pressure.nnnFINDINGSnIncreased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2.08 mm Hg change per g sodium increase) compared with individuals without hypertension (1.22 mm Hg change per g; pinteraction<0.0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 1.23 [95% CI 1.11-1.37]; p<0.0001) and less than 3 g/day (7006 [11%] of population with hypertension: 1.34 [1.23-1.47]; p<0.0001) were both associated with increased risk compared with sodium excretion of 4-5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4-5 g/day (18,508 [27%] of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (≥ 7 g/day in 6271 [9%] of the population without hypertension; HR 0.90 [95% CI 0.76-1.08]; p=0.2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 [11%] of the population without hypertension; HR 1.26 [95% CI 1.10-1.45]; p=0.0009).nnnINTERPRETATIONnCompared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets.nnnFUNDINGnFull funding sources listed at end of paper (see Acknowledgments).

Oral anticoagulants in patients with coronary artery disease.

Oral anticoagulants have been used in patients with vascular disease for over 40 years, yet their role in the secondary prevention of recurrent cardiovascular (CV) events remains controversial. The objectives of this systematic review are to more reliably determine the role of oral anticoagulants with and without antiplatelet therapy in patients with established coronary artery disease (CAD). Randomized trials in which oral anticoagulants were tested in CAD patients who were treated for at least three months were identified, and each trial was classified by the targeted level of intensity of anticoagulation. Data from the trials were combined using the modified Mantel-Haenszel method, and odds ratios were computed. Data from over 20,000 patients indicated that high-intensity oral anticoagulation (international normalized ratio [INR] >2.8) significantly reduced CV complications and increased bleeding compared with controls. Moderate-intensity oral anticoagulation (INR 2 to 3) also reduced CV complications compared with controls. The combination of moderate-intensity oral anticoagulation and aspirin is more effective and equally as safe as aspirin alone. Low-intensity oral anticoagulation (INR <2) in the presence of aspirin does not reduce CV complications and increases bleeding compared with aspirin alone.

Polygenic determinants of severe hypertriglyceridemia

Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects.