Leonelo E. Bautista

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

BACKGROUND Obesity 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. METHODS We 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. FINDINGS BMI 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. INTERPRETATION Waist-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.

Homocysteine and stroke: evidence on a causal link from mendelian randomisation

BACKGROUND Individuals homozygous for the T allele of the MTHFR C677T polymorphism have higher plasma homocysteine concentrations (the phenotype) than those with the CC genotype, which, if pathogenetic, should put them at increased risk of stroke. Since this polymorphism is distributed randomly during gamete formation, its association with stroke should not be biased or confounded. We investigated consistency between the expected odds ratio for stroke among TT homozygotes, extrapolated from genotype-phenotype and phenotype-disease studies, and the observed odds ratio from a meta-analysis of genotype-disease association studies. METHODS We searched MEDLINE and EMBASE up to June, 2003, for all relevant studies on the association between homocysteine concentration and the MTHFR polymorphism, and until December, 2003, for those on the association between the polymorphism and the risk of stroke. Pooled odds ratios and 95% CI were calculated by random-effects and fixed-effects models. Consistency between expected and observed odds ratios was assessed by interaction test. FINDINGS 111 studies met the selection criteria. Among 15635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1.93 micromol/L (95% CI 1.38 to 2.47). The expected odds ratio for stroke corresponding to this difference based on previous observational studies was 1.20 (1.10 to 1.31). In our genetic meta-analysis (n=13928) the odds ratio for stroke was 1.26 (1.14 to 1.40) for TT versus CC homozygotes, similar to the expected odds ratio (p=0.29). Consistency between the odds ratios was preserved in analyses by age-group, ethnic background, and geographical location. INTERPRETATION The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant. This concordance is consistent with a causal relation between homocysteine concentration and stroke.

Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension

High blood pressure (HBP) has been associated with elevated C-reactive protein (CRP), a marker of chronic mild inflammation. However, the association between HBP and other inflammatory markers, particularly interleukin 6 (IL-6) and tumour necrosis alpha (TNF-α), has not been evaluated in well-controlled studies. We examined the cross-sectional relationship between IL-6, TNF-α, and CRP and HBP in a random sample of 196 healthy subjects. All markers were measured in duplicate with high-sensitivity ELISA tests. Three blood pressure (BP) measurments were averaged for the analysis, and subjects with systolic BP ⩾140 and/or diastolic BP ⩾90 mmHg were considered hypertensive. Log binomial regression was used to estimate multivariate-adjusted prevalence ratios (PR) of HBP. Of the subjects, 40% (79) were hypertensive (mean age: 44 years; range 30–64). After adjustment for age, sex, body mass index, family history of HBP, and the level of the other inflammatory markers, subjects in the second (PR: 3.10, P=0.003), third (PR: 2.32; P=0.031), and fourth quartiles (PR: 2.30; P=0.036) of IL-6 were more than twice as likely to be hypertensive than those in the first quartile. Corresponding PR estimates for TNF-α levels were 1.41 (P=0.014) for the second; 1.59 (P=0.001) for the third; and 1.61 (P=0.025) for the fourth quartile. The CRP–HBP association was not statistically significant. Our results suggest that TNF-α and IL-6 could be independent risk factors for HBP in apparently healthy subjects. Nevertheless, the temporal relationship between elevated inflammation markers and HBP should be ascertained in prospective cohort studies.

Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects

Background—Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may influence the risk of ischemic heart disease (IHD), but data from published studies with individually low statistical power are conflicting. To evaluate the role of polymorphisms in the eNOS gene in IHD, we considered all available studies in a meta-analysis. Methods and Results—Case-control studies evaluating the association between the Glu298Asp, −786T>C, and intron-4 polymorphisms and IHD were searched in MEDLINE and EMBASE up to January 2003. The principal prior hypothesis was that homozygosity for eNOS Asp298, the −786C allele in the promoter, or the intron-4 (a allele) would be associated with an increased risk of IHD. Data were available for 9867 cases and 13 161 controls from 26 studies. Homozygosity for the Asp298 was associated with an increased risk of IHD (OR, 1.31; 95% CI, 1.13 to 1.51). Although there was significant heterogeneity among studies of Asp298 (PHet=0.0002), which was largely accounted for by a single study, the increase in risk was still significant after exclusion of that study from analysis. Homozygosity for the intron-4 a allele was also significantly associated with higher risk of IHD (OR, 1.34; 95% CI, 1.03 to 1.75). However, no significant association was found with the −786C allele (OR, 1.06; 95% CI, 0.89, 1.25). Conclusions—Individuals homozygous for the Asp298 and intron-4 a alleles of eNOS are at moderately increased risk of IHD. These findings support the proposal that common genetic variations in the eNOS gene contribute to atherosclerosis susceptibility, presumably by effects on endothelial NO availability.

Risk Factors for Acute Myocardial Infarction in Latin America The INTERHEART Latin American Study

Background— Current knowledge of the impact of cardiovascular risk factors in Latin America is limited. Methods and Results— As part of the INTERHEART study, 1237 cases of first acute myocardial infarction and 1888 age-, sex-, and center-matched controls were enrolled from Argentina, Brazil, Colombia, Chile, Guatemala, and Mexico. History of smoking, hypertension, diabetes mellitus, diet, physical activity, alcohol consumption, psychosocial factors, anthropometry, and blood pressure were recorded. Nonfasting blood samples were analyzed for apolipoproteins A-1 and B-100. Logistic regression was used to estimate multivariate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Persistent psychosocial stress (OR, 2.81; 95% CI, 2.07 to 3.82), history of hypertension (OR, 2.81; 95% CI, 2.39 to 3.31), diabetes mellitus (OR, 2.59; 95% CI, 2.09 to 3.22), current smoking (OR, 2.31; 95% CI, 1.97 to 2.71), increased waist-to-hip ratio (OR for first versus third tertile, 2.49; 95% CI, 1.97 to 3.14), and increased ratio of apolipoprotein B to A-1 (OR for first versus third tertile, 2.31; 95% CI, 1.83 to 2.94) were associated with higher risk of acute myocardial infarction. Daily consumption of fruits or vegetables (OR, 0.63; 95% CI, 0.51 to 0.78) and regular exercise (OR, 0.67; 95% CI, 0.55 to 0.82) reduced the risk of acute myocardial infarction. Abdominal obesity, abnormal lipids, and smoking were associated with high population-attributable risks of 48.5%, 40.8%, and 38.4%, respectively. Collectively, these risk factors accounted for 88% of the population-attributable risk. Conclusions— Interventions aimed at decreasing behavioral risk factors, lowering blood pressure, and modifying lipids could have a large impact on the risk of acute myocardial infarction among Latin Americans.

Is C-reactive protein an independent risk factor for essential hypertension?

Context C-reactive protein (CRP), predicts coronary heart disease incidence in healthy subjects and has been associated with decreased endothelium-dependent relaxation, a potential risk factor for hypertension. However, the relationship between CRP and hypertension has not been studied. Objective To assess whether circulating levels of CRP are independently related to essential hypertension. Design Cross-sectional population survey. We measured circulating levels of CRP, blood pressure and cardiovascular risk factors among participants. Binomial regression was used to calculate the adjusted effect of CRP on the prevalence of hypertension. Setting General community of Bucaramanga, Colombia. Participants A random sample of 300 subjects ⩾ 30 years old. Main outcome measure Arterial blood pressure. Results Overall hypertension prevalence was 46.0%. The unadjusted prevalence of hypertension was 58.7% in the highest quartile of CRP, but only 34.7% in the lowest quartile. After adjustment for age, sex, body mass index, family history of hypertension, fasting glycemia, sedentary behaviour, and alcohol consumption, the prevalence of hypertension was 1.14 [95% confidence interval (CI), 0.82, 1.58;P = 0.442], 1.36 (95% CI, 0.99, 1.87;P = 0.057) and 1.56 (95% CI, 1.14, 2.13;P = 0.005) times higher in subjects in the second, third and fourth quartiles of CRP, as compared to subjects in the first quartile. Conclusions Our results suggest, for the first time, that CRP level may be an independent risk factor for the development of hypertension. However, because of the cross-sectional nature of our study, this finding should be confirmed in prospective cohort studies, aimed at elucidating the role of CRP in the prediction, diagnosis and management of hypertension.

Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials

Summary Background The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. Methods We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks). Findings The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, −0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. Interpretation In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. Funding Full funding sources listed at end of paper (see Acknowledgments).

Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies.

The role of homocysteine as a risk factor for cardiovascular disease remains controversial because positive reports from case-control studies may be the consequence of reverse causality bias, and positive and negative results have been reported in cohort studies. This is a meta-analysis of published cohort studies. An average relative risk (ARR) was calculated using fixed and random effect models. The likelihood of publication and selection bias, and the impact of each study on the ARR were also evaluated. Fourteen eligible studies were retrieved. We found no evidence of publication bias (P =.62) nor heterogeneity (P =.56). The ARRs from a fixed effect model were 1.49 (95% CI: 1.31-1.70) for cardiac events, and 1.37 (95% CI: 0.99- 1.99) for ischemic stroke. Duration of follow up and age did not significantly change the ARRs. Hyperhomocysteinemia moderately increases the risk of a first cardiovascular event, regardless of age and follow-up duration.

Indoor air pollution and blood pressure in adult women living in rural China.

Background: Almost half of the world’s population uses coal and biomass fuels for domestic energy. Limited evidence suggests that exposure to air pollutants from indoor biomass combustion may be associated with elevated blood pressure (BP). Objective: Our aim was to assess the relationship between air pollution exposure from indoor biomass combustion and BP in women in rural China. Methods: We measured 24-hr personal integrated gravimetric exposure to fine particles < 2.5 µm in aerodynamic diameter (PM2.5) and systolic BP (SBP) and diastolic BP (DBP) in the winter and summer among 280 women ≥ 25 years of age living in rural households using biomass fuels in Yunnan, China. We investigated the association between PM2.5 exposure and SBP and DBP using mixed-effects models with random intercepts to account for correlation among repeated measures. Results: Personal average 24-hr exposure to PM2.5 ranged from 22 to 634 µg/m3 in winter and from 9 to 492 µg/m3 in summer. A 1-log-µg/m3 increase in PM2.5 exposure was associated with 2.2 mm Hg higher SBP [95% confidence interval (CI), 0.8 to 3.7; p = 0.003] and 0.5 mm Hg higher DBP (95% CI, –0.4 to 1.3; p = 0.31) among all women; estimated effects varied by age group. Among women > 50 years of age, a 1-log-µg/m3 increase in PM2.5 exposure was associated with 4.1 mm Hg higher SBP (95% CI, 1.5 to 6.6; p = 0.002) and 1.8 mm Hg higher DBP (95% CI, 0.4 to 3.2; p = 0.01). PM2.5 exposure was positively associated with SBP among younger women, but the association was not statistically significant. Conclusion: PM2.5 exposure from biomass combustion may be a risk factor for elevated BP and hence for cardiovascular events. Our findings should be corroborated in longitudinal studies.

Patterns and predictors of personal exposure to indoor air pollution from biomass combustion among women and children in rural China.

UNLABELLED Indoor air pollution (IAP) from domestic biomass combustion is an important health risk factor, yet direct measurements of personal IAP exposure are scarce. We measured 24-h integrated gravimetric exposure to particles < 2.5 μm in aerodynamic diameter (particulate matter, PM₂.₅) in 280 adult women and 240 children in rural Yunnan, China. We also measured indoor PM₂.₅ concentrations in a random sample of 44 kitchens. The geometric mean winter PM₂.₅ exposure among adult women was twice that of summer exposure [117 μg/m³ (95% CI: 107, 128) vs. 55 μg/m³ (95% CI: 49, 62)]. Childrens geometric mean exposure in summer was 53 μg/m³ (95% CI: 46, 61). Indoor PM₂.₅ concentrations were moderately correlated with womens personal exposure (r=0.58), but not for children. Ventilation during cooking, cookstove maintenance, and kitchen structure were significant predictors of personal PM₂.₅ exposure among women primarily cooking with biomass. These findings can be used to develop exposure assessment models for future epidemiologic research and inform interventions and policies aimed at reducing IAP exposure. PRACTICAL IMPLICATIONS Our results suggest that reducing overall PM pollution exposure in this population may be best achieved by reducing winter exposure. Behavioral interventions such as increasing ventilation during cooking or encouraging stove cleaning and maintenance may help achieve these reductions.