Lyle G. Best

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Haptoglobin Phenotype Is an Independent Risk Factor for Cardiovascular Disease in Individuals With Diabetes: The Strong Heart Study

OBJECTIVES The goal of this study was to determine if the haptoglobin phenotype was predictive of cardiovascular disease (CVD) in diabetic mellitus (DM). BACKGROUND Cardiovascular disease is the most frequent, severe, and costly complication of type 2 DM. There are clear geographic and ethnic differences in the risk of CVD among diabetic patients that cannot be fully explained by differences in conventional CVD risk factors. We have demonstrated that a functional allelic polymorphism in the haptoglobin gene acts as a major determinant of susceptibility for the development of diabetic microvascular complications. METHODS We sought to determine if this paradigm concerning the haptoglobin gene could be extended to CVD in DM. We tested this hypothesis in a case-control sample from the Strong Heart study, a population-based longitudinal study of CVD in American Indians. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis in 206 CVD cases and 206 matched controls age 45 to 74 years. Median follow-up was six years. RESULTS In multivariate analyses controlling for conventional CVD risk factors, haptoglobin phenotype was a highly statistically significant, independent predictor of CVD in DM. The odds ratio of having CVD in DM with the haptoglobin 2-2 phenotype was 5.0 times greater than in DM with the haptoglobin 1-1 phenotype (p = 0.002). An intermediate risk of CVD was associated with the haptoglobin 2-1 phenotype. CONCLUSIONS This study suggests that determination of haptoglobin phenotype may contribute to the algorithm used in CVD risk stratification, and in evaluation of new therapies to prevent CVD in the diabetic patient.

Prehypertension, Diabetes, and Cardiovascular Disease Risk in a Population-Based Sample. The Strong Heart Study

There are few data about the impact of the recently-defined category of prehypertension (systolic blood pressure 120 to 139 mm Hg or diastolic blood pressure 80 to 89 mm Hg) on cardiovascular disease incidence. It is also unknown whether this association differs between individuals with or without diabetes. A total of 2629 Strong Heart Study participants free from hypertension and cardiovascular disease at baseline examination were followed for 12 years to observe incident cardiovascular disease. Approximately 42% of the 2629 participants had diabetes. We assessed the prevalence of prehypertension and the hazard ratios of incident cardiovascular disease associated with prehypertension. Prehypertension was more prevalent in diabetic than nondiabetic participants (59.4% versus 48.2%, P<0.001 adjusted for age). Compared with nondiabetic participants with normal blood pressure, the hazard ratios of cardiovascular disease were 3.70 (95% confidence interval: 2.66, 5.15) for those with both prehypertension and diabetes, 1.80 (1.28, 2.54) for those with prehypertension alone and 2.90 (2.03, 4.16) for those with diabetes alone. Impaired glucose tolerance or impaired fasting glucose also greatly increased the cardiovascular disease risk in prehypertensive people. Clinical investigation of more aggressive interventions, such as drug treatment for blood pressure control for prehypertensive individuals with impaired fasting glucose, impaired glucose tolerance, or diabetes is warranted.

A Longitudinal Study of Hypertension Risk Factors and Their Relation to Cardiovascular Disease: The Strong Heart Study

This study estimated hypertension incidence and explored hypertension risk factors and their association with cardiovascular disease. Data collected from 4549 American Indian participants in the 3 exams of the Strong Heart Study were used. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or current use of antihypertensive medication. Generalized linear models were used to identify the risk factors for hypertension and the correlates of blood pressures. Cox proportional models with time-dependent covariates and the mixed models were used to explore the association of hypertension with cardiovascular disease. There was no sex difference in hypertension. After adjustment for other risk factors, the risks of developing hypertension among subgroups in each characterized group were as follows: prehypertensive versus normotensive, 3.21 times; macroalbuminuria and microalbuminuria versus normal, 3.47 and 1.72; diabetic versus nondiabetic, 1.56; overweight and obese versus normal weight, 1.30 and 1.51; and current alcohol drinking versus not, 1.22. Moreover, systolic blood pressure was significantly and positively associated with age, obesity, and albuminuria and negatively with smoking. After adjusting all other risk factors, those pretreated, untreated, controlled, and uncontrolled hypertensive participants had ≈1.74, 1.81, 2.19, and 2.77 times higher risks of developing cardiovascular disease compared with normotensive participants, respectively. In 45- to 74-year-old American Indians, the risk of developing hypertension was rising. Prehypertensive participants had 3.2/1.74 times higher risk of developing hypertension/cardiovascular disease than normotensive participants. Age, diabetes, and macro/microalbuminuria were independently significant risk factors of both hypertension and cardiovascular disease.

Cardiac and Systemic Hemodynamic Characteristics of Hypertension and Prehypertension in Adolescents and Young Adults The Strong Heart Study

Background— The epidemic of overweight is increasing the prevalence of both prehypertension and early-onset hypertension, but few population-based data exist on their impact on cardiac structure and function in adolescents and young adults. Methods and Results— We analyzed clinical characteristics, hemodynamic parameters, and left ventricular structure and function in 1940 participants, 14 to 39 years of age, in the Strong Heart Study. Hypertension occurred in 294 participants (15%), who were more often men (70% versus 30%), older (age, 31±7 versus 25±8 years), and more commonly diabetic (23% versus 4.5%; all P<0.001) than their normotensive counterparts. Prehypertension occurred in 675 (35%) of participants with similar trends in gender, age, and diabetes status. After adjustment for covariates, both hypertensive and prehypertensive participants had higher left ventricular wall thickness (0.83 and 0.78 versus 0.72 cm), left ventricular mass (182 and 161 versus 137 g), and relative wall thickness (0.30 and 0.29 versus 0.28 cm) and 3- and 2-fold-higher prevalences of left ventricular hypertrophy than their normotensive counterparts (all P<0.001). Hypertension and prehypertension also were associated with higher mean pulse pressure/stroke volume index (1.24 and 1.15 versus 1.02 mm Hg/mL · m2) and total peripheral resistance index (3027 and 2805 versus 2566 dynes · s · cm−5 · m2; all P<0.001). Conclusions— In a population with high prevalences of obesity and diabetes, hypertension and prehypertension are associated with increases in both cardiac output and peripheral resistance index. Despite the young age of participants with hypertension and prehypertension, they had prognostically adverse preclinical cardiovascular disease, including left ventricular hypertrophy and evidence of increased arterial stiffness.

Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons >15 years of age

Nomograms to predict normal aortic root diameter for body surface area (BSA) in broad ranges of age have been widely used but are limited by lack of consideration of gender effects, jumps in upper limits of aortic diameter among age strata, and data from older teenagers. Sinus of Valsalva diameter was measured by American Society of Echocardiography convention in normal-weight, nonhypertensive, nondiabetic subjects ≥15 years old without aortic valve disease from clinical or population-based samples. Analyses of covariance and linear regression with assessment of residuals identified determinants and developed predictive models for normal aortic root diameter. In 1,207 apparently normal subjects ≥15 years old (54% women), aortic root diameter was 2.1 to 4.3 cm. Aortic root diameter was strongly related to BSA and height (r = 0.48 for the 2 comparisons), age (r = 0.36), and male gender (+2.7 mm adjusted for BSA and age, p <0.001 for all comparisons). Multivariable equations using age, gender, and BSA or height predicted aortic diameter strongly (R = 0.674 for the 2 comparisons, p <0.001) with minimal relation of residuals to age or body size: for BSA 2.423 + (age [years] × 0.009) + (BSA [square meters] × 0.461) - (gender [1 = man, 2 = woman] × 0.267), SEE 0.261 cm; for height 1.519 + (age [years] × 0.010) + (height [centimeters] × 0.010) - (gender [1 = man, 2 = woman] × 0.247), SEE 0.215 cm. In conclusion, aortic root diameter is larger in men and increases with body size and age. Regression models incorporating body size, age, and gender are applicable to adolescents and adults without limitations of previous nomograms.

Association between exposure to low to moderate arsenic levels and incident cardiovascular disease. A prospective cohort study.

BACKGROUND Long-term exposure to high levels of arsenic is associated with increased risk for cardiovascular disease, whereas risk from long-term exposure to low to moderate arsenic levels (< 100μg/L in drinking water) is unclear. OBJECTIVE To evaluate the association between long-term exposure to low to moderate arsenic levels and incident cardiovascular disease. DESIGN Prospective cohort study. SETTING The Strong Heart Study baseline visit between 1989 and 1991, with follow-up through 2008. PATIENTS 3575 American Indian men and women aged 45 to 74 years living in Arizona, Oklahoma, and North and South Dakota. MEASUREMENTS The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of long-term arsenic exposure. Outcomes were incident fatal and nonfatal cardiovascular disease. RESULTS A total of 1184 participants developed fatal and nonfatal cardiovascular disease. When the highest and lowest quartiles of arsenic concentrations (> 15.7 vs. < 5.8 μg/g creatinine) were compared,the hazard ratios for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for sociodemographic factors, smoking, body mass index, and lipid levels were 1.65 (95%CI, 1.20 to 2.27; P for trend < 0.001), 1.71 (CI, 1.19 to 2.44; P for trend < 0.001), and 3.03 (CI, 1.08 to 8.50; P for trend = 0.061),respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (CI,1.09 to 1.59; P for trend = 0.002), 1.30 (CI, 1.04 to 1.62; P for trend = 0.006), and 1.47 (CI, 0.97 to 2.21; P for trend = 0.032).These associations varied by study region and were attenuated after further adjustment for diabetes, hypertension, and kidney disease measures. LIMITATION Direct measurement of individual arsenic levels in drinking water was unavailable. CONCLUSION Long-term exposure to low to moderate arsenic levels was associated with cardiovascular disease incidence and mortality.

Risk Factors for Arterial Hypertension in Adults With Initial Optimal Blood Pressure: The Strong Heart Study

Whether metabolic factors and their change over time influence development of arterial hypertension in adults with initially optimal blood pressure (BP) is unknown. We analyzed associations of BP in the optimal range (<120/80 mm Hg), metabolic risk factors, and their changes over 4-year follow-up, with 8-year incident hypertension, in a cohort of American Indians with a high prevalence of obesity. At baseline, 967 participants with optimal BP and no prevalent cardiovascular disease (69.5% women; mean age, 54±7 years) were evaluated and reexamined after 4 (second examination) and 8 years to evaluate predictors of 8-year incident arterial hypertension. In participants with normal glucose tolerance, baseline BP and decrease in high-density lipoprotein cholesterol from baseline to the second examination were the most potent predictors of 8-year arterial hypertension (both P<0.0001), with additional effects of baseline waist circumference and its increase, increase in BP, and presence of diabetes at the second examination (all P<0.04). In participants with impaired glucose tolerance or diabetes, the most potent predictor of 8-year incident hypertension was diabetes at the second examination (P<0.0001) followed by a increase in BP and LDL cholesterol over the first 4 years (both P<0.001). Thus, incident arterial hypertension can be predicted by initial metabolic profile and unfavorable metabolic variations over time, in addition to initial BP. At optimal levels of initial BP, increasing abdominal obesity, and abnormal lipid profile are major predictors of development of arterial hypertension. Possible implications of these findings for primary cardiovascular prevention should be tested in prospective studies.

Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

Incidence and Risk Factors for Stroke in American Indians The Strong Heart Study

Background— There are few published data on the incidence of fatal and nonfatal stroke in American Indians. The aims of this observational study were to determine the incidence of stroke and to elucidate stroke risk factors among American Indians. Methods and Results— This report is based on 4549 participants aged 45 to 74 years at enrollment in the Strong Heart Study, the largest longitudinal, population-based study of cardiovascular disease and its risk factors in a diverse group of American Indians. At baseline examination in 1989 to 1992, 42 participants (age- and sex-adjusted prevalence proportion 1132/100 000, adjusted to the age and sex distribution of the US adult population in 1990) had prevalent stroke. Through December 2004, 306 (6.8%) of 4507 participants without prior stroke suffered a first stroke at a mean age of 66.5 years. The age- and sex-adjusted incidence was 679/100 000 person-years. Nonhemorrhagic cerebral infarction occurred in 86% of participants with incident strokes; 14% had hemorrhagic stroke. The overall age-adjusted 30-day case-fatality rate from first stroke was 18%, with a 1-year case-fatality rate of 32%. Age, diastolic blood pressure, fasting glucose, hemoglobin A1c, smoking, albuminuria, hypertension, prehypertension, and diabetes mellitus were risk factors for incident stroke. Conclusions— Compared with US white and black populations, American Indians have a higher incidence of stroke. The case-fatality rate for first stroke is also higher in American Indians than in the US white or black population in the same age range. Our findings suggest that blood pressure and glucose control and smoking avoidance may be important avenues for stroke prevention in this population.