Steven C. Hunt

Relationship between left ventricular diastolic relaxation and systolic function in hypertension: The Hypertension Genetic Epidemiology Network (HyperGEN) Study.

The relation of impaired left ventricular relaxation, as measured by prolonged isovolumic relaxation time, to ventricular systolic function in hypertension remains uncertain in population-based samples. In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, echocardiograms were analyzed in 1457 hypertensive participants without diabetes, ≥2+ valvular regurgitation, or coronary disease. Impaired relaxation (isovolumic relaxation time >100 ms) was present in 219 (15%) of the participants; they were older and had higher arterial pressure than did those with normal relaxation. Ventricular chamber size, wall thicknesses, mass, and relative wall thickness were greater, and stress-corrected midwall shortening and end-systolic stress/end-systolic volume index were lower with impaired relaxation than with normal relaxation time. Fractional shortening and ejection fraction did not differ between the groups. In logistic regression, the likelihood of prolonged isovolumic relaxation time decreased with higher stress-corrected midwall shortening (odds ratio, 0.97%; 95% confidence interval, 0.96 to 0.99), independently of age, heart rate, and ventricular mass. Neither ejection fraction nor the end-systolic stress/end-systolic volume index was independently related to isovolumic relaxation time. In hypertension, impaired left ventricular relaxation parallels ventricular midwall dysfunction but not systolic chamber function. Whether combined diastolic and systolic dysfunction identifies hypertensive patients at especially high risk of cardiovascular events requires further study.

Association of Patient Age at Gastric Bypass Surgery With Long-term All-Cause and Cause-Specific Mortality

IMPORTANCE Bariatric surgery is effective in reducing all-cause and cause-specific long-term mortality. Whether the long-term mortality benefit of surgery applies to all ages at which surgery is performed is not known. OBJECTIVE To examine whether gastric bypass surgery is equally effective in reducing mortality in groups undergoing surgery at different ages. DESIGN, SETTING, AND PARTICIPANTS All-cause and cause-specific mortality rates and hazard ratios (HRs) were estimated from a retrospective cohort within 4 categories defined by age at surgery: younger than 35 years, 35 through 44 years, 45 through 54 years, and 55 through 74 years. Mean follow-up was 7.2 years. Patients undergoing gastric bypass surgery seen at a private surgical practice from January 1, 1984, through December 31, 2002, were studied. Data analysis was performed from June 12, 2013, to September 6, 2015. A cohort of 7925 patients undergoing gastric bypass surgery and 7925 group-matched, severely obese individuals who did not undergo surgery were identified through driver license records. Matching criteria included year of surgery to year of driver license application, sex, 5-year age groups, and 3 body mass index categories. INTERVENTION Roux-en-Y gastric bypass surgery. MAIN OUTCOMES AND MEASURES All-cause and cause-specific mortality compared between those undergoing and not undergoing gastric bypass surgery using HRs. RESULTS Among the 7925 patients who underwent gastric bypass surgery, the mean (SD) age at surgery was 39.5 (10.5) years, and the mean (SD) presurgical body mass index was 45.3 (7.4). Compared with 7925 matched individuals not undergoing surgery, adjusted all-cause mortality after gastric bypass surgery was significantly lower for patients 35 through 44 years old (HR, 0.54; 95% CI, 0.38-0.77), 45 through 54 years old (HR, 0.43; 95% CI, 0.30-0.62), and 55 through 74 years old (HR, 0.50; 95% CI, 0.31-0.79; P < .003 for all) but was not lower for those younger than 35 years (HR, 1.22; 95% CI, 0.82-1.81; P = .34). The lack of mortality benefit in those undergoing gastric bypass surgery at ages younger than 35 years primarily derived from a significantly higher number of externally caused deaths (HR, 2.53; 95% CI, 1.27-5.07; P = .009), particularly among women (HR, 3.08; 95% CI, 1.4-6.7; P = .005). Patients undergoing gastric bypass surgery had a significantly lower age-related increase in mortality than severely obese individuals not undergoing surgery (P = .001). CONCLUSIONS AND RELEVANCE Gastric bypass surgery was associated with improved long-term survival for all patients undergoing surgery at ages older than 35 years, with externally caused deaths only elevated in younger women. Gastric bypass surgery is protective against mortality even for older patients and also reduces the age-related increase in mortality observed in severely obese individuals not undergoing surgery.

Telomeres and the natural lifespan limit in humans

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the ‘telomeric brink’, which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

Plasma Concentrations of Afamin Are Associated With Prevalent and Incident Type 2 Diabetes: A Pooled Analysis in More Than 20,000 Individuals

OBJECTIVE The human vitamin E–binding glycoprotein afamin is primarily expressed in the liver and has been associated with prevalent and incident metabolic syndrome. These data were in line with observations in transgenic mice. We thus investigated whether afamin concentrations are associated with prediabetes, type 2 diabetes, and insulin resistance (IR). RESEARCH DESIGN AND METHODS Individual-level baseline (n = 20,136) and follow-up data (n = 14,017) of eight prospective cohort studies were investigated. Study-level data were combined using random-effects meta-analyses. Main outcomes were prevalent and incident type 2 diabetes, prediabetes, and IR. Discrimination and reclassification of participants was analyzed for incident type 2 diabetes. RESULTS Mean afamin concentrations between studies ranged from 61 to 73 mg/L. The eight studies included 1,398 prevalent and 585 incident cases of type 2 diabetes. Each increase of afamin by 10 mg/L was associated with prevalent type 2 diabetes (odds ratio [OR] 1.19 [95% CI 1.12–1.26], P = 5.96 × 10−8). Afamin was positively associated with IR assessed by HOMA-IR (β 0.110 [95% CI 0.089–0.132], P = 1.37 × 10−23). Most importantly, afamin measured at baseline was an independent predictor for 585 incident cases of type 2 diabetes (OR 1.30 [95% CI 1.23–1.38], P = 3.53 × 10−19) and showed a significant and valuable gain in risk classification accuracy when added to this extended adjustment model. CONCLUSIONS This pooled analysis in >20,000 individuals showed that afamin is strongly associated with IR, prevalence, and incidence of type 2 diabetes independent of major metabolic risk factors or parameters. Afamin might be a promising novel marker for the identification of individuals at high risk for the development of type 2 diabetes.

Association of Central Adiposity With Adverse Cardiac Mechanics Findings From the Hypertension Genetic Epidemiology Network Study

Background— Central obesity, defined by increased waist circumference or waist:hip ratio (WHR), is associated with increased cardiovascular events, including heart failure. However, the pathophysiological link between central obesity and adverse cardiovascular outcomes remains poorly understood. We hypothesized that central obesity and larger WHR are independently associated with worse cardiac mechanics (reduced left ventricular strain and systolic [s′] and early diastolic [e′] tissue velocities). Methods and Results— We performed speckle-tracking analysis of echocardiograms from participants in the Hypertension Genetic Epidemiology Network (HyperGEN) study, a population- and family-based epidemiological study (n=2181). Multiple indices of systolic and diastolic cardiac mechanics were measured. We evaluated the association between central obesity and cardiac mechanics using multivariable-adjusted linear mixed-effects models to account for relatedness among participants. The mean age of the cohort was 51±14 years, 58% were women, and 47% were black. Mean body mass index was 30.8±7.1 kg/m2, waist circumference was 102±17 cm, WHR was 0.91±0.08, and 80% had central obesity based on waist circumference and WHR criteria. After adjusting for multiple potential confounders (including age, sex, race, physical activity, body mass index, heart rate, smoking status, systolic blood pressure, fasting glucose, total cholesterol, antihypertensive medication use, glomerular filtration rate, left ventricular mass index, wall motion abnormalities, and ejection fraction), central obesity and WHR remained associated with worse global longitudinal strain, early diastolic strain rate, s′ velocity, and e′ velocity ( P <0.05 for all comparisons). There were no significant statistical interactions between WHR and obesity status. Conclusions— In this cross-sectional study of participants with multiple comorbidities, central obesity was found to be associated with adverse cardiac mechanics.Background—Central obesity, defined by increased waist circumference or waist:hip ratio (WHR), is associated with increased cardiovascular events, including heart failure. However, the pathophysiological link between central obesity and adverse cardiovascular outcomes remains poorly understood. We hypothesized that central obesity and larger WHR are independently associated with worse cardiac mechanics (reduced left ventricular strain and systolic [s′] and early diastolic [e′] tissue velocities). Methods and Results—We performed speckle-tracking analysis of echocardiograms from participants in the Hypertension Genetic Epidemiology Network (HyperGEN) study, a population- and family-based epidemiological study (n=2181). Multiple indices of systolic and diastolic cardiac mechanics were measured. We evaluated the association between central obesity and cardiac mechanics using multivariable-adjusted linear mixed-effects models to account for relatedness among participants. The mean age of the cohort was 51±14 years, 58% were women, and 47% were black. Mean body mass index was 30.8±7.1 kg/m2, waist circumference was 102±17 cm, WHR was 0.91±0.08, and 80% had central obesity based on waist circumference and WHR criteria. After adjusting for multiple potential confounders (including age, sex, race, physical activity, body mass index, heart rate, smoking status, systolic blood pressure, fasting glucose, total cholesterol, antihypertensive medication use, glomerular filtration rate, left ventricular mass index, wall motion abnormalities, and ejection fraction), central obesity and WHR remained associated with worse global longitudinal strain, early diastolic strain rate, s′ velocity, and e′ velocity (P<0.05 for all comparisons). There were no significant statistical interactions between WHR and obesity status. Conclusions—In this cross-sectional study of participants with multiple comorbidities, central obesity was found to be associated with adverse cardiac mechanics.

A genome-wide association meta-analysis on apolipoprotein A-IV concentrations

Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 − 44), rs5104 in APOA4 (P = 1.79 × 10−24) and rs4241819 in KLKB1 (P = 5.6 × 10−14). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 − 07). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10−05). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1. The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.

Coffee consumption and calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study

BACKGROUND & AIMS While a recent meta-analysis of prospective studies reported that coffee consumption is associated with a lower risk of cardiovascular disease mortality, limited and inconsistent data are available on the relation of coffee intake with subclinical disease. Thus, the aim of the present study was to see the association of coffee consumption with the prevalence of atherosclerotic plaque in the coronary arteries in NHLBI Family Heart Study. METHODS In a cross-sectional design, we studied 1929 participants of the NHLBI Family Heart Study without known coronary heart disease. Coffee consumption was assessed by a semi-quantitative food frequency questionnaire and coronary-artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC as an Agatston score of ≥100 and used generalized estimating equations to calculate prevalence ratios of CAC as well as a sensitivity analysis at a range of cutpoints for CAC. RESULTS Mean age was 56.7 years and 59% of the study subjects were female. In adjusted analysis for age, sex, BMI, smoking, alcohol, physical activity, field center, and energy intake, prevalence ratio (95% CI) for CAC was 1.0 (reference), 0.92 (0.57-1.49), 1.34 (0.86-2.08), 1.30 (0.84-2.02), and 0.99 (0.60-1.64) for coffee consumption of almost never, <1/day, 1/day, 2-3/day, and ≥4 cups/day, respectively. In a sensitivity analysis, there was no evidence of association between coffee consumption and prevalent CAC when CAC cut points of 0, 50, 150, 200, and 300 were used. CONCLUSIONS These data do not provide evidence for an association between coffee consumption and prevalent CAC in adult men and women.

The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

Fitness versus adiposity in cardiovascular disease risk

Obesity and low cardiorespiratory fitness are both established predictors of cardiovascular disease morbidity and mortality. Whether the protective effects of fitness outweigh the deleterious effects of obesity, however, remains a topic of debate. To extend knowledge of the relative influence of fitness and fatness on cardiovascular disease outcomes, however, attention must be paid to measurement quality. Eliminating inherent bias of self-report and including the highest quality assessments of cardiorespiratory fitness and fatness simultaneously are imperative for head-to-head comparisons. Studies must move beyond body mass index and total body fat percentage to differentiate the heterogenous effects of various adipose tissue depots on cardiovascular risk. Imaging techniques that measure visceral adiposity and other risk-laden ectopic adipose depots while also quantifying cardioprotective adipose depots such as lower body subcutaneous fat and even non-adipose tissues such as skeletal muscle may further illuminate the influence of body composition on cardiovascular health. This review underscores key studies within a large body of literature that provide the foundation for the fit-vs.-fat debate in the context of cardiovascular disease risk, and identifies important considerations for future research.