[Show abstract][Hide abstract] ABSTRACT: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
[Show abstract][Hide abstract] ABSTRACT: Objective
We used magnetic resonance imaging (MRI) to study the prevalence and associated clinical characteristics of high-risk plaque (defined as presence of lipid-rich necrotic core [LRNC] and intraplaque hemorrhage) in the superficial femoral arteries (SFA) among people with peripheral artery disease (PAD).
The prevalence and clinical characteristics associated with high-risk plaque in the SFA are unknown.
Three-hundred-three participants with PAD underwent MRI of the proximal SFA using a 1.5 T S platform. Twelve contiguous 2.5 mm cross-sectional images were obtained.
LRNC was present in 68 (22.4%) participants. Only one had intra-plaque hemorrhage. After adjusting for age and sex, smoking prevalence was higher among adults with LRNC than among those without LRNC (35.9% vs. 21.4%, p = 0.02). Among participants with vs. without LRNC there were no differences in mean percent lumen area (31% vs. 33%, p = 0.42), normalized mean wall area (0.71 vs. 0.70, p = 0.67) or maximum wall area (0.96 vs. 0.92, p = 0.54) in the SFA. Among participants with LRNC, cross-sectional images containing LRNC had a smaller percent lumen area (33% ± 1% vs. 39% ± 1%, p < 0.001), greater normalized mean wall thickness (0.25 ± 0.01 vs. 0.22 ± 0.01, p < 0.001), and greater normalized maximum wall thickness (0.41 ± 0.01 vs. 0.31 ± 0.01, p < 0.001), compared to cross-sectional images without LRNC.
Fewer than 25% of adults with PAD had high-risk plaque in the proximal SFA using MRI. Smoking was the only clinical characteristic associated with presence of LRNC. Further study is needed to determine the prognostic significance of LRNC in the SFA.
Clinical trial registration—URL
http://www.clinicaltrials.gov. Unique identifier: NCT00520312.
[Show abstract][Hide abstract] ABSTRACT: The Multidimensional Prognostic Index (MPI) is a validated predictive tool for long-term mortality based on information collected in a standardized Comprehensive Geriatric Assessment. We investigated whether the MPI is an effective predictor of intrahospital mortality and length of hospital stay after admission to acute geriatric wards.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2014; · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Slow gait speed increases morbidity and mortality in older adults. We examined how preferred gait speed is associated with energetic requirements of walking, fatigability, and fatigue.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2014; · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We used magnetic resonance imaging (MRI) to study the prevalence and associated clinical characteristics of high-risk plaque (defined as presence of lipid-rich necrotic core [LRNC] and intraplaque hemorrhage) in the superficial femoral arteries (SFA) among people with peripheral artery disease (PAD).
[Show abstract][Hide abstract] ABSTRACT: A localized hypertrophy of the subaortic segment of the ventricular septum-ventricular septal bulge (VSB)-has been frequently described in series of elderly population, but its prevalence with age, clinical correlates, and impact on cardiac function and exercise capacity remain uncertain. We explored these associations in a cross-sectional sample without known cardiac disease from the Baltimore Longitudinal Study of Aging. We randomly selected 700 participants (50% men, mean age 64 ± 15, range 26 to 95 years) and reviewed their echocardiograms. We identified 28 men and 21 women with VSB (7% overall prevalence). The prevalence of VSB significantly increased with age in both genders (p <0.0001). In multivariate logistic regression including hypertension and other cardiovascular risk factors, only age displayed a significant independent association with VSB (OR 1.06 per year, 95% confidence interval 1.03 to 1.10, p = 0.0001). After multiple adjustments, participants with VSB compared with those without had enhanced global left ventricular contractility (fractional shortening 41 ± 1.3 vs 38 ± 0.3%, p = 0.04; ejection fraction 71 ± 1.6 vs 67 ± 0.4%, p = 0.06; systolic velocity of the mitral annulus 8.4 ± 0.1 vs 8.9 ± 0.3, p = 0.06), and larger aortic root diameters (3.3 ± 0.06 vs 3.1 ± 0.02 cm, p = 0.02). In subgroup of participants who completed a maximal treadmill test (177 women and 196 men), those with VSB (19, 5.1%) had significantly lower peak oxygen consumption than their counterparts (19.6 ± 3.8 vs 22.9 ± 6.6 ml/kg/min, p = 0.03). However, this association was no longer significant after multiple adjustments. In conclusion, the presence of VSB is independently associated with older age and determines enhanced left ventricular contractility, without any evident impact on exercise capacity.
The American journal of cardiology. 09/2014; 114(5):796-802.
[Show abstract][Hide abstract] ABSTRACT: The Foundation for the National Institutes of Health Sarcopenia Project developed data-driven cut-points for clinically meaningful weakness and low lean body mass. This analysis describes strength and function response to interventions based on these classifications.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 08/2014; · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Experimental evidence indicates that circulating insulin-like growth factor-1 (IGF-1) counteracts vascular aging and atherosclerosis, for which increased carotid artery intima-media thickness (IMT) is a marker. Yet, IGF-1 concentrations have been inconsistently associated with carotid IMT in epidemiological studies. Since vitamin D is also implicated in vascular protection and affects IGF-1 biology, we hypothesized that it would influence the effect of IGF-1 on IMT.
[Show abstract][Hide abstract] ABSTRACT: Objective. During the aging process in men testosterone (T) levels progressively fall and inflammatory biomarkers increase. Although a relationship between these two phenomena has been tested in previous clinical trials, there is inconclusive evidence about the potential anti-inflammatory action of T.Methods. A total of 108 healthy men >65 years with serum T concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University, and randomized to 60-cm2 T or placebo patch for 36-months. Ninety-six subjects completed the trial. Information and stored serum specimens from this trial were used to test the hypothesis of T inhibitory effect on inflammation. 70 men (42 in the T group) who had banked specimens available for assays of T, C-reactive protein (CRP), Tumor necrosis factor (TNF)-alpha, soluble TNF-alpha receptor-1 (TNFR1), interleukin-6 (IL-6) and soluble IL-6 receptors (sIL6r and sgp130) at multiple time points, were evaluated.Results. The mean age ± SD at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months did not induce a significant decrease in inflammatory markers. A trend toward a significant increase was observed in the placebo group for TNF-alpha (p=0.03) and sgp130 (p=0.01). Significant differences, in estimated means of TNFR1 (but not of other inflammatory markers), with lower levels in T group, were observed at 36 month-time point. In T-treated subjects we found an almost significant treatment-time interaction term TNFR1 (p=0.02) independent of total body fat content assessed by DXA. No serious adverse effect was observed.Conclusions. Transdermal T treatment of older men for 36 months is not associated with significant changes in inflammatory markers.
[Show abstract][Hide abstract] ABSTRACT: Sunlight exposure has been shown to alter DNA methylation patterns across several human cell-types, including T-lymphocytes. Since epigenetic changes establish gene expression profiles, changes in DNA methylation induced by sunlight exposure warrant investigation. The purpose of this study was to assess the effects of sunlight exposure on CD4+ T-cell methylation patterns on an epigenome-wide scale in a North American population of European origin (n = 991). In addition, we investigated the genetic contribution to epigenetic variation (methylQTL). We used linear regression to test the associations between methylation scores at 461 281 cytosine-phosphate-guanine (CpG) sites and sunlight exposure, followed by a genome-wide association analysis (methylQTL) to test for associations between methylation at the top CpG locus and common genetic variants, assuming an additive genetic model. We observed an epigenome-wide significant association between sunlight exposure and methylation status at cg26930596 (p = 9.2 × 10−8), a CpG site located in protein kinase C zeta (PRKCZ), a gene previously shown to be entrained by light. MethylQTL analysis resulted in significant associations between cg26930596 and two intergenic single nucleotide polymorphisms on chromosome 3, rs4574216 (p = 1.5 × 10−10) and rs4405858 (p = 1.9 × 10−9). These common genetic variants reside downstream of WWTR1, a transcriptional co-activator of PRKCZ. Associations observed in the North American population, however, did not replicate in an independent Mediterranean cohort. Our preliminary results support the role of sunlight exposure in epigenetic processes, and lay the groundwork for future studies of the molecular link between sunlight and physiologic processes such as tumorigenesis and metabolism.
[Show abstract][Hide abstract] ABSTRACT: Associations of collateral vessels and lower extremity plaque with functional decline are unknown. Among people with peripheral artery disease (PAD), we determined whether greater superficial femoral artery (SFA) plaque burden combined with fewer lower extremity collateral vessels was associated with faster functional decline, compared to less plaque and/or more numerous collateral vessels. A total of 226 participants with ankle-brachial index (ABI) <1.00 underwent magnetic resonance imaging of lower extremity collateral vessels and cross-sectional imaging of the proximal SFA. Participants were categorized as follows: Group 1 (best), maximum plaque area < median and collateral vessel number ≥6 (median); Group 2, maximum plaque area < median and collateral vessel number <6; Group 3, maximum plaque area > median and collateral vessel number ≥6; Group 4 (worst), maximum plaque area > median and collateral vessel number <6. Functional measures were performed at baseline and annually for 2 years. Analyses adjust for age, sex, race, comorbidities, and other confounders. Annual changes in usual-paced walking velocity were: Group 1, +0.01 m/s; Group 2, -0.02 m/s; Group 3, -0.01 m/s; Group 4, -0.05 m/s (p-trend=0.008). Group 4 had greater decline than Group 1 (p<0.001), Group 2 (p=0.029), and Group 3 (p=0.010). Similar trends were observed for fastest-paced 4-meter walking velocity (p-trend=0.018). Results were not substantially changed when analyses were repeated with additional adjustment for ABI. However, there were no associations of SFA plaque burden and collateral vessel number with decline in 6-minute walk. In summary, a larger SFA plaque burden combined with fewer collateral vessels is associated with a faster decline in usual and fastest-paced walking velocity in PAD.
Vascular medicine (London, England). 07/2014; 19(4):281-288.
[Show abstract][Hide abstract] ABSTRACT: Although the accumulation of highly-differentiated and granzyme B (GrB)-expressing CD8(+)CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques and mice and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+)CD8(+) T cells by presenting endogenous antigens and utilizing the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and their capacity to evoke the generation of GrB(+)CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4-1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly.
[Show abstract][Hide abstract] ABSTRACT: Anxiety and other psychological dispositions are thought to be associated with blood pressure. This study tests whether personality traits have long-term associations with masked and white-coat effects.
[Show abstract][Hide abstract] ABSTRACT: Our objective is to report prevalence of motoric cognitive risk syndrome (MCR), a newly described predementia syndrome characterized by slow gait and cognitive complaints, in multiple countries, and its association with dementia risk.METHODS: Pooled MCR prevalence analysis of individual data from 26,802 adults without dementia and disability aged 60 years and older from 22 cohorts from 17 countries. We also examined risk of incident cognitive impairment (Mini-Mental State Examination decline ≥4 points) and dementia associated with MCR in 4,812 individuals without dementia with baseline Mini-Mental State Examination scores ≥25 from 4 prospective cohort studies using Cox models adjusted for potential confounders.RESULTS: At baseline, 2,808 of the 26,802 participants met MCR criteria. Pooled MCR prevalence was 9.7% (95% confidence interval [CI] 8.2%-11.2%). MCR prevalence was higher with older age but there were no sex differences. MCR predicted risk of developing incident cognitive impairment in the pooled sample (adjusted hazard ratio [aHR] 2.0, 95% CI 1.7-2.4); aHRs were 1.5 to 2.7 in the individual cohorts. MCR also predicted dementia in the pooled sample (aHR 1.9, 95% CI 1.5-2.3). The results persisted even after excluding participants with possible cognitive impairment, accounting for early dementia, and diagnostic overlap with other predementia syndromes.CONCLUSION: MCR is common in older adults, and is a strong and early risk factor for cognitive decline. This clinical approach can be easily applied to identify high-risk seniors in a wide variety of settings.
[Show abstract][Hide abstract] ABSTRACT: Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.
[Show abstract][Hide abstract] ABSTRACT: Many biodemographic studies use biomarkers of inflammation to understand or predict chronic disease and aging. Inflamm-aging, i.e. chronic low-grade inflammation during aging, is commonly characterized by pro-inflammatory biomarkers. However, most studies use just one marker at a time, sometimes leading to conflicting results due to complex interactions among the markers. A multidimensional approach allows a more robust interpretation of the various relationships between the markers. We applied principal component analysis (PCA) to 19 inflammatory biomarkers from the InCHIANTI study. We identified a clear, stable structure among the markers, with the first axis explaining inflammatory activation (both pro- and anti-inflammatory markers loaded strongly and positively) and the second axis innate immune response. The first but not the second axis was strongly correlated with age (r=0.56, p<0.0001, r=0.08 p=0.053), and both were strongly predictive of mortality (hazard ratios per PCA unit (95% CI): 1.33 (1.16-1.53) and 0.87 (0.76-0.98) respectively) and multiple chronic diseases, but in opposite directions. Both axes were more predictive than any individual markers for baseline chronic diseases and mortality. These results show that PCA can uncover a novel biological structure in the relationships among inflammatory markers, and that key axes of this structure play important roles in chronic disease.
[Show abstract][Hide abstract] ABSTRACT: Motivated by aging research, we propose an estimator of the effect of a time-varying exposure on an outcome in longitudinal studies with dropout and truncation by death. We use an inverse-probability weighted (IPW) estimator to derive a doubly robust augmented inverse-probability weighted (AIPW) estimator. IPW estimation involves weights for the exposure mechanism, dropout, and mortality; AIPW estimation additionally involves estimating data-generating models via regression. We demonstrate that the estimators identify a causal contrast that is a function of principal strata effects under a set of assumptions. Simulations show that AIPW estimation is unbiased when weights or outcome regressions are correct, and that AIPW estimation is more efficient than IPW estimation when all models are correct. We apply the method to a study of vitamin D and gait speed among older adults.