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Background Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. Methods We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography–tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults. Results In 2 599 participants (age 75.2 ± 4.3) followed for 10.8 ± 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function. Conclusions Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-β superfamily pathways as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

This article explores the relationship between adiponectin, a hormone produced by fat cells, and cardiovascular disease (CVD). Early studies suggested that higher levels of adiponectin were beneficial for preventing CVD, but recent research has shown a U-shaped association, with both low and high levels of adiponectin being linked to increased risk of CVD. The use of Mendelian randomization analysis to investigate the causal relationship between adiponectin and CVD has yielded inconclusive results. The article emphasizes the need for further research to fully understand the role of adiponectin in cardiovascular health. [Extracted from the article]

Background Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models. Methods We assessed growth differentiation factors (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in the Cardiovascular Health Study (CHS; N = 1 506) and the Health, Aging and Body Composition (Health ABC) Study (N = 1 237). CLL-11 and beta-2 microglobulin (β2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only), and incident dementia using correlations, linear regression, and Cox proportional hazards models. Results In CHS, levels of GDF-11, GDF-8, and follistatin were not correlated cross-sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy, or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities, and atrophy on MRI, as well as with incident dementia with an adjusted hazard ratio (HR) of 1.72 (95% CI = 1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95% CI = 1.07, 2.10) per doubling of GDF-8. Conclusions Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicate TGFβ superfamily inhibition in the pathogenesis of dementia. [ABSTRACT FROM AUTHOR]

Aims: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.Methods and Results: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78).Conclusions: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) and heart failure (HF) are disproportionately high in people living with HIV and differ by sex. Few CVD-related studies focus on drug use, yet it is common in low-income women living with HIV (WLWH) and increases cardiac dysfunction.Setting: We recruited unsheltered and unstably housed WLWH from San Francisco community venues to participate in a six-month cohort study investigating linkages between drug use, inflammation, and cardiac dysfunction.Methods: Adjusting for CVD risk factors, co-infections, medications, and menopause, we examined the effects of toxicology-confirmed drug use and inflammation (C-reactive protein, sCD14, sCD163 and sTNFR2) on levels of NT-proBNP, a biomarker of cardiac stretch and HF.Results: Among 74 WLWH, the median age was 53 years and 45 % were Black. At baseline, 72 % of participants had hypertension. Substances used included tobacco (65 %), cannabis (53 %), cocaine (49 %), methamphetamine (31 %), alcohol (28 %), and opioids (20 %). Factors significantly associated with NT-proBNP included cannabis use (Adjusted Relative Effect [ARE]: -39.6 %) and sTNFR2 (ARE: 65.5 %). Adjusting for heart failure and restricting analyses to virally suppressed persons did not diminish effects appreciably. Cannabis use was not significantly associated with sTNFR2 and did not change the association between sTNFR2 and NT-proBNP.Conclusions: Among polysubstance-using WLWH, NT-proBNP levels signaling cardiac stretch were positively associated with sTNFR2, but 40 % lower in people who used cannabis. Whether results suggest that cardiovascular pathways associated with cannabis use mitigate cardiac stress and dysfunction independent of inflammation in WLWH who use multiple substances merits further investigation. [ABSTRACT FROM AUTHOR]

Objective: Obesity is associated with changes in both right (RV) and left (LV) ventricular morphology, but the biological basis of this finding is not well established. We examined whether adipokine levels were associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease. Methods: We examined relationships of leptin, resistin, TNF-α, and adiponectin with RV morphology and function (from cardiac MRI) in participants (n = 1,267) free of clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of each adipokine with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Results: Higher leptin levels were associated with significantly lower levels of RV mass, RVEDV, RVESV and stroke volume, but not RVEF, after adjustment for age, gender, race, height and weight. These associations were somewhat attenuated but still significant after adjustment for traditional risk factors and covariates, and were completely attenuated when correcting for the respective LV measures. There were no significant interactions of age, gender, or race/ethnicity on the relationship between the four adipokines and RV structure or function. Conclusions: Leptin levels are associated with favorable RV morphology in a multi-ethnic population free of cardiovascular disease, however these associations may be explained by a yet to be understood bi-ventricular process as this association was no longer present after adjustment for LV values. These findings complement the associations previously shown between adipokines and LV structure and function in both healthy and diseased patients. The mechanisms linking adipokines to healthy cardiovascular function require further investigation. [ABSTRACT FROM AUTHOR]

Background: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and post-prandial levels are under different homeostatic regulation. The relationships of fasting and post-load glucose and NEFA with incident heart failure (HF) remain incompletely defined.Methods: Serum glucose and NEFA were measured during fasting and 2 hours post oral glucose tolerance test, performed in Cardiovascular Health Study participants not receiving hypoglycemic medication. Participants with prevalent HF or lacking relevant data were excluded. Outcomes were incident HF (primary), and HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (secondary).Results: Among 2238 participants (age 78±4) with median follow-up of 9.9 years, there were 737 HF events. After adjustment for demographic and lifestyle factors, both fasting (HR=1.11 per SD [95% CI=1.01-1.23], p=0.040) and post-load (HR=1.14 per SD [1.05-1.24], p=0.002) glucose were significantly associated with incident HF. No association was seen for fasting or post-load NEFA. Upon mutual adjustment, only post-load glucose (HR=1.11 [1.003-1.22], p=0.044), but not fasting glucose (HR=1.06 [0.94-1.20], p=0.340), remained associated with HF. Further adjustment for cardiovascular disease and other risk factors in the causal pathway did not affect the association for post-load glucose, but eliminated that for fasting glucose. Associations for fasting and post-load glucose appeared stronger with higher adiposity, and were observed specifically for HFrEF, but not HFpEF.Conclusions: Fasting and post-load glucose, but not NEFA, were associated with incident HF. The association was especially robust for post-load glucose, suggesting that pathways involved in post-prandial dysglycemia could offer new targets for HF prevention late in life. [ABSTRACT FROM AUTHOR]

Abstract: Background: Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress – such as diabetes, chronic kidney disease and aging – where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined. Methods: To test the hypothesis that circulating levels of Nɛ-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older. Results: During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase=1.11, 95% confidence interval [CI]=1.03–1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke. Conclusions: In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML’s value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population. [Copyright &y& Elsevier]

Background-Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk). Methods and Results-In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio=0.81 per 1 SD [95% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio=1.19 [95% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio=1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality. Conclusions-Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To investigate the association of lipoprotein-associated phospholipase A2 (LpPLA2;) mass and activity with incident cardiovascular disease (CVD) in a population with high prevalences of insulin resistance and diabetes, conditions for which epidemiological data remain sparse. RESEARCH DESIGN AND METHODS--We conducted a nested, case-control study (n = 1,008) within a population-based cohort of American Indians. Case subjects were defined by incidence of first-ever CVD up to 10 years later. Control subjects comprised participants free of CVD events during the follow-up period who were frequency matched to case subjects by age, sex, and diabetes status. LpPLA2 mass and activity were measured using commercially available assays. RESULTS--LpPLA2 mass and activity were moderately correlated with each other (r = 0.30), but only LpPLA2 activity exhibited moderate correlations with lipid fractions. After extensive adjustment for covariates, both LpPLA2 measures were significantly associated with incident CVD, but the relationship was inverse for LpPLA2 mass (highest versus lowest tertile, relative risk [RR] 0.55 [95% CI 0.39-0.79]) and positive for LpPLA2 activity (highest versus lowest tertile, 1.65 [1.12-2.42]). These associations were similar when participants with and without diabetes were examined separately. CONCLUSIONS--In this population-based cohort enriched with dysmetabolic phenotypes, LpPLA2 mass and activity showed divergent associations with CVD. The inverse relationship for LpPLA2 mass is contrary to observations from predominantly nondiabetic populations and will require independent replication. Whether this finding relates to redistribution of LpPLA2 to lipoprotein classes where it is less atherogenic or reflects incomplete measurement of LpPLA2 mass associated with altered lipoprotein composition in insulin resistance warrants further investigation. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults. RESEARCH DESIGN AND METHODS--Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals. RESULTS--Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39-0.63]) and HMW adiponectin (0.42 [0.32-0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables. CONCLUSIONS--In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation. [ABSTRACT FROM AUTHOR]

Background. Adiponectin has anti-inflammatory properties, and its production is suppressed by inflammatory factors. Although elevated levels of adiponectin and inflammatory markers each predict mortality in older adults, the implications of their interdependent actions have not been examined. Methods. We investigated the joint associations of levels and interval changes in adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6) with risk of death in 840 older adults participating in a population-based study. Adiponectin, CRP, and IL-6 were measured in samples collected 8.9 (8.2–9.8) years apart, and all-cause mortality was subsequently ascertained (n = 176). Results. Interval changes and end levels of adiponectin, CRP, and IL-6 showed mostly positive, independent associations with mortality, without evidence of multiplicative interaction. Joint models, however, showed an U-shaped relationship between end level of adiponectin and outcome (hazard ratio [HR] [95% CI] = 0.72 [0.52–0.99] per standard deviation [SD] for levels <20.0 mg/L; HR = 1.91 [1.61–3.44] per SD for levels ≥20.0 mg/L). Participants with the greatest longitudinal increases (upper quartile) in both adiponectin and inflammatory markers had a higher risk of death (HR = 2.85 [1.78–4.58]) than those with large increases in adiponectin alone (HR = 1.87 [1.20–2.92]) (p = .043), but not inflammatory markers alone (HR = 2.48 [1.67–3.67]) (p = .55), as compared with smaller changes for both. Conclusion. Higher levels or interval change in adiponectin and inflammatory markers predict increased mortality in older persons independent of each other, although for adiponectin, the association appears inverse below 20 mg/L. These findings suggest that inflammatory and noninflammatory mechanisms governing aging-related decline operate in parallel and provide a potential explanation for paradoxical adiponectin–outcome associations reported previously. [ABSTRACT FROM PUBLISHER]

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989–2007) in 3,754 community-dwelling US adults aged 65–100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥30 kg/m2) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25–29.9 kg/m2) was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints. [ABSTRACT FROM PUBLISHER]

Background. Cross-sectional studies show that adiponectin is higher in older than in younger adults but long-term change in adiponectin, its determinants, and its relationship to functional decline or survival in the elderly population have not been evaluated. Methods. We investigated predictors of longitudinal change in adiponectin, and the association of this adipokine or its antecedent change with physical deterioration and all-cause mortality in 988 participants in a population-based study who completed examinations in 1996–1997 and 2005–2006, had serial adiponectin measurements and underwent follow-up through June 2009. Results. Adiponectin level rose significantly during follow-up, but the increase was smaller in blacks, was associated with declining weight or fasting glucose and, in men, lower albumin, and was affected by medications. Adiponectin was independently associated with greater physical decline, but the relationship for adiponectin change was driven by concomitant weight decrease. Both adiponectin and its change independently predicted mortality, even after adjustment for weight change. The association for adiponectin and mortality was observed in whites but not in blacks and only for levels in the upper range (hazard ratio = 1.85, 95% confidence interval = 1.36–2.52 per SD ≥ 20 mg/L), whereas that for adiponectin change was linear throughout in both racial groups (hazard ratio = 1.30, 95% confidence interval = 1.10–1.52 per SD). Conclusions. Adiponectin levels increase over time in long-lived adults and are associated with greater physical disability and mortality. Such increases may occur in response to age-related homeostatic dysregulation. Additional investigation is required to define the underlying mechanisms and whether this represents a marker or causal factor for mortality in this age group. [ABSTRACT FROM PUBLISHER]

Multiple randomized controlled trials (RCTs) have established the efficacy of statins for the prevention of cardiovascular disease. The benefits observed are often framed in terms of percentage reductions in low-density lipoprotein (LDL) cholesterol from baseline or percentage reductions between control and treatment groups, although epidemiologic data suggest that the absolute intergroup difference in LDL cholesterol (ΔLDLControl-Rx) is the more informative measure. A systematic review of large-scale trials of statins versus placebo, usual care, or active (lower dose statin) control was conducted to calculate updated summary estimates of risk reduction in coronary artery disease and all-cause mortality. Meta–regression analysis was used to ascertain the relations of different LDL cholesterol metrics to outcomes. In 20 eligible RCTs, there were significant overall reductions for coronary artery disease (odds ratio 0.72, 95% confidence interval 0.67 to 0.78) and mortality (odds ratio 0.89, 95% confidence interval 0.84 to 0.94), but with substantial variability in trial results. ΔLDLControl-Rx was the strongest determinant of coronary artery disease risk reduction, particularly after excluding active-comparator studies, and was independent of baseline LDL cholesterol. In contrast, baseline LDL cholesterol edged out ΔLDLControl-Rx as the strongest determinant of mortality, but neither was significant after the exclusion of active-comparator studies. The exclusion of 3 RCTs involving distinct populations, however, rendered ΔLDLControl-Rx the predominant determinant of mortality reduction. In conclusion, these findings underscore the primacy of absolute reductions in LDL cholesterol in the design and interpretation of RCTs of lipid-lowering therapies and in framing treatment recommendations on the basis of the proved coronary benefits of these drugs. [Copyright &y& Elsevier]

Several biomarkers have been documented, singly or jointly, to improve risk prediction, but the extent to which they improve prediction-model performance in populations with high prevalences of obesity and diabetes has not been specifically examined. The aim of this study was to evaluate the ability of various biomarkers to improve prediction-model performance for death and major cardiovascular disease (CVD) events in a high-risk population. The relations of 6 biomarkers with outcomes were examined in 823 American Indians free of prevalent CVD or renal insufficiency, as were their contributions to risk prediction. In single-marker models adjusting for standard clinical and laboratory risk factors, 4 of 6 biomarkers significantly predicted mortality and major CVD events. In multimarker models, these 4 biomarkers—urinary albumin/creatinine ratio (UACR), glycosylated hemoglobin, B-type natriuretic peptide, and fibrinogen—significantly predicted mortality, while 2—UACR and fibrinogen—significantly predicted CVD. On the basis of its robust association in participants with diabetes, UACR was the strongest predictor of mortality and CVD, individually improving model discrimination or classification in the entire cohort. Singly, all remaining biomarkers also improved risk classification for mortality and enhanced average sensitivity for mortality and CVD. The addition of ≥1 biomarker to the single marker UACR further improved discrimination or average sensitivity for these outcomes. In conclusion, biomarkers derived from diabetic cohorts, and novel biomarkers evaluated primarily in lower risk populations, improve risk prediction in cohorts with prevalent obesity and diabetes. Risk stratification of these populations with multimarker models could enhance selection for aggressive medical or surgical approaches to prevention. [Copyright &y& Elsevier]

Introduction: The myocardial performance index (MPI) introduced by Tei, a Doppler-derived echocardiographic measure that reflects both left ventricular (LV) systolic and diastolic function, has been shown to have prognostic value in several clinical settings, including myocardial infarction and congestive heart failure. There are scant data on the correlates and prognostic value of MPI in a population without overt cardiovascular (CV) disease. Methods: We investigated clinical and physiologic correlates of MPI, as assessed from echocardiographic Doppler recordings in 1,862 American Indian participants free of coronary or valvular disease or LV systolic dysfunction in the population-based strong heart study (SHS). We then assessed the prognostic value of MPI for incident CV events, including nonfatal stroke, coronary heart disease, congestive heart failure, and CV death. Results: The study population was 59 ± 8 years old (66% women); 48% had diabetes, 44% hypertension, and 54% were obese. In univariable analyses, MPI (mean = 0.24 ± 0.17) showed significant negative associations with creatinine clearance, C-reactive protein (CRP), LV ejection fraction (EF), mitral valve E- and A-wave velocities, cardiac index (CI), stroke index (SI) and stroke index/pulse pressure (SI/PP), and significant positive associations with serum creatinine and total peripheral resistance index (TPRI) (all P < 0.05). There were no significant associations of MPI with hypertension or diabetes status, systolic or diastolic blood pressure, body mass index, hemoglobin A1C or LV mass. After adjusting for age, sex, diabetes, and hypertension, MPI remained weakly but significantly correlated with CRP, EF, CI, SI, SI/PP, mitral E- and A-wave velocities, and TPRI. MPI did not predict fatal and nonfatal CV events (risk ratio 1.06 per unit MPI, 95% C.I. 0.56–2.04; P = 0.85) at a mean follow-up of 7.1 ± 2.2 years. Conclusions: In a population-based sample of adults with high prevalence of diabetes, hypertension, and obesity but without overt CV disease, MPI has weak associations with clinical and physiologic determinants of cardiac function. Moreover, MPI does not provide prognostic information for CV events in this population. Though conceptually attractive as a global measure of cardiac function, MPI has limited utility in a high-risk population without clinical CV disease. [ABSTRACT FROM AUTHOR]

Background: Pulmonary fibrosis and atherosclerosis have many similarities at the histopathologic level. Moreover, fibrotic lung diseases exhibit systemic effects and have the potential to affect the vasculature beyond the lung. The existence of a relationship between the two, however, has not been studied. Methods: To investigate whether fibrotic lung disorders may predispose to atherosclerosis, we conducted a cross-sectional study of 630 patients referred for lung transplantation evaluation at a university hospital. We compared the prevalence of angiographic coronary artery disease (CAD) in patients with fibrotic vs nonfibrotic lung diseases. Results: Fibrotic lung diseases were associated with an increased prevalence of CAD compared with nonfibrotic diseases after adjustment for traditional risk factors (odds ratio, 2.18; 95% confidence interval, 1.17-4.06). The magnitude and significance of this association were maintained when only nongranulomatous fibrotic disease or its subset, idiopathic pulmonary fibrosis, was examined. The strength of the relationship between fibrotic disorders and CAD increased when multivessel disease was analyzed (odds ratio, 4.16; 95% confidence interval, 1.46-11.9). No significant association was detected for granulomatous fibrotic disorders (odds ratio, 1.56; 95% confidence interval, 0.47-5.16; P = .47), although this subgroup had fewer cases of CAD for analysis. Conclusions: These findings support an association between fibrotic lung disorders and CAD. Further research is necessary to confirm this relationship and to explore the pathologic processes underlying, and potentially linking, these 2 conditions. [ABSTRACT FROM AUTHOR]

Little is known about the distribution of cardiac sources of embolism among African-Americans with cryptogenic cerebrovascular events. We compared the prevalence of potential cardiac sources of embolism between black and white patients referred to our laboratory for transesophageal echocardiographic (TEE) evaluation of unexplained stroke or transient ischemic attack. Records were reviewed to exclude subjects with high-risk cardiac or vascular disorders likely to explain the index event. Of 297 patients satisfying the inclusion criteria, 196 were white and 87 black. Potential cardioembolic sources were significantly less common in blacks than in whites (adjusted odds ratio [OR], 0.44; 95% confidence interval [CI] 0.26 to 0.75), and related largely to the difference in prevalence of interatrial communication (OR 0.40; 95% CI 0.21 to 0.74). In contrast, African-Americans had a higher prevalence of left ventricular (LV) hypertrophy (OR 3.50; 95% CI 1.97 to 6.22), and particularly, moderate or severe hypertrophy (OR 4.03; 95% CI 1.88 to 9.65) compared with whites. In conclusion, in African-Americans with unexplained cerebrovascular events, the yield of TEE for potential cardioembolic sources, and especially interatrial communication, is lower than in their white counterparts. African-Americans exhibit a substantially higher prevalence of LV hypertrophy, which may be a marker for a higher burden of subclinical cerebrovascular disease involved in the pathogenesis of cryptogenic cerebral ischemia in this population. [Copyright &y& Elsevier]

Reevaluates the function of calcium channel blocker (CCB) drugs in patients with uncomplicated and diabetic hypertension. Adverse coronary events related to the use of CCB; Effect of CCB in patients with acute coronary syndromes; Comparison of CCB versus beta blockers in coronary artery disease-stable angina; Effect of CCB in left ventricular dysfunction.

Objective: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population. Methods: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics. Results: Mean age for the 2433 included participants was 72.0 years, 33.6% were male, and 3.7% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95% confidence interval = 0.03–0.33). Conclusion: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity. [ABSTRACT FROM AUTHOR]

The author discusses research on the relationship of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) with subclinical cardiac dysfunction. He references the study "Subclinical Left Ventricular Dysfunction and Silent Cerebrovascular Disease" by Cesare Russo that was published in the current issue. He believes that the study provides evidence of the link between microvascular disease and subclinical end-organ damage of major organs such as the heart and brain.

The author comments on a study published in this issue of the journal which examined the link between adiponectin and insulin sensitivity in a group of older Swedish men. He expresses concern over the study's assumption on the correlation between AdipoQ single nucleotide polymorphisms (SNPs) and adiposity. He points out that there is a lack of independent support for the idea that reduced adiposity serves as mediator of adiponectin's role in insulin sensitivity.

Pheochromocytoma is a notorious clinical entity. Although suspicion is aroused by severe hypertension in young patients, this sign is often absent. We present a case in which early absence of hypertension and nonspecific signs and symptoms led to failure of prompt diagnosis. The delay proved fatal when the patient developed fulminant pheochromocytoma crisis. This case illustrates a variety of clinical features seen from the vantage of the evolution of the disease as it went unrecognized. The patient's course underscores the importance of familiarity with the gamut of manifestations for timely diagnosis, and the priority of the latter given the looming risk of overwhelming complications. [ABSTRACT FROM AUTHOR]

Introduction: Non‐alcoholic fatty liver disease (NAFLD) has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD. Methods: We conducted a prospective cohort study of 6,928 adults of Hispanic/Latino background who had no diabetes, did not report excessive alcohol use, and no hepatitis B and C infection at baseline (2008–2011). We estimated risk ratios (RR) for incident diabetes, identified from visit 2 examination by glucose measurements or antidiabetic medication use, with baseline liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma‐glutamyl transpeptidase (GGT)). Results: A total of 738 adults developed diabetes during 6 years of follow‐up. After adjusting for participant characteristics at baseline, versus the lowest quartile, highest quartiles of ALT and GGT were associated with risks for incident diabetes (RR for ALT: 1.51 [95% CI 1.03–2.22], p‐trend = 0.006; RR for GGT: 2.39 [1.60–3.55], p‐trend = 0.001). Higher GGT levels predicted increased risk of incident diabetes even among those with ALT or AST below the median levels. The associations of ALT and GGT with incident diabetes were similar among most Hispanic background but were not seen among Dominicans (p for interaction <0.05). The association of AST with incident diabetes was found only among light‐to‐moderate alcohol drinkers (RR = 1.50 [1.20–1.86]) but not abstainers (RR = 0.91 [0.69–1.20], p for interaction = 0.006). Conclusion: Higher ALT and GGT levels are associated with increased risk of developing diabetes among Latinos. Liver enzyme tests might aid in diabetes prevention by identifying high‐risk individuals. [ABSTRACT FROM AUTHOR]

Aim: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF‐associated clinical variables. Methods and results: In the prospective population‐based Age, Gene/Environment Susceptibility Reykjavik Study (AGES‐RS), 440 individuals developed HF after their first visit with a median follow‐up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non‐parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre‐established clinical parameters linked to HF. A subset of 8–10 distinct or overlapping serum proteins predicted different future HF outcomes, and C‐statistics were used to assess discrimination, revealing proteins combined with a C‐index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES‐RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N‐terminal pro‐B‐type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study. Conclusion: A small number of circulating proteins accurately predicted future HF in the AGES‐RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study. [ABSTRACT FROM AUTHOR]

Background Hypertension-related diseases are major causes of morbidity among women living with HIV. We evaluated cross-sectional associations of race/ethnicity and HIV infection with hypertension prevalence, awareness, treatment, and control. Methods Among women recruited into Southern sites of the Women's Interagency HIV Study (2013–2015), hypertension was defined as (1) systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg according to clinical guidelines when data were collected, (2) self-report of hypertension, or (3) use of antihypertensive medication. Awareness was defined as self-report of hypertension, and treatment was self-report of any antihypertensive medication use. Blood pressure control was defined as <140/90 mm Hg at baseline. Prevalence ratios for each hypertension outcome were estimated through Poisson regression models with robust variance estimators adjusted for sociodemographic, behavioral, and clinical risk factors. Results Among 712 women, 56% had hypertension and 83% were aware of their diagnosis. Of those aware, 83% were using antihypertensive medication, and 63% of those treated had controlled hypertension. In adjusted analyses, non-Hispanic White and Hispanic women had 31% and 48% lower prevalence of hypertension than non-Hispanic Black women, respectively. Women living with HIV who had hypertension were 19% (P =.04) more likely to be taking antihypertension medication when compared with women living without HIV. Conclusions In this study population of women living with and without HIV in the US South, the prevalence of hypertension was lowest among Hispanic women and highest among non-Hispanic Black women. Despite similar hypertension prevalence, women living with HIV were more likely to be taking antihypertensive medication when compared with women living without HIV. [ABSTRACT FROM AUTHOR]

Background Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. Methods Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). Results GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. Conclusions GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength. [ABSTRACT FROM AUTHOR]

A response from the author to a letter to the editor about their article "Higher Circulating Adiponectin Levels Are Associated With Increased Risk of Atrial Fibrillation in Older Adults" in the 2015 (Volume 101) issue of the journal "Heart" is presented.

Background We sought to determine the associations between individual nonesterified fatty acids (NEFAs) and disability and mobility limitation. Methods We studied 1 734 participants in the Cardiovascular Health Study (CHS), an ongoing population-based cohort study of community-living older American adults. We measured 35 individual NEFA species in fasting serum samples obtained at the 1996–1997 clinic visit. Using yearly assessments of activities of daily living and self-reported mobility, we identified participants with incident disability or mobility limitation during 15 years of follow-up. Cox proportional hazards regression models were used to determine the associations between per SD increment in the individual NEFAs and incident disability and mobility limitations with adjustment for potential confounding factors. Results Higher concentrations of total and a broad range of individual NEFA species were associated with risk of disability and mobility limitation (disability: HR per SD of total NEFA [ SD  = 174.70] = 1.11, 95% CI = 1.04–1.18, p  = .001; mobility limitation: HR per SD of total NEFA = 1.09, 95% CI = 1.02–1.16, p  = .01). Among individual saturated NEFAs (SFAs), myristic (14:0) and palmitic (16:0) acids were significantly associated with higher risk of both disability and mobility limitations, but longer-chain FAs were not. Most individual monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFAs), and trans FAs were positively significantly associated with higher risks of both disability and mobility limitation. In contrast, most n-3 PUFA species were not associated with disability or mobility limitation. Conclusions Higher risks of disability and mobility limitation were observed for proinflammatory intermediate-chain SFAs, MUFAs, n-6 PUFAs, and trans FAs. Our findings indicated no significant association for anti-inflammatory n-3 PUFAs. [ABSTRACT FROM AUTHOR]

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. Article Highlights: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response. [ABSTRACT FROM AUTHOR]

Non-esterified fatty acids have been implicated in the pathogenesis of diabetes and cardiovascular disease. No longitudinal study has assessed their effects on peripheral artery disease (PAD). We determined the relationships between NEFAs and incident clinical PAD and abnormal ankle-brachial index (ABI) in a population-based cohort of older persons. We evaluated 4575 community living participants aged >65 years who underwent measurement of circulating NEFAs in fasting specimens and ABI in 1992–1993. Participants were assessed annually for clinical PAD until 2015 and underwent repeat ABI in 1998–1999. We used Cox proportional hazards regression to model the associations between NEFAs and risk of clinical PAD and logistic regression to model the associations of NEFAs with incident abnormal ABI. Mean age was 74.8 years, 59% were female, and 17% were Black. NEFAs were associated with higher risk of clinical PAD in unadjusted and adjusted models. The adjusted hazard ratios for incident clinical PAD were 1.51 (95%CI = 1.06–2.13, p = 0.02) across extreme tertiles, and 1.14 (95%CI = 0.99–1.31, p = 0.08) per standard deviation higher NEFA. The corresponding odds ratios for abnormal ABI were 0.95 (95%CI = 0.69–1.32, p = 0.76) across extreme tertiles, and 1.03 (95%CI = 0.89–1.20, p = 0.68) per standard deviation higher NEFA. Relationships appeared similar irrespective of sex, race, or pre-existing cardiovascular disease, but were stronger later than earlier in follow-up. Higher serum levels of NEFAs are significantly associated with increased likelihood of clinical PAD over long-term follow-up but not with 6-year decline in ABI. NEFAs may offer a potential target for intervention against clinical PAD. [Display omitted] • Higher non-esterified fatty acids (NEFAs) were significantly associated with incident clinical peripheral artery disease (PAD) over a long-term follow-up. • NEFAs may have a relationship with downstream consequences of progressive atherosclerosis. • NEFAs may represent part of the link between oxidative stress and resulting health outcomes like PAD. • This is the first study to longitudinally examine the association between NEFAs and PAD. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be racedependent. Methods: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC. Results: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm² decrement [95% CI = 1.23–1.62]), and showed the same to be true for White men (HR = 1.12 [1.03–1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70–0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men. Conclusions: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: Heart failure is a prevalent disorder whose prognosis remains poor despite advances in treatment. Women with or at risk for HIV may be particularly susceptible, yet the metabolic pathways that promote myocardial disease and heart failure in this context remain incompletely characterized. Methods: To evaluate the metabolomic signatures of cardiac magnetic resonance measured phenotypes, we used available plasma metabolomic measures from participants in the Women's Interagency HIV Study who underwent cardiac magnetic resonance imaging. Our primary outcomes were myocardial extracellular volume fraction (MECV) and intramyocardial triglyceride content (IMTG). We applied partial least squares and identified the top 10 lipid and polar metabolites associated with MECV and IMTG. We used multivariable linear regression to evaluate these metabolites' individual associations with each phenotype. Results: The mean age of participants (n = 153) was 53 ± 7, 93% were Black or Hispanic, and 74% were HIV positive. Phenylacetylglutamine, a microbial metabolite, was positively associated with MECV after full adjustment and false discovery rate correction. Three phosphatidylcholine species, N-acetylaspartic acid, and a lysophosphatidylcholine species were inversely associated with IMTG, while prolylglycine, methionine sulfoxide, sphingosine, taurine, and phosphorylcholine were positively associated with this phenotype. We found no evidence of interaction by HIV for the observed associations, but there was effect modification by hepatitis C virus of taurine's and phosphorylcholine's associations with IMTG. Conclusion: Among women with or at risk for HIV, we related various lipid and polar metabolites to cardiac fibrosis or steatosis, of which phenylacetylglutamine, N-acetylaspartic acid, and prolylglycine are novel. These findings implicate plausible mechanisms that could be targetable for therapeutics. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity is a major driver of physical and cognitive impairment, but rates of decline are also related to ageing. We sought to determine trajectories of decline in a large cohort by disease status, and examined their correspondence with biomarkers of ageing processes including growth hormone, sex steroid, inflammation, visceral adiposity and kidney function pathways.Methods: We have followed the 5888 participants in the Cardiovascular Health Study (CHS) for healthy ageing and longevity since 1989-90. Gait speed, grip strength, modified mini-mental status examination (3MSE) and the digit symbol substitution test (DSST) were assessed annually to 1998-99 and again in 2005-06. Insulin-like growth hormone (IGF-1), dehydroepiandrosterone sulphate (DHEAS), interleukin-6 (IL-6), adiponectin and cystatin-C were assessed 3-5 times from stored samples. Health status was updated annually and dichotomized as healthy vs not healthy. Trajectories for each function measure and biomarker were estimated using generalized estimating equations as a function of age and health status using standardized values.Results: Trajectories of functional decline showed strong age acceleration late in life in healthy older men and women as well as in chronically ill older adults. Adiponectin, IL-6 and cystatin-C tracked with functional decline in all domains; cystatin-C was consistently associated with functional declines independent of other biomarkers. DHEAS was independently associated with grip strength and IL-6 with grip strength and gait speed trajectories.Conclusions: Functional decline in late life appears to mark a fundamental ageing process in that it occurred and was accelerated in late life regardless of health status. Cystatin C was most consistently associated with these functional declines. [ABSTRACT FROM AUTHOR]

Background People with human immunodeficiency virus (HIV) have been reported to have increased risk of clinical and subclinical cardiovascular disease. Existing studies have focused on men and often have been uncontrolled or lacked adequate HIV-negative comparators. Methods We performed echocardiography in the Women's Interagency HIV Study to investigate associations of HIV and HIV-specific factors with cardiac phenotypes, including left ventricular systolic dysfunction (LVSD), isolated LV diastolic dysfunction (LVDD), left atrial enlargement (LAE), LV hypertrophy (LVH), and increased tricuspid regurgitation velocity (TRV). Results Of 1654 participants (age 51 ± 9 years), 70% had HIV. Sixty-three (5.4%) women with HIV (WWH) had LVSD; 71 (6.5%) had isolated LVDD. Compared with women without HIV (WWOH), WWH had a near-significantly increased risk of LVSD (adjusted relative risk = 1.69; 95% confidence interval = 1.00 to 2.86; P =.051). No significant association was noted for HIV seropositivity with other phenotypes, but there was a risk gradient for decreasing CD4+ count among WWH that approached or reached significance for isolated LVDD, LAE, and LVH. WWH with CD4+ count <200 cells/mm3 had significantly higher prevalence of LAE, LVH, and high TRV than WWOH. There were no consistent associations for viral suppression or antiretroviral drug exposure. Conclusions This study suggests that WWH have a higher risk of LVSD compared with sociodemographically similar WWOH, but their risk for isolated LVDD, LAE, LVH, and high TRV is increased only with reduced CD4+ count. Although these findings warrant replication, they support the importance of cardiovascular risk-factor and HIV-disease control for heart disease prevention in this population. [ABSTRACT FROM AUTHOR]

A response by Jorge R. Kizer and Richard B. Devereux by to several letters to the editor about their article "Patent Foramen Ovale and Unexplained Stroke" in the December 1, 2005 issue is presented.

The article offers a case vignette of patent foramen ovale in young adults with unexplained stroke. Strokes in young people are often cryptogenic. The most prevalent potential source of cardioembolism in young adults with cryptogenic stroke is patent foramen ovale. The case discussed in this article focuses on patent foramen ovale occurring in young patients or middle-aged patients who have minimal risk factors for atherosclerosis and in whom evaluations for vascular disease or systemic illness are negative. The article looks at the treatment options in patients with cryptogenic stroke.

Objective: The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes.Research Design and Methods: Heart rate (HR) and measures of HR variability (HRV) were derived from 24-h electrocardiographic monitoring. Blood pressure, seated and standing, was measured. Cox proportional hazards models and linear mixed models were used to analyze the associations between HRV, HR, and orthostatic hypotension (SBP >20 mmHg decline) and incident diabetes or longitudinal FG change.Results: The mean annual unadjusted FG change was 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged over 4-11 (DFA1) or 12-20 beats (DFA2)-reflecting greater versus less organization of beat-to-beat intervals-were associated with less FG increase over time (per 1-SD increment: DFA1: -0.49 mg/dL/year [-0.96, -0.03]; DFA2: -0.55 mg/dL/year [-1.02, -0.09]). In mutually adjusted analyses, higher SD of the N-N interval (SDNN) was associated with less FG increase over time (per 1-SD increment: SDNN: -0.62 mg/dL/year [-1.22, -0.03]). Higher values of DFA1, DFA2, and SDNN were each associated with greater insulin secretion and insulin sensitivity but not with incident diabetes. We observed no association of HR or orthostatic hypotension with diabetes or FG change.Conclusions: Specific measures of cardiac autonomic function are prospectively related to FG level changes and insulin secretion and action. [ABSTRACT FROM AUTHOR]

Matrix Gla protein (MGP) is an inhibitor of calcification that requires carboxylation by vitamin K for activity. The inactive form of MGP, dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP), has been associated with increased calcification. However, it is not known whether there is a longitudinal relationship between dephosphorylated-uncarboxylated matrix Gla protein levels and coronary and aortic calcification in large population cohorts. The Multi-Ethnic Study of Atherosclerosis (MESA) followed participants with serial cardiac computed tomography (CT) measures of vascular calcification. Dp-ucMGP was measured at baseline in a subset of participants who completed baseline and follow-up CTs approximately 10 years later and had available plasma specimens (n = 2663). Linear mixed effects models (LMMs) were used to determine the association of dp-ucMGP with the simultaneous incidence and progression of coronary artery, ascending thoracic aortic, or descending thoracic aortic calcification (CAC, ATAC, DTAC)]. For every one standard deviation (SD, 178 pmol/L) increment in dp-ucMGP, CAC increased by 3.44 ([95% CI = 1.68, 5.21], p < 0.001) Agatston units/year (AU/year), ATAC increased by 0.63 ([95% CI = 0.27, 0.98], p = 0.001) AU/year, and DTAC increased by 8.61 ([95% CI = 4.55, 12.67], p < 0.001) AU/year. The association was stronger for DTAC in those ≥65 years and with diabetes. We found a positive association of the inactive form of matrix Gla protein, dp-ucMGP, and long-term incidence/progression of CAC, ATAC, and DTAC. Future studies should investigate dp-ucMGP as a calcification regulator and MGP as a possible therapeutic target to slow progression of calcification in the vasculature. [Display omitted] • Matrix Gla protein inhibits calcification. • The inactive dephosphorylated-uncarboxylated form of matrix Gla protein may increase calcification risk. • Inactive matrix Gla protein was related to coronary artery, ascending and descending thoracic aortic calcification. • Dephosphorylated-uncarboxylated matrix Gla protein may be a useful biomarker for calcification risk. [ABSTRACT FROM AUTHOR]

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989–1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996–1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders. [ABSTRACT FROM AUTHOR]

Purpose Loss of muscle mass and strength are associated with long‐term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults. Methods: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996–1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub‐cohort, 1331 participants underwent dual energy X‐ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus. Results: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6 mg/dl) was associated with greater grip strength (kg force) β = 0.44 [0.16, 0.72]; p = 0.002) and higher lean muscle mass (kg) (β = 0.43 [0.08, 0.78]; p = 0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p = 0.65). Conclusion: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community‐living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults. [ABSTRACT FROM AUTHOR]

The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)2) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥65 years at baseline (1989–1990 or 1992–1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age. [ABSTRACT FROM PUBLISHER]

Objectives: This study was designed to facilitate clinical use of central pulse pressure (PP). We sought to determine a value that might predict adverse outcome and thereby provide a target for assessment of intervention strategies. Background: We previously documented that central PP more strongly relates to carotid hypertrophy and extent of atherosclerosis and, more importantly, better predicts incident cardiovascular disease (CVD) than brachial PP. Methods: Radial applanation tonometry was performed in the third Strong Heart Study examination to determine central blood pressure. Cox regression analyses were performed using pre-specified covariates and quartiles of central and brachial PP. Results: Among 2,405 participants without prevalent CVD, 344 suffered CVD events during 5.6 ± 1.7 years. Quartiles of central PP (p < 0.001) predicted outcome more strongly than quartiles of brachial PP (p = 0.052). With adjustment for covariates, only the event rate in the fourth quartile of central PP (≥50 mm Hg) was significantly higher than that in the first quartile (hazard ratio [HR]: 1.69, 95% confidence interval [CI]: 1.20 to 2.39, p = 0.003). Central PP ≥50 mm Hg was related to outcome in both men (HR: 2.06, 95% CI: 1.39 to 3.04, p < 0.001) and women (HR: 2.03, 95% CI: 1.55 to 2.65, p < 0.001); in participants with (HR: 1.84, 95% CI: 1.41 to 2.39, p < 0.001) and without diabetes (HR: 1.91, 95% CI: 1.29 to 2.83, p = 0.001); and in individuals younger (HR: 2.51, 95% CI: 1.59 to 3.95, p < 0.001) and older (HR: 1.53, 95% CI: 1.19 to 1.97, p = 0.001) than the age of 60 years. Conclusions: Central PP ≥50 mm Hg predicts adverse CVD outcome and may serve as a target in intervention strategies if confirmed in other populations and in prospective studies. [Copyright &y& Elsevier]