Carlee Moser

Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium

Background Tools for the prediction of atrial fibrillation (AF) may identify high‐risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors. Methods and Results Individual‐level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment—Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5‐year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C‐statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C‐statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, −0.0032; 95% CI, −0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C‐statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C‐statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate. Conclusion A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies

AIMS B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information. METHODS AND RESULTS We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS. CONCLUSION B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

Risk assessment for incident heart failure in individuals with atrial fibrillation

Atrial fibrillation (AF) is a strong risk factor for heart failure (HF); HF onset in patients with AF is associated with increased morbidity and mortality. Risk factors that predict HF in individuals with AF in the community are not well established.

Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir

BACKGROUND Specific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation. METHODS We compared the percentage change in BMD over 96 weeks in 328 HIV-infected, treatment-naive individuals randomized equally to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). We also determined whether baseline levels of inflammation markers and immune activation were independently associated with BMD loss. RESULTS At week 96, the mean percentage changes from baseline in spine and hip BMDs were similar in the protease inhibitor (PI) arms (spine: -4.0% in the ATV/r group vs -3.6% in the DRV/r [P = .42]; hip: -3.9% in the ATV/r group vs -3.4% in the DRV/r group [P = .36]) but were greater in the combined PI arms than in the RAL arm (spine: -3.8% vs -1.8% [P < .001]; hip: -3.7% vs -2.4% [P = .005]). In multivariable analyses, higher baseline concentrations of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip BMD loss, whereas markers of CD4(+) T-cell senescence and exhaustion (CD4(+)CD28(-)CD57(+)PD1(+)) and CD4(+) T-cell activation (CD4(+)CD38(+)HLA-DR(+)) were associated with lumbar spine BMD loss. CONCLUSIONS BMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving PIs, ATV/r, or DRV/r but lowest among those receiving RAL. Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss.

Body Composition Changes After Initiation of Raltegravir or Protease Inhibitors: ACTG A5260s

BACKGROUND Fat gain after antiretroviral therapy (ART) occurs, and its association with protease inhibitors (PIs) is unclear. METHODS Peripheral and central fat depots and lean mass were measured using standardized and centrally read abdominal CT scans and whole-body dual-energy absorptiometry scans over a 96-week period in human immunodeficiency virus (HIV)-infected treatment-naive participants. The patients were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) in ACTG A5260s, a substudy of A5257. Within arm changes were assessed with signed-rank tests. The 96-week percentage changes in fat and lean mass in the 2 PI arms were not different, thus the PI arms were combined and compared to the RAL arm. Associations between baseline biomarkers and changes in body composition were assessed. All analyses used linear regression models. RESULTS 328 patients were randomized (90% male, 44% white non-Hispanic). The median age was 36 years, HIV-1 RNA 4.6 log10 copies/mL, and CD4 349 cells/μL. Overall, at week 96, increases in limb fat (13.4%), subcutaneous (19.9%) and visceral abdominal fat (25.8%), trunk fat (18%), and lean mass (1.8%) were apparent (P < .001 for changes within each arm). Changes for all fat and lean outcomes were not different between the PI arms or between the RAL and the combined PI arms. Higher baseline HIV-1 RNA levels were associated with greater gains in peripheral and central fat. CONCLUSIONS In treatment-naive participants initiating ART with TDF/FTC, no differences in lean mass and regional fat were found with RAL when compared with ATV/r or DRV/r over 96 weeks. CLINICAL TRIALS REGISTRATION NCT00811954 and NCT00851799.

Association of Sex Hormones, Aging and Atrial Fibrillation in Men: The Framingham Heart Study

Background—Endogenous sex hormones have been related to cardiovascular outcomes and mortality. We hypothesized that sex hormones are related to atrial fibrillation (AF) in a community-based cohort of middle-aged to older men. Methods and Results—We examined testosterone, estradiol, and dehydroepiandrosterone sulfate in relation to incident AF in men participating in the Framingham Heart Study. We assessed the 10-year risk of AF in multivariable-adjusted hazard models. The cohort consisted of 1251 men (age, 68.0±8.2 years), of whom 275 developed incident AF. We identified a significant interaction between age and testosterone and, therefore, stratified men into age 55 to 69 years (n=786), 70 to 79 years (n=351), and ≥80 years (n=114). In men aged 55 to 69 years, each 1 SD decrease in testosterone was associated with hazard ratio (HR) 1.30 (95% confidence interval [CI], 1.07–1.59) for incident AF. The association between testosterone and 10-year incident AF in men 70 to 79 years did not reach statistical significance. In men ≥80 years, a 1 SD decrease in testosterone was associated with HR 3.53 (95% CI, 1.96–6.37) for AF risk. Estradiol was associated with incident AF (HR, 1.12; 95% CI, 1.01–1.26). Dehydroepiandrosterone sulfate had a borderline association with risk of AF that was not statistically significant (HR, 1.12; 95% CI, 0.99–1.28). Conclusions—Testosterone and estradiol are associated with incident AF in a cohort of older men. Testosterone deficiency in men ≥80 years is strongly associated with AF risk. The clinical and electrophysiological mechanisms underlying the associations between sex hormones and AF in older men merit continued investigation.

Atrial Fibrillation Patterns and Risks of Subsequent Stroke, Heart Failure, or Death in the Community

Background Atrial fibrillation (AF) patterns and their relations with long‐term prognosis are uncertain, partly because pattern definitions are challenging to implement in longitudinal data sets. We developed a novel AF classification algorithm and examined AF patterns and outcomes in the community. Methods and Results We characterized AF patterns between 1980 and 2005 among Framingham Heart Study participants who survived ≥1 year after diagnosis. We classified participants based on their pattern within the first 2 years after detection as having AF without recurrence, recurrent AF, or sustained AF. We examined associations between AF patterns and 10‐year survival using proportional hazards regression. Among 612 individuals with AF, mean age was 72.5±10.8 years, and 53% were men. Of these, 478 participants had ≥2 electrocardiograms (median, 3; limits 2 to 23) within 2 years after initial AF and were classified as having AF without 2‐year recurrence (n=63, 10%), recurrent AF (n=162, 26%) or sustained AF (n=207, 34%), although some (n=46, 8%) were indeterminate. Of 432 classified participants, 363 died, 75 had strokes, and 110 were diagnosed with heart failure during the next 10 years. Relative to individuals without AF recurrence, the multivariable‐adjusted mortality was higher among people with recurrent AF (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.26 to 3.29) and sustained AF (HR, 2.36; 95% CI, 1.49 to 3.75). Conclusions In our community‐based AF sample, only 10% had AF without early‐term (2‐year) recurrence. Compared with individuals without 2‐year AF recurrences, the 10‐year prognosis was worse for individuals with either sustained or recurrent AF. Our proposed AF classification algorithm may be applicable in longitudinal datas ets.

Age of Natural Menopause and Atrial Fibrillation: the Framingham Heart Study

BACKGROUND Early menopausal age is associated with risk of cardiovascular events including myocardial infraction, stroke, and increased mortality. Relations between menopausal age and atrial fibrillation (AF) have not been investigated. We examined the association between menopausal age and AF. METHODS Framingham Heart Study women ≥ 60 years old without prevalent AF and natural menopause were followed up for 10 years or until incident AF. Menopausal age was modeled as a continuous variable and by categories (<45, 45-53, and >53 years). We used Cox proportional hazards regression to determine associations between menopausal age and AF risk. RESULTS In 1,809 Framingham women (2,662 person-examinations, mean baseline age 71.4 ± 7.6 years, menopausal age 49.8 ± 3.6 years), there were 273 unique participants with incident AF. We did not identify a significant association between the SD of menopausal age (3.6 years) and AF (hazard ratio [HR] per SD 0.94, 95% CI 0.83-1.06; P = .29). In a multivariable model with established risk factors for AF, menopausal age was not associated with incident AF (HR per SD 0.97, 95% CI 0.86-1.09; P = .60). Examining categorical menopausal age, earlier menopausal age (<45 years) was not significantly associated with increased AF risk compared with older menopausal age >53 years (HR 1.20, 95% CI 0.74-1.94; P = .52) or menopausal age 45 to 53 years (HR 1.38, 95% CI 0.93-2.04; P = .11). CONCLUSION In our moderate-sized, community-based sample, we did not identify menopausal age as significantly increasing AF risk. However, future larger studies will need to examine whether there is a small effect of menopausal age on AF risk.

Dolutegravir Plus Lamivudine Maintains Human Immunodeficiency Virus-1 Suppression Through Week 48 in a Pilot Randomized Trial

Clinical Trials Registration NCT02263326.

Changes in Insulin Resistance After Initiation of Raltegravir or Protease Inhibitors With Tenofovir-Emtricitabine: AIDS Clinical Trials Group A5260s

HIV-infected treatment-naive participants were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) over 96 weeks. Insulin resistance increased rapidly and then plateaued and no differences were found with RAL when compared to ATV/r or DRV/r.