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BACKGROUND: High-sensitivity C-reactive protein (CRP), low-density lipoprotein (LDL) cholesterol, and lipoprotein(a) levels contribute to 5-year and 10-year predictions of cardiovascular risk and represent distinct pathways for pharmacologic intervention. More information about the usefulness of these biomarkers for predicting cardiovascular risk over longer periods of time in women is needed because early-life intervention represents an important risk-reduction method. METHODS: We measured high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels at baseline in 27,939 initially healthy U.S. women who were subsequently followed for 30 years. The primary end point was a first major adverse cardiovascular event, which was a composite of myocardial infarction, coronary revascularization, stroke, or death from cardiovascular causes. We calculated the adjusted hazard ratios and 95% confidence intervals across quintiles of each biomarker, along with 30-year cumulative incidence curves adjusted for age and competing risks. RESULTS: The mean age of the participants at baseline was 54.7 years. During the 30-year follow-up, 3662 first major cardiovascular events occurred. Quintiles of increasing baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) all predicted 30-year risks. Covariable-adjusted hazard ratios for the primary end point in a comparison of the top with the bottom quintile were 1.70 (95% confidence interval [CI], 1.52 to 1.90) for high-sensitivity CRP, 1.36 (95% CI, 1.23 to 1.52) for LDL cholesterol, and 1.33 (95% CI, 1.21 to 1.47) for lipoprotein(a). Findings for coronary heart disease and stroke appeared to be consistent with those for the primary end point. Each biomarker showed independent contributions to overall risk. The greatest spread for risk was obtained in models that incorporated all three biomarkers. CONCLUSIONS: A single combined measure of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels among initially healthy U.S. women was predictive of incident cardiovascular events during a 30-year period. These data support efforts to extend strategies for the primary prevention of atherosclerotic events beyond traditional 10-year estimates of risk. (Funded by the National Institutes of Health; Women's Health Study ClinicalTrials.gov number, NCT00000479.).
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BACKGROUND: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. METHODS: Using a nontargeted mass spectrometry approach, over 11â 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. RESULTS: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. CONCLUSIONS: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.
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Biomarcadores , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Prevenção Primária , Rosuvastatina Cálcica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/sangue , Biomarcadores/sangue , Prevenção Primária/métodos , Fatores de Tempo , Resultado do Tratamento , LDL-Colesterol/sangue , Lipídeos/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/diagnóstico , LipidômicaRESUMO
Importance: Higher adherence to the Mediterranean diet has been associated with reduced risk of all-cause mortality, but data on underlying molecular mechanisms over long follow-up are limited. Objectives: To investigate Mediterranean diet adherence and risk of all-cause mortality and to examine the relative contribution of cardiometabolic factors to this risk reduction. Design, Setting, and Participants: This cohort study included initially healthy women from the Women's Health Study, who had provided blood samples, biomarker measurements, and dietary information. Baseline data included self-reported demographics and a validated food-frequency questionnaire. The data collection period was from April 1993 to January 1996, and data analysis took place from June 2018 to November 2023. Exposures: Mediterranean diet score (range, 0-9) was computed based on 9 dietary components. Main Outcome and Measures: Thirty-three blood biomarkers, including traditional and novel lipid, lipoprotein, apolipoprotein, inflammation, insulin resistance, and metabolism measurements, were evaluated at baseline using standard assays and nuclear magnetic resonance spectroscopy. Mortality and cause of death were determined from medical and death records. Cox proportional hazards regression was used to calculate hazard ratios (HRs) for Mediterranean diet adherence and mortality risk, and mediation analyses were used to calculate the mediated effect of different biomarkers in understanding this association. Results: Among 25â¯315 participants, the mean (SD) baseline age was 54.6 (7.1) years, with 329 (1.3%) Asian women, 406 (1.6%) Black women, 240 (0.9%) Hispanic women, 24â¯036 (94.9%) White women, and 95 (0.4%) women with other race and ethnicity; the median (IQR) Mediterranean diet adherence score was 4.0 (3.0-5.0). Over a mean (SD) of 24.7 (4.8) years of follow-up, 3879 deaths occurred. Compared with low Mediterranean diet adherence (score 0-3), adjusted risk reductions were observed for middle (score 4-5) and upper (score 6-9) groups, with HRs of 0.84 (95% CI, 0.78-0.90) and 0.77 (95% CI, 0.70-0.84), respectively (P for trend < .001). Further adjusting for lifestyle factors attenuated the risk reductions, but they remained statistically significant (middle adherence group: HR, 0.92 [95% CI, 0.85-0.99]; upper adherence group: HR, 0.89 [95% CI, 0.82-0.98]; P for trend = .001). Of the biomarkers examined, small molecule metabolites and inflammatory biomarkers contributed most to the lower mortality risk (explaining 14.8% and 13.0%, respectively, of the association), followed by triglyceride-rich lipoproteins (10.2%), body mass index (10.2%), and insulin resistance (7.4%). Other pathways, including branched-chain amino acids, high-density lipoproteins, low-density lipoproteins, glycemic measures, and hypertension, had smaller contributions (<3%). Conclusions and Relevance: In this cohort study, higher adherence to the Mediterranean diet was associated with 23% lower risk of all-cause mortality. This inverse association was partially explained by multiple cardiometabolic factors.
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Biomarcadores , Dieta Mediterrânea , Humanos , Dieta Mediterrânea/estatística & dados numéricos , Feminino , Pessoa de Meia-Idade , Biomarcadores/sangue , Estudos de Coortes , Cooperação do Paciente/estatística & dados numéricos , Mortalidade , Causas de Morte , Idoso , Adulto , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
BACKGROUND: Premature coronary heart disease (CHD) is a major cause of death in women. We aimed to characterize biomarker profiles of women who developed CHD before and after age 65 years. METHODS: In the Women's Health Study (median follow-up 21.5 years), women were grouped by age and timing of incident CHD: baseline age <65 years with premature CHD by age 65 years (25 042 women; 447 events) and baseline age ≥65 years with nonpremature CHD (2982 women; 351 events). Associations of 44 baseline plasma biomarkers measured using standard assays and a nuclear magnetic resonance (NMR)-metabolomics assay were analyzed using Cox models adjusted for clinical risk factors. RESULTS: Twelve biomarkers showed associations only with premature CHD and included lipoprotein(a), which was associated with premature CHD [adjusted hazard ratio (HR) per SD: 1.29 (95% CI 1.17-1.42)] but not with nonpremature CHD [1.09(0.98-1.22)](Pinteraction = 0.02). NMR-measured lipoprotein insulin resistance was associated with the highest risk of premature CHD [1.92 (1.52-2.42)] but was not associated with nonpremature CHD (Pinteraction <0.001). Eleven biomarkers showed stronger associations with premature vs nonpremature CHD, including apolipoprotein B. Nine NMR biomarkers showed no association with premature or nonpremature CHD, whereas 12 biomarkers showed similar significant associations with premature and nonpremature CHD, respectively, including low-density lipoprotein (LDL) cholesterol [1.30(1.20-1.45) and 1.22(1.10-1.35)] and C-reactive protein [1.34(1.19-1.50) and 1.25(1.08-1.44)]. CONCLUSIONS: In women, a profile of 12 biomarkers was selectively associated with premature CHD, driven by lipoprotein(a) and insulin-resistant atherogenic dyslipoproteinemia. This has implications for the development of biomarker panels to screen for premature CHD.
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Biomarcadores , Doença das Coronárias , Humanos , Feminino , Biomarcadores/sangue , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Pessoa de Meia-Idade , Idoso , Lipoproteína(a)/sangue , Espectroscopia de Ressonância Magnética , Fatores de RiscoRESUMO
BACKGROUND: Longer effects of multivitamin-mineral (MVM) supplementation on late-life cognitive function remain untested using in-person, detailed neuropsychological assessments. Furthermore, insufficient evidence exists for healthcare providers to recommend daily MVM supplements to prevent cognitive decline. OBJECTIVES: This study aimed to test MVM effects on cognitive change using in-person, detailed neuropsychological assessments and conduct a meta-analysis within COSMOS (COcoa Supplement and Multivitamin Outcomes Study) cognitive substudies for a robust evaluation of MVM effects on cognition. METHODS: COSMOS is a 2 × 2 factorial trial of cocoa extract (500 mg flavanols/d) and/or a daily MVM supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests administered at baseline. For the meta-analysis, we included nonoverlapping participants across 3 COSMOS cognitive substudies: COSMOS-Clinic (n = 573); COSMOS-Mind (n = 2158); COSMOS-Web (n = 2472). RESULTS: In COSMOS-Clinic, we observed a modest benefit of MVM compared with placebo on global cognition over 2 y {mean difference [95% confidence interval (CI)] = 0.06 SD units (SU) (-0.003, 0.13)}, with a significantly more favorable change in episodic memory [mean difference (95% CI) = 0.12 SU (0.002, 0.23)] but not in executive function or attention [mean difference (95% CI) = 0.04 SU (-0.04, 0.11)]. The meta-analysis of COSMOS substudies showed clear evidence of MVM benefits on global cognition [mean difference (95% CI) = 0.07 SU (0.03, 0.11); P = 0.0009] and episodic memory [mean difference (95% CI) = 0.06 SU (0.03, 0.10); P = 0.0007]; the magnitude of effect on global cognition was equivalent to reducing cognitive aging by 2 y. CONCLUSIONS: In COSMOS-Clinic, daily MVM supplementation leads to a significantly more favorable 2-y change in episodic memory. The meta-analysis within COSMOS cognitive substudies indicates that daily MVM significantly benefits both global cognition and episodic memory. These findings within the COSMOS trial support the benefits of a daily MVM in preventing cognitive decline among older adults. This trial was registered at COSMOS-clinicaltrials.gov as NCT02422745, at COSMOS-Mind-clinicaltrials.gov as NCT03035201, and at COSMOS-Web-clinicaltrials.gov as NCT04582617.
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Cacau , Disfunção Cognitiva , Humanos , Idoso , Vitaminas/farmacologia , Vitaminas/uso terapêutico , Suplementos Nutricionais , Cognição , Disfunção Cognitiva/prevenção & controle , Minerais/farmacologia , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Some prior randomized clinical trials (RCTs) that tested the effects of cocoa extract (CE), a source of flavanols, on late-life cognition have yielded promising findings. A long-term RCT using in-person neuropsychological tests covering multiple cognitive domains may clarify the cognitive effects of CE. OBJECTIVES: To test whether daily supplementation with CE, compared with placebo, produces better cognitive change over 2 y. METHODS: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a 2 × 2 factorial RCT of CE [500 mg flavanols/d, including 80 mg (-)-epicatechin] and/or a daily multivitamin-mineral supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests at baseline; of these, 492 completed 2-y follow-up assessments. The primary outcome was global cognition (averaging z-scores across 11 tests). Secondary outcomes were episodic memory and executive function/attention. Repeated measures models were used to compare randomized groups. RESULTS: Participants' mean age (standard deviation) was 69.6 (5.3); 49.2% were females. Daily supplementation with CE, compared with placebo, had no significant effect on 2-y change in global cognition {mean difference [95% confidence interval (CI)]: -0.01 (-0.08, 0.05) standard deviation units (SU)}. CE, compared with placebo, had no significant effects on 2-y change in episodic memory [mean difference (95% CI): -0.01 (-0.13, 0.10) SU] or executive function/attention [mean difference (95% CI): 0.003 (-0.07, 0.08) SU]. Subgroup analyses uncorrected for multiple-testing suggested cognitive benefits of CE supplementation, compared with placebo among those with poorer baseline diet quality. CONCLUSIONS: Among 573 older adults who underwent repeat in-person, detailed neuropsychological assessments over 2 y, daily CE supplementation, compared with placebo, showed no overall benefits for global or domain-specific cognitive function. Possible cognitive benefits of CE among those with poorer diet quality warrant further study. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov with identifier - NCT02422745.
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Cacau , Vitaminas , Idoso , Feminino , Humanos , Masculino , Cognição , Suplementos Nutricionais , Método Duplo-Cego , Função ExecutivaRESUMO
Background: Higher consumption of Mediterranean diet (MED) intake has been associated with reduced risk of all-cause mortality but limited data are available examining long-term outcomes in women or the underlying molecular mechanisms of this inverse association in human populations. We aimed to investigate the association of MED intake with long-term risk of all-cause mortality in women and to better characterize the relative contribution of traditional and novel cardiometabolic factors to the MED-related risk reduction in morality. Methods: In a prospective cohort study of 25,315 initially healthy women from the Women's Health Study, we assessed dietary MED intake using a validated semiquantitative food frequency questionnaire according to the usual 9-category measure of MED adherence. Baseline levels of more than thirty cardiometabolic biomarkers were measured using standard assays and targeted nuclear magnetic resonance spectroscopy, including lipids, lipoproteins, apolipoproteins, inflammation, glucose metabolism and insulin resistance, branched-chain amino acids, small metabolites, and clinical factors. Mortality and cause of death was ascertained prospectively through medical and death records. Results: During a mean follow-up of 25 years, 3,879 deaths were ascertained. Compared to the reference group of low MED intake (0-3, approximately the bottom tertile), and adjusting for age, treatment, and energy intake, risk reductions were observed for the middle and upper MED groups with respective HRs of 0.84 (95% CI 0.78-0.90) and 0.77 (95% CI 0.70-0.84), p for trend <0.0001. Further adjusting for smoking, physical activity, alcohol intake and menopausal factors attenuated the risk reductions which remained significant with respective HRs of 0.92 (95% CI 0.85-0.99) and 0.89 (95% CI 0.82-0.98), p for trend 0.0011. Risk reductions were generally similar for CVD and non-CVD mortality. Small molecule metabolites (e.g., alanine and homocysteine) and inflammation made the largest contributions to lower mortality risk (accounting for 14.8% and 13.0% of the benefit of the MED-mortality association, respectively), followed by triglyceride-rich lipoproteins (10.2%), adiposity (10.2%) and insulin resistance (7.4%), with lesser contributions (<3%) from other pathways including branched-chain amino acids, high-density lipoproteins, low-density lipoproteins, glycemic measures, and hypertension. Conclusions: In the large-scale prospective Women's Health Study of 25,315 initially healthy US women followed for 25 years, higher MED intake was associated with approximately one fifth relative risk reduction in mortality. The inverse association was only partially explained by known novel and traditional cardiometabolic factors.
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BACKGROUND: A familial predisposition to sudden and/or arrhythmic death (SAD) in the setting of coronary artery disease (CAD) exists; however, the genetic basis is poorly understood. OBJECTIVES: The purpose of this study was to determine whether a genome-wide polygenic score for coronary artery disease (GPSCAD) might have utility in SAD risk stratification in CAD patients without severe systolic dysfunction. METHODS: A previously validated GPSCAD was generated utilizing genome-wide genotyping in 4,698 PRE-DETERMINE participants of European ancestry with CAD and left ventricular ejection fraction >30%-35%. The population was dichotomized according to top GPSCAD decile as defined by the general population, and absolute, proportional, and relative risks for SAD and non-SAD were estimated using competing risk analyses. RESULTS: Over a median follow-up of 8.0 years, participants in the top GPSCAD decile were at elevated absolute SAD risk (8.0%; 95% CI: 5.1%-12.4% vs 4.8%; 95% CI: 3.3%-7.0%; P = 0.005) and proportional SAD risk (29% vs 16%; P = 0.0003) compared with the remainder. After controlling for left ventricular ejection fraction, clinical factors, and electrocardiogram parameters, the top GPSCAD decile was associated with SAD (subdistribution HR: 1.77; 95% CI: 1.23-2.54; P = 0.002) but not non-SAD (subdistribution HR: 1.00; 95% CI: 0.80-1.25; P = 0.98) (P for Δ = 0.003). The addition of the top GPSCAD decile to the multivariable model significantly improved net reclassification indexes (NRIs) (continuous NRI: 14.0%; P = 0.024; and categorical NRI: 6.6%; P = 0.005) but not the C-index (difference in C-index: 0.007; P = 0.143). CONCLUSIONS: Among CAD patients without severe systolic dysfunction, high GPSCAD specifically predicted SAD and enriched for both absolute and proportional SAD risk, identifying a population who might benefit from defibrillator therapy.
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Doença da Artéria Coronariana , Doença da Artéria Coronariana/genética , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Humanos , Medição de Risco , Fatores de Risco , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Sudden cardiac death from arrhythmia is a major cause of mortality worldwide. Here, we develop a novel deep learning (DL) approach that blends neural networks and survival analysis to predict patient-specific survival curves from contrast-enhanced cardiac magnetic resonance images and clinical covariates for patients with ischemic heart disease. The DL-predicted survival curves offer accurate predictions at times up to 10 years and allow for estimation of uncertainty in predictions. The performance of this learning architecture was evaluated on multi-center internal validation data and tested on an independent test set, achieving concordance index of 0.83 and 0.74, and 10-year integrated Brier score of 0.12 and 0.14. We demonstrate that our DL approach with only raw cardiac images as input outperforms standard survival models constructed using clinical covariates. This technology has the potential to transform clinical decision-making by offering accurate and generalizable predictions of patient-specific survival probabilities of arrhythmic death over time.
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BACKGROUND: Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested. OBJECTIVES: We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults. METHODS: We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina. RESULTS: During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns. CONCLUSIONS: Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.
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Cacau , Doenças Cardiovasculares , Infarto do Miocárdio , Neoplasias , Acidente Vascular Cerebral , Idoso , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Masculino , Infarto do Miocárdio/prevenção & controle , Neoplasias/prevenção & controle , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polifenóis , Fatores de Risco , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Vitaminas/uso terapêuticoRESUMO
BACKGROUND: Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited. OBJECTIVES: The study objective was to determine if a daily MVM decreases total invasive cancer among older adults. METHODS: We performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major CVD and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020. This article reports on the MVM intervention. Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer. RESULTS: During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). We observed no significant effect of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). We observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns. CONCLUSIONS: A daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults. This trial is registered at www.clinicaltrials.gov as NCT02422745.
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Neoplasias da Mama , Cacau , Doenças Cardiovasculares , Idoso , Neoplasias da Mama/tratamento farmacológico , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Promoção da Saúde , Humanos , Masculino , Vitaminas/uso terapêuticoRESUMO
BACKGROUND: The prognosis of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals is unclear. OBJECTIVES: This study sought to investigate whether high-grade PVCs during stress testing predict mortality in asymptomatic individuals. METHODS: A cohort of 5,486 asymptomatic individuals who took part in the Lipid Research Clinics prospective cohort had baseline interview, physical examination, blood tests, and underwent Bruce protocol treadmill testing. Adjusted Cox survival models evaluated the association of exercise-induced high-grade PVCs (defined as either frequent (>10 per minute), multifocal, R-on-T type, or ≥2 PVCs in a row) with all-cause and cardiovascular mortality. RESULTS: Mean baseline age was 45.4 ± 10.8 years; 42% were women. During a mean follow-up of 20.2 ± 3.9 years, 840 deaths occurred, including 311 cardiovascular deaths. High-grade PVCs occurred during exercise in 1.8% of individuals, during recovery in 2.4%, and during both in 0.8%. After adjusting for age, sex, diabetes, hypertension, lipids, smoking, body mass index, and family history of premature coronary disease, high-grade PVCs during recovery were associated with cardiovascular mortality (hazard ratio [HR]: 1.82; 95% CI: 1.19-2.79; P = 0.006), which remained significant after further adjusting for exercise duration, heart rate recovery, achieving target heart rate, and ST-segment depression (HR: 1.68; 95% CI: 1.09-2.60; P = 0.020). Results were similar by clinical subgroups. High-grade PVCs occurring during the exercise phase were not associated with increased risk. Recovery PVCs did not improve 20-year cardiovascular mortality risk discrimination beyond clinical variables. CONCLUSIONS: High-grade PVCs occurring during recovery were associated with long-term risk of cardiovascular mortality in asymptomatic individuals, whereas PVCs occurring only during exercise were not associated with increased risk.
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Teste de Esforço/efeitos adversos , Exercício Físico/fisiologia , Frequência Cardíaca/fisiologia , Medição de Risco/métodos , Complexos Ventriculares Prematuros/etiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências , Complexos Ventriculares Prematuros/mortalidade , Complexos Ventriculares Prematuros/fisiopatologiaRESUMO
Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. Design, Setting, and Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25â¯119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). Main Outcomes and Measures: The primary outcome was incident AF confirmed by medical record review. Results: Among the 25â¯119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24â¯127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). Conclusions and Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.
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Fibrilação Atrial/tratamento farmacológico , Colecalciferol/uso terapêutico , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Vitaminas/uso terapêutico , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Deficiência de Vitamina D/tratamento farmacológicoRESUMO
Importance: Risk profiles for premature coronary heart disease (CHD) are unclear. Objective: To examine baseline risk profiles for incident CHD in women by age at onset. Design, Setting, and Participants: A prospective cohort of US female health professionals participating in the Women's Health Study was conducted; median follow-up was 21.4 years. Participants included 28â¯024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020. Exposures: More than 50 clinical, lipid, inflammatory, and metabolic risk factors and biomarkers. Main Outcomes and Measures: Four age groups were examined (<55, 55 to <65, 65 to <75, and ≥75 years) for CHD onset, and adjusted hazard ratios (aHRs) were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusting for clinical factors. Women contributed to different age groups over time. Results: Of the clinical factors in the women, diabetes had the highest aHR for CHD onset at any age, ranging from 10.71 (95% CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95% CI, 2.47-4.87) at CHD onset in those 75 years or older. Risks that were also noted for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95% CI, 3.60-10.29), hypertension (aHR, 4.58; 95% CI, 2.76-7.60), obesity (aHR, 4.33; 95% CI, 2.31-8.11), and smoking (aHR, 3.92; 95% CI, 2.32-6.63). Myocardial infarction in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years. From approximately 50 biomarkers, lipoprotein insulin resistance had the highest standardized aHR: 6.40 (95% CI, 3.14-13.06) for CHD onset in women younger than 55 years, attenuating with age. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for low-density lipoprotein cholesterol (aHR, 1.38; 95% CI, 1.10-1.74), non-high-density lipoprotein cholesterol (aHR, 1.67; 95% CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95% CI, 1.52-2.35), triglycerides (aHR, 2.14; 95% CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold)-all attenuating with age. Some biomarkers had similar CHD age associations (eg, physical inactivity, lipoprotein[a], total high-density lipoprotein particles), while a few had no association with CHD onset at any age. Most risk factors and biomarkers had associations that attenuated with increasing age at onset. Conclusions and Relevance: In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages.
Assuntos
Doença das Coronárias/etiologia , Inflamação/sangue , Lipídeos/sangue , Fatores Etários , Idade de Início , Idoso , Apolipoproteínas B/sangue , Biomarcadores/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Hipertensão/sangue , Hipertensão/complicações , Incidência , Resistência à Insulina , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Obesidade/complicações , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fumar/efeitos adversos , Triglicerídeos/sangue , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Eleven criteria correlating electrocardiogram (ECG) findings with reduced left ventricular ejection fraction (LVEF) have been previously published. These have not been compared head-to-head in a single study. We studied their value as a screening test to identify patients with reduced LVEF estimated by cardiac magnetic resonance (CMR) imaging. METHODS: ECGs and CMR from 548 patients (age 61 + 11 years, 79% male) with previous myocardial infarction (MI), from the DETERMINE and PRE-DETERMINE studies, were analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each criterion for identifying patients with LVEF ≤ 30% and ≤ 40% were studied. A useful screening test should have high sensitivity and NPV. RESULTS: Mean LVEF was 40% (SD = 11%); 264 patients (48.2%) had LVEF ≤ 40%, and 96 patients (17.5%) had LVEF ≤ 30%. Six of 11 criteria were associated with a significant lower LVEF, but had poor sensitivity to identify LVEF ≤ 30% (range 2.1%-55.2%) or LVEF ≤ 40% (1.1%-51.1%); NPVs were good for LVEF ≤ 30% (range 82.8%-85.9%) but not for LVEF ≤ 40% (range 52.1%-60.6%). Goldberger's third criterion (RV4/SV4 < 1) and combinations of maximal QRS duration > 124 ms + either Goldberger's third criterion or Goldberger's first criterion (SV1 or SV2 + RV5 or RV6 ≥ 3.5 mV) had high specificity (95.4%-100%) for LVEF ≤ 40%, although seen in only 48 (8.8%) patients; predictive values were similar on subgroup analysis. CONCLUSIONS: None of the ECG criteria qualified as a good screening test. Three criteria had high specificity for LVEF ≤ 40%, although seen in < 9% of patients. Whether other ECG criteria can better identify LV dysfunction remains to be determined.
Assuntos
Eletrocardiografia/métodos , Infarto do Miocárdio/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Importance: Higher Mediterranean diet (MED) intake has been associated with reduced risk of type 2 diabetes, but underlying biological mechanisms are unclear. Objective: To characterize the relative contribution of conventional and novel biomarkers in MED-associated type 2 diabetes risk reduction in a US population. Design, Setting, and Participants: This cohort study was conducted among 25â¯317 apparently healthy women. The participants with missing information regarding all traditional and novel metabolic biomarkers or those with baseline diabetes were excluded. Participants were invited for baseline assessment between September 1992 and May 1995. Data were collected from November 1992 to December 2017 and analyzed from December 2018 to December 2019. Exposures: MED intake score (range, 0 to 9) was computed from self-reported dietary intake, representing adherence to Mediterranean diet intake. Main Outcomes and Measures: Incident cases of type 2 diabetes, identified through annual questionnaires; reported cases were confirmed by either telephone interview or supplemental questionnaire. Proportion of reduced risk of type 2 diabetes explained by clinical risk factors and a panel of 40 biomarkers that represent different physiological pathways was estimated. Results: The mean (SD) age of the 25â¯317 female participants was 52.9 (9.9) years, and they were followed up for a mean (SD) of 19.8 (5.8) years. Higher baseline MED intake (score ≥6 vs ≤3) was associated with as much as a 30% lower type 2 diabetes risk (age-adjusted and energy-adjusted hazard ratio, 0.70; 95% CI, 0.62-0.79; when regression models were additionally adjusted with body mass index [BMI]: hazard ratio, 0.85; 95% CI, 0.76-0.96). Biomarkers of insulin resistance made the largest contribution to lower risk (accounting for 65.5% of the MED-type 2 diabetes association), followed by BMI (55.5%), high-density lipoprotein measures (53.0%), and inflammation (52.5%), with lesser contributions from branched-chain amino acids (34.5%), very low-density lipoprotein measures (32.0%), low-density lipoprotein measures (31.0%), blood pressure (29.0%), and apolipoproteins (23.5%), and minimal contribution (≤2%) from hemoglobin A1c. In post hoc subgroup analyses, the inverse association of MED diet with type 2 diabetes was seen only among women who had BMI of at least 25 at baseline but not those who had BMI of less than 25 (eg, women with BMI <25, age- and energy-adjusted HR for MED score ≥6 vs ≤3, 1.01; 95% CI, 0.77-1.33; P for trend = .92; women with BMI ≥25: HR, 0.76; 95% CI, 0.67-0.87; P for trend < .001). Conclusions and Relevance: In this cohort study, higher MED intake scores were associated with a 30% relative risk reduction in type 2 diabetes during a 20-year period, which could be explained in large part by biomarkers of insulin resistance, BMI, lipoprotein metabolism, and inflammation.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Dieta Mediterrânea/estatística & dados numéricos , Adiposidade , Adulto , Aminoácidos de Cadeia Ramificada/metabolismo , Apolipoproteína A-I/metabolismo , Apolipoproteína B-100/metabolismo , Apolipoproteínas/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dieta/estatística & dados numéricos , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Inflamação/metabolismo , Resistência à Insulina , Molécula 1 de Adesão Intercelular/metabolismo , Lipoproteína(a)/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/metabolismo , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Proteção , Espectroscopia de Prótons por Ressonância Magnética , Triglicerídeos/metabolismoRESUMO
OBJECTIVES: This study evaluated whether plasma miRNAs were specifically associated with sudden cardiac and/or arrhythmic death (SCD) in a cohort of patients with coronary heart disease (CHD), most of whom were without primary prevention implantable cardioverter-defibrillators. BACKGROUND: Novel biomarkers for sudden death risk stratification are needed in patients with CHD to more precisely target preventive therapies, such as implantable cardioverter-defibrillators. miRNAs have been implicated in regulating inflammation and cardiac fibrosis in cells, and plasma miRNAs have been shown to predict cardiovascular death in patients with CHD. METHODS: We performed a nested case control study within a multicenter cohort of 5,956 patients with CHD followed prospectively for SCD. Plasma levels of 18 candidate miRNAs previously associated with cardiac remodeling were measured in 129 SCD cases and 258 control subjects matched on age, sex, race, and left ventricular ejection fraction. RESULTS: miR-150-5p, miR-29a-3p, and miR-30a-5p were associated with increased SCD risk (odds ratios and 95% confidence intervals: 2.03 [1.12 to 3.67]; p = 0.02; 1.93 [1.07 to 3.50]; p = 0.02; 0.55 [0.31 to 0.97]; p = 0.04, respectively, for third vs. first tertile miRNA level). Unfavorable levels of all 3 miRNAs was associated with a 4.8-fold increased SCD risk (1.59 to 14.51; p = 0.006). A bioinformatics-based approach predicted miR-150-5p, miR-29a-3p, and miR-30a-5p to be involved in apoptosis, fibrosis, and inflammation. CONCLUSIONS: These findings suggest that plasma miRNAs may regulate pathways important for remodeling and may be useful in identifying patients with CHD at increased risk of SCD.
Assuntos
Doença das Coronárias , Morte Súbita Cardíaca/epidemiologia , MicroRNAs , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Citocinas/sangue , Feminino , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Medição de RiscoRESUMO
The Middle East and North Africa (MENA) region has a high burden of morbidity and mortality due to premature (≤55 years in men; ≤65 years in women) myocardial infarction (MI) and acute coronary syndrome (ACS). Despite this, the prevalence of risk factors in patients presenting with premature MI or ACS is incompletely described. We compared lifestyle, clinical risk factors, and biomarkers associated with premature MI/ACS in the MENA region with selected non-MENA high-income countries. We identified English-language, peer-reviewed publications through PubMed (up to March 2018). We used the World Bank classification system to categorize countries. Patients with premature MI/ACS in the MENA region had a higher prevalence of smoking than older patients with MI/ACS but a lower prevalence of diabetes, hypertension, and dyslipidemia. Men with premature MI/ACS had a higher prevalence of smoking than women but a lower prevalence of diabetes and hypertension. The MENA region had sparse data on lifestyle, diet, psychological stress, and physical activity. To address these knowledge gaps, we initiated the ongoing Gulf Population Risks and Epidemiology of Vascular Events and Treatment (Gulf PREVENT) case-control study to improve primary and secondary prevention of premature MI in the United Arab Emirates, a high-income country in the MENA region.