The stress associated with informal caregiving has been shown to be associated with poor health, including coronary heart disease (CHD). However, it is unclear if the risk of CHD is attributable to ...caregiving or prior poor health of the caregiver.
We used data from the Whitehall II cohort study. Caregiving and caregiver's health (using 3 measures: self-rated health, mental health using the General Health Questionnaire, and physical component score of the SF-36) were assessed in 1991-1993 among 5,468 men and 2,457 women aged 39-63 years. CHD (fatal CHD, clinically verified nonfatal myocardial infarction, and definite angina) incidence was recorded for a mean 17 years; sociodemographic variables, health behaviors, and cardiovascular risk factors were included as covariates.
Cox regression showed the risk of CHD in caregivers not to be higher (hazard ratio = 1.18; 95% CI: 0.96, 1.45) compared with noncaregivers. Analyses stratified by health status showed that compared with noncaregivers in good health, caregivers with poor self-rated (hazard ratio = 2.00; 95% CI: 1.44, 2.78), mental (hazard ratio = 1.63; 95% CI: 1.16, 2.30), or physical (hazard ratio =1.87; 95% CI: 1.34, 2.62) health had greater risk of CHD. A similar elevated risk was observed in noncaregivers with poor health; no excess risk was observed among caregivers reporting good health, and the combined effect of poor health and caregiving did not exceed their independent effects.
Caregiving in midlife is not in itself associated with greater risk of CHD, but it is associated with increased risk for CHD among caregivers who report being in poor health.
To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among ...Atherosclerosis Risk in Communities (ARIC) study participants.
Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non-diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21-1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04-2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors.
sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.
Cardiac rehabilitation (CR) is the standard of care for patients with coronary heart disease. Despite considerable epidemiological evidence that high stress is associated with worse health outcomes, ...stress management training (SMT) is not included routinely as a component of CR.
One hundred fifty-one outpatients with coronary heart disease who were 36 to 84 years of age were randomized to 12 weeks of comprehensive CR or comprehensive CR combined with SMT (CR+SMT), with assessments of stress and coronary heart disease biomarkers obtained before and after treatment. A matched sample of CR-eligible patients who did not receive CR made up the no-CR comparison group. All participants were followed up for up to 5.3 years (median, 3.2 years) for clinical events. Patients randomized to CR+SMT exhibited greater reductions in composite stress levels compared with those randomized to CR alone (P=0.022), an effect that was driven primarily by improvements in anxiety, distress, and perceived stress. Both CR groups achieved significant, and comparable, improvements in coronary heart disease biomarkers. Participants in the CR+SMT group exhibited lower rates of clinical events compared with those in the CR-alone group (18% versus 33%; hazard ratio=0.49; 95% confidence interval, 0.25-0.95; P=0.035), and both CR groups had lower event rates compared with the no-CR group (47%; hazard ratio=0.44; 95% confidence interval, 0.27-0.71; P<0.001).
CR enhanced by SMT produced significant reductions in stress and greater improvements in medical outcomes compared with standard CR. Our findings indicate that SMT may provide incremental benefit when combined with comprehensive CR and suggest that SMT should be incorporated routinely into CR.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00981253.
Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates ...lowers low-density lipoprotein cholesterol (LDL-C) levels.
Participants (n=203, 45-65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS ((+)GRS). Participants in the (+)GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or (+)GRS (n=103). At the end of the study period, the (+)GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P=0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants (P=0.02) but not participants with low GRS (100.9±32.2 mg/dL; P=0.18). Statins were initiated more often in the (+)GRS group than in the CRS group (39% versus 22%, P<0.01). No significant differences in dietary fat intake and physical activity levels were noted.
Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936675.
D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and ...arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial (Long-Term Intervention with Pravastatin in Ischaemic Disease) in the context of other risk factors.
LIPID randomized patients to placebo or pravastatin 40 mg/d 5 to 38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total.
Baseline D-dimer levels for 7863 patients were grouped by quartile (≤112, 112-173, 173-273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function, and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P<0.001). During the first 6 years, after adjustment for up to 30 additional risk factors, higher D-dimer was associated with a significantly increased risk of a major coronary event (quartile 4 versus 1: hazard ratio HR, 1.45; 95% confidence interval, 1.21-1.74), major cardiovascular disease (CVD) event (HR, 1.45; 95% confidence interval, 1.23-1.71) and venous thromboembolism (HR, 4.03; 95% confidence interval, 2.31-7.03; each P<0.001). During the 16 years overall, higher D-dimer was an independent predictor of all-cause mortality (HR, 1.59), CVD mortality (HR, 1.61), cancer mortality (HR, 1.54), and non-CVD noncancer mortality (HR, 1.57; each P<0.001), remaining significant for deaths resulting from each cause occurring beyond 10 years of follow-up (each P≤0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR, 1.16; P=0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6.
D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality independent of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years' follow-up.
Coronary heart disease (CHD) is the single most common cause of death globally. However, with falling CHD mortality rates, an increasing number of people live with CHD and may need support to manage ...their symptoms and prognosis. Exercise-based cardiac rehabilitation (CR) aims to improve the health and outcomes of people with CHD. This is an update of a Cochrane systematic review previously published in 2011.
To assess the effectiveness and cost-effectiveness of exercise-based CR (exercise training alone or in combination with psychosocial or educational interventions) compared with usual care on mortality, morbidity and HRQL in patients with CHD.To explore the potential study level predictors of the effectiveness of exercise-based CR in patients with CHD.
We updated searches from the previous Cochrane review, by searching Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 6, 2014) from December 2009 to July 2014. We also searched MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCO) and Science Citation Index Expanded (December 2009 to July 2014).
We included randomised controlled trials (RCTs) of exercise-based interventions with at least six months' follow-up, compared with a no exercise control. The study population comprised men and women of all ages who have had a myocardial infarction (MI), coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), or who have angina pectoris, or coronary artery disease. We included RCTs that reported at least one of the following outcomes: mortality, MI, revascularisations, hospitalisations, health-related quality of life (HRQL), or costs.
Two review authors independently screened all identified references for inclusion based on the above inclusion and exclusion criteria. One author extracted data from the included trials and assessed their risk of bias; a second review author checked data. We stratified meta-analysis by the duration of follow up of trials, i.e. short-term: 6 to 12 months, medium-term: 13 to 36 months, and long-term: > 3 years.
This review included 63 trials which randomised 14,486 people with CHD. This latest update identified 16 new trials (3872 participants). The population included predominantly post-MI and post-revascularisation patients and the mean age of patients within the trials ranged from 47.5 to 71.0 years. Women accounted for fewer than 15% of the patients recruited. Overall trial reporting was poor, although there was evidence of an improvement in quality of reporting in more recent trials.As we found no significant difference in the impact of exercise-based CR on clinical outcomes across follow-up, we focused on reporting findings pooled across all trials at their longest follow-up (median 12 months). Exercise-based CR reduced cardiovascular mortality compared with no exercise control (27 trials; risk ratio (RR) 0.74, 95% CI 0.64 to 0.86). There was no reduction in total mortality with CR (47 trials, RR 0.96, 95% CI 0.88 to 1.04). The overall risk of hospital admissions was reduced with CR (15 trials; RR 0.82, 95% CI 0.70 to 0.96) but there was no significant impact on the risk of MI (36 trials; RR 0.90, 95% CI 0.79 to 1.04), CABG (29 trials; RR 0.96, 95% CI 0.80 to 1.16) or PCI (18 trials; RR 0.85, 95% CI 0.70 to 1.04).There was little evidence of statistical heterogeneity across trials for all event outcomes, and there was evidence of small study bias for MI and hospitalisation, but no other outcome. Predictors of clinical outcomes were examined across the longest follow-up of studies using univariate meta-regression. Results show that benefits in outcomes were independent of participants' CHD case mix (proportion of patients with MI), type of CR (exercise only vs comprehensive rehabilitation) dose of exercise, length of follow-up, trial publication date, setting (centre vs home-based), study location (continent), sample size or risk of bias.Given the heterogeneity in outcome measures and reporting methods, meta-analysis was not undertaken for HRQL. In five out of 20 trials reporting HRQL using validated measures, there was evidence of significant improvement in most or all of the sub-scales with exercise-based CR compared to control at follow-up. Four trial-based economic evaluation studies indicated exercise-based CR to be a potentially cost-effective use of resources in terms of gain in quality-adjusted life years.The quality of the evidence for outcomes reported in the review was rated using the GRADE method. The quality of the evidence varied widely by outcome and ranged from low to moderate.
This updated Cochrane review supports the conclusions of the previous version of this review that, compared with no exercise control, exercise-based CR reduces the risk of cardiovascular mortality but not total mortality. We saw a significant reduction in the risk of hospitalisation with CR but not in the risk of MI or revascularisation. We identified further evidence supporting improved HRQL with exercise-based CR. More recent trials were more likely to be well reported and include older and female patients. However, the population studied in this review still consists predominantly of lower risk individuals following MI or revascularisation. Further well conducted RCTs are needed to assess the impact of exercise-based CR in higher risk CHD groups and also those presenting with stable angina. These trials should include validated HRQL outcome measures, explicitly report clinical event outcomes including mortality and hospital admissions, and assess costs and cost-effectiveness.
Understanding the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease (CHD) is important to improving public health initiatives. Our objective was to quantify ...remaining lifetime risk and years free of CHD according to polygenic risk and the American Heart Association's Life's Simple 7 (LS7) guidelines in a population-based cohort study.
Our analysis included data from participants of the ARIC (Atherosclerosis Risk in Communities) study: 8372 White and 2314 Black participants; 45 years of age and older; and free of CHD at baseline examination. A polygenic risk score (PRS) comprised more than 6 million genetic variants was categorized into low (<20th percentile), intermediate, and high (>80th percentile). An overall LS7 score was calculated at baseline and categorized into "poor," "intermediate," and "ideal" cardiovascular health. Lifetime risk and CHD-free years were computed according to polygenic risk and LS7 categories.
The overall remaining lifetime risk was 27%, ranging from 16.6% in individuals with an ideal LS7 score to 43.1% for individuals with a poor LS7 score. The association of PRS with lifetime risk differed according to ancestry. In White participants, remaining lifetime risk ranged from 19.8% to 39.3% according to increasing PRS categories. Individuals with a high PRS and poor LS7 had a remaining lifetime risk of 67.1% and 15.9 fewer CHD-free years than did those with intermediate polygenic risk and LS7 scores. In the high-PRS group, ideal LS7 was associated with 20.2 more CHD-free years compared with poor LS7. In Black participants, remaining lifetime risk ranged from 19.1% to 28.6% according to increasing PRS category. Similar lifetime risk estimates were observed for individuals of poor LS7 regardless of PRS category. In the high-PRS group, an ideal LS7 score was associated with only 4.5 more CHD-free years compared with a poor LS7 score.
Ideal adherence to LS7 recommendations was associated with lower lifetime risk of CHD for all individuals, especially in those with high genetic susceptibility. In Black participants, adherence to LS7 guidelines contributed to lifetime risk of CHD more so than current PRSs. Improved PRSs are needed to properly evaluate genetic susceptibility for CHD in diverse populations.
To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the ...associations of key modifiable CHD risk factors-specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking-with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age.
Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non-high-density lipoprotein cholesterol (non-HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed.
Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non-HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non-HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to <130 mm Hg or lowering low-density lipoprotein cholesterol by 30% would be expected to lower a baseline 10-year CHD risk of 10.7% to 7.0 and 8.0, respectively (absolute risk reductions: 3.7% and 2.7%, respectively). Prognostic performance decreases with age (C indices for age groups 45-54, 55-64, 65-74, 75-84 are 0.75, 0.72, 0.66, and 0.62, respectively), whereas absolute risk reductions increase (SBP: 1.1%, 2.3%, 5.4%, 10.3%, respectively; non-HDL-C: 1.1%, 2.0%, 3.7%, 5.9%, respectively).
Although individual modifiable CHD risk factors contribute only modestly to prognostic performance, our models indicate that eliminating or controlling these individual factors would lead to substantial reductions in total population CHD events. Metrics used to judge importance of risk factors should be tailored to the research objectives.
Coronary heart disease (CHD) is the single most common cause of death globally. However, with falling CHD mortality rates, an increasing number of people live with CHD and may need support to manage ...their symptoms and improve prognosis. Cardiac rehabilitation is a complex multifaceted intervention which aims to improve the health outcomes of people with CHD. Cardiac rehabilitation consists of three core modalities: education, exercise training and psychological support. This is an update of a Cochrane systematic review previously published in 2011, which aims to investigate the specific impact of the educational component of cardiac rehabilitation.
1. To assess the effects of patient education delivered as part of cardiac rehabilitation, compared with usual care on mortality, morbidity, health-related quality of life (HRQoL) and healthcare costs in patients with CHD.2. To explore the potential study level predictors of the effects of patient education in patients with CHD (e.g. individual versus group intervention, timing with respect to index cardiac event).
We updated searches from the previous Cochrane review, by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 6, 2016), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) in June 2016. Three trials registries, previous systematic reviews and reference lists of included studies were also searched. No language restrictions were applied.
1. Randomised controlled trials (RCTs) where the primary interventional intent was education delivered as part of cardiac rehabilitation.2. Studies with a minimum of six-months follow-up and published in 1990 or later.3. Adults with a diagnosis of CHD.
Two review authors independently screened all identified references for inclusion based on the above inclusion criteria. One author extracted study characteristics from the included trials and assessed their risk of bias; a second review author checked data. Two independent reviewers extracted outcome data onto a standardised collection form. For dichotomous variables, risk ratios and 95% confidence intervals (CI) were derived for each outcome. Heterogeneity amongst included studies was explored qualitatively and quantitatively. Where appropriate and possible, results from included studies were combined for each outcome to give an overall estimate of treatment effect. Given the degree of clinical heterogeneity seen in participant selection, interventions and comparators across studies, we decided it was appropriate to pool studies using random-effects modelling. We planned to undertake subgroup analysis and stratified meta-analysis, sensitivity analysis and meta-regression to examine potential treatment effect modifiers. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the quality of the evidence and the GRADE profiler (GRADEpro GDT) to create summary of findings tables.
This updated review included a total of 22 trials which randomised 76,864 people with CHD to an education intervention or a 'no education' comparator. Nine new trials (8215 people) were included for this update. We judged most included studies as low risk of bias across most domains. Educational 'dose' ranged from one 40 minute face-to-face session plus a 15 minute follow-up call, to a four-week residential stay with 11 months of follow-up sessions. Control groups received usual medical care, typically consisting of referral to an outpatient cardiologist, primary care physician, or both.We found evidence of no difference in effect of education-based interventions on total mortality (13 studies, 10,075 participants; 189/5187 (3.6%) versus 222/4888 (4.6%); random effects risk ratio (RR) 0.80, 95% CI 0.60 to 1.05; moderate quality evidence). Individual causes of mortality were reported rarely, and we were unable to report separate results for cardiovascular mortality or non-cardiovascular mortality. There was evidence of no difference in effect of education-based interventions on fatal and/or non fatal myocardial infarction (MI) (2 studies, 209 participants; 7/107 (6.5%) versus 12/102 (11.8%); random effects RR 0.63, 95% CI 0.26 to 1.48; very low quality of evidence). However, there was some evidence of a reduction with education in fatal and/or non-fatal cardiovascular events (2 studies, 310 studies; 21/152 (13.8%) versus 61/158 (38.6%); random effects RR 0.36, 95% CI 0.23 to 0.56; low quality evidence). There was evidence of no difference in effect of education on the rate of total revascularisations (3 studies, 456 participants; 5/228 (2.2%) versus 8/228 (3.5%); random effects RR 0.58, 95% CI 0.19 to 1.71; very low quality evidence) or hospitalisations (5 studies, 14,849 participants; 656/10048 (6.5%) versus 381/4801 (7.9%); random effects RR 0.93, 95% CI 0.71 to 1.21; very low quality evidence). There was evidence of no difference between groups for all cause withdrawal (17 studies, 10,972 participants; 525/5632 (9.3%) versus 493/5340 (9.2%); random effects RR 1.04, 95% CI 0.88 to 1.22; low quality evidence). Although some health-related quality of life (HRQoL) domain scores were higher with education, there was no consistent evidence of superiority across all domains.
We found no reduction in total mortality, in people who received education delivered as part of cardiac rehabilitation, compared to people in control groups (moderate quality evidence). There were no improvements in fatal or non fatal MI, total revascularisations or hospitalisations, with education. There was some evidence of a reduction in fatal and/or non-fatal cardiovascular events with education, but this was based on only two studies. There was also some evidence to suggest that education-based interventions may improve HRQoL. Our findings are supportive of current national and international clinical guidelines that cardiac rehabilitation for people with CHD should be comprehensive and include educational interventions together with exercise and psychological therapy. Further definitive research into education interventions for people with CHD is needed.
Abstract
A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of ...interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This “multivariable Mendelian randomization” approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.
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