Abstract Background Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene ...angiopoietin-like 3 ( ANGPTL3 ). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. Objectives The study goal was to leverage 3 distinct lines of evidence—a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)—to test whether ANGPTL3 deficiency is associated with lower risk for CAD. Methods We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. Results The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). Conclusions ANGPTL3 deficiency is associated with protection from CAD.
Abstract Background Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers associated with these ...changes remain unclear. Objectives This study sought to describe the metabolomic profiles of patients along the spectrum of systolic HF, determine their association with adverse outcomes in a clinical trial of HF, and evaluate whether identified metabolites change with treatment for end-stage systolic HF. Methods To assess association of metabolites with clinical outcomes, we evaluated a population of 453 chronic systolic HF patients who had been randomized to exercise training versus usual care. To assess change in metabolites with mechanical circulatory support, 41 patients with end-stage HF who underwent left ventricular assist device (LVAD) placement were studied. Targeted, quantitative profiling of 60 metabolites using tandem flow injection mass spectrometry was performed on frozen plasma samples obtained prior to randomization, as well as prior to and ≥90 days post-placement in the LVAD group. Principal components analysis was used for data reduction. Results Five principal components analysis–derived factors were significantly associated with peak V o2 levels at baseline in fully adjusted models. Of these, factor 5 (composed of long-chain acylcarnitines) was associated with increased risk of all 3 pre-specified clinical trial outcomes: all-cause mortality/all-cause hospitalization, all cause-hospitalization, and cardiovascular death or cardiovascular hospitalization. Individual components of factor 5 were significantly higher in patients with end-stage HF prior to LVAD placement and decreased significantly post-implantation. Conclusions In chronic HF patients, circulating long-chain acylcarnitine metabolite levels were independently associated with adverse clinical outcomes and decreased after long-term mechanical circulatory support. These metabolites may serve as potential targets for new diagnostics or therapeutic interventions. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437 )
Peak oxygen uptake (pV o2 ) is an important parameter in assessing the functional capacity and prognosis of patients with heart failure. In heart failure trials, change in pV o2 was often used to ...assess the effectiveness of an intervention. However, the within-subject variability of pV o2 on serial testing may limit its usefulness. This study was designed to evaluate the within-subject variability of pV o2 over 2 baseline cardiopulmonary exercise tests. As a substudy of the HF-ACTION trial, 398 subjects (73% men, 27% women; mean age 59 years) with heart failure and left ventricular ejection fraction ≤35% underwent 2 baseline cardiopulmonary exercise tests within 14 days. Mean pV o2 was unchanged from test 1 to test 2 (15.16 ± 4.97 vs 15.18 ± 4.97 ml/kg/min; p = 0.78). However, mean within-subject absolute change was 1.3 ml/kg/min (10th, 90th percentiles 0.1, 3.0), with 46% of subjects increasing and 48% decreasing on the second test. Other parameters, including the ventilation-to-carbon-dioxide production slope and V o2 at ventilatory threshold, also showed significant within-subject variation with minimal mean differences between tests. In conclusion, pV o2 showed substantial within-subject variability in patients with heart failure and should be taken into account in clinical applications. However, on repeated baseline cardiopulmonary exercise tests, there appears to be no familiarization effect for V o2 in patients with HF. Therefore, in multicenter trials, there is no need to perform >1 baseline cardiopulmonary exercise test.
Abstract Background Data from a cardiopulmonary exercise (CPX) test are used to determine prognosis in patients with chronic heart failure (HF). However, few published studies have simultaneously ...compared the relative prognostic strength of multiple CPX variables. Objectives The study sought to describe the strength of the association among variables measured during a CPX test and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF), including the influence of sex and patient effort, as measured by respiratory exchange ratio (RER). Methods Among patients (n = 2,100, 29% women) enrolled in the HF-ACTION (HF-A Controlled Trial Investigating Outcomes of exercise traiNing) trial, 10 CPX test variables measured at baseline (e.g., peak oxygen uptake V o2 , exercise duration, percent predicted peak V o2 %ppV o2 , ventilatory efficiency) were examined. Results Over a median follow-up of 32 months, there were 357 deaths. All CPX variables, except RER, were related to all-cause mortality (all p < 0.0001). Both %ppV o2 and exercise duration were equally able to predict (Wald chi-square: ∼141) and discriminate (c-index: 0.69) mortality. Peak V o2 (ml·kg–1 ·min–1 ) was the strongest predictor of mortality among men (Wald chi-square: 129) and exercise duration among women (Wald chi-square: 41). Multivariable analyses showed that %ppV o2 , exercise duration, and peak V o2 (ml·kg–1 ·min–1 ) were similarly able to predict and discriminate mortality. In men, a 10% 1-year mortality rate corresponded to a peak V o2 of 10.9 ml·kg–1 ·min–1 versus 5.3 ml·kg–1 ·min–1 in women. Conclusions Peak V o2 , exercise duration, and % ppV o2 carried the strongest ability to predict and discriminate the likelihood of death in patients with HFrEF. The prognosis associated with a given peak V o2 differed by sex. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437 )
Background The strength of race as an independent predictor of long-term outcomes in a contemporary chronic heart failure (HF) population and its association with exercise training response have not ...been well established. We aimed to investigate the association between race and outcomes and to explore interactions with exercise training in patients with ambulatory HF. Methods We performed an analysis of HF-ACTION, which randomized 2331 patients with HF having an ejection fraction ≤35% to usual care with or without exercise training. We examined characteristics and outcomes (mortality/hospitalization, mortality, and cardiovascular mortality/HF hospitalization) by race using adjusted Cox models and explored an interaction with exercise training. Results There were 749 self-identified black patients (33%). Blacks were younger with significantly more hypertension and diabetes, less ischemic etiology, and lower socioeconomic status versus whites. Blacks had shorter 6-minute walk distance and lower peak VO2 at baseline. Over a median follow-up of 2.5 years, black race was associated with increased risk for all outcomes except mortality. After multivariable adjustment, black race was associated with increased mortality/hospitalization (hazard ratio HR 1.16, 95% CI 1.01-1.33) and cardiovascular mortality/HF hospitalization (HR 1.46, 95% CI 1.20-1.77). The hazard associated with black race was largely caused by increased HF hospitalization (HR 1.58, 95% CI 1.27-1.96), given similar cardiovascular mortality. There was no interaction between race and exercise training on outcomes ( P > .5). Conclusions Black race in patients with chronic HF was associated with increased prevalence of modifiable risk factors, lower exercise performance, and increased HF hospitalization, but not increased mortality or a differential response to exercise training.
Summary Background The extent to which change in physical activity can modify the risk of cardiovascular disease in individuals at high cardiovascular risk is uncertain. We investigated whether ...baseline and change in objectively-assessed ambulatory activity is associated with the risk of a cardiovascular event in individuals at high cardiovascular risk with impaired glucose tolerance. Methods We assessed prospective data from the NAVIGATOR trial involving 9306 individuals with impaired glucose tolerance who were recruited in 40 countries between January, 2002, and January, 2004. Participants also either had existing cardiovascular disease (if age ≥50 years) or at least one additional cardiovascular risk factor (if age ≥55 years). Participants were followed-up for cardiovascular events (defined as cardiovascular mortality, non-fatal stroke, or myocardial infarction) for 6 years on average and had ambulatory activity assessed by pedometer at baseline and 12 months. Adjusted Cox proportional hazard models quantified the association of baseline and change in ambulatory activity (from baseline to 12 months) with the risk of a subsequent cardiovascular event, after adjustment for each other and potential confounding variables. This study is registered with ClinicalTrials.gov NCT00097786. Findings During 45 211 person-years follow-up, 531 cardiovascular events occurred. Baseline ambulatory activity (hazard ratio HR per 2000 steps per day 0·90, 95% CI 0·84–0·96) and change in ambulatory activity (0·92, 0·86–0·99) were inversely associated with the risk of a cardiovascular event. Results for change in ambulatory activity were unaffected when also adjusted for changes in body-mass index and other potential confounding variables at 12 months. Interpretation In individuals at high cardiovascular risk with impaired glucose tolerance, both baseline levels of daily ambulatory activity and change in ambulatory activity display a graded inverse association with the subsequent risk of a cardiovascular event. Funding Novartis Pharmaceuticals.
Multivariable risk scores and exercise measures are well-validated risk prediction methods. Combining information from a functional evaluation and a risk model may improve accuracy of risk ...predictions. We analyzed whether adding exercise measures to the Seattle Heart Failure Model (SHFM) improves risk prediction accuracy in systolic heart failure.
We used a sample of patients from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) study (http://www.clinicaltrials.gov; unique identifier: NCT00047437) to examine the addition of peak oxygen consumption, expired volume per unit time/volume of carbon dioxide slope, 6-minute walk distance, or cardiopulmonary exercise duration to the SHFM. Multivariable Cox proportional hazards models were used to test the association between the combined end point (death, left ventricular assist device, or cardiac transplantation) and the addition of exercise variables to the SHFM.
The sample included 2,152 patients. The SHFM and all exercise measures were associated with events (all p < 0.0001) in proportional hazards models. There was statistically significant improvement in risk estimation when exercise measures were added to the SHFM. However, the improvement in the C index for the addition of peak volume of oxygen consumption (+0.01), expired volume per unit time/volume of carbon dioxide slope (+0.02), 6-minute walk distance (-0.001), and cardiopulmonary exercise duration (+0.001) to the SHFM was small or slightly worse than the SHFM alone. Changes in risk assignment with the addition of exercise variables were minimal for patients above or below a 15% 1-year mortality.
Exercise performance measures and the SHFM are independently useful for predicting risk in systolic heart failure. Adding cardiopulmonary exercise testing measures and 6MWD to the SHFM offers only minimal improvement in risk reassignment at clinically meaningful cut points.
Background Cardiovascular risk models remain incomplete. Small-molecule metabolites may reflect underlying disease and, as such, serve as novel biomarkers of cardiovascular risk. Methods We studied ...2,023 consecutive patients undergoing cardiac catheterization. Mass spectrometry profiling of 69 metabolites and lipid assessments were performed in fasting plasma. Principal component analysis reduced metabolites to a smaller number of uncorrelated factors. Independent relationships between factors and time-to-clinical events were assessed using Cox modeling. Clinical and metabolomic models were compared using log-likelihood and reclassification analyses. Results At median follow-up of 3.1 years, there were 232 deaths and 294 death/myocardial infarction (MI) events. Five of 13 metabolite factors were independently associated with mortality: factor 1 (medium-chain acylcarnitines: hazard ratio HR 1.12 95% CI, 1.04-1.21, P = .005), factor 2 (short-chain dicarboxylacylcarnitines: HR 1.17 1.05-1.31, P = .005), factor 3 (long-chain dicarboxylacylcarnitines: HR 1.14 1.05-1.25, P = .002); factor 6 (branched-chain amino acids: HR 0.86 0.75-0.99, P = .03), and factor 12 (fatty acids: HR 1.19 1.06-1.35, P = .004). Three factors independently predicted death/MI: factor 2 (HR 1.11 1.01-1.23, P = .04), factor 3 (HR 1.13 1.04-1.22, P = .005), and factor 12 (HR 1.18 1.05-1.32, P = .004). For mortality, 27% of intermediate-risk patients were correctly reclassified (net reclassification improvement 8.8%, integrated discrimination index 0.017); for death/MI model, 11% were correctly reclassified (net reclassification improvement 3.9%, integrated discrimination index 0.012). Conclusions Metabolic profiles predict cardiovascular events independently of standard predictors.
Objectives This study determined whether greater volumes of exercise were associated with greater reductions in clinical events. Background The HF-ACTION (Heart Failure: A Controlled Trial ...Investigating Outcomes of Exercise Training) trial showed that among patients with heart failure (HF), regular exercise confers a modest reduction in the adjusted risk for all-cause mortality or hospitalization. Methods Patients randomized to the exercise training arm of HF-ACTION who were event-free at 3 months after randomization were included (n = 959). Median follow-up was 28.2 months. Clinical endpoints were all-cause mortality or hospitalization and cardiovascular mortality or HF hospitalization. Results A reverse J-shaped association was observed between exercise volume and adjusted clinical risk. On the basis of Cox regression, exercise volume was not a significant linear predictor but was a logarithmic predictor (p = 0.03) for all-cause mortality or hospitalization. For cardiovascular mortality or HF hospitalization, exercise volume was a significant (p = 0.001) linear and logarithmic predictor. Moderate exercise volumes of 3 to <5 metabolic equivalent (MET)-h and 5 to <7 MET-h per week were associated with reductions in subsequent risk that exceeded 30%. Exercise volume was positively associated with the change in peak oxygen uptake at 3 months (r = 0.10; p = 0.005). Conclusions In patients with chronic systolic HF, volume of exercise is associated with the risk for clinical events, with only moderate levels (3 to 7 MET-h per week) of exercise needed to observe a clinical benefit. Although further study is warranted to confirm the relationship between volume of exercise completed and clinical events, our findings support the use of regular exercise in the management of these patients. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training HF-ACTION; NCT00047437 )
Patterns of medical resource use near the end of life may differ across modes of death. The aim of this study was to characterize patterns of inpatient resource use and direct costs for patients with ...heart failure (HF) who died of sudden cardiac death (SCD), HF, other cardiovascular causes, or noncardiovascular causes during the last year of life. Data were from a randomized trial of exercise training in patients with HF. Mode of death was adjudicated by an end point committee. Generalized estimating equations were used to compare hospitalizations, inpatient days, and inpatient costs incurred during the final year of life in patients who died of different causes, adjusting for clinical and treatment characteristics. Of 2,331 patients enrolled in the trial, 231 died after ≥1 year of follow-up with an adjudicated mode of death, including 72 of SCD, 80 of HF, 34 of other cardiovascular causes, and 45 of noncardiovascular causes. Patients who died of SCD were younger, had less severe HF, and incurred fewer hospitalizations, fewer inpatient days, and lower inpatient costs than patients who died of other causes. After adjustment for patient characteristics, inpatient resource use varied by 2 to 4 times across modes of death, suggesting that cost-effectiveness analyses of interventions that reduce mortality from SCD compared to other causes should incorporate mode-specific end-of-life costs. In conclusion, resource use and associated medical costs in the last year of life differed markedly in patients with HF who experienced SCD and patients who died of other causes.
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