Predicting Risk for Incident Heart Failure With Omega-3 Fatty Acids: From MESA.

OBJECTIVES: The aim of this study was to determine if plasma eicosapentaenoic acid (EPA) abundance (%EPA) is associated with reduced hazard for primary heart failure (HF) events in the MESA (Multi-Ethnic Study of Atherosclerosis) trial. BACKGROUND: Clinical trials suggest that omega-3 polyunsaturated fatty acids (ω3 PUFAs) prevent sudden death in coronary heart disease and HF, but this is controversial. In mice, the authors demonstrated that the ω3 PUFA EPA prevents contractile dysfunction and fibrosis in an HF model, but whether this extends to humans is unclear. METHODS: In the MESA cohort, the authors tested if plasma phospholipid EPA predicts primary HF incidence, including HF with reduced ejection fraction (EF) (EF <45%) and HF with preserved EF (EF ≥45%) using Cox proportional hazards modeling. RESULTS: A total of 6,562 participants 45 to 84 years of age had EPA measured at baseline (1,794 black, 794 Chinese, 1,442 Hispanic, and 2,532 white; 52% women). Over a median follow-up period of 13.0 years, 292 HF events occurred: 128 HF with reduced EF, 110 HF with preserved EF, and 54 with unknown EF status. %EPA in HF-free participants was 0.76% (0.75% to 0.77%) but was lower in participants with HF at 0.69% (0.64% to 0.74%) (p = 0.005). Log %EPA was associated with lower HF incidence (hazard ratio: 0.73 [95% confidence interval: 0.60 to 0.91] per log-unit difference in %EPA; p = 0.001). Adjusting for age, sex, race, body mass index, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, albuminuria, and the lead fatty acid for each cluster did not change this relationship. Sensitivity analyses showed no dependence on HF type. CONCLUSIONS: Higher plasma EPA was significantly associated with reduced risk for HF, with both reduced and preserved EF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

Relation of omega-3 fatty acid and dietary fish intake with brachial artery flow-mediated vasodilation in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The relation between dietary fish intake and brachial artery measures, including brachial artery flow-mediated dilation (FMD), has not been well established across sex and racial-ethnic groups. OBJECTIVE: We hypothesized that consumption of nonfried fish and plasma phospholipid measures of long-chain omega-3 (n-3) fatty acids would be positively associated with larger FMD in men and women across racial-ethnic groups. DESIGN: We investigated cross-sectional associations of brachial artery measures with fish intake (ascertained with a food-frequency questionnaire) and plasma phospholipid omega-3 concentrations in 3045 adults, aged 45-84 y, who were free of clinical cardiovascular disease. RESULTS: In overall multivariate-adjusted analyses, there were no significant associations between fish intake or any brachial artery measures. However, when stratified by sex, there was an association between the highest quartile of nonfried fish consumption and a 0.10-mm lower (1 SD) brachial artery diameter in men (P = 0.01) and a 0.27% smaller FMD in women (P = 0.02) compared with the lowest quartile of nonfried fish intake in each respective sex strata. When stratified by race-ethnicity and race-ethnicity by sex, additional heterogeneity was noted, but results were difficult to interpret because of small sample sizes. Plasma phospholipid omega-3 concentrations showed a similar directionality of association with brachial artery measures observed for nonfried fish consumption, although statistical significance was not achieved in fully adjusted models. CONCLUSION: This study indicates that the association between nonfried fish intake and baseline brachial artery size varies by sex, with suggestive evidence of sex differences in the association between nonfried fish intake and FMD.

Effect of muscadine grape seed supplementation on vascular function in subjects with or at risk for cardiovascular disease: a randomized crossover trial.

BACKGROUND: Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function. OBJECTIVES: To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk. DESIGN: In a randomized, double-blind, placebo-controlled crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout. Resting brachial diameter and brachial flow-mediated dilation (FMD) and biomarkers of inflammation, lipid peroxidation, and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models. RESULTS: There was no evidence of improved FMD (% change) with muscadine grape seed (muscadine grape seed: pre 5.2% ± 0.3%, post 4.6% ± 0.3%, p = 0.06; placebo: pre 5.3% ± 0.4%, post 5.2% ± 0.4%, p = 0.82; p for muscadine grape seed vs. placebo = 0.25). However, there was a significant increase in baseline diameter (mm) with muscadine grape seed supplementation (muscadine grape seed: pre 4.05 ± 0.09, post 4.23 ± 0.10, p = 0.002; placebo: pre 4.12 ± 0.11, post 4.12 ± 0.10, p = 0.93; p for muscadine grape seed vs. placebo = 0.026). All other biomarkers were not significantly altered by muscadine grape seed supplementation. CONCLUSIONS: Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation, lipid peroxidation, or antioxidant capacity. However, the muscadine grape seed supplement did result in a significant increase in resting brachial diameter. The clinical significance of the effect on resting diameter is not yet established. More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits.

Submaximal exercise coronary artery flow increases in postmenopausal women without coronary artery disease after estrogen and atorvastatin.

OBJECTIVE: The aim of this study was to determine the effect of statins and hormone therapy on submaximal exercise-induced coronary artery blood flow in postmenopausal women without a history of coronary artery disease. Hormone therapy or statin therapy in early postmenopausal women without coronary artery disease has been shown to enhance arterial endothelial function; we hypothesized that these agents would improve submaximal exercise-induced coronary artery blood flow. METHODS: Sixty-four postmenopausal women, aged 50 to 65 years without documented coronary artery disease, were randomized in a double-blind, crossover fashion to receive 8 weeks of hormone therapy versus placebo, with or without 80 mg/day of atorvastatin. Before receipt of any therapy and after each treatment period, each woman underwent measures of coronary artery blood flow at rest and stress. RESULTS: The combination of hormone therapy and atorvastatin increased submaximal exercise-induced coronary artery blood flow (P = 0.04). In the subgroups of women compliant with treatment, resting coronary artery blood flow increased in those receiving hormone therapy (P = 0.03) or statin therapy (P = 0.02). CONCLUSIONS: In postmenopausal women aged 50 to 65 years without documented coronary artery disease, resting and submaximal exercise-induced coronary artery blood flow improves after receipt of high-dose atorvastatin and conjugated estrogens therapy.

Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease.

BACKGROUND: Increased life expectancy is associated with an increase in the burden of chronic cardiovascular disease. OBJECTIVE: To assess the efficacy and safety of high-dose atorvastatin in patients 65 years of age or older. DESIGN: A prespecified secondary analysis of the Treating to New Targets study, a randomized, double-blind clinical trial. SETTING: 256 sites in 14 countries participating in the Treating to New Targets study. PARTICIPANTS: 10,001 patients (3809 patients > or =65 years of age) with coronary heart disease (CHD) and low-density lipoprotein cholesterol levels less than 3.4 mmol/L (<130 mg/dL). INTERVENTION: Patients were randomly assigned to receive atorvastatin, 10 or 80 mg/d. MEASUREMENTS: The primary end point was the occurrence of a first major cardiovascular event (death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke). RESULTS: In patients 65 years of age or older, absolute risk was reduced by 2.3% and relative risk by 19% for major cardiovascular events in favor of the high-dose atorvastatin group (hazard ratio, 0.81 [95% CI, 0.67 to 0.98]; P = 0.032). Among the components of the composite outcome, the mortality rates from CHD, nonfatal non-procedure-related myocardial infarction, and fatal or nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin) were all lower in older patients who received high-dose atorvastatin, although the difference was not statistically significant for each individual component. The improved clinical outcome in patients 65 years of age or older was not associated with persistent elevations in creatine kinase levels. LIMITATION: Because the study was a secondary analysis, the findings should be interpreted within the context of the main study results. CONCLUSIONS: The analysis suggests that additional clinical benefit can be achieved by treating older patients with CHD more aggressively to reduce low-density lipoprotein cholesterol levels to less than 2.6 mmol/L (<100 mg/dL). The findings support the use of intensive low-density lipoprotein cholesterol-lowering therapy in high-risk older persons with established cardiovascular disease. Click here for related information on atorvastatin.

Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease.

BACKGROUND: Higher intakes of fish and n-3 fatty acids are associated with a reduced risk of cardiovascular events and mortality. However, limited data exist on the effect of fish intake on actual measures of progression of coronary artery atherosclerosis. OBJECTIVE: The aim was to examine the association between fish intake and the progression of coronary artery atherosclerosis in women with coronary artery disease. DESIGN: This was a prospective cohort study of postmenopausal women (n = 229) participating in the Estrogen Replacement and Atherosclerosis trial. Usual fish intake was estimated at baseline with a food-frequency questionnaire. Quantitative coronary angiography was performed at baseline and after 3.2 +/- 0.6 (x +/- SD) y to evaluate changes in the mean minimum coronary artery diameter, the mean percentage of stenosis, and the development of new coronary lesions. RESULTS: Compared with lower fish intakes, consumption of > or =2 servings of fish or > or =1 serving of tuna or dark fish per week was associated with smaller increases in the percentage of stenosis (4.54 +/- 1.37% compared with -0.06 +/- 1.59% and 5.12 +/- 1.48% compared with 0.35 +/- 1.47%, respectively; P < 0.05 for both) in diabetic women after adjustments for age, cardiovascular disease risk factors, and dietary intakes of fatty acids, cholesterol, fiber, and alcohol. These associations were not significant in nondiabetic women. Higher fish consumption was also associated with smaller decreases in minimum coronary artery diameter and fewer new lesions. CONCLUSIONS: Consumption of fish is associated with a significantly reduced progression of coronary artery atherosclerosis in women with coronary artery disease.

Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?

The Treating to New Targets (TNT) trial is a parallel-group study that has randomized 10,003 patients from 14 countries to double-blind treatment with either atorvastatin 10 or 80 mg. During the double-blind period, low-density lipoprotein (LDL) cholesterol levels are expected to reach approximate mean values of 100 mg/dl (2.6 mmol/L) for the low-dose atorvastatin group and 75 mg/dl (1.9 mmol/L) for the high-dose group. Randomized patients are expected to be followed for an average of 5 years. The primary end point is the time to occurrence of a major cardiovascular event, defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. The large patient numbers in the TNT study and long follow-up should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit.

No effect of an L-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia.

BACKGROUND: Providing L-arginine as a precursor for nitric oxide has been proposed to improve endothelial function in populations at high risk for cardiovascular events. We studied the effects of dietary L-arginine supplementation with HeartBars (a medical food rich in L-arginine, Cooke Pharma, Belmont, Calif) on flow-mediated dilation and markers of endothelial function in subjects with hypercholesterolemia. METHODS: We randomly assigned 47 subjects with hypercholesterolemia to receive one HeartBar containing 3.3 g L-arginine each, or a placebo bar, consumed twice daily for 2 weeks. Flow-mediated dilation, platelet aggregation studies, and soluble levels of endothelial and platelet adhesion molecules were obtained before and after the 2-week treatment period. RESULTS: Baseline and follow-up levels of L-arginine were 78.5 +/- 28.2 micromol/L and 80.7 +/- 26.7 micromol/L, respectively (P =.54). The HeartBar group had no improvement in flow-mediated dilation; changes in brachial artery diameter at baseline and follow-up were 5.52% +/- 3.32% and 4.96% +/- 2.39%, respectively. There were also no changes in the soluble levels of E-selectin and P-selectin by treatment group. CONCLUSIONS: In our study, 2 weeks of HeartBar supplementation in subjects with hypercholesterolemia showed no favorable effects on endothelial or platelet function.

Vascular effects of dietary L-arginine supplementation.

The vascular endothelium is acknowledged to play an important role in vascular physiology. Attention has focused on endothelial production of nitric oxide as a key element in many of the processes associated with the development of atherosclerosis. L-arginine is the substrate for the enzyme nitric oxide synthase (NOS), which is responsible for the endothelial production of nitric oxide. Therefore, many investigators have been interested in whether dietary L-arginine supplementation can augment nitric oxide production and thereby improve vascular health. The effects of oral L-arginine on vascular health and disease have been examined both in human beings and in various animal models. In this review, we summarize the results of studies of oral L-arginine supplementation on atherosclerotic lesion formation, as well as markers of endothelial function (e.g. macrophage function, platelet aggregation and adhesion, and in vitro vascular ring studies). Although results of oral L-arginine supplementation in hypercholesterolemic animals have generally shown beneficial effects, the data in humans are varied, possibly because of small sample sizes and brief periods of study. Long-term randomized clinical trials are needed to more definitively address whether oral L-arginine supplementation could be advantageous for vascular health.