Dyslipidemia in American Indian Adolescents and Young Adults: Strong Heart Family Study.

BACKGROUND: Although many studies on the association between dyslipidemia and cardiovascular disease (CVD) exist in older adults, data on the association among adolescents and young adults living with disproportionate burden of cardiometabolic disorders are scarce. METHODS AND RESULTS: The SHFS (Strong Heart Family Study) is a multicenter, family-based, prospective cohort study of CVD in an American Indian populations, including 12 communities in central Arizona, southwestern Oklahoma, and the Dakotas. We evaluated SHFS participants, who were 15 to 39 years old at the baseline examination in 2001 to 2003 (n=1440). Lipids were measured after a 12-hour fast. We used carotid ultrasounds to detect plaque at baseline and follow-up in 2006 to 2009 (median follow-up=5.5 years). We identified incident CVD events through 2020 with a median follow-up of 18.5 years. We used shared frailty proportional hazards models to assess the association between dyslipidemia and subclinical or clinical CVD, while controlling for covariates. Baseline dyslipidemia prevalence was 55.2%, 73.6%, and 78.0% for participants 15 to 19, 20 to 29, and 30 to 39 years old, respectively. Approximately 2.8% had low-density lipoprotein cholesterol ≥160 mg/dL, which is higher than the recommended threshold for lifestyle or medical interventions in young adults of 20 to 39 years old. During follow-up, 9.9% had incident plaque (109/1104 plaque-free participants with baseline and follow-up ultrasounds), 11.0% had plaque progression (128/1165 with both baseline and follow-up ultrasounds), and 9% had incident CVD (127/1416 CVD-free participants at baseline). Plaque incidence and progression were higher in participants with total cholesterol ≥200 mg/dL, low-density lipoprotein cholesterol ≥160 mg/dL, or non-high-density lipoprotein cholesterol ≥130 mg/dL, while controlling for covariates. CVD risk was independently associated with low-density lipoprotein cholesterol ≥160 mg/dL. CONCLUSIONS: Dyslipidemia is a modifiable risk factor that is associated with both subclinical and clinical CVD, even among the younger American Indian population who have unexpectedly high rates of significant CVD events. Therefore, this population is likely to benefit from a variety of evidence-based interventions including screening, educational, lifestyle, and guideline-directed medical therapy at an early age.

Embedding clinical interventions into observational studies.

Novel approaches to observational studies and clinical trials could improve the cost-effectiveness and speed of translation of research. Hybrid designs that combine elements of clinical trials with observational registries or cohort studies should be considered as part of a long-term strategy to transform clinical trials and epidemiology, adapting to the opportunities of big data and the challenges of constrained budgets. Important considerations include study aims, timing, breadth and depth of the existing infrastructure that can be leveraged, participant burden, likely participation rate and available sample size in the cohort, required sample size for the trial, and investigator expertise. Community engagement and stakeholder (including study participants) support are essential for these efforts to succeed.

Differential impacts of blood pressure and lipid lowering on regression of ventricular and arterial mass: the Stop Atherosclerosis in Native Diabetics Trial.

The relative impacts of lowering blood pressure versus lowering low-density lipoprotein (LDL) cholesterol on regression of ventricular and arterial mass have not been systematically examined. Changes in left ventricular mass and arterial mass (common carotid artery cross-sectional area) after 36 months of simultaneous lowering of systolic blood pressure and LDL cholesterol were examined in the Stop Atherosclerosis in Native Diabetics Trial of standard versus aggressive LDL cholesterol and blood pressure targets in American Indians with type 2 diabetes mellitus. The 2 treatment groups were combined to examine changes in left ventricular and arterial mass over a spectrum of achieved blood pressure and lipid levels. Among the combined group of 413 Stop Atherosclerosis in Native Diabetics Trials participants, systolic blood pressure, LDL cholesterol, and left ventricular mass were all significantly reduced, whereas arterial mass significantly increased, after 36 months of therapy (P<0.001 for all). In linear regression models, a decrease in arterial mass was significantly related to achieved systolic blood pressure and, to a lesser extent, achieved LDL cholesterol, after adjustment for important covariates. Left ventricular mass progressively decreased with lower achieved levels of systolic blood pressure, independent of baseline levels of left ventricular mass. In conclusion, achieved levels of systolic blood pressure are important determinants of the extent of regression of arterial and ventricular mass during prolonged therapy in diabetic individuals. Achieved levels of LDL cholesterol influence regression of arterial but not ventricular mass. Our findings suggest that there is no threshold of systolic blood pressure below which regression of cardiovascular target organ damage cannot be achieved.

Heart rate is associated with red blood cell fatty acid concentration: the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study.

BACKGROUND: Consumption of omega-3 fatty acids (FAs) is associated with a reduction in deaths from coronary heart disease, arrhythmia, and sudden death. Although these FAs were originally thought to be antiatherosclerotic, recent evidence suggests that their benefits are related to reducing risk for ventricular arrhythmia and that this may be mediated by a slowed heart rate (HR). METHODS: The study was conducted in Alaskan Eskimos participating in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study, a population experiencing a dietary shift from unsaturated to saturated fats. We compared HR with red blood cell (RBC) FA content in 316 men and 391 women ages 35 to 74 years. RESULTS: Multivariate linear regression analyses of individual FAs with HR as the dependent variable and specific FAs as covariates revealed negative associations between HR and docosahexaenoic acid (22:6n-3; P = .004) and eicosapentaenoic acid (20:5n-3; P = .009) and positive associations between HR and palmitoleic acid (16:1n-7; P = .021), eicosanoic acid (20:1n9; P = .007), and dihomo-gamma-linolenic acid (DGLA; 20:3n-6; P = .021). Factor analysis revealed that the omega-3 FAs were negatively associated with HR (P = .003), whereas a cluster of other, non-omega-3 unsaturated FAs (16:1, 20:1, and 20:3) was positively associated. CONCLUSIONS: Marine omega-3 FAs are associated with lower HR, whereas palmitoleic and DGLA, previously identified as associated with saturated FA consumption and directly related to cardiovascular mortality, are associated with higher HR. These relations may at least partially explain the relations between omega-3 FAs, ventricular arrhythmia, and sudden death.

Cost-effectiveness of lower targets for blood pressure and low-density lipoprotein cholesterol in diabetes: the Stop Atherosclerosis in Native Diabetics Study (SANDS) .

BACKGROUND: The Stop Atherosclerosis in Native Diabetics Study (SANDS) reported cardiovascular benefit of aggressive versus standard treatment targets for both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) in diabetic individuals. OBJECTIVE: In this analysis, we examined within trial cost-effectiveness of aggressive targets of LDL-C ≤70 mg/dL and systolic BP ≤115 mmHg versus standard targets of LDL-C ≤100 mg/dL and systolic BP ≤130 mmHg. DESIGN: Randomized, open label blinded-to-endpoint 3-year trial. DATA SOURCES: SANDS clinical trial database, Quality of Wellbeing survey, Centers for Medicare and Medicaid Services, Wholesale Drug Prices. TARGET POPULATION: American Indians ≥ age 40 years with type 2 diabetes and no previous cardiovascular events. TIME HORIZON: April 2003 to July 2007. PERSPECTIVE: Health payer. INTERVENTIONS: Participants were randomized to aggressive versus standard groups with treatment algorithms defined for both. OUTCOME MEASURES: Incremental cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: Compared with the standard group, the aggressive group had slightly lower costs of medical services (-$116) but a 54% greater cost for BP medication ($1,242) and a 116% greater cost for lipid-lowering medication ($2,863), resulting in an increased cost of $3,988 over 3 years. Those in the aggressively treated group gained 0.0480 quality-adjusted life-years (QALY) over the standard group. When a 3% discount rate for costs and outcomes was used, the resulting cost per QALY was $82,589. RESULTS OF SENSITIVITY ANALYSIS: The use of a 25%, 50%, and 75% reduction in drug costs resulted in a cost per QALY of $61,329, $40,070, and $18,810, respectively. LIMITATIONS: This study was limited by use of a single ethnic group and by its 3-year duration. CONCLUSIONS: Within this 3-year study, treatment to lower BP and LDL-C below standard targets was not cost-effective because of the cost of the additional medications required to meet the lower targets. With the anticipated availability of generic versions of the BP and lipid-lowering drugs used in SANDS, the cost-effectiveness of this intervention should improve. Published by Elsevier Inc on behalf of the National Lipid Association.

Cardiovascular disease prevalence and its relation to risk factors in Alaska Eskimos.

BACKGROUND AND AIMS: Although Eskimos were thought to be protected from cardiovascular disease (CVD), state health data show a large proportion of deaths from CVD, despite traditional lifestyles and high omega-3 fatty acid intake. This article explores CVD prevalence and its relation to risk factors in Alaska Eskimos. METHODS AND RESULTS: A population-based cohort of 499 Alaska Eskimos > age 45 from the Norton Sound region was examined in 2000-2004 for CVD and associated risk factors as part of the Genetics of Coronary Artery Disease in Alaska Natives study. CVD and atherosclerosis were evaluated and adjudicated using standardized methods. Average age was 58 years; diabetes prevalence was low and high-density lipoprotein cholesterol (HDL-C) concentrations were high, but a large proportion smoked and had high pathogen burden. CVD was higher in men (12.6%) than in women (5.3%) (prevalence ratio 2.4, CI 1.3-4.4). Rates of stroke (6.1% in men, 1.8% in women) were similar to those for coronary heart disease (CHD) (6.1% men, 2.5% women). MI prevalence was low in both genders (1.9% and 0.7%). CVD was higher in men and in those >60 years. Hypertension, diabetes, high LDL-C, high apoB, and low HDL-C were all strong correlates (<.002) and albuminuria and CRP were also correlated with CVD (p<.05) after adjustment for age and gender. Carotid atherosclerosis was correlated with CVD (p=.0079) independent of other risk factors. CONCLUSION: These data show high CHD and stroke prevalence in Alaska Eskimos, despite low average LDL-C and high HDL-C. Hypertension and high LDL-C were independent correlates; identifying these risk factors early and treating to target is recommended.

Relation among lipoprotein subfractions and carotid atherosclerosis in Alaskan Eskimos (from the GOCADAN Study).

Studies have been inconsistent regarding whether lipoprotein particle subfraction measures are useful indicators of cardiovascular risk. The present study evaluated the relation between lipoprotein particle concentrations and size, analyzed using nuclear magnetic resonance spectroscopy and measures of carotid atherosclerosis in a population with high cardiovascular risk but little hyperlipidemia. In this cross-sectional, population-based sample of Alaska Eskimos >or=35 years old (n = 656), a greater carotid intimal medial thickness was associated with greater low-density lipoprotein (LDL) cholesterol (p = 0.03) and total LDL particle concentration (p = 0.04), independently of other traditional risk factors. The effects of LDL cholesterol and LDL particle concentration on intimal medial thickness were additive (p = 0.015). Carotid plaque was associated with greater levels of LDL cholesterol (p = 0.01), greater concentrations of large LDL particles (p = 0.003), and a reduction in the size of the very-low-density lipoprotein particles (p = 0.03). The effects of LDL cholesterol and large LDL particles on the plaque score were additive. In conclusion, the carotid intimal medial thickness was associated with greater LDL particle concentrations. The association was strongest in those with greater LDL cholesterol levels. Plaque was associated with greater concentrations of LDL cholesterol, large LDL particles, and smaller very-low-density lipoprotein particles. It might be beneficial to determine the lipoprotein subfractions in populations with little hyperlipidemia.

PREVENTION OF ATHEROSCLEROSIS WITH LDL-C LOWERING - LIPOPROTEIN CHANGES AND INTERACTIONS: THE SANDS STUDY.

BACKGROUND: Lowering low-density lipoprotein cholesterol (LDL-C) with statins reduces atherosclerosis. LDL and high-density lipoprotein (HDL) are commonly measured by their cholesterol content, but non-HDL cholesterol, LDL particle number (LDL-P), or total apolipoprotein B (apoB) may better predict cardiovascular risk. Few studies have examined relations among lipoprotein levels and composition before and after interventions to lower LDL-C and non-HDL-C. OBJECTIVE: To measure changes in carotid artery intimal media thickness (CIMT) and lipid concentration and composition during 36 months of statin therapy. METHODS: Analyses were conducted on 418 diabetic individuals, with complete data and no prior cardiovascular events, who were randomized to aggressive (AG) versus standard (STD) treatment for LDL-C, non-HDL-C, and systolic blood pressure (SBP) as part of the Stop Atherosclerosis in Native Diabetics Study (SANDS). RESULTS: The AG group achieved average LDL-C and non-HDL-C of 71mg/dL and 100mg/dL and a decrease in CIMT. No significant interactions were observed between treatment effect and initial levels of LDL-C, non-HDL-C, HDL-C, triglycerides, apoB, or LDL-P. Decreases in LDL-C (p<.005) and non-HDL-C (p<.001) were independently correlated with CIMT regression in the AG group. Changes in apoB and LDL-P showed borderline correlations with CIMT regression (p=.07 and p=.09). CONCLUSIONS: In diabetic adults with no prior cardiovascular events, treatment to current targets for lipids and SBP reduces atherosclerosis progression and when more aggressive targets are met, atherosclerosis regresses. The aggressive targets for LDL-C and non-HDL-C appeared to be the main determinants of CIMT regression and were more predictive of this outcome than changes in LDL-P or apoB.

Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial.

OBJECTIVES: This secondary analysis from the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial examines the effects of lowering low-density lipoprotein cholesterol (LDL-C) with statins alone versus statins plus ezetimibe on common carotid artery intima-media thickness (CIMT) in patients with type 2 diabetes and no prior cardiovascular event. BACKGROUND: It is unknown whether the addition of ezetimibe to statin therapy affects subclinical atherosclerosis. METHODS: Within an aggressive group (target LDL-C 40 years of age receiving statins plus ezetimibe versus statins alone. The CIMT changes in both aggressive subgroups were compared with changes in the standard subgroups (target LDL-C

C-Reactive protein, insulin resistance, and metabolic syndrome in a population with a high burden of subclinical infection: insights from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study.

OBJECTIVE: To explore relationships between C-reactive protein (CRP), subclinical infection, insulin resistance, and metabolic syndrome. RESEARCH DESIGN AND METHODS: Data from 1,174 Eskimos, aged >/=18 years, from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study were analyzed; 40 participants with diabetes were eliminated. Baseline assessment included interviews, physical exam, and blood and urine sampling. Metabolic syndrome was assessed using Adult Treatment Panel III criteria. CRP and antibodies to common pathogens were measured. RESULTS: Although CRP was related in univariate analyses to insulin resistance and metabolic syndrome, relations were attenuated or eliminated after adjustment for relevant covariates. CRP was not higher among those with impaired fasting glucose (IFG), and pathogen burden was not related to insulin resistance, metabolic syndrome, or IFG. CONCLUSIONS: Pathogen burden and inflammation do not seem to be related to insulin resistance, metabolic syndrome, or IFG in this population. The inflammatory process may reflect insulin resistance or its correlates but most likely is not causative.

Lipoprotein particle distribution and size, insulin resistance, and metabolic syndrome in Alaska Eskimos: the GOCADAN study.

BACKGROUND: Metabolic syndrome (MS) is associated with dyslipidemia, and insulin resistance (IR) may be a main determinant of this dyslipidemia. OBJECTIVE: To determine how lipoprotein particle concentration and size are related to MS and IR in a population-based sample of Alaska Eskimos. DESIGN: Participants underwent a physical exam, personal interview, collection of biological specimens, and diagnostic tests. SETTING: This study was conducted in the Norton Sound region of Alaska. PARTICIPANTS: One thousand one hundred fifty-eight Inupiat Eskimo adults (women=653, men=505). MAIN OUTCOME MEASURES: Lipoprotein particle profile was evaluated by nuclear magnetic resonance (NMR) and related to presence of MS and level of IR. RESULTS: Participants with MS had (a) significantly higher concentrations of all VLDLs and a larger VLDL size (women, p=0.007; men, p=0.0001); (b) higher concentrations of small LDL (women, p<0.0001; men, p=0.09) and lower concentrations of large LDL (women, p<0.0001), leading to a smaller overall LDL size (women, p<0.0001; men, p<0.05); (c) significantly lower concentrations of large HDL (both genders, p<0.0001) and an increase in intermediate (women, p<0.05) and small HDL (women, p<0.0001; men, p<0.004). Lipoprotein profile with increasing HOMA-IR resembled that of individuals with MS. CONCLUSIONS: In this population MS is characterized by lipoprotein distribution and size abnormalities independent of obesity, age, and other cardiovascular risk factors, including lipid concentration. IR seems the major determinant.

Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial.

CONTEXT: Individuals with diabetes are at increased risk for cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested. OBJECTIVE: To compare progression of subclinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and systolic blood pressure (SBP) of 115 mm Hg or lower vs standard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, blinded-to-end point, 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma, Arizona, and South Dakota. Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events. INTERVENTIONS: Participants were randomized to aggressive (n=252) vs standard (n=247) treatment groups with stepped treatment algorithms defined for both. MAIN OUTCOME MEASURES: Primary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness (IMT). Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events. RESULTS: Mean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (-0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (-0.02 mm(2) vs 1.05 mm(2); P < .001); and there was greater decrease in left ventricular mass index (-2.4 g/m(2.7) vs -1.2 g/m(2.7); P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87) did not differ significantly between groups. CONCLUSIONS: Reducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00047424.

Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes: the strong heart study.

OBJECTIVE: To determine whether non-HDL cholesterol, a measure of total cholesterol minus HDL cholesterol, is a predictor of CVD in patients with diabetes. RESEARCH DESIGN AND METHODS: The Strong Heart Study, a population-based study of CVD and its risk factors in 13 American Indian communities in three geographic areas in the U.S. The baseline examination, conducted between July 1989 and January 1992, consisted of a personal interview, a physical examination, and laboratory tests. Of the 4,549 women and men aged 45-74 years participating in the study, 2,108 had diabetes but no CVD at baseline. Data on fatal and nonfatal CVD were collected during the follow-up period through 31 December 1998 (average 9 years). RESULTS: Multivariable analyses indicated that non-HDL cholesterol is a strong predictor of CVD in men and women with diabetes and is particularly indicative of coronary events. Hazard ratios for the highest tertile of non-HDL cholesterol in men and women with diabetes (2.23 and 1.80, respectively) were higher than those for either LDL cholesterol or triglycerides alone in both men and women and were higher than the ratio of total/HDL cholesterol in women. The utility of non-HDL cholesterol in predicting CVD extended over a wide range of triglyceride concentrations. CONCLUSIONS: This study suggests that non-HDL cholesterol index may be particularly useful in predicting CVD risk in patients with diabetes.