Racial differences in low-density lipoprotein particle size in families at high risk for premature coronary heart disease.

OBJECTIVE: Although small, dense low-density lipoprotein (LDL) has been implicated in atherogenesis and coronary heart disease (CHD) events, little is known about possible racial differences in LDL particle size. This study was designed to examine racial differences in the prevalence of small, dense LDL among 159 African-American and 477 White siblings of persons with premature (<60 years of age) CHD. METHODS AND RESULTS: This study examined fasting levels of total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, apolipoprotein B (ApoB), apolipoprotein A-1, and triglycerides, as well as factors known to be associated with small, dense LDL, including age, sex, obesity, hypertension, and diabetes. Relative LDL particle size was defined by the LDL cholesterol to ApoB ratio. Direct measurement of LDL particle size was obtained by proton NMR spectroscopy in a subset of 64 siblings. Despite similar levels of total and LDL cholesterol, White siblings were more likely to have low LDL cholesterol to ApoB ratios, indicative of atherogenic small, dense LDL, compared with African-American siblings. Multiple logistic regression analysis predicting the presence of LDL cholesterol/ApoB < or = 1.0 demonstrated that race (P = .009), triglyceride level (P = .0001), and diabetes (P = .02) were independent predictors, controlling for age and all other variables. Direct measurement of LDL particle size by NMR spectroscopy supported these findings. CONCLUSION: These findings provide the first known evidence that White individuals from a population at high risk for premature CHD have a greater probability of having a preponderance of small, dense LDL particles than do African Americans, independent of triglyceride levels, and despite comparable levels of total and LDL cholesterol.

Higher prevalence of GPIIIa PlA2 polymorphism in siblings of patients with premature coronary heart disease.

BACKGROUND: The Pl(A2) polymorphism of GPIIIa has been associated with unstable coronary syndromes in some studies, but the association has remained debated. None of the previous studies have focused on families at high risk. Risk factors tend to cluster within kindreds with high prevalence of premature coronary heart disease (CHD). Therefore, a heightened prevalence of the Pl(A2) polymorphism among siblings of patients with CHD would support the hypothesis that Pl(A2) is linked, directly or indirectly, to CHD. OBJECTIVES: To measure the prevalence of the Pl(A2) polymorphism among siblings of patients with CHD before the age of 60 years and to seek an association between the Pl(A2) polymorphism and established atherosclerotic and thrombogenic risk factors. METHODS: From January 1994 to April 1996, we genotyped 116 asymptomatic siblings (60 Caucasians, 56 Afro-Caribbeans) of patients with CHD manifestations before the age of 60 years for the Pl(A) polymorphism (also called HPA-1). A control cohort was used for comparison, consisting of individuals that were matched for race and geographic area but were free of CHD (n = 268, 168 Caucasians and 100 Afro-Caribbeans). In addition, we have characterized the sibling cohort for other atherogenic and thrombogenic risk factors. RESULTS: The prevalence of Pl(A2)-positive individuals (Pl(A2)[+], Pl(A1/A2) heterozygotes plus Pl(A2/A2) homozygotes) in the sibling cohort was high: 41.4%. When analyzed separately, the prevalence of Pl(A2)(+) siblings was 53.3% among Caucasians and 28.6% among Afro-Caribbeans. There was no association between Pl(A2) and other established atherogenic or thrombogenic risk factors. Interestingly, the clustering of other risk factors was lesser among Pl(A2)(+) siblings than their Pl(A1) counterparts. CONCLUSIONS: This study supports the hypothesis that the prevalence of Pl(A2)(+) individuals is high in kindreds with premature CHD. Hence, like the established risk factors that tend to cluster in families with premature CHD and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GPIIIa may represent an inherited risk that promotes the thromboembolic complications of CHD. That these asymptomatic Pl(A2)(+) siblings had overall less established risk factors than their Pl(A1) counterparts might represent an explanation for why they remained asymptomatic despite their Pl(A2) positivity.

Markedly high prevalence of coronary risk factors in apparently healthy African-American and white siblings of persons with premature coronary heart disease.

Among persons with a family history of premature coronary heart disease (CHD), siblings bear an excess risk of CHD that is as high as 12 times that of the general population. Aggressive, new, national guidelines for CHD risk reduction have focused on high-risk families, yet little is known about actual remediable risk factors in siblings of persons with premature CHD. To determine the magnitude of the problem relative to the general population, we screened 846 unaffected siblings (ages 30 to 59 years) of persons with documented CHD before age 60 years and compared their risk factor values with population reference norms obtained in the Third National Health and Nutrition Examination Survey (NHANES III) and the National Health Interview Survey (NHIS). Mean levels of low-density lipoprotein cholesterol were 0.52 mmol/L (20 mg/dl) higher in siblings; the prevalence of low-density lipoprotein cholesterol > or =4.14 mmol/L (160 mg/dl) was nearly twice that of race, sex, and age-specific values from NHANES III. Levels of high-density lipoprotein cholesterol <0.91 mmol/L (35 mg/dl) were similar between siblings and NHANES III (11% and 12%, respectively). Only 4% of all siblings had triglyceride levels > or =4.52 mmol/L (400 mg/dl). Hypertension prevalence was twice as high among siblings as among the NHANES III. Current smoking was 33.9% in white siblings and 25.5% in the NHIS, whereas smoking in African-Americans was similar to that in the NHIS (31.1% vs 29.2%). A mere 13% to 29% of siblings were without any major remediable risk factors. The overwhelming need for risk factor modification in this easily identifiable high-risk population supports aggressive national guidelines and demonstrates the lack of adequate treatment of apparently healthy siblings of persons with premature CHD.

Nurse-mediated cholesterol management compared with enhanced primary care in siblings of individuals with premature coronary disease.

BACKGROUND: Siblings of individuals with premature coronary heart disease have a high prevalence of low-density lipoprotein cholesterol (LDL-C) levels requiring treatment. OBJECTIVE: To evaluate management strategies for high LDL-C levels in apparently healthy 30- to 59-year-old siblings of individuals with documented coronary heart disease prior to age 60 years. METHODS: In a 2-year trial of care provided by either a nurse trained in lipid management (NURS) or enhanced primary care (EPC), in which physicians received recommendations based on national guidelines, 156 siblings with LDL-C levels of 4.14 mmol/L (160 mg/dL) were randomized by family. The LDL-C goal levels below 3.36 mmol/L (130 mg/dL) were compared between and within intervention groups. Multiple logistic regression analyses were applied to predict 2-year achievement of the goal. RESULTS: The NURS group achieved a significantly greater percentage of goal LDL-C levels than the EPC group (26% vs 10%; P=.008). The NURS LDL-C levels decreased an average of 0.91 mmol/L (35 mg/dL) while EPC levels decreased by 0.52 mmol/L (24 mg/dL) (P=.09). In the final multivariate model, siblings taking lipid-lowering drug treatment were 6.02 times more likely (95% confidence interval, 2.24-16.18) than those not receiving pharmacotherapy to achieve LDL-C goals; nurse management (P=.09) was marginally significant. Pharmacotherapy was instituted in 45.2% of NURS and 16.7% of EPC siblings (P=.001). CONCLUSIONS: High LDL-C levels in siblings were more effectively treated by a trained nurse, probably related to greater adherence to the application of national guidelines. Nonetheless, the majority of siblings with high LDL-C levels did not meet goal levels 2 years after an index case coronary heart disease event.

Hypertension among siblings of persons with premature coronary heart disease.

To determine the extent to which the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) guidelines were implemented in high-risk families with premature coronary heart disease, we examined the prevalence of hypertension and associated coronary risk factors in asymptomatic siblings of persons with documented premature coronary disease (<60 years of age). A total of 859 apparently healthy siblings (51% male, 19% African American) were screened for coronary risk factors. Siblings were classified as normotensive or hypertensive (BP > or = 140/90 and/or current antihypertensive pharmacotherapy). The prevalence of hypertension, awareness, treatment, and control among siblings was compared with published national estimates from the third National Health and Nutrition Examination Survey. The prevalence of hypertension in siblings was 44%. Among all hypertensives, only 60% were aware of being hypertensive, 45% were being treated, and 16% were under control. A high prevalence of other coronary risk factors was found among hypertensive siblings: 72% were hypercholesterolemic; 61% were obese; 29% were current smokers; 82% were consuming >30% of calories from fat; and only 14% were participating in vigorous physical activity three or more times per week. Comparisons with the national reference population revealed siblings to have a significantly higher prevalence of hypertension, along with significantly lower levels of awareness, treatment, and control. These findings demonstrate the intersection of multiple risk factors among hypertensive siblings and emphasize the need for more aggressive screening and treatment in this easily identifiable high-risk population.

Exaggerated reactivity to mental stress is associated with exercise-induced myocardial ischemia in an asymptomatic high-risk population.

BACKGROUND: This study was done to determine whether cardiovascular reactivity to mental stress is associated with exercise-induced occult ischemia in an asymptomatic population at high risk for premature coronary heart disease (CHD). METHODS AND RESULTS: One hundred fifty-two siblings of persons with premature CHD underwent mental stress testing. Exercise thallium tomography and 24-hour Holter monitoring were also performed. Hemodynamic changes were monitored during both stressors. Siblings positive for exercise-induced ischemia were offered cardiac catheterization. During mental stress, siblings with an abnormal exercise ECG and/or thallium scan (n=15) had greater maximal increases in systolic blood pressure (SBP, P=.0004) and diastolic blood pressure (DBP, P=.05) and had greater heart rate variability in the normalized low frequency domain of an analysis of Holter monitor recordings, compared with siblings without exercise-induced ischemia. Coronary arteriography confirmed coronary atherosclerosis in 85% of siblings with exercise-induced ischemia. Regression analyses showed that occult ischemia during exercise was a strong independent predictor of maximal change in SBP and DBP during mental stress. A multivariate logistic model demonstrated that siblings with exercise-induced occult ischemia were 21 times more likely to be "hot" responders (top quartile of change in SBP and DBP) during mental stress. CONCLUSIONS: An exaggerated cardiovascular response to mental stress is associated with exercise-induced myocardial ischemia in persons with preclinical coronary heart disease.