Preventive cardiology
Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia

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Abstract

Age at onset of clinically manifested coronary artery disease (CAD) varies widely among patients with familial hypercholesterolemia (FH). A number of factors in addition to high low-density lipoprotein cholesterol (LDL) have been suggested as predictors of risk among patients with FH, but a comprehensive examination of their utility is lacking. We therefore measured plasma lipids, carotid intima-medial thickness, and a variety of coronary risk factors in 262 patients with FH ≥30 years old (68 of whom had premature CAD). Age (p <0.0001) and gender were the most important determinants of premature CAD risk, with men having 5.64 times the risk of women (p <0.0001). In addition, cigarette smoking (odds ratio [OR] 2.71, p = 0.026), smaller LDL as determined by the LDL cholesterol/LDL apolipoprotein B ratio (OR 2.60, p = 0.014), and white blood cell count (p = 0.014) were also statistically significant risk factors. Lipoprotein(a) and the presence of xanthoma were associated with risk only in very early coronary cases. After correction for age, carotid intima-media thickness was not associated with CAD risk. Insulin, fibrinogen, homocysteine, plasma C-reactive protein, and the angiotensin-converting enzyme insertion/deletion polymorphism were unrelated to risk in this cohort. These results provide little justification for extensive investigation of risk factors among patients with FH, at least for the risk factors examined here. Rather, the inherent high LDL cholesterol of these patients should be the focus of preventive efforts. The novel finding of increased risk with smaller LDL may prove useful but needs further confirmation.

Section snippets

Methods

FH was diagnosed clinically using published, objective LDL cholesterol and clinical criteria shown to have 98% positive predictive value compared with DNA-based diagnoses.4, 5 All available patients with FH ≥18 years old in the Utah Make Early Diagnoses–Prevent Early Deaths registry (estimated to include 20% to 25% of patients with FH living in Utah) were invited for participation in this study by mail and phone follow-up. Over 90% of those invited agreed to participate.

This study comprised 68

Results

There were 262 patients with FH ≥30 years old included in this analysis of early onset CAD. A comparison of clinical characteristics among the 68 FH cases (22 women, 46 men) with early onset CAD and the 194 patients with FH (128 women, 66 men) without clinically evident CAD is presented in Table 1. Ages of the cases ranged from 30 to 74 years, whereas the range for controls was 30 to 88 years. The oldest male control was 63 years old. All older controls were women. Average age of CAD onset was

Discussion

This study began with the expectation that well-established risk factors and several more recently suggested risk factors would increase the inherently high risk of our patients with FH, thus, contributing importantly to risk prediction. Similarly, we expected carotid intima-medial thickness measurements to be strongly associated with coronary risk in these patients. Not surprisingly, we did find age and gender to be strongly associated with early onset CAD among our patients with FH. The

Acknowledgements

We greatly appreciate the work of our staff, including Mike McGinty for his outstanding laboratory work, Laurie Hokanson for her recruitment efforts, clinic assistance, and ultrasonography, Karen Nielsen for ultrasonography, and the MEDPED staff for their help with recruitment.

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    This study was supported by grant R01 HL47561 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland.

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