LAUSR

Familial hypercholesterolemia (FH) is a common autosomal dominant disease associated with premature coronary artery disease (CAD). However, manifestations of atherosclerosis outside the coronary arteries are less well-defined. In homozygous FH, both ostial CAD and postvalvular aortic stenosis with extensive aortic arch atheroma are common; findings in heterozygous FH are more variable. In a previous issue of Angiology, Akioyamen et al metaanalyze cohort data from 5 studies representing 179 835 participants with FH and show an increased risk of peripheral arterial disease (PAD) in FH (odds ratio [OR]: 3.59 [95% confidence interval, CI: 1.90-9.89]). If only genetically confirmed monogenic FH is considered, then the excess risk for PAD remains in these cohorts (OR: 2.96 [0.68-12.880]) but this is nonsignificant due to lower numbers. In the analysis, the risk of PAD was associated with disease severity as defined by a low-density lipoprotein cholesterol (LDL-C) >4.9 mmol/L (190 mg/dL) (OR: 1.42 [1.33-1.66]). However, no association was seen with risk of stroke in monogenic FH (OR: 0.76 [0.37-1.58]). This analysis used cohort studies with control groups to ascertain risks of atheroma. Other excluded studies include the Simon Broome cohort study which has now been running for >20 years comprising 2871 patients and 22 992 patient-years of follow-up. In that cohort where mortality data are used, a large excess of CAD events is seen while strokes are less frequent than expected in FH with only 5% of deaths being due to stroke with a standardized mortality ratio of 0.79 (CI: 0.36-1.50). No data has been reported on PAD possibly as it is not often listed as a cause of death. Early studies in FH reported a high prevalence of PAD of up to 30% to 40% in patients with FH. Later studies using peripheral arterial ultrasound assessment and ankle-brachial indices also showed a raised prevalence of subclinical PAD ranging from 30% to 65% but were limited by small numbers of subjects. A recent study in 202 patients with FH mostly with monogenic disease (total cholesterol 8.7 mmol/L; 336 mg/dL; 35% smokers) suggested 17% had PAD based on an ankle-brachial index <0.9. Recent registry data from France identified PAD as the initial presentation in 9% of patients with FH and as a second event in 15% but did not detail original LDL-C or current rates of smoking. The current study based on large cohorts is far more robust in showing an increased prevalence of PAD in FH in large assembled group of cohort studies. Many reports confirm that CAD risk is strongly associated with high LDL-C in FH. However, the findings of these studies that form the basis of this meta-analysis seem to be at variance with the practice of lipid clinics. While lipid clinics in the United Kingdom commonly see patients for diagnosis and management of FH, presentations with PAD seem to be rare as only 1% of presentations were for PAD. Furthermore, as screening for FH becomes more common and genetic testing is introduced, cascade screening is becoming routine and the historical selection bias toward greater severity abates; thus rates of diagnosed CAD are falling in clinic FH populations. The extent of referral bias can be seen in the fact that many reported clinic cohorts have untreated LDL-C 6.0-8.0 mmol/L (240-320 mg/dL) with a treated LDL-C around 4.5 mmol/L (180 mg/dL). The average LDL-C in general unselected FH populations based on untreated relatives is around 4.5 mmol/L (180 mg/dL) and is only moderately higher than that in the general population. The prevalence of risk factors strongly associated with PAD is also changing. Three are commonly recognized factors— smoking, type 2 diabetes, and raised lipoprotein (a) concentrations. In wider society, rates of smoking are falling attenuating risks for CAD and likely more strongly for PAD given the stronger relationship of PAD with smoking. Rates of smoking are often lower in patients with FH than the general population with rates of 13% reported in a recent UK audit compared to up to 20% in the general population. Diabetes is commonly associated with PAD and the prevalence of this disease is increasing in the general population in line with the occurrence of obesity, yet there is a suggestion that patients with FH may be protected against developing diabetes