Hyperlipidemia and cardiovascular disease with focus on familial hypercholesterolemia


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The concept of total lifelong cholesterol burden defining the risk of cardiovascular disease (CVD) has been proven over the last years [1], and risk modification by cholesterol-lowering treatment is proven beyond ‘doubt’ [2]. Hypercholesterolemia is primarily lifestyle induced in adult life, or caused by genetic dispositions such as familial hypercholesterolemia, leading to increased cholesterol levels from birth and early manifestations of high cholesterol [3]. Khera et al.[4▪▪] assessed the risk of coronary artery disease (CAD) in familial hypercholesterolemia patients (lifelong cholesterol exposure) compared with lifestyle-induced hypercholesterolemia in adult life. In total, 20 485 CAD-free persons with hypercholesterolemia measured in adult life from seven case–control studies were genotyped. Familial hypercholesterolemia mutation-positive study participants compared with familial hypercholesterolemia mutation-negative study participants had significant elevated CAD risk (ranging from 2 to 6-fold) at similar LDL cholesterol levels, underscoring the increased risk associated with lifelong exposure. The impact of clinical signs (xanthoma and/or family history) and familial hypercholesterolemia mutation status on risk of CAD was also investigated in study participants with LDL cholesterol levels in the top 4 percentile of the Japanese population [5]. When adjusted for the cholesterol levels, both presence of clinical signs only, and familial hypercholesterolemia mutation only increased the risk (odds ratio (OR) of 4.6 and 3.4, respectively). However, presence of both clinical signs and familial hypercholesterolemia mutation further increased the risk of CAD to an OR of 11.6 [4▪▪] indicating an additive effect of clinical signs of familial hypercholesterolemia and familial hypercholesterolemia mutation status on the risk of CAD. Among 102 familial hypercholesterolemia patients, asymptomatic for CVD patients with tendon xanthomas were shown to have higher LDL cholesterol and lipoprotein (a) levels and greater coronary artery calcium scores, underscoring that clinical characteristics of familial hypercholesterolemia may contribute to identify study patients at enhanced risk [6].LIFELONG CHOLESTEROL BURDEN: THE RISK IN FAMILIAL HYPERCHOLESTEROLEMIA PATIENTSThe increased mortality and morbidity among familial hypercholesterolemia study participants has recently been demonstrated with a mean age at first CVD event in familial hypercholesterolemia patients of 44 years [7], and mean age at first hospitalization and first rehospitalization of 45.1 and 47.6 years, respectively, with no sex differences [8]. In total, 90% of the hospitalizations were caused by coronary heart disease (CHD). Interestingly, despite having a genetically verified diagnosis of familial hypercholesterolemia at the time of hospitalization, this important diagnose in CHD risk was only registered in approximately half of the patients at discharge [8]. Mean age at the time of death was only 60 years in familial hypercholesterolemia study participants, with no sex difference. About 93% of the familial hypercholesterolemia patients had experienced CVD during life, of whom 69% had experienced one or more myocardial infarctions (MI) [7]. Even though only 50% of the study participants had CVD as main cause of death, CVD was the most common cause of death among familial hypercholesterolemia patients, and CVD mortality was significantly higher in familial hypercholesterolemia patients compared with the general Norwegian population under 70 years of age [9]. Most of the study participants in these studies were diagnosed late and treatment was, therefore, started late; however, underscoring the severity of this disease and the increased morbidity in familial hypercholesterolemia patients even within the statin era.UNDERDIAGNOSED AND UNDERTREATEDThe prevalence of familial hypercholesterolemia is ∼200 in White populations [10]. Although the condition is well documented, and genetic diagnosis is easy, the condition is underdiagnosed in most countries [1,10], especially among young MI patients. Patients referred to hospitals with MI at premature age, may in fact be undiagnosed familial hypercholesterolemia patients and Mortensen et al.

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