Diagnosis and Management of Individuals With Heterozygous Familial Hypercholesterolemia
Too Late and Too Little
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- acute coronary syndrome
- cardiovascular disease
- coronary artery disease
- familial hypercholesterolemia
Article, see p 698
It was the Norwegian Internist Carl Müller who, almost a century ago, wrote about his observation that patients with xanthomas and lipoidosis were “at risk of dying suddenly and unexpectedly, apparently with symptoms of paralysis of the heart.”1 He was among the first not only to describe the association, but also to suggest that lipoidosis was causally related to premature cardiovascular disease (CVD).
Prospective observational studies conducted in the 1950s further bolstered the hypothesis that dyslipidemia, characterized by high levels of low-density lipoprotein-cholesterol (LDL-C), are a major cause of CVD.2 Forty years later, in 1994 to be precise, another Norwegian, cardiologist Terje Pedersen, closed the loop on the LDL-hypothesis by demonstrating in the Scandinavian Simvastatin Survival Study (4S) that statin therapy decreased both total and cardiovascular mortality.3 Since that time, the pathophysiologic role of LDL-C in atherosclerosis has been defined and the molecular basis unraveled for familial hypercholesterolemia (FH), the genetic disease underlying the triad described by Müller. More recently, the heterozygous form of FH (heFH) was shown to be much more prevalent than previously anticipated, and it is remarkable to observe the similarity in these novel prevalence estimates of 1:200 to 250, irrespective of the geographic region (the United States, Denmark, or The Netherlands) or the method of defining heFH.4–6
Many studies, including our own, have shown unequivocally that coronary risk is 3.5- to 16-fold increased in patients with heFH compared with individuals without non-FH, and the severity of the underlying mutation is considered to be a major determinant of the observed variation in risk for CVD.4,5 A crucial question is whether the presence of a genetic defect per se adds to the risk prediction based on LDL-C levels and, in their seminal article, Khera and …