Author + information
- Received November 24, 2013
- Revision received January 5, 2014
- Accepted January 7, 2014
- Published online May 20, 2014.
- ∗Division of Cardiology, Department of Medicine, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada
- †Department of Medicine, University of California San Diego, La Jolla, California
- ‡Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- ↵∗Reprint requests and correspondence:
Dr. Allan Sniderman, 687 Pine Avenue West, Montreal, Quebec, Canada H3C 3R6.
- ↵∗∗Dr. Sotirios Tsimikas, Department of Medicine, University of California San Diego, BSB-1080, 9500 Gilman Drive, La Jolla, California, 92093-0682.
- ↵∗∗∗Dr. Sergio Fazio, Vanderbilt University Medical Center, Section of Cardiovascular Disease Prevention, 2220 Pierce Avenue–383 PRB, Nashville, Tennessee, 37232-6300.
The severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels. The most common cause is autosomal dominant hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor, apolipoprotein B (APOB), or proprotein convertase subtilisin kexin type 9 (PCSK9) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. These cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects. Because the clinical consequences of extreme hypercholesterolemia are the same no matter the cause, the focus should be on the identification of subjects with severe hypercholesterolemia, followed by phenotypic screening of family members. Genetic screening is not necessary to diagnose or initiate treatment for the severe hypercholesterolemia phenotype. Management of severe hypercholesterolemia is based on risk factor modification and use of multiple lipid-lowering medications. Lipoprotein apheresis is indicated for coronary artery disease (CAD) patients taking maximally tolerated therapy and with LDL-C levels >200 mg/dl (>300 mg/dl if without CAD). A microsomal triglyceride transfer protein inhibitor and an antisense oligonucleotide against APOB have recently been approved for use in subjects with clinically diagnosed homozygous familial hypercholesterolemia. PCSK9 inhibitors, currently in phase II and III trials, lower LDL-C up to an additional 70% in the setting of maximally tolerated medical therapy and have the potential to reduce LDL-C to <70 mg/dl in most patients. Early identification of affected individuals and aggressive treatment should significantly reduce the burden of cardiovascular disease in society.
Dr. Tsimikas is supported by National Institutes of Health/National Heart, Lung, and Blood Institute grants R01-HL119828, R01-HL093767, and P01-HL055798; has received royalties from patents held by the University of California; has received research grants from Pfizer, ISIS, and Genentech; and is a consultant to ISIS, Genzyme, and Sanofi. Dr. Fazio is supported by NIH/NHLBI grants R01-HL106845 and R01-HL57986; has received research grants from ISIS, Merck, Pfizer, and Amarin; and is a consultant for Merck, Roche, Kowa, Sanofi, Gilead, Aegerion, Genzyme, and Amarin. Dr. Sniderman has received honoraria from Merck and Genzyme.
Leslie Cho, MD, served as Guest Editor for this paper.
- Received November 24, 2013.
- Revision received January 5, 2014.
- Accepted January 7, 2014.
- American College of Cardiology Foundation
- Prevalence of Severe Hypercholesterolemia Phenotype and Risk of CHD
- Clinical Diagnosis
- Genetic Screening
- Cascade Screening
- Aggressive Lipid Lowering and CVD Outcomes
- Current Therapies for FH
- Recently Approved Therapies for HoFH
- Future Therapies: PCSK9 Inhibitors