Applying clinical and mutation criteria for familial hypercholesterolemia (FH) to the general population only identified a minor fraction of patients with familial premature myocardial infarction (MI), according to study results published in The Journal of Clinical Endocrinology & Metabolism.

Atherosclerotic coronary disease is the most important cause of premature MI. FH, characterized by highly elevated low-density lipoprotein (LDL) cholesterol levels, is associated with diagnosis of MI at a very young age. The objective of this study was to compare different FH criteria and LDL cholesterol cut points to identify familial premature MI in the general population.

In total, 8 different approaches to identify familial premature MI were compared, including 3 clinical FH criteria: Dutch Lipid Clinic Network criteria, Simon Broome criteria, and Make Early Diagnosis to Prevent Early Death criteria; FH mutations; and 4 LDL cholesterol cut points.

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The association between these different approaches and familial premature MI (6754 cases) and personal premature MI (1046 cases) was examined in 106,732 individuals from the Copenhagen General Population Study, a prospective cohort study initiated in 2003 that includes individuals of Danish descent from the general population age 20 to ≥100.

The researchers reported that applying clinical and FH mutation criteria only identified a small fraction of individuals with a family history of premature MI (898 cases, 13%), while the vast majority of cases remained undetected (5856 cases, 87%). Using the Dutch Lipid Clinic Network criteria in individuals with FH, the odds ratios were 16 (95% CI, 12-22) and 4.7 (95% CI, 3.7-6.0), respectively, for personal and family history of premature MI. Corresponding odds ratios were 4.4 (95% CI, 4.0-4.7) and 2.7 (95% CI, 2.2-3.3) for FH using Simone Broome criteria and 2.1 (95% CI, 1.7-2.6) and 2.7 (95% CI, 1.8-4.2) for FH using the Make Early Diagnosis to Prevent Early Death criteria, compared with individuals unlikely to have FH. Compared with universal screening of a similar fraction of the population, the use of clinical FH criteria based on the Dutch Lipid Clinic Network, and Simon Broome criteria resulted in a 3.8- and 3.3-fold higher sensitivity, respectively.

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Compared with patients without an FH mutation, the odds ratios in individuals with an FH mutation for a personal and family history of premature MI were 4.6 (95% CI, 2.3-9.4) and 2.1 (95% CI, 1.4-3.3), respectively.

With regard to LDL cholesterol cut points, the odds ratios for personal and family history of premature MI were most significant in individuals with LDL cholesterol ≥6 mmol/L vs <6 mmol/L (232 mg/dL): 2.4 (95% CI, 1.6-3.7) and 1.8 (95% CI, 1.5-2.2), respectively.

The study had several limitations, including over-simplification of the real effect of statins, as total and LDL cholesterol concentrations were multiplied by 1.43 in individuals using lipid-lowering therapy, corresponding to the 30% average reduction with lipid-lowering therapy. Additional limitations include the lack of data regarding children of participants and clinical features of FH.

Choosing the best criteria to identify families with premature MI requires thorough consideration of the patient, the setting, and healthcare cost aspects. The researchers concluded that “[a]ctively identifying families with premature MI would be of potential preventive importance, and this study provides data that could be used to choose the best method for such family identification depending on available healthcare resources.”


Beheshti S, Madsen CM, Varbo A, Nordestgaard BG. How to identify familial premature myocardial infarction: comparing approaches to identify familial hypercholesterolemia [published online February 7, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2018-02261

This article originally appeared on Endocrinology Advisor