Population Science
Can We Apply the Cumulative Exposure to Low-Density Lipoprotein-Cholesterol Hypothesis in Clinical Practice?
2021 Volume 85 Issue 11 Pages 2079-2080
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2021 Volume 85 Issue 11 Pages 2079-2080
Familial hypercholesterolemia (FH), which is an autosomal dominant genetic disorder caused by pathogenic variants, impairs the clearance of low-density lipoprotein (LDL) from the blood, leading to elevated LDL-cholesterol (LDL-C) levels. Lifelong elevated LDL-C levels in FH increase the risk of atherosclerotic cardiovascular disease (ASCVD). A cohort study from the Copenhagen General Population Study demonstrated that the risk of coronary artery disease (CAD) was increased ~13-fold among individuals with clinical FH diagnosis not receiving statins compared with the general population.1 Recently, it was reported that the prevalence of FH is 1 in ≈200–300 in general populations, and 1 in 15 among those with premature CAD or acute coronary syndrome (ACS).2–4 Despite the high prevalence and high-risk conditions of premature CAD in patients with FH, it has become an emergency that the diagnostic rate is very low worldwide.3 Both early diagnosis and early optimal LDL-C lowering therapy for FH are important to prevent progression of atherosclerosis and to improve prognosis. However, nobody knows at what age atherosclerotic plaque burden becomes irreversible or when LDL-C lowering therapy should start. There are not any clear guidelines to describe the criterion for initiating drug therapy such as statins in adult patients with heterozygous FH. According to the Japanese Atherosclerosis Society guidelines for prevention of ASCVD 2017, stratification based on the Suita score should be performed in individuals for primary prevention.5 However, risk calculation with the Suita score is not appropriate for patients with FH because of their higher risk of CAD due to lifelong elevated LDL-C levels.
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In this issue of the Journal, Tada, et al6 evaluate whether cholesterol-year-score, an indicator of cumulative exposure to LDL-C, is associated with ASCVD events among patients with FH. They retrospectively investigated the health records of 1,050 patients with clinical FH diagnosis and assessed the association between cholesterol-year-score and major adverse cardiovascular events (MACE). Cholesterol-year-score was calculated as maximum LDL-C value × (age at diagnosis or statin initiation) + LDL-C value at inclusion × (age at inclusion − age at diagnosis or statin initiation). The median follow-up period for MACE evaluation was 12.3 years. Cholesterol-year-score was significantly associated with MACE (hazard ratio 1.35 per 1,000 mg-year/dL; 95% confidence interval: 1.07–1.53, P=0.0034) independent of traditional risk factors. Moreover, cholesterol-year-score improved the discrimination ability of other traditional risk factors for ASCVD events (C-index 0.901 vs. 0.889, P=0.00473). Calculation of cholesterol-year-score might have predictive value in the risk assessment of CAD and might be useful for deciding the timing of pharmacological LDL-C lowering therapy for patients with FH in clinical practice.
Nordegaard et al proposed the concept of a cumulative LDL-C burden, which illustrates the importance of early treatment (Figure).3 The cumulative LDL-C burden of a 55-year-old person without FH is typically 160 mmol, a burden sufficient for developing CAD. For a patient with heterozygous FH, this LDL-C burden, which is the threshold for developing CAD, is reached by age 35 if untreated, and by age 48 if treated since age 18. Therefore, LDL-C lowering therapy should start earlier in patients with FH. Nevertheless, whether diagnosed clinically or through a causative mutation, not all patients with FH develop atherosclerosis or CAD to the same extent. The absolute risk of CAD even in patients with FH is modified by traditional risk factors, and Lp(a). It remains to be established who are the high-risk patients for CAD and the timing of pharmacological LDL-C lowering therapy depending on the individual CAD risk in patients with FH. In asymptomatic patients at low or moderate risk who would be eligible for statin therapy, assessment of ASCVD with imaging may influence medical treatment, both from the physician’s and the patient’s points of view. Although patients with FH are at high risk of ASCVD, examinations even with non-invasive imaging modalities, are not needed for all of them. From this aspect, the calculation of cholesterol-year-score might be useful for individual risk assessment of CAD and to decide the timing of pharmacological LDL-C lowering therapy in patients with FH. Moreover, the estimation model of cumulative exposure to LDL-C might be a useful tool not only for patients with FH but also hypercholesterolemia patients without FH. Two American cohort studies suggested that cumulative exposure to hypercholesterolemia in young adulthood increases the subsequent CAD risk in a dose-dependent fashion.7,8 Further study is needed to confirm this in individuals with hypercholesterolemia in Japan.
Low-density lipoprotein-cholesterol (LDL-C) burden in individuals with and without familial hypercholesterolemia (FH) as a function of age at initiation of statin therapy. (Adapted with permission from Nordestgaard BG, et al3). CHD, coronary heart disease; HDL-C, high-density lipoprotein-cholesterol.
There are some limitations to the study. First, it was conducted in a single center and all participating patients underwent genetic analysis after the clinical diagnosis of FH. Most individuals with the phenotype of clinical FH have a polygenic, environmental, or unknown monogenic cause for their hypercholesterolemia.9,10 Among individuals with hypercholesterolemia, genetic determinants of LDL-C levels may impose additional risk of ASCVD.11 Therefore, it remains to be elucidated whether this hypothesis can be adopted for patients with clinical FH without a genetic analysis. Second, this hypothesis might not be suitable for predicting the incidence of ACS. As demonstrated in supplemental figure 2, the cholesterol-year-score was significantly associated with total MACE, death associated with ASCVD, and staged PCI/CABG but not with myocardial infarction (MI) or unstable angina (UAP). Cholesterol-year-score may reflect accumulation of LDL-C burden over time since birth, which means stable coronary plaque. On the other hand, ACS, including MI and UAP, is caused by rupture of vulnerable plaque. Therefore, the results of this study are reasonable and we should understand the concept of cholesterol-year scoreis not suitable for predicting ACS.
In conclusion, early identification of individuals and optimal lowering of LDL-C over the lifespan reduces the cumulative LDL-C burden and offers health and socioeconomic benefits for patient with FH. In addition, further studies are expected to establish a threshold cholesterol-year-score for starting pharmacological LDL-C lowering therapy.
