Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long‐Term Response to Treatment, Coronary Atherosclerosis Burden, and Cardiovascular Events

Figure 1. Distribution of genotypes according to Dutch Lipid Clinic Network Criteria scores. Percentage is reported for each class of DLCNC score. Possible FH are patients with a DLCNC score between 3 and 5 points whereas Probable and Definite FH are those with a DLCNC scores between 6 and 8 points and higher than 8 points, respectively. Patients have been defined as FH/M+ if carrying a monogenic mutation, PHC if having a weighted polygenic risk score >0.69, and FH/M− undetermined if having elevated LDL‐C and LDL‐C raising genetic risk score ≤0.69 (see Methods). DLCNC indicates Dutch Lipid Clinic Network Criteria; FH, familial hypercholesterolemia; LDL‐C, low‐density lipoprotein cholesterol; N, number; and PHC, polygenic hypercholesterolemia.

Figure 2. LDL‐C levels at last visit according to intensity of lipid‐lowering therapy. We have reported the median LDL‐C levels obtained at last visit according with genotypes and intensity of lipid‐lowering therapies. Patients have been classified as FH/M+ if carrying a monogenic mutations and FH/M− if they were PHC or FH/M− undetermined (see Methods). For definition of LLT intensity see Methods. FH indicates familial hypercholesterolemia; LDL‐C, low‐density lipoprotein cholesterol; LLT, lipid‐lowering therapies; PCKS9i, proprotein convertase subtilisin/kexin type 9 inhibitors; and PHC, polygenic hypercholesterolemia.

Figure 3. Coronary atherosclerosis burden according to genotypes. A, Distribution of genotypes according to CAC categories. B, Distribution of severity of coronary stenosis expressed by CAD‐RADS categories according to FH genotypes. Patients have been classified as FH/M+ if carrying a monogenic mutation (N=79), FH/M− if they were defined as PHC or FH/M− undetermined (N=40), and controls (N=135). CAC values were available in only 77 controls. For definition of CAD‐RADS see Methods. CAC indicates coronary artery calcium; CAD‐RADS, Coronary Artery Disease‐Data and Reporting System; FH, familial hypercholesterolemia; and PHC, polygenic hypercholesterolemia.

Figure 4. MACE‐free survival curves according to genotypes. Kaplan‐Meier survival curves for incident major adverse cardiovascular events (MACE) occurred during follow‐up in the cohort of clinical FH patients (322 subjects) according to genotypes. Patients have been defined as FH/M+ monogenic if carrying a monogenic mutation (N=182) and FH/M− if they are PHC or FH/M− undetermined (N=140). MACE have been defined as reported in Methods. FH indicates familial hypercholesterolemia; IC, confidence interval; and PHC, polygenic hypercholesterolemia.