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1.
Among the more common inherited causes of CVD among younger individuals include genetic abnormalities leading to vasculopathies, aneurysmal disorders, and coagulopathies [190]. Within the clinical practice of preventive cardiology, genetic dyslipidemia is the most common treatable cause of inherited premature coronary heart disease [190].
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2.
Heterozygous Familial Hypercholesterolemia (HeFH) is most commonly an autosomal dominant genetic metabolic disorder resulting in extreme elevations of low-density lipoprotein (LDL) cholesterol levels (i.e., typically ≥ 190 mg/dL in adults), and a 10–17 fold increased risk of atherosclerotic CVD in untreated patients with HeFH, and 8–15 fold increase in patients treated with statins. The residual CVD risk among statin-treated patients suggests under-treatment with statins and other lipid-altering drugs, and/or delay of introduction of lipid-altering too late in life [183].
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3.
In a patient with a FH phenotype, a negative DNA genetic testing does not exclude a diagnosis of FH [179]. Many lipid center clinicians believe 10–50% of DNA FH testing negative patients still having an unidentified FH mutation. This helps account for why many clinicians utilize clinical diagnosis over DNA genetic blood testing to diagnose FH [191].
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4.
While tendon xanthomas can rarely be associated with increases in non-cholesterol sterol concentration (i.e., sitosterolemia) [192], tendon xanthomas are the physical exam finding most pathognomonic for FH, and the physical exam finding most included in FH diagnostic criteria (see Table 10c, Table 10a, Table 10b a – b). Aortic stenosis is also often found in patients with FH, potentially detected by heart murmur upon auscultation of the heart, and whose onset and severity are dependent lifetime exposure to increased cholesterol levels [193].
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5.
Cascade (family) screening for FH is recommended in individuals and families with very high LDL-C levels [194].
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6.
High intensity statin (atorvastatin 80 mg or 40 mg per day, or rosuvastatin 40 or 20 mg per day) is the drug treatment of first choice for patients with FH [50].
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7.
Commonly cited lipid goals in patients with HeFH are a low-density lipoprotein cholesterol level of <100 mg/dL and <70 mg/dL being a goal for HeFH patients having CVD and/or other CVD risk factors placing them at very high risk [50]. Lipoprotein (a) is an additional lipid parameter that should be assessed in patients with HeFH [57].
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8.
Largely due to very high baseline LDL cholesterol levels, and high rate of atherosclerotic CVD, it is common that patients with FH do not achieve their LDL-cholesterol treatment goals with statins alone. Patients with FH who do not achieve their LDL cholesterol treatment goals with maximally tolerated high intensity statins may benefit from adding proprotein convertase subtilisin kexin 9 inhibitors, bempedoic acid, ezetimibe (alone or combined with bempedoic acid), or other lipid-altering drugs (e.g., bile acid sequestrants such as colesevelam HCl) [50,58,62,63,188,195,196].
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9.
The increase in atherosclerotic CVD risk is not only dependent upon the degree of increased LDL cholesterol blood levels, but also the lifetime exposure/burden of elevated LDL cholesterol. The threshold age for onset of clinical coronary heart disease can be extended by earlier administration of statin therapy. Thus, statin treatment should strongly be considered in patients with HeFH, beginning at 8–10 years of age [183].
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10.
Lipoprotein apheresis is another treatment option for patients with FH who are unable to achieve LDL cholesterol treatment goals with nutrition, physical activity, and lipid-altering drug therapy [197].
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