Hyperlipidemias and Atherosclerotic Cardiovascular Disease ________________________________________
LIPOPROTEIN PATTERNS OF HYPERLIPIDEMIAS (FREDRICKSON PHENOTYPES)
Phenotype
Elevated Lipoproteins
Elevated Lipids
I
Chylomicrons
Triglycerides Cholesterol
IIa IIb III IV
LDL
LDL and VLDL
Triglycerides and cholesterol Triglycerides and cholesterol
VLDL and chylomicron remnants
VLDL
Triglycerides
V
Chylomicrons and VLDL
Triglycerides and cholesterol
Source: [46; 98]
Table 3
Advances in genetics, genomics, and proteomics have contributed to a better understanding of the pathophysiology of numerous diseases and to the development of new and selective therapies. However, their contribution to the study of primary hyperlipidemias is still limited [99]. While gene therapy is being developed to treat some patients with known genetic abnormalities, the genetic profile and molecular basis of primary hypertriglyceridemia has been determined in only 5% to 10% of cases, and the percentage is even lower for secondary hyperlipidemia [100; 101; 102]. PRIMARY HYPERLIPIDEMIAS Primary hyperlipidemias result from single or multiple genetic mutations that target any of the molecules that participate in the endogenous and exogenous lipid pathways. These mutations result in increased plasma concentrations of cholesterol (pure or isolated hypercholesterolemia), triglycerides (pure or isolated hypertriglyceridemia), or both (mixed or combined hyperlipidemia) and are the result of either increased synthesis or decreased clearance. HDL concentrations may be lower than normal, either from decreased synthesis or increased clearance. At the early stages, primary hyperlipidemias are asymptomatic. However, as the disease progresses, a constellation of signs and symptoms develop, such as eruptive xanthomas (located on the trunk, back, buttocks, elbows, knees, hands, and feet), severe hypertriglyceridemia (greater than 2,000 mg/dL), lipemic plasma (i.e., plasma develops a creamy supernatant when incubated overnight), and lipemia retinalis (i.e., creamy white-colored blood vessels in the fundus) often associated with premature CHD or peripheral vascular disease [46; 100; 103]. Familial hypercholesterolemia and familial defective Apo B-100 are examples of clinical conditions that result from LDL receptor and Apo B-100 deficiencies, respectively [82; 83; 104]. Other genetic mutations cause familial hypertriglyceridemia, familial combined hyperlipidemia, familial chylomicronemia, and familial dysbetalipoproteinemia [31; 46; 100; 105; 106]. Polygenic hypercholesterolemia, also labeled nonfamilial hypercholesterolemia, is the most common form of hyperlipidemia, with a prevalence of more than 25% in the American population [106]. Polygenic hypercholesterolemia is a typical example of the combination of multiple genetic deficiencies that result in decreased activity of the LDL
receptor and reduction of LDL clearance. This underlying genetic susceptibility, not yet completely understood, becomes apparent with the combination of dietary intake of saturated fats, obesity, and sedentary lifestyle. Twenty percent of polygenic hypercholesterolemia patients have a family history of CHD. Patients present with mild-to-high increases in total cholesterol (250–350 mg/dL or 6.5–9.0 mmol/L) and LDL (130–250 mg/dL or 3.33–6.45 mmol/L). A combination of lifestyle changes (e.g., reduction in saturated fat) and lipid- lowering drugs (e.g., statins, bile acid sequestrants, ezetimibe, niacin) effectively control the condition [31; 107]. Familial hypercholesterolemia is an autosomal dominant disease responsible for defective LDL receptors that results in either reduction in receptor synthesis or inability of the receptor to bind and/or efficiently remove LDL. The heterozygous form (caused by a single abnormal copy of the gene) has a prevalence of 1 per every 500 in the United States, and the homozygous form (from two abnormal copies) occurs in 1 of every 1 million Americans [107; 108]. Patients with this disorder have elevated plasma levels of LDL cholesterol (>140 mg/dL) throughout life and an increased risk of cardiovascular events; in such persons, signs of atherosclerosis can start as early as 10 years of age [241]. Patients typically present with tendon xanthomas, premature MI (5% by 30 years of age and 50% by 50 years of age in untreated heterozygotes), elevated total cholesterol (275–500 mg/dL in heterozygotes and 700–1,200 mg/dL in homozygotes), and elevated triglycerides (250–500 mg/dL in heterozygotes and >500 mg/dL in homozygotes) [107; 108]. Familial hypercholesterolemia heterozygotes respond to lifestyle changes and drug therapy that combines statins with other drugs that upregulate the LDL receptors, such as bile acid sequestrants, ezetimibe, or niacin. Due to the high risk of CHD and MI in homozygous patients, the clinical management requires early treatment in medical centers specialized in lipid treatment and often requires LDL apheresis (i.e., extracorporeal removal of LDL) and liver transplantation [30; 31; 46; 107; 108]. Three drugs have been approved by the U.S. Food and Drug Administration (FDA) for homozygous familial hypercholesterolemia since 2012, a microsomal triglyceride transfer protein inhibitor (lomitapide), an antisense oligonucleotide inhibitor (mipomersen), and an adenosine triphosphate-citrate lyase inhibitor (bempedoic acid). A box warning for risk of hepatotoxicity was added to
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MDAK1526
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