Hyperlipidemias and Atherosclerotic Cardiovascular Disease ________________________________________
with the presence of focal vulnerable plaque, but not with lipid deposition and degree of coronary plaque burden. These findings suggest a unique role for lipoprotein(a) in atherosclerosis progression and plaque vulnerably, which may portend a heightened risk for early myocardial infarction [246]. An inherited predisposition to elevated levels of lipoprotein(a) affects as many as 1.5 billion people worldwide, including 20% of persons living in the United States [247; 248]. Despite availability of clinical testing for lipoprotein(a) levels, less than 1% of affected persons have had levels measured. Patients with high levels of lipoprotein(a) (greater than 30 mg/dL) and an elevated total cholesterol:HDL ratio (>5.5) or other major risk factors benefit from a more aggressive therapy to lower LDL [23; 49]. Lowering circulating LDL remains the initial goal of treatment and prevention of atherosclerosis and ASCVD. However, for this subset of patients, new approaches have emerged that target the liver, down-regulate production, and reduce lipoprotein(a) levels by 90%; clinical trials are in progress. High-Density Lipoproteins HDLs are the smallest (5–12 nm in diameter) but the densest lipoproteins (33% protein content). HDL removes cholesterol from the periphery and transports it to the liver [53]. HDLs are a heterogeneous population classified based on size, density, and apoprotein content. The two most important subclasses of HDL express either Apo A-I alone or both Apo A-I and A-II, but the clinical relevance of the various subtypes is unknown [88]. HDL concentration in the plasma is inversely related to the risk of ASCVD, and for this reason HDL is also known as “good cholesterol.” The role played by HDL in the transport of cholesterol from the periphery to the liver, known as reverse cholesterol transport, and subsequent excretion in bile is a very well-understood mechanism through which HDL protects against atherosclerosis [88; 89]. Two main factors are involved in cholesterol removal from the periphery. First, a cell membrane protein (ABCA1) promotes the efflux of cholesterol from cell membranes; second, ABCA1 interacts with Apo A-I from HDL and captures cholesterol. Cholesterol, in the form of cholesteryl esters, is subsequently transferred to LDL, which will carry it to the liver. In the liver, hepatic extraction requires binding to the LDL receptor. Genetic mutations that cause loss of function of ABCA1 result in extremely low levels of HDL and cholesterol accumulation in the liver, spleen, tonsils, and central and peripheral nervous systems. This results in early-life coronary and peripheral artery disease, a condition known as Tangier disease or familial alpha- lipoprotein deficiency [90; 91]. In vitro and in vivo studies have revealed that HDL has anti-inflammatory and antioxidant properties and inhibits atherogenesis. It has been suggested that high levels of HDL have a protective effect on the development of atherosclerosis and ASCVD [88; 92].
However, authors of a systematic review of clinical studies concluded that “simply increasing the amount of circulating HDL does not necessarily confer cardiovascular benefits” and that reduction of LDL should remain “the primary goal for lipid-modifying interventions” [93]. Other researchers concluded that raising endogenous HDL levels in humans to reduce the development of atherosclerosis “has yet to be established conclusively” [88]. Together, these studies further support the recommendation that lowering LDL should remain the target goal for patients with hyperlipidemia and/ or at risk for ASCVD-related conditions [22; 24]. CLASSIFICATION OF HYPERLIPIDEMIAS Hyperlipidemias, also known as dyslipidemias, are elevations of LDL cholesterol either alone or in conjunction with triglycerides. As noted, they may also be associated with low HDL. In 2013, the National Heart, Lung, and Blood Institute (NHLBI) discontinued its publication of clinical practice guidelines, instead choosing to provide its systemic evidence reviews to professional organizations, who then publish guidelines based on these and other findings [94]. This change affected five cardiovascular disease-related documents that were in the process of being crafted, including those addressing cholesterol, blood pressure, risk assessment, lifestyle interventions, and obesity. The AHA and the ACC published guidelines intended to update the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) recommendations in 2013, but these guidelines focused primarily on optimal statin use and did not address specific risk factors or lifestyle changes [95]. In the 2013 ACC/AHA update to the NCEP-ATP III, one major change in the treatment recommendations was the removal of specific LDL and non-HDL-cholesterol target values. The NCEP-ATP III guidelines indicated that the target goal for LDL should be <100 mg/dL; however, the Expert Panel determined that there was not sufficient evidence to support treatment to a specific target goal [96; 97]. The 2018 AHA/ACC update to the 2013 guideline includes a limited restoration of LDL treatment targets, particularly in higher-risk groups, based on the results of U.S. population studies and randomized controlled trials confirming the general principle that for LDL, “lower is better” [24]. For the purposes of this course, the 2018 AHA/ACC guideline recommendations will be discussed. Hyperlipidemias are classified by etiology as primary or secondary, or by phenotype according to identification of lipoprotein patterns, as with Fredrickson phenotypic classification ( Table 3 ). In practice, a combination of both classifications is used, as the patient’s condition is first identified based on clinical evidence and lipid profile, providing the data required for classification based on etiology [31; 46; 67; 79; 98].
37
MDNE1526
Powered by FlippingBook