Hyperlipidemias and Atherosclerotic Cardiovascular Disease ________________________________________
UNIVERSAL ONE-TIME SCREENING FOR LONG- TERM CVD RISK A prospective European study of initially healthy men and women demonstrates the potential value of screening for long-term risk of ASCVD early in life, using the combination of three available, inexpensive biomarkers. Plasma levels of baseline LDL cholesterol, hsCRP, and lipoprotein(a) were measured at study entry in 17,087 individuals, who were subsequently followed a median of 20 years for major adverse cardiovascular events (hospitalization or death from CVD or ischemic stroke). A total of 3,249 first adverse cardiovascular events occurred during the study period. Higher quintiles (biomarker elevation) of LDL, hsCRP, and lipoprotein(a) were each independently predictive of long-term risk, with the highest risk observed in subjects having baseline elevation of all three biomarkers. Compared with study participants having no biomarker elevations, the adjusted hazard ratios for incident major adverse cardiovascular events were 1.33, 1.68, and 2.41 for those with one, two, or three biomarkers in the top quintile respectively [244]. Thus, a one-time baseline screening for LDL cholesterol, hsCRP, and lipoprotein(a) among initially healthy adults was predictive of long-term (20-year) risk of clinical ASCVD events, with greatest risk discrimination observed when all biomarkers were combined. These findings, and similar results from an American cohort study, support one- time universal screening for all three biomarkers in primary prevention of ASCVD [244; 245]. The biomarkers used for assessment of long-term risk of ASCVD in these studies are standardized, readily available, and inexpensive. For persons at risk, ASCVD evolves gradually over a lifetime, where early prevention achieves the greatest gains, hence the value of early life detection of risk. Society guidelines for dietary intervention, smoking cessation, and daily exercise are examples of the dictum that early intervention provides greatest benefit. Clinical data derived from a one- time simultaneous determination of LDL cholesterol, hsCRP, and lipoprotein(a) can assist clinicians with both lifestyle interventions and selection of specific pharmacologic agents that address aspects of ASCVD risk unique to individual patients [244]. TARGETED SCREENING: CHILDHOOD AND ADOLESCENCE Because of increasing prevalence of childhood obesity, hyperlipidemia in children and adolescents has become a serious public health issue in the United States. Universal screening for hyperlipidemia within the pediatric population is controversial, of uncertain value, and costly from a public health perspective [241]. However, universal screening for all children 9 to 11 years of age and again at 17 to 21 years of age has been recommended by the National Heart, Lung, and Blood Institute, and endorsed by the American Academy of Pediatrics. Selective cholesterol screening based on risk factors has been suggested for children 2 to 10 years of age
40 years of age and older. The identification of familial hypercholesterolemia is a priority in children, adolescents, and young adults. Across all age groups, the emphasis is on reducing lifetime ASCVD risk through a heart-healthy lifestyle [24]. Experimental studies in animals with genetic abnormalities of lipid metabolism identical to human familial hypercholesterolemia (absence or 50% reduction in LDL receptors in homozygous or heterozygous individuals, respectively) as well as epidemiologic studies of human populations have established that high levels of LDL cholesterol are atherogenic [35; 36; 37]. Numerous clinical studies, including the Framingham Heart Study, the Multiple Risk Factor Intervention Trial, and the Lipid Research Clinics, have also reported a direct relationship between elevated concentrations of LDL cholesterol (or total cholesterol) and an increase in cardiovascular morbidity and mortality [1; 17; 18; 19; 20; 21; 23; 25; 38; 39]. Lipid management with a combination of pharmacotherapy and lifestyle changes aimed at the reduction of cholesterol levels effectively slows the progression of atherosclerosis and plays a pivotal role in the primary and secondary prevention of ASCVD [1; 17; 18; 19; 20; 21; 22; 23; 25; 37; 39; 40; 41]. Chronically high levels of CRP, and high sensitivity CRP (hsCRP) in particular, are biomarkers of ASCVD, regardless of whether they play a causal role in atherogenesis or if they are the result of underlying atherosclerosis [12; 27; 42]. The AHA and the Centers for Disease Control and Prevention have issued a joint statement regarding hsCRP values [43]. Concentrations of hsCRP less than 1 mg/L are associated with low risk, and 1–3 mg/L is correlated with moderate risk for ASCVD. Patients with levels greater than 3 mg/L are at high risk for ASCVD [43]. An hsCRP level >10 mg/L has been observed in acute plaque rupture, which may lead to thrombosis [44]. Ongoing clinical studies suggest that lowering the plasma levels of both hsCRP and LDL may be a main goal in the secondary prevention of ASCVD [42]. High homocysteine blood levels (greater than 15 mcmol/L) are associated with increased oxidative stress and secretion of proinflammatory factors. Both mechanisms stimulate smooth cell proliferation and accelerate atherosclerosis [27; 45]. Numerous clinical studies have also revealed that high levels of lipoprotein(a) are associated with significant increases in ASCVD [12; 27; 31; 46; 47; 48]. Lipoprotein(a) is a subtype of LDL that includes apoprotein A (Apo A) in its structure. The role of lipoprotein(a) in atherogenesis relates to a variety of mechanisms including inhibition of fibrinolysis by preventing the transformation of plasminogen to plasmin, enhanced capacity to traverse the arterial endothelium, and low affinity for the LDL-receptor mediated clearance from circulation [47]. High lipoprotein(a) concentrations (greater than 30 mg/dL) in patients with an elevated total cholesterol:HDL ratio (greater than 5.5) or other major risk factors indicates the need for a more aggressive therapy to further lower LDL [23; 49].
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