Conrad B. Blum

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Preamble and Transition to ACC/AHA Guidelines to Reduce Cardiovascular Risk S2 The goals of the …

High Density Lipoprotein Metabolism in Man

The turnover of (125)I-high density lipoprotein (HDL) was examined in a total of 14 studies in eight normal volunteers in an attempt to determine the metabolic relationship between apolipoproteins A-I (apoA-I) and A-II (apoA-II) of HDL and to define further some of the determinants of HDL metabolism. All subjects were first studied under conditions of an isocaloric balanced diet (40% fat, 40% carbohydrate). Four were then studied with an 80% carbohydrate diet, and two were studied while receiving nicotinic acid (1 g three times daily) and ingesting the same isocaloric balanced diet. The decay of autologous (125)I-HDL and the appearance of urinary radioactivity were followed for at least 2 wk in each study. ApoA-I and apoA-II were isolated by Sephadex G-200 chromatography from serial plasma samples in each study. The specific activities of these peptides were then measured directly. It was found that the decay of specific activity of apoA-I and apoA-II were parallel to one another in all studies. The mean half-life of the terminal portion of decay was 5.8 days during the studies with a balanced diet.Mathematical modeling of the decay of plasma radioactivity and appearance of urinary radioactivity was most consistent with a two-compartment model. One compartment is within the plasma and exchanges with a nonplasma component. Catabolism occurs from both of these compartments. With a balanced isocaloric diet, the mean synthetic rate for HDL protein was 8.51 mg/kg per day. HDL synthesis was not altered by the high carbohydrate diet and was only slightly decreased by nicotinic acid treatment. These perturbations had effects on HDL catabolic pathways that were reciprocal in many respects. With an 80% carbohydrate diet, the rate of catabolism from the plasma compartment rose by a mean of 39.1%; with nicotinic acid treatment, it fell by 42.2%. Changes in the rate of catabolism from the second compartment were generally opposite those in the rate of catabolism from the plasma compartment, suggesting that these two catabolic pathways may be reciprocally regulated.

Apolipoprotein B–Gene DNA Polymorphisms Associated with Myocardial Infarction

Levels of apolipoprotein B, the protein component of low-density lipoproteins, correlate with the risk of coronary heart disease. We examined whether genetic variation in apolipoprotein B is associated with myocardial infarction by studying apolipoprotein B-gene restriction-fragment-length polymorphisms in 84 patients with myocardial infarction and an equal number of matched controls. Southern blot analysis with apolipoprotein B-gene probes, performed after DNA was digested with the endonucleases XbaI and EcoRI, revealed alleles that we designated as X1, X2, and X3 and as R1 and R2, respectively. Similar studies with the endonuclease MspI revealed alleles of many different sizes (the difference was due to an insertion-deletion polymorphism), which we grouped as larger and smaller alleles and designated as ID1 and ID2, respectively. The frequencies of the X1, R1, and ID1 alleles were all significantly higher (P less than 0.01) in the cases than in the controls. None of the alleles, however, was significantly associated with variation in levels of low-density lipoprotein cholesterol or apolipoprotein B, and the functional importance of these alleles is therefore uncertain. Nonetheless, in addition to quantitative variation in apolipoprotein B levels in plasma, genetic variation at the apolipoprotein B locus may be a new and independent risk factor for myocardial infarction.

Human Intestinal Lipoproteins: STUDIES IN CHYLURIC SUBJECTS

To explore the role of the human intestine as a source of apolipoproteins, we have studied intestinal lipoproteins and apoprotein secretion in two subjects with chyluria (mesenteric lymphatic-urinary fistulae). After oral corn oil, apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) output in urine increased in parallel to urinary triglyceride. One subject, on two occasions, after 40 g of corn oil, excreted 8.4 and 8.6 g of triglyceride together with 196 and 199 mg apoA-I and on one occasion, 56 mg apoA-II. The other subject, after 40 g corn oil, excreted 0.3 g triglyceride and 17.5 mg apoA-I, and, after 100 g of corn oil, excreted 44.8 mg apoA-I and 5.8 mg apoA-II. 14.5+/-2.1% of apoA-I and 17.7+/-4.3% of apoA-II in chylous urine was in the d < 1.006 fraction (chylomicrons and very low density lipoprotein). Calculations based on the amount of apoA-I and apoA-II excreted on triglyceride-rich lipoproteins revealed that for these lipid loads, intestinal secretion could account for 50 and 33% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Similarly, subject 2 excreted 48-70% and 14% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Chylous urine contained chylomicrons, very low density lipoproteins and high density lipoproteins, all of which contained apoA-I. Chylomicrons and very low density lipoproteins contained a previously unreported human apoprotein of 46,000 mol wt. We have called this apoprotein apoA-IV because of the similarity of its molecular weight and amino acid composition to rat apoA-IV. In sodium dodecyl sulfate gels, chylomicron apoproteins consisted of apoB 3.4+/-0.7%, apoA-IV 10.0+/-3.3%, apoE 4.4+/-0.3%, apoA-I 15.0+/-1.8%, and apoC and apoA-II 43.3+/-11.3%. Very low density lipoprotein contained more apoB and apoA-IV and less apoC than chylomicrons. Ouchterlony immunodiffusion of chylomicron apoproteins revealed the presence of apoC-I, apoC-II, and apoC-III. In contrast, plasma chylomicrons isolated during a nonchyluric phase revealed a markedly altered chylomicron apoprotein pattern when compared with urinary chylomicrons. The major apoproteins in plasma chylomicrons were apoB, apoE, and the C peptides: no apoA-I or apoA-IV were present in sodium dodecyl sulfate gels indicating that major changes in chylomicron apoproteins occur during chylomicron metabolism. When incubated in vitro with plasma, urinary chylomicrons lost apoA-I and apoA-IV and gained apoE and apoC. Loss of apoA-I and apoA-IV was dependent upon the concentration of high density lipoproteins in the incubation mixture. These studies demonstrate that the human intestine secretes significant amounts of apoA-I and apoA-II during lipid absorption. Subsequent transfer of apoproteins from triglyceride-rich lipoproteins to other plasma lipoproteins may represent a mechanism whereby the intestine contributes to plasma apoprotein levels.

The Hyperlipidemia of the Nephrotic Syndrome

Lipid abnormalities in patients with the nephrotic syndrome have long been recognized. However, the significance of these lipid abnormalities, the mechanisms producing them, and their potential treatment have all been a cause of debate. Recent data have helped clarify each of these areas of controversy. Studies of the lipoprotein abnormalities of patients with the uncomplicated nephrotic syndrome have shown that many will have elevated levels of total and low-density lipoprotein cholesterol, whereas only a few will have elevated levels of high-density lipoprotein cholesterol. If these lipid abnormalities have the same significance in this population as in other populations studied, then some patients with unremitting nephrotic syndrome will be at high risk for cardiovascular disease. The elevated cholesterol levels noted in the nephrotic syndrome are caused primarily by enhanced hepatic synthesis, with lesser contributions by decreased clearance and altered enzyme activities. The signal for enhanced hepatic lipogenesis may relate to changes in plasma albumin concentration, plasma oncotic pressure, a local effect of viscosity at the hepatic sinusoidal level, or a loss of urinary proteins or other liporegulatory substances. Recently, a number of short-term studies in nephrotic patients have documented the safety and efficacy of lipid-lowering drugs such as the bile acid-binding resins, probucol, and the HMGCoA (hydroxymethylglutaryl coenzyme A) reductase inhibitors.

Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Four inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia. Three of these are fungal metabolites or derivatives thereof: lovastatin, simvastatin, and pravastatin. The fourth, fluvastatin, is totally synthetic. Its structure, containing a fluorophenyl-substituted indole ring, is distinct from that of the fungal metabolites. Lovastatin and simvastatin are administered as prodrugs, which undergo in vivo transformation to active inhibitory forms; fluvastatin and pravastatin are administered as active agents. The HMG-CoA reductase inhibitors are all effective in reducing plasma concentrations of low density lipoprotein. They have differing pharmacokinetic properties, which may be of importance in some patients. All of these drugs are very well tolerated, and there do not appear to be major differences in toxicity or adverse effects. When LDL reductions > 30% are needed, simvastatin is the most cost-effective HMG-CoA reductase inhibitor. However, these drugs are most commonly used in dosages that reduce LDL-C by 20-30%. For this degree of LDL reduction, fluvastatin is the most cost-effective HMG-CoA reductase inhibitor.

Metabolism of high-density lipoprotein apolipoproteins in Tangier disease.

To define the metabolic defect in Tangier disease, we studied the kinetics of [125I]-high-density lipoprotein apolipoproteins (apolipoproteins A-I and A-II) in 11 normal subjects, two obligate heterozygotes, and two homozygotes. Mean synthesis of apolipoproteins A-1 and A-11 was 8.24 mg per kilogram per day in the normal group, 7.94 in heterozygotes and 3.66 in homozygotes. The mean plasma-residence time for both apolipoproteins was 5.21 days in the normal subjects, 3.41 days in heterozygotes, and 0.52 days in homozygotes. In normal subjects and heterozygotes the apolipoproteins were catabolized at similar rates, whereas in homozygotes apolipoprotein A-I was catabolized at a much greater fractional rate than apolipoprotein A-II. These findings indicate that the deficiency of these apolipoproteins in Tangier disease is largely due to rapid and altered catabolism.

Radioimmunoassay studies of human apolipoprotein E.

This report describes the development and first applications of a sensitive and specific double antibody radioimmunoassay for human apoplipoprotein E (apoE). ApoE was purified from the very low density lipoproteins of hypertriglyceridemic patients by heparin-agarose affinity chromatography, DEAE-cellulose chromatography, and preparative polyacrylamide gel electrophoresis. The purified apoprotein had an amino acid composition characteristic of apoE and resulted in the production of monospecific antisera when injected into rabbits. The radioimmunoassay, which was carried out in the presence of 5 mM sodium decyl sulfate, had a working range of 0.8-12 ng. The withinassay coefficient of variation was 9% and the coefficient of variation for systematic between-assay variability was 3%. Prior delipidation of samples with organic solvents did not alter their immunoreactivity. In 26 normal volunteers, the mean plasma apoE concentration was 36 +/- 13 microgram/ml. Hyperlipidemic patients (n = 68) had higher mean apoE levels. A single patient with type III hyperlipoproteinemia had a plasma apoE level of 664 microgram/ml. The plasma apoE level was independently related to plasma cholesterol and triglyceride levels in a population of 108 normal and nonchylomicronemic hyperlipidemic patients. The multiple correlation coefficient for this relationship was 0.73. Thus, variation in plasma cholesterol and triglyceride concentrations described 53% of the variation in apoE concentrations in this population. The lipoprotein distribution of apoE was investigated by agarose column chromatography and ultracentrifugation of plasma. Agarose column chromatography demonstrated that all or nearly all plasma apoE is associated with lipoproteins. In plasma from normal volunteers and hypercholesterolemic patients, apoE was found in two discrete lipoprotein classes: very low density lipoproteins and a set of lipoprotein particles with size and density characteristics similar to HDL2. In hypertriglyceridemic patients, nearly all apoE was associated with the triglyceride-rich lipoproteins.

Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death, decreased quality of life, and medical costs in the United States. Nearly 1 in 3 Americans die of heart disease and stroke (1). Most ASCVD is preventable through a healthy lifestyle and effective treatment of cholesterol and blood pressure. The 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults from the American College of Cardiology and American Heart Association (ACC/AHA) provides an evidence-based approach to reducing ASCVD risk (2). Guideline Development Process In 2008, the National Heart, Lung, and Blood Institute (NHLBI) convened the Adult Treatment Panel (ATP) IV to update the 2001 ATP-III cholesterol guidelines using a rigorous systematic process to identify and review randomized, controlled trials (RCTs) with cardiovascular outcomes and meta-analyses of these RCTs. The panel comprised experts and clinicians from the fields of cardiology, epidemiology, primary care, and endocrinology (2) and received support from the Lifestyle Management and Risk Assessment Work Groups (3, 4). Systematic evidence reviews conducted according to principles recommended by the Institute of Medicine (5) were performed to answer 3 questions relevant to clinical care. Two questions focused on the evidence supporting low-density lipoprotein cholesterol (LDL-C) and nonhigh-density lipoprotein cholesterol (HDL-C) levels as targets of treatment. One question examined the reduction in ASCVD events and adverse effects for each cholesterol-lowering drug class. The panel synthesized the evidence from these 3 reviews as well as from Lifestyle Management and Risk Assessment Work Groups reviews (3, 4) that addressed 5 additional critical questions. Systematic electronic searches of relevant databases of the peer-reviewed English-language literature published from 1 January 1995 through 1 December 2009 for each critical question were conducted by an NHLBI-selected independent contractor and focused on RCTs and systematic reviews and meta-analyses of RCTs assessed as fair to good quality. In addition, RCTs with ASCVD outcomes that included coronary heart disease, stroke, and cardiovascular deaths published after that date were eligible for consideration through July 2013. Evidence tables were constructed, and the strength of evidence was rated according to the NHLBI (Table 1 of the Supplement). Recommendations were graded according to criteria from the NHLBI (Table 2 of the Supplement) and ACC/AHA (Table 3 of the Supplement). Because of the inherent differences in grading systems and the clinical questions driving the recommendations, alignment between the NHLBI and ACC/AHA formats was imperfect. A complete description of the methods used and results of the evidence review are provided in the guideline (2) and the NHLBI evidence report (www.nhlbi.nih.gov/guidelines/cholesterol/ser/index.htm). Supplement. NHLBI and ACC/AHA Criteria for Rating Strength of Evidence To help clinicians estimate ASCVD risk, the risk assessment working group developed the Pooled Cohort Equations using data from 5 NHLBI-sponsored longitudinal, population-based cohorts of African American and non-Hispanic white men and women to estimate risk for a first myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke on the basis of age, sex, race, smoking status, total cholesterol level, HDL-C level, systolic blood pressure, antihypertensive therapy, and diabetes (4, 6). These equations significantly advance ASCVD risk estimation by providing sex- and race-specific estimates and including stroke as an outcome. The earlier Framingham equations calculated only coronary heart disease risk for non-Hispanic whites. The draft recommendations were reviewed by 23 experts and representatives of federal agencies identified by the NHLBI. In September 2013, the recommendations developed by the panel were transitioned to the ACC/AHA and had additional review by 4 experts nominated by the ACC Foundation and the AHA. The governing bodies of the ACC and AHA approved the guideline, which also received endorsement from the American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women with Heart Disease. Recommendations The guideline focuses on treatment of blood cholesterol to reduce ASCVD risk in adults. Major recommendations are summarized here and in Table 1. The guideline report provides a complete listing of recommendations and supporting evidence behind each recommendation (2). Table 1. Major Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults* 1. Encourage Adherence to a Healthy Lifestyle A healthy lifestyle is the foundation for cardiovascular health. The panel endorsed the 2013 ACC/AHA Lifestyle Management Guideline (3) for a diet that is low in saturated fat, trans fat, and sodium; emphasizes vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts; and limits sweets, sugar-sweetened beverages, and red meats and engage in regular aerobic physical activity. Adults also should maintain a healthy body weight, avoid smoking, and control hypertension and diabetes when present. 2. Statin Therapy Is Recommended for Adults in Groups Demonstrated to Benefit Strong RCT evidence shows that reduction in ASCVD events from statin therapy exceeds adverse events for 4 patient groups: those with clinical ASCVD (acute coronary syndromes, myocardial infarction, stable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease of atherosclerotic origin) when statins are used for secondary prevention, and those with LDL-C levels 190 mg/dL; those aged 40 to 75 years with diabetes and LDL-C levels 70 to 189 mg/dL; and those aged 40 to 75 years without diabetes and with a 10-year ASCVD risk 7.5% when statins are used for primary prevention. Moderate evidence supports consideration of statin therapy for primary prevention in individuals with a 10-year ASCVD risk of 5% to <7.5%. Routine initiation of statin therapy is not recommended in adults with New York Heart Association heart failure class II to IV or those receiving maintenance hemodialysis. Randomized, controlled trials in these groups showed no reduction in ASCVD. 3. Statins have an Acceptable Margin of Safety When Used in Properly Selected Individuals and Appropriately Monitored Strong RCT evidence supports safety of statins when they are used as directed in conjunction with regular follow-up assessments in properly selected patients. Adjustment of statin intensity is recommended in individuals older than 75 years with a history of statin intolerance or other characteristics (2) or those receiving drug therapy that may increase statin adverse events. Routine monitoring of hepatic aminotransferase level or creatine kinase level is not recommended unless clinically indicated by symptoms suggesting hepatotoxicity or myopathy. Given the potential for decreasing ASCVD events and death, the relationship of muscle and other symptoms to statin treatment must be confirmed. Therefore, eliciting a history of muscle symptoms before statin initiation and carefully monitoring symptoms during statin discontinuation and rechallenge is recommended. Severe myopathy, rhabdomyolysis, and possibly hemorrhagic stroke are rare complications of statin therapy. Although statin therapy modestly increases the risk for type 2 diabetes, ASCVD risk reduction outweighs the excess risk for diabetes for high-intensity statins in secondary prevention or for 10-year ASCVD risk 7.5%. Similarly, ASCVD risk reduction outweighs the excess risk for diabetes for moderate-intensity statin therapy in adults with a 10-year ASCVD risk 5%. 4. Engage in a ClinicianPatient Discussion Before Initiating Statin Therapy, Especially for Primary Prevention in Patients With Lower ASCVD Risk Decisions to initiate statin therapy in primary prevention should be based on clinical judgment and preferences of informed patients. In adults without clinical ASCVD or diabetes whose LDL-C level is <190 mg/dL, calculating the estimated 10-year ASCVD risk should be the start of the clinicianpatient discussion and should not automatically lead to statin initiation. As the absolute risk for ASCVD events decreases, so does the net benefit of the intervention. Therefore, discussion of the potential for ASCVD event reduction, adverse effects, drugdrug interactions, and patient preferences is especially important for lower-risk primary prevention. The discussion provides the opportunity to encourage healthy lifestyle habits and control other risk factors. Additional factors may be considered when a risk-based decision is uncertain, including LDL-C levels 160 mg/dL, family history of premature ASCVD, elevated lifetime ASCVD risk, high-sensitivity C-reactive protein level 2.0 mg/L, coronary artery calcification score >300 Agatston units, and anklebrachial index <0.9. After age 75 years, comorbid conditions, anticipated longevity, safety considerations, and patient preferences should play a large role in decision making. 5. Use the Newly Developed Pooled Cohort Equations for Estimating 10-Year ASCVD Risk The Pooled Cohort Equations are currently the best available method for estimating 10-year ASCVD risk to guide statin initiation (4, 6). Application of the inclusion and exclusion criteria from RCTs is cumbersome and results in underidentifying high-risk and overidentifying low-risk individuals for statin treatment. The Pooled Cohort Equations were developed using recent data from 5 NHLBI-sponsored, longitudinal, population-based cohorts of African American and white men and women (ARIC [Atherosc

Effects of Sirolimus on Lipids in Renal Allograft Recipients: An Analysis Using the Framingham Risk Model

This report describes the effects of sirolimus on plasma lipids, and uses the Framingham risk model to assess the clinical importance of these effects.