Robert S. Rosenson

ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: A report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents

ACCF TASK FORCE MEMBERS Robert A. Harrington, MD, FACC, Chair; Eric R. Bates, MD, FACC; Charles R. Bridges, MD, MPH, FACC; Mark J. Eisenberg, MD, MPH, FACC; Victor A. Ferrari, MD, FACC; Mark A. Hlatky, MD, FACC; Sanjay Kaul, MBBS, FACC; Jonathan R. Lindner, MD, FACC‡; David J. Moliterno, MD, FACC; Debabrata Mukherjee, MD, FACC; Richard S. Schofield, MD, FACC‡; Robert S. Rosenson, MD, FACC; James H. Stein, MD, FACC; Howard H. Weitz, MD, FACC; Deborah J. Wesley, RN, BSN

Cholesterol Efflux and Atheroprotection Advancing the Concept of Reverse Cholesterol Transport

High-density lipoprotein (HDL) has been proposed to have several antiatherosclerotic properties, including the ability to mediate macrophage cholesterol efflux, antioxidant capacity, antiinflammatory properties, nitric oxide–promoting activity, and ability to transport proteins with their own intrinsic biological activities.1 HDL particles are critical acceptors of cholesterol from lipid-laden macrophages and thereby participate in the maintenance of net cholesterol balance in the arterial wall and in the reduction of proinflammatory responses by arterial cholesterol-loaded macrophages. The pathways that regulate HDL-mediated macrophage cholesterol efflux and disposition of cholesterol involve cell membrane–bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL-mediated cholesterol efflux,2,3 the concentration of the cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse cholesterol transport” (RCT) process; however, macrophage-derived cholesterol represents a minor component of the cholesterol transported by HDL particles.4–7 One important pathway for cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) and cholesterol-deficient and phospholipid-depleted apolipoprotein (apo) A-I complexes (pre-β migrating HDL or very small HDL [HDL-VS]; Figure 2).1,8 Subsequently, the ATP-binding cassette transporter G1 (ABCG1) mediates macrophage cholesterol efflux through interactions (Figure 3) with spherical, cholesterol-containing α-HDL particles (small HDL [HDL-S], medium HDL [HDL-M], large HDL [HDL-L], and very large (HDL-VL).1 In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor that mediates bidirectional lipid transport in the macrophage, which is dependent on the content of cholesterol in lipid-laden macrophages. A more established role for SR-BI in cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this cholesterol …

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein‐related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid‐lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL−1 in high‐risk patients should be reassessed in the light of the new clinical trial results and a new ultra‐low target of <80 mg dL−1 be considered. The evidence also indicates that the apo B/apo A‐I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein‐related risk of vascular disease.

Lipoprotein Particle Profiles by Nuclear Magnetic Resonance Compared With Standard Lipids and Apolipoproteins in Predicting Incident Cardiovascular Disease in Women

Background— Nuclear magnetic resonance (NMR) spectroscopy measures the number and size of lipoprotein particles instead of their cholesterol or triglyceride content, but its clinical utility is uncertain. Methods and Results— Baseline lipoproteins were measured by NMR in 27 673 initially healthy women followed up for incident cardiovascular disease (n=1015) over an 11-year period. After adjustment for nonlipid risk factors, hazard ratios and 95% confidence intervals for the top versus the bottom quintile of NMR-measured lipoprotein particle concentration (measured in particles per liter) were 2.51 (1.91 to 3.30) for low-density lipoprotein (LDLNMR), 0.91 (0.75 to 1.12) for high-density lipoprotein (HDLNMR), 1.71 (1.38 to 2.12) for very low–density lipoprotein (VLDLNMR), and 2.25 (1.80 to 2.81) for the LDLNMR/HDLNMR ratio. Similarly adjusted results for NMR-measured lipoprotein particle size (measured in nanometers) were 0.64 (0.52 to 0.79) for LDLNMR size, 0.65 (0.51 to 0.81) for HDLNMR size, and 1.37 (1.10 to 1.70) for VLDLNMR size. Hazard ratios for NMR measures were comparable but not superior to standard lipids (total cholesterol 2.08 [1.63 to 2.67], LDL cholesterol 1.74 [1.40 to 2.16], HDL cholesterol 0.52 [0.42 to 0.64], triglycerides 2.58 [1.95 to 3.41], non-HDL cholesterol 2.52 [1.95 to 3.25], total/HDL cholesterol ratio 2.82 [2.23 to 3.58]) and apolipoproteins (B100 2.57 [1.98 to 3.33], A-1 0.63 [0.52 to 0.77], and B100/A-1 ratio 2.79 [2.21 to 3.54]). Essentially no reclassification improvement was found with the addition of the LDLNMR particle concentration or apolipoprotein B100 to a model that already included the total/HDL cholesterol ratio and nonlipid risk factors (net reclassification index 0% and 1.9%, respectively), nor did the addition of either variable result in a statistically significant improvement in the c-index. Conclusions— In this prospective study of healthy women, cardiovascular disease risk prediction associated with lipoprotein profiles evaluated by NMR was comparable but not superior to that of standard lipids or apolipoproteins.

Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the pravastatin limitation of atherosclerosis in the coronary arteries (PLAC-I) trial☆

Lipoprotein subclass measurements may enhance the prediction of coronary artery disease (CAD) risk, but clinical application of such information has been hindered by the relatively laborious and time-consuming nature of laboratory measurement methods. In this study, lipoprotein subclass analyses were performed on frozen plasma samples from 241 participants in the Pravastatin Limitation of Atherosclerosis in the Coronary arteries Trial using an automated nuclear magnetic resonance technique. The objective was to determine if levels of these subclasses provided additional information on the progression of CAD, based on the change in the minimum lumen diameter, over a 3-year period. After adjustment for race, sex, age, treatment group, baseline lumen diameter, and chemically measured levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, on-trial predictors (p <0.05) of progression included an elevated LDL particle number, and levels of small LDL and small HDL. Within treatment groups, CAD progression was most strongly related to the LDL particle number (placebo) and levels of small HDL (pravastatin). In logistic regression models that adjusted for chemically determined lipid levels and other covariates, a small LDL level > or = 30 mg/dl (median) was associated with a ninefold increased risk of CAD progression (p <0.01) in the placebo group. These results indicate that levels of various lipoprotein subclasses may provide useful information on CAD risk even if levels of traditional risk factors are known.

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

BACKGROUND A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk. CONTENT In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux. SUMMARY We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.

CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease Application to Clinical and Public Health Practice: Report From the Clinical Practice Discussion Group

The Centers for Disease Control and Prevention/American Heart Association (CDC/AHA) Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice was convened on March 14 and 15, 2002, in Atlanta, Ga, to examine the selection and use of inflammatory markers to predict cardiovascular disease (CVD) risk. Three discussion groups on issues related to laboratory, clinical, and population science were organized. The present report contains a summary of the discussions and recommendations of the clinical practice discussion group.This article summarizes epidemiological studies of inflammation markers, particularly C-reactive protein, and cardiovascular disease as of early 2002. Gaps in the research and the public health practice implications are also discussed. Although considerable work has been published since this review was completed, the perspectives and issues presented are still useful in evaluating the use of inflammation markers for risk stratisfication and prevention.

Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes A Position Statement of the American Diabetes Association, a Scientific Statement of the American Heart Association, and an Expert Consensus Document of the American College of Cardiology Foundation

The burden of cardiovascular disease (CVD) among patients with diabetes is substantial. Individuals with diabetes are at 2- to 4-fold increased risk of cardiovascular events compared with age- and sex-matched individuals without diabetes. In diabetic patients over the age of 65 years, 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke.1 A number of mechanisms for the increased cardiovascular risk with diabetes have been proposed, including increased tendency toward intracoronary thrombus formation,2 increased platelet reactivity,3 and worsened endothelial dysfunction.4 The increased risk for cardiovascular events and mortality in patients with diabetes has led to considerable interest in identifying effective means for cardiovascular risk reduction. Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with myocardial infarction (MI) or stroke (secondary prevention).5 The Food and Drug Administration has not approved aspirin for use in primary prevention, and its net benefit among patients with no previous cardiovascular events is more controversial, for both patients with and without a history of diabetes.5 The U.S. Preventive Services Task Force recently updated its recommendation about aspirin use for primary prevention. The Task Force recommended encouraging aspirin use in men age 45–79 years and women age 55–79 years and not encouraging aspirin use in younger adults. They did not differentiate their recommendations based on the presence or absence of diabetes.6,7 In 2007, the American Diabetes Association (ADA) and the American Heart Association (AHA) jointly recommended that aspirin therapy (75–162 mg/d) be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).8 These recommendations were derived from several older …

ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

This document has been developed as an Expert Consensus Document (ECD) by the American College of Cardiology Foundation (ACCF), American Association for Clinical Chemistry (AACC), American College of Chest Physicians (ACCP), American College of Emergency Physicians (ACEP), American College of

Statins and sepsis: multiple modifications at multiple levels

Sepsis, an infection-induced inflammatory syndrome, is a leading and increasing cause of mortality worldwide. Animal and human observational studies suggest statins may prevent the morbidity and mortality associated with the sepsis syndrome. In this Review, we describe the demonstrated mechanisms through which statins modulate the inflammatory response associated with sepsis. These mechanisms include effects on cell signalling with consequent changes at the transcriptional level, the induction of haem oxygenase, the direct alteration of leucocyte-endothelial cell interaction, and the reduced expression of MHC II. Since statins do not target individual inflammatory mediators, but possibly reduce the overall magnitude of the systemic response, this effect could prove an important distinguishing feature modulating the host response to septic insults. This work establishes the biological plausibility needed for future trials of statins in critical illness.