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Weiss S.A.,University of Chicago | Blumenthal R.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Redberg R.F.,University of California at San Francisco | Mora S.,Harvard University
Circulation | Year: 2010

BACKGROUND-: Individuals with exaggerated exercise blood pressure (BP) tend to develop future hypertension. It is controversial whether they have higher risk of death from cardiovascular disease (CVD). METHODS AND RESULTS-: A total of 6578 asymptomatic Lipid Research Clinics Prevalence Study participants (45% women; mean age, 46 years; 74% with untreated baseline BP <140/90 mm Hg [nonhypertensive]) performing submaximal Bruce treadmill tests were followed for 20 years (385 CVD deaths occurred). Systolic and diastolic BP at rest, Bruce stage 2, and maximal BP during exercise were significantly associated with CVD death. When we compared multivariate hazard ratios and 95% confidence intervals per 10/5-mm Hg BP increments, the association was strongest for rest BP (systolic, 1.21 [1.14 to 1.27]; diastolic, 1.20 [1.14 to 1.26]), then Bruce stage 2 BP (systolic, 1.09 [1.04 to 1.14]; diastolic, 1.09 [1.05 to 1.13]), then maximal exercise BP (systolic, 1.06 [1.01 to 1.10]; diastolic, 1.04 [1.01 to 1.08]). Overall, exercise BP was not significant after adjustment for rest BP. However, hypertension status modified the risk associated with exercise BP (Pinteraction=0.03). Among nonhypertensives, whether they had normal BP (<120/80 mm Hg) or prehypertension, Bruce stage 2 BP >180/90 versus ≤180/90 mm Hg carried increased risk independent of rest BP and risk factors (adjusted hazard ratio for systolic, 1.96 [1.40 to 2.74], P<0.001; diastolic, 1.48 [1.06 to 2.06], P=0.02) and added predictive value (net reclassification improvement, systolic, 12.0% [-0.1% to 24.2%]; diastolic, 9.9% [-0.3% to 20.0%]; relative integrated discrimination improvement, 14.3% and 12.0%, respectively). CONCLUSIONS-: In asymptomatic individuals, elevated exercise BP carried higher risk of CVD death but became nonsignificant after accounting for rest BP. However, Bruce stage 2 BP >180/90 mm Hg identified nonhypertensive individuals at higher risk of CVD death. © 2010 American Heart Association, Inc.


Martin S.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Jones S.R.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Toth P.P.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease
Trends in Endocrinology and Metabolism | Year: 2014

High-density lipoprotein (HDL) is astonishingly complex, but the de facto standard for its measurement has been remarkably simple: total cholesterol content. It is time to prioritize higher-resolution HDL measurement techniques that capture better the biologically and clinically important characteristics of HDL. Scientific advances have ushered in a new era in which we view HDL in terms of its subfractions, particle structure, metabolism, and functional integration of its proteome and lipidome. HDL subfractions appear to be associated with function. In general, smaller, denser HDL3 is more tightly linked to favorable atheroprotective functions and clinical outcomes. Techniques to measure the cholesterol content or particle concentrations of HDL subfractions are available clinically. In the future, we anticipate subfractionating HDL based on its functional properties. © 2014 Elsevier Ltd.


Berger J.S.,New York University | Berger J.S.,University of Pennsylvania | Jordan C.O.,University of Minnesota | Lloyd-Jones D.,Northwestern University | Blumenthal R.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease
Journal of the American College of Cardiology | Year: 2010

Cardiovascular disease is the number 1 cause of death in the western world and 1 of the leading causes of death worldwide. The lifetime risk of atherosclerotic cardiovascular disease (CVD) for persons at age 50 years, on average, is estimated to be 52% for men and 39% for women, with a wide variation depending on risk factor burden. Assessing patients' cardiovascular risk may be used for the targeting of preventive treatments of individual patients who are asymptomatic but at sufficiently high risk for the development of CVD. Risk stratifying patients for CVD remains challenging, particularly for those with low or intermediate short-term risk. Several algorithms have been described to facilitate the assessment of risk in individual patients. We describe 6 risk algorithms (Framingham Risk Score for coronary heart disease events and for cardiovascular events, Adult Treatment Panel III, SCORE [Systematic Coronary Risk Evaluation] project, Reynolds Risk Score, ASSIGN [Assessing Cardiovascular Risk to Scottish Intercollegiate Guidelines Network/SIGN to Assign Preventative Treatment], and QRISK [QRESEARCH Cardiovascular Risk Algorithm]) for outcomes, population derived/validated, receiver-operating characteristic, variables included, and limitations. Areas of uncertainty include 10-year versus lifetime risk, prediction of CVD or coronary heart disease end points, nonlaboratory-based risk scores, age at which to start, race and sex differences, and whether a risk score should guide therapy. We believe that the best high-risk approach to CVD evaluation and prevention lies in routine testing for cardiovascular risk factors and risk score assessment. We recommend that health care providers discuss the global cardiovascular risk and lifetime cardiovascular risk score assessment with each patient to better explain each patient's future risk. Appropriate intervention, guided by risk assessment, has the potential to bring about a significant reduction in population levels of risk. © 2010 American College of Cardiology Foundation.


Yousuf O.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Mohanty B.D.,Mount Sinai School of Medicine | Martin S.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Joshi P.H.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | And 7 more authors.
Journal of the American College of Cardiology | Year: 2013

The role of inflammation in the propagation of atherosclerosis and susceptibility to cardiovascular (CV) events is well established. Of the wide array of inflammatory biomarkers that have been studied, high-sensitivity C-reactive protein (hsCRP) has received the most attention for its use in screening and risk reclassification and as a predictor of clinical response to statin therapy. Although CRP is involved in the immunologic process that triggers vascular remodeling and plaque deposition and is associated with increased CV disease (CVD) risk, definitive randomized evidence for its role as a causative factor in atherothrombosis is lacking. Whether measurement of hsCRP levels provides consistent, clinically meaningful incremental predictive value in risk prediction and reclassification beyond conventional factors remains debated. Despite publication of guidelines on the use of hsCRP in CVD risk prediction by several leading professional organizations, there is a lack of clear consensus regarding the optimal clinical use of hsCRP. This article reviews 4 distinct points from the literature to better understand the current state and application of hsCRP in clinical practice: 1) the biology of hsCRP and its role in atherosclerosis; 2) the epidemiological association of hsCRP with CVD; 3) the quality of hsCRP as a biomarker of risk; and 4) the use of hsCRP as a tool to initiate or tailor statin therapy. Furthermore, we highlight recommendations from societies and important considerations when using hsCRP to guide treatment decisions in the primary prevention setting.


Martin S.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Blumenthal R.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Miller M.,University of Maryland, Baltimore
Medical Clinics of North America | Year: 2012

High cholesterol is often a prerequisite for atherosclerotic plaque. Low-density lipoprotein cholesterol (LDL-C) is the focus of the National Cholesterol Education Program Adult Treatment Panel guidelines. LDL-C ranges from 50 to 70 mg/dL in native hunter-gatherers, healthy human neonates, free-living primates, and other wild mammals, who are notably free of atherosclerotic vascular disease. Multiple statin trials and meta-analyses support a treatment target of LDL-C levels less than 70 mg/dL, as this is associated with improved clinical outcomes and atherosclerosis regression. In fact, no threshold has yet been identified below which patients do not benefit from lowering of LDL-C. © 2012 Elsevier Inc.


Martin S.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Blaha M.J.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Elshazly M.B.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Toth P.P.,Illinois College | And 3 more authors.
JAMA - Journal of the American Medical Association | Year: 2013

IMPORTANCE: In clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels. OBJECTIVE: To derive and validate a more accurate method for LDL-C estimation from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio. DESIGN, SETTING, AND PARTICIPANTS: We used a convenience sample of consecutive clinical lipid profiles obtained from 2009 through 2011 from 1 350 908 children, adolescents, and adults in the United States. Cholesterol concentrations were directly measured after vertical spin density-gradient ultracentrifugation, and triglycerides were directly measured. Lipid distributions closely matched the population-based National Health and Nutrition Examination Survey (NHANES). Samples were randomly assigned to derivation (n = 900 605) and validation (n = 450 303) data sets. MAIN OUTCOMES AND MEASURES: Individual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated vs directly measured LDL-C (LDL-CD). RESULTS: In the derivation data set, the median TG:VLDL-C was 5.2 (IQR, 4.5-6.0). The triglyceride and non-high-density lipoprotein cholesterol (HDL-C) levels explained 65% of the variance in the TG:VLDL-C ratio. Based on strata of triglyceride and non-HDL-C values, a 180-cell table of median TG:VLDL-C values was derived and applied in the validation data set to estimate the novel LDL-C (LDL-CN). For patients with triglycerides lower than 400 mg/dL, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% CI, 91.6%-91.8%) for LDL-CN vs 85.4% (95% CI, 85.3%-85.5%) for Friedewald LDL-C (LDL-CF) (P < .001). The greatest improvement in concordance occurred in classifying LDL-C lower than 70 mg/dL, especially in patients with high triglyceride levels. In patients with an estimated LDL-C lower than 70 mg/dL, LDL-CD was also lower than 70 mg/dL in 94.3% (95% CI, 93.9%-94.7%) for LDL-CN vs 79.9% (95% CI, 79.3%-80.4%) for LDL-CF in samples with triglyceride levels of 100 to 149mg/dL; 92.4% (95% CI, 91.7%-93.1%) for LDL-CN vs 61.3% (95% CI, 60.3%-62.3%) for LDL-CF in samples with triglyceride levels of 150 to 199mg/dL; and 84.0% (95% CI, 82.9%-85.1%) for LDL-CN vs 40.3% (95% CI, 39.4%-41.3%) for LDL-CF in samples with triglyceride levels of 200 to 399 mg/dL (P < .001 for each comparison). CONCLUSIONS AND RELEVANCE: A novel method to estimate LDL-C using an adjustable factor for the TG:VLDL-C ratio provided more accurate guideline risk classification than the Friedewald equation. These findings require external validation, as well as assessment of their clinical importance. The implementation of these findings into clinical practice would be straightforward and at virtually no cost. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01698489 Copyright 2013 American Medical Association. All rights reserved.


Patel J.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease
Current atherosclerosis reports | Year: 2014

Pharmacogenetics uses the genetic variation in metabolic pathways to identify groups of patients who may respond differently in terms of therapeutic and adverse effects. Much clinical interest lies in drug metabolism and the opportunity to improve prescribing efficacy and safety. Owing to widespread use and increasing concern regarding side effects, statins are of significant interest in this area. Among other benefits, statins have been shown to improve lipid profiles and reduce coronary heart disease event rates in many populations. However, variability in drug response exists, and genetic variability may be a contributing factor. Our primary goal is to feature the most important genes involved in lipid metabolism, clinical outcomes, and statin-induced side effects, highlighting genome-wide association studies and the candidate gene approach.


Dominique Ashen M.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease
Current Treatment Options in Cardiovascular Medicine | Year: 2013

Opinion statement: There is growing evidence that consumption of a vegetarian diet as well as specific components of a vegetarian diet lower the incidence of cardiovascular disease (CVD) and death. Vegetarian diets lower the probability of developing CVD, are effective in altering serum lipids, are beneficial in reducing blood pressure, improve glycemic control and insulin sensitivity, reduce weight, and lower mortality. Vascular effects of a vegetarian diet include a thinner carotid IMT and lower brachial artery resistance. Health care providers should be aware of the types of vegetarian diets and their risks and benefits in order to guide patients' dietary habits with the ultimate goal of reducing their CVD risk. While a patient does not have to become a complete vegetarian to reduce their CVD risk, they can make simple changes in their diet that are effective in risk reduction. © 2013 Springer Science+Business Media New York.


Desai C.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Martin S.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Blumenthal R.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease
BMJ (Online) | Year: 2014

Statins form the pharmacologic cornerstone of the primary and secondary prevention of atherosclerotic cardiovascular disease. In addition to beneficial cardiovascular effects, statins seem to have multiple non-cardiovascular effects. Although early concerns about statin induced hepatotoxicity and cancer have subsided owing to reassuring evidence, two of the most common concerns that clinicians have are myopathy and diabetes. Randomized controlled trials suggest that statins are associated with a modest increase in the risk of myositis but not the risk of myalgia. Severe myopathy (rhabdomyolysis) is rare and often linked to a statin regimen that is no longer recommended (simvastatin 80 mg). Randomized controlled trials and meta-analyses suggest an increase in the risk of diabetes with statins, particularly with higher intensity regimens in people with two or more components of the metabolic syndrome. Other non-cardiovascular effects covered in this review are contrast induced nephropathy, cognition, cataracts, erectile dysfunction, and venous thromboembolism. Currently, systematic reviews and clinical practice guidelines indicate that the cardiovascular benefits of statins generally outweigh non-cardiovascular harms in patients above a certain threshold of cardiovascular risk. Literature is also accumulating on the potential non-cardiovascular benefits of statins, which could lead to novel applications of this class of drug in the future.


Martin S.S.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Abd T.T.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Jones S.R.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | Michos E.D.,Johns Hopkins Ciccarone Center for the Prevention of Heart Disease | And 2 more authors.
Journal of the American College of Cardiology | Year: 2014

Five years after convening the expert panel, the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults was released. The American College of Cardiology and American Heart Association issued the guideline on the basis of a systematic review of cholesterol treatment trials performed by the National Heart, Lung, and Blood Institute. This report critically appraises the guideline and provides our view of what was done well and what could be done better. In particular, we propose that the guideline succeeds in prioritizing statin therapy, expanding the focus to atherosclerotic cardiovascular disease (including stroke), and emphasizing absolute cardiovascular risk to determine eligibility for statin therapy. We contend that the guideline could be enhanced by refining the use of lipid goals rather than removing them, enhancing guidance on evaluation of cholesterol, and broadening the concept of age underpinning risk-based decision making to include vascular and physiological age. We further suggest that the next guideline panel could comprehensively review current best evidence, build on existing guidelines, and cultivate broader national and international consensus. Overall, we aim to continue discussions about the important contributions and shortfalls of the guideline and create momentum for effective implementation and timely updates. © 2014 by the American College of Cardiology Foundation.

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