Donald M Lloyd-Jones

University of Maryland, Baltimore, Baltimore, Maryland, United States

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Publications (250)2486.63 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Basic research suggests that rapid increases in circulating inflammatory and hemostatic blood markers may trigger or indicate impending plaque rupture and coronary thrombosis, resulting in acute ischemic heart disease (IHD) events. However, these associations are not established in humans. The Biomarker Risk Assessment in Vulnerable Outpatients (BRAVO) Study will determine whether levels of inflammatory and hemostatic biomarkers rapidly increase during the weeks prior to an acute IHD event in people with lower extremity peripheral artery disease (PAD). The BRAVO Study will determine whether biomarker levels measured immediately prior to an IHD event are higher than levels not preceding an IHD event; whether participants who experience an IHD event (cases) have higher biomarker levels immediately prior to the event and higher biomarker levels at each time point leading up to the IHD event than participants without an IHD event (controls); and whether case participants have greater increases in biomarkers during the months leading up to the event than controls. BRAVO enrolled 595 patients with PAD, a population at high risk for acute IHD events. After a baseline visit, participants returned every two months for blood collection, underwent an electrocardiogram to identify new silent myocardial infarctions, and were queried about new hospitalizations since their prior study visit. Mortality data were also collected. Participants were followed prospectively for up to three years. BRAVO results will provide important information about the pathophysiology of IHD events and may lead to improved therapies for preventing IHD events in high-risk patients.
    Contemporary clinical trials 04/2014; · 1.51 Impact Factor
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    ABSTRACT: IMPORTANCE The American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort risk equations were developed to estimate atherosclerotic cardiovascular disease (CVD) risk and guide statin initiation. OBJECTIVE To assess calibration and discrimination of the Pooled Cohort risk equations in a contemporary US population. DESIGN, SETTING, AND PARTICIPANTS Adults aged 45 to 79 years enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between January 2003 and October 2007 and followed up through December 2010. We studied participants for whom atherosclerotic CVD risk may trigger a discussion of statin initiation (those without clinical atherosclerotic CVD or diabetes, low-density lipoprotein cholesterol level between 70 and 189 mg/dL, and not taking statins; n = 10 997). MAIN OUTCOMES AND MEASURES Predicted risk and observed adjudicated atherosclerotic CVD incidence (nonfatal myocardial infarction, coronary heart disease [CHD] death, nonfatal or fatal stroke) at 5 years because REGARDS participants have not been followed up for 10 years. Additional analyses, limited to Medicare beneficiaries (n = 3333), added atherosclerotic CVD events identified in Medicare claims data. RESULTS There were 338 adjudicated events (192 CHD events, 146 strokes). The observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a 10-year predicted atherosclerotic CVD risk of less than 5% was 1.9 (95% CI, 1.3-2.7) and 1.9, respectively, risk of 5% to less than 7.5% was 4.8 (95% CI, 3.4-6.7) and 4.8, risk of 7.5% to less than 10% was 6.1 (95% CI, 4.4-8.6) and 6.9, and risk of 10% or greater was 12.0 (95% CI, 10.6-13.6) and 15.1 (Hosmer-Lemeshow χ2 = 19.9, P = .01). The C index was 0.72 (95% CI, 0.70-0.75). There were 234 atherosclerotic CVD events (120 CHD events, 114 strokes) among Medicare-linked participants and the observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a predicted risk of less than 7.5% was 5.3 (95% CI, 2.8-10.1) and 4.0, respectively, risk of 7.5% to less than 10% was 7.9 (95% CI, 4.6-13.5) and 6.4, and risk of 10% or greater was 17.4 (95% CI, 15.3-19.8) and 16.4 (Hosmer-Lemeshow χ2 = 5.4, P = .71). The C index was 0.67 (95% CI, 0.64-0.71). CONCLUSIONS AND RELEVANCE In this cohort of US adults for whom statin initiation is considered based on the ACC/AHA Pooled Cohort risk equations, observed and predicted 5-year atherosclerotic CVD risks were similar, indicating that these risk equations were well calibrated in the population for which they were designed to be used, and demonstrated moderate to good discrimination.
    JAMA The Journal of the American Medical Association 03/2014; · 29.98 Impact Factor
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    ABSTRACT: Single measures of blood pressure (BP) levels are associated with the development of atherosclerosis; however, long-term patterns in BP and their effect on cardiovascular disease risk are poorly characterized. To identify common BP trajectories throughout early adulthood and to determine their association with presence of coronary artery calcification (CAC) during middle age. Prospective cohort data from 4681 participants in the CARDIA study, who were black and white men and women aged 18 to 30 years at baseline in 1985-1986 at 4 urban US sites, collected through 25 years of follow-up (2010-2011). We examined systolic BP, diastolic BP, and mid-BP (calculated as [SBP+DBP]/2, an important marker of coronary heart disease risk among younger populations) at baseline and years 2, 5, 7, 10, 15, 20, and 25. Latent mixture modeling was used to identify trajectories in systolic, diastolic, and mid-BP over time. Coronary artery calcification greater than or equal to Agatston score of 100 Hounsfield units (HU) at year 25. We identified 5 distinct mid-BP trajectories: low-stable (21.8%; 95% CI, 19.9%-23.7%; n=987), moderate-stable (42.3%; 40.3%-44.3%; n=2085), moderate-increasing (12.2%; 10.4%-14.0%; n=489), elevated-stable (19.0%; 17.1%-20.0%; n=903), and elevated-increasing (4.8%; 4.0%-5.5%; n=217). Compared with the low-stable group, trajectories with elevated BP levels had greater odds of having a CAC score of 100 HU or greater. Adjusted odds ratios were 1.44 (95% CI, 0.83-2.49) for moderate-stable, 1.86 (95% CI, 0.91-3.82) for moderate-increasing, 2.28 (95% CI, 1.24-4.18), for elevated-stable, and 3.70 (95% CI, 1.66-8.20) for elevated-increasing groups. The adjusted prevalence of a CAC score of 100 HU or higher was 5.8% in the low-stable group. These odds ratios represent an absolute increase of 2.7%, 5%, 6.3%, and 12.9% for the prevalence of a CAC score of 100 HU or higher for the moderate-stable, moderate-increasing, elevated-stable and elevated-increasing groups, respectively, compared with the low-stable group. Associations were not altered after adjustment for baseline and year 25 BP. Findings were similar for trajectories of isolated systolic BP trajectories but were attenuated for diastolic BP trajectories. Blood pressure trajectories throughout young adulthood vary, and higher BP trajectories were associated with an increased risk of CAC in middle age. Long-term trajectories in BP may assist in more accurate identification of individuals with subclinical atherosclerosis.
    JAMA The Journal of the American Medical Association 02/2014; 311(5):490-7. · 29.98 Impact Factor
  • Circulation 01/2014; 129(4):516-26. · 15.20 Impact Factor
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    ABSTRACT: The objective of this study was to assess the evolution of T1 contrast (T1c) between cardiovascular tissues, contrast agents, and magnetic field strengths. This Health Insurance Portability and Accountability Act-compliant study was approved by the institutional review board, and written informed consent was obtained from all participants. Eight healthy volunteers were recruited to undergo 4 consecutive magnetic resonance (MR) scans with the same imaging parameters. Scans 1 and 2 were performed using a 3-T MR scanner, and scans 3 and 4 were performed using a 1.5-T MR scanner. Gadofosveset trisodium (0.03 mmol/kg) was injected for scans 1 and 3, and gadopentetate dimeglumine (Gd-DTPA) (0.1 mmol/kg) was used for scans 2 and 4. Modified Look-Locker inversion recovery T1 maps with a midventricular short-axis view were acquired before contrast and repeated every 5 minutes until 45 minutes after contrast agent administration. T1 contrast tissue (T1myocardium - T1blood), T1c agent (T1Gd-DTPA - T1Gadofosveset), and T1c field (T13T - T11.5T) were calculated and compared using t tests. The T1c tissue of the 3-T scanner was larger than that of the 1.5-T scanner for both contrast agents. In both the myocardium and the blood pool, the T1c agent of the 1.5-T scanner was larger than that of the 3-T scanner. Gadofosveset trisodium exhibited a larger T1c field and T1c tissue than did Gd-DTPA. The T1c tissue induced by Gd-DTPA diminished faster than that induced by gadofosveset trisodium at both 1.5 and 3 T. Our study demonstrates the independent effects of timing, contrast agent type, and magnetic field strength on postcontrast T1c under general physiological conditions. The behaviors of T1c can be used to tailor quantitative MR imaging protocols for various clinical purposes.
    Investigative radiology 01/2014; · 4.85 Impact Factor
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    ABSTRACT: Background Basic research suggests that rapid increases in circulating inflammatory and hemostatic blood markers may trigger or indicate impending plaque rupture and coronary thrombosis, resulting in acute ischemic heart disease (IHD) events. However, these associations are not established in humans. Methods and Results The Biomarker Risk Assessment in Vulnerable Outpatients (BRAVO) Study will determine whether levels of inflammatory and hemostatic biomarkers rapidly increase during the weeks prior to an acute IHD event in people with lower extremity peripheral artery disease (PAD). The BRAVO Study will determine whether biomarker levels measured immediately prior to an IHD event are higher than levels not preceding an IHD event; whether participants who experience an IHD event (cases) have higher biomarker levels immediately prior to the event and higher biomarker levels at each time point leading up to the IHD event than participants without an IHD event (controls); and whether case participants have greater increases in biomarkers during the months leading up to the event than controls. BRAVO enrolled 595 patients with PAD, a population at high risk for acute IHD events. After a baseline visit, participants returned every two months for blood collection, underwent an electrocardiogram to identify new silent myocardial infarctions, and were queried about new hospitalizations since their prior study visit. Mortality data were also collected. Participants were followed prospectively for up to three years. Conclusions BRAVO results will provide important information about the pathophysiology of IHD events and may lead to improved therapies for preventing IHD events in high-risk patients.
    Contemporary Clinical Trials. 01/2014;
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    ABSTRACT: http://jama.jamanetwork.com/article.aspx?articleid=1853203
    Journal of the American Medical Association 01/2014;
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    ABSTRACT: The association between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) events is not well described in individuals with very high levels of HDL-C (>80 mg/dL). Using pooled data from 6 community-based cohorts we examined CHD and total mortality risks across a broad range of HDL-C, including values in excess of 80 mg/dL. We used Cox proportional hazards models with penalized splines to assess multivariable, adjusted, sex-stratified associations of HDL-C with the hazard for CHD events and total mortality, using HDL-C 45 mg/dL and 55 mg/dL as the referent in men and women, respectively. Analyses included 11 515 men and 12 925 women yielding 307 245 person-years of follow-up. In men, the association between HDL-C and CHD events was inverse and linear across most HDL-C values; however at HDL-C values >90 mg/dL there was a plateau effect in the pattern of association. In women, the association between HDL-C and CHD events was inverse and linear across lower values of HDL-C, however at HDL-C values >75 mg/dL there were no further reductions in the hazard ratio point estimates for CHD. In unadjusted models there were increased total mortality risks in men with very high HDL-C, however mortality risks observed in participants with very high HDL-C were attenuated after adjustment for traditional risk factors. We did not observe further reductions in CHD risk with HDL-C values higher than 90 mg/dL in men and 75 mg/dL in women.
    Journal of the American Heart Association. 01/2014; 3(2):e000519.
  • Donald M Lloyd-Jones, David Goff, Neil J Stone
    The Lancet 12/2013; · 39.06 Impact Factor
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    ABSTRACT: Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown. Investigate inflammatory markers' individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD). In 3888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA2) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA2 values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA2 was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events. CHD incidence (per 1000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR = 1.50, p < 0.01) or highest IL-6 tertile (HR = 1.40, p < 0.05), but not with highest Lp-PLA2 tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index. The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.
    Atherosclerosis 12/2013; 231(2):246-251. · 3.71 Impact Factor
  • Circulation 11/2013; · 15.20 Impact Factor
  • Circulation 11/2013; · 15.20 Impact Factor
  • Journal of the American College of Cardiology 11/2013; · 14.09 Impact Factor
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    ABSTRACT: The aim of the present study was to assess the incremental benefit of compensating asynchronous cardiac quiescence in coronary wall MR imaging. With the approval of IRB, black-blood coronary wall MR imaging was performed on 30 older subjects (90 coronary wall segments). For round 1 coronary wall MR imaging, acquisition windows were traditionally set within rest period4-chamber. Totally 51 of 90 images were ranked as "good" images and resulted in an interpretability rate of 57 %. Then, an additional cine-MR was centered at coronary segments to obtain rest periodcross-sectional. The rest periodoverlap (the intersection between rest period4-chamber and rest periodcross-sectional) was measured for each coronary segment. The "good" images had a longer rest periodoverlap and higher acquisition coincidence rate (the percentage of acquisition window covered by the rest periodoverlap) than "poor" images. Coronary wall rescans (round 2) were completed at 39 coronary segments that were judged as having "poor" images in round 1 scans. The acquisition window was set within the rest periodoverlap. For the round 2 images, 17 of 39 (44 %) coronary segments were ranked as "good" images. The overall interpretability rate (68 of 90, 76 %) was significantly higher than that of the round 1 images alone. Our data demonstrated that asynchronous cardiac quiescence adversely affects the performance of coronary wall MR imaging. Individualizing acquisition windows based on multi-plane cine-MR helps to compensate for this motion discrepancy and to improve image quality.
    The international journal of cardiovascular imaging 10/2013; · 2.15 Impact Factor
  • Kai Lin, Donald M Lloyd-Jones, Mark E Molitch, Debiao Li, James C Carr
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is a prevalent condition in aged populations. Cardiovascular diseases are leading causes of death and disability in patients with T2DM. Traditional strategies for controlling the cardiovascular complications of diabetes primarily target a cluster of well-defined risk factors, such as hyperglycemia, lipid disorders and hypertension. However, there is controversy over some recent clinical trials aimed at evaluating efficacy of intensive treatments for T2DM. As a powerful tool for quantitative cardiovascular risk estimation, multi-disciplinary cardiovascular imaging have been applied to detect and quantify morphological and functional abnormalities in the cardiovascular system. Quantitative imaging biomarkers acquired with advanced imaging procedures are expected to provide new insights to stratify absolute cardiovascular risks and reduce the overall costs of health care for people with T2DM by facilitating the selection of optimal therapies. This review discusses principles of state-of-the-art cardiovascular imaging techniques and compares applications of those techniques in various clinical circumstances. Individuals measurements of cardiovascular disease burdens from multiple aspects, which are closely related to existing biomarkers and clinical outcomes, are recommended as promising candidates for quantitative imaging biomarkers to assess the responses of the cardiovascular system during diabetic regimens.
    Journal of diabetes and its complications 10/2013; · 2.11 Impact Factor
  • Source
    Circulation 10/2013; · 15.20 Impact Factor
  • Hongyan Ning, Linda Van Horn, Christina M Shay, Donald M Lloyd-Jones
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    ABSTRACT: Dietary fiber intake might reduce cardiovascular risk factor levels and, in turn, might lower the long-term risk of cardiovascular disease (CVD). A total of 11,113 subjects, aged 20 to 79 years with no history of CVD, from the 2005 to 2010 National Health and Nutrition Examination Survey were included in the present study to examine associations of dietary fiber intake with predicted lifetime CVD risk and C-reactive protein levels. Dietary fiber intake showed a significant gradient association with the likelihood of having a low or an intermediate predicted lifetime CVD risk among young and middle-age adults. In fully adjusted multinomial logistic models, dietary fiber intake was related to a low lifetime CVD risk with an odds ratio of 2.71 (95% confidence interval 2.05 to 3.59) in the young adults and 2.13 (95% confidence interval 1.42 to 3.20) in the middle-age adults and was related to an intermediate lifetime risk of 2.65 (95% confidence interval 1.79 to 3.92) in the young and 1.98 (95% confidence interval 1.32 to 2.98) in the middle-age adults compared with a high lifetime risk. A significant inverse linear association was seen between dietary fiber intake and log-transformed C-reactive protein levels with a regression coefficient ± standard error of -0.18 ± 0.04 in the highest quartile of fiber intake compared with the lowest fiber intake. In conclusion, these data suggest that dietary fiber intake is independently associated with the predicted lifetime CVD risk, especially in young and middle-age adults. A greater amount of dietary fiber intake might be associated with lower C-reactive protein levels.
    The American journal of cardiology 10/2013; · 3.58 Impact Factor
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    ABSTRACT: Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD.
    Contemporary clinical trials 09/2013; · 1.51 Impact Factor
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    ABSTRACT: Abnormal frontal QRS-T angle on a 12-lead electrocardiogram is associated with incident coronary heart disease and total mortality in a biracial cohort, but there have been no studies to date examining QRS-T angle's prognostic value across multiple ethnicities. We studied 6,814 participants (52.7% women, mean age 62 years) from Multi-Ethnic Study of Atherosclerosis, a multiethnic cohort aged 45 to 84 years free of clinical cardiovascular disease (CVD) at enrollment. Baseline examination included measurement of traditional risk factors and 12-lead electrocardiograms. Frontal QRS-T axis was defined as normal (less than seventy-fifth percentile), borderline (seventy-fifth to ninety-fifth percentile), or abnormal (ninety-fifth percentile or more), and participants were followed for the composite end point of incident CVD events: cardiovascular death, myocardial infarction, angina pectoris, or heart failure. After 7.6 years of follow-up, there were 444 total events. Borderline (HR [hazard ratio] 1.37, 95% confidence interval [CI] 1.10 to 1.70) and abnormal QRS-T angles (HR 2.2, 95% CI 1.63 to 2.97) were associated with incident CVD events in multivariate-adjusted models. However, after adjusting for T-wave abnormalities, there was no statistically significant association of either borderline (HR 1.12, 95% CI 0.90 to 1.41) or abnormal (HR 1.31, 95% CI 0.93 to 1.84) QRS-T angle with incident CVD events. Abnormal frontal QRS-T angle predicts incident CVD events in a multiethnic population, and this increased risk is primarily mediated through T-wave abnormalities. QRS-T angle provides an easily interpretable continuous marker of abnormal ventricular repolarization that can aid the everyday clinician in risk prediction.
    The American journal of cardiology 09/2013; · 3.58 Impact Factor
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    ABSTRACT: The association of electrocardiographic (ECG) abnormalities with cardiovascular disease and risk factors has been extensively studied in whites and African-Americans. Comparable data have not been reported in Hispanics/Latinos. The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, community-based, prospective cohort study of men and women of diverse backgrounds aged 18 to 74 years who self-identified as Hispanic/Latinos. Participants (n = 16,415) enrolled from March 2008 to June 2011. We describe the prevalence of minor and major ECG abnormalities and examined their cross-sectional associations with cardiovascular disease and risk factors. The Minnesota code criteria were used to define minor and major ECG abnormalities. Previous cardiovascular disease and risk factors were based on data obtained at baseline examination. Significant differences in prevalent ECG findings were found between men and women. Major ECG abnormalities were present in 9.2% (95% confidence interval 8.3 to 10.1) of men and 6.6% (95% confidence interval 5.8 to 7.3) of women (p <0.0001). The odds of having major ECG abnormalities significantly increased with age, presence of ≥3 cardiovascular risk factors, and prevalent cardiovascular disease, in both men and women. Significant differences in major ECG abnormalities were found among the varying groups; Puerto Ricans and Dominicans had more major abnormalities compared with Mexican men and women. In conclusion, in a large cohort of Hispanic/Latino men and women, prevalence of major abnormalities was low, yet strong associations of major ECG abnormalities with cardiovascular disease and risk factors were observed in both men and women.
    The American journal of cardiology 09/2013; · 3.58 Impact Factor

Publication Stats

17k Citations
2,486.63 Total Impact Points

Institutions

  • 2013
    • University of Maryland, Baltimore
      • Division of Cardiology
      Baltimore, Maryland, United States
  • 2011–2013
    • University of Oklahoma Health Sciences Center
      • Department of Biostatistics and Epidemiology
      Oklahoma City, OK, United States
    • Wake Forest University
      Winston-Salem, North Carolina, United States
    • Harvard University
      • Department of Biostatistics
      Cambridge, MA, United States
  • 2005–2013
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • Hospital of the University of Pennsylvania
      • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2004–2013
    • Northwestern University
      • • Division of Cardiology (Dept. of Medicine)
      • • Department of Medicine
      • • Department of Preventive Medicine
      • • Division of General Internal Medicine and Geriatrics
      Evanston, IL, United States
  • 2011–2012
    • Wayne State University
      • Division of Cardiology
      Detroit, MI, United States
  • 2009–2012
    • University of Texas Southwestern Medical Center
      • • Division of Cardiology
      • • Department of Internal Medicine
      • • Medical School
      Dallas, TX, United States
  • 2010
    • University of Liverpool
      • Department of Public Health and Policy
      Liverpool, ENG, United Kingdom
  • 1998–2010
    • Massachusetts General Hospital
      • • Division of Cardiology
      • • Department of Medicine
      • • Department of Emergency Medicine
      Boston, MA, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2008
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2007
    • Hospital de la Santa Creu i Sant Pau
      Barcino, Catalonia, Spain
    • Athens State University
      Athens, Alabama, United States
  • 2006
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
    • Duke University Medical Center
      • Division of Cardiology
      Durham, NC, United States
  • 1999–2006
    • National Heart, Lung, and Blood Institute
      • Division of Cardiovascular Sciences (DCVS)
      Maryland, United States
  • 1999–2002
    • National Institutes of Health
      Maryland, United States
  • 2000
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States