Steven E Nissen

University of Adelaide, Tarndarnya, South Australia, Australia

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Publications (421)4652.37 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Statins can regress coronary atheroma and lower clinical events. Although pre-clinical studies suggest procalcific effects of statins in vitro, it remains unclear if statins can modulate coronary atheroma calcification in vivo.
    Journal of the American College of Cardiology 04/2015; DOI:10.1016/j.jacc.2015.01.036 · 15.34 Impact Factor
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    ABSTRACT: Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated. Six hundred forty-seven patients with angiographic coronary artery disease who were commenced on statin therapy underwent serial imaging with intravascular ultrasound. Responders were defined as a percentage reduction in LDL-C of <15%. Disease progression was compared in responders (n=517) and hyporesponders (n=130) to statin therapy. Twenty percentage of patients demonstrated minimal changes in LDL-C, despite commencement of statin therapy. Statin hyporesponders were younger (55 versus 57 years; P=0.01), more likely to be male (79% versus 66%; P=0.005), and obese (body mass index, 31.5±6.1 versus 30.3±5.9 kg/m(2); P=0.04) and less likely to have a history of dyslipidemia (50% versus 66%; P<0.001). Baseline levels of systolic blood pressure (127±15 versus 132±17 mm Hg; P=0.01) and LDL-C (2.5±0.6 versus 3.4±0.8 mmol/L; P<0.001) were lower in statin hyporesponders. Baseline percent atheroma volume was similar between statin hyporesponders and responders (36.9±9.8% versus 38.3±9.2%; P=0.13). On serial evaluation, greater progression of percent atheroma volume (1.19±0.48% versus 0.09±0.43%; P=0.003) was observed in statin hyporesponders. After adjusting for baseline clinical characteristics and measures of plaque burden, statin hyporesponders still exhibited greater atheroma progression (+0.83±0.58% versus -0.21±0.52%; P=0.006). A substantial proportion of patients with coronary artery disease fail to achieve effective reductions in LDL-C, despite prescription of statin therapy. Greater progression of atherosclerosis is observed in these patients. Our current study underscores monitoring LDL-C level after the commencement of statin to ensure adequate response to statin therapy. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2015; DOI:10.1161/ATVBAHA.114.304477 · 5.53 Impact Factor
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    ABSTRACT: Controversy exists regarding benefits of raising HDL-C in statin-treated coronary artery disease (CAD) patients. We assessed the anti-atherosclerotic efficacy of raising HDL-C in statin-treated individuals with CAD across a range of achieved LDL-C, including lower (<70 mg/dL) versus higher (≥70 mg/dL) levels. In seven prospective randomized trials utilizing serial coronary intravascular ultrasound, 3469 statin-treated CAD patients were stratified according to achieved LDL-C (< vs ≥70 mg/dL) and changes in HDL-C (≥ vs < median), as well as across a broader spectrum of changes in HDL-C and achieved LDL-C levels. Changes in coronary percent atheroma volume and MACE (cardiovascular death, non-fatal MI, stroke, coronary revascularization, hospitalization for unstable angina) were evaluated across these groups. Overall, median change in HDL-C was +6.03%, and mean achieved LDL-C in the lower and higher LDL-C groups were 55.1 ± 11 and 97.4 ± 22 mg/dL, respectively. Following multivariable adjustment, in patients with achieved LDL-C < 70 mg/dL, greater HDL-C-raising did not associate with disease progression/regression. In those with achieved LDL-C ≥ 70 mg/dL, greater HDL-C-raising associated with less disease progression (OR 0.80 (95% CI 0.67, 0.97)) and MACE (HR 0.78 (95% CI 0.64, 0.96)). Greater increases in HDL-C (up to 25% from baseline) across the continuous range of on-treatment LDL-C levels associated with less disease progression )OR 0.90 (95% CI 0.83, 0.98)) and lower MACE (HR 0.87 (95% CI 0.77, 0.998)). Increasing HDL-C via a broad spectrum of mechanisms appears beneficial in statin-treated CAD patients, but is likely of greater benefit in patients with achieved LDL-C levels ≥70 mg/dL. © The European Society of Cardiology 2015 Reprints and permissions:
    European Journal of Preventive Cardiology 02/2015; DOI:10.1177/2047487315572920 · 2.68 Impact Factor
  • Journal of the American College of Cardiology 02/2015; 65(6):630-632. DOI:10.1016/j.jacc.2014.11.039 · 15.34 Impact Factor
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    ABSTRACT: Objective This study investigated the effect of type 2 diabetes duration on glucose regulation 24 months post-bariatric surgery.Methods Twenty-seven adults with short- (<5 years) and long-duration (≥10 years) type 2 diabetes received a mixed-meal tolerance test at baseline and 24 months postsurgery. Body weight, insulin sensitivity, first- and second-phase meal-stimulated insulin secretion, disposition index (i.e., DI or pancreatic β-cell function), and incretin responses were examined.ResultsAdults with short-duration type 2 diabetes had better HbA1c, greater insulin secretory capacity, and greater DI compared with adults with long-duration type 2 diabetes, despite similar weight loss and incretin responses. Diabetes duration correlated with smaller improvements in HbA1c and DI but not weight loss.Conclusions Enhanced β-cell function characterizes the effect of bariatric surgery in adults with diabetes for <5 years, independent of weight loss or incretins. Additional therapy postsurgery may be required to improve glycemia for people with long-standing type 2 diabetes.
    Obesity 02/2015; DOI:10.1002/oby.21021 · 4.39 Impact Factor
  • Steven E Nissen
    Clinical Trials 12/2014; DOI:10.1177/1740774514561661 · 1.94 Impact Factor
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    ABSTRACT: Spotty calcification is a morphological characteristic of a vulnerable plaque phenotype. While this calcium pattern is considered an active process, promoted by inflammation, it is unknown whether spotty calcification associates with development of microstructures observed in vulnerable plaques. As frequency-domain optical coherence tomography (FD-OCT) enables visualization of microstructures associated with plaque vulnerability, we investigated the association between spotty calcification and plaque microstructures by using FD-OCT. A total of 300 patients with stable coronary artery disease (CAD), having clinical indication for percutaneous coronary intervention (PCI), were analyzed. Totally 280 non-culprit lipid plaques within the target vessel requiring PCI were evaluated by FD-OCT. Spotty calcification was defined as a presence of lesion <4 mm in length, containing an arc of calcification <90° on FD-OCT. Plaque microstructures were compared in non-culprit lipid-rich plaques with and without spotty calcification. Spotty calcification was observed in 39.6% of non-culprit lipid-rich plaques, with 30.6% of these plaques demonstrating multiple spotty calcifications. Plaques containing spotty calcification exhibited a greater lipid index (= averaged lipid arc × lipid length); 1,511.8±1,522.3 vs. 815.2±1,040.3 mm°, P<0.0001), thinner fibrous caps (89.0±31.6 vs. 136.5±32.5 µm, P=0.002) and a higher prevalence of microchannels (45.9% vs. 17.7%, P=0.007). A significant association was observed between the number of spotty calcifications per plaque and fibrous cap thickness (r=-0.40, P=0.006). Increased number of spotty calcification was also associated with a higher prevalence of microchannel within plaques (P=0.01). In patients with stable CAD requiring PCI, the presence of spotty calcification imaged by FD-OCT was associated with features of greater plaque vulnerability.
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    ABSTRACT: Patients with acute coronary syndromes (ACS) display diffuse coronary atheroma instability and heightened risk of early and late recurrent coronary events. We compared the long-term antiatherosclerotic efficacy of high-intensity statins in patients with ACS when compared with stable disease.
    Arteriosclerosis Thrombosis and Vascular Biology 09/2014; 34(11). DOI:10.1161/ATVBAHA.114.303932 · 5.53 Impact Factor
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    ABSTRACT: The study sought to explore sex-related differences in coronary atheroma regression following high-intensity statin therapy.
    JACC Cardiovascular Imaging 09/2014; 7(10). DOI:10.1016/j.jcmg.2014.04.019 · 6.99 Impact Factor
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    ABSTRACT: Although statins can induce coronary atheroma regression, this benefit has yet to be demonstrated in diabetic individuals. We tested the hypothesis that high-intensity statin therapy may promote coronary atheroma regression in patients with diabetes.
    Diabetes Care 09/2014; DOI:10.2337/dc14-1121 · 8.57 Impact Factor
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    ABSTRACT: Guidelines now recommend high-intensity statin therapy in all patients with proven atherosclerotic disease. Yet the impact of baseline lipoprotein and C-reactive protein (CRP) levels on measures of disease regression to this therapy are unknown. The aim of this study was to test the hypothesis that high-intensity statin therapy causes equivalent degrees of coronary atheroma regression irrespective of baseline lipoprotein and CRP levels. In 8 prospective randomized trials using serial coronary intravascular ultrasound, 1,881 patients who maintained or switched to 18- to 24 months of high-intensity statin therapy (rosuvastatin 40 mg or atorvastatin 80 mg) were stratified according to baseline lipoprotein and CRP levels. Changes in coronary percentage atheroma volume (PAV) and total atheroma volume (TAV) were evaluated. High-intensity statin therapy produced significant reductions from baseline in low-density lipoprotein cholesterol by 38.4%, non-high-density lipoprotein (HDL) cholesterol by 33.6%, triglycerides by 13.1%, and CRP by 33.3%, while increasing HDL cholesterol by 11.7% (p <0.001 for all). This was associated with regression of PAV by 0.7% and of TAV by 8.2 mm(3) (p <0.001 for both). No significant differences of changes in PAV and TAV were observed across baseline quintiles of low-density lipoprotein cholesterol, HDL cholesterol, non-HDL cholesterol, triglycerides, or CRP. Moreover, across all measured lipoproteins and CRP, most patients demonstrated plaque regression (defined as any change from baseline in PAV or TAV <0). In conclusion, high-intensity statin therapy attenuated the natural progression of coronary atherosclerosis in all strata of patients with coronary artery disease irrespective of baseline lipoprotein or CRP levels. These findings provide support for the latest United States guideline recommendations for the broad use of high-intensity statin therapy in all patients with atherosclerosis, regardless of baseline lipid status.
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    ABSTRACT: AimBariatric surgery improves glycemic control, but not all patients achieve type 2 diabetes (T2D) remission. Thus, we aimed to identify metabolic determinants of T2D non-remission status following bariatric surgery at 12 and 24 months (m).Methods Forty adults (BMI: 36±3kg/m2, Age: 48±9y, HbA1c: 9.7±2%) undergoing bariatric surgery (i.e. RYGB or SG) were enrolled in STAMPEDE. T2D remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl without anti-diabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide during a 120 min MMTT. Body fat (DXA), incretins (GLP-1, GIP, ghrelin), and adipokines (adiponectin, leptin, TNF-α, hs-CRP) were also assessed.ResultsAt 24m, 37 subjects had follow-up data (n = 18 RYGB and n = 19 SG). Bariatric surgery-induced 40% and 27% T2D remission rates at 12 and 24m, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity, and β-cell function (C-peptide0–120/Glucose0–120 x Matsuda index) improved more in remitters at 12 and 24m than non-remitters. Incretin levels were unrelated to T2D remission, but, compared to non-remitters, hs-CRP decreased and adiponectin increased more in remitters. Only baseline adiponectin predicted lower HbA1c at 12 and 24m, and elevated adiponectin correlated with enhanced β-cell function, lower triglycerides and fat loss.Conclusions Smaller rises in adiponectin, a mediator of insulin action and adipose mass, depict T2D non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key for higher T2D remission rates after bariatric surgery.
    Diabetes Obesity and Metabolism 08/2014; 16(12). DOI:10.1111/dom.12376 · 5.46 Impact Factor
  • Atherosclerosis 08/2014; 235(2):e12. DOI:10.1016/j.atherosclerosis.2014.05.005 · 3.97 Impact Factor
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    ABSTRACT: High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels are inversely associated with adverse cardiovascular outcomes. Associations between these HDL-C-related measurements and coronary plaque progression have not been studied. We performed a retrospective analysis of 2,566 statin-treated patients with angiographic coronary artery disease who underwent serial evaluation of atheroma burden with intravascular ultrasound. Relations between achieved levels of HDL-related measurements with clinical characteristics and changes in plaque burden were determined. A strong correlation between HDL-C and apoA-I (r = 0.80, p <0.001) was observed. HDL-C, apoA-I, and the HDL-C:apoA-I ratio demonstrated negative correlations with the change in percent atheroma volume and total atheroma volume (all p ≤0.001). Increasing levels of achieved HDL-C:apoA-I (p = 0.04), but not HDL-C (p = 0.18) or apoA-I (p = 0.67), were associated with less progression of percent atheroma volume. Similar results were seen for change in total atheroma volume, with less progression seen with increased HDL-C:apoA-I (p = 0.002) but not with increases in HDL-C (p = 0.09) or apoA-I (p = 0.19). In conclusion, increasing levels of HDL-C:apoA-I associated with less progression of coronary atherosclerosis. This suggests that interventions increasing the cholesterol content of HDL particles may be of cardiovascular benefit.
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    ABSTRACT: Potent statin therapy has been demonstrated to reduce cardiovascular events. Although statins have been considered to stabilize atherosclerotic plaque, this effect has not been well characterized in vivo. We investigated the relation between potent statin therapy and plaque microstructures imaged by frequency-domain optical coherence tomography. Two hundred ninety nonculprit lipid plaques in 275 patients with stable coronary artery disease receiving atorvastatin or rosuvastatin were analyzed. Patients were stratified into no statin, low-, and high-dose statin groups. Plaques in the high-dose statin group demonstrated a smaller lipid arc (p = 0.02) and a greater fibrous cap thickness (p = 0.01). In patients receiving statin therapy, high-dose statin therapy was associated with a greater fibrous cap thickness in patients with smaller (148.2 ± 30.5 vs 105.3 ± 41.1 μm, p = 0.004) but not larger lipid index (91.1 ± 32.6 vs 78.1 ± 43.3 μm, p = 0.21). In conclusion, potent statin therapy is associated with less vulnerable plaque features on frequency-domain optical coherence tomography imaging. This finding varies according to the size of plaque lipid content, being less effective in lipid-loaded plaques.
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    ABSTRACT: Large plaque burden, expansive vascular remodelling, and spotty calcification have been considered as important morphologies of high-risk plaques causing acute coronary events. Although non-occlusive rupture of high-risk plaques has been proposed as a mechanism for disease progression in post-mortem studies, the natural history of coronary atherosclerosis in stable patients with high-risk plaques has not been fully elucidated. We sought to evaluate coronary atheroma progression in stable patients with greyscale intravascular ultrasound (IVUS)-derived high-risk plaques. We analysed 4477 patients with stable coronary artery disease underwent serial greyscale IVUS imaging in eight clinical trials. We compared volumetric intravascular ultrasound (IVUS) data in the non-culprit segments between patients with and without high-risk plaques, defined as the combination of per cent atheroma volume (PAV) >63%, positive remodelling and spotty calcification. High-risk plaques were observed in 201 (4.5%) of patients. Patients with high-risk plaques exhibited a greater PAV (47.1 ± 8.4 vs. 37.7 ± 8.7%, P < 0.001) at baseline. On serial evaluation, however, regression of PAV (-0.26 ± 0.39 vs. 0.24 ± 0.32%, P = 0.03) was observed. In patients with high-risk plaques, the non-statin use was associated with the accelerated atheroma progression, whereas atheroma regression was observed under statin therapy (change in PAV: 1.87 ± 0.68% vs. -0.83 ± 0.53%, P = 0.01). Patients with high-risk plaques exhibit extensive atheroma burden, which is modifiable with anti-atherosclerotic therapies. These findings underscore risk modification using a statin in patients with high-risk plaques.
    04/2014; DOI:10.1093/ehjci/jeu065
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    ABSTRACT: Background In short-term randomized trials (duration, 1 to 2 years), bariatric surgery has been associated with improvement in type 2 diabetes mellitus. Methods We assessed outcomes 3 years after the randomization of 150 obese patients with uncontrolled type 2 diabetes to receive either intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary end point was a glycated hemoglobin level of 6.0% or less. Results The mean (±SD) age of the patients at baseline was 48±8 years, 68% were women, the mean baseline glycated hemoglobin level was 9.3±1.5%, and the mean baseline body-mass index (the weight in kilograms divided by the square of the height in meters) was 36.0±3.5. A total of 91% of the patients completed 36 months of follow-up. At 3 years, the criterion for the primary end point was met by 5% of the patients in the medical-therapy group, as compared with 38% of those in the gastric-bypass group (P<0.001) and 24% of those in the sleeve-gastrectomy group (P=0.01). The use of glucose-lowering medications, including insulin, was lower in the surgical groups than in the medical-therapy group. Patients in the surgical groups had greater mean percentage reductions in weight from baseline, with reductions of 24.5±9.1% in the gastric-bypass group and 21.1±8.9% in the sleeve-gastrectomy group, as compared with a reduction of 4.2±8.3% in the medical-therapy group (P<0.001 for both comparisons). Quality-of-life measures were significantly better in the two surgical groups than in the medical-therapy group. There were no major late surgical complications. Conclusions Among obese patients with uncontrolled type 2 diabetes, 3 years of intensive medical therapy plus bariatric surgery resulted in glycemic control in significantly more patients than did medical therapy alone. Analyses of secondary end points, including body weight, use of glucose-lowering medications, and quality of life, also showed favorable results at 3 years in the surgical groups, as compared with the group receiving medical therapy alone. (Funded by Ethicon and others; STAMPEDE number, NCT00432809 .).
    New England Journal of Medicine 03/2014; 370(21). DOI:10.1056/NEJMoa1401329 · 54.42 Impact Factor
  • 03/2014; 9(1):e10. DOI:10.1016/j.gheart.2014.03.1256
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    ABSTRACT: Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 μg and 100 μg eprotirome in patients with familial hypercholesterolaemia. For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 μg eprotirome, 100 μg eprotirome, or placebo. This trial was planned for 52-76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with, number NCT01410383. We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 μg eprotirome, and 77 to receive 100 μg eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 μg eprotirome, and 22 given 100 μg eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0·0677 vs placebo) in the 50 μg eprotirome group, and decreased by 22% (-32 to -13%; p=0·0045 vs placebo) in the 100 μg eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; p<0·0001), alanine aminotransferase (ALT; p<0·0001), conjugated bilirubin (p=0·0006), and gamma-glutamyltranspeptidase (p<0·0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 μg eprotirome group and 27% (30 to 23) in the 100 μg eprotirome group (p<0·0001 vs placebo for both groups). Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations. Karo Bio AB.
    02/2014; DOI:10.1016/S2213-8587(14)70006-3

Publication Stats

25k Citations
4,652.37 Total Impact Points


  • 2013–2015
    • University of Adelaide
      • South Australian Research and Development Institute (SARDI)
      Tarndarnya, South Australia, Australia
    • South Australian Health and Medical Research Institute
      Adelaide Hills, South Australia, Australia
  • 2001–2015
    • Cleveland Clinic
      • • Department of Cardiology
      • • Department of Cardiovascular Biology
      • • Department of Cardiovascular Medicine
      Cleveland, Ohio, United States
    • McLaren Regional Medical Center
      Michigan City, Indiana, United States
  • 2010–2014
    • Metropolitan Heart and Vascular Institute
      Minneapolis, Minnesota, United States
  • 2012
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 2011
    • University of Florida
      Gainesville, Florida, United States
    • Queen's University Belfast
      • Centre for Public Health
      Béal Feirste, Northern Ireland, United Kingdom
  • 2008
    • Sungkyunkwan University
      • School of Medicine
      Seoul, Seoul, South Korea
  • 2007
    • Northwestern University
      Evanston, Illinois, United States
    • Washington Hospital Center
      Washington, Washington, D.C., United States
  • 2005–2007
    • Montreal Heart Institute
      Montréal, Quebec, Canada
    • The Ohio State University
      Columbus, Ohio, United States
  • 1994–2007
    • American College of Cardiology
      Washington, Washington, D.C., United States
  • 2006
    • University of Colorado
      Denver, Colorado, United States
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2004
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States
  • 2003
    • Hospital of the University of Pennsylvania
      • Division of Cardiovascular Medicine
      Filadelfia, Pennsylvania, United States
    • Toho University
      Edo, Tōkyō, Japan
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 2001–2003
    • Yale University
      • Section of Cardiovascular Medicine
      New Haven, Connecticut, United States
  • 1991–2003
    • Case Western Reserve University
      • Department of Biomedical Engineering
      Cleveland, Ohio, United States
    • Lexington VA Medical Center
      Washington, Washington, D.C., United States
  • 1998–1999
    • Cleveland Clinic Laboratories
      Cleveland, Ohio, United States
  • 1994–1995
    • National Cerebral and Cardiovascular Center
      • Department of Cardiovascular Medicine
      Ōsaka, Ōsaka, Japan
  • 1985–1992
    • Lexington Medical Center
      West Columbia, South Carolina, United States
  • 1988–1991
    • University of Kentucky
      • • Department of Medicine
      • • College of Medicine
      Lexington, KY, United States