Amir Lerman

Mayo Clinic - Rochester, Rochester, Minnesota, United States

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Publications (703)

  • Poster · Nov 2016
  • Article · Nov 2016 · American Journal of Hematology
  • [Show abstract] [Hide abstract] ABSTRACT: Emerging nanotechnologies have enabled the use of magnetic forces to guide the movement of magnetically-labeled cells, drugs, and other therapeutic agents. Endothelial cells labeled with superparamagnetic iron oxide nanoparticles (SPION) have previously been captured on the surface of magnetizable 2205 duplex stainless steel stents in a porcine coronary implantation model. Recently, we have coated these stents with electrospun polyurethane nanofibers to fabricate prototype stent-grafts. Facilitated endothelialization may help improve the healing of arteries treated with stent-grafts, reduce the risk of thrombosis and restenosis, and enable small-caliber applications. When placed in a SPION-labeled endothelial cell suspension in the presence of an external magnetic field, magnetized stent-grafts successfully captured cells to the surface regions adjacent to the stent struts. Implantation within the coronary circulation of pigs (n=13) followed immediately by SPION-labeled autologous endothelial cell delivery resulted in widely patent devices with a thin, uniform neointima and no signs of thrombosis or inflammation at 7 days. Furthermore, the magnetized stent-grafts successfully captured and retained SPION-labeled endothelial cells to select regions adjacent to stent struts and between stent struts, whereas the non-magnetized control stent-grafts did not. Early results with these prototype devices are encouraging and further refinements will be necessary in order to achieve more uniform cell capture and complete endothelialization. Once optimized, this approach may lead to more rapid and complete healing of vascular stent-grafts with a concomitant improvement in long-term device performance.
    Article · Nov 2016 · Journal of Magnetism and Magnetic Materials
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    [Show abstract] [Hide abstract] ABSTRACT: Extracellular vesicles (EVs) isolated from mesenchymal stem/stromal cells (MSCs) contribute to recovery of damaged tissue. We have previously shown that porcine MSC-derived EVs transport mRNA and miRNA capable of modulating cellular pathways in recipient cells. To identify candidate factors that contribute to the therapeutic effects of porcine MSC-derived EVs, we characterized their protein cargo using proteomics. Porcine MSCs were cultured from abdominal fat, and EVs characterized for expression of typical MSC and EV markers. LC-MS/MS proteomic analysis was performed and proteins classified. Functional pathway analysis was performed and five candidate proteins were validated by western blot. Proteomics analysis identified 5,469 distinct proteins in MSCs and 4,937 in EVs. The average protein expression was higher in MSCs vs. EVs. Differential expression analysis revealed 128 proteins that are selectively enriched in EVs versus MSCs, whereas 563 proteins were excluded from EVs. Proteins enriched in EVs are linked to a broad range of biological functions, including angiogenesis, blood coagulation, apoptosis, extracellular matrix remodeling, and regulation of inflammation. Excluded are mostly nuclear proteins, like proteins involved in nucleotide binding and RNA splicing. EVs have a selectively-enriched protein cargo with a specific biological signature that MSCs may employ for intercellular communication to facilitate tissue repair.
    Full-text available · Article · Oct 2016 · Scientific Reports
  • File available · Data · Oct 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Stent-grafts are widely used for the treatment of various conditions such as aortic lesions, aneurysms, emboli due to coronary intervention procedures and perforations in vasculature. Such stent-grafts are manufactured by covering a stent with a polymer membrane. An ideal stentgraft should have a biocompatible stent covered by a porous, thromboresistant, and biocompatible polymer membrane which mimics the extracellular matrix thereby promoting injury site healing. The goal of this protocol is to manufacture a small caliber stent-graft by encapsulating a balloon expandable stent within two layers of electrospun polyurethane nanofibers. Electrospinning of polyurethane has been shown to assist in healing by mimicking native extracellular matrix, thereby promoting endothelialization. Electrospinning polyurethane nanofibers on a slowly rotating mandrel enabled us to precisely control the thickness of the nanofibrous membrane, which is essential to achieve a small caliber balloon expandable stent-graft. Mechanical validation by crimping and expansion of the stent-graft has shown that the nanofibrous polyurethane membrane is sufficiently flexible to crimp and expand while staying patent without showing any signs of tearing or delamination. Furthermore, stent-grafts fabricated using the methods described here are capable of being implanted using a coronary intervention procedure using standard size guide catheters.
    Full-text available · Article · Oct 2016 · Journal of Visualized Experiments
  • Shi-Wei Yang · Rebecca R. Hennessy · Sundeep Khosla · [...] · Amir Lerman
    [Show abstract] [Hide abstract] ABSTRACT: Background: There is increasing evidence implying that the early and functionally highly active circulating endothelial progenitor cell (CEPC) phenotype (CD34-/CD133+/KDR+) with osteogenic potential (OCN+) might link between vascular atherosclerotic calcification and mechanisms of bone metabolism. We sought to evaluate the early OCN+ CEPC counts as an independent biomarker for the severity of coronary artery disease (CAD). Methods: Peripheral blood samples were drawn from 593 patients undergoing clinically indicated coronary angiography. CAD severity was assessed by the presence of significant coronary artery stenosis (CAS) as well as an ordinal categorical variable. Subjects were followed for all-cause death over a median follow-up of 40months. Results: OCN+ early CEPC counts (square-root transformed) were independently associated with the presence of significant CAS [odds ratio (OR) per standard deviation (SD) increment: 1.389, 95% confidence interval [CI]: 1.131 to 1.707, p=0.002). Similar association was observed with an increase in levels of CAS (OR: 1.353, 95% CI: 1.157 to 1.582, p<0.001). There was a weak tendency between OCN+ early CEPC counts and all-cause mortality (p=0.090), whereas the highest decile of OCN+ early CEPC counts had a 2.991-fold increased risk of all-cause death (p=0.047). Conclusions: We demonstrate for the first time an independent, significant, and strong correlation between OCN+ early CEPC counts and CAD severity. Additionally, very high numbers of OCN+ early CEPC tend to be linked to the risk of all-cause mortality.
    Article · Oct 2016 · International journal of cardiology
  • [Show abstract] [Hide abstract] ABSTRACT: Floyd Dunn’s extensive research career contributed significantly to safety and efficacy of diagnostic and therapeutic ultrasound. Positive effects of low-energy shock wave therapy (SWT) show preclinical promise in renal disease in pigs and in cardiovascular disease in humans. Preclinical: a set of 26 pigs were divided into four groups, normal + SWT, atherosclerotic renal artery stenosis (ARAS) + SWT, and Normal and ARAS pigs. After three weeks of ARAS or sham, SWT was applied twice a week for three weeks. SWT after ARAS decreased blood pressure, recovered the stenotic microvascular density, improved renal blood flow and glomerular filtration rate, and decreased fibrosis. No noticeable kidney injury was observed. Low-energy SWT recovers the stenotic kidney toward normal function by preserving intra-renal microcirculation and may also alleviate renovascular hypertension. 72 patients with refractory angina, 43 were treated with low-energy SWT in the area peripheral to their infarct and 29 patients were in the control group. No adverse effects were seen in the treated group. At six months post-treatment angina class score was decreased (p = 0.0002), nitroglycerine use was reduced (p = 0.03), and hospitalization rate was reduced (p = 0.03). Low-energy shockwave therapy may be a tool for treating diseases caused by ischemia.
    Article · Oct 2016 · The Journal of the Acoustical Society of America
  • [Show abstract] [Hide abstract] ABSTRACT: The objective of this study was to determine the incidence of arrhythmias and device (internal cardiac defibrillator/cardiac resynchronization therapy defibrillator) therapies in patients with a diagnosis of cardiomyopathy and anthracycline exposure.
    Article · Sep 2016 · JACC Clinical Electrophysiology
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    Yasushi Matsuzawa · Mahmoud Suleiman · Raviteja R Guddeti · [...] · Amir Lerman
    [Show abstract] [Hide abstract] ABSTRACT: Background: The mechanisms of atrial fibrillation (AF) are highly divergent. The prevalence of AF increases significantly with age, and underling mechanisms might vary with age. Endothelial dysfunction may be associated with AF and atrial arrhythmia recurrence after catheter ablation. We tested the hypothesis that the impact of endothelial dysfunction on arrhythmia recurrence following catheter ablation is age dependent. Methods and results: This study enrolled 92 participants with AF undergoing catheter ablation. Endothelial function was assessed by peripheral arterial tonometry before ablation, and the natural logarithmic transformation of reactive hyperemia index was calculated. Endothelial dysfunction was defined as a natural logarithmic transformation of reactive hyperemia index <0.618 (median). Participants were followed for atrial tachycardia, flutter, and fibrillation recurrence for a median of 14 months. The mean age was 57±10 years. There was significant interaction between age and endothelial dysfunction in association with recurrence of AF (P=0.029) and any atrial arrhythmia (P=0.015), and the risk associated with endothelial dysfunction for arrhythmia recurrence was higher in younger versus older participants. Participants were divided into 2 age groups at a threshold of 60 years. Among participants aged ≤60 years, multivariate Cox proportional hazards analysis revealed the independent association between endothelial dysfunction and increased risk of arrhythmia recurrence (hazard ratio for AF 4.18 [95% CI 1.33-15.82], P=0.014, and for any atrial arrhythmia 3.62 [95% CI 1.29-11.81], P=0.014). Kaplan-Meier analysis showed that participants with endothelial dysfunction had significantly higher rates of recurrence of AF (P=0.01) and any atrial arrhythmia (P=0.002). Conclusions: The risk associated with endothelial dysfunction for arrhythmia recurrence following catheter ablation was age dependent and was higher in younger participants.
    Full-text available · Article · Sep 2016 · Journal of the American Heart Association
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    [Show abstract] [Hide abstract] ABSTRACT: Background The study compared downstream coronary and conduit disease progression in the left anterior descending coronary artery treated with coronary artery bypass grafting using the left internal mammary artery (LIMA) versus percutaneous coronary intervention with bare metal stent (BMS) or drug eluting stent (DES). Methods and Results A total of 12 301 consecutive patients underwent isolated primary coronary revascularization, of which 2386 met our inclusion criteria (Percutaneous coronary intervention, n=1450; coronary artery bypass grafting, n=936). Propensity score analysis matched 628 patients, of which 468 were treated to the left anterior descending with coronary artery bypass grafting with LIMA (n=314), percutaneous coronary intervention with BMS (n=94), and DES (n=60). Coronary angiograms were analyzed by quantitative coronary angiography (QCA; n=433). Cumulative downstream coronary and conduit disease progression were estimated by Kaplan–Meier method and effect of treatment type by Cox proportional hazard models. Patients treated with LIMA had significantly lower risk of downstream coronary disease progression at follow‐up angiogram compared with BMS and DES (hazard ratio [HR] [95% CI], 0.34; [0.20–0.59]; P=0.0002; and HR [95% CI], 0.39; [0.20–0.79]; P=0.01, respectively). LIMA was associated with a lower risk of conduit disease progression compared to BMS and DES (HR [95% CI], 0.18; [0.12–0.28]; P<0.001; and HR [95% CI], 0.27; [0.16–0.46]; P<0.001, respectively). BMS was associated with higher HR for downstream coronary and conduit disease progression compared with DES, but the difference did not reach statistical significance (HR [95% CI], 1.13; [0.57–2.36]; P=0.73; and HR [95% CI], 1.46; [0.88–2.50]; P=0.14, respectively). Conclusions LIMA grafting to left anterior descending is associated with significantly lower risk of downstream coronary and conduit disease progression compared to percutaneous coronary intervention with BMS and DES.
    Full-text available · Article · Sep 2016 · Journal of the American Heart Association
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    S Suedfeld · F Wang · J Herrmann · [...] · A Lerman
    File available · Poster · Aug 2016
  • Raviteja R Guddeti · Abhiram Prasad · Yasushi Matsuzawa · [...] · Amir Lerman
    [Show abstract] [Hide abstract] ABSTRACT: Objectives Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor, and its expression is increased in atherosclerosis and after PCI. In this study, we aim to define the role of endothelin in regulating coronary microvascular blood flow and myocardial perfusion following PCI in patients with non-ST elevation acute coronary syndromes (NSTACS), by assessing whether adjunctive therapy with a selective endothelin A (ETA) receptor antagonist acutely improves postprocedural coronary microvascular blood flow. Methods In a randomised, double-blinded, placebo-controlled trial, 23 NSTACS patients were enrolled to receive an intracoronary infusion of placebo (n=11) or BQ-123 (n=12) immediately before PCI. Post-PCI coronary microvascular blood flow and myocardial perfusion were assessed by measuring Doppler-derived average peak velocity (APV), and cardiac biomarker levels were quantified. Results Compared with the placebo group, APV was significantly higher in the drug group immediately after PCI (30 (20, 37) vs 19 (9, 26) cm/s; p=0.03). Hyperaemic APV, measured post-adenosine administration, was higher in the BQ-123 group, but the difference did not achieve statistical significance (56 (48, 72) vs 46 (34, 64) cm/s; p=0.090). Maximum coronary flow reserve postprocedure was not different between the two groups (2.1 (1.6, 2.3) vs 2.5 (1.8, 3.0)). Per cent change in creatine kinase isoenzyme MB from the time of PCI to 8 and 16 hours post-PCI was significantly lower in the drug group compared with the placebo group (−17 (−26, −10) vs 26 (−15, 134); p=0.02 and −17 (−38, 14) vs 107 (2, 446); p=0.007, respectively). Conclusions Endothelin is a mediator of microvascular dysfunction during PCI in NSTACS, and adjunctive selective ETA antagonist may augment myocardial perfusion during PCI. Trial registration number NCT00586820; Results.
    Article · Aug 2016
  • Kyoung-Ha Park · Tao Sun · Felipe Diez-Delhoyo · [...] · Amir Lerman
    [Show abstract] [Hide abstract] ABSTRACT: Background and aims: The vasa vasorum (VV) plays a role in the initial phase of atherosclerosis, and abnormalities in microvascular function may be sensitive measures of the early development of atherosclerosis. The current study was designed to access the association between coronary microvascular function and VV density in patients undergoing cardiac catheterization. Methods: Twenty-four patients with early coronary artery disease underwent endothelium-dependent (coronary blood flow, CBF) and endothelium-independent (coronary flow velocity reserve, CFVR) coronary microvascular function testing, and optical coherence tomography (OCT) imaging of the left anterior descending coronary artery (LAD). Using an intracoronary Doppler guidewire, CBF was examined by evaluating changes in blood flow in response to acetylcholine and CFVR in response to adenosine. VV density (VV volume/vessel volume × 100, %VV) of the proximal 10 mm of the LAD was quantified by OCT. Results: The median values (Q1, Q3) of CFVR, % changes in CBF in response to acetylcholine, and the %VV were 2.70 (2.30, 2.90), -16.82 (-42.34, 54.52), and 2.62 (2.35, 3.35), respectively. %VV correlated inversely with CBF (r = -0.614, p = 0.001) and directly with CFVR (r = 0.423, p = 0.040). Multivariate analysis showed that only %VV was significantly correlated with CBF and the association was independent of other clinical variables, Framingham risk score, body mass index, and a family history of coronary heart disease. Conclusions: This study demonstrates that VV density has negative correlation with endothelium-dependent microvascular function in patients with early coronary atherosclerosis. These observations link adventitial VV structure and function to microvascular dysfunction in early coronary atherosclerosis.
    Article · Aug 2016 · Atherosclerosis
  • Soumen Jana · Amir Lerman
    [Show abstract] [Hide abstract] ABSTRACT: A two-dimensional (2D) nanofibrous membrane cannot keep its morphology and shape intact without an underlying support such as glass coverslip (GC). As cellular processes and the behavior of cells depend on the mechanical properties of a substrate, an underlying support that generally has higher stiffness than a nanofibrous membrane could have unwanted influence on culturing cells. In this study, we investigated the influence of a GC on the cells by preparing a 2D standalone concentric nanofibrous (CN) substrate and a CN membrane with an underlying glass coverslip (CN-GC) substrate. We then cultured stiffness-sensitive valvular interstitial cells (VICs) onto them. Sole GC substrate was used as a negative control. While VICs were stretched and spindle-shaped on the CN substrates, they were flat and rectangular-shaped on the CN-GC substrates. On the GC substrates, all the VICs formed an almost continuous flat sheet of cells spreading in all directions without any alignment. VICs showed fibroblast phenotype on the CN substrates whereas same VICs showed myofibroblast phenotype on the CN-GC and GC substrates. Further, GC substrates bent due to contraction of cultured cells. Collagen fibril deposit rates were lowest on the CN substrates and highest on the GC substrates. These findings indicate that cellular processes and behavior can be influenced by the underlying supporting substrate in a nanofibrous membrane system, which is very significant for tissue engineering and regenerative medicine where cell is a vital ingredient. We have proposed several easy means to fabricate standalone 2D nanofibrous substrates without any underlying support for in vitro and in vivo research and applications.
    Article · Jul 2016
  • Taek-Geun Kwon · Rajiv Gulati · Yasushi Matsuzawa · [...] · Amir Lerman
    Article · Jul 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes cytochrome-c oxidase-3 and NADH dehydrogenase subunit-1 by quantitative polymerase chain reaction in essential (n=25) and renovascular (RVH, n=34) hypertensive patients and compared them with healthy volunteers (n=22). Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin served as indices of renal injury. Renal blood flow and oxygenation were assessed by multidetector computed tomography and blood oxygen level-dependent magnetic resonance imaging. Blood pressure, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were similarly elevated in essential hypertension and RVH, and estimated glomerular filtration rate was lower in RVH versus healthy volunteers and essential hypertension. Renal blood flow was lower in RVH compared with essential hypertension. Urinary mtDNA copy number was higher in hypertension compared with healthy volunteers, directly correlated with urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 and inversely with estimated glomerular filtration rate. In RVH, urinary mtDNA copy number correlated directly with intrarenal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared with healthy volunteers (n=10 each). The change in serum creatinine levels and estimated glomerular filtration rate 3 months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.
    Full-text available · Article · Jun 2016 · Hypertension
  • Alfonso Eirin · Amir Lerman · Lilach O. Lerman
    [Show abstract] [Hide abstract] ABSTRACT: Renal disease affects millions of people worldwide, imposing an enormous financial burden for health-care systems. Recent evidence suggests that mitochondria play an important role in the pathogenesis of different forms of renal disease, including genetic defects, acute kidney injury, chronic kidney disease, aging, renal tumors, and transplant nephropathy. Renal mitochondrial abnormalities and dysfunction affect several cellular pathways, leading to increased oxidative stress, apoptosis, microvascular loss, and fibrosis, all of which compromise renal function. Over recent years, compounds that specifically target mitochondria have emerged as promising therapeutic options for patients with renal disease. Although the most compelling evidence is based on preclinical studies, several compounds are currently being tested in clinical trials. This chapter provides an overview of the involvement of mitochondrial dysfunction in renal disease and summarizes the current knowledge on mitochondria-targeted strategies to attenuate renal disease.
    Chapter · Jun 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Microvascular rarefaction distal to renal artery stenosis is linked to renal dysfunction and poor outcomes. Low-energy shockwave therapy stimulates angiogenesis, but the effect on the kidney microvasculature is unknown. We hypothesized that low-energy shockwave therapy would restore the microcirculation and alleviate renal dysfunction in renovascular disease. Normal pigs and pigs subjected to 3 weeks of renal artery stenosis were treated with six sessions of low-energy shockwave (biweekly for 3 consecutive weeks) or left untreated. We assessed BP, urinary protein, stenotic renal blood flow, GFR, microvascular structure, and oxygenation in vivo 4 weeks after completion of treatment, and then, we assessed expression of angiogenic factors and mechanotransducers (focal adhesion kinase and β1-integrin) ex vivo A 3-week low-energy shockwave regimen attenuated renovascular hypertension, normalized stenotic kidney microvascular density and oxygenation, stabilized function, and alleviated fibrosis in pigs subjected to renal artery stenosis. These effects associated with elevated renal expression of angiogenic factors and mechanotransducers, particularly in proximal tubular cells. In additional pigs with prolonged (6 weeks) renal artery stenosis, shockwave therapy also decreased BP and improved GFR, microvascular density, and oxygenation in the stenotic kidney. This shockwave regimen did not cause detectable kidney injury in normal pigs. In conclusion, low-energy shockwave therapy improves stenotic kidney function, likely in part by mechanotransduction-mediated expression of angiogenic factors in proximal tubular cells, and it may ameliorate renovascular hypertension. Low-energy shockwave therapy may serve as a novel noninvasive intervention in the management of renovascular disease.
    Article · Jun 2016 · Journal of the American Society of Nephrology
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    [Show abstract] [Hide abstract] ABSTRACT: Background Renovascular hypertension (RVH) impairs cardiac structure and left ventricular (LV) function, but whether mitochondrial injury is implicated in RVH‐induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. Methods and Results After 12 weeks of hypercholesterolemic (HC)‐RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial‐targeted peptide (MTP), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner‐membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector‐computed tomography and oxygenation by blood‐oxygen‐level–dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic‐reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert‐butyl hydroperoxide (tBHP) untreated or treated with MTP. Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin‐sensitive sarcoplasmic reticulum Ca²⁺‐ATPase activity that declined in HC‐RVH normalized in MTP‐treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP‐treated pigs. In tBHP‐treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics. Conclusions Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC‐RVH, suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.
    Full-text available · Article · Jun 2016 · Journal of the American Heart Association

Publication Stats

30k Citations


  • 1999-2012
    • Mayo Clinic - Rochester
      • • Department of Cardiovascular Diseases
      • • Department of Internal Medicine
      Rochester, Minnesota, United States
  • 2011
    • University of Florida
      Gainesville, Florida, United States
  • 2003
    • Aarhus University
      Aarhus, Central Jutland, Denmark
    • Second University of Naples
      Caserta, Campania, Italy
  • 2002
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
    • Saint Louis University
      Сент-Луис, Michigan, United States
  • 2000
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
  • 1998
    • University of Rome Tor Vergata
      Roma, Latium, Italy
    • University of Zurich
      Zürich, Zurich, Switzerland