Publications by authors named "Michael P Robich"

77 Publications

Protective role of ErbB3 signaling in myeloid cells during adaptation to cardiac pressure overload.

J Mol Cell Cardiol 2021 03 28;152:1-16. Epub 2020 Nov 28.

Maine Medical Center Research Institute, Scarborough, ME, United States of America. Electronic address:

Background: Myeloid cells play an important role in a wide variety of cardiovascular disorders, including both ischemic and non-ischemic cardiomyopathies. Neuregulin-1 (NRG-1)/ErbB signaling has recently emerged as an important factor contributing to the control of inflammatory activation of myeloid cells after an ischemic injury. However, the role of ErbB signaling in myeloid cells in non-ischemic cardiomyopathy is not fully understood. This study investigated the role of ErbB3 receptors in the regulation of early adaptive response using a mouse model of transverse aortic constriction (TAC) for non-ischemic cardiomyopathy.

Methods And Results: TAC surgery was performed in groups of age- and sex-matched myeloid cell-specific ErbB3-deficient mice (ErbB3) and control animals (ErbB3). The number of cardiac CD45 immune cells, CD11b myeloid cells, Ly6G neutrophils, and Ly6C monocytes was determined using flow cytometric analysis. Five days after TAC, survival was dramatically reduced in male but not female ErbB3 mice or control animals. The examination of lung weight to body weight ratio suggested that acute pulmonary edema was present in ErbB3 male mice after TAC. To determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3 male mice, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. Myeloid cells accumulated in control but not in ErbB3 male mouse hearts. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and fibroblasts) in control but not ErbB3 male mice. No significant differences in intramyocardial accumulation of myeloid cells or proliferation of Sca-1 cells were found between the groups of ErbB3 and ErbB3 female mice. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3 mice hearts compared to control animals after TAC.

Conclusion: Our data demonstrate the crucial role of myeloid cell-specific ErbB3 signaling in the cardiac accumulation of myeloid cells, which contributes to the activation of cardiac endothelial cells and fibroblasts and development of an early adaptive response to cardiac pressure overload in male mice.
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http://dx.doi.org/10.1016/j.yjmcc.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981250PMC
March 2021

"When You Don't Know What to Do, Do What You Know How to Do".

Authors:
Michael P Robich

Ann Thorac Surg 2021 03 19;111(3):904-905. Epub 2020 Sep 19.

Department of Cardiovascular Surgery, Heart and Vascular Institute, Maine Medical Center, 818 Congress St, Portland, ME 04102. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2020.06.134DOI Listing
March 2021

Comparative effectiveness of revascularization strategies for early coronary artery disease: A multicenter analysis.

J Thorac Cardiovasc Surg 2020 May 20. Epub 2020 May 20.

Departments of Medicine and Surgery, Heart and Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

Objectives: The goal of this analysis was to examine the comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention among patients aged less than 60 years.

Methods: We performed a multicenter, retrospective analysis of all cardiac revascularization procedures from 2005 to 2015 among 7 medical centers. Inclusion criteria were age less than 60 years and 70% stenosis or greater in 1 or more major coronary artery distribution. Exclusion criteria were left main 50% or greater, ST-elevation myocardial infarction, emergency status, and prior revascularization procedure. After applying inclusion and exclusion criteria, the final study cohort included 1945 patients who underwent cardiac surgery and 2938 patients who underwent percutaneous coronary intervention. The primary end point was all-cause mortality stratified by revascularization strategy. Secondary end points included stroke, repeat revascularization, and 30-day mortality. We used inverse probability weighting to balance differences among the groups.

Results: After adjustment, there was no significant difference in 30-day mortality (surgery: 0.8%; percutaneous coronary intervention: 0.7%, P = .86) for patients with multivessel disease. Patients undergoing surgery had a higher risk of stroke (1.3% [n = 25] vs 0.07% [n = 2], P < .001). Overall, surgery was associated with superior 10-year survival compared with percutaneous coronary intervention (hazard ratio, 0.71; 95% confidence interval, 0.57-0.88; P = .002). Repeat procedures occurred in 13.4% (n = 270) of the surgery group and 36.4% (n = 1068) of the percutaneous coronary intervention group, with both groups mostly undergoing percutaneous coronary intervention as their second operation. Accounting for death as a competing risk, at 10 years, surgery resulted in a lower cumulative incidence of repeat revascularization compared with percutaneous coronary intervention (subdistribution hazard ratio, 0.34; 95% confidence interval, 0.28-0.40; P < .001).

Conclusions: Among patients aged less than 60 years with 2-vessel disease that includes the left anterior descending or 3-vessel coronary artery disease, surgery was associated with greater long-term survival and decreased risk of repeat revascularization.
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http://dx.doi.org/10.1016/j.jtcvs.2020.03.164DOI Listing
May 2020

High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta.

Life Sci 2020 Jun 3;251:117634. Epub 2020 Apr 3.

Maine Medical Center Research Institute, Scarborough, ME, United States of America. Electronic address:

Neuregulin-1β (NRG-1) is a membrane-bound or secreted growth and differentiation factor that mediates its action by binding to ErbB receptors. Circulating levels of NRG-1 are characterized by large inter-individual variability with the range of absolute values covering two orders of magnitude, from hundreds to tens of thousands of picograms per milliliter of blood. NRG-1 signaling via ErbB receptors contributes to the cell survival and downregulation of the inflammatory response. A higher level of circulating NRG-1 may indicate increased shedding of membrane-bound NRG-1, which in turn can contribute to better protection against cardiovascular stress or injury. However, it is unknown whether circulating NRG-1 can induce activation of ErbB receptors. In the current study, we performed an analysis of circulating NRG-1 functional activity using a cell-based ELISA measuring phosphorylation of ErbB3 induced by blood plasma obtained from healthy donors. We found high levels of ErbB3 activating activity in human plasma. No correlations were found between the levels of circulating NRG-1 and plasma ErbB3 activating activity. To determine the direct effect of circulating NRG-1, we incubated plasma with neutralizing antibody, which prevented the stimulatory effect of recombinant NRG-1 on activation of ErbB3. No effect of the neutralizing antibody was found on plasma-induced phosphorylation of ErbB3. We also found that a significant portion of circulating NRG-1 is comprised of full-length NRG-1 associated with large extracellular vesicles. Our results demonstrate that circulating NRG-1 does not contribute to plasma-induced ErbB3 activating activity and emphasizes the importance of functional testing of NRG-1 proteins in biological samples.
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http://dx.doi.org/10.1016/j.lfs.2020.117634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233313PMC
June 2020

Tissue versus mechanical aortic valve replacement in younger patients: A multicenter analysis.

J Thorac Cardiovasc Surg 2019 12 1;158(6):1529-1538.e2. Epub 2019 Mar 1.

Section of Cardiac Surgery, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

Objective: The goal of this study was to examine the long-term survival of patients between the ages of 50 and 65 years who underwent tissue versus mechanical aortic valve replacement (AVR) in a multicenter cohort.

Methods: A multicenter, retrospective analysis of all AVR patients (n = 9388) from 1991 to 2015 among 7 medical centers reporting to a prospectively maintained clinical registry was conducted. Inclusion criteria were: patients aged 50 to 65 years who underwent isolated AVR. Baseline comorbidities were balanced using inverse probability weighting for a study cohort of 1449 AVRs: 840 tissue and 609 mechanical. The primary end point of the analysis was all-cause mortality. Secondary end points included in-hospital morbidity, 30-day mortality, length of stay, and risk of reoperation.

Results: During the study period, there was a significant shift from mechanical to tissue valves (P < .001). There was no significant difference in major in-hospital morbidity, mortality, or length of hospitalization. Also, there was no significant difference in adjusted 15-year survival between mechanical versus tissue valves (hazard ratio, 0.87; 95% confidence interval [CI], 0.67-1.13; P = .29), although tissue valves were associated with a higher risk of reoperation with a cumulative incidence of 19.1% (95% CI, 14.4%-24.3%) versus 3.0% (95% CI, 1.7%-4.9%) for mechanical valves. The reoperative 30-day mortality rate was 2.4% (n = 2) for the series.

Conclusions: Among patients 50 to 65 years old who underwent AVR, there was no difference in adjusted long-term survival according to prosthesis type, but tissue valves were associated with a higher risk of reoperation.
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http://dx.doi.org/10.1016/j.jtcvs.2019.02.076DOI Listing
December 2019

Successful rebuilding after disaster, even in the heart, starts with infrastructure.

J Thorac Dis 2018 Nov;10(Suppl 33):S4165-S4167

Maine Medical Center, Cardiovascular Institute, Portland, ME, USA.

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http://dx.doi.org/10.21037/jtd.2018.10.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297528PMC
November 2018

Surgical Atrial Fibrillation Ablation Improves Long-Term Survival: A Multicenter Analysis.

Ann Thorac Surg 2019 01 6;107(1):135-142. Epub 2018 Oct 6.

Department of Medicine, Section of Cardiology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Background: The Society of Thoracic Surgeons guidelines recommend surgical ablation (SA) at the time of concomitant mitral operations, aortic valve replacement, coronary artery bypass grafting (CABG), and aortic valve replacement plus CABG for patients in atrial fibrillation (AF). The goal of this analysis was to assess the influence of SA on long-term survival.

Methods: A retrospective analysis of 20,407 consecutive CABG or valve procedures from 2008 to 2015 among seven centers reporting to a prospectively maintained clinical registry was conducted. Patients undergoing operation with documented preoperative AF were included (n = 2,740). Patients receiving SA were compared with patients receiving no SA. The primary end point was all-cause mortality. Secondary end points included in-hospital morbidity and mortality.

Results: The frequency of SA was 23.1% (n = 634), and an increase was seen in the rate of SA over the study period (p < 0.001). Concomitant SA was performed in 16.2% of CABG, 30.6% of valve, and 24.3% of valve plus CABG procedures. A substantial improvement was found in unadjusted survival among patients undergoing SA (hazard ratio 0.54, 95% confidence interval: 0.42 to 0.70). Moreover, no differences were found in postoperative complications. SA did have longer bypass times (p < 0.001) but a shorter overall length of stay (p < 0.001). After risk adjustment, SA patients had an improved 5-year survival (hazard ratio 0.69, 95% confidence interval: 0.51 to 0.92), and the effect was observed across all operations.

Conclusions: In a multicenter cohort of patients with AF, concomitant SA resulted in substantially improved long-term survival across patients who underwent CABG, valve, and valve plus CABG. These findings support current guidelines from The Society of Thoracic Surgeons that recommend broader application of concomitant SA.
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http://dx.doi.org/10.1016/j.athoracsur.2018.08.022DOI Listing
January 2019

Intensity of Glycemic Control Affects Long-Term Survival After Coronary Artery Bypass Graft Surgery.

Ann Thorac Surg 2019 02 28;107(2):477-484. Epub 2018 Sep 28.

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Background: A patient's hemoglobin (Hb) A level, regardless of diabetic status, is a measure of glycemic control. Studies have found it is an independent predictor of short-term death in patients undergoing coronary artery bypass grafting (CABG). In this study, we used preoperative HbA to assess whether levels are associated with short-term and long-term survival after CABG.

Methods: From a regional registry of consecutive cases, we identified 6,415 patients undergoing on-pump isolated CABG from 2008 to 2015 with documented preoperative HbA level. We defined four HbA groups: less than 5.7% (n = 1,713), 5.7% to 6.4% (n = 2,505), 6.5% to 8.0% (n = 1,377), and more than 8% (n = 820). Relationship to in-hospital outcomes and long-term survival was assessed. Outcome rates and hazard ratios were adjusted for patient and disease risk factors using multivariable logistic regression and Cox models.

Results: The study included 3,740 patients (58%) not diagnosed as having diabetes and 2,674 with diabetes. Prediabetes (HbA 5.7% to 6.4%) was documented in 52% (n = 1,933) of nondiabetic patients. Higher HbA values were associated with younger age, female sex, greater body mass index, more comorbid diseases, lower ejection fraction, more 3-vessel coronary disease, and recent myocardial infarction (p < 0.05 trend for all). After adjustment for patient risk, greater HbA values were not associated with higher rates of in-hospital death or morbidity. Long-term survival was significantly worse as HbA increased. Risk of death increased by 13% for every unit increase in HbA (adjusted hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.19; p < 0.001).

Conclusions: Preadmission glycemic control, as assessed by HbA, is predictive of long-term survival, with higher levels associated with poorer prognosis. Whether this risk can be modified by better glycemic control postoperatively remains to be determined.
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http://dx.doi.org/10.1016/j.athoracsur.2018.07.078DOI Listing
February 2019

Comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention in a real-world Surgical Treatment for Ischemic Heart Failure trial population.

J Thorac Cardiovasc Surg 2018 10 1;156(4):1410-1421.e2. Epub 2018 Jun 1.

Section of Cardiac Surgery, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

Objective: There are no prospective randomized trial data to guide decisions on optimal revascularization strategies for patients with multivessel coronary artery disease and reduced ejection fraction. In this analysis, we describe the comparative effectiveness of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in this patient population.

Methods: A multicenter, retrospective analysis of all CABG (n = 18,292) and PCIs (n = 55,438) performed from 2004 to 2014 among 7 medical centers reporting to the Northern New England Cardiovascular Disease Study Group. After applying inclusion and exclusion criteria from the Surgical Treatment for Ischemic Heart Failure trial, there were 955 CABG and 718 PCI patients with an ejection fraction ≤ 35% and 2- or 3-vessel disease. Inverse probability weighting was used for risk adjustment. The primary end point was all-cause mortality. Secondary end points included rates of 30-day mortality, stroke, acute kidney injury, and incidence of repeat revascularization.

Results: The median duration of follow-up was 4.3 years (range, 1.59-6.71 years). CABG was associated with improved long-term survival compared with PCI after risk adjustment (hazard ratio, 0.59; 95% confidence interval, 0.50-0.71; P < .01). Although CABG and PCI had similar 30-day mortality rates (P = .14), CABG was associated with a higher frequency of stroke (P < .001) and acute kidney injury (P < .001), whereas PCI was associated with a higher incidence of repeat revascularization (P < .001).

Conclusions: Among patients with reduced ejection fraction and multivessel disease, CABG was associated with improved long-term survival compared with PCI. CABG should be strongly considered in patients with ischemic cardiomyopathy and multivessel coronary disease.
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http://dx.doi.org/10.1016/j.jtcvs.2018.04.121DOI Listing
October 2018

ErbB2 promotes endothelial phenotype of human left ventricular epicardial highly proliferative cells (eHiPC).

J Mol Cell Cardiol 2018 02 29;115:39-50. Epub 2017 Dec 29.

Maine Medical Center Research Institute, Scarborough, ME, United States; Maine Medical Center, Portland, ME, United States. Electronic address:

The adult human heart contains a subpopulation of highly proliferative cells. The role of ErbB receptors in these cells has not been studied. From human left ventricular (LV) epicardial biopsies, we isolated highly proliferative cells (eHiPC) to characterize the cell surface expression and function of ErbB receptors in the regulation of cell proliferation and phenotype. We found that human LV eHiPC express all four ErbB receptor subtypes. However, the expression of ErbB receptors varied widely among eHiPC isolated from different subjects. eHiPC with higher cell surface expression of ErbB2 reproduced the phenotype of endothelial cells and were characterized by endothelial cell-like functional properties. We also found that EGF/ErbB1 induces VEGFR2 expression, while ligands for both ErbB1 and ErbB3/4 induce expression of Tie2. The number of CD31CD45 endothelial cells is higher in LV biopsies from subjects with high ErbB2 (ErbB2) eHiPC compared to low ErbB2 (ErbB2) eHiPC. These findings have important implications for potential strategies to increase the efficacy of cell-based revascularization of the injured heart, through promotion of an endothelial phenotype in cardiac highly proliferative cells.
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http://dx.doi.org/10.1016/j.yjmcc.2017.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926239PMC
February 2018

The most important lessons I learned in training.

Authors:
Michael P Robich

J Thorac Cardiovasc Surg 2017 09 23;154(3):1015-1016. Epub 2017 Apr 23.

Cardiovascular Institute, Maine Medical Center, Portland, Me. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2017.04.027DOI Listing
September 2017

Analysis of "never events" following adult cardiac surgical procedures in the United States.

J Cardiovasc Surg (Torino) 2017 Oct 16;58(5):755-762. Epub 2017 Mar 16.

Department of Surgery Boston University, School of Medicine, Boston, MA, USA -

Background: This study was conducted to determine the risk factors, nature, and outcomes of "never events" following open adult cardiac surgical procedures. Understanding of these events can reduce their occurrence, and thereby improve patient care, quality metrics, and cost reduction.

Methods: "Never events" for patients included in the Nationwide Inpatient Sample who underwent coronary artery bypass graft, heart valve repair/replacement, or thoracic aneurysm repair between 2003-2011 were documented. These events included air embolism, catheter-based urinary tract infection (UTI), pressure ulcer, falls/trauma, blood incompatibility, vascular catheter infection, poor glucose control, foreign object retention, wrong site surgery and mediastinitis. Analysis included characterization of preoperative demographics, comorbidities and outcomes for patients sustaining never events, and multivariate analysis of predictive risk factors and outcomes.

Results: A total of 588,417 patients meeting inclusion criteria were identified. Of these, never events occurred in 4377 cases. The majority of events were in-hospital falls, vascular catheter infections, and complications of poor glucose control. Rates of falls, catheter based UTIs, and glucose control complications increased between 2009-2011 as compared to 2003-2008. Analysis revealed increased hospital length of stay, hospital charges, and mortality in patients who suffered a never event as compared to those that did not.

Conclusions: This study establishes a baseline never event rate after cardiac surgery. Adverse patient outcomes and increased resource utilization resulting from never events emphasizes the need for quality improvement surrounding them. A better understanding of individual patient characteristics for those at risk can help in developing protocols to decrease occurrence rates.
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http://dx.doi.org/10.23736/S0021-9509.17.09866-4DOI Listing
October 2017

Glycogen Synthase Kinase 3β Inhibition Improves Myocardial Angiogenesis and Perfusion in a Swine Model of Metabolic Syndrome.

J Am Heart Assoc 2016 07 12;5(7). Epub 2016 Jul 12.

Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI

Background: Inhibition of glycogen synthase kinase 3β (GSK-3β) has been reported to be cardioprotective during stressful conditions.

Methods And Results: Pigs were fed a high-fat diet for 4 weeks to develop metabolic syndrome, then underwent placement of an ameroid constrictor to their left circumflex artery to induce chronic myocardial ischemia. Two weeks later, animals received either: no drug (high cholesterol control group [HCC]) or a GSK-3β inhibitor (GSK-3β inhibited group [GSK-3βI]), which were continued for 5 weeks, followed by myocardial tissue harvest. Coronary blood flow and vessel density were significantly increased in the GSK-3βI group compared to the HCC group. Expression levels of the following proteins were greater in the GSK-3βI group compared to the HCC group: vascular endothelial growth factor receptor 1 , vascular endothelial cadherin, γ-catenin, β-catenin, protein kinase B, phosphorylated forkhead box O1, and superoxide dismutase 2.

Conclusions: In the setting of metabolic syndrome, inhibition of GSK-3β increases blood flow and vessel density in chronically ischemic myocardium. We identified several angiogenic, cell survival, and differentiation pathways that include β-catenin signaling and AKT/FOXO1, through which GSK-3β appears to improve vessel density and blood flow. These results may provide a potential mechanism for medical therapy of patients suffering from coronary artery disease and metabolic syndrome.
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http://dx.doi.org/10.1161/JAHA.116.003694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015402PMC
July 2016

Risk Factors and Outcomes of Patients Requiring a Permanent Pacemaker After Aortic Valve Replacement in the United States.

J Card Surg 2016 Aug 22;31(8):476-85. Epub 2016 Jun 22.

Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.

Introduction: The need for permanent pacemaker implantation (PCM) following surgical aortic valve replacement (SAVR) is uncommon but can lead to increased hospital resource utilization. Using nationwide data, we sought to (1) identify hospital, patient, and procedure-level risk factors for PCM after SAVR and (2) determine incremental resource utilization.

Methods: We identified 659,692 patients from the Nationwide Inpatient Sample database who underwent SAVR with or without coronary artery bypass grafting (CABG), mitral valvuloplasty (MVr), or mitral valve replacement (MVR) between 1998 and 2009. Patients with pre-existing pacemakers, a concomitant Maze procedure, or endocarditis were excluded. Multivariable regression analysis and propensity matching were used for comparisons of outcomes and costs.

Results: Overall prevalence of PCM was 5.1% (n = 34,020; SAVR alone, 4.8%; SAVR + CABG, 4.6%; SAVR + MVr, 7.7%; SAVR + MVR, 10%). Important risk factors for PCM after SAVR were coexisting comorbidities, older age, and addition of mitral valve surgery. Hospital volume and teaching status, location, race, and sex were not associated with PCM. Among matched pairs, patients requiring PCM had lower in-hospital mortality (3.1% vs. 6.4%, p < 0.001) but longer median length of stay (12 vs. 9 days, p < 0.001) and higher hospital costs ($50,000 vs. $37,000, p < 0.001), and they were less likely to be discharged home (33% vs. 36%, p < 0.001). Factors associated with later PCM (postoperative day ≥6) included SAVR + MVR, female sex, fewer comorbidities, northeastern region, and higher hospital volume. Median hospital costs were greater ($57,000 vs. $48,000, p < 0.001) among patients whose pacemakers were implanted later.

Conclusions: PCM following SAVR is associated with lower hospital mortality, but increased cost and length of stay. doi: 10.1111/jocs.12769 (J Card Surg 2016;31:476-485).
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http://dx.doi.org/10.1111/jocs.12769DOI Listing
August 2016

Gender and Cardiothoracic Surgery Training: Specialty Interests, Satisfaction, and Career Pathways.

Ann Thorac Surg 2016 Jul 5;102(1):200-6. Epub 2016 May 5.

Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address:

Background: The cardiothoracic surgical workforce is changing. Although 5% of practicing surgeons are women, 20% of current cardiothoracic surgery residents are women. The purpose of this study was to evaluate the influence of gender on specialty interest, satisfaction, and career pathways of current residents.

Methods: Responses to the mandatory 2015 Thoracic Surgery Residents Association/Thoracic Surgery Directors Association in-training examination survey taken by 354 residents (100% response rate) were evaluated. The influence of gender was assessed with the use of standard univariate analyses.

Results: Women accounted for 20% of residents, and the percentage did not vary with postgraduate year or program type (traditional versus integrated). Although no differences were found between the genders related to specialty interest, academic versus private practice career, or pursuit of additional training, women were more likely to pursue additional training in minimally invasive thoracic surgery (10% versus 2.5%, p = 0.001) and less likely to perform research in their careers (65% versus 88%, p = 0.043). Although women were equally satisfied with their career choice, had similar numbers of interviews and job offers, and felt equally prepared for their boards, graduating women felt less prepared technically (77% versus 90%, p = 0.01) and for practicing independently (71% versus 87%, p = 0.01). Women were less likely to be married (26% versus 62%, p < 0.001) and have children (19% versus 49%, p < 0.001).

Conclusions: Although career satisfaction and specialty interest were similar between the genders, women were less likely to intend to perform research during their careers despite similar previous research experience. Women also demonstrated lower rates of marriage and childbearing compared with their male counterparts.
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http://dx.doi.org/10.1016/j.athoracsur.2016.03.043DOI Listing
July 2016

The Future of the Academic Cardiothoracic Surgeon: Results of the TSRA/TSDA In-Training Examination Survey.

Ann Thorac Surg 2016 Aug 27;102(2):643-50. Epub 2016 Apr 27.

Division of Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Background: Traditionally cardiothoracic residents spent dedicated research time during general surgery equipping them for a potential academic career. Recent changes in training paradigms, including integrated programs that may not include research time, could affect the development of future academic cardiothoracic surgeons.

Methods: Responses to the 2015 Thoracic Surgery Directors' Association/Thoracic Surgery Residents' Association survey accompanying the in-training examination taken by current cardiothoracic surgery residents were analyzed. Three hundred fifty-four residents were surveyed with a response rate of 100%, although one was excluded from the analysis because of inconsistencies in responses. Statistical analysis included χ(2), Fisher's exact test, and multinomial logistic regression with significance set at a probability value of 0.05.

Results: Two hundred sixty-seven of 353 residents (76%) intended on performing research as part of their careers. Integrated residents as opposed to traditional residents (85% versus 69%; p = 0.003), males (78% versus 65%; p = 0.02), those pursuing additional training (85% versus 69%; p = 0.003), and those interested in academic careers (93% versus 33%; p < 0.001) were more likely to pursue research. Differences were also noted in specialty interest, with congenital and heart failure specialties most likely to pursue research careers (92% and 100%, respectively; p < 0.05). Residents intending on research careers were more likely to have had previous research experience, and the most common type of intended research was clinical outcomes (78%). On multinomial logistic regression, previous clinical outcomes research and academic practice were identified as predictors of a research career (odd ratios of 9.7 and 4.1, respectively; each p < 0.05).

Conclusions: The majority of residents plan on pursuing research during their careers. Previous research experience appears to be a key determinant as well as specialty interest.
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http://dx.doi.org/10.1016/j.athoracsur.2016.01.106DOI Listing
August 2016

Development and Evaluation of a Three-Dimensional Multistation Cardiovascular Simulator.

Ann Thorac Surg 2016 Jul 26;102(1):62-8. Epub 2016 Mar 26.

Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.

Background: To facilitate deliberate practice, we developed and evaluated a three-dimensional multistation cardiovascular simulator with low-fidelity, anatomically correct materials.

Methods: Surgical educators and senior fellows at several national institutions who are a part of the Thoracic Education Cooperative Group completed expert validation surveys that feature a self-report rating scale, ranging from 0 (don't know) to 4 (highly realistic, no changes needed), and a global recommendation rating scale, ranging from 0 to 3. To analyze the survey results, we used paired Student t tests and a many-facet Rasch model.

Results: We analyzed the results of 18 expert validation surveys (completed by 9 senior fellows and by 9 staff surgeons). The overall realism-of-experience rating for the simulator was 3.23 (of 4), suggesting adequate realism with room remaining for improvement. Senior fellows rated the aortic graft replacement station and overall physical attributes more favorably than staff. Staff surgeons favored the simulator for realism of the mitral valve annuloplasty station and the cannulation station and for its use as a training tool. The overall global recommendation rating for the simulator was 2.38 (of 3), suggesting that the simulator can be considered for use in cardiovascular surgery training programs with minor improvements.

Conclusions: This three-dimensional multistation cardiovascular simulator has adequate realism and can be considered for use in cardiovascular training programs. Platforms such as this may facilitate deliberate home practice and reinforcement of technical skills.
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http://dx.doi.org/10.1016/j.athoracsur.2015.12.070DOI Listing
July 2016

Two Cases of Late Shone Syndrome With Pulmonary Hypertension: Heart-Lung Transplant or Valve Surgery?

World J Pediatr Congenit Heart Surg 2016 Jan;7(1):100-3

Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

Two cases of Shone syndrome with severe mitral and aortic valve problems and pulmonary hypertension were referred for heart-lung transplantation. Severely elevated pulmonary vascular resistance (PVR) was confirmed as was severe periprosthetic mitral and aortic regurgitation. Based on the severity of the valve lesions in both patients, surgery was decided upon and undertaken. Both experienced early pulmonary hypertensive crises, one more than the other, that gradually subsided, followed by excellent recovery and reversal of pulmonary hypertension and PVR. These cases illustrate Braunwald's concept that pulmonary hypertension secondary to left-sided valve disease is reversible.
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http://dx.doi.org/10.1177/2150135115577671DOI Listing
January 2016

Understanding Why Residents May Inaccurately Log Their Role in Operations: A Look at the 2013 In-Training Examination Survey.

Ann Thorac Surg 2016 Jan 9;101(1):323-8. Epub 2015 Oct 9.

Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Background: With increased time and quality pressures, it may be more difficult for residents in cardiothoracic surgery residency programs to get independent operative experience. That may lead residents to inaccurately report their role as "surgeon" to meet American Board of Thoracic Surgery (ABTS) case requirements.

Methods: The 2013 In-Training Examination surveyed 312 cardiothoracic surgery residents and was used to contrast residents in traditional 2-year and 3-year cardiothoracic surgery residencies (traditional, n = 216) with those in 6-year integrated or 3+4-year programs (integrated, n = 96).

Results: Traditional program residents reported a higher percentage of cases that met the ABTS criteria of surgeon than did integrated program residents (p = 0.05) but were less likely to meet requirements if all cases were logged accurately (p = 0.03). The majority of residents in each program believed that their case log accurately reflected their experience as "surgeon." Residents who tended to log cases incorrectly had lower self-reported 2012 In-Training Examination percentiles, were less likely to meet case requirements if logged properly, and felt less prepared for board examinations and eventual practice compared with residents who logged cases correctly (all p < 0.001). Residents who believed they would not meet case requirements if logged correctly cited limited surgical opportunities, poor case diversity, and a compromised training environment but not the 80-hour work week, excessive simulation, or disproportionate number of complex cases as causes.

Conclusions: Overall cardiothoracic surgery residents appear to be satisfied with their training. There were specific subsets of trainees in both traditional and Integrated programs that are misrepresenting their role on cases because they otherwise may not meet the requirements.
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http://dx.doi.org/10.1016/j.athoracsur.2015.07.047DOI Listing
January 2016

A Decade of Change: Training and Career Paths of Cardiothoracic Surgery Residents 2003 to 2014.

Ann Thorac Surg 2015 Oct 11;100(4):1305-13; discussion 1313-4. Epub 2015 Jul 11.

Department of Cardiothoracic and Vascular Surgery, University of Texas Memorial Hermann-Texas Medical Center, Houston, Texas. Electronic address:

Background: During the past decade, cardiothoracic surgery (CTS) education has undergone tremendous change with the advent of new technologies and the implementation of integrated programs, to name a few. The goal of this study was to assess how residents' career paths, training, and perceptions changed during this period.

Methods: The 2006 to 2014 surveys accompanying the Thoracic Surgery Residents Association/Thoracic Surgery Directors' Association in-training examination taken by CTS residents were analyzed, along with a 2003 survey of graduating CTS residents. Of 2,563 residents surveyed, 2,434 (95%) responded.

Results: During the decade, fewer residents were interested in mixed adult cardiac/thoracic practice (20% in 2014 vs 52% in 2003, p = 0.004), more planned on additional training (10% in 2003 vs 41% to 47% from 2011 to 2014), and the frequent use of simulation increased from 1% in 2009 to 24% in 2012 (p < 0.001). More residents recommended CTS to potential trainees (79% in 2014 vs 65% in 2010, p = 0.007). Job offers increased from a low of 12% in 2008 with three or more offers to 34% in 2014. Debt increased from 0% with more than $200,000 in 2003 to 40% in 2013 (p < 0.001). Compared with residents in traditional programs, more integrated residents in 2014 were interested in adult cardiac surgery (53% vs 31%) and congenital surgery (22% vs 7%), fewer were interested in general thoracic surgery (5% vs 31%, p < 0.001), and more planned on additional training (66% vs 36%, p < 0.001).

Conclusions: With the evolution in CTS over the last decade, residents' training and career paths have changed substantially, with increased specialization and simulation accompanied by increased resident satisfaction and an improved job market.
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http://dx.doi.org/10.1016/j.athoracsur.2015.04.026DOI Listing
October 2015

Predictors of Career Choice Among Cardiothoracic Surgery Trainees.

Ann Thorac Surg 2015 Nov 7;100(5):1849-54; discussion 1853. Epub 2015 Jul 7.

Memorial Hermann Hospital-Heart and Vascular Institute, University of Texas Medical School at Houston, Houston, Texas. Electronic address:

Background: The impact of factors influencing career choice by cardiothoracic surgery (CTS) trainees remains poorly defined in the modern era. We sought to examine the associations between CTS trainee characteristics and future career aspirations.

Methods: The 2012 Thoracic Surgery In-Training Examination survey results were used to categorize responders according to career interest: congenital, adult cardiac, mixed cardiac/thoracic, and general thoracic surgery. Univariate and multivariable analyses were used to identify and analyze characteristics associated with career interest categories.

Results: With a 100% response rate, 300 responses from trainees in programs accredited by the Accreditation Council for Graduate Medical Education were included in the analysis. Multinomial logistic regression identified three factors associated with career choice in CTS: level of training (p < 0.001), type of training pathway (p < 0.001), and primary motivating factor to pursue CTS (p = 0.002). Trainees interested in general thoracic surgery were more likely to commit to CTS during their senior years of general surgery training and were more likely to enroll in 2-year or 3-year traditional fellowships, whereas individuals pursuing adult or congenital cardiac surgery were more likely to commit earlier during training and were more commonly interested in 6-year integrated or joint training pathways. Moreover, trainees interested in general thoracic surgery were predominantly influenced by early mentorship (p = 0.025 vs adult cardiac), and trainees interested in adult cardiac surgery were more likely to be influenced by types of operations (p = 0.047 vs general thoracic).

Conclusions: Career choice in CTS appears strongly associated with level of training, exposure to mentors, and training paradigm. These results demonstrate the importance of maintaining all four currently approved training pathways to retain balance and diversity in future CTS practices.
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http://dx.doi.org/10.1016/j.athoracsur.2015.04.073DOI Listing
November 2015

Prolonged effect of postoperative infectious complications on survival after cardiac surgery.

Ann Thorac Surg 2015 May 14;99(5):1591-9. Epub 2015 Feb 14.

Department of Cardiothoracic Anesthesia, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Background: Whether patients having infections after cardiac surgery are at a survival disadvantage after hospital discharge is unclear. Our objectives were (1) to identify characteristics of such patients and (2) to determine whether this complication is associated with increased mortality beyond hospital discharge.

Methods: In all, 30,414 patients were discharged after isolated coronary artery bypass grafting, valve, ascending aorta repair, or combined procedures from January 2000 to January 2011. Surgical site infection, septicemia, pneumonia, and urinary tract infection occurred in 1,868 patients (6.1%). Propensity matching was used to account for differences in perioperative characteristics and postoperative in-hospital events between these patients and those not having postoperative infections, to give 1,593 propensity-matched pairs. Time-related mortality and instantaneous risk were compared.

Results: Surgical site infection occurred in 122 patients (0.40%), sternal wound infection in 263 (0.86%), septicemia in 656 (2.2%), urinary tract infection in 853 (2.8%), and pneumonia in 513 (1.7%). Infections were associated with older age, female sex, larger body mass index, and multiple comorbidities. Among 1,593 propensity-matched pairs, postdischarge survival at 6 months and at 1, 5, and 10 years, respectively, was 89%, 86%, 67%, and 45% for patients without infections, and 86%, 83%, 63%, and 43% (p = 0.008) for patients with infections. Survival differences resulted from a higher, but gradually declining, early instantaneous risk during the first year after surgery. Elevated risk was of shorter duration for surgical site infections than for other infections.

Conclusions: Postoperative infection is associated with a high-risk patient profile, and risk of death is elevated early after hospital discharge. Reasons for this prolonged effect are unclear.
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http://dx.doi.org/10.1016/j.athoracsur.2014.12.037DOI Listing
May 2015

del Nido versus Buckberg cardioplegia in adult isolated valve surgery.

J Thorac Cardiovasc Surg 2015 Feb 22;149(2):626-634; discussion 634-6. Epub 2014 Oct 22.

Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.

Background: del Nido solution is a non-glucose-based, single-dose cardioplegic solution with few data supporting its safety in adults. We hypothesized that it and Buckberg solution offer myocardial protection of equivalent safety for isolated adult valve surgery.

Methods: Adult patients undergoing primary isolated aortic or mitral valve surgery with del Nido or Buckberg solution from January 2010 to September 2013 were 1:1 propensity matched (85 aortic valve, 110 mitral valve), and outcomes were compared.

Results: After aortic valve operations, no hospital deaths occurred, and troponin T levels (median 0.19 ng · mL(-1) for del Nido vs 0.21 ng · mL(-1) for Buckberg) were similar, with no statistically significant change in left ventricular ejection fraction (P = .4). Aortic clamp, bypass, and operating room times were shorter with del Nido solution (44 ± 14 vs 56 ± 19; 56 ± 18 vs 70 ± 24; and 285 ± 44 vs 308 ± 61 minutes, respectively; P < .0001). Peak intraoperative glucose levels (170 ± 31 vs 240 ± 41 mg · dL(-1); P < .0001) and postoperative insulin-drip requirements (46% vs 82%; P < .0001) were lower. After mitral operations, there were no hospital deaths and no statistically significant cardioplegia-specific changes in troponin T levels (median 0.37 ng · mL(-1) for del Nido vs 0.4 ng · mL(-1) for Buckberg) or postoperative left ventricular ejection fraction (P = .13). We found no clear time differences with del Nido solution in mitral cases, but intraoperative glucose levels and postoperative insulin-drip requirements (184 ± 37 vs 250 ± 60 mg · dL(-1) and 50% vs 67% mg · dL(-1), respectively; P = .009) were lower.

Conclusions: del Nido solution can be used safely and effectively as an alternative to Buckberg solution in adult isolated valve surgery and is associated with lower insulin requirements and potential time and cost savings.
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http://dx.doi.org/10.1016/j.jtcvs.2014.10.085DOI Listing
February 2015

Trends in blood utilization in United States cardiac surgical patients.

Transfusion 2015 Apr 2;55(4):805-14. Epub 2014 Nov 2.

Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.

Background: We sought to determine whether publication of blood conservation guidelines by the Society of Thoracic Surgeons in 2007 influenced transfusion rates and to understand how patient- and hospital-level factors influenced blood product usage.

Study Design And Methods: We identified 4,465,016 patients in the Nationwide Inpatient Sample database who underwent cardiac operations between 1999 and 2010 (3,202,404 before the guidelines and 1,262,612 after). Hierarchical linear modeling was used to account for hospital- and patient-level clustering.

Results: Transfusion rates of blood products increased from 13% in 1999 to a peak of 34% in 2010. Use of all blood components increased over the study period. Aortic aneurysm repair had the highest transfusion rate with 54% of patients receiving products in 2010. In coronary artery bypass grafting, the number of patients receiving blood products increased from 12% in 1999 to 32% in 2010. Patients undergoing valvular operations had a transfusion rate of 15% in 1999, increasing to 36% in 2010. Patients undergoing combined operations had an increase from 13% to 40% over 11 years. Risk factors for transfusion were anemia (odds ratio [OR], 2.05; 95% confidence interval [CI], 2.01-2.09), coagulopathy (OR, 1.54; 95% CI, 1.51-1.57), diabetes (OR, 1.32; 95% CI, 1.28-1.36), renal failure (OR, 1.29; 95% CI, 1.26-1.32), and liver disease (OR, 1.23; 95% CI, 1.16-1.31). Compared to the Northeast, the risk for transfusion was significantly lower in the Midwest; higher-volume hospitals used fewer blood products than lower-volume centers. Cell salvage usage remained below 5% across all years.

Conclusion: Independent of patient- and hospital-level factors, blood product utilization continues to increase for all cardiac operations despite publication of blood conservation guidelines in 2007.
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http://dx.doi.org/10.1111/trf.12903DOI Listing
April 2015

Outcomes of patients with human immunodeficiency virus infection undergoing cardiovascular surgery in the United States.

J Thorac Cardiovasc Surg 2014 Dec 4;148(6):3066-73. Epub 2014 Aug 4.

Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Introduction: Advances in highly active antiretroviral therapy have dramatically improved the lifespan of patients infected with human immunodeficiency virus (HIV). We sought to examine the impact of HIV status on outcomes in patients undergoing cardiovascular surgery.

Methods: We identified 5,621,817 patients who underwent coronary artery bypass graft (CABG), valve, aortic, or other cardiovascular surgery between 1998 and 2009 from the Nationwide Inpatient Sample. Of these, 9771 (0.17%) patients were seropositive for HIV. Using multivariable logistic regression modeling and 1:1 propensity-score matching, we determined the influence of HIV infection on outcomes.

Results: The percentage of HIV+ patients undergoing cardiovascular surgery increased significantly from 0.09% to 0.23%. HIV+ patients were more often male, black, younger than 55 years of age, and on Medicaid, and they were more likely to undergo valve and other cardiovascular surgeries, but less likely to have CABG. Among propensity-matched pairs, patients with HIV were at no increased risk for in-patient mortality. HIV+ patients were more likely to receive a blood transfusion and have any postoperative complication. Patients with HIV were less likely to have a postoperative stroke. Rates of pneumonia, renal complications, and wound infection were similar between the groups. The median length of stay and mean total cost were not different between the groups. Factors that predicted in-hospital death in HIV+ patients included metastatic cancer, coagulopathy, renal failure, and aortic, other, or combined surgical procedure.

Conclusions: Cardiovascular surgery can be performed safely on patients with HIV with no increased hospital mortality and only minimal increased need for blood transfusion.
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http://dx.doi.org/10.1016/j.jtcvs.2014.07.074DOI Listing
December 2014

Investigating the effects of resveratrol on chronically ischemic myocardium in a swine model of metabolic syndrome: a proteomics analysis.

J Med Food 2015 Jan;18(1):60-6

Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University , Providence, Rhode Island, USA .

Resveratrol has been shown to improve cardiac perfusion and ventricular function after chronic ischemic injury. Using proteomic analysis, we sought to objectively investigate potential mechanisms, by which resveratrol exerts its cardioprotective effects in the setting of metabolic syndrome and chronic myocardial ischemia. Yorkshire swine were divided into two groups based on diet: high cholesterol (n=7) or a high-cholesterol diet with supplemental resveratrol (n=6). Four weeks later, all animals underwent surgical placement of an ameroid constrictor to their left circumflex artery. Diets were continued for another 7 weeks, and then the ischemic myocardium was harvested for proteomics analysis. Proteomic analysis identified 669 common proteins between the two groups. Of these proteins, 76 were statistically different, of which 41 were characterized (P<.05). Pathway analysis demonstrated that in animals supplemented with resveratrol, there was a downregulation in several proteins involved with mitochondrial dysfunction, cell death, and unfavorable cardiac remodeling. Furthermore, there was an upregulation in proteins involved in free radical elimination. We conclude that resveratrol supplementation significantly alters several critical protein markers in the chronically ischemic myocardium. Further investigation of these proteins may help elucidate the mechanisms by which resveratrol exerts its cardioprotective effects.
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http://dx.doi.org/10.1089/jmf.2014.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281852PMC
January 2015

Improved biocompatibility of poly(lactic-co-glycolic acid) orv and poly-L-lactic acid blended with nanoparticulate amorphous calcium phosphate in vascular stent applications.

J Biomed Nanotechnol 2014 Jun;10(6):900-10

Biodegradable polymers used as vascular stent coatings and stent platforms encounter a major challenge: biocompatibility in vivo, which plays an important role in in-stent restenosis (ISR). Co-formulating amorphous calcium phosphate (ACP) into poly(lactic-co-glycolic acid) (PLGA) or poly-L-lactic acid (PLLA) was investigated to address the issue. For stent coating applications, metal stents were coated with polyethylene-co-vinyl acetate/poly-n-butyl methacrylate (PEVA/PBMA), PLGA or PLGA/ACP composites, and implanted into rat aortas for one and three months. Comparing with both PEVA/PBMA and PLGA groups after one month, the results showed that stents coated with PLGA/ACP had significantly reduced restenosis (PLGA/ACP vs. PEVA/PBMA vs. PLGA: 21.24 +/- 2.59% vs. 27.54 +/- 1.19% vs. 32.12 +/- 3.93%, P < 0.05), reduced inflammation (1.25 +/- 0.35 vs. 1.77 +/- 0.38 vs. 2.30 +/- 0.21, P < 0.05) and increased speed of re-endothelialization (1.78 +/- 0.46 vs. 1.17 +/- 0.18 vs. 1.20 +/- 0.18, P < 0.05). After three months, the PLGA/ACP group still displayed lower inflammation score (1.33 +/- 0.33 vs. 2.27 +/- 0.55, P < 0.05) and higher endothelial scores (2.33 +/- 0.33 vs. 1.20 +/- 0.18, P < 0.05) as compared with the PEVA/PBMA group. Moreover, for stent platform applications, PLLA/ACP stent tube significantly reduced the inflammatory cells infiltration in the vessel walls of rabbit iliac arteries relative to their PLLA cohort (NF-kappaB-positive cells: 23.31 +/- 2.33/mm2 vs. 9.34 +/- 1.35/mm2, P < 0.05). No systemic biochemical or pathological evidence of toxicity was found in either PLGA/ACP or PLLA/ACP. The co-formulation of ACP into PLGA and PLLA resulted in improved biocompatibility without systemic toxicity.
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http://dx.doi.org/10.1166/jbn.2014.1856DOI Listing
June 2014

Microvascular notch signaling is upregulated in response to vascular endothelial growth factor and chronic myocardial ischemia.

Circ J 2014 21;78(3):743-51. Epub 2013 Dec 21.

Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert Medical School of Brown University.

Background:  Notch signaling is a highly conserved pathway that promotes vascular and myocardial growth. The hypothesis that exogenous vascular endothelial growth factor (VEGF) administration to ischemic myocardium would enhance the neovascular response and upregulate Notch signaling was assessed.

Methods And Results:  Fourteen male Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery to induce chronic myocardial ischemia with half of the animals receiving perivascular VEGF to the ischemic area. The remote territory served as the normal ventricle control (NV), while the 2 experimental groups consisted of the area at risk of the non-VEGF animals (AAR) and the area at risk of animals treated with VEGF (VEGF). Capillary and arteriolar density was significantly increased in the VEGF group as compared to both NV and AAR. Expression of Notch receptors and pro-neovascular Notch ligands was significantly higher in the VEGF group. Both Jagged 1 and Notch 3 were the most highly concentrated in the smooth muscle wall of arterioles.

Conclusions:  VEGF administration to chronically ischemic myocardium significantly augmented the neovascular response by an increase in both capillary and arteriolar density, and resulted in an upregulation of several Notch receptors and ligands, which were not upregulated with ischemia alone. These findings suggest that the augmented neovascular response seen with VEGF administration was through the VEGF-induced upregulation of Notch signaling.  
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http://dx.doi.org/10.1253/circj.cj-13-0685DOI Listing
December 2014

Resveratrol regulates autophagy signaling in chronically ischemic myocardium.

J Thorac Cardiovasc Surg 2014 Feb 20;147(2):792-8; Discussion 798-9. Epub 2013 Nov 20.

Division of Cardiothoracic Surgery, Cardiovascular Research Center, Brown University Warren Alpert School of Medicine, Providence, RI. Electronic address:

Objective: Autophagy is a cellular process by which damaged components are removed. Although autophagy can result in cell death, when optimally regulated, it might be cardioprotective. Resveratrol is a naturally occurring polyphenol also believed to be cardioprotective. Using a clinically relevant swine model of metabolic syndrome, we investigated the effects of resveratrol on autophagy in the chronically ischemic myocardium.

Methods: Yorkshire swine were fed a regular diet (n = 7), a high cholesterol diet (n = 7), or a high cholesterol diet with supplemental resveratrol (n = 6). After 4 weeks, an ameroid constrictor was surgically placed on the left circumflex artery to induce chronic myocardial ischemia. The diets were continued another 7 weeks, and then the ischemic and nonischemic myocardium were harvested for protein analysis.

Results: In the ischemic myocardium, a high cholesterol diet partly attenuated the autophagy, as determined by an increase in phosphorylated mammalian target of rapamycin (p-mTOR) and a decrease in p70 S6 kinase (P70S6K), lysosome-associated membrane protein (LAMP)-2, and autophagy-related gene 12-5 conjugate (ATG 12-5; P < .05). The addition of resveratrol blunted many of these changes, because the p-mTOR, P70S6K, and LAMP-2 levels were not significantly altered from those of the pigs fed a regular diet. Other autophagy markers were increased with a high cholesterol diet, including light chain 3A-II and beclin 1 (P < .05). In the nonischemic myocardium, beclin 1 was decreased in the high cholesterol-fed pigs (P < .05); otherwise no significant changes in protein expression were noted among the 3 groups.

Conclusions: In the chronically ischemic myocardium, resveratrol partly reversed the effects of a high cholesterol diet on autophagy. This might be a mechanism by which resveratrol exerts its cardioprotective effects.
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http://dx.doi.org/10.1016/j.jtcvs.2013.06.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947125PMC
February 2014

Local infiltration of neuropeptide Y as a potential therapeutic agent against apoptosis and fibrosis in a swine model of hypercholesterolemia and chronic myocardial ischemia.

Eur J Pharmacol 2013 Oct 17;718(1-3):261-70. Epub 2013 Sep 17.

Beth Israel Deaconess Medical Center, Department of Anesthesia and Critical Care, CC-454, 1 Deaconess Road, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address:

While the angiogenic effects of Neuropeptide Y (NPY) in myocardial ischemia and hypercholesterolemia have been studied, its effects on altering oxidative stress, fibrosis and cell death are not known. We hypothesized that local infiltration of NPY in a swine model of chronic myocardial ischemia and hypercholesterolemia will induce nerve growth and cell survival, while reducing oxidative stress and fibrosis. Yorkshire mini-swine (n=15) were fed a high cholesterol diet for 5 weeks. Three weeks after surgical induction of focal myocardial ischemia, an osmotic pump was implanted, which delivered NPY (n=8, high cholesterol treated, HCT) or the vehicle (n=7, high cholesterol control, HCC) for 5 weeks. Then myocardium was harvested for analysis. Assessment of myocardial function and perfusion was made the last intervention. Immunoblotting demonstrated significantly decreased levels of MMP-9 (p=0.001) and TGF-β (p=0.05) and significantly increased levels of Ang-1 (p=0.002), MnSOD (p=0.006) and NGF (p=0.01) in HCT. Immunohistochemistry results revealed significantly decreased TUNEL staining (p=0.005) and GLUT4 translocation (p=0.004) in HCT. The functional data showed significantly improved blood flow reserve (p=0.02) and improved diastolic function -dP/dt (p=0.009) in the treated animals. Local infiltration of NPY results in positive remodeling in ischemic myocardium in the setting of hypercholesterolemia. By initiating angio and neurogenesis, NPY infiltration improves blood flow reserve and restoration of fatty acid metabolism. The associated increased cell survival and decreased fibrosis result in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease.
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http://dx.doi.org/10.1016/j.ejphar.2013.08.023DOI Listing
October 2013