Publications by authors named "Cesario Bianchi"

94 Publications

A better treatment for saphenous vein graft disease after coronary artery bypass surgery: Might statins be the answer at the right dose to the right patient at the right time?

J Thorac Cardiovasc Surg 2019 01 19;157(1):162-163. Epub 2018 Jul 19.

Department of Surgery, Faculty of Medical Science, State University of Campinas, Campinas, São Paulo, Brazil.

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http://dx.doi.org/10.1016/j.jtcvs.2018.07.003DOI Listing
January 2019

Working toward an evidence-based cutoff recommendation for myocardial infarction detection after cardiac surgery.

J Thorac Cardiovasc Surg 2018 03;155(3):1055

Faculdade de Medicina, Núcleos de Pesquisa Tecnológica/Biotecnológica, Universidade de Mogi das Cruzes e Clinica Integracta, Mogi das Cruzes, São Paulo, Brazil.

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http://dx.doi.org/10.1016/j.jtcvs.2017.11.050DOI Listing
March 2018

Time to dot the I's and cross the T's of high-sensitivity cardiac troponin.

J Thorac Cardiovasc Surg 2017 09 31;154(3):904-905. Epub 2017 May 31.

Universidade de Mogi das Cruzes and Clinica Integracta, Núcleos de Pesquisa Tecnológica/Biotecnológica, Faculdade de Medicina, Mogi das Cruzes, São Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2017.05.067DOI Listing
September 2017

Another off-label novel oral anticoagulant to HIT cardiac surgery patients.

J Thorac Cardiovasc Surg 2015 Aug 12;150(2):e20-2. Epub 2015 May 12.

Department of Surgery, Faculty of Medical Science, State University of Campinas, Campinas, Brazil.

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http://dx.doi.org/10.1016/j.jtcvs.2015.05.024DOI Listing
August 2015

Atorvastatin regulates apoptosis in chronically ischemic myocardium.

J Card Surg 2015 Feb 16;30(2):218-23. Epub 2014 Dec 16.

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

Background: We previously demonstrated that atorvastatin upregulates proangiogenic proteins and increases arteriolar density in ischemic myocardium. Despite this, there was a lack of collateral-dependent perfusion, possibly related to apoptosis. We utilized a swine model of metabolic syndrome and chronic myocardial ischemia to investigate the effects of atorvastatin on apoptosis.

Materials And Methods: Sixteen Ossabaw miniswine were fed a high-cholesterol diet for 14 weeks then underwent surgical placement of an ameroid constrictor to their circumflex artery inducing chronic ischemia. Eight pigs additionally received supplemental atorvastatin (1.5 mg/kg daily). Myocardium was harvested six months later for western blotting and TUNEL staining.

Results: Animals supplemented with atorvastatin had significant increases in markers associated with apoptosis including p-38, BAX, and caspase 3 (p < 0.05). Atorvastatin supplementation also resulted in significant increases in expression of cell survival proteins Bcl-2 and P-ERK and an overall decrease in apoptosis demonstrated by TUNEL staining (p < 0.05).

Conclusions: Atorvastatin acts on multiple pathways and its effects on angiogenesis remain unclear. Although there is increased expression in several markers of apoptosis, key anti-apoptotic proteins were also upregulated with an overall decrease in apoptosis. Further investigation of these pathways may provide insight into the role of statins on myocardial protection after ischemia.
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http://dx.doi.org/10.1111/jocs.12488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645063PMC
February 2015

Preoperative gene expression may be associated with neurocognitive decline after cardiopulmonary bypass.

J Thorac Cardiovasc Surg 2015 Feb 14;149(2):613-22; discussion 622-3. Epub 2014 Oct 14.

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

Objective: Despite advances in surgical techniques, neurocognitive decline after cardiopulmonary bypass remains a common and serious complication. We have previously demonstrated that patients with neurocognitive decline have unique genetic responses 6 hours after cardiopulmonary bypass when compared with normal patients. We used genomic microarray to objectively investigate whether patients with neurocognitive decline had associated preoperative gene expression profiles and how these profiles changed up to 4 days after surgery.

Methods: Patients undergoing cardiac surgery underwent neurocognitive assessments preoperatively and 4 days after surgery. Skeletal muscle was collected intraoperatively. Whole blood collected before cardiopulmonary bypass, 6 hours after cardiopulmonary bypass, and on postoperative day 4 was hybridized to Affymetrix Gene Chip U133 Plus 2.0 microarrays (Affymetrix Inc, Santa Clara, Calif). Gene expression in patients with neurocognitive decline was compared with gene expression in the normal group using JMP Genomics (SAS Institute Inc, Cary, NC). Only genes that were commonly expressed in the 2 groups with a false discovery rate of 0.05 and a fold change greater than 1.5 were carried forward to pathway analysis using Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, Calif). Microarray gene expression was validated by Green real-time polymerase chain reaction and Western blotting.

Results: Neurocognitive decline developed in 17 of 42 patients. A total of 54,675 common transcripts were identified on microarray in each group across all time points. Preoperatively, there were 140 genes that were significantly altered between the normal and neurocognitive decline groups (P < .05). Pathway analysis demonstrated that preoperatively, patients with neurocognitive decline had increased regulation in genes associated with inflammation, cell death, and neurologic dysfunction. Of note, the number of significantly regulated genes between the 2 groups changed over each time point and decreased from 140 preoperatively to 64 six hours after cardiopulmonary bypass and to 25 four days after surgery. There was no correlation in gene expression between the blood and the skeletal muscle.

Conclusions: Patients in whom neurocognitive decline developed after cardiopulmonary bypass had increased differential gene expression before surgery versus patients in whom neurocognitive decline did not develop. Although significant differences in gene expression also existed postoperatively, these differences gradually decreased over time. Preoperative gene expression may be associated with neurologic injury after cardiopulmonary bypass. Further investigation into these genetic pathways may help predict patient outcome and guide patient selection.
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http://dx.doi.org/10.1016/j.jtcvs.2014.10.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207964PMC
February 2015

Differential effects of atorvastatin on autophagy in ischemic and nonischemic myocardium in Ossabaw swine with metabolic syndrome.

J Thorac Cardiovasc Surg 2014 Dec 13;148(6):3172-8. Epub 2014 Aug 13.

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

Objectives: The perioperative administration of pleomorphic statin drugs has been implicated in improving outcomes after cardiac surgery. Adaptive autophagy is a highly conserved cellular process that allows for the elimination of dysfunctional cell components in response to stress and survival under starving conditions. We sought to investigate the effects of the statin drug atorvastatin on autophagy in ischemic and nonischemic myocardia using a clinically relevant porcine model of metabolic syndrome.

Methods: Male Ossabaw swine were fed a regular diet (n = 8), a high-cholesterol diet (n = 8), or a high-cholesterol diet with supplemental atorvastatin (1.5 mg/kg/d) (n = 8). After 14 weeks, all animals underwent surgical placement of an ameroid constrictor to the circumflex coronary artery to induce chronic ischemia. Nonischemic and ischemic myocardia were harvested 6 months after initiation of the diet and processed for Western blotting.

Results: In the nonischemic myocardium, Western blot results demonstrate that a high cholesterol diet resulted in a statistically significant decrease in autophagy as indicated by an increase in mammalian target of rapamycin and the accumulation of several essential autophagy markers, including Beclin-1, light chain 3B-I, and light chain 3B-II. Atorvastatin supplementation prevented these changes and resulted in an increase in autophagy as indicated by a decrease in autophagy flux marker P62. In the ischemic myocardium, atorvastatin had the opposite effect, with a decrease in autophagy flux as indicated by an increase in p62 and an accumulation of light chain 3B-I, light chain B-II, and lysosome-associated membrane protein 2.

Conclusions: Atorvastatin administration has differential effects on autophagy in ischemic and nonischemic myocardia. In the setting of metabolic syndrome, atorvastatin stimulates autophagy in nonischemic myocardium while partly inhibiting autophagy in ischemic myocardium. The differential regulation on autophagy may, in part, explain the cardioprotective effect of statins in both ischemic and nonischemic myocardia, and these findings may have implications in the setting of cardiac surgery.
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http://dx.doi.org/10.1016/j.jtcvs.2014.07.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250390PMC
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

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

Rapamycin treatment of healthy pigs subjected to acute myocardial ischemia-reperfusion injury attenuates cardiac functions and increases myocardial necrosis.

Ann Thorac Surg 2014 Mar 20;97(3):901-7. Epub 2013 Nov 20.

Rhode Island Hospital Division of Cardiothoracic Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island. Electronic address:

Background: The mammalian target of rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplantation. However, it has other nonimmune functions: in the cardiovascular system, it is a regulator of heart hypertrophy and locally, in coated vascular stents, it inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism, and survival, we hypothesized that inhibiting it with rapamycin before an acute myocardial ischemia-reperfusion injury (IRI) would confer cardioprotection by virtue of slowing down cardiac function and metabolism.

Methods: Yorkshire pigs received either placebo or 4 mg/d rapamycin orally for 7 days before the IRI. All animals underwent median sternotomy, and the mid-left anterior descending coronary artery was occluded for 60 minutes followed by 120 minutes of reperfusion. Left ventricular pressure-volume data were collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively, and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by Western blotting with specific antibodies against mTOR substrates phosphorylating sites.

Results: Rapamycin before treatment impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities.

Conclusions: Acute myocardial IRI, in healthy pigs treated with rapamycin, is associated with decreased cardiac function and higher myocardial necrosis.
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http://dx.doi.org/10.1016/j.athoracsur.2013.09.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943541PMC
March 2014

Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens.

Cell Cycle 2014 12;13(2):315-23. Epub 2013 Nov 12.

Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.

Despite recent advances in medical procedures, cardiovascular disease remains a clinical challenge and the leading cause of mortality in the western world. The condition causes progressive smooth muscle cell (SMC) dedifferentiation, proliferation, and migration that contribute to vascular restenosis. The incidence of disease of the internal mammary artery (IMA), however, is much lower than in nearly all other arteries. The etiology of this IMA disease resistance is not well understood. Here, using paired primary IMA and coronary artery SMCs, serum stimulation, siRNA knockdowns, and verifications in porcine vessels in vivo, we investigate the molecular mechanisms that could account for this increased disease resistance of internal mammary SMCs. We show that the residue-specific phosphorylation profile of the retinoblastoma tumor suppressor protein (Rb) appears to differ significantly between IMA and coronary artery SMCs in cultured human cells. We also report that the differential profile of Rb phosphorylation may follow as a consequence of differences in the content of cyclin-dependent kinase 2 (CDK2) and the CDK4 phosphorylation inhibitor p15. Finally, we present evidence that siRNA-mediated CDK2 knockdown alters the profile of Rb phosphorylation in coronary artery SMCs, as well as the proliferative response of these cells to mitogenic stimulation. The intrinsic functional and protein composition specificity of the SMCs population in the coronary artery may contribute to the increased prevalence of restenosis and atherosclerosis in the coronary arteries as compared with the internal mammary arteries.
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http://dx.doi.org/10.4161/cc.27056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906247PMC
November 2014

Altered apoptosis-related signaling after cardioplegic arrest in patients with uncontrolled type 2 diabetes mellitus.

Circulation 2013 Sep;128(11 Suppl 1):S144-51

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

Background: We investigated the effects of cardioplegic arrest and reperfusion (CP/Rep) on myocardial apoptosis and key apoptotic mediators, such as apoptosis-inducing factor, caspase 3, caspase 8, caspase 9, poly(adenosine diphosphate-ribose) polymerase, B-cell lymphoma 2 (Bcl-2) family proteins, and protein kinase C (PKC), in uncontrolled type 2 diabetic, controlled type 2 diabetic, and nondiabetic patients.

Methods And Results: Right atrial tissue was harvested pre- and post-CP/Rep from uncontrolled type 2 diabetic patients (hemoglobin A1c=9.6 ± 0.25), controlled type 2 diabetic patients (hemoglobin A1c=6.5 ± 0.15), and nondiabetic patients (hemoglobin A1c=5.4 ± 0.12) undergoing coronary artery bypass grafting (n=8/group). Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used for the identification of apoptotic cells. Total and modified apoptosis-inducing factor, Bcl-2 family proteins, phospho-PKC-α, phospho-PKC-β1, and poly(adenosine diphosphate-ribose) polymerase were quantified by immunoblotting or immunohistochemistry. At baseline, the number of apoptotic cells and expression of total apoptosis-inducing factor, Bcl-2, Bak, and Bax in the pre-CP/Rep atrial tissue from uncontrolled type 2 diabetic patients were significantly increased compared with those of nondiabetic or controlled type 2 diabetic patients (P<0.05). After CP/Rep, the amount of apoptotic cells, apoptosis-inducing factor, phospho-Bad, phospho-PKC-α, phospho-PKC-β1, and cleaved poly(adenosine diphosphate-ribose) polymerase in post-CP/Rep atrial tissue were increased in all 3 groups compared with pre-CP/Rep. These increases after CP/Rep were more pronounced in the uncontrolled type 2 diabetic group. In addition, there were significant increases in the expression of cleaved caspase 8 and caspase 9 in the basal and post-CP/Rep atrium of uncontrolled type 2 diabetic group compared with nondiabetic or controlled type 2 diabetic group.

Conclusions: Uncontrolled diabetes mellitus is associated with increases in myocardial apoptosis and expression of key apoptosis mediators at baseline and in the setting of CP/Rep.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815526PMC
September 2013

Oxidative stress improves coronary endothelial function through activation of the pro-survival kinase AMPK.

Aging (Albany NY) 2013 Jul;5(7):515-30

Cardiovascular Research Center, Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, Providence, RI 02903, USA.

Age-associated decline in cardiovascular function is believed to occur from the deleterious effects of reactive oxygen species (ROS). However, failure of recent clinical trials using antioxidants in patients with cardiovascular disease, and the recent findings showing paradoxical role for NADPH oxidase-derived ROS in endothelial function challenge this long-held notion against ROS. Here, we examine the effects of endothelium-specific conditional increase in ROS on coronary endothelial function. We have generated a novel binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) that induces endothelial cell (EC)-specific overexpression of Nox2/gp91 (NADPH oxidase) and 1.8?0.42-fold increase in EC-ROS upon tetracycline withdrawal (Tet-OFF). We examined ROS effects on EC signaling and function. First, we demonstrate that endothelium-dependent coronary vasodilation was significantly improved in Tet-OFF Nox2 compared to Tet-ON (control) littermates. Using EC isolated from mouse heart, we show that endogenous ROS increased eNOS activation and nitric oxide (NO) synthesis through activation of the survival kinase AMPK. Coronary vasodilation in Tet-OFF Nox2 animals was CaMKK?-AMPK-dependent. Finally, we demonstrate that AMPK activation induced autophagy and thus, protected ECs from oxidant-induced cell death. Together, these findings suggest that increased ROS levels, often associated with cardiovascular conditions in advanced age, play a protective role in endothelial homeostasis by inducing AMPK-eNOS axis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765580PMC
http://dx.doi.org/10.18632/aging.100569DOI Listing
July 2013

Altered expression and activation of mitogen-activated protein kinases in diabetic heart during cardioplegic arrest and cardiopulmonary bypass.

Surgery 2013 Sep;154(3):436-43

Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02905, USA.

Background: We investigated whether mitogen-activated protein kinases (MAPKs) are changed in the hearts of patients with diabetes after cardioplegia and cardiopulmonary bypass (CP/CPB) operations.

Methods: Biopsies from the right atrial appendage were harvested pre- and post-CP/CPB from nondiabetic (ND) patients (n = 8, hemoglobin A1c (HbA1c) = 5.4 ± 0.12); patients with controlled diabetes (CDM) (n = 8, HbA1c = 6.5 ± 0.15); and patients with uncontrolled diabetes (UDM) (n = 8, HbA1c = 9.6 ± 0.3) undergoing coronary artery bypass grafting. The expression and/or activation of the p38-MAPK, ERK1/2, JNK, and MKP-1 in the right-atrial tissues were analyzed by Western blotting. The vasomotor function of coronary arterioles was measured by videomicroscopy.

Results: The post-CP/CPB levels of total p38-MAPK were decreased in the 3 groups as compared with their pre-CP/CPB levels (P < .05). There were increases in phospho-p38-MAPK, phospho-ERK1/2, and MKP-1 in UDM patients as compared with ND and CDM patients at baseline (P < .05). Compared to pre-CP/CPB, the post-CP/CPB levels of phospho-p38-MAPK decreased in the UDM group but were unaltered in the ND and CDM groups; however, the post-CP/CPB levels of phospho-p38-MAPK still remained greater than the post-CP/CPB levels of the other 2 groups. Post-CP/CPB levels of phospho-ERK1/2 were increased in the ND and CDM groups but were decreased in the UDM group compared to their pre-CP/CPB levels, respectively (P < .05). There were no significant differences in phospho-JNK in 3 groups at baseline. Post-CP/CPB levels of phospho-JNK, however, were increased in the 3 groups and were more pronounced in the myocardium of the UDM group (P < .05). After CP/CPB, the protein levels of MKP-1 were unchanged in the 3 groups when compared with their pre-CP/CPB levels. Post-CP/CPB levels of MKP-1, however, remained greater in the UDM group than in the ND and CDM groups. The post-CP/CPB contractile responses to the thromboxane A2 analog U46619 were significantly impaired in all 3 groups compared with pre-CP/CPB contractile responses. These impairments were more pronounced in the UDM group.

Conclusion: Uncontrolled diabetes is associated with changes in expression of and activation of MAPKs and vasomotor dysfunction in the setting of CP/CPB.
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http://dx.doi.org/10.1016/j.surg.2013.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793891PMC
September 2013

Changes in microvascular reactivity after cardiopulmonary bypass in patients with poorly controlled versus controlled diabetes.

Circulation 2012 Sep;126(11 Suppl 1):S73-80

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

Background: We investigated the effects of cardiopulmonary bypass (CPB) on peripheral arteriolar reactivity and associated signaling pathways in poorly controlled (UDM), controlled (CDM), and case-matched nondiabetic (ND) patients undergoing coronary artery bypass grafting (CABG).

Methods And Results: Skeletal muscle arterioles were harvested before and after CPB from the UDM patients (hemoglobin A1c [HbA1c]=9.0 ± 0.3), the CDM patients (HbA1c=6.3 ± 0.15), and the ND patients (HbA1c=5.2 ± 0.1) undergoing CABG surgery (n=10/group). In vitro relaxation responses of precontracted arterioles to endothelium-dependent vasodilators adenosine 5'-diphosphate (ADP) and substance P and the endothelium-independent vasodilator sodium nitroprusside (SNP) were examined. The baseline responses to ADP, substance P, and SNP of arterioles from the UDM patients were decreased as compared with microvessels from the ND or CDM patients (P<0.05). The post-CPB relaxation responses to ADP and substance P were significantly decreased in all 3 groups compared with pre-CPB responses (P<0.05). However, these decreases were more pronounced in the UDM group (P<0.05). The post-CPB response to SNP was significantly decreased only in the UDM group, not in the other 2 groups compared with pre-CPB. The expression of protein kinase C (PKC)-α, PKC-β, protein oxidation, and nitrotyrosine in the skeletal muscle were significantly increased in the UDM group as compared with those of ND or CDM groups (P<0.05).

Conclusions: Poorly controlled diabetes results in impaired arteriolar function before and after CPB. These alterations are associated with the increased expression/activation of PKC-α and PKC-β and enhanced oxidative and nitrosative stress.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.111.084590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448935PMC
September 2012

Vodka and wine consumption in a swine model of metabolic syndrome alters insulin signaling pathways in the liver and skeletal muscle.

Surgery 2012 Sep;152(3):414-22

Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.

Background: The purpose of this study was to examine the effects of alcohol in the context of metabolic syndrome on insulin signaling pathways in the liver and skeletal muscle.

Methods: Twenty-six Yorkshire swine were fed a hypercaloric, high-fat diet for 4 weeks then split into 3 groups: hypercholesterolemic diet alone (HCC, n = 9), hypercholesterolemic diet with vodka (HCVOD, n = 9), and hypercholesterolemic diet with wine (HCW, n = 8) for 7 weeks. Animals underwent intravenous dextrose challenge before euthanasia and tissue collection.

Results: HCC, HCVOD, and HCW groups had similar blood fasting glucose levels, liver function test, and body mass index. Thirty and 60 minutes after dextrose infusion, HCVOD and HCW groups had significantly increased blood glucose levels compared with the HCC group. The HCW group had significantly increased levels of insulin compared with the HCC group. Immunoblotting in skeletal muscle demonstrated that alcohol up-regulates p-IRS1, IRS2, AKT, AMPKα, PPARα, Fox01, and GLUT4. In the liver, HCW had up-regulation of AKT, AMPKα, and GLUT4 compared with HCC. Skeletal muscle immunohistochemistry demonstrated increased sarcolemmal expression of GLUT4 in both alcohol groups compared with HCC.

Conclusion: Moderate alcohol consumption in a swine model of metabolic syndrome worsens glucose metabolism by altering activation of the insulin signaling pathway in the liver and skeletal muscle.
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http://dx.doi.org/10.1016/j.surg.2012.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435558PMC
September 2012

Histone deacetylase 6 (HDAC6) deacetylates survivin for its nuclear export in breast cancer.

J Biol Chem 2012 Mar 9;287(14):10885-93. Epub 2012 Feb 9.

Department of Pediatrics, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island 02903, USA.

Survivin is an oncogenic protein that is highly expressed in breast cancer and has a dual function that is dependent on its subcellular localization. In the cytosol, survivin blocks programmed cell death by inactivating caspase proteins; however, in the nucleus it facilitates cell division by regulating chromosomal movement and cytokinesis. In prior work, we showed that survivin is acetylated by CREB-binding protein (CBP), which restricts its localization to the nuclear compartment and thereby inhibits its anti-apoptotic function. Here, we identify histone deacetylase 6 (HDAC6) as responsible for abrogating CBP-mediated survivin acetylation in the estrogen receptor (ER)-positive breast cancer cell line, MCF-7. HDAC6 directly binds survivin, an interaction that is enhanced by CBP. In quiescent breast cancer cells in culture and in malignant tissue sections from ER+ breast tumors, HDAC6 localizes to a perinuclear region of the cell, undergoing transport to the nucleus following CBP activation where it then deacetylates survivin. Genetically modified mouse embryonic fibroblasts that lack mhdac6 localize survivin predominantly to the nuclear compartment, whereas wild-type mouse embryonic fibroblasts localize survivin to distinct cytoplasmic structures. Together, these data imply that HDAC6 deacetylates survivin to regulate its nuclear export, a feature that may provide a novel target for patients with ER+ breast cancer.
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http://dx.doi.org/10.1074/jbc.M111.308791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322878PMC
March 2012

Essential roles of Raf/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, YY1, and Ca2+ influx in growth arrest of human vascular smooth muscle cells by bilirubin.

J Biol Chem 2012 May 18;287(19):15418-26. Epub 2012 Jan 18.

Medicine, Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

The biological effects of bilirubin, still poorly understood, are concentration-dependent ranging from cell protection to toxicity. Here we present data that at high nontoxic physiological concentrations, bilirubin inhibits growth of proliferating human coronary artery smooth muscle cells by three events. It impairs the activation of Raf/ERK/MAPK pathway and the cellular Raf and cyclin D1 content that results in retinoblastoma protein hypophosphorylation on amino acids S608 and S780. These events impede the release of YY1 to the nuclei and its availability to regulate the expression of genes and to support cellular proliferation. Moreover, altered calcium influx and calpain II protease activation leads to proteolytical degradation of transcription factor YY1. We conclude that in the serum-stimulated human vascular smooth muscle primary cell cultures, bilirubin favors growth arrest, and we propose that this activity is regulated by its interaction with the Raf/ERK/MAPK pathway, effect on cyclin D1 and Raf content, altered retinoblastoma protein profile of hypophosphorylation, calcium influx, and YY1 proteolysis. We propose that these activities together culminate in diminished 5 S and 45 S ribosomal RNA synthesis and cell growth arrest. The observations provide important mechanistic insight into the molecular mechanisms underlying the transition of human vascular smooth muscle cells from proliferative to contractile phenotype and the role of bilirubin in this transition.
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http://dx.doi.org/10.1074/jbc.M111.266510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346106PMC
May 2012

Effects of cyclooxygenase inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia.

Am J Physiol Heart Circ Physiol 2012 Jan 28;302(2):H479-88. Epub 2011 Oct 28.

Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA.

The cardiovascular effects of cyclooxygenase (COX) inhibition remain controversial, especially in the setting of cardiovascular comorbidities. We examined the effects of nonselective and selective COX inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia. Twenty-four intact male Yorkshire swine underwent left circumflex ameroid constrictor placement and were subsequently given either no drug (HCC; n = 8), a nonselective COX inhibitor (440 mg/day naproxen; HCNS; n = 8), or a selective COX-2 inhibitor (200 mg/day celecoxib; HCCX; n = 8). After 7 wk, myocardial functional was measured and myocardium from the nonischemic ventricle and ischemic area-at-risk (AAR) were analyzed. Regional function as measured by segmental shortening was improved in the AAR of HCCX compared with HCC. There was no significant difference in perfusion to the nonischemic ventricle between groups, but myocardial perfusion in the AAR was significantly improved in the HCCX group compared with controls at rest and during pacing. Endothelium-dependent microvessel relaxation was diminished by ischemia in HCC animals, but both naproxen and celecoxib improved vessel relaxation in the AAR compared with controls, and also decreased the vasoconstrictive response to serotonin. Thromboxane levels in the AAR were decreased in both HCNS and HCCX compared with HCC, whereas prostacyclin levels were decreased only in HCNS, corresponding to a decrease in prostacyclin synthase expression. Chronic ischemia increased apoptosis in Troponin T negative cells and intramyocardial fibrosis, both of which were reduced by celecoxib administration in the AAR. Capillary density was decreased in both the HCNS and HCCX groups. Protein oxidative stress was decreased in both HCNS and HCCX, whereas lipid oxidative stress was decreased only in the HCCX group. Thus nonselective and especially selective COX inhibition may have beneficial myocardial effects in the setting of hypercholesterolemia and chronic ischemia. Whether these effects modulate cardiovascular risk in patients taking these drugs remains to be seen, but evidence to date suggests that they do not.
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http://dx.doi.org/10.1152/ajpheart.00146.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339859PMC
January 2012

Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts.

Circulation 2011 Sep;124(11 Suppl):S55-61

Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital and Alpert Medical School, Brown University, Coro 5.230, 1 Hoppin St, Providence, RI 02903, USA.

Background: Cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to complex injurious stimuli that can result in cardiomyocyte and vascular contractile abnormalities. Rottlerin, originally identified as a delta-protein kinase C inhibitor, has a number of known additional effects that may be beneficial in the setting of CP/CPB. We tested the hypothesis that rottlerin mitigates deleterious effects associated with CP/CPB.

Methods And Results: Langendorff-perfused isolated rat hearts were subjected to 2 hours intermittent cold (10°C) CP (St Thomas II) followed by 30 minutes normothermic reperfusion. CP was delivered every 30 minutes for 1 minute. Hearts were treated with rottlerin 1 μmol/L (CP+R) (n=7) or without rottlerin (CP) (n=9), and the BK(Ca++) channel inhibitor paxilline 100 nmol/L was supplied in the CP. Hearts constantly perfused with KHB served as controls (n=6). Baseline parameters of cardiac function were similar between groups. CP resulted in reduced cardiac function (left ventricular diastolic pressure, 39 ± 3.8%; ± dP/dt, 32 ± 4.4%, -41 ± 5.1% decrease compared to baseline). Treatment with rottlerin 1 μmol/L significantly improved CP-induced cardiac function (left ventricular diastolic pressure, 20 ± 5.9%; ± dP/dt, 5.2 ± 4.5%, -11.6 ± 4.7% decrease versus baseline; P<0.05 CP+R versus CP). Rottlerin also caused a significant increase in coronary flow postreperfusion (CP, 34 ± 4.2% decrease from baseline; CP+R, 26 ± 9.6% increase over baseline; P=0.01). Independent of vascular effects, CP significantly decreased isolated myocyte contraction, which was restored by rottlerin treatment. The BK(Ca++) channel inhibitor greatly reduced the majority of beneficial effects associated with rottlerin.

Conclusions: Rottlerin significantly improves cardiac performance after CP arrest through improved cardiomyocyte contraction and coronary perfusion.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.110.012112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358121PMC
September 2011

Thromboxane-induced contractile response of human coronary arterioles is diminished after cardioplegic arrest.

Ann Thorac Surg 2011 Sep;92(3):829-36

Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.

Background: We investigated the contractile response of human coronary microvasculature to thromboxane A-2 (TXA-2), with and without the blockade of TXA-2 receptors or the inhibition of phospholipase-C (PLC) or of protein kinase C-α (PKC-α) in the human coronary microvasculature before and after cardioplegia, followed by reperfusion (CP/Rep). Protein/gene expression and localization of TXA-2 receptors, TXA-2 synthase, PLC, and other TXA-2-related proteins was also examined.

Methods: Right atrial tissue was harvested before and after cold blood cardioplegia, followed by about 10 minutes of reperfusion, from 28 patients undergoing cardiac operations. Coronary arterioles (90 to 170 μm in diameter) were dissected from the harvested tissue.

Results: The post-CP/Rep contractile response of coronary arterioles to TXA-2 analog U-46619 was significantly impaired vs pre-CP/Rep (p<0.05). The TXA-2 receptor antagonist SQ-29548 (10(-6) M) prevented the contractile response to U-46619 (p<0.05). Pretreatment with the PLC inhibitor U73122 (10(-6) M) significantly inhibited the U-46619-induced contractile response (p<0.05). Administration of the PKC-α inhibitor safingol failed to affect U-46619-induced contraction. Total protein levels and gene expression of TXA-2 receptors, TXA-2 synthase, PLC-β3, phospho-PLC-β3, PLC-γ1, and phospho-PLC-γ1 were not altered after CP/Rep. Confocal microscopy showed no significant differences in the expression of TXA-2 receptors or PLC-β3 in the microcirculation. TXA-2 receptors and PLC-β3 were both present in smooth muscle and endothelium.

Conclusions: Cardioplegia/Rep decreases the contractile response of human coronary arterioles to TXA-2 soon after cardiac operations. The contractile response to the TXA-2 analog U-46619 is through activation of TXA-2 receptors and PLC.
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http://dx.doi.org/10.1016/j.athoracsur.2011.04.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281190PMC
September 2011

Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion.

J Pharmacol Exp Ther 2011 Oct 27;339(1):143-51. Epub 2011 Jul 27.

Cardiovascular Research Center, Division of Cardiothoracic Surgery, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.

Chymase is activated after acute myocardial ischemia/reperfusion (AMI-R) and is associated with an early activation of matrix metalloproteinase-9 (MMP-9), which increases infarct size after experimental AMI, and late fibrosis. We assessed the effect of chymase inhibition on myocardial protection and early signs of fibrosis after AMI-R. Fourteen pigs underwent AMI-R and received intravenously either vehicle (V; n = 7) or chymase inhibitor (CM; n = 7). Separately, rat myocardial fibroblast was incubated with vehicle (n = 4), low-dose chymase (n = 4), high-dose chymase (n = 4), or high-dose chymase plus chymase inhibitor (n = 4). Infarct size (V, 41 ± 5; CM, 24 ± 5; P < 0.01) and serum troponin T (P = 0.03) at the end of reperfusion were significantly reduced in CM. Chymase activity in both the area at risk (AAR) (P = 0.01) and nonischemic area (P = 0.02) was significantly lower in CM. Myocardial levels of pro, cleaved, and cleaved/pro-MMP-9 in the AAR were significantly lower in CM than V (P < 0.01, < 0.01, and = 0.02, respectively), whereas phospho-endothelial nitric-oxide synthase (eNOS) (P < 0.01) and total eNOS (P = 0.03) were significantly higher in CM. Apoptotic cells (P = 0.05), neutrophils (P < 0.05), and MMP-9-colocalizing mast cells (P < 0.05) in the AAR were significantly reduced in CM. Interleukin-18 (P < 0.05) and intercellular adhesion molecule-1 (P < 0.05) mRNA levels were significantly lower in CM. In cultured cardiac fibrosis, Ki-67-positive cells were significantly higher in the high-dose chymase groups (P < 0.03). This study demonstrates that chymase inhibition plays crucial roles in myocardial protection related to MMP-9, inflammatory markers, and the eNOS pathway. It may also attenuate fibrosis induced by activated chymase after AMI-R.
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http://dx.doi.org/10.1124/jpet.111.179697DOI Listing
October 2011

Improving glucose metabolism with resveratrol in a swine model of metabolic syndrome through alteration of signaling pathways in the liver and skeletal muscle.

Arch Surg 2011 May;146(5):556-64

Division of Cardiothoracic Surgery, Department of Surgery, and Cardiovascular Research Center, Rhode Island Hospital, Providence, USA.

Hypothesis: We hypothesized that supplemental resveratrol would affect glucose metabolism in the skeletal muscle and liver to improve blood glucose control.

Design: Case-control study.

Setting: Hospital laboratory.

Subjects: Yorkshire miniswine.

Intervention: The swine developed metabolic syndrome by consuming a high-calorie, high–fat/cholesterol diet for 11 weeks. Pigs were fed either a normal diet (control) (n = 7), a hypercholesterolemic diet (HCC) (n = 7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d) (HCRV) (n = 7). Animals underwent dextrose challenge prior to euthanasia and tissue collection.

Main Outcome Measures: Measurements of glucose and insulin levels, skeletal muscle and liver protein expression, and liver function test results.

Results: The HCC group had significantly increased blood glucose levels at 30 minutes as compared with the control and HCRV groups. The HCC group demonstrated increased fasting serum insulin levels and levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Oil red O staining demonstrated increased lipid deposition in the livers of the HCC animals. Immunoblotting in the liver showed increased levels of mammalian target of rapamycin, insulin receptor substrate 1, and phosphorylated AKT in the HCRV group. Immunoblotting in skeletal muscle tissue demonstrated increased glucose transporter type 4 (Glut 4), peroxisome proliferating activation receptor coactivator 1α, peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor , and phosphorylated AKT at threonine 308 expression as well as decreased retinol binding protein 4 in the HCRV group. Immunofluorescence staining for Glut 4 in the skeletal muscle demonstrated increased Glut 4 staining in the HCRV group compared with the HCC or control groups.

Conclusion: Supplemental resveratrol positively influences glucose metabolism pathways in the liver and skeletal muscle and leads to improved glucose control in a swine model of metabolic syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285438PMC
http://dx.doi.org/10.1001/archsurg.2011.100DOI Listing
May 2011

Chronic type II diabetes mellitus leads to changes in neuropeptide Y receptor expression and distribution in human myocardial tissue.

Eur J Pharmacol 2011 Aug 28;665(1-3):19-28. Epub 2011 Apr 28.

Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Neuropeptide Y is one of the most abundant neurotransmitters in the myocardium, and is known to influence cardiovascular remodeling. We hypothesized that diabetic neuropathy could possibly be associated with altered neuropeptide Y and its receptor expression levels in myocardium and plasma. Plasma neuropeptide Y levels in diabetic (n=24, HgbA1c 7.9 ± 1.1%) and non-diabetic (n=27, HgbA1c 5.8 ± 0.5%) patients undergoing cardiac surgery utilizing cardiopulmonary bypass were analyzed. Right atrial tissue of these patients was used to determine the expression of neuropeptide Y, the receptors 1-5, and leptin by immunoblotting, real-time PCR and immunofluorescence. Apoptosis signaling and endostatin and angiostatin were measured to determine the effects of leptin. Plasma neuropeptide Y levels were significantly increased in patients with Type II diabetes mellitus as compared to non-diabetic patients (P=0.026). Atrial tissue neuropeptide Y mRNA levels were lower in diabetic patients (P=0.036). There was a significant up-regulation of myocardial Y(2) and Y(5) receptors (P=0.009, P=0.01 respectively) in the diabetic patients. Leptin, involved with apoptosis and angiogenesis, was down regulated in diabetic patients (P=0.05). The levels of caspase-3, endostatin and angiostatin were significantly elevated in diabetic patients (P=0.003, P=0.008, P=0.01 respectively). Y(1) receptors were more likely to be localized within the nuclei of cardiomyocytes and vascular smooth muscle cells. Neuropeptide expression is altered differentially in the serum and myocardium by diabetes. Altered regulation of this system in diabetics may be in part responsible for the decreased angiogenesis, increased apoptosis, and increased vascular smooth muscle proliferation leading to coronary artery disease and heart failure in this patient population.
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http://dx.doi.org/10.1016/j.ejphar.2011.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281191PMC
August 2011

p38 MAPK-dependent small HSP27 and αB-crystallin phosphorylation in regulation of myocardial function following cardioplegic arrest.

Am J Physiol Heart Circ Physiol 2011 May 25;300(5):H1669-77. Epub 2011 Feb 25.

Cardiovascular Research Center, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA.

We previously demonstrated that myocardial p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27) are phosphorylated following cardioplegic arrest in patients undergoing cardiac surgery and correlate with reduced cardiac function. The following studies were performed to determine whether inhibition of p38 MAPK and/or overexpression of nonphosphorylatable HSP27 improves cardiac function following cardioplegic arrest. Langendorff-perfused isolated rat hearts were subjected to 2 h of intermittent cold cardioplegia followed by 30 min of reperfusion. Hearts were treated with (CP+SB) or without (CP) the p38 MAPK inhibitor SB-203580 (5 μM) supplied in the cardioplegia. Sham-treated hearts served as controls. In separate experiments, isolated rat ventricular myocytes infected with either green fluorescent protein (GFP) or a nonphosphorylatable HSP27 mutant (3A-HSP27) were subjected to 3 h of cold hypoxic cardioplegia and simulated reperfusion (CP) followed by video microscopy and length change measurements. Baseline parameters of cardiac function were similar between groups [left ventricular developed pressure (LVDP), 119 ± 4.9 mmHg; positive and negative first derivatives of LV pressure (± dP/dt), 3,139 ± 245 and 2, 314 ± 110 mmHg/s]. CP resulted in reduced cardiac function (LVDP, 72.2 ± 5.8 mmHg; ± dP/dt, 2,076 ± 231 and -1,317 ± 156 mmHg/s) compared with baseline. Treatment with 5 μM SB-203580 significantly improved CP-induced cardiac function (LVDP, 101.9 ± 0 mmHg; ± dP/dt, 2,836 ± 163 and -2,108 ± 120 mmHg/s; P = 0.03, 0.01, and 0.04, CP+SB vs. CP). Inhibition of p38 MAPK significantly lowered CP-induced p38 MAPK, HSP27, and αB-crystallin (cryAB) phosphorylation. In vitro CP decreased myocyte length changes from 10.3 ± 1.5% (GFP) to 5.7 ± 0.8% (GFP+CP). Infection with 3A-HSP27 completely rescued CP-induced decreased myocyte contraction (11.1 ± 1.0%). However, infection with 3A-HSP27 did not block the endogenous HSP27 response. We conclude that inhibition of p38 MAPK and subsequent HSP27 and cryAB phosphorylation and/or overexpression of nonphosphorylatable HSP27 significantly improves cardiac performance following cardioplegic arrest. Modulation of HSP27 phosphorylation may improve myocardial stunning following cardiac surgery.
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http://dx.doi.org/10.1152/ajpheart.00272.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094077PMC
May 2011

In vitro and in vivo degradation of poly(D, L-lactide-co-glycolide)/amorphous calcium phosphate copolymer coated on metal stents.

J Biomed Mater Res A 2011 Mar 25;96(4):632-8. Epub 2011 Jan 25.

Biomedical Engineering and Biotechnology Doctoral Program, University of Massachusetts, Lowell, Massachusetts 01854, USA.

The purpose of this study was to optimize a novel biodegradable polymer for drug eluting stent (DES) applications. Degradation profiles of different poly(D,L-lactide-co-glycolide)/amorphous calcium phosphate (PLGA/ACP) composites coated on stents were studied both in vitro and in vivo for three months. For the in vitro study, stents were immersed into the phosphate buffered saline (37 °C, pH 7.4) with constant shaking. The polymer weight loss was measured weekly and morphological changes were analyzed. The results demonstrated that approximately 60% of polymer was degraded within the three-month period and there was no significant difference between the different PLGA/ACP composites. However, the composite of 50% PLGA (65/35) with 50% ACP showed a slightly faster degradation rate than other composites. Morphologically, all stent surfaces changed from a micro-porous before degradation to a corrugated solid micro-net-like structure at two months post degradation. Based on in vitro results, 65% PLGA (65/35) with 35% ACP) coated stents were selected and implanted into rat aortas (n = 12) for the in vivo study. Microscopic observation showed that no composite was found on any of the implanted stents at 12 weeks post implantation, which indicated the selected PLGA/ACP composite is desired for DES applications.
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http://dx.doi.org/10.1002/jbm.a.33016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291328PMC
March 2011

Effects of selective cyclooxygenase-2 and nonselective cyclooxygenase inhibition on myocardial function and perfusion.

J Cardiovasc Pharmacol 2011 Jan;57(1):122-30

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

Nonselective nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors are purported to increase adverse cardiovascular events. We hypothesized that COX-2 inhibitors would alter myocardial blood flow, microvascular reactivity, oxidative stress, and prostaglandin levels. Adult Yorkshire swine were divided into 3 groups: no drug (control, n = 7), a nonselective COX inhibitor (naproxen 400 mg daily, NAP, n = 7), or a selective COX-2 inhibitor (celecoxib 200 mg daily, CBX, n = 7). After 7 weeks, physiologic measurements were taken and tissue harvested. Animals in the CBX group demonstrated significantly higher blood pressure and rate-pressure product. The NAP and CBX groups demonstrated an increased microvascular contraction response to serotonin. The NAP group showed increased myocardial levels of thromboxane and lower levels of prostacyclin. Levels of protein oxidative stress were increased in the CBX group. Myocardial apoptosis was lowest in the NAP group. Immunoblotting demonstrated decreased vascular endothelial growth factor and phosphorylated endothelial nitric oxide synthase expression in the NAP and CBX groups. Myocardial tumor necrosis factor-α was increased in both treated groups. Immunostaining for thromboxane A2 synthase and receptor demonstrated expression within the vascular smooth muscle and no observable differences between groups. Nonselective and selective COX inhibition does not alter myocardial perfusion but results in altered myocardial and vascular physiology that may have implications regarding cardiovascular risk.
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http://dx.doi.org/10.1097/FJC.0b013e3182010a96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077444PMC
January 2011

Trans-iliac rat aorta stenting: a novel high throughput preclinical stent model for restenosis and thrombosis.

J Surg Res 2011 Mar 9;166(1):e91-5. Epub 2010 Dec 9.

Division of Cardiothoracic Surgery, Brown Medical School, Providence, Rhode Island, USA.

Background: Currently, preclinical stent development requires elaborate large animal models, which are time consuming and expensive. We herein report a high throughput rat aorta stenting model which could provide a rapid and low-cost platform for preclinical stent development.

Methods: A total of 86 metal stents (316L stainless steel 13 mm, VasoTech, Inc.) coated with poly (D, L-lactide-co-glycolide)/amorphous calcium phosphate (PLGA/ACP) copolymer were pre-mounted on 1.5 mm × 15 mm balloon catheters and were implanted into aspirin treated Sprague-Dawley rats (500-700 g) initially using either direct placement in the abdominal aorta (group A, n = 7) or a trans-iliac approach (cut-down, group B, n = 79). The surviving rats were sacrificed at 1, 2, 4, and 12 wk post-implantation and the stented arteries were analyzed histopathologically.

Results: Four rats died in group A and nine rats died in group B within 48 h post-stent implantation (mortality: 57% versus 11%, P < 0.05). All animals that died had stent thrombosis/paralysis with visible thrombus on necropsy. Histologically, neointimal growth peaked at approximately 4 wk post-implantation.

Conclusion: This result suggests that human-sized stents can be successfully implanted into the rat aorta via iliac artery insertion with a significantly higher survival rate than trans-aorta implantation. The model system allows rapid (4-12 wk) assessment of stent biocompatibility with mortality/paralysis used as an indicator of stent thrombosis.
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http://dx.doi.org/10.1016/j.jss.2010.11.882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071592PMC
March 2011

Paclitaxel/sirolimus combination coated drug-eluting stent: in vitro and in vivo drug release studies.

J Pharm Biomed Anal 2011 Mar 10;54(4):807-11. Epub 2010 Nov 10.

Biomedical Engineering and Biotechnology Doctoral Program, University of Massachusetts, Lowell, MA 01854, USA.

Paclitaxel and sirolimus are the two major drugs for the treatment of coronary arterial disease in current drug-eluting stents. The two drugs can effectively inhibit the in-stent restenosis through their independent pathways and show synergistic effect in preventing tumor tissue growth. We hypothesize that the combination of the two drugs in a drug-eluting stent (DES) can also effectively suppress the neointima growth in the stented artery. The present work was focused on the investigation of paclitaxel/sirolimus combination release profiles from a novel biodegradable polymer (poly (D, L-lactide-co-glycolide)/amorphous calcium phosphate, PLGA/ACP) coated stent both in vitro and in vivo. For the in vitro, the drug releasing profiles were characterized by measuring the drug concentration in a drug release medium (Dulbecco's phosphate buffered saline, DPBS, pH 7.4) at predetermined time points. For the in vivo, a rat aorta stenting model was employed. The results showed that both paclitaxel and sirolimus had a two-phase release profile both in vitro and in vivo, which is similar to the drug release profile of their individual coated DESs, and there is no evident of interference between two drugs. The data suggest that paclitaxel and sirolimus can be combined pharmacokinetically in a DES for the treatment of coronary arterial diseases.
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http://dx.doi.org/10.1016/j.jpba.2010.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008332PMC
March 2011

Resveratrol improves myocardial perfusion in a swine model of hypercholesterolemia and chronic myocardial ischemia.

Circulation 2010 Sep;122(11 Suppl):S142-9

Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA.

Background: Resveratrol may provide protection against coronary artery disease. We hypothesized that supplemental resveratrol will improve cardiac perfusion in the ischemic territory of swine with hypercholesterolemia and chronic myocardial ischemia.

Methods And Results: Yorkshire swine were fed either a normal diet (control, n=7), a hypercholesterolemic diet (HCC, n=7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d orally, HCRV, n=7). Four weeks later, an ameroid constrictor was placed on the left circumflex artery. Animals underwent cardiac MRI and coronary angiography 7 weeks later before euthanasia and tissue harvest. Total cholesterol was lowered about 30% in HCRV animals (P<0.001). Regional wall motion analysis demonstrated a significant decrease in inferolateral function from baseline to 7 weeks in HCC swine (P=0.04). There was no significant change in regional function in HCRV swine from baseline to 7 weeks (P=0.32). Tissue blood flow during stress was 2.8-fold greater in HCRV swine when compared with HCC swine (P=0.04). Endothelium-dependent microvascular relaxation response to Substance P was diminished in HCC swine, which was rescued by resveratrol treatment (P=0.004). Capillary density (PECAM-1 staining) demonstrated fewer capillaries in both HCC and HCRV swine versus control swine (P=0.02). Immunoblot analysis demonstrated significantly greater expression in HCRV versus HCC swine of the following markers of angiogenesis: VEGF (P=0.002), peNOS (ser1177) (P=0.04), NFkB (P=0.004), and pAkt (thr308) (P=0.001).

Conclusions: Supplemental resveratrol attenuates regional wall motion abnormalities, improves myocardial perfusion in the collateral dependent region, preserves endothelium-dependent coronary vessel function, and upregulates markers of angiogenesis associated with the VEGF signaling pathway.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.109.920132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943855PMC
September 2010