Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Sep 11.
Published in final edited form as: Circulation. 2012 Sep 11;126(11 Suppl 1):S73–S80. doi: 10.1161/CIRCULATIONAHA.111.084590

Changes in Microvascular Reactivity after Cardiopulmonary Bypass in Patients with Poorly Controlled versus Controlled Diabetes

Jun Feng 1, Yuhong Liu 1, Louis M Chu 1, Arun K Singh 1, Dobrilovic N Nikola 1, James G Fingleton 1, Richard T Clements 1, Cesario Bianchi 1, Frank W Sellke 1
PMCID: PMC3448935  NIHMSID: NIHMS397829  PMID: 22965996

Abstract

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 non-diabetic (ND) patients undergoing coronary artery bypass grafting.

Methods and Results

Skeletal muscle arterioles were harvested pre- and post-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 pre-contracted 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 to 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 three groups compared to 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 two groups compared to pre-CPB. The expression of 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).

Conclusion

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.

Keywords: Microvascular Reactivity, Cardiopulmonary Bypass, Diabetes, Coronary Artery Bypass Grafting

Introduction

Cardiopulmonary bypass (CPB) is widely recognized to induce a systemic inflammatory response that leads to various degrees of organ dysfunction in multiple systems.1 For instance, CPB is associated with reduced vascular resistance in the peripheral microcirculation, which can lead to systemic hypotension and subsequent organ/tissue malperfusion.1-4 We and others have observed that CPB impairs contractile responses of peripheral arterioles to phenylephrine, endothelin-1, and thromboxane-A2, 1-3 and mitigates microvascular endothelial function. 4-5

Diabetes is associated with increased risk of microvascular disease and with increased morbidity and mortality after surgical procedures.6-8 This is especially true in poorly controlled diabetic patients after open heart operations involving CPB. 6-8 Whether glycemic control improves microvascular function in patients with diabetes after CPB and cardiac surgery is unknown. The goal of this research is to compare the effect of CPB on microvascular function among non-diabetic, well controlled diabetic and poorly controlled diabetic patients. Specifically, this study was designed to directly test the effect of CPB on microvascular responses of human peripheral arterioles to endothelium-dependent and -independent vasodilators, and to relate these responses to possible alterations in endothelium-related-protein expression/localization and gene expression in human peripheral vasculature and tissues.

Methods

Human Subjects and Tissue Harvesting

Samples of skeletal muscle from the left internal mammary artery bed were harvested pre- and post-CPB from 100 patients undergoing coronary artery bypass grafting (CABG). Hemoglobin A1C (HbA1c) was measured in all patients. The patients were then divided into the following three groups: 1) those patients with a normal HgbA1c and no history or treatment for diabetes were considered non-diabetic (ND); 2) those patients with a history of diabetes with a HgbA1c >5.5 and <7 were considered controlled (CDM); 3) diabetic patients with a HgbA1c > or = 8.5 were considered poorly controlled (UDM). Patients who also underwent valve surgery were excluded from the study. Patients with crossclamp time greater than 120 minutes and/or CPB time greater than 180 minutes, the patient will be excluded in the study. Ten randomly chosen patients in each of three groups from 100 cases were finally included for analysis in this study. The pre-CPB specimen was taken after cannulation, and the post-CPB specimen was collected from a different location in the left internal mammary artery bed after removal of the aortic cross-clamp and weaning from CPB. Tissue samples for immunoblot analysis assay were immediately frozen in liquid nitrogen. Tissue for immunofluorescent staining was fixed in 10% formalin buffered solution for 24 hours followed by paraffin mounting and sectioning into 5-μm slices. Tissue for microvascular studies was placed in cold (5° to 10°C) Krebs buffer solution. All procedures were approved by the Institutional Review Board of Rhode Island Hospital, Alpert Medical School of Brown University, and informed consent was obtained from all enrolled patients as required by the Institutional Review Board.

Microvessel Reactivity

Skeletal muscle arterioles (90-180 μm internal diameters) from the left internal mammary artery bed were dissected from pre- and post-CPB tissue samples. Microvessel studies were performed by in vitro organ bath videomicroscopy as described previously.2-5 We have previously determined that human skeletal muscle microvascular responses to 5’-diphosphate (ADP) and Substance P are endothelium dependent and the response to sodium nitroprusside (SNP) is endothelium independent. 5

Immunoblot

Skeletal muscle from six patients per group were dissected and cleaned of connective tissues, then solubilized in SDS-PAGE buffer. Total protein (40 μg) was fractionated on an 8-16% SDS-PAGE gel, then transferred to a polyvinylidene difluoride membrane (Millipore Corporation, Bedford, MA). Membranes were incubated for 1 hour at room temperature with 1:200 dilutions of individual rabbit polyclonal primary antibodies to PKC-α, and PKC-β (Santa Cruz biotechnology, Santa Cruz, CA). The detailed methods have been previously described. 2-5

Protein Oxidation

Total protein oxidation in skeletal muscle samples was measured according to the manufacturer's recommendation (OxyBlot, Chemicon International, Inc).

Immunofluorescence Microscopy

The detailed methods have been previously described.3-5 After PBS wash of skeletal-muscle tissue sections, sections were incubated overnight with anti-PKC-α (phospho S657 + Y658), and anti-PKC-β1 (phospho T642) (abcam, Cambridge, MA) and nitrotyrosine polyclonal rabbit antibodies (Millipore Corporation, Bedford, MA, each used at 1:200) at 4°C.

RNA Isolation and Microarray Processing

The methods for RNA isolation and microarray processing were described in detail in supplemental data.

Microarray Analysis

The methods for microarray analysis are described in detail in supplemental data

Chemicals

ADP, Substance P, and SNP were obtained from Sigma-Aldrich and dissolved in ultrapure distilled water on the day of the study.

Data Analysis

Data are presented as the mean and standard error of the mean (SEM). Microvessel responses are expressed as percent relaxation of the pre-constricted diameter. Microvascular reactivity was analyzed using 2 way repeated-measures ANOVA with a post hoc Bonferroni test. Clinical, Western blot and Oxyblot data were analyzed by Kruskal-Wallis tests followed with Dunn's multiple comparison test (GraphPad Software, Inc, San Diego, CA). A growth model was used to test the degree to which CPB (pre/post) and diabetes (ND/CDM/UDM) affected the degree to which vasodilators-induced relaxation, as well as whether or not there was evidence the two factors interacted. Procedure Glimmix was used in SAS version 9.3 (The SAS Institute, Cary, NC). To analyze the correlation between pre-CPB HbA1c levels and relaxation responses, Pearson correlation was used (GraphPad Software, Inc, San Diego, CA). P values < 0.05 were considered significant.

Results

Patient Characteristics

The patient characteristics are listed in table 1. All patients with preoperative hypertension were on anti-hypertensive medication (β-blocker, aspirin, calcium channel blocker, or angiotensin-converting enzyme inhibitor). The pre-operative blood HbA1c levels were 9.0 ± 0.3 in the UDM patients, 6.3 ± 0.15 in the CDM patients, and 5.2 ± 0.1 in the ND patients.

Table 1.

Patient Characteristics

Patient Characteristics Non-diabetes Controlled Diabetes Uncontrolled Diabetes P values
Age (y)* 68 ± 4.5 66 ± 3.0 64 ± 4.0 0.7
Male/Female (n) 7/3 8/2 7/3 0.96
Patient Blood Glucose (mg/dL, Pre-CPB)* 108 ± 10.0 145 ± 12.0 258 ± 16.0# 0.0001
Patient Blood Glucose (mg/dL, During-CPB)* 110 ± 16.0 134 ± 17 175 ± 15# 0.001
HbA1c (%)* 5.2 ± 0.1 6.3 ± 0.15 9.0 ± 0.3# 0.001
Obesity (BMI>30) 3 4 4 0.96
Hypertension (n) 9 8 9 0.94
Atrial fibrillation (n) 2 2 1 0.96
Hypercholestesterolemia (n) 10 10 10 1.0
Duration of CPB (min)* 119 ± 12 121 ± 12 135 ± 10 0.8
Crossclamp time (min)* 90 ± 10 100 ± 11 108 ± 10 0.6
CABG only (n) 10 10 10 1.0
Number of Grafts 3.5 ± 0.17 3.6 ± 0.16 3.6 ± 0.16 0.9
Pre-operative Insulin (n) (u/h*) 1 (1 ± 1) 2(2.0 ± 1.4) 4 (5.3 ± 2.4 )# 0.2
Intra-operative Insulin (n) (u/h*) 3 (2.7 ± 1.4) 5 (8.4 ± 2.9) 10 (18.6 ± 3.4)# 0.0002
Post-operative Insulin (n) (u/h*) 1(0.9 ± 0.87) 5 (4 ± 1.4) 10 (11.5 ± 2.7)# 0.001
Open in a new tab

NS: no significance; BMI: body mass index

*

Data expressed as mean ± standard error of mean.

#

vs. nondiabetics.

Microvascular Reactivity

There was no significant difference in the baseline diameter of the microvessels among the three groups (ND: 158 ± 11; CDM: 164 ± 9; UDM: 150 ± 8; P =0.74). Vasodilatory responses to ADP and substance P comparing relative changes induced by CPB were similar within each group. The degrees of pre-contraction by the thromboxane A2 analog U46619 were 33 ± 3 % in the ND group, 31 ± 4% in the CDM group and 28 ± 3% in the UDM group, respectively. The relaxation responses to ADP, substance P and SNP in the three groups were dose dependent both pre- and post-CPB (Figure 1-3). There were no significant differences in the arteriolar responses to ADP, substance P and SNP between the ND and CDM patients before CPB (Figure 1-3A, respectively). There were significant decreases in the arteriolar responses to ADP substance P and SNP of the UDM patients compared with those of ND or CDM before CPB (P <0.05, Figure 1-3A).

Figure 1.

Figure 1

Open in a new tab

Microvascular vasodilation in response to the endothelium -dependent vasodilator adenosine 5’-diphosphate (ADP): (A) pre-CPB arterioles from non-diabetic (ND), controlled (CDM) and uncontrolled diabetic (UDM) groups; (B) post-CPB arterioles of ND, CDM and UDM groups; (C) pre-CPB vs. post-CPB (ND); (D) pre-CPB vs. post-CPB (CDM); (E) pre-CPB vs. post-CPB (UDM); *P<0.05 vs. pre-CPB, or ND or CDM; n =10/group.

Figure 3.

Figure 3

Open in a new tab

Microvascular vasodilation in response to the endothelium-independent vasodilator sodium nitroprusside (SNP): (A) pre-CPB arterioles from ND, CDM and UDM groups; (B) Post-CPB arterioles of ND, CDM and UDM groups; (C) pre-CPB vs. post-CPB (ND); (D) pre-CPB vs. post-CPB (CDM); (E) pre-CPB vs. post-CPB (UDM); *P<0.05 vs. ND; #P<0.05 vs. CDM; n = 10/group.

There were significant decreases in the vasodilatory response to endothelium-dependent vasodilators ADP (P = 0.001 for ND; P = 0.006 for CDM and P = 0.004 for UDM) and substance P (P = 0.003) after CPB compared to pre-CPB in all three groups (Figure 1C-E and Figure 2C-E). Vasodilatory responses to ADP and substance P comparing the relative degree of change induced by CPB were similar within each group (analyzed by a Growth Model and Procedure Glimmix, SAS). Although there were no statistically significant differences in the degree of CPB-induced changes (pre/post) between groups (UDM vs. ND or CDM; ADP: P = 0.645 or P = 0. 453; substance P: P = 0.766 or P= 0.562, respectively, Figure 1C-E and Figure 2C-E), the decreases in absolute values were more pronounced in the UDM group (ADP: P = 0.001 or P = 0.004 vs. ND or CDM, substance P: P =0.0001 or P = 0.00013 vs. ND or CDM, respectively, Figure 1-2B).

Figure 2.

Figure 2

Open in a new tab

Microvascular vasodilation in response to the endothelium-dependent vasodilator substance P: (A) pre-CPB arterioles from non-diabetics (ND), controlled diabetic (CDM) and uncontrolled diabetic (UDM) groups; (B) post-CPB arterioles of ND, CDM and UDM groups; (C) pre-CPB vs. post-CPB (ND); (D) pre-CPB vs. post-CPB (CDM); (E) pre-CPB vs. post-CPB of (UDM); *P<0.05 vs. pre-CPB or ND or CDM. n = 10/group.

There were no significant changes in the vasodilatory response to SNP post-CPB in ND and CDM groups compared to pre-CPB (Figure 3C, D). In contrast, the post-CPB response to SNP in poorly controlled diabetic patients was significantly decreased compared to pre-CPB (P = 0.003, Figure 3E). There was a significant decrease in the relaxation response to SNP of UDM patients compared with those of ND or CDM after CPB (P = 0.004 or P = 0.01, Figure 3B).

There were significant direct correlations between ADP at 10-4M (pre-CPB: r = -0.877, P= 0.0001; post-CPB: r = 0.0001), or substance P at 10-7M (pre-CPB: r = -0.551, P = 0.0016; post-CPB: r = -0.53; P = 0.0026) or SNP at 10-4M (pre-CPB: r = -0.581 P = 0.008; post-CPB: r = -0.672; P = 0.0001) relaxation response and pre-CPB HgbA1C levels.

Effect of CPB on Levels of PKC-α and PKC-β

The post-CPB levels of PKC-α and PKC-β were slightly, but insignificantly, increased in the CDM and UDM groups compared with pre-CPB levels (Figure 4). The pre- and post-CPB levels of PKC-α and PKC-β were also slightly, but insignificantly increased in the CDM group than those of the ND group (P = 0.06 at pre-CPB and P = 0.07 at post-CPB). However, the pre- and post-CPB levels of PKC-α and PKC-β were significantly higher in the UDM group than those of the ND group (P = 0.008 at pre-CPB; P = 0.0001 at post-CPB, Figure 4).

Figure 4.

Figure 4

Open in a new tab

Representative immunoblots of human skeletal muscles for PKC-α and PKC-β (n = 6/group). Immunoblot quantitation (graphs) shows significantly enhanced expression in the poorly controlled diabetic (UDM) group; *P = 0.001 vs. non-diabetics (ND) of pre-CPB; #P = 0.003 vs. ND of post-CPB; †P = 0.0008 vs. ND of pre-CPB; ‡P = 0.0001 vs. ND of post-CPB.

Effect of CPB on Microvessel Distribution of Phosphorylated PKC-α and PKC-β1

Immunofluorescent staining of skeletal muscle microvessels displayed a strong signal for phosphorylated PKC-α and PKC-β1 localized to the microvasculature and stronger signals in post-CPB vessels compared with pre-CPB vessels (Figure 5A). The phosphorylated PKC-α and PKC-β1 were localized to smooth muscle (orange) and endothelial cells (red) (Figure 5B). Negative controls documented a low level of background fluorescence and a strong signal of α-actin stained on smooth muscle (green, Figure 5A, B).

Figure 5.

Figure 5

Figure 5

Open in a new tab

Immuno-localization of phospho-PKC-α and phospho-PKC-β1 in human skeletal microvessels (n = 6/group). Vessels were co-stained for smooth muscle actin (green) and either (A) phosphorylated-PKC-α or (B) phosphorylated-PKC-β (red). Matched negative controls are displayed below each row of primary antibody.

Protein Oxidation and Nitrotyrosine

Pre- and post-CPB protein oxidation in skeletal muscle was significantly increased in the uncontrolled diabetic group compared to ND or CDM groups (P = 0.02 vs. ND of pre-CPB or P = 0.001 vs. ND of post-CPB, Figure 6A). Post-CPB protein oxidation was slightly, but insignificantly, increased in the all three groups as compared with their respective pre-CPB samples, respectively. Immunofluorescent staining of skeletal muscle microvessels displayed a strong signal for nitrotyrosine localized to the microvasculature and relatively stronger signals in UDM vessels compared with ND or CDM vessels (Figure 5B).

Figure 6.

Figure 6

Figure 6

Open in a new tab

(A) Oxyblot protein oxidation detection (n = 6/group): protein oxidation of skeletal muscle was significantly increased in the uncontrolled diabetic (UDM) group (*P = 0.02 vs. ND of pre-CPB or #P = 0.001 vs. ND of post-CPB); (B) Immuno-localization of nitrotyrosine in human skeletal microvessels (n = 6/group). Vessels were co-stained for smooth muscle actin (green) and nitrotyrosine antibody (red). Matched negative controls are displayed below each row of primary antibody.

Effect of Uncontrolled Diabetes and CPB on the Gene Expression of Endothelium Markers

There were no significant changes in the gene expression of endothelial markers between poorly controlled diabetic and non-diabetic groups, pre- or post-CPB. The data obtained from microarray analysis are summarized in supplemental data (Supplemental Tables 1 and 2).

4. Discussion

Diabetes mellitus is often associated with vascular and other complications in patients undergoing cardiac surgery. Recent clinical trials have reported that intensive glycemic control significantly reduces microvascular complications, such as, retinopathy, nephropathy and peripheral arterial disease.9,10 In addition, aggressive perioperative glucose control is associated with improved outcomes after CABG surgery .11 We have previously observed that poorly controlled diabetes impairs peripheral arteriolar responses to endothelin-1.3 In the present study, using isolated skeletal muscle arterioles, we observed that poorly controlled diabetes, but not well controlled diabetes significantly impairs endothelium-dependent and -independent relaxation of human peripheral microvasculature as compared to non-diabetes. These changes may contribute to the less favorable postoperative outcomes after cardiac surgery in poorly controlled diabetic patients.

We have previously reported that CPB is associated with reduced myogenic tone and endothelial function of peripheral arterioles.2-5 Recently, we have also found that expression of permeability-modulating proteins such as vascular endothelial growth factor /vascular permeability factor (VEGF/VPF) is increased in poorly controlled diabetic patients and these changes are associated with increased edema formation and length of hospital stay.12 In the present study, we further observed that poorly controlled diabetes worsens the recovery of endothelium-dependent and independent relaxation of peripheral arterioles after CPB.

PKC-α and PKC-β are two major isoforms of PKC family found in the smooth muscle and endothelial cells that are activated under conditions of hyperglycemia.13,14 Treatment with a PKC-β inhibitor improves endothelial function in patients with diabetes mellitus.15 In the present study, we demonstrate that diabetes significantly up-regulates PKC-α and PKC-β protein expression and activation in skeletal muscle microvessels, which may contribute to diabetes-related endothelial dysfunction of the human microvasculature. After CPB, expression of PKC-α and β in uncontrolled diabetes is still higher than those of non-diabetics or controlled diabetics, which may partially explain why CPB worsens arteriolar endothelium function in the uncontrolled diabetic group.

Oxidative and nitrosative stress play an important role in the pathogenesis of diabetic vascular complications. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through multiple mechanisms.16,17 Consistent with these findings, we found that protein oxidation and nitrotyrosine were significantly increased in the skeletal muscle and microvessels of poorly controlled diabetic patients. CPB further enhanced protein oxidation and nitrotyrosine in the poorly controlled diabetic group. These increases in oxidative and nitrosative stress may also contribute to microvascular endothelial dysfunction in diabetic arterioles after CPB. Taken together, hyperglycemia, PKC activation, and oxidative/nitrosative stress may cumulatively participate in the microvascular endothelial dysfunction of diabetic patients.

We have recently found that differential gene and protein expression of growth factors and their related genes between the patients with poorly controlled diabetes and patients without diabetes.12,18 In this study, microarray analysis showed that neither degree of diabetes nor CPB was associated with significant changes in the gene expression of endothelial markers such as, cadherin, integrin, or platelet/endothelial cell adhesion molecules.

There are several limitations of the current study that deserve mention. First, this work should be considered a pilot study considering the relatively small number of patients and samples. Another limitation is the heterogeneity of the patients; even thought they were reasonably well matched, there were differences in medications and the incidence of coexisting illnesses that may affect the findings. This is a limitation of all studies dealing with patients. Third, little clinical outcome data was presented. Fourth, the effects of insulin therapy might have also contributed to the recovery of microvascular function in patients with chronic, poorly controlled diabetes. Future work will be directed at correlating the microvascular and signaling changes with clinical outcomes.

In conclusion, poorly controlled, but not well controlled diabetes is associated with arteriolar endothelium-dependent independent dysfunction and worsens the recovery of arteriolar endothelial and smooth muscle function after CPB. Increased expression/activation of PKC-α and PKC-β, and enhanced oxidative and nitrosative stress may cumulatively contribute to microvascular endothelial and smooth muscle dysfunction of poorly controlled diabetes. In contrast, the well controlled diabetes is associated with improved peripheral arteriolar function after CPB and cardiac surgery.

Supplementary Material

01

Acknowledgment

We would like to thank all nurses, physician assistants, perfusionists at cardiac-surgery-operation rooms in Lifespan Hospitals for collecting tissue samples and the data of patient characteristics. We would also like to thank nurses and physician assistants at Division of Cardiac Surgery, Lifespan Hospitals for collecting patient consent forms.

Funding

This research project was supported in part by the National Heart, Lung, and Blood Institute HL-46716 and HL-69024 (F.W.S). L.M.C was supported by NIH training grants (T32-HL094300) and the Irving Bard Memorial Fellowship.

Footnotes

Presented at the American Heart Association Scientific Sessions, Nov. 12–16, 2011, Orlando, Fla.

Disclosures

No Disclosure

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Ruel M, Khan TA, Voisine P, Bianchi C, Sellke FW. Vasomotor dysfunction after cardiac surgery. Eur J Cardiothorac Surg. 2004;26:1002–1014. doi: 10.1016/j.ejcts.2004.07.040. [DOI] [PubMed] [Google Scholar]
  • 2.Sodha NR, Feng J, Clements RT, Bianchi C, Boodhwani M, Ramlawi R, Mieno S, Sellke FW. Protein Kinase C-α modulates microvascular reactivity in the human coronary and skeletal microcirculation. Surgery. 2007;142:243–252. doi: 10.1016/j.surg.2007.03.010. [DOI] [PubMed] [Google Scholar]
  • 3.Feng J, Chu LM, Robich M, Clements RT, Khabbaz K, Hagberg R, Liu YH, Osipov RM, Sellke FW. Endothelin-1 induced contraction and signaling in the human skeletal muscle microcirculation. Circulation. 2010;122:S150–S155. doi: 10.1161/CIRCULATIONAHA.109.928226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Feng J, Liu YH, Singh AK, Dobrilovic N, Feng WC, Chu LM, Robich MP, Khabbaz KR, Sellke FW. Impaired contractile response of human peripheral arterioles to thromboxane A-2 after cardiopulmonary bypass. Surgery. 2011;150:263–271. doi: 10.1016/j.surg.2011.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Liu YH, Sellke EW, Feng J, Clements RT, Sodha NR, Khabbaz K, Senthilnathan V, Alper SL, Sellke FW. Calcium-activated potassium channels contribute to human skeletal muscle microvascular endothelial dysfunction related to cardiopulmonary bypass. Surgery. 2008;144:239–244. doi: 10.1016/j.surg.2008.03.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Thourani VH, Weintraub WS, Stein B, Gebhart SS, Craver JM, Jones EL, Guyton RA. Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting. Ann Thorac Surg. 1999;67:1045–1052. doi: 10.1016/s0003-4975(99)00143-5. [DOI] [PubMed] [Google Scholar]
  • 7.Feng J, Liu YH, Khabbaz K, Hagberg R, Robich MP, Clements RT, Bianchi C, Sellke FW. Decreased contractile response to endothelin-1 of peripheral microvasculature from diabetic patients. Surgery. 2011;149:247–252. doi: 10.1016/j.surg.2010.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–234. doi: 10.1056/NEJM199807233390404. [DOI] [PubMed] [Google Scholar]
  • 9.Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, Cuddihy R, Cushman WC, Genuth S, Grimm RH, Jr, Hamilton BP, Hoogwerf B, Karl D, Katz L, Krikorian A, O'Connor P, Pop-Busui R, Schubart U, Simmons D, Taylor H, Thomas A, Weiss D, Hramiak I, ACCORD trial group Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–430. doi: 10.1016/S0140-6736(10)60576-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff DC, Jr, Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ, ACCORD Study Group. ACCORD Eye Study Group Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363:233–244. doi: 10.1056/NEJMoa1001288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Furnary AP. Rationale for glycemic control in cardiac surgical patients: The portland diabetic project. Insulin. 2006;1:S24–S29. [Google Scholar]
  • 12.Emani S, Ramlawi B, Sodha NR, Li J, Bianchi C, Sellke FW. Increased vascular permeability after cardiopulmonary bypass in patients with diabetes is associated with increased expression of vascular growth factor and hepatocyte growth factor. J Thorac Cardiovasc Surg. 2009;138:185–191. doi: 10.1016/j.jtcvs.2008.12.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.King GL, Geraldes Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010;106:1319–1331. doi: 10.1161/CIRCRESAHA.110.217117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord. 2010;11:61–74. doi: 10.1007/s11154-010-9134-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase C-β prevents impaired endothelium dependent vasodilation caused by hyperglycemia in humans. Circ Res. 2002;90:107–111. doi: 10.1161/hh0102.102359. [DOI] [PubMed] [Google Scholar]
  • 16.Szabo C. Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. Br J Pharmacol. 2009;156:713–727. doi: 10.1111/j.1476-5381.2008.00086.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Shenouda SM, Widlansky ME, Chen K, Xu G, Holbrook M, Tabit CE, Hamburg NM, Frame AA, Caiano TL, Kluge MA, Duess MA, Levit A, Kim B, Hartman ML, Joseph L, Shirihai OS, Vita JA. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation. 2011;124:444–453. doi: 10.1161/CIRCULATIONAHA.110.014506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Voisine P, Ruel M, Khan TA, Bianchi C, Xu S, Kohane I, Libermann TA, Out H, Saltier AR, Sellke FW. Differences in gene expression profiles of diabetic and non-diabetic patients undergoing cardiopulmonary bypass and cardioplegic arrest. Circulation. 2004;110:II280–II286. doi: 10.1161/01.CIR.0000138974.18839.02. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

01
NIHMS397829-supplement-01.pdf (80KB, pdf)

RESOURCES