Timing of Blood Transfusions and 30-Day Patient Outcomes After Coronary Artery Bypass Graft Surgery.

OBJECTIVE: Packed red blood cell transfusion during coronary artery bypass graft surgery is known to be associated with adverse outcomes. However, the association of the timing between transfusions in relation to discharge and 30-day postoperative outcomes has not been studied. The study authors investigated the impact of transfusion timing on 30-day surgical outcomes. DESIGN: A retrospective review. SETTING: At a single tertiary-care academic hospital. PARTICIPANTS: A total of 2,481 adult patients underwent primary coronary artery bypass graft surgery between January 2014 and December 2020. MEASUREMENTS AND MAIN RESULTS: The relationship between the timing of packed red blood cell transfusion (intraoperative, postoperative, or both) and 30-day postoperative outcome variables was calculated as an odds ratio. The influence of timing of transfusion on adjusted probability of postoperative complications was plotted against the lowest intraoperative hematocrit. The median age of the population was 67 years (60.0-74.0), body mass index was 28.5 (25.6-32.3) kg/m2, and 497 (20.0%) were female. A total of 1,588 (36%) patients received packed red blood cell transfusions; 182 (7.3%) received intraoperative transfusions, 489 (19.7%) received postoperative transfusions, and 222 (9.0%) received both (intraoperative and postoperative transfusions). Postoperative transfusion was associated with significantly higher odds of readmission (1.83 [1.32-2.54], p = 0.002) and heart failure (1.64 [1.2-2.23], p = 0.008) compared to patients with no transfusions; whereas intraoperative transfusions were not. CONCLUSION: The authors' data suggested that the postoperative timing of transfusion in patients undergoing coronary artery bypass graft surgery may be associated with an increased incidence of 30-day heart failure and readmission. Prospective research is needed to conclusively confirm these findings.

Geometric Indices for Predicting Ischemic Mitral Regurgitation: Correlation of Mitral Valve Coaptation Area With Tenting Height, Tenting Area and Tenting Volume.

OBJECTIVES: Ischemic remodeling of the left ventricle in patients with coronary artery disease (CAD) results in geometric changes of the mitral valve (MV) apparatus, leading to reduced MV leaflet coaptation. Although the calculation of the coaptation area has value in assessing the effects of left ventricular remodeling on the MV, it is difficult and time-consuming to measure. In this study the authors hypothesized that the tenting volume (TV) would have a greater association with coaptation area than tenting height (TH) or tenting area (TA). DESIGN: A retrospective review. SETTING: A single tertiary-care academic hospital. PARTICIPANTS: There were 145 adult patients who underwent coronary artery bypass graft surgery between April 2018 and July 2020. MEASUREMENTS AND MAIN RESULTS: Intraoperative 2- and 3-dimensional transesophageal echocardiographic studies were obtained in the precardiopulmonary bypass period. Offline analysis was used to obtain TH, TA, TV and coaptation area for each patient. Correlation between the coaptation area and the TH, TA, and TV was conducted using Pearson's correlation. The median age of the population was 68.0 years (61.0-73.3), the body mass index was 29.0 kg/m2 (25.7-33.5), and 17.8% were females. Increases in TV were the most reliable predictor of decreases in coaptation area (R2 = 0.75) followed by TA (R2 = 0.48) and TH (R2 = 0.47). CONCLUSION: As a representative of the complete topography of the MV, the authors' study demonstrated that in patients with CAD, TV has a greater negative correlation with coaptation area as compared to TH or TA.

Perioperative Multimodal General Anesthesia Focusing on Specific CNS Targets in Patients Undergoing Cardiac Surgeries: The Pathfinder Feasibility Trial.

Multimodal general anesthesia (MMGA) is a strategy that utilizes the well-known neuroanatomy and neurophysiology of nociception and arousal control in designing a rational and clinical practical paradigm to regulate the levels of unconsciousness and antinociception during general anesthesia while mitigating side effects of any individual anesthetic. We sought to test the feasibility of implementing MMGA for seniors undergoing cardiac surgery, a high-risk cohort for hemodynamic instability, delirium, and post-operative cognitive dysfunction. Twenty patients aged 60 or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries were enrolled in this non-randomized prospective observational feasibility trial, wherein we developed MMGA specifically for cardiac surgeries. Antinociception was achieved by a combination of intravenous remifentanil, ketamine, dexmedetomidine, and magnesium together with bupivacaine administered as a pecto-intercostal fascial block. Unconsciousness was achieved by using electroencephalogram (EEG)-guided administration of propofol along with the sedative effects of the antinociceptive agents. EEG-guided MMGA anesthesia was safe and feasible for cardiac surgeries, and exploratory analyses found hemodynamic stability and vasopressor usage comparable to a previously collected cohort. Intraoperative EEG suppression events and postoperative delirium were found to be rare. We report successful use of a total intravenous anesthesia (TIVA)-based MMGA strategy for cardiac surgery and establish safety and feasibility for studying MMGA in a full clinical trial. Clinical Trial Number: www.clinicaltrials.gov; identifier NCT04016740 (https://clinicaltrials.gov/ct2/show/NCT04016740).

Update: Gender differences in CABG outcomes-Have we bridged the gap?

BACKGROUND: Appreciation of unique presentation, patterns and underlying pathophysiology of coronary artery disease in women has driven gender based risk stratification and risk reduction efforts over the last decade. Data regarding whether these advances have resulted in unequivocal improvements in outcomes of CABG in women is conflicting. The objective of our study was to assess gender differences in post-operative outcomes following CABG. METHODS: Retrospective analyses of institutional data housed in the Society of Thoracic Surgeons (STS) database for patients undergoing CABG between 2002 and 2020 were conducted. Multivariable regression analysis was conducted to investigate gender differences in post-operative outcomes. P-values were adjusted using Bonferroni correction to reduce type-I errors. RESULTS: Our final cohort of 6,250 patients had fewer women than men (1,339 vs. 4,911). more women were diabetic (52.0% vs. 41.2%, p<0.001) and hypertensive (89.1% vs. 84.0%, p<0.001). Women had higher adjusted odds of developing ventilator dependence >48 hours (OR: 1.65 [1.21, 2.45], p = 0.002) and cardiac readmissions (OR: 1.56 [1.27, 2.30], p = 0.003). After adjustment for comorbidity burden, mortality rates in women were comparable to those of age-matched men. CONCLUSION: The findings of our study indicate that despite apparent reduction of differences in mortality, the burden of postoperative morbidity is still high among women.

Cardiopulmonary Bypass Suppresses Forkhead Box O3 and Downstream Autophagy in the Diabetic Human Heart.

BACKGROUND: Autophagy is an integral component of cellular homeostasis and metabolism. The exact mechanism of impaired autophagy in diabetes mellitus is unknown. Forkhead Box O3 (FOXO3α) is a key regulator of oxidative stress-related responses. We hypothesize FOXO3α is a direct upstream regulator of the autophagy pathway, and its upregulation is compromised in diabetic patients during stress of cardiopulmonary bypass (CPB). METHODS: The study enrolled 32 diabetic and 33 nondiabetic patients undergoing a cardiac surgical procedure on CPB. Right atrial tissue and serum samples were collected before and after CPB per protocol. A set of key components were quantitatively assessed and compared by microarray, immunoblotting, and immunohistochemistry studies. Data were analyzed using paired or unpaired student test. A P of <.05 or less was considered significant. RESULTS: Serum microarray showed FOXO3α was upregulated in the diabetic vs nondiabetic group after CPB (P = .033), autophagy-related 4B gene and Beclin 1 gene were greatly upregulated in the nondiabetic group (P = .028 and P = .002, respectively). On immunoblotting, there was upregulation of FOXO3α in the nondiabetic patients after CPB (P = .003). There were increased levels of Beclin-1, Bcl-2, and light chain 3B after CPB in the nondiabetic group only (P = .016, P = .005, P = .002, respectively). Sirtuin 1, Unc-51-like autophagy activating kinase 1 (ULK1), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), and mammalian target of rapamycin (mTOR) were not significantly changed in the nondiabetic group after CPB. CONCLUSIONS: Compared with nondiabetic patients, there was no significant upregulation of FOXO3α in diabetic patients, which could possibly explain the lack of upregulation of the autophagy process after CPB. FOXO3α could potentially serve as a therapeutic target to improve cellular homeostasis.

Mitochondrial DAMPs Are Released During Cardiopulmonary Bypass Surgery and Are Associated With Postoperative Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most frequent complication of surgery performed on cardiopulmonary bypass (CPB) and recent work associates CPB with postoperative inflammation. We have shown that all tissue injury releases mitochondrial damage associated molecular patterns (mtDAMPs) including mitochondrial DNA (mtDNA). This can act as a direct, early activator of neutrophils (PMN), eliciting a systemic inflammatory response syndrome (SIRS) while suppressing PMN function. Neutrophil Extracellular Traps (NETs) are crucial to host defence. They carry out NETosis wherein webs of granule proteins and chromatin trap and kill bacteria. We hypothesised that surgery performed on CPB releases mtDAMPs into the circulation. Molecular patterns thus mobilised during CPB might then participate in the pathogenesis of SIRS and predict postoperative complications like AF [1]. METHODS: We prospectively studied 16 patients undergoing elective operations on CPB. Blood was sampled preoperatively, at the end of CPB and on days 1-2 postoperatively. Plasma samples were analysed for mtDNA. Neutrophil IL-6 gene expression was studied to assess induction of SIRS. Neutrophils were also assayed for the presence of neutrophil extracellular traps (NETs/NETosis). These biologic findings were then correlated to clinical data and compared in patients with and without postoperative AF (POAF). RESULTS: Mitochondrial DNA was significantly elevated following CPB (six-fold increase post-CPB, p=0.008 and five-fold increase days 1-2, p=0.02). Patients with POAF showed greater increases in mtDNA post-CPB than those without. Postoperative AF was seen in all patients with a ≥2-fold increase of mtDNA (p=0.037 vs. <2-fold). Neutrophil IL-6 gene transcription increased postoperatively demonstrating SIRS that was greatest days 1-2 (p=0.039). Neutrophil extracellular trap (NET) formation was markedly suppressed in the post-CPB state. CONCLUSION: Mitochondrial DNA is released by CPB surgery and is associated with POAF. IL-6 gene expression increases after CPB, demonstrating the evolution of postoperative SIRS. Lastly, cardiac surgery on CPB also suppressed PMN NETosis. Taken together, our data suggest that mtDNA released during surgery on CPB, may be involved in the pathogenesis of SIRS and related postoperative inflammatory events like POAF and infections. Mitochondrial DNA may therefore prove to be an early biomarker for postoperative complications with the degree of association to be determined in appropriately sized studies. If mtDNA is directly involved in cardiac inflammation, mtDNA-induced toll-like receptor-9 (TLR9) signalling could also be targeted therapeutically.

Changes in Tricuspid Annular Geometry in Patients with Functional Tricuspid Regurgitation.

OBJECTIVE: To determine whether the indices of tricuspid annular dynamics that signify irreversible tricuspid valvular remodeling can improve surgical decision making by helping to better identify patients with functional tricuspid regurgitation who could benefit from annuloplasty. DESIGN: Retrospective analysis study. SETTING: Tertiary hospital. PARTICIPANTS: A total number of 55 patients were selected, 18 with functional tricuspid valve (TV) regurgitation and 37 normal nonregurgitant TVs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: When comparing the basal, mid, and longitudinal diameters of the right ventricle between the nonregurgitant valve (NTR) group and the functional tricuspid regurgitation (FTR) group, tricuspid annulus was more dilated (p < 0.001, p = 0.001, and p = 0.006, respectively) and less nonplanar (p < 0.001) in the FTR group. At end-systole (ES), the posterolateral-anteroseptal axis was significantly greater in the FTR group than in the NTR group (mean difference = 7.15 mm; p < 0.001). The right ventricle in the FTR group was also significantly dilated with greater leaflet restriction (p = 0.015). CONCLUSIONS: As compared to NTR TVs, FTR is associated with identifiable indices of tricuspid annular structural changes that are indicative of irreversible remodeling.

Mitochondrial Dysfunction in Atrial Tissue of Patients Developing Postoperative Atrial Fibrillation.

BACKGROUND: Mitochondria are the major site of cellular oxidation. Metabolism and oxidative stress have been implicated as possible mechanisms for postoperative atrial fibrillation (POAF) after cardiac operations. Establishing the precise nature of mitochondrial dysfunction as an etiologic factor for oxidative stress-related cell death and apoptosis could further the understanding of POAF. To establish this relationship, mitochondrial function was studied in patients undergoing cardiac operations that developed POAF and compared it with patients without POAF. METHODS: Right atrial tissue and serum samples were collected from 85 patients before and after cardiopulmonary bypass. Microarray analysis (36 patients) and RNA sequencing (5 patients) were performed on serum and atrial tissues, respectively, for identifying significantly altered genes in patients who developed POAF. On the basis of these results, Western blot was performed in 52 patients for the genes that were most altered, and functional pathways were established. RESULTS: POAF developed in 30.6% (n = 26) of patients. Serum microarray showed significant fold changes in the expression of 49 genes involved in inflammatory response, oxidative stress, apoptosis, and amyloidosis (p < 0.05) in the POAF group. Similarly, RNA sequencing demonstrated an increased expression of genes associated with inflammatory response, fatty acid metabolism, and apoptosis in the POAF group (false discovery rate > 0.05). Immunoblotting showed a significant increase in TNFAIP6 (tumor necrosis factor, α-induced protein 6; p = 0.02) and transforming growth factor-ß (p = 0.04) after cardiopulmonary bypass in the POAF group. There was a significant decrease in PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α; p = 0.002) and CPT1 (carnitine palmitoyltransferase I; p < 0.0005) in the POAF group after cardiopulmonary bypass. CONCLUSIONS: Compared with patients without POAF, those with POAF demonstrated mitochondrial dysfunction at various levels that are suitable for potential pharmacotherapy.

Tricuspid annulus: A spatial and temporal analysis.

BACKGROUND: Traditional two-dimensional (2D) echocardiographic evaluation of tricuspid annulus (TA) dilation is based on single-frame measurements of the septolateral (S-L) dimension. This may not represent either the axis or the extent of dynamism through the entire cardiac cycle. In this study, we used real-time 3D transesophageal echocardiography (TEE) to analyze geometric changes in multiple axes of the TA throughout the cardiac cycle in patients without right ventricular abnormalities. MATERIALS AND METHODS: R-wave-gated 3D TEE images of the TA were acquired in 39 patients undergoing cardiovascular surgery. The patients with abnormal right ventricular/tricuspid structure or function were excluded from the study. For each patient, eight points along the TA were traced in the 3D dataset and used to reconstruct the TA at four stages of the cardiac cycle (end- and mid-systole, end- and mid-diastole). Statistical analyses were applied to determine whether TA area, perimeter, axes, and planarity changed significantly over each stage of the cardiac cycle. RESULTS: TA area (P = 0.012) and perimeter (P = 0.024) both changed significantly over the cardiac cycle. Of all the axes, only the posterolateral-anteroseptal demonstrated significant dynamism (P < 0.001). There was also a significant displacement in the vertical axis between the points and the regression plane in end-systole (P < 0.001), mid-diastole (P = 0.014), and mid-systole (P < 0.001). CONCLUSIONS: The TA demonstrates selective dynamism over the cardiac cycle, and its axis of maximal dynamism is different from the axis (S-L) that is routinely measured with 2D TEE.

Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial.

BACKGROUND: Thiamine is a vitamin that is essential for adequate aerobic metabolism. The objective of this study was to determine if thiamine administration prior to coronary artery bypass grafting would decrease post-operative lactate levels as a measure of increased aerobic metabolism. METHODS: We performed a randomized, double-blind, placebo-controlled trial of patients undergoing coronary artery bypass grafting. Patients were randomized to receive either intravenous thiamine (200 mg) or placebo both immediately before and again after the surgery. Our primary endpoint was post-operative lactate levels. Additional endpoints included pyruvate dehydrogenase activity, global and cellular oxygen consumption, post-operative complications, and hospital and intensive care unit length of stay. RESULTS: Sixty-four patients were included. Thiamine levels were significantly higher in the thiamine group as compared to the placebo group immediately after surgery (1200 [683, 1200] nmol/L vs. 9 [8, 13] nmol/L, p < 0.001). There was no difference between the groups in the primary endpoint of lactate levels immediately after the surgery (2.0 [1.5, 2.6] mmol/L vs. 2.0 [1.7, 2.4], p = 0.75). Relative pyruvate dehydrogenase activity was lower immediately after the surgery in the thiamine group as compared to the placebo group (15% [11, 37] vs. 28% [15, 84], p = 0.02). Patients receiving thiamine had higher post-operative global oxygen consumption 1 hour after the surgery (difference: 0.37 mL/min/kg [95% CI: 0.03, 0.71], p = 0.03) as well as cellular oxygen consumption. We found no differences in clinical outcomes. CONCLUSIONS: There were no differences in post-operative lactate levels or clinical outcomes between patients receiving thiamine or placebo. Post-operative oxygen consumption was significantly increased among patients receiving thiamine. TRIAL REGISTRATION: clinicaltrials.gov NCT02322892, December 14, 2014.

Early Cellular Changes in the Ascending Aorta and Myocardium in a Swine Model of Metabolic Syndrome.

BACKGROUND: Metabolic syndrome is associated with pathological remodeling of the heart and adjacent vessels. The early biochemical and cellular changes underlying the vascular damage are not fully understood. In this study, we sought to establish the nature, extent, and initial timeline of cytochemical derangements underlying reduced ventriculo-arterial compliance in a swine model of metabolic syndrome. METHODS: Yorkshire swine (n = 8 per group) were fed a normal diet (ND) or a high-cholesterol (HCD) for 12 weeks. Myocardial function and blood flow was assessed before harvesting the heart. Immuno-blotting and immuno-histochemical staining were used to assess the cellular changes in the myocardium, ascending aorta and left anterior descending artery (LAD). RESULTS: There was significant increase in body mass index, blood glucose and mean arterial pressures (p = 0.002, p = 0.001 and p = 0.024 respectively) in HCD group. At the cellular level there was significant increase in anti-apoptotic factors p-Akt (p = 0.007 and p = 0.002) and Bcl-xL (p = 0.05 and p = 0.01) in the HCD aorta and myocardium, respectively. Pro-fibrotic markers TGF-ß (p = 0.01), pSmad1/5 (p = 0.03) and MMP-9 (p = 0.005) were significantly increased in the HCD aorta. The levels of pro-apoptotic p38MAPK, Apaf-1 and cleaved Caspase3 were significantly increased in aorta of HCD (p = 0.03, p = 0.04 and p = 0.007 respectively). Similar changes in coronary arteries were not observed in either group. Functionally, the high cholesterol diet resulted in significant increase in ventricular end systolic pressure and-dp/dt (p = 0.05 and p = 0.007 respectively) in the HCD group. CONCLUSION: Preclinical metabolic syndrome initiates pro-apoptosis and pro-fibrosis pathways in the heart and ascending aorta, while sparing coronary arteries at this early stage of dietary modification.

Management of a patient with lupus anticoagulant and antiphospholipid syndrome for off-pump coronary artery bypass grafting using the Hepcon system.

Patients with serum lupus anticoagulant antibodies (LAC) with or without antiphospholipid syndrome who present for cardiac surgery provide a unique set of challenges. Chief among these are the interference with anticoagulation monitoring by LAC. We present a case of such a patient who presented to us for coronary artery bypass grafting. We follow with a review of LAC and antiphospholipid syndrome and present a strategy for ensuring adequate anticoagulation during cardiac surgery in the background of previously published reports.

Pilot proteomic profile of differentially regulated proteins in right atrial appendage before and after cardiac surgery using cardioplegia and cardiopulmonary bypass.

BACKGROUND: Although highly protective, cardiac surgery using cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function which results in a greatly enhanced risk of mortality. Acute changes in myocardial contractile activity are likely regulated via protein modifications. We performed the following study to determine changes in the protein profile of human myocardium following CP/CPB. METHODS AND RESULTS: Right atrial appendage was collected from 8 male patients pre and post-CP/CPB. Atrial tissue lysates were subjected to 2-dimensional electrophoresis, total protein staining, gel averaging, and quantitative densitometry. Ten prominent spots regulated in response to CP/CPB were identified using mass spectrometry. Two hundred twenty-five and 256 protein spots were reliably detected in 2D-gels from pre- and post-CP/CPB patients, respectively. Five unique (ie, not detected post-CP/CPB) and 17 significantly increased spots were detected pre-CP/CPB. Thirty-four unique and 25 significantly increased spots were detected in the post-CP/CPB group. Identified proteins that changed after CP/CPB included: MLC-2a, ATP-synthase delta chain and Enoyl-CoenzymeA hydratase, glutathione-s-transferase omega, alpha-1-acid-glycoprotein, and phosphatidylethanolamine-binding protein. CONCLUSIONS: Cardiac surgery results in multiple consistent changes in the human myocardial protein profile. CP/CPB modifies specific cytoskeletal, metabolic, and inflammatory proteins potentially involved in deleterious effects of CP/CPB.

Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest.

BACKGROUND: Cardioplegic arrest (CP) followed by reperfusion after cardiopulmonary bypass induces coronary microvascular dysfunction. We investigated the role of calcium-activated potassium (K(Ca)) channels in this dysfunction in the human coronary microvasculature. METHODS AND RESULTS: Human atrial tissue was harvested before CP from a nonischemic segment and after CP from an atrial segment exposed to hyperkalemic cold blood CP (mean CP time, 58 minutes) followed by 10-minute reperfusion. In vitro relaxation responses of precontracted arterioles (80 to 180 mum in diameter) in a pressurized no-flow state were examined in the presence of K(Ca) channel activators/blockers and several other vasodilators. We also examined expression and localization of K(Ca) channel gene products in the coronary microvasculature using reverse transcriptase-polymerase chain reaction, immunoblot, and immunofluorescence photomicroscopy. Post-CP reperfusion relaxation responses to the activator of intermediate and small conductance K(Ca) channels (IK(Ca)/SK(Ca)), NS309 (10(-5) M), and to the endothelium-dependent vasodilators, substance P (10(-8) M) and adenosine 5diphosphate (10(-5) M), were significantly reduced compared with pre-CP responses (P<0.05, n=8/group). In contrast, relaxation responses to the activator of large conductance K(Ca) channels (BK(Ca)), NS1619 (10(-5) M), and to the endothelium-independent vasodilator, sodium nitroprusside (10(-4) M), were unchanged pre- and post-CP reperfusion (n=8/group). Endothelial denudation significantly diminished NS309-induced vasodilatation and abolished substance P- or adenosine 5 diphosphate-induced relaxation (P<0.05), but had no effect on relaxation induced by either NS1619 or sodium nitroprusside. The total polypeptide levels of BK(Ca), IK(Ca), and SK(Ca) and the expression of IK(Ca) mRNA were not altered post-CP reperfusion. CONCLUSIONS: Cardioplegic arrest followed by reperfusion after cardiopulmonary bypass causes microvascular dysfunction associated with and likely in part due to impaired function of SK(Ca) and IK(Ca) channels in the coronary microcirculation. These results suggest novel mechanisms of endothelial and smooth muscle microvascular dysfunction after cardiac surgery.

Calcium-activated potassium channels contribute to human skeletal muscle microvascular endothelial dysfunction related to cardiopulmonary bypass.

BACKGROUND: We investigated the role of calcium-activated potassium (K(Ca)) channel activity in human skeletal muscle microvascular function in the setting of cardiopulmonary bypass (CPB). METHODS AND RESULTS: Human skeletal muscle arterioles (80- to 180 microm in diameter) were dissected from tissue harvested before and after CPB. In vitro relaxation responses of precontracted arterioles in a pressurized no-flow state were examined in the presence of K(Ca) channel activators/blockers and several other vasodilators. Post-CPB responses to the activator of intermediate (IK(Ca)) and small conductance (SK(Ca)) K(Ca) channels, NS309, to the endothelium-dependent vasodilator adenosine 5'-diphosphate (ADP), and to substance P were reduced compared with pre-CPB responses (P < .05), respectively, whereas responses to the activator of large conductance (BK(Ca)) K(Ca) channels, NS1619, and to the endothelium-independent vasodilator, sodium nitroprusside (SNP) were unchanged. Endothelial denudation decreased NS309-induced relaxation and abolished that induced by ADP or substance P (P < .05), but had no effect on relaxation induced by either NS1619 or SNP. Polypeptide levels of BK(Ca), IK(Ca), and SK3(Ca) were not altered post-CPB. CONCLUSION: IK/SK-mediated relaxation is predominantly endothelium dependent, whereas BK-mediated relaxation seems to be largely independent of endothelial function in human skeletal muscle microvasculature. CPB-associated microvascular dysfunction likely arises in part from impaired function of endothelial SK and IK channels in the peripheral microvasculature.