Preoperative rectus femoris muscle ultrasound, its relationship with frailty scores, and the ability to predict recovery after cardiac surgery: a prospective cohort study.

BACKGROUND: Frailty is common in patients undergoing cardiac surgery and is associated with poorer postoperative outcomes. Ultrasound examination of skeletal muscle morphology may serve as an objective assessment tool as lean muscle mass reduction is a key feature of frailty. METHODS: This study investigated the association of ultrasound-derived muscle thickness, cross-sectional area, and echogenicity of the rectus femoris muscle (RFM) with preoperative frailty and predicted subsequent poor recovery after surgery. Eighty-five patients received preoperative RFM ultrasound examination and frailty-related assessments: Clinical Frailty Scale (CFS) and 5-m gait speed test (GST5m). Association of each ultrasound measurement with frailty assessments was examined. Area under receiver-operating characteristic curve (AUROC) was used to assess the discriminative ability of each ultrasound measurement to predict days at home within 30 days of surgery (DAH30). RESULTS: By CFS and GST5m criteria, 13% and 34% respectively of participants were frail. RFM cross-sectional area alone demonstrated moderate predictive association for frailty by CFS criterion (AUROC: 0.76, 95% CI: 0.66-0.85). Specificity improved to 98.7% (95% CI: 93.6%-100.0%) by utilising RFM cross-sectional area as an 'add-on' test to a positive gait speed test, and thus a combined muscle size and function test demonstrated higher predictive performance (positive likelihood ratio: 40.4, 95% CI: 5.3-304.3) for frailty by CFS criterion than either test alone (p < 0.001). The combined 'add-on' test predictive performance for DAH30 (AUROC: 0.90, 95% CI: 0.81-0.95) may also be superior to either CFS or gait speed test alone. CONCLUSIONS: Preoperative RFM ultrasound examination, especially when integrated with the gait speed test, may be useful to identify patients at high risk of frailty and those with poor outcomes after cardiac surgery. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trials Registry (ChiCTR2000031098) on 22 March 2020.

Effect of prehabilitation-related DIETary protein intake on Quality of Recovery after elective cardiac surgery (DIETQoR) study: protocol of a randomised controlled trial.

INTRODUCTION: Protein malnutrition is associated with higher risks of postoperative complications, mortality, prolonged postoperative stays in hospital, slower physical and mental recovery after surgery and lower subsequent health-related quality of life. To reduce the risk of postoperative morbidity and mortality, nutritional prehabilitation programmes have been developed recently to build up patient's nutritional reserve to withstand the stress of surgery. The intervention involves nutritional screening and counselling, and increasing dietary protein intake in protein-malnourished patients in the several weeks before surgery. However, there are few well-conducted preoperative studies to examine the effect of increasing dietary protein intake on the quality of recovery of malnourished patients after elective cardiac surgery. METHOD AND ANALYSIS: This randomised controlled trial of malnourished patients undergoing major elective cardiac surgery will compare the quality of postoperative recovery in patients with or without nutritional prehabilitation. One hundred and thirty-two patients will be randomised to receive nutritional prehabilitation (target-adjusted whey protein powder supplementation and an individualised 1 hour session/week counselling by a dietician 1 month before operation date) or standard care (no nutritional prehabilitation). Primary outcomes will be the quality of recovery after surgery (15-item Quality of Recovery) on the third postoperative day. Secondary outcomes will include days (alive and) at home within 30 days, changes in the WHO Disability Assessment Schedule 2.0, changes in health-related quality of life (EQ-5D) and Cardiac Postoperative Morbidity Survey. An outcomes assessor will be blinded to the treatment allocation. Appropriate univariate analyses, generalised estimating equations and multiple regressions will be performed for intention-to-treat and per-protocol analyses. ETHICS AND DISSEMINATION: The Joint CUHK-NTEC Clinical Research Ethics Committee approved the study protocol (CREC Ref. No.: 2021.703 T). The findings will be presented at scientific meetings, peer-reviewed journals and to study participants. TRIAL REGISTRATION NUMBER: ChiCTR2200057463.

Hepatorenal dysfunction predicts operative mortality after triple valve surgery: Utility of MELD-Na.

BACKGROUND: Despite significant advancements in operative techniques and myocardial protection, triple valve surgery (TVS) remains a formidable operation with a relatively high in-hospital mortality. We evaluated the prognostic value of Model for End-stage Liver Disease score including sodium (MELD-Na) for mortality after TVS and its predictive value when incorporated in the EuroSCORE risk model. METHODS: We performed a retrospective cohort study of 61 consecutive patients who underwent TVS from November 2005 to June 2016. Demographics, clinical, biochemical, and operative data were collected and analyzed. RESULTS: Median follow-up duration was 8.0 years. The majority (70.5%) of patients suffered from rheumatic heart disease and underwent mechanical double valve replacement with tricuspid valve repair. There were six operative deaths (9.84%), with the most common cause of death being multiorgan failure (83.3%). In 26.2% of the cohort, the MELD-Na score was moderately elevated at 9 to 15. A small fraction (4.9%) had a severely elevated MELD-Na greater than 15. Patients with a MELD-Na greater than 9 had a higher unadjusted rate of operative mortality, prolonged ventilation, need for dialysis and acute liver failure after TVS. Hierarchical logistic regression was performed using logistic EuroSCORE as the base model. After risk adjustment, each point of MELD-Na score increase was associated with 1.405 times increase in odds of operative mortality. The regression analysis was repeated by incorporating individual components of the MELD-Na score, including bilirubin, sodium, and albumin. All three biochemical parameters were significantly associated with operative mortality CONCLUSION: MELD-Na score as a quantifier of hepatorenal dysfunction is sensitive and specific for operative mortality after triple valve surgery.

Effect of preparative rehabilitation on recovery after cardiac surgery: A systematic review.

BACKGROUND: Physical prehabilitation (preparative rehabilitation) programs may have beneficial effects on enhancing physical strength and functional status before surgery, but their effects on postoperative recovery are unclear. OBJECTIVES: This systematic review investigated the effectiveness of physical prehabilitation programs before cardiac surgery on postoperative recovery and other perioperative outcomes. METHODS: We searched for reports of randomised controlled trials of any prehabilitation programs that included physical activity or an exercise training component in adults undergoing elective cardiac surgery, published in any language, from six bibliographic databases (last search on June 20, 2019). We assessed trials for risk of bias, overall certainty of evidence and quality of intervention reporting using the Cochrane Risk of Bias Assessment Tool, GRADE system and the Template for Intervention Description and Replication checklist and guide, respectively. RESULTS: All 7 studies (726 participants) were at high risk of bias because of lack of blinding. The quality of prehabilitation reporting was moderate because program adherence was rarely assessed. The timing of prehabilitation ranged from 5 days to 16 weeks before surgery and from face-to-face exercise prescription to telephone counselling and monitoring. We found uncertain effects of prehabilitation on postoperative clinical outcomes (among the many outcomes assessed): perioperative mortality (Peto odds ratio 1.30, 95% confidence interval [CI] 0.28 to 5.95; I2=0%; low-certainty evidence) and postoperative atrial fibrillation (relative risk 0.75, 95% CI 0.38 to 1.46; I2=50%; very low-certainty evidence). However, prehabilitation may improve postoperative functional capacity and slightly shorten the hospital stay (mean difference -0.66 days, 95% CI -1.29 to -0.03; I2=45%; low-certainty evidence). CONCLUSION: Despite the high heterogeneity among physical prehabilitation trials and the uncertainty regarding robust clinical outcomes, physical prehabilitation before cardiac surgery seems to enhance selected postoperative functional performance measures and slightly reduce the hospital length of stay after cardiac surgery.

Pocket-Size Mobile Echocardiographic Screening of Thoracic Aortic Aneurysms in Hypertensive Patients.

BACKGROUND: Patients with hypertension may develop a thoracic aortic aneurysm (TAA) that can be asymptomatic but potentially life-threatening. We sought to assess the prevalence of asymptomatic TAA among hypertensive patients with a point-of-care screening program using pocket-size mobile echocardiographic (PME) devices. METHODS: We prospectively performed transthoracic aortic ultrasound using a PME device on patients attending our hypertension clinics between June 2016 and July 2018. The echo examinations were performed by a research fellow to obtain aortic diameter measurements including the aortic sinus, sinotubular junction, ascending aorta, aortic arch, and descending thoracic aorta through various standard echo views. Images were stored on the PME and transferred to a desktop computer for measurements and further statistical analysis. RESULTS: During the study period 1529 hypertensive patients (mean age, 62 years [range, 30-85]; 824 men) were recruited. The prevalence of TAA (defined as maximum aortic diameter ≥ 4.5 cm and/or >50% larger than the diameter of the adjacent normal aorta) in our study population was 7.5% (115/1529). Multiple logistic regression analysis identified male gender (odds ratio, 2.120; P < .001) and older age (odds ratio, 1.031; P < .001) as independent factors associated with TAA. CONCLUSIONS: Silent TAA is common among hypertensive patients in Hong Kong. We found the PME device to be effective in detecting TAA in a clinic setting. Such an approach may be useful for early detection of TAA among at-risk patients, allowing aggressive blood pressure control and early surgical intervention to prevent catastrophic complications.

Effect of preoperative education and ICU tour on patient and family satisfaction and anxiety in the intensive care unit after elective cardiac surgery: a randomised controlled trial.

BACKGROUND: Preoperative education may help participants to psychologically prepare themselves for surgery, but the outcomes of such preparation have rarely been assessed in patients requiring postoperative care in the intensive care unit (ICU) as well as in family members. OBJECTIVE: To assess the effect of a preoperative multifaceted education intervention on patient and family satisfaction levels in the ICU and measures of perioperative patients' anxiety and depression. TRIAL DESIGN: Single-centre, two-armed, parallel, superiority, randomised controlled trial. Healthcare professionals in ICU and outcome assessor were blinded to treatment allocation. PARTICIPANTS: 100 elective coronary artery bypass grafting±valve surgery patients and their family members. INTERVENTIONS: Preoperative education comprising of a video and ICU tour in addition to standard care (treatment), versus standard care (control). OUTCOMES: Patient and family satisfaction levels with ICU using validated PS-ICU23 and FS-ICU24 questionnaires (0-100), respectively; change in perioperative anxiety and depression scores between 1 day presurgery and 3 days postsurgery. RESULTS: Among 100 (50 treatment, 50 control) patients and 98 (49 treatment, 49 control) family members, 94 (48 treatment, 46 control) patients and 94 (47 treatment, 47 control) family members completed the trial. Preoperative education was associated with higher overall patient (mean difference (MD) 6.7, 95% CI 0.2 to 13.2) and family (MD 10.0, 95% CI 3.8 to 16.3) satisfaction scores. There was a weak association between preoperative education and a reduction in patient's anxiety scores over time (MD -1.7, 95% CI -3.5 to 0.0). However, there was no evidence of a treatment effect on patient's depression scores over time (MD -0.6, 95% CI -2.3 to 1.2). CONCLUSION: Providing comprehensive preoperative information about ICU to elective cardiac surgical patients improved patient and family satisfaction levels and may decrease patients' anxiety levels. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-15006971.

PREhabilitation for improving QUality of recovery after ELective cardiac surgery (PREQUEL) study: protocol of a randomised controlled trial.

INTRODUCTION: Frailty is a multidimensional syndrome in which multiple small physiological deficits accumulate gradually, resulting in a loss of physiological reserve and adaptability, putting a patient that is exposed to a stressor at a higher risk of adverse outcomes. Both pre-frailty and frailty are associated with poor patient outcomes and higher healthcare costs. The effect of a prehabilitation programme and standard care on the quality of recovery in pre-frail and frail patients undergoing elective cardiac surgery will be compared. METHOD AND ANALYSIS: A single-centre, superiority, stratified randomised controlled trial with a blinded outcome assessment and intention-to-treat analysis. Pre-frail and frail patients awaiting elective coronary artery bypass graft, with or without valvular repair/replacement, will be recruited. 164 participants will be randomly assigned to either prehabilitation (intervention) or standard care (no intervention) groups. The prehabilitation group will attend two sessions/week of structured exercise (aerobic and resistance) training, supervised by a physiotherapist, for 6-10 weeks before surgery with early health promotion advice in addition to standard care. The standard care group will receive the usual routine care (no prehabilitation). Frailty will be assessed at baseline, hospital admission and at 1 and 3 months after surgery. The primary outcomes will be participants' perceived quality of recovery (15-item Quality of Recovery questionnaire) after surgery (day 3), days at home within 30 days of surgery and the changes in WHO Disability Assessment Schedule 2.0 score between baseline and at 1 and 3 months after surgery. Secondary outcomes will include major adverse cardiac and cerebrovascular events, psychological distress levels, health-related quality of life and healthcare costs. ETHICS AND DISSEMINATION: The Joint CUHK-NTEC Clinical Research Ethics Committee approved the study protocol (CREC Ref. No. 2017.696 T). The findings will be presented at scientific meetings, in peer-reviewed journals and to study participants. TRIAL REGISTRATION NUMBER: ChiCTR1800016098; Pre-results.

Effect of motor subtypes of delirium in the intensive care unit on fast-track failure after cardiac surgery.

OBJECTIVE: The purpose of the study was to evaluate the association between motor subtypes of postoperative delirium in the intensive care unit and fast-track failure (a composite outcome of prolonged stay in the intensive care unit >48 hours, intensive care unit readmission, and 30-day mortality) after cardiac surgery. METHODS: This was a secondary analysis of a prospective cohort study of 600 consecutive adults undergoing cardiac surgery at a university hospital in Hong Kong (July 2013 to July 2015). The motor subtypes of delirium were classified using the Richmond Agitation Sedation Score and Confusion Assessment Method intensive care unit assessments performed by trained bedside nurses. A generalized estimating equation was used to estimate a common relative risk of fast-track failure associated with motor subtypes. RESULTS: The incidences of hypoactive, hyperactive, and mixed motor subtypes were 4.3% (n = 26), 4.0% (n = 24), and 5.5% (n = 33), respectively. Fast-track failure occurred in 88 patients (14.7%). There was an association between delirium (all subtypes) and fast-track failure (P = .048); hyperactive delirium (relative risk, 1.95; 95% confidence interval, 0.96-3.94); hypoactive delirium (relative risk, 2.79; 95% confidence interval, 1.34-5.84); and mixed delirium (relative risk, 2.55; 95% confidence interval, 1.11-5.88). Hypoactive and mixed subtypes were associated with prolonged intensive care unit stay (both P = .001). CONCLUSIONS: Patients with pure hypoactive delirium had a similar risk of developing fast-track failure as other motor subtypes. Differentiation of motor subtypes is unlikely to be clinically important for prognostication of fast-track failure. However, because delirium is associated with poor outcomes, potential treatment strategies should address all subtypes equally.

Activation of PERK branch of ER stress mediates homocysteine-induced BKCa channel dysfunction in coronary artery via FoxO3a-dependent regulation of atrogin-1.

The molecular mechanism of endoplasmic reticulum (ER) stress in vascular pathophysiology remains inadequately understood. We studied the role of ER stress in homocysteine-induced impairment of coronary dilator function, with uncovering the molecular basis of the effect of ER stress on smooth muscle large-conductance Ca2+-activated K+ (BKCa) channels. The vasodilatory function of BKCa channels was studied in a myograph using endothelium-denuded porcine small coronary arteries. Primary cultured porcine coronary artery smooth muscle cells were used for mRNA and protein measurements and current recording of BKCa channels. Homocysteine inhibited vasorelaxant response to the BKCachannel opener NS1619, lowered BKCa ß1 subunit protein level and suppressed BKCa current. Inhibition of ER stress restored BKCa ß1 protein level and NS1619-evoked vasorelaxation. Selective blockade of the PKR-like ER kinase (PERK) yielded similarly efficient restoration of BKCa ß1, preserving BKCa current and BKCa-mediated vasorelaxation. The restoration of BKCa ß1 by PERK inhibition was associated with reduced atrogin-1 expression and decreased nuclear localization of forkhead box O transcription factor 3a (FoxO3a). Silencing of atrogin-1 prevented homocysteine-induced BKCa ß1 loss and silencing of FoxO3a prevented atrogin-1 upregulation induced by homocysteine, accompanied by preservation of BKCa ß1 protein level and BKCa current. ER stress mediates homocysteine-induced BKCa channel inhibition in coronary arteries. Activation of FoxO3a by PERK branch underlies the ER stress-mediated BKCa inhibition through a mechanism involving ubiquitin ligase-enhanced degradation of the channel ß1 subunit.

Impairment of Coronary Endothelial Function by Hypoxia-Reoxygenation Involves TRPC3 Inhibition-mediated KCa Channel Dysfunction: Implication in Ischemia-Reperfusion Injury.

Despite increasing knowledge of the significance of calcium-activated potassium (KCa) and canonical transient receptor potential (TRPC) channels in endothelial physiology, no studies so far have investigated the link between these two distinct types of channels in the control of vascular tone in pathological conditions. We previously demonstrated that hypoxia-reoxygenation (H-R) inhibits endothelial KCa and TRPC3 channels in porcine coronary arteries (PCAs). The present study further investigated whether modulation of TRPC3 is involved in H-R-induced KCa channel inhibition and associated vasodilatory dysfunction using approaches of wire myography, whole-cell voltage-clamp, and coimmunoprecipitation. Pharmacological inhibition or siRNA silencing of TRPC3 significantly suppressed bradykinin-induced intermediate- and small-conductance KCa (IKCa and SKCa) currents in endothelial cells of PCAs (PCAECs). TRPC3 protein exists in physical association with neither IKCa nor SKCa. In H-R-exposed PCAECs, the response of IKCa and SKCa to bradykinin-stimulation and to TRPC3-inhibition was markedly weakened. Activation of TRPC3 channels restored H-R-suppressed KCa currents in association with an improved endothelium-derived hyperpolarizing factor (EDHF)-type vasorelaxation. We conclude that inhibition of TRPC3 channels contributes to H-R-induced suppression of KCa channel activity, which serves as a mechanism underlying coronary endothelial dysfunction in ischemia-reperfusion (I-R) injury and renders TRPC3 a potential target for endothelial protection in I-R conditions.

Patient and family satisfaction levels in the intensive care unit after elective cardiac surgery: study protocol for a randomised controlled trial of a preoperative patient education intervention.

INTRODUCTION: Patients and their families are understandably anxious about the risk of complications and unfamiliar experiences following cardiac surgery. Providing information about postoperative care in the intensive care unit (ICU) to patients and families may lead to lower anxiety levels, and increased satisfaction with healthcare. The objectives of this study are to evaluate the effectiveness of preoperative patient education provided for patients undergoing elective cardiac surgery. METHODS AND ANALYSIS: 100 patients undergoing elective coronary artery bypass graft, with or without valve replacement surgery, will be recruited into a 2-group, parallel, superiority, double-blinded randomised controlled trial. Participants will be randomised to either preoperative patient education comprising of a video and ICU tour with standard care (intervention) or standard education (control). The primary outcome measures are the satisfaction levels of patients and family members with ICU care and decision-making in the ICU. The secondary outcome measures are patient anxiety and depression levels before and after surgery. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (reference number CREC 2015.308). The findings will be presented at conferences and published in peer-reviewed journals. Study participants will receive a 1-page plain language summary of results. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-15006971.

Cellular and molecular mechanisms of endothelial ischemia/reperfusion injury: perspectives and implications for postischemic myocardial protection.

Ischemia/reperfusion (I/R) injury is a major cause of myocardial damage. Despite continuous efforts, minimizing I/R injury still represents a great challenge in standard medical treatments of ischemic heart disease, i.e., thrombolytic therapy, primary percutaneous coronary intervention, and coronary arterial bypass grafting. Development of effective interventions and strategies to prevent or reduce myocardial I/R injury is therefore of great clinical significance. Endothelial dysfunction plays a significant role in myocardial I/R injury, which renders endothelial cells an attractive target for postischemic myocardial protection. The rapidly evolving knowledge of the mechanisms of endothelial I/R injury helps broaden perspective for future development of novel strategies targeting endothelium for alleviating myocardial I/R damage. This review provides a comprehensive summary of the cellular and molecular mechanisms of endothelial I/R injury. Current perspectives and future directions for developing endothelium targeting therapeutics for postischemic myocardial protection are further discussed.

ER stress mediates homocysteine-induced endothelial dysfunction: Modulation of IKCa and SKCa channels.

OBJECTIVE: It remains incompletely understood how homocysteine impairs endothelial function. Whether mechanisms such as calcium-activated potassium (KCa) channels are involved is uncertain and the significance of endoplasmic reticulum (ER) stress in KCa channel-dependent endothelial function in hyperhomocysteinemia remains unexplored. We investigated the effect of homocysteine on endothelial KCa channels in coronary vasculature with further exploration of the role of ER stress. METHODS: Vasorelaxation mediated by intermediate- and small-conductance KCa (IKCa and SKCa) channels was studied in porcine coronary arteries in a myograph. IKCa and SKCa channel currents were recorded by whole-cell patch-clamp in coronary endothelial cells. Protein levels of endothelial IKCa and SKCa channels were determined for both whole-cell and surface expressions. RESULTS: Homocysteine impaired bradykinin-induced IKCa and SKCa-dependent EDHF-type relaxation and attenuated the vasorelaxant response to the channel activator. IKCa and SKCa currents were suppressed by homocysteine. Inhibition of ER stress during homocysteine exposure enhanced IKCa and SKCa currents, associated with improved EDHF-type response and channel activator-induced relaxation. Homocysteine did not alter whole-cell protein levels of IKCa and SKCa whereas lowered surface expressions of these channels, which were restored by ER stress inhibition. CONCLUSIONS: Homocysteine induces endothelial dysfunction through a mechanism involving ER stress-mediated suppression of IKCa and SKCa channels. Inhibition of cell surface expression of these channels by ER stress is, at least partially, responsible for the suppressive effect of homocysteine on the channel function. This study provides new mechanistic insights into homocysteine-induced endothelial dysfunction and advances our knowledge of the significance of ER stress in vascular disorders.

Protection of coronary endothelial function during cardiac surgery: potential of targeting endothelial ion channels in cardioprotection.

Vascular endothelium plays a critical role in the control of blood flow by producing vasoactive factors to regulate vascular tone. Ion channels, in particular, K(+) channels and Ca(2+)-permeable channels in endothelial cells, are essential to the production and function of endothelium-derived vasoactive factors. Impairment of coronary endothelial function occurs in open heart surgery that may result in reduction of coronary blood flow and thus in an inadequate myocardial perfusion. Hyperkalemic exposure and concurrent ischemia-reperfusion during cardioplegic intervention compromise NO and EDHF-mediated function and the impairment involves alterations of K(+) channels, that is, KATP and KCa, and Ca(2+)-permeable TRP channels in endothelial cells. Pharmacological modulation of these channels during ischemia-reperfusion and hyperkalemic exposure show promising results on the preservation of NO and EDHF-mediated endothelial function, which suggests the potential of targeting endothelial K(+) and TRP channels for myocardial protection during cardiac surgery.

Activation of canonical transient receptor potential channels preserves Ca2+ entry and endothelium-derived hyperpolarizing factor-mediated function in vitro in porcine coronary endothelial cells and coronary arteries under conditions of hyperkalemia.

OBJECTIVES: Although membrane depolarization by hyperkalemia is known to reduce Ca2+ influx in endothelial cells, the mechanism by which endothelial Ca2+ channel is affected by hyperkalemia remains poorly studied. We studied the effect of hyperkalemia on canonical transient receptor potential channels, in particular canonical transient receptor potential channel 3, in modulation of endothelial intracellular Ca2+ concentration. Endothelium-derived hyperpolarizing factor-mediated function is Ca2+ dependent, and hyperkalemic cardioplegia/organ preservation solutions impair endothelium-derived hyperpolarizing factor-mediated function. We explored the role of canonical transient receptor potential channel 3 in endothelium-derived hyperpolarizing factor-mediated function and investigated whether modulation of these channels preserves endothelial Ca2+ influx and endothelium-derived hyperpolarizing factor-mediated function under the condition of hyperkalemic/cardioplegic exposure. METHODS: Intracellular Ca2+ concentration was measured with fluorescent dye in primary cultured porcine coronary endothelial cells exposed to hyperkalemic/cardioplegic solutions containing mild to extreme high K+ concentration. Endothelium-derived hyperpolarizing factor-mediated relaxation under hyperkalemic/cardioplegic exposure was studied in small porcine coronary arteries in a myograph in the presence of cyclooxygenase and nitric oxide synthase inhibitors and nitric oxide scavenger. RESULTS: Canonical transient receptor potential channel 3 blocker inhibited bradykinin-induced Ca2+ influx and attenuated endothelium-derived hyperpolarizing factor-mediated response. Hyperkalemic exposure inhibited canonical transient receptor potential channel 3-mediated Ca2+ influx in a K+ concentration-dependent manner (120>20>10 mmol/L). Ca2+ influx decreased in porcine coronary endothelial cells exposed to histidine-tryptophan-ketoglutarate, St Thomas' Hospital, and University of Wisconsin solutions that contained mild (10 mmol/L), moderate (20 mmol/L), and extreme high (125 mmol/L) K+ concentration, respectively. Canonical transient receptor potential channel activator prevented the reduction of Ca2+ influx in porcine coronary endothelial cells exposed to solutions containing mild to moderate high [K+]o and restored endothelium-derived hyperpolarizing factor-mediated response that was impaired by hyperkalemic exposure. CONCLUSIONS: Canonical transient receptor potential channel 3 is involved in endothelium-derived hyperpolarizing factor-mediated function in coronary arteries. Hyperkalemia inhibited canonical transient receptor potential channel 3-mediated Ca2+ influx in endothelial cells. Canonical transient receptor potential channel activation restores Ca2+ influx suppressed by hyperkalemia and prevents dysfunction of endothelium-derived hyperpolarizing factor.

Mechanistic studies of AVE3085 against homocysteine in endothelial protection.

PURPOSE: Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases that impairs endothelial function. We investigated whether the impaired endothelial function can be restored by the eNOS transcription enhancer AVE3085 in porcine coronary arteries. The effects of AVE3085 against Hcy on eNOS-NO function were studied and further investigations were conducted to reveal the role of arginase and the signaling pathway of eNOS activation in the effect of AVE3085 on endothelial dysfunction caused by Hcy. METHODS: Myograph study of vasorelaxation, electrochemical measurement of NO, RT-PCR and Western blot analysis of eNOS, iNOS expression, and eNOS phosphorylation were performed. Arginase activity was determined by urea production and O2 (.-) generation by lucigenin-enhanced chemiluminenscence. RESULTS: Exposure to Hcy for 24 h attenuated bradykinin-induced relaxation and NO release, downregulated eNOS mRNA expression and protein expressions of eNOS and p-eNOS(Ser1177) whereas it upregulated iNOS expression. AVE3085 restored NO release and relaxation, enhanced eNOS but decreased iNOS expression. Inhibition of protein kinase Akt or PI3 kinase attenuated the effect of AVE3085 on relaxation and eNOS phosphorylation. Arginase activity and O2 (.-) production were inhibited by AVE3085 in Hcy-exposed vessels. CONCLUSIONS: AVE3085 prevents Hcy-induced endothelial dysfunction in coronary arteries by preservation of NO production and suppression of O2 (.-) generation. Preservation of NO is attributed to upregulation of eNOS expression, activation of eNOS via phosphorylation of Ser1177 through a PI3 kinase/Akt-dependent pathway, and inhibition of arginase. Reduction of O2 (.-) generation results from reversal of eNOS uncoupling and inhibition of arginase and iNOS.

Fast-track failure after cardiac surgery: external model validation and implications to ICU bed utilization.

OBJECTIVE: To facilitate the planning of perioperative care pathways, a fast-track failure prediction model has been developed in patients undergoing cardiac surgery. This study externally validated such a fast-track failure risk prediction model and determined the potential clinical consequences to ICU bed utilization. DESIGN: Prospective cohort study. SETTING: Cardiothoracic Surgery Department and Intensive Care Unit of Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. PATIENTS: The St. Mary's Hospital fast-track failure risk prediction model was applied to patients included in an adult cardiac surgery database (January 2006 to June 2011). INTERVENTIONS: The performance of the fast-track failure risk model was assessed by discrimination and calibration methods. The potential clinical consequences of applying the model on ICU bed utilization was assessed using a decision curve analysis. MEASUREMENTS AND MAIN RESULTS: Of the 1,597 patients, 175 (11%) failed fast-track management. The final updated model showed very good discrimination (area under the receiver operating characteristic curve = 0.82, 95% confidence interval 0.78-0.86) and adequate calibration (Hosmer-Lemeshow goodness-of-fit statistic, p = 0.80). A decision curve analysis showed that if a threshold probability range of fast-track failure of 5% to 20% is used to determine who should be electively admitted to the ICU and who should be admitted to a fast-track recovery unit, it would lead to a substantial benefit (23%-67%) in terms of effective bed utilization, even after taking into account the negative consequences of unplanned admissions. CONCLUSIONS: As the performance of the final updated fast-track failure model was very good, it can be used to estimate the predicted probability of fast-track failure on individual patients. The clinical consequence of applying the final model appears substantial with regard to the potential increase in effective ICU bed utilization.

AVE3085 protects coronary endothelium from the impairment of asymmetric dimethylarginine by activation and recoupling of eNOS.

PURPOSE: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of eNOS and it is recognized as a risk factor for endothelial dysfunction in cardiovascular diseases. We investigated the effect of AVE3085, a newly developed transcription enhancer of eNOS, on ADMA-induced endothelial dysfunction in coronary arteries with underlying mechanisms explored. METHODS: Porcine coronary small arteries (diameter 600-800 µm) were studied in a myograph for endothelium-dependent relaxation to bradykinin and endothelium-independent relaxation to sodium nitroprusside. Protein expressions of eNOS and phosphorylated-eNOS (p-eNOS(Ser1177) and p-eNOS(Thr495)), and nitrotyrosine formation were determined by Western blot. NO release was directly measured with a NO microsensor. Productions of O(2) (.-) and peroxynitrite (ONOO(-)) were determined by lucigenin- and luminol- enhanced chemiluminescence respectively. RESULTS: Exposure to ADMA significantly decreased the bradykinin-induced vasorelaxation and reduced the protein expression of p-eNOS(Ser1177) whereas increased the expression of p-eNOS(Thr495) and nitrotyrosine. Pre-incubation with AVE3085 restored the bradykinin-induced relaxation, reversed the decrease of p-eNOS(Ser1177), and lowered the level of p-eNOS(Thr495) and nitrotyrosine. NO release in response to bradykinin was significantly reduced by ADMA and such reduction was restored by AVE3085. AVE3085 also prevented the elevation of O (2) (.-) and ONOO(-) levels in coronary arteries exposed to ADMA. CONCLUSIONS: AVE3085 prevents ADMA-induced endothelial dysfunction in coronary arteries. The protective effect of AVE3085 may be attributed to increased NO production resulting from enhanced eNOS activation, and decreased oxidative stress that involves inhibition of O (2) (.-) generation by eNOS recoupling. The present study suggested the therapeutic potential of AVE3085 in endothelial dysfunction in cardiovascular disorders.

NO and EDHF pathways in pulmonary arteries and veins are impaired in COPD patients.

We investigated endothelial function of both pulmonary arteries and veins in patients with chronic obstructive pulmonary disease (COPD) of varying severity in regard to the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Lung tissues were obtained from patients undergoing lobectomy or pneumonectomy. Patients were grouped to control, moderate COPD, and severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Pulmonary arteries and veins were studied for endothelium-dependent relaxations. NO concentration was measured by electrochemical method. Protein expressions of eNOS and phosphorylated eNOS were determined by Western-blot. Endothelium-dependent relaxation was more significant in pulmonary arteries than in veins. The vasorelaxation was decreased in patients of moderate COPD and further decreased in severe COPD. The severity of endothelial dysfunction in both pulmonary arteries and veins correlated with the degree of airflow obstruction. COPD patients exhibited reduced endothelial NO production, decreased eNOS protein expression and decreased eNOS phosphorylation. The EDHF component was abolished in the pulmonary vasculature of patients with severe COPD. NO and EDHF pathways are both involved in the regulation of vascular tone in human pulmonary arteries and veins. Both pathways are impaired in COPD patients and the severity of the impairment increases with the progress of the disease. Downregulation of eNOS expression and inhibition of eNOS activation underlie the reduction of NO in COPD patients.

TRPC3 channel contributes to nitric oxide release: significance during normoxia and hypoxia-reoxygenation.

AIMS: Intracellular Ca(2+) ([Ca(2+)](i)) regulation in endothelial cells depends on transient receptor potential channels (TRPs), and the role of canonical TRPs (TRPCs) during hypoxia-reoxygenation (H-R) is unclear. We hypothesized that TRPC3 contributes to endothelial nitric oxide (NO) release and that H-R may reduce TRPC3 activity and the associated endothelial function, including NO release. METHODS AND RESULTS: Measurements of [Ca(2+)](i) and patch-clamp study in primary cultured porcine coronary endothelial cells, measurements of NO and endothelium-dependent relaxation in porcine coronary arteries, and RT-PCR and western blot were conducted. Pre-treatment with SKF96365 (an inhibitor of TRPCs) or the selective TRPC3 inhibitor Pyr3 significantly decreased bradykinin-induced vasorelaxation. One hour of hypoxia followed by reoxygenation significantly reduced the vasorelaxation (70.3 ± 6.4 vs. 88.9 ± 3.5%) and NO concentration (24.0 ± 1.3 vs. 45.2 ± 2.8 nmol/L), and they were restored by pre-incubation with the TRPC3/6/7 activator 1-oleoyl-2-acetyl-sn-glycerol (96.4 ± 1.8% and 41.1 ± 4.7 nmol/L, respectively). In porcine coronary endothelial cells, H-R inhibited bradykinin-activated membrane current (8.6 ± 0.4 vs. 14.0 ± 1.5 pA/pF) and Pyr3-sensitive TRPC3 current (3.8 ± 0.3 vs. 6.3 ± 0.6 pA/pF; P< 0.01). H-R also inhibited bradykinin-induced Ca(2+) influx and the Ca(2+) influx via TRPC3. Cell surface expression of TRPC3 was decreased after H-R. CONCLUSIONS: We have, for the first time, demonstrated that Ca(2+) entry via endothelial TRPC3 contributes to NO release and have revealed that H-R is associated with inhibition of TRPC3 activity. Inhibition of channel trafficking to the cell surface is involved in the underlying mechanism of the decrease of TRPC3 current and the reduction in Ca(2+) entry through TRPC3 during H-R. This study suggests that TRPC3 may have the potential to be a new target for endothelial protection during H-R.