Rakesh C. Arora

Adipose-derived stem cells are an effective cell candidate for treatment of heart failure: an MR imaging study of rat hearts

This study assessed the potential therapeutic efficacy of adipose-derived stem cells (ASCs) on infarcted hearts. Myocardial infarction was induced in rat hearts by occlusion of the left anterior descending artery (LAD). One week after LAD occlusion, the rats were divided into three groups and subjected to transplantation of ASCs or transplantation of cell culture medium (CCM) or remained untreated. During a 1-mo recovery period, magnetic resonance imaging showed that the ASC-treated hearts had a significantly greater left ventricular (LV) ejection fraction and LV wall thickening than did the CCM-treated and untreated hearts. The capillary density in infarct border zone was significantly higher in the ASC-treated hearts than in the CCM-treated and untreated hearts. However, only 0.5% of the ASCs recovered from the ASC-treated hearts were stained positive for cardiac-specific fibril proteins. It was also found that ASCs under a normal culture condition secreted three cardiac protective growth factors: vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1. Results of this study suggest that ASCs were able to improve cardiac function of infarcted rat hearts. Paracrine effect may be the mechanism underlying the improved cardiac function and increased capillary density.

IL-10 attenuates TNF-α-induced NFκB pathway activation and cardiomyocyte apoptosis

AIMS We have recently reported that tumour necrosis factor-alpha (TNF-alpha) increases oxidative stress and apoptosis in cardiomyocytes by upregulating p38 mitogen-activated protein (MAP) kinase (MAPK) phosphorylation. Interleukin-10 (IL-10) blocked these effects of TNF-alpha by upregulating extracellular signal-regulated kinase 1/2 (ERK 1/2) MAPK phosphorylation. However, the precise site of this IL-10 action is still unknown, and this is investigated in the present study. METHODS AND RESULTS Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to TNF-alpha (10 ng/mL), IL-10 (10 ng/mL), and IL-10+TNF-alpha (ratio 1) for 4 h. Hydrogen peroxide and antioxidant trolox were used as positive controls. Exposure to TNF-alpha resulted in an increase in the production of reactive oxygen species, the number of apoptotic cells, caspase-3 activation, and poly-ADP ribose polymerase (PARP) cleavage. Increased oxidative stress by using hydrogen peroxide also caused apoptosis. The changes due to TNF-alpha were associated with an increase in the inhibitor of kappaB kinase (IKK) and nuclear factor kappa-B (NF kappaB) phosphorylation. IL-10 by itself had no effect, but it prevented the above mentioned TNF-alpha-induced changes. Trolox also mitigated TNF-alpha induced changes. Pre-exposure of cells to an IKK inhibitor (PS-1145) prevented TNF-alpha-induced caspase-3 and PARP cleavage. Inhibition of ERK 1/2 MAPK with PD98059 attenuated the protective role of IL-10 against TNF-alpha-induced activation of IKK and NF kappaB as well as cardiomyocyte apoptosis. CONCLUSION The present study shows that TNF-alpha-induced activation of the NF kappaB pathway plays a critical role in cardiomyocyte apoptosis. IL-10 prevents TNF-alpha-induced NF kappaB activation and pro-apoptotic changes in cardiomyocytes by inhibiting IKK phosphorylation through the activation of ERK 1/2 MAPK.

The impact of frailty on outcomes after cardiac surgery: A systematic review

OBJECTIVE Current preoperative assessments for cardiac surgery, such as the European System for Cardiac Operative Risk Evaluation II and the Society of Thoracic Surgeons risk score, are limited in their ability to predict postoperative outcomes. This is thought to be due to the reliance on chronological age as a predictor of health. In geriatrics, frailty assessments have been developed as a tool in determining physiologic functioning capacity. Whether or not frailty predicts postoperative outcomes independent of existing cardiac preoperative risk scores remains unknown. METHODS We performed a systematic review to determine the association of frailty with negative postoperative outcomes such as major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing cardiac surgery. We searched PubMed, EMBASE, the Cochrane library, and Ageline from inception until July 2013 and screened 5913 abstracts for potential inclusion. Of these, 6 studies examined the relationship between objective frailty assessments and postoperative outcomes. Our included studies evaluated 4756 patients undergoing cardiac surgery. RESULTS Frailty, defined using multiple criteria, had a strong positive relationship with the risk of MACCE (odds ratio, 4.89; 95% confidence interval, 1.64-14.60). Relationships were stronger in older patients undergoing transcatheter aortic valve replacement (TAVR) than younger patients undergoing coronary artery bypass grafting and valvular surgery (hazard ratio for frailty in TAVR, 3.31-4.89 vs hazard ratio for non-TAVR, 1.10-3.16). CONCLUSIONS Patients deemed frail, determined using an objective assessment tool, have a higher likelihood of experiencing mortality, morbidity, functional decline, and MACCE following cardiac surgery, regardless of definition. Further study is needed to determine which components of frailty are most predictive of negative postoperative outcomes before integration in risk prediction scores.

Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis

OBJECTIVES We performed a systematic review and meta-analysis to understand the role of flow-mediated dilatation (FMD) of the brachial artery (BA) and peripheral arterial tonometry (PAT) in predicting adverse events, including cardiovascular (CV) events and all-cause mortality. BACKGROUND FMD of the BA and PAT are non-invasive measures of endothelial function. Impairment of endothelial function is associated with increased CV events. While FMD is the more widely used and studied technique, PAT offers several advantages. The purpose of this systematic review and meta-analysis is to determine whether brachial FMD and PAT are independent risk factors for future CV events and mortality. METHODS Multiple electronic databases were searched for articles relating FMD or PAT to CV events. Data were extracted on study characteristics, study quality, and study outcomes. Relative risks (RRs) from individual studies were combined and a pooled multivariate RR was calculated. RESULTS Thirty-six studies for FMD were included in the systematic review, of which 32 studies consisting of 15, 191 individuals were meta-analysed. The pooled RR of CV events and all-cause mortality per 1% increase in brachial FMD, adjusting for potential confounders, was 0.90 (0.88-0.92). In contrast, only three studies evaluated the prognostic value of PAT for CV events, and the pooled RR per 0.1 increase in reactive hyperaemia index was 0.85 (0.78-0.93). CONCLUSION Brachial FMD and PAT are independent predictors of CV events and all-cause mortality. Further research to evaluate the prognostic utility of PAT is necessary to compare it with FMD as a non-invasive endothelial function test in clinical practice.

Delirium as a predictor of sepsis in post-coronary artery bypass grafting patients: a retrospective cohort study

IntroductionDelirium is the most common neurological complication following cardiac surgery. Much research has focused on potential causes of delirium; however, the sequelae of delirium have not been well investigated. The objective of this study was to investigate the relationship between delirium and sepsis post coronary artery bypass grafting (CABG) and to determine if delirium is a predictor of sepsis.MethodsPeri-operative data were collected prospectively on all patients. Subjects were identified as having agitated delirium if they experienced a short-term mental disturbance marked by confusion, illusions and cerebral excitement. Patient characteristics were compared between those who became delirious and those who did not. The primary outcome of interest was post-operative sepsis. The association of delirium with sepsis was assessed by logistic regression, adjusting for differences in age, acuity, and co-morbidities.ResultsAmong 14,301 patients, 981 became delirious and 227 developed sepsis post-operatively. Rates of delirium increased over the years of the study from 4.8 to 8.0% (P = 0.0003). A total of 70 patients of the 227 with sepsis, were delirious. In 30.8% of patients delirium preceded the development of overt sepsis by at least 48 hours. Multivariate analysis identified several factors associated with sepsis, (receiver operating characteristic (ROC) 79.3%): delirium (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6 to 3.4), emergent surgery (OR 3.3, CI 2.2 to 5.1), age (OR 1.2, CI 1.0 to 1.3), pre-operative length of stay (LOS) more than seven days (OR 1.6, CI 1.1 to 2.3), pre-operative renal insufficiency (OR 1.9, CI 1.2 to 2.9) and complex coronary disease (OR 3.1, CI 1.8 to 5.3).ConclusionsThese data demonstrate an association between delirium and post-operative sepsis in the CABG population. Delirium emerged as an independent predictor of sepsis, along with traditional risk factors including age, pre-operative renal failure and peripheral vascular disease. Given the advancing age and increasing rates of delirium in the CABG population, the prevention and management of delirium need to be addressed.

Serum Creatinine Measurement Immediately After Cardiac Surgery and Prediction of Acute Kidney Injury

BACKGROUND After heart surgery, acute kidney injury (AKI) confers substantial long-term risk of death and chronic kidney disease. We hypothesized that small changes in serum creatinine (SCr) levels measured within a few hours of exit from the operating room could help discriminate those at low versus high risk of AKI. STUDY DESIGN Prospective cohort of 350 elective cardiac surgery patients (valve or coronary artery bypass grafting) recruited in Winnipeg, Canada. Baseline SCr level was obtained at the preoperative visit 2 weeks before surgery. The postoperative SCr level was drawn within 6 hours of completion of surgery and then daily while the patient was in the hospital. PREDICTOR Immediate (ie, <6 hours) postoperative SCr level change (ΔSCr), categorized as within 10% (reference), decrease >10%, or increase >10% relative to baseline. OUTCOME AKI, defined according to the new KDIGO (Kidney Disease: Improving Global Outcomes) consensus definition as an increase in SCr level >0.3 mg/dL within 48 hours or >1.5 times baseline within 1 week. MEASUREMENTS We compared the C statistic of logistic models with and without inclusion of immediate postoperative ΔSCr. RESULTS After surgery, 176 patients (52%) experienced a decrease >10% in SCr level, 26 (7.4%) experienced an increase >10%, and 143 had ΔSCr within ±10% of baseline. During hospitalization, 53 (14%) developed AKI. Bypass pump time, baseline estimated glomerular filtration rate, and European System for Cardiac Operative Risk Evaluation (euroSCORE) were associated with AKI in a parsimonious base logistic model. Added to the base model, immediate postoperative ΔSCr was associated strongly with subsequent AKI and significantly improved model discrimination over the base model (C statistic, 0.78 [95% CI, 0.71-0.85] vs 0.69 [95% CI, 0.62-0.77]; P < 0.001). A ≥10% SCr level decrease predicted significantly lower AKI risk (OR, 0.37; 95% CI, 0.18-0.76), whereas a ≥10% SCr level increase predicted significantly higher (OR, 6.38; 95% CI, 2.37-17.2) AKI risk compared with the reference category. LIMITATIONS We used a surrogate marker of AKI. External validation of our results is warranted. CONCLUSION In elective cardiac surgery patients, measurement of immediate postoperative ΔSCr improves prediction of AKI.

A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death

BACKGROUND Ex vivo heart perfusion (EVHP) has been proposed as a means to facilitate the resuscitation of donor hearts after cardiocirculatory death (DCD) and increase the donor pool. However, the current approach to clinical EVHP may exacerbate myocardial injury and impair function after transplant. Therefore, we sought to determine if a cardioprotective EVHP strategy that eliminates myocardial exposure to hypothermic hyperkalemia cardioplegia and minimizes cold ischemia could facilitate successful DCD heart transplantation. METHODS Anesthetized pigs sustained a hypoxic cardiac arrest and a 15-minute warm ischemic standoff period. Strategy 1 hearts (S1, n = 9) underwent initial reperfusion with a cold hyperkalemic cardioplegia, normothermic EVHP, and transplantation after a cold hyperkalemic cardioplegic arrest (current EVHP strategy). Strategy 2 hearts (S2, n = 8) underwent initial reperfusion with a tepid adenosine-lidocaine cardioplegia, normothermic EVHP, and transplantation with continuous myocardial perfusion (cardioprotective EVHP strategy). RESULTS At completion of EVHP, S2 hearts exhibited less weight gain (9.7 ± 6.7 [S2] vs 21.2 ± 6.7 [S1] g/hour, p = 0.008) and less troponin-I release into the coronary sinus effluent (4.2 ± 1.3 [S2] vs 6.3 ± 1.5 [S1] ng/ml; p = 0.014). Mass spectrometry analysis of oxidized pleural in post-transplant myocardium revealed less oxidative stress in S2 hearts. At 30 minutes after wean from cardiopulmonary bypass, post-transplant systolic (pre-load recruitable stroke work: 33.5 ± 1.3 [S2] vs 19.7 ± 10.9 [S1], p = 0.043) and diastolic (isovolumic relaxation constant: 42.9 ± 6.7 [S2] vs 65.2 ± 21.1 [S1], p = 0.020) function were superior in S2 hearts. CONCLUSION In this experimental model of DCD, an EVHP strategy using initial reperfusion with a tepid adenosine-lidocaine cardioplegia and continuous myocardial perfusion minimizes myocardial injury and improves short-term post-transplant function compared with the current EVHP strategy using cold hyperkalemic cardioplegia before organ procurement and transplantation.

Prehabilitation program for elective coronary artery bypass graft surgery patients: a pilot randomized controlled study:

Objective: To determine the feasibility of a cardiac prehabilitation (Prehab) program for patients waiting for elective coronary artery bypass graft (CABG). Design: A two-group parallel randomized controlled trial. Setting: Medical fitness facility. Subjects: Seventeen preoperative elective CABG surgery patients were randomized to standard care (n = 9) or Prehab (n = 8). Intervention: Standard care: three-hour preassessment appointment. Prehab: exercise and education classes for 60 minutes/day, twice weekly for at least four weeks. Main measures: Data were collected at baseline, one week preoperatively, and three months postoperatively. The primary outcome measure was walking distance using a 6-minute walk test. Secondary outcome variables included 5-meter gait speed, and cardiac rehabilitation attendance three months postoperatively. Results: Fifteen patients (standard care, n = 7; Prehab, n = 8) completed the study. No Prehab patients developed cardiac symptoms during study participation. Walking distance remained unchanged in the standard care group; whereas, the Prehab group increased their walking distance to mean ± SD 474 ±101 and 487 ±106 m at the preoperative and three month postoperative assessments (p < 0.05). Gait speed was unchanged in the standard care group, but improved in the Prehab group by 27% and 33% preoperatively and three months postoperatively, respectively (p < 0.05). Enrollment in cardiac rehabilitation three months postoperatively was higher for Prehab participants (100%) than standard care participants (43%; p < 0.05). Conclusion: These data provide evidence for the feasibility of a Prehab intervention to improve the health status of patients waiting for elective CABG surgery. A larger trial of 92 patients will be utilized to demonstrate the safety and efficacy of Prehab.

Canadian recommendations for critical care ultrasound training and competency

OBJECTIVE To achieve national consensus on standards of training, quality assurance and maintenance of competence for critical care ultrasound for intensivists and critical care trainees in Canada using recently published international training statements. DATA SOURCES Existing internationally endorsed guidelines and expert opinion. DATA SYNTHESIS In November 2013, a day-long consensus meeting was held with 15 Canadian experts in critical care ultrasound in which essential topics relevant to training ultrasound were discussed. CONCLUSIONS Consensus was achieved to direct training curriculum, oversight, quality assurance and maintenance of competence for critical care ultrasound. In providing the first national guideline of its kind, these Canadian recommendations may also serve as a model of critical care ultrasound dissemination for other countries.

Hearts From DCD Donors Display Acceptable Biventricular Function After Heart Transplantation in Pigs

Cardiac transplantation is in decline, in contrast to other solid organs where the number of solid organ transplants from donors after circulatory death (DCD) is increasing. Hearts from DCD donors are not currently utilized due to concerns that they may suffer irreversible cardiac injury with resultant poor graft function. Using a large animal model, we tested the hypothesis that hearts from DCD donors would be suitable for transplantation. Donor pigs were subjected to hypoxic cardiac arrest (DCD) followed by 15 min of warm ischemia and resuscitation on cardiopulmonary bypass, or brainstem death (BSD) via intracerebral balloon inflation. Cardiac function was assessed through load‐independent measures and magnetic resonance imaging and spectroscopy. After resuscitation, DCD hearts had near normal contractility, although stroke volume was reduced, comparable to BSD hearts. DCD hearts had a significant decline in phosphocreatine and increase in inorganic phosphate during the hypoxic period, with a return to baseline levels after reperfusion. After transplantation, cardiac function was comparable between BSD and DCD groups. Therefore, in a large animal model, the DCD heart maintains viability and recovers function similar to that of the BSD heart and may be suitable for clinical transplantation. Further study is warranted on optimal reperfusion strategies.