Neil J. Howell

Glucose-Insulin-Potassium Reduces the Incidence of Low Cardiac Output Episodes After Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Hypertrophy Results From the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) Trial

Background— Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery. Methods and Results— Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5′ adenosine monophosphate–activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked &bgr;-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands. Conclusions— Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis. Clinical Trial Registration— URL: http://www.controlled-trials.com. Reference number: ISRCTN 05758301.

Patient-Prosthesis Mismatch in Patients With Aortic Stenosis Undergoing Isolated Aortic Valve Replacement Does Not Affect Survival

BACKGROUND Data suggest that patient-prosthesis mismatch (PPM) adversely effects late survival after aortic valve replacement (AVR). This study examined the incidence and implications of PPM in patients undergoing isolated AVR. METHODS Prospectively collected data on patients undergoing isolated AVR for aortic stenosis between January 1, 1997 and December 31, 2007 were analyzed. The projected effective valve orifice area from in vivo data was indexed to body surface area (EOAi). PPM was defined as moderate for EOAi of < or = 0.85 cm(2)/m(2) and severe if < or = 0.6 cm(2)/m(2). The reference group comprised patients with EOAi > 0.85 cm(2)/m(2). The effect of PPM on postoperative survival was assessed by multivariate analysis. RESULTS Of 801 patients, PPM was severe in 48 (6.0%), moderate in 462 (57.8%), and nonexistent in 291 (36.4%). Mismatch was associated with increasing age and female gender, thus resulting in an increase in the EuroSCORE (reference group, 4.9 +/- 2.6; moderate PPM, 5.8 +/- 2.4; and severe PPM, 6.1+/-2.1; p < 0.001). PPM did not significantly increase hospital mortality. Four deaths occurred in the reference group (1.4%), 12 in the moderate PPM (2.6%), and none in the severe PPM group (p = 0.311). The 5-year survival estimates were 83% in reference, 86% in moderate PPM, and 89% in severe PPM (p = 0.25). By multivariate analysis, PPM was not an independent risk factor for reduced in-hospital or late survival. CONCLUSIONS Moderate PPM is common in patients undergoing AVR for aortic stenosis, but severe mismatch is rare. Patients with PPM have similar early and late postoperative survival rate.

Mild renal dysfunction predicts in-hospital mortality and post-discharge survival following cardiac surgery

OBJECTIVES To assess the impact of preoperative renal dysfunction on in-hospital mortality and late survival outcome following adult cardiac surgery. METHODS Prospectively collected data were analysed on 7621 consecutive patients not requiring preoperative renal-replacement therapy, who underwent CABG, valve surgery or combined procedures from 1/1/98 to 1/12/06. Preoperative estimated glomerular filtration rate was calculated using Cockcroft-Gault formula. Patients were classified in the four chronic kidney disease (CKD) stage classes defined by the National Kidney Foundation Disease Outcome Quality Initiative Advisory Board. Late survival data were obtained from the UK Central Cardiac Audit Database. RESULTS There were 243 in-hospital deaths (3.2%). There was a stepwise increase in operative mortality with each CKD class independent of the type of surgery. Multivariate analysis confirmed CKD class to be an independent predictor of in-hospital mortality (class 2 OR 1.45, 95% CI 1.1-2.35, p=0.001; class 3 OR 2.8, 95% CI 1.68-4.46, p=0.0001; class 4 OR 7.5, 95% CI 3.76-15.2, p=0.0001). The median follow-up after surgery was 42 months (IQR 18-74) and there were 728 late deaths. Survival analysis using a Cox regression model confirmed CKD class to be an independent predictor of late survival (class 2 HR 1.2, 95% CI 1.1-1.6, p=0.0001; class 3 HR 1.95, 95% CI 1.6-2.4, p=0.0001; and class 4 HR 3.2, 95% CI 2.2-4.6, p=0.0001). Ninety-eight percent (7517/7621) of patients had a preoperative creatinine <200 micromol/l, which is not included as a risk factor in most risk stratification systems. CONCLUSIONS Mild renal dysfunction is an important independent predictor of in-hospital and late mortality in adult patients undergoing cardiac surgery.

Glucose-Insulin-Potassium Reduces the Incidence of Low Cardiac Output Episodes After Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Hypertrophy

Background— Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery. Methods and Results— Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5′ adenosine monophosphate–activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked &bgr;-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands. Conclusions— Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis. Clinical Trial Registration— URL: http://www.controlled-trials.com. Reference number: ISRCTN 05758301.

Bleeding in cardiac surgery: The use of aprotinin does not affect survival

OBJECTIVE The antifibrinolytic drug aprotinin has been the most widely used agent to reduce bleeding and its complications in cardiac surgery. Several randomized trials and meta-analyses have demonstrated it to be effective and safe. However, 2 recent reports from a single database have implicated the use of aprotinin as a risk for postoperative complications and reduced long-term survival. METHODS In this single-institution observational study involving 7836 consecutive patients (1998-2006), we assessed the safety of using aprotinin in risk reduction strategy for postoperative bleeding. RESULTS Aprotinin was used in 44% of patients. Multivariate analysis identified aprotinin use in risk reduction for reoperation for bleeding (odds ratio, 0.51; 95% confidence interval, 0.36-0.72; P = .001) and need for blood transfusion postoperatively (odds ratio, 0.67; 95% confidence interval, 0.57-0.79; P = .0002). The use of aprotinin did not affect in-hospital mortality (odds ratio, 1.03; 95% confidence interval, 0.71-1.49; P = 0.73), intermediate-term survival (median follow-up, 3.4 years; range, 0-8.9 years; hazard ratio, 1.09; 95% confidence interval, 0.93-1.28; P = .30), incidence of postoperative hemodialysis (odds ratio, 1.16; 95% confidence interval, 0.73-1.85; P = .49), and incidence of postoperative renal dysfunction (odds ratio, 0.78; 95% confidence interval, 0.59-1.03; P = .07). CONCLUSION This study demonstrates that aprotinin is effective in reducing bleeding after cardiac surgery, is safe, and does not affect short- or medium-term survival.

The new EuroSCORE II does not improve prediction of mortality in high-risk patients undergoing cardiac surgery: A collaborative analysis of two European centres

OBJECTIVES Prediction of operative risk in adult patients undergoing cardiac surgery remains a challenge, particularly in high-risk patients. In Europe, the EuroSCORE is the most commonly used risk-prediction model, but is no longer accurately calibrated to be used in contemporary practice. The new EuroSCORE II was recently published in an attempt to improve risk prediction. We sought to assess the predictive value of EuroSCORE II compared with the original EuroSCOREs in high-risk patients. METHODS Patients who underwent surgery between 1 April 2006 and 31 March 2011 with a preoperative logistic EuroSCORE ≥ 10 were identified from prospective cardiac surgical databases at two European institutions. Additional variables included in EuroSCORE II, but not in the original EuroSCORE, were retrospectively collected through patient chart review. The C-statistic to predict in-hospital mortality was calculated for the additive EuroSCORE, logistic EuroSCORE and EuroSCORE II models. The Hosmer-Lemeshow test was used to assess model calibration by comparing observed and expected mortality in a number of risk strata. The fit of EuroSCORE II was compared with the original EuroSCOREs using Akaikes Information Criterion (AIC). RESULTS A total of 933 patients were identified; the median additive EuroSCORE was 10 (interquartile range [IQR] 9-11), median logistic EuroSCORE 15.3 (IQR 12.0-24.1) and median EuroSCORE II 9.3 (5.8-15.6). There were 90 (9.7%) in-hospital deaths. None of the EuroSCORE models performed well with a C-statistic of 0.67 for the additive EuroSCORE and EuroSCORE II, and 0.66 for the logistic EuroSCORE. Model calibration was poor for the EuroSCORE II (chi-square 16.5; P = 0.035). Both the additive EuroSCORE and logistic EuroSCORE had a numerically better model fit, the additive EuroSCORE statistically significantly so (difference in AIC was -5.66; P = 0.017). CONCLUSIONS The new EuroSCORE II does not improve risk prediction in high-risk patients undergoing adult cardiac surgery when compared with original additive and logistic EuroSCOREs. The key problem of risk stratification in high-risk patients has not been addressed by this new model. Future iterations of the score should explore more advanced statistical methods and focus on developing procedure-specific algorithms. Moreover, models that predict complications in addition to mortality may prove to be of increasing value.

Social deprivation and prognostic benefits of cardiac surgery: observational study of 44 902 patients from five hospitals over 10 years

Objective To assess the effects of social deprivation on survival after cardiac surgery and to examine the influence of potentially modifiable risk factors. Design Analysis of prospectively collected data. Prognostic models used to examine the additional effect of social deprivation on the end points. Setting Birmingham and north west England. Participants 44 902 adults undergoing cardiac surgery, 1997-2007. Main outcome measures Social deprivation with census based 2001 Carstairs scores. All cause mortality in hospital and at mid-term follow-up. Results In hospital mortality for all cardiac procedures was 3.25% and mid-term follow-up (median 1887 days; range 1180-2725 days) mortality was 12.4%. Multivariable analysis identified social deprivation as an independent predictor of mid-term mortality (hazard ratio 1.024, 95% confidence interval 1.015 to 1.033; P<0.001). Smoking (P<0.001), body mass index (BMI, P<0.001), and diabetes (P<0.001) were associated with social deprivation. Smoking at time of surgery (1.294, 1.191 to 1.407, P<0.001) and diabetes (1.305, 1.217 to 1.399, P<0.001) were independent predictors of mid-term mortality. The relation between BMI and mid-term mortality was non-linear and risks were higher in the extremes of BMI (P<0.001). Adjustment for smoking, BMI, and diabetes reduced but did not eliminate the effects of social deprivation on mid-term mortality (1.017, 1.007 to 1.026, P<0.001). Conclusions Smoking, extremes of BMI, and diabetes, which are potentially modifiable risk factors associated with social deprivation, are responsible for a significant reduction in survival after surgery, but even after adjustment for these variables social deprivation remains a significant independent predictor of increased risk of mortality.

Putting the record straight on aprotinin as safe and effective: results from a mixed treatment meta-analysis of trials of aprotinin.

OBJECTIVE Meta-analysis of small, randomized, placebo-controlled trials demonstrated efficacy and safety of aprotinin. After highly publicized retrospective studies and the early stopping of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), aprotinin was withdrawn. We conducted a new meta-analysis (including BART) on safety and efficacy of aprotinin in cardiac surgery. METHODS We conducted a mixed treatment comparisons network meta-analysis estimating the effects of aprotinin and alternative agents in reducing blood loss during surgery. We implemented a combination of direct and indirect evidence in mixed treatment comparisons and estimated relative effects for different agents on all-cause mortality and return to the operating room for bleeding and conducted a supportive analysis of the effects of different agents with only directly randomized trials. RESULTS Mixed treatment analysis of 88 trials randomizing 15,528 patients to 1 of 3 antifibrinolytic agents demonstrated no difference in mortality between placebo and antifibrinolytic agents. Analysis of aprotinin versus tranexamic acid and ε-aminocaproic acid in 17 and 6 trials, respectively and tranexamic acid versus ε-aminocaproic acid in 5 trials demonstrated no difference in mortality between treatment allocations. All agents were superior to placebo in reducing reexploration for bleeding, with aprotinin numerically superior: aprotinin odds ratio, 2.6 (95% confidence interval, 1.9-3.7); tranexamic acid odds ratio, 1.79 (1.2-2.9), and ε-aminocaproic acid odds ratio, 2.4 (1.3-6.6). CONCLUSIONS This mixed treatment comparisons meta-analysis demonstrates no increased mortality risk with aprotinin versus other antifibrinolytic agents. All agents were superior to placebo in reducing reexploration for bleeding after adult cardiac surgery.

Titin isoform expression in aortic stenosis.

Titin is a giant sarcomeric protein that plays a major role in determining passive myocardial stiffness. The shorter N2B isoform results in a higher passive myocardial stiffness than the longer N2BA isoform. We hypothesised that the expression of the short N2B isoform would be increased in patients with aortic stenosis compared with healthy controls in response to pressure overload, in order to act as a modulator for the increased demand placed on the left ventricle during the early stages of the hypertrophic response. Myocardial biopsies were obtained from the left ventricle of 19 patients undergoing aortic valve replacement for aortic stenosis who had no significant co-existing coronary artery disease. Left ventricular biopsies were also obtained from 13 donor hearts for comparison. SDS-agarose gels revealed small N2B and large N2BA cardiac titin isoforms, with a mean N2BA/N2B ratio that was significantly decreased in the 19 aortic stenotic patients compared with the 13 controls (0.66+/-0.04 in the normal donor hearts compared with 0.48+/-0.03 in patients with aortic stenosis; P=0.02). However, total titin remained unchanged (0.28+/-0.02 compared with 0.24+/-0.02 respectively; P=0.29). In conclusion, the expression of less N2BA and more N2B titin in response to pressure overload may result in the generation of higher passive tension upon stretch to a given sarcomere length and this might affect cardiac performance.

Changes in Cardiac Substrate Transporters and Metabolic Proteins Mirror the Metabolic Shift in Patients with Aortic Stenosis

In the hypertrophied human heart, fatty acid metabolism is decreased and glucose utilisation is increased. We hypothesized that the sarcolemmal and mitochondrial proteins involved in these key metabolic pathways would mirror these changes, providing a mechanism to account for the modified metabolic flux measured in the human heart. Echocardiography was performed to assess in vivo hypertrophy and aortic valve impairment in patients with aortic stenosis (n = 18). Cardiac biopsies were obtained during valve replacement surgery, and used for western blotting to measure metabolic protein levels. Protein levels of the predominant fatty acid transporter, fatty acid translocase (FAT/CD36) correlated negatively with levels of the glucose transporters, GLUT1 and GLUT4. The decrease in FAT/CD36 was accompanied by decreases in the fatty acid binding proteins, FABPpm and H-FABP, the β-oxidation protein medium chain acyl-coenzyme A dehydrogenase, the Krebs cycle protein α-ketoglutarate dehydrogenase and the oxidative phosphorylation protein ATP synthase. FAT/CD36 and complex I of the electron transport chain were downregulated, whereas the glucose transporter GLUT4 was upregulated with increasing left ventricular mass index, a measure of cardiac hypertrophy. In conclusion, coordinated downregulation of sequential steps involved in fatty acid and oxidative metabolism occur in the human heart, accompanied by upregulation of the glucose transporters. The profile of the substrate transporters and metabolic proteins mirror the metabolic shift from fatty acid to glucose utilisation that occurs in vivo in the human heart.