Effect of donor smoking on survival after lung transplantation: a cohort study of a prospective registry.

BACKGROUND: The risk that a positive smoking history in lung donors could adversely affect survival of transplant recipients causes concern. Conversely, reduction of the donor pool by exclusion of donors with positive smoking histories could compromise survival of patients waiting to receive a transplant. We examined the consequences of donor smoking on post-transplantation survival, and the potential effect of not transplanting lungs from such donors. METHODS: We analysed the effect of donor smoking on 3 year survival after first adult lung transplantation from brain-dead donors done between July 1, 1999, and Dec 31, 2010, by Cox regression modelling of data from the UK Transplant Registry. We estimated the effect of acceptance of lungs from donors with positive smoking histories on survival and compared it with the effect of remaining on the waiting list for a potential transplant from a donor with a negative smoking history donor, by analysing all waiting-list registrations during the same period with a risk-adjusted sequentially stratified Cox regression model. FINDINGS: Of 1295 lung transplantations, 510 (39%) used lungs from donors with positive smoking histories. Recipients of such lungs had worse 3 year survival after transplantation than did those who received lungs from donors with negative smoking histories (unadjusted hazard ratio [HR] 1·46, 95% CI 1·20-1·78; adjusted HR 1·36, 1·11-1·67). Independent factors affecting survival were recipient's age, donor-recipient cytomegalovirus matching, donor-recipient height difference, donor's sex, and total ischaemic time. Of 2181 patients registered on the waiting list, 802 (37%) died or were removed from the list without receiving a transplant. Patients receiving lungs from donors with positive smoking histories had a lower unadjusted hazard of death after registration than did those who remained on the waiting list (0·79, 95% CI 0·70-0·91). Patients with septic or fibrotic lung disease registered in 1999-2003 had risk-adjusted hazards of 0·60 (95% CI 0·42-0·87) and 0·39 (0·28-0·55), respectively. INTERPRETATION: In the UK, an organ selection policy that uses lungs from donors with positive smoking histories improves overall survival of patients registered for lung transplantation, and should be continued. Although lungs from such donors are associated with worse outcomes, the individual probability of survival is greater if they are accepted than if they are declined and the patient chooses to wait for a potential transplant from a donor with a negative smoking history. This situation should be fully explained to and discussed with patients who are accepted for lung transplantation. FUNDING: National Health Service Blood and Transplant.

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 ß-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.

Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment?

BACKGROUND: We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. METHODS AND RESULTS: This was a single-center, prospective, randomized (1:1), placebo-controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (×3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL(-1)/48 h(-1)); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL(-1)); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL(-1)); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL(-1) (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO(2):FiO(2) ratios 255 (195, 323) versus 263 (210, 308) were similar. CONCLUSIONS: In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. Clinical Trial Registration-URL: http://www.ukcrn.org.uk. Unique identifier: 4659.

The haemodynamic effects of adjunctive hormone therapy in potential heart donors: a prospective randomized double-blind factorially designed controlled trial.

AIMS: The aim of this study was to assess the haemodynamic effects of tri-iodothyronine (T3) and methylprednisolone in potential heart donors. METHODS AND RESULTS: In a prospective randomized double-blind trial, 80 potential cardiac donors were allocated to receive T3 (0.8 microg kg(-1) bolus; 0.113 microg kg(-1) h(-1) infusion) (n = 20), methylprednisolone (1000 mg bolus) (n = 19), both drugs (n = 20), or placebo (n = 21) following initial haemodynamic assessment. After hormone or placebo administration, cardiac output-guided optimization was initiated, using vasopressin as a pressor and weaning norepinephrine and inotropes. Treatment was administered for 5.9 +/- 1.3 h until retrieval or end-assessment. Cardiac index increased significantly (P < 0.001) but administration of T3 and methylprednisolone alone or in combination did not affect this change or the heart retrieval rate. Thirty-five per cent (14/40) of initially marginal or dysfunctional hearts were suitable for transplant at end-assessment. At end-assessment, 50% of donor hearts fulfilled criteria for transplant suitability. CONCLUSION: Cardiac output-directed donor optimization improves donor circulatory status and has potential to increase the retrieval rate of donor hearts. Tri-iodothyronine and methylprednisolone therapy do not appear to acutely affect cardiovascular function or yield.

Composite aortic valve graft replacement: mortality outcomes in a national registry.

BACKGROUND: Composite aortic valve and root replacement (CVG) is a complex surgical procedure, but excellent center-specific outcomes are reported. We sought to report outcomes in a national cohort. METHODS AND RESULTS: The United Kingdom Heart Valve Registry was interrogated for 1962 first-time CVG (and 37,102 aortic valve replacements [AVR] as a reference group) procedures from 1986 to 2004. We analyzed 30-day mortality, long-term survival (97.2% complete follow-up), and examined available risk factors for mortality using univariate and multivariate logistic regression analysis and causes of death. CVG patients were younger, received larger valve sizes and were more likely to be emergent than AVR patients. Overall 30-day mortality was 10.7% (CVG) and 3.6% (AVR). For CVG, multivariate analysis identified advanced age (> 70 years), concomitant coronary artery surgery, impaired left ventricular function, urgent or emergency status, prosthetic valve size < or = 23 mm and hospital activity volume < or = 8 procedures per annum as significant factors for 30-day mortality. Kaplan-Meier, 1-year, 5-year, 10-year and 20-year survival were 85.2%, 77.1%, 70% and 59.3%, respectively. The conditional (post-30-day) survival was similar to the AVR cohort. CONCLUSIONS: These Registry data provide a unique national insight into CVG outcomes. After a higher initial mortality risk, CVG has equivalent conditional longer-term survival to AVR.

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.

Near-infrared spectroscopy: an important monitoring tool during hybrid aortic arch replacement.

Near-infrared spectroscopy can be helpful for monitoring the adequacy of cerebral perfusion during cardiovascular surgery. We report changes seen in regional oxygen saturation due to intraoperative thrombosis of the left common carotid artery graft during hybrid aortic arch replacement for traumatic aortic injury.

How does glucose insulin potassium improve hemodynamic performance? Evidence for altered expression of beta-adrenoreceptor and calcium handling genes.

BACKGROUND: Glucose insulin potassium (GIK) improves hemodynamic performance after coronary artery surgery (CABG). We investigated whether this is associated with changes in gene expression of beta1-adrenergic receptor (ADRB1) or other calcium handling proteins. METHODS AND RESULTS: During a randomized double-blind placebo-controlled trial, 48 patients undergoing on-pump CABG, allocated to receive pre-ischemic placebo (5% dextrose) or GIK (40% dextrose, K+ 100 mmol.L(-1), insulin 70 u.L(-1); 0.75 mL.kg(-1).h(-1)) continued for 6 hours after the removal of the aortic cross-clamp (AXC), underwent left ventricular biopsy for analysis of specific mRNAs immediately before AXC, before release of AXC, and 10 minutes after reperfusion (placebo n=24, GIK n=24). GIK or placebo was infused for a mean of 79+/-21 minutes or 79+/-18 minutes pre-ischemia respectively. Serial hemodynamic measurements were performed. Biopsy samples were snap-frozen and stored at -80 degrees C, mRNA was extracted and TaqMan real-time polymerase chain reaction was performed to investigate expression of ADRB1, sarcoplasmic reticulum Ca-ATPase (SERCA2a), and phospholamban (PLB). GIK significantly increased cardiac index versus placebo (P=0.037). TaqMan reverse-transcriptase polymerase chain reaction showed significantly greater ADRB1 mRNA expression at all time points (4.9-fold, 7.4-fold, and 15.6-fold increase, respectively; P<0.001), significantly greater SERCA2a mRNA expression after reperfusion (13.2-fold; P<0.001), and increased PLB mRNA expression at pre-ischemia and reperfusion (P<0.001 for both time-points) in GIK groups versus placebo. CONCLUSIONS: The beneficial hemodynamic effects of GIK therapy are associated with increased ADRB1 and SERCA2a mRNA expression. Further work is therefore warranted to investigate these mRNA effects at the protein level.

Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.

BACKGROUND: Both glucose-insulin-potassium (GIK) and tri-iodothyronine (T3) may improve cardiovascular performance after coronary artery surgery (CABG) but their effects have not been directly compared and the effects of combined treatment are unknown. METHODS AND RESULTS: In 2 consecutive randomized double-blind placebo-controlled trials, in patients undergoing first time isolated on-pump CABG between January 2000 and September 2004, 440 patients were recruited and randomized to either placebo (5% dextrose) (n=160), GIK (40% dextrose, K+ 100 mmol.L(-1), insulin 70 u.L(-1)) (0.75 mL.kg(-1) h(-1)) (n=157), T3 (0.8 microg.kg(-1) followed by 0.113 microg.kg(-1) h(-1)) (n=63) or GIK+T3 (n=60). GIK/placebo therapy was administered from start of operation until 6 hours after removal of aortic cross-clamp (AXC) and T3/placebo was administered for a 6-hour period from removal of AXC. Serial hemodynamic measurements were taken up to 12 hours after removal of AXC and troponin I (cTnI) levels were assayed to 72 hours. Cardiac index (CI) was significantly increased in both the GIK and GIK/T3 group in the first 6 hours compared with placebo (P<0.001 for both) and T3 therapy (P=0.009 and 0.029, respectively). T3 therapy increased CI versus placebo between 6 and 12 hours after AXC removal (P=0.01) but combination therapy did not. Release of cTnI was lower in all treatment groups at 6 and 12 hours after removal of AXC. CONCLUSIONS: Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery. Combination therapy does not provide added hemodynamic effect.

Presentation and outcome of Marfan's syndrome patients with dissection and thoraco-abdominal aortic aneurysm.

BACKGROUND: In Marfan's syndrome, there is a paucity of data regarding intervention criteria for surgery of the dissected thoraco-abdominal aorta. METHODS: A retrospective analysis of 22 Marfan's patients with distal aortic dissection managed between September 1999 and April 2006 was performed. Serial diameters and linear expansion rates were calculated from imaging studies and the outcome of intervention was analysed. RESULTS: There were 14/22 male patients (median age 38 years), and 18 had prior aortic surgery. Surgery was recommended in 20 patients and undertaken in 19 (1 died prior to operation). Of the operated patients, 2 presented with rupture, 2 with airway obstruction, 1 with intermittent paraplegia and 14 underwent planned surgery for increased expansion rate or pain. All patients had residual type A or chronic type B dissection. The median aortic dimension at surgery was 6.7 cm (interquartile range (IQR) 5.5-8.2). The preoperative mean expansion rate increased from 0.5 cm/year to 1.7 cm/year (p<0.001), prior to operation. Fifteen patients underwent Crawford Extent II, two underwent Extent I and two underwent Extent III repair. Profound hypothermia and CSF drainage was used in 16 and 18 patients, respectively. There was no early mortality, paraplegia or renal failure. At a median postoperative follow-up of 56 months (range 6-86), the survival of the operated cohort was 90%. CONCLUSIONS: Thoraco-abdominal aortic aneurysm repair in Marfan's syndrome can be performed with good outcomes. Intervention should be based on size or accelerated expansion. Any role of endovascular management needs careful consideration.

Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting.

BACKGROUND: Risk stratification algorithms for coronary artery bypass grafting (CABG) do not include a weighting for preoperative mild renal impairment defined as a serum creatinine 130 to 199 micromol/L (1.47 to 2.25 mg/dL), which may impact mortality and morbidity after CABG. METHODS AND RESULTS: We reviewed prospectively collected data between 1997 and 2004 on 4403 consecutive patients undergoing first-time isolated CABG with a preoperative serum creatinine <200 micromol/L (2.26 mg/dL)] in a single institution. The in-hospital mortality was 2.5% (112 of 4403), the need for new dialysis/hemofiltration was 1.3% (57 of 4403), and the stroke rate was 2.5% (108 of 4403). There were 458 patients with a serum creatinine 130 to 199 micromol/L or 1.47 to 2.25 mg/dL (mild renal dysfunction group) and 3945 patients with a serum creatinine <130 micromol/L (<1.47 mg/dL). Operative mortality was higher in the mild renal dysfunction group (2.1% versus 6.1%; P<0.001) and increased with increasing preoperative serum creatinine level. New dialysis/hemofiltration (0.8%versus 5.2%; P<0.001) and postoperative stroke (2.2% versus 5.0%; P<0.01) were also more common in the patients with mild renal impairment. Multivariate analysis adjusting for known risk factors confirmed preoperative mild renal impairment (creatinine 130 to 199 micromol/L or 1.47 to 2.25 mg/dL; odd ratio, 1.91; 95% CI, 1.18 to 3.03; P=0.007) or glomerular filtration rate estimates <60 mL/min per 1.73 m2, derived using the Cockroft-Gault formula, (odds ratio, 1.98; 95% CI, 1.16 to 3.48; P=0.015) as independent predictors of in-hospital mortality. Preoperative mild renal dysfunction adversely affected the 3-year survival probability after CABG (93% versus 81%; P<0.001). CONCLUSIONS: Mild renal dysfunction is an important predictor of outcome in terms of in-hospital mortality, morbidity, and midterm survival in patients undergoing CABG.

Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease.

INTRODUCTION: Inflammation contributes to cardiovascular disease and is exacerbated with increased adiposity, particularly omental adiposity; however, the role of epicardial fat is poorly understood. METHODS: For these studies the expression of inflammatory markers was assessed in epicardial fat biopsies from coronary artery bypass grafting (CABG) patients using quantitative RT-PCR. Further, the effects of chronic medications, including statins, as well as peri-operative glucose, insulin and potassium infusion, on gene expression were also assessed. Circulating resistin, CRP, adiponectin and leptin levels were determined to assess inflammation. RESULTS: The expression of adiponectin, resistin and other adipocytokine mRNAs were comparable to that in omental fat. Epicardial CD45 expression was significantly higher than control depots (p < 0.01) indicating significant infiltration of macrophages. Statin treated patients showed significantly lower epicardial expression of IL-6 mRNA, in comparison with the control abdominal depots (p < 0.001). The serum profile of CABG patients showed significantly higher levels of both CRP (control: 1.28 +/- 1.57 microg/mL vs CABG: 9.11 +/- 15.7 microg/mL; p < 0.001) and resistin (control: 10.53 +/- 0.81 ng/mL vs CABG: 16.8 +/- 1.69 ng/mL; p < 0.01) and significantly lower levels of adiponectin (control: 29.1 +/- 14.8 microg/mL vs CABG: 11.9 +/- 6.0 microg/mL; p < 0.05) when compared to BMI matched controls. CONCLUSION: Epicardial and omental fat exhibit a broadly comparable pathogenic mRNA profile, this may arise in part from macrophage infiltration into the epicardial fat. This study highlights that chronic inflammation occurs locally as well as systemically potentially contributing further to the pathogenesis of coronary artery disease.

Patient-prosthesis mismatch does not affect survival following aortic valve replacement.

OBJECTIVE: Patient-prosthesis mismatch (PPM) has been reported to increase perioperative mortality and reduce postoperative survival in patients undergoing aortic valve replacement (AVR). We analysed the effect of PPM at values predicting severe mismatch on survival following AVR in our unit. METHODS: Prospectively collected data on 1481 consecutive patients who had undergone AVR with or without coronary artery revascularisation between 1997 and 2005 were analysed. Projected in vitro valve effective orifice area (EOA) and geometric prosthesis internal orifice area (GOA) were evaluated and values were indexed to body surface area (cm(2)m(-2)). PPM was defined as EOAi<0.6 and/or GOAi<1.1. Long-term survival data were obtained from the National Institute of Statistics. RESULTS: One thousand four hundred and eighteen patients were identified. 67/1418 (4.7%) patients had GOAi<1.1; 122/1418 (8.6%) had EOAi<0.6 and 38 (2.6%) patients exhibited both forms of mismatch. One thousand two hundred and sixty-seven patients (89%) demonstrated no mismatch (reference group). There were 75 in-hospital deaths (overall mortality 5.3%) with no significant difference between the mismatch and the reference groups. Survival data were available for up to 8 years (median 36 months, IQR 6-60 months). There were 160 late deaths (13/143 PPM group vs 147/1198 reference group). The 5-year survival estimate was similar for both groups (83% PPM group; 81% reference group; p=0.47). Cox-hazard analysis identified advanced age as the only predictor of reduced survival (age>80, RR 2.13, 95% CI 1.38-4.586, p=0.004). CONCLUSIONS: Severe patient-prosthesis mismatch was predicted in 4-10% of patients undergoing AVR but this did not affect in-hospital mortality or mid-term survival.

Multicentre analysis of current strategies and outcomes in open aortic arch surgery: heterogeneity is still an issue.

OBJECTIVES: The study was conducted to evaluate, on the basis of a multicentre analysis, current results of elective open aortic arch surgery performed during the last decade. METHODS: Data of 1232 consecutive patients who underwent aortic arch repair with reimplantation of at least one supra-aortic artery between 2004 and 2013 were collected from 11 European cardiovascular centres, and retrospective statistical examination was performed using uni- and multi-variable analyses to identify predictors for 30-day mortality. Acute aortic dissections and arch surgeries not involving the supra-aortic arteries were not included. RESULTS: Arch repair involving all 3 arch arteries (total), 2 arch arteries (subtotal) or 1 arch artery (partial) was performed in 956 (77.6%), 155 (12.6%) and 121 (9.8%) patients, respectively. The patients' characteristics as well as the surgical techniques, including the method of cannulation, perfusion and protection, varied considerably between the clinics participating in the study. The in-hospital and 30-day mortality rates were 11.4 and 8.8% for the entire cohort, respectively, ranging between 1.7 and 19.0% in the surgical centres. Multivariable logistic regression analysis identified surgical centre, patient's age, number of previous surgeries with sternotomy and concomitant surgeries as independent risk factors of 30-day mortality. The follow-up of the study group was 96.5% complete with an overall follow-up duration of 3.3 ± 2.9 years, resulting in 4020 patient-years. After hospital discharge, 176 (14.3%) patients died, yielding an overall mortality rate of 25.6%. The actuarial survival after 5 and 8 years was 72.0 ± 1.5% and 64.0 ± 2.0, respectively. CONCLUSIONS: The surgical risk in elective aortic arch surgery has remained high during the last decade despite the advance in surgical techniques. However, the patients' characteristics, numbers of surgeries, the techniques and the results varied considerably among the centres. The incompleteness of data gathered retrospectively was not effective enough to determine advantages of particular cannulation, perfusion, protection or surgical techniques; and therefore, we strongly recommend further prospective multicentre studies, preferably registries, in which all relevant data have to be clearly defined and collected.

Systemic inhibition of nitric oxide synthase unmasks neural constraint of maximal myocardial blood flow in humans.

BACKGROUND: Nitric oxide (NO) is an endothelial mediator that regulates vascular smooth muscle tone, but it may exert its cardiovascular action also by modulating the autonomic control of vasomotor tone. We assessed the effect of simultaneous inhibition of both endothelial (eNOS) and neuronal (nNOS) NO synthase isoforms on myocardial blood flow (MBF) and coronary flow reserve (CFR) in volunteers and in (denervated) transplant recipients. METHODS AND RESULTS: MBF (mL x min(-1) x g(-1)) was measured at rest and during adenosine-induced hyperemia with positron emission tomography and 15O-labeled water. CFR was calculated as adenosine/resting MBF. Measurements were repeated during one of the following intravenous infusions: group 1 (n=12), saline; group 2 (n=9), 3 mg/kg N(G)-monomethyl-L-arginine (L-NMMA), which crosses the blood-brain barrier and inhibits both eNOS and nNOS; group 3 (n=13), 10 mg/kg L-NMMA; group 4 (n=8), phenylephrine titrated to simulate the hemodynamic changes in group 3; and group 5 (n=6), 10 mg/kg L-NMMA infused into the heart transplant recipients. After intervention, hyperemic MBF and CFR were unchanged in groups 1, 2, and 4. By contrast, both hyperemic MBF (+53%, P<0.0001 versus baseline) and CFR (+52%, P<0.0001 versus baseline) increased in group 3, whereas they remained unchanged in group 5, which suggests that an intact cardiac innervation was required for the increase in MBF and CFR observed in group 3. CONCLUSIONS: The results of the present study suggest that maximal adenosine-induced hyperemia and CFR in humans are constrained by neurally mediated vasoconstriction, which can be relieved by systemic NOS inhibition with L-NMMA.

The effects of hypothermia on human left ventricular contractile function during cardiac surgery.

OBJECTIVES: We investigated the interaction of heart rate (HR), temperature and contractility using a validated load independent method. BACKGROUND: Temperature manipulation is an integral part of cardiac surgery, and postoperative hypothermia is extremely common. Myocardial contraction is a series of enzymatic and physico-chemical reactions that may be differentially affected by temperature. METHODS: Ten patients undergoing coronary artery bypass grafting were studied during moderately hypothermic cardiopulmonary bypass. After conduit procurement and heparinization but before grafting, the patient was placed on cardiopulmonary bypass and rewarmed to 37 degrees C, and the left ventricle (LV) was instrumented with a conductance catheter allowing continuous pressure and volume measurement. The LV pressure volume relationship was examined to assess the contractility at 37, 35, 33 and 31 degrees C, with fixed atrial pacing (100 beats/min) in five patients and at 80 and 120 beats/min, at 33 and 37 degrees C in five patients. RESULTS: At a HR of 100 beats/min, lower temperature resulted in a highly significant decrease in maximal elastance (100% at 37 degrees C, 29 +/- 3.5% at 31 degrees C, p < 0.0001). At 37 degrees C, increasing HR increased contractility (80 beats/min 100%, 120 beats/min 205.9%, p = 0.0021); however, at 33 degrees C contractility fell with increasing HR (80 beats/min 100%, 120 beats/min, 53.7%, p = 0.0014). CONCLUSIONS: At normothermia LV contractility has a direct relationship with HR. In hypothermic conditions this relationship inverses. Clinical strategies maintaining higher HRs at colder temperatures result in reduced contractility. These factors are important in the management of cardiac surgical patients.

Donor cause of death and medium-term survival after heart transplantation: a United Kingdom national study.

OBJECTIVE: Donor cause of death may be a risk factor for early mortality after heart transplantation, but its effect on medium-term survival is uncertain. METHODS: By means of a national prospective database, we investigated the influence of donor cause of death on survival to 3 years in 1254 adult recipients of cadaveric heart transplantation between July 1995 and June 2002. Donor cause of death was categorized a priori as vascular and tumor (group V, n = 739), trauma (group T, n = 407), hypoxic (group H, n = 82), and infective causes (group I, n = 26). Risk factors for early (30-day), late (30-day to 3-year), and overall mortality were identified with Cox regression. RESULTS: Group V donors were more likely to be older ( P < .001) and female ( P < .001). There were 297 deaths in the 3-year period, and the unadjusted 3-year survivals varied significantly (group V 73%, group T 79%, group H 85%, group I 80%, P = .01). Cox analysis identified donor age, organ ischemia time, recipient creatinine clearance, recipient diagnosis, peripheral vascular disease, ventilation, diabetes, and donor-recipient size mismatch as risk factors for early, late, or overall mortality ( P < .10). After adjustment for these factors, donor cause of death was no longer a significant predictor of recipient death (early death P = .36, late death P = .79, overall mortality P = .37). CONCLUSION: We confirmed that there is an apparent association between cause of donor death and posttransplantation survival, but this was not maintained after adjustment for confounding variables. Donor cause of death therefore should not influence donor organ acceptance or donor-recipient matching and does not identify marginal donors.

Cumulative risk adjusted monitoring of 30-day mortality after cardiothoracic transplantation: UK experience.

OBJECTIVE: Guidelines are needed for real-time quality monitoring in heart and lung transplantation. The cumulative sum (CUSUM) methodology with boundary limits derived from the sequential probability ratio test (SPRT) provide a means of monitoring performance without the need for repeated statistical testing. The variable life adjusted display (VLAD) complements the SPRT chart and provides a directly interpretable assessment of performance. We present our experience with these charts in monitoring cardiothoracic transplant outcomes in the UK. METHODS: Thirty-day-post-transplantation mortality after isolated first time transplantation of the heart (n=1634) or lung (n=1162) in adults, between July 1995 and March 2004 in eight centres were monitored. CUSUM charts, with and without risk-adjustment and risk-adjusted VLAD plots were constructed. Thirty-day mortality rates for the UK as a whole were taken as the reference values for the unadjusted charts and a 50% increase in risk provided the basis for construction of boundary lines for the SPRT. Risk-adjustment was based on multivariate models previously developed from the national database. RESULTS: For heart transplantation without risk-adjustment, four centres crossed the lower boundary, indicating 30-day mortality was in-line with or better than seen nationally. Two centres were close to signalling an alert, warning of a rise in mortality rate, but neither chart signalled an alarm. After risk-adjustment one centre's graph moved towards the centre of the chart, indicating monitoring should continue and the other signalled an alarm. For lung transplantation the unadjusted mortality rate at one centre was confirmed acceptable and the results remained inconclusive for five. At the other centre, following an alert to a possible increase in mortality half-way through the sequence, results improved. Case-mix adjustment served to pull the charts away from the upper boundary lines; no chart suggested any cause for concern. For most centres the VLAD charts oscillated around the horizontal axis. CONCLUSIONS: CUSUM charts are useful tools for monitoring performance, and provide a basis for visually comparing results between centres and identifying periods of 'bad runs'. Risk-adjustment, which down-weights higher risk activity, avoids inappropriate reaction to unadjusted breaches of alert and alarm lines.

Glucose and insulin influences on heart and brain in cardiac surgery.

The elective global ischemia of on-pump coronary artery bypass surgery contributes to the incidence of postoperative mortality, complications, and use of resources. In addition to cardiopulmonary bypass and techniques for myocardial protection such as aortic cross clamp, ventricular fibrillation, and cardioplegia, the administration of systemic glucose-insulin-potassium (GIK) in the perioperative period may act as both a metabolic modulator and potential inodilator. GIK may therefore serve to protect the myocardium and promote adequate cardiac and hemodynamic performance that would improve patient recovery. Cell, tissue, and animal experiments have determined a number of mechanisms of action by which this may be achieved, with increasing focus on insulin as the key component. The original concepts centered on GIK during or after ischemia switching metabolism away from that based on non-esterified fatty acids toward a more favorable glucose-based metabolism and thus improving the efficiency of adenosine triphosphate production and glycogen preservation. Insulin's ability to reduce intracellular fatty acid metabolism may also reduce cellular membrane damage. More recently other mechanisms have also been suggested, including osmotic, oxygen free radical scavenging, and antiapoptotic and anti-inflammatory effects. However, trials that have examined the role of GIK in cardiac surgery have been small, open label, and involved a wide variety of regimens. They have demonstrated improved glycogen preservation, reduced infarct size, reduced incidences of dysrhythmias, need for inotropic agents, and low cardiac output state, and overall reduced lengths of stay. The perceived need to achieve strict blood glucose control to reduce neurologic injury and improve overall mortality have conflicted with its practical difficulties, particularly during cold cardiopulmonary bypass, and the exact role of supplemental glucose administration and resulting hyperglycemia require re-examination.