Impact of minimal invasive extracorporeal circulation on systemic inflammatory response - a randomized trial.

BACKGROUND: Extracorporeal circulation causes a systemic inflammatory response, that may cause postoperative haemodynamic instability and end-organ dysfunction. This study aimed to investigate the impact of minimal invasive extracorporeal circulation (MiECC) on the systemic inflammatory response compared with conventional extracorporeal circulation (CECC). METHODS: Patients undergoing coronary artery bypass grafting were randomized to MiECC (n = 30) and CECC (n = 30). Primary endpoint was tumor necrosis factor-α. Secondary endpoints were other biochemical markers of inflammation (IL1ß, IL6 and IL8, C-reactive protein, leukocytes), and markers of inadequate tissue perfusion and tissue damage (lactate dehydrogenase, lactate and creatine kinase-MB). In addition, we registered signs of systemic inflammatory response syndrome, haemodynamic instability, atrial fibrillation, respiratory dysfunction, and infection. RESULTS: Patients treated with MiECC showed significantly lower levels of tumor necrosis factor-α than CECC during and early after extracorporeal circulation (median: MiECC 3.4 pg/mL; CI 2.2-4.5 vs. CECC 4.6 pg/mL; CI 3.4-5.6; p = 0.01). Lower levels of creatine kinase-MB and lactate dehydrogenase suggested less tissue damage. However, we detected no other significant differences in any other markers of inflammation, tissue damage or in any of the clinical outcomes. CONCLUSIONS: Lower levels of TNF-α after MiECC compared with CECC may reflect reduced inflammatory response, although other biochemical markers of inflammation were comparable. Our results suggest better end-organ protection with MiECC compared with CECC. Clinical parameters related to systemic inflammatory response were comparable in this study. CLINICAL REGISTRATION NUMBER: NCT03216720.

Comparison of free arterial and saphenous vein grafting in outcomes after coronary bypass surgery.

Objectives. The goal of this study was to examine whether the use of free arterial grafts could reduce the need for repeated revascularization and all-cause mortality in patients undergoing coronary artery grafting. Design. The cohort study included 17,354 consecutive adults with isolated coronary artery grafting from 2000 to 2016 in three cardiac surgery centers. Data were obtained from the Western Denmark Heart Registry. Propensity matching with 24 factors was used to establish comparable groups of patients receiving either vein grafts (n = 1019) or free arterial grafts (n = 1019) for outcome analysis. Results. The need for repeated revascularization and all-cause mortality was similar in both graft groups at 10 years of follow-up. Creatine-Kinase MB Isoenzyme >100 µg/L increased the risk of repeated revascularization rate after 1, 5 and 10 years. Conclusions. Long-term outcomes in revascularization and survival are comparable after free arterial or saphenous vein grafting.

Development of a human heart-sized perfusion system for metabolic imaging studies using hyperpolarized [1-13 C]pyruvate MRI.

PURPOSE: Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1-13 C]pyruvate, provide a novel means of investigating metabolic status without the use of ionizing radiation. We demonstrate the use of this methodology to examine ex vivo perfused porcine heart grafts. METHODS: Hearts from three 40-kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR-compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1-13 C]pyruvate were used to investigate and quantify the functional and metabolic status of the grafts. RESULTS: Hearts were perfused with whole blood for 120 min, using a dynamic contrast-enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1-13 C]pyruvate MRI was used to assess the metabolic state of the myocardium. Functional assessment was performed using CINE imaging and ventricular pressure data. High lactate and modest alanine levels were observed in the hyperpolarized experiment. The functional assessment produced reduced functional parameters. This suggests an altered functional and metabolic profile compared with corresponding in vivo values. CONCLUSION: We investigated the metabolic and functional status of machine-perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information-in combination with already established MR methods for cardiac investigation-provides a powerful tool to aid the progress of donor heart preservation.

Cardioprotective effect of succinate dehydrogenase inhibition in rat hearts and human myocardium with and without diabetes mellitus.

Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p < 0.05). Mitochondrial respiration was reduced by DiMAL 0.6 mM compared to sham and DiMAL 0.1 mM (p < 0.05). In diabetic hearts an increased concentration of DiMAL (0.6 mM) was required for protection compared to IR (64 ± 13% vs. 79 ± 8%, p < 0.05). Mitochondrial function remained unchanged. In trabeculae from humans without diabetes, IPC and DiMAL improved contractile force recovery compared to IR (43 ± 12% and 43 ± 13% vs. 23 ± 13%, p < 0.05) but in patients with diabetes only IPC provided protection compared to IR (51 ± 15% vs. 21 ± 8%, p < 0.05). Neither IPC nor DiMAL modulated mitochondrial respiration in patients. Cardioprotection by SDH inhibition is possible in human tissue, but depends on diabetes status. The narrow therapeutic range and discrepancy in respiration between experimental and human studies may limit clinical translation.

Impact of minimally invasive extracorporeal circulation on coagulation-a randomized trial.

OBJECTIVES: Minimally invasive extracorporeal circulation (MiECC) is suggested to have favourable impact on blood loss compared to conventional extracorporeal circulation. We aimed to compare the impact of both systems on coagulation. METHODS: Randomized trial comparing endogenous thrombin-generating potential early after elective coronary surgery employing either MiECC group (n = 30) or conventional extracorporeal circulation group (n = 30). Secondary outcomes were in vivo thrombin generation, bleeding end points and haemodilution, as well as morbidity and mortality up to 30-day follow-up. RESULTS: Compared to the conventional extracorporeal circulation group, the MiECC group showed (i) a trend towards a higher early postoperative endogenous thrombin-generating potential (P = 0.06), (ii) lower intraoperative levels of thrombin-antithrombin complex and prothrombin fragment 1 + 2 (P < 0.001), (iii) less haemodilution early postoperatively as measured by haematocrit and weight gain, but without correlation to coagulation factors or bleeding end points. Moreover, half as many patients required postoperative blood transfusion in the MiECC group (17% vs 37%, P = 0.14), although postoperative blood loss did not differ between groups (P = 0.84). Thrombin-antithrombin complex levels (rs = 0.36, P = 0.005) and prothrombin fragment 1 + 2 (rs = 0.45, P < 0.001), but not early postoperative endogenous thrombin-generating potential (rs = 0.05, P = 0.72), showed significant correlation to increased transfusion requirements. The MiECC group demonstrated significantly lower levels of creatine kinase-MB, lactate dehydrogenase and free haemoglobin indicating superior myocardial protection, less tissue damage and less haemolysis, respectively. Perioperative morbidity and 30-day mortality did not differ between groups. CONCLUSIONS: Conventional but not MiECC is associated with significant intraoperative thrombin generation despite full heparinization. No correlation between coagulation factors or bleeding end points with the degree of haemodilution could be ascertained. CLINICALTRIALS.GOV IDENTIFIER: NCT03216720.

To jump or not to jump? A multicentre propensity-matched study of sequential vein grafting of the heart†.

OBJECTIVES: In this propensity-matched study we investigated the outcome after grafting with either a single vein or a sequential vein grafting strategy. Outcomes were primarily risk of reintervention and death in the short, intermediate and long term (10 years). MATERIALS: In the period from 2000 to 2016, data from 24 742 patients undergoing coronary artery bypass grafting were extracted from the Western Denmark Heart Registry, where data are registered perioperatively. We used a propensity-matched study in which the study groups were matched on parameters primarily from the EuroSCORE. The numbers of patients in both groups after matching were 3380. RESULTS: Single grafts resulted in significantly more postoperative bleeding and were more time-consuming. No differences were seen regarding in-hospital events such as stroke, acute myocardial infarction, dialysis or arrhythmias. After 30 days, patients in the jump graft group showed an increased rate of reintervention due to ischaemia after adjusting for confounding factors [hazard ratio (HR) 2.08, 95% confidence interval 1.01-4.34]. In addition, after adjusting for known confounders, sequential grafts were found to increase the risk of mortality at 6 months (HR 1.51, 95% confidence limits 1.07-2.11) and 5 years (HR 1.23, 95% confidence limits 1.04-1.46). CONCLUSIONS: This propensity-matched analysis suggested, although discretely, that a jump graft as a grafting strategy is associated with a slightly increased risk of mortality and early graft failure and that a single grafting strategy to the coronary arteries should be preferred when feasible.

Blood cardioplegia benefits only patients with a long cross-clamp time.

INTRODUCTION: A clear advantage of blood versus crystalloid cardioplegia has not yet been observed in smaller population studies. The purpose of this article was to further investigate the clinical outcomes of blood versus crystalloid cardioplegia in a large propensity-matched cohort of patients who underwent cardiac surgery. METHODS: The study was a single-centre study. Data was withdrawn from the Western Denmark Heart Registry, which comprises a perfusion section for each procedure. A total of 4,852 patients were propensity matched into crystalloid (CC) vs blood cardioplegia (BC) groups. The primary end points were creatinine kinase-MB (CKMB) elevation, acute myocardial infarction (AMI), stroke, dialysis, coronary angiography (CAG) and mortality (30 days and 6 months). RESULTS: We found lower odds ratio in 30-day mortality in the BC group (OR 0.21; CI 0.06-0.68), but no difference in overall 6-month mortality. There was no difference in CKMB elevation, AMI, dialysis or stroke. Several end points were further analysed for different cross-clamp times. In the CC group, ventilation time above 600 minutes was seen more often in almost all cross-clamp time intervals (23.5 % vs 12.2 %; p<0.0001; χ2-test) and 6-month mortality was significantly higher when the cross-clamp time exceeded 210 minutes (64.3 vs 23.8; p=0.018; χ2-test). CONCLUSIONS: We did not find clear evidence of superiority of either type in the uncomplicated patient. When prolonged cross-clamp time or postoperative ventilation is expected, this study indicates that blood cardioplegia might be preferable.

A dose-response study of glutamate supplementation in isolated, perfused rat hearts undergoing ischaemia and cold cardioplegia.

OBJECTIVES: Several studies have reported superior post-cardioplegic recovery after glutamate supplementation. The optimum dose of glutamate supplementation is unknown. The purpose of this study was to find the optimal protective concentration of glutamate supplementation in a model of ischaemia/cardioplegia and reperfusion. METHODS: Isolated rat hearts (n = 77) were perfused with the Krebs-Henseleit buffer. After stabilization, the hearts were subjected to 25 min of normothermic ischaemia followed by a single 3-min infusion of cold (4-6 °C) St. Thomas' Hospital II cardioplegia and 87 min of cardioplegic ischaemic arrest and 60 min of reperfusion. Sodium-l-glutamate was added to the perfusate (control group had zero glutamate) in increasing concentrations (0.01, 0.1, 1, 10, 20, 30 and 100 mM) and given throughout perfusion. Corresponding concentrations were added to the cardioplegic solution. A balloon in the left ventricle inserted via the left atrium measured left ventricular pressures isometrically. Left ventricular developed pressure was calculated. Myocardial exchange of glucose and lactate was measured prior to ischaemia and during reperfusion. Myocardial content of glycogen and glutamate was measured at the end of reperfusion. RESULTS: During reperfusion left ventricular developed pressure increased (P < 0.0001) in groups supplemented with 0.1, 1.0, 10, 20 and 30 mM glutamate, whereas left ventricular end-diastolic pressure was attenuated (P = 0.008) when compared with the controls. No additional benefit on the continuous data left ventricular developed pressure and left ventricular end-diastolic pressure was observed with glutamate concentrations above 1 mM. Onset of LV pressure rise during the period of ischaemia was delayed by 100 mM of glutamate (P = 0.02). Myocardial content of glutamate was increased in a dose-related manner in Groups 10, 20, 30 and 100 compared with the control hearts (P < 0.0001). Glycogen was increased in the hearts supplemented with 100 mM of glutamate (P = 0.02). CONCLUSIONS: Even low concentrations of l-glutamate improved postischaemic and post-cardioplegic heart function and 1 mM seems to be optimal.

Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart.

Prostacyclins are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostacyclins on right heart function are still not clarified. The aim of this study was to investigate the possible direct inotropic properties of clinical available prostacyclin mimetics in the normal and the pressure-overloaded human right atrium. Trabeculae from the right atrium were collected during surgery from chronic thromboembolic pulmonary hypertension (CTEPH) patients with pressure-overloaded right hearts, undergoing pulmonary thromboendarterectomy (n = 10) and from patients with normal right hearts operated by valve replacement or coronary bypass surgery (n = 9). The trabeculae were placed in an organ bath, continuously paced at 1 Hz. They were subjected to increasing concentrations of iloprost, treprostinil, epoprostenol, or MRE-269, followed by isoprenaline to elicit a reference inotropic response. The force of contraction was measured continuously. The expression of prostanoid receptors was explored through quantitative polymerase chain reaction (qPCR). Iloprost, treprostinil, epoprostenol, or MRE-269 did not alter force of contraction in any of the trabeculae. Isoprenaline showed a direct inotropic response in both trabeculae from the pressure-overloaded right atrium and from the normal right atrium. Control experiments on ventricular trabeculae from the pig failed to show an inotropic response to the prostacyclin mimetics. qPCR demonstrated varying expression of the different prostanoid receptors in the human atrium. In conclusion, prostacyclin mimetics did not increase the force of contraction of human atrial trabeculae from the normal or the pressure-overloaded right heart. These data suggest that prostacyclin mimetics have no direct inotropic effects in the human right atrium.

Re-exploration due to bleeding is not associated with severe postoperative complications.

OBJECTIVES: In cardiac surgery, postoperative bleeding remains a frequent complication with various possible adverse outcomes. Re-exploration due to bleeding is frequent in this type of patient. Sternal wound infection is an infrequent but serious and devastating complication. Whether re-exploration due to bleeding significantly affects the incidence of sternal wound infection is uncertain. There is no consensus on allowed severity of bleeding and timing of intervention. METHODS: A retrospective, observational cohort study of 15 350 consecutive patients who underwent cardiac surgical procedures from 1 April 2006 through 31 December 2013 in 3 different university hospitals in Denmark was performed. Re-exploration due to postoperative bleeding occurred in 873 patients. To adjust for possible confounders, propensity score matching and logistic regression analyses were performed based on the centre, EuroSCORE I/II factors, extracorporeal circulation time, drugs affecting bleeding and coagulation, postoperative bleeding and units of blood transfusions. Patients were matched into 2 groups of 779 patients each for further analysis. The short-term outcomes were sternum infection, 30-day mortality and acute renal failure needing dialysis. The long-term outcome was the number of deaths 6 months after surgery. RESULTS: The incidence of re-exploration was 5.7%. In the raw data, sternal infection was higher in the re-exploration group (2.4% vs 1.4; P = 0.020). After propensity score matching, no differences in sternal infection or other measured outcomes were found between the groups, either by crude or adjusted analyses. CONCLUSIONS: Our study indicates that re-exploration is not associated with a higher frequency of severe postoperative complications. Probably the time of intervention for bleeding is important.

Durability after aortic valve replacement with the Mitroflow versus the Perimount pericardial bioprosthesis: a single-centre experience in 2393 patients.

OBJECTIVES: This study compares the durability and risk of reoperation in patients undergoing aortic valve replacement (AVR) with either a Mitroflow or a Carpentier-Edwards (CE) pericardial bioprosthesis. Since AVR with bioprosthetic valves has increased progressively in recent years as compared to mechanical valves, especially in patients aged 60-70 years, there has been renewed interest in the long-term durability of current pericardial bioprostheses. METHODS: We compared 440 AVR with Mitroflow valves with 1953 AVR with CE pericardial valves implanted from 1999 to 2014 with regard to reoperation, reoperation for structural valve deterioration (SVD) and all-cause mortality. RESULTS: Ten-year freedom from explant of any cause was higher for CE Perimount (98 ± 0.7%) than for Mitroflow (95 ± 1.4%, P < 0.01). Reasons for explant for CE Perimount were SVD (n = 2), endocarditis (n = 8) and paraprosthetic leak (n = 10). The reasons for explant for Mitroflow were SVD (n = 11), endocarditis (n = 3) SVD and pericarditis (n = 1) and paraprosthetic leak (n = 2). Ten-year freedom from explant due to SVD was higher for CE Perimount (100%) than for Mitroflow (96%) (P < 0.01). In small aortic annuli (bioprosthesis size 19-21 mm), freedom from SVD at 10 years for CE Perimount and Mitroflow was 100 versus 96%, respectively. By multivariate analysis, it was found that bioprosthesis size was not a risk factor for SVD. The choice of valve type could not be demonstrated to influence long-term survival. CONCLUSIONS: The Mitroflow pericardial bioprosthesis provides less than optimal mid- and long-term durability compared with the CE Perimount pericardial valve, especially for small aortic diameter implants (19 and 21 mm). This study hereby confirms the existence of a real risk of valvular deterioration of the Mitroflow valve that might compromise the prognosis of the patients.

Impact of O-GlcNAc on cardioprotection by remote ischaemic preconditioning in non-diabetic and diabetic patients.

AIMS: Post-translational modification of proteins by O-linked ß-N-acetylglucosamine (O-GlcNAc) is cardioprotective but its role in cardioprotection by remote ischaemic preconditioning (rIPC) and the reduced efficacy of rIPC in type 2 diabetes mellitus is unknown. In this study we achieved mechanistic insight into the remote stimulus mediating and the target organ response eliciting the cardioprotective effect by rIPC in non-diabetic and diabetic myocardium and the influence of O-GlcNAcylation. METHODS AND RESULTS: The cardioprotective capacity and the influence on myocardial O-GlcNAc levels of plasma dialysate from eight healthy volunteers and eight type 2 diabetic patients drawn before and after subjection to an rIPC stimulus were tested on human isolated atrial trabeculae subjected to ischaemia/reperfusion injury. Dialysate from healthy volunteers exposed to rIPC improved post-ischaemic haemodynamic recovery (40 ± 6 vs. 16 ± 2%; P < 0.01) and increased myocardial O-GlcNAc levels. Similar observations were made with dialysate from diabetic patients before exposure to rIPC (43 ± 3 vs. 16 ± 2%; P < 0.001) but no additional cardioprotection or further increase in O-GlcNAc levels was achieved by perfusion with dialysate after exposure to rIPC (44 ± 4 and 42 ± 5 vs. 43 ± 3%; P = 0.7). The glutamine:fructose-6-phosphate amidotransferase (GFAT) inhibitor azaserine abolished the cardioprotective effects and the increment in myocardial O-GlcNAc levels afforded by plasma from diabetic patients and healthy volunteers treated with rIPC. CONCLUSIONS: rIPC and diabetes mellitus per se influence myocardial O-GlcNAc levels through circulating humoral factors. O-GlcNAc signalling participates in mediating rIPC-induced cardioprotection and maintaining a state of inherent chronic activation of cardioprotection in diabetic myocardium, restricting it from further protection by rIPC.

Proteomic analysis identifies mitochondrial metabolic enzymes as major discriminators between different stages of the failing human myocardium.

OBJECTIVES: Our aim was to identify patterns in differentially regulated proteins associated with the progression of chronic heart failure. We specifically studied proteomics in chronic reversibly (RDM) and irreversibly dysfunctional myocardium (IRDM), as well as end-stage failing myocardium (ESFM). METHODS: We studied biopsies from 9 patients with stable chronic heart failure undergoing coronary artery bypass surgery (CABG) (EF 34% +/- 3%) and from 4 patients with ESFM undergoing heart transplantation (EF 17% +/- 5%). In CABG patients paired echocardiographic studies before and 6 months after revascularization classified dysfunctional myocardium as RDM or IRDM. Regions with preserved contractile function served as control. We used two-dimensional gel electrophoresis (2D-PAGE) and computerized image analysis to investigate myocardial protein expression. Proteins were identified by in-gel digestion and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Among 3 significantly altered protein spots in RDM we identified 2 up-regulated glycolytic enzymes. In IRDM 15 proteins were signficantly altered of which we identified 10, among these 6 were down-regulated mitochondrial enzymes. In ESFM 9 of 12 significantly altered protein spots were identified. Six were down-regulated mitochondrial enzymes. CONCLUSION: Myocardial metabolism may be involved in the progression of heart failure to irreversible dysfunction and end-stage heart failure.

Cardioprotection by L-glutamate during postischaemic reperfusion: reduced infarct size and enhanced glycogen resynthesis in a rat insulin-free heart model.

1. Previously, we found that administration of high-dose L-glutamate during postischaemic reperfusion improves haemodynamic recovery and enhances glycogen resynthesis. In the present study, we investigated whether the same effect occurs in an insulin-free model and whether glutamate administration reduces infarct size. Further, we studied whether the cardioprotective effect of glutamate depends on preserved glutamate transamination and K(ATP) channel activity. 2. In a rat isolated, insulin-free, perfused heart model, we compared the effects of administration of L-glutamate (10 mmol/L) during either 45 min no-flow regional ischaemia plus 120 min reperfusion or reperfusion alone on infarct size and left ventricular (LV) recovery. The effect of glutamate on glycogen metabolism was studied in a model of 30 min global no-flow ischaemia and 60 min reperfusion. In both models, the effects of inhibition of glutamate transamination and K(ATP) channel activity were examined by adding amino-oxyacetate (an aminotransferase inhibitor; 0.1 mmol/L) and glibenclamide (a K(ATP) blocker; 10 mmol/L), respectively. 3. Administration of L-glutamate reduced infarct size by 60% (P < 0.01) and improved postischaemic LV function (developed pressure and rate pressure product; P < 0.05). L-Glutamate increased glycogen content after 60 min reperfusion by 65% (P < 0.01). Amino-oxyacetate, as well as glibenclamide, abolished the glutamate-mediated reduction in infarct size, haemodynamic improvement and glycogen resynthesis during reperfusion. 4. In conclusion, L-glutamate administration from the start of postischaemic reperfusion exerts cardioprotective effects, including reduced infarct size, improved haemodynamic recovery and enhanced glycogen resynthesis. These effects depend on preserved transamination of glutamate and K(ATP) channel activity, but not on insulin administration.

L-glutamate and glutamine improve haemodynamic function and restore myocardial glycogen content during postischaemic reperfusion: A radioactive tracer study in the rat isolated heart.

1. L-Glutamate and glutamine have been suggested to have cardioprotective effects. However, the issue is controversial and the metabolic mechanisms underlying a beneficial effect are not well understood. 2. In the present study we investigated the effects of L-glutamate and glutamine on haemodynamic recovery, the rate of de novo glycogen synthesis and myocardial glucose uptake during postischaemic reperfusion. 3. Hearts from male Wistar rats (250-300 g) were divided into three groups as follows: (i) control (n = 12); (ii) L-glutamate (n = 12); and (iii) glutamine (n = 12). Hearts were mounted in a Langendorff preparation and perfused with oxygenated Krebs'-Henseleit solution at 80 mmHg and 37C. Global ischaemia for 20 min was followed by 15 min reperfusion, during which L-glutamate (50 mmol/L) or glutamine (20 mmol/L) were administered. Left ventricular developed pressure (LVDP), de novo synthesis of glycogen using [14C]-glucose and myocardial glucose uptake using D-[2-3H]-glucose were measured. 4. L-Glutamate and glutamine increased postischaemic LVDP (P < 0.01 vs control hearts for both). L-Glutamate and glutamine increased de novo glycogen synthesis by 78% (P < 0.001) and 55% (P < 0.01), respectively. At the end of reperfusion, total myocardial glycogen content was increased by both L-glutamate and glutamine (5.7 +/- 0.3 and 6.2 +/- 0.7 micromol/g wet weight, respectively; P < 0.05 and 0.01, respectively) compared with that in control hearts (3.6 +/- 0.4 micromol/g wet weight). Neither L-glutamate nor glutamine affected myocardial glucose uptake during reperfusion. 5. Improved postischaemic haemodynamic recovery after L-glutamate and glutamine supplementation during reperfusion is associated with increased de novo glycogen synthesis, suggesting a favourable modulation of intracellular myocardial carbohydrate metabolism.

Suppressed phospholamban levels differentiate irreversibly dysfunctional from hibernating myocardium in humans.

OBJECTIVES: We studied whether dysfunction of human hibernating (HIB) and irreversibly dysfunctional myocardium (IRDM) are associated with altered levels of the sarcoplasmatic reticulum calcium handling proteins Ca2+-ATPase (SERCA2a) and its inhibitor phospholamban (PLB). DESIGN: In 12 patients myocardial biopsies were taken during bypass surgery and analysed for contents of these proteins. We classified regions as control, HIB, or IRDM based on echocardiographic studies before and 6 months after surgery. RESULTS: SERCA2a content (mean+/-SEM) was similar to control in HIB and IRDM (2.6 +/- 1.7, 3.8 +/- 2.0, and 3.4 +/- 1.9 units/g non-collagen protein (NCP), p = 0.40). PLB content was similar to control in HIB (2.6 +/- 0.4 and 3.5 +/- 0.5 units/microg NCP) but reduced in IRDM (0.9 +/- 0.2 units/microg NCP, p < 0.05). SERCA2a:PLB ratio, an indicator of SERCA2a activity, did not differ between control and HIB (1.2 +/- 0.3 and 1.4 +/- 0.4 units/microg NCP) but was increased in IRDM (5.1 +/- 1.7 units/microg NCP, p < 0.05). CONCLUSIONS: Inappropriate SERCA2a activity due to suppressed PLB levels may represent a maladaptive mechanism in chronic ischemic myocardium being causally linked to irreversibility of left ventricular dysfunction.

Angiotensin II inhibition increases cellular glucose transport during reperfusion but not ischemia in pig hearts.

OBJECTIVE: To study whether ACE inhibition and AT-II receptor blockade modulates myocardial glucose uptake during ischemia and reperfusion. DESIGN: We developed a method for in vivo sampling of large trans-myocardial tissue samples from beating pig hearts and in vitro measurement of sarcolemmal glucose transport, in a series of experiments in which hearts were exposed to stimuli (glucose-insulin and pacing) known to promote cellular glucose transport. In the subsequent study we compared three experimental groups: (i) ACE inhibition (ACE-I, n = 6): increasing oral doses of benazepril up to 40 mg daily for 3 weeks, (ii) angiotensin II receptor antagonist (AT II-A, n = 7): increasing oral doses of valsartan up to 320 mg for 3 weeks, (iii) control (n = 7). Samples were harvested at baseline, following 20 min of regional ischemia, and following 5 and 15 min of reperfusion. The samples were incubated with 3-O-methylglucose (MeGlu), and cellular MeGlu uptake was measured. RESULTS: Insulin-glucose, pacing, and ischemia increased cellular MeGlu transport two- to fourfold (p < 0.001). Cellular MeGlu transport was increased in ACE-I and AT II-A animals during reperfusion (p < 0.001), but not at baseline or during ischemia, compared with controls. CONCLUSION: Enhanced capacity for glucose transport during reperfusion may be a mechanism underlying the beneficial effects of ACE inhibition and AT II-antagonism in ischemic heart disease.