ATP-Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model.

Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; P=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; P=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; P<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (P<0.01) and maximum change in ventricular pressure during isovolumetric contraction (P<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.

The mKATP Channels and protein-kinase C Are Involved in the Cardioprotective Effects of Genistein on Estrogen-Deficient Rat Hearts Exposed to Ischemia/Reperfusion: Energetic Study.

Estrogenic deficiency is considered a risk of coronary disease in women. The phytoestrogen genistein could be a safe preventive strategy. The first aim of this work was to validate a model of cardiac stunning in which natural estrogenic deficiency rats, ie, adult young male (YM) and aged female (AgF), are compared with young female rats (YF). The second aim was to study whether the in vivo administration of genistein prevents the stunning in estrogenic deficiency rats. The third aim was to evaluate whether in our estrogenic deficiency model exists a synergy between genistein and estradiol. The fourth aim was to characterize the underlying mechanisms of genistein. Stunning was induced by ischemia/reperfusion (I/R) in isolated hearts inside a calorimeter. The left ventricular pressure (P) and total heat rate (Ht) were simultaneously measured, while diastolic contracture and muscle economy (P/Ht) were calculated. During R, P/Ht and P recovered less in AgF and YM than in YF rat hearts. Genistein through i.p. (GST-ip) improved P and P/Ht in AgF and YM, but not in YF. In YM, the cardioprotections of GST-ip and estradiol were synergistic. After ischemia, GST-ip increased SR Ca leak causing diastolic contracture. The GST-ip cardioprotection neither was affected by blockade of PI3K-Akt, NO synthases, or phosphatases, but it was sensitive to blockade of protein-kinase C and mKATP channels. Results suggest that (1) estrogenic deficiency worsens cardiac stunning, (2) GST-ip was more cardioprotective in estrogenic deficiency and synergistic with estradiol, and (3) cardioprotection of GST-ip depends on the protein-kinase C and mKATP channel pathway activation.

Suppression of Superoxide-Hydrogen Peroxide Production at Site IQ of Mitochondrial Complex I Attenuates Myocardial Stunning and Improves Postcardiac Arrest Outcomes.

OBJECTIVES: Cardiogenic shock following cardiopulmonary resuscitation for sudden cardiac arrest is common, occurring even in the absence of acute coronary artery occlusion, and contributes to high rates of postcardiopulmonary resuscitation mortality. The pathophysiology of this shock is unclear, and effective therapies for improving clinical outcomes are lacking. DESIGN: Laboratory investigation. SETTING: University laboratory. SUBJECTS: C57BL/6 adult female mice. INTERVENTIONS: Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent a 4, 8, 12, or 16-minute potassium chloride-induced cardiac arrest followed by 90 seconds of cardiopulmonary resuscitation. Mice were then blindly randomized to a single IV injection of vehicle (phosphate-buffered saline) or suppressor of site IQ electron leak, an inhibitor of superoxide production by complex I of the mitochondrial electron transport chain. Suppressor of site IQ electron leak and vehicle were administered during cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: Using a murine model of asystolic cardiac arrest, we discovered that duration of cardiac arrest prior to cardiopulmonary resuscitation determined postresuscitation success rates, degree of neurologic injury, and severity of myocardial dysfunction. Post-cardiopulmonary resuscitation cardiac dysfunction was not associated with myocardial necrosis, apoptosis, inflammation, or mitochondrial permeability transition pore opening. Furthermore, left ventricular function recovered within 72 hours of cardiopulmonary resuscitation, indicative of myocardial stunning. Postcardiopulmonary resuscitation, the myocardium exhibited increased reactive oxygen species and evidence of mitochondrial injury, specifically reperfusion-induced reactive oxygen species generation at electron transport chain complex I. Suppressor of site IQ electron leak, which inhibits complex I-dependent reactive oxygen species generation by suppression of site IQ electron leak, decreased myocardial reactive oxygen species generation and improved postcardiopulmonary resuscitation myocardial function, neurologic outcomes, and survival. CONCLUSIONS: The severity of cardiogenic shock following asystolic cardiac arrest is dependent on the length of cardiac arrest prior to cardiopulmonary resuscitation and is mediated by myocardial stunning resulting from mitochondrial electron transport chain complex I dysfunction. A novel pharmacologic agent targeting this mechanism, suppressor of site IQ electron leak, represents a potential, practical therapy for improving sudden cardiac arrest resuscitation outcomes.

Intradialytic exercise preconditioning: an exploratory study on the effect on myocardial stunning.

BACKGROUND: Exercise preconditioning provides immediate protection against cardiac ischemia in clinical/preclinical studies in subjects without chronic kidney disease. In individuals requiring renal replacement therapy, hemodialysis (HD) results in significant circulatory stress, causing acute ischemia with resultant recurrent and cumulative cardiac injury (myocardial stunning). Intradialytic exercise (IDE) has been utilized to improve functional status in individuals receiving HD. The objective of this study was to explore the role of IDE as a preconditioning intervention and assess its effect on HD-induced myocardial stunning. METHODS: We performed a single-center cross-sectional exploratory study in adults on chronic HD participating in a clinical IDE program. HD-induced cardiac stunning was evaluated over two HD sessions within the same week: a control visit (no exercise) and an exposure visit (usual intradialytic cycling). Echocardiography was performed at the same three time points for each visit. Longitudinal strain values for 12 left ventricular segments were generated using speckle-tracking software to assess the presence of HD-induced regional wall motion abnormalities (RWMAs), defined as a ≥20% reduction in strain; two or more RWMAs represent myocardial stunning. RESULTS: A total of 19 patients were analyzed (mean age 57.2 ± 11.8 years, median dialysis vintage 3.8 years). The mean number of RWMAs during the control visit was 4.5 ± 2.6, falling to 3.6 ± 2.7 when incorporating IDE (a reduction of -0.95 ± 2.9; P = 0.17). At peak HD stress, the mean number of RWMAs was 5.8 ± 2.7 in the control visit versus 4.0 ± 1.8 during the exposure visit (a reduction of -1.8 ± 2.8; P = 0.01). CONCLUSION: We demonstrated for the first time that IDE is associated with a significant reduction in HD-induced acute cardiac injury.

Acute Cardiac Complications in Critical Brain Disease.

Acute cardiac complications in critical brain disease should be understood as a clinical condition representing an intense brain-heart crosstalk and might mimic ischemic heart disease. Two main entities (neurogenic stunned myocardium [NSM] and stress cardiomyopathy) have been better characterized in the neurocritically ill patients and they portend worse clinical outcomes in these cases. The pathophysiology of NSM remains elusive. However, significant progress has been made on the early identification of neurocardiac compromise following acute critical brain disease. Effective prevention and treatment interventions are yet to be determined.

Effects of preadmission beta-blockers on neurogenic stunned myocardium after aneurysmal subarachnoid hemorrhage: A meta- analysis.

OBJECTIVE: Spontaneous subarachnoid hemorrhage is mostly caused by the rupture of an aneurysm. Neurogenic stunned myocardium (NSM) is one of the most frequent complications caused by aneurysmal subarachnoid hemorrhage (aSAH). The possible pathogenesis of NSM may be that the catecholamine peak resulting from aSAH leads to subendocardial ischemia or coronary artery spasm. We designed this meta-analysis to find out whether beta-blockers (BB) can significantly reduce the incidence of NSM and improve the outcomes of aSAH. PATIENTS AND METHODS: We systematically searched PubMed, Embase, Cochrane library, Elsevier and Medline from inception to Feb 2016. All studies related to the preadmission beta-blocker with aSAH were included. RESULTS: Three retrospective studies and 691 patients were included. The incidence of mortality [OR=0.68, 95%CI (0.08-3.50), P=0.57], cardiac dysfunction [OR = 0.55, 95% CI (0.05-6.49), P=0.63], cerebral vasospasm (OR=0.52 95% CI(0.18-2.56), P=0.50] had no statistical difference between the preadmission BB group and no BB group. CONCLUSION: The preadmission beta-blocker cannot decrease the incidence of mortality, cardiac dysfunction, cerebral vasospasm in patients with aSAH. A further research of the usefulness of preadmission beta-blocker in patients with aSAH will be needed.

Impact of basal inferolateral scar burden determined by automatic analysis of 99mTc-MIBI myocardial perfusion SPECT on the long-term prognosis of cardiac resynchronization therapy.

AIMS: Left-ventricular (LV) scarring may be associated with a poor response to cardiac resynchronization therapy (CRT). The automatic analysis of myocardial perfusion single-photon emission computed tomography (MP-SPECT) may provide objective quantification of LV scarring. We investigated the impact of LV scarring determined by an automatic analysis of MP-SPECT on short-term LV volume response as well as long-term outcome. METHODS AND RESULTS: We studied consecutive 51 patients who were eligible to undergo 99mTc-MIBI MP-SPECT both at baseline and 6 months after CRT (ischaemic cardiomyopathies 31%). Quantitative perfusion SPECT was used to evaluate the defect extent (an index of global scarring) and the LV 17-segment regional uptake ratio (an inverse index of regional scar burden). The primary outcome was the composite of overall mortality or first hospitalization for worsening heart failure. A high global scar burden and a low mid/basal inferolateral regional uptake ratio were associated with volume non-responders to CRT at 6 months. The basal inferolateral regional uptake ratio remained as a predictor of volume non-response after adjusting for the type of cardiomyopathy. During a median follow-up of 36.1 months, the outcome occurred in 28 patients. The patients with a low basal inferolateral regional uptake ratio with a cutoff value of 57% showed poor prognosis (log-rank P= 0.006). CONCLUSION: The scarring determined by automatic analysis of MP-SPECT images may predict a poor response to CRT regardless of the pathogenesis of cardiomyopathy. The basal inferolateral scar burden in particular may have an adverse impact on long-term prognosis.

Evaluation of acute ischemia in pre-procedure ECG predicts myocardial salvage after primary PCI in STEMI patients with symptoms >12hours.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) is recommended in patients with ST Elevation Myocardial Infarction (STEMI) and symptom duration <12hours. However, a considerable amount of myocardium might still be salvaged in STEMI patients with symptom durations >12hours (late-presenters). The Anderson-Wilkin's score (AW-score) estimates the acuteness of myocardial ischemia from the electrocardiogram (ECG) in STEMI patients. We hypothesized that the AW-score is superior to symptom duration in identifying substantial salvage potential in late-presenters. METHODS: The AW-score (range 1-4) was obtained from the pre-pPCI ECG in 55 late-presenters and symptoms 12-72 hours. Myocardial perfusion imaging was performed to assess area at risk before pPCI and after 30days to assess myocardial salvage index (MSI). We correlated both the AW-score and pain-to-balloon with MSI and determined the salvage potential (MSI) according to AW-score ≥3 (acute ischemia) and AW-score <3 (late ischemia). RESULTS: Late-presenters had median MSI 53% (inter quartile range (IQR) 27-89). The AW-score strongly correlated with MSI (ß=0.60, R(2)=0.36, p<0.0001), while pain-to-balloon time did not (ß=-0.21, R(2)=0.04, p=0.14). Patients with AW-score ≥3 (n=16) compared to those with AW-score <3 (n=27) had significant larger MSI (82.7% vs 41.5%, p=0.014). MSI>median was observed in 79% in patients with AW-score ≥3 vs 32% in patients with AW-score <3 (adjusted OR 6.74 [95% CI 1.35-33.69], p=0.02). CONCLUSION: AW-score was strongly associated with myocardial salvage while pain-to-balloon time was not. STEMI patients with symptom duration between 12 -72hours and AW-score ≥3 achieved substantial salvage after pPCI.

Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia.

Ivabradine is an effective treatment for angina in patients with stable coronary artery disease (CAD) and for heart failure. Experiments in a canine model have shown that ivabradine reduces both acute left ventricular (LV) dysfunction and post-ischaemic stunning. Aim of this study was to investigate the effect of ivabradine on LV dysfunction and stunning in patients with CAD and exercise-inducible ischaemia. Fifteen patients with ejection fraction >40 % and heart rate >70 bpm were enrolled. After pharmacologic washout, echocardiography was performed at rest, at peak treadmill exercise and during recovery until return to baseline. After 2 weeks of ivabradine (7.5 mg bid) stress echocardiography was repeated at the same workload achieved during washout. Peak global and segmental (ischaemic vs. remote normal segments) LV longitudinal strain (LS) was assessed by 2D speckle tracking analysis. At washout, LS was significantly impaired in ischaemic compared to remote segments at peak stress and for several minutes during recovery. After ivabradine a smaller, albeit still significant, impairment of LS in ischaemic segments was observed at peak whilst no difference with remote segments was present during recovery. Furthermore, the average global LS value improved significantly after treatment. In conclusion, ivabradine reduces both acute LV dysfunction and stunning in patients with CAD and exercise-inducible ischaemia. We hypothesise that this mechanism might contribute to reduce chronic LV dysfunction in patients with CAD. In this setting the drug might limit the development of hibernating myocardium which is believed to result from repeated episodes of ischaemia and stunning.

Cardioprotective effect of hyperthyroidism on the stunned rat heart during ischaemia-reperfusion: energetics and role of mitochondria.

NEW FINDINGS: What is the central question of this study? Hyperthyroidism is a cardiac risk factor, but thyroid therapy is used on myocardial stunning. What is the consequence of hyperthyroidism for mitochondrial metabolism and Ca(2+) handling of the postischaemic stunned heart? What is the main finding and its importance? Hyperthyroidism reduced stunning and improved muscle economy of the postischaemic rat heart. The activities of the mitochondrial sodium-calcium exchanger and mitochondrial K(+) channel in hyperthyroid rat hearts were different from those in the euthyroid rat hearts. These findings contribute to the understanding of mitochondrial bioenergetics in pathology and support thyroid therapy in the stunning induced by ischaemia. Transient ischaemia and hyperthyroidism are cardiovascular risk factors. Nevertheless, 3,5,3'-triiodothyronine/thyroxine therapy has been used to revert myocardial stunning. We studied the influence of hyperthyroidism on the role played by mitochondria in myocardial stunning consequent to ischaemia-reperfusion. Rats were injected s.c. daily with 20 µg kg(-1) triiodothyronine for 15 days (HpT group). Isolated ventricles from either HpT or euthyroid (EuT) rats were perfused in a calorimeter, and left intraventricular pressure (in millimetres of mercury) and heat release (Ht; in milliwatts per gram) were measured. Stunning was evoked by 20 min of no-flow ischaemia and 45 min reperfusion. The HpT hearts developed higher postischaemic contractile recovery (PICR) and improved total muscle economy (P/Ht) with lower diastolic contracture (ΔLVEDP) than EuT hearts. Release of Ca(2+) from the sarcoplasmic reticulum during reperfusion with 10 mm caffeine in low-[Na(+) ] Krebs solution evoked a higher contracture in EuT than in HpT hearts. Blockade of the mitochondrial sodium-calcium exchanger with clonazepam increased ΔLVEDP and reduced P/Ht and PICR in HpT but not in EuT hearts. The clonazepam-induced dysfunction in HpT hearts was reduced by ciclosporin, suggesting a dependance on activation of the mitochondrial permeability transition pore. Blockade of the mitochondrial Ca(2+) uniporter with Ru360 reduced P/Ht and PICR to ∼10% in both HpT and EuT hearts. Blockade of mitochondrial K(+) channels with 5-hydroxydecanoate increased LVEDP and reduced PICR and P/Ht in HpT hearts, while it only increased LVEDP in EuT hearts. The results suggest that hyperthyroidism prevents the stunning with high dependence on the mitochondrial sodium-calcium exchanger and mitochondrial K(+) channels. Both HpT and EuT hearts showed a similar and critical role of the uniporter. The HpT hearts have a slow sarcoplasmic reticulum Ca(2+) loss and low mitochondrial Ca(2+) uptake.

Pre-treatment with glucagon-like Peptide-1 protects against ischemic left ventricular dysfunction and stunning without a detected difference in myocardial substrate utilization.

OBJECTIVES: This study sought to determine whether pre-treatment with intravenous glucagon-like peptide-1 (GLP-1)(7-36) amide could alter myocardial glucose use and protect the heart against ischemic left ventricular (LV) dysfunction during percutaneous coronary intervention. BACKGROUND: GLP-1 has been shown to have favorable cardioprotective effects, but its mechanisms of action remain unclear. METHODS: Twenty patients with preserved LV function and single-vessel left anterior descending coronary artery disease undergoing elective percutaneous coronary intervention were studied. A conductance catheter was placed into the LV, and pressure-volume loops were recorded at baseline, during 1-min low-pressure balloon occlusion (BO), and at 30-min recovery. Patients were randomized to receive an infusion of either GLP-1(7-36) amide at 1.2 pmol/kg/min or saline immediately after baseline measurements. Simultaneous coronary artery and coronary sinus blood sampling was performed at baseline and after BO to assess transmyocardial glucose concentration gradients. RESULTS: BO caused both ischemic LV dysfunction and stunning in the control group but not in the GLP-1 group. Compared with control subjects, the GLP-1 group had a smaller reduction in LV performance during BO (delta dP/dTmax, -4.3 vs. -19.0%, p = 0.02; delta stroke volume, -7.8 vs. -26.4%, p = 0.05), and improved LV performance at 30-min recovery. There was no difference in transmyocardial glucose concentration gradients between the 2 groups. CONCLUSIONS: Pre-treatment with GLP-1(7-36) amide protects the heart against ischemic LV dysfunction and improves the recovery of function during reperfusion. This occurs without a detected change in myocardial glucose extraction and may indicate a mechanism of action independent of an effect on cardiac substrate use. (Effect of Glucgon-Like-Peptide-1 [GLP-1] on Left Ventricular Function During Percutaneous Coronary Intervention [PCI]; ISRCTN77442023).

Cardioprotection acquired through exercise: the role of ischemic preconditioning.

A great bulk of evidence supports the concept that regular exercise training can reduce the incidence of coronary events and increase survival chances after myocardial infarction. These exercise-induced beneficial effects on the myocardium are reached by means of the reduction of several risk factors relating to cardiovascular disease, such as high cholesterol, hypertension, obesity etc. Furthermore, it has been demonstrated that exercise can reproduce the "ischemic preconditioning" (IP), which refers to the capacity of short periods of ischemia to render the myocardium more resistant to subsequent ischemic insult and to limit infarct size during prolonged ischemia. However, IP is a complex phenomenon which, along with infarct size reduction, can also provide protection against arrhythmia and myocardial stunning due to ischemia-reperfusion. Several clues demonstrate that preconditioning may be directly induced by exercise, thus inducing a protective phenotype at the heart level without the necessity of causing ischemia. Exercise appears to act as a physiological stress that induces beneficial myocardial adaptive responses at cellular level. The purpose of the present paper is to review the latest data on the role played by exercise in triggering myocardial preconditioning.

High-dose erythropoietin during cardiac resuscitation lessens postresuscitation myocardial stunning in swine.

We investigated the metabolic and functional myocardial effects of erythropoietin (EPO) administered during resuscitation from cardiac arrest using an open-chest pig model of ventricular fibrillation and resuscitation by extracorporeal circulation, after having reported in rats a reversal of postresuscitation myocardial dysfunction associated with activation of mitochondrial protective pathways. Ventricular fibrillation was induced in 16 male domestic pigs and left untreated for 8 minutes, after which extracorporeal circulation was started and maintained for 10 additional minutes, adjusting the extracorporeal flow to provide a coronary perfusion pressure of 10 mmHg. Defibrillation was accomplished and the extracorporeal flow was adjusted to secure a mean aortic pressure of 40 mmHg or greater during spontaneous circulation for up to 120 minutes. Pigs were randomized 1:1 to receive EPO (1200 U/kg) or 0.9% NaCl before starting extracorporeal circulation. Severe postresuscitation myocardial dysfunction developed in both groups. However, recovery of myocardial function-comparing baseline with 120 minutes postresuscitation-was better in pigs treated with EPO than NaCl, as shown for left ventricular ejection fraction (from 45 ± 8% to 36 ± 9% in EPO, not significant; and from 46 ± 8% to 26 ± 8% in NaCl, P < 0.001) and for peak systolic pressure/end-systolic volume (from 2.7 ± 0.8 mmHg/mL to 2.4 ± 0.7 mmHg/mL in EPO, not significant; and from 3.0 ± 1.1 mmHg/mL to 1.8 ± 0.6 mmHg/mL, P < 0.001 in NaCl). The EPO effect was associated with significantly higher myocardial O2 consumption (12 ± 6 mL/min/unit of tissue vs 6 ± 2 mL/min/unit of tissue, P < 0.017) without effects on myocardial lactate consumption. Thus, EPO administered during resuscitation from ventricular fibrillation lessened postresuscitation myocardial stunning-an effect that could be useful clinically to help promote postresuscitation hemodynamic stability.

Usefulness of scintigraphy to predict electrical storms in severe idiopathic dilated cardiomyopathy.

BACKGROUND: Although several predictors of an electrical storm (ES) are indicated in patients with idiopathic dilated cardiomyopathy (IDCM), whether the severity of the myocardial tissue damage (SMTD) evaluated by myocardial perfusion SPECT (MPS) has an association with an ES remains unclear. The purpose of this study was to elucidate the clinical significance of SMTD for the prediction of ES in IDCM patients with an ICD. METHODS: Thirty-seven (27 men, mean age 58 ± 15 years) IDCM patients receiving ICD implantations for secondary prevention with preoperative MPS were enrolled in this study. The medical history, physical and laboratory findings, electrocardiograms, echocardiograms and MPS findings were evaluated. The SMTD was assessed by the summed scores of 17 segments using a 4-point system (0, normal ~3, severe defect). RESULTS: During a mean follow-up of 43.9 ± 30.7 months, an ES developed in 12/37 (32.4 %) patients. The SMTD score predicted an ES with a 92 % sensitivity and 56 % specificity, at a cut-off score of 10. In addition, a multivariate analysis showed that the SMTD score remained an independent predictor of an ES (HR 1.09/score 1 increase, 95 % CI 1.01-1.19, p = 0.02). The SMTD score was significantly associated with three indices of late potentials on the signal-averaged electrocardiograms, and was significantly higher in patients with positive late potentials (p = 0.0006). CONCLUSION: SMTD score assessed by MPS has a strong correlation to the late potentials and higher SMTD score may increase the risk of ES among patients with IDCM and an ICD.

Hot shot induction and reperfusion with a specific blocker of the es-ENT1 nucleoside transporter before and after hypothermic cardioplegia abolishes myocardial stunning in acutely ischemic hearts despite metabolic derangement: hot shot drug delivery before hypothermic cardioplegia.

OBJECTIVE: Simultaneous inhibition of the cardiac equilibrative-p-nitrobenzylthioinosine (NBMPR)-sensitive (es) type of the equilibrative nucleoside transport 1 (ENT1) nucleoside transporter, with NBMPR, and adenosine deaminase, with erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA), prevents release of myocardial purines and attenuates myocardial stunning and fibrillation in canine models of warm ischemia and reperfusion. It is not known whether prolonged administration of hypothermic cardioplegia influences purine release and EHNA/NBMPR-mediated cardioprotection in acutely ischemic hearts. METHODS: Anesthetized dogs (n = 46), which underwent normothermic aortic crossclamping for 20 minutes on-pump, were divided to determine (1) purine release with induction of intermittent antegrade or continuous retrograde hypothermic cardioplegia and reperfusion, (2) the effects of postischemic treatment with 100 µM EHNA and 25 µM NBMPR on purine release and global functional recovery, and (3) whether a hot shot and reperfusion with EHNA/NBMPR inhibits purine release and attenuates ventricular dysfunction of ischemic hearts. Myocardial biopsies and coronary sinus effluents were obtained and analyzed using high-performance liquid chromatography. RESULTS: Warm ischemia depleted myocardial adenosine triphosphate and elevated purines (ie, inosine > adenosine) as markers of ischemia. Induction of intermittent antegrade or continuous retrograde hypothermic (4°C) cardioplegia releases purines until the heart becomes cold (<20°C). During reperfusion, the levels of hypoxanthine and xanthine (free radical substrates) were >90% of purines in coronary sinus effluent. Reperfusion with EHNA/NBMPR abolished ventricular dysfunction in acutely ischemic hearts with and without a hot shot and hypothermic cardioplegic arrest. CONCLUSIONS: Induction of hypothermic cardioplegia releases purines from ischemic hearts until they become cold, whereas reperfusion induces massive purine release and myocardial stunning. Inhibition of cardiac es-ENT1 nucleoside transporter abolishes postischemic reperfusion injury in warm and cold cardiac surgery.

Milrinone and levosimendan administered after reperfusion improve myocardial stunning in swine.

OBJECTIVES: We assessed the effect of milrinone application timing after reperfusion against myocardial stunning as compared with levosimendan in swine. Furthermore, we examined the role of p38 mitogen-activated protein kinase (p38 MAPK) in the milrinone-induced cardioprotection. DESIGN: All swine were subjected to 12-minutes ischemia followed by 90-minutes reperfusion to generate stunned myocardium. Milrinone or levosimendan was administered intravenously either for 20 minutes starting just after reperfusion or for 70 minutes starting 20 minutes after reperfusion. In another group, SB203580, a selective p38 MAPK inhibitor, was administered with and without milrinone. Regional myocardial contractility was assessed by percent segment shortening (%SS). RESULTS: Milrinone starting just after reperfusion, but not starting 20 minutes after reperfusion, improved %SS at 30, 60, and 90 minutes after reperfusion compared with that in the control group. SB203580 abolished the beneficial effect of milrinone. On the other hand, levosimendan starting 20 minutes after reperfusion, but not for 20 minutes starting just after reperfusion, improved %SS at 60 and 90 minutes after reperfusion. CONCLUSIONS: Milrinone should be administered just after reperfusion to protect myocardial stunning through p38 MAPK, whereas levosimendan improvement of contractile function could be mainly dependent on its positive inotropic effect.

Protective effects of NHE1 inhibition with sabiporide in an experimental model of asphyxia-induced cardiac arrest in piglets.

The present study investigated the protective effects of a novel NHE1 selective inhibitor, sabiporide, in a porcine model of asphyxia-induced cardiac arrest. Asphyxial cardiac arrest was induced by endotracheal tube clamping (ETC). The animals remained untreated for 3 min after loss of aortic pulsations (LOAP), and followed by chest compression and defibrillation. Sixteen of eighteen pigs had return of spontaneous circulation (ROSC), and were randomly assigned to two study groups. Group 1: vehicle control. Group 2: 3mg/kg sabiporide was given at 15 min after ROSC. Post-arrest myocardial dysfunction was present in both groups, and progressed over hours. Animals treated with sabiporide had less wall motion abnormality and higher left ventricular ejection fraction than control animals (33% in control group vs. 47% in sabiporide group). Sabopiride treatment also significantly improved post-arrest arterial blood pressure by 25% and cardiac stroke volume by 44%, and improved mixed-venous blood oxygen saturation by 38% and oxygen delivery by 118%. Furthermore, compared to the control group, the sabiporide group also had higher blood flows in the brain, heart, kidney, liver and spleen at 30 min after ROSC. There was no significant blood flow difference in distal ileum mucosa between control and sabiporide groups. In addition, sabiporide treatment significantly reduced cardiac myeloperoxidase (MPO) activity by 53% and cardiac troponin I by 51%, and reduced the plasma level of TNF-α by 52% and IL-6 by 41%. This study shows that post-arrest pharmacological conditioning with sabiporide affords protection from whole body ischemia-reperfusion injury in this model of asphyxia-induced cardiac arrest and resuscitation.

Preadmission beta-blockers are associated with decreased incidence of neurogenic stunned myocardium in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Neurogenic stunned myocardium (NSM) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on disease course. The presumed cause is catecholamine surge at the time of aneurysm rupture. Beta-blockers, which reduce the impact of the catecholamine surge, may decrease the risk of developing NSM. METHODS: A chart review of 234 consecutive patients admitted to the Oregon Health and Science University Neurosurgery service between March 6, 2008 and June 23, 2010 with a diagnosis of aneurysmal SAH was performed. This group was further subdivided by patients who received echocardiograms on admission, by gender, and by the prehospital administration of ß-blockers. RESULTS: One hundred thirty of 234 patients had echocardiograms on or shortly after admission, and 18 of these developed NSM (13.8%). None of the 22 patients taking prehospital ß-blockers developed NSM. Using the Fisher exact test to compare the 2 groups, patients who were administered prehospital ß-blockers were significantly less likely to develop stunning compared to those who were not (P = .04). After correcting for other variables using multiple logistic regression analysis, the previous use of ß-blockers was still found to be significantly associated with a decreased incidence of NSM after SAH (P = .049). There was no significant difference in hospital length of stay, peribleed stroke, vasospasm, or death. Of the 18 patients with stunning, 15 were women, 5 of whom were on estrogen supplementation. The mean peak troponin elevation of women who developed NSM on estrogen supplementation was significantly higher than for those who were not (mean peak troponin 9.97 ± 2.01 mg/dL; P < .001). CONCLUSION: Prehospital ß-blockers are associated with decreased risk of developing NSM in patients with aSAH. Estrogen may play an additional role in shaping the degree of NSM in women.