Metabolomics of repetitive myocardial stunning in chronic multivessel coronary artery stenosis: Effect of non-selective and selective ß1-receptor blockers.

Chronic coronary artery stenosis can lead to regional myocardial dysfunction in the absence of myocardial infarction by repetitive stunning, hibernation or both. The molecular mechanisms underlying repetitive stunning-associated myocardial dysfunction are not clear. We used non-targeted metabolomics to elucidate responses to chronically stunned myocardium in a canine model with and without ß-adrenergic blockade treatment. After development of left ventricular systolic dysfunction induced by ameroid constrictors on the coronary arteries, animals were randomized to 3 months of placebo, metoprolol or carvedilol. We compared these two ß-blockers with their different ß-adrenergic selectivities on myocardial function, perfusion and metabolic pathways involved in tissue undergoing chronic stunning. Control animals underwent sham surgery. Dysfunction in stunned myocardium was associated with reduced fatty acid oxidation and enhanced ketogenic amino acid metabolism, together with alterations in mitochondrial membrane phospholipid composition. These changes were consistent with impaired mitochondrial function and were linked to reduced nitric oxide and peroxisome proliferator-activated receptor signalling, resulting in a decline in adenosine monophosphate-activated protein kinase. Mitochondrial changes were ameliorated by carvedilol more than metoprolol, and improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. In summary, repetitive myocardial stunning commonly seen in chronic multivessel coronary artery disease is associated with adverse metabolic remodelling linked to mitochondrial dysfunction and specific signalling pathways. These changes are reversed by ß-blockers, with the non-selective inhibitor having a more favourable impact. This is the first investigation to demonstrate that ß-blockade-associated improvement of ventricular function in chronic myocardial stunning is associated with restoration of mitochondrial function. KEY POINTS: The mechanisms responsible for the metabolic changes associated with repetitive myocardial stunning seen in chronic multivessel coronary artery disease have not been fully investigated. In a canine model of repetitive myocardial stunning, we showed that carvedilol, a non-selective ß-receptor blocker, ameliorated adverse metabolic remodelling compared to metoprolol, a selective ß1-receptor blocker, by improving nitric oxide synthase and adenosine monophosphate protein kinase function, enhancing calcium/calmodulin-dependent protein kinase, probably increasing hydrogen sulphide, and suppressing cyclic-adenosine monophosphate signalling. Mitochondrial fatty acid oxidation alterations were ameliorated by carvedilol to a larger extent than metoprolol; this improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. Both ß-blockers improved the cardiac energy imbalance by reducing metabolites in ketogenic amino acid and nucleotide metabolism. These results elucidated why metabolic remodelling with carvedilol is preferable to metoprolol when treating chronic ischaemic left ventricular systolic dysfunction caused by repetitive myocardial stunning.

Atorvastatin can ameliorate left atrial stunning induced by radiofrequency ablation for atrial fibrillation.

The objective of this study was to study the functional changes of the left atrium after radiofrequency ablation treatment for atrial fibrillation and the therapeutic effect of atorvastatin. Fifty-eight patients undergoing radiofrequency ablation for atrial fibrillation were randomly divided into non-atorvastatin group and atorvastatin group. Patients in the atorvastatin group were treated with atorvastatin 20 mg p.o. per night in addition to the conventional treatment of atrial fibrillation; patients in the non-atorvastatin group received conventional treatment of atrial fibrillation only. Echocardiography was performed before radiofrequency ablation operation and 1 week, 2 weeks, 3 weeks, and 4 weeks after operation. Two-dimensional ultrasound speckle tracking imaging system was used to measure the structural indexes of the left atrium. Results indicated that there was no significant change for indexes representing the structural status of the left atrium within a month after radiofrequency ablation (P > 0.05); however, there were significant changes for indexes representing the functional status of the left atrium. There were also significant changes in indexes reflecting left atrial strain status: the S and SRs of atorvastatin group were higher than those of non-atorvastatin group (P < 0.05). In summary, atorvastatin could improve left atrial function and shorten the duration of atrial stunning after radiofrequency ablation of atrial fibrillation.

Citric Acid Cycle Metabolites Predict the Severity of Myocardial Stunning and Mortality in Newborn Pigs.

OBJECTIVES: Myocardial infarction and chronic heart failure induce specific metabolic changes in the neonatal myocardium that are closely correlated to outcome. The aim of this study was to examine the metabolic responses to noninfarct heart failure and inotropic treatments in the newborn heart, which so far are undetermined. DESIGN: A total of 28 newborn pigs were instrumented with a microdialysis catheter in the right ventricle, and intercellular citric acid cycle intermediates and adenosine metabolite concentrations were determined at 20-minute intervals. Stunning was induced by 10 cycles of 3 minutes of ischemia, which was performed by occluding the right coronary artery, followed by 3 minutes of reperfusion. Animals were randomized for treatment with epinephrine + milrinone, dopamine + milrinone, dobutamine, or saline. SETTING: University hospital animal laboratory. MAIN RESULTS: Ischemia-reperfusion induced right ventricular stunning and increased the concentrations of pyruvate lactate, succinate, malate, hypoxanthine, and xanthine (all, p < 0.01). During inotrope infusion, no differences in metabolite concentrations were detected between the treatment groups. In nonsurviving animals (n = 8), concentrations of succinate (p < 0.0001), malate (p = 0.009), and hypoxanthine (p = 0.04) increased compared with survivors, while contractility was significantly reduced (p = 0.03). CONCLUSIONS: Accumulation of citric acid cycle intermediates and adenosine metabolites reflects the presence of myocardial stunning and predicts mortality in acute noninfarct right ventricular heart failure in newborn pigs. This phenomenon occurs independently of the type of inotrope, suggesting that citric acid cycle intermediates represent potential markers of acute noninfarct heart failure.

Role of levosimendan in the management of subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the leading causes of neurologic disability accounting for dismal long term survival rates. aSAH leads to a sudden increase in intracranial pressure and a massive sympathetic discharge. Excessive sympathetic stimulation leads to catecholamine mediated myocardial dysfunction and hemodynamic instability which may critically hamper brain perfusion and oxygenation. In the setting of acute aSAH, administration of vasoactive drugs aims at stabilizing impaired hemodynamics. However, studies have shown that conventional treatment with vasoactive drugs that lead to Ca(+2) overload and increase myocardial oxygen consumption, fail to restore hemodynamics and decrease cerebral blood flow. Levosimendan is a non-adrenergic inotropic Ca(+2) sensitizer with not only beneficial hemodynamic properties but also pleiotropic effects, contributing to its cardioprotective and neuroprotective role. Although there have been limited data available regarding the use of levosimendan in patients with aSAH, current evidence suggests that levosimendan may have a role in the setting of post-aSAH cardiomyopathy and decreased cerebral blood flow both in the emergency departments and in intensive care units. The purpose of this review is to provide an overview of studies of levosimendan therapy for aSAH, and describe current knowledge about the effects of levosimendan in the management of aSAH.

Expression of uncoupling protein-2 remains increased within hibernating myocardium despite successful coronary artery bypass grafting at 4 wk post-revascularization.

BACKGROUND: We have previously shown that mitochondrial uncoupling protein-2 (UCP-2) is increased in a swine model of hibernating myocardium (HM). Although UCP-2 reduces oxidant stress, it can promote inefficiency of the electron transport chain. In this study, we tested whether UCP-2 remains increased in revascularized HM (RHM) after coronary artery bypass grafting (CABG). METHODS: Seven swine underwent thoracotomy with placement of a constrictor on the left anterior descending artery (LAD). Twelve weeks later, a left internal mammary artery graft was placed on the distal LAD. Four weeks post-CABG, computed tomography angiography documented patent grafts and function. At the terminal study, blood flow to the LAD and remote territories were assessed during high dose dobutamine and mitochondria isolated from both regions for analysis. Comparisons were made to a group of swine with HM who underwent constrictor placement without bypass grafting (n = 4). RESULTS: During dobutamine infusion, RHM demonstrated lower blood flows (2.44 ± 0.23 versus 3.43 ± 0.30 mL/min/g; P < 0.05) and reduced wall thickening (33 ± 9% versus 52 ± 13%; P < 0.05) compared with remote regions. RHM had lower respiratory control indices (3.7 ± 0.3 versus 4.3 ± 0.4; P < 0.05) with persistently increased UCP-2 content. CONCLUSIONS: Despite patent grafts, RHM demonstrates a submaximal response to dobutamine infusion and increased mitochondrial UCP-2 expression. These data support the notion that recovery of the mitochondria in RHM is delayed early post-CABG and may contribute to impaired oxygen consumption and contractile reserve during catecholamine challenges.

Usefulness of cardiac arrest centers - extending lifesaving post-resuscitation therapies: the Arizona experience - .

The post-cardiac arrest syndrome is a complex, multisystems response to the global ischemia and reperfusion injury that occurs with the onset of cardiac arrest, its treatment (cardiopulmonary resuscitation) and the re-establishment of spontaneous circulation. Regionalization of post-cardiac arrest care, utilizing specified cardiac arrest centers (CACs), has been proposed as the best solution to providing optimal care for those successfully resuscitated after out-of-hospital cardiac arrest. A multidisciplinary team of intensive care specialists, including critical care/pulmonologists, cardiologists (general, interventional, and electrophysiology), neurologists, and physical medicine/rehabilitation experts, is crucial for such centers. Particular attention to the timely initiation of targeted temperature management and early coronary angiography/percutaneous coronary intervention is best provided by such CACs. A State-wide program of CACs was started in Arizona in 2007. This is a voluntary program, whereby medical centers agree to provide all resuscitated cardiac arrest patients brought to their facility with state-of-the-art post-resuscitation care, including targeted temperature management for comatose patients and strong consideration for emergent coronary angiography for all patients with a likely cardiac etiology for their cardiac arrest. Survival improved by more than 50% at facilities that became CACs with a commitment to provide aggressive post-resuscitation care to all such patients. Providing aggressive, post-resuscitation care is the next real opportunity to increase long-term survival for cardiac arrest patients.

New perspectives of nitric oxide donors in cardiac arrest and cardiopulmonary resuscitation treatment.

Nitric oxide (NO) is often used to treat heart failure accompanied with pulmonary edema. According to present knowledge, however, NO donors are contraindicated when systolic blood pressure is less than 90 mmHg. Based on recent findings and our own clinical experience, we formulated a hypothesis about the new breakthrough complex lifesaving effects of NO donors in patients with cardiac arrest and cardiopulmonary resuscitation therapy. It includes a direct hemodynamic effect of NO donors mediated through vasodilation of coronary arteries in cooperation with improvement of cardiac function and cardiac output through reversible inhibition of mitochondrial complex I and mitochondrial NO synthase, followed by reduction in reactive oxygen species and correction of myocardial stunning. Simultaneously, an increase in vascular sensitivity to sympathetic stimulation could lead to an increase in diastolic blood pressure. Confirmation of this hypothesis in clinical practice would mean a milestone in the treatment for cardiac arrest and cardiopulmonary resuscitation.

Enhancement of myocardial function and reduction of injury with levosimendan after percutaneous coronary intervention for acute myocardial infarction: a pilot study.

OBJECTIVES: To determine the short-term clinical effects of levosimendan in acute myocardial infarction (AMI) patients with myocardial stunning after emergency percutaneous coronary intervention (PCI). METHODS: The study population consisted of 30 patients with AMI who received emergency PCI and satisfied the inclusion criteria. Levosimendan was given as a continuous infusion of 0.1 µg/kg/min for 24 h, and the remaining 10 patients received placebo treatment. The patients were observed with invasive haemodynamic monitoring and were evaluated biochemically and echocardiographically before and after the drug infusion. RESULTS: Following treatment, biochemical indices (not including creatine kinase and its MB fraction) were significantly lower in the levosimendan group than in the placebo group. Meanwhile, left-ventricular (LV) end-systolic volume, mean pulmonary arterial pressure, pulmonary capillary wedge pressure and systemic vascular resistance were significantly reduced in the levosimendan group, whereas the early-to-late diastolic velocities ratio, LV ejection fraction, cardiac index and cardiac power index were increased. Troponin I levels were reduced and fewer stunned and infarction segments were observed in the patients treated with levosimendan. CONCLUSIONS: Levosimendan can significantly improve the myocardium function of patients with myocardial stunning after PCI.

[Clinical research of safflower injection on hibernating myocardial revascularization].

Coronary artery disease (CAD) is one of the leading causes of death. Safflower attracts great attention owing to its anti-ischemia/reperfusion injury effect. Ninety-three patients with CAD were included and randomized into safflower treatment group, PCI group and control group. Low-dose dobutamine stress echocardiography (DSE) was performed to measure end-systolic volume (ESV), end-diastolic volume (EDV), left ventricular ejection fraction (LVEF) and wall motion score index (WMSI) to determine the recovery of hibernating myocardium and cardiac function in all patients before treatment and after 3-month follow-up. The study was to investigate the effects of safflower on hibernating myocardial revascularization and cardiac function. It was found that LVEF was significantly improved, while the ESV and WMSI were significantly reduced after 2-week treatment in safflower and PCI treatment groups. No significant differences were found between safflower and PCI treatment groups in ESV, EDV, WMSI and LVEF after treatment Safflower injection effectively improved hibernating myocardial function.

Neurogenic stunned myocardium after embolization in two children with vein of Galen aneurysmal malformation.

INTRODUCTION: This study reports the first cases of neurogenic stunned myocardium in two children with vein of Galen aneurysmal malformation after interventional treatment. PATIENTS: Two newborns with vein of Galen aneurysmal malformation and high output cardiac failure developed a severe reversible left ventricular dysfunction shortly after embolization, concurrently with acute hydrocephalus. RESULTS: There was a resolution of the cardiac symptoms of left ventricular dysfunction within a few days under treatment with milrinone and dobutamine. CONCLUSIONS: Reversible left ventricular dysfunction is observed in adult patients mainly after subarachnoid hemorrhage and is called neurogenic stunned myocardium (NSM). Other forms of brain injuries have also been identified accounting for this condition in adults. In pediatric population especially with specific cerebral diseases, NSM may be underdiagnosed.

Calcium antagonists in myocardial ischemia/reperfusion--update 2012.

The present article briefly reviews the processes underlying excitation-contraction coupling in cardiomyocytes and vascular smooth muscle cells, their perturbations during reversible and irreversible myocardial ischemia and reperfusion, notably the pathogenetic role of increased intracellular calcium concentrations, and finally the beneficial effects of calcium antagonists on the impairment of coronary vasomotor tone, on cardiac contractile dysfunction and on myocardial infarction.

Pharmacological inhibition of translocon is sufficient to alleviate endoplasmic reticulum stress and improve Ca2+ handling and contractile recovery of stunned myocardium.

INTRODUCTION: The function of endoplasmic reticulum (ER), a Ca2+ storage compartment and site of protein folding, is altered by disruption of intracellular homeostasis. Misfolded proteins accumulated in the ER lead to ER stress (ERS), unfolded protein response (UPR) activation and ER Ca2+ loss. Myocardial stunning is a temporary contractile dysfunction, which occurs after brief ischemic periods with minimal or no cell death, being oxidative stress and Ca2+ overload potential underlying mechanisms. Myocardial stunning induces ERS response with negatively impact on the post-ischemic mechanical performance through an unknown mechanism. AIMS: In this study, we explored whether ER Ca2+ efflux through the translocon, a major Ca2+ leak channel, contributes to Ca2+ mishandling and the consequent contractile abnormalities of the stunned myocardium. METHODS: Mechanical performance, cytosolic Ca2+, UPR markers and oxidative state were evaluated in perfused rat/mouse hearts subjected to a brief ischemia followed by reperfusion (I/R) in absence or presence of the translocon inhibitor, emetine (1 µM), comparing its effects with those of the chaperones TUDCA (30 µM) and 4-PBA (3 mM). RESULTS: Emetine treatment precluded the I/R-induced increase in UPR signaling markers and improved the contractile recovery together with a remarkable attenuation in myocardial stiffness when compared to I/R hearts with no drug. This alleviation of I/R-induced mechanical abnormalities was more effective than that obtained with the chemical chaperones, TUDCA and 4-PBA. Moreover, emetine treatment produced a striking improvement in diastolic Ca2+ handling with a partial recovery of the I/R-induced oxidative stress. CONCLUSION: Blocking ER Ca2+ store depletion via translocon suppressed ER stress and improved mechanical performance and diastolic Ca2+ handling of stunned myocardium. Modulation of translocon permeability emerges as a therapeutic approach to face dysfunctional consequences of the I/R injury.

Long-term preservation of myocardial energetic in chronic hibernating myocardium.

We previously reported that the myocardial energetic state, as defined by the ratio of phosphocreatine to ATP (PCr/ATP), was preserved at baseline (BL) in a swine model of chronic myocardial ischemia with mild reduction of myocardial blood flow (MBF) 10 wk after the placement of an external constrictor on the left anterior descending coronary artery. It remains to be seen whether this stable energetic state is maintained at a longer-term follow-up. Hibernating myocardium (HB) was created in minipigs (n = 7) by the placement of an external constrictor (1.25 mm internal diameter) on the left anterior descending coronary artery. Function was assessed with MRI at regular intervals until 6 mo. At 6 mo, myocardial energetic in the HB was assessed by (31)P-magnetic resonance spectrometry and myocardial oxygenation was examined from the deoxymyoglobin signal using (1)H-magnetic resonance spectrometry during BL, coronary vasodilation with adenosine, and high cardiac workload with dopamine and dobutamine (DpDb). MBF was measured with radiolabeled microspheres. At BL, systolic thickening fraction was significantly lower in the HB compared with remote region (34.4 ± 9.4 vs. 50.1 ± 10.7, P = 0.006). This was associated with a decreased MBF in the HB compared with the remote region (0.73 ± 0.08 vs. 0.97 ± 0.07 ml · min(-1) · g, P = 0.03). The HB PCr/ATP at BL was normal. DpDb resulted in a significant increase in rate pressure product, which caused a twofold increase in MBF in the HB and a threefold increase in the remote region. The systolic thickening fraction increased with DpDb, which was significantly higher in the remote region than HB (P < 0.05). The high cardiac workload was associated with a significant reduction in the HB PCr/ATP (P < 0.02), but this response was similar to normal myocardium. Thus HB has stable BL myocardial energetic despite the reduction MBF and regional left ventricular function. More importantly, HB has a reduced contractile reserve but has a similar energetic response to high cardiac workload like normal myocardium.

Levosimendan in cardiac failure after subarachnoid hemorrhage.

The aim of this study is to report the development of cardiac failure after subarachnoid hemorrhage (SAH) with recovery of heart and cerebral function. This is a case report of a 38-year-old woman who was admitted to the intensive care unit (ICU) at Policlinico di Modena, Italy. This woman developed a deep state of coma because of severe SAH. After cerebral hemorrhage, patient showed a cardiogenic shock, which needed invasive monitoring. Cerebral perfusion pressure had to be restored, so fluids, dopamine, norepinephrine, and dobutamine were in administered sequentially. Despite these supportive treatments, hemodynamic parameters further worsened and echocardiography showed a global depressed left ventricular (LV) contraction with poor ejection fraction (EF) and restrictive type of LV relaxation pattern. Twenty-four hours after ICU admission, levosimendan was started with the aim to improve cardiac function because of the refractoriness of all other treatments. Eight hours after levosimendan infusion, cardiac function improved and, within the after 24 hours, EF and LV relaxation pattern recovered. Neurologic state and computed tomography images improved day by day, and after 9 days from the ICU admission, we transferred the patient to the neurosurgical ward with very good neurologic conditions and no deficits in motility. The conventional management of post-SAH cardiovascular failure is based on the use of norepinephrine, dobutamine, and high amount of fluids. This strategy did not provide any improvement, so we decided for levosimendan infusion to counteract myocardial stunning. The improvement in cardiac EF, LV wall motion, and filling pressure observed in our patient could be explained due to the antistunning triple-mechanism action of levosimendan. Data available on the levosimendan effectiveness in patients with SAH and its effect on intracranial pressure are still lacking, but we think that neurogenic cardiac failure can be treated at first with levosimendan.

Chemical chaperones improve the functional recovery of stunned myocardium by attenuating the endoplasmic reticulum stress.

AIM: Myocardial ischaemia/reperfusion (I/R) produces structural and functional alterations depending on the duration of ischaemia. Brief ischaemia followed by reperfusion causes reversible contractile dysfunction (stunned heart) but long-lasting ischaemia followed by reperfusion can result in irreversible injury with cell death. Events during I/R can alter endoplasmic reticulum (ER) function leading to the accumulation of unfolded/misfolded proteins. The resulting ER stress induces activation of several signal transduction pathways, known as unfolded protein response (UPR). Experimental evidence shows that UPR contributes to cell death in irreversible I/R injury; however, there is still uncertainty for its occurrence in the stunned myocardium. This study investigated the ER stress response and its functional impact on the post-ischaemic cardiac performance of the stunned heart. METHODS: Perfused rat hearts were subjected to 20 minutes of ischaemia followed by 30 minutes of reperfusion. UPR markers were evaluated by qRT-PCR and western blot. Post-ischaemic mechanical recovery was measured in absence and presence of two chemical chaperones: tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). RESULTS: Analysis of mRNA and protein levels of various ER stress effectors demonstrated that different UPR signalling cascades, involving both pro-survival and pro-apoptotic pathways, are activated. Inhibition of the UPR with chemical chaperones improved the post-ischaemic recovery of cardiac mechanical function without affecting the I/R-induced increase in oxidative stress. CONCLUSION: Our results suggest that prevention of ER stress by chemical chaperones could be a therapeutic tool to limit deterioration of the contractile function in clinical settings in which the phenomenon of myocardial stunning is present.

Hyperinsulinemic euglycemia therapy for stunned myocardium following subarachnoid hemorrhage.

The authors describe the clinical course of a 50-year-old woman who presented with life-threatening cardiac dysfunction after aneurysmal subarachnoid hemorrhage (Fisher Grade 4). The pathophysiology of cardiac injury in this setting is not fully understood, but excess sympathetic activation can lead to neurogenic stressed myocardium. A metabolic intervention using the continuous intravenous infusion of high doses of insulin with euglycemia resulted in a rapid improvement of cardiac contractility. The observed benefit could be due to better myocardial glucose utilization that could not have been achieved by catecholamine administration.

Myocardial stunning after electroconvulsive therapy in patients with an apparently normal heart.

Myocardial stunning refers to contractile dysfunction that persists after an ischemic episode and restoration of coronary blood flow. In this article, 2 cases of myocardial stunning after electroconvulsive therapy in patients with an apparently normal heart are presented. The incidence of this condition is unknown. It is observed that this condition seems to occur in females and in the obese and is generally associated with rapid recovery. This occurrence seems to be brought about by autonomic changes that occur during electroconvulsive therapy. Several drugs have been used to ameliorate the condition, although studies were limited to establish efficacy of regimens.

Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats.

AIMS: Thrombopoietin (Tpo) is known for its ability to stimulate platelet production. However, it is currently unknown whether Tpo plays a physiological function in the heart. METHODS AND RESULTS: We assessed the potential protective role of Tpo in vitro and in vivo in two rat models of myocardial ischaemia/reperfusion. Tpo receptor (c-mpl) message was detected in the heart using RT-PCR, and the Tpo receptor protein was detected using western blotting and immunohistochemistry. Tpo treatment immediately before ischaemia reduced myocardial necrosis, apoptosis, and decline in ventricular function following ischaemia/reperfusion in the rat in a concentration- and dose-dependent manner with an optimal concentration of 1.0 ng/mL in vitro and an optimal dose of 0.05 microg/kg iv in vivo. Tpo also reduced infarct size when given after the onset of ischaemia or at reperfusion. Tpo activated JAK-2 (Janus kinase-2) and p44 MAPK (mitogen-activated protein kinase) during reperfusion but not prior to ischaemia. Inhibition of JAK-2 (AG-490), p42/44 MAPK (PD98059), mitochondrial K(ATP) channels (5-HD), and sarcolemmal K(ATP) channels (HMR 1098) abolished Tpo-induced resistance to injury from myocardial ischaemia/reperfusion. AG-490, PD98059, 5-HD, and HMR1098 alone had no effect on cardioprotection. Treatment with a single dose of Tpo (0.05 or 1.0 microg/kg iv) did not result in the elevation of platelet count or haematocrit over a 16-day period. CONCLUSION: A single treatment of Tpo confers cardioprotection through JAK-2, p42/44 MAPK, and K(ATP) channels, suggesting a potential therapeutic role of Tpo in the treatment of injury resulting from myocardial ischaemia and reperfusion.

Ca2+ sensitizer superior to catecholamine during myocardial stunning?

BACKGROUND: After open-chest cardiac surgery, ventricular function remains depressed (myocardial stunning). Catecholamines (epinephrine) improve ventricular function by increasing the intracellular Ca(2+) concentration. In parallel, the oxygen consumption is increased, so that the hitherto intact myocardium can be jeopardized. In the very insufficient ventricle, epinephrine can even become ineffective. Since Ca(2+) sensitizers provide another therapeutic avenue, the effects of epinephrine and levosimendan on postischemic hemodynamics were investigated. METHODS: After hemodynamic steady state, isolated, blood (erythrocyte-enriched Krebs-Henseleit solution)-perfused rabbit hearts were subjected to 25 min normothermic, no-flow ischemia and 20 min reperfusion. Heart rate (HR), cardiac output (CO), left ventricular pressure (LVP), coronary blood flow (CBF), and arterio-venous oxygen difference (AVDO(2)) were recorded during reperfusion and after administration of either epinephrine (n=16; 0.03 micromol), or levosimendan (n=11; 0.75 micromol) or epinephrine plus levosimendan (n=5). RESULTS: Epinephrine increased HR (19%, p=0.01) and improved hemodynamics in terms of CO (62%, p=0.0006), stroke volume SV (46%, p=0.02), stroke work W (158%, p=0.01), LVP(max) (58%, p=0.0001), maximal pressure increase dP/dt(max)(140%, p=0.0004), minimal pressure increase dP/dt(min) (104%, p=0.0002), LVP(ed) (-26%, p=0.02), and increased coronary resistance CR (31%, p=0.05). Epinephrine impaired hemodynamics in terms of AVDO(2) (+63%, p=0.003), myocardial oxygen consumption MVO(2) (+67%, p=0.0003) and MVO(2)/beat (+36%, p=0.01). External efficiency eta was increased by 92% (p=0.02). Levosimendan in postischemic hearts increased HR (32%, p=0.009) and improved hemodynamics in terms of CO (85%, p=0.01), SV (44%, p=0.03), W (115%, p=0.04), LVP(max) (95%, p=0.04), dP/dt(max) (133%, p=0.009), dP/dt(min) (121%, p=0.007), LVP(ed) (-63%, p=0.0006), and CR (-17%; n.s., p=0.1). It altered hemodynamics in terms of AVDO(2) (+7.0%; n.s., p=0.3) and MVO(2) (+32%, p=0.007) and MVO(2)/beat (+2.3%; n.s., p=0.4). External efficiency was increased by 307% (p=0.04). In five additional extremely dysfunctional rabbit hearts, epinephrine was ineffective. Additional levosimendan increased hemodynamics in terms of HR (56%; n.s., p=0.1), CO (159%, p=0.04), SV (89%, p=0.03), W (588%, p=0.02), LVP(max) (168%, p=0.03), dP/dt(max) (102%, p=0.005), dP/dt(min) (78%, p=0.006), LVP(ed) (-98%, p=0.0006), and CR (-50%, p=0.02). It altered hemodynamics in terms of AVDO(2) (-11%; n.s., p=0.05), MVO(2) (+131%, p=0.04) and MVO(2)/beat (+171%, p=0.03). External efficiency was increased by 212% (p=0.04). CONCLUSION: In contrast to epinephrine, levosimendan improves ventricular function without increasing oxygen demand, thereby considerably improving external efficiency. Even during epinephrine resistance in extremely dysfunctional hearts, levosimendan successfully improves ventricular function.

Administration of milrinone before ischemia, in the presence of beta-blockade, to treat metabolic impairment and myocardial stunning in pigs.

BACKGROUND: We examined effects of phosphodiesterase type III inhibition on regional myocardial metabolism and global left ventricular function, during ischemia, in the presence of beta-blockade. METHODS: Twenty-three pigs were randomized and studied to completion in four groups: C, did not receive drugs; M, received 50 microg/kg milrinone; E, received esmolol (150 microg/kg/min); E+M, received both. The left anterior descending artery (LADa) was then occluded for 15 min, followed by a 60-min reperfusion. Left ventricular (LV) function data obtained included LV pressures, cardiac output (CO), slope of end-systolic pressure-volume relationship (Emax), and dP/dT. Blood lactate concentrations were obtained from the aorta, LADa, and vein at baseline, end of occlusion, and during early (5 min) and late (1 h) reperfusion. RESULTS: During ischemia, occlusion produced significant depression in LV dP/dT, Emax and concomitant elevation of LVEDP that persisted over early reperfusion in groups not treated with milrinone. After ischemia, measurements of CO were higher, with lower LVEDP and SVR; LV dP/dT and the Emax were higher, with lower LVEDP in the E+M group vs. the E group. Ischemic region lactate extraction during ischemia was better with E group vs. C group. Esmolol without or with milrinone was associated with nonsignificant lactate ischemic production during early reperfusion from baseline values. CONCLUSION: We demonstrated that the pre-emptive administration of milrinone before ischemia was associated with less ischemic hemodynamic effects, without worsening the ischemic metabolic process. The combination E+M diminished ischemic metabolic impairment, and preserved left ventricular function and baseline hemodynamics.