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.

Preservation of myocardium during coronary artery bypass surgery.

Myocardial protection aims to prevent reversible post-ischemic cardiac dysfunction (myocardial stunning) and irreversible myocardial cell death (myocardial infarction) that occur as a consequence of myocardial ischemia and/or ischemic-reperfusion injury. Although the mortality rate for isolated coronary artery bypass grafting has been markedly reduced during the past decade, myocardial death, as evidenced by elevation in creatine kinase-myocardial band and/or cardiac troponin, is common. This is ascribed to suboptimal myocardial protection during cardiopulmonary bypass or with off-pump technique, early graft failure, distal embolization, and regional or global myocardial ischemia during surgery. An unmet need in contemporary coronary bypass surgery is to find more effective cardioprotective strategies that have the potential for decreasing the morbidity and mortality associated with suboptimal cardioprotection. In the present review article on myocardial protection in contemporary coronary artery bypass surgery, we attempt to elucidate the clinical problems, summarize the outcomes of selected phase III trials, and introduce new perspectives.

The impact of myocardial viability on the clinical outcome of cardiac resynchronization therapy.

INTRODUCTION: Around 30% of patients do not respond to cardiac resynchronization therapy (CRT). Nonischemic cardiomyopathy has been identified as an independent predictor of response to CRT, probably due to the absence of compact scar. METHODS AND RESULTS: The relationship between cardiac scar, ischemia, and hibernation (both at the left-ventricular pacing site and as a total burden) and response to CRT was studied in patients with ischemic cardiomyopathy using the perfusion-viability positron emission tomography (PET) test. Sixty-six patients with ischemic cardiomyopathy and traditional criteria for CRT were included. All patients underwent PET scan prior to CRT. Using PET, the amount and location of scarred, ischemic, and hibernating myocardium were characterized. No revascularization was indicated. Responders were defined by an improvement of left-ventricular ejection fraction (LVEF) >or= 5% and/or New York Heart Association (NYHA) class >or= 1 degree. During a mean follow-up of 26.2 +/- 22.2 months, there was a significant improvement in NYHA class and reverse remodeling in patients with the LV lead inserted remotely from the scar. However, reverse remodeling of a similar degree was present also in patients with extensive scarring including the lateral wall. The presence of ischemia, hibernation, or nontransmural scar at the pacing-site did not significantly modify the outcome of CRT as compared with viable myocardium. There were only 38% of CRT-nonresponders. Neither the extent of scar, ischemia, hibernation, or viability predicted outcome or mortality. Twenty patients died during the follow-up, one patient underwent heart transplant. CONCLUSIONS: At follow-up, response to CRT is observed regardless of the presence of extensive scarring. Left ventricular (LV) pacing at sites with ischemia, hibernation, or nontransmural scar does not appear to modify the effect of CRT as compared to viable tissue.

Slow conduction within lateral myocardial scar and response to cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) improves symptoms and survival in some selected heart failure patients. However, around 30% of patients still do not respond to CRT. In these patients, methodological approach of any potential cause of nonresponse should be reviewed. We describe the case of limited left ventricle (LV) myocardium capture by LV lead during biventricular pacing secondary to a slow conduction from LV lead impulse, located in a scar zone, and the benefit of interventricular delay optimization in this setting. This case emphasizes the interest of considering 12-lead electrocardiogram during management of patients with CRT.

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.

[Cardioversion and atrial stunning]. / Kardiowersja a ogluszenie przedsionków.

Stunned atrium is defined as a state of temporary mechanic atrial dysfunction with preserved bioeletrical function. It may follow up to 38-80% successful cardioversions performed to convert atrial fibrillation to regular sinus rhythm. Lack of effective atrial contractility leads to hemodynamic changes, which may result in thrombus formation with subsequent thromboembolic events. It becomes a priority to research in depth the pathophysiology of stunned atrium phenomenon and form strategies to avoid complications associated with it. Studies have shown, that even patients who had no evidence of thrombotic material (as proven by transesophageal echocardiography performed prior to cardioversion), are still at increased risk of embolic events. This fact created basis for hypothesis, that conditions for clot formation may be met only when sinus rhythm is restored. 93% of thrombi are accompanied by so-called spontaneous contrast phenomenon. The purpose of our study was to find relations between factors contributing to stunned atrium and its cellular mechanisms. It is suggested, that stunned atrium results from changes in atrial muscular membrane which occur during atrial fibrillation. Stunned atrium is encountered more frequently in patients with coronary artery disease than in hypertensive heart disease or even lone atrial fibrillation. It is also associated with rheumatic valvular abnormalities and left ventricular dysfunction from other causes. Studies have shown no correlation between the frequency of stunned atrium and the mode of cardioversion. It was observed, that duration of atrial fibrillation and dimensions of atria have substantial impact on time to mechanical function recovery and magnitude of atrial stunning. Studies on subjects undergoing cardioversion due to atrial fibrillation proved that there is a higher tendency to stunned atrium in patients with atrial enlargement. Due to significant delay until full mechanical function recovery, it is of prominent importance to continue anticoagulation for at least 4 weeks after cardioversion.

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.

Effects of off-pump versus on-pump coronary surgery on reversible and irreversible myocardial injury: a randomized trial using cardiovascular magnetic resonance imaging and biochemical markers.

BACKGROUND: There is biochemical evidence that off-pump coronary artery bypass grafting (OPCABG) reduces myocardial injury compared with the use of cardiopulmonary bypass (ONCABG), but the functional significance of this is uncertain. We hypothesized that OPCABG surgery would result in reduced postoperative reversible (stunning) and irreversible myocardial injury, as assessed by cardiovascular MRI (CMRI). METHODS AND RESULTS: In a single-center randomized trial, 60 patients undergoing multivessel total arterial revascularization were randomly assigned: 30 to OPCABG and 30 to ONCABG. Patients underwent preoperative and early postoperative cine MRI for assessment of global left ventricular function, and contrast-enhanced CMRI for assessment of irreversible myocardial injury. Serial troponin I measurements were obtained perioperatively and correlated with the CMRI findings. The mean preoperative cardiac index was similar in the 2 surgical groups (2.9+/-0.7 ONCABG; 2.9+/-0.8 OPCABG; P=0.9). After surgery, the cardiac index was significantly higher in the OPCABG group (2.7+/-0.6 ONCABG; 3.2+/-0.8 OPCABG; P=0.04). New irreversible myocardial injury was similar in incidence (36% ONCABG; 44% OPCABG; P=0.8) and magnitude (6.3+/-3.6 g ONCABG; 6.8+/-4.0 g OPCABG; P=0.9) across the 2 groups. The median area-under-the-curve (AUC) troponin I values were significantly larger in the ONCABG group (182 versus 135 microg/L; P=0.02). There was a moderate correlation between the troponin I AUC values and mean mass of new myocardial hyperenhancement (r(2)=0.4; P=0.008). CONCLUSIONS: OPCABG results in significantly better left ventricular function early after surgery but does not reduce the incidence or extent of irreversible myocardial injury.

Clinical and therapeutic implications of chronic left ventricular dysfunction in coronary artery disease.

In patients with myocardial ischemia, left ventricular dysfunction (LV) may arise from irreversible damage (cell death), myocardial stunning (postischemic dysfunction), or myocardial hibernation (persistent myocardial dysfunction at rest due to underperfusion). Chronic LV dysfunction usually refers to hibernating myocardium. However, stunning might also become chronic, producing persistent myocardial dysfunction. Clinical studies have demonstrated that many patients with coronary artery disease have subsequent recurring ischemic (symptomatic or silent) episodes at short intervals in the same area and that each episode may be followed by myocardial stunning. In these patients the myocardium may not recover fully between episodes and function may remain reversibly depressed for long periods or may even be clinically depressed. The recognition of both stunning and hibernation is very important clinically and therapeutically, since chronic LV dysfunction may have a negative effect on mortality and morbidity in patients with coronary artery disease. Moreover, both clinical states are potentially correctable. Pharmacologic intervention with beta blockers, angiotensin-converting enzyme inhibitors, or calcium antagonists might improve or protect hibernating myocardium. The acute hemodynamic effects of the dihydropyridine calcium antagonist nisoldipine have been investigated in patients with chronic LV dysfunction probably arising from hibernating myocardium. Nisoldipine was found to improve both left ventricular systolic and diastolic function without activating the adrenergic system. The improvement in systolic function may be due to a redistribution of coronary blood flow and to a slight reduction in afterload induced by nisoldipine. On the other hand, nisoldipine may improve diastolic function in these patients by an intrinsic mechanism, Reducing intracellular calcium overload or balancing intracellular calcium homeostasis in the ischemic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Free radicals, calcium homeostasis, heat shock proteins, and myocardial stunning.

Repeated brief ischemic episodes result in prolonged depression of contractile function despite the absence of irreversible damage, a phenomenon called myocardial stunning. Considerable evidence exists to suggest that oxygen radicals, particularly the hydroxyl radical formed as a result of Fenton reaction or nitric oxide-peroxynitrite pathway, may contribute to the pathogenesis of myocardial stunning. The generation of free radicals may cause sarcoplasmic reticulum dysfunction, and both of these mechanisms may lead to calcium overload, which in turn could exacerbate the damage initiated by oxygen radicals. Antioxidant therapy has been shown to effectively attenuate or even prevent the development of prolonged depression of contractility in many studies. In addition, preconditioning with brief ischemic insults is able to trigger protection, which appears to attenuate stunning 24 to 48 hours later. The mechanism of this protection is not known, although one or more members of the heat shock protein family may have a role in protection against stunning.

Clinical evidence for stunned myocardium after coronary artery bypass surgery.

Stunned myocardium is defined as postischemic dysfunction of viable myocardium. This phenomenon was initially described in animal models of brief ischemia followed by reperfusion, but is becoming increasingly recognized in clinical situations. One of these situations is ventricular dysfunction following coronary artery bypass surgery. Several clinical reports have demonstrated depressed ventricular function in the initial hours after coronary artery bypass surgery: this dysfunction is usually resolved within 24 to 48 hours, and does not appear to be dependent upon alterations in preload, afterload, or temperature. New therapies for improving postischemic myocardial function following cardiopulmonary bypass are under investigation.

[Magnesium therapy in acute myocardial infarction. New points of view]. / Magnesiumbehandling ved akutt hjerteinfarkt. Nyere synspunkter.

In some smaller placebo-controlled, randomized studies, and in one larger such study (LIMIT-2, 2,136 patients), intravenous infusion of magnesium was shown to reduce early and late mortality of ischaemic heart disease in patients admitted with suspected acute myocardial infarction. In contrast, the ISIS-4 trial, which included 58,050 patients, did not show any benefit from magnesium. These discrepancies may be explained as follows; In LIMIT-2, magnesium was given early and before spontaneous or therapeutic thrombolysis (36% of the patients), in ISIS-4, however, the patients were likely to have undergone myocardial reperfusion in response to thrombolysis (70% of the patients) before receiving magnesium. Myocardial stunning may develop in association with reperfusion. Magnesium given before and during ischaemia attenuates postischaemic myocardial dysfunction. The absence of effect of magnesium in ISIS-4 is also thought to be related to the higher dose administered during the first 24 hours in this study. Early infusion of magnesium in acute myocardial infarction is a useful addition to standard therapy, and is simple, cheap and safe to administer.

Oxygen radicals and myocardial stunning.

There is compelling, although indirect, evidence that oxygen free radicals, generated during ischemia as well as upon reperfusion and reoxygenation of the ischemic heart, contribute to the reversible ventricular dysfunction characterized as myocardial stunning. Evidence of cell membrane damage as well as depression of sarcoplasmic reticulum and mitochondrial function with resulting calcium overload of the cell may be a result of lipid peroxidation of the cell by free radical products. Radical scavenger enzymes have been shown to greatly reduce the appearance of mRNA of a stress response protein (heat shock protein 71) in a pig heart model of stunning. The potential role for the introduction of antioxidant enzymes or stress protein in the cell is presented as a possible strategy for attenuating free radical damage during postischemic reflow.

Isoflurane produces only minor preconditioning in coronary artery bypass grafting.

OBJECTIVE: To investigate whether administration of isoflurane prior to cardiopulmonary bypass (CPB) could partly account for the observed protection of the myocardial function and to decrease myocardial injury in patients undergoing coronary artery bypass grafting (CABG). METHODS: Thirty-four patients with stable angina who were scheduled for isolated elective CABG operations were randomized into the control group or isoflurane (ISO) group. In the ISO group, isoflurane was inhaled for 5 min followed by another 5-min washout period before commencing CPB. The control group did not receive isoflurane. Hemodynamic data and biochemical markers of myocardial injury were measured perioperatively. RESULTS: There were no adverse effects related to isoflurane. Cardiac index (CI) increased postoperatively as compared with the baseline. In the ISO group, there was a tendency for a greater increase of CI than that in the control group (p = 0.054, ANOVA for repeated measurements). At 1 h after CPB, the change of CI was much higher in the ISO group than that in the controls (p = 0.001). Both the creatine kinase cardiac isoenzyme (CK-MB) and troponin I (TnI) reached peak value at 6 h after CPB. Isoflurane patients released slightly less CK-MB than the controls postoperatively, but the difference was not significant (p = 0.16, ANOVA for repeated measurements). The release of TnI was similar in both groups (p = 0.65, ANOVA for repeated measurements). CONCLUSIONS: Administration of isoflurane prior to commencing CPB may bring an improvement in early hemodynamic performance after CABG operations.