M-Saadeh Suleiman

Mitochondria: a target for myocardial protection

The ischemic heart requires reperfusion using clinical interventions, such as coronary artery bypass graft surgery, in order to recover. Despite recent developments in myocardial protection techniques, reperfusion damage still occurs, and significant morbidity remains a problem. Therefore, the search continues for techniques that will limit myocardial damage and that will enhance recovery upon reperfusion. Mitochondria are known to be intimately involved in the processes that lead to cell death following reperfusion, in both necrotic and apoptotic forms of cell death, and so are potential targets for protective intervention. In this review, we consider several aspects of mitochondrial function that we believe to be possible targets for myocardial protection; namely, mitochondrial Ca(2+) transport, the permeability transition pore, and improved mitochondrial substrate supply. We discuss work by ourselves and others in these areas, and also consider the recently proposed role of mitochondrial ATP-dependent K(+) channels in mediating myocardial protection by ischemic preconditioning. Finally, we describe use of cardioplegic solutions in the clinical setting, and discuss how improved understanding of the aspects of mitochondrial function summarised above may lead to better protective strategies in the future.

Inflammatory response and cardioprotection during open-heart surgery: the importance of anaesthetics

Open‐heart surgery triggers an inflammatory response that is largely the result of surgical trauma, cardiopulmonary bypass, and organ reperfusion injury (e.g. heart). The heart sustains injury triggered by ischaemia and reperfusion and also as a result of the effects of systemic inflammatory mediators. In addition, the heart itself is a source of inflammatory mediators and reactive oxygen species that are likely to contribute to the impairment of cardiac pump function. Formulating strategies to protect the heart during open heart surgery by attenuating reperfusion injury and systemic inflammatory response is essential to reduce morbidity. Although many anaesthetic drugs have cardioprotective actions, the diversity of the proposed mechanisms for protection (e.g. attenuating Ca2+ overload, anti‐inflammatory and antioxidant effects, pre‐ and post‐conditioning‐like protection) may have contributed to the slow adoption of anaesthetics as cardioprotective agents during open heart surgery. Clinical trials have suggested at least some cardioprotective effects of volatile anaesthetics. Whether these benefits are relevant in terms of morbidity and mortality is unclear and needs further investigation. This review describes the main mediators of myocardial injury during open heart surgery, explores available evidence of anaesthetics induced cardioprotection and addresses the efforts made to translate bench work into clinical practice.

Local Inhibition of MicroRNA-24 Improves Reparative Angiogenesis and Left Ventricle Remodeling and Function in Mice With Myocardial Infarction

Myocardial infarction (MI) is the leading cause of death worldwide. MicroRNAs regulate the expression of their target genes, thus mediating a plethora of pathophysiological functions. Recently, miRNA-24 emerged as an important but controversial miRNA involved in post-MI responses. Here, we aimed at clarifying the effect of adenovirus-mediate intra-myocardial delivery of a decoy for miRNA-24 in a mouse MI model and to investigate the impact of miRNA-24 inhibition on angiogenesis and cardiovascular apoptosis. After MI induction, miRNA-24 expression was lower in the peri-infarct tissue and its resident cardiomyocytes and fibroblasts; while it increased in endothelial cells (ECs). Local adenovirus-mediated miRNA-24 decoy delivery increased angiogenesis and blood perfusion in the peri-infarct myocardium, reduced infarct size, induced fibroblast apopotosis and overall improved cardiac function. Notwithstanding these beneficial effects, miRNA-24 decoy increased cardiomyocytes apoptosis. In vitro, miRNA-24 inhibition enhanced ECs survival, proliferation and networking in capillary-like tubes and induced cardiomyocyte and fibroblast apoptosis. Finally, we identified eNOS as a novel direct target of miR-24 in human cultured ECs and in vivo. Our findings suggest that miRNA-24 inhibition exerts distinct biological effects on ECs, cardiomyocytes and fibroblasts. The overall result of post-infarction local miRNA-24 inhibition appears to be therapeutic.

Myocardial injury in hypertrophic hearts of patients undergoing aortic valve surgery using cold or warm blood cardioplegia

OBJECTIVES Myocardial protection techniques during cardiac surgery have been largely investigated in the clinical setting of coronary revascularisation. Few studies have been carried out on patients with left ventricular hypertrophy where the choice of delivery, and temperature of cardioplegia remain controversial. This study investigates metabolic changes and myocardial injury in hypertrophic hearts of patients undergoing aortic valve surgery using antegrade cold or warm blood cardioplegia. METHODS Thirty-five patients were prospectively randomised to intermittent antegrade cold or warm blood cardioplegia. Left ventricular biopsies were collected at 5min following institution of cardiopulmonary bypass, 30min after cross-clamping the aorta and 20min after cross-clamp removal, and used to determine metabolic changes during surgery. Metabolites (adenine nucleotides, amino acids and lactate) were measured using high pressure liquid chromatography and enzymatic techniques. Postoperative myocardial troponin I release was used as a marker of myocardial injury. RESULTS Ischaemic arrest was associated with significant increase in lactate and alanine/glutamate ratio only in the warm blood group. During reperfusion, alanine/glutamate ratio was higher than preischaemic levels in both groups, but the extent of the increase was considerably greater in the warm blood group. Troponin I release was markedly (P<0.05, Mean+/-SD) lower at 1, 24 and 48h postoperatively in the cold compared to the warm blood group (0.51+/-0.37, 0.37+/-0.22 and 0.27+/-0.19 vs. 0.75+/-0.42, 0.73+/-0.51 and 0.54+/-0.38ng/ml for cold vs. warm group, respectively). CONCLUSIONS Cold blood cardioplegia is associated with less ischaemic stress and myocardial injury compared to warm blood cardioplegia in patients with aortic stenosis undergoing valve replacement surgery. Both cardioplegic techniques, however, confer sub-optimal myocardial protection.

Intermittent antegrade hyperkalaemic warm blood cardioplegia supplemented with magnesium prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery

OBJECTIVE The influence of the addition of magnesium on myocardial protection with intermittent antegrade warm blood hyperkalaemic cardioplegia in patients undergoing coronary artery surgery was investigated and compared with intermittent antegrade warm blood hyperkalaemic cardioplegia only. METHODS Twenty-three patients undergoing primary elective coronary revascularization were randomized to one of two different techniques of myocardial protection. In the first group, myocardial protection was induced using intermittent antegrade warm blood hyperkalaemic cardioplegia. In the second group, the same technique was used except that magnesium was added to the cardioplegia. Intracellular substrates (ATP, lactate and amino acids) were measured in left ventricular biopsies collected 5 min after institution of cardiopulmonary bypass, after 30 min of ischaemic arrest and 20 min after reperfusion. RESULTS There were no significant changes in the intracellular concentration of ATP or free amino acid pool in biopsies taken at the end of the period of myocardial ischaemia. However, the addition of magnesium prevented the significant increase in the intracellular concentration of lactate seen with intermittent antegrade warm blood hyperkalaemic cardioplegia. Upon reperfusion there was a significant fall in ATP and amino acid concentration when the technique of intermittent antegrade warm blood hyperkalaemic cardioplegia was used but not when magnesium was added to the cardioplegia. CONCLUSIONS This work shows that intermittent antegrade warm blood hyperkalaemic cardioplegia supplemented with magnesium prevents substrate derangement early after reperfusion.

Effect of ischaemia and reperfusion on the intracellular concentration of taurine and glutamine in the hearts of patients undergoing coronary artery surgery.

Taurine and glutamine are the most abundant intracellular free amino acids in mammalian hearts where changes in their intracellular concentrations are likely to influence a number of cellular activities. In this study we investigated the effects of ischaemia and reperfusion on the intracellular concentrations of taurine and glutamine in the hearts of patients undergoing coronary artery bypass surgery using cold crystalloid or cold blood cardioplegic solutions. Ischaemic arrest (30 min), using cold crystalloid cardioplegic solution (n = 19), decreased the intracellular concentrations (micromol/g wet weight) of taurine (from 9.8 +/- 0.8 to 7.7 +/- 0.7, P < 0.05) and glutamine (8.7 +/- 0.5 to 7.2 +/- 0.6). After 20 min of normothermic reperfusion the fall in taurine and glutamine was maintained (7.5 +/- 0.5 and 7.4 +/- 0.7 for taurine and glutamine respectively). Myocardial ischaemic arrest with cold blood cardioplegic solution (n = 16) did not cause a significant fall in tissue taurine or glutamine. However, on reperfusion there was a marked fall in the intracellular concentrations of taurine (9.4 +/- 0.5 to 6.5 +/- 0.7) and glutamine (8.0 +/- 0.7 to 5.8 +/- 0.4). The fall in amino acids was associated with a fall in ATP and a rise in tissue lactate. This work demonstrates that irrespective of the cardioplegic solution used to arrest the heart, there is a marked fall in tissue taurine and glutamine which may influence the extent of recovery following surgery. The fall in taurine is largely due to efflux whereas changes in glutamine are due to both transport and metabolism. Ischaemia, hypothermia and changes in the transmembrane concentration gradients are the likely factors responsible for the changes in tissue amino acids.

Cold blood versus cold crystalloid cardioplegia for repair of ventricular septal defects in pediatric heart surgery: a randomized controlled trial

BACKGROUND There is little evidence in the literature on the benefits of cold blood cardioplegia in pediatric cardiac surgery. This study investigates the effects of cold crystalloid versus cold blood cardioplegia on myocardial metabolism, reperfusion injury, and clinical outcomes in patients undergoing ventricular septal defect (VSD) repair. METHODS Patients were randomly assigned to receive antegrade cold (4 to 6 degrees C) St Thomass I crystalloid (CCC) or blood (CBC) cardioplegia. Changes in myocardial adenine nucleotides and purine levels were monitored in right ventricular biopsies and postoperative serum troponin I (TnI) and lactate release were measured. RESULTS Forty patients were randomly assigned to CCC (n = 21; age 21.1 +/- 40.8 months) or to CBC (n = 19; age 27.4 +/- 39.3 months). Patient characteristics were similar in the two groups and there was no mortality. After the ischemic period there was a significant drop in adenosine triphosphate levels compared with control values in the CCC (40.4 +/- 9.9 versus 27.5 +/- 12.5 nmol/mg protein, p = 0.01) but not in the CBC group (40.3 +/- 23.2 versus 37.3 +/- 18.9 nmol/mg protein). The fall was more marked in infants compared with children (40% versus 10%, respectively, p = 0.01). Mean total TnI release was 42% lower in the CBC than the CBC group (95% confidence interval 10% to 62%, p = 0.015). Total TnI release was significantly associated with age (p < 0.001) but as levels in infants in the CBC group were the same as for children, the reduction with age was seen almost entirely in the CCC group. There were no differences in the duration of inotropic support, ventilation time, intensive care unit, or hospital stay in the two groups. CONCLUSION The use of CBC is associated with less metabolic myocardial ischemic stress and reperfusion injury when compared with CCC in pediatric patients undergoing VSD repair.

Inflammation, oxidative stress and postoperative atrial fibrillation in cardiac surgery

Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery that occurs in up to 60% of patients. POAF is associated with increased risk of cardiovascular mortality, stroke and other arrhythmias that can impact on early and long term clinical outcomes and health economics. Many factors such as disease-induced cardiac remodelling, operative trauma, changes in atrial pressure and chemical stimulation and reflex sympathetic/parasympathetic activation have been implicated in the development of POAF. There is mounting evidence to support a major role for inflammation and oxidative stress in the pathogenesis of POAF. Both are consequences of using cardiopulmonary bypass and reperfusion following ischaemic cardioplegic arrest. Subsequently, several anti-inflammatory and antioxidant drugs have been tested in an attempt to reduce the incidence of POAF. However, prevention remains suboptimal and thus far none of the tested drugs has provided sufficient efficacy to be widely introduced in clinical practice. A better understanding of the cellular and molecular mechanisms responsible for the onset and persistence of POAF is needed to develop more effective prediction and interventions.

Short periods of regional ischaemia and reperfusion provoke release of troponin I from the human hearts

Whether cardiac troponin I (cTnI) is better at detecting minor myocardial damage than other biochemical markers, is still controversial. In this report we monitored the response of the human heart to short periods of regional ischaemia and reperfusion (3 min each) by measuring cTnI release in the coronary sinus and the radial artery of patients undergoing coronary revascularisation surgery on beating heart without cardiopulmonary bypass. Our data show for the first time that the human heart releases significant amounts of cTnI in response to minor cardiac insults. However because of dilution, this release cannot be easily detected outside the coronary circulation. Therefore, an improved sensitivity of the assays used to measure cTnI may provide an ideal tool for assessing minor myocardial damage.

Cardiopulmonary bypass and oxidative stress

The development of the cardiopulmonary bypass (CPB) revolutionized cardiac surgery and contributed immensely to improved patients outcomes. CPB is associated with the activation of different coagulation, proinflammatory, survival cascades and altered redox state. Haemolysis, ischaemia, and perfusion injury and neutrophils activation during CPB play a pivotal role in oxidative stress and the associated activation of proinflammatory and proapoptotic signalling pathways which can affect the function and recovery of multiple organs such as the myocardium, lungs, and kidneys and influence clinical outcomes. The administration of agents with antioxidant properties during surgery either intravenously or in the cardioplegia solution may reduce ROS burst and oxidative stress during CPB. Alternatively, the use of modified circuits such as minibypass can modify both proinflammatory responses and oxidative stress.