Experimental investigations in prolonged myocardial ischaemia. Note I. Biology of the myocardial fiber after transient myocardial fiber after transient myocardial ischaemia

The first ten days' evolution of post-ischaemic lesions of the premonitory or angina pectoris syndrome type was experimentally studied by the challenge of a short-term (10 and 15 min) ischaemia, of an adaptation to ischaemia and an adaptation followed by prolonged ischaemia (20 and 35 min). Worthy of note was the persistence of reversible lesions after short-term ischaemia and adaptation, and the progressive evolution towards cytolysis and cicatrization of some pancicellular foci after adaptation followed by prolonged ischaemia. The role of mitochondrial lesions, of lysosomal hydrolases, the inefficiency of renewed circulation, as well as problems of diagnosis are discussed.     

Pregnancy-related myocardial infarction

Introduction

The risk of acute myocardial infarction in young women is low, but increases during pregnancy due to the physiological changes in pregnancy, including hypercoagulability. Ischaemic heart disease during pregnancy is not only associated with increased maternal morbidity and mortality, but also with high neonatal complications. Advancing maternal age and other risk factors for cardiovascular diseases may further increase the risk of ischaemic heart disease in young women.

Methods

We searched the coronary angiography database of a Dutch teaching hospital to identify women with acute myocardial infarction who presented during pregnancy or postpartum between 2011 and 2013.

Results

We found two cases. Both women were in their early thirties and both suffered from myocardial infarction in the postpartum period. Acute myocardial infarction was due to coronary stenotic occlusion in one patient and due to coronary artery dissection in the other patient. Coronary artery dissection is a relatively frequent cause of myocardial infarction during pregnancy. Both women were treated by percutaneous coronary intervention and survived.

Conclusion

Physicians should be aware of the increased risk of myocardial infarction when encountering pregnant or postpartum women presenting with chest pain.

     

Dysfunction of myocardial sarcoplasmic reticulum in rats with myocardial calcification

We investigated the relationship between cardiac dysfunction and Ca2+ transport in the myocardial sarcoplasmic reticulum (SR) during the pathogenesis of cardiovascular calcification in rats. The possible mechanism of SR dysfunction was explored by detecting the alteration of the nitric oxide/nitric oxide synthase (NO/NOS) pathway in the SR. Using the vitamin D plus nicotine (VDN treatment for 2 week and 6 week) experimental model of cardiac calcification, cardiac function and sarcoplasmic reticulum function were measured. Inhibition of cardiac functions in vivo (peak rate of contraction and peak rate of relaxation, P < 0.05 or P < 0.01) were observed in all calcification groups, simultaneously, Ca2+ release and uptake in the SR as well as the Ca2+ release channel and Ca2+ pump activity were inhibited. Myocardial Ca2+ concentration and cardiac and SR dysfunction were inversely related (P < 0.05). The specific NO/NOS pathway (NO production, NOS activity and nNOS expression in the SR) was upregulated in the SR and associated with calcification (both 2- and 6 week VDN groups). These results indicate that cardiac dysfunction associated with myocardial calcification might be mediated by SR dysfunction, which may result from an impaired SR-specific NO/NOS pathway.     

Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSCs) into the acutely ischemic myocardium. Two weeks postinfarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were twofold stiffer than myocardium from noninfarcted animals but softer than myocardium from vehicle-treated infarcted animals. After 8 wk, the following variables were evaluated: MSC engraftment and left ventricular geometry by histological methods, cardiac function with a pressure-volume conductance catheter, myocardial fibrosis by Masson Trichrome staining, vascularity by immunohistochemistry, and apoptosis by TdT-mediated dUTP nick-end labeling assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated postinfarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.     

Non-ischemic myocardial preconditioning

The reduction of infarct size produced by brief ischemic episodes prior to a sustained occlusion of a coronary artery, called ischemic preconditioning, is a well known phenomenon that occurs in several species, but its mechanism is still under investigation. Recent reports support the idea that this protection can also be obtained by non-ischemic maneuvers like distention of the left ventricle and metabolic stimulation of myocardial cells. The features of non-ischemic preconditioning (temporal limitation, second window, tolerance development, remote preconditioning and efficiency of the protection), as opposed to those of ischemic preconditioning, are still to be determined. Neither is it known if non-ischemic preconditioning occurs in humans. From a physiological point of view the protective effect of an increase in metabolic rate of the heart means a constant feed-back mechanism in the myocardial cell that counteracts the presumptive damage consequent to the increase in metabolism. Therefore, in the presence of a sudden coronary occlusion the metabolic rate of the heart immediately before the occlusion would have a dual role of increasing the degree of ischemia and of protecting against it.     

Multivessel myocardial infarction

A 56-year-old female patient with hypertension, obesity and chronic intermittent cauda equina compression suffered an acute myocardial infarction five days after a lumbar hernia operation. The electrocardiogram (ECG) showed ST-segment elevation in multiple leads, consistent with an extensive acute apical and lateral myocardial infarction (figure 1, panel A). Acute coronary angiography revealed occlusion of the end-arteries of the left coronary artery in the absence of significant atherosclerotic disease (figure 1, panel B).     

Imaging myocardial metabolism

The prevalence of coronary artery disease and heart failure is increasing in modern industrialized countries, fueling the search for novel therapies. Because metabolism and function in the heart are inextricably linked, energy substrate metabolism has provided a potential target for novel therapies and the development of technologies to image myocardial metabolism has been crucial in establishing new therapeutic approaches. Nuclear imaging probes have been used to successfully evaluate aerobic fatty acid metabolism, anaerobic glucose metabolism, and oxidative metabolism and can be used for the accurate, sensitive, and physiological evaluation of therapeutic effects. More recently, with the advent of stem-cell technologies, imaging approaches have been employed to track the fate of stem cells and to monitor the success of these treatments. In the future, our ability to image myocardial metabolism is likely to assist the development of other new therapies to improve the function of the failing heart.     

Increases in myocardial cyclic GMP attenuate contractile delay in myocardial stunning

We tested the hypothesis that the effects of myocardial stunning would be reduced by cyclic GMP in rabbit hearts. In three groups of anesthetized open-chest New Zealand white rabbits, myocardial stunning was produced by 15 min of occlusion of the left anterior descending coronary artery followed by 15 min of reperfusion repeated twice. Either control vehicle (saline plus 1% dimethyl sulfoxide) or 8-bromo-cyclic GMP (8-Br-cGMP (10(-4) and 10(-3) M)) was topically applied to the left ventricular surface. Hemodynamic (left ventricular and aortic pressures) and functional parameters (wall thickening, delay in onset of wall thickening, and rate of wall thickening) were determined. Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) were used to determine myocardial O2 consumption (VO2). Myocardial stunning was observed in the control group through an increased delay in onset of myocardial wall thickening (29 +/- 7 versus 55 +/- 16 ms) and decreased maximal rate of wall thickening (20 +/- 8 versus 11 +/- 3 mm x s(-1)). After treatment with 8-Br-cGMP 10(-4) and 10(-3) M, stunning did not increase the delay (37 +/- 5 versus 39 +/- 7 and 39 +/- 7 versus 28 +/- 8 ms). Myocardial stunning did not significantly alter VO2. 8-Br-cGMP 10(-3) M significantly decreased subepicardial VO2 (6.2 +/- 0.8 versus 3.7 +/- 0.6 mL O2 x min(-1) 100 g(-1)) and insignificantly decreased subendocardial VO2 (8.6 +/- 0.9 versus 6.3 +/- 1.2 mL O2 x min(-1) x 100 g(-1)) when compared with the vehicle-treated rabbits. We conclude that increasing cyclic GMP reduced the effects of myocardial stunning in the rabbit heart by ameliorating the delay in onset of wall thickening and decreasing the local O2 costs in the stunned region.     

Improved myocardial performance induced by clofibrate during reperfusion after acute myocardial infarction

The increase of cellular fatty acids appears to be one of the causes of the myocardial injury during ischemia and reperfusion. This study was designed to examine whether a hypolipidemic drug such as clofibrate can reduce the myocardial injury during ischemia and reperfusion. Clofibrate was fed to experimental pigs for 9 days. Isolated in situ hearts from both experimental and control pigs were subjected to 60 min of regional ischemia induced by occluding the left anterior descending coronary artery, followed by 60 min of global ischemia by hypothermic cardioplegic arrest and 60 min of reperfusion. The clofibrate feeding resulted in the better cardiac performance as judged by increased coronary blood flow, improved left ventricular function, and reduced myocardial injury as judged by creatine kinase release. Although the clofibrate-fed animals contained higher levels of thiobarbituric reactive materials, the free fatty acid levels of plasma and myocardium were much lower compared with control animals. The clofibrate feeding was also associated with increased peroxisomal catalase and beta-oxidation of fatty acids. These results suggest that decreased levels of free fatty acids in the plasma and the myocardium and increased catalase activity induced by antilipolytic therapy appear to provide beneficial effects to the myocardium during ischemia and reperfusion.     

Myoglobin concentration and the state of myocardial organelles following myocardial infarction]

A study was made of the quantitative changes in myoglobin and the subcellular organization of the myocardium at early periods of experimental infarction of the heart in dogs. There proved to be a correlative relationship between the myoglobin content and the state of subcellular organization of the cardiomyocytes in the ischemic area and the so-called intact portions of the right and the left ventricles.     

Impaired myocardial perfusion reserve in experimental hypercholesterolemia is independent of myocardial neovascularization

Our objective was to investigate the functional role of hypercholesterolemia-associated myocardial neovascularization in early atherosclerosis using the antiangiogenic thalidomide. Experimental atherosclerosis is characterized by myocardial neovascularization, associated with a decrease in myocardial perfusion response to challenge, coronary endothelial dysfunction, and high oxidative stress. However, the functional significance of these neovessels is not known. Three groups of pigs (n = 6 each) were studied after 12 wk of normal or hypercholesterolemic diet without (HC) or with thalidomide (HC + Thal). Myocardial perfusion and permeability were assessed at baseline and in response to cardiac challenge, using electron beam computed tomography, and coronary endothelial function was assessed using organ chambers. Myocardial samples were scanned ex vivo with a three-dimensional microscopic computed tomography scanner, and the spatial density of the myocardial microvessels was quantified. Growth factors and oxidative stress were measured in the myocardial tissue. As a results of these procedures, myocardial perfusion response to adenosine and dobutamine was blunted in both HC and HC + Thal pigs compared with normal pigs (P < 0.05, HC and HC + Thal vs. normal) as was the coronary endothelial function. Myocardial permeability response to adenosine was increased in both HC and HC + Thal pigs compared with normal pigs (P < 0.05, HC and HC + Thal vs. normal, and HC + Thal vs. HC). The microvascular density was increased in HC pigs compared with normal pigs but normalized in HC + Thal pigs (P < 0.001 HC vs. normal and HC + Thal). HC + Thal pigs showed decreased expression of Flk-1 and basic FGF but increased expression of VEGF compared with normal and HC pigs. Oxidative stress was increased in both HC and HC + Thal pigs compared with normal pigs. In conclusion, chronic administration of thalidomide attenuates myocardial neovascularization in experimental HC pigs without affecting myocardial perfusion response to stimulation. This suggests that the myocardial neovascularization may not contribute to the attenuated myocardial perfusion response in hypercholesterolemia.