Early markers for myocardial ischemia and sudden cardiac death.

The post-mortem diagnosis of acute myocardial ischemia remains a challenge for both clinical and forensic pathologists. We performed an experimental study (ligation of left anterior descending coronary artery in rats) in order to identify early markers of myocardial ischemia, to further apply to forensic and clinical pathology in cases of sudden cardiac death. Using immunohistochemistry, Western blots, and gene expression analyses, we investigated a number of markers, selected among those which are currently used in emergency departments to diagnose myocardial infarction and those which are under investigation in basic research and autopsy pathology studies on cardiovascular diseases. The study was performed on 44 adult male Lewis rats, assigned to three experimental groups: control, sham-operated, and operated. The durations of ischemia ranged between 5 min and 24 h. The investigated markers were troponins I and T, myoglobin, fibronectin, C5b-9, connexin 43 (dephosphorylated), JunB, cytochrome c, and TUNEL staining. The earliest expressions (≤30 min) were observed for connexin 43, JunB, and cytochrome c, followed by fibronectin (≤1 h), myoglobin (≤1 h), troponins I and T (≤1 h), TUNEL (≤1 h), and C5b-9 (≤2 h). By this investigation, we identified a panel of true early markers of myocardial ischemia and delineated their temporal evolution in expression by employing new technologies for gene expression analysis, in addition to traditional and routine methods (such as histology and immunohistochemistry). Moreover, for the first time in the autopsy pathology field, we identified, by immunohistochemistry, two very early markers of myocardial ischemia: dephosphorylated connexin 43 and JunB

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.status: publishe

Myocardial salvage by intravenous nitroglycerin in conscious dogs: loss of beneficial effect with marked nitroglycerin-induced hypotension.

We studied the effect of nitroglycerin-induced decreases in mean arterial pressure (MAP) on myocardial salvage. Two hours after occlusion of the left anterior descending coronary artery, 65 conscious dogs were randomly allocated to receive 4 hr intravenous infusions of saline (group 1, 19 dogs), or nitroglycerin in doses to decrease MAP by 10% (group 2, 18 dogs), 25% (group 3, 14 dogs), and 50% (group 4, 14 dogs), respectively. At 7 days, 41 dogs were killed for measurement of infarct size; 24 dogs, given 7 to 10 micron radioactive microspheres for flow calculations, were killed 6 hr after occlusion. Boundaries of the occluded bed were defined by postmortem coronary arteriography. Infarct and occluded bed masses were measured by planimetry of weighed transverse sections of the left ventricle. Compared with saline infusions in group 1, nitroglycerin infusions produced sustained reductions (p less than .001) in mean left atrial pressure and MAP in all dogs, but heart rate was unchanged. The decreases in MAP achieved in groups 2, 3, and 4 were 10% (range, 5% to 19%), 23%, and 39%, respectively, with average levels of 96 (range, 83 to 113), 83, and 64 mm Hg, respectively. Despite similar masses of the occluded bed and left ventricle among the four groups, infarct size was significantly smaller (p less than .025) in group 2 compared with groups 1, 3, or 4, expressed both as percent of the left ventricle (6% vs 14% vs 13% vs 15%) and as percent of the occluded bed (13% vs 37% vs 34% vs 44%). Myocardial salvage (expressed as percent of the occluded bed) with nitroglycerin correlated inversely with the percent of decrease in MAP (r = -.77, p less than .001). Collateral blood flow increased (p less than .005) throughout the occluded bed in group 2 compared with group 1 but was unchanged in groups 3 and 4. In contrast, coronary vascular resistance decreased (p less than .025) in all nitroglycerin groups. These results suggest that perfusion pressure is an important determinant of myocardial salvage during nitroglycerin therapy. An increase in the dose of nitroglycerin to decrease MAP by more than 10%, and to levels below 96 mm Hg, might offset its potential for myocardial salvage in the conscious dog.</jats:p

Function and fate of myofibroblasts after myocardial infarction.

The importance of cardiac fibroblasts in the regulation of myocardial remodelling following myocardial infarction (MI) is becoming increasingly recognised. Studies over the last few decades have reinforced the concept that cardiac fibroblasts are much more than simple homeostatic regulators of extracellular matrix turnover, but are integrally involved in all aspects of the repair and remodelling of the heart that occurs following MI. The plasticity of fibroblasts is due in part to their ability to undergo differentiation into myofibroblasts. Myofibroblasts are specialised cells that possess a more contractile and synthetic phenotype than fibroblasts, enabling them to effectively repair and remodel the cardiac interstitium to manage the local devastation caused by MI. However, in addition to their key role in cardiac restoration and healing, persistence of myofibroblast activation can drive pathological fibrosis, resulting in arrhythmias, myocardial stiffness and progression to heart failure. The aim of this review is to give an appreciation of both the beneficial and detrimental roles of the myofibroblast in the remodelling heart, to describe some of the major regulatory mechanisms controlling myofibroblast differentiation including recent advances in the microRNA field, and to consider how this cell type could be exploited therapeutically