Rudolf Strasser

Hibernating Myocardium An Incomplete Adaptation to Ischemia

BACKGROUND We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply. METHODS AND RESULTS In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, alpha-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3). CONCLUSIONS Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.

Tumor necrosis factor-alpha is expressed by monocytes/macrophages following cardiac microembolization and is antagonized by cyclosporine.

Abstract The time course of expression of TNF-α in myocardial wound healing following ischemic injury was investigated in the porcine heart. Microembolization was used to induce focal ischemia and necrosis in hearts of 39 adult pigs. The animals were sacrified after 3, 6, 12, 24 h, 3 and 7 days, and after 4 weeks, and the myocardial tissue was studied by immunofluorescence using specific antibodies. TNF-α containing cells were identified as monocytes/macrophages by double staining with a muramidase antibody. Monocytes/macrophages were the only source of TNF-α. Microembolization caused multiple necrotic foci with loss of myocytes in the left ventricular myocardium. These foci contained numerous monocytes/macrophages and showed an inflammatory reaction typical of wound healing followed by replacement with scar tissue. The number of TNF-α positive cells increased after 24 h, peaked between 3–7 days and slowly decreased thereafter. Expression of TNF-α in monocytes/macrophages was significantly reduced after pretreatment of pigs with cyclosporine or dexamethasone. It is concluded that 1.) in myocardial tissue monocytes/macrophages are the only cell type expressing TNF-α, 2.) TNF-α is involved in wound healing after ischemia, and 3.) synthesis of TNF-α and inflammatory angiogenesis can be inhibited be treatment with either cyclosporine or dexamethasone.

Assessment of myocardial viability: Dobutamine echocardiography and thallium-201 single-photon emission computed tomographic imaging predict the postoperative improvement of left ventricular function after bypass surgery ☆ ☆☆ ★

The aim of this study was to evaluate the usefulness of dobutamine echocardiography and quantitative thallium-201 single photon emission computed tomography myocardial scintigraphy with reinjection in the detection of viable myocardium in patients with coronary artery disease and reduced left ventricular function, which will improve after aortocoronary bypass surgery. Forty-eight patients (47 men, aged 61 +/- 6 years) with angiographically documented reduced left ventricular function (ejection fraction 35 +/- 14, 63% with chronic transmural myocardial infarction) were examined by dobutamine two-dimensional echocardiography (before and during low dosage), 201Tl, and gated radionuclide ventriculography before and 3 +/- 2 months after aortocoronary bypass surgery. Four of 55 areas classified viable before operation were revascularized inadequately and discarded. Global left ventricular ejection fraction at rest rose from 35% +/- 14% before operation to 40% +/- 13% (p < 0.05) after operation. Stress-induced perfusion defects involved 40% +/- 19% of the left ventricle circumference after stress and showed a significant reduction of size to 23% +/- 14% (p < 0.01) at rest, 4 hours later, and after reinjection. This value fell to 16% +/- 12% (p < 0.05) 3 months after aortocoronary bypass surgery. We conclude that both dobutamine echocardiography (sensitivity 95%, specificity 80%, positive predictive value 87%, negative predictive value 88%) and 201Tl studies (sensitivity 87%, specificity 98%, positive predictive value 97%, negative predictive value 93%) are suitable and comparable accurate methods for predicting improvement in systolic function 3 months after revascularization in a selected population with a high prevalence of viable but hypokinetic or akinetic myocardium.

Tedisamil (KC 8857) is a new specific bradycardic drug: does it also influence myocardial contractility? Analysis by the conductance (volume) technique in coronary artery disease.

To determine whether inotropism influences the bradycardic action of tedisamil, hemodynamic assessment was performed in 13 patients with ischemic coronary artery disease including analysis of end-systolic pressure-volume relationships after an infusion of tedisamil, 0.3 mg/kg, at rest, and during paced tachycardia stress. Slope Emax fell by 14% at rest (13 patients) and by 10% during tachycardia (6/13 patients), whereas loops of end-systolic pressure-volume relationships moved rightward; all parameter changes indicated a lack of significant inotropism loss with tedisamil (p > 0.05). Although the mean heart rate decreased from 77.5 to 64.7 beats/min and QTc duration increased by 14% (p < 0.05), filling pressure and dp/dtmin remained unchanged and vascular resistance increased by 30%. Parameters of left ventricular pump function (ejection fraction, stroke volume, left ventricular efficiency) decreased slightly (between 3% and 13%), whereas left ventricular volumes increased (end-diastolic volume by 6%, end-systolic volume by 23%). The respective parameter changes during tachycardia were comparable in tendency, and angina could no longer be induced during postdrug pacing stress. We concluded that the bradycardic effects of tedisamil are selectively generated without impairing either ventricular pump function or contractility in a clinically relevant fashion, whereas the postdrug anginal threshold appears elevated. Thus tedisamil can be used safely in ischemic coronary artery disease.

Time course of mitosis and collateral growth following coronary microembolization in the porcine heart.

Abstract.In ischaemic porcine myocardium, the growth of collateral vessels by angiogenesis is observed in clusters in the vicinity of focal necroses. Because mitosis of endothelial cells is a prerequisite for angiogenesis, the purpose of this study has been to evaluate the time course of mitosis as an indicator of vascular growth in a porcine model of coronary microembolization. Ischaemia was induced by injection of 25-µm microspheres in the left circumflex artery, followed by tissue collection from non-ischaemic and ischaemic areas of the same heart after 24, 72 or 168 h microembolization. Tissue was studied by histone H3 in-situ hybridization, PCNA/cyclin immunohistochemistry and electron microscopy. The number of blood vessels in ischaemic myocardium was compared with that in normal control tissue. Capillary growth started as early as 24 h after microembolization, as indicated by increasing numbers of proliferating, histone H3- and PCNA/cyclin-positive cells in the necrotic inflammatory foci of the ischaemic area. At 72 h and 168 h, the number of blood vessels was significantly higher in ischaemic than in normal myocardium, whereas at 168 h, mitosis of cells was, as in normal myocardium, a rare event. Coronary microembolization of porcine myocardium thus leads to an increased cellular proliferation rate between 24 h and less than 7 days after the onset of microembolization, followed by enhanced capillary growth. In-situ hybridization with histone H3 and PCNA/cyclin immunohistochemistry seem to be reliable markers for proliferation and vascular growth in non-cancerogenic tissue.

Proof for piroximone's inotropic influence; can it safely be used in coronary artery disease? Analysis of end-systolic pressure-volume relations (conductance technique).

Summary: Improved contractility after applying piroxi-mone (PIR) a new phosphodiesterase HI inhibitor drug, is difficult to prove clinically. However, augmented contractility could increase the risk of myocardial ischemia when used in coronary artery disease (CAD). Analysis of the end-systolic pressure-volume relationship (ESPVR) as a load-independent parameter of the contractile left ventricular (LV) function allows for differentiation of PIRs effects: contractility vs. unloading. We therefore analyzed ESPVR and LV function in 16 CAD patients before and after PIR, 0.75 mg/kg intravenously. Emax increased by 39% (9/16 patients) and loops of the ESPVR (16 patients) moved leftward, indicating improved contractility. The difference in percent change PIR versus control (16 patients) demonstrated augmentation of LV function via unloading: LV volumes decreased (ESV by 37%, EDV by 19%), LV-filling pressure by 34%, and sys- temic vascular resistance by 19%; dP/dtmax increased by 28%, LV efficiency by 24%, cardiac index by 21%, and ejection fraction by 13%. Pacing-induced anginal threshold increased by 47% after PIR while the ischemic post-pacing LV-filling pressure and ST-segment changes tended to normalize under the drugs influence. Thus, PIR improved LV function both by unloading and by positive inotropy. Lack of PIR-induced angina and an increased anginal threshold indicate that the drug can be used safely in CAD patients as well. The analysis of ESPVR proved to be safe and reliable in identifying contractility during the diagnostic cardiac catheterization routine.

Salvage of jeopardized myocardium by ischemic preconditioning: Is the quest over?

Helmholtz is quoted to have said that if he’d had any influence in creation he would have returned the human eye to its maker for revisions. The same could be said of the heart with its only very rudimentary ability to defend itself against ischemia. Ischemia was obviously not a problem during evolution: Early man did not live much longer than prime time for reproduction and no selection bias existed to prevent vascular diseases, an affliction of later life. In spite of this natural disadvantage of aged males the number of existing although not very efficient defense mechanisms is surprisingly large. It is the general belief that the knowledge of these mechanisms may lead to the development of new therapies that hopefully improve the imperfect product of natural selection. (Mol Cell Biochem 160/161:209–215, 1996)