Notes: [Auszug] The gene for vascular endothelial growth factor (VEGF) encodes three spliced isoforms. Although the heparin binding capacities of these isoforms differ, little is known about their differential functions in vivo. We generated mice expressing exclusively the VEGF120 isoform (VEGF 120/120 mice) ...

Notes: [Auszug] Deletion of amino-acid residues 1505–1507 (KPQ) in the cardiac SCN5A Na+ channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with ...

Notes: Membrane Potentials in Human Ventricle. Introduction: The effect of chronic ischemia on the electrical properties of human cardiac tissue is not well understood. Methods and Results: Membrane potentials were studied using microelectrode techniques in isolated human ventricular tissues obtained from nonischemic (n = 17) or chronically ischemic (n = 71 myocardium. In normal Tyrode's solution, resting potential (Vr) was lower in ischemic (−70.1 · 2.12 mV) than in nonischemic muscles (−77.6 · 0.93 mV; mean · SKM; P 〈 0.051. In high [K]0 (〉 10 mM) media, V, was of similar magnitude in both types of tissue (in 21.6 mM [K]0 Vr was −53.1 · 2.24 mV in nonischcmic and −49.6 · 2.03 mV in ischemic preparations; n = 7 each; P 〉 0.05). Lowering [K]0. caused persistent Hyperpolarization in nonischemic muscles, but caused depolarization in chronically ischemic preparations (in 2,7 mM [K]0 Vr was −84.9 · 2.74 mV and –61.7 · 7.72 mV, respectively; n = 7; P 〈 0.05). Pinacidil (100 μM) normalized the response of chronically ischemic preparations to [K]0. Action potentials (APs) from nonischemic tissues varied in shape and could show aberrations. Kpinephrine (1.5 μM) and 4-aminopyridine (3 mM) increased the AP duration, while butanedione monoxime (20 mM) and tetrodotoxin (1 μM) shortened it. In chronically ischemic muscles, the AP was characterized by the absence of a plateau and the presence of a slow phase of final repolarization. Conclusion: The differential effect of tow [K]0 on the resting membrane potential of nonischemic and chronically ischemic tissues suggests a change in the properties or the regulation of background K+ channels during chronic ischemia.

Notes: Abstract We studied protein kinase C (PKC) isozyme expression and activity distribution in two models of chronically ischemic canine myocardium: (1) single vessel obstruction (SVO), produced by tight stenosis of LAD followed by preconditioning and acute ischemia (40 min); (2) three vessel obstruction (3VO), produced by LAD-stenosis and gradual occlusion of right coronary artery and left circumflex. In both models after 8 weeks of chronic ischemia the dogs were either sacrificed or had PTCA of the LAD with a follow up of another 4 weeks. Control dogs were sham operated. PKC activity was measured in subcellular fractions of tissue samples from anterior and posterior regions in the presence of histone and γ-[32P]-ATP. PKC isozymes were detected by Western blotting. All regions perfused by the obstructed coronaries were dysfunctional at 8 weeks when compared to baseline, with improvement of anterior wall function after PTCA of LAD. PKC activity was elevated in the membrane fraction of SVO, but unchanged in the 3VO model. PKCs α, ε, and ζ prevailed in cytosol fraction of the controls (cytosol/membrane ratios were ± 3.34, 1.38 and 4.56 for α, ε and ζ, respectively), consistent with PKC activity distribution, while δ was not detected. There was no significant difference between the groups concerning the relative membrane amount of the isozymes. PKCs α and ε were decreased in the cytosol fraction of both models at 8 weeks (for anterior region, by 56 and 57% in SVO and by 49 and 46% in 3VO, respectively) without there being any differences between anterior and posterior regions, and were low also in the PTCA group. PKC ζ distribution however varied between the two models. The amount of PKC ζ isozyme was downregulated by 45% after 8 weeks of chronic ischemia and returned towards the control values after PTCA in the anterior region of SVO, while it did not change in anterior wall after 8 weeks in 3VO but was significantly decreased (by 47%) in posterior region after PTCA. In conclusion, our results suggest modified PKC signalling in chronically ischemic canine myocardium.

Notes: Abstract Chronic left ventricular dysfunctional but viable myocardium of patients with chronic hibernation is characterized by structural changes, which consist of depletion of contractile elements, accumulation of glycogen, nuclear chromatin dispersion, depletion of sarcoplasmic reticulum and mitochondrial shape changes. These alterations are not reminiscent of degeneration but are interpreted as de-differentiation of the cardiomyocytes. The above mentioned changes are accompanied by a marked increase in the interstitial space. The present study describes qualitative and quantitative changes in the cellular and non-cellular compartments of the interstitial space. In chronic hibernating myocardial segments the increased extracellular matrix is filled with large amounts of type I collagen, type III collagen and fibronectin. An increase in the number of vimentin-positive cells (endothelial cells and fibroblasts) compared with normal myocardium is seen throughout the extracellular matrix. The increase in interstitial tissue is considered as one of the main determinants responsible for the lack of immediate recovery of contractile function after restoration of the blood flow to the affected myocardial segments of patients with chronic left ventricular dysfunction.

Notes: Summary Coronary reserve and contractile reserve were compared between crystalloid-perfused and bloodperfused rabbit hearts at various perfusion pressures (40–110mmHg). Contractile function of the crystalloidperfused hearts was dependent on the perfusion pressure, according to Gregg's phenomenon. Developed left ventricular pressure (LVP) increased from 67 ± 6 mmHg to 121 ± 5 mmHg and positive dP/dt maximum (dP/dt max) from 1,083 ± 75 to 2,233 ± 126 mmHg/s at perfusion pressures between the lowest and highest perfusion pressure. In the blood-perfused hearts, the perfusion pressure-induced changes were less pronounced: developed LVP changed from 107 ± 11 mmHg to 138 ± 8mmHg and dP/dt max from 1,517 ± 181 to 2,008 ± 187mmHg/s. The blood-perfused hearts showed better cardiac function, especially negative dP/dt minimum (dP/dt min), compared to the crystalloidperfused hearts. Contractile reserve estimated by paired pacing technique was quite independent of the perfusion pressure in the blood-perfused hearts but not in the crystalloid-perfused hearts, and was significantly better in the blood-perfused hearts (e.g., 81% increase of developed LVP with blood perfusion, and 26% increase with crystalloid perfusion at a perfusion pressure of 80mmHg). Coronary reserve, estimated by reactive hyperemia, was independent of the perfusion pressure in both groups. Coronary reserve was small in the crystalloid-perfused hearts (〈23%) and more than double the control value in the blood-perfused hearts. It is proposed that blood-perfused hearts are more suitable for physiological and pathophysiological studies.

Notes: Abstract In patients with chronic coronary artery disease, follow-up measurements of myocardial blood flow, metabolism and function were correlated with histology. In 41 patients with chronic coronary artery disease and a severely stenosed left anterior descending coronary artery, a positron emission tomographic (PET) flow/metabolism study and nuclear angiography were performed immediately before and 3 months after bypass surgery. Biopsies were taken from the left ventricular anterior wall at the time of surgery. Control biopsies were taken from donor hearts for cardiac transplantation and from hearts of patients with a defect of the atrial septum. A significant improvement of flow (P〈0.01) and regional contractile function (P〈0.01) was observed in the mismatch group. Glucose utilization was significantly lower (P〈0.001) as compared to preoperative values. The group with preserved flow and the PET match group revealed no significant changes in flow, metabolism or function. Control biopsies revealed significantly less myolytic cells as compared to biopsies taken from both match and mismatch groups (P〈0.01) and less fibrosis as compared to biopsies taken from the match group (P〈0.01). Postoperatively, linear relationships were found between flow and both % fibrosis (r = 0.71,P〈0.001) and regional anterior ejection fraction (r = 0.7,P〈0.001). Only mismatch areas revealed significant recovery of both flow and function after revascularization with a disappearance of enhanced glucose uptake. The better linear correlation between flow and % fibrosis after surgery as compared to preoperatively was probably due to improvement of flow values in the mismatch group.

Notes: Summary Objectives. To study the effects of oral pretreatment with metoprolol over 3 days on hemodynamics, left ventricular function, regional myocardial blood flow, and infarct size in an anesthetized dog model of thrombotic occlusion of the anterior descending coronary artery treated with thrombolysis.Methods. Ten dogs received 200 mg metoprolol (Selozok) orally and 8 dogs received placebo for 3 days twice daily and 1 hour before the experiment. Under general anesthesia, thrombotic occlusion was provoked by the copper-coil technique. Intracardiac pressures and their derivatives, cardiac output (thermodilution method), regional coronary blood flow (microspheres), global and regional left ventricular function (ventriculography), and infarct size (triphenyltetrazolium staining) were measured. Measurements were performed during control, after 60 minutes of occlusion, and after 30 and 90 minutes of reperfusion. Thrombolysis was performed in all dogs 60 minutes after occlusion by intravenous infusion of 10 µg/kg/min of rt-PA for 30 minutes.Results. During control cardiac output was lower, total peripheral resistance higher, and Tau and the left ventricular isovolumic relaxation time greater in the metoprolol group. During occlusion and after reperfusion, there were no significant hemodynamic differences between both groups. Blood flow to the area at risk and circumflex territory during occlusion were, respectively, 12.8±5.80 ml/100 g/min versus 9.65±8.35 ml/100 g/min (p〉0.05) and 42.58±7.86 ml/100 g/min versus 61.52±20.43 ml/100 g/min (p=0.01) in the metoprolol- and placebo-treated dogs. The ratios of flow area at risk/circumflex territories in the epicardial, midmyocardial, and endocardial layers were, respectively, 0.44±0.20, 0.19±0.09, and 0.20±0.13 in the metoprolol- versus 0.24±0.16, 0.08±0.06, and 0.06±0.07 (p≥0.04) in the placebo-treated dogs. The ratio of flow endocardium/epicardium was higher (p≥0.02) in the active treatment group during the control period, both in the area at risk and circumflex territory; this was also the case in the circumflex territory at the end of the experiment (p=0.003). Thirty minutes after occlusion, blood flow to the three layers of the area at risk rose to 2–3 times control values in both groups; a significant increase above control values also occurred in the circumflex territory. After 90 minutes reperfusion, blood flow to both territories was similar in both groups but was comparable to the control; however, in necrotic tissue of the subendocardial layer of both groups, flow fell below control values (p〈0.05). End-systolic volume rose from 21.2±7.4 ml to 36.1±11.5 ml (p〈0.05), end-diastolic volume remained constant (46.0±13.8 vs. 47.9±12.1 ml; p〉0.05), and ejection fraction fell from 53.9±8.3% to 25.8±10.2% (p〈0.05) at the end of the experiment in the metoprolol group. Respective figures for the placebo group were 19.4±7.9 versus 27.9±10.9 (p〈0.05), 38.5±13.0 versus 42.1±11.0 (p〉0.05), and 50.6±5.7 versus 35.5±11.7 (p〈0.05). Fractional shortening of the chords analyzed was similar in both groups during the control period; it fell significantly at the end of the experiment in three chords of the metoprolol group and in five chords of the placebo group. The apical chord in the placebo, but not in the metoprolol, dogs was dyskinetic: fractional shortening was −0.86±9.7 versus 7.5±13.5% (p〉0.05). The area at risk was 41.6±10.6 cm2 in metoprolol- and 40.5±7.2 cm2 in placebo-treated dogs (p〉0.05); the infarct size, expressed as a percentage of the area at risk, was 29.0±22.5% and 45.3±23.6% (p=0.02), respectively.Conclusions. Oral pretreatment with metoprolol limited infarct size and improved regional left ventricular function, probably due to its negative chronotropic and inotropic effects, and also due to an enhancement of collateral flow from the circumflex territory to the area at risk.

Notes: Abstract Background: Accurate localization and sizing of a myocardial infarction are necessary for clinical decision making and even more in research. Gd-Mesoporphyrin enhanced magnetic resonance imaging (MRI) was recently shown to specifically delineate necrosis in liver tumors, renal and muscle necrosis and myocardial infarction in rats. In this study, we investigated this technique's potential to accurately delineate myocardial infarction in a larger animal species, the dog. Methods: Myocardial infarction was induced in 8 dogs by ligation of the left anterior descending coronary artery, 4 of which were reperfused after 3 hr. Gd-Mesoporphyrin (0.05 mmol/kg) was injected intravenously 210 min after the onset of ischemia (n = 6) or after 24 hr in 2 dogs with non-reperfused infarctions. MRI was performed 10 hr. after administration of Gd-Mesoporphyrin. In vivo MRI consisted of EKG-triggered, respiratory gated T1-weighted spin echo and segmented turboFLASH long and short axis measurements. Post-mortem, a spin echo short axis measurement was repeated. Infarct size was determined planimetrically by TTC staining of left ventricular slices. Results: In all instances, there was a very close qualitative agreement between the MRI and TTC defined myocardial infarction. Quantitatively, the linear regression from post-mortem MRI to TTC determined infarct size yielded a result very close to the line of identity (regression coefficient: 0.980 ± 0.026, p〈0.000001, adjusted R2 = 0.964). Conclusion: We conclude that Gd-Mesoporphyrin enhanced MRI is a promising tool for the accurate delineation of myocardial infarction.