Acute Regional Myocardial Ischemia Research Articles

Inhibition of Sodium Glucose Cotransporter‐2 Preserves Cardiac Function during Regional Myocardial Ischemia via a Frank‐Starling Mechanism

Recent evidence indicates that sodium glucose cotransporter-2 inhibitors (SGLT2i) significantly reduce the incidence of major adverse cardiovascular events in high risk patients. However, the specific effects of SGLT2i on the cardiovascular system remain poorly defined. This study tested the hypothesis that SGLT2i improves cardiac function during acute regional myocardial ischemia and reperfusion. Lean domestic swine (~50 kg; control (n = 6), SGLT2i (n = 5)) were randomized to receive either placebo or oral doses of canagliflozin (300 mg) 24 hours prior to and the morning of a terminal experimental procedure. Measurements were obtained in open chest, anesthetized swine at baseline, during a 30 min complete occlusion of the circumflex coronary artery, and during a 2 hour reperfusion period. Blood pressure (85 ± 6 mmHg), heart rate (78 ± 7 beats/min), coronary flow (0.40 ± 0.05 mL/min/g), and myocardial oxygen consumption (43 ± 6 μL O2/min/g) were unaffected by canagliflozin treatment at rest and were not significantly altered by ischemia/reperfusion in either group. At the onset of ischemia, SGLT2i produced a significant parallel increase in both left ventricular end diastolic (85 ± 9 mL to 129 ± 10 mL; P < 0.05) and end systolic volumes (29 ± 8 mL to 78 ± 9 mL; P < 0.01) that was manifest ~30 to 90 sec post coronary artery occlusion. Left ventricular volumes remained elevated throughout the ischemic period and returned to baseline levels following ~30 min of reperfusion. Ventricular volumes remained unchanged in control swine throughout the entire protocol. Canagliflozin-mediated increases in end diastolic volume were directly associated with significant increases in stroke volume (P < 0.05) and stroke work (P < 0.05) relative to untreated controls swine during ischemia. SGLT2i also increased cardiac efficiency (P < 0.05), as defined by stroke work/myocardial oxygen consumption. No differences in myocardial substrate uptake of glucose (P = 0.54) or lactate (P = 0.16) were noted between groups at any experimental time point. These data support the hypothesis that SGLT2i preserves cardiac contractile function during regional myocardial ischemia via activation of a Frank-Starling mechanism and independent of alterations in myocardial substrate selection. Attached figure illustrates control responses (black) and SGLT2i responses (red). Support or Funding Information NIH HL117620 Representative pressure volume loops from control (black) and SGLT2i treated (red) animals under baseline (solid) and ischemic (dashed) conditions are presented in panels A & B. Panels C & D illustrate the rate of change to ventricular volume parameters present in treated (D) but not control (C) animals subsequent to onset of ischemia. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Adenosine, lidocaine, and Mg2+ (ALM): From cardiac surgery to combat casualty care--Teaching old drugs new tricks.

New frontline drugs and therapies are urgently required to protect the body from primary and secondary injuries. We review more than 10 years of work on adenosine, lidocaine, and magnesium (ALM) and its possible significance to civilian and military medicine. Adenosine is an endogenous nucleoside involved in nucleotide production, adenosine triphosphate turnover, and restoration of supply and demand imbalances. Lidocaine is a local anesthetic and Class 1B antiarrhythmic, and magnesium is essential for ionic regulation and cellular bioenergetics. Individually, each plays important roles in metabolism, immunomodulation, inflammation, and coagulation. The original idea to combine all three was as a "polarizing" cardioplegia, an idea borrowed from natural hibernators. Two recent prospective, randomized human trials have demonstrated its safety and superiority in myocardial protection over high-potassium "depolarizing" solutions. The next idea came from witnessing how the human heart spontaneously reanimated after complex operations with little inotropic support. At high doses, ALM arrests the heart, and at lower doses, it resuscitates the heart. In rat and pig models, we have shown that ALM intravenous bolus and infusion "drip" protects against acute regional myocardial ischemia, lethal arrhythmias, cardiac arrest, compressible and noncompressible blood loss and shock, endotoxemia, and sepsis. Individually, adenosine, lidocaine, or magnesium fails to protect. Protection is afforded in part by reducing inflammation, correcting coagulopathy, and lowering energy demand. We propose a unifying hypothesis involving improved central, cardiovascular and endothelium coupling to maintain sufficient tissue oxygenation and reduce primary and secondary "hit" complications. As with any new drug innovation, translation into humans is challenging.

Dynamics of the activity of lipid peroxidation under conditions of acute regional myocardial ischemia

The effect of quinoline ethanamide on the activity of lipid peroxidation has been investigated in acute regional ischemia of the heart muscle. It has been shown that the antioxidant effect of quinoline ethanamide is implemented as a result of reduction in the content of primary molecular products of lipid peroxidation in tissues and blood. The results of the biochemical study have been confirmed by submicroscopic examination of the myocardium paying attention to the ultrastructure of the cardiomyocyte nucleus, sarcoplasm, the presence of mitochondria in the juxtanuclear area, borders of the “insert disc” between sarcomeres, etc. After introduction of quinoline ethanamide in animals the number of mitochondria significantly increased, borders of “insert discs” between sarcomeres slightly “expanded”, a lot of different organelles appeared in the sarcoplasm. Restoration of the myocardiocyte ultrastructure has been confirmed by the changes revealed appearring due to hypoxia and in the presence of the antioxidant action of both tocopheryl acetate and quinoline ethanamide. Data concerning the content of conjugated dienes and trienes in the myocardium and the blood serum of animals show that vitamin E and quinoline ethanamide significantly inhibited generation of both the primary and secondary products of free-radical oxidation. Unidirectionality of shifts in the myocardium and the blood serum is also notable. The results of studying the content of Schiff bases have shown that Vitamin E and quinoline ethanamide inhibited generation of such bases both in the myocardium and the blood serum. When comparing the drugs’ activity, it has been found that quinoline ethanamide to a greater degree prevented accumulation of peroxidation products.

Application of “In Vivo Cryotechnique” to Morphological and Immunohistochemical Analyses of Living Mouse Subepicardial Microcirculation Under Various Pathological Conditions

"In vivo cryotechnique" (IVCT), which involves immediately cryofixing cells and tissues of living animals in situ, can display more native morphology in vivo and eliminate artificial changes in conventional preparations. However, the technical characteristics of IVCT are not known for the practical examination of subepicardial microcirculation of beating heart tissue. Histological sections of subepicardial area were prepared using IVCT and conventional fixation methods: quick freezing, immersion fixation, or perfusion fixation followed by alcohol dehydration, respectively from healthy mice. In addition, changes of erythrocyte shape, T-tubule, and microvasculature in mouse heart from a variety of models (acute increase of left ventricular afterload, myocardial ischemia, and cardiac arrest) were examined by IVCT. With IVCT, flowing erythrocytes, blood flow, microvasculature, and myocyte structure could be well preserved without artificial change of erythrocyte shape and translocation of serum proteins as displayed in conventional preparation samples. Furthermore, in various pathological models prepared by IVCT, T-tubules with albumin immuno-positive staining were arranged in a disorderly way and were decreased in volume in samples of acute increase of left ventricular afterload (IVCT-LAA). This was more evident in acute regional myocardial ischemia (IVCT-IC) and less evident in heart arrest (IVCT-HA). In addition, the leakage of serum proteins from microvasculature into myocyte was found only in IVCT-IC but not in IVCT-LAA and in IVCT-HA. In conclusion, IVCT is a new technique for examining morphology of subepicardial microcirculation without artifacts compared with conventional methods and is a more sensitive fixation technique in detecting pathological changes of the heart.

Studies on the cardiotoxicity of noradrenaline in isolated rabbit hearts.

The concentration-dependent toxic effects of exogenous noradrenaline (NA, CAS 51-41-2) on acute regional myocardial ischemia (MI) was investigated with and without alpha- and beta-adrenoceptor blockade. Electrically-driven rabbit Langendorff-hearts with depleted catecholamine stores were used (reserpin 7.0 mg/kg i.p. 16-24 h before preparation, constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature, and quantitated from epicardial NADH-fluorescence photography. Starting after a reperfusion period of 20 min, hearts were treated with exogenous NA (10(-7), 10(-6) or 10(-5) mol/l). Adrenoceptors were blocked by propranolol (10(-6) mol/l) and phentolamine (10(-6) mol/l). Without adrenoceptor blockers, NA 10(-6) mol/l induced an increase in left ventricular pressure and a reduction in the relative coronary flow. Concomitantly, MI was enhanced. After adrenoceptor blockade, NA 10(-7) or 10(-6) mol/l had no influence on functional parameters. MI was not affected by NA 10(-7) mol/l, but MI was significantly enhanced by NA 10(-6) mol/l. MI enhancement by NA 10(-6) mol/l was completely prevented by superoxide dismutase (30 U/ml). Functional effects of NA 10(-5) mol/l were not completely inhibited by adrenoceptor blockers at the concentrations used, and arrythmias were observed. MI was also enhanced by NA 10(-5) mol/l. Deleterious effects on MI, that are independent on functional effects, are induced by NA in a micromolar concentration. These direct toxic effects are mediated by superoxide anion radicals. In lower concentrations (10(-7) mol/l), there is no evidence for direct toxic actions of NA independent of functional effects. MI enhancement by NA 10(-5), or 10(-6) mol/l without adrenoceptor blockers may have been caused in part by functional and arrythmogenic effects and/or through the generation of oxygen free radicals.

Modulation of Programmed Forms of Cell Death by Intracoronary Levosimendan During Regional Myocardial Ischemia in Anesthetized Pigs

Powerful mediators of programmed cell death, such as apoptosis and autophagy, can contribute to myocyte cell loss during pathological cardiac conditions. Levosimendan has been shown to exert beneficial hemodynamic effects in presence of global myocardial ischemia and heart failure through vasodilatation and increase of cardiac contractility. Recently, the intracoronary administration of a bolus levosimendan was found to exert favourable cardiac anti-stunning effects without lowering arterial pressure, which limits the use of levosimendan mainly in coronary artery disease. Here we tested whether the intracoronary administration of levosimendan can beneficially modulate programmed cell death in acute regional myocardial ischemia. Acute regional myocardial ischemia was induced in 20 anaesthetized pigs and intracoronary levosimendan 15 min bolus administration was started 4 h afterwards. The effects of levosimendan on coronary blood flow and cardiac function were evaluated and myocardial biopsies were examined for criteria of autophagy and apoptosis. The administration of levosimendan caused a significant increase of coronary blood flow (p < 0.05) in absence of changes in cardiac function. Moreover, levosimendan prevented the down-regulation of the anti-apoptotic gene, Bcl-2, and the up-regulation of the apoptotic markers Bax and cytochrome c, which resulted in a reduced expression of TUNEL fragmented nuclei (p < 0.05). Furthermore, levosimendan maintained Beclin 1 at 4 h and potentiated LC3 II expression, these results being consistent with autophagy activation. Such effects of intracoronary levosimendan bolus administration during regional myocardial ischemia indicate the occurrence of cardio-protection by modulation of programmed form of cell death.

Local effects and mechanisms of antiarrhythmic peptide AAP10 in acute regional myocardial ischemia: electrophysiological and molecular findings

Previously, it was shown that antiarrhythmic peptides and our lead substance AAP10 enhance electrical intercellular communication via gap junctions. Now, we wanted to elucidate whether AAP10 acts preferably in the ischemic area and the molecular mechanism of this peptide. Seventeen rabbit hearts were isolated, perfused according to Langendorff, and submitted to 30-min local ischemia by LAD occlusion with/without AAP10 (50 nM). Electrophysiology was assessed by 256 channel epicardial mapping. Finally, the ischemic zone, border zone, and non-ischemic zone were excised, and the cardiac gap junction protein connexin43 (Cx43), its phosphorylation state, and the distribution at the polar and lateral membrane of cardiomyocytes were determined by Western blot and immunofluorescence. Ischemia led to a decrease in activation recovery interval (ARI) homogeneity, which could be completely prevented by AAP10. Moreover, ischemia-induced activation wave slowing in the ischemic border zone was antagonized by AAP10. In ischemic center and border zone, but not in the non-ischemic area, (phospho-Cx43/dephospho-Cx43)-ratio decreased. This was also significantly antagonized by AAP10. Serine 368 was identified as one phosphorylation site for the activity of AAP10. In the non-ischemic area, AAP10 had no influence on Cx43 phosphorylation state. Interestingly, ischemia led to a loss of Cx43 from the cell poles and lateral sides in the ischemic area and border zone. AAP10 completely prevented the ischemia-induced decrease in polar Cx43 presence. In the ischemic area, AAP10 prevents from ischemia-induced Cx43 dephosphorylation and loss of Cx43 from the gap junction at cell poles and in parallel prevents the decrease in ARI homogeneity and attenuates ischemia-induced slowing of activation wave propagation. The AAP10 action seems confined to the ischemic area.

Speckle Tracking Echocardiography is a Sensitive Tool for the Detection of Myocardial Ischemia: A Pilot Study from the Catheterization Laboratory During Percutaneous Coronary Intervention

Analysis of rotational myocardial motion has been reported to be a sensitive index of myocardial ischemia. In this study, circumferential and radial myocardial strain and displacement was monitored during angioplasty balloon-induced myocardial ischemia in 8 patients undergoing percutaneous coronary intervention. The circumferential and radial variables were measured simultaneously in parasternal short-axis view at the papillary muscle level using the recently introduced speckle tracking echocardiography technique that allows 2-dimensional, angle-independent, real-time evaluation of the myocardial motion (2-dimensional strain modality). Acute regional myocardial ischemia caused a significant reduction of circumferential (-35.6 +/- 23.1%) and radial (-27.1 +/- 23.2%) strain and displacement (-49.6 +/- 27.2% and -43.2 +/- 26.8%, respectively). Simultaneously, time to the respective peak systolic values became significantly prolonged, the circumferential ischemic response in temporal domain being more pronounced (P < .05). Speckle tracking echocardiography-based analysis of rotational myocardial motion has a potential to become an efficient clinical bedside tool in the detection of acute ischemic regional myocardial dysfunction.

Dietary n-3 fatty acids promote arrhythmias during acute regional myocardial ischemia in isolated pig hearts☆

Dietary supplementation with fish oil-derived n-3 fatty acids reduces mortality in patients with myocardial infarction, but may have adverse effects in angina patients. The underlying electrophysiologic mechanisms are poorly understood. We studied the arrhythmias and the electrophysiologic changes during regional ischemia in hearts from pigs fed a diet rich in fish oil. Pigs received diets rich in fish oil, in sunflower oil, or a control diet for 8 weeks. Hearts were isolated and perfused. Ischemia was created by occluding the left anterior descending artery. Diastolic stimulation threshold, refractory period, conduction velocity, activation recovery intervals and the maximum downstroke velocity of 176 electrograms were measured in the ischemic zone. Spontaneous arrhythmias during 75 min of regional ischemia were counted. More episodes of spontaneous ischemia-induced sustained ventricular tachycardia and ventricular fibrillation occurred in the fish oil and sunflower oil group than in the control group. More inexcitable myocardium was present in the ischemic zone in the group fed fish oil or sunflower oil than in the control group after 20 min of ischemia. After 40 min of ischemia, more block occurred in the control group than in the other groups. The downstroke velocity of the electrograms in the ischemic border zone was lower in the fish oil group and sunflower oil group than in the control after 20 min. A diet rich in fish oil results in proarrhythmia compared to a control diet during regional ischemia in pigs. Myocardial excitability is reduced in the fish oil and sunflower oil group during the early phase of arrhythmogenesis. In the late phase of arrhythmogenesis, excitability is more reduced in the control group than in the fish oil and sunflower oil group.

Effect of Levosimendan and Milrinone on Regional Myocardial Ischemia/Reperfusion-Induced Arrhythmias in Dogs

Phosphodiesterase inhibitors as inodilators in heart failure are associated with promotion of arrhythmias. Calcium sensitizers have been proposed for the treatment of severe decompensated heart failure. The effect of levosimendan, a calcium sensitizer, and milrinone, a phosphodiesterase inhibitor, on ventricular arrhythmias was compared in a model of acute regional myocardial ischemia and reperfusion. The left anterior descending coronary artery in dogs was occluded for 25 minutes, followed by reperfusion. The 2 drugs were administered in a hemodynamically equieffective dose (0.1 micromol/kg) 10 minutes before coronary occlusion. Levosimendan, but not milrinone, significantly attenuated the pronounced increase in the number of ventricular premature beats (-63%), tachycardia (-50%), fibrillation (-70%), and inhomogeneity of ventricular electrical activation. Levosimendan significantly improved the overall survival rate. Levosimendan has a more beneficial profile than milrinone regarding the development of ventricular arrhythmias during and after regional myocardial ischemia.

ELECTRICAL ACTIVITY AND REENTRY DURING ACUTE REGIONAL MYOCARDIAL ISCHEMIA: INSIGHTS FROM SIMULATIONS

In this work, the authors use computer modeling to theoretically investigate the mechanisms involved in figure-of-eight reentry during acute regional myocardial ischemia, a pattern of excitation which may lead to ventricular fibrillation and sudden cardiac death. For this purpose, a modified version of the Luo–Rudy dynamic model for the action potential and ionic currents has been used, together with a two-dimensional model of the regionally ischemic ventricle. The virtual tissue comprises several realistically dimensioned and located transitional border zones for hyperkalemia, hypoxia and acidosis, simulating the substrate heterogeneity created by acute ischemia. Different types of patterns of excitation following the delivery of a premature stimulus were obtained, including figure-of-eight reentry. Action potentials and selected ionic currents which explain the reentry process are analyzed. The effect of the degree of ATP-sensitive current activation in the vulnerability to reentry is also studied. The results are in accordance with experimental observations, and demonstrate the ability of second-generation mathematical models to analyze and explain the mechanisms involved in ischemic reentry.

Sphingosine modulates myocyte electrophysiology, induces negative inotropy, and decreases survival after myocardial ischemia.

Contractility studies in isolated feline myocytes have demonstrated that sphingosine, a metabolite stimulated by tumor necrosis factor (TNF) binding, decreases intracellular calcium release and depresses inotropic activity. This study investigated the electrophysiologic effects of sphingosine in isolated cat myocytes as well as the cardiodynamic consequence of TNF, sphingosine, and its metabolic precursors in vivo. In cat myocytes, sphingosine markedly decreased action potential duration, lowered action potential plateau, and inhibited L-type calcium current (I(Ca-L)). After administration of TNF, sphingomyelin, C2-ceramide, or sphingosine, only C2-ceramide and sphingosine depressed cardiac function in normal rats. Negative inotropic effects of C2-ceramide were attenuated by N-oleoylethanolamine (NOE), a ceramidase inhibitor that blocks sphingosine formation. Rats pretreated with NOE before undergoing 30 min of acute regional myocardial ischemia followed by 150 min of reperfusion exhibited improved survival. Most deaths could be attributed to acute pump failure accompanied by bradycardia. Myocardial infarct size and peak serum TNF were not different between NOE- and vehicle-treated groups (3,908 +/- 1097 pg/ml and 3,027 +/- 846 pg/ml, respectively). These results indicate that sphingosine exerts direct inhibitory effects on the action potential and I(Ca-L) in isolated feline myocytes, consistent with previously reported sphingosine activity on I(Ca-L) in isolated rat myocytes. The in vivo study suggests that reducing sphingosine production with N-oleoylethanolamine attenuates cardiodepression and can improve overall survival after ischemic injury. Clearly, agents that modulate sphingosine production limit cardiodepression and may provide a therapeutic benefit in clinical conditions of myocardial inflammatory injury.

Acute regional myocardial ischemia identified by 2-dimensional multiregion Doppler imaging tissue technique

Background and Objective: Tissue Doppler echocardiography (TDE) is a promising method for the assessment of regional myocardial function, but pulsed TDE does not provide quantitative data from multiple regions simultaneously. This feature is important for the objective assessment of regional differences in myocardial function. In the present study, we investigated a new off-line TDE method that provides quantitative pulsed velocity data from an unlimited number of regions selected within a 2-dimensional (2D) image. The goal of the study was to determine the ability of this new approach to quantify regional myocardial function during acute myocardial ischemia induced by balloon angioplasty. Methods: Twenty-two patients undergoing angioplasty of the left anterior descending coronary artery (LAD) were studied. Left ventricular longitudinal wall motion was assessed by 2D TDE from the apical 4-chamber view before, during, and after angioplasty. Images were sampled at a rate of 69 ± 15 frames/s, and the off-line analysis allowed simultaneous measurement of velocities in multiple myocardial segments. Results: There were 3 major alterations in the systolic velocity pattern during LAD occlusion. Peak early systolic velocities along the apical septum were significantly reduced during LAD occlusion (2.8 ± 1.2 cm/s to 0.6 ± 1.7 cm/s, P <.001). Myocardial velocities in mid systole suggested paradoxical wall motion (1.0 ± 1.2 cm/s to −0.8 ± 0.9 cm/s, P <.001). When comparing the ischemic regions of the left ventricle with the nonischemic regions, each patient demonstrated lower myocardial systolic velocities in the ischemic region. Furthermore, during early diastole, the wall motion of the ischemic segments showed a postsystolic contraction pattern with velocities changing from −0.9 ± 1.0 cm/s to 1.9 ± 1.3 cm/s (P <.001). Conclusion: This new 2D TDE approach is able to quantify detailed myocardial velocity profiles from multiple regions simultaneously. Single-beat comparisons of ischemic and nonischemic regions might enhance the sensitivity for diagnosing ischemic heart disease. Reversed systolic wall motion during midsystole and marked positive velocity during early diastole might be new and important markers of myocardial wall ischemia. (J Am Soc Echocardiogr 2000;13:986-94.)

Aprotinin Pretreatment Diminishes Postischemic Myocardial Contractile Dysfunction in Dogs

We evaluated the effect of aprotinin, administered before the onset of acute regional myocardial ischemia, on reversible contractile dysfunction induced by ischemia and reperfusion in pentobarbital-anesthetized dogs. Animals were randomized to receive either aprotinin 30,000 kallikrein inactivator units (KIU)/kg and 7000 KIU x kg(-1) x hr(-1) (n = 8) or equivalent volumes of 0.9% sodium chloride (n = 7) IV 60 min before a 15-min interruption of circumflex coronary artery blood flow and then reperfusion. There were no intra- or intergroup differences in hemodynamic variables or regional myocardial mechanics (sonomicrometry) before onset of ischemia. Immediately before reperfusion, systolic dysfunction characterized by significantly decreased percent systolic shortening was present in the circumflex coronary artery area of both study groups. After reestablishment of perfusion, aprotinin animals had preserved percent systolic shortening whereas saline animals exhibited regional systolic dysfunction. Regional myocardial contractility as assessed by the slope Mw of the preload recruitable stroke work relation was preserved during reperfusion in animals who received aprotinin but depressed in the control group. We conclude that functional recovery from myocardial ischemia-reperfusion injury at normothermia is improved by IV administration of aprotinin before the onset of acute regional myocardial ischemia in physiologically intact dogs. Administration of clinically relevant doses of aprotinin IV before the onset of regional myocardial ischemia, in contrast to control conditions, preserved regional systolic function and contractility at baseline values after reestablishment of myocardial perfusion in dogs.

Aprotinin Pretreatment Diminishes Postischemic Myocardial Contractile Dysfunction in Dogs

We evaluated the effect of aprotinin, administered before the onset of acute regional myocardial ischemia, on reversible contractile dysfunction induced by ischemia and reperfusion in pentobarbital-anesthetized dogs. Animals were randomized to receive either aprotinin 30,000 kallikrein inactivator units (KIU)/kg and 7000 KIU · kg−1 · hr−1 (n = 8) or equivalent volumes of 0.9% sodium chloride (n = 7) IV 60 min before a 15-min interruption of circumflex coronary artery blood flow and then reperfusion. There were no intra- or intergroup differences in hemodynamic variables or regional myocardial mechanics (sonomicrometry) before onset of ischemia. Immediately before reperfusion, systolic dysfunction characterized by significantly decreased percent systolic shortening was present in the circumflex coronary artery area of both study groups. After reestablishment of perfusion, aprotinin animals had preserved percent systolic shortening whereas saline animals exhibited regional systolic dysfunction. Regional myocardial contractility as assessed by the slope Mw of the preload recruitable stroke work relation was preserved during reperfusion in animals who received aprotinin but depressed in the control group. We conclude that functional recovery from myocardial ischemia-reperfusion injury at normothermia is improved by IV administration of aprotinin before the onset of acute regional myocardial ischemia in physiologically intact dogs. Implications Administration of clinically relevant doses of aprotinin IV before the onset of regional myocardial ischemia, in contrast to control conditions, preserved regional systolic function and contractility at baseline values after reestablishment of myocardial perfusion in dogs.

Left-ventricular unloading by transvalvular axial flow pumping in experimental cardiogenic shock and during regional myocardial ischemia: Cardiology 1994; 84/3 (202–210)

The efficacy of the transfemoral left-ventricular assist device Hemopump (HP; 21 Fr outer diameter) was examined in experiments with adult sheep in two different models of cardiogenic shock (tachycardia shock; ischemia shock), and during ventricular fibrillation. During tachycardia (high frequency pacing-induced; n = 14), HP assist led to a significant increase in cardiac output (from 2.2 to 2.8 liters/min), mean aortic pressure (from 47.6 to 65.6 mmHg), and myocardial perfusion pressure (from 25.5 to 59.0 mmHg). Simultaneously, a normalization of body oxygen-uptake (from 1.4 to 2.5 ml/min.kg), a decrease in myocardial oxygen consumption (from 6.1 to 4.8 ml/min.100 g), and a normalization of myocardial lactate metabolism were observed during HP assist. During regional myocardial ischemia (PTCA balloon occlusion of the proximal LAD (3.5 min; n = 12), HP assist led to significant decrease in LV end-diastolic pressure (from 21.1 to 12.1 mmHg), and increase in diastolic aortic pressure (from 58 to 67 mmHg) resulting in significant increase in coronary perfusion pressure. In the early reperfusion period, myocardial release of both lactate and potassium was significantly lowered with HP assist. During ventricular fibrillation (induced by electrical stimulation; n = 9), HP flow rates decreased from 2.5 (after 10 min) to 2.1 liters/min (after 30 min). Mean aortic pressures simultaneously decreased from 64.0 to 54.6 mmHg. Perfusion conditions were sufficient for maintenance of aerobic myocardial metabolism, but were borderline for peripheral circulation. Our hemodynamic and metabolic data demonstrate beneficial effects of cardiac assist with the Hemopump 21 Fr in both tachycardia-induced severe cardiogenic shock and during acute regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute regional myocardial ischemia and recovery after cardiopulmonary bypass: effects of intensity of antecedent ischemia.

Aortic cross-clamping with inadequate myocardial preservation has been shown to cause postoperative decreases in myocardial performance following coronary artery bypass graft surgery. We have demonstrated a mild decrement in myocardial beta-receptor function associated with cold cardioplegia in a normal animal model; in normal human hearts, however, response to beta-adrenergic inotropic stimulation was diminished significantly. Beta-receptor dysfunction also is associated with chronic myocardial ischemia that is associated with severe ischemic heart disease. Although the change in beta-receptor function with acute regional myocardial ischemia associated with severe ischemic heart disease is not understood fully, we found that the intensity of regional ischemia significantly affects functional recovery after cardiopulmonary bypass (CPB). Myocardial stunning does not appear to be significant in this dysfunction; however, alterations in beta-receptor density and function may play a critical role in post-CPB ventricular function.

The effect of left ventricular chamber compliance on early diastolic filling during coronary reperfusion.

This study was designed to assess the changes in left ventricular (LV) diastolic filling and to evaluate the dynamic determinants of LV diastolic filling during coronary reperfusion after acute myocardial ischemia. We examined LV diastolic pressure-volume relations (D-PVRs) using the conductance catheter technique with a high-fidelity micromanometer, and the transmitral flow using transesophageal pulsed Doppler echocardiography in 9 open-chest anesthetized dogs with the pericardium opened. We measured early diastolic peak flow velocity (E), late diastolic peak flow velocity (A), the ratio of peak E to peak A (E/A), operational chamber compliance at the minimum LV pressure [(dV/VdP) nadir], and the time constant of LV relaxation (TC). Acute regional myocardial ischemia was produced by occluding the proximal portion of the left anterior descending coronary artery. Data were acquired at baseline, 10 min after acute myocardial ischemia, and after 15 and 90 min of reperfusion under left atrial pacing at 100 beats/min. During myocardial ischemia, D-PVRs shifted upward and rightward on the same curvilinear relationship compared with that at baseline (LV end-diastolic pressure (LVEDP) from 7.3 to 10.5 mmHg, LVEDV from 25 to 31 ml, both p < 0.01), accompanied by a decrease in peak E and E/A (E from 41 to 25 cm/sec, E/A from 1.7 to 1.1, both p < 0.01) and a prolongation of TC (from 25.4 to 30.3 msec, p < 0.01). After coronary reperfusion, D-PVRs returned to baseline accompanied by an improvement in the peak E and E/A ratio. No significant changes in peak A were observed in any of the stages. There was no correlation between peak E and TC, however, a significant positive correlation was observed between peak E and (dV/VdP) nadir (r = 0.76, p < 0.01). In conclusion, this study demonstrated that, using pulsed Doppler echocardiography, the improvement of diastolic filling after coronary reperfusion was based mainly on changes in early diastolic filling, and that LV operational chamber compliance at early diastole, rather than a LV relaxation property, might play an important role in determining early diastolic filling during coronary reperfusion.

Functional and antiischaemic effects of the phosphodiesterase inhibitor levosimendan in isolated rabbit hearts.

Several phosphodiesterase inhibitors have been reported to possess antiischaemic properties by improving myocardial oxygen demand/supply balance. Levosimendan is a new phosphodiesterase inhibitor with calcium-sensitizing properties. We investigated the functional and antiischaemic properties of levosimendan in isolated electrically-driven rabbit hearts (Langendorff, constant perfusion pressure: 70 cm H2O, Tyrode solution, Ca++ 1.8 mmol/l, 37 degrees, 200 beats/min.). Acute regional myocardial ischaemia was induced by ligature of a circumflex artery branch and quantified from epicardial NADH-fluorescence photography. The left ventricular pressure was similarly enhanced by levosimendan 10(-7) M or 5 x 10(-6) M (+15%) (P < 0.05). The global coronary flow was increased more markedly by levosimendan 5 x 10(-6) M (+35-50%) compared to 10(-7) M (+25%) (P < 0.05). The relative coronary flow (= global coronary flow/pressure-rate-product) was significantly enhanced only by levosimendan 5 x 10(-6) M (+20-35%) (P < 0.05), but not by levosimendan 10(-7) M (+10-15%) (P > 0.05). Epicardial NADH-fluorescence area and intensity were significantly diminished by levosimendan (-20%) (P < 0.05), and there was no significant difference between myocardial ischaemia reduction by levosimendan 10(-7) M and 5 x 10(-6) M (P > 0.05). Levosimendan is an inotrope with coronary dilator activity, showing antiischaemic effects in isolated rabbit hearts. These may be caused by (1) phosphodiesterase-inhibition and improvement of myocardial perfusion and/or (2) by oxygen-sparing effects, related to calcium sensitization of myofilaments, particularly at lower concentrations associated with a lower coronary dilator activity.

Mechanically induced changes in action potential duration and left ventricular segment length in acute regional ischaemia in the in situ porcine heart.

The electrophysiological events accompanying early ischaemia are important. The aim of this study was to investigate mechano-electric feedback in acute regional myocardial ischaemia in the intact heart in situ by measuring the change in action potential duration in response to increased ventricular loading imposed by transient aortic occlusion. 11 landrace pigs were anaesthetised and their hearts exposed. A pneumatically operated blood pressure clamp was placed around the aorta. Monophasic action potentials and an index of segment motion were recorded from the epicardium in and around the ischaemic area produced by a snare placed around a coronary artery. Ventricular and systemic arterial pressures were measured. An initial aortic clamp was performed during which control recordings were taken. The coronary artery was then tied and the aorta clamped for 5-10 s every 5 min for the duration of the 30 min tie. Recordings were taken from the ischaemic area and non-ischaemic areas. Aortic clamp before ischaemia increased intraventricular diastolic and systolic pressure and reduced action potential duration in all the areas studied (p < 0.001). During acute regional myocardial ischaemia aortic clamping resulted in significantly more shortening of the action potential in the ischaemic area after 10 min of ischaemia than in the control area (5 ms v 10 ms, p = 0.008). Over the following 20 min the degree of shortening decreased. The greater shortening at 10 min could not be attributed to changes in the end diastolic segment length or peak ventricular pressure and could thus represent a change in the expression of mechano-electric feedback by ischaemic myocardium rather than a change in loading conditions. During the first 30 min following a coronary artery occlusion mechano-electric feedback in the ischaemic myocardium varies with time.