Mitsuru Osada

Modification of ischemia-reperfusion-induced changes in cardiac sarcoplasmic reticulum by preconditioning

To examine the effects of ischemic preconditioning on ischemia-reperfusion-induced changes in the sarcoplasmic reticulum (SR) function, isolated rat hearts were either perfused with a control medium for 30 min or preconditioned with three episodes of 5-min ischemia and 5-min reperfusion before sustained ischemia for 30 min followed by reperfusion for 30 min was induced. Preconditioning itself depressed cardiac function (left ventricular developed pressure, peak rate of contraction, and peak rate of relaxation) and SR Ca2+-release and -uptake activities as well as protein content and Ca2+/calmodulin-dependent protein kinase (CaMK) phosphorylation of Ca2+-release channels by 25-60%. Global ischemia for 30 min produced marked depressions in SR Ca2+-release and -uptake activities as well as SR Ca2+-pump protein content in control hearts; these changes were significantly attenuated by preconditioning. Compared with the control preparations, preconditioning improved the recovery of cardiac function and SR Ca2+-release and -uptake activities as well as Ca2+-release channel and Ca2+-pump protein contents in the ischemic-reperfused hearts. Unlike the protein kinase A-mediated phosphorylation in SR membranes, the CaMK-mediated phosphorylations at Ca2+-release channels, Ca2+ pump, and phospholamban were depressed in the ischemic hearts; these changes were prevented by preconditioning. These results indicate that ischemic preconditioning may exert beneficial effects on ischemia-reperfusion-induced alterations in SR function by preventing changes in Ca2+-release channel and Ca2+-pump protein contents in the SR membrane.To examine the effects of ischemic preconditioning on ischemia-reperfusion-induced changes in the sarcoplasmic reticulum (SR) function, isolated rat hearts were either perfused with a control medium for 30 min or preconditioned with three episodes of 5-min ischemia and 5-min reperfusion before sustained ischemia for 30 min followed by reperfusion for 30 min was induced. Preconditioning itself depressed cardiac function (left ventricular developed pressure, peak rate of contraction, and peak rate of relaxation) and SR Ca2+-release and -uptake activities as well as protein content and Ca2+/calmodulin-dependent protein kinase (CaMK) phosphorylation of Ca2+-release channels by 25-60%. Global ischemia for 30 min produced marked depressions in SR Ca2+-release and -uptake activities as well as SR Ca2+-pump protein content in control hearts; these changes were significantly attenuated by preconditioning. Compared with the control preparations, preconditioning improved the recovery of cardiac function and SR Ca2+-release and -uptake activities as well as Ca2+-release channel and Ca2+-pump protein contents in the ischemic-reperfused hearts. Unlike the protein kinase A-mediated phosphorylation in SR membranes, the CaMK-mediated phosphorylations at Ca2+-release channels, Ca2+ pump, and phospholamban were depressed in the ischemic hearts; these changes were prevented by preconditioning. These results indicate that ischemic preconditioning may exert beneficial effects on ischemia-reperfusion-induced alterations in SR function by preventing changes in Ca2+-release channel and Ca2+-pump protein contents in the SR membrane.

Coronary arterial involvement and QT dispersion in Kawasaki disease

For the early detection of myocardial ischemia in patients with severe involvement of the coronary arteries after Kawasaki disease, a method with high sensitivity and low cost is desirable because these patients require frequent follow-up and diagnostic tests. For this purpose, electrocardiographic, echocardiographic, Holter, and stress testing or angiography are repeated. However, these tests have some limitations due to cost, convenience, or sensitivity. It is uncertain that increased QT dispersion would exactly indicate progression of myocardial ischemia after Kawasaki disease, but this is the first study to present that QT dispersion of > or = 60 ms had higher sensitivity for detection of severe involvement of coronary artery after Kawasaki disease. This study is limited due to the small number of patients; larger prospective studies are required to clarify the usefulness of QT dispersion analysis in detecting the progression of myocardial ischemia after Kawasaki disease.

The Inhibitory Effects of Carvedilol Against Arrhythmias Induced by Coronary Reperfusion in Anesthetized Rats

Background: Previous study has shown the antiarrhythmic effects of carvedilol on isolated rat hearts, but little is known about the mechanism of this protective action. This article examines the inhibitory effect of carvedilol against arrhythmias induced by reperfusion in anesthetized rats. In addition, the results are compared with those with propranolol, super oxide dismutase (SOD) plus catalase, and a combination of both in order to elucidate the mechanism of the protective actions. Methods and Materials: Ninety percent of the rats in the control group showed lethal ventricular fibrillation (VF). Carvedilol at the doses of 0.03, 0.1, and 0.3 mg/kg significantly reduced the incidence of lethal VF to 0%, 0%, and 10%, respectively ( P < .05). In contrast, propranolol at the doses of 0.3, 1.0, and 3.0 mg/kg and SOD (35,000 units/kg) plus catalase (400,000 units/kg) did not reduce the incidence of lethal VF (80%, 60%, 70%, and 70%, respectively). However, administration of a combination of propranolol (1.0 mg/kg) and SOD plus catalase completely inhibited the occurrence of lethal VF to 0% ( P < .05). Conclusion: These results indicate that carvedilol has the inhibitory effect against reperfusion arrhythmias in rats and suggest that the mechanism of action of this compound is related to the combined effects of beta-blocking and antioxidant.

Protein kinase C is involved in cardioprotective effects of ischemic preconditioning on infarct size and ventricular arrhythmia in rats in vivo

Protein kinase C (PKC) has been known to play an important role in ischemic preconditioning (IP). This study was designed to examine whether the translocation of PKC is associated with the cardioprotective effects of IP in vivo on infarct size and ventricular arrhythmias in a rat model.Using anesthetized rats, heart rate, systolic blood pressure, infarct size and ventricular arrhythmias during 45 min of coronary occlusion were measured. PKC activity was assayed in both the cytosolic and cell membrane fraction . Brief 3-min periods of ischemia followed by 10 min of reperfusion were used to precondition the myocardium. Calphostin C was used to inhibit PKC.Infarct size was significantly reduced by IP (68.1 (2.5)%, mean (S.E.) vs. 45.2 (3.4)%, p < 0.01). The reduction in infarct size by IP was abolished by pretreatment with calphostin C. The total number of ventricular premature complex (VPC) during 45 min of coronary occlusion was reduced by IP (1474 (169) beats/45 min vs. 256 (82) beats/45 min, p < 0.05). The reduction the total number of VPC induced by IP was abolished by the administration of calphostin C before the episode of brief ischemia. The same tendency was observed in the duration of ventricular tachycardia and the incidence of ventricular fibrillation. PKC activity in the cell membrane fraction transiently increased immediately after IP (100 vs. 142%, p < 0.01) and returned to baseline 15 min after IP. Pretreatment with calphostin C prevented the translocation of PKC.The translocation of PKC plays an important role in the cardioprotective effect of IP on infarct size and ventricular arrhythmias in anesthetized rats.

T lymphocyte activation and restenosis after percutaneous transluminal coronary angioplasty.

We investigated the relation between the activation of T lymphocytes and the occurrence of restenosis after percutaneous transluminal coronary angioplasty (PTCA) in 10 stable angina patients. Recent studies have suggested that PTCA causes an inflammatory response, which may affect restenosis after angioplasty. Soluble interleukin-2 receptor (sIL-2R) is a useful marker to evaluate the activation of T lymphocytes. sIL-2R was measured before and 2 h after successful PTCA, and 3-month follow-up coronary angiography was done to observe restenosis. Four of 10 patients showed restenosis. The restenosis group of 4 patients had a higher level of sIL-2R after PTCA than the no-restenosis group of 6 patients (495 vs. 274 U/ml, p < 0.01). This study suggests that sIL-2R may offer prognostic information after elective PTCA and identify a subgroup of patients at high risk for clinical restenosis in a few months.

Improvement of exercise tolerance by single lead VDD pacemaker: evaluation using cardiopulmonary exercise test.

We used a Cardiopulmonary test to assess the physiological benefit of single lead VDD pacing in ten patients (six men, four women; aged 32–84 years, mean 69 years) with atrioventricular block. Maximal symptom‐limited treadmill exercise test using a ramp protocol was performed under VDD and VVIR or VVI pacing (VVI) in random sequence. The pacemaker was then programmed to the VDD mode, and Holter ECG was recorded in nine patients. Compared with findings during the VVI, the VDD mode had a greater chronotropic response (mean maximal heart rate, VDD 106 ± 17 beats/mm vs VVI 79 ± 19 beats/min, P = 0.03), and was associated with prolongation of exercise duration (VDD 11.2 ± 2.9 minute vs VVI 10.5 ± 3.1 minute; P = 0.01), and the onset of anaerobic threshold at a higher oxygen uptake (VDD 12.4 ± 3.4 mL/min per kilogram vs WI 10.0 ± 2.1 mL/min per kilogram; P < 0.01). Atriai sensing was recognized in almost all normal sinus P waves for all cases examined using Holter ECG. Thus, chronotropic response during exercise by VDD pacemaker improved exercise tolerance, indicating that a VDD pacemaker might be useful for patients requiring physical activity.

Antiarrhythmic effect of magnesium sulfate against occlusion-induced arrhythmias

The antiarrhythmic effect of magnesium sulfate (Mg) as well as the hemodynamics were studied using the coronary ligation and reperfusion models in rats.In the study on coronary ligation arrhythmia, i.v. administration of Mg (0.6, 2, 6, 20 and 60 \sgmaelig;mol) was conducted at 5 min after coronary ligation. Mg had an action to decrease the total number of premature ventricular contraction (PVC), the duration of ventricular tachycardia (VT), the frequency of VT and ventricular fibrillation (Vf) and the mortality ratio for 30 min after coronary ligation. In the 6-60 \sgmaelig;mol groups, significant antiarrhythmic action (p < 0.01 vs. control) was attained.In the study on reperfusion arrhythmia, i.v. administration of Mg (20, 60 and 200 \sgmaelig;mol) was conducted at 4 min after coronary ligation, and at 1 min after ligation, the coronary artery was reperfused. Mg had an action to decrease the frequency of Vf, the mortality ratio and the duration of VT and Vf and to extend the interval between the initiation of reperfusion and the occurrence of VT and Vf for 10 min after reperfusion. In the 200 \sgmaelig;mol group, significant antiarrhythmic action (p < 0.05 vs. control) was attained. Administration of Mg decreased the heart rate and blood pressure.We concluded that Mg can control myocardial ischemia-induced and reperfusion-induced arrhythmia and that sudden cardiac death which occurs as a result of arrhythmia can be prevented.

Successful resuscitation using nitroglycerin for refractory pulseless electrical activity in intensive care unit

Sir: Conventional cardiopulmonary resuscitation (CPR) has been used during the past three decades, and there have been dramatic advances in emergency cardiac care of victims of cardiac arrest. On the other hand, recent studies continue to indicate some limitations of CPR for cardiac arrest, both in and out of hospital [1, 2]. We report on an in-hospital cardiac arrest victim in whom effective circulation was restored upon administration of nitroglycerin, after lengthy unsuccessful advanced cardiac life-support attempts. A 40-year-old healthy man was admitted to the intensive care unit (ICU) due to burn injury. The extent of the burn injuries was 20% of the total body surface area. The standard therapy for burns was employed. On ICU day 3, his monitored arterial blood pressure suddenly decreased and the electrocardiogram showed marked elevation of ST segment. In a few minutes blood pressure was lost completely and CPR was initiated for cardiac arrest with pulseless electrical activity (PEA). One milligram of epinephrine was administered and doses repeated at 3to 5-min intervals. One milligram of atropine was also given and doses repeated every 3±5 min up to a total of 3 mg. CPR was continued for 30 min; however, the patient did not respond to it and external chest compression was stopped. The most probable cause was massive acute myocardial infarction. After the cardiac arrest was observed for 1 min more, 2.5 mg of nitroglycerin was injected and CPR was resumed. Five minutes after the administration of nitoglycerin, atrial fibrillation appeared and systolic arterial blood pressure dramatically recovered to over 80 mmHg. Atrial fibrillation returned spontaneously to normal sinus rhythm in a few minutes. The patient showed no neurological abnormality and had an uneventful ICU course on isosorbide dinitrate and diltiazem hydrochloride. Coronary artery spasm can be a cause of acute myocardial infarction and sudden death [3]. The incidence of coronary spasm is relatively high in Japanese as compared to Caucasians [3]. We assume that persistent coronary spasms were causing myocardial contractile dysfunction in this case and nitroglycerin released them. There are few clinical reports describing a possible link between burn injury and coronary spasm; however, it is noteworthy that, in an animal study, the endogenous factors in the serum increase after burn injury induce coronary spasms because of changes of coronary vessel sensitivity [4]. If this patient had collapsed in the same way outside the hospital and been transported to the emergency room, we would have performed conventional CPR for PEA and never considered the administration of nitroglycerin: because it would be very difficult to confirm recent ST-elevation on ECG showing slow agonal rhythms and to make a diagnosis of acute myocardial infarction. A recent report has shown that the rates of survival to hospital admission with spontaneous circulation from PEA after CPR was 28% and discharge from hospital was only 3% [5]. This survival rate is tragic. Bearing in mind the dismal prognosis of PEA after prolonged resuscitation, the good outcome in our patient may suggest the use of nitroglycerin in PEA due to acute myocardial infarction, when no other course is left. References