Ryuzo Nawada

Coordinate interaction between ATP-sensitive K+ channel and Na+, K+-ATPase modulates ischemic preconditioning

BACKGROUND We reported that digoxin abolishes the infarct size (IS)-limiting effect of ischemic preconditioning (IPC). Because ATP-sensitive K+ (KATP) channels are involved in IPC, we studied whether Na+,K+-ATPase and KATP channels functionally interact, thereby modulating IPC. METHODS AND RESULTS Rabbits received 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occlusion followed by 10 minutes of reperfusion. The IS, expressed as a percentage of the area at risk, was 40.2+/-2.8% in control and 39.8+/-5.0% in digoxin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a KATP channel opener, reduced IS to 11.8+/-1.8% and 13.4+/-2.6% (P<0. 05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5+/-3.3%), whereas it did not change that induced by cromakalim (18.8+/-3.0%). In patch-clamp experiments, digoxin was found to inhibit the opening of KATP channels in single ventricular myocytes in which ATP depletion had been induced by metabolic stress. In contrast, digoxin had little effect on the channel opening induced by cromakalim. Moreover, the inhibitory action of digoxin on channel activities was dependent on subsarcolemmal ATP concentration. CONCLUSIONS The IS-limiting effect of IPC is modulated by an interaction between KATP channels and Na+,K+-ATPase through subsarcolemmal ATP.

Inhibition of Sarcolemmal Na+,K+-ATPase Activity Reduces the Infarct Size–Limiting Effect of Preconditioning in Rabbit Hearts

BACKGROUND The inhibition of sarcolemmal Na+,K+-ATPase activity is closely related to ischemic myocardial cell injury. However, the involvement of this enzyme in preconditioning has not been determined. METHODS AND RESULTS We assessed the effect of ischemia on sarcolemmal Na+,K+-ATPase activity. Control and preconditioned rabbits were subjected to 0, 10, 20, 30, and 60 minutes of coronary occlusion. Ten to 60 minutes of ischemia reduced Na+,K+-ATPase activity, whereas preconditioning preserved the activity of this enzyme only during the first 20 minutes of ischemia. To determine whether the preservation of Na+,K+-ATPase activity in the early phase of ischemia contributed to limiting the infarct size, additional rabbits underwent 30 minutes of occlusion followed by 3 hours of reperfusion with or without pretreatment with digoxin, an inhibitor of Na+,K+-ATPase. Infarct size in animals pretreated with digoxin in the absence of preconditioning did not differ from that in controls. It was markedly reduced by preconditioning, whereas digoxin reduced the infarct size-limiting effect. Moreover, preconditioning increased sarcolemmal Na+-Ca2+ exchange activity in rabbits subjected to 20 minutes of ischemia, whereas digoxin diminished this increase. CONCLUSIONS Preconditioning preserves the ischemia-induced reduction in sarcolemmal Na+,K+-ATPase activity in the early phase of ischemia in rabbit hearts. Inhibition of Na+,K+-ATPase activity reduces the infarct size-limiting effect of preconditioning with a loss of increased Na+-Ca2+ exchange activity, implying that this preservation is responsible for the cardioprotective effect of preconditioning.

KATP channels are common mediators of ischemic and calcium preconditioning in rabbits

Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 +/- 3% (mean +/- SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 +/- 2, 17 +/- 2, and 12 +/- 3%, respectively (P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 +/- 4 and 41 +/- 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.

Effects of losartan and its combination with quinapril on the cardiac sympathetic nervous system and neurohormonal status in essential hypertension.

Objective Sympathetic nervous and renin–angiotensin systems play important roles in essential hypertension. This study was aimed at assessing the effects of losartan or its combination with quinapril on the cardiac nervous system and neurohormonal status in essential hypertension. Design and methods Randomized, comparative study of 105 patients with mild essential hypertension, carried out at Shizuoka General Hospital. In phase 1, 40 hypertensives were allocated randomly into the losartan (50 mg) group or the quinapril (10 mg) group. In phase 2, 65 hypertensives, after 3 months 10 mg quinapril monotherapy, were allocated randomly into groups with 50 mg losartan (n = 32) or 5 mg amlodipine (n = 33) added to quinapril, and were treated for a further 3 months. All patients underwent [123I]metaiodobenzylguanidine (MIBG) imaging and neurohormonal measurements before and 3 months after treatment. Results Both monotherapies significantly increased renin activity, while losartan monotherapy also increased angiotensin II (AII) concentration. In both the losartan and quinapril groups, the washout rate was significantly decreased (18.1 ± 11.4 versus 13.9 ± 11.0%, P < 0.0002 and 13.3 ± 9.3 versus 12.3 ± 9.1%, P < 00001, respectively) without changes in the heart to mediastinum ratio (H/M ratio). Both combined therapies lowered blood pressure to similar levels. A combination therapy with losartan and quinapril significantly increased the H/M ratio (1.93 ± 0.29 and 2.02 ± 0.29, P < 0.01) and decreased the washout rate (17.6 ± 11.0 and 15.3 ± 9.2%, P < 0.02) without affecting AII concentration, whereas a combination therapy with amlodipine and quinapril therapy did not affect the scintigraphic parameters with an increase in the AII concentration. Conclusions With a usual antihypertensive dose, both losartan and quinapril had a little suppressive effect on the cardiac sympathetic activity in essential hypertension. In contrast, the combination therapy with losartan and quinapril, which results in a higher degree of inhibition of the renin–angiotensin system, could suppress the cardiac sympathetic activity effectively.

Diffuse and Severe Left Ventricular Dysfunction Induced by Epicardial Coronary Artery Spasm

Endothelial dysfunction and effectiveness of treatment of calcium antagonists are sugges tive of coronary artery spasm as an underlying disorder in dilated cardiomyopathy (DCM). The aim of this study is to determine whether or not the epicardial coronary artery spasm can induce severe cardiac dysfunction like DCM. Thirty-four consecutive patients with angiographically normal coronary arteries and diffuse left ventricular hypokinesis whose causes had been unknown underwent acetylcholine provocation test and left ventricular biopsy. Eight patients were excluded according to the clinical and laboratory data and biopsy findings suggesting myocarditis or other systemic diseases. According to the results of the acetylcholine provocation test, 17 patients were finally diagnosed as having DCM, and nine patients (35% of the study patients), who had acetyl choline-induced diffuse and multivessel coronary spasm, were diagnosed as having DCM- like vasospastic angina pectoris (VSA). Clinical and cardiac catheterization data including hemodynamics and biopsy findings were similar between the two groups except that left ventricular end-systolic volume was significantly greater in DCM than in DCM-like VSA. After the acetylcholine provocation test, DCM patients received both a beta blocker and an angiotensin-converting enzyme inhibitor, and DCM-like VSA patients received antiang inal drugs. In echocardiographic findings at predischarge and those after 6-month drug (continued on next page) treatment, both DCM-lke VSA and DCM showed significant reduction in end-diastolic and end-systolic diameters and significant increase in fractional shortening and ejection fraction, whereas changes in ejection fraction and fractional shortening were significantly greater in DCM-like VSA than those in DCM. Epicardial coronary artery spasm can induce diffuse and severe left ventricular dysfunction like DCM in VSA. Although antianginal drugs markedly improve left ventricular function of these patients, only the acetylcholine provocation test can identify DCM-like VSA.

Scintigraphic assessment of regional cardiac sympathetic nervous system in patients with single-vessel coronary artery disease

In coronary artery disease, the cardiac sympathetic nervous system is closely associated with myocardial ischemia. I-123 metaiodobenzylguanidine (MIBG) imaging allows us to assess the cardiac sympathetic nervous system regionally. One-hundred and eleven patients with singlevessel disease underwent regional quantitative analysis of MIBG imaging before successful percutaneous transluminal coronary angioplasty (PTCA), and repeat angiography 6 months after PTCA. Based on the results of the follow-up left ventriculogram, patients were divided into 3 groups: 39 angina pectoris (AP), 48 prior myocardial infarction without asynergy (MI without asynergy) and 24 prior myocardial infarction with asynergy (MI with asynergy). AP and MI without asynergy had significant correlations between uptake parameters and, regional washout in the territory of diseased vessels, among which the severity score in AP was the most closely correlated with regional washout (r=0.79, p<0.0001). These correlations disappeared in MI with asynergy. To compare regional MIBG parameters in the territory of the diseased vessel as well as in the territories of the other major coronary arteries among the 3 groups, we examined MIBG parameters in 57 patients with left anterior descending artery (LAD) disease selected from among the study patients. Regional washout in the territory of the LAD was significantly higher in the MI without asynergy group than in the other two groups. The left circumflex artery (LCX) region showed significantly reduced MIBG uptake and an increased extent score in the MI with asynergy group compared with the AP group, although only a difference in the extent score existed between the MI with asynergy group and the AP group in the right coronary artery (RCA) region. In addition, the global ejection fraction before PTCA showed a significant negative correlation with each regional washout rate. In this way, regional quantitative analysis of MIBG imaging can detect the regional differences in the cardiac sympathetic nervous system in coronary artery disease, which may be associated with the degree of regional left ventricular dysfunction due to myocardial ischemia.

Endless loop tachycardia below the upper tracking rate of a pacemaker: A case report

An 82‐year‐old female with a history of hypertrophic cardiomyopathy (HCM), sick sinus syndrome (SSS), and an implanted DDD pacemaker was admitted to our hospital for congestive heart failure caused by rapid atrial fibrillation. After administration of amiodarone, atrial fibrillation (AF) became atrial flutter (AFL). Electrophysiological investigation revealed counterclockwise AFL. Catheter ablation of the cavotricuspid isthmus was performed. Burst pacing from the coronary sinus ostium to confirm the block line of the isthmus induced rapid, regular, ventricular pacing at a rate of 110 bpm. The differential diagnosis of this tachycardia included ectopic atrial tachycardia and pacemaker‐mediated, endless loop tachycardia (ELT). We diagnosed this arrhythmia as ELT, because temporary reprogramming of the pacemaker mode from DDD to VVI terminated the tachycardia. In this patient, pacing parameters favored ELT (long atrioventricular delay [AVD] and short postventricular atrial refractory period [PVARP]), and atrioventricular and ventriculoatrial conduction time was prolonged as a result of amiodarone administration.

A case of ventricular septal rupture associated with major septal branch occlusion after percutaneous coronary intervention

A 67-year-old man underwent elective percutaneous coronary intervention (PCI) of the left anterior descending artery. The major septal branch became occluded during coronary stenting. The patient developed dyspnea 19 days later. Chest radiography revealed lung congestion and a pleural effusion. Transthoracic echocardiography revealed a basal ventricular septal rupture. Emergency coronary angiography did not reveal any in-stent restenosis, and the major septal branch remained occluded. Therefore, the patient underwent closure of the ventricular septal rupture. The postoperative period was uneventful, and he was discharged 29 days after the operation. Septal branch occlusion due to coronary stenting occasionally occurs during routine PCI for which recanalization is sometimes not attempted. However, this case demonstrates that occluded septal branches, although rare, may cause serious complications. <Learning objective: Rupture of the ventricular septum, a complication of acute myocardial infarction, is usually observed in the setting of acute myocardial infarction associated with major coronary artery occlusion. However, ventricular septal rupture associated with side branch occlusion due to coronary stenting for stable angina pectoris is uncommon. Awareness of this rare complication is useful during routine percutaneous coronary intervention.>.

Diagnostic value of 3T whole heart coronary magnetic resonance angiography (MRA) without contrast medium

Methods From May 1 to September 6 in 2012, 31 consecutive patients received whole heart coronary MRA without contrast medium in 3T MRI scanner (Ingenia 3.0T, Philips Healthcare). 26 patients (84%) had sufficient quality to analyze. In these, 21 patients (16 men; mean age 69 years) received coronary angiography within 1 month of MRA. In MRA, coronary arteries were segmented to proximal, mid, distal RCA (segment 1, 2, 3), LMT (segment 5), proximal, mid, distal LAD (segment 6, 7, 8), and proximal, distal LCX (segment 11, 13). In coronary angiography, a stenosis of over 50% was defined to be significant. The segments after stent implantation were excluded.