Masayuki Sakurai

Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation.

Background—Subclinical mutations in genes associated with the congenital long-QT syndromes (LQTS) have been suggested as a risk factor for drug-induced LQTS and accompanying life-threatening arrhythmias. Recent studies have identified genetic variants of the cardiac K+ channel genes predisposing affected individuals to acquired LQTS. We have identified a novel Na+ channel mutation in an individual who exhibited drug-induced LQTS. Methods and Results—An elderly Japanese woman with documented QT prolongation and torsade de pointes during treatment with the prokinetic drug cisapride underwent mutational analysis of LQTS-related genes. A novel missense mutation (L1825P) was identified within the C-terminus region of the cardiac Na+ channel (SCN5A). The L1825P channel heterologously expressed in tsA-201 cells showed Na+ current with slow decay and a prominent tetrodotoxin-sensitive noninactivating component, similar to the gain-of-function phenotype most commonly observed for SCN5A-associated congenital LQTS (LQT3). In addition, L1825P exhibited loss of function Na+ channel features characteristic of Brugada syndrome. Peak Na+ current density observed in cells expressing L1825P was significantly diminished, and the voltage dependence of activation and inactivation was shifted toward more positive and negative potentials, respectively. Conclusions—This study demonstrates that subclinical mutations in the LQTS-related gene SCN5A may predispose certain individuals to drug-induced cardiac arrhythmias.

Significance of reduced uptake of iodinated fatty acid analogue for the evaluation of patients with acute chest pain

OBJECTIVES To assess whether 15-(p-[iodine-123] iodophenyl)-3-(R,S) methylpentadecanoic acid (BMIPP) imaging can identify previous ischemic areas, BMIPP SPECT was performed in patients with acute chest pain to compare its findings with those of technetium-99m-tetrofosmin (tetrofosmin) SPECT and coronary angiography. BACKGROUND Basic studies indicate that BMIPP can identify previous ischemia as reduced tracer uptake. METHODS This study prospectively enrolled 111 consecutive patients with acute chest pain without myocardial infarction. Tetrofosmin SPECT was performed at rest within 24 h after the last episode of chest pain. Coronary angiography and BMIPP SPECT were also performed on the following day. RESULTS Sixty-four of the 87 patients with coronary stenosis or spasm showed BMIPP abnormalities corresponding to the areas of coronary abnormalities (sensitivity 74%), whereas only 33 of them showed perfusion abnormalities (sensitivity 38%) (p < 0.001). Of 24 patients [corrected] without coronary stenosis or spasm, 22 showed normal BMIPP SPECT (specificity = 92%) [corrected] and 23 showed normal tetrofosmin SPECT (sensitivity = 96%) [corrected]. Coronary stenosis was more often seen in the group with abnormal tetrofosmin/abnormal BMIPP (82%) and with normal tetrofosmin/abnormal BMIPP (69%) than in the group with normal tetrofosmin/normal BMIPP (36%) (p < 0.05). Coronary spasm was observed more often in the group with abnormal tetrofosmin/abnormal BMIPP (83%) and with normal tetrofosmin/abnormal BMIPP (90%) than in the group with normal tetrofosmin/normal BMIPP (27%) (p < 0.05). The extent and severity scores of tetrofosmin and BMIPP in the patients with organic stenosis were significantly higher than those of patients with no organic stenosis or spasm (p < 0.0001). CONCLUSIONS These data indicate that BMIPP SPECT may specifically identify previous ischemic lesions due to coronary stenosis or spasm in patients with acute chest pain.

Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)

AIMS Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension. METHODS AND RESULTS The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group (P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL. CONCLUSIONS In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

Acute and chronic effects of verapamil in patients with paroxysmal supraventricular tachycardia.

Efficacy of acute intravenous verapamil, 10 mg, and chronic oral verapamil, 320 mg, daily were studied electrophysiologically in 15 patients with paroxysmal supraventricular tachycardia (PSVT). Plasma verapamil concentrations were measured concurrently. Both intravenous and oral verapamil significantly increased the AV node conduction time, the cycle length producing a Wenckebach period, and the refractory period of the AV node. These changes were reflected in changes in plasma verapamil concentration. The echo zone and the supraventricular tachycardia (SVT) zone markedly narrowed after administration of both intravenous and chronic oral verapamil. Verapamils efficacy was found to be related to the type of SVT. For instance, verapamil was more effective in SVT due to AV nodal re-entry than in SVT due to concealed accessory pathway. Fourteen patients were followed from 3 to 31 months and all except one were well controlled. In conclusion, verapamil was effective in prophylaxis of paroxysmal SVT.

Investigation of gastric and duodenal mucosal defects caused by low-dose aspirin in patients with ischemic heart disease.

Background Low-dose aspirin is used for secondary prevention of ischemic heart disease and ischemic cerebrovascular disease. Currently, the frequency of gastrointestinal disorder among usersof low-dose aspirin is unknown. Aims To investigate through endoscopic examination the frequency of gastroduodenal disorder associated with buffered and enteric-coated aspirin (ECA). Methods Screening upper endoscopic examinations were prospectively performed on 236 patients with ischemic heart disease. Endoscopic findings including ulcers and flat erosions were assessed as mucosal defects. Results Mucosal defects were found in 92 of 190 (48.4%) users of low-dose aspirin and 6 of 46 (13.0%) nonusers. There were significantly more mucosal defects among users of low-dose aspirin than among those using no aspirin (P<0.0001). Mucosal defects were found in 54 of 98 (60.7%) users of buffered aspirin (BA), whereas 38 of 101 (37.6%) users of ECA had mucosal defects. Users of ECA had significantly fewer erosions than did those of BA (P=0.0015). The frequency of ulcer is similar between BA users and ECA users. Conclusions As endoscopy frequently reveals gastroduodenal disorder among low-dose aspirin users, both administration of BA and of enteric-coated aspirin warrant concern for gastroduodenal ulcer.

Endoscopic survey of low-dose-aspirin-induced gastroduodenal mucosal injuries in patients with ischemic heart disease.

Background and Aim:  Low‐dose aspirin is effective for the prevention of cardiovascular and cerebrovascular events, but the frequency of gastrointestinal injuries among users of low‐dose aspirin in Japan is currently unknown. In the present study endoscopic examination was performed to investigate the frequency of gastroduodenal injuries associated with low‐dose aspirin in patients with ischemic heart disease (IHD).

Pleomorphic ventricular tachycardia originating from Purkinje fiber network of left anterior fascicle

A 55-year-old woman with recurrent syncope and palpitation experienced polymorphic ventricular tachycardia (VT) and more than 3 monomorphic VTs with a right bundle branch block configuration as inferior, middle, and superior axis. During the pleomorphic VT, the diastolic potential (dp) was recorded at the anterolateral left ventricle. Changes in the QRS morphology were associated with the time between dp and onset of QRS complex (dp-V interval), and prolongation of dp-V interval terminated the VT. In addition, the delayed potentials were seen during sinus rhythm around this area. Delivery of radiofrequency current targeting the delayed potentials abolished all the VTs. Different exits from relatively large area of slow conduction in the left anterior fascicle might have produced the pleomorphic VTs.

Positional Ventricular Tachycardia

A 60‐year‐old man showed nonsustained repetitive monomorphic VT in the left lateral position, but this was terminated by deep inspiration. Echocardiography and MRI demonstrated a false tendon extending from the apex to the basal septum where the VT could have originated. Spontaneous remission occurred during the16‐year follow‐up.

Diastolic potentials in verapamil-sensitive ventricular tachycardia : True potentials or bystanders of the reentry circuits?

BACKGROUND Diastolic potentials (DP) are reported to be recorded in intracardiac electrograms during verapamil-sensitive ventricular tachycardia (VT) in which QRS complexes show complete right bundle branch block with a superior axis. The purpose of this study was to ascertain whether the DP recorded in the endocardial mapping during VT reflects the activation of the VT circuit. METHODS AND RESULTS The study group consisted of 16 men and 2 women. The earliest activation site (EA site) was determined and the DP was recorded in the endocardial mapping during VT. We evaluated the response of the cycle length of VT, the interval between the ventricular activation and the DP (V-DP), and the interval between the DP and the ventricular activation (DP-V) to intravenous verapamil. Radiofrequency current was delivered to the EA site, the site where the DP was recorded, and the site where the DP and the Purkinje fiber potential of the left bundle branch (LB) were simultaneously recorded. In 15 patients, the DP was recorded in the wide posterior fascicle region of the LB. After verapamil, the cycle length of VT, the V-DP, and the DP-V were prolonged from 365 +/- 53 to 490 +/- 65, 315 +/- 30 to 368 +/- 30, and 50 +/- 27 to 123 +/- 36 ms, respectively, in 6 patients. The LB was recorded in all patients and the DP was recorded preceding the LB in 12 patients. VT was successfully ablated at the site where the DP and the LB were simultaneously recorded in all these patients. Ablation at the other sites failed. CONCLUSIONS Radiofrequency ablation at the site where the DP was simultaneously recorded preceding the LB completely abolished the verapamil-sensitive VT. The DP recorded with the LB simultaneously might reflect the slow conduction zone activity of the reentry circuit located within the Purkinje fiber network.

Regional Differences in Frequency of Warfarin Therapy and Thromboembolism in Japanese Patients With Non-Valvular Atrial Fibrillation – Analysis of the J-RHYTHM Registry –

BACKGROUND The proportion of patients with atrial fibrillation (AF) treated with anticoagulation varies from country to country. In Japan, little is known about regional differences in frequency of warfarin use or prognosis among patients with non-valvular AF (NVAF). METHODSANDRESULTS In J-RHYTHM Registry, the number of patients recruited from each of 10 geographic regions of Japan was based on region population density. A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, significant differences in various clinical characteristics including age, sex, type of AF, comorbidity, and CHADS2score, were detected among the regions. The highest mean CHADS2score was recorded in Shikoku. Frequency of warfarin use differed between the regions (P<0.001), with lower frequencies observed in Hokkaido and Shikoku. Baseline prothrombin time international normalized ratio differed slightly but significantly between the regions (P<0.05). On univariate analysis, frequency of thromboembolic events differed among the regions (P<0.001), with the highest rate seen in Shikoku. An inverse correlation was detected between frequency of thromboembolic and of major hemorrhagic events (P=0.062). On multivariate analysis, region emerged as an independent risk for thromboembolism. CONCLUSIONS Thromboembolic risk, frequency of warfarin use, and intensity and quality of warfarin treatment differed significantly between geographic regions of Japan. Region was found to be an independent predictor of thromboembolic events. (Circ J 2016; 80: 1548-1555).