Yoshio Arakaki

Effects of verapamil and propranolol on early afterdepolarizations and ventricular arrhythmias induced by epinephrine in congenital long QT syndrome

OBJECTIVES This study used monophasic action potentials to investigate the effects of verapamil and propranolol on epinephrine-induced repolarization abnormalities in congenital long QT syndrome. BACKGROUND Early afterdepolarizations have been suggested to play a significant role in QT prolongation and ventricular arrhythmias in congenital long QT syndrome. Calcium channel blocking as well as beta-adrenergic blocking agents are reported to be effective in the management of this syndrome. METHODS Monophasic action potentials from 2 to 4 sites were recorded simultaneously in eight patients with the long QT syndrome (22 sites) and in eight control patients (23 sites) and were obtained during constant atrial pacing 1) before epinephrine infusion; 2) during epinephrine infusion (0.1 microgram/kg body weight min); 3) after verapamil injection (0.1 mg/kg) during epinephrine infusion; and 4) after both propranolol (0.1 mg/kg) and verapamil injections. RESULTS Early afterdepolarizations were recorded in two of the eight patients (2 of 22 sites) during the control state. During epinephrine infusion, early afterdepolarizations were recorded in six patients (six sites), and ventricular premature complexes were induced in three and torsade de pointes in one. Epinephrine prolonged 90% monophasic action potential duration from 348 +/- 48 (mean +/- SD) to 381 +/- 49 ms (22 sites, p < 0.0005) and increased the dispersion of action potential duration (difference between the longest and shortest action potential duration) from 36 +/- 20 to 64 +/- 34 ms (p < 0.005). Verapamil eliminated (two sites) or reduced (four sites) early afterdepolarizations and abolished ventricular premature complexes in two of the three patients as well as suppressing torsade de pointes. Verapamil shortened the action potential duration to 355 +/- 28 ms (p < 0.01 vs. epinephrine) and decreased the dispersion to 44 +/- 19 ms (p < 0.05 vs. epinephrine). Propranolol further eliminated (two sites) or reduced (two sites) early after depolarizations, abolished ventricular premature complexes in the remaining one patient and further shortened the action potential duration to 337 +/- 32 ms (p = 0.09 vs. verapamil). In the control patients, none of the early afterdepolarizations, ventricular arrhythmias or marked prolongations of action potential duration were induced by epinephrine, and neither verapamil nor propranolol changed repolarization variables. CONCLUSIONS These results indicate that both verapamil and propranolol can improve repolarization abnormalities induced by epinephrine in congenital long QT syndrome.

Functional behavior and morphology of the coronary artery wall in patients with Kawasaki disease assessed by intravascular ultrasound

OBJECTIVES To examine the development of coronary artery lesions in Kawasaki disease, we assessed the functional behavior and morphology of coronary arteries by intravascular ultrasound. BACKGROUND Long-term follow-up studies of patients with Kawasaki disease have demonstrated the development of localized coronary stenoses even after aneurysms have regressed. It is also possible that angiographically normal coronary segments in patients with this disease may retain histologic changes. METHODS Twenty-three patients followed up by serial coronary angiography were examined at a mean age +/- SD of 14.9 +/- 2.9 years. The thickness of the intima-media complex was measured by intravascular ultrasound (30 MHz; 3.5 or 4.3 F; 1,800 rpm). Coronary reactivity to nitroglycerin was determined by measuring percent changes in cross-sectional coronary artery area after intracoronary injection (7 microgram/kg body weight) of this agent. RESULTS A remarkably thickened intima-media complex was observed at the sites with persisting (0.54 +/- 0.20 mm, n = 19) and regressed (0.84 +/- 0.40 mm, n = 23) aneurysms. Mild thickening of the intima-media complex was often observed even in angiographically normal segments (0.22 +/- 0.05 mm, n = 31), in the left main coronary artery (0.47 +/- 0.15 mm, n = 20) and at normal branches (0.36 +/- 0.09 mm, n = 13). Coronary reactivity to nitroglycerin was significantly lower at the sites of regressed aneurysms (12.8 +/- 6.6%, n = 9) than in normal segments (32.8 +/- 10.9%, n = 13, p < 0.01), indicating the presence of functional impairment at the sites with regressed aneurysms. Decreased nitroglycerin reactivity was also observed in some segments without evidence of aneurysm. CONCLUSIONS These results indicate that in patients with Kawasaki disease the coronary disease accompanying impaired reactivity to nitroglycerin is present at the sites of regressed aneurysms as well as in angiographically normal coronary segments. We suggest that these sites with morphologic and functional abnormalities are related to the development of significant stenosis.

Heart rate recovery after exercise and cardiac autonomic nervous activity in children.

To investigate the difference in heart rate (HR) recovery after exercise between children and young adults, we administered a constant load of light exercise intensity and progressive treadmill exercise tests to nine children (aged 9 to 12 y, group A) and eight young adults (six male and two female, aged 17 to 21 y, group B) who had a history of Kawasaki disease without significant coronary arterial lesions. HR after both exercise protocols was analyzed. The low-frequency (LF) and high-frequency (HF) components of HR variability were measured, and LF/HF was calculated (log LF, log HF, log L/H). Arterial baroreflex sensitivity was assessed by the phenylephrine method. There were no differences between groups A and B in resting HR, peak HR, peak oxygen uptake, and decreases in systolic blood pressure during the recovery period. HR 1 and 2 min after peak exercise and 1 min after constant-load exercise was significantly lower in group A than in group B (p < 0.05), and the changes in HR from peak values after both exercise tests were also greater in group A than in group B (p < 0.05–0.01). Although no difference in arterial baroreflex sensitivity was observed, log HF was significantly higher in group A than in group B (p < 0.01), and log L/H was significantly lower in group A than in group B (p < 0.05). The value of log HF correlated inversely with the decrease in HR immediately after both exercise protocols (p < 0.05–0.01). Although log L/H correlated with the decrease in HR after peak exercise (p < 0.05–0.0005), the early decline in HR after constant-load exercise did not correlate with log L/H. Arterial baroreflex sensitivity did not correlate with the decrease in HR at any recovery time. These data suggest that the early phase of HR recovery after light to severe exercise is influenced by the cardiac parasympathetic nervous activity at rest and that the greater central cholinergic modulation of HR in children than in young adults may be responsible in part for childrens faster HR recovery after exercise.

Fate of coronary arterial aneurysms in Kawasaki disease

Abstract It has recently become clear that significant and progressive localized stenoses often appear >8 years after the onset of Kawasaki disease, even after regression of aneurysms. 1 If the fate of aneurysms could be predicted from an early stage of the disease, this information would be invaluable in choosing the appropriate long-term follow-up schedule for each individual patient. In an attempt to provide this information, we have measured the maximal diameter of the largest aneurysm and the total length of the aneurysms on each coronary artery in a group of patients with Kawasaki disease and then charted the findings according to the subsequent outcome of the lesions.

Coagulation profile, hepatic function, and hemodynamics following Fontan-type operations.

We analyzed retrospectively the relationship between coagulation profile, and either hepatic function or hemodynamics, in patients who had undergone a Fontan-type procedure, comparing them, first, with a control group of 12 patients without significant hemodynamic abnormality, and, second, with a group of 14 patients who had not undergone a Fontan procedure, but whose mean right atrial pressure exceeded 8 mmHg. Follow-up catheterization had been performed in all 30 patients submitted to the Fontan-type operation. Prothrombin time, and factor XIII, were significantly lower in those who had undergone the Fontan procedure than in the other groups. Those submitted to the Fontan operation also had lower levels of protein C than controls, and their levels of plasminogen were lower than the patients with high right atrial pressure. Both aspartate aminotransferase and alanine aminotransferase were higher in those undergoing the Fontan procedure than in the other groups, while gamma-glutamyltranspeptidase in these patients was higher than in the control group. Mean right atrial pressure was highest in those undergoing the Fontan procedure, while cardiac index was lowest. Prothrombin time was correlated to some extent with aspartate aminotransferase, mean right atrial pressure, and cardiac index. Protein C correlated with both aspartate aminotransferase and mean right atrial pressure, while factor XIII correlated with alanine aminotransferase, mean right atrial pressure, and cardiac index. Aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase, parameters of hepatic function, correlated significantly with mean right atrial pressure. In those who had undergone the Fontan procedure, decreased synthesis of pro-and anti-coagulant factors is a risk factor for both thrombosis and bleeding. Abnormal hemodynamics, in the absence of a right sided pumping chamber, may predispose to subclinical hepatic dysfunction, leading to selective disturbances of protein synthesis.

Changes in causes of sudden deaths by decade in patients with coronary arterial lesions due to Kawasaki disease

Over a 25-year period, we encountered 12 patients who died suddenly with coronary arterial lesions due to Kawasaki disease. We report their clinical course, and analyze the happenings of their deaths. Of the 12 patients, 10 were dead on arrival at hospital. Their age at death ranged from 13 months to 27 years, with a median of 16 years, and the interval from the onset of Kawasaki disease to death ranged from 2 months to 24 years. In 4 patients, death was found to be due to myocardial infarction, while in the remaining 8, it could not be determined. In 7 patients, coronary angiograms obtained less than 4 months after the acute onset of Kawasaki disease showed lesions bilaterally, most being giant aneurysms. Myocardial infarction had occurred in 6 patients prior to their death. In 1 patient of the late 1970s, who collapsed after running, cardiac sequels had not been suspected prior to autopsy. During the 1980s, 3 infants with bilateral giant aneurysms died within a year of the initial onset of Kawasaki disease, with acute myocardial infarction being the cause in 2 of them. In the late 1990s, and the 2000s, 5 patients died suddenly with left ventricular dysfunction, their ejection fractions being less than 40 percent more than 20 years after the initial onset of Kawasaki disease. Prior to their sudden deaths, they had had no cardiac events for many years, but had suffered previous myocardial infarctions. Multifocal premature ventricular contractions, and non-sustained ventricular tachycardia, are probable risk factors in such patients. Careful follow-up, checking for ventricular arrhythmia, is needed to prevent sudden death in patients suffering left ventricular dysfunction in the setting of Kawasaki disease.

Comparison of the right and left ventricle as a systemic ventricle during exercise in patients with congenital heart disease.

BACKGROUND Few studies have investigated the clinical advantages of surgical correction with the morphologic left ventricle (MLV) instead of the morphologic right ventricle as a systemic ventricle (SV) in patients with congenital heart disease. METHODS Twenty-four healthy control subjects (group A1), 6 patients with isolated congenitally corrected transposition of the great arteries (TGA) (group A2), 16 patients with TGA who had undergone an arterial switch operation (group B1), 18 patients with TGA who had undergone a venous switch operation (group B2), 9 patients with atrioventricular and ventriculoarterial discordance who had undergone a double switch operation (group C1), and 6 patients with atrioventricular and ventriculoarterial discordance who had undergone a conventional external conduit operation from the MLV to the pulmonary artery (group C2), performed treadmill exercise testing. Their heart rate (HR), oxygen uptake (VO2), and oxygen pulse (O2 pulse), which reflects individual stroke volume, were measured, and contractile function was assessed by echocardiography. RESULTS The peak HR for the patients after a definitive operation were significantly lower than that in group A1 and was correlated with peak VO2 (r =.67, P <.0001). The peak VO2 and peak O2 pulse for the groups A2 and B2 were significantly lower than those for the groups A1 and B1, respectively. The peak O2 pulse data were strongly correlated with those of peak VO 2 (r = 0.91, P <.0001). The left ventricular ejection fraction was significantly lower in groups B1 and C1 than in group A1 and was correlated with peak VO 2 (r =.50, P <.01). No significant differences in VO2, HR, and O 2 pulse at peak exercise were observed between groups C1 and C2. CONCLUSIONS Chronotropic incompetence and an impaired response of the stroke volume of the MRV during exercise are partly responsible for the reduced exercise capacity in groups A2 and B2 compared with groups with the MLV as an SV, and the SV function at rest is also related to exercise capacity. Superiority of the double-switch operation compared with the conventional conduit operation was not observed. A longer-term follow-up is necessary before the advantages of these 2 operations can be compared.

Abnormal Cardiac Autonomic Nervous Activity After Right Ventricular Outflow Tract Reconstruction

BackgroundThere are few studies of cardiac autonomic nervous activity (CANA) in patients with congenital heart disease. Methods and ResultsWe evaluated CANA in 54 patients after closure of an atrial/ventricular septal defect (group A), 54 patients after successful right ventricular outflow tract reconstruction (RVOTR) (group B1), 35 RVOTR patients with residual stenosis (group B2), and 47 controls. Cardiac parasympathetic nervous activity (PSNA) was estimated by heart rate (HR) change after cholinergic blockade, HR variability, and arterial baroreflex sensitivity (BRS). Cardiac sympathetic nervous activity was estimated by the heart-to-mediastinum 123I-metaiodobenzylguanidine activity ratio (H/M) and HR increase after isoproterenol infusion (&bgr;). HR response (&Dgr;HR) and peak oxygen uptake (&OV0312;o2) were measured by exercise test. There was no difference in &bgr; among study groups. Group A exhibited mildly impaired PSNA, which recovered 1 year after surgery, and no change in H/M. Impaired PSNA and low H/M were found in groups B1 and B2 compared with controls (P <0.001), although the PSNA tended to recover 1 year after re-RVOTR. In group B1, PSNA and &bgr; were related to &Dgr;HR, and BRS correlated inversely with the number of surgical procedures and age at RVOTR and positively correlated with the follow-up period, whereas &Dgr;HR correlated with peak &OV0312;o2 (P <0.01 to 0.001). ConclusionsAfter RVOTR, postsynaptic &bgr;-sensitivity is maintained and is important in &Dgr;HR during exercise, as is PSNA, although ventricular sympathetic denervation is common. Impaired PSNA immediately after RVOTR improves with improved &Dgr;HR and results in future amelioration of aerobic capacity, whereas ventricular sympathetic reinnervation is uncertain.

Evolution of aortic regurgitation following simple patch closure of doubly committed subarterial ventricular septal defect

We reviewed the Doppler echocardiographic findings of the aortic valve and associated aortic regurgitation (AR) in 55 patients who underwent patch closure of doubly committed subarterial ventricular septal defect (VSD). The maximal diameter of the VSD measured > or = 5 mm, whereas the postoperative follow-up interval was > or = 5 years. Twenty-three patients underwent closure before they developed aortic cusp prolapse or AR (group A). In 15 patients the VSD was closed when aortic cusp prolapse was recognized, but AR was absent (group B). Aortic cusp prolapse with AR was detected before closure in a further 15 patients (group C). Of 8 patients with no AR before closure, AR was detected during follow-up in 6 group A and in 2 group B patients. In group C, AR resolved after surgery in 4 patients, whereas AR grade improved in a further 8 patients and remained unchanged in 3. Although residual AR was more frequent in patients with aortic cusp prolapse and AR before closure, it was silent and asymptomatic.

Abnormal Response to Exercise, Face Immersion, and Isoproterenol in Children with the Long QT Syndrome

The present study was performed to observe the change of QT interval by sympathetic stimulations in patients with the long QT syndrome (LQTS). The study group consisted of 6 children with LQTS and 6 healthy children without QT prolongation. All LQTS patients had syncopal episodes. The QTc and ΔQTc% ([QTC interval after examination ‐ QTc interval at rest]/QTc interval at rest × 100) by treadmill testing, face immersion, and isoproterenol were examined. One minute after peak exercise of treadmill testing, the changes in the QTr, interval were not significant in either group, but ΔQTC% was larger in the LQTS group than in the control group (+ 11.0 ± 12.1% vs ‐2.6 ± 3.2%;P= 0.02). The QTc interval at the shortest RR interval during face immersion was prolonged in the LQTS group (0.47 ± 0.01 s to 0.51 ± 0.04 s; P = 0.02), but there were no significant changes in the control group (0.40 ± 0.03 s to 0.41 ± 0.03 s; P = NS). ΔQTC% was larger in the LQTS group than in the control group (+ 10.0 ± 7.3% vs +1.1 ± 5.5%; P = 0.04). In the LQTS group, the RR interval was shortened (P = 0.009) and QTc interval was prolonged (P = 0.0008) after isoproterenol infusion. These sympathetic stimulations amplified the TU abnormality in the LQTS group. By observing the TU changes caused by face immersion, we hoped to find a possible new method with which to diagnose LQTS. The combination of these examinations may be helpful in screening the borderline cases of TU abnormalities.