One of the main mechanisms for dilated cardiomyopathy is likely to be autoimmune mediated myocardial damage. So far, a variety of autoantibodies have been detected against a number of putative autoantigens in the sera of patients with dilated cardiomyopathy. A growing body of studies have confirmed that autoantibodies against the second extracellular loop of β₁-adrenoceptors and M2-muscarinic receptor are present in 30-40% of patients with dilated cardiomyopathy. These anti-β₁-adrenoceptor and anti-M2-muscarinic receptor antibodies can not only decrease the binding sites of antagonist but also recognize the target receptors. Moreover, these two autoantibodies possess an 'agonist-like' stimulatoty effect on the target receptors. In order to elucidate whether the autoantibodies against these autoimmune epitopes play an important role in the pathogenesis of dilated cardiomyopathy, we immunized rabbits over a period of one year with synthetic peptides corresponding to the second extracellular loop of the β₁-adrenoceptor and the M2-muscarinic receptor. These peptides induced morphological changes in the heart similar to those found in dilated cardiomyopathy. These clinical and experimental findings suggest that these receptor autoantigens are of pathogenic importance in the development of dilated cardiomyopathy in vivo.

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Ischemic myocardium avidly incorporates fluorine-18 fluorodeoxyglucose (F-18 FDG) in the fasting state, in contrast to the relative absence of F-18 FDG uptake in normal myocardium with sufficient blood flow in the fasting state. Although many studies have attempted to use F-18 FDG uptake to discriminate ischemic but viable myocardium from scarred myocardium, little is known clinically about the correlation between blood flow and F-18 FDG uptake in ischemic myocardium. We studied the critical level of blood flow that causes avid F-18 FDG uptake in myocardium in 9 patients. All patients had angiographically proven ischemic heart disease but no diabetes. Regional myocardial blood flow (RMBF) was measured quantitatively by positron emission tomography (PET) using nitrogen-13 ammonia in the resting state, in which the normal value was 80.2±13.0ml/min/100cm³. The F-18 FDG uptake in myocardium was assessed with the differential uptake ratio (DUR) scale. We constructed circumferential profiles of radioactivity uptake in myocardium for each study, and chose 780 sections of myocardium in which the relation between the two factors could be analyzed. In moderately ischemic to normal myocardium with RMBF of 50 to 90l/min/100cm³, RMBF and F-18 FDG uptake were negatively correlated (r=-0.44, p<0.01). When RMBF was 50 to 60ml/min/100cm³ (n=121), the peak DUR value of F-18 FDG uptake was 4.0±2.0. The two factors were not correlated when RMBF was less than 50ml/min/100cm³ or 90ml/min/100cm³ or higher. Our results suggest that RMBF and F-18 FDG uptake values as measured with PET may provide valuable information on the possible benefit of intervention in ischemic heart disease.

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Atrial flutter is a rare arrhythmia in the neonate and early infancy. We retrospectively reviewed the clinical presentations, treatment and outcome of seven patients who presented clinically with atrial flutter. The age of onset ranged from 1 day to 3 months. Atrial flutter was diagnosed in the first 3 days of life in 4. Three cases presented as atrial flutter with 2:1 atrioventricular conduction and the remaining 4 with variable AV block. Heart failure was present in 3 patients and 6 patients showed normal intracardiac structure on echocardiography.
Electrical cardioversion was attempted as the first treatment in 4 cases, followed by digoxin in three of the four. Digoxin was given as an initial therapy in 2 patients. One patient recovered spontaneously without treatment. In the 6 patients who received therapy, 5 converted to normal sinus rhythm within 2 days. The remaining patient had ventricular ectopic beats for about 4 months. Only 2 cases were maintained on oral digoxin for at least 4 months after discharge. No patient had a recurrence of atrial flutter during the follow-up period which ranged from 6 months to 7 years.
We conclude that there is a good long-term prognosis for atrial flutter in the neonate. Digoxin and DC cardioversion may be effective as initial therapy. Long-term digoxin prophylaxis after conversion to sinus rhythm may be not necessary.

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The effects of intravenous MS-551, a new class III antiarrhythmic drug, on atrium and ventricle were evaluated in 6 patients with ventricular tachyarrhythmias (4 males and 2 females; mean age 45±21 years) in an electrophysiologic study. Two patients had sustained ventricular tachycardia (VT) and 4 patients had ventricular fibrillation (VF). Electrophysiologic study was performed before and after the administration of MS-551 (loading infusion 0.3mg/kg for 5min+0.01mg/kg/min).
The QT and QTc intervals were significantly prolonged by MS-551 from 359±52 to 411±63 msec (p=0.01) and from 410±36 to 452±47 (p=0.0172), respectively. No effect was observed on the sinus cycle length, QRS duration, or AH and HV intervals in sinus rhythm.
The effective refractory periods of the right atrium (AERP) were significantly prolonged at paced cycle lengths of 600 (from 222±19 to 250±23 msec, p=0.0009), 400 (from 207±15 to 228±15, p<0.0001) and 300 (from 193±10 to 205±8 msec, p=0.0127) msec. Similarly, the right ventricular ERP (VERP) were significantly prolonged at paced cycle lengths of 600 (from 240±23 to 268±23 msec, p<0.0001), 400 (from 225±22 to 250±24 msec, p=0.0007), and 300 msec (from 213±14 to 228±18 msec, p=0.0071). MS-551 prolonged AERP and VERP in a "reverse" use-dependent manner without changing the conduction time in patients with ventricular tachyarrhythmias.
MS-551 prevented the induction of VT in 1 patient and VF in only 1 patient in this electrophysiologic study. Further evaluation of the therapeutic potential of MS-551 using higher dosages is necessary.

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Electrophysiologic testing was performed in 31 patients with ventricular tachycardia (21 cases) and fibrillation (10 cases) to characterize the electrophysiologic properties of patients responding or not responding to therapy with class III antiarrhythmic drugs.
At the baseline, there were no differences among the patients in the monomorphic VT cycle length (CL), block CL or the width of the zone of entrainment. Ventricular tachyarrhythmias after the administration of class III drugs (sotalol: 9, amiodarone: 15 and E-4031/MS-551: 7) were inducible (non-responders) in 17 patients and non-inducible (responders) in 14 (45%).
The class III drugs prolonged the sinus cycle length (SCL), QT interval and right ventricular effective refractory period (VERP), but had little effect on ventricular conduction time in the responders and non-responders. The SCL, QT interval and VERP at the three drive cycle lengths of 600, 400 and 300 msec were significantly longer in the responders than in the non-responders, but the class III drug action on VERP showed a reverse use-dependency.
Isoproterenol administered to the responder did not fully reverse the class III antiarrhythmic drug-induced prolongation of QT, QTc and VERP, which remained significantly prolonged compared to the baseline values. Furthermore, when the VERP after the administration of class III drugs were greater than 270, 250 and 240 msec at the three drive cycle lengths of 600, 400 and 300 msec, respectively, it was associated with the non-inducibility of VT/VF.
Though the precise mechanism of the drug efficacy is not yet known, these observations help to clarify the ability of class III drugs to prevent the induction of ventricular tachyarrhythmia.

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The aim of this work was to study the prevalence of Q-T prolongation in patients with liver cirrhosis and the modifications of the Q-T interval after liver transplantation. Q-T interval corrected for heart rate (QT_c) and dispersion of Q-T interval were evaluated in 75 cirrhotic patients and in 24 controls by means of a 12-lead electrocardiogram. In addition, 15 patients were evaluated before and after liver transplantation. Forty-five patients (60%) had a prolonged Q-T_c. Compared with controls, both patients with alcoholic and non alcoholic cirrhosis had increased Q-T_c (414±28 msec^1/2, 463±31 and 444±32 respectively; p<0.001 and <0.001); Q-T_c was significantly higher in alcoholic than in non-alcoholic cirrhosis (p<0.02). Q-T dispersion was normal in cirrhotics. No correlation was found between Q-T_c interval and severity of the cirrhosis, haemodynamic variables (stroke volume, cardiac output) and s-calcium and potassium concentrations. After transplantation, Q-T_c decreased significantly (415±26 msec_1/2 vs 449±31; p<0.0001) returning to the values of the normal subjects, but no modification of the Q-T dispersion was observed. These data show that 1) prolongation of Q-T interval is frequent in cirrhosis, being higher in alcoholic than in non-alcoholic cirrhosis, 2) is not related to the severity of the disease, and 3) is reversible after transplantation.

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We studied the differences between isosorbide dinitrate (ISDN) and L-arginine (L-Arg), the precursor of nitric oxide, regarding autonomic nervous function by assessing changes in heart rate variability and blood levels of various vasoactive substances.
Healthy volunteers received infused L-arginine (L-Arg group) or isosorbide dinitrate (ISDN group). ECGs were monitored and analyzed. Blood levels of catecholamines, endothelin, renin activity, angiotensin, human atrial natriuretic peptide, aldosterone, arginine, and citrulline were examined. Timedomain analyses of heart rate variability showed no significant changes in occurrence of R-R variability or coefficient of R-R variability, indicators of parasympathetic activity, after administration of ISDN. By contrast, both measures showed significantly more variation following administration of L-Arg. Frequency-domain analyses showed that high frequency power, an indicator of parasympathetic activity, was significantly elevated in the L-Arg group, whereas there was no significant change in the ISDN group. The blood levels of the measured vasoactive substances in L-Arg and ISDN groups were significantly different.
The differences in autonomic nervous function and various kinds of vasoactive substances between the L-Arg and ISDN groups suggest that L-Arg had other actions on humoral factors in addition to vasodilation. Thus, arginine/nitric oxide may act as a neurotransmitter, altering parasympathetic nervous tension.

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To evaluate the effect of tricuspid annuloplasty (TAP) on right heart flow dynamics, we analyzed tricuspid inflow velocity pattern, jugular venous pulse and color Doppler flow signal of tricuspid regurgitation (TR) before and after surgery in 16 patients who underwent TAP (TAP group). Cardiac rhythm was atrial fibrillation in all patients. Twelve patients with lone atrial fibrillation served as controls (AF group). Patients in the TAP group were studied before and serially after surgery with a mean follow-up period of 2.7 years. TAP was performed according to the modified De Vega technique in all patients. In a comparison of the most recent data in the TAP group and the data in the AF group, the maximum tricuspid inflow velocity was significantly increased, and both the deceleration time of the tricuspid inflow velocity wave and the y-h interval of the jugular venous pulse were significantly prolonged in the TAP group compared to the AF group. Immediately after surgery, in the TAP group, the area of the TR jet was markedly decreased, and the deceleration time of the tricuspid inflow velocity wave was significantly prolonged compared to those before surgery. The area of the TR jet was dramatically decreased and remained small during the follow-up period. Thus, TAP may produce mild tricuspid stenosis but may also confer sustained preventive effects against TR.

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The study was designed to investigate whether the acute antihypertensive effects of calcium channel blockers are affected by calcium supplementation in patients with essential hypertension. The antihypertensive effects of calcium channel blockers (oral manidipine or intravenous nicardipine) were studied before and during calcium supplementation (1200mg/day for 8 weeks) in 30 hospitalized patients with essential hypertension. The averages of systolic and diastolic blood pressure during a 24-hour period were not decreased by calcium supplementation. The acute antihypertensive effects of the calcium channel blockers nicardipine (0.25, 0.5, 1.5, 2.0μg/kg/min, intravenous infusion) or manidipine (20mg, once a day, orally) were not enhanced by calcium supplementation. Thus, calcium channel blockers can be safely combined with calcium supplementation in terms of blood pressure.

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To clarify whether a circadian rhythm of peripheral resistance exists in humans and whether hypertensive patients represent a homogeneous category in this respect, 15 normotensives aged 31±4 years and 30 hypertensives aged 41±13 years were confined to bed for 22h and forearm flow recorded automatically. Night-time BP values were higher in hypertensive patients (Group B) whose night/day ratios of mean BP were below the 95% C. I. of the normal regression of the normotensives, than in those falling within the 95% C. I. (Group A). Forearm resistance was lower during sleep than during waking in Group A and in the normotensive controls, paralleling the nocturnal blood pressure fall. On the contrary, in the Group B hypertensives, despite a comparable night-time BP decrease, forearm resistance was higher during sleep than during waking.

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This study was undertaken to clarify the effects of nicorandil on electrophysiological changes during acute ischemia and following reperfusion. We prepared an acute ischemic heart model by ligating the left anterior descending coronary artery in 27 dogs. After 10 minutes, reperfusion was performed. The changes in ventricular effective refractory period (ERP) and intramyocardial conduction time (ICT) were compared between the nicorandil group (n=12) which received nicorandil intravenously before the coronary ligation and the control group (n=15). In the control group, the ERP was shortened during ischemia, and rapidly shortened immediately after reperfusion, but was slightly prolonged 10 minutes after reperfusion. The ICT was prolonged during ischemia, but returned to the pre-ischemia value after reperfusion. In the nicorandil group, the changes in ERP and ICT were significantly inhibited compared to those in the control group. The incidence of ventricular fibrillation (VF) during reperfusion was 42% in the control group. However, there was no VF during reperfusion in the nicorandil group. Therefore, nicorandil may correct both the delayed conduction and the uneven ventricular effective refractory period detected during acute ischemia and following reperfusion, inhibiting the development of ventricular arrhythmia during reperfusion.

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The purpose of this study was to examine left ventricular function and cardiac gene expressions at an acute phase after myocardial infarction (MI). MI was induced in rats by ligation of the left coronary artery. Two days after MI, we performed Doppler-echocardiography and measured the systolic and diastolic function. We then analyzed the contractile protein and extracellular matrix mRNAs of cardiac tissues in the infarcted region, including the adjacent noninfarcted myocardium (the adjacent noninfarcted myocardium) and the remote noninfarcted myocardium, by Northern blot hybridization. Fractional shortening decreased significantly to 28%. Peak early diastolic filling wave (E wave) velocity increased in MI rats (MI; 90±3cm/s versus the control; 71±2cm/s, p<0.05), and the deceleration rate of the E wave velocity was more rapid in MI rats (MI; 22.0±2.6m/s² versus the control; 16.5±2.0m/s², p<0.01). Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity (MI; 3.1±0.3 versus the control; 2.1±0.2, p<0.01). In the adjacent noninfarcted myocardium, mRNA levels for Α-skeletal actin, atrial natriuretic polypeptide (ANP), transforming growth factor-β1(TGF-β1), fibronectin, and collagen types I and III increased significantly. In the remote noninfarcted myocardium, mRNA levels for α-skeletal actin, ANP, and collagen types I and III increased, while mRNA levels for β-myosin heavy chain, TGF-β1 and fibronectin did not change. We observed left ventricular dysfunction and different gene expressions between adjacent noninfarcted myocardium and in the remote noninfarcted myocardium two days after MI. These findings suggest that cardiac gene expression after MI may be a compensation reaction for cardiac dysfunction induced by myocardial damage.

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Pilsicainide, a class Ic agent, is known to be an effective drug particularly for treating atrial tachyarrhythmias. However, its electrophysiological effects on the atrium have not been well studied. To characterize the electrophysiologic effects of pilsicainide on atrial myocytes in class Ic drugs, we examined the effects of this drug on membrane currents in single rabbit atrial myocytes using the tight-seal whole cell voltage-clamp technique. Under the current-clamp condition, pilsicainide did not affect the action potential duration at therapeutic ranges (_≤_3μM) and slightly shortened it at higher concentrations (_≥_10μM). These observations were quite different from those with other class Ic agents including flecainide and propafenone which prolong the atrial action potential duration. The drug did not affect the resting membrane potential. Under the voltage-clamp condition, pilsicainide inhibited the transient outward current (I_to) that is more prominent in the atrium than in the ventricle in a concentration-dependent manner. However, in contrast to other class Ic agents, the inhibition of I_to by pilsicainide was observed only at much higher concentrations (IC₅₀∼300μM) and did not affect the inactivation time-course of I_to. Moreover, the drug (10μM) did not significantly affect the Ca²⁺, delayed rectifier K⁺, inward rectifying K⁺, acetylcholine-induced K⁺ or ATP-sensitive K⁺ currents. From these results, pilsicainide could be differentiated as a pure Na⁺ channel blocker from other class Ic agents with diverse effects on membrane currents and should be recognized accordingly in clinical situations.

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We examined the efficacy and safety of ultrasound energy in eliminating the arrhythmogenic substrates of atrial as well as ventricular tissue using a newly developed instrument in both in vivo and in vitro experiments. Ultrasound (US) applicators were tested on 79 lesions created on a beating heart in canine cardiac tissue, and on 64 lesions in porcine heart specimens. US lesions were created by using transducers with frequencies around 5-10MHz. In the in vivo study, we observed a significant decrease in the amplitude of the electrograms recorded from the tip of the ablation catheter during the US application (p<0.01). In some sites transmural lesions could be created which were well demarcated. Blood coagulum formation was observed on the tip of the ablation catheter on several occasions. In one dog ventricular fibrillation was provoked by the delivery of ultrasound energy to the left ventricle. In the in vitro study, lesion depth increased significantly with a longer duration of energy delivery when the temperature was maintained stable (p<0.001), and the lesion depth increased significantly with higher temperatures of energy delivery when the duration of US application was maintained (p<0.05). In both cases, no significant change in surface area was observed. The maximum depth of the lesion was 10.3mm. Conclusions: An ultrasound energy system is relatively safe and effective for creating lesions large enough to eliminate arrhythmogenic substrates deep in the ventricular myocardium. Although the US system is free from pop phenomenon, the problem of blood coagulation on the catheter tip remains to be settled.

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