Naoki Gondo

Angiotensin II Antagonist Prevents Electrical Remodeling in Atrial Fibrillation

BACKGROUND The blockade of angiotensin II (Ang II) formation has protective effects on cardiovascular tissue; however, the role of Ang II in atrial electrical remodeling is unknown. The purpose of this study was to investigate the effects of candesartan and captopril on atrial electrical remodeling. METHODS AND RESULTS In 24 dogs, the atrial effective refractory period (AERP) was measured before, during, and after rapid atrial pacing. Rapid atrial pacing at 800 bpm was maintained for 180 minutes. The infusion of saline (n=8), candesartan (n=5), captopril (n=6), or Ang II (n=5) was initiated 30 minutes before rapid pacing and continued throughout the study. In the saline group, AERP was significantly shortened during rapid atrial pacing (from 149+/-11 to 132+/-16 ms, P<0.01). There was no significant difference in AERP shortening between the saline group and the Ang II group. However, in the candesartan and captopril groups, shortening of the AERP after rapid pacing was completely inhibited (from 142+/-9 to 147+/-12 ms with candesartan, from 153+/-15 to 153+/-14 ms with captopril, P=NS). Although rate adaptation of the AERP was lost in the saline group, this phenomenon was preserved in the candesartan and captopril groups. CONCLUSIONS The inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing. These results indicate for the first time that Ang II may be involved in the mechanism of atrial electrical remodeling and that the blockade of Ang II may lead to the better therapeutic management of human atrial fibrillation.

Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation

UNLABELLED The purpose of the present study was to evaluate the effect of angiotensin II type 1 receptor (AT1R) antagonist on chronic structural remodeling in atrial fibrillation (AF). BACKGROUND We previously reported that an AT1R antagonist, candesartan, prevents acute electrical remodeling in a rapid pacing model. However, the effect of candesartan on chronic structural remodeling in AF is unclear. METHODS Sustained AF was induced in 20 dogs (10 in a control group and 10 in a candesartan group) by rapid pacing of the right atrium (RA) at 400 beats/min for five weeks. Candesartan was administered orally (10 mg/kg/day) for one week before rapid pacing and was continued for five weeks. The AF duration, atrial effective refractory period (AERP) at four sites in the RA, and intra-atrial conduction time (CT) from the RA appendage to the other three sites were measured every week. RESULTS The mean AF duration in the control group after five weeks was significantly longer than that with candesartan (1,333 +/- 725 vs. 411 +/- 301 s, p < 0.01). The degree of AERP shortening after five weeks was not significantly different between the two groups. The CT from the RA appendage to the low RA after five weeks with candesartan was significantly shorter than that in the control (43 +/- 14 vs. 68 +/- 10 ms, p < 0.05). The candesartan group had a significantly lower percentage of interstitial fibrosis than the control group (7 +/- 2% vs. 16 +/- 1% at the RA appendage, p < 0.001). CONCLUSIONS Candesartan can prevent the promotion of AF by suppressing the development of structural remodeling.

Role of rapid focal activation in the maintenance of atrial fibrillation originating from the pulmonary veins.

Most episodes of focal atrial fibrillation (AF) can be initiated by premature beats originating from the pulmonary veins (PV). However, the role of rapid focal activation in the maintenance of AF is unclear. Thirty‐two patients with focal AF who underwent focal ablation of triggering ectopic beats were studied. Bipolar electrograms from all four PVs were recorded simultaneously. The cycle length (CL) of RFA at sites that triggered AF was measured at AF onset, after 5 minutes of sustained AF, and just before the spontaneous termination of 32 episodes of nonsustained AF. Fifteen episodes of sustained AF (> 10 minutes) and 17 episodes of nonsustained AF (5–120 seconds, mean 56 ± 59 seconds) were analyzed. In sustained AF, the mean CL of RFA in the PV from which it originated was not significantly different than in the other PVs, and RFA was continuously observed. In nonsustained AF, the mean CL of RFA in a PV from which it originated was significantly shorter than in other PVs and, when RFA disappeared, AF terminated. RFA in 1 PV induced RFA in another PV. In conclusion, widespread conduction of RFA from a PV at its source to the other sites may be necessary for the sustenance of AF. A PV interaction, a RFA triggering another, may be involved in the maintenance of AF. RFA arising from PVs is important not only as a trigger of onset, but also in the maintenance of AF.

Antiarrhythmic Effects of JTV-519, a Novel Cardioprotective Drug, on Atrial Fibrillation/Flutter in a Canine Sterile Pericarditis Model

Introduction: A new cardioprotective drug, JTV‐519, blocks Na+ current and inwardly rectifying K+ current and inhibits Ca2+ current. However, its role in atrial electrophysiology is unknown. We investigated the antiarrhythmic effects of JTV‐519 on atrial fibrillation/flutter in the canine sterile pericarditis model.

Treatment of mixed atrial fibrillation and typical atrial flutter by hybrid catheter ablation.

Successful isthmus ablation of typical atrial flutter mixed with atrial fibrillation (AF) may favorably modify the subsequent course of paroxysmal AF. However, the source of ectopic beats triggering AF may be located in the pulmonary veins (PV). This study compared the results of combined isthmus and focal ablation with ablation limited to the isthmus in patients with mixed AF and typical atrial flutter. Thirty patients with typical atrial flutter and AF were treated. Ablation limited to the isthmus was performed in 14 patients (group A), and 16 patients underwent focal ablation of triggering ectopic beats combined with isthmus ablation (group B). Successful linear ablation of the isthmus was accomplished in all patients. In group A, AF was eliminated in 4 patients (29%) after isthmus ablation. In group B, the origin of 26 foci triggering AF (1 focus in 38% of patients, 2 foci in 31 %, 3–4 foci in 31 %) was found in the PV in 93% (left superior: 46% left inferior: 21%, right superior: 25%) and the right atrium in 7% of instances. AF was eliminated in 11 patients (69%) after ablation of these foci. The success rate in group B was significantly higher than in group A (P < 0.05). In conclusion, in cases of mixed AF and typical atrial flutter, episodes of AF originated from PV foci in >90% of instances. These findings suggest that isthmus ablation combined with PV focal ablation may be effective in mixed AF and typical atrial flutter.

Wavelength index: a predictor of the response to disopyramide in paroxysmal lone atrial fibrillation.

We investigated whether the new parameter wavelength index could predict the response to chronic disopyramide therapy in patients with paroxysmal atrial fibrillation (AF). Twenty-seven patients with AF underwent electrophysiologic studies and the wavelength index was determined before and after intravenous administration of disopyramide. Then all patients were treated with oral disopyramide for 6 months. In 17 patients, AF was eliminated (group A), while it persisted in another 10 patients (group B). The ratio of the wavelength index before and after intravenous disopyramide was higher in group A than in group B. Thus, the wavelength index proved useful for predicting the response of AF to disopyramide.

New Technique for Simultaneous Catheter Mapping of Pulmonary Veins for Catheter Ablation in Focal Atrial Fibrillation

Introduction: Most focal atrial fibrillation (AF) can be triggered by premature beats from pulmonary veins (PVs), and ablation of these foci could cure AF. However, it is difficult to locate the trigger points of PVs using only one mapping catheter. The purpose of the present study was to investigate the efficacy of using four mapping catheters in four PVs simultaneously in the ablation of focal AF. Methods and Results: Thirty-two patients with frequent attacks of paroxysmal AF triggered by PV foci were included. After a transseptal procedure, three 2-french microcatheters and one 7-french catheter for ablation were placed into each of the PVs, and mapping of the four PVs was performed simultaneously. Fifty-eight foci were identified; 51 triggers (88%) originated from the PV and 7 (12%) from atrial tissue. The trigger points of AF were found in a single focus in 14 patients, in 2 foci in 12 patients, and in 3–4 foci in 6 patients. During a mean follow-up period of 10 ± 4 months, ablation eliminated AF without drugs in 86, 50 and 33% of the patients with 1, 2 and 3–4 targeted PVs, respectively; 20 patients (63%) were successfully ablated. Age, history of AF, the dimension of the left atrium and the number of focal origins were significant predictors of success. Conclusion: The technique of simultaneous mapping of PVs using quadruple catheters is a feasible and effective method for mapping the trigger points and ablation of focal AF originating from PVs.

Angiotensin II provokes cesium-induced ventricular tachyarrhythmias

OBJECTIVE The purpose of this study was to investigate whether angiotensin II provokes ventricular tachyarrhythmias and to clarify its mechanism using the cesium-induced arrhythmia model, which has been widely used as an afterdepolarization and triggered activity model. METHODS Eighteen adult mongrel dogs of either sex weighing 9.6-23.0 kg were studied. The dogs were randomly divided into three groups. In the control group (n=6), the subjects received intravenous saline solution at a 0.45 ml/kg/h, and intravenous bolus injections of cesium (0.25, 0.5, 1.0 mmol/kg) were given at 20-min intervals. In the captopril-treated group (n=6), captopril was administered intravenously at 15 microg/kg/min, and cesium was injected as above. After the infusion of only captopril, in the captopril-treated group, angiotensin II was simultaneously infused at a dose of 0.1 ng/kg/min, and cesium was injected as above. When the dog survived, the dose of angiotensin II was increased to 1.0 ng/kg/min, and the same procedure was repeated. The remaining six dogs were simultaneously infused with captopril (15 microg/kg/min), angiotensin II (1.0 ng/kg/min), and U-73122 (10 microg/kg/min), a selective phospholipase C blocker, and injected with cesium (1.0 mmol/kg). Forty minutes after termination of U-73122 infusion, the dogs were injected with the same dose of cesium. RESULTS Sustained ventricular tachycardia or ventricular fibrillation was induced by cesium in all of the dogs in the control group. In the captopril-treated group, none of the dogs showed these arrhythmias when only captopril was infused. The treatment of captopril significantly reduced lethal arrhythmias (P<0.01 vs. control group). During the simultaneous infusion of captopril and angiotensin II (0.1 ng/kg/min), cesium produced sustained ventricular tachycardia in all six dogs and the arrhythmia developed into ventricular fibrillation in three dogs. By increasing the dose of angiotensin II (1.0 ng/kg/min), the surviving three dogs died following induced ventricular fibrillation. The additional infusion of angiotensin II (0.1 and 1.0 ng/kg/min) significantly increased fatal arrhythmias (P<0.01 vs. only captopril- infused period, respectively). None of the dogs in the third group exhibited ventricular tachycardia during the infusion of U-73122, and ventricular fibrillations were recorded in all six dogs in the absence of U-73122. The treatment of U-73122 significantly reduced lethal arrhythmias. (P<0.01 vs. control period). CONCLUSIONS These results suggest that angiotensin II provokes cesium-induced ventricular tachyarrhythmias by increasing calcium release from sarcoplasmic reticulum in myocytes via activation of a phosphatidylinositol response.

Electrophysiological Properties in Paroxysmal Atrial Fibrillation Complicated with the Wolff-Parkinson-White Syndrome: Comparison with Paroxysmal Atrial Fibrillation Alone

Electrophysiological studies were performed in 26 patients with atrial fibrillation (AF). Thirteen patients had the Wolff-Parkinson-White (WPW) syndrome (group A), and another 13 patients did not have the WPW syndrome (group B). The right atrium effective refractory period was significantly shorter in group A than in group B. The wavelength index which was defined as the ratio of the refractory period to the conduction delay was significantly lower in group A than in group B. Accordingly, patients in group A had a greater tendency to produce atrial reentry than those in group B.

Efficacy and Tolerability of Nilvadipine in Combination with an Angiotensin II Receptor Antagonist in Patients with Essential Hypertension: A Multicenter, Open-Label, Uncontrolled Study.

BACKGROUND Combination therapy with different classes of antihypertensive drugs often is needed to achieve controlled blood pressure (BP). The combination of an angiotensin II receptor antagonist (AIIA) and a calcium antagonist is a preferred option for reducing uncontrolled BP. OBJECTIVE The aim of this study was to assess the clinical efficacy and tolerability of nilvadipine, a dihydropyridine calcium antagonist, in combination with an AIIA. METHODS Patients with essential hypertension whose BP was not controlled by an AIIA alone were eligible for this multicenter, open-label, uncontrolled study. One of 3 AIIAs (candesartan cilexetil, losartan potassium, or valsartan) was given for at least 10 weeks before the addition of nilvadipine (daily dose, 4 or 8 mg orally). This combination therapy was given for 8 weeks. BP and heart rate were measured between 2 and 4 weeks before and 0, 4, and 8 weeks after the start of combination therapy. Adverse events were monitored at each visit. RESULTS Thirty-one patients (18 women [58.1%], 13 men [41.9%]; mean [SD] age, 58.5 [10.5] years) were enrolled. At weeks 4 and 8 of combination therapy, mean systolic BP (SBP) and diastolic BP (DBP) were significantly decreased (P<0.01) (at week 8, by 22.0 mm Hg and 12.5 mm Hg, respectively). The mean BP-lowering effect did not differ significantly between the 3 AIIAs tested. Pulse pressure also decreased significantly at week 8, by 9.6 mm Hg (P<0.01). The responder rate (ie, the percentage of patients with DBP <90 mm Hg or a decrease in DBP ≥10 mm Hg) was 72.0% at week 8. Three patients experienced a total of 4 adverse events: mild or severe flushing, mild headache, and mild palpitation. All of these symptoms resolved after nilvadipine treatment was discontinued. CONCLUSIONS Nilvadipine in combination with an AIIA showed good antihypertensive efficacy and was well tolerated in the hypertensive patients in this study. This combination also significantly decreased pulse pressure, suggesting that this combination therapy also may have a beneficial effect in elderly patients with isolated systolic hypertension.