Efficacy and safety of angiotensin II type 1 receptor blocker/calcium channel blocker combination therapy for hypertension: focus on a single-pill fixed-dose combination of valsartan and amlodipine.

Adequate lowering of blood pressure reduces the risk of hypertension-induced cardiovascular events. Worldwide, blood pressure is not optimally controlled and more effective management is needed. The efficacy and tolerability of angiotensin II type 1 receptor blockers (ARBs) have led to their widespread use. Calcium channel blockers (CCBs) are highly effective antihypertensives and amlodipine has a long half-life in the circulation. The combination of an ARB with a CCB as a single-pill, fixed-dose treatment is emerging as possibly the best therapy for preventing cardiovascular disease. Although many kinds of ARB are used in such combinations, amlodipine is mainly used as the CCB. Thus, differences in safety and efficacy among single-pill ARB/CCBs depend mainly on the ARB. Not all ARBs have the same effects and some of these may be molecular (or differential) rather than class (or common) effects. This review discusses the safety and efficacy of ARB/CCB combination therapy, with particular focus on a single-pill, fixed-dose combination of valsartan/amlodipine.

Significance of plasma levels of pigment epithelium-derived factor as determined by multidetector row computed tomography in patients with mild chronic kidney disease and/or coronary artery disease.

Little is known about the association between plasma levels of pigment epithelium-derived factor (PEDF), coronary artery disease (CAD) and/or chronic kidney disease (CKD). This study evaluated 289 consecutive patients with chest pain or at least one coronary risk factor who underwent coronary angiography using multidetector row computed tomography (MDCT). Presence of CAD and CKD, CAD severity (i.e. number of significantly stenosed coronary vessels, described as vessel disease [VD]), coronary calcification scores, visceral fat area (VFA), subcutaneous fat area on MDCT, and metabolic biomarkers were recorded. PEDF levels correlated significantly with sex, VFA, CKD presence/hyperuricaemia and high-density lipoprotein cholesterol levels. PEDF levels were closely associated with CKD and were significantly higher in CKD patients than in non-CKD patients, regardless of the presence of CAD. CKD patients with two-VD or three-VD had higher plasma PEDF levels than non-CKD patients with two-VD or three-VD. It is concluded that PEDF may be associated with CKD regardless of the presence of CAD.

Do all angiotensin II type 1 receptor blockers have the same beneficial effects?

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are highly selective for the AT(1) receptor, which is a member of the G protein-coupled receptor superfamily (GPCRs), and block the diverse effects (hypertension, hypertrophy, heart failure, proteinuria etc.) of angiotensin II. Many ARBs are in clinical use and have been shown to be safe and effective. Over the past several years, reports have discussed the different degrees of the beneficial effects of ARBs. As ARBs do not all have the same effects, the benefits conferred by ARBs may not be class effects. These different effects may be due to differences in the molecular characteristics of ARBs. The results reported by Le et al. in this issue highlight the different characteristics of two ARBs, olmesartan and telmisartan, and suggest that the higher degree of insurmountability, slower dissociation, and higher affinity of olmesartan compared to telmisartan for AT(1) receptors may help it to form a tight binding complex with this receptor. A better understanding of the different molecular mechanisms for each ARB could be useful for the treatment of patients.

Paraoxonase (Pon1) Q192R polymorphism and serum Pon1 activity in diabetic patients on maintenance hemodialysis.

Patients with diabetic nephropathy have an increased risk of coronary heart disease (CHD). Paraoxonase (Pon1) is a high-density lipoprotein- (HDL) associated enzyme that protects low-density lipoprotein from oxidation and also protects against atherosclerosis. We investigated the relationship of serum Pon1 activity, Pon1 Q192R polymorphism and HDL-C level to type 2 diabetes mellitus (DM) in patients on maintenance hemodialysis (HD). DM patients (n = 56, F/M = 17/39, aged 64.5 +/- 7.5 years) and non-DM patients (n = 89, F/M = 28/61, aged 62.7 +/- 8.3 years) under HD were included in this study. Salt-stimulated serum Pon1 activities were measured using paraoxon as a substrate. Pon1 Q192R polymorphism was detected by the mutagenically separated polymerase chain reaction. DM patients on HD had significantly lower HDL-C levels and serum Pon1 activities than non-DM patients on HD (657 +/- 277 vs. 763 +/- 257 IU/l, p < 0.01). The distribution of Pon1 Q 192R genotypes in all subjects did not differ from that predicted from the Hardy-Weinberg equilibrium. Serum Pon1 activities in both DM and non-DM patients on HD were regulated by Pon1 Q192R polymorphism: RR > QR > QQ. However, the reduced Pon1 activities in DM patients on HD were related to DM independent of the Pon1 genotype: reduced Pon1 activity was related to DM in RR carriers. Serum Pon1 activities were positively correlated with HDL-C levels. The association between HDL-C and DM in hemodialyzed patients was independent of Pon1 activity as assessed by an analysis of variance. But the relation between Pon1 activity and DM was modified by HDL-C levels: significantly when HDL-C was below 50 mg/dl, but not significantly when HDL-C was above 50 mg/dl. The results of a logistic regression analysis show that reduced serum Pon1 activities and low HDL-C levels were additively associated with DM. In conclusion, Pon1 status and HDL levels are independently associated with DM in patients on hemodialysis and may contribute to the increased risk of CHD in diabetic nephropathy.

The I allele of the angiotensin-converting enzyme gene is associated with an increased percentage of slow-twitch type I fibers in human skeletal muscle.

The insertion (I) allele of the human angiotensin-converting enzyme (ACE) gene is associated with lower serum and tissue ACE activity, and with greater endurance performance and enhanced mechanical efficiency of trained muscle. We tested the hypothesis that the ACE-I allele may be associated with increased slow-twitch fiber, which is more efficient than fast-twitch fiber in low-velocity contraction, by examining the association between the ACE genotype and skeletal muscle fiber (SMF) types in 41 untrained healthy young volunteer subjects (31 males, 10 females, age 24 +/- 3 years). Skeletal muscle samples were taken from the left vastus lateralis using the needle-biopsy method. Slow-twitch type I fibers and fast-twitch type IIa and IIb fibers were classified histochemically based on staining for myosin adenosine triphosphatase (ATPase) activity at different pH values. Amylase-periodic acid-Schiff staining was used to visualize capillaries around fibers. ACE-II subjects had significantly (p < 0.01) higher percentages of type I fibers (50.1 +/- 13.9%vs 30.5 +/- 13.3%) and lower percentages of type IIb fibers (16.2 +/- 6.6%vs 32.9 +/- 7.4%) than ACE-DD subjects. The linear trends for decreases in type I fibers and increases in type IIb fibers from ACE-II --> ID --> DD genotypes were significant as assessed by an analysis of variance. The ratio of type I:II fibers also differed according to the ACE genotype. A multivariate logistic regression analysis showed that the ACE-I allele had significant additive and recessive (codominant) effects on the increased type I fibers and the ratio of type I:II fibers. No specific pattern of capillarization was observed among the three ACE genotypes. In conclusion, the ACE-I allele was associated with increased type I SMF, which may be a mechanism for the association between the ACE genotype and endurance performance.

Association of angiotensin-converting-enzyme gene polymorphism with the depressor response to mild exercise therapy in patients with mild to moderate essential hypertension.

We studied the association of angiotensin I-converting enzyme (ACE) gene polymorphism with the depressor response to exercise therapy in 64 Japanese subjects with mild to moderate essential hypertension. Each subject performed 10 weeks of mild (lactate threshold intensity: approximately 50% maximum oxygen consumption) exercise therapy on a bicycle ergometer. Systolic blood pressure (SPB), diastolic blood pressure (DPB), and mean arterial pressure (MAP) were significantly decreased by exercise therapy in subjects with the ACE-II and ID genotypes but not in DD subjects. The time-by-genotype interaction effects were significant for DBP and MAP. According to a multiple logistic regression analysis, the age- and baseline plasma renin activity-adjusted relative risk (odds ratio) for the lack of a depressor response conferred by the D allele (assuming an additive effect) was 2.72 [95% confidence interval (CI), 1.07-6.91; p = 0.034]; for DD genotypes, as compared with the DI and II genotypes (assuming that the D allele is recessive), it was 11.7 (95% CI, 2.25-60.6; p = 0.003). ACE gene I/D polymorphism is associated with the depressor response of essential hypertensives to mild exercise therapy, which suggests that genetic features may underlie, at least in part, the heterogeneity of the depressor response in essential hypertensives to mild exercise therapy.

The associations among thoracic aortic atherosclerosis, coronary atherosclerosis and the function of high density lipoprotein.

We sought to determine the associations among thoracic aortic atherosclerosis, coronary atherosclerosis and the function of high density lipoprotein (HDL) in a case-control study. The function of HDL can be assessed by the fractional esterification rate of cholesterol in low density lipoprotein (LDL)- and very low density lipoprotein (VLDL)-depleted plasma (FER(HDL)), which reflects a balance of cholesterol uptake by HDL and cholesterol ester (CE) transport in the reverse cholesterol transport (RCT) system in humans. Cases (n=51, age: 64.3+/-8.0 years) and controls (n=51, age: 58.7+/-13.1 years) were defined as subjects with/without angiographically proven coronary artery disease (CAD), respectively and examined for thoracic aortic atherosclerosis (TAA) by transesophageal echocardiography. The severity of TAA was determined by the ratio of average sclerotic areas (ASA) and average sclerotic lengths (ASL). The cases had significantly (P<0.05) higher values of ASA (0.22+/-0.18 vs. 0.10+/-0.11), ASL (0.82+/-0.56 vs. 0.48+/-0.45), ASA/ASL ratio (0.23+/-0.08 vs. 0.17+/-0.09) and FER(HDL) (10.3+/-3.8 vs. 8.3+/-3.5% per hour) and lower HDL-C and apolipoprotein A-I levels than the controls. A receiver operating characteristic (ROC) curve analysis showed that ASA/ASL and FER(HDL) had moderate discriminating ability for CAD and the diagnostic accuracy of ASA/ASL was better than that of FER(HDL) (area under ROC curve: 0.703 and 0.656, respectively). Multivariate logistic regression analysis indicated that ASA/ASL and FER(HDL) were independent indicators for CAD [odds ratio (95% CI): 7.5 (2.4-27), P<0.01 and 4.0 (1.2-15), P<0.05] after adjusting for age, gender and other conventional risk factors, and that a high FER(HDL) value greatly increased the relative risk of CAD associated with a high ASA/ASL. The function of HDL, as assessed by FER(HDL), enhances the ability of TAA to predict CAD.

Effects of high-dose troglitaz one on insulin sensitivity and beta-cell function in Watanabe heritable hyperlipidemic rabbits.

UNLABELLED: To clarify the dose-response effects of troglitazone on insulin sensitivity and beta-cell function, we examined the effects of high-dose troglitazone (100 mg/day per animal, administered as a food admixture) on glucose and insulin metabolism in hyperinsulinemic Watanabe heritable hyperlipidemic (WHHL) rabbits, and compared the results with our previous results with low-dose troglitazone (10 mg /day per animal). MATERIALS AND METHODS: Glucose and insulin metabolism were quantitatively characterized by a minimal model technique as reported previously. RESULTS: When troglitazone was administrated at a high dose for 6 months, it reduced hyperinsulinemia as reflected by a reduced basal (steady-state) insulin concentration lb and the insulin response to a glucose load, improved beta-cell function as reflected by decreased second-phase post-hepatic insulin delivery to glucose phi2, and reduced insulin resistance as reflected by increased insulin sensitivity to glucose disposal Si, without affecting glucose tolerance as reflected by an unchanged rate of glucose utilization Kg or insulin-independent glucose disposal Sg. The reductions in Ib and phi2 and the increases in Si in WHHL rabbits treated with a high dose of troglitazone were greater (p<0.05) than those observed in WHHL rabbits treated with a low dose of troglitazone, as assessed by a two-way repeated measures analysis of variance and the Wilcoxon-Mann-Whitney test. CONCLUSION: In WHHL rabbits, troglitazone dose-dependently reduced hyperinsulinemia, improved beta-cell function, and increased insulin sensitivity.

A giant left ventricular thrombus in a patient with acute myocardial infarction--a case report.

The authors report a patient with acute anteroseptal myocardial infarction with a giant left ventricular thrombus at the apex. The patient also had nephrotic syndrome due to diabetic nephropathy. Coronary angiography showed 90% stenosis at segment 6 of the left anterior descending coronary artery. Percutaneous transluminal coronary angioplasty and intracoronary stenting were performed on the 30th day, and effective coronary blood flow was obtained. Heparin was injected intravenously for the first 7 days, and warfarin was administered thereafter. The left ventricular thrombus disappeared after 46 days. No evidence of arterial thromboembolism was found during the disappearance of the left ventricular thrombus as determined by echocardiography.

The D allele of the angiotensin-converting enzyme gene and reperfusion-induced ventricular arrhythmias in patients with acute myocardial infarction.

The renin-angiotensin system may play a pivotal role in reperfusion ventricular arrhythmias (RVA). The purpose of this study was to investigate the association between angiotensin-converting enzyme (ACE) gene polymorphism and RVA in patients with acute myocardial infarction (AMI) in a case-control study. Patients who had undergone successful coronary intervention for AMI were enrolled (n= 127, male/female: 97/30, mean age, 62.6 years). The incidence of RVA was continuously monitored by ECG at a coronary care unit. The severity of ventricular arrhythmias was evaluated in terms of the Lown's grade and patients with a high risk of ventricular arrhythmias that may cause sudden cardiac death (Lown's grade > or =2) within 5 h of coronary intervention were defined as cases (n=59), and otherwise as controls (n=68). A receiver operating characteristic curve was used to determine the discriminatory ability of continuous variables and to produce dummy variables for use in a logistic regression analysis. Cases had a significantly higher body mass index, higher maximal levels of serum creatine kinase, and a shorter time preceding coronary intervention than controls. The severity of coronary atherosclerosis was similar between the 2 groups. The frequency distribution of ACE genotypes in cases differed from that in controls (II/ID/DD: 22.0%/52.6%/25.4% vs 44.1%/41.4%/14.7%, p<0.05, by the Mantel-Haenzel chi-square test). The ACE-D allele had additive and dominant effects with regard to the occurrence of significant ventricular arrhythmias after adjusting for other risk factors. The ACE-D allele may play a pivotal role in sudden cardiac death in patients with AMI.

Spontaneous right ventricular outflow tract tachycardia in a patient with Brugada syndrome.

We report the case of a 28-year-old man with no structural heart disease, who exhibited clearly augmented ST segment elevation in the right precordial leads, followed by induction of spontaneous right ventricular outflow tract tachycardia with intravenous administration of Class IA antiarrhythmic drugs. The electrophysiologic mechanism of this tachycardia was thought to be triggered activity due to delayed afterdepolarizations. Due to the existence of substrates that were similar to Brugada syndrome combined with right ventricular outflow tract tachycardia, this case may represent a subtype of Brugada syndrome.

Effects of cavotricuspid isthmus catheter ablation on paroxysmal atrial fibrillation.

It has been demonstrated that successful cavotricuspid isthmus ablation of typical atrial flutter combined with atrial fibrillation (AF) sometimes influences the preablation history of paroxysmal AF. However, the effectiveness of only isthmus ablation on AF itself is unclear. Endocardial catheter mapping during induced AF was performed around the tricuspid annulus using duodecapolar clectrode catheters in 39 patients with drug-refractory paroxysmal AF. Isthmus ablation was performed in 16 patients (41%) in whom catheter mapping during AF showed an organized activation pattern around the tricuspid annulus. During a mean follow-up of 12.3 months, isthmus ablation was successful in preventing AF in 12 (75%) patients, 8 without medication and 4 with a previously ineffective drug. This success group had a significantly higher F wave amplitude in lead V1 (0.29+/-0.10 vs 0. 15+/-0.04 mV, p < 0.01), a higher left ventricular ejection fraction (74+/-9 vs 58+/-2%, p < 0.05), and a smaller left atrial dimension (35+/-6 vs 43+/-4 mm, p < 0.05) than the failure group. Isthmus ablation may be effective in preventing paroxysmal AF with an organized activation pattern around the tricuspid annulus. F wave amplitude, left ventricular ejection fraction, and left atrial dimension were significant predictors of success.

Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury.

Inhibition of the renin-angiotensin system (RAS) has been shown to be beneficial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effects and mechanism of RAS inhibitors on ischemia/reperfusion (IR)-induced myocardial injury in rats. Rats were randomly divided into five groups and treated with vehicle (C), angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 receptor antagonist (AT1-A), angiotensin II type 2 receptor antagonist (AT2-A) or ACE-I plus bradykinin B2 antagonist. Ten minutes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min. IR-induced cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) activity in the ischemic zone were measured by an in vitro kinase assay. The duration of ventricular tachycardia (VT) during ischemia was reduced by AT2-A and ACE-I, and increased by AT1-A and ACE-I+icatibant. ACE-I and AT2-A reduced apoptosis (by 54% and 53%) and infarct size (by 42% and 41%), while AT1-A increased apoptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptosis and infarct size were abolished by the coadministration of icatibant. Apoptosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT2 receptor are cardioprotective against IR injury through the activation of ERK, but not JNK.

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.

Angiotensin II type-1 receptor antagonist, CS-866, reduces blood pressure without affecting glucose/insulin metabolism in cholesterol-fed rabbits.

CS-866 is an angiotensin II type-1 receptor antagonist, the effects of which on systolic blood pressure (BP) and glucose/insulin metabolism are investigated under hyperlipidaemic conditions produced by cholesterol feeding. Thirty-two female Japanese White rabbits (two months old) were assigned randomly into a CS-866-treated group (n = 17) fed a food admixture that contained 0.03% CS-866 and 0.2% cholesterol, or into a control group (n = 15) fed a food admixture containing 0.2% cholesterol only. Systolic BP was measured by an ear-cuff method. Glucose and insulin metabolism was characterised quantitatively from the results of an intravenous glucose tolerance test by a minimal model technique reported previously. After six months treatment, systolic BP in the CS-866-treated group was lower than in the control group (105 +/- 14 mmHg versus 115 +/- 18 mmHg; P <0.05), as assessed by analysis of variance and the Wilcoxon rank-sum test. No significant differences were seen in plasma aldosterone concentration, plasma renin activity, or angiotensin-converting enzyme activity between the groups. Administration of CS-866 for six months did not affect either glucose tolerance or insulin sensitivity. Other model parameters such as basal (steady-state) insulin and glucose concentration, first- and second-phase post-hepatic insulin delivery to glucose, and insulin clearance rate constant were unaffected. In conclusion, CS-866 treatment reduced systolic BP without affecting glucose/insulin metabolism under hyperlipidaemic conditions produced by cholesterol feeding.

[Electrophysiological mechanism of combination therapy with disopyramide and propranolol for paroxysmal atrial fibrillation].

OBJECTIVES: Combined administration of propranolol and disopyramide treatment often leads to better results in patients with atrial fibrillation refractory to only disopyramide administration. The electrophysiological mechanism of this combination therapy was investigated. METHODS: Nineteen patients with paroxysmal atrial fibrillation without organic heart disease were studied. The indices for atrial vulnerability were compared in the control state, 10 min after injection of disopyramide (2 mg/kg) and 10 min after additional administration of propranolol (0.2 mg/kg). RESULTS: Administration of both drugs did not significantly change the percentage fragmented atrial activity and the interatrial conduction delay. Disopyramide increased the atrial effective refractory period and the wavelength index, defined as the ratio of the atrial effective refractory period to the interatrial conduction delay and represented the length of the reentry circuit. Additional injection of propranolol caused further increases in both values. CONCLUSIONS: Combination therapy with disopyramide and propranolol improves atrial vulnerability by increasing the wavelength.

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.

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.

Single oral administration of pilsicainide versus infusion of disopyramide for termination of paroxysmal atrial fibrillation: a multicenter trial.

A single oral dose of pilsicainide (PLS) is effective in terminating acute-onset atrial fibrillation (AF). However, the effectiveness of this single oral treatment has not been compared with the infusion of other antiarrhythmic drugs. The effects of a single oral dose of PLS on the termination of AF were compared with an infusion of disopyramide (DISO) in a multicenter trial. Seventy-two patients with electrocardiographically confirmed, symptomatic, paroxysmal AF (< 48-hour duration) were randomized to receive either a single 100- to 150-mg dose of PLS versus a 2 mg/kg (maximum dose = 100 mg) infusion of DISO. Successful defibrillation was defined as termination of AF within 2 hours of drug administration. Conversion of AF to sinus rhythm was achieved within 2 hours in 29 of 40 patients (73%) treated with PLS, and in 18 of 32 patients (56%) treated with DISO (NS). The mean time to return of sinus rhythm was 60 +/- 30 minutes in the PLS group versus 23 +/- 18 minutes in the DISO group (P < 0.001). DISO was particularly effective in terminating nocturnal AF, whereas PLS had a stable circadian effect. PLS was significantly more effective than DISO between 6 AM and 12 PM (64% vs 17%, P < 0.05). No adverse effect was observed in either group. In conclusion, a single oral dose of PLS was as effective as an infusion of DISO to restore sinus rhythm in patients with recent-onset AF. PLS consistently terminated AF regardless of its time of onset.