Pre-ablation levels of brain natriuretic peptide are independently associated with the recurrence of atrial fibrillation after radiofrequency catheter ablation in patients with nonvalvular atrial fibrillation.

Association between pre-ablation levels of biomarkers of cardiac and endothelial dysfunctions, CHADS2, CHA2DS2-VASc, and APPLE scores and the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation has not been fully studied. A total of 254 patients with nonvalvular AF were prospectively followed for AF recurrence after a single ablation procedure. During a two-year follow-up period, AF recurred in 65 (25.6%) patients. Patients with AF recurrence had significantly greater baseline ln brain natriuretic peptide (BNP) than those without AF recurrence (P < 0.01), whereas there were no significant differences in the levels of biomarkers of endothelial dysfunction and points of scoring systems. In the Cox regression analyses, the baseline ln BNP was significantly independently associated with AF recurrence (adjusted HR =1.286, 95% CI =1.000-1.655, P < 0.05). The baseline levels of ln BNP were significantly associated with rhythm at blood collection, age, sex, and left atrial diameter, and left ventricular ejection fraction (P < 0.05).The subgroup analysis showed a significant interaction on the risk of AF recurrence between ln BNP, sex difference, and rhythm at blood collection (P for interaction < 0.05). In conclusion, the results suggest that the pre-ablation levels of ln BNP are useful to evaluate the risk of AF recurrence after ablation therapy; however, there is a need to be careful while using BNP as a biomarker for the risk of AF recurrence by taking account of the effects of rhythm status at blood collection and sex difference.

Different Effects of Pulmonary Vein Isolation on Quality of Life Between Patients with Persistent and Paroxysmal Atrial Fibrillation.

The effect of restoring sinus rhythm by pulmonary vein isolation (PVI) on the quality of life (QOL) of patients with persistent atrial fibrillation (PerAF) has not been adequately investigated. This study was performed to compare the changes in QOL after extended PVI between patients with PerAF and paroxysmal AF (PAF).Patients with PAF (n = 38) and PerAF (n = 22) who underwent their first PVI and developed no AF recurrence 6 months after PVI were enrolled. QOL surveys were performed at baseline and 6 months post-ablation using Short Form-36 surveys.The mental component summary score (MCS) (53.4 ± 10.2 to 56.5 ± 7.1, P = 0.019) and physical component summary score (PCS) (46.1 ± 10.6 to 48.5 ± 8.3, P = 0.015) improved after PVI in the PAF group. The PCS, but not the MCS, improved after PVI in the PerAF group (45.8 ± 7.9 to 51.5 ± 6.2, P < 0.001). Changes in the PCS were greater in the PerAF group than in the PAF group (8.6 ± 6.9 versus 2.8 ± 5.2, P = 0.009). Multivariate regression analysis demonstrated that a low baseline MCS and the type of AF (PAF) were independent predictors of an increased MCS and that a low baseline PCS and the type of AF (PerAF) were independent predictors of an increased PCS.The changes in QOL differed between PAF and PerAF after PVI. Although most patients with PerAF were asymptomatic before PVI, their improvement in physical QOL was greater than that in patients with PAF. Such beneficial effects on physical QOL are likely expected in patients with PerAF with a low PCS before PVI.

Exact location of the branching bundle in the living heart.

AIMS: The His bundle electrogram is believed to reflect the exact location of the His bundle. However, the distinction between distal His bundle potential and proximal right bundle branch potential is challenging. The aim of this study was to pinpoint the location of the branching point of the His bundle, and to compare that site with the site of recording of the largest His bundle electrogram (LH) during sinus rhythm. METHODS: We hypothesized that the site of earliest His activation (EH) during retrograde conduction via the left bundle branch is the branching point. We studied 15 nonconsecutive patients (mean age = 40 +/- 22 years; eight men). We performed a programmed stimulation from right ventricular apex until retrograde right bundle branch block appeared. At that point we measured (1) the distance between antegrade LH site and retrograde EH site and (2) the atrial-to-ventricular amplitude ratio (A/V ratio) at both sites. RESULTS: EH was recorded at the proximal electrode of the His bundle catheter in all patients. Mean distance between EH and LH was 9.8 +/- 2.5 mm. The mean A/V ratios at the EH site and the LH site were 1.01 +/- 0.42 and 0.08 +/- 0.06, respectively. DISCUSSION: This study showed that the EH site is located approximately 10-mm proximal to the LH site. The mean A/V ratio at the EH site during sinus rhythm is approximately 1.0. These observations suggest that the majority of His potentials reflect proximal right bundle activation. Before delivering radiofrequency energy in the para-Hisian area, attention should be paid to the presence of a His potential and to the A/V ratio, rather to the amplitude of the His electrogram.

Pharmacokinetic Drug Interaction Between Rosuvastatin and Tanjin in Healthy Volunteers and Rats.

BACKGROUND: Tanjin is an herbal medicine made from the root of salvia miltiorrhiza. It is predominantly given to arteriosclerotic patients as a supplement to ameliorate the clinical symptoms of cardiovascular diseases. In China, tanjin is used frequently in combination treatment for hypercholesterolemia. Thus, there is a high probability of combination of tanjin and statins in these arteriosclerotic patients. This study investigated the interaction between tanjin and rosuvastatin. METHODS: We performed a randomized single-blind, two-period crossover clinical trial on six healthy male volunteers. Volunteers were administered rosuvastatin with placebo or a tanjin-containing drug randomly. The blood samples were collected before drug administration, and at 0.5, 1, 1.5, 2, 4, 8, and 12 hours after administration. Lymphocytes were isolated from blood samples before and 12 hours after drug administration to measure mRNA. As an animal experiment, an in situ intestinal injection with portal vein sampling model was used to examine the interaction between tanjin and rosuvastatin during the absorption phase. Rosuvastatin or rosuvastatin combined with tanjin solution was injected into the intestine. After injection, blood from the portal vein was collected and the concentration of rosuvastatin was measured by LC/MS/MS analysis. A portion of the intestine and liver from the rats was collected and stored at -80°C for mRNA measurement. RESULTS: In the clinical trial, co-administration of tanjin decreased the maximum plasma concentration (Cmax) of rosuvastatin by 26.85% compared with rosuvastatin alone, and also decreased the area under the plasma concentration-time curve of rosuvastatin from 0 to 12 h (AUC0-12) by 19.43%. The relative expression of BCRP and OATP mRNA in human lymphocytes was increased by co-administration of tanjin. In the animal experiment, co-administration of tanjin extract reduced the concentration of rosuvastatin to 84.4, 64.4, and 50.0% at 15, 30, and 45 minutes, respectively. The tanjin-containing drug had a similar effect to tanjin extract. Furthermore, tanjin significantly reduced the absorption of rosuvastatin and the inhibitory effects lasted for at least 24 hours. Tanjin increased the relative expression of BCRP mRNA in the intestine, but it did not change the expression of OATP. Moreover, the concentration of rosuvastatin in the portal vein and systemic blood was reduced. In the liver, tanjin increased both BCRP and OATP mRNA expression, which was consistent with the results from human lymphocytes. CONCLUSION: The clinical trial and animal experiment revealed that tanjin can significantly reduce the absorption of rosuvastatin. This interaction occurred, at least, at the absorption phase in the small intestine due to the enhanced efflux transport. Thus, as tanjin and rosuvastatin were found to interact, their combination needs to be paid attention to.

Long-term reliability of AAI mode pacing in patients with sinus node dysfunction and low Wenckebach block rate.

AIMS: To compare the risk of atrioventricular (AV) conduction disturbance between patients with sinus node dysfunction on AAI pacing who had a low or high Wenckebach block rate (WBR). METHODS AND RESULTS: Patients with sinus node dysfunction and normal AV conduction those underwent an electrophysiological study were studied. The patients were classified into two groups: Group L was with the patients with a WBR of 100 to 129 per minute and Group H was with the patients with a WBR > or = 130 per minute. All patients followed up every 3-6 months after an AAI pacemaker implantation. A total of 102 patients, including 35 Group L and 67 Group H, were followed for 90 +/- 44 months. Six patients died from non-cardiac cause and five patients required a new atrial lead implantation due to lead failure during follow-up. Symptomatic bradycardia requiring a new ventricular lead implantation developed in four patients (annual incidence 0.5%). In Group L, two patients developed AV block (annual incidence 0.7%). In Group H, two patients developed bradycardic atrial fibrillation (annual incidence 0.4%). Kaplan-Meier analysis revealed no significant difference between the two groups (P = 0.2983). CONCLUSION: These results suggest that a long-term risk of developing AV conduction disturbance is low even in patients with a WBR of 100 to 129 per minute.

Radiofrequency catheter ablation for atrial tachycardia originating from the left atrial appendage.

A 36-year-old woman presented with drug-refractory atrial tachycardia. During the tachycardia episodes, P waves were positive in leads II, III, aVF, and V1, while they were negative in leads I and aVL. It was hard to determine whether the origin was the left atrial appendage or left superior pulmonary vein on the surface electrocardiogram. Electrophysiologic evaluation revealed that the earliest endocardial activation occurred at the base of the left atrial appendage, preceding the onset of P waves by 38 ms. On initiation of the tachycardia, a warm-up phenomenon was observed. There was a fixed relation between the coupling interval of a single extrastimulus and the return cycle length during the tachycardia. These findings suggested that the mechanism of the tachycardia was automaticity. Application of radiofrequency energy at the left atrial appendage terminated the tachycardia and it was not inducible after ablation.

Macroreentrant atrial tachycardia with an isolated pathway mimicking focal activation on three-dimensional electroanatomical mapping.

A 76-year-old man with two different sustained atrial arrhythmias that occurred after coronary artery bypass grafting underwent electrophysiological studies. Macroreentrant atrial tachycardias were detected with an isolated slow pathway mimicking focal activation on three-dimensional electroanatomical mapping. The slow conduction pathway in the right atrial free wall was assumed to represent tissue damaged by right atrial cannulation during previous coronary artery bypass grafting.

Molecular mechanisms underlying the pilsicainide-induced stabilization of hERG proteins in transfected mammalian cells.

BACKGROUND: Pilsicainide, classified as a relatively selective Na+ channel blocker, also has an inhibitory action on the rapidly-activating delayed-rectifier K+ current (IKr ) through human ether-a-go-go-related gene (hERG) channels. We studied the effects of chronic exposure to pilsicainide on the expression of wild-type (WT) hERG proteins and WT-hERG channel currents, as well as on the expression of mutant hERG proteins, in a heterologous expression system. METHODS: HEK293 cells stably expressing WT or mutant hERG proteins were subjected to Western blotting, immunofluorescence microscopy and patch-clamp experiments. RESULTS: Acute exposure to pilsicainide at 0.03-10 µM influenced neither the expression of WT-hERG proteins nor WT-hERG channel currents. Chronic treatment with 0.03-10 µM pilsicainide for 48 h, however, increased the expression of WT-hERG proteins and channel currents in a concentration-dependent manner. Chronic treatment with 3 µM pilsicainide for 48 h delayed degradation of WT-hERG proteins and increased the channels expressed on the plasma membrane. A cell membrane-impermeant pilsicainide derivative did not influence the expression of WT-hERG, indicating that pilsicainide stabilized the protein inside the cell. Pilsicainide did not influence phosphorylation of Akt (protein kinase B) or expression of heat shock protein families such as HSF-1, hsp70 and hsp90. E4031, a chemical chaperone for hERG, abolished the pilsicainide effect on hERG. Chronic treatment with pilsicainide could also increase the protein expression of trafficking-defective mutant hERG, G601S and R752W. CONCLUSIONS: Pilsicainide penetrates the plasma membrane, stabilizes WT-hERG proteins by acting as a chemical chaperone, and enhances WT-hERG channel currents. This mechanism could also be applicable to modulations of certain mutant-hERG proteins.

Extension of the inferior vena cava into the posteroinferior right atrium.

BACKGROUND: The inferior vena cava (IVC) is obliquely connected to the right atrium (RA), and often a low-voltage area is observed in the posteroinferior RA. OBJECTIVES: The purpose of this study was investigate the size of the IVC extension into RA and its anatomic background. METHODS: We investigated 30 human hearts [11 men and 19 women; mean age 79 +/- 10 years; 7 cardiac deaths (group A) and 23 noncardiac deaths (group B)]. After obtaining macroscopic measurements around the RA-IVC junction, serial sections were cut and examined histologically. We defined a horizontal baseline at the level of the cavotricuspid isthmus and measured (1) the length of IVC extension, which was defined as the distance from the baseline to the top of the RA-IVC junction, and (2) the width of the RA-IVC junction at the baseline level. RESULTS: The top of the RA-IVC junction was always located in the posteroinferior RA. The mean length of the IVC extension was 17.6 +/- 6.6 mm, and the mean width was 29.6 +/- 7.5 mm. The IVC extension was wider in group A than in group B (35.8 +/- 9.0 mm vs 27.5 +/- 5.9 mm; P = .0277). The right and left borders of the RA-IVC junction corresponded to the reflection of the pericardium. Histologic examination showed no myocardium in the IVC extension. CONCLUSION: The IVC extension into the posteroinferior RA always exists and varies in size. Because this area lacks myocardium, it is important to consider when analyzing catheter mapping from this area.

Impact of postprocedural antiarrhythmic drug therapy with bepridil on maintaining sinus rhythm after catheter ablation for persistent atrial fibrillation.

BACKGROUND: Although several studies have assessed the predictors of recurrent atrial fibrillation (AF) after catheter ablation for persistent AF, the impact of antiarrhythmic drug (AAD) therapy on maintaining sinus rhythm after catheter ablation for persistent AF has not been fully evaluated. This case-control study aimed to evaluate the effect of bepridil on maintaining sinus rhythm after catheter ablation for persistent AF. METHODS AND RESULTS: We enrolled 122 consecutive patients (87 men; mean age: 62.3 years) who underwent catheter ablation for persistent AF and were administered AAD therapy after the initial procedure. Restoration of sinus rhythm was achieved in all of the patients by catheter ablation and cardioversion after the initial procedure. After a median 12-month follow up, 51 of 122 (41.8%) patients had recurrence of AF. In Cox proportional hazard regression analysis, postprocedural AAD therapy with bepridil was a significantly correlated factor with freedom from recurrent AF after the initial ablation procedure (hazard ratio 0.446, 95% confidence interval 0.236-0.842, p=0.012). In Kaplan-Meier analysis, AF-free survival was significantly better with bepridil compared with amiodarone (AMD) and sodium channel blocker (SCB) (log-rank test, bepridil vs AMD, p=0.012; bepridil vs SCB, p=0.018). CONCLUSIONS: Bepridil reduced the recurrence of AF compared with AMD and SCB in patients who underwent catheter ablation for persistent AF.

Characterization of the novel mutant A78T-HERG from a long QT syndrome type 2 patient: Instability of the mutant protein and stabilization by heat shock factor 1.

BACKGROUND: The human ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). METHODS: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein. A78T-HERG and wild-type HERG (WT-HERG) were expressed in HEK293 cells and analyzed by immunoblotting, immunoprecipitation, immunofluorescence, and whole-cell patch clamping. RESULTS: When expressed in HEK293 cells, WT-HERG gave rise to immature and mature forms of the protein at 135 and 155 kDa, respectively. A78T-HERG gave rise only to the immature form, which was heavily ubiquitinated. The proteasome inhibitor MG132 increased the expression of immature A78T-HERG and increased both the immature and mature forms of WT-HERG. WT-HERG, but not A78T-HERG, was expressed on the plasma membrane. In whole-cell patch clamping experiments, depolarizing pulses evoked E4031-sensitive HERG channel currents in cells transfected with WT-HERG, but not in cells transfected with A78T-HERG. The A78V mutant, but not A78G mutant, remained in the immature form similarly to A78T. Maturation of the A78T-HERG protein was facilitated by HS, expression of HSF-1, or exposure to geranyl geranyl acetone. CONCLUSIONS: A78T-HERG was characterized by protein instability and reduced expression on the plasma membrane. The stability of the mutant was partially restored by HSF-1, indicating that HSF-1 is a target for the treatment for LQT2 caused by the A78T mutation in HERG.

Left atrial branches of coronary arteries; clinical implications related to linear catheter ablation for atrial fibrillation.

BACKGROUND: Coronary artery damage has been reported during catheter ablation procedures. Recently, linear ablation of thin left atrial tissue has been performed for atrial fibrillation. OBJECTIVE AND METHODS: Because we have little information about the arteries in the left atrium, this study was performed to evaluate the anatomy of these arteries, and to compare them with previously reported ablation lines. Coronary angiography was performed in 262 patients. Atrial coronary arteries between the left atrial appendage and the left superior pulmonary vein (LAA-LSPV region), as well as between the left inferior pulmonary vein and the mitral annulus ("mitral isthmus" region) were examined. RESULTS: Atrial coronary arteries extending to the LAA-LSPV region were found in 92 subjects (35%), while arteries crossing the mitral isthmus region were found in 119 subjects (46%). Atrial coronary arteries crossed the ablation line in about 69% of subjects overall. CONCLUSION: These results might suggest a risk of acute complications due to left atrial ablation. Alternatively, recurrence of atrial fibrillation might be caused by protected myocardium around the atrial arteries. We should note that atrial coronary arteries cross the ablation line in many patients.

QRS complex widening due to loss of left bundle branch capture: pitfall of para-Hisian pacing.

During para-Hisian pacing, widening of the paced QRS complex usually indicates loss of His bundle capture. We describe a patient without any accessory pathways in whom widening of the paced QRS complex occurred due to loss of left bundle branch capture during para-Hisian pacing. After initial widening of the QRS complex, further widening was observed due to loss of His bundle capture. With the initial QRS widening, the stimulus-atrial interval and retrograde atrial activation sequence were almost unchanged, so the findings mimicked retrograde conduction over an accessory pathway. This may be a pitfall of the para-Hisian pacing technique.

Inhibition of beta-adrenergic signaling by intracellular AMP is independent of cell-surface adenosine receptors in rat cardiac cells.

We report a novel action of intracellular adenosine monophosphate (AMP) to inhibit beta-adrenergic signaling in isolated rat ventricular myocytes. Extracellular application of adenosine or AMP suppressed isoproterenol (Iso)-induced prolongation of action potential duration (APD). This effect was completely abolished by an A(1)-receptor antagonist, DPCPX. Intracellular application of AMP, but not adenosine, attenuated Iso-induced APD prolongation. Iso-induced increases in the L-type Ca(2+) current (I(Ca,L)) were also inhibited by intracellular AMP. These inhibitory effects were not affected by either DPCPX or glibenclamide. In vitro, AMP directly inhibited PKA activity via binding to its regulatory subunit. These results suggest that intracellular AMP attenuates beta-adrenergic signaling by directly inhibiting PKA activity, independently of A(1)-purinergic receptor.

Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine.

ATP-sensitive K+ channels (K(ATP):SUR2A+Kir6.2) play a pivotal role in cardiac protection against ischemia and reperfusion injury. When expressed in COS cells, Kir6.2 was short-lived with a half-life time of 1.9 h. The half-life time of Kir6.2 was prolonged by proteasome inhibitors MG132, ALLN, proteasome inhibitor 1, and lactacystine, but not at all by a lysosomal inhibitor chloroquine. MG132 also increased the level of ubiquitinated Kir6.2 without affecting its localization in the endoplasmic reticulum and Golgi apparatus. In electrophysiological recordings, MG132 augmented nicorandil-activated K(ATP) currents in COS cells expressing SUR2A and Kir6.2 as well as the same currents in neonatal rat cardiomyocytes. Like MG132, a Na+ channel blocker aprindine prolonged the half-life time of Kir6.2 and augmented K(ATP). Finally, both aprindine and MG132 inhibited the 20S proteasome activity in vitro. These results suggest a novel activity of aprindine to enhance K(ATP) currents by inhibiting proteasomal degradation of Kir 6.2 channels, which may be beneficial in the setting of cardiac ischemia.