Comparison of touch-up ablation rate and pulmonary vein isolation durability between hot balloon and cryoballoon.

INTRODUCTION: This study aimed to compare touch-up ablation (TUA) rates and pulmonary vein isolation (PVI) durability of hot balloon ablation (HBA) and cryoballoon ablation (CBA) in paroxysmal atrial fibrillation (PAF) patients. METHODS: In total, 137 PAF patients were enrolled in the study. Among them, 59 underwent two HBA procedures at 6-month intervals and 78 patients underwent two CBA sessions, both regardless of atrial fibrillation recurrence. Propensity score matching was performed to estimate similar patient characteristics between the HBA and CBA groups. RESULTS: Each group comprised of 46 matched patients for comparison. The TUA rate at the first session was higher for HBA (49 of 184 PVs) than for CBA (20 PVs) (P = .01), with the highest incidence at the left superior pulmonary vein (LSPV). The rates of PVI durability at the second session performed 7 months later were similar between HBA (168 of 184 PVs) and CBA (162 PVs) groups. The PVI durability rate at the TUA sites of the first session was higher for HBA than for CBA (41 of 49 PVs vs 10 PVs, respectively; P = .01). Fifty percent of the patients underwent HBA at 73°C for the LSPV. HBA performed at 73°C yielded a lower TUA rate than that at 70°C (16 of 23 PVs vs 7 of 23 PVs; P = .008). CONCLUSIONS: While PVI durability was similar between HBA and CBA, the TUA rate was higher for HBA than for CBA, especially on the LSPV. For LSPV, HBA at a balloon temperature of 73°C may reduce the TUA rate.

Recurrent ischemic stroke in patients with atrial fibrillation ablation and prior stroke: A study based on etiological classification.

BACKGROUND: Different subtypes of ischemic stroke may have different risk factors, clinical features, and prognoses. This study investigated the incidence and mode of stroke recurrence in patients with a history of stroke who underwent atrial fibrillation (AF) ablation. METHODS: Of 825 patients who underwent AF ablation from 2006 to 2016, 77 patients (9.3%, median age 69 years) with a prior ischemic stroke were identified. Patients were classified as those with prior cardioembolic (CE) stroke (n = 55) and those with prior non-CE stroke (n = 22). The incidence and pattern of stroke recurrence were investigated. RESULTS: The incidence of asymptomatic AF (54.5% vs 22.7%; P = .011) and left atrial volume (135.8 mL vs 109.3 mL; P = .024) was greater in the CE group than in the non-CE group. Anticoagulation treatment was discontinued at an average of 28.1 months following the initial ablation in 34 (44.2%) patients. None of the patients developed CE stroke during a median 4.1-year follow-up. In the non-CE group, 2 patients experienced recurrent non-CE stroke (lacunar infarction in 1 and atherosclerotic stroke in 1); however, AF was not observed at the onset of recurrent ischemic stroke. CONCLUSIONS: In patients with a history of stroke who underwent catheter ablation for AF, the incidence of recurrent stroke was 0.54/100 patient-years. The previous stroke in these patients may not have been due to AF in some cases; therefore, a large-scale prospective study is warranted to identify the appro priate antithrombotic therapy for the prevention of potentially recurrent stroke.

The relationship between obstructive sleep apnea and recurrence of atrial fibrillation after pulmonary vein isolation using a contact force-sensing catheter.

PURPOSE: Our aim was to elucidate the relationship between obstructive sleep apnea (OSA) and atrial fibrillation (AF) recurrence after repeated pulmonary vein isolation (PVI). METHODS: We conducted a non-randomized observational study, with the data prospectively collected. One hundred patients (paroxysmal AF, n = 89) underwent PVI using a contact force-sensing catheter. All patients underwent an electrophysiological study and additional ablation for left atrium-pulmonary vein (PV) reconnection and non-PV foci, 6 months after the first treatment session, regardless of AF recurrence. Those with an apnea-hypopnea index ≥ 15 were diagnosed with OSA. Continuous positive air pressure (CPAP) therapy was initiated after the second treatment session, based on results of a sleep study. For analysis, patients were classified into the non-OSA (n = 66), treated OSA (OSA patients undergoing CPAP; n = 11), and untreated OSA (n = 23) groups, and between-group differences evaluated. RESULTS: After the first session, AF recurrence was observed in 18.2% (12/66) and 14.7% (5/34) of patients without and with OSA, respectively (P = 0.678). After the second procedure, the rate of AF recurrence was 12.1% (8/66) in the non-OSA group, 9.1% (1/11) in the treated OSA group, and 8.7% (2/23) in the untreated OSA group (log-rank P = 0.944). CONCLUSIONS: The rate of AF recurrence might not be greater in patients with untreated OSA than in those without OSA and those with treated OSA after repeated PVI, using a contact force-sensing catheter, for patients with paroxysmal or short-term persistent AF.

Development of Nonpulmonary Vein Foci Increases Risk of Atrial Fibrillation Recurrence After Pulmonary Vein Isolation.

OBJECTIVES: The aim of this paper was to clarify the impact of nonpulmonary vein foci (NPVF) on atrial fibrillation (AF) recurrence after pulmonary vein (PV) isolation. BACKGROUND: NPVF are considered contributing factors for the recurrence of AF after PV isolation, but their exact role remains unclear. METHODS: We retrospectively reviewed 216 patients (paroxysmal AF, n = 172; persistent AF, n = 44) who underwent a second electrophysiological study 6 months after the original PV isolation. Patients with AF recurrence underwent additional ablation procedures for reconnected PV and NPVF. NPVF were detected in the control group and with drug infusion (isoproterenol or isoproterenol with adenosine triphosphate) during the first and second procedure. NPVF detected for the first time in the second session were defined as newly developed, and their effect on AF recurrence after the second procedure was investigated, along with the predictive factors for NPVF development. RESULTS: Patients with AF recurrence after the first session had a significantly higher reconnected PV (91.5% vs. 68.2% in patients without recurrence). NPVF were detected in 20 and 54 patients in the first and second sessions, respectively. Patients with newly developed NPVF had a significantly higher AF recurrence (24.1% vs. 7.4% in patients without newly developed NPVF). Newly developed NPVF and AF recurrence after the first session were independent predictors for AF recurrence after the second procedure, whereas AF history and NPVF in the first session were independent predictors for newly developed NPVF. CONCLUSIONS: NPVF detection and ablation may represent important therapeutic options to prevent AF recurrence, especially in patients who require repeated procedures.

Peri-Mitral Atrial Tachycardia Using the Marshall Bundle Epicardial Connections.

OBJECTIVES: The aim of this study was to determine whether re-entrant circuits were associated with the ligament of Marshall (LOM). BACKGROUND: Peri-mitral atrial tachycardias (PMATs) following pulmonary vein isolation (PVI) or mitral valve surgery are common. METHODS: Six PMATs involving epicardial circuits were identified from 38 patients. Of these, 4 PMATs involved the LOM (PMAT-LOM, mean cycle length 308 ± 53 ms), as confirmed by the insertion of a 2-F electrode in the vein of Marshall (VOM). All patients underwent PVI and mitral isthmus ablation. The PMAT-LOMs were diagnosed based on left atrium (LA) activation maps that covered <90% of tachycardia cycle length (TCL), and a difference between the post-pacing interval and TCL that was: 1) ≤20 ms at the VOM, the ridge between the left pulmonary vein and appendage, the anterior wall of the LA, and along the 6 to 11 o'clock direction of the mitral annulus; and 2) >20 ms at the distal coronary sinus (CS), the posterior wall of the LA, and the mitral isthmus ablation line (or noncapture). Catheter ablation was performed at the ridge for all PMAT-LOMs. RESULTS: Three tachycardias were successfully terminated at the ridge, which showed continuous fractionated potential lasting >100 ms, confirming the bidirectional block of Marshall bundle (MB)-LA connections. The remaining tachycardia required ablation for the CS-MB connections, confirming bidirectional block of CS-MB connections. CONCLUSIONS: PMAT-LOMs following PVI or valve surgery accounted for up to 11% of PMATs. The bidirectional block of either MB-LA or CS-MB connections is required to eliminate PMAT-LOMs.

Hsp90 prevents interaction between CHIP and HERG proteins to facilitate maturation of wild-type and mutant HERG proteins.

AIMS: We examined the role of Hsp90 in expression and maturation of wild-type (WT) and mutant ether-a-go-go related gene (HERG) proteins by using Hsp90 inhibitors, geldanamycin (GA) and radicicol, and Hsp90 overexpression. METHODS AND RESULTS: The proteins were expressed in HEK293 cells or collected from HL-1 mouse cardiomyocytes, and analysed by western blotting, immunoprecipitation, immunofluorescence, and whole-cell patch-clamp techniques. GA and radicicol suppressed maturation of HERG-FLAG proteins and increased their immature forms. Co-expression of Hsp90 counteracted the effects of Hsp90 inhibitors and suppressed ubiquitination of HERG proteins. Overexpressed Hsp90 also inhibited the binding of endogenous C-terminus of Hsp70-interacting protein (CHIP) to HERG-FLAG proteins. Hsp90-induced increase of functional HERG proteins was verified by their increased expression on the cell surface and enhanced HERG channel currents. CHIP overexpression decreased both mature and immature forms of HERG-FLAG proteins in cells treated with GA. Hsp90 facilitated maturation of endogenous ERG proteins, whereas CHIP decreased both forms of ERG proteins in HL-1 cells. Mutant HERG proteins harbouring disease-causing missense mutations were mainly in the immature form and had a higher binding capacity to CHIP than the WT; Hsp90 overexpression suppressed this association. Overexpressed Hsp90 increased the mature form of HERG(1122fs/147) proteins, reduced its ubiquitinated form, increased its immunoreactivity in the endoplasmic reticulum and on the plasma membrane, and increased the mutant-mediated membrane current. CHIP overexpression decreased the immature form of HERG(1122fs/147) proteins. CONCLUSION: Enhancement of HERG protein expression through Hsp90 inhibition of CHIP binding might be a novel therapeutic strategy for long QT syndrome 2 caused by trafficking abnormalities of HERG proteins.

Macroreentrant atrial tachycardia in patients without previous atrial surgery or catheter ablation: clinical and electrophysiological characteristics of scar-related left atrial anterior wall reentry.

INTRODUCTION: Macroreentrant atrial tachycardia (MRAT) has been described most frequently in patients with prior cardiac surgery. Left atrial tachycardia and flutter are common in patients who undergo atrial fibrillation ablation; however, few reports describe left atrial MRAT involving the regions of spontaneous scarring. Here, we describe left atrial MRAT in patients without prior cardiac surgery or catheter ablation (CA) and discuss the clinical and electrophysiological characteristics of tachycardia and outcome of CA. METHODS AND RESULTS: An electrophysiological study and CA were performed in 6 patients (3 men; age 76 ± 6 years) with MRAT originating from the left atrial anterior wall (LAAW). No patient had a history of cardiac surgery or CA in the left atrium. Spontaneous scars (areas with bipolar voltage ≤ 0.05 mV) were observed in all patients. The activation map showed a figure-eight circuit with loops around the mitral annulus (4 counterclockwise and 2 clockwise) and a low-voltage area with LAAW scarring. The mean tachycardia cycle length was 303 ± 49 milliseconds. The conduction velocity was significantly slower in the isthmus between the scar in the LAAW and the mitral annulus than in the lateral mitral annulus (0.17 ± 0.05 m/s vs 0.94 ± 0.35 m/s; P = 0.003). Successful ablation of the isthmus caused interruption of the tachycardia and rendered it noninducible in all patients. CONCLUSION: Spontaneous LAAW scarring is an unusual cause of MRAT, showing activation patterns with a figure-eight configuration. Radiofrequency CA is a feasible and effective treatment in such cases.

Various morphologies of bidirectional ventricular tachycardia caused by aconite "Torikabuto" poisoning.

A 43-year-old man presented with nausea. The patient developed ventricular fibrillation (VF), which was refractory to antiarrhythmic drugs and defibrillation. A coronary angiogram showed no coronary artery stenosis. We recorded various fatal arrhythmias, including bidirectional ventricular tachycardia (BVT). The presence of multiple types of BVTs that were refractory to drugs such as adenosine triphosphate, isoproterenol, verapamil, propranolol, and pilsicainide, and easily recurred after defibrillation indicated aconite poisoning. After persisting for 24 h, VF spontaneously resolved and sinus rhythm was restored. Laboratory data revealed lethal concentrations of aconitine. To the best of our knowledge, this is the first report of aconite poisoning-induced BVTs manifesting with multiple morphologies on 12-lead electrocardiogram. The arrhythmogenic effects of aconitine are well recognized. In addition to causing VT and VF, aconitine also can cause BVT. Aconitine can lead to delayed afterdepolarization which has an important role in triggering and maintaining BVT. However, in this case, the concentration of aconitine was high enough to render these drugs ineffective. Prompt application of percutaneous cardio-pulmonary support, which was continued until the aconitine was metabolized, proved successful in this case and should be considered as a management approach in cases of severe aconite poisoning.

Clinical and electrophysiological characteristics in patients with sustained monomorphic reentrant ventricular tachycardia associated with dilated-phase hypertrophic cardiomyopathy.

AIMS: Little is known about sustained monomorphic ventricular tachycardia (SMVT) associated with dilated-phase hypertrophic cardiomyopathy (DHCM). The purpose of this study was to clarify the clinical characteristics and effectiveness of catheter ablation for SMVTs in DHCM patients. METHODS AND RESULTS: Five patients with DHCM (mean age; 67.0 years old, five males) who underwent catheter ablation for drug-refractory SMVTs were included the study. Four of five patients suffered from electrical storm. When the endocardial ablation failed, epicardial and/or intracoronary ethanol ablation, or surgical cryoablation was performed. We reviewed all ablation procedures and electrocardiogram (ECG) of targeted SMVTs. A total of 13 SMVTs were targeted for ablation. Mechanism of all ventricular tachycardias (VTs) was diagnosed as reentry. Endocardial ablation successfully eliminated all VTs in two patients. The remaining three patients needed epicardial ablation, intracoronary ethanol ablation, and surgical cryoablation. All but one VT arose from the basal septum, basal anterior to anterolateral left ventricle (LV). Although the ECGs demonstrated similar features of idiopathic outflow or mitral annulus VTs reflecting the origins, there were characteristic multiple QRS deflections. Following the ablation, four (80%) of the five patients are free from VT recurrence during 18 months of the follow-up period. CONCLUSIONS: In DHCM patients, VT circuits predominantly distributed in the basal septum and the basal anterior to anterolateral LV. In addition to the endocardial ablation, alternative approaches were required in some patients.

Reciprocal control of hERG stability by Hsp70 and Hsc70 with implication for restoration of LQT2 mutant stability.

RATIONALE: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the potassium current I(Kr). It is highly expressed in cardiomyocytes and its mutations cause long QT syndrome type 2. Heat shock protein (Hsp)70 is known to promote maturation of hERG. Hsp70 and heat shock cognate (Hsc70) 70 has been suggested to play a similar function. However, Hsc70 has recently been reported to counteract Hsp70. OBJECTIVE: We investigated whether Hsc70 counteracts Hsp70 in the control of wild-type and mutant hERG stability. METHODS AND RESULTS: Coexpression of Hsp70 with hERG in HEK293 cells suppressed hERG ubiquitination and increased the levels of both immature and mature forms of hERG. Immunocytochemistry revealed increased levels of hERG in the endoplasmic reticulum and on the cell surface. Electrophysiological studies showed increased I(Kr). All these effects of Hsp70 were abolished by Hsc70 coexpression. Heat shock treatment of HL-1 mouse cardiomyocytes induced endogenous Hsp70, switched mouse ERG associated with Hsc70 to Hsp70, increased I(Kr), and shortened action potential duration. Channels with disease-causing missense mutations in intracellular domains had a higher binding capacity to Hsc70 than wild-type channels and channels with mutations in the pore region. Knockdown of Hsc70 by small interfering RNA or heat shock prevented degradation of mutant hERG proteins with mutations in intracellular domains. CONCLUSIONS: These results indicate reciprocal control of hERG stability by Hsp70 and Hsc70. Hsc70 is a potential target in the treatment of LQT2 resulting from missense hERG mutations.

Autonomic and pharmacological responses of idiopathic ventricular tachycardia arising from the left ventricular outflow tract.

BACKGROUND: It is well recognized that the mechanism of idiopathic ventricular tachycardia (VT) arising from the right ventricular outflow tract (RVOT) is mostly due to cyclic AMP-mediated triggered activity. The mechanism of VT arising from the left ventricular outflow tract (LVOT) has not been well clarified whether it is the same as VT of RVOT. METHODS: We studied autonomic modulations and pharmacological interventions on VT/premature ventricular contractions (PVCs) from LVOT to explore its possible mechanism in six patients (age: 49 +/- 14, three males). None of them had structural heart diseases. RESULTS: Isoproterenol application easily induced VT and/or PVCs from LVOT. Valsalva maneuvers suppressed isoproterenol-induced VT in two and PVCs in two, and carotid sinus massage (CSM) suppressed PVCs in one patient. Adenosine triphosphate inhibited both VT and PVCs in all six patients. Propranolol, lidocaine, and procainamide eliminated VT/PVCs in four, three, and four patients, respectively. Verapamil terminated VT in one and PVCs in another one patient, but aggravated PVCs to VT in one patient. CONCLUSION: The results suggest that the mechanism of VT from LVOT is mostly due to cAMP-mediated triggered activity as similar to that in VT from RVOT.

Hypotonic stress enhances slope conductivity of ATP-sensitive K+ channels activated pharmacologically.

The aim of this paper was to find out the effects of hypotonic stress on the slope conductivity of ATP-sensitive K(+) channels. Using patch clamp technique, rilmakalim and pinacidil as the activators and glibenclamide as an inhibitor of mentioned channels, we have demonstrated that short hypotonic challenge doubled slope conductivity of exploring channels by augmentation of their open probability.

Metabolic pathways for ion homeostasis and persistent Na(+) current.

ATP supply in heart cells is preserved by a number of different mechanisms to maintain a constant level of ATP concentration. ADP, phosphocreatine, inorganic phosphate, and cAMP-activated kinases are effectively involved in ATP supply in abnormal conditions such as ischemia. Intracellular Na(+) and Ca(2+) concentrations in the heart cells are maintained at low levels through the operation of ion transport across the plasma membrane, such as Na(+)-K(+) pumps, as well as Na(+)-Ca(2+), and Na(+)-H(+) exchangers. The activity of the latter two exchanger mechanisms depends on their expression levels and the concentration gradients of Na(+) and Ca(2+) across the membrane. These exchangers may interact, and both are strongly regulated by intracellular Na(+), which is maintained by the Na(+)-K(+) pump, utilizing ATP as an energy source. The mitochondria and the sarcoplasmic reticulum are the organelles responsible for intracellular Ca(2+) stores and release sites for maintaining very low cytoplasmic concentration of Ca(2+). Ischemia disrupts the delicate interactions of these transport mechanisms. This may cause intracellular Na(+) and Ca(2+) accumulation, which can cause decreased contractility and electrical instability. Further, a persistent (noninactivating) Na(+) current may be enhanced during ischemia, and this can contribute to action potential prolongation, and the development of early afterdepolarizations. The Na(+) influx via the persistent Na(+) current may induce further Na(+) and Ca(2+) accumulation in the cells.

Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivation.

OBJECTIVE: The function of the C-terminus region of the human ether-a-go-go related gene (HERG) has not been well characterized except for its involvement in trafficking. To understand further the role of C-terminus region, we performed a functional analysis of a novel frameshift mutation (1122fs/147) identified in a Japanese long QT syndrome 2 (LQT2) patient who had recurrent episodes of syncope. METHODS: Wild type (WT) and mutant HERG plasmids were transfected into human embryonic kidney (HEK-293) cells, and whole-cell current was recorded by the patch-clamp technique. Confocal microscopy was performed to examine the membrane distribution of channel protein using a green fluorescent protein tagged to the N-terminus of HERG. RESULTS: The mutant 1122fs/147 alone could express current, but reduced density by 74% of control. No dominant negative effect was noted with co-expression of WT and 1122fs/147. Activation and deactivation time constants were not changed, while inactivation was accelerated in 1122fs/147 compared to WT, and V(1/2) of steady-state inactivation curve shifted by 11 mV in the negative direction. Current density of 1123stop mutant revealed 49% reduction compared to WT and showed no shift in steady-state inactivation. Confocal microscopy revealed reduced protein expression on the cell surface both in 1122fs/147 and 1123stop mutants compared to WT. CONCLUSION: Frameshift mutation at the C-terminus region with additional 147 amino acids evoked a loss of function of the HERG channel. A negative shift in steady-state inactivation induced by the additional 147 amino acids and trafficking defect contribute to a reduced current amplitude of 1122fs/147.

Functional expression of Ca2+ signaling pathways in mouse embryonic stem cells.

Mouse embryonic stem (mES) cells have the potential to differentiate into all types of cells, but the physiological properties of undifferentiated mES cells, including Ca2+ signaling systems, are not fully understood. In this study, we investigated Ca2+ signaling pathways in mES cells by using confocal Ca2+ imaging systems, patch clamp techniques and RT-PCR. The stimulations with ATP and histamine (His) induced a transient increase of intracellular Ca2+ concentration ([Ca2+]i), which were prevented by the pretreatment of 2-amino-ethoxydiphenyl borate (2-APB), a blocker for inositol-1,4,5-triphosphate receptors (InsP3Rs). The application of caffeine (Caff) or ryanodine (Ry) did not change [Ca2+]i. When stores were depleted with Ca2+ -ATPase blocker, thapsigargin (TG), or histamine, the capacitative Ca2+ entry (CCE) was observed. In whole cell patch clamp mode, store-operated Ca2+ currents could be recorded in cells treated with histamine and thapsigargin. On the other hand, voltage-operated Ca2+ channels (VOCCs) could not be elicited. The application of blockers for plasma membrane Ca2+ pump (PMCAs) (carboxeosin or caloxin2A1) induced a large increase of [Ca2+]i. When the Na+/Ca2+ exchangers (NCXs) were blocked by Na+ free solution or KBR7943, [Ca2+]i was also elevated. Using RT-PCR, mRNAs for InsP3Rs type-1, -2, and -3, PMCA-1 and -4, NCX-1, -2, and -3 could be detected. From these results, we conclude that Ca2+ release from ER is mediated by InsP3Rs in mES cells before differentiation and Ca2+ entry through plasma membrane is mainly mediated by the store-operated Ca2+ channels (SOCs). For the Ca2+ extrusion systems, both NCXs and PMCAs play important roles for maintaining the low level of [Ca2+]i.

Block of HERG current expressed in HEK293 cells by the Na+-channel blocker cibenzoline.

A Na(+)-channel blocker, cibenzoline, blocks the delayed rectifier potassium current ( I(k)), but its detailed action on the rapidly activating component ( I(kr)) of I(k) encoded by the human ether-a-go-go-related gene ( HERG) has not been clarified. We examined the effects of cibenzoline on stably expressed HERG current in HEK293 cells recorded by the patch-clamp technique of whole-cell configuration. Cibenzoline blocked HERG current expressed in HEK293 cells with IC(50) = 3.7 +/- 0.963 micro M and Hill coefficient = 0.74 +/- 0.12. Voltage-depended activation was shifted in a negative direction by cibenzoline. No block or minor block was induced at test depolarization of -40 to -30 mV, and the block increased with depolarization reaching a plateau at 0 mV without a further increase at positive voltages. Voltage-dependent activation of HERG currents became faster at negative test voltages but there were no changes at positive voltages after cibenzoline. No frequency-dependent block of HERG tail current by cibenzoline after equilibration was noted between 1.33 and 0.2 Hz. Steady-state inactivation of the HERG current was shifted in a negative direction by approximately 8 mV but the time constants of fast inactivation were little affected by cibenzoline. Cibenzoline blocks the I(kr)-like current reconstituted by HERG clone transfection with an IC(50) value comparable to therapeutic concentrations. Cibenzoline has a preferential affinity, at least, to the open state of the HERG channel with a rapid access to the binding site.