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It remains unknown whether P wave duration (PWD) ≥ 150 ms measured after extensive radiofrequency catheter ablation (RFCA) can identify non-paroxysmal atrial fibrillation (non-PAF) patients at increased risk of atrial tachyarrhythmia recurrence. We investigated the predicting power of PWD and its association with left atrial (LA) reverse remodeling in patients with non-PAF undergoing pulmonary vein isolation with LA linear ablation.We retrospectively evaluated 136 patients who underwent RFCA for drug-refractory non-PAF. Electroanatomic mapping was acquired during AF. Low-voltage area (LVA) was defined as an area with bipolar voltage ≤0.5 mV. Electrocardiography and echocardiography were performed during sinus rhythm 1 day and 3 months after RFCA. PWD was measured using amplified 12‑lead electrocardiography. Prolonged PWD was defined as maximum PWD ≥ 150 ms.Over a mean follow-up duration of 48 ± 35 months, 28 patients experienced atrial tachyarrhythmia recurrence. PWD was positively correlated with LVA (r = 0.527, p 0.001) and inversely correlated with LA emptying fraction (r = -0.399, p 0.001). PWD was shortened and LA emptying fraction (LAEF) was increased in patients without atrial tachyarrhythmia recurrence during follow-up. Atrial tachyarrhythmia-free survival was significantly more likely in patients without a prolonged PWD (83.5% vs 60.7%, p = 0.002). Multivariate analysis showed that LAEF and PWD were independent predictors of atrial tachyarrhythmia recurrence.PWD ≥ 150 ms measured after RFCA can identify patients with non-PAF at increased risk of atrial tachyarrhythmia recurrence. PWD is correlated with LVA and LAEF and reflects LA reverse remodeling.

Background Coronary artery disease is the most common cause of heart failure (HF) in developed countries. The aim of this study was to elucidate the mechanisms of reduction of arrhythmias after sacubitril/valsartan (LCZ696) therapy in a myocardial infarction (MI)-HF rabbit model. Methods and Results Chronic MI in rabbits with HF were divided into 3 groups: placebo control, valsartan 30 mg/day and LCZ696 60 mg/day. After 4 weeks of therapy, an electrophysiologic study and a dual voltage-calcium optical mapping study were performed. The LCZ696 group had significantly better left ventricular ejection fraction and lower ventricular tachyarrhythmia inducibility than the valsartan and placebo groups. The most common ventricular tachyarrhythmia pattern was 1 or 2 ectopic beats originating from the peri-infarct areas, followed by re-entrant beats surrounding phase singularity points. Compared to the valsartan and placebo groups, the LCZ696 group had significantly shorter action-potential duration, shorter intracellular calcium tau constant, faster conduction velocity, and shorter pacing cycle length to induce arrhythmogenic alternans. LCZ696 therapy reduced the phosphorylated calmodulin-dependent protein kinase II (CaMKII-p) expression. Conclusions In a rabbit model with chronic MI and HF, LCZ696 therapy ameliorated postinfarct heart function impairment and electrophysiologic remodeling and altered CaMKII-p expression, leading to reduced ventricular tachyarrhythmia inducibility.

Aims: Whether therapeutic hypothermia (TH) is proarrhythmic in preexisting failing hearts with acute ischemia–reperfusion (IR) injury is unknown. Additionally, the effectiveness of rotigaptide on improving conduction slowing in hearts with IR injury is ambiguous. We investigated the electrophysiological effects of TH and rotigaptide in failing rabbit hearts with acute IR injury and determined the underlying molecular mechanisms.Methods and Results: Heart failure was induced by right ventricular pacing (320 beats/min, 4 weeks). Rabbits with pacing-induced heart failure were randomly divided into TH (n = 14) and non-TH (n = 7) groups. The IR rabbit model was created by ligating the coronary artery for 60 min, followed by reperfusion for 15 min in vivo. Then, the hearts were excised quickly and Langendorff-perfused for simultaneous voltage and intracellular Ca2+ (Cai) optical mapping. Electrophysiological studies were conducted, and vulnerability to ventricular fibrillation (VF) was evaluated using pacing protocols. TH (33°C) was instituted after baseline studies, and electrophysiological studies were repeated. Rotigaptide (300 nM) was infused for 20 min, and electrophysiological studies were repeated under TH. Cardiac tissues were sampled for Western blotting. TH increased the dispersion and beat-to-beat variability of action potential duration (APD), aggravated conduction slowing, and prolonged Cai decay to facilitate spatially discordant alternans (SDA) and VF induction. Rotigaptide reduced the dispersion and beat-to-beat variability of APD and improved slowed conduction to defer the onset of arrhythmogenic SDA by dynamic pacing and elevate the pacing threshold of VF during TH. However, the effect of rotigaptide on TH-enhanced VF inducibility was statistically insignificant. TH attenuated IR-induced dysregulation of protein expression, but its functional role remained uncertain.Conclusion: Therapeutic hypothermia is proarrhythmic in failing hearts with acute IR injury. Rotigaptide improves TH-induced APD dispersion and beat-to-beat variability and conduction disturbance to defer the onset of arrhythmogenic SDA and elevate the VF threshold by dynamic pacing, but these beneficial electrophysiological effects are unable to suppress TH-enhanced VF inducibility significantly.

Background: Studies have demonstrated that db/db mice have increased susceptibility to myocardial ischemia-reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury.Methods: Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies and optical mapping to simultaneously record intracellular Ca2+ (Cai) and membrane voltage in Langendorff-perfused hearts were performed. Western blotting and whole-cell patch clamp study were performed to evaluate the effect of ranolazine in the non-IR and IR zones. Results: The severity of VA inducibility by burst pacing was higher in db/db mice than db/+ mice with acute IR injury. Ranolazine suppressed VA inducibility and severity in db/db and db/+ mice. Optical mapping studies showed that ranolazine significantly shortened action potential duration (APD80), Cai transient duration (CaiTD80), Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. The expression of pThr17-phospholamban, calsequestrin 2 and SCN5A in the IR zone was significantly downregulated in db/db mice, which was ameliorated by ranolazine. Conclusions: Ranolazine pretreatment shortens APD80 and CaiTD80, reduces Cai decay time, and ameliorates conduction velocity inhomogeneity to suppress induction of arrhythmogenic alternans and VA; and amelioration of downregulation of pThr17-phospholamban, calsequestrin 2 and SCN5A may partly underlie the anti-arrhythmic molecular mechanisms of ranolazine in db/db mouse hearts with IR injury.

To evaluate the performance of a single‑lead, 14-day continuous electrocardiogram (ECG) patch for the detection of arrhythmias compared to conventional 24-h monitoring.This prospective clinical trial enrolled patients suspected of arrhythmias but not diagnosed by 12‑lead ECGs. Each patient underwent a 24-h Holter and 14-day ECG patch simultaneously. Seven types of arrhythmias were classified: supraventricular tachycardia (SVT, repetitive atrial beats4 beats), irregular SVT without P wave (4 beats), AF/AFL (irregular SVT without P wave ≥30 s), pause ≥3 s, atrioventricular block (AVB; Mobitz type II, third-degree, two to one or high degree AVB), ventricular tachycardia (VT), and polymorphic VT.A total of 158 patients were recruited (mean wear time:12.3 ± 3.2 days). The overall arrhythmia detection rate was higher with 14-day ECG patches (59.5%) compared to 24-h Holter (19.0%, P0.001). Up to 87.2% of arrhythmias recorded with 14-day ECG patches were not associated with symptoms. The 14-day ECG patch was associated with higher detection rates compared to the 24-h Holter in patients with SVT (52.5% versus 15.8%, P0.001), irregular SVT without P wave (12.7% versus 4.4%, P = 0.002), AF/AFL (9.5% versus 3.8%, P = 0.042), and critical arrhythmias (pause ≥3 s, AVB, VT, polymorphic VT) (16.5% versus 2.5%, P0.001). The 14-day ECG patch detected more than 2 types of arrhythmias in 5.1% of patients. No serious adverse events in patients wearing the 14-day ECG patch were reported.The 14-day ECG patch outperformed 24-h Holter to detect overall, asymptomatic, critical and multiple arrhythmias. It is safe and has the potential to identify individuals with hidden arrhythmias, especially those with critical arrhythmias.

Aims: Curved M-mode images of global strain (GS) and strain rate (GSR) provide sufficiently detailed spatiotemporal information of deformation mechanics. This study investigated whether a deep convolutional neural network (CNN) could accurately classify these images in patients with atrial fibrillation (AF) who underwent radiofrequency catheter ablation (RFCA) with different outcomes.Methods and Results: We retrospectively evaluated 606 consecutive patients who underwent RFCA for drug-refractory AF. Patients were divided into AF-free (n = 443) and AF-recurrent (n = 163) groups. Transthoracic echocardiography was performed within 24 h after RFCA. Left atrial curved M-mode speckle-tracking images were acquired from randomly selected 163 patients in AF-free group and 163 patients in AF-recurrent group as the dataset for deep CNN modeling. We used the ReLu activation function and repeatedly performed CNN model for 32 times to evaluate the stability of hyperparameters. Logistic regression models with the left atrial dimension, emptying fraction, and peak systolic GS as predictor variables were used for comparisons. Images from the apical 2-chamber (2-C) and 4-chamber (4-C) views had distinct features, leading to different CNN performance between settings; of them, the “4-C GS+4-C GSR” setting provided the highest performance index values. All four predictor variables used for logistic regression modeling were significant; however, none of them, individually or in any combined form, could outperform the optimal CNN model.Conclusion: The novel approach using deep CNNs for learning features of left atrial curved M-mode speckle-tracking images seems to be optimal for classifying outcome status after AF ablation.

Aims This study aimed to compare the efficacy of angiotensin receptor–neprilysin inhibitor (ARNI) therapy with angiotensin receptor blocker (ARB) therapy for cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction. Methods and results Data were obtained from the Chang Gung Research Database. The cohort entry date of the ARB group was assigned as that of the ARNI group to avoid immortal time bias. Additionally, 1:1 propensity score matching based on age, sex, and baseline left ventricular ejection fraction was conducted. The expectation–maximization imputation method with inverse probability of treatment weighting was used to compare outcomes between the two groups. The primary outcome was a composite of cardiovascular death and hospitalization for worsening HF. Patients who received ARNI therapy had a significantly lower risk of the primary composite outcome occurring than patients who received ARBs (hazard ratio, 0.74; 95% confidence interval, 0.57–0.96). The reduction of hospitalization for worsening HF contributed most to the primary outcome benefits. In addition to the primary outcome, the ARNI group had a significantly lower risk of non‐fatal myocardial infarction. The improvement of ejection fraction was not significantly different between the groups. The medication doses of ARNI were lower than in clinical trials. Conclusions In patients with HF with reduced ejection fraction, sacubitril/valsartan was superior to ARB therapy in reducing the occurrence of the primary outcome endpoint of hospitalization for worsening HF and cardiovascular death.

BACKGROUND Piceatannol, a grape-derived polyphenol, has been linked to proarrhythmic properties by aggravating inhomogeneous conduction delay in the ischemia-reperfusion (IR) zone to enhance arrhythmogenic alternans in heart failure (HF) rabbits. The underlying molecular mechanisms of piceatannol-induced conduction disturbance were unclear in this model. METHODS HF was induced by 4 weeks' rapid ventricular pacing. IR injury was induced in vivo using a protocol of left coronary artery ligation and release. Left ventricular cardiomyocytes were isolated enzymatically for whole-cell patch-clamp studies. Piceatannol (10 μM) was administrated to test its inhibitory effect on sodium current (INa ). Immunoblots studies and immunoenzymological staining were conducted in tissues sampled from the IR and remote zones. RESULTS Peak INa density was less in failing cardiomyocytes than control cardiomyocytes. IR injury further reduces peak INa density in both groups. Piceatannol showed a greater INa inhibitory effect in HF than control cardiomyocytes. Western blots showed reduced NaV 1.5 protein expression in the HF group compared to the control group but no significant difference between remote and IR zones. Immunostaining showed that IR led to cytosolic redistribution of NaV 1.5, especially in failing hearts. CONCLUSIONS Downregulation of NaV 1.5 protein expression and reduced peak INa density are found in the failing hearts. Piceatannol exerts a greater inhibitory effect on peak INa in the failing cardiomyocytes than in the controls. IR injury further decreases peak INa density, which is more prominent in the failing hearts than in the control hearts.

Background. LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods. We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results. The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion. As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis of secondary Ca rise and EAD-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca rise, EADs development, and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM-10103 had a neutral effect on the amplitude of secondary Cai rise in control and heart failure groups. In this model, most EADs generated from long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced premature ventricular beat burden but was unable to suppress secondary Ca rise, EADs development, or inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.

Background The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients with chronic kidney disease (CKD) after acute myocardial infarction (AMI) are unclear. Methods We analyzed data from the Taiwan National Health Insurance Research Database between March 1st, 2009 and December 31st, 2011. A total of 1025 AMI patients with diabetes with chronic kidney disease were selected as the study cohort. The study evaluated the cardiovascular safety and efficacy of sitagliptin by comparing 205 subjects (20%) who use sitagliptin to 820 matched subjects (80%) who do not. The primary outcomes included myocardial infarction, ischemic stroke or cardiovascular death. Results Primary composite outcomes occurred in 54 patients in the sitagliptin group (26.3%) and in 164 patients in the comparison group (20.0%) (HR, 1.32; 95% CI, 0.97–1.79; P =0.079) during the mean follow-up of 1.02years ( SD =0.71years). The sitagliptin group had similar risks of ischemic stroke, all-cause mortality or hospitalization for heart failure (HF) compared to the non-sitagliptin group ( P =0.938, 0.523 and 0.795 respectively). However, sitagliptin use was associated with increased risks of recurrent myocardial infarction (HR, 1.73; 95% CI, 1.15–2.58; P =0.008) and percutaneous coronary revascularization (HR, 1.43; 95% CI, 1.04–1.95; P =0.026). Conclusions Among type 2 diabetic patients with CKD after AMI, the use of sitagliptin was not associated with an increased risk of cardiovascular death, ischemic stroke or hospitalization for HF but was associated with increased risks of recurrent MI and percutaneous coronary revascularization.

Dantrolene was reported to suppress ventricular fibrillation (VF) in failing hearts with acute myocardial infarction, but its antiarrhythmic efficacy in regional ischemia-reperfusion (IR) hearts remains debatable. Heart failure (HF) was induced by right ventricular pacing. The IR rabbit model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo in both HF and non-HF groups (n= 9 in each group). Simultaneous voltage and intracellular Ca2+(Cai) optical mapping was then performed in isolated Langendorff-perfused hearts. Electrophysiological studies were conducted and VF inducibility was evaluated by dynamic pacing. Dantrolene (10 μM) was administered after baseline studies. The HF group had a higher VF inducibility than the control group. Dantrolene had both antiarrhythmic (prolonged action potential duration (APD) and effective refractory period) and proarrhythmic effects (slowed conduction velocity, steepened APD restitution slope, and enhanced arrhythmogenic alternans induction) but had no significant effects on ventricular premature beat (VPB) suppression and VF inducibility in both groups. A higher VF conversion rate in the non-HF group was likely due to greater APD prolonging effects in smaller hearts compared to the HF group. The lack of significant effects on VPB suppression by dantrolene suggests that triggered activity might not be the dominant mechanism responsible for VPB induction in the IR model.

Background Diabetes mellitus is associated an increased risk of ventricular arrhythmias (VAs), but the underlying electrophysiological mechanisms are not fully explored. This study was aimed to test whether dynamic factors and Cai handling play roles in arrhythmogenesis of a diabetic animal model. Methods We used 26 db/db type 2 diabetes mice and 28 control mice in this study. VA inducibility was evaluated in vivo under isoflurane general anesthesia. The intracellular Ca2+ (Cai ) and membrane voltage (Vm ) signals of the Langendorff-perfused mouse hearts were simultaneously recorded using the optical mapping technique. Action potential duration (APD), Cai dynamics conduction velocity (CV), and arrhythmogenic alternans were analyzed. Western blot was conducted to examine expressions of calcium handling and associated ion channels proteins. Results The diabetic db/db mice showed significantly increased VA inducibility and severity. Longer APD and Cai transient duration and slower Cai decay and CV in the db/db mice than these in the control ones were observed. Dynamic pacing showed increased incidence of spatially discordant alternans leading to more VA inducibility in the db/db mice. Western blot analyses revealed increased phosphorylated-Ca2+ /calmodulin-dependent protein kinase II protein expression and decreased ryanodine receptor protein expression, which probably underlay the molecular mechanisms of enhanced arrhythmogenicity in db/db mice. Conclusions The type 2 diabetic mouse hearts show impaired repolarization, Cai handling homeostasis, and cardiac conduction reserve, leading to vulnerability of spatially discordant alternans development and induction of VA. Altered Cai -handling protein expressions probably underlie the molecular mechanisms of arrhythmogenicity in the type 2 diabetes animal model.

Background Cardiac arrhythmias are common causes of death in patients with myotonic dystrophy (dystrophia myotonica [ DM ]). Evidence shows that atrial tachyarrhythmia is an independent risk factor for sudden death; however, the relationship is unclear. Methods and Results Control wild‐type ( Mbnl1 +/+ ; Mbnl2 +/+ ) and DM mutant ( Mbnl1 −/− ; Mbnl2 +/− ) mice were generated by crossing double heterozygous knockout ( Mbnl1 +/− ; Mbnl2 +/− ) mice. In vivo electrophysiological study and optical mapping technique were performed to investigate mechanisms of ventricular tachyarrhythmias. Transmission electron microscopy scanning was performed for myocardium ultrastructural analysis. DM mutant mice were more vulnerable to anesthesia medications and program electrical pacing: 2 of 12 mice had sudden apnea and cardiac arrest during premedication of general anesthesia; 9 of the remaining 10 had atrial tachycardia and/or atrioventricular block, but none of the wild‐type mice had spontaneous arrhythmias; and 9 of 10 mice had pacing‐induced ventricular tachyarrhythmias, but only 1 of 14 of the wild‐type mice. Optical mapping studies revealed prolonged action potential duration, slower conduction velocity, and steeper conduction velocity restitution curves in the DM mutant mice than in the wild‐type group. Spatially discordant alternans was more easily inducible in DM mutant than wild‐type mice. Transmission electron microscopy showed disarranged myofibrils with enlarged vacuole‐occupying mitochondria in the DM mutant group. Conclusions This DM mutant mouse model presented with clinical myofibril ultrastructural abnormality and cardiac arrhythmias, including atrial tachyarrhythmias, atrioventricular block, and ventricular tachyarrhythmias. Optical mapping studies revealed prolonged action potential duration and slow conduction velocity in the DM mice, leading to vulnerability of spatially discordant alternans and ventricular arrhythmia induction to pacing.

Background Macroreentrant atrial tachycardia (MRAT) is frequently unresponsive to antiarrhythmic drugs. The application of three-dimensional (3D) mapping and entrainment pacing contributes to a high success rate for radiofrequency ablation, but programmed electrical pacing may either terminate or transform clinical tachyarrhythmias. On the basis of clinical experiences of the use of ventricular tachycardia ablation, channels with continuous activation are suitable for reentrant circuits, and ablation at these channels can lead to noninducibility of ventricular tachycardias. We reviewed patients referred for symptomatic MRAT with identified channels with continuous activation and evaluated the efficacy of MRAT ablation by targeting these channels. Methods Fifteen consecutive patients (10 men, 49 ± 14 years) with MRAT illustrated by endocardial activation maps using a 3D electroanatomical mapping system (CARTO™, Biosense Webster, Diamond Bar, CA, USA) were included in this study. Continuous activation was defined as double or continuous potentials without an isoelectric interval, and sites with continuous activation were tagged for measurements of channel properties. Radiofrequency ablation was performed at those targeted sites located within the reentrant circuit. Results Radiofrequency ablation successfully eliminated MRAT in all patients. The mean cycle length was 283 ± 60 ms, and the longest activation duration was 112 ± 38 ms. The minimal and maximal bipolar voltage amplitudes were 0.13 ± 0.1 mV and 0.7 ± 0.6 mV, respectively. The targeted ablation length and width were 28.9 ± 15.3 mm and 9.4 ± 3.3 mm, respectively. Conclusion Radiofrequency ablation of MRAT targeting channels with continuous activation using a 3D electroanatomical mapping system yields a high success rate.

Background The stability of dynamic factors has been reported to play a role in the antiarrhythmic actions of adenosine triphosphate (ATP)-sensitive potassium channel (KATP) opener in phase-2 myocardial infarction (MI) hearts. In the situation of the downregulation of KATP, the effects of KATP blocker (HMR1098) on the dynamic factors and electrophysiological changes during phase-2 MI remain unclear. Methods Dual voltage and intracellular Ca2+ (Cai) optical mapping was performed in nine Langendorff-perfused hearts 4–5 hours after coronary artery ligation and five control hearts. Electrophysiology studies, including action potential duration (APD) restitution, conduction velocity (CV), inducibility of ventricular fibrillation (VF), VF dominant frequency, APD and Cai alternans, and Cai decay, were performed. The same protocol was repeated in the presence of HMR1098 (10 μm) after the baseline studies. Results HMR1098 significantly prolonged APD and effective refractory period to prevent sustained VF in five of nine MI hearts and two of five control hearts compared to none at baseline in both groups. On the other hand, HMR1098 steepened APD restitution slope to enhance spatially concordant alternans in both groups. In the phase-2 MI group, HMR1098 steepened CV restitution slope and enhanced spatially discordant alternans (SDA), which might account for a decreased pacing threshold of VF induction during HMR1098 infusion in phase-2 MI hearts. Conclusions In phase-2 MI hearts, HMR1098 has contrasting effects on arrhythmogenesis, suppressing reentry and VF persistence but facilitating VF inducibility. The mechanism is the intensified induction of SDA because of the steepened APD and CV restitution slopes.

Dantrolene in Failing Hearts with AMIIntroduction Dantrolene prevents arrhythmogenic Ca2+ release during heart failure (HF). However, direct evidence to support its antiarrhythmic effects in failing hearts with acute myocardial infarction (AMI) is lacking. Methods and Results HF was induced by right ventricular pacing (312 beats/min, 4 weeks) in 19 rabbits. AMI was induced by coronary artery ligation in rabbits surviving chronic pacing (n = 17). The hearts were quickly excised and Langendorff-perfused for simultaneous membrane potential and intracellular Ca2+ (Cai) optical mapping when ventricular fibrillation (VF) occurred or 4 hours after AMI. The VF inducibility was defined as the ability to provoke sustained VF (>2 minutes) by pacing. Dantrolene (10 μM) was administered after baseline studies. Spontaneous VF occurred in 5 rabbits (SVF group). The ventricular premature beat (VPB) burden was significantly higher in the SVF group than the non-SVF group (P < 0.05). Dantrolene suppressed VPB burden (P = 0.03) and prolonged action potential duration (APD; P < 0.05) to reduce VF inducibility (P < 0.05). However, dantrolene shortened immediate postshock APD50 even if VF storm was suppressed. Conclusion In failing hearts with AMI, VPB burden plays a pivotal role in SVF occurrence. Dantrolene suppresses VPBs and/or prolongs repolarization to inhibit spontaneous VF and reduce VF inducibility.

Background The effects of SEA0400, a Na+/Ca2+ exchanger (NCX) blocker, on dynamic factors and arrhythmogenic alternans in 1-month myocardial infarction (MI) hearts remain unknown. Methods Simultaneous voltage and intracellular Ca2+ (Cai) optical mapping was performed in 12 rabbit hearts with MI for 1 month and six normal rabbit hearts as control. Western-blot studies were performed in both groups in an additional six hearts for each. Action potential duration (APD) restitution was constructed and arrhythmogenic alternans was induced by dynamic pacing. SEA0400 (0.03, 3 μM) was administered after baseline studies. Results SEA0400 suppressed pacing-induced ventricular premature beats in a concentration-dependent manner. SEA0400 at 0.03 μM steepened APD restitution slopes and enhanced spatially discordant alternans (SDA), which became insignificant at 3 μM. The VF inducibility was seven of nine at baseline, nine of nine at 0.03 μM SEA0400, and five of nine at 3 μM SEA0400 (P = NS). Significant upregulation of NCX in the remote but not periinfarct zone and less degree downregulation of DHP1α in the remote versus periinfarct zone may play a role in enhancing SDA induction by SEA0400 in 1-month MI hearts. Conclusions In 1-month MI hearts, SEA0400 suppresses pacing-induced ventricular premature beats, but also is proarrhythmic by steepening APD restitution and enhancing SDA via NCX inhibition. Heterogeneous upregulation of NCX and downregulation of DHP1α may contribute to SDA augmentation by SEA0400 in this model. The insignificant effect of SEA0400 on VF inducibility suggests that suppression of both reentry and triggered activity is required to suppress VF induction in this model.

BackgroundTo compare potential risk factors for complications and recurrence after radiofrequency catheter ablation in symptomatic atrioventricular reentrant tachycardia in children and adolescents.MethodsWe retrospectively reviewed the data of 213 consecutive patients with symptomatic atrioventricular reentrant tachycardia who underwent both electrophysiological study and radiofrequency catheter ablation, divided these patients into two groups, children (age ResultsThe position of the accessory pathway was mostly right sided in children (61.3%) and left sided in adolescents (61.5%). Children had significantly more congenital heart disease than adolescents (6.4% versus 0.8%). Univariate analysis showed children or adolescents with right-sided accessory pathways to be 6.84 times and those with accessory pathways on both sides of the septum 25 times more likely to relapse than those with a single accessory pathway. Multivariate analysis indicated that children or adolescents with two accessory pathways were six times, and those with intermittent ventricular pre-excitation nine times more at risk of relapsing following radiofrequency ablation than those with single accessory pathways. All five complications occurred in children.ConclusionsThe findings suggest that the position and number of accessory pathways and presence of intermittent ventricular pre-excitation are related to risks of recurrence of atrioventricular reentrant tachycardia in children and adolescents.

Background Radiofrequency catheter ablation (RFCA) is a potentially curative treatment for atrial fibrillation (AF), however, whether or not additional left atrial (LA) linear ablation for recurrent AF adversely affects LA remodeling is unknown. Methods Thirty-eight patients experiencing AF recurrence after the 1st circumferential pulmonary vein isolation (CPVI) underwent a repeat RFCA, including 20 and 18 patients receiving a repeat CPVI (group I) or CPVI plus LA linear ablation (group II), respectively. 2-D echocardiography was performed during sinus rhythm within 24h, at 1-m and 6-m after RFCA. Longitudinal strains and strain rate were measured with speckle-tracking echocardiography. The standard deviation of contraction duration was defined as LA mechanical dispersion. Results One and two patients experienced AF recurrence after the 2nd RFCA in group I and II, respectively (P=NS). The 1st CPVI with AF recurrence did not reduce LA size significantly in two groups. After a repeat CPVI, LA diameter but not LA maximal and minimal volume was significantly reduced in group I; additional LA linear ablation significantly decreased LA diameter, maximal and minimal volume in group II. However, there was no significant difference in LA emptying function, global and segmental LA strain and strain rate among the baseline, 1-m and 6-m follow-up in two groups. RFCA did not significantly increase LA mechanical dispersion regardless of the AF ablation strategies. Conclusions In patients with recurrent AF, a successful repeat CPVI with or without additional LA linear ablation reduced LA size without significant deleterious effects on LA function and mechanical dispersion.

Background Radiofrequency catheter ablation (RFCA) of ventricular arrhythmias (VAs) originating from the left ventricular (LV) papillary muscles (PMs) is challenging. Methods We enrolled 16 consecutive patients who received RFCA for VAs from LV PMs. Three-dimensional electroanatomical mapping was used to construct activation and/or pace maps. RFCA was performed first at the earliest activation site or at the best matched site in the pace maps. When an acceleration or reduction in the incidence of VAs was observed during the first few seconds of the application, the ablation energy was delivered continuously for 60–120s. Additional ablation was then circumferentially delivered at the base of the PMs. Results RFCA was successfully performed in all 16 patients with no cases of recurrence of VAs after a mean follow-up of 20±12months. VAs originated from the anterior (n=8) and posterior (n=8) PMs. Purkinje potentials were identified at the target sites in seven patients. All VAs were temporarily suppressed by one to two long-duration shots of RFCA at the initial targeted site, but recurrence was subsequently noted. In six patients, the QRS morphologies of the VAs changed after the initial RFCA. A subsequent circumferential approach with multiple ablations applied to the base of the PMs completely eliminated all VAs. In all but one patient, successful RFCA was achieved using an open-irrigated ablation catheter. Conclusions Circumferential RFCA at the base of the PMs overcame anatomical limitations, leading to a high success rate of RFCA for VAs from LV PMs.

Background Nicorandil (a KATP opener) administration is reported to reduce ventricular arrhythmias 4.8 ± 2.2 hours after myocardial infarction (MI). The electrophysiological changes and the effects on dynamic factors and dynamically induced spatially discordant alternans by nicorandil during phase-2 MI are unclear. Methods Simultaneous voltage and intracellular Ca2+ (Cai) optical mapping was performed in nine Langendorff-perfused hearts 4–5 hours after coronary artery ligation and nine control hearts. Action potential duration (APD) restitution was constructed and arrhythmogenic alternans was induced by dynamic pacing. Western blot studies (Kir6.1 and Kir6.2) were performed in six more hearts for both groups. Nicorandil (100 μM) was administered after baseline studies. Results Phase-2 MI hearts showed longer APD, slower conduction velocity (CV), and higher ventricular fibrillation (VF) inducibility than the control hearts. Nicorandil shortened and restored APD without significant arrhythmogenic effects, and also increased the rate of Cai reuptake and flattened CV restitution to suppress spatially discordant alternans, which might account for a tendency toward higher VF threshold with nicorandil infusion in phase-2 MI hearts. Immunoblotting studies showed significant down-regulation of KATP protein expression, which was functionally correlated to the blunted APD shortening response to nicorandil. Conclusions KATP expression is down-regulated in phase-2 MI hearts. Nicorandil restores APD, increases the rate of Cai reuptake, and flattens CV restitution to suppress spatially discordant alternans induction, which ameliorates its proarrhythmic effects during phase-2 MI.

ObjectivesThe purpose of this study was to provide direct evidences that rotor ablation suppresses atrial fibrillation (AF) inducibility.BackgroundMicro–re-entrant wavefronts have been suggested to serve as sources of rapid activations during AF. Whether AF inducibility is suppressed by elimination of rotors remains unknown.MethodsWe used optical mapping to study Langendorff-perfused left pulmonary vein (PV)–left atrium (LA) preparations from 13 dogs with pacing-induced heart failure. Atrial arrhythmias were induced by pacing and mapped during acetylcholine infusion (1 μmol/l). Rotors were identified from optical recordings. Epicardial ablation was performed targeting the rotor anchoring sites in preparations with sustained (>10 min) or incessant spontaneous AF. Non-rotor ablation was performed in 4 preparations. Repeated pacing was performed to test the AF inducibility after ablation.ResultsSustained AF (n = 12) and incessant spontaneous AF (n = 1) were induced after acetylcholine infusion. Pulmonary vein focal discharge was found in 9 preparations (9.2 ± 4.2 beats/s), and rotor anchoring was found at the left superior PV-LA junction in 13 preparations (9.1 ± 4.6 beats/s) and at the ligament of Marshall-PV-LA junction in 1 preparation. Epicardial rotor ablation successfully inhibited the inducibility of sustained AF in 12 of 13 preparations (p < 0.01), including 4 with the maximal dominant frequency sites located on the PV-LA junctional rotor zones (direct elimination of mother rotors). The longest AF duration was shortened significantly by rotor ablation (Wilcoxon Z = 3.60, p = 0.002, n = 13), but not by non-rotor ablation (Wilcoxon Z = 1.00, p = 0.317, n = 4).ConclusionsEpicardial ablation of the rotor anchoring sites suppresses AF inducibility. The arrhythmogenicity at the maximal dominant frequency sites is directly/indirectly suppressed by the rotor ablation.

Background Compared with left atrial (LA) dimension, LA emptying fraction (LAEF) has received less emphasis as a predictor of atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA). In addition, patients experiencing post-RFCA AF recurrence may respond to previously ineffective antiarrhythmic drugs (AADs). Classifying these patients into a third RFCA outcome category is recommended. Objective To identify predictors of RFCA outcome classified into three categories, and to build proportional odds logistic regression models for clinical applicability to predict AF recurrence. Methods Data were retrospectively collected from 483 consecutive patients with drug-refractory AF undergoing RFCA (328 men; age 58.4 ± 11.5 years; 383 paroxysmal). Patients were classified into 3 groups based on the last RFCA outcome: group 1, free from AF without AADs; group 2, free from AF with AADs; and group 3, recurrence of AADs-refractory atrial tachyarrhythmia. Results After a mean follow-up duration of 64.5 ± 43.2 months and mean ablation procedure number of 1.37 ± 0.68, the RFCA outcome showed 76.0%, 9.5% and 14.5% of patients in groups 1, 2, and 3, respectively. In multivariate analysis, LAEF was the most stable and important predictor of AF recurrence, followed by body mass index, stroke, AF duration, mitral regurgitation, and LA linear ablation. For patients undergoing repeat RFCA, LAEF was the only independent predictor (cutoffs: 43% and 35% for groups 1 and 3, respectively). Conclusion LAEF provides optimal prognostic information regarding the risk stratification of AF patients undergoing RFCA.

Atrial fibrillation (AF) is a complex arrhythmia with multiple possible mechanisms. It requires a trigger for initiation and a favorable substrate for maintenance. Pulmonary vein myocardial sleeves have the potential to generate spontaneous activity, and such arrhythmogenic activity is surfaced by modulation of intracellular calcium dynamics. Direct autonomic nerve recordings in canine models demonstrate that simultaneous sympathovagal discharges are the most common triggers of paroxysmal atrial tachycardia and paroxysmal AF. Autonomic modulation as a potential therapeutic strategy has been targeted clinically and experimentally, but its effectiveness as an adjunctive therapeutic modality to catheter ablation of AF has been inconsistent. Further studies are warranted before application can be widely implied for therapies of clinical AF.

Background Heart failure increases autonomic nerve activities and changes intracellular calcium (Ca i ) dynamics. Objective The purpose of this study was to investigate the hypothesis that abnormal Ca i dynamics are responsible for triggered activity in the pulmonary veins (PVs) during acetylcholine infusion in a canine model of heart failure. Methods Simultaneous optical mapping of Ca i and membrane potential was performed in isolated Langendorff-perfused PV–left atrial (LA) preparations from nine dogs with ventricular pacing-induced heart failure. Mapping was performed at baseline, during acetylcholine (1 μmol/L) infusion (N = 9), and during thapsigargin and ryanodine infusion (N = 6). Results Acetylcholine abbreviated the action potential. In four tissues, long pauses were followed by elevated diastolic Ca i , late phase 3 early afterdepolarizations, and atrial fibrillation (AF). The incidence of PV focal discharges during AF was increased by acetylcholine from 2.4 ± 0.6 beats/s (N = 4) to 6.5 ± 2.2 beats/s (N = 8; P = .003). PV focal discharge and PV–LA microreentry coexisted in 6 of 9 preparations. The spatial distribution of dominant frequency demonstrated a focal source pattern, with the highest dominant frequency areas colocalized with PV focal discharge sites in 35 (95%) of 37 cholinergic AF episodes (N = 8). Thapsigargin and ryanodine infusion eliminated focal discharges in 6 of 6 preparations and suppressed the inducibility of AF in 4 of 6 preparations. PVs with focal discharge have higher densities of parasympathetic nerves than do PVs without focal discharges ( P = .01), and periodic acid–Schiff (PAS)-positive cells were present at the focal discharge sites. Conclusion Ca i dynamics are important in promoting triggered activity during acetylcholine infusion in PVs from pacing-induced heart failure. PV focal discharge sites have PAS-positive cells and high densities of parasympathetic nerves.

Atrial fibrillation (AF) is a complex disease with many possible mechanisms. Studies indicate that the arrhythmogenic foci within the thoracic veins are AF initiators. Once initiated, AF alters atrial electrical and structural properties in a way that promotes its own maintenance and recurrences and may alter the response to antiarrhythmic drugs. The exact mechanisms by which the initiators trigger AF remain elusive, however. Evidence to date suggests that autonomic modulation does have an adjunctive role to play in catheter AF ablation, especially when applied selectively. Further mechanistic and clinical studies are warranted before a wider application can be recommended.

We hypothesize that remodelling of action potential and intracellular calcium (Cai) dynamics in the peri-infarct zone contributes to ventricular arrhythmogenesis in the postmyocardial infarction setting. To test this hypothesis, we performed simultaneous optical mapping of Cai and membrane potential (Vm) in the left ventricle in 15 rabbit hearts with myocardial infarction for 1 week. Ventricular premature beats frequently originated from the peri-infarct zone, and 37% showed elevation of Cai prior to Vm depolarization, suggesting reverse excitation–contraction coupling as their aetiology. During electrically induced ventricular fibrillation, the highest dominant frequency was in the peri-infarct zone in 61 of 70 episodes. The site of highest dominant frequency had steeper action potential duration restitution and was more susceptible to pacing-induced Cai alternans than sites remote from infarct. Wavebreaks during ventricular fibrillation tended to occur at sites of persistently elevated Cai. Infusion of propranolol flattened action potential duration restitution, reduced wavebreaks and converted ventricular fibrillation to ventricular tachycardia. We conclude that in the subacute phase of myocardial infarction, the peri-infarct zone exhibits regions with steep action potential duration restitution slope and unstable Cai dynamics. These changes may promote ventricular extrasystoles and increase the incidence of wavebreaks during ventricular fibrillation. Whereas increased tissue heterogeneity after subacute myocardial infarction creates a highly arrhythmogenic substrate, dynamic action potential and Cai cycling remodelling also contribute to the initiation and maintenance of ventricular fibrillation in this setting.

BACKGROUND:The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients after acute myocardial infarction (AMI) has so far remained uncertain. METHODS:We analyzed data from the National Health Insurance Research Database (NHIRD), a government-operated, population-based database, from March 1st, 2009 to December 31st, 2011. Type 2 diabetic patients hospitalized for AMI were included in our study. We compared subjects using sitagliptin with comparison group to evaluate its cardiovascular safety and efficacy. The primary endpoint was a composite of cardiovascular death, myocardial infarction, and ischemic stroke. RESULTS:We identified a total of 3,282 type 2 diabetic patients hospitalized for AMI (mean follow-up 1.15 years). Of these patients, 547 (16.7%) who were exposed to sitagliptin were defined as the sitagliptin group and 2,735 (83.3 %) who did not use sitagliptin were the comparison group. The incidence of primary composite cardiovascular outcomes was 9.50 per 100 person-years in the sitagliptin group and was 9.70 per 100 person-years in the comparison group (hazard ratio (HR), 0.97; 95% CI, 0.73-1.29, P=0.849). Compared to the non-sitagliptin group, the sitagliptin group had similar risks of all-cause mortality, hospitalization for heart failure (HF) or percutaneous coronary intervention (PCI) with a HR of 0.82 (95% CI, 0.61-1.11, P=0.195), 0.93 (95% CI, 0.67-1.29, P=0.660), and 0.93 (95% CI, 0.75-1.14, P=0.473), respectively. CONCLUSION:The use of sitagliptin in type 2 diabetic patients with recent AMI was not associated with increased risk of adverse cardiovascular events.

Effects of Catheter Ablation. Background: Papillary muscle (PM) ablation may terminate ventricular fibrillation (VF) in rabbit hearts. Whether or not PM ablation prevents ventricular fibrillation (VF) induction in large animals is unknown. Methods: We performed noncontact endocardial mapping and/or high-density epicardial mapping during VF in 12 dogs and 16 swine and tested the effects of posterior PM (PPM) ablation on VF inducibility. Results: During VF in progressive global ischemia (3 swine and 2 dogs), the highest dominant frequency (DF) was near PPM. The majority of the reentrant wavefronts during a propranolol infusion (swine) were anchored to the PPM. Purkinje potentials onset were recorded on the PPM both during sinus rhythm and during VF. Radiofrequency (RF) ablation of the endocardium on the PPM with a linear extension of the ablation line from the PPM to the mitral valve annulus and then the left ventricular apex in 7 dogs reduced the VF inducibility from 100% at baseline to 22% after ablation (P < 0.0001). RF applications to the anterolateral wall of dogs (n = 3) did not prevent VF induction. The application of RF energy near the PPM frequently initiated VF in swine (n = 7), preventing subsequent testing of VF inducibility. Conclusion: In dogs and swine, the highest DF and majority of reentrant wavefronts during VF with acute global ischemia or during a propranolol infusion were located on the PPM. RF ablation targeted at the PPM reduced the inducibility of VF in normal dogs. However, the same ablation provoked incessant VF in swine, preventing subsequent testing of VF inducibility.

The importance of the ligament of Marshall (LOM) to rapid activations within the left superior pulmonary vein (LSPV) during atrial fibrillation (AF) remains poorly understood. We aimed to characterize the importance of electrical coupling between the LSPV with the left atrium (LA) and the LOM in the generation of high-frequency activations within this PV. We performed high-density mapping of the LSPV-LA-LOM junction in eight dogs, using 1,344 electrodes with a 1-mm resolution before and after posterior ostial ablation to diminish PV-LA electrical connections. A LOM potential was recordable up to 6.5 mm (SD 2.2) into the LSPV in all dogs during sinus rhythm (SR) and LA pacing. Functional LOM-LSPV electrical connections bypassing the PV-LA junction were present in five of eight dogs. Direct LOM-LSPV connections contributed to 46.5% (SD 16.0) of LSPV activations during AF, resulting in a greater propensity to develop focal activations ( P < 0.05) and a higher activation rate during AF of LSPVs with direct LOM connections compared with those without ( P < 0.03). Posterior LSPV ostial ablation without damaging the anterior wall or LOM slowed residual LA-PV conduction ( P < 0.001). This diminished PV-LA coupling prevented the reinduction of LSPV focal activations in all dogs. However, persistent LOM focal activations in two dogs continued to activate the LSPV rapidly [cycle length 151.8 ms (SD 4.8)] via direct LOM-LSPV connections. LOM-LSPV connection forms an accessory pathway that contributes to the electrical coupling between LSPV and LA during SR and AF. This pathway may contribute to rapid activations within the LSPV during AF.

Ibutilide can prolong refractory period and terminate reentry. Whether ibutilide has the same effects on pulmonary vein (PV) focal discharge (FD) is unclear. We induced sustained atrial fibrillation (AF) in seven dogs by rapid left atrial (LA) pacing for 74 +/- 46 days. Ibutilide was repeatedly infused until it terminated AF (0.02 +/- 0.01 mg/kg) or when a cumulative dose was reached (0.04 mg/kg). High-resolution computerized epicardial mapping was performed. We found intermittent FD at the PVs and reentry at the PV-LA junction during AF. Ibutilide increased the cycle length of consecutive reentry from 97 +/- 13 to 112 +/- 18 ms and increased FD from 96 +/- 7 to 113 +/- 9 ms. In four dogs with both FD and reentry at the PVs, the incidence of reentry decreased from 3.5 +/- 1.9/s at baseline to 2.2 +/- 1.8/s after ibutilide administration. However, the incidence of FD remained unchanged. The conducted wave fronts between PV and LA were significantly reduced by ibutilide (10.4 +/- 2.0/s vs. 8.0 +/- 1.6/s). The ibutilide dose needed to terminate AF correlated negatively with the baseline effective refractory period of PV and LA. We conclude that ibutilide reduces reentrant wave fronts but not PV FD in a canine model of pacing-induced sustained AF. These findings suggest that the PV FD during AF is due to nonreentrant mechanisms. High doses of ibutilide may completely terminate all reentrant activity, converting AF to PV tachycardia before the resumption of sinus rhythm.

We describe two patients who presented with a history of recurrent palpitations on swallowing of solid food. The event-recorder and Holter monitoring documented episodic supraventricular tachycardia (SVT) initiated by atrial premature contractions (APCs). During electrophysiological study (EPS), swallowing of solid food consistently induced APCs and their activation sequence, morphology of P wave were suggestive of their right atrial origin in them. Drug challenge did not affect the APC onset during the swallowing. During EPS, slow-fast variety of atrioventricular nodal reentrant tachycardia (AVNRT) was induced and successful radiofrequency (RF) catheter ablation of slow pathway resulted in total relief of their symptoms.

Objectives The purpose of this study was to test the hypothesis that radiofrequency (RF) catheter ablation results in cardiac nerve sprouting. Background Nerve sprouting plays a role in cardiac arrhythmogenesis. Whether or not nerve sprouting occurs after RF catheter ablation is unclear. Methods We performed RF catheter ablation in the right atrium (RA) and right ventricle (RV) in 10 dogs, which then were sacrificed in 2 hours (acute group, n=5) or 1 month (chronic group, n=5). Seven normal dogs were used as control. Immunohistochemical staining for growth-associated protein 43 (GAP-43) was performed to measure growing (sprouting) nerves. Results A significant increase of GAP-43 immunoreactive nerve fiber density was observed at the RA ablation sites in 2 hours (4,410 ± 1,379 μm 2 /mm 2 ) and in 1 month (2,948 ± 666 μm 2 /mm 2 ) after ablation compared to controls (1,377 ± 471 μm 2 /mm 2 , P = .0001). At remote sites (>2 cm away from ablation sites) of RA, RF ablation also resulted in robust nerve sprouting in both the acute group (5,846 ± 3241μm 2 /mm 2 ) and the chronic group (6,030 ± 2226 μm 2 /mm 2 ). RF ablation in the RV did not increase nerve density at the ablation sites, but nerve density was increased at remote sites in 2 hours (1,345 ± 451 μm 2 /mm 2 , P = .0136) that was reduced down to the normal control level (722 ± 337 μm 2 /mm 2 ) in 1 month. Conclusions Nerve sprouting occurred within 2 hours after RF ablation in both the RA and RV and persisted for at least 1 month in the RA but not the RV. The increased GAP-43 + nerve densities developed at both the ablation and the remote sites.

The long-term performance of two high impedance, steroid-eluting, passive-fixation ventricular leads, porous platinum iridium electrode CPI Selute Picotip 4035 (131 patients), and platinized platinum electrode Medtronic Capsure Z 5034 (57 patients), was compared with one conventional 8.0-mm2 porous platinum iridium electrode CPI Selute 4285 (38 patients). The mean follow-up period was 28 +/- 14 months. Capture threshold, R wave amplitude, and pacing impedance were measured at the time of implantation, immediately after implantation, 1 week, 1, 3, and 6 months after implantation and then every 6 months thereafter. The two high impedance leads revealed a higher sensing slew rate than the conventional lead, the R wave amplitude was similar among the three groups, but the voltage threshold at 0.5-ms pulse width was significantly higher in porous platinum iridium groups at the time of implantation. During follow-up, the conventional lead revealed a significantly higher R wave amplitude within the first 3 months, however, this pattern disappeared after 3 months. Pacing impedance was significantly higher in the high impedance porous platinum iridium electrode groups. Voltage threshold at 0.5-ms pulse width was similar among the three groups in the first 3 months, however, it increased gradually and was significantly higher in porous platinum iridium electrode groups subsequently. The energy threshold at 0.5 ms was significantly lower in the two high impedance groups than the conventional group, but no difference was found in the two high impedance groups. Lead related complications were similar among the three groups. In conclusion, high impedance electrodes with different design and materials had different properties; platinized platinum electrode showed a lower pacing impedance but had a more stable long-term capture threshold as compared to the porous platinum iridium electrode. Further studies are mandatory for the development of an ideal pacing lead.

Cytochalasin D in Rabbit Ventricle.Cytochalasin D (cyto-D) has been used as an excitation-contraction uncoupler during optical mapping studies. However, its effects on action potential duration restitution (APDR) and dynamics during ventricular fibrillation (VF) are unclear.Langendorff-perfused rabbit hearts (N = 6) were immersed in a tissue chamber. Transmembrane potential was recorded using glass microelectrodes. APD measured to 90% repolarization (APD90) was used to construct the APDR curve. During regular pacing at 300-msec cycle length, increasing concentrations of cyto-D resulted in progressively prolonged APD90 (131 +/- 26 msec, 171 +/- 14 msec, and 177 +/- 14 msec) and steepened maximum slope of the APDR curve (1.1 +/- 0.2, 1.3 +/- 0.2, and 1.6 +/- 0.4 for control, 5 micromoles, and 10 micromoles, respectively; P0.01). Resting membrane potential, AP amplitude, and maximum dV/dt did not change. Cyto-D lengthened VF cycle length and APD90, and steepened the maximum slope of the APDR curve. However, cyto-D did not significantly change the diastolic interval. The dominant frequency of pseudoelectrocardiogram progressively decreased with increasing concentrations of cyto-D (15.2 +/- 0.6 Hz, 11.1 +/- 2.4 Hz, and 9.8 +/- 3.2 Hz for control, 5 micromoles, and 10 micromoles, respectively; P0.01). Sustained (1 min) VF was repeatedly inducible at baseline and with 5 or 10 micromoles of cyto-D.Continuous perfusion of cyto-D at 5 or 10 micromoles prolonged APD90, steepened APDR slope, and reduced dominant frequency in rabbit ventricles. Cyto-D at these concentrations allowed induction of sustained VF.

Data on the effectiveness of implantable implantable cardioverter defibrillators (ICDs) with respect to reducing mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) are lacking. The purpose of this meta-analysis was to compare the mortality of patients with ESRD who have received and not received an ICD. A search was conducted on January 31, 2013 of Medline, Cochrane, EMBASE, and Google Scholar. Studies were selected for inclusion based on the following criteria. 1) Randomized controlled trial. 2) ESRD patients with heart failure. 3) Device therapy (ICD, CRT-defibrillator [CRT-D]) used to treat heart failure. 4) Primary outcome is survival analysis. 5) Retrospective study if survival analysis was performed. The primary outcome was overall survival (OS), and the secondary outcome was 2-year survival. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated, and a χ2-based test of homogeneity was performed. Three studies were included in the analysis. The combined OR for OS was 2.245 (95% CI 1.871 to 2.685, P

We report a case of successful radiofrequency ablation for atypical atrioventricular nodal reentrant tachycardia in a patient with complete situs inversus, secundum atrial septal defect and an "inverse" persistent left superior vena cava. The procedure was performed under the monoplane fluoroscopic guidance using the inferior approach.

Background Piceatannol, a hydroxystilbene natural product, has been reported to exert antiarrhythmic action via I Na inhibition and slow I Na inactivation in ischemia-reperfused (IR) rat hearts. The present study aimed to clarify the proarrhythmic property of piceatannol during regional IR injury in failing rabbit hearts. Methods Heart failure (HF) was induced by rapid right ventricular pacing for 4weeks. The IR model was created by coronary artery ligation for 30min, followed by reperfusion for 15min in vivo. Simultaneous voltage and intracellular Ca 2+ (Ca i ) optical mapping was then performed in isolated Langendorff-perfused hearts ( n =11 in each HF and control group). Action potential duration (APD) restitution, arrhythmogenic alternans and VF inducibility were evaluated by a dynamic pacing protocol. Conduction velocity was measured along lines across the IR and non-IR zones during pacing. Piceatannol (10μM) was administered after baseline studies. Results In the HF group, piceatannol decreased conduction velocity, induced rate-dependent regional inhomogeneity of conduction delay and wavelength shortening, slowed Ca i decay, and facilitated arrhythmogenic alternans instead of APD prolongation to increase VF inducibility. In the control group, the proarrhythmic effects of piceatannol on APD restitution, arrhythmogenic alternans and conduction delay were offset by its antiarrhythmic effects (APD and wavelength prolongation), resulting in a neutral effect on VF inducibility. Conclusions Piceatannol (10μM) is proarrhythmic in failing rabbit hearts with regional IR injury. The increased VF inducibility by piceatannol in HF suggests that its undesirable effects are more pronounced than its benefits in failing hearts.

Intracellular Ca2+ (Ca1) dynamics plays an important role in the initiation and maintenance of atrial fibrillation (AF). Specific intrinsic action potential properties and pacemaking cells within the pulmonary veins (PVs) contribute to PV arrhythmogenicity. Simultaneous sympathovagal activation could increase Cai and shorten action potential duration at the same time, resulting in triggered activity from the PVs and initiating AF. The maintenance of AF depends on both the triggered activity within the PVs and reentrant wave fronts in the atria and in the PVs. The reentrant wave fronts that conduct from the atria into the PVs increase the activation rate in the PVs, hence increasing Cai accumulation and triggered discharges. In the meantime, the wave fronts that conduct from the PVs into the atria may add complexities to atrial activations and support further wave break and reentry. Overload of Cai is likely to be a primary factor mediating both the short-term and chronic electrophysiological remodeling associated with AF.

Background Single strong premature electrical stimulation (S 2 ) may induce figure-eight reentry. We hypothesize that Ca current-mediated slow-response action potentials (APs) play a key role in the propagation in the central common pathway (CCP) of the reentry. Methods We simultaneously mapped optical membrane potential (V m ) and intracellular Ca (Ca i ) transients in isolated Langendorff-perfused rabbit ventricles. Baseline pacing (S 1 ) and a cathodal S 2 (40–80 mA) were given at different epicardial sites with a coupling interval of 135 ± 20 ms. Results In all 6 hearts, S 2 induced graded responses around the S 2 site. These graded responses propagated locally toward the S 1 site and initiated fast APs from recovered tissues. The wavefront then circled around the refractory tissue near the site of S 2 . At the side of S 2 opposite to the S 1 , the graded responses prolonged AP duration while the Ca i continued to decline, resulting in a Ca i sinkhole (an area of low Ca i ). The Ca i in the sinkhole then spontaneously increased, followed by a slow V m depolarization with a take-off potential of −40 ± 3.9 mV, which was confirmed with microelectrode recordings in 3 hearts. These slow-response APs then propagated through CCP to complete a figure-eight reentry. Conclusion We conclude that a strong premature stimulus can induce a Ca i sinkhole at the entrance of the CCP. Spontaneous Ca i elevation in the Ca i sinkhole precedes the V m depolarization, leading to Ca current-mediated slow propagation in the CCP. The slow propagation allows more time for tissues at the other side of CCP to recover and be excited to complete figure-eight reentry.

The nanofibrous biodegradable drug-loaded membranes that sustainably released recombinant human platelet-derived growth factor (rhPDGF-BB) to repair diabetic wounds were developed in this work. rhPDGF-BB and poly(lactic-co-glycolic acid) (PLGA) were mixed in hexafluoroisopropyl alcohol, followed by the electrospinning of the solutions into biodegradable membranes to equip the nanofibrous membranes. An elution technique and an enzyme-linked immunosorbent assay kit were used to determine the rhPDGF-BB release rates in vitro and in vivo from this membrane. Eighteen Sprague-Dawley streptozotocin-induced diabetic rats were randomized into 3 groups: rhPDGF-BB-loaded nanofibrous membrane group, PLGA only membrane group, and conventional gauze sponge group for the wound associated with diabetes of rat in each group. The nanofibrous biodegradable membranes released effective concentrations of rhPDGF-BB for over 21 days. The nanofibrous rhPDGF-BB-loaded PLGA membranes contained more water and were further hydrophilic than PLGA only fibers. The rhPDGF-BB-loaded PLGA membranes considerably helped the diabetic wounds repairing. Furthermore, the proliferative cells and angiogenesis of rats associated with diabetes by rhPDGF-BB-loaded nanofibrous membranes were greater than those of other groups, owing to the increased matrix metalloproteinase 9. These biodegradable rhPDGF-BB-loaded membranes were effective in treating diabetic wounds as very advanced accelerators during the initial phases of wound-healing process.

Supplemental Digital Content is available in the text, The cerebrovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus (T2DM) with ischemic stroke remains uncertain. The aim of this study was to assess the efficacy and safety of sitagliptin in patients with T2DM with recent ischemic stroke. We analyzed data from the Taiwan National Health Insurance Research Database between March 1, 2009, and December 31, 2011. Ischemic stroke patients were identified from individuals with T2DM. Patients who received sitagliptin were compared with those who did not to evaluate the cardiovascular safety and efficacy of sitagliptin. The primary outcome was a composite of ischemic stroke, myocardial infarction, or cardiovascular death. A total of 5145 type 2 diabetic patients with ischemic stroke met our inclusion criteria and were followed for up to 2.83 years (mean, 1.17 years). Overall, 1715 patients (33.3%) received sitagliptin and 3430 patients (66.7%) did not. The primary composite outcome occurred in 190 patients in the sitagliptin group (11.1%) and in 370 patients in the comparison group (10.8%) (hazard ratio [HR] = 1.02; 95% confidence interval [CI], 0.85–1.21). Patients treated with sitagliptin had a similar risk of ischemic stroke, hemorrhagic stroke, and all-cause mortality with an HR of 0.95 (95% CI, 0.78–1.16, P = 0.612), 1.07 (95% CI, 0.55–2.11, P = 0.834), and 1.00 (95% CI, 0.82–1.22, P = 0.989), respectively, compared with patients not treated with sitagliptin. Treatment with sitagliptin in type 2 diabetic patients with recent ischemic stroke was not associated with increased or decreased risks of adverse cerebrovascular outcomes.

In this article we have reviewed the mechanisms of atrial fibrillation (AF) with special emphasis on the thoracic veins. Based on a number of features, the thoracic veins are highly arrhythmogenic. The pulmonary vein (PV)-left atrial (LA) junction has discontinuous myocardial fibers separated by fibrotic tissues. The PV muscle sleeve is highly anisotropic. The vein of Marshall (VOM) in humans has multiple small muscle bundles separated by fibrosis and fat. Insulated muscle fibers can promote reentrant excitation, automaticity, and triggered activity. The PV muscle sleeves contain periodic acid-Schiff (PAS)-positive large pale cells that are morphologically reminiscent of Purkinje cells. These special cells could be the sources of focal discharge. Antiarrhythmic drugs have significant effects on PV muscle sleeves both at baseline and during AF. Both class I and III drugs have effects on wavefront traveling from PV to LA and from LA to PV. Separating the thoracic veins and the LA with ablation techniques also prevents PV-LA interaction. By reducing PV-LA interaction, pharmacological therapy and PV isolation reduce the activation rate in PV, intracellular calcium accumulation, and triggered activity. Therefore, thoracic vein isolation is an important technique in AF control. We conclude that thoracic veins are important in the generation and maintenance of AF.

Background— Rapid activations due to either focal discharge or reentry are often present during atrial fibrillation (AF) in the pulmonary veins (PVs). The mechanisms of these rapid activations are unclear. Methods and Results— We studied 7 isolated, Langendorff-perfused canine left atrial (LA) and PV preparations and used 2 cameras to map membrane potential alone (Vm, n=3) or Vm and intracellular calcium simultaneously (Ca i , n=4). Rapid atrial pacing induced 26 episodes of focal discharge from the proximal PVs in 5 dogs. The cycle lengths were 223±52 ms during ryanodine infusion (n=13) and 133±59 ms during ryanodine plus isoproterenol infusion (n=13). The rise of Ca i preceded Vm activation at the sites of focal discharge in 6 episodes of 2 preparations, compatible with voltage-independent spontaneous Ca i release. Phase singularities during pacing-induced reentry clustered specifically at the PV-LA junction. Periodic acid-Schiff (PAS) stain identified large cells with pale cytoplasm along the endocardium of PV muscle sleeves. There were abrupt changes in myocardial fiber orientation and increased interstitial fibrosis in the PV and at the PV-LA junction. Conclusions— PV muscle sleeves may develop voltage-independent Ca i release, resulting in focal discharge. Focal discharge may also be facilitated by the presence of PAS-positive cells that are compatible with node-like cells. During reentry, phase singularities clustered preferentially at sites of increased anisotropy such as the PV-LA junction. These findings suggest that focal discharge caused by spontaneous calcium release and anisotropic reentry both contribute to rapid activations in the PVs during AF.