Effect of Empagliflozin Versus Placebo on Body Fluid Balance in Patients With Acute Myocardial Infarction and Type 2 Diabetes Mellitus: Subgroup Analysis of the EMBODY Trial.

BACKGROUND: The development of heart failure is associated with fluid balance, including that of extracellular water (ECW) and intracellular water (ICW). This study determined whether sodium-glucose cotransporter 2 inhibitors affect fluid balance and improve heart failure in patients after acute myocardial infarction. METHODS AND RESULTS: EMBODY was a prospective, randomized, double-blinded, placebo-controlled trial of Japanese patients with acute myocardial infarction and type 2 diabetes. Overall, 55 patients who underwent bioelectrical impedance analysis were randomized to receive once daily 10 mg empagliflozin or placebo 2 weeks after acute myocardial infarction onset. We investigated the time course of body fluid balance measured using the bioelectrical impedance analysis device, InBody. The primary end points were changes in body fluid balance from weeks 0 to 24. Changes between baseline and week 24 in the empagliflozin and placebo groups were -0.21 L (P = .127) and +0.40 L (P = .001) in ECW (P = .001) and -0.23 L (P = .264) and +0.74 L (P < .001) in ICW (P < .001), respectively. In a stratified analysis, the rise in ECW and ICW was significantly attenuated in the empagliflozin group in contrast to the placebo group in participants with a body mass index of 25 or higher but not in those with a body mass index of less than 25. CONCLUSIONS: Early sodium-glucose cotransporter 2 inhibitor administration may attenuate changes in ECW and ICW.

Distal type of nodo-ventricular pathway: Unique electrophysiological characteristics mimicking fasciculo-ventricular pathway.

Fasciculo-ventricular and nodo-ventricular pathways (FVP and NVP) are rare preexcitation variants. Normally, NVP is electrophysiologically different from FVP. We describe a unique type of NVP emerging from the distal part of the slow pathway, designated as "distal type" NVP. The distal type NVP resembled FVP but was proven by unexpected elimination of the NVP during the slow pathway ablation. Also, NVP was distinguishable from FVP by a careful comparison of the HV intervals during conduction over the fast and slow pathways. Demonstration of this novel type NVP provides insights into how the insertion site of NVP affects its electrophysiologic behaviors.

Efficacy of electrical isolation of the left atrial posterior wall depends on the existence of left atrial low-voltage zone in patients with persistent atrial fibrillation.

BACKGROUND: Modification of the low-voltage zone in the left atrium (LA-LVZ) in addition to pulmonary vein isolation (PVI) has not shown sufficient improvement in arrhythmia-free survival in patients with persistent atrial fibrillation (PerAF). Further, the effect of electrical posterior wall isolation (PWI) is controversial. We investigated the impact of existence of LA-LVZ on the outcome of patients undergoing additional PWI for PerAF. METHODS: A total of 347 patients with PerAF who underwent primary catheter ablation with LA-LVZ based strategy were retrospectively analyzed. Voltage mapping in the left atrium (LA) was performed during sinus rhythm. Additional LVZ ablation was performed in patients with LA-LVZ. The operators decided whether additional PWIs were to be performed. RESULTS: Of 347 patients, 108 had LA-LVZ. In the LVZ group, patients with additional PWI (N = 70) had higher rates of freedom from tachyarrhythmia recurrence than those without (77.1% vs. 42.1%, p < 0.001). Furthermore, even when patients were limited to those with LA-LVZ in areas other than the posterior wall (N = 85), PWI had higher success rates (80.9% vs. 42.1%, p < 0.001). In contrast, in patients without LVZ (N = 239), there was no significant difference in the rate of successful outcome between those with and without PWI (81.3% vs. 88.1%, p = 0.112). On the other hand, the patients with PWI had greater atrial tachycardia (AT) recurrence rate than those without PWI (10.0% vs. 2.5%, p = 0.003). CONCLUSIONS: PWI, in addition to PVI and LVZ modification, may improve single procedural outcomes in patients with PerAF who have LVZ, regardless of the distribution in the LA. A combination of voltage-guided ablation and PWI may be a simple, tailored, and effective ablation strategy.

Re-definition of blanking period in radiofrequency catheter ablation of atrial fibrillation in the contact force era.

INTRODUCTION: Early recurrence (ER) of atrial fibrillation (AF) is defined as the recurrence of atrial tachyarrhythmias within 3 months after AF ablation, however, this definition is based on data from the era of radiofrequency catheter ablation (RFCA), without contact force (CF) technology. We investigated the significance of ER as a risk factor for late recurrence (LR) in paroxysmal AF (PAF) patients treated with CF and non-CF-guided ablation. METHODS AND RESULTS: We studied 395 patients with PAF who underwent RFCA. Of these, 97 patients underwent RFCA without-CF technology (non-CF group) and 298 underwent with CF technology (CF group). Over a 2-year postablation follow-up period, LR occurred in 54 (55.7%) patients in the non-CF group, and in 105 (35.2%) patients in the CF group. ER had a more significant relationship with LR in the CF group, and all patients in the CF group with ER in the third month developed LR. CONCLUSION: PAF patients with ER who have undergone CF-guided ablation have a greater risk of LR than those who have undergone non-CF-guided ablation. ER in the third month after CF-guided ablation may indicate an absolute risk of LR. Blanking period could be defined as 2 months in the CF era.

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.

BACKGROUND: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. RESULTS: Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. CONCLUSIONS: This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. TRIAL REGISTRATION: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .

Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12.

Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.

Clinical and Electrocardiographic Characteristics of Electrical Storms Due to Monomorphic Ventricular Tachycardia Refractory to Intravenous Amiodarone.

BACKGROUND: Few reports are available on the characteristics of electrical storms of ventricular tachycardia (VT storm) refractory to intravenous (IV) amiodarone. METHODS AND RESULTS: IV-amiodarone was administered to 60 patients with ventricular tachyarrhythmia between 2007 and 2012. VT storms, defined as 3 or more episodes of VT within 24 h, occurred in 30 patients (68±12 years, 7 female), with 12 having ischemic and 18 non-ischemic heart disease. We compared the clinical and electrocardiographic characteristics of the patients with VT storms suppressed by IV-amiodarone (Effective group) to those of patients not affected by the treatment (Refractory group). IV-amiodarone could not control recurrence of VT in 9 patients (30%). The Refractory group comprised 5 patients with acute myocardial infarctions. Although there was no difference in the VT cycle length, the QRS duration of both the VT and premature ventricular contractions (PVCs) followed by VT was narrower in the Refractory group than in the Effective group (140±30 vs. 178±25 ms, P<0.01; 121±14 vs. 179±22 ms, P<0.01). In the Refractory group, additional administration of IV-mexiletine and/or Purkinje potential-guided catheter ablation was effective. CONCLUSIONS: IV-amiodarone-refractory VT exhibited a relatively narrow QRS tachycardia. The narrow triggering PVCs, suggesting a Purkinje fiber origin, may be treated by additional IV-mexiletine and endocardial catheter ablation.

Carvedilol analog modulates both basal and stimulated sinoatrial node automaticity.

The membrane voltage clock and calcium (Ca(2+)) clock jointly regulate sinoatrial node (SAN) automaticity. VK-II-36 is a novel carvedilol analog that suppresses sarcoplasmic reticulum (SR) Ca(2+) release but does not block the ß-receptor. The effect of VK-II-36 on SAN function remains unclear. The purpose of this study was to evaluate whether VK-II-36 can influence SAN automaticity by inhibiting the Ca(2+) clock. We simultaneously mapped intracellular Ca(2+) and membrane potential in 24 isolated canine right atriums using previously described criteria of the timing of late diastolic intracellular Ca elevation (LDCAE) relative to the action potential upstroke to detect the Ca(2+) clock. Pharmacological interventions with isoproterenol (ISO), ryanodine, caffeine, and VK-II-36 were performed after baseline recordings. VK-II-36 caused sinus rate downregulation and reduced LDCAE in the pacemaking site under basal conditions (P < 0.01). ISO induced an upward shift of the pacemaking site in SAN and augmented LDCAE in the pacemaking site. ISO also significantly and dose-dependently increased the sinus rate. The treatment of VK-II-36 (30 µmol/l) abolished both the ISO-induced shift of the pacemaking site and augmentation of LDCAE (P < 0.01), and it suppressed the ISO-induced increase in sinus rate (P = 0.02). Our results suggest that the sinus rate may be partly controlled by the Ca(2+) clock via SR Ca(2+) release during ß-adrenergic stimulation.

Electrophysiological and Histopathological Characteristics of Ventricular Tachycardia Associated With Primary Cardiac Tumors.

BACKGROUND: Ventricular tachycardia (VT) associated with primary cardiac tumors (PCTs) originating from the ventricles is rare, but lethal, in young patients. OBJECTIVES: This study aimed to clarify the mechanisms underlying primary cardiac tumor-related ventricular tachycardia (PCT-VT) and establish a therapeutic strategy for this form of VT. METHODS: Among 67 patients who underwent surgery for VT at our institute between 1981 and 2020, 4 patients aged 1 to 34 years, including 3 males, showed PCT-VT (fibroma, 2; lipoma, 1; and hamartoma, 1), which was investigated using a combination of intraoperative electroanatomical mapping and histopathological studies. RESULTS: All 4 patients developed electrical storms of sustained VTs refractory to multiple drugs and repetitive endocardial ablations. The VT mechanism was re-entry, and intraoperative electroanatomical mapping showed a centrifugal activation pattern originating from the border between the tumor and healthy myocardium, where fractionated potentials were detected during sinus rhythm. Histopathological studies of serial sections of specimens acquired from these areas revealed tumor infiltration into the surrounding myocardium with cell disorganization, exhibiting myocardial disarray. Several myocardia entrapped in the tumor edges contributed to the development and sustainment of re-entrant VT activation. In the 2 patients in whom complete resection was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing VT occurrence. CONCLUSIONS: The mechanism underlying PCT-VT involves re-entry localized at the tumor edges. Myocardial disarray associated with tumor infiltration is a substrate for this form of VT. Cryoablation along the border between the tumor and myocardium is a promising therapeutic option for unresectable PCT-VT.

Systematic observation-based diagnosis of atrioventricular nodal reentrant tachycardia with a bystander concealed nodoventricular pathway.

Background: This study aimed to establish a systematic method for diagnosing atrioventricular nodal reentrant tachycardia (AVNRT) with a bystander concealed nodoventricular pathway (cNVP). Methods: We analyzed 13 cases of AVNRT with a bystander cNVP, 11 connected to the slow pathway (cNVP-SP) and two to the fast pathway (cNVP-FP), along with two cases of cNVP-related orthodromic reciprocating tachycardia (ORT). Results: The diagnostic process was summarized in three steps. Step 1 was identification of the presence of an accessory pathway by resetting the tachycardia with delay (n = 9) and termination without atrial capture (n = 4) immediately after delivery of a His-refractory premature ventricular contraction (PVC). Step 2 was exclusion of ORT by atrio-His block during the tachycardia (n = 4), disappearance of the reset phenomenon after the early PVC (n = 7), or dissociation of His from the tachycardia during ventricular overdrive pacing (n = 1). Moreover, tachycardia reset/termination without the atrial capture (n = 2/2) 1 cycle after the His-refractory PVC was specifically diagnostic. Exceptionally, the disappearance of the reset phenomenon was also observed in the two cNVP-ORTs. Step 3 was verification of the AVN as the cNVP insertion site, evidenced by an atrial reset/block preceding the His reset/block in fast-slow AVNRT with a cNVP-SP and slow-fast AVNRT with a cNVP-FP or His reset preceding the atrial reset in slow-fast AVNRT with a cNVP-SP. Conclusion: AVNRT with a bystander cNVP can be diagnosed in the three steps with few exceptions. Notably, tachycardia reset/termination without atrial capture one cycle after delivery of a His-refractory PVC is specifically diagnostic.

Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive. We generated Jup mutant mice by ablating Jup in cardiomyocytes. Jup mutant mice largely recapitulated the clinical manifestation of human ARVC: ventricular dilation and aneurysm, cardiac fibrosis, cardiac dysfunction and spontaneous ventricular arrhythmias. Ultra-structural analyses revealed that desmosomes were absent in Jup mutant myocardia, whereas adherens junctions and gap junctions were preserved. We found that ventricular arrhythmias were associated with progressive cardiomyopathy and fibrosis in Jup mutant hearts. Massive cell death contributed to the cardiomyocyte dropout in Jup mutant hearts. Despite the increase of ß-catenin at adherens junctions in Jup mutant cardiomyoicytes, the Wnt/ß-catenin-mediated signaling was not altered. Transforming growth factor-beta-mediated signaling was found significantly elevated in Jup mutant cardiomyocytes at the early stage of cardiomyopathy, suggesting an important pathogenic pathway for Jup-related ARVC. These findings have provided further insights for the pathogenesis of ARVC and potential therapeutic interventions.

Apamin-sensitive calcium-activated potassium currents in rabbit ventricles with chronic myocardial infarction.

INTRODUCTION: The apamin-sensitive small-conductance calcium-activated potassium current (IKAS ) is increased in heart failure. It is unknown if myocardial infarction (MI) is also associated with an increase of IKAS . METHODS AND RESULTS: We performed Langendorff perfusion and optical mapping in 6 normal hearts and 10 hearts with chronic (5 weeks) MI. An additional 6 normal and 10 MI hearts were used for patch clamp studies. The infarct size was 25% (95% confidence interval, 20-31) and the left ventricular ejection fraction was 50 (46-54). The rabbits did not have symptoms of heart failure. The action potential duration measured to 80% repolarization (APD80 ) in the peri-infarct zone (PZ) was 150 (142-159) milliseconds, significantly (P = 0.01) shorter than that in the normal ventricles (167 [158-177] milliseconds. The intracellular Ca transient duration was also shorter in the PZ (148 [139-157] milliseconds) than that in normal ventricles (168 [157-180] milliseconds; P = 0.017). Apamin prolonged the APD80 in PZ by 9.8 (5.5-14.1)%, which is greater than that in normal ventricles (2.8 [1.3-4.3]%, P = 0.006). Significant shortening of APD80 was observed at the cessation of rapid pacing in MI but not in normal ventricles. Apamin prevented postpacing APD80 shortening. Patch clamp studies showed that IKAS was significantly higher in the PZ cells (2.51 [1.55-3.47] pA/pF, N = 17) than in the normal cells (1.08 [0.36-1.80] pA/pF, N = 15, P = 0.019). CONCLUSION: We conclude that IKAS is increased in MI ventricles and contributes significantly to ventricular repolarization especially during tachycardia.

FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice.

RATIONALE: FK506 binding protein (FKBP)12 is a known cis-trans peptidyl prolyl isomerase and highly expressed in the heart. Its role in regulating postnatal cardiac function remains largely unknown. METHODS AND RESULTS: We generated FKBP12 overexpressing transgenic (αMyHC-FKBP12) mice and cardiomyocyte-restricted FKBP12 conditional knockout (FKBP12(f/f)/αMyHC-Cre) mice and analyzed their cardiac electrophysiology in vivo and in vitro. A high incidence (38%) of sudden death was found in αMyHC-FKBP12 mice. Surface and ambulatory ECGs documented cardiac conduction defects, which were further confirmed by electric measurements and optical mapping in Langendorff-perfused hearts. αMyHC-FKBP12 hearts had slower action potential upstrokes and longer action potential durations. Whole-cell patch-clamp analyses demonstrated an ≈ 80% reduction in peak density of the tetrodotoxin-resistant, voltage-gated sodium current I(Na) in αMyHC-FKBP12 ventricular cardiomyocytes, a slower recovery of I(Na) from inactivation, shifts of steady-state activation and inactivation curves of I(Na) to more depolarized potentials, and augmentation of late I(Na), suggesting that the arrhythmogenic phenotype of αMyHC-FKBP12 mice is attributable to abnormal I(Na). Ventricular cardiomyocytes isolated from FKBP12(f/f)/αMyHC-Cre hearts showed faster action potential upstrokes and a more than 2-fold increase in peak I(Na) density. Dialysis of exogenous recombinant FKBP12 protein into FKBP12-deficient cardiomyocytes promptly recapitulated alterations in I(Na) seen in αMyHC-FKBP12 myocytes. CONCLUSIONS: FKBP12 is a critical regulator of I(Na) and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of I(Na) may underlie clinical arrhythmias associated with FK506 administration.

Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles.

RATIONALE: Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). OBJECTIVE: We hypothesized that activation of apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels is responsible for the postshock APD shortening in failing ventricles. METHODS AND RESULTS: A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca(2+) and membrane potential (V(m)) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 µmol/L) eliminated recurrent SVF and increased postshock APD(80) in the SVF group from 126±5 to 153±4 ms (P<0.05) and from 147±2 to 162±3 ms (P<0.05) in the no-SVF group but did not change APD(80) in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K(+) current (I(KAS)) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial I(KAS) density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca(2+) response of I(KAS) was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca(2+) sensitivity of I(KAS) in failing ventricles. The K(d) was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes (P=0.002). CONCLUSIONS: Heart failure heterogeneously increases the sensitivity of I(KAS) to intracellular Ca(2+), leading to upregulation of I(KAS), postshock APD shortening, and recurrent SVF.

Efficacy and limitations of oral inotropic agents for the treatment of chronic heart failure.

The heart failure guideline in Japan has stated the necessity of investigating the role of oral inotropic agents in patients with chronic heart failure (CHF), which are clinically available only in Japan. A total of 1,846 consecutive patients with heart failure (mean: 69.5 years old, 1,279 males) treated at our institute from November 2009 to August 2010 were investigated retrospectively. Thirty-one patients (1.84%) who had taken oral inotropic agents (pimobendan 27, docarpamine 6, and denopamine 4) were extracted for this study, and the efficacy and limitations of the treatments were analyzed. Following the oral inotropic treatment, the NYHA functional class (P = 0.017), cardiothoracic ratio (P = 0.002) and B-type natriuretic peptide levels (P = 0.011) were significantly improved, and the number of emergency room (ER) visits (P < 0.001) and hospitalizations (P < 0.001) were significantly reduced. The nonsurviving patients (n = 7/31, 22.6%) were significantly older (P = 0.02) and tended to have a larger cardiothoracic ratio (P = 0.084) compared with the survivors. An absence of concomitant beta-blocker therapy was significantly associated with a worse prognosis (oneyear mortality 2/21 versus 5/10, log rank, P = 0.011). Oral inotropic agents brought about improvements in the clinical parameters of CHF and a reduction in ER visits and hospitalizations. However, concomitant beta-blocker therapy should be considered for patients receiving oral inotropic treatment.

Atrial fibrillatory wave amplitude revisited: A predictor of recurrence after catheter ablation independent of the degree of left atrial structural remodeling.

BACKGROUND: The fibrillatory wave amplitude (FWA) during atrial fibrillation (AF) is thought to reflect structural atrial remodeling, but it remains unclear what determines the FWA. METHODS: 114 consecutive patients were prospectively studied who underwent catheter ablation of AF. The mean FWA was computed by automated surface ECG analyses. The extent of the left atrial (LA) voltage-defined atrial fibrosis and conduction properties were estimated by a three-dimensional high-density electroanatomical mapping system. The LA size was evaluated by transthoracic echocardiography. The study patients were divided into 2 groups according to an FWA in lead V1 above the median value of 46 µV (high FWA group, n=57) or below 46 µV (low FWA group, n=57). RESULTS: There were no differences in the age, gender, CHADS2 score, prevalence of paroxysmal AF, medications, ablation strategy, and LA volume index between the two groups. The LA low voltage areas in the low FWA group were not different from those in the high FWA group. The total LA activation time and local LA conduction velocity did not differ between the two groups. During a median follow-up of 710 days, the recurrence rate after ablation was significantly higher in patients with a low FWA than a high FWA (log-rank P=0.02). In a multivariate analysis, non-paroxysmal AF, the LA volume index, and FWA were independent predictors of recurrence after　ablation. CONCLUSIONS: The FWA was not correlated with the markers of atrial structural remodeling. Nevertheless, the FWA could still provide information for predicting the clinical outcome after AF ablation.

Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines.

BACKGROUND: We hypothesize that left-sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. METHODS AND RESULTS: We implanted a neurostimulator in 12 dogs to stimulate the left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activity, vagal nerve activities, and ECGs. Group 1 dogs (N=6) underwent 1 week of continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated stellate ganglion nerve activity was significantly reduced during LL-VNS (7.8 mV/s; 95% confidence interval [CI] 6.94 to 8.66 versus 9.4 mV/s [95% CI, 8.5 to 10.3] at baseline; P=0.033) in group 1. The reduction was most apparent at 8 am, along with a significantly reduced heart rate (P=0.008). Left-sided low-level vagus nerve stimulation did not change vagal nerve activity. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion 1 week after cessation of LL-VNS were 99 684 µm(2)/mm(2) (95% CI, 28 850 to 170 517) in LL-VNS dogs and 186 561 µm(2)/mm(2) (95% CI, 154 956 to 218 166; P=0.008) in normal dogs. In group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/d (95% CI, 0.5 to 5.1) and 8.0/d (95% CI, 5.3 to 12.0), respectively, significantly lower than during sham stimulation (9.2/d [95% CI, 5.3 to 13.1]; P=0.001 and 22.0/d [95% CI, 19.1 to 25.5], P<0.001, respectively). CONCLUSIONS: Left-sided low-level vagus nerve stimulation suppresses stellate ganglion nerve activities and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident 1 week after cessation of continuous LL-VNS.

Heart failure decreases nerve activity in the right atrial ganglionated plexus.

OBJECTIVE: We tested the hypothesis that heart failure (HF) results in right atrial ganglionated plexus (RAGP) denervation that contributes to sinoatrial node dysfunction. BACKGROUND: HF is associated with sinoatrial node dysfunction. However, the detailed mechanisms remain unclear. METHODS: We recorded nerve activity (NA) from the RAGP, right stellate ganglion (SG), and right vagal nerve in 7 ambulatory dogs at baseline and after pacing-induced HF. We also determined the effects of RAGP stimulation in isolated normal and HF canine RA. RESULTS: NAs in both the SG and vagal were significantly higher in HF than at baseline. The relationship between 1-minute integrated NAs of vagal and RAGP showed either a positive linear correlation (Group 1, n = 4) or an L-shaped correlation (Group 2, n = 3). In all dogs, a reduced heart rate was observed when vagal-NA was associated with simultaneously increased RAGP-NA. On the other hand, when vagal-NA was not associated with increased RAGP-NA, the heart rate was not reduced. The induction of HF significantly decreased RAGP-NA in all dogs (P < 0.05). Stimulating the superior RAGP in isolated RA significantly reduced the sinus rate in normal but not the HF hearts. Immunohistochemical staining revealed lower densities of tyrosine hydroxylase- and choline acetyltransferase-positive nerve tissues in HF RAGP than normal (P < 0.001 and P = 0.001, respectively). CONCLUSIONS: The RAGP-NA is essential for the vagal nerve to counterbalance the SG in sinus rate control. In HF, RAGP denervation and decreased RAGP-NA contribute to the sinus node dysfunction.