Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis.

Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 µM, an inhibitor of protein kinase A, PKA), KN93 (1 µM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 µM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis.

Circulating level of microRNA-142-5p is a potential biomarker for predicting in-stent restenosis: a case-control study.

BACKGROUND: Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers. METHODS: In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR. RESULTS: Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively. CONCLUSIONS: The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.

The AMP-activated protein kinase modulates hypothermia-induced J wave.

BACKGROUND: The mechanism underlying the occurrence of the J wave in low temperature remains unclear. However, low temperature is associated with metabolic disorder and 5' AMP-activated protein kinase (AMPK), which modulates ionic currents and cardiac metabolism. This study investigated whether AMPK regulation can modulate the occurrence of the J wave at low temperature. METHODS: Unipolar and bipolar leads were used to record monophasic action potential (the endocardium and epicardium) and pseudo-electrocardiograms (inferior leads) to study the cardiac electrical activity. Measurements were taken in isolated Langendorff rabbit hearts at both 30℃ and 37℃ before and after administration of 4-aminopyridine (an ultrarapid delayed rectifier potassium current inhibitor, IKur , 50 µmol L-1 ), PF06409577 (an AMPK activator, 1 µmol L-1 ), compound C (an AMPK inhibitor, 10 µmol L-1 ) and glibenclamide (an ATP-sensitive inward rectifier potassium channel inhibitor, IKATP , 20 µmol L-1 ). RESULTS: The amplitude of the J wave (2.46 ± 0.34 mV vs. 1.11 ± 0.23 mV, P < .01) at 30℃ (n = 15) was larger than that at 37℃ (n = 15). PF06409577 (1 µmol L-1 ) increased the J waves at both 30℃ and 37℃. In contrast, compound C (10 µmol L-1 ) reduced J wave at both 37℃ and 30℃. Low-temperature-induced J waves were individually suppressed by 4-AP (50 µmol L-1 ) and glibenclamide (20 µmol L-1 ). CONCLUSIONS: AMPK inhibition reduces low-temperature-induced J waves and possible ventricular arrhythmogenesis by modulating IKATP and IKur channels.

Heart Failure Differentially Modulates Natural (Sinoatrial Node) and Ectopic (Pulmonary Veins) Pacemakers: Mechanism and Therapeutic Implication for Atrial Fibrillation.

Heart failure (HF) frequently coexists with atrial fibrillation (AF) and dysfunction of the sinoatrial node (SAN), the natural pacemaker. HF is associated with chronic adrenergic stimulation, neurohormonal activation, abnormal intracellular calcium handling, elevated cardiac filling pressure and atrial stretch, and fibrosis. Pulmonary veins (PVs), which are the points of onset of ectopic electrical activity, are the most crucial AF triggers. A crosstalk between the SAN and PVs determines PV arrhythmogenesis. HF has different effects on SAN and PV electrophysiological characteristics, which critically modulate the development of AF and sick sinus syndrome. This review provides updates to improve our current understanding of the effects of HF in the electrical activity of the SAN and PVs as well as therapeutic implications for AF.

Hydrogen sulphide increases pulmonary veins and atrial arrhythmogenesis with activation of protein kinase C.

Hydrogen sulphide (H2 S), one of the most common toxic air pollutants, is an important aetiology of atrial fibrillation (AF). Pulmonary veins (PVs) and left atrium (LA) are the most important AF trigger and substrate. We investigated whether H2 S may modulate the arrhythmogenesis of PVs and atria. Conventional microelectrodes and whole-cell patch clamp were performed in rabbit PV, sinoatrial node (SAN) or atrial cardiomyocytes before and after the perfusion of NaHS with or without chelerythrine (a selective PKC inhibitor), rottlerin (a specific PKC δ inhibitor) or KB-R7943 (a NCX inhibitor). NaHS reduced spontaneous beating rates, but increased the occurrences of delayed afterdepolarizations and burst firing in PVs and SANs. NaHS (100 µmol/L) increased IKATP and INCX in PV and LA cardiomyocytes, which were attenuated by chelerythrine (3 µmol/L). Chelerythrine, rottlerin (10 µmol/L) or KB-R7943 (10 µmol/L) attenuated the arrhythmogenic effects of NaHS on PVs or SANs. NaHS shortened the action potential duration in LA, but not in right atrium or in the presence of chelerythrine. NaHS increased PKC activity, but did not translocate PKC isoforms α, ε to membrane in LA. In conclusion, through protein kinase C signalling, H2 S increases PV and atrial arrhythmogenesis, which may contribute to air pollution-induced AF.

Heart Failure Differentially Modulates the Effects of Ivabradine on the Electrical Activity of the Sinoatrial Node and Pulmonary Veins.

BACKGROUND: Ivabradine increases the risk of atrial fibrillation (AF). Heart failure (HF) or sinoatrial node (SAN) dysfunction increases the risk of AF, and pulmonary veins (PVs) play a critical role in the pathophysiology of AF. This study investigated the electrophysiologic effects of ivabradine on SANs and PVs in a rabbit model of HF. METHODS AND RESULTS: Conventional microelectrodes were used to simultaneously record the electrical activities and conduction properties of control and HF rabbit SAN-PV preparations before and after perfusion with ivabradine (0.1, 1, or 10 µmol/L), either alone or with isoproterenol (1 µmol/L). HF SANs exhibited a lower beating rate than the control SANs. SAN automaticity exit blocks and SAN-PV conduction blocks were observed in 25% and 50% of samples, respectively, with P < .05 for HF SANs (n = 8) but not for control SANs (n = 6). Delayed afterdepolarization (DAD) was observed in 37.5% of HF PVs but not in control PVs. HF PVs exhibited a faster beating rate and more severe fibrosis than control PVs. Ivabradine reduced the SAN beating rates and increased the occurrences of SAN-PV conduction blocks and PV DADs in control and HF preparations. However, ivabradine induced SAN automaticity exit blocks only in HF preparations. Isoproterenol induced PV burst firing and shifting electrical conduction in control and HF preparations. A combination of isoproterenol and ivabradine (10 µmol/L) in HF preparations resulted in the highest incidences of PV burst firing and SAN-PV electrical shifting. CONCLUSIONS: HF differentially modulates the effects of ivabradine on the electrical activities of SAN and PVs, which may increase PV arrhythmogenesis and contribute to the risk of AF in HF patients.

Atrial fibrillation originating from superior vena cava with atrial flutter-electrocardiogram pattern.

BACKGROUNDS: Substrate property is related to the genesis and maintenance of atrial fibrillation (AF). The aim of the study was to investigate the impact of substrate property on the electrocardiogram (ECG) in patients with AF originating from the superior vena cava (SVC). METHODS AND RESULTS: Seventy-six patients with AF originating from SVC who underwent catheter ablation were included from 2004 to 2013. Of these patients, 16 had a presentation of atrial flutter (AFL)-pattern ECG during AF (group 1), and 60 patients did not (group 2). There was no significant difference in clinical characteristics between the groups. The percentage of low voltage zone (LVZ) in SVC below the level of pulmonary artery in group 1 was significantly larger than that in group 2. The polarities of the flutter wave in 12-lead ECG were compared with another 26 subjects with reverse typical AFL. The ECG morphology was characterized by negative or biphasic P waves in lead V1 in most of the patients in group 1 (62.5%), which was analogous to that in reverse typical AFL. The negative polarity of flutter waves in aVL might distinguish SVC AF with an AFL-pattern from reverse typical AFL. CONCLUSION: The ECG characteristics of AF originating from SVC can mimic atypical AFL. LVZ in the SVC may be associated with the presentation of AFL-pattern ECG.

Arterial Stiffness Index and Coronary Artery Plaques in Patients with Subclinical Coronary Atherosclerosis.

BACKGROUND: Arterial stiffness is a physiologic quantitative value used to measure arterial compliance. It is predictive of coronary atherosclerosis in patients with intermediate to high cardiovascular risk. However, a correlation between arterial stiffness and subclinical coronary atherosclerosis has yet to be established. Therefore, the purpose of this study was to evaluate arterial stiffness using an arterial stiffness index (ASI) and investigate its association with coronary artery plaque in patients with subclinical coronary atherosclerosis. METHODS: Our study enrolled 156 consecutive subjects who underwent health screening using a 64-slice cardiac computed tomography angiography (CCTA). Their arterial stiffness index was assessed noninvasively by CardioVision(®) MS-2000. The atheroma on the coronary vessel walls was analyzed. RESULTS: Of the 156 patients, 53 displayed at least one > 50% stenotic lesion over the coronary arteries in CCTA images. The patients with at least one > 50% coronary stenotic plaque were older and had higher systolic blood pressure and ASI values than patients without > 50% coronary stenotic plaque. After dividing the study population into 2 groups by those patients over and under 50 years of age, the ASI positively correlated with the presentation of at least one > 50% coronary stenotic plaque in patients aged ≥ 50 years (odds ratio = 1.02, 95% confidence interval: 1.00-1.04, p = 0.03). CONCLUSIONS: The ASI could play a role in risk stratification systems for coronary artery disease in patients with subclinical coronary atherosclerosis, and is a useful clinical marker for the correlation of early coronary plaque. KEY WORDS: Arterial stiffness; Arterial stiffness index; Atherosclerosis; Coronary artery plaque.

Long-Term Outcomes of Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction and Coexisting End-Stage Renal Disease.

Sacubitril/valsartan (Entresto) has proven therapeutic effects in heart failure (HF) patients, but its impact on those with advanced chronic kidney disease (CKD) remains unclear, particularly in HF patients with coexisting end-stage renal disease (ESRD). This study aims to assess the long-term survival of patients with heart failure with reduced ejection fraction (HFrEF) and coexisting ESRD treated with sacubitril/valsartan. A retrospective cohort study included 2,860 HFrEF and ESRD patients between January 2008 and December 2020. After propensity score matching, data from a sacubitril/valsartan group (n = 61) and a candesartan or valsartan group (n = 117) were analyzed. Patients on sacubitril/valsartan for at least 9 months had significantly lower 5-year all-cause mortality (39.3%) compared with the non-sacubitril/valsartan group (54.7%) (HR 0.46; 95% CI, 0.25-0.82; P = 0.0094). Left ventricular ejection fraction (LVEF) improvement after 3 years in the sacubitril/valsartan group (14.51 ±18.98) was significantly greater than the non-sacubitril/valsartan group (6.91 ±18.44) (P = 0.0408). Average hospitalizations in sacubitril/valsartan and non-sacubitril/valsartan groups were 1.39 and 0.97, respectively (incidence rate ratio, 1.59; 95% CI, 0.90-2.82; P = 0.1106). Sacubitril/valsartan treatment demonstrated significantly lower 5-year mortality rates and greater LVEF improvement in HFrEF patients with coexisting ESRD compared with candesartan or valsartan. These findings suggest that sacubitril/valsartan is a beneficial treatment option for this patient population.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, regulates ventricular electromechanical activities and enhances arrhythmogenesis.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor used in cancer therapy, exerts ventricular proarrhythmic effects; however, the underlying mechanisms remain unclear. Excitation-contraction coupling (E-C) disorders are pivotal for the genesis of ventricular arrhythmias (VAs), which arise mainly from the right ventricular outflow tract (RVOT). In this study, we aimed to comprehensively investigate whether ibrutinib regulates the electromechanical activities of the RVOT, leading to enhanced arrhythmogenesis, and explore the underlying mechanisms. METHODS: We utilized conventional microelectrodes to synchronously record electrical and mechanical responses in rabbit RVOT tissue preparations before and after treatment with ibrutinib (10, 50, and 100 nM) and investigated their electromechanical interactions and arrhythmogenesis during programmed electrical stimulation. The fluorometric ratio technique was used to measure intracellular calcium concentration in isolated RVOT myocytes. RESULTS: Ibrutinib (10-100 nM) shortened the action potential duration. Ibrutinib at 100 nM significantly increased pacing-induced ventricular tachycardia (VT) (from 0% to 62.5%, n = 8, p = 0.025). Comparisons between pacing-induced VT and non-VT episodes demonstrated that VT episodes had a greater increase in contractility than that of non-VT episodes (402.1 ± 41.4% vs. 232.4 ± 29.2%, p = 0.003). The pretreatment of ranolazine (10 µM, a late sodium current blocker) prevented the occurrence of ibrutinib-induced VAs. Ibrutinib (100 nM) increased late sodium current, reduced intracellular calcium transients, and enhanced calcium leakage in RVOT myocytes. CONCLUSION: Ibrutinib increased the risk of VAs in the RVOT due to dysregulated electromechanical responses, which can be attenuated by ranolazine or apamin.

Combined Framingham Risk Score and Coronary Artery Calcium Score Predict Subclinical Coronary Plaque Assessed by Coronary Computed Tomography Angiogram in Asymptomatic Taiwanese Population.

BACKGROUND: We sought to determine the predictive value of the combined traditional Framingham risk score (FRS) and coronary artery calcium score (CACS) for subclinical coronary plaque detected by computed tomography coronary angiogram (CTCA) in asymptomatic subjects. METHOD: We evaluated 167 asymptomatic Taiwanese subjects (mean age, 57 ± 11.2 years), who underwent CTCA as part of a health evaluation. We examined the associations between FRS, CACS, serum biomarkers, and coronary plaque assessed by CTCA. RESULTS: Out of 167 subjects in the study, 95 had coronary artery atheroma. Of those possible predictors for coronary atherosclerosis, both FRS and CACS were independent predictors for the presence of coronary plaque [relative risk (RR): 1.29, 95% confidence interval (CI): 1.07-1.54, p = 0.006 and RR: 1.42, 95% CI: 1.16-1.75, p = 0.001, respectively]. Receiver operating characteristics curve analysis revealed that CACS and FRS were indicators of the presence of coronary plaque. The area under the curve for FRS and CACS was 0.729 and 0.889, respectively (p < 0.001). Furthermore, the area under the curve for combination of FRS and CACS was 0.936 (95% CI: 0.887-0.969, p < 0.001), and this combination provided a better diagnostic advantage than either FRS or CACS alone (p < 0.001 and p = 0.012 by C-statistic, respectively). CONCLUSIONS: In asymptomatic Taiwanese subjects with low to intermediate cardiovascular risk, both FRS and CACS were independently related to subclinical atherosclerosis. A combined FRS and CACS evaluation improved the efficacy of prediction for atherosclerotic plaque burden. KEY WORDS: Atherosclerosis; Computed coronary tomography angiogram; Coronary artery calcium score; Framingham risk score; Subclinical coronary plaque.

Modulation of post-pacing action potential duration and contractile responses on ventricular arrhythmogenesis in chloroquine-induced long QT syndrome.

BACKGROUND: Excitation-contraction (E-C) coupling, the interaction of action potential duration (APD) and contractility, plays an essential role in arrhythmogenesis. We aimed to investigate the arrhythmogenic role of E-C coupling in the right ventricular outflow tract (RVOT) in the chloroquine-induced long QT syndrome. METHODS: Conventional microelectrodes were used to record electrical and mechanical activity simultaneously under electrical pacing (cycle lengths from 1000-100 ms) in rabbit RVOT tissue preparations before and after chloroquine with and without azithromycin. KB-R7943 (a Na+-Ca2+ exchanger [NCX] inhibitor), ranolazine (a late sodium current inhibitor), or MgSO4 were used to assess their pharmacological responses in the chloroquine-induced long QT syndrome. RESULTS: Sequential infusion of chloroquine and chloroquine plus azithromycin triggered ventricular tachycardia (VT) (33.7%) after rapid pacing compared to baseline (6.7%, p = 0.004). There were greater post-pacing increases of the first occurrence of contractility (ΔContractility) in the VT group (VT vs. non-VT: 521.2 ± 50.5% vs. 306.5 ± 26.8%, p < 0.001). There was no difference in the first occurrence of action potential at 90% repolarization (ΔAPD90) (VT vs. non-VT: 49.7 ± 7.4 ms vs. 51.8 ± 13.1 ms, p = 0.914). Pacing-induced VT could be suppressed to baseline levels by KB-R7943 or MgSO4. Ranolazine did not suppress pacing-induced VT in chloroquine-treated RVOT. ΔContractility was reduced by KB-R7943 and MgSO4, but not by ranolazine. CONCLUSION: ΔContractility (but not ΔAPD) played a crucial role in the genesis of pacing-induced VT in the long QT tissue model, which can be modulated by NCX (but not late sodium current) inhibition or MgSO4.

Mirabegron, a ß3­adrenoreceptor agonist, regulates right and left atrial arrhythmogenesis differently.

Mirabegron increases atrial fibrillation (AF) risk. The left atrium (LA) is the most critical 'substrate' for AF and has higher arrhythmogenesis compared with the right atrium (RA). The present study aimed to investigate the electrophysiological and arrhythmogenic effects of mirabegron on the LA and RA and clarify the potential underlying mechanisms. Conventional microelectrodes, a whole-cell patch clamp and a confocal microscope were used in rabbit LA and RA preparations or single LA and RA myocytes before and after mirabegron administration with or without cotreatment with KT5823 [a cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor]. The baseline action potential duration at repolarization extents of 20 and 50% (but not 90%) were shorter in the LA than in the RA. Mirabegron at 0.1 and 1 µM (but not 0.01 µM) reduced the action potential duration at repolarization extents of 20 and 50% in the LA and RA. Mirabegron (0.1 µM) increased the occurrence of tachypacing-induced burst firing in the LA but not in the RA, where it was suppressed by KT5823 (1 µM). Mirabegron (0.1 µM) increased the L-type Ca2+ current (ICa-L), ultrarapid component of delayed rectifier K+ current (IKur), Ca2+ transients and sarcoplasmic reticulum Ca2+ content but reduced transient outward K+ current (Ito) in the LA myocytes. However, mirabegron did not change the Na+ current and delayed rectifier K+ current in the LA myocytes. Moreover, pretreatment with KT5823 (1 µM) inhibited the effects of mirabegron on ICa-L, Ito and IKur in the LA myocytes. Furthermore, in the RA myocytes, mirabegron reduced ICa-L but did not change Ito. In conclusion, mirabegron differentially regulates electrophysiological characteristics in the LA and RA. Through the activation of the cAMP-dependent protein kinase pathway and induction of Ca2+ dysregulation, mirabegron may increase LA arrhythmogenesis, leading to increased AF risk.

Association of multiple preventive therapies postdischarge and long-term health outcomes after acute myocardial infarction.

BACKGROUND: Statins, beta-blockers, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers have been advocated by guidelines as secondary prevention medications to improve the long-term outcomes of post-acute myocardial infarction (AMI) patients. However, adequate drug adherence has always been challenging, and different treatment regimens may lead to divergent outcomes that remain unclear under current myocardial infarction (MI) care standards. This study investigated the association between use of different preventive regimens post-AMI and patients' long-term outcomes. METHODS: This cohort study used data files from the Taiwan National Health Insurance Research Database. A total of 77 520 people who were hospitalized with AMI between 2002 and 2015 were assessed. On the basis of medication possession ratio (MPR) to individual medications, eight treatment groups were examined in this study. Receiving therapy was defined as MPR ≥40%. We investigated the association between different treatment groups and all-cause mortality in 24 months. RESULTS: Overall, 51 322 patients with ST-elevation MI and 26 198 with non-ST-elevation MI were included in the study. Patients received all three preventive medications show the lowest mortality in 24 months follow-up periods among all treatment groups. Patients who did not usage of any of these three preventive medications had the highest mortality in 24 months (adjusted hazard ratio, 1.78; 95% CI, 1.64-1.93). This mortality rate had the same pattern across the three cohort generations (2002-2005, 2006-2010, and 2011-2015). CONCLUSION: In this large population-based real-world study, usage of three preventive therapies post-MI was associated with the lowest rate of all-cause mortality.

Atrial arrhythmogenesis in a rabbit model of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) increases the risk of atrial fibrillation (AF), however, its arrhythmogenic mechanisms are unclear. This study investigated the effects of COPD on AF triggers (pulmonary veins, PVs) and substrates (atria), and their potential underlying mechanisms. Electrocardiographic, echocardiographic, and biochemical studies were conducted in control rabbits and rabbits with human leukocyte elastase (0.3 unit/kg)-induced COPD. Conventional microelectrode, Western blotting, and histological examinations were performed on PV, left atrium (LA), right atrium, and sinoatrial node (SAN) preparations from control rabbits and those with COPD. The rabbits with COPD had a higher incidence of atrial premature complexes, PV burst firing and delayed afterdepolarizations, higher sympathetic activity, larger LA, and faster PV spontaneous activity than did the control rabbits; but they exhibited a slower SAN beating rate. The LA of the rabbits with COPD had a shorter action potential duration and longer tachyarrhythmia induced by tachypacing (20 Hz) and isoproterenol (1 µM). Additionally, the rabbits with COPD had higher fibrosis in the PVs, LA, and SAN. H89 (10 µM), KN93 (1 µM), and KB-R7943 (10 µM) significantly suppressed burst firing and delayed afterdepolarizations in the PVs of the rabbits with COPD. Moreover, compared with the control rabbits, those with COPD had lower expression levels of the ß1 adrenergic receptor, Cav 1.2, and Na+/Ca2+ exchanger in the PVs; Cav 1.2 in the LA; and hyperpolarization-activated cyclic nucleotide-gated K+ channel 4 in the SAN. COPD increases atrial arrhythmogenesis by modulating the distinctive electrophysiological characteristics of the PVs, LA, and SAN.

Impact of aortic encroachment to left atrium on non-pulmonary vein triggers of atrial fibrillation.

BACKGROUND: Aortic dilatation was frequently observed in patients with atrial fibrillation (AF) and non-pulmonary vein (PV) triggers are important for mapping and ablation of AF. We hypothesized that the aortic encroachment area over left atrium (LA) could contribute to the local substrate characteristics. METHODS: We studied 32 consecutive patients of AF (age=57.34±8.07, male=30), including 26 paroxysmal and 6 persistent AFs. Anatomic relationship between LA and aorta, and electrophysiological characteristics of the encroachment areas were investigated. IRB approval was taken. RESULTS: The LA bipolar voltage (mean 0.49±0.26mV) was lower at aortic encroached area compared to global LA (mean 1.52±0.48mV) and it was statistically significant (p<0.001). There was a linear correlation between the voltages of LA and distance from the aorta to the aortic encroachment area of LA (p<0.001, R=0.616). Non-PV triggers were observed in 34.37% (n=11) of total patients. The initiation of AF in aortic encroached area was seen in 45.45% (n=5) of non-PV trigger and 15.62% of total patients. All the patients were followed up for 6months and 4 (14.81%) out of 27 patients without trigger at aortic encroached site of LA and 1 (20%) out of 5 patients with trigger at aortic encroached site of LA had recurrence of AF. CONCLUSION: The aorta contributed to low voltages on its encroachment area over the anterior wall of LA. Non-pulmonary vein triggers originating from the aortic encroachment area were found in 15.62% of total patients. Careful evaluation of the anatomical relationship between LA and aorta is important during AF ablation for a better long term outcome.

Characteristics and long-term catheter ablation outcome in long-standing persistent atrial fibrillation patients with non-pulmonary vein triggers.

BACKGROUND: There are limited literatures regarding the non-pulmonary vein (NPV) triggers in long-standing persistent atrial fibrillation (LSPAF). The goal of the present study was to investigate the characteristics and long-term outcome of catheter ablation among these patients. METHODS: The study included 776 patients (age 53.59±11.38years-old, 556 males) who received catheter ablation for drug-refractory atrial fibrillation (AF). We divided these patients into 3 groups. Group 1 consisted of 579 patients with paroxysmal AF (PAF), group 2 consisted of 103 patients with persistent AF (PerAF) and group 3 consisted of 94 patients with long-standing persistent AF (LSPAF). The average follow-up duration was 28.53±23.21months. RESULTS: The clinical endpoint was the recurrence of atrial tachyarrhythmia. Among these 3 groups, higher percentages of male (93.6%, P<0.001), NPV triggers (44.7%, P<0.001), longer AF duration (6.65±6.72years, P=0.029), larger left atrium diameter (44.44±6.79mm, P<0.001), and longer procedure time (181.94±70.02min, P<0.001) were noted in LSPAF. After the first catheter ablation, the recurrence rate of AF was highest in LSPAF (Log Rank, P<0.001). Larger left atrium diameters (LAD) (P=0.006; HR: 1.063; CI: 1.018-1.111) and NPV triggers (P=0.035; HR: 1.707; 1.037-2.809) independently predicted AF recurrence in LSPAF. CONCLUSIONS: Compared with PAF and PerAF, LSPAF had a higher incidence of NPV triggers and worse long-term outcome after catheter ablation. NPV triggers and LAD independently predicted AF recurrence after catheter ablation in LSPAF.

Early repolarization of surface ECG predicts fatal ventricular arrhythmias in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy and symptomatic ventricular arrhythmias.

BACKGROUND: The clinical characteristics and prognostic value of early repolarization (ER) in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and symptomatic ventricular arrhythmias remain unclear. We investigated the prevalence, clinical features, and cardiovascular outcomes of patients with symptomatic ARVD/C and ER. METHODS: A total of 59 consecutive ARVD/C patients hospitalized for catheter ablation, presenting with and without J-point elevations of ≥0.1mV in at least 2 inferior leads or lateral leads were enrolled. Clinical characteristics, electrophysiological study, substrate mapping, catheter ablation, and future clinical outcomes in a prospective patient registry were investigated. RESULTS: ER was observed in 38 patients (64.4%). Among these patients, ER was found in the inferior leads in 18 patients (47.4%), in the lateral leads in 2 patients (5.3%), and in both inferior and lateral leads in 18 patients (47.4%). Patients exhibiting ER were commonly men, had lower right ventricular ejection fraction, had higher incidence of clinical ventricular fibrillation or aborted sudden cardiac death, had more defibrillator implantations, had higher the need of epicardial ablation, and had more major criteria according to the task force criteria. Significant higher incidence of induced ventricular fibrillation and shorter tachycardia cycle length of induced ventricular tachycardia were found during procedure. The recurrence rate of ventricular arrhythmias did not differ between patients with and without ER after catheter ablation. CONCLUSIONS: A high prevalence of electrocardiographic ER was found among symptomatic ARVD/C patients undergoing catheter ablation. ER in 12-lead ECG is associated with an increased risk of clinical fatal ventricular arrhythmias.

The Different Substrate Characteristics of Arrhythmogenic Triggers in Idiopathic Right Ventricular Outflow Tract Tachycardia and Arrhythmogenic Right Ventricular Dysplasia: New Insight from Noncontact Mapping.

BACKGROUND: The aim of this study was to investigate the different substrate characteristics of repetitive premature ventricular complexed (PVC) trigger sites by the non-contact mapping (NCM). METHODS: Thirty-five consecutive patients, including 14 with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) and 21 with idiopathic right ventricular outflow tract tachycardia (RVOT VT), were enrolled for electrophysiological study and catheter ablation guided by the NCM. Substrate and electrogram (Eg) characteristics of the earliest activation (EA) and breakout (BO) sites of PVCs were investigated, and these were confirmed by successful PVC elimination. RESULTS: Overall 35 dominant focal PVCs were identified. PVCs arose from the focal origins with preferential conduction, breakout, and spread to the whole right ventricle. The conduction time and distance from EA to BO site were both longer in the ARVC than the RVOT group. The conduction velocity was similar between the 2 groups. The negative deflection of local unipolar Eg at the EA site (EA slope3,5,10ms values) was steeper in the RVOT, compared to ARVC patients. The PVCs of ARVC occurred in the diseased substrate in the ARVC patients. More radiofrequency applications were required to eliminate the triggers in ARVC patients. CONCLUSIONS/INTERPRETATION: The substrate characteristics of PVC trigger may help to differentiate between idiopathic RVOT VT and ARVC. The slowing and slurred QS unipolar electrograms and longer distance from EA to BO in RVOT endocardium suggest that the triggers of ARVC may originate from mid- or sub-epicardial myocardium. More extensive ablation to the trigger site was required in order to create deeper lesions for a successful outcome.

Different characteristics and electrophysiological properties between early and late recurrences after acute successful catheter ablation of idiopathic right ventricular outflow tract arrhythmias during long-term follow-up.

BACKGROUND: Radiofrequency catheter ablation (RFCA) is an effective therapeutic strategy in eliminating drug-refractory idiopathic right ventricular outflow tract ventricular arrhythmias (RVOT VAs). It remains unclear what factors affect early and late VA recurrences after ablation. OBJECTIVE: The aim of our study was to elucidate the differences between early and late recurrences after acute successful RFCA of RVOT VAs in a long-term follow-up. METHODS: A total of 220 patients with acute successful RFCA of RVOT VAs were enrolled. Detailed clinical characteristics and assessments by noninvasive and invasive electrophysiology study were explored to predict the overall, early (≤1 year), and late VA (>1 year) recurrences. RESULTS: During a mean follow-up of 34.15 ± 33.74 months, 45 of 220 patients (20.5%) documented recurrence of RVOT VAs after the initial RFCA. Of these patients, 26 patients (57.8%) with recurrent VAs showed similar morphology, and 19 (42.2%) were different. Patients with recurrent VAs were associated with a higher incidence of hypertension, higher systolic blood pressure, identification of foci by pace mapping alone, shorter earliest activation time, more radiofrequency pulses required, and VA originating from the anterior free wall. Multivariate analysis demonstrated that mapping strategy and shorter earliest activation time preceding VA were associated with early recurrences (hazard ratio [HR] 2.26; 95% confidence interval [CI] 1.49-3.42; P < .001; and HR 0.91; 95% CI 0.85-0.98; P = .008, respectively), whereas hypertension was associated with late recurrence (HR 3.48; 95% CI 1.34-9.07; P = .001). CONCLUSION: RFCA is an effective strategy in the elimination of RVOT VAs. However, early and late recurrences occur commonly. Patients with early and late VA recurrences demonstrated nonuniform patterns of clinical characteristics and electrophysiological properties.