The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling.

Atrial structural remodelling including atrial hypertrophy and fibrosis is a key mediator of atrial fibrillation (AF). We previously demonstrated that the matricellular protein CCN5 elicits anti-fibrotic and anti-hypertrophic effects in left ventricles under pressure overload. We here determined the utility of CCN5 in ameliorating adverse atrial remodelling and arrhythmias in a murine model of angiotensin II (AngII) infusion. Advanced atrial structural remodelling was induced by AngII infusion in control mice and mice overexpressing CCN5 either through transgenesis (CCN5 Tg) or AAV9-mediated gene transfer (AAV9-CCN5). The mRNA levels of pro-fibrotic and pro-inflammatory genes were markedly up-regulated by AngII infusion, which was significantly normalized by CCN5 overexpression. In vitro studies in isolated atrial fibroblasts demonstrated a marked reduction in AngII-induced fibroblast trans-differentiation in CCN5-treated atria. Moreover, while AngII increased the expression of phosphorylated CaMKII and ryanodine receptor 2 levels in HL-1 cells, these molecular features of AF were prevented by CCN5. Electrophysiological studies in ex vivo perfused hearts revealed a blunted susceptibility of the AAV9-CCN5-treated hearts to rapid atrial pacing-induced arrhythmias and concomitant reversal in AngII-induced atrial action potential prolongation. These data demonstrate the utility of a gene transfer approach targeting CCN5 for reversal of adverse atrial structural and electrophysiological remodelling.

Supraventricular tachyarrhythmias in patients with a persistent left superior vena cava.

Aims: A persistent left superior vena cava (PLSVC) is the most common thoracic venous anomaly. This venous anomaly can impact the evaluation and treatment of supraventricular tachyarrhythmia (SVA). The aim of this study was to assess the proportion and characteristics of PLSVC in adult SVA patients. Methods and results: From July 2002 to July 2012, clinical and procedural data from databases of 10 cardiac electrophysiology laboratories in the Yeungnam region of the Republic of Korea were reviewed. Of 6662 adult SVA patients who underwent an EP study or catheter ablation of SVA during the 10-year study period, 18 patients had PLSVC (mean age 47.6 ± 14.8 years, 10 men). The proportion of PLSVC in adult SVA patients was 0.27% (18/6662). SVA type and procedural outcomes of radiofrequency (RF) catheter ablation in these patients were investigated and the results were as follows: successful slow pathway modification in six of seven patients with atrioventricular nodal reentrant tachycardia (AVNRT), successful ablation of accessory pathway in three of four patients with atrioventricular reentrant tachycardia, and successful ablation of atrial tachycardia (cavotricuspid isthmus-dependent in two, septal macroreentry in one, focal from the PLSVC in one) in three of four patients. In one patient with junctional tachycardia, catheter ablation failed. In two patients with atrial fibrillation, catheter ablation was successful. Conclusion: Among adult SVA patients who underwent an EP study or RF catheter ablation during the 10-year study period, 0.27% had PLSVC. The most common type of SVA was AVNRT. The success rate of catheter ablation was 82% in SVA patients with PLSVC. There were no procedure-related complications.

Impact of duration and dosage of statin treatment and epicardial fat thickness on the recurrence of atrial fibrillation after electrical cardioversion.

The purpose of this study was to investigate the time-dependent effect of statin treatment and echocardiographic epicardial fat thickness (EFT) on the maintenance of sinus rhythm (SR) in atrial fibrillation (AF) patients after electrical cardioversion (EC). One hundred sixty-three AF patients without previous statin treatment who underwent EC were consecutively enrolled. The maintenance rate of SR after EC (1, 3, 6, and 12 months) as documented by electrocardiogram and EFT were compared between patients with statin treatment (statin group, n = 63) and those without (no statin group, n = 100). There was no significant difference in the maintenance rate of SR between the groups soon after EC (statin group; 85.7 % vs. no statin; 84.8%, p = 0.535), after 1 month (71.0 vs. 59.1%, p = 0.091), and after 3 months (63.2 vs. 50.0%, p = 0.086). However, the maintenance rate of SR was significantly higher in the statin group compared to no statin group (61.8 vs. 42.9%, p = 0.024) after 6 months, and this significant difference persisted up to 12 months of follow up (60.1 vs. 36.4%, p = 0.001). Patients with recurrence showed higher baseline EFT (7.4 ± 2.7 vs. 8.5 ± 3.0 mm, p = 0.014). Multivariate linear regression analysis indicated that EFT, left atrial diameter, high-density lipoprotein cholesterol, statin treatment, and dose were the significant contributors to the maintenance of SR for all periods after EC. Statin treatment and low EFT were associated with a higher maintenance rate of SR in AF patients after EC. Significant benefit of statin was realized 6 months after EC, and this benefit was shown to be maintained over time.

Simvastatin attenuates the oxidative stress, endothelial thrombogenicity and the inducibility of atrial fibrillation in a rat model of ischemic heart failure.

Increased atrial oxidative stress has an important role in inducing and maintaining atrial fibrillation (AF), and the activation of the small GTPase Rac1 contributes to the oxidative stress. We investigated the relationship of Rac1, atrial endothelial thromboprotective markers and AF inducibility and if simvastatin has a potential beneficial effect on a myocardial infarction (MI)-induced heart failure (HF) rat model. Rats were randomized into three groups (shams, MI group and simvastatin treatment group) and underwent echocardiography, AF induction studies and left atrial (LA) fibrosis analysis. Atrial Rac 1, sodium calcium exchanger (INCX), sarcoplasmic reticulum calcium ATPase (SERCA), endothelial nitric oxide synthase (eNOS) and induced nitric oxide synthase (iNOS) were measured. AF inducibility, AF duration and LA fibrosis were significantly higher in the MI group (p < 0.001 vs. sham), which were significantly reduced by simvastatin (p < 0.05 vs. MI). The reduced expressions of atrial eNOS, SERCA, thrombomodulin, tissue factor pathway inhibitor and tissue plasminogen activator in the MI group were significantly improved by simvastatin. Furthermore, the increased expression of atrial iNOS, INCX and Rac1 activity were significantly decreased by the simvastatin. Oxidative stress, endothelial dysfunction and thrombogenicity are associated with the promotion of AF in a rat model of ischemic HF. These were associated with increased Rac1 activity, and simvastatin treatment prevents these changes.

Randomized trial comparing the efficacy between different types of paclitaxel-eluting stents: the comparison of efficacy between COroflex PLEASe ANd Taxus stent (ECO-PLEASANT) randomized controlled trial.

AIMS: Paclitaxel-eluting stents (PESs) have been shown to inhibit neointimal hyperplasia after percutaneous coronary intervention. Coroflex Please (B Braun, Melsungen, Germany) is a newly developed PES. We compared the clinical and angiographic efficacy of Coroflex Please with Taxus Liberte (Boston Scientific, Natick, MA) in a real-world practice. METHODS AND RESULTS: We performed a prospective, open-label, randomized, controlled study that enrolled 945 patients undergoing percutaneous coronary interventions in 18 centers in Korea. The primary end point was clinically driven target vessel revascularization at 9 months. The baseline characteristics were mostly similar and comparable between 2 groups. At 9 months, the incidence of clinically driven target vessel revascularization was 14.6% for Coroflex and 6.4% for Taxus, which was significantly different (hazard ratio 2.43, 95% CI 1.50-3.94, noninferiority P value = 1.000). This is well corroborated by the difference of in-stent late loss between 2 stents (0.71 ± 0.64 mm vs 0.52 ± 0.50 mm, P < .001) by 9-month follow-up angiography (n = 415 vs 215). Among secondary clinical end points, stent thrombosis (definite and probable) for 1 year was 2.2% in Coroflex and 1.3% in Taxus (P = .317). Also, myocardial infarction for 9 months was higher in Coroflex group than that in Taxus (4.9% vs 1.6%, P = .012), which was partly contributed by the higher incidence of periprocedural myocardial infarction in Coroflex arm (2.2% vs 0.3%, P = .028). CONCLUSIONS: Coroflex Please was inferior to Taxus Liberte with regard to clinical and angiographic efficacy.

Left atrial responses to acute right ventricular apical pacing in patients with sick sinus syndrome.

Chronic right ventricular apical (RVA) pacing can lead to an increased risk of heart failure and atrial fibrillation, but the acute effects of RVA pacing on left atrial (LA) function are not well known. Twenty-four patients with sick sinus syndrome and intact intrinsic atrioventricular conduction were included. All patients received dual-chamber pacemaker implants with the atrial lead in the right atrial appendage and the ventricular lead in the right ventricular (RV) apex. Transthoracic standard and strain echocardiography (measured by tissue Doppler imaging and speckle tracking image) were performed to identify functional changes in the left ventricle (LV) and LA before and after 1 hour of RVA pacing. The LA volume index did not change after pacing; however, the ratio of peak early diastolic mitral flow velocity (E) to peak early diastolic mitral annular velocity (Ea) was significantly increased and peak systolic LA strain (Sm), mean peak systolic LA strain rate (SmSR), peak early diastolic LA strain rate (EmSR), and peak late diastolic LA strain rate (AmSR) were significantly reduced after RV pacing. LV dyssynchrony, induced by RV pacing, had a significant correlation with E/Ea, Sm, and SmSR after pacing. E/Ea also had a negative correlation with Sm and SmSR after pacing. Multivariate regression analysis identified LV dyssynchrony and E/Ea as important factors that affect Sm, SmSR, EmSR, and AmSR after acute RVA pacing. Acute RVA pacing results in LA functional change and LV dyssynchrony and higher LV filling pressures reflected by E/Ea are important causes of LA dysfunction after acute RVA pacing.

An Angiotensin receptor blocker prevents arrhythmogenic left atrial remodeling in a rat post myocardial infarction induced heart failure model.

This study investigated the role of angiotensin II receptor blocker in atrial remodeling in rats with atrial fibrillation (AF) induced by a myocardial infarction (MI). MIs were induced by a ligation of the left anterior descending coronary artery. Two days after, the rats in the losartan group were given losartan (10 mg/kg/day for 10 weeks). Ten weeks later, echocardiography and AF induction studies were conducted. Ejection fraction was significantly lower in the MI rats. Fibrosis analysis revealed much increased left atrial fibrosis in the MI group than sham (2.22 ± 0.66% vs 0.25 ± 0.08%, P = 0.001) and suppression in the losartan group (0.90 ± 0.27%, P 0.001) compared with the MI group. AF inducibility was higher in the MI group than sham (39.4 ± 43.0% vs 2.0 ± 6.3%, P = 0.005) and significantly lower in losartan group (12.0 ± 31.6%, P = 0.029) compared with the MI. The left atrial endothelial nitric oxide synthase (NOS) and sarco/endoplasmic reticulum Ca(2+)-ATPase levels were lower in the MI group and higher in the losartan group significantly. The atrial inducible NOS and sodium-calcium exchanger levels were higher in the MI and lower in the losartan group significantly. Losartan disrupts collagen fiber formation and prevents the alteration of the tissue eNOS and iNOS levels, which prevent subsequent AF induction.

A Multi-Center, Prospective Observational Study to Investigate the Safety, Compliance, and Efficacy of Omethyl QTlet Soft Capsule.

Omega-3 fatty acids have been shown to be effective in lowering triglyceride (TG) levels; however, tolerability issues arise due to the large size of the pills. The purpose of this study was to examine the safety, compliance, and efficacy of Omethyl QTlet soft capsules (OQCs). This multi-center, prospective, observational study evaluated the safety, compliance, and efficacy of OQCs. Patients with hypertriglyceridemia with a history of omega-3 fatty acid intake were enrolled in this study and were prescribed OQCs (2 g−4 g/day) for eight weeks. All adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) were recorded for safety evaluation. Adherence to treatment was assessed using questionnaires, and efficacy was assessed by changes in lipid and lipoprotein levels after eight weeks from baseline. The convenience of taking medication was analyzed for 580 patients, and the efficacy test was performed for 563 patients. The AE and ADR rates were 8.2% and 5.7%, respectively. There were only two SAEs. Of the patients, 55.8% responded that the OQC improved medication convenience, and mean changes in TG, total cholesterol, LDL-C, and non-HDL-C from baseline to eight weeks were −37.88 mg/dL, −11.56 mg/dL, −5.55 mg/dL, and −10.87 mg/dL, respectively (p-values < 0.001). In patients who had previously taken omega-3 fatty acids, OQCs showed safety and efficacy in lowering TG, and it was confirmed that compliance with medicine also improved compared to omega-3 fatty acids.

Prevalence of electrocardiographic findings suggestive of sudden cardiac death risk in 10,867 apparently healthy young Korean men.

BACKGROUND: The objective of this study was to determine the prevalence of electrocardiographic (ECG) findings suggestive of sudden cardiac death risk in apparently healthy young Korean men. METHODS: We administered questionnaires that elicited personal and family histories and performed ECGs on 10,867 male subjects (mean age, 20.9 years). The subjects with abnormal ECG findings underwent echocardiography, a treadmill test, Holter monitoring, a flecainide provocation test, or an electrophysiologic study (EPS) according to the ECG findings and histories. RESULTS: Of the subjects, 5.95% had left ventricular hypertrophy on ECG, but no subjects had hypertrophic cardiomyopathy by echocardiography. The percentage of subjects with a Brugada ECG pattern was 0.90%. We identified one subject with a positive result on the flecainide provocation test. The percentage of subjects with a preexcitation ECG was 0.17%. In two of the subjects, supraventricular tachycardia was induced in the EPS. Of the subjects, 0.05% had epsilon waves, but there were no subjects with arrhythmogenic right ventricular dysplasia/cardiomyopathy by echocardiography. The percentage of subjects with long QT intervals was 0.02%, but there were no arrhythmias on the treadmill test or Holter monitoring. CONCLUSIONS: The prevalence of a Brugada ECG pattern in apparently healthy young men is higher in Korea than other countries.

Adherence to dabigatran and the influence of dabigatran-induced gastrointestinal discomfort in the real-world practice.

BACKGROUND: Dabigatran-induced gastrointestinal discomfort (DGID) is an important factor influencing the adherence to dabigatran. We investigated the incidence and risk factors of DGID and its impact on the adherence and persistence to dabigatran. METHODS: We prospectively enrolled the patients prescribed with dabigatran in 10 tertiary hospitals of the South Korea. The adherence was assessed using the percentage of the prescribed doses of the medication presumably taken by the patient (PDT by pill count). We evaluated the relationship between DGID and the baseline GI symptoms or the previous GI disease history using a questionnaire. RESULTS: A total of 474 patients (mean age 67.8 ± 9.3 years, male 68.6%, and mean CHA2DS2-VASc score 2.2 ± 1.2) were enrolled. The adherence assessed by the PDT was 93.5 ± 5.5% at 1-month and 96.4 ± 8.4% at 6-months among the persistent patients. During the 6-month follow-up, 82 (18.1%) patients discontinued dabigatran, and the most common reason for dabigatran discontinuation was DGID (49, 59.8%). Sixty-eight (14.3%) patients experienced DGID, and there was no difference in the clinical factors between those with or without DGID. Among the patients who experienced DGID, 42 discontinued dabigatran (61.8%). In a multivariate analysis, DGID was the only predictor of dabigatran discontinuation and a low adherence. CONCLUSION: Overall adherence of dabigatran was excellent, but those with DGID showed low adherence and persistence. Furthermore, it was challenging to predict DGID by clinical parameters. Therefore, it is recommended to follow the patients closely to check for DGID when prescribing dabigatran.

Role of constitutively active acetylcholine-mediated potassium current in atrial contractile dysfunction caused by atrial tachycardia remodelling.

AIMS: Atrial fibrillation (AF)-induced contractile dysfunction contributes importantly to thrombo-embolic stroke, the most serious AF complication. Atrial cardiomyocytes have a constitutively active acetylcholine-regulated K(+)-current (I(KAChc)) that is enhanced by atrial tachycardia (AT). I(KAChc) contributes to action potential duration (APD) shortening in AT-remodelled atrial cardiomyocytes; APD regulates contractility by controlling Ca(2+)-loading and systolic Ca(2+)-release. This study investigated the potential role of I(KAChc) in AF-related contractile dysfunction. METHODS AND RESULTS: Dogs were divided into two groups: (i) unpaced control (CTL); (ii) AT (400 bpm for at least 7 days). Tertiapin-Q (TQ), a selective I(KAChc) blocker, was used to define I(KAChc) contributions to contractility. Single-cell left atrial (LA) intracellular Ca(2+)-transients (CaTrs), cell-shortening (CS), and whole LA tissue tension-generation were measured. Atrial tachycardia increased I(KAChc). Whole LA contractility was decreased in AT (0.17 ± 0.05 g) compared with CTL (0.40 ± 0.09 g), with significant reversal (0.30 ± 0.06 g) after TQ administration. Ca(2+)-transient amplitude and CS in single-cell were decreased by AT compared with CTL (167 ± 14 vs. 88 ± 10 nM; 10.3 ± 1.3 vs. 1.7 ± 0.3 µm, respectively; P < 0.001). The AT-induced reductions in single-cell CaTr amplitude and CS were partly reversed by TQ administration (88 ± 10 vs. 112 ± 16 nM; P < 0.001; 1.7 ± 0.3 vs. 3.6 ± 0.7 µm; P < 0.01). We then measured CaTr and CS with carbachol and/or TQ to vary I(KACh) at various extracellular [Ca(2+)]. The CaTr-CS relationship was linear and AT results fell on the regression line, indicating that AT-remodelling effects on contractility are attributable to reduced CaTr. CONCLUSION: Up-regulated I(KAChc) contributes to AF-related contractile dysfunction and could be a novel target to prevent hypocontractility-related thrombo-embolic complications.

Changes in QRS Duration Are Associated with a Therapeutic Response to Sacubitril-valsartan in Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Recent studies have demonstrated that angiotensin receptor neprilysin inhibitors (ARNIs) can reverse the cardiac remodeling effects that occur in heart failure with reduced ejection fraction (HFrEF). These studies have also suggested that ARNIs have favorable effects on ventricular dyssynchrony. We assessed the changes in QRS duration associated with ARNIs in patients with HFrEF. METHODS: We retrospectively investigated patients with HFrEF (defined by a left ventricular ejection fraction [LVEF] ≤ 35%) who were treated with ARNIs for at least six months. We divided the patients into QRS shortening and non-QRS shortening groups according to their electrocardiogram (ECG) findings. We also compared changes in echocardiographic parameters between the groups. RESULTS: A total of 68 patients with HFrEF were included (mean age: 62.5 years, 74.6% male). Twenty-one patients had significant ischemic heart disease (IHD). Thirty-five patients exhibited QRS-duration shortening on follow-up ECGs (mean change: -7.8 msec), and 33 patients showed no changes or increased QRS duration (mean change: 5.1 msec). The QRS shortening group exhibited significant improvement in LVEF (12.5 ± 15.3% vs. 1.7 ± 9.5%; p < 0.001) when compared with the non-QRS shortening group. The QRS shortening group also had significantly lower LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD) and LV mass index (LVMI) than did the non-QRS shortening group. The change in QRS duration was significantly correlated with the change in LVEF (r = -0.329, p = 0.011) and LVESD (r = 0.298, p = 0.022). CONCLUSIONS: Among patients with HFrEF treated with ARNIs, the QRS shortening group showed favorable LV systolic function recovery, and reversal of cardiac remodeling compared to those of the non-QRS shortening group. Change in the QRS duration, which reflects LV synchrony, may be associated with response to ARNIs in patients with HFrEF.

Efficacy and Safety of Omega-3 Fatty Acids in Patients Treated with Statins for Residual Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and <500 mg/dL and LDL-C levels <110 mg/dL. Eligible subjects were randomized to ATOMEGA (OM3-FAs 4,000 mg plus atorvastatin calcium 20 mg) or atorvastatin 20 mg plus placebo groups. The primary efficacy endpoints were the percent changes in TG and non-HDL-C levels from baseline at the end of treatment. RESULTS: After 8 weeks of treatment, the percent changes from baseline in TG (-29.8% vs. 3.6%, P<0.001) and non-HDL-C (-10.1% vs. 4.9%, P<0.001) levels were significantly greater in the ATOMEGA group (n=97) than in the atorvastatin group (n=103). Moreover, the proportion of total subjects reaching TG target of <200 mg/dL in the ATOMEGA group was significantly higher than that in the atorvastatin group (62.9% vs. 22.3%, P<0.001). The incidence of adverse events did not differ between the two groups. CONCLUSION: The addition of OM3-FAs to atorvastatin improved TG and non-HDL-C levels to a significant extent compared to atorvastatin alone in subjects with residual hypertriglyceridemia.

Anomalous bronchial artery originating from the right coronary artery in a patient with angina (2009: 4b).

Bronchial artery origins are subject to a wide range of anatomic variations, of which interventional radiologists should be aware. The authors report a patient with angina in whom an anomalous bronchial artery originated from the sinus node branch of the right coronary artery, causing a coronary steal phenomenon. The patient's symptom was successfully treated by transcatheter embolisation of the anomalous bronchial artery, which seems to be an effective alternative to surgery.

Medical Resource Consumption and Quality of Life in Peripheral Arterial Disease in Korea: PAD Outcomes (PADO) Research.

BACKGROUND AND OBJECTIVES: We aimed to investigate the history of medical resource consumption and quality of life (QoL) in peripheral arterial disease (PAD) patients in Korea. METHODS: This was a prospective, multi-center (23 tertiary-hospitals, division of cardiology), non-interventional study. Adult patients (age ≥20 years) suffering from PAD for the last 12-month were enrolled in the study if they met with any of following; 1) ankle-brachial index (ABI) ≤0.9, 2) lower-extremity artery stenosis on computed tomography angiography ≥50%, or 3) peak-systolic-velocity-ratio (PSVR) on ultrasound ≥2.0. Medical chart review was used to assess patient characteristics/treatment patterns while the history of medical resource consumption and QoL data were collected using a patient survey. QoL was measured using EuroQoL-5-dimensions-3-level (EQ-5D-3L) score system, and the factors associated with QoL were analyzed using multiple linear regression analysis. RESULTS: This study included 1,260 patients (age: 69.8 years, male: 77.0%). The most prevalent comorbidities were hypertension (74.8%), hyperlipidemia (51.0%) and diabetes-mellitus (50.2%). The 94.1% of the patients took pharmacotherapy including aspirin (76.2%), clopidogrel (53.3%), and cilostazol (33.6%). The 12.6% of the patients were receiving smoking cessation education/pharmacotherapy. A considerable number of patients (500 patients, 40.0%) had visit history to another hospital before diagnosis/treatment at the current hospital, with visits to orthopedic units (50.4%) being the most common. At the time, 29% (or higher) of the patients were already experiencing symptoms of critical limb ischemia. Baseline EQ-5D index and EQ VAS were 0.64±0.24 and 67.49±18.29. Factors significantly associated with QoL were pharmacotherapy (B=0.05053; p=0.044) compared to no pharmacotherapy, and Fontaine stage improvement/maintain stage I (B=0.04448; p<0.001) compared to deterioration/maintain stage II-IV. CONCLUSIONS: Increase in disease awareness for earlier diagnosis and provision of adequate pharmacotherapy is essential to reduce disease burden and improve QoL of Korean PAD patients.

Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias.

BACKGROUND: We previously characterized a novel K+ current (IKH) with properties of constitutively active acetylcholine-related current in dog atrium. I(KH) is sensitive to tertiapin-Q (IC50 approximately 10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role of IKH in atrial tachycardia (AT)-remodeled canine left atrium (LA) with the use of tertiapin-Q as a probe. METHODS AND RESULTS: Dogs were subjected to 7 to 13 days of AT (400 bpm). Coronary-perfused LA preparations were studied intact or subjected to cardiomyocyte isolation. IKH was recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current (IKH) at -110 mV from -1.8+/-0.3 (control) to -3.4+/-0.5 pA/pF (AT) and the 100-nmol/L tertiapin-sensitive component from -1.5+/-0.4 (control) to -3.3+/-0.6 pA/pF (AT). Prolonged atrial tachyarrhythmias could be induced with single extrastimuli in AT-remodeled, but not control, preparations, reflecting the atrial fibrillation-promoting effects of AT remodeling. In AT-remodeled preparations, tachyarrhythmia duration averaged 11.0+/-5.2 seconds, with a cycle length of 108+/-6 ms. Tertiapin-Q decreased tachyarrhythmia duration (to 0.6+/-0.1 second; P<0.001) and increased tachyarrhythmia cycle length (to 175+/-10 ms; P<0.001). Atrial action potential duration (APD) was increased 65+/-6% by tertiapin in AT-remodeled hearts versus 19+/-2% (P<0.001) in control. In 2 AT-remodeled preparations, tachyarrhythmia lasted uninterrupted for >20 minutes; tertiapin-Q slowed and then terminated arrhythmia in both. Tertiapin had no effect on left ventricular cardiomyocyte currents or APD. CONCLUSIONS: AT remodeling increases IKH, and a highly selective Kir3 current antagonist, tertiapin-Q, increases APD and suppresses atrial tachyarrhythmias in AT-remodeled preparations without affecting ventricular electrophysiology. Constitutive acetylcholine-related K+ current contributes to AT-remodeling effects in dogs and is a potentially interesting antiarrhythmic target.

Study protocol for a randomised controlled trial: harmonising optimal strategy for treatment of coronary artery stenosis - coronary intervention with next-generation drug-eluting stent platforms and abbreviated dual antiplatelet therapy (HOST-IDEA) trial.

INTRODUCTION: We have recently seen the introduction of newer generation drug-eluting stents with ultrathin struts that use advanced polymer technologies. However, the efficacy and safety of these newest stents have not yet been fully explored. In addition, there are still controversies over the optimal duration of dual antiplatelet therapy (DAPT) after stent implantation, particularly for ultrathin stents with the newest polymer technologies. METHODS AND ANALYSIS: The HOST-IDEA trial is a randomised, open-label, multicentre, non-inferiority trial and the first study to directly compare two of these ultrathin sirolimus-eluting stents: Orsiro stent with biodegradable polymer, and polymer-free Coroflex ISAR (CX-ISAR) stent. This study has a scheme of 2×2 factorial design according to the stent type and DAPT duration (3 vs 12 months). A total of 2152 patients will be randomised and stratified to demonstrate the non-inferiority of CX-ISAR to Orsiro, or of the abbreviated DAPT duration to the conventional 12 months (both in 1:1 ratio). For the comparison of stent type, the primary endpoint is target lesion failure (TLF), which is a composite of cardiac death, target vessel-related myocardial infarction and clinically driven target lesion revascularisation. For the comparison of DAPT duration, the net adverse clinical event is the coprimary endpoint, which is defined as a composite of TLF, definite/probable stent thrombosis and major bleeding. ETHIC APPROVAL AND DISSEMINATION: All the institutions involved in this study are required to have ethical approval prior to patient enrolment. This multicentre study will recruit patients through competitive registration, but institutions that have not yet obtained ethical approvals have made it impossible to enrol patients in a centralised web database. The final results will be presented at relevant international conferences and will be materialised in the form of papers. TRIAL REGISTRATION NUMBER: NCT02601157; Pre-results.

Atrial tachycardia remodeling of pulmonary vein cardiomyocytes: comparison with left atrium and potential relation to arrhythmogenesis.

BACKGROUND: The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation (AF), as is atrial tachycardia (AT) remodeling. The relative importance of AT remodeling in PVs versus other atrial sites is unknown. The present study assessed AT-induced cellular changes in PVs versus left atrium (LA) and their relationship to arrhythmogenesis. METHODS AND RESULTS: We studied ionic currents (single-cell patch clamp) and action potentials (APs; coronary-perfused multicellular preparations) in the PVs and LA free wall of dogs after 7-day AT pacing (400 bpm), as well as in nonpaced control dogs. In controls, rapid (I(Kr)) and slow (I(Ks)) delayed-rectifier currents were larger in PVs; transient-outward (I(to)), inward-rectifier (I(K1)), and L-type Ca2+ (I(Ca)) currents and AP duration were smaller. AT remodeling reduced I(Ca) and I(to), left I(Kr) and I(Ks) unchanged, and increased I(K1) in both LA and PV. AT reduced action potential duration in both LA and PV. LA-PV AP differences became smaller in AT than in control dogs. Premature extrastimuli induced atrial tachyarrhythmias at 4.5+/-2.8% (mean+/-SEM) sites in 6 control multicellular preparations compared with 64.2+/-7.3% sites in 9 AT-remodeled preparations (P<0.001). Resection of all PVs failed to alter atrial tachyarrhythmia inducibility in AT-remodeled preparations (67.5+/-13.1%). PV resection did not significantly change tachyarrhythmia duration (mean 3.9 seconds per heart, range 0.7 to 15.7 seconds before resection; mean 7.0 seconds per heart, range 0.9 to 36.0 seconds after resection) or cycle length (120+/-6 ms before resection, 115+/-8 ms after resection). CONCLUSIONS: AT produces qualitatively similar ionic remodeling in LA and PVs but reduces PV-LA AP differences. PVs are not essential for AT-induced atrial tachyarrhythmia promotion in this model, which may relate to the failure of PV isolation to prevent AF in some patient populations.

Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium.

BACKGROUND: Cardiomyocytes in pulmonary vein (PV) sleeves are important in atrial fibrillation (AF), but underlying mechanisms are poorly understood. Pulmonary veins have different ionic current properties compared to left atrium, with pulmonary vein inward-rectifier currents being smaller and delayed-rectifier currents larger than in left atrium. METHODS: Expression and distribution of the inward-rectifier subunits Kir2.1 and Kir2.3, the rapid delayed-rectifier alpha-subunit ERG, the slow delayed-rectifier alpha-subunit KvLQT1, the beta-subunit minK, the L-type Ca(2+)-subunit Ca(v)1.2, and the Na(+),Ca(2+)-exchanger were quantified by Western blot on isolated cardiomyocytes and localized by immunohistochemistry in tissue sections obtained from canine hearts. RESULTS: Western blotting indicated significantly greater expression of ERG (by 28%, P<0.05) and KvLQT1 (by 34%, P<0.05) in pulmonary vein versus left atrial (LA) cardiomyocytes, but smaller Kir2.3 and similar Kir2.1, Ca(v)1.2 and Na(+),Ca(2+)-exchanger expression in PV. Kir2.1 exhibited weak transverse tubular distribution in both regions. Kir2.3 localized to intercalated disks in both regions, and to transverse tubules in left atrium but not pulmonary vein. ERG staining was more intense in pulmonary vein than left atrium, localizing to transverse tubules in both regions and intercalated disks in pulmonary veins. KvLQT1 was more intensely expressed in pulmonary veins, with a transverse tubular and intercalated disk localization, versus a more diffuse signal in left atrium. The Na(+),Ca(2+)-exchanger localized to transverse tubules, plasma membranes and intercalated disks with similar intensity in each region. CONCLUSIONS: Greater ERG and KvLQT1 abundance in pulmonary vein cardiomyocytes, lower abundance of Kir2.3 in pulmonary veins and differential pulmonary vein subcellular distribution of Kir2.3, ERG and KvLQT1 subunits may contribute to ionic current differences between pulmonary vein and left atrial cardiomyocytes.

Association between the N-terminal plasma brain natriuretic peptide levels or elevated left ventricular filling pressure and thromboembolic risk in patients with non-valvular atrial fibrillation.

BACKGROUND: We aimed to investigate the role of brain natriuretic peptide (BNP) levels and left ventricular (LV) filling pressures in thromboembolic risk in patients with non-valvular atrial fibrillation (AF). METHODS: Among 327 patients with non-valvular AF, the ratio of peak early filling velocity to mitral annulus velocity (E/Ea) and N-terminal proBNP (NT-proBNP) was compared according to the presence of left atrial appendage (LAA) dysfunction [presence of spontaneous echo contrast (SEC)≥grade 3 and/or reduced LAA emptying flow velocity <20cm/s]. RESULTS: Compared to patients without LAA dysfunction, patients with LAA dysfunction presented with significantly higher CHADS2 scores (1.24±1.14 vs. 1.68±1.31, p=0.005), high-sensitivity C-reactive protein (0.36±1.18mg/dl vs. 0.66±1.32mg/dl, p=0.043), and NT-proBNP (765.3±2534.8pg/ml vs. 2266.9±6117.4pg/ml, p=0.002). Furthermore, patients with LAA dysfunction showed significantly higher left atrial volume index (LAVI, 25.1±10.9 vs. 43.1±22.1, p<0.001) and E/Ea (10.8±7.27 vs. 7.97±2.50mg/dl, p<0.001). Plasma logNT-proBNP levels were significantly correlated with the presence of SEC (r=0.276, p<0.001), LAA emptying flow velocity (r=-0.492, p<0.001), LAVI (r=0.405, p<0.001), and E/Ea (r=0.353, p<0.001). Binary logistic regression analysis showed that high NT-proBNP level >249.7pg/ml (odds ratio, OR 6.79, 95% confidence interval, CI 3.16-15.55, p<0.001) and E/Ea >10 (OR 4.41, 95% CI 2.39-8.15, p<0.001) were independent predictors of LAA dysfunction after adjustment of known thromboembolic risk factors. CONCLUSION: Elevated plasma NT-proBNP concentrations and LV filling pressures represented by LAA dysfunction may be reliable surrogate markers for predicting thromboembolic risk in patients with AF.