Risk Factors for Left Ventricular Thrombus Formation in Patients with Dilated Cardiomyopathy.

BACKGROUND: Left ventricular thrombus (LVT) is a common complication of dilated cardiomyopathy (DCM), causing morbidity and mortality. METHODS: This study retrospectively analyzed patients with DCM from January 2002 to August 2020 in Beijing Anzhen Hospital. Clinical characteristics were compared between the LVT group and the age and sex 1:4 matched with the LVT absent group. The receiver operator characteristic (ROC) curve was plotted to evaluate the diagnostic value of D-dimer predicting LVT occurrence in DCM. RESULTS: A total of 3,134 patients were screened, and LVT was detected in 72 (2.3%) patients on echocardiography. The patients with LVT had higher D-dimer, fibrinogen, and lower systolic blood pressure than those without LVT. The ejection fraction (EF) was lower and left ventricular end-systolic diameter was larger in the LVT group. Severe mitral regurgitation (MR) was more common in the LVT absent groups. The prevalence of atrial fibrillation was lower in the LVT group. The ROC curve analysis yielded an optimal cut-off value of 444 ng/mL DDU (D-dimer units) for D-dimer to predict the presence of LVT. Multivariable binary logistic regression analysis revealed that EF (OR = 0.90, 95% CI = 0.86-0.95), severe MR (OR = 0.19, 95% CI = 0.08-0.48), and D-dimer level (OR = 15.4, 95% CI = 7.58-31.4) were independently associated with LVT formation. CONCLUSION: This study suggested that elevated D-dimer levels (>444 ng/mL DDU) and reduced EF were independently associated with increased risk of LVT formation. Severe MR could decrease the incidence of LVT.

Chronic kidney disease and risks of adverse clinical events in patients with atrial fibrillation.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in patients with atrial fibrillation (AF). However, the association between CKD and clinical consequences in AF patients is still under debate. METHODS: We included 19,079 nonvalvular AF patients with available estimated glomerular filtration rate (eGFR) values in the Chinese Atrial Fibrillation Registry from 2011 to 2018. Patients were classified into no CKD (eGFR ≥ 90 mL/min per 1.73 m2), mild CKD (60 ≤ eGFR < 90 mL/min per 1.73 m 2), moderate CKD (30 ≤ eGFR < 60 mL/min per 1.73 m 2), and severe CKD (eGFR < 30 mL/min per 1.73 m 2) groups. The risks of thromboembolism, major bleeding, and cardiovascular mortality were estimated with Fine-Gray regression analysis according to CKD status. Cox regression was performed to assess the risk of all-cause mortality associated with CKD. RESULTS: Over a mean follow-up of 4.1 ± 1.9 years, there were 985 thromboembolic events, 414 major bleeding events, 956 cardiovascular deaths, and 1,786 all-cause deaths. After multivariate adjustment, CKD was not an independent risk factor of thromboembolic events. As compared to patients with no CKD, those with mild CKD, moderate CKD, and severe CKD had a 45%, 47%, and 133% higher risk of major bleeding, respectively. There was a graded increased risk of cardiovascular mortality associated with CKD status compared with no CKD group: adjusted hazard ratio [HR] was 1.34 (95% CI: 1.07-1.68,P = 0.011) for mild CKD group, 2.17 (95% CI: 1.67-2.81,P < 0.0001) for moderate CKD group, and 2.95 (95% CI: 1.97-4.41, P < 0.0001) for severe CKD group, respectively. Risk of all-cause mortality also increased among patients with moderate or severe CKD. CONCLUSIONS: CKD status was independently associated with progressively higher risks of major bleeding and mortality, but didn't seem to be an independent predictor of thromboembolism in AF patients.

Modifications of the Langendorff Method for Simultaneous Isolation of Atrial and Ventricular Myocytes from Adult Mice.

A single cardiomyocyte is a vital tool in the cellular and subcellular level studies of cardiac biology and diseases as a fundamental unit of contraction and electrical activity. Hence, isolating viable, high-quality cardiomyocytes from the heart is the initial and most crucial experimental step. Comparing the various protocols for isolating the cardiomyocytes of adult mice, the Langendorff retrograde perfusion is the most successful and reproducible method reported in the literature, especially for isolating ventricular myocytes. However, isolating quality atrial myocytes from the perfused heart remains challenging, and few successful isolation reports are available. Solving this complicated problem is extremely important because apart from ventricular disease, atrial disease accounts for a large part of heart diseases. Therefore, further investigations on the cellular level to reveal the mechanisms are warranted. In this paper, a protocol based on the Langendorff retrograde perfusion method is introduced and some modifications in the depth of aorta cannulation and the steps that may affect the digestion process to isolate atrial and ventricular myocytes were simultaneously made. Moreover, the isolated cardiomyocytes are confirmed to be amenable to patch clamp investigation.

The Association of New-Onset Atrial Fibrillation and Risk of Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: There are distinct results for the relationship between new-onset atrial fibrillation (NOAF) and subsequent incident cancer. To date, no systematic analysis has been conducted on this issue. This study aims to explore the relationship between NOAF and the risk of developing cancer through a meta-analysis with a large sample size. METHODS: Electronic databases, such as PubMed and EMBASE, were searched for published relevant studies on NOAF patients diagnosed with cancer after and during follow-ups, including reported records of baseline information and the statistical result of morbidity. Two investigators independently reviewed the articles and extracted the data using uniform standards and definitions. The meta-analysis was conducted using the Cochrane Program Review Manager. RESULTS: This meta-analysis consisted of five cohort studies and one case-control study, which comprised 533,514 participants. The pooled relative risk (RR) for incident cancer was 1.24 (95% CI: 1.10-1.39, P=0.0003). The temporal trend analysis demonstrated that an increased risk of cancer was observed during the initial 90 days (RR: 3.44, 95% CI: 2.29-5.57, P < 0.00001), but not after that. Lung cancer (RR: 1.51, 95% CI: 1.47-1.55, P < 0.00001) was associated with NOAF, but not colorectal cancer and breast cancer. CONCLUSION: This meta-analysis provides evidence that NOAF is associated with increased risk of cancer. The risk of incident cancer particularly increases within 90 days after NOAF diagnosis, but not after that.

Depolarization and repolarization parameters on ECG predict recurrence after atrial fibrillation ablation in patients with hypertrophic cardiomyopathy.

INTRODUCTION: The outcomes of atrial fibrillation (AF) ablation remain suboptimal. It is important to identify which AF patients will most likely benefit from ablation and who are more likely to show treatment failure, especially in those with structural heart disease such as hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We enrolled 120 HCM patients who underwent primary AF ablation (48 with persistent AF). Preprocedural QTc was measured and corrected using the Bazett's formula, and the distribution of fragmentation of the QRS complex (fQRS) was recorded. Arrhythmia recurrence was defined as any kind of documented atrial tachyarrhythmia of more than 30 seconds. Overall, arrhythmia recurrence occurred in 69 patients after 13.4 months' follow-up. fQRS was present in 71 (59.17%) patients and was most commonly (81.69%) observed in the inferior leads. QTc more than 448 ms could predict arrhythmia recurrence with a sensitivity of 68.1% and specificity of 68.6%. Patients with QTc more than 448 ms (hazard ratio [HR]: 1.982; 95% confidence interval [CI]: 1.155-3.402; P = .013) or those with fQRS+ (HR: 1.922; 95% CI: 1.151-3.210; P = .012) were at an increased risk of recurrence. A combination of fQRS+ and QTc more than 448 ms was superior to fQRS or QTc alone in predicting arrhythmia recurrence. CONCLUSION: In patients with HCM undergoing AF ablation, QTc prolongation, specifically >448 ms, and presence of fQRS are independent risk factors for arrhythmia recurrence at follow-up. The combination of these two parameters has greater predictive value and would help to identify patients who are at the highest risk of procedural failure.

Female Sex as a Risk Factor for Ischemic Stroke and Systemic Embolism in Chinese Patients With Atrial Fibrillation: A Report From the China-AF Study.

Background Previous studies have provided conflicting results as to whether women are at higher risk than men for thromboembolism in the setting of atrial fibrillation ( AF ). We investigated whether women with AF were at higher risk of ischemic stroke in the China-AF (China Atrial Fibrillation Registry) Study. Methods and Results A total of 19 515 patients were prospectively enrolled between August 2011 and December 2016 in the China- AF Study. After exclusion of patients receiving anticoagulation or ablation therapy, 6239 patients (2574 women) with results from at least 6 months of follow-up were used for the analysis. Cox proportional hazards models were performed to evaluate whether female sex was an independent risk factor for thromboembolism after multivariate adjustment. The primary outcome was the time to the first occurrence of ischemic stroke or systemic embolism. After a mean follow-up of 2.81±1.46 years, 152 female patients reached the primary outcome, as compared with 172 male patients. Crude incidence rates of thromboembolism between women and men were of borderline statistical significance (2.08 versus 1.68 per 100 patient-years, P=0.058). After multivariable analysis, female sex was not independently associated with an increased thromboembolism risk (hazard ratio 1.09, 95% confidence interval 0.86-1.39). There was no significant difference in thromboembolism risk by sex stratified by age and presence or absence of risk factors ( P for interaction all >0.1). Conclusions Although crude incidence rates of thromboembolism were higher in Chinese female patients with AF compared with male patients, female sex did not emerge as an independent risk factor for thromboembolism on multivariate analysis. Clinical Trial Registration URL : http://www.chictr.org.cn/ . Unique identifier: Chi CTR - OCH -13003729.

Acute administration of tumour necrosis factor-α induces spontaneous calcium release via the reactive oxygen species pathway in atrial myocytes.

Aims: The arrhythmogenic mechanisms of atrial fibrillation (AF) that are induced by acute inflammation, such as postoperative AF, are not well understood. We investigated the acute effects of tumour necrosis factor-α (TNF-α) that mimic acute inflammation on Ca2+ handling in isolated atrial myocytes and its underlying mechanisms. Methods and results: Cytosol Ca2+ handling and mitochondrial reactive oxygen species (ROS) production were studied in freshly isolated atrial myocytes of wild-type mice that were exposed to TNF-α (0.05 ng/mL) for 2 h by Ionoptix and confocal microscopy. The acute effects of TNF-α on Ca2+ handling were decreased amplitudes and prolonged decay times of Ca2+ transients in isolated atrial myocytes. A significant reduction in the sarcoplasmic reticulum (SR) Ca2+ content was detected in TNF-α treated cells, which was associated with increased spontaneous Ca2+ release events. In particular, physiological concentrations of TNF-α dramatically promoted the frequency of spontaneous Ca2+ waves and Ca2+ sparks, while the spark mass presented with reduced amplitudes and prolonged durations. The underlying mechanisms of pro-arrhythmic effects of TNF-α were further investigated. Acute exposure to TNF-α rapidly promoted mitochondrial ROS production that was correlated with the acute effect of TNF-α on Ca2+ handling, and enhanced the oxidation of calcium/calmodulin-dependent protein kinase II (CaMKII) and the phosphorylation of RyR2. However, the performance of ROS inhibitor, DL-Dithiothreitol (DTT), reversed Ca2+ handling disorders induced by TNF-α. Conclusion: Tumour necrosis factor-α rapidly increases spontaneous Ca2+ release and promotes atrial arrhythmogenesis via the ROS pathway, which suggests that antioxidant therapy is a promising strategy for acute inflammation related AF.

Right atrial diameter and outcome of catheter ablation of atrial fibrillation.

PURPOSE: While AF is considered more like a left atrial (LA) disease, to what extent the right atrium contributes to the pathogenesis and ablation outcome of AF remains unclear. This study aimed to identify if right atrial diameter (RAD) could predict arrhythmia recurrence after catheter ablation of atrial fibrillation (AF). METHODS: Four hundred and seventy patients with drug-resistant AF [paroxysmal AF (PAF) 196; non-PAF 274] who underwent primary catheter ablation were enrolled. Ablation strategy included complete bilateral pulmonary vein isolation (PVI) in all patients and additional linear ablation across mitral isthmus, LA roof, and tricuspid isthmus in non-PAF cases. Risk factors associated with recurrence were determined by a Cox regression model, and the predictive power was evaluated by using receiver operating characteristic curve. RESULTS: After 24.3 ± 18.0 months, 284 patients (60.6%) experienced atrial tachyarrhythmia recurrence (111 in PAF, 173 in non-PAF). RAD was moderately associated with LA diameter (r = 0.371, P < 0.001), left ventricular ejection fraction (r = -0.205, P < 0.001), and left ventricular end-diastolic diameter (r = 0.319, P < 0.001). Multivariate Cox regression analysis demonstrated that RAD was an independent predictor for recurrence only in PAF patients with LAD ≥35 mm (HR 1.044, 95% CI 1.007-1.082, P = 0.021). The RAD cutoff value of 35.5 mm predicts atrial tachyarrhythmia recurrence with 85.4% sensitivity and 29.2% specificity. Kaplan-Meier analysis indicated that RAD over 35.5 mm is associated with more recurrence after PAF ablation (log-rank P = 0.034), comparing to those with RAD <35.5 mm. CONCLUSIONS: RAD predicts outcome of ablation only in patients with PAF and concurrent LA enlargement. Under this condition, RAD <35.5 mm is associated with a more favorable recurrence-free survival at over 2-year follow-up.

QTc interval predicts outcome of catheter ablation in paroxysmal atrial fibrillation patients with type 2 diabetes mellitus.

Catheter ablation has been recommended as a treatment option for paroxysmal atrial fibrillation (PAF) patients complicated with type 2 diabetes mellitus (T2DM). PAF patients with T2DM have a higher recurrence rate after catheter ablation. Prolongation of corrected QT (QTc) interval has been linked to poor outcomes in T2DM patients. Whether the abnormal QTc interval is associated with the ablation outcome in the PAF patients with T2DM remains unknown. In this study, 134 PAF patients with T2DM undergoing primary catheter ablation were retrospectively enrolled. Pre-procedural QTc interval was corrected by using the Bazett's formula. Cox proportional hazards models were constructed to assess the relationship between QTc interval and the recurrence of AF. After a 29.1-month follow-up period, 61 patients experienced atrial tachyarrhythmia recurrence. Recurrent patients had a longer QTc interval than non-recurrent patients (425.2±21.5 ms vs. 414.1±13.4 ms, P=0.002). Multivariate Cox regression analysis revealed that QTc interval [hazard ratio (HR)=1.026, 95% confidence interval (CI) 1.012-1.040, P=0.005] and left atrial diameter (LAD) (HR=1.125, 95% CI 1.062-1.192, P=0.003) were independent predictors of recurrent atrial tachyarrhythmia. Receiver operating characteristic analysis demonstrated that the cut-off value of QTc (418 ms) predicted arrhythmia recurrence with a sensitivity of 55.7% and a specificity of 69.9%. A combination of LAD and QTc was more effective than LAD alone (P<0.001) in predicting arrhythmia recurrence after the procedure. QTc interval could be used as an independent predictor of arrhythmia recurrence in T2DM patients undergoing AF ablation, thus providing a simple method to identify those patients who likely have a better outcome following the procedure.

Long-Term Persistence of Newly Initiated Warfarin Therapy in Chinese Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Despite its therapeutic efficacy, warfarin is extremely underused in Chinese patients with nonvalvular atrial fibrillation (AF). Whether the nonpersistence of warfarin treatment contributes to its underuse is not known. The aims of this study were to determine nonpersistence rates of newly started warfarin treatment in Chinese patients with nonvalvular AF and to identify the factors associated with discontinuation of the treatment. METHODS AND RESULTS: We identified 1461 patients with nonvalvular AF enrolled in the Chinese Atrial Fibrillation Registry (CAFR) who newly started on warfarin therapy in the period between August 1, 2011, and June 30, 2014. During a follow-up of 426±232 days, 22.1% of patients discontinued warfarin within 3 months, 44.4% within 1 year, and 57.6% within 2 years of initiation of therapy. Patients with no or partial insurance coverage had a higher likelihood to discontinue warfarin than those with full insurance coverage (adjusted hazard ratio 1.65, 95% confidence interval [1.03-2.64]; P=0.038 and 1.66 [1.13-2.42]; P=0.009, respectively). Paroxysmal AF (1.56 [1.28-1.92]; P<0.0001), no prior stroke/transient ischemic attack/thromboembolism (1.60 [1.24-2.05]; P=0.0003), and no dyslipidemia (1.34 [1.06-1.70]; P=0.016) were also found to be independent predictors for nonpersistence of warfarin therapy. CONCLUSIONS: Nonpersistence of warfarin treatment becomes a serious problem for stroke prevention in Chinese patients with nonvalvular AF. Our findings can be used to identify patients who require closer attention or to develop better management strategy for oral anticoagulation therapy.

Over 1-year efficacy and safety of left atrial appendage occlusion versus novel oral anticoagulants for stroke prevention in atrial fibrillation: A systematic review and meta-analysis of randomized controlled trials and observational studies.

BACKGROUND: A direct comparison of the efficacy and safety profiles of left atrial appendage occlusion (LAAO) devices and novel oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation is warranted but currently unavailable. OBJECTIVE: The aim of this study was to compare the >1-year efficacy and safety of LAAO devices and NOACs for stroke prevention in patients with atrial fibrillation. METHODS: We performed a systematic review on randomized controlled trials (RCTs) and observational studies. RCTs were analyzed by means of a network meta-analysis method using warfarin as a bridge to compare LAAO to individual NOAC or all NOACs as a whole. Observational studies were analyzed with the meta-proportion function where pooled event rates were compared. RESULTS: A total of 6 RCTs and 27 observational studies were included. A network meta-analysis of RCTs indicated that LAAO was less effective than NOACs for stroke prevention (odds ratio 0.86), but had a lower rate of hemorrhagic events during follow-up. However, a meta-proportion analysis of observational studies revealed that LAAO devices were associated with a lower rate of both thromboembolic events (1.8 events per 100 patient-years vs 2.4 events per 100 patient-years) and major bleeding events during follow-up (2.2 events per 100 patient-years vs 2.5 events per 100 patient-years) as compared with NOACs. With prolonged follow-up duration after LAAO implantation, the rate of thromboembolic events decreased (2.1, 1.8, and 1.0 events per 100 person-years for 1, 1-2, and >2 years, respectively). CONCLUSION: Although superiority of LAAO over NOACs was not demonstrated by RCTs in terms of stroke prevention, LAAO was found to be consistently associated with a lower rate of both thromboembolic and hemorrhagic events as compared with NOACs in observational studies.

QTc Interval Prolongation Predicts Arrhythmia Recurrence After Catheter Ablation of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM) patients complicated with atrial fibrillation (AF), catheter ablation has been recommended as a treatment option. Meanwhile, prolongation of QTc interval has been linked to an increased AF incidence in the general population and to poor outcomes in HCM patients. However, whether QTc prolongation predicts arrhythmia recurrence after AF ablation in the HCM population remains unknown. METHODS AND RESULTS: Thirty-nine HCM patients undergoing primary AF ablation were enrolled. The ablation strategy included bilateral pulmonary vein isolation (PVI) for paroxysmal AF (n=27) and PVI plus left atrial roof, mitral isthmus and tricuspid isthmus linear ablations for persistent AF (n=12). Pre-procedural QTc was corrected by using the Bazett's formula. At a 14.8-month follow up, 23 patients experienced atrial tachyarrhythmia recurrence. Recurrent patients had longer QTc than non-recurrent patients (461.0±28.8 ms vs. 434.3±18.2 ms, P=0.002). QTc and left atrial diameter (LAD) were independent predictors of recurrence. The cut-off value of QTc 448 ms predicted arrhythmia recurrence with a sensitivity of 73.9% and a specificity of 81.2%. A combination of LAD and QTc (global chi-squared=13.209) was better than LAD alone (global chi-squared=6.888) or QTc alone (global chi-squared=8.977) in predicting arrhythmia recurrence after AF ablation in HCM patients. CONCLUSIONS: QTc prolongation is an independent predictor of arrhythmia recurrence in HCM patients undergoing AF ablation, and might be useful for identifying those patients likely to have a better outcome following the procedure.

Catheter ablation of atrial fibrillation in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased incidence of atrial fibrillation (AF). This study evaluated the safety and efficacy of catheter ablation (CA) in the treatment of AF in patients with RA, which has not been previously reported. METHODS: A total of 15 RA patients with AF who underwent CA were enrolled. For each RA patient, we selected 4 individuals (control group, 60 patients in total) who presented for AF ablation in the absence of structural heart or systemic disease and matched the RA patients with same gender, age (±2 years), type of AF, and procedure date. RESULTS: Patients with RA had a significantly higher C-reactive protein level (1.81 ± 2.35 mg/dl vs. 4.14 ± 2.30 mg/dl, p=0.0320), white blood cell count (5632 ± 1200 mm(3) vs. 6361 ± 1567 mm(3), p=0.0482), and neutrophil count (3308 ± 973 mm(3) vs. 3949 ± 1461 mm(3), p=0.0441). At 2-year follow-up, atrial tachyarrhythmia (ATa) recurrence rate in the RA group (33.3%, 5/15) was similar to that in the control group (31.7%, 19/60; p=0.579) after single procedure. In all the five patients from the RA group who developed recurrence, ATa relapsed within 90 days following index procedure (median recurrence time 18 days vs. 92 days in control group; p=0.0373). Multivariate Cox regression analysis showed that hypertension and left atrial diameter but not RA, C-reactive protein, white blood cell count, and neutrophil count were independent predictors of ATa recurrence. CONCLUSIONS: Catheter ablation of AF can be safely performed in patients with RA, with a success rate comparable to that of patients without RA. RA patients tend to develop early ATa recurrence after AF ablation.

Incidence and clinical characteristics of transient ST-T elevation during transseptal catheterization for atrial fibrillation ablation.

AIMS: Transient ST-T elevation (STE) is a rare complication that occurs during transseptal catheterization. This study aims to delineate the incidence and characteristics of transient STE during transseptal catheterization for atrial fibrillation (AF) ablation. METHODS AND RESULTS: Consecutive patients who underwent fluoroscopy-guided transseptal catheterization for circumferential pulmonary vein radiofrequency ablation in Beijing An Zhen Hospital from January 2006 to January 2013 were enrolled in this study. Out of 2965 patients with a total of 3452 transseptal catheterization procedures, 13 patients (0.38%, mean age 57 ± 8, 6 female, 12 paroxysmal AF, mean left atrial diameter 35.4 ± 3.8 mm) had STE. ST-T elevation occurred after transseptal puncture in 10 patients and after pulmonary vein venography in three patients. Systolic blood pressure (129 ± 10 vs. 104 ± 20 mmHg, P < 0.001), diastolic blood pressure (78 ± 6 vs. 64 ± 11 mmHg, P < 0.001), and heart rate (83 ± 19 bpm vs. 64 ± 23 b.p.m., P = 0.022) significantly decreased when STE occurred. Eleven patients complained of chest pain, one patient complained of dizziness, and one patient had no symptoms. Patients recovered in about 4.6 min (2-10 min) with dopamine or fast saline drip. Catheter ablation of AF was completed in all the 13 patients without sequelae or other complications. Four of the 13 patients (30.8%) had recurrence of AF after a mean follow-up of 21.7 months. CONCLUSION: ST-T elevation is a rare complication associated with transseptal catheterization without sequelae. Catheter ablation of AF could be safely completed in these patients.

[The effects of calmodulin kinase II inhibitor on ventricular arrhythmias in rabbits with cardiac hypertrophy].

OBJECTIVE: To investigate the effect of KN-93, a calmodulin kinase II inhibitor, on ventricular arrhythmias in rabbits with cardiac hypertrophy. METHODS: Female New Zealand white rabbits were randomly divided into four groups (n = 10 each): Sham; LVH; LVH + KN-92 and LVH + KN-93 group. LVH was induced by partially constricting the abdominal aorta. In Sham group, the abdominal aorta was exposed without constriction. Eight weeks later, the arterially perfused left ventricular wedge preparations were made and transmembrane action potentials (TAP) from epicardium and endocardium and transmural ECG were simultaneously recorded. Incidence of early after depolarization (EAD) and torsade de pointes (Tdp), QT interval, action potential duration (APD) and transmural depolarization dispersion (TDR) at different cycle lengths were observed under slow stimulation (2000 - 4000 ms), hypokalemic (2 mmol/L) and hypomagnesaemic (0.25 mmol/L) Tyrode's solution perfusion. RESULTS: Left ventricular hypertrophy was detected in LVH group by echocardiography and not affected by KN-92 and KN-93. Perfused with hypokalemic, hypomagnesaemic Tyrode's solution and under slow stimulation (2000 - 4000 ms), the incidences of EAD and Tdp in Sham group, LVH group, LVH + KN-92 group (0.5 micromol/L) and LVH + KN-93 group (0.5 micromol/L) were 0/10, 10/10, 9/10, 5/10 and 0/10, 5/10, 4/10, 1/10, respectively. With 1 micromol/L KN-92 and KN-93, the incidences of EAD and Tdp in LVH + KN-92 and LVH + KN-93 group were 9/10, 3/10 and 4/10, 1/10 respectively. The QT interval, APD and TDR were not affected by KN-93. CONCLUSION: The calmodulin kinase II inhibitor KN-93 can effectively suppress ventricular arrhythmias in rabbits with cardiac hypertrophy by decreasing EAD.

[The effects of antiarrhythmic peptide AAP10 on ventricular arrhythmias in rabbits with healed myocardial infarction].

OBJECTIVE: To evaluate the effects of antiarrhythmic peptide (AAP10) on ventricular arrhythmias in rabbits with healed myocardial infarction (OMI). METHODS: Thirty rabbits were randomly divided into three groups (n = 10 each): Sham group, left thoracotomy was performed without coronary ligation; OMI group and OMI + AAP10 group, the circumflex coronaries were ligated. Three months post operation, the electrophysiological and antiarrhythmic effects of AAP10 were assessed in the arterially perfused rabbit left ventricular wedge preparation. Sham and OMI group were perfused with Tyrode's solution and OMI + AAP10 group was perfused with Tyrode's solution + AAP10 (80 nmol/L). Transmembrane action potentials were recorded simultaneously from endocardium and epicardium together with a transmural ECG by use of 2 separate intracellular floating microelectrodes. The stimulus-response-interval (SRI) of the epicardium and the incidence of ventricular tachycardia (VT) were observed. Whole heart and left ventricular weights, the left ventricular thickness at infarct border zone were measured. RESULTS: Whole heart and left ventricular weights as well as the left ventricular thickness at the infarct border zone significantly increased post infarction. VT was induced in 8 out of 10 rabbits in OMI group and in 2 out of 10 rabbits in OMI + AAP10 group (P < 0.05). SRI was also significantly shortened in OMI + AAP10 group compared to OMI group [SRI-1: (20.59 +/- 0.79) ms vs. (28.71 +/- 0.55) ms; SRI-2: (30.42 +/- 0.74) ms vs. (38.67 +/- 0.49) ms, all P < 0.01]. However, the action potential morphology and duration were similar between OMI and OMI + AAP10 groups. CONCLUSION: The antiarrhythmic peptide (AAP10) can increase gap junctional intercellular conductance without affecting the action potential morphology and duration and decrease the incidence of inducible ventricular tachycardia.

Experimental study on the mechanism of sex difference in the risk of torsade de pointes.

BACKGROUND: Torsade de pointes (TdP) is a form of polymorphic ventricular tachycardia featuring prolonged QT intervals. Female gender is associated with an increased risk of TdP. However, the causes of the sex difference in risk are poorly understood. Recently, transmural dispersion of repolarization (TDR) has been implicated in the genesis of TdP. Consequently, we compared TdP incidence and TDR between male and female rabbit hearts in order to investigate the mechanism of sex difference in TdP risk in rabbits in vitro. METHODS: By means of monophasic action potential recording techniques, the monophasic action potential of the epicardium, midmyocardium, and endocardium were simultaneously recorded using specially designed plunge-needle electrodes placed across the left ventricular free wall of both female (n = 8) and male (n = 8) rabbit hearts purfused by the Langendorff method. TdP was induced by bradycardia, d-sotalol, and low-K+, Mg2+ Tyrode solution. RESULTS: TDR measurements in all three myocardial layers of male and female rabbit hearts were (18 +/- 2) ms and (21 +/- 2) ms, respectively (n = 8, P > 0.05). After perfusion with d-sotalol, the 90% monophasic action potential duration was prolonged in both male and female rabbits. TDR in male and female rabbit hearts increased to (29 +/- 2) ms and (61 +/- 2) ms, respectively, a difference that is significant. Eight female rabbit hearts had early afterdepolarization and 7 of them developed TdP. Seven male rabbit hearts had early after depolarization, but only one of these hearts developed TdP. CONCLUSION: Greater TDR may play an important role in the higher incidence of TdP in female rabbit hearts.

[Influence of pacing site on myocardial transmural dispersion of repolarization in intact normal and dilated cardiomyopathy dogs].

In order to verify the hypothesis that left ventricular epicardial (LV-Epi) pacing and biventricular (BiV) pacing unavoidably influence the myocardial electrophysiological characters and may result in high risk of malignant ventricular arrhythmia, we calculated, in both normal mongrel dogs and dog models with rapid-right-ventricular-pacing induced dilated cardiomyopathy congestive heart failure (DCM-CHF), the monophasic action potential duration (MAPD) and the transmural dispersion of repolarization (TDR) in intracardiac electrogram together with the QT interval and T(peak)-T(end) (T(p(-T(e)) interval in surface electrocardiogram (ECG) during LV-Epi and BiV pacing, compared with those during right ventricular endocardial (RV-Endo) pacing. To prepare the DCM-CHF dog model, rapid right ventricular pacing (250 bpm) was performed for 23.6+/-2.57 days to the dog. All the normal and DCM-CHF dogs were given radio frequency catheter ablation (RFCA) to His bundle with the guide of X-ray fluoroscopy. After the RFCA procedures, the animals were under the situation of complete atrioventricular block so that the canine heart rates could be voluntarily controlled in the following experiments. After a thoracotomy, ECG and monophasic action potentials (MAP) of subendocardial, subepicardial and mid-layer myocardium were recorded synchronously in 8 normal and 5 DCM-CHF dogs during pacing from endocardium of RV apex (RV-Endo), epicardium of LV anterior wall (LV-Epi) and simultaneously both of the above (biventricular, BiV), the later was similar to the ventricular resynchronization therapy to congestive heart failure patients in clinic. The Tp-Te) meant the interval from the peak to the end of T wave, which was a representative index of TDR in surface ECG. The TDR was defined as the difference between the longest and the shortest MAPD of subendocardial, subepicardial and mid-layer myocardium. Our results showed that in normal dogs, pacing participating of LV (LV-Epi, BiV) prolonged MAPD of all the three layers of the myocardium (P<0.05) with the character that mid-layer MAPD was the longest and subepicardial MAPD was the shortest following subendocardial MAPD. At the same time, TDR prolonged from 26.75 ms at RV-Endo pacing to 37.54 ms at BiV pacing and to 47.16 ms at LV-Epi pacing (P<0.001). Meanwhile in surface ECG, BiV and LV-Epi pacing resulted in a longer Tp-Te) interval compared with RV-Endo pacing (P<0.01), without parallel QT interval prolongation. Furthermore, all the DCM-CHF model dogs showed manifestations of congestive heart failure and enlargement of left ventricles. Based on the lengthening of mid-layer MAPD from 257.35 ms to 276.30 ms (P<0.0001) and increase of TDR from 27.58 ms to 33.80 ms (P equals;0.002) in DCM-CHF model due to the structural disorders of myocardium compared with the normal dog, LV-Epi and BiV pacing also led to the effect of prolonging MAPD of three layers of the myocardium and enlarging TDR. From these results we make the conclusions that prolongation of MAPD of subendocardial, subepicardial and mid-layer myocardium and increase in TDR during pacing participating of LV (LV-Epi, BiV) may contribute to the formation of unidirectional block and reentry, which play roles or at least are the high risk factors in the development of malignant ventricular arrhythmia, especially in case of structural disorders of myocardium. These findings must be considered seriously when ventricular resynchronization therapy is performed to congestive heart failure patients.

Effect of imidapril on heterogeneity of slow component of delayed rectifying K+ current in rabbit left ventricular hypertrophic myocytes.

AIM: To investigate the transmural heterogeneous change of slow component of delayed rectifying potassium current in rabbit left ventricular hypertrophic myocytes and the effect of long-term treatment with imidapril (Imi). METHODS: Rabbits were divided into hypertrophy group (left ventricular hypertrophy induced by partial ligation of abdominal aorta), Imi-treated group (surgical treatment as hypertrophy group was treated with Imi), and Sham-operated group as control. Whole-cell patch-clamp technique was used to record potassium currents. RESULTS: (1) Membrane capacitance was larger in hypertrophic cells than in sham-operated and Imi-treated cells. Action potential durations (APD) of epicardium (Epi), midmyocardium (M), and endocardium (Endo) were remarkably longer in hypertrophic cells than those in Imi-treated and sham-operated cells. The prolongation of APD90 of M was the most pronounced in three layer myocytes of hypertrophic group. (2) The densities of I(Ks,tail) of hypertrophic cells were reduced by Epi 25.3 %+/-2.9 %, M 38.0 %+/-3.7 % and Endo 20.3 %+/-4.7 % compared with those of sham-operated cells. The decrease of IKs,tail density was more pronounced in M than in Epi and Endo (n = 13, P<0.01 vs Epi or Endo). (3) The density of I(Kr,tail) in Imi-treated cells was not different from that in sham-operated cells significantly (n=10). CONCLUSION: Imi reduced prolongation of APD and inhibited the heterogeneous change of I(Ks,tail) in rabbit left ventricular hypertrophic myocytes.