Yun-Yu Chen

Radiofrequency Catheter Ablation of Ventricular Arrhythmias Originating from the Continuum between the Aortic Sinus of Valsalva and the Left Ventricular Summit: Electrocardiographic Characteristics and Correlative Anatomy.

BACKGROUND Radiofrequency ablation of ventricular arrhythmias (VAs) originating from the continuum between the aortic sinus of Valsalva (ASV) and the left ventricular (LV) summit is a challenge. OBJECTIVES The objectives of this study were to investigate the electrocardiographic, electrophysiological, and anatomical characteristics of VAs and to develop an algorithm for predicting the successful ablation site. METHODS We recruited 66 patients (mean age, 47 ± 15 years; 42 male patients) with symptomatic VAs originating from the continuum between the ASV and the LV summit who underwent radiofrequency ablation. Patients were classified into 4 groups (group 1: ASV, n = 20; group 2: subvalvular region, n = 15; group 3: great cardiac vein/anterior interventricular vein [GCV/AIV], n = 16; group 4: epicardium requiring pericardial access, n = 15). The QRS morphological characteristics of VAs were compared between the 4 groups. RESULTS Electrocardiographic analysis revealed that the aVL/aVR Q-wave ratio is useful in the prediction of successful ablation sites in the ASV, subvalvular area, GCV/AIV, and epicardium requiring pericardial access at cutoff values of ≤1.415, 1.416-1.535, 1.536-1.740, and >1.740, respectively. The aVL/aVR Q-wave ratio was well correlated with the distance between the successful ablation site and the tip of the LV summit. A distance of >18.9 mm and an LV myocardial thickness of >9.1 mm predicted the need for the epicardial or GCV/AIV approaches. There were no major procedural complications. Eight patients (12.1%) developed VA recurrence during a mean follow-up of 15.9 months (interquartile range 9.2-24.2 months). CONCLUSION The aVL/aVR Q-wave ratio is a useful parameter for predicting the successful ablation sites of VAs originating from the continuum between the ASV and the LV summit.

The impact of diabetes mellitus and corresponding HbA1c levels on the future risks of cardiovascular disease and mortality: a representative cohort study in Taiwan.

Background This study explored the relationship between the glycated hemoglobin (HbA1c) level in patients with or without diabetes mellitus and future risks of cardiovascular disease and death. Methods Based on a national representative cohort, a total of 5277 participants (7% with diabetes) were selected from Taiwans Triple High Survey in 2002. The comorbidities, medication usages, and outcomes of cardiovascular disease and death, were extracted from the Taiwan’s National Health Insurance Research Database and National Death Registry. Results After a median follow-up of 9.7 years, participants with diabetes had higher incidence of new onset cardiovascular disease (17.9 versus 3.16 cases per 1000 person-years) and death (20.1 versus 4.96 cases per 1000 person-years) than those without diabetes (all P < 0.001). Diabetes showed increased risk of all-cause death after adjusting for all confounders (adjusted hazard ratio [HR]: 2.29, 95% confidence interval [CI]: 1.52-3.45). Every 1% increment of HbA1c was positively associated with the risk of total cardiovascular disease (HR: 1.2, 95% CI: 1.08-1.34) and the risk of death (HR: 1.14, 95% CI: 1.03-1.26) for all participants. As compared to the reference group with HbA1c below 5.5%, participants with HbA1c levels ≥7.5% had significantly elevated future risks of total cardiovascular disease (HR: 1.82, 95% CI: 1.01-3.26) and all-cause death (HR: 2.45, 95% CI: 1.45-4.14). Conclusions/Interpretation Elevated HbA1C levels were associated with increased risks of cardiovascular disease and death, the suboptimal glycemic control with HbA1c level over 7.5% (58.5 mmol/mol) was strongly associated with increased risks of cardiovascular disease and all-cause death.

A neuronal death model: overexpression of neuronal intermediate filament protein peripherin in PC12 cells

BackgroundAbnormal accumulation of neuronal intermediate filament (IF) is a pathological indicator of some neurodegenerative disorders. However, the underlying neuropathological mechanisms of neuronal IF accumulation remain unclear. A stable clone established from PC12 cells overexpressing a GFP-Peripherin fusion protein (pEGFP-Peripherin) was constructed for determining the pathway involved in neurodegeneration by biochemical, cell biology, and electronic microscopy approaches. In addition, pharmacological approaches to preventing neuronal death were also examined.ResultsResults of this study showed that TUNEL positive reaction could be detected in pEGFP-Peripherin cells. Swollen mitochondria and endoplasmic reticulum (ER) were seen by electron microscopy in pEGFP-Peripherin cells on day 8 of nerve growth factor (NGF) treatment. Peripherin overexpression not only led to the formation of neuronal IF aggregate but also causes aberrant neuronal IF phosphorylation and mislocation. Western blots showed that calpain, caspase-12, caspase-9, and caspase-3 activity was upregulated. Furthermore, treatment with calpain inhibitor significantly inhibited cell death.ConclusionsThese results suggested that the cytoplasmic neuronal IF aggregate caused by peripherin overexpression may induce aberrant neuronal IF phosphorylation and mislocation subsequently trapped and indirectly damaged mitochondria and ER. We suggested that the activation of calpain, caspase-12, caspase-9, and caspase-3 were correlated to the dysfunction of the ER and mitochondria in our pEGFP-Peripherin cell model. The present study suggested that pEGFP-Peripherin cell clones could be a neuronal death model for future studies in neuronal IFs aggregate associated neurodegeneration.

Prognostic Significance of Premature Atrial Complexes Burden in Prediction of Long‐Term Outcome

Background The prognostic significance of premature atrial complex (PAC) burden is not fully elucidated. We aimed to investigate the relationship between the burden of PACs and long-term outcome. Methods and Results We investigated the clinical characteristics of 5371 consecutive patients without atrial fibrillation (AF) or a permanent pacemaker (PPM) at baseline who underwent 24-hour electrocardiography monitoring between January 1, 2002, and December 31, 2004. Clinical event data were retrieved from the Bureau of National Health Insurance of Taiwan. During a mean follow-up duration of 10±1 years, there were 1209 deaths, 1166 cardiovascular-related hospitalizations, 3104 hospitalizations for any reason, 418 cases of new-onset AF, and 132 PPM implantations. The optimal cut-off of PAC burden for predicting mortality was 76 beats per day, with a sensitivity of 63.1% and a specificity of 63.5%. In multivariate analysis, a PAC burden >76 beats per day was an independent predictor of mortality (hazard ratio: 1.384, 95% CI: 1.230 to 1.558), cardiovascular hospitalization (hazard ratio: 1.284, 95% CI: 1.137 to 1.451), new-onset AF (hazard ratio: 1.757, 95% CI: 1.427 to 2.163), and PPM implantation (hazard ratio: 2.821, 95% CI: 1.898 to 4.192). Patients with frequent PAC had increased risk of mortality attributable to myocardial infarction, heart failure, and sudden cardiac death. Frequent PACs increased risk of PPM implantation owing to sick sinus syndrome, high-degree atrioventricular block, and/or AF. Conclusions The burden of PACs is independently associated with mortality, cardiovascular hospitalization, new-onset AF, and PPM implantation in the long term.

Long-term outcome of multiform premature ventricular complexes in structurally normal heart.

BACKGROUND Multiform premature ventricular complexes (PVCs) are common electrocardiographic abnormalities in patients with structurally normal hearts. However, the prognostic value of these complexes remains unclear. This study aimed to clarify the role of PVC polymorphism in predicting adverse outcomes. METHODS AND RESULT We examined the database for 24-hour electrocardiography monitoring between January 1, 2002 and December 31, 2004. We analyzed 3351 individuals with apparently normal hearts. Kaplan-Meier curves and multivariate Cox proportional hazards models were employed to estimate the effect of multiform PVC and uniform PVC on the number of incident adverse events. Average follow-up time was 10±1years. Patients with multiform PVC were older and had a higher prevalence of comorbidities. In multivariate analysis, patients with multiform PVC had an increased incidence of mortality (hazard ratio [HR]: 1.642, 95% confidence interval [CI]: 1.327-2.031), hospitalization (HR: 1.196, 95% CI: 1.059-1.350), cardiovascular hospitalization (HR: 1.289, 95% CI: 1.030-1.613), new-onset heart failure (HF; HR: 1.456, 95% CI: 1.062-1.997), transient ischemic accident (HR: 1.411, 95% CI 1.063-1.873), and new-onset atrial fibrillation (AF; HR: 1.546, 95% CI: 1.058-2.258) compared to the group without PVC. Patients with multiform PVC had a higher rate of mortality (HR: 1.231, 95% CI: 1.033-1.468) and all cause-hospitalization (HR: 1.147, 95% CI: 1.025-1.283) compared with patients with uniform PVC. CONCLUSION The presence of multiform PVC was associated with a higher incidence of mortality, hospitalization, transient ischemic attack, new-onset AF, and new-onset HF independent of other clinical risk factors.

Risk stratification of arrhythmogenic right ventricular cardiomyopathy based on signal averaged electrocardiograms

BACKGROUND Signal averaged electrocardiogram (SAECG) is a specific and non-invasive tool useful for arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis. However, its role in risk stratification of patients with ARVC remains largely undefined. METHODS Sixty-four patients fulfilling Task Force ARVC criteria (mean age: 47 ± 14 years-old, 56% male, 50% definite ARVC) were enrolled. The baseline demographic, electrocardiographic, structural, and electrophysiological characteristics were collected. Patients with SAECG fulfilling all 3 Task Force criteria (3+ SAECG) were categorized into group 1, and those fulfilled 2 or less criterion were categorized into group 2. The study endpoints were unstable ventricular arrhythmia (VA), device detectable sustained fast VA (cycle lengths < 240 ms) and cardiovascular death. RESULTS During a mean follow-up of 21 ± 20 months, 15 primary endpoints including 12 unstable VAs and 3 device-detected fast VAs were met. One patient died of electrical storm, and one patient underwent heart transplantation. The presence of 3+ SAECG predicted malignant events in all patients with definite and non-definite ARVC (p < 0.01, OR = 30.5, 95% CI = 2.5-373.7) and in patients with definite ARVC alone (p = 0.03, OR = 11.1, 95% CI = 1.3-93.9). Patients diagnosed with non-definite ARVC without 3+ SAECG were free from malignant events. CONCLUSIONS SAECG fulfilling all 3 Task Force criteria was an independent risk predictor of malignant events in ARVC patients. SAECG may play a valuable role in ARVC risk stratification.

Suppression of Extensive Neurofilament Phosphorylation Rescues α-Internexin/Peripherin-Overexpressing PC12 Cells from Neuronal Cell Death

Intermediate filament (IF) overproduction induces abnormal accumulation of neuronal IF, which is a pathological indicator of some neurodegenerative disorders. In our study, α-Internexin- and peripherin-overexpressing PC12 cells (pINT-EGFP and pEGFP-peripherin) were used as models to study neuropathological pathways responsible for neurodegenerative diseases. Microarray data revealed that Cdk5-related genes were downregulated and Cdk5 regulatory subunit-associated protein 3 (GSK-3α and GSK-3β) were upregulated in pINT-EGFP cells. Increased expression of phosphorylated neurofilament and aberrant activation of Cdk5 and GSK-3β were detected in both pEGFP-peripherin and pINT-EGFP cells by Western blotting. In addition, pharmacological approaches to retaining viability of pINT-EGFP and pEGFP-peripherin cells were examined. Treatment with Cdk5 inhibitor and GSK-3β inhibitor significantly suppressed neuronal death. Dynamic changes of disaggregation of EGFP-peripherin and decrease in green fluorescence intensity were observed in pEGFP-peripherin and pINT-EGFP cells by confocal microscopy after GSK-3β inhibitor treatment. We conclude that inhibition of Cdk5 and GSK-3β suppresses neurofilament phosphorylation, slows down the accumulation of neuronal IF in the cytoplasm, and subsequently avoids damages to cell organelles. The results suggest that suppression of extensive neurofilament phosphorylation may be a potential strategy for ameliorating neuron death. The suppression of hyperphosphorylation of neuronal cytoskeletons with kinase inhibitors could be one of potential therapeutic treatments for neurodegenerative diseases.

Long-Term Follow-Up of Catheter Ablation of Ventricular Arrhythmias: Experiences from a Tertiary Referral Center in Taiwan

BACKGROUND Radiofrequency catheter ablation (RFCA) is an alternative therapeutic management for drug-refractory ventricular arrhythmias (VA). However, long-term follow-up of clinical outcome after RFCA for VAs in Taiwan remains unknown. METHODS From 1999 to 2013, patients undergoing RFCA for VAs from a single referral center were consecutively enrolled. The annual distribution of cases, clinical characteristics, etiology, disease entity and electrophysiological studies were investigated. The clinical outcomes and recurrences between distinct entities were compared. RESULTS A total of 502 patients receiving RFCA of VAs were eligible, including 388 patients for idiopathic VAs and 114 for substrate VAs. The annual distribution displayed a tendency towards a gradual increase in ablation cases within 2009-2013 compared with the prior decade (p < 0.001). Acute success was achieved in 453 patients (90.2%), partial success in 3 (0.6%), and failed ablation in 46 (9.2%). During a mean follow-up of 39.77 ± 48.75 months, 126 (25.1%) patients developed recurrences. Kaplan-Meier analysis demonstrated better prognosis after RFCA in patients with idiopathic fascicular VT and RVOT VAs (p < 0.001) and attenuation of the occurrences of sustained VT/VF, ICD therapies, and mortality in patients with BrS and ARVD/C (p = 0.036), as well as overall ICD interventions in substrate VAs (p < 0.001). CONCLUSIONS RFCA could be an effective and alternative strategy in the elimination of idiopathic VAs and prevention of malignant events in substrate VAs at an experienced referral center in Taiwan. Distinct location of arrhythmogenic trigger and disease entities may result in non-uniform recurrences and prognosis. KEY WORDS Idiopathic; Radiofrequency catheter ablation; Recurrence; Substrate; Ventricular arrhythmias.

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.

Factors predisposing to ventricular proarrhythmia during antiarrhythmic drug therapy for atrial fibrillation in patients with structurally normal heart

BACKGROUND Ventricular arrhythmia (VA) can occur during propafenone therapy in atrial fibrillation (AF) patients with structurally normal heart. OBJECTIVE The purpose of this study was to evaluate the incidence and characteristics of propafenone-associated VAs in AF patients with structurally normal heart. METHODS We studied and compared the risk of new-onset VAs between AF patients with structurally normal heart taking and those not taking propafenone in a nationwide longitudinal cohort in Taiwan (n = 127,197 since 2000). We then investigated the association between propafenone and VA in AF patients with structurally normal heart in a single-center database (n = 396). RESULTS In the nationwide cohort, 102 patients (0.008% per patient-year) developed ventricular tachycardia (VT)/ventricular fibrillation (VF) during a follow-up period of 9.8 ± 3.5 years. After multivariate Cox regression analysis, propafenone treatment was a significant risk factor for new-onset VT/VF with a hazard ratio (HR) of 3.59 (95% confidence interval [CI] 1.30-9.89, P = .0136). Propafenone treatment offered protection against ischemic stroke with HR 0.649 (95% CI 0.55-0.77, P<.001). In the single-center study using ECG and medical records, the presence of inferior J wave, wider QRS, and old age were independent risk factors for VA after adjustment for clinical, biochemical, and echocardiographic variables. CONCLUSION Albeit with low incidence, propafenone therapy for AF was associated with new-onset VA in the nationwide longitudinal cohort study in Taiwan. Old age, presence of inferior lead J wave, and wider QRS on ECG were significant risk factors in our single-center study.