Abdul Shokor Parwani

In vitro Modeling of Ryanodine Receptor 2 Dysfunction Using Human Induced Pluripotent Stem Cells

Background/Aims: Induced pluripotent stem (iPS) cells generated from accessible adult cells of patients with genetic diseases open unprecedented opportunities for exploring the pathophysiology of human diseases in vitro. Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited cardiac disorder that is caused by mutations in the cardiac ryanodine receptor type 2 gene (RYR2) and is characterized by stress-induced ventricular arrhythmia that can lead to sudden cardiac death in young individuals. The aim of this study was to generate iPS cells from a patient with CPVT1 and determine whether iPS cell-derived cardiomyocytes carrying patient specific RYR2 mutation recapitulate the disease phenotype in vitro. Methods: iPS cells were derived from dermal fibroblasts of healthy donors and a patient with CPVT1 carrying the novel heterozygous autosomal dominant mutation p.F2483I in the RYR2. Functional properties of iPS cell derived-cardiomyocytes were analyzed by using whole-cell current and voltage clamp and calcium imaging techniques. Results: Patch-clamp recordings revealed arrhythmias and delayed afterdepolarizations (DADs) after catecholaminergic stimulation of CPVT1-iPS cell-derived cardiomyocytes. Calcium imaging studies showed that, compared to healthy cardiomyocytes, CPVT1-cardiomyocytes exhibit higher amplitudes and longer durations of spontaneous Ca2+ release events at basal state. In addition, in CPVT1-cardiomyocytes the Ca2+-induced Ca2+-release events continued after repolarization and were abolished by increasing the cytosolic cAMP levels with forskolin. Conclusion: This study demonstrates the suitability of iPS cells in modeling RYR2-related cardiac disorders in vitro and opens new opportunities for investigating the disease mechanism in vitro, developing new drugs, predicting their toxicity, and optimizing current treatment strategies.

Steerable Versus Nonsteerable Sheath Technology in Atrial Fibrillation Ablation A Prospective, Randomized Study

Background— Steerable sheath technology is designed to facilitate catheter access, stability, and tissue contact in target sites of atrial fibrillation (AF) catheter ablation. We hypothesized that rhythm control after interventional AF treatment is more successful using a steerable as compared with a nonsteerable sheath access. Methods and Results— One hundred thirty patients with paroxysmal or persistent drug-refractory AF undergoing their first ablation procedure were prospectively included in a randomized fashion in 2 centers. Ablation was performed by 10 operators with different levels of clinical experience. Treatment outcome was measured with serial 7-day Holter ECGs and additional symptom-based arrhythmia documentation. Single procedure success (freedom from AF and/or atrial macroreentrant tachycardia) was significantly higher in patients ablated with a steerable sheath (78% versus 55% after 3 months, P=0.005; 76% versus 53% after 6 months, P=0.008). Rate of pulmonary vein isolation, procedure duration, and radiofrequency application time did not differ significantly, whereas fluoroscopy time was lower in the steerable sheath group (33±14 minutes versus 45±17 minutes, P<0.001). Complication rates showed no significant difference (3.2% versus 5%, P=0.608). On multivariable analysis, steerable sheath usage remained the only powerful predictor for rhythm outcome after 6 months of follow-up (hazard ratio, 2.837 [1.197 to 6.723]). Conclusions— AF catheter ablation using a manually controlled, steerable sheath for catheter navigation resulted in a significantly higher clinical success rate, with comparable complication rates and with a reduction in periprocedural fluoroscopy time. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00469638.

Atrial fibrillation-induced cardiac troponin I release

BACKGROUND Cardiac troponin I (cTnI) is highly specific for myocardial damage and for the diagnosis of acute coronary syndrome. We investigated cTnI utility and predictive value in patients with atrial fibrillation (AF) in the acute setting. METHOD We studied 354 consecutive patients with the primary diagnosis of AF and clinical symptoms suggestive of myocardial ischemia presenting to our emergency department. cTnI was obtained on presentation. Patients with ST-segment elevation myocardial infarction were excluded. Coronary angiography was performed in 100 patients. RESULTS cTnI was elevated (>0.09 μg/L) in 51 of 354 (15%) patients. The mean cTnI in these patients was 0.37 μg/L (0.09-3.14). In 23 of 100 patients undergoing coronary angiography, cTnI was elevated. Only 6 of these 23 patients (26%) had significant stenosis. In 77 of 100 patients undergoing coronary angiography, cTnI was normal, revealing significant stenosis in 25 patients (33%). The positive predictive value of elevated cTnI for a coronary intervention was 26% and the negative predictive value was 68%. Using multivariate logistic regression, we found that heart rate on presentation, the presence of angina pectoris, left ventricular ejection fraction, serum creatinine, and hemoglobin independently predicted elevated cTnI level. CONCLUSION These data are the first to show that AF in the acute setting is frequently associated with cTnI elevations. AF patients with high heart rate and/or angina pectoris often show false elevated cTnI levels. These findings are relevant for clinicians evaluating patients with acute AF and myocardial ischemia symptoms. Appropriate clinical guidelines must be established that also consider AF-related elevations in cTnI.

Safety aspects of deep sedation during catheter ablation of atrial fibrillation.

Background:  The combination of intravenous propofol and midazolam is frequently used to provide unconscious sedation during catheter ablation of atrial fibrillation (AF), but only a very few reports are available on the influence of prolonged propofol infusion on arterial blood gas, blood pressure, and anesthesia‐associated complications during ablation of AF. The purpose of this study was to assess tolerance and safety of unconscious sedation with intravenous propofol and midazolam during catheter ablation of AF.

Effects of deep sedation on cardiac electrophysiology in patients undergoing radiofrequency ablation of supraventricular tachycardia: impact of propofol and ketamine

AIMS Propofol is commonly used as an anaesthetic during catheter ablation. Bradycardia and termination of supraventricular tachycardia (SVT) under propofol are reported. Ketamine is used for cardiac catheterization procedures and increases heart rate and blood pressure. Our study aimed to determine the effects of propopfol and ketamine on atrial electrophysiology. METHODS AND RESULTS Thirty-one patients undergoing electrophysiological study prior to SVT ablation were enrolled. Patients received a combination of propofol/midazolam (n = 10), ketamine/midazolam (n = 9), or midazolam alone (n = 12). Electrophysiological study was performed before and after administration of the anaesthetic agents. Blood pressure, corrected sinus node recovery time, Wenckebach cycle length, and atrial conduction time were measured. We found a significant increase in heart rate, systolic, and diastolic blood pressure and a significant shortening of atrial conduction time after administration of ketamine compared with propofol and the control. Results for ketamine, propofol and the control, respectively: mean (SD) change in heart rate was 12.4 (8.3), -1.4 (8), and 1 (7.5) b.p.m. (P = 0.002); mean (SD) change in systolic blood pressure was 19.2 (8.1), -22 (9), and 0.1 (5.7) mmHg (P < 0.001); mean (SD) change in diastolic blood pressure was 6.6 (9.7), -7.8 (2.9), and 2.3 (4.5) mmHg (P = 0.001); and mean (SD) change in atrial conduction time was -13.7 (16.4), 4.5 (11.1), and -0.3 (3.8) ms (P = 0.008). No significant affection of sinus node or antrioventricular node function was seen. CONCLUSION Our results show stimulatory effects of ketamine on heart rate, atrial conduction, and blood pressure. Ketamine, therefore, may be beneficial in patients with pre-existing hypotension and bradycardia.

Mutational analysis of the PITX2 and NKX2-5 genes in patients with idiopathic atrial fibrillation

Atrial fibrillation (AF) is the most frequently encountered arrhythmia in clinical practice. In a subgroup of patients, AF is regarded as idiopathic when no signs of structural heart disease or other causes of the arrhythmia can be identified during conventional clinical work-up. Recent studies have demonstrated that AF has a substantial genetic basis in a number of cases. The entire coding sequences, including intron-exon boundaries, of the genes PITX2 and NKX2-5 were screened for genetic variants by means of initial polymerase chain reaction followed by DNA sequencing in 96 patients with idiopathic AF. Although we detected a number of variants, our candidate gene approach did not result in identification of mutations associated with AF in the coding regions of PITX2 or NKX2-5 in our well characterized AF cohort.

Contact force mapping during catheter ablation for atrial fibrillation: procedural data and one-year follow-up.

Introduction Pulmonary vein isolation (PVI) is the state-of-the-art treatment of atrial fibrillation (AF). Pulmonary vein reconnection is one of the main mechanisms of AF recurrence after ablation. Catheter-tissue contact is essential for effective ablation lesions. The aim of this study was to evaluate the impact of catheter contact monitoring during PVI on AF recurrence rate. Material and methods One hundred and forty-three patients who underwent PVI were analysed. In 31 patients, PVI was performed by monitoring the catheter-tissue contact with a contact force (CF) sensing catheter. One hundred and twelve patients in whom conventional PVI was performed without CF information served as the control group. Procedural data and recurrence rate within 12-month follow-up were compared. Results A significant reduction in procedure duration was seen in the CF mapping group (128.4 ±29 min vs. 157.7 ±30.8 min, p = 0.001). Complete pulmonary vein isolation was achieved in 100% of the patients. Rate of AF recurrence within 12 months after ablation was significantly lower in the contact force group (16.1%) when compared to the standard ablation group (36.6%) (p = 0.031). Conclusions Pulmonary vein isolation with the use of contact force information results in a shorter procedure duration and a lower rate of AF recurrence after 12 months compared to conventional PVI without this information. Catheter-tissue contact monitoring may have a beneficial effect on mid-term and long-term results of PVI procedures.

Clinical Significance of the Assessment of the Systolic and Diastolic Myocardial Function of the Left Atrium in Patients With Paroxysmal Atrial Fibrillation and Low CHADS2 Index Treated With Catheter Ablation Therapy

The purpose of this study was to determine the clinical significance of the assessment of the diastolic and systolic myocardial function of the left atrium in patients with paroxysmal atrial fibrillation (AF) and low CHADS(2) scores treated with catheter ablation therapy. In a cohort of 84 symptomatic patients with paroxysmal AF and low CHADS(2) scores (≤1), the clinical significance of the systolic and diastolic myocardial function of the left atrium (assessed using 2-dimensional speckle-tracking echocardiography) were studied to predict the risk for recurrence of AF after catheter ablation therapy in the course of a follow-up period of ≥1 year. During a mean follow-up period of 19.2 ± 5.4 months, patients with left atrial (LA) myocardial diastolic dysfunction (LA strain <18.8%) had a significantly higher rate of recurrence of AF (42.4% vs 9.8%, p <0.05) compared to those without LA diastolic dysfunction. In line with this finding, patients with impaired LA myocardial systolic function (LA strain rate >-0.85 s(-1)) had worse outcomes after catheter ablation therapy than those with normal LA systolic function (rate of recurrence of AF 42.9% vs 12.5%, respectively, p <0.05). In relation to these results, in a logistic regression analysis including co-morbidities, left ventricular dysfunction, LA enlargement, and LA myocardial alterations, diastolic and systolic LA myocardial dysfunction were the principal variable associated with the recurrence of AF (odds ratios 6.8 and 5.2, respectively). In conclusion, in symptomatic patients with paroxysmal AF and low CHADS(2) scores, these findings suggest that the assessment of diastolic and systolic LA myocardial function using 2-dimensional speckle-tracking echocardiography could be of great utility to distinguish those patients with high or low risk for recurrence of AF after catheter ablation therapy.

Optimal heart failure therapy and successful cardioversion in heart failure patients with atrial fibrillation

BACKGROUND Effectiveness, safety, and other factors associated with success of cardioversion (CV) of atrial fibrillation (AF) have not yet been evaluated in patients with reduced left ventricular ejection fraction. We studied 148 consecutive patients with left ventricular dysfunction (ejection fraction < or = 45%), who underwent electrical CV for AF in our department. The patients had New York Heart Association heart failure ranging from class II to IV. The overall CV success rate was 71%. We relied on univariate and multivariate regression and sought variables influencing success rate. Conversion success did not correlate with New York Heart Association class. Instead, we found that the greatest predictor was the degree of heart failure treatment. Patients receiving beta-blockers, angiotensin-converting enzyme inhibitors or angiotension receptor blockers, plus mineralocorticoid receptor blockers had the greatest chance for conversion success. Success was more likely in patients with coronary artery disease (91%) than in patients with nonischemic cardiomyopathy. CONCLUSIONS Cardioversion is a safe and effective method for the restoration of sinus rhythm in patients with AF and reduced left ventricular ejection fraction. Our findings underscore the value of aggressive heart failure treatment before CV in patients with AF.

Variations in the human soluble epoxide hydrolase gene and recurrence of atrial fibrillation after catheter ablation

BACKGROUND Single nucleotide polymorphisms (SNPs) of EPHX2 alter sEH activity and are associated with increased [rs41507953 (K55R)] or reduced [rs751141 (R287Q)] cardiovascular risk via modulation of fibrosis, inflammation or cardiac ion channels. This indicates an effect on development and therapy response of AF. This study tested the hypothesis that variations in the EPHX2 gene encoding human soluble epoxide hydrolase (sEH) are associated with atrial fibrillation (AF) and recurrence of atrial fibrillation after catheter ablation. METHODS AND RESULTS A total of 218 consecutive patients who underwent catheter ablation for drug refractory AF and 268 controls were included. Two SNPs, rs41507953 and rs751141, were genotyped by direct sequencing. In the ablation group, holter recordings 3, 12 and 24 months after ablation were used to detect AF recurrence. No significant association of the SNPs and AF at baseline was detected. In the ablation group, recurrence of AF occurred in 20% of the patients 12 months after ablation and in 35% 24 months after ablation. The presence of the rs751141 polymorphism significantly increased the risk of AF recurrence 12 months (odds ratio [OR]: 3.2, 95% confidence interval [CI]: 1.237 to 8.276, p=0.016) and 24 months (OR: 6.076, 95% CI: 2.244 to 16.451, p<0.0001) after catheter ablation. CONCLUSIONS The presence of rs751141 polymorphism is associated with a significantly increased risk of AF recurrence after catheter ablation. These results point to stratification of catheter ablation by genotype and differential use of sEH-inhibitory drugs in the future.