Roger Villuendas

Autonomic Remodeling in the Left Atrium and Pulmonary Veins in Heart Failure – Creation of a Dynamic Substrate for Atrial Fibrillation

Background—Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF. Methods and Results—Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular–paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, &bgr;-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and &bgr;-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in &bgr;1-adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. &bgr;-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration. Conclusions—In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.Background— Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF. Methods and Results— Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular–paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and β-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in β1-adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. β-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration. Conclusions— In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.

Measuring the Complexity of Atrial Fibrillation Electrograms

AF Electrogram Complexity.  Introduction: Complex fractionated atrial electrograms (CFAE) have been identified as targets for atrial fibrillation (AF) ablation. Robust automatic algorithms to objectively classify these signals would be useful. The aim of this study was to evaluate Shannons entropy (ShEn) and the Kolmogorov‐Smirnov (K‐S) test as a measure of signal complexity and to compare these measures with fractional intervals (FI) in distinguishing CFAE from non‐CFAE signals.

Targeted G-Protein Inhibition as a Novel Approach to Decrease Vagal Atrial Fibrillation by Selective Parasympathetic Attenuation

AIMS The parasympathetic nervous system is thought to play a key role in atrial fibrillation (AF). Since parasympathetic signalling is primarily mediated by the heterotrimeric G-protein, Galpha(i)betagamma, we hypothesized that targeted inhibition of Galpha(i) interactions in the posterior left atrium (PLA) would modify the substrate for vagal AF. METHODS AND RESULTS Cell-penetrating(cp)-Galpha(i)1/2 and cp-Galpha(i)3 C-terminal peptides were assessed for their ability to attenuate cholinergic-parasympathetic signalling in isolated feline atrial myocytes and in canine left atrium (LA). Confocal fluorescence microscopy indicated that cp-Galpha(i)1/2 and/or cp-Galpha(i)3 peptides moderated carbachol attenuation of cellular Ca(2+) transients in isolated atrial myocytes. High-density epicardial mapping of dog PLA, left atrial pulmonary veins (PVs), and left atrial appendage (LAA) indicated that the delivery of cp-Galpha(i)1/2 peptide or cp-Galpha(i)3 peptide into the PLA prolonged effective refractory periods at baseline and during vagal stimulation in the PLA and to varying extents also in the LAA and PV regions. After delivery of cp-Galpha(i) peptides into the PLA, AF inducibility during vagal stimulation was significantly diminished. CONCLUSION These results demonstrate the feasibility of using specific G(i)-protein inhibition to achieve selective parasympathetic denervation in the PLA, with a resulting change in vagal responsiveness across the entire LA.

Left Atrial Geometry Improves Risk Prediction of Thromboembolic Events in Patients With Atrial Fibrillation.

Left atrial (LA) sphericity (LASP) is a new remodeling parameter based on LA shape analysis, with independent predictive value for recurrence after atrial fibrillation (AF) ablation.

Cardiac Magnetic Resonance for Risk Stratification: The Sudden Death Risk Portrayed

Risk stratification of patients with structural heart disease remains problematic. While patients with low ejection fractions have been shown to be at significant risk for sudden cardiac death, a risk that can be decreased by ICD implantation, the sensitivity and specificity of ejection fraction for predicting sudden death are sub-optimal. Contrast enhanced magnetic resonance imaging (CMRI) has been shown to carefully delineate the extent and morphology of myocardial scar. Recent studies have suggested that the extent of myocardial scar and potentially its heterogeneity can help risk stratify patient with coronary artery disease. Ongoing clinical studies will help determine the utility of incorporating CMRI into a risk prediction algorithm.

Assessment of Smith Algorithms for the Diagnosis of Acute Myocardial Infarction in the Presence of Left Bundle Branch Block

INTRODUCTION AND OBJECTIVES Recently, a new electrocardiography algorithm has shown promising results for the the diagnosis of acute myocardial infarction in the presence of left bundle branch block (LBBB). We aimed to assess these new electrocardiography rules in a cohort of patients referred for primary percutaneous coronary intervention (pPCI). METHODS Retrospective observational cohort study that included all patients with suspected myocardial infarction and LBBB on the presenting electrocardiogram, referred for pPCI to 4 tertiary hospitals in Barcelona, Spain. RESULTS A total of 145 patients were included. Fifty four (37%) had an ST-segment elevation myocardial infarction (STEMI) equivalent. Among patients with STEMI, 25 (46%) presented in Killip class III or IV, and in-hospital mortality was 15%. Smith I and II rules performed better than Sgarbossa algorithms and showed good specificity (90% and 97%, respectively) but their sensitivity was 67% and 54%, respectively. In a strategy guided by Smith I or Smith II rules, 18 (33%) or 25 (46%) patients with STEMI would have not received a pPCI, respectively. Moreover, the severity and prognosis of STEMI patients was similar regardless of the positivity of Smith rules. Cardiac biomarkers were positive in 54% of non-STEMI patients, limiting their usefulness for initial diagnostic screening. CONCLUSIONS Diagnosis of STEMI in the presence of LBBB remains a challenge. Smith rules can be useful but are limited by suboptimal sensitivity. The search for new electrocardiography algorithms should be encouraged to avoid unnecessary aggressive treatments in the majority of patients, while providing timely reperfusion to a high-risk subgroup of patients.

Left atrial geometry and outcome of atrial fibrillation ablation: results from the multicentre LAGO-AF study

Aims Left atrial (LA) remodelling is a key determinant of atrial fibrillation (AF) ablation outcome. Optimal methods to assess this process are scarce. LA sphericity is a shape-based parameter shown to be independently associated to procedural success. In a multicentre study, we aimed to test the feasibility of assessing LA sphericity and evaluate its capability to predict procedural outcomes. Methods and results This study included consecutive patients undergoing first AF ablation during 2013. A 3D model of the LA chamber, excluding pulmonary veins and LA appendage, was used to quantify LA volume (LAV) and LA sphericity (≥82.1% was considered spherical LA). In total, 243 patients were included across 9 centres (71% men, aged 56 ± 10 years, 44% with hypertension and 76% CHA2DS2-VASc ≤ 1). Most patients had paroxysmal AF (66%) and underwent radiofrequency ablation (60%). Mean LA diameter (LAD), LAV, and LA sphericity were 42 ± 6 mm, 100 ± 33 mL, and 82.6 ± 3.5%, respectively. Adjusted Cox models identified paroxysmal AF [hazard ratio (HR 0.54, P = 0.032)] and LA sphericity (HR 1.87, P = 0.035) as independent predictors for AF recurrence. A combined clinical-imaging score [Left Atrial Geometry and Outcome (LAGO)] including five items (AF phenotype, structural heart disease, CHA2DS2-VASc ≤ 1, LAD, and LA sphericity) classified patients at low (≤2 points) and high risk (≥3 points) of procedural failure (35% vs. 82% recurrence at 3-year follow-up, respectively; HR 3.10, P < 0.001). Conclusion In this multicentre, real-life cohort, LA sphericity and AF phenotype were the strongest predictors of AF ablation outcome after adjustment for covariates. The LAGO score was easy to implement, identified high risk of procedural failure, and could help select optimal candidates. Clinical Trial Registration Information NCT02373982 (http://clinicaltrials.gov/ct2/show/NCT02373982).

Iatrogenic pleuropericardial communication: A rare complication of percutaneous epicardial mapping

Ablation of ventricular tachycardia (VT) is a wellestablished treatment for patients with recurrent implantable cardioverter-defibrillator shocks. Epicardial access is increasingly performed when epicardial arrhythmogenic substrate is suspected and may be considered as a first-line approach in the subset of myocardial diseases with preferential epicardial substrate, namely, idiopathic dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia, or chagasic cardiomyopathy. Cardiac complications of this approach include right ventricular puncture, pericardial bleeding, coronary vessel damage, and pericarditis. Damage to extracardiac structures may occur during puncture, mapping, and ablation; deep knowledge of the anatomic relationships of the heart and prompt recognition of complications are paramount to minimize procedural risk. We report the first case of acute iatrogenic pleuropericardial communication during epicardial mapping in a patient with chagasic cardiomyopathy.

Importance of sudden cardiac death risk stratification in hypertrophic cardiomyopathy. Response.

We are grateful for the comments of Martinez-Moreno et al in relation to our work on the results of implantable cardioverterdefibrillator (ICD) implantation in hypertrophic cardiomyopathy. Whilst it is true that our study was a small series with a relatively short follow-up, we believe that it was representative of the hypertrophic cardiomyopathy population in nonspecialized centers. This nonspecialization would explain the low rate of appropriate therapies compared with that in previous studies, which are from large specialized centers attending patients with the most severe disease. The authors’ observations are appropriate, given the recent publication of the new European Society of Cardiology guidelines on hypertrophic cardiomyopathy, which recommend the use of HCM Risk-SCD, a new tool for evaluating sudden cardiac death risk, which naturally was not used in our cohort when the decision was made on ICD implantation. We calculated this risk a posteriori in the 48 primary prevention patients from our cohort, with the following results: 12 patients (25%) would have had a calculated risk of < 4%, and therefore no indication for ICD implantation according to the new guidelines; 7 patients (14.6%) would have had a risk of between 4% and 6% (class IIb ICD indication), and 29 patients (60.4%) would have had a risk > 6% (class IIa indication). Interestingly, the 3 patients in our cohort who received appropriate therapies would have had a risk of > 6%. Had we applied the new guidelines to our cohort, we would have ‘‘saved’’ ICD implantation in 39.6% of the patients, who, in addition, had received no shocks at the time of follow-up. Also, as noted in the original article, secondary prevention patients have a paradoxically low risk profile, and although HCM Risk-SCD is not valid for secondary prevention, in which ICD implantation has a class I indication, we calculated the risk for our cohort patients, using the data available. All patients would have had a theoretical risk of < 6%, and consequently would have had no indication for ICD prior to their episode of ventricular arrhythmia. We agree that HCM Risk-SCD improves patient selection in those with 1 or more risk factors, but it does not solve the problem that many sudden cardiac deaths occur in patients who are theoretically low risk, and so cannot be identified using tools based on classic risk factors. It surprises us that, in the development of HCM Risk-SCD, there was no evaluation of imaging (such as fibrosis on magnetic resonance), electrophysiological, or genetic parameters, which could help to better identify at risk patients in the future.

Implantable Cardioverter-defibrillator Therapy for Hypertrophic Cardiomyopathy: Usefulness in Primary and Secondary Prevention.

INTRODUCTION AND OBJECTIVES Hypertrophic cardiomyopathy is a frequent cause of sudden death. Clinical practice guidelines indicate defibrillator implantation for primary prevention in patients with 1 or more risk factors and for secondary prevention in patients with a history of aborted sudden death or sustained ventricular arrhythmias. The aim of the present study was to analyze the follow-up of patients who received an implantable defibrillator following the current guidelines in nonreferral centers for this disease. METHODS This retrospective observational study included all patients who underwent defibrillator implantation between January 1996 and December 2012 in 3 centers in the province of Barcelona. RESULTS The study included 69 patients (mean age [standard deviation], 44.8 [17] years; 79.3% men), 48 in primary prevention and 21 in secondary prevention. The mean number of risk factors per patient was 1.8 in the primary prevention group and 0.5 in the secondary prevention group (P=.029). The median follow-up duration was 40.5 months. The appropriate therapy rate was 32.7/100 patient-years in secondary prevention and 1.7/100 patient-years in primary prevention (P<.001). Overall mortality was 10.1%. Implant-related complications were experienced by 8.7% of patients, and 13% had inappropriate defibrillator discharges. CONCLUSIONS In patients with a defibrillator for primary prevention, the appropriate therapy rate is extremely low, indicating the low predictive power of the current risk stratification criteria.