Rishi Arora

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.

Quantitative analysis of parasympathetic innervation of the porcine heart

BACKGROUND Parasympathetic control of the heart is an important component in the regulation of normal cardiac function. However, the anatomic course of parasympathetic innervation of the heart is unclear. OBJECTIVE The purpose of this study was to apply a gross parasympathetic nerve stain technique to reveal the details of the morphology of the cardiac parasympathetic nervous system. METHODS Ten whole pig hearts were stained using a histochemical method. Immediately after sacrifice, hearts were placed in a buffered solution containing acetylthiocholine, which precipitates with acetylcholinesterase, allowing identification of cholinergic nerves. The epicardial and endocardial surfaces of the atria and ventricles were examined for nerve thickness and density. RESULTS In both atria, nerve density was significantly greater on the endocardium, but nerve thickness was significantly greater on the epicardium. The right atrium (RA) was more densely innervated than the left atrium (LA) on the endocardium, whereas the LA was more densely innervated than the RA on the epicardium. In the ventricles, numerous thick cholinergic nerves were clearly identifiable across the epicardium, generally running parallel to the left anterior descending artery. The endocardial surfaces of the ventricles revealed a dense network of fine parasympathetic nerve fibers. As in the atria, nerve density was greater on the ventricular endocardium, but nerve thickness was greater on the epicardium. The right ventricle (RV) was more densely innervated than the left ventricle (LV), whereas the LV endocardium was more densely innervated than the RV endocardium. CONCLUSION The epicardial and endocardial surfaces of the atria and ventricles are richly innervated by parasympathetic nerves. The density of parasympathetic innervation is heterogeneous across both the epicardial and endocardial surfaces of the heart.

Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.

Background: Abnormalities in intracellular calcium (Ca) cycling during Ca overload can cause triggered activity because spontaneous calcium release (SCR) activates sufficient Ca-sensitive inward currents to induce delayed afterdepolarizations (DADs). However, little is known about the mechanisms relating SCR and triggered activity on the tissue scale. Methods and Results: Laser scanning confocal microscopy was used to measure the spatiotemporal properties of SCR within large myocyte populations in intact rat heart. Computer simulations were used to predict how these properties of SCR determine DAD magnitude. We measured the average and standard deviation of the latency distribution of SCR within a large population of myocytes in intact tissue. We found that as external [Ca] is increased, and with faster pacing rates, the average and SD of the latency distribution decreases substantially. This result demonstrates that the timing of SCR occurs with less variability as the sarcoplasmic reticulum (SR) Ca load is increased, causing more sites to release Ca within each cell. We then applied a mathematical model of subcellular Ca cycling to show that a decrease in SCR variability leads to a higher DAD amplitude and is dictated by the rate of SR Ca refilling following an action potential. Conclusions: Our results demonstrate that the variability of the timing of SCR in a population of cells in tissue decreases with SR load and is dictated by the time course of the SR Ca content.

Use of an electrocardiographic screening tool to determine candidacy for a subcutaneous implantable cardioverter-defibrillator

BACKGROUND An electrocardiographic (ECG) screening test has been developed to identify patients being considered for a totally subcutaneous implantable cardioverter-defibrillator (S-ICD) at risk for T-wave oversensing. OBJECTIVE The purpose of this study was to determine the proportion of potential S-ICD recipients who fail the ECG screening test and to identify predictors of failure. METHODS Patients who already have an ICD but are not receiving antibradycardia pacing are representative of patients who might be considered for an S-ICD. One hundred such outpatients were enrolled in the study. Surface rhythm strips were recorded along the sensing vectors of the S-ICD system and the screening template applied. Clinical and standard ECG characteristics of patients who failed the test were compared to those who passed. RESULTS Patients had the following characteristics: 72% male, age 57 ± 16 years, body mass index 29 ± 6 kg/m(2), left ventricular ejection fraction 43% ± 17%, QRS duration 109 ± 23 ms, QTc interval 447 ± 39 ms, 44% had coronary disease, and 55% had heart failure. Among the 100 patients, 8% failed the screening test. There were no differences in patient clinical characteristics and most standard ECG measurements. However, patients with T-wave inversions in standard ECG leads I, II, and aVF had a 45% chance of failing. CONCLUSION Eight percent of potential S-ICD patients were not eligible for the S-ICD after failing the screening test designed to identify patients susceptible to T-wave oversensing. Patients with T-wave inversions in leads I, II, and aVF on a standard ECG were 23 times more likely to fail. More work is needed in S-ICD sensing algorithms to increase patient eligibility for the S-ICD.

Where does atrial fibrillation surgery fail? Implications for increasing effectiveness of ablation

OBJECTIVE Surgical ablation of atrial fibrillation is generally safe and effective, but atrial fibrillation redevelops in approximately 20% of patients. We sought to determine anatomic factors, technology factors, or both that contribute to these failures. METHODS Four hundred eight patients underwent 5 types of atrial fibrillation ablation depending on their atrial fibrillation history and need for concomitant surgical intervention: the classic maze procedure, high-intensity focused ultrasound, the left atrial maze procedure, the biatrial maze procedure, and pulmonary vein isolation. Ninety-five percent of patients with preoperative atrial fibrillation underwent surgical ablation. RESULTS Patients undergoing high-intensity focused ultrasound had a high rate of late postoperative percutaneous ablation (37.5%) after surgical intervention (P < .001 vs the other groups). At last follow-up, freedom from atrial fibrillation and need for ablation was as follows: classic maze procedure, 90%; high-intensity focused ultrasound, 43%; left atrial maze procedure, 79%; biatrial maze procedure, 79%; and pulmonary vein isolation, 69% (P < .001 between groups). For those with atrial fibrillation, mapping and ablation were performed in 23.6% (n = 27), and all patients with high-intensity focused ultrasound had failure of the box lesion around the pulmonary veins. Of those with just the left atrial maze procedure or pulmonary vein isolation, the right atrium was the source for failure in 75% (6/8). CONCLUSIONS Patients undergoing high-intensity focused ultrasound had a high need for postoperative ablation and low freedom from atrial fibrillation. The classic maze procedure had the best results. Left atrial ablation might allow failure from right atrial foci. Matching the technology and lesion set to the patient yields good results and can be applied in 95% of patients. We suggest others obtain late catheter ablation to correct remaining atrial fibrillation, and add to the paucity of late data regarding failure mode.

Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate

Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with the evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years before the onset of AF, there is no current evaluation to identify the preclinical atrial myopathy. Atrial fibrosis is 1 component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding the success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. Although thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new-onset AF and suggest specific pathways that could be targeted for prevention.

Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure

Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca(2+) transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca(2+) cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca(2+) transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca(2+) cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.

Spatiotemporal characterization of atrial activation in persistent human atrial fibrillation: multisite electrogram analysis and surface electrocardiographic correlations--a pilot study.

BACKGROUND The mechanisms of persistent human atrial fibrillation (AF) are not well understood. OBJECTIVE The purpose of this study was to examine whether left atrial (LA) drivers are present in persistent AF by performing a comprehensive evaluation of atrial activation frequency and organization using multisite atrial recordings and correlating the findings with atrial waveform frequency and organization on surface ECG. METHODS Nine patients undergoing catheter ablation for persistent AF were studied. Electrograms were recorded from at least 10 sites in each atrium, tagged to an electroanatomic map, and subjected to spectral analysis. Dominant frequency (DF) and regularity index were calculated at each site. Surface ECG recordings were analyzed to obtain precordial lead DFs and AF vector stability index. RESULTS Mean, maximum, and minimum DF and mean regularity index were higher in LA than right atrium (RA). DF was correlated with regularity index (R = 0.59, P <.0001) and negatively correlated with distance from maximal DF site (R = -0.80, P <.0001). Precordial lead DFs were highly correlated with atrial DFs. Vector stability index was 0.39 +/- 0.12 (P <.01 vs predicted if AF vector direction was random). LA-RA DF gradient and vector stability index were negatively correlated (R = -0.83, P <.05). CONCLUSION The existence of LA-RA frequency gradients in most patients in this study along with the regularity of LA activation and centrifugal dissipation of activation frequency suggest that LA drivers are often present in persistent AF. Analysis of AF vectors from surface ECG demonstrates spatial stability and correlates with intracardiac recordings. These findings may have implications for catheter ablation of persistent AF.

Early development of intracellular calcium cycling defects in intact hearts of spontaneously hypertensive rats.

Defects in excitation-contraction coupling have been reported in failing hearts, but little is known about the relationship between these defects and the development of heart failure (HF). We compared the early changes in intracellular Ca(2+) cycling to those that underlie overt pump dysfunction and arrhythmogenesis found later in HF. Laser-scanning confocal microscopy was used to measure Ca(2+) transients in myocytes of intact hearts in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) at different ages. Early compensatory mechanisms include a positive inotropic effect in SHRs at 7.5-9 mo compared with 6 mo. Ca(2+) transient duration increased at 9 mo in SHRs, indicating changes in Ca(2+) reuptake during decompensation. Cell-to-cell variability in Ca(2+) transient duration increased at 7.5 mo, decreased at 9 mo, and increased again at 22 mo (overt HF), indicating extensive intercellular variability in Ca(2+) transient kinetics during disease progression. Vulnerability to intercellular concordant Ca(2+) alternans increased at 9-22 mo in SHRs and was mirrored by a slowing in Ca(2+) transient restitution, suggesting that repolarization alternans and the resulting repolarization gradients might promote reentrant arrhythmias early in disease development. Intercellular discordant and subcellular Ca(2+) alternans increased as early as 7.5 mo in SHRs and may also promote arrhythmias during the compensated phase. The incidence of spontaneous and triggered Ca(2+) waves was increased in SHRs at all ages, suggesting a higher likelihood of triggered arrhythmias in SHRs compared with WKY rats well before HF develops. Thus serious and progressive defects in Ca(2+) cycling develop in SHRs long before symptoms of HF occur. Defective Ca(2+) cycling develops early and affects a small number of myocytes, and this number grows with age and causes the transition from asymptomatic to overt HF. These defects may also underlie the progressive susceptibility to Ca(2+) alternans and Ca(2+) wave activity, thus increasing the propensity for arrhythmogenesis in HF.

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.