Atrial Arrhythmogenic Substrate Research Articles

Inhibition of the acetylcholine-regulated potassium current prevents transient apnea-related atrial arrhythmogenic changes in a porcine model

BackgroundMore than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient, vagally mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs. ObjectiveThe purpose of this study was to investigate the effect of pharmacologic inhibition of the G-protein–gated acetylcholine-regulated potassium current (IK,ACh) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events. MethodsIn 21 pigs, SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by an S1S2 atrial pacing-protocol. Pigs were randomized into 3 groups—group 1: vehicle (n = 4); group 2: XAF-1407 (IK,ACh inhibitor) (n = 7); and group 3: nicotine followed by XAF-1407 (n = 10). ResultsIn group 1, INAP shortened aERP (ΔaERP –42.6 ms; P = .004) and transiently increased AF inducibility from 0% to 31%. In group 2, XAF-1407 prolonged aERP by 25.2 ms (P = .005) during normal breathing and prevented INAP-induced aERP shortening (ΔaERP –3.6 ms; P = .3) and AF inducibility. In group 3, INAP transiently shortened aERP during nicotine perfusion (ΔaERP –33.6 ms; P = .004) and increased AF inducibility up to 61%, which both were prevented by XAF-1407. ConclusionSimulated obstructive respiratory events transiently shorten aERP and increase AF inducibility, which can be prevented by the IK,ACh-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether IK,ACh channels represent a target for SDB-related AF in humans warrants further study.

Abstract 18225: Left Atrial Volume Index and Outcomes in Paroxysmal Atrial Fibrillation (pAF) in the Real-AF Registry

Introduction: Catheter ablation via pulmonary vein isolation Is one of the most commonly performed procedures for treating paroxysmal atrial fibrillation (pAF). Left atrium size affects ablation strategies and outcomes in patients with pAF. We analyzed the left atrium index (LAi) to determine associations with recurrent arrhythmias at 12 months post-ablation and the ablation strategies used. Methods: The Real-world Experience of Catheter Ablation for the Treatment of Symptomatic Paroxysmal (pAF) and Persistent (PsAF) Atrial Fibrillation registry (Real-AF) is a multicenter prospective registry that is enrolling patients undergoing AF ablation at high-volume centers. Left atrial volume was reconstructed using CARTO 3D. LAi was separated into normal range: < 34 ml/m2, mildly enlarged 35 - 41 ml/m2, moderately enlarged 42 - 48 ml/m2, and severely enlarged > 49 ml/m2 based on the American Society of Echocardiogram guidelines. Ablation strategies were divided into pulmonary vein isolation (PVI) alone or PVI+ ablation, including PVI and additional atrial arrhythmogenic substrates. Recurrence of arrhythmias at 12 months post-ablation and ablation strategies were compared. Results: A total of 1824 were included. In patients with pAF 12.2% developed recurrent arrhythmia at 12 months. When compared to normal LAi, patients with pAF with moderately and severely enlarged LAi were more likely to have a recurrence of arrhythmias at 12 months (Table 1). Women with pAF and moderately and severely enlarged LAi were more likely to have recurrence of arrhythmias (Table 1). A total of 1433 underwent PVI only ablations, and 391 underwent PVI+ ablations. Abnormal LAi was also associated with patients undergoing PVI+ ablations compared to PVI only ablations (Table 1). Conclusions: In patients with pAF and abnormal LA size was associated with more recurrent arrhythmias at 12 months post-ablation. Patients with enlarged LAi were more likely to have PVI+ ablations.

Abstract 13928: Targeted Atrial Inhibition of Galphaq Signaling With Inhibitory Peptides Attenuates Fibrosis and Inducibility of Atrial Fibrillation in a Canine Heart Failure Model

Introduction: Endothelial dysfunction, a hallmark of heart failure (HF), is closely associated with atrial fibrillation (AF). However, the precise role of endothelial dysfunction in creating an atrial arrhythmogenic substrate is unknown. Endothelin-1 (ET-1) and its downstream Gα q signaling are significantly upregulated in the atria of patients with HF. We therefore hypothesized that ET-1-Gα q signaling contributes to adverse structural remodeling in the atria in the setting of HF. Hypothesis: Inhibition of atrial ET-1-Gα q signaling with Gα q inhibitory peptides (Gα q -ct) will attenuate the development of atrial fibrosis and AF inducibility in a HF model. Methods: Plasmids expressing Gα q -ct were injected and electroporated in the left atria of 4 dogs. LacZ or scrambled plasmids were used in 8 control dogs. HF was induced by ventricular tachypacing (VTP) at 240 bpm for 3 weeks. At terminal EP study, left atrial conduction vectors were recorded with high-density mapping and AF inducibility assessed. Left atrial fibrosis was quantified by Masson Trichrome. Results: All animals developed clinical HF (prolonged capillary refill time, ascites, reduced activity level) and LV systolic dysfunction by echocardiogram (LVEF 17.5±8.3% in Gα q -ct, 13.7±3.1% in controls, p=0.55). Conduction inhomogeneity was reduced in Gα q -ct animals (example of posterior left atrium recordings in Fig. A). AF was less inducible in Gα q -ct than control animals (4.8% of pacing attempts Vs 17.8%, p<0.001, Fig. B) and AF episodes were shorter (5.6±0.9 sec Vs 63.8±11.9 sec). Left atrial fibrosis was significantly attenuated in Gα q -ct animals Vs controls (Fig. C). Conclusions: Gα q signaling contributes to atrial fibrosis and subsequent AF susceptibility in VTP-induced HF, thereby highlighting an important role for ET-1 signaling in HF-related atrial remodeling. Future optimization of gene therapy targeting ET-1 signaling may lead to novel, mechanism-guided treatments for AF in the context of HF.

Does the spatial distribution of atrial arrhythmogenic substrate matter? Insights from the DECAAF II trial.

Does the spatial distribution of atrial arrhythmogenic substrate matter? Insights from the DECAAF II trial.

Local conduction velocities determined by non-invasive electrocardiographic imaging predict arrhythmia-free survival after pulmonary vein isolation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This project has received funding from the European Union's Horizon Research and Innovation Programme under the Marie-Sklodowska Curie Grant Agreement No. 860974 Background Recurrence rates after atrial fibrillation (AF) ablation are still unsatisfactory. As catheter ablation is primarily targeting pulmonary vein (PV) ectopic activity, it is not surprising that extra-PV arrythmogenic substrate is a key determinant of arrhythmia recurrence. Against this background, several studies have proposed assessment of extra-PV substrate in terms of atrial fibrosis or locally reduced conduction velocities (CV) to guide treatment. However, to date no non-invasive method directly assessing electrical arrhythmogenic substrate has been established in clinical practice, and treatment decisions are commonly based on crude surrogates like AF type or left atrial size. Here we establish and validate a novel non-invasive method based on electrocardiographic imaging (ECGi) to determine atrial arrhythmogenic substrate in terms of reduced local CVs and its predictive value regarding arrhythmia recurrence after PVI. Methods and results 52 consecutive patients scheduled for AF ablation (PVI-only) and 19 healthy controls were prospectively included and received ECGi to assess left and right atrial arrhythmogenic substrate. This ECGi-based method uses 64 electrodes placed on the torso. Subsequently, a 3D model of the torso is acquired as an anatomical reference using a 3D reconstruction camera. A personalised 3D atrial geometry is then derived from a database of human atria using an artificial intelligence-based algorithm. Finally, unipolar surface electrograms are projected onto the cardiac geometry and local CVs are estimated. Mean ECGi-determined atrial CVs were significantly lower in AF patients than in healthy controls, both in a global analysis (1.45±0.15 m/s vs. 1.64±0.15 m/s; p<0.0001) and a regional analysis of 19 predefined left and right atrial segments (Fig. 1). Considering only the segments with the lowest average CV in each patient, differences in CVs were more pronounced (0.80±0.22 vs. 1.08±0.26 m/s; p<0.0001). Multivariate logistic regression analyses combined with c-statistics including other previously proposed predictors found this mean CV of the "slowest" segment to be the strongest predictor of arrhythmia recurrence. A ROC analysis revealed that a cut-off for this variable of 0.72 m/s best discriminates PVI responders from non-responders: patients with a mean CV >0.72 m/s in all atrial regions showed a 6-months arrhythmia-free survival of 90.9%, whereas patients with one or more atrial regions with a mean CV <0.72 m/s had a poor outcome with an arrhythmia-free survival rate of only 57.9% (Fig. 2). Conclusion This was the first study to investigate local atrial CV non-invasively and to validate their predictive value regarding outcome after PVI. The absence of ECGi-determined areas of slow conduction well discriminated PVI responders from non-responders. Such non-invasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and be an important step towards personalised AF therapy.

PO-02-243 IMPACT OF PARTIAL CONSTRICTION OF THE ARTERIAL PULMONARY TRUNK ON THE DEVELOPMENT OF SUSCEPTIBILITY TO ATRIAL FIBRILLATION IN RATS

Atrial Fibrillation (AF) is the most frequent and clinically important form of cardiac arrhythmia. It has been demonstrated that cardiovascular comorbidities such as myocarditis, myocardial infarction, obesity, or pulmonary hypertension (PH) promote cardiac remodeling associated with the development of atrial arrhythmogenic substrates. Right-heart disease (RHD), characterized by chronic right-sided cardiac structural and functional anomalies, has also been designated among AF risk factors. Inflammation is one of the common denominators between cardiovascular risk factors and AF vulnerability. However, no study has described the progression of the molecular and cellular changes involved in the causal link relating RHD, the activation of atrial inflammation, and the development of AF substrate. This study aims to establish the characterization of the progression of atrial arrhythmogenic inflammation in a rat model of RHD. Hypothesis Permanent constriction of the pulmonary artery trunk (PAT) provokes severe RHD associated with progressive atrial inflammation and fibrosis responsible for enhanced AF vulnerability. Pulmonary Artery Banding (PAB) reducing the PAT diameter to 1 mm, was surgically performed on 225-275g Wistar rats to induce permanent PH and severe RHD. Sham animals received PAB-mimicking intervention without ligation. Echocardiography and electrophysiological studies (EPS) were performed in vivo, on all the animals at Day0, Day7, Day14 and Day21 post-surgery. The atrial tissues were analyzed by optical mapping, histology (Masson's Trichrome), qPCR and immunoblotting. Within three weeks, PAB rats developed severe right heart remodeling characterized by progressive ventricular and atrial hypertrophy and dilation. Right atrial (RA) optical mapping revealed a reduction in conduction velocity and refractory periods in PAB rats compared to Sham. PAB rats were more vulnerable to AF than Sham starting at 7th-day until the 21st-day post-surgery. Histological analysis shows that since the 14th day until the 21st-day post-surgery RA fibrosis significantly increased in PAB rats compared to sham. Quantitative polymerase chain reaction performed on inflammation and fibrosis-related genes such as IL6, Tgfb1 or Col1a1 revealed a progressive aggravation of RA inflammatory and fibrotic status in PAB rats from Day7, Day14 to Day2 Severe RHD is associated with progressive and unresolved RA inflammation and fibrosis provoking an aggravation of AF vulnerability overtime

Mechanisms and Management of Thyroid Disease and Atrial Fibrillation: Impact of Atrial Electrical Remodeling and Cardiac Fibrosis.

Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with increased cardiovascular morbidity and mortality. The pathophysiology of AF is characterized by electrical and structural remodeling occurring in the atrial myocardium. As a source of production of various hormones such as angiotensin-2, calcitonin, and atrial natriuretic peptide, the atria are a target for endocrine regulation. Studies have shown that disorders associated with endocrine dysregulation are potential underlying causes of AF. The thyroid gland is an endocrine organ that secretes three hormones: triiodothyronine (T3), thyroxine (T4) and calcitonin. Thyroid dysregulation affects the cardiovascular system. Although there is a well-established relationship between thyroid disease (especially hyperthyroidism) and AF, the underlying biochemical mechanisms leading to atrial fibrosis and atrial arrhythmias are poorly understood in thyrotoxicosis. Various animal models and cellular studies demonstrated that thyroid hormones are involved in promoting AF substrate. This review explores the recent clinical and experimental evidence of the association between thyroid disease and AF. We highlight the current knowledge on the potential mechanisms underlying the pathophysiological impact of thyroid hormones T3 and T4 dysregulation, in the development of the atrial arrhythmogenic substrate. Finally, we review the available therapeutic strategies to treat AF in the context of thyroid disease.

Atrial fibrillation post-coronary or cardiac surgery: A transient inflammation-related event or the expression of a pre-existing arrhythmogenic atrial substrate?

Atrial fibrillation post-coronary or cardiac surgery: A transient inflammation-related event or the expression of a pre-existing arrhythmogenic atrial substrate?

Predictors of the voltage derived left atrial fibrosis in patients with long-standing persistent atrial fibrillation.

BackgroundLeft atrial (LA) arrhythmogenic substrate beyond the pulmonary veins (PV) seems to play a crucial role in the maintenance of atrial fibrillation (AF). The aim of this study was to evaluate the association of selected parameters with the presence and extent of voltage-defined LA fibrosis in patients with long-standing persistent AF (LSPAF) undergoing catheter ablation.MethodsOne hundred and sixteen consecutive patients underwent high density-high resolution voltage mapping of the LA with a multielectrode catheter following PV isolation and restoration of sinus rhythm with cardioversion. A non-invasive dataset, such as clinical variables, two- and three-dimensional echocardiography determined LA size and function and fibrillatory-wave amplitude on a standard surface electrocardiogram were obtained during AF before ablation.ResultsLow-voltage areas (LVA; 15 cm2 [IQR 8–31]) were detected in 56% of patients. Twenty nine percent of them presented mild, 43% moderate and 28% severe global LVA burden. In univariate analysis, age ≥ 57 years old, female sex, body surface area ≤ 1.76 m2, valvular heart disease, moderate mitral regurgitation, chronic coronary syndrome, hypothyroidism, CHA2DS2-VASc score ≥ 3 and ≥ 4 predicted the presence of LVA. In multivariate analysis only female sex, valvular heart disease and CHA2DS2-VASc ≥ 4 remained statistically significant. AF duration, LA size and function and fibrillatory-waves amplitude were neither associated with the prediction of the LVA, nor severe LVA burden.ConclusionsA LSPAF diagnosis does not indicate the presence of voltage defined fibrosis in many cases. Simple non-invasive screening of the LSPAF population could predict LVA prevalence.

Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD.

In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown. Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated glomerular filtration rate [eGFR], <60 mL/min per 1.73 m2) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red. Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function. In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure.

Artificially Created Reentry Circuit by Laser Irradiation Causes Atrial Tachycardia to Persist in Murine Atria.

There is a gradual progression from paroxysmal to persistent atrial fibrillation (AF) in humans. To elucidate the mechanism involved, the creation of an artificial atrial substrate to persist AF in mice was attempted.Methods and Results:This study used wild type (WT) mice, but it is difficult to induce AF in them. A novel antegrade perfusion method from the left ventricle (LV) to enlarge both atria for artificial atrial modification was proposed in this study. Short duration AF was induced by burst pacing under this method. Optical mapping analysis revealed non-sustained focal type and meandering spiral reentrants after short duration AF. A tiny artificial substrate (~1.2 mm in diameter) was added in by laser irradiation to create a critical atrial arrhythmogenic substrate. Burst pacing was performed in a non-laser group (n=8), a circular-shape laser group (n=8), and a wedge-shaped dent laser group (n=8). We defined AF and atrial tachycardia (AT) as atrial arrhythmia (AA). Long-lasting AA was defined as lasting for ≥30 min. Long-lasting AA was observed in 0/8, 0/8, and 6/8 (75%) mice in each group. Optical mapping analysis revealed that the mechanism was AT with a stationary rotor around the irradiated margin. Regrettably, this study failed to reproduce persistent AF, but succeeded in creating an arrhythmic substrate that causes sustained AT in WT mice.

Abstract 12053: Age is a Predictor of Right Atrial Drivers in Human Persistent Atrial Fibrillation

Introduction: Persistent atrial fibrillation (perAF) may be maintained by localized extra-pulmonary vein (PV) drivers. Most clinical studies have focused on left atrial (LA) sources ablation, but right atrial (RA) arrhythmogenic substrate, due to certain comorbidities, may also maintain perAF. Hypothesis: Patient (Pt)-specific characteristics and comorbidities may predict occurrence of RA AF drivers. Methods: Consecutive Pts (n=105) underwent driver ablation in addition to PV isolation for perAF after panoramic multi-electrode mapping (MEM) at a single medical center. Logistic regression (LR) models were used to characterize the relationship between Pt characteristics and presence of AF drivers in each atrium. LR was used to predict 12-month AF-free survival. Results: Pts were 63.1±9.9 years old, 24.8% female, 21.9% in HF, 76.2% had HTN, 24.8% had DM, 22.9% had CAD and 59.0% had OSA. MEM identified a mean of 1.6±1.2 LA drivers and 1.4±1.2 RA drivers per Pt. Forty two Pts had drivers in both LA and RA, 19 in RA only, and 26 in LA only. Older age was a predictor of RA drivers presence (p=0.06), factors that predicted presence of LA drivers were female gender (p=0.19), HTN (p=0.03), and comorbidity score (p = 0.07). CHADS 2 -VASc score and LVEF predicted both LA and RA drivers. Following ablation, 75% of the Pts sustained sinus rhythm after 6 months, 70% after 12 months and 72% after 18 months. AF recurrence within 12 months of ablation was associated with DM (p=0.03), BMI (p=0.03) and RV systolic pressure (p=0.07). Presence of RA drivers was not associated with the 12 and 18-months freedom from AF. Conclusions: In this cohort of perAF patients, older age and higher CHADS 2 -VASc score predicted RA driver occurrence. These preliminary findings suggest that patient-specific clinical characteristics may uniquely impact LA vs RA myocardium by promoting development of chamber-specific arrhythmogenic structural and functional substrates of AF drivers.

B-011-04 ABLATION SCAR IN A SINGLE PULMONARY VEIN CAUSES PROARRHYTHMIC MECHANICAL DESTABILIZATION IN HEALTHY SHEEP ATRIA

Atrial and pulmonary vein (PV) stretch is proarrhythmic, but the mechanical effect of PV ablation scar on atrial fibrillation (AF) arrhythmogenesis is unknown. We hypothesize that discontinuous PV ablation scars are proarrhythmic because they create heterogeneous stretch. To measure local atrial strain and AF inducibility in healthy sheep hearts with and without PV ablation scar. Functional cardiac MRIs acquired in vivo in sheep (n=12) before and 3 months after discontinuous PV ablation by radiofrequency in the right PV (RPV) were analyzed with a feature-tracking algorithm to obtain local strain in the left atrium (LA). Explanted hearts were perfused with 1:4 blood:Tyrode’s solution in a dual-chamber working-heart set-up. Multi-electrode endocardial catheters were positioned in the RPV and left PV (LPV) for premature stimulation during low (∼12mmHg) and high (∼25mmHg) LA pressure. Control hearts (n=12) underwent similar ex vivo investigation. The maximum longitudinal strain of the myocardial wall between the RPV and LPV increased from 20±6 (mean±SD) to 34±16% (pre vs. post-ablation, respectively; p=0.032), whereas the maximum radial motion fraction of the LA septum close to the RPV decreased from 46±10 to 36±7% (pre vs. post, p=0.035). Sustained AF (>30s) was more often induced during stimulation in ablated than in control hearts (22% vs. 9% of induction attempts (n=73 vs. n=87), respectively, p=0.025). In ablated hearts, an increase in LA pressure augmented AF inducibility (11% vs. 34% of induction attempts, n=38 vs. n=35, low vs. high LA pressure, respectively, p=0.024), whereas this was not the case in control hearts (2% vs. 17% of induction attempts (n=45 vs. n=42), low vs. high, p=0.237). Moreover, the diastolic stimulation threshold was higher in ablated than control hearts (90 (60) (median (IQR)) and 75 (40) mA, p=0.007). Local PV ablation scar caused localized disparate mechanical changes and increased inducibility of sustained AF, especially during increased LA pressure. This was associated with decreased tissue excitability. Therefore, ablation scar in a single PV causes an atrial arrhythmogenic substrate. Ablation lesion sets that homogenize atrial mechanics may improve the AF ablation success.

B-PO01-013 ABLATION SCAR IN A SINGLE PULMONARY VEIN CAUSES PROARRHYTHMIC MECHANICAL DESTABILIZATION IN HEALTHY SHEEP ATRIA

Atrial and pulmonary vein (PV) stretch is proarrhythmic, but the mechanical effect of PV ablation scar on atrial fibrillation (AF) arrhythmogenesis is unknown. We hypothesize that discontinuous PV ablation scars are proarrhythmic because they create heterogeneous stretch. To measure local atrial strain and AF inducibility in healthy sheep hearts with and without PV ablation scar. Functional cardiac MRIs acquired in vivo in sheep (n=12) before and 3 months after discontinuous PV ablation by radiofrequency in the right PV (RPV) were analyzed with a feature-tracking algorithm to obtain local strain in the left atrium (LA). Explanted hearts were perfused with 1:4 blood:Tyrode’s solution in a dual-chamber working-heart set-up. Multi-electrode endocardial catheters were positioned in the RPV and left PV (LPV) for premature stimulation during low (∼12mmHg) and high (∼25mmHg) LA pressure. Control hearts (n=12) underwent similar ex vivo investigation. The maximum longitudinal strain of the myocardial wall between the RPV and LPV increased from 20±6 (mean±SD) to 34±16% (pre vs. post-ablation, respectively; p=0.032), whereas the maximum radial motion fraction of the LA septum close to the RPV decreased from 46±10 to 36±7% (pre vs. post, p=0.035). Sustained AF (>30s) was more often induced during stimulation in ablated than in control hearts (22% vs. 9% of induction attempts (n=73 vs. n=87), respectively, p=0.025). In ablated hearts, an increase in LA pressure augmented AF inducibility (11% vs. 34% of induction attempts, n=38 vs. n=35, low vs. high LA pressure, respectively, p=0.024), whereas this was not the case in control hearts (2% vs. 17% of induction attempts (n=45 vs. n=42), low vs. high, p=0.237). Moreover, the diastolic stimulation threshold was higher in ablated than control hearts (90 (60) (median (IQR)) and 75 (40) mA, p=0.007). Local PV ablation scar caused localized disparate mechanical changes and increased inducibility of sustained AF, especially during increased LA pressure. This was associated with decreased tissue excitability. Therefore, ablation scar in a single PV causes an atrial arrhythmogenic substrate. Ablation lesion sets that homogenize atrial mechanics may improve the AF ablation success.

Cardiorespiratory fitness and electroanatomical remodelling in patients with atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Atrial fibrillation (AF) is the most common clinically-relevant arrhythmia. Its initiation and maintenance is linked to the presence cardiovascular risk factors such as hypertension and obesity. Higher cardiorespiratory fitness (CRF) has been associated with a better prognosis. However, specific electroanatomical features associated with baseline CRF have not been described. Purpose Compare electroanatomical substrate across exercise capacity levels in patients with AF Methods Patients referred for de novo AF radiofrequency ablation at the Centre for Heart Rhythm Disorders from August 2017 until June 2020 were screened for inclusion and CRF was evaluated in metabolic equivalents (METs) by a symptom-limited maximal treadmill exercise test using the standard Bruce protocol prior to ablation. Predicted CRF was calculated based on established equations and patients were categorized according to the percentage of predicted CRF achieved; low (&amp;lt;85%), adequate (85-100%) and high (&amp;gt;100%). Total mean and regional peak-to-peak bipolar voltages, percent of low voltage areas (% LVA), conduction velocity (CV) and percent of complex fractionated electrograms (% CFE) in sinus rhythm were compared across groups. Results There were no between-group differences in baseline characteristics, medication use or echocardiographic features. Total mean voltage was significantly lower in the low CRF group compared to both adequate and high CRF. Compared to the high CRF group, roof (3.25 ± 1.2 mV vs 1.9 ± 1.3 mV, p &amp;lt; 0.05), posterior (3.8 ± 1.8 mV vs 1.7 ± 0.9 mV, p &amp;lt; 0.001) and inferior mean voltages (3.4 ± 2 mV vs 1.6 ± 0.7 mV, p &amp;lt; 0.05) were significantly lower in the low CRF group (figure 1A). Furthermore, compared with the adequate CRF group, mean voltages were significantly lower in the posterior (3.7 ± 1.5 mV vs 1.7 ± 0.9 mV, p &amp;lt; 0.001), inferior (3.4 ± 1 mV vs 1.6 ± 0.7 mV, p &amp;lt; 0.001) and lateral (4.2 ± 2.2 mV vs 2.1 ± 1.4 mV, p &amp;lt; 0.05) walls of the low CRF group. Anterior and septal mean voltages were not significantly different across CRF groups (P for trend = 0.07, 0.3 and 0.15, respectively). Conduction velocities were not significantly different across groups. The inferior %LVA was significantly higher in the low CRF (5.6 ± 6%) compared to adequate CRF group (23 ± 18%) (p &amp;lt; 0.05) (figure 1B). Total and regional % CFE was higher in the low CRF compared to adequate and high CRF. Conclusion Participants in the lower baseline CRF category showed significant reductions in regional voltages along with higher fractionation with preserved conduction velocities. Research on the effect of physical activity and CRF on left atrial arrhythmogenic substrate is required. Abstract Figure. Global and regional mV and % LVA by CRF

Decrement Evoked Potential Mapping to Guide Ventricular Tachycardia Ablation: Elucidating the Functional Substrate.

Empirical approaches to targeting the ventricular tachycardia (VT) substrate include mapping of late potentials, local abnormal electrogram, pace-mapping and homogenisation of the abnormal signals. These approaches do not try to differentiate between the passive or active role of local signals as the critical components of the VT circuit. By not considering the functional components, these approaches often view the substrate as a fixed anatomical barrier. Strategies to improve the success of VT ablation need to include the identification of critical functional substrate. Decrement-evoked potential (DeEP) mapping has been developed to elucidate this using an extra-stimulus added to a pacing drive train. With knowledge translation in mind, the authors detail the evolution of the DeEP concept by way of a study of simultaneous panoramic endocardial mapping in VT ablation; an in silico modelling study to demonstrate the factors influencing DeEPs; a multicentre VT ablation validation study; a practical approach to DeEP mapping; the potential utility of DeEPs to identify arrhythmogenic atrial substrate; and, finally, other functional mapping strategies.

Comparison of Unipolar and Bipolar Voltage Mapping for Localization of Left Atrial Arrhythmogenic Substrate in Patients With Atrial Fibrillation.

Background: Presence of left atrial low voltage substrate in bipolar voltage mapping is associated with increased arrhythmia recurrences following pulmonary vein isolation for atrial fibrillation (AF). Besides local myocardial fibrosis, bipolar voltage amplitudes may be influenced by inter-electrode spacing and bipole-to-wavefront-angle. It is unclear to what extent these impact low voltage areas (LVA) in the clinical setting. Alternatively, unipolar electrogram voltage is not affected by these factors but requires advanced filtering.Objectives: To assess the relationship between bipolar and unipolar voltage mapping in sinus rhythm (SR) and AF and identify if the electrogram recording mode affects the quantification and localization of LVA.Methods: Patients (n = 28, 66±7 years, 46% male, 82% persistent AF, 32% redo-procedures) underwent high-density (>1,200 sites, 20 ± 10 sites/cm2, using a 20-pole 2-6-2 mm-spaced Lasso) voltage mapping in SR and AF. Bipolar LVA were defined using four different thresholds described in literature: <0.5 and <1 mV in SR, <0.35 and <0.5 mV in AF. The optimal unipolar voltage threshold resulting in the highest agreement in both unipolar and bipolar mapping modes was determined. The impact of the inter-electrode distance (2 vs. 6 mm) on the correlation was assessed. Regional analysis was performed using an 11-segment left atrial model.Results: Patients had relevant bipolar LVA (23 ± 23 cm2 at <0.5 mV in SR and 42 ± 26 cm2 at <0.5 mV in AF). 90 ± 5% (in SR) and 85 ± 5% (AF) of mapped sites were concordantly classified as high or low voltage in both mapping modes. Discordant mapping sites located to the border zone of LVA. Bipolar voltage mapping using 2 vs. 6 mm inter-electrode distances increased the portion of matched mapping points by 4%. The unipolar thresholds (y) which resulted in a high spatial concordance can be calculated from the bipolar threshold (x) using following linear equations: y = 1.06x + 0.26mV (r = 0.994) for SR and y = 1.22x + 0.12mV (r = 0.998) for AF.Conclusion: Bipolar and unipolar voltage maps are highly correlated, in SR and AF. While bipole orientation and inter-electrode spacing are theoretical confounders, their impact is unlikely to be of clinical importance for localization of LVA, when mapping is performed at high density with a 20-polar Lasso catheter.

Accuracy of left atrial fibrosis detection with cardiac magnetic resonance: correlation of late gadolinium enhancement with endocardial voltage and conduction velocity.

Myocardial fibrosis is a hallmark of atrial fibrillation (AF) and its characterization could be used to guide ablation procedures. Late gadolinium enhanced-magnetic resonance imaging (LGE-MRI) detects areas of atrial fibrosis. However, its accuracy remains controversial. We aimed to analyse the accuracy of LGE-MRI to identify left atrial (LA) arrhythmogenic substrate by analysing voltage and conduction velocity at the areas of LGE. Late gadolinium enhanced-magnetic resonance imaging was performed before ablation in 16 patients. Atrial wall intensity was normalized to blood pool and classified as healthy, interstitial fibrosis, and dense scar tissue depending of the resulting image intensity ratio. Bipolar voltage and local conduction velocity were measured in LA with high-density electroanatomic maps recorded in sinus rhythm and subsequently projected into the LGE-MRI. A semi-automatic, point-by-point correlation was made between LGE-MRI and electroanatomical mapping. Mean bipolar voltage and local velocity progressively decreased from healthy to interstitial fibrosis to scar. There was a significant negative correlation between LGE with voltage (r = -0.39, P < 0.001) and conduction velocity (r = -0.25, P < 0.001). In patients showing dilated atria (LA diameter ≥45 mm) the conduction velocity predictive capacity of LGE-MRI was weaker (r = -0.40 ± 0.09 vs. -0.20 ± 0.13, P = 0.02). Areas with higher LGE show lower voltage and slower conduction in sinus rhythm. The enhancement intensity correlates with bipolar voltage and conduction velocity in a point-by-point analysis. The performance of LGE-MRI in assessing local velocity might be reduced in patients with dilated atria (LA diameter ≥45).

Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality

BackgroundClinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined. ObjectivesThe purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF. MethodsPatients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance. ResultsHigher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity. ConclusionsThese findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate.

Pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut reduces atrial fibrillation susceptibility in obese spontaneously hypertensive rats

BackgroundIncreased sodium uptake has been shown to contribute to hypertension and cardiac end-organ damage. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. Whether a reduction in intestinal sodium absorption can prevent the development of an atrial arrhythmogenic substrate in hypertension is unknown. MethodsEight-week-old obese spontaneously hypertensive rats (SHR-ob) were treated for six weeks with the gut-specific NHE3-inhibitor SAR (1-(β-D-glucopyranosyl)-3-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-chinolin-4-yl]phenyl}urea, 1 mg/kg/d in chow, SHR-ob SAR, n = 7) and compared to aged-matched placebo-treated SHR-ob (SHR-ob PLAC, n = 8). Cardiac magnetic resonance imaging was performed at the end of the treatment period to assess atrial emptying function. Afterwards, local conduction disturbances and inducible atrial fibrillation (AF) duration were determined and histological analysis to quantify atrial fibrosis amount were performed. ResultsInhibition of intestinal NHE3 by SAR increased fecal sodium excretion, resulted in marked changes in feces electrolyte concentrations and water content, reduced blood pressure and preserved atrial emptying function (active total percent emptying: SHR-ob SAR: 0.47 ± 0.05% vs. SHR-ob PLAC: 0.38 ± 0.007, p < 0.0001). Atrial fibrosis content was lower (21.4 ± 2.5% vs. 36.7 ± 1.2%, p < 0.0001) and areas of slow conduction were smaller (2.5 ± 0.09% vs. 5.3 ± 0.2%, p < 0.0001) in SHR-ob SAR compared to SHR-ob PLAC. Left atrial burst stimulation resulted in shorter inducible AF-durations in SHR-ob SAR compared to SHR-ob PLAC. ConclusionsReduction of intestinal sodium absorption and subsequent changes in feces milieu by pharmacological NHE3 inhibition in the gut preserved atrial emptying function and reduced AF susceptibility. Whether pharmacological NHE3 inhibition in the gut prevents AF in humans warrants further study.