Finding a cause in sudden cardiac arrest survivors: Getting the testing right.

Sudden cardiac arrest (SCA) survivors are optimally managed by a multidisciplinary team with expertise in cardiac electrophysiology and cardiac genetics with the capacity to deal with both the medical and psychological needs of patients and their families. Consideration is given to an appropriate selection of second-line investigation, genetic testing, and cascade testing.

Rapid Access Arrhythmia Clinics (RAACs) Versus Usual Care: Improving Efficiency and Safety of Arrhythmia Management.

BACKGROUND: Rapid access cardiology services have been proposed for assessment of acute cardiac conditions via an outpatient model-of-care that potentially could reduce hospitalisations. We describe a new Rapid Access Arrhythmia Clinic (RAAC) and compare major safety endpoints to usual care. METHODS: We matched 312 adult patients with suspected arrhythmia in RAAC to historical age and sex-matched controls discharged from hospital within Western Sydney Local Health District with suspected arrhythmia. The primary endpoint was a composite of time to first unplanned cardiovascular hospitalisation or cardiac death over 12 months. RESULTS: The average age of RAAC patients was 52.2±18.8 years and 51.6±18.8 years for controls, and 48.4% were female in both groups. Mean time from referral to first attended RAAC appointment was 10.5 days. Most were referred from emergency (177, 56.7%) and cardiologists at time of discharge (65, 20.8%). The most common reason for referral was palpitations (180, 57.7%). In total, 155 (49.7%) had a documented arrhythmia, with the most common being atrial fibrillation/flutter (88, 28.2%). The primary endpoint occurred in 35 (11.2%) patients in the RAAC pathway (97.1[95% CI 70-131.3] per 1,000 person-years), compared to 72 (23.1%) patients for usual care controls (229.5[95% CI 180.2-288.1] per 1,000 person-years). Using a propensity score analysis, RAAC pathway significantly reduced the primary endpoint by 59% compared to usual care (HR 0.41, 95% CI 0.27-0.62; p<0.001). CONCLUSIONS: RAACs for the early investigation and management of suspected arrhythmia is superior to usual care in terms of reduction in unplanned cardiovascular hospitalisation and death.

Subclinical device-detected atrial fibrillation and stroke risk: a systematic review and meta-analysis.

Aims: To determine stroke risk in subclinical atrial fibrillation (AF) and temporal association between subclinical AF and stroke. Methods and results: Pubmed/Embase was searched for studies reporting stroke in subclinical AF in patients with cardiac implantable electronic devices (CIEDs). After exclusions, 11 studies were analysed. Of these seven studies reported prevalence of subclinical AF, two studies reported association between subclinical and clinical AF, seven studies reported stroke risk in subclinical AF, and five studies reported temporal relationship between subclinical AF and stroke. Subclinical AF was noted after CIEDs implant in 35% [interquartile range (IQR) 34-42] of unselected patients with pacing indication over 1-2.5 years. The definition and cut-off duration (for stroke risk) of subclinical AF varied across studies. Subclinical AF was strongly associated with clinical AF (OR 5.7, 95% CI 4.0-8.0, P < 0.001, I2 = 0%). The annual stroke rate in patients with subclinical AF > defined cut-off duration was 1.89/100 person-year (95% CI 1.02-3.52) with 2.4-fold (95% CI 1.8-3.3, P < 0.001, I2 = 0%) increased risk of stroke as compared to patients with subclinical AF < cut-off duration (absolute risk was 0.93/100 person-year). Three studies provided mean CHADS2 score. In these studies, with mean CHADS2 score of 2.1 ± 0.1, subclinical AF was associated with annual stroke rate of 2.76/100 person-years (95% CI 1.46-5.23). After excluding patients without AF, only 17% strokes occurred in presence of ongoing AF. Subclinical AF was noted in 29% [IQR 8-57] within 30 days preceding stroke. Conclusion: Subclinical AF strongly predicts clinical AF and is associated with elevated absolute stroke risk albeit lower than risk described for clinical AF.

The Impact of Diet and Lifestyle on Atrial Fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans, affecting more than 33 million people globally. Its association with complex, resource intensive medical conditions such as stroke, heart failure and dementia have had profound impacts across existing health care structures. The global prevalence of AF has enjoyed significant growth despite significant improvement in our armamentarium for arrhythmia treatment. RECENT FINDINGS: Efforts aimed at curtailing the incidence, prevalence, or progression of AF have prompted re-evaluation of traditional frameworks for understanding and managing this debilitating disease. It is in this context that focus has shifted toward lifestyle-associated factors such as obesity, hypertension, sleep apnoea, exercise, alcohol and diet, as mechanistic drivers and putative targets for therapy. Compelling evidence exists for weight loss and management of associated risk factors to improve outcomes of AF treatment. This review will address the epidemiologic and mechanistic evidence that link lifestyle-associated factors with AF and in light of this analysis evaluate the clinical impacts of their upstream management. Traditional paradigms of AF are shifting in light of emerging evidence, such that risk factor modification has become positioned as the fourth pillar of AF management.

Pericardial adipose and aromatase: A new translational target for aging, obesity and arrhythmogenesis?

A correlation exists between the extent of pericardial adipose and atrial fibrillation (AF) risk, though the underlying mechanisms remain unclear. Selected adipose depots express high levels of aromatase, capable of converting androgens to estrogens - no studies have investigated aromatase occurrence/expression regulation in pericardial adipose. The Women's Health Initiative reported that estrogen-only therapy in women elevated AF incidence, indicating augmented estrogenic influence may exacerbate cardiac vulnerability. The aim of this study was to identify the occurrence of pericardial adipose aromatase, evaluate the age- and sex-dependency of local cardiac steroid synthesis capacity and seek preliminary experimental evidence of a link between pericardial adipose aromatase capacity and arrhythmogenic vulnerability. Both human atrial appendage and epicardial adipose exhibited immunoblot aromatase expression. In rodents, myocardium and pericardial adipose aromatase expression increased >20-fold relative to young controls. Comparing young, aged and aged-high fat diet animals, a significant positive correlation was determined between the total aromatase content of pericardial adipose and the occurrence/duration of triggered atrial arrhythmias. Incidence and duration of arrhythmias were increased in hearts perfused with 17ß-estradiol. This study provides novel report of pericardial adipose aromatase expression. We show that aromatase expression is remarkably upregulated with aging, and aromatase estrogen conversion capacity significantly elevated with obesity-related cardiac adiposity. Our studies suggest an association between adiposity, aromatase estrogenic capacity and atrial arrhythmogenicity - additional investigation is required to establish causality. The potential impact of these findings may be considerable, and suggests that focus on local cardiac steroid conversion (rather than systemic levels) may yield translational outcomes.

A comparison of the electrophysiologic and electroanatomic characteristics between the right and left atrium in persistent atrial fibrillation: Is the right atrium a window into the left?

INTRODUCTION: The right atrium (RA) is readily accessible; however, it is unclear whether changes in the RA are representative of the LA. We performed detailed biatrial electroanatomic mapping to determine the electrophysiological relationship between the atria. METHODS AND RESULTS: Consecutive patients with persistent AF underwent biatrial electroanatomical mapping with a contact force catheter acquiring points with a CF >10 g prior to ablation. Points were analyzed for tissue voltage, complex electrograms, low voltage (<0.5 mV), scar (<0.05 mV), and conduction velocity (CV). Forty patients (mean age 59 ± 9.2 years, AF duration 12.9 ± 9.2 months, LA area: 28 ± 5.2, RA area: 25 ± 6.4 mm2 , LVEF: 44 ± 15%) underwent mapping during CS pacing. Bipolar voltage (R = 0.57, P <0.001), unipolar voltage (R = 0.68, P <0.001), low voltage (<0.5 nV) (R = 0.48, P = 0.002), fractionation (R = 0.73, P <0.001), and CV (R = 0.49, P = 0.001) correlated well between atria. There was no difference in global bipolar voltage (LA 1.89 ± 0.77 vs. RA 1.77 ± 0.57 mV, P = 0.57); complex electrograms (LA 20% vs. RA 20%, P = 0.99) or low voltage (LA 15% vs. RA 16%, P = 0.84). Global unipolar voltage was significantly higher in the LA compared to the RA (2.95 ± 1.14 vs. 2.28 ± 0.65 mV, P = 0.002) and CV was significantly slower in the RA compared to the LA (0.93 ± 0.15 m/s vs. 1.01 ± 0.19 m/s, P = 0.001). CONCLUSION: AF is associated with remodeling processes affecting both atria. The more accessible RA provides an insight into the biatrial process associated with AF in various disease states without trans-septal access.

Determining the Optimal Dose of Adenosine for Unmasking Dormant Pulmonary Vein Conduction Following Atrial Fibrillation Ablation: Electrophysiological and Hemodynamic Assessment. DORMANT-AF Study.

INTRODUCTION: ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. DORMANT-AF STUDY: The significance of adenosine induced dormant pulmonary vein (PV) conduction in atrial fibrillation (AF) ablation remains controversial. The optimal dose of adenosine to determine dormant PV conduction is yet to be systematically explored. METHODS AND RESULTS: ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. DORMANT-AF STUDY: Consecutive patients undergoing index AF ablation received 3 adenosine doses (12, 18, and 24 mg) in a randomized blinded order, immediately after pulmonary vein isolation (PVI). Electrophysiological (PR prolongation, AV block (AVB) and PV reconnection) and hemodynamic (BP) parameters were measured. A total, 339 doses (113/dose) assessed 191 PVs in 50 patients (66% male, 72% PAF, 52% hypertensive). Dormant PV conduction occurred in 28% of patients (16.5% [32] of PVs). All cases were associated with AVB (AVB: PV reconnection vs. no PV reconnection 100% vs. 83%, P = 0.007). AVB occurred more frequently at 24 mg versus 12 mg (92% vs. 82%, P = 0.019) but not versus 18 mg (91%, P = 0.62). AVB duration progressed between 12 mg (12.0 ± 8.9 seconds), 18 mg (16.1 ± 9.1 seconds, P = 0.001), and 24 mg (19.0 ± 9.3 seconds, P < 0.001) doses. MBP fell further at 24 mg (ΔMBP: 27 ± 12 mmHg) and 18 mg (26 ± 13 mmHg) doses compared to 12 mg (22 ± 10 mmHg vs., P < 0.001). A significant reduction in AVB in patients >110 kg (65% vs. 91% in 70-110 kg group, P < 0.001) in response to adenosine was seen. CONCLUSION: ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. DORMANT-AF STUDY: An adenosine dose producing AVB is required to unmask dormant PV conduction. AVB is significantly reduced in patients >110 kg. Weight and dosing variability may in part explain the conflicting results of studies evaluating the clinical utility of adenosine in PVI.

Obstructive Sleep Apnea Treatment and Atrial Fibrillation: A Need for Definitive Evidence.

Prevalence rates of atrial fibrillation (AF) and obstructive sleep apnea (OSA) are rising on a global scale. Epidemiological data have consistently demonstrated an independent association between the 2 conditions. Investigators pose that pathophysiologic features of OSA enable progression of the AF substrate; these features include abnormalities of gas exchange, autonomic remodeling, atrial stretch, and inflammation. Furthermore, many of the mechanistic perturbations that impact the AF substrate in OSA can be substantially attenuated by effective treatment with continuous positive airway pressure (CPAP). Clear associations of OSA treatment and improved AF control have been observed across multiple clinical contexts. However, the precision and generalizability of these findings are unclear in view of the data's observational nature. Although risk factor management has emerged as a critical component of AF treatment, effective control of many AF risk factors can be challenging in the longer term. In view of the efficacy and sustainability of CPAP therapy, OSA raises its profile as a prime candidate for intervention. However, translation of this strategy to the broader framework for AF management requires robust data from randomized controlled trials.

Coronary artery reperfusion for ST elevation myocardial infarction is associated with shorter cycle length ventricular tachycardia and fewer spontaneous arrhythmias.

AIMS: Ventricular tachycardia (VT) induction at electrophysiological (EP) study early after ST elevation myocardial infarction (STEMI) has been a predictor of spontaneous ventricular arrhythmia. Reperfusion therapy for STEMI may have resulted in altered VT character. We attempted to determine differences in VT cycle length (CL) and VT recurrence rates, in patients who received early and late reperfusion treatment for STEMI. METHODS AND RESULTS: Of 180 consecutive patients with left ventricular ejection fraction < 40%, 77 patients had positive EP studies. Forty-nine patients receiving early reperfusion treatment (group 1, n = 49) were compared with 28 patients who received late reperfusion (group 2; n = 28). Seventy-five patients had defibrillators implanted for primary prevention of sudden death. Patients were followed for up to 6 years to assess long-term rates of spontaneous ventricular tachyarrhythmia. Patients who received early reperfusion demonstrated shorter CL inducible VT (231 ± 43 ms vs. 252 ± 56 ms; P = 0.016). They also had fewer spontaneous arrhythmias (adjusted hazard ratio of 2.94, 95% confidence interval: 1.07-8.13; P = 0.03) with shorter CL spontaneous VT (266 ± 54 ms vs. 320 ± 80 ms; P = 0.02) at 53 ± 33 months. Ventricular tachycardia CL was the only independent predictor of spontaneous arrhythmia or sudden cardiac death (1.22, 1.07-1.47; P = 0.016). CONCLUSIONS: Patients receiving early reperfusion for STEMI had faster inducible and spontaneous VT and fewer spontaneous recurrences. This may be due to changes in the myocardial substrate as a result of early coronary artery reperfusion.

Comparison of the arrhythmogenic substrate for ventricular tachycardia in patients with ischemic vs non-ischemic cardiomyopathy - insights from high-density, multi-electrode catheter mapping.

PURPOSE: The purpose of this study was to compare the differences of arrhythmogenic substrate using high-density mapping in ventricular tachycardia (VT) patients with ischemic (ICM) vs non-ischemic cardiomyopathy (NICM). METHODS: Data from patients presenting for VT ablation from December 2016 to December 2020 at Westmead Hospital were reviewed. RESULTS: Sixty consecutive patients with structural heart disease (ICM 57%, NICM 43%, mean age 66 years) having catheter ablation of scar-related VT with pre-dominant left ventricular involvement were included. ICM was associated with larger proportion of dense scar area (bipolar; 19 [12-29]% vs 6 [3-10]%, P < 0.001, unipolar; 20 [12-32]% vs 11 [7-19]%, P = 0.01) compared with NICM. However, the scar ratio (unipolar dense scar [%]/bipolar dense scar [%]) was significantly higher in NICM patients (1.2 [0.8-1.7] vs 1.7 [1.3-2.3], P = 0.003). Larger scar area in ICM was paralleled by higher proportion of complex electrograms (6 [2-13] % vs 3 [1-5] %, P = 0.01), longer and wider voltage based conducting channels, higher incidence of late potential-based conducting channels, longer VT cycle-length (399 ± 80 ms vs 359 ± 68 ms, P = 0.04) and greater maximal stimulation-QRS interval among sites with good pace-map correlation (75 [51-99]ms vs 48 [31-73]ms, P = 0.02). Ventricular arrhythmia (VA) storm was more highly prevalent in ICM than NICM (50% vs 23%, P = 0.03). During the follow-up period, NICM had a significantly higher cumulative incidence for the VA recurrence than ICM (P = 0.03). CONCLUSIONS: High-density multi-electrode catheter mapping of left ventricular arrhythmogenic substrate of NICM tends to show smaller dense scar area and higher scar ratio, compared with ICM, suggestive the extent of epicardial/intramural substrate, with paucity of substrate targets for ablation, which results in the worse outcomes with ablation.

Sex-Related Differences in Atrial Remodeling in Patients With Atrial Fibrillation: Relationship to Ablation Outcomes.

BACKGROUND: Population studies have demonstrated a range of sex differences including a higher prevalence of atrial fibrillation (AF) in men and a higher risk of AF recurrence in women. However, the underlying reasons for this higher recurrence are unknown. This study evaluated whether sex-based electrophysiological substrate differences exist to account for worse AF ablation outcomes in women. METHODS: High-density electroanatomic mapping of the left atrium was performed in 116 consecutive patients with AF. Regional analysis was performed across 6 left atrium segments. High-density maps were created using a multipolar catheter (Biosense Webster) during distal coronary sinus pacing at 600 and 300 ms. Mean voltage and conduction velocity was determined. Complex fractionated signals and double potentials were manually annotated. RESULTS: Overall, 42 (36%) were female, mean age was 61±8 years and AF was persistent in 52%. Global mean voltage was significantly lower in females compared with males at 600 ms (1.46±0.17 versus 1.84±0.15 mV, P<0.001) and 300 ms (1.27±0.18 versus 1.57±0.18 mV, P=0.013) pacing. These differences were seen uniformly across the left atrium. Females demonstrated significant conduction velocity slowing (34.9±6.1 versus 44.1±6.9 cm/s, P=0.002) and greater proportion of complex fractionated signals (9.9±1.7% versus 6.0±1.7%, P=0.014). After a median follow-up of 22 months (Q1-Q3: 15-29), females had significantly lower single-procedure (22 [54%] versus 54 [75%], P=0.029) and multiprocedure (24 [59%] versus 60 [83%], P=0.005) arrhythmia-free survival. Female sex and persistent AF were independent predictors of single and multiprocedure arrhythmia recurrence. CONCLUSIONS: Female patients demonstrated more advanced atrial remodeling on high-density electroanatomic mapping and greater post-AF ablation arrhythmia recurrence compared with males. These changes may contribute to sex-based differences in the clinical course of females with AF and in part explain the higher risk of recurrence. Graphic Abstract: A graphic abstract is available for this article.

Impact of CPAP on the Atrial Fibrillation Substrate in Obstructive Sleep Apnea: The SLEEP-AF Study.

BACKGROUND: Observational studies report that obstructive sleep apnea (OSA) is associated with an increasingly remodeled atrial substrate in atrial fibrillation (AF). However, the impact of OSA management on the electrophysiologic substrate has not been evaluated. OBJECTIVES: In this study, the authors sought to determine the impact of OSA management on the atrial substrate in AF. METHODS: We recruited 24 consecutive patients referred for AF management with at least moderate OSA (apnea-hypopnea index [AHI] ≥15). Participants were randomized in a 1:1 ratio to commence continuous positive airway pressure (CPAP) or no therapy (n = 12 CPAP; n = 12 no CPAP). All participants underwent invasive electrophysiologic study (high-density right atrial mapping) at baseline and after a minimum of 6 months. Outcome variables were atrial voltage (mV), conduction velocity (m/s), atrial surface area <0.5 mV (%), proportion of complex points (%), and atrial effective refractory periods (ms). Change between groups over time was compared. RESULTS: Clinical characteristics and electrophysiologic parameters were similar between groups at baseline. Compliance with CPAP therapy was high (device usage: 79% ± 19%; mean usage/day: 268 ± 91 min) and resulted in significant AHI reduction (mean reduction: 31 ± 23 events/h). There were no differences in blood pressure or body mass index between groups over time. At follow-up, the CPAP group had faster conduction velocity (0.86 ± 0.16 m/s vs 0.69 ± 0.12 m/s; P (time × group) = 0.034), significantly higher voltages (2.30 ± 0.57 mV vs 1.94 ± 0.72 mV; P < 0.05), and lower proportion of complex points (8.87% ± 3.61% vs 11.93% ± 4.94%; P = 0.011) compared with the control group. CPAP therapy also resulted in a trend toward lower proportion of atrial surface area <0.5 mV (1.04% ± 1.41% vs 4.80% ± 5.12%; P = 0.065). CONCLUSIONS: CPAP therapy results in reversal of atrial remodeling in AF and provides mechanistic evidence advocating for management of OSA in AF.

Epicardial-Endocardial Reentry in Ischemic Cardiomyopathy.

In ischemic cardiomyopathy, endocardial reentry has traditionally been the mechanistic paradigm for understanding ventricular tachycardia (VT). However, recognition is growing that epicardial myocardium is a critical component for VT substrate, even in patients with ischemic cardiomyopathy. In this report, we present a novel case of a three-dimensional VT reentry involving epicardial components and an endocardial exit.

Functional Atrial Endocardial-Epicardial Dissociation in Patients With Structural Heart Disease Undergoing Cardiac Surgery.

OBJECTIVES: The goal of this study was to describe functional endocardial-epicardial dissociation (FEED), signal complexities, and three-dimensional activation dynamics of the human atrium with structural heart disease (SHD). BACKGROUND: SHD commonly predisposes to arrhythmias. Although progressive remodeling is implicated, direct demonstration of FEED in the human atrium has not been reported previously. METHODS: Simultaneous intraoperative mapping of the endocardial and epicardial lateral right atrial wall was performed by using 2 high-density grid catheters during sinus rhythm, pacing drive (600 ms and 400 ms cycle length), and premature extrastimulation (PES). Unipolar electrograms (EGMs) were exported into custom-made software for activation and phase mapping. Difference of ≥20 ms between paired endocardial and epicardial electrodes defined dissociation. EGMs with ≥3 deflections were classified as fractionated. RESULTS: Sixteen patients (mean age 60.5 ± 4.1 years; 18.7% with a history of atrial fibrillation) with SHD (43% ischemia, 57% valvular disease) were included. A total of 9,218 EGMs were analyzed. Compared with sinus rhythm, phase and activation analyses showed significant FEED during pacing at 600 ms and 400 ms (phase mapping 22.4% vs. 10% [p < 0.0001] and 25.8% vs. 10% [p < 0.0001], respectively; activation mapping 25.4% vs. 7.8% [p < 0.0001] and 27.7% vs. 7.8% [p < 0.0001]) and PES (phase mapping 34% vs. 10% [p < 0.0001]; activation mapping 29.5% vs. 7.8% [p < 0.0001]). Fractionated EGMs occurred significantly more during PES compared with sinus rhythm (50.2% vs. 39.5%; p < 0.0001). Activation patterns differed significantly during pacing drive and PES, with preferential epicardial exit during the latter (15.9% vs. 13.8%; p = 0.046). CONCLUSIONS: Simultaneous endocardial-epicardial mapping revealed significant FEED with signal fractionation and preferential epicardial breakthroughs with PES. Such complex three-dimensional interaction in electrical activation provides mechanistic insights into atrial arrhythmogenesis with SHD.

Genetic Susceptibility to Atrial Fibrillation Is Associated With Atrial Electrical Remodeling and Adverse Post-Ablation Outcome.

OBJECTIVES: This study sought to assess the atrial electrophysiological properties and post-ablation outcomes in patients with atrial fibrillation (AF) with and without the rs2200733 single nucleotide variant. BACKGROUND: The phenotype associated with chromosome 4q25 of the AF-susceptibility locus remains unknown. METHODS: In this study, 102 consecutive patients (ages 61 ± 9 years, 64% male) with paroxysmal or persistent AF were prospectively recruited prior to ablation. Patients were genotyped for rs2200733 and high-density left atrial (LA) electroanatomic maps were created using a multipolar catheter during distal coronary sinus (CS) pacing at 600 ms. Voltage, conduction velocity (CV), CV heterogeneity, and fractionated signals of 6 LA segments were determined. Arrhythmia recurrence was assessed by continuous device (51%) and Holter monitoring. RESULTS: Overall, 41 patients (40%) were single nucleotide variant carriers (38 heterozygous, 3 homozygous). A mean of 2,239 ± 852 points per patient were collected. Carriers had relatively increased CV heterogeneity (45.7 ± 7.5% vs. 35.9 ± 2.3%; p < 0.001), complex signals (9.4 ± 2.9% vs 6.0 ± 1.2%; p = 0.008), regional LA slowing, or conduction block (31.7 ± 8.2% vs. 17.9 ± 1.9%; p = 0.013) particularly in the posterior and lateral walls. There were no differences in CV, voltage, atrial refractoriness, or sinus node function. At follow-up (median: 27 months; range 19 to 31 months), carriers had lower arrhythmia-free survival (51% vs. 80%; p = 0.003). On multivariable analysis, carrier status was independently associated with CV heterogeneity (p = 0.001), complex signals (p = 0.002), and arrhythmia recurrence (p = 0.019). CONCLUSIONS: These data provide the first evidence that the rs2200733-tagged haplotype alters LA electrical remodeling and is a determinant of long-term outcome following AF ablation. The molecular mechanisms underpinning these changes warrant further investigation.

Endocardial-Epicardial Phase Mapping of Prolonged Persistent Atrial Fibrillation Recordings: High Prevalence of Dissociated Activation Patterns.

BACKGROUND: Endocardial-epicardial dissociation and focal breakthroughs in humans with atrial fibrillation (AF) have been recently demonstrated using activation mapping of short 10-second AF segments. In the current study, we used simultaneous endo-epi phase mapping to characterize endo-epi activation patterns on long segments of human persistent AF. METHODS: Simultaneous intraoperative mapping of endo- and epicardial lateral right atrium wall was performed in patients with persistent AF using 2 high-density grid catheters (16 electrodes, 3 mm spacing). Filtered unipolar and bipolar electrograms of continuous 2-minute AF recordings and electrodes locations were exported for phase analyses. We defined endocardial-epicardial dissociation as phase difference of ≥20 ms between paired endo-epi electrodes. Wavefronts were classified as rotations, single wavefronts, focal waves, or disorganized activity as per standard criteria. Endo-Epi wavefront patterns were simultaneously compared on dynamic phase maps. Complex fractionated electrograms were defined as bipolar electrograms with ≥5 directional changes occupying at least 70% of sample duration. RESULTS: Fourteen patients with persistent AF undergoing cardiac surgery were included. Endocardial-epicardial dissociation was seen in 50.3% of phase maps with significant temporal heterogeneity. Disorganized activity (Endo: 41.3% versus Epi: 46.8%, P=0.0194) and single wavefronts (Endo: 31.3% versus Epi: 28.1%, P=0.129) were the dominant patterns. Transient rotations (Endo: 22% versus Epi: 19.2%, P=0.169; mean duration: 590±140 ms) and nonsustained focal waves (Endo: 1.2% versus Epi: 1.6%, P=0.669) were also observed. Apparent transmural migration of rotational activations (n=6) from the epi- to the endocardium was seen in 2 patients. Electrogram fractionation was significantly higher in the epicardium than endocardium (61.2% versus 51.6%, P<0.0001). CONCLUSIONS: Simultaneous endo-epi phase mapping of prolonged human persistent AF recordings shows significant Endocardial-epicardial dissociation marked temporal heterogeneity, discordant and transitioning wavefronts patterns and complex fractionations. No sustained focal activity was observed. Such complex 3-dimensional interactions provide insight into why endocardial mapping alone may not fully characterize the AF mechanism and why endocardial ablation may not be sufficient. Graphic Abstract: A graphic abstract is available for this article.

Simultaneous epicardial-endocardial mapping of the sinus node in humans with structural heart disease: Impact of overdrive suppression on sinoatrial exits.

BACKGROUND: The 3-dimensional (3D) nature of sinoatrial node (SAN) function has not been characterized in the intact human heart. OBJECTIVE: The purpose of this study was to characterize the 3D nature of SAN function in patients with structural heart disease (SHD) using simultaneous endocardial-epicardial (endo-epi) phase mapping. METHODS: Simultaneous intraoperative endo-epi SAN mapping was performed during sinus rhythm at baseline (SRbaseline) and postoverdrive suppression at 600 ms (SRpost-pace600) and 400 ms (SRpost-pace400) using 2 Abbott Advisor HD Grid Mapping Catheters. Unipolar and bipolar electrograms (EGMs) were exported for phase analysis to determine (1) activation exits; (2) wavefront propagation sequence; (3) endo-epi dissociation; and (4) fractionation. Comparison of these variables was made among the 3 rhythms from an endo-epi perspective. RESULTS: Sixteen patients with SHD were included. SRbaseline activations were unicentric and predominantly exited cranially (87.5%) with endo-epi synchrony. However, with overdrive suppression, a tendency for caudal exit shift and endo-epi asynchrony was observed: SRpost-pace600 vs SRbaseline: cranial endo 75% vs 87.5% (P = .046); cranial epi 68.8% vs 87.5% (P = 0.002); caudal endo 12.5% vs 6.2% (P = 0.215); caudal epi 25% vs 6.2% (P = .0003); and SRpost-pace400 vs SRbaseline: cranial endo 81.3% vs 87.5% (P = 0.335); cranial epi 68.7% vs 87.5% (P = 0.0034; caudal endo 12.5% vs 6.2% (P = .148); caudal epi 31.2% vs 6.2% (P = 0.0017), consistent with multicentricity. EGM fractionation was more prevalent with overdrive suppression. CONCLUSION: During mapping of the intact human heart, SAN demonstrated redundancy of sinoatrial exits with postoverdrive shift in sites of earliest activation and epi-endo dissociation of sinoatrial exits.

Arrhythmia recurrence is more common in females undergoing multiple catheter ablation procedures for persistent atrial fibrillation: Time to close the gender gap.

BACKGROUND: Female gender is associated with an increased recurrence of atrial fibrillation (AF) after catheter ablation (CA). Although AF is more common in men, women constitute a significant proportion with persistent atrial fibrillation (PsAF). OBJECTIVE: The purpose of this study was to determine whether multiple ablation procedures improves arrhythmia outcomes in females with PsAF compared to men. METHODS: We performed a multicenter observational study to determine long-term arrhythmia outcomes in patients undergoing >1 CA for PsAF. CA involved pulmonary vein (PV) isolation with additional ablation including linear, posterior wall isolation, electrogram-guided, or a combination of these. RESULTS: A total of 281 patients had >1 ablation procedure for PsAF and were included in this analysis (mean age 58.7 ± 9.3 years; 86 [30.6%] female; left atrial [LA] area 27.0 ± 5.3 cm2; PsAF duration 1.7 ± 1.7 years). At mean follow-up of 45.5 ± 31.8 months, freedom from recurrent AF was present in 148 patients(52.7%) after 2.2 ± 0.5 procedures. After multivariate analysis, female gender (hazard ratio [HR] 2.10; P <.001) and enduring PV isolation (HR 1.64; P = .01) were independently associated with AF recurrence. Enduring PV isolation was significantly higher in women than in men (33.7% vs 19.5%; P = .01). CONCLUSION: Female gender was independently and strongly associated with arrhythmia recurrence in patients undergoing multiple procedures for PsAF. PV reconnection was less likely, and fewer reconnected PVs occurred in women. Further studies are required to better understand the mechanisms responsible for AF in females to assist in closing the gender gap in the success of CA.

Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality.

BACKGROUND: Clinical 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. OBJECTIVES: The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF. METHODS: Patients 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. RESULTS: Higher 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. CONCLUSIONS: These 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.

Mitral valve prolapse and sudden cardiac death: a systematic review and meta-analysis.

OBJECTIVES: Mitral valve prolapse (MVP) is commonly observed as a benign finding. However, the literature suggests that it may be associated with sudden cardiac death (SCD). We performed a meta-analysis and systematic review to determine the: (1) prevalence of MVP in the general population; (2) prevalence of MVP in all SCD and unexplained SCD; (3) incidence of SCD in MVP and (4) risk factors for SCD. METHODS: The English medical literature was searched for: (1) MVP community prevalence; (2) MVP prevalence in SCD cohorts; (3) incidence SCD in MVP and (4) SCD risk factors in MVP. Thirty-four studies were identified for inclusion. This study was registered with PROSPERO (CRD42018089502). RESULTS: The prevalence of MVP was 1.2% (95% CI 0.5 to 2.0) in community populations. Among SCD victims, the cause of death remained undetermined in 22.1% (95% CI 13.4 to 30.7); of these, MVP was observed in 11.7% (95% CI 5.8 to 19.1). The incidence of SCD in the MVP population was 0.14% (95% CI 0.1 to 0.3) per year. Potential risk factors for SCD include bileaflet prolapse, ventricular fibrosis complex ventricular ectopy and ST-T wave abnormalities. CONCLUSION: The high prevalence of MVP in cohorts of unexplained SCD despite low population prevalence provides indirect evidence of an association of MVP with SCD. The absolute number of people exposed to the risk of SCD is significant, although the incidence of life-threatening arrhythmic events in the general MVP population remains low. High-risk features include bileaflet prolapse, ventricular fibrosis, ST-T wave abnormalities and frequent complex ventricular ectopy. TRIAL REGISTRATION: PROSPERO (CRD42018089502).