Computational simulations of asymmetric fluxes of large molecules through gap junction channel pores.

Gap junction channels are formed out of connexin isoforms, which enable molecule and ion selective diffusion amongst neighboring cells. HeLa cells expressing distinct connexins (Cx) allow the formation of heterotypic channels, where we observed a molecular charge-independent preferential flux of large fluorescent molecules in the Cx45 to Cx43 direction. We hypothesize that the pore's shape is a significant factor along-side charge and transjunctional voltages for this asymmetric flux. To test this hypothesis, we developed a 3D computational model simulating Brownian diffusion of large molecules in a gap junction channel pore. The basic pore contour was derived from x-ray crystallographic structures of Cx43 and Cx26 and approximated using basic geometric shapes. Lucifer yellow dye molecules and cesium counter-ions were modeled as spheres using their respective Stokes radii. Our simulation results from simple diffusion and constant concentration gradient experiments showed that only charged particles yield asymmetric fluxes in heterotypic pores. While increasing the inner mouth size resulted in a near-quadratic rise in flux, the rise was asymptotic for outer mouth radii increase. Probability maps and average force per particle per pore section explain the asymmetric flux with variation in pore shape. Furthermore, the simulation results are in agreement with our in vitro experimental results with HeLa cells in Cx43-Cx45 heterotypic configurations. The presence of asymmetric fluxes can help us to understand effects of the molecular structure of the pore and predict potential differences in vivo.

"Vasovagal" response during ventricular fibrillation: incidence and implications.

BACKGROUND: The purpose of this study was to assess the relationship between changes in sinus node cycle length (SNCL) during ventricular fibrillation (VF) and the peripheral changes in blood pressure (BP) and sympathetic nerve activity (SNA) in human subjects. We hypothesized that patients with no SNCL shortening during VF have a vasovagal-like response with a greater decrease in BP and SNA when compared to patients with SNCL shortening. METHODS: SNCL, BP, and SNA recordings were attempted in 24 patients undergoing the implantation of a dual-chamber implantable defibrillator. Changes were measured during the first 5 seconds of VF and compared with the 5 seconds prior to VF induction. RESULTS: SNCL shortened during VF in nine patients (mean%∆SNCL = -12 ± 8%) and remained unchanged or lengthened in seven patients (mean%∆SNCL = 7 ± 7%). Eight patients had ventriculoatrial (VA) conduction prohibiting assessment of SNCL changes. In patients with SNCL shortening, the %∆MBP (mean BP) was -47 ± 6% compared to -58 ± 8% in patients with no SNCL shortening (P < 0.01). In patients with VA conduction, the %∆MBP was -54 ± 3%. SNA recordings were successfully obtained in four patients. When compared to baseline, SNA increased by 34 ± 30% in two patients with SNCL shortening, decreased by 25% in one patient with SNCL lengthening, and by 90% in the fourth patient with VA conduction. CONCLUSIONS: We have shown that patients with no SNCL shortening have a significantly greater decrease in MBP during VF when compared to patients with SNCL shortening. The underlying mechanism appears to be reflex mediated with a vasovagal-like response in patients with no SNCL shortening.

Comparison of left atrial area marked ablated in electroanatomical maps with scar in MRI.

BACKGROUND: Three-dimensional electroanatomic mapping (EAM) is routinely used to mark ablated areas during radiofrequency ablation. We hypothesized that, in atrial fibrillation (AF) ablation, EAM overestimates scar formation in the left atrium (LA) when compared to the scar seen on late-gadolinium enhancement magnetic resonance imaging (LGE-MRI). METHODS AND RESULTS: Of the 235 patients who underwent initial ablation for AF at our institution between August 2011 and December 2012, we retrospectively identified 70 patients who had preprocedural magnetic resonance angiography merged with LA anatomy in EAM software and had a 3-month postablation LGE-MRI for assessment of scar. Ablated area was marked intraprocedurally using EAM software and quantified retrospectively. Scarred area was quantified in 3-month postablation LGE-MRI. The mean ablated area in EAM was 30.5 ± 7.5% of the LA endocardial surface and the mean scarred area in LGE-MRI was 13.9 ± 5.9% (P < 0.001). This significant difference in the ablated area marked in the EAM and scar area in the LGE-MRI was present for each of the 3 independent operators. Complete pulmonary vein (PV) encirclement representing electrical isolation was observed in 87.8% of the PVs in EAM as compared to only 37.4% in LGE-MRI (P < 0.001). CONCLUSIONS: In AF ablation, EAM significantly overestimates the resultant scar as assessed with a follow-up LGE-MRI.

Atrial bigeminy results in decreased left ventricular function: an insight into the mechanism of PVC-induced cardiomyopathy.

BACKGROUND: Premature ventricular complexes have been recently recognized as a reversible cause of cardiomyopathy. The purpose of this study was to determine if premature complexes independent of "dyssynchrony" resulted in increased left ventricular (LV) dimensions and decreased LV function. METHODS: Ten mongrel dogs underwent the implantation of a pacemaker and were randomized to a control group (n = 5) or a paced group (n = 5). In the paced group, the pacemaker was connected to two endocardial atrial leads, one inserted into the atrial port and the other one into the ventricular port with an atrioventricular delay adjusted to ensure the presence of coupled pacing simulating atrial bigeminy with conducted beats in the absence of aberrancy. Echocardiographic parameters of LV size (LV end-diastolic diameter [LV-EDD], LV end-systolic diameter [LV-ESD]), and LV ejection fraction (LVEF) were measured at baseline and after 4 weeks of monitoring (control group) or pacing (paced group). RESULTS: In the control group, LV size decreased with no significant changes in LVEF: 55% at baseline versus 70% at 4 weeks (P = 0.23). In the paced group, LV-EDD decreased with no significant change in LV-ESD. Unlike the control group, LVEF decreased significantly from 69 ± 9% at baseline to 32 ± 22% after 4 weeks of pacing (P = 0.05). CONCLUSION: We have shown that 4 weeks of coupled pacing simulating atrial bigeminy significantly reduced LV function. Our findings suggest that premature complexes independent of ventricular dyssynchrony might lead to the development of cardiomyopathy.

Irregular ventricular activation results in QT prolongation and increased QT dispersion: a new insight into the mechanism of AF-induced ventricular arrhythmogenesis.

INTRODUCTION: Atrial fibrillation (AF) has been shown to be associated with increased risk of ventricular arrhythmias. We have previously shown reverse electrical remodeling of the ventricles following successful restoration of sinus rhythm in patients with persistent AF. The purpose of this study was to assess the relative role of irregular ventricular activation in mediating the previously observed changes. METHODS AND RESULTS: Twenty-two patients referred for an invasive electrophysiologic study were randomized to 30 minutes of regular or irregular atrioventricular (AV) sequential pacing at 100 beats per minute (bpm) with a programmed AV interval of 100 ms. Irregular pacing was triggered from prerecorded digital signal with a mean rate of 100 bpm, and a standard deviation of 150 ms (25% of the mean rate). In the regular pacing group, QT and QTc decreased from 448 ± 102 ms and 453 ± 105 ms to 428 ± 109 ms and 442 ± 104 ms, respectively (P < 0.001 for QT interval and P < 0.001 for QTc interval). There was no significant change in QT dispersion. In the irregular pacing group, QT and QTc increased from 477 ± 104 ms and 486 ± 78 ms to 489 ± 106 ms and 500 ± 106 ms (P < 0.01 for QT interval and P = 0.03 for QTc interval). In addition, there was a significant increase in QT dispersion from 50 ± 22 ms to 66 ± 22 ms (P = 0.001). Since the rate and pacing sites were similar between the groups, we attribute the repolarization changes in the irregular pacing group to the irregular activation of the ventricles. CONCLUSION: The detrimental effects of irregular pacing go beyond the hemodynamic changes and include electrical remodeling that favors an arrhythmogenic substrate.

An animal model for ectopy-induced cardiomyopathy.

BACKGROUND: Ectopy-induced cardiomyopathy is an increasingly recognized cause of reversible left ventricular (LV) dysfunction. The underlying mechanisms remain unknown. Our goal was to create an animal model for ectopy-induced cardiomyopathy. METHODS: Eleven mongrel dogs underwent the implantation of a dual-chamber pacemaker. Four dogs served as the control group and seven as the paced group. In the paced group, the pacemaker was connected to two endocardial right ventricular leads, one inserted into the atrial port and the other one into the ventricular port with an atrioventricular delay adjusted to ensure the presence of coupled pacing simulating ventricular bigeminy. Echocardiographic measurements of LV size (LV end-diastolic diameter [LV-EDD], LV end-systolic diameter [LV-ESD]), LV ejection fraction (LVEF), and mitral regurgitation (MR) were obtained at baseline and after 4 weeks of monitoring or pacing in all dogs except one who had lead dislodgement. RESULTS: In the control group (n = 4), no significant changes in LV dimensions or function were noted. In the paced group (n = 6), LV-EDD and LV-ESD increased from 3.58 ± 0.65 cm and 2.47 ± 0.55 cm to 4.15 ± 0.59 cm and 3.21 ± 0.47 cm, respectively (P < 0.01). In addition, LVEF decreased from 60 ± 7% to 46 ± 9% (P < 0.05). No changes in MR were noted. CONCLUSION: We have shown that coupled pacing simulating ventricular bigeminy was feasible and resulted in increased LV dimensions and decreased LV function. By controlling the percentage of pacing, the coupling interval and the location of the pacing lead, this new model will allow the assessment of the relative roles of these variables in the development of ectopy-induced cardiomyopathy.

Incidence and Predictors of 30-day Acute Cerebrovascular Accidents Post Atrial Fibrillation Catheter Ablation (From the Nationwide Readmissions Database).

Catheter-based ablation is increasingly being used as first-line therapy for atrial fibrillation (AF). Cerebrovascular accidents (CVA) are a known complication. In this study, we investigate the 30-day incidence and predictors of acute CVA postcatheter ablation for AF. The Nationwide Readmissions Database from 2010 to September 2015 was queried for hospitalizations with an ablation procedure and a concurrent AF diagnosis. The primary end point was a composite end point of CVA during index admission or readmission for CVA within 30 days of admission for index hospitalization. The associations between the incidence of end points and the covariates of interest; which included age, gender, hospital characteristics (size, procedural volume, urban/rural status, and teaching status), CHA2DS2-VASc co-morbidity score and its components was assessed using logistic regression. Appropriate survey weighting methodology was applied to generate nationally representative estimates. Of 67,090 weighted hospitalizations for AF ablation, 566 (0.8%) had CVA within 30 days post-ablation. In multivariate regression analysis, factors associated with CVA included hypertension (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.04, 1.85), heart failure (OR 4.97, 95% CI 3.32, 7.44), previous stroke/ transient ischemic attack (OR 3.25, 95% CI 2.39, 4.42) and a lower procedural volume (OR for higher procedural volume: 0.6, 95% CI 0.42, 0.85). CHA2DS2-VASc score (OR 1.27, 95% CI 1.17, 1.39) was associated with CVA in univariate analysis. In conclusion, the CVA incidence within 30-day of catheter-based AF ablation therapy was 0.8%. Higher CHA2DS2-VASc score was associated with higher risk of CVA post-ablation. Hypertension, heart failure, previous stroke/transient ischemic attack, and procedural volume were independently associated with CVA post-ablation.

Renal sympathetic denervation in addition to pulmonary vein isolation reduces the recurrence rate of atrial fibrillation: an updated meta-analysis of randomized control trials.

BACKGROUND/PURPOSE: Atrial fibrillation (AF) is the most common arrhythmia worldwide. The sympathetic nervous system plays an important role in initiation and maintenance of AF. Recent studies have shown that renal sympathetic denervation (RSD) reduced AF recurrences after conventional pulmonary vein isolation (PVI). Studies that have evaluated the role of RSD as an adjuvant to PVI have included different patient populations, ablation strategies, and follow-up approaches. We performed a meta-analysis to assess the potential incremental impact of RSD to PVI. METHODS: We searched the databases of MEDLINE and EMBASE from inception to January 2020. Included studies were randomized controlled trials (RCTs) that compared the recurrence rates of AF in patients who underwent PVI and RSD versus PVI alone. Data from each study were combined using the random effects model to calculate odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: Three RCTs consisted of four different studies during 2014-2020 involving 451 AF patients (223 patients underwent PVI alone and 228 patients underwent PVI with RSD) were included in the meta-analysis. Compared with PVI alone, the PVI with RSD group had a significantly lower risk of AF recurrence (pooled OR = 0.63, 95%CI 0.50-0.80, p < 0.001, I2 = 0.0%). There was no publication bias observed in funnel plot as well as no small-study effect observed in Egger's test. CONCLUSIONS: Our systematic review and meta-analysis demonstrated a significant reduction of AF recurrence in select hypertensive patients who underwent RSD in addition to PVI compared with PVI alone. Larger studies are needed to validate the benefits of this approach in other AF populations and across different ablation strategies.

The effects of rate and rhythm control on blood pressure and antihypertensive drug usage in patients with atrial fibrillation and hypertension enrolled in the AFFIRM trial.

INTRODUCTION: Atrial fibrillation (AF) has been shown to be associated with activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and increased sympathetic activity, all of which could lead to hypertension (HTN). While the effects of HTN on AF incidence and arrhythmogenesis have been reported, the long-term effects of AF on blood pressure (BP) remain unknown. We hypothesized that a rate control strategy is associated with an increase in BP and/or antihypertensive drug therapy when compared with a rhythm control strategy in patients with a history of AF and HTN. METHODS AND RESULTS: Using the intention to treat method, BP readings and the number of antihypertensive medication categories were analyzed over the first year of follow-up in patients with AF and HTN enrolled in the AFFIRM trial. No clinically significant changes in BP occurred. Medication data were available in 2,876 patients. In the rate control group, 27.8% of patients required a net increase in the number of antihypertensive medications when compared to 18.3% in the rhythm control group (P < 0.001). Furthermore, 27.1% of patients in the rate control group had a net decrease in the number of antihypertensive medications when compared with 41.7% in the rhythm control group (P < 0.001). CONCLUSIONS: Our findings suggest that AF could be contributing to BP elevation in patients with a history of HTN and that a rhythm control strategy might result in a decrease in BP in these patients. This hypothesis however, requires future testing.

Reverse electrical remodeling of the ventricles following successful restoration of sinus rhythm in patients with persistent atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) has been shown to be associated with reduced survival and increased ventricular arrhythmogenesis. The purpose of this study was to assess the effects of AF with adequate rate control on the electrophysiologic properties of the ventricles. We hypothesized that AF results in increased ventricular arrhythmogenic risk and that reverse remodeling occurs post-successful cardioversion. METHODS: In nine patients with persistent AF, we recorded 12-lead electrocardiograms (ECGs) and 1-hour high-resolution Holter ECGs (H12+, Mortara Instrument, Inc. Milwaukee, WI, USA; recorders [1000 sps] immediately following cardioversion (Day 1) and after 30 days of maintaining sinus rhythm (Day 30). We measured QTc, QT dispersion, and calculated estimates of mean ventricular action potential duration (RT), diastolic interval (DI), T-wave width (TW), T-wave peak-to-end, and their respective scatter on Day 1 and Day 30. Maintenance of normal sinus rhythm was confirmed with a weekly trans-telephonic ECG transmission. RESULTS: The average QTc interval decreased from 449 ± 28 ms on Day 1 to 422 ± 36 ms on Day 30 (P = 0.04). There was no significant difference in the average QT dispersion. A significant decrease was also noted in DI and TW scatter at Day 30 when compared with Day 1 (P = 0.03 and 0.04, respectively). A decrease in RT scatter was also noted albeit not statistically significant (P = 0.07). CONCLUSION: Our results suggest a greater propensity to ventricular arrhythmogenesis in the immediate period following restoration of sinus rhythm and reverse electrical remodeling of the ventricles during the first month after successful maintenance of sinus rhythm. (PACE 2010; 33:1198-1202).

MRI of the left atrium: predicting clinical outcomes in patients with atrial fibrillation.

Atrial fibrillation is a significant public health burden, with clinically, epidemiologically and economically significant repercussions. In the last decade, catheter ablation has provided an improvement in morbidity and quality of life, significantly reducing long-term healthcare costs and avoiding recurrences compared with drug therapy. Despite recent progress in techniques, current catheter ablation success rates fall short of expectations. Late gadolinium-enhancement cardiovascular MRI is a well-established tool to image the myocardium and, most specifically, the left atrium. Unique imaging protocols allow for left atrial structural remodeling and fibrosis assessment, which has been demonstrated to correlate with clinical outcomes after catheter ablation, assessment of the individual's risks of thromboembolic events, and effective imaging of patients with left atrial appendage thrombus. Late gadolinium-enhancement MRI aids in the individualized treatment of atrial fibrillation, stratifying recurrence risk and guiding specific ablation strategies. Real-time MRI offers significant safety and effectiveness profiles that would optimize the invasive treatment of atrial fibrillation.

Real-time magnetic resonance imaging-guided radiofrequency atrial ablation and visualization of lesion formation at 3 Tesla.

BACKGROUND: Magnetic resonance imaging (MRI) allows visualization of location and extent of radiofrequency (RF) ablation lesion, myocardial scar formation, and real-time (RT) assessment of lesion formation. In this study, we report a novel 3-Tesla RT -RI based porcine RF ablation model and visualization of lesion formation in the atrium during RF energy delivery. OBJECTIVE: The purpose of this study was to develop a 3-Tesla RT MRI-based catheter ablation and lesion visualization system. METHODS: RF energy was delivered to six pigs under RT MRI guidance. A novel MRI-compatible mapping and ablation catheter was used. Under RT MRI, this catheter was safely guided and positioned within either the left or right atrium. Unipolar and bipolar electrograms were recorded. The catheter tip-tissue interface was visualized with a T1-weighted gradient echo sequence. RF energy was then delivered in a power-controlled fashion. Myocardial changes and lesion formation were visualized with a T2-weighted (T2W) half Fourier acquisition with single-shot turbo spin echo (HASTE) sequence during ablation. RESULTS: RT visualization of lesion formation was achieved in 30% of the ablations performed. In the other cases, either the lesion was formed outside the imaged region (25%) or the lesion was not created (45%) presumably due to poor tissue-catheter tip contact. The presence of lesions was confirmed by late gadolinium enhancement MRI and macroscopic tissue examination. CONCLUSION: MRI-compatible catheters can be navigated and RF energy safely delivered under 3-Tesla RT MRI guidance. Recording electrograms during RT imaging also is feasible. RT visualization of lesion as it forms during RF energy delivery is possible and was demonstrated using T2W HASTE imaging.

Evaluation of left atrial lesions after initial and repeat atrial fibrillation ablation: lessons learned from delayed-enhancement MRI in repeat ablation procedures.

BACKGROUND: We evaluated scar lesions after initial and repeat catheter ablation of atrial fibrillation (AF) and correlated these regions to low-voltage tissue on repeat electroanatomic mapping. We also identified gaps in lesion sets that could be targeted and closed during repeat procedures. METHODS AND RESULTS: One hundred forty-four patients underwent AF ablation and received a delayed-enhancement MRI at 3 months after ablation. The number of pulmonary veins (PV) with circumferential lesions were assessed and correlated with procedural outcome. Eighteen patients with AF recurrence underwent repeat ablation. MRI scar regions were compared with electroanatomic maps during the repeat procedure. Regions of incomplete scar around the PVs were then identified and targeted during repeat ablation to ensure complete circumferential lesions. After the initial procedure, complete circumferential scarring of all 4 PV antrum (PVA) was achieved in only 7% of patients, with the majority of patients (69%) having <2 completely scarred PVA. After the first procedure, the number of PVs with complete circumferential scarring and total left atrial wall (LA) scar burden was associated with better clinical outcome. Patients with successful AF termination had higher average total left atrial wall scar of 16.4%+/-9.8 (P=0.004) and percent PVA scar of 66.2+/-25.4 (P=0.01) compared with patients with AF recurrence who had an average total LA wall scar 11.3%+/-8.1 and PVA percent scar 50.0+/-24.7. In patients who underwent repeat ablation, the PVA scar percentage was 56.1%+/-21.4 after the first procedure compared with 77.2%+/-19.5 after the second procedure. The average total LA scar after the first ablation was 11.0%+/-4.1, whereas the average total LA scar after second ablation was 21.2%+/-7.4. All patients had an increased number of completely scarred pulmonary vein antra after the second procedure. MRI scar after the first procedure and low-voltage regions on electroanatomic mapping obtained during repeat ablation demonstrated a positive quantitative correlation of R(2)=0.57. CONCLUSIONS: Complete circumferential PV scarring difficult to achieve but is associated with better clinical outcome. Delayed-enhancement MRI can accurately define scar lesions after AF ablation and can be used to target breaks in lesion sets during repeat ablation.