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OBJECTIVES: This study examined whether African American race was associated with an elevated risk of chronic kidney disease (CKD) post-cardiac transplantation. BACKGROUND: CKD often occurs after cardiac transplantation and may require renal replacement therapy (RRT) or renal transplant. African American patients have a higher risk for kidney disease as well as worse post-cardiac transplant morbidity and mortality. It is unclear, however, if there is a propensity for African Americans to develop CKD after cardiac transplant. METHODS: The Institutional Review Board of Columbia University Medical Center approved the retrospective study of 151 adults (57 African American and 94 non-African American) who underwent single-organ heart transplant from 2013-2016. The primary outcome was a decrease in estimated glomerular filtration rate (eGFR), development of CKD, and end stage renal disease (ESRD) requiring RRT after 2 years. RESULTS: African American patients had a significant decline in eGFR post-cardiac transplant compared to non-African American patients (−34 ± 6 vs. −20 ± 4 mL/min/1.73 m2, P

Prophylactic DeVega tricuspid annuloplasty (DVA) of the donor heart has been reported to improve tricuspid regurgitation (TR), renal dysfunction, and mortality in cardiac transplant recipients. This is the first study to investigate the electrical, as well as, hemodynamic effects of DVA during orthotopic heart transplantation (OHT). Electrocardiographic, echocardiographic, and hemodynamic data of 76 patients with DVA and 104 patients without DVA who underwent OHT between 2013 and 2017 at Columbia University Medical Center (New York, NY) were studied. Patients with DVA were older (56.5 ± 1.2 vs. 52.4 ± 1.0 years of age; p = 0.017) and predominantly men (78% vs. 68%; p = 0.02). There were no significant differences in right ventricular function and TR. Patients with DVA had increased incidence of right bundle branch block compared with without DVA (37% ± 5.9% vs. 9% ± 2.9%; p < 0.001). Three patients with DVA developed complete heart block (CHB), whereas no patients without DVA developed CHB (p = 0.04). Four patients with DVA received a pacemaker (PPM), whereas only one patient in the without DVA group received a PPM. Complete heart block was significantly increased in patients who received prophylactic DVA. Possible risk of conduction abnormalities should be considered with performance of DVA annuloplasty in cardiac transplant recipients.

Background Leadless pacemakers (LPMs) have been shown to have lower postoperative complications than traditional permanent pacemakers but there have been no studies on the outcomes of LPMs in patients with transcatheter heart valve replacements (THVRs). This study determined outcomes of LPMs compared to transvenous single-chamber pacemakers (SCPs) post-THVR. Methods This is a retrospective single-center study including 10 patients who received LPMs post-THVR between February 2017 and August 2018 and a comparison group of 23 patients who received SCP post-THVR between July 2008 and August 2018. LPM or SCP was implanted at the discretion of electrophysiologists for atrial fibrillation with slow ventricular response or sinus node dysfunction with need for single-chamber pacing only. Results LPMs were associated with decreased tricuspid regurgitation (P = 0.04) and decreased blood loss during implantation (7.5 ± 2.5 cc for LPMs vs 16.8 ± 3.2 cc for SCPs, P = 0.03). Five LPM patients had devices positioned in the right ventricular septum as seen on transthoracic echocardiogram. Frequency of ventricular pacing was similar between LPM and SCP groups. In the LPM group, one case was complicated by a pseudoaneurysm and one death was due to noncardiac causes. There was one pneumothorax and one pocket infection in the SCP group. Conclusions In this small retrospective study, LPMs were feasible post-THVR and found to perform as well as SCPs, had less intraprocedural blood loss, and were associated with less tricuspid regurgitation. Further, larger studies are required to follow longer-term outcomes and complications.

Reentrant cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF) are common cardiac arrhythmias that account for substantial morbidity and mortality throughout the world. However, the mechanisms and optimal ablation treatment strategies for such arrhythmias are still unclear. Using 2D optical mapping of a mouse model with AF and VF, we have identified regional heterogeneity of the action potential duration (APD) in the atria and ventricles of the heart as key drivers for the initiation and persistence of reentry. The purpose of this paper is to discuss theoretical patterns of dispersion, demonstrate patterns of dispersion seen in our mouse model and discuss the computational analysis of APD dispersion patterns. These analyses and discussions may lead to better understanding of dispersion patterns in patients with these arrhythmias, as well as help comprehend whether and how reducing dispersion can lead to arrhythmia risk stratification and treatment strategies for arrhythmias.

Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which require improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We cross-bred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mitochondrial catalase attenuated mitochondrial and cellular reactive oxygen species (ROS), and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidence of both spontaneous AF and pacing-induced after-depolarizations and AF was substantially reduced. Expression of mitochondrial catalase markedly reduced persistent Na+ current induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induces atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality. Recently, we created a mouse model with spontaneous and sustained AF caused by a mutation in the Na(V)1.5 channel (F1759A) that enhances persistent Na(+) current, thereby enabling the investigation of molecular mechanisms that cause AF and the identification of potentially novel treatment strategies. The mice have regional heterogeneity of action potential duration of the atria similar to observations in patients with AF. In these mice, we found that the initiation and persistence of the rotational reentrant AF arrhythmias, known as spiral waves or rotors, were dependent upon action potential duration heterogeneity. The centers of the rotors were localized to regions of greatest heterogeneity of the action potential duration. Pharmacologically attenuating the action potential duration heterogeneity reduced both spontaneous and pacing-induced AF. Computer-based simulations also demonstrated that the action potential duration heterogeneity is required to generate rotors that manifest as AF. Taken together, these findings suggest that action potential duration heterogeneity in mice and humans is one mechanism by which AF is initiated and that reducing action potential duration heterogeneity can lessen the burden of AF.

Background The use of intracardiac electrograms to guide atrial fibrillation (AF) ablation has yielded conflicting results. Objectives The authors evaluated the usefulness of spatiotemporal dispersion, a visually recognizable electric footprint of AF drivers, for the ablation of all forms of AF. Methods The authors prospectively enrolled 105 patients admitted for AF ablation. AF was sequentially mapped in both atria with a 20-pole PentaRay catheter. The authors tagged and ablated only regions displaying electrogram dispersion during AF. Results were compared to a validation set in which a conventional ablation approach was used (pulmonary vein isolation/stepwise approach). To establish the mechanism underlying spatiotemporal dispersion of AF electrograms, the authors conducted realistic numerical simulations of AF drivers in a 2-dimensional model and optical mapping of ovine atrial scar-related AF. Results Ablation at dispersion areas terminated AF in 95% of the 105 patients. After ablation of 17 ± 10% of the left atrial surface and 18 months of follow-up, the atrial arrhythmia recurrence rate was 15% after 1.4 ± 0.5 procedures per patient versus 41% in the validation set after 1.5 ± 0.5 procedures per patient (arrhythmia free-survival: 85% vs. 59%; log-rank p Conclusions The clustering of intracardiac electrograms exhibiting spatiotemporal dispersion is indicative of AF drivers. Their ablation allows for a nonextensive and patient-tailored approach to AF ablation. (Substrate Ablation Guided by High Density Mapping in Atrial Fibrillation [SUBSTRATE HD]; NCT02093949)

Objectives This study sought to evaluate the impact of a complex fractionated atrial electrogram (CFAE)–guided ablation strategy on atrial fibrillation (AF) dynamics in patients with persistent AF. Background It is still unclear whether complete pulmonary vein isolation (PVI) is required or if the ablation of well-delineated pulmonary vein (PV) subregions could achieve similar outcomes in persistent AF. Methods CFAE-guided ablations were performed in 76 patients (65.2 ± 10 years of age) with persistent AF. In 47 patients, we measured mean PVs and left atrial appendage (LAA) cycle length (CL) values (PV-CL and LAA-CL), before ablation and before AF termination. We defined “active” PVs as PV-CL ≤ LAA-CL, “rapid fires” as PV-CL ≤80% of LAA-CL, and “PV-LAA CL gradient” as a significant CL difference between the 2 regions. Results AF termination (sinus rhythm [SR] or atrial tachycardia [AT] conversion) occurred in 92% and SR conversion in 75%. The radiofrequency time for AF termination and total radiofrequency time were 26 ± 25 min and 61.1 ± 21.6 min, respectively. Thirty of 47 patients had active PV (with 19 PV “rapid fires”). Ablation significantly increased median CL, both at PVs and LAA from 188 ms (interquartile range [IQR]: 161 to 210 ms) to 227.5 ms (IQR: 200 to 256 ms) (p Conclusions CFAE-guided ablation leads to a large decrease in PV frequency of activation, preceding AF termination. A PV modulation approach, rather than complete PVI, may be preferable for persistent AF.

Pulmonary embolism (PE) is associated with atrial fibrillation (AF). This study sought to explore if the CHADS2 score could predict the prognosis of PE in patients with AF. In a tertiary hospital, 4,288 consecutive patients with diagnosis of PE were screened. In total, 305 patients with PE had AF and were included in this retrospective study. In-hospital outcome was defined as at least one of the following: death from any cause, need for intravenous catecholamine administration, endotracheal intubation, cardiopulmonary resuscitation, or thrombolytic therapy. The in-hospital outcome occurred in 10.2% of the patients. Patients with adverse outcome had higher CHADS2 score, CHA2DS2-VASc score, and simplified pulmonary embolism severity index (sPESI) score. The area under the receiver operating characteristics curve was 0.66, 0.62, and 0.71 for CHADS2 score, CHA2DS2-VASc score, and sPESI score, respectively, in predicting in-hospital outcome. The incidence of in-hospital outcome was 3.4 and 14.4% in sPESI = 0 and sPESI ≥1 groups (p

Background: The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI). Methods and Results: LAMI was created by ligating the atrial branch of the left anterior descending coronary artery. ECG loop recorders were implanted to monitor AF episodes. In 7 sheep, dantrolene—a ryanodine receptor blocker—was administered in vivo during the 8-day observation period (LAMI-D, 2.5 mg/kg, IV, BID). LAMI animals experienced numerous spontaneous AF episodes during the 8-day monitoring period that were suppressed by dantrolene (LAMI, 26.1±5.1; sham, 4.3±1.1; LAMI-D, 2.8±0.8; mean±SEM episodes per sheep, P 3 H]ryanodine binding to cardiac RyR2 (ryanodine receptors) in the ischemic zone. Dantrolene restored the physiological binding of CaM to RyR2. Conclusions: Atrial ischemia causes spontaneous AF episodes in sheep, caused by SFDs that initiate reentry. Nitroso–redox imbalance in the ischemic zone is associated with intense reactive oxygen species production and altered RyR2 responses to CaM. Dantrolene administration normalizes the CaM response, prevents LAMI-related SFDs, and AF initiation. These findings provide novel insights into the mechanisms underlying ischemia-related atrial arrhythmias.

Aims Transient ST-T elevation (STE) is a rare complication that occurs during transseptal catheterization. This study aims to delineate the incidence and characteristics of transient STE during transseptal catheterization for atrial fibrillation (AF) ablation. Methods and results Consecutive patients who underwent fluoroscopy-guided transseptal catheterization for circumferential pulmonary vein radiofrequency ablation in Beijing An Zhen Hospital from January 2006 to January 2013 were enrolled in this study. Out of 2965 patients with a total of 3452 transseptal catheterization procedures, 13 patients (0.38%, mean age 57 ± 8, 6 female, 12 paroxysmal AF, mean left atrial diameter 35.4 ± 3.8 mm) had STE. ST-T elevation occurred after transseptal puncture in 10 patients and after pulmonary vein venography in three patients. Systolic blood pressure (129 ± 10 vs. 104 ± 20 mmHg, P < 0.001), diastolic blood pressure (78 ± 6 vs. 64 ± 11 mmHg, P < 0.001), and heart rate (83 ± 19 bpm vs. 64 ± 23 b.p.m., P = 0.022) significantly decreased when STE occurred. Eleven patients complained of chest pain, one patient complained of dizziness, and one patient had no symptoms. Patients recovered in about 4.6 min (2–10 min) with dopamine or fast saline drip. Catheter ablation of AF was completed in all the 13 patients without sequelae or other complications. Four of the 13 patients (30.8%) had recurrence of AF after a mean follow-up of 21.7 months. Conclusion ST-T elevation is a rare complication associated with transseptal catheterization without sequelae. Catheter ablation of AF could be safely completed in these patients.

Background Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling. Objective To determine whether myofibroblasts contribute to atrial myocyte electromechanical remodeling via direct physical contact and platelet-derived growth factor (PDGF) signaling. Methods Myofibroblasts and myocytes from adult sheep atria were co-cultured for 24 hours. Alternatively adult sheep atrial myocytes were exposed to 1ng/mL recombitant PDGF AB peptide for 24 hours. Results Myocytes making contact with myofibroblasts demonstrated significant reduction (P ≤ .05) in peak L-type calcium current density, shortening of action potential duration (APD), and reduction in calcium transients. These effects were blocked by pretreatment with a PDGF-AB neutralizing anti-body. Heterocellular contact also severely disturbed the localization of the L-type calcium channel. Myocytes exposed to recombinant PDGF-AB peptide for 24 hours demonstrated reduced APD50, APD80 and Peak L-type calcium current. Pretreatment with a PDGF-AB neutralizing antibody prevented these effects. Finally, while control atrial myocytes did not respond in a 1:1 manner to pacing frequencies of 3Hz or higher, atrial myocytes from hearts that were tachypaced for 2 months and normal myocytes treated with PDGF-AB for 24 hours could be paced up to 10Hz. Conclusions In addition to leading to fibrosis, atrial myofibroblasts contribute to electromechanical remodeling of myocytes via direct physical contact and release of PDGF-AB, which may be a factor in PAF-induced remodeling.

The mechanisms by which acute left atrial ischemia (LAI) leads to atrial fibrillation (AF) initiation and perpetuation remain unclear.To investigate the electrophysiological mechanisms of AF perpetuation in the presence of regional atrial ischemia.LAI (90-minute ischemia) was obtained in isolated sheep hearts by selectively perfusing microspheres into the left anterior atrial artery. Two charge-coupled device cameras and several bipolar electrodes enabled recording from multiple atrial locations: with a dual-camera setup (protocol 1, n = 10, and protocol 1', n = 4, for biatrial or atrioventricular camera setups, respectively), in the presence of propranolol/atropine (1 μM) added to the perfusate after LAI (protocol 2, n = 3) and after a pretreatment with glibenclamide (10 μM; protocol 3, n = 4).Spontaneous AF occurred in 41.2% (7 of 17) of the hearts that were in sinus rhythm before LAI. LAI caused action potential duration shortening in both the ischemic (IZ) and nonischemic (NIZ) zones by 21% ± 8% and 34% ± 13%, respectively (pacing, 5 Hz; P.05 compared to baseline). Apparent impulse velocity was significantly reduced in the IZ but not in the NIZ (-65% ± 19% and 9% ± 18%; P = .001 and NS, respectively). During LAI-related AF, a significant NIZ maximal dominant frequency increase from 7.4 ± 2.5 to 14.0 ± 5.5 Hz (P.05) was observed. Glibenclamide, an ATP-sensitive potassium current (IKATP) channel blocker, averted LAI-related maximal dominant frequency increase (NIZ: LAI vs glibenclamide 14.0 ± 5.5 Hz vs 5.9 ± 1.3 Hz; P.05). An interplay between spontaneous focal discharges and rotors, locating at the IZ-NIZ border zone, maintained LAI-related AF.LAI leads to an IKATP conductance-dependent action potential duration shortening and spontaneous AF maintained by both spontaneous focal discharges and reentrant circuits locating at the IZ border zone.

Background— Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF), and left atrial (LA)-to-right atrial (RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in vivo the time course in atrial DF values from paroxysmal to persistent AF in sheep and testing the hypothesis that an LA-to-RA DF difference is associated with LA drivers in persistent AF. Methods and Results— AF was induced using RA tachypacing (n=8). Electrograms were obtained weekly from an RA lead and an implantable loop recorder implanted near the LA. DFs were determined for 5-second-long electrograms (QRST subtracted) during AF in vivo and in ex vivo optical mapping. Underlying structural changes were compared with weight-matched controls (n=4). After the first AF episode, DF increased gradually during a 2-week period (7±0.21 to 9.92±0.31 Hz; n=6; P P P Conclusions— In the sheep, transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in vivo together with enlargement of the posterior LA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.

Over the last decades, various cardiac ablation technologies and procedures have been developed for patients with drug-resistant cardiac arrhythmias. It is now widely accepted that in selected patient populations, catheter ablation is an advantageous alternative to lifelong pharmacologic treatment.1-3 Ablation consists of delivering physical energy locally to specific myocardial regions to abolish arrhythmogenic tissue. Regardless of the energy employed, be it radiofrequency energy, cryoenergy, laser, or ultrasound, ablation techniques are limited by the non-specific nature of the resultant cellular damage. Myocytes perpetuating the arrhythmia experience similar damage to that of bystander cells, such as fibroblasts, adipocytes or neurons. This can result in complications such as atrioesophageal fistula, pulmonary veins stenosis, or coronary artery injury.4-8 In addition, the lack of cellular discrimination increases the required energy for ablation and can prolong procedure times.

Atrial dilatation and myocardial stretch are strongly associated with atrial fibrillation (AF). However, the mechanisms by which the three-dimensional (3D) atrial architecture and heterogeneous stretch contribute to AF perpetuation are incompletely understood. We compared AF dynamics during stretch-related AF (pressure: 12 cmH(2)O) in normal sheep hearts (n = 5) and in persistent AF (PtAF, n = 8)-remodelled hearts subjected to prolonged atrial tachypacing. We hypothesized that, in the presence of stretch, meandering 3D atrial scroll waves (ASWs) anchor in regions of large spatial gradients in wall thickness.We implemented a high-resolution optical mapping set-up that enabled simultaneous epicardial- and endoscopy-guided endocardial recordings of the intact atria in Langendorff-perfused normal and PtAF (AF duration: 21.3 ± 11.9 days) hearts. The numbers and lifespan of long-lasting ASWs (3 rotations) were greater in PtAF than normal (lifespan 0.9 ± 0.5 vs. 0.4 ± 0.2 s/(3 s of AF), P0.05). Than normal hearts, focal breakthroughs interacted with ASWs at the posterior left atrium and left atrial appendage to maintain AF. In PtAF hearts, ASW filaments seemed to span the atrial wall from endocardium to epicardium. Numerical simulations using 3D atrial geometries (Courtemanche-Ramirez-Nattel human atrial model) predicted that, similar to experiments, filaments of meandering ASWs stabilized at locations with large gradients in myocardial thickness. Moreover, simulations predicted that ionic remodelling and heterogeneous distribution of stretch-activated channel conductances contributed to filament stabilization.The heterogeneous atrial wall thickness and atrial stretch, together with ionic and anatomic remodelling caused by AF, are the main factors allowing ASW and AF maintenance.

Heart disease, a leading cause of death in the developed world, is overwhelmingly correlated with arrhythmias, where heart muscle cells, myocytes, beat abnormally. Cardiac arrhythmias are usually managed by electric shock intervention, antiarrhythmic drugs, surgery, and/or catheter ablation. Despite recent improvements in techniques, ablation procedures are still limited by the risk of complications from unwanted cellular damage, caused by the nonspecific delivery of ablative energy to all heart cell types. We describe an engineered nanoparticle containing a cardiac-targeting peptide (CTP) and a photosensitizer, chlorin e6 (Ce6), for specific delivery to myocytes. Specificity was confirmed in vitro using adult rat heart cell and human stem cell-derived cardiomyocyte and fibroblast cocultures. In vivo, the CTP-Ce6 nanoparticles were injected intravenously into rats and, upon laser illumination of the heart, induced localized, myocyte-specific ablation with 85% efficiency, restoring sinus rhythm without collateral damage to other cell types in the heart, such as fibroblasts. In both sheep and rat hearts ex vivo, upon perfusion of CTP-Ce6 particles, laser illumination led to the formation of a complete electrical block at the ablated region and restored the physiological rhythm of the heart. This nano-based, cell-targeted approach could improve ablative technologies for patients with arrhythmias by reducing currently encountered complications.

Objectives This study used advanced optical mapping techniques to examine atrial fibrillation (AF) dynamics before and after 2 distinct electrogram-based ablation strategies: complex fractionated atrial electrograms (CFAEs) and DFmax/rotor ablation. Background Among the electrogram analytical features proposed to unravel the atrial regions that perpetuate AF, CFAEs, highest dominant frequency sites (DFmax), and, more recently, phase analysis-enabled rotor mapping have received the largest attention. Still, the mechanisms by which these approaches modulate AF dynamics and lead to AF termination are unknown. Methods In Langendorff-perfused sheep hearts, AF was maintained by the continuous perfusion of acetylcholine and high-resolution endocardial-epicardial optical videos were recorded from the left atrial free wall and the posterior left atrium. Then, DFmax/rotor regions (n = 7), or CFAE regions harboring the highest wavebreak density (HWD) (n = 5), were targeted with a 4F ablation catheter (5 to 15 W, 30 to 60 s/point). Thereafter, we examined the changes in AF dynamics and whether AF terminated. Results DFmax/rotor point ablation resulted in a significant decrease in DFmax values. In 2 animals AF terminated, whereas in the remaining 5 animals the post-ablation DFmax domain remained in the vicinity of its pre-ablation location. However, after HWD/CFAEs density ablation, DFmax values did not change, AF did not terminate, and post-ablation DFmax domains relocated from the left atrial free wall to the pulmonary vein–posterior left atrium region. In another group of hearts (n = 12), we observed that upon a progressive increase in acetylcholine concentration—mimicking the acute electrophysiological changes occurring after ablation—3-dimensional rotors drifted from one atrial region to another along large gradients of myocardial thickness. Conclusions “On-target” DFmax/rotor ablation leads to the annihilation of the fibrillation-driving rotor. This translates into large decreases in AF frequency or AF termination. In contrast, “nearly missed” HWD/CFAEs ablation spares the fibrillation-driving rotor, and set the stage for rotor drift along large myocardial thickness gradients.

Background Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown. Objective To determine the mechanisms underlying electrophysiological effects of palmitic (PA), stearic (SA) and oleic (OA) FFAs on sheep atrial myocytes. Methods We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min), short-term (4–6 hour) or 24-hour application of individual FFAs (10 μM) on isolated ovine left atrial myocytes (LAMs). Results Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs). 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p

Introduction: Recently, electrogram-based ablation strategies aiming at reentrant atrial fibrillation (AF) sources have demonstrated substantial efficacy. Still, the mechanisms by which these strategies modulate AF dynamics are unknown. Objective: Here, we employed advanced optical mapping approaches to examine AF dynamics before and after two distinct electrogram-based ablation strategies: highest dominant frequency sites/rotor ablation (DFmax/rotor, “on-target”); and complex fractionated atrial electrograms ablation (CFAE, “nearly-missed”). Methods: We implemented a high-resolution optical mapping set-up that enabled simultaneous epicardial and endoscopy guided endocardial recordings in Langendorff-perfused sheep hearts. After inducing AF in the presence of continuous perfusion of acetylcholine (ACh), we recorded optical movies from the left atrial free wall (LAFW) as well as the posterior left atrium (PLA). Then, DFmax regions (n=4) or CFAE regions harboring the highest wavebreak density (HWD, n=5) were targeted with a 4F ablation catheter (5-15W, 30-60 sec/point). Results: On-target DFmax/rotor point ablation resulted in a significant decrease in bi-atrial DFmax values (18.02±3.16 to 12.9±2.6, p Conclusions: On-target DFmax/rotor ablation leads to large decreases in AF frequency and AF termination. In contrast, nearly-missed CFAE/HWD ablation leads to scroll wave relocation and/or drift along large myocardial thickness gradients.

In this issue of Circulation , readers will find a fascinating study presented by Dr Haissaguerre and several members of a promising and newly created institute for cardiovascular research located in Bordeaux, France, the LIRYC (L’institut de Rythmologie et de Modelisation Cardiaque [The Institute for Arrhythmia and Computer Modeling Research]).1 This is yet another pioneering contribution from the Bordeaux group that, if confirmed, may improve the management of patients with persistent atrial fibrillation (AF). Article see p 530 AF is commonly classified as paroxysmal (PAF) or persistent (PsAF), depending on the duration of the arrhythmic episodes, 7 days.2 PsAF may also be subclassified as long-standing persistent (LPsAF) when fibrillation has been continuous for >1 year.2 In the late 1990s, Dr Haissaguerre and team’s seminal work indicated that, in patients with PAF, a catheter ablation procedure may be targeted at discrete pulmonary vein (PV) electric foci and that PV electric isolation from the remainder of the atrial muscle may prevent AF reinitiation.3,4 Although the exact nature of PV foci has never been fully elucidated, this procedure proved successful in terminating AF and in preventing its recurrence.5,6 Later, a consensus emerged to propose PV isolation to patients with PAF, alone or in combination with an antiarrhythmic drug therapy.2 Thereafter, many suggested that this procedure may also improve the outcome of patients with PsAF,7–9 with, however, the need for adjustments in the ablation strategy.8–11 Despite these efforts, the success rate of catheter ablation for patients with PsAF, let alone LPsAF, has remained substantially lower than that of PAF ablation.5,6 A nearly unanimous view is that ablation works well for PAF but that the procedure is more tedious and the outcome less predictable …

Background— Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Methods and Results— Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (Ca V 1.2, Na V 1.5, and K V 4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up. Conclusions— In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.

RATIONALE: Doppler echocardiography has been demonstrated to be accurate in diagnosing valvular lesions in rheumatic heart disease (RHD) when compared to clinical evaluation alone. OBJECTIVE: To perform Doppler echocardiography in children clinically diagnosed by the Jones criteria to have acute rheumatic fever (ARF), and to then compare the effectiveness of echo in detecting single/multi-valvular lesions with that of the initial clinical evaluation. METHODS AND RESULTS: We enrolled 93 children who were previously diagnosed with ARF by clinical examination. Presence of valvular lesions were enlisted, first by clinical auscultation, and then by performing Doppler echocardiography. We found that Doppler echocardiography was a sensitive technique, capable of detecting valvular lesions that were missed by clinical auscultation alone. Echocardiography of patients with carditis revealed mitral regurgitation to be the most common lesion present (53 patients, 56.98%), followed by aortic regurgitation in 21 patients (22.6%). The difference between clinical and echocardiographic diagnosis in ARF children with carditis was statistically significant for mitral regurgitation, aortic regurgitation and tricuspid regurgitation. Clinical auscultation alone revealed 4 cases of mitral stenosis, 39 mitral regurgitation, 14 aortic regurgitation, 9 tricuspid regurgitation; in contrast, echo revealed 5 cases of mitral stenosis, 53 mitral regurgitation, 21 aortic regurgitation, 18 tricuspid regurgitation. CONCLUSION: Doppler echocardiography is a more sensitive technique for detecting valvular lesions. In the setting of ARF, echo enables a 46.9% higher detection level of carditis, as compared to the clinical examination alone. Echo was very significant in detecting regurgitation lesions, especially for cases of tricuspid regurgitation in the setting of multivalvular involvement. The results of our study are in accordance with previous clinical studies, all of which clearly demonstrate the advantages of Doppler echocardiography, paving the way for its probable inclusion as one of the Jones major criteria for diagnosing ARF.

Background Radiofrequency ablation (RFA) has proven to be an effective and safe treatment in patients with ventricular and atrial tachyarrhythmias. Among complications arising after RFA, the incidence of coronary artery (CA) injury is exceedingly low. When CA injury does occur, however, it can be clinically devastating. The proximity of CAs to common ablation sites suggests that the relationship between RFA and CA perfusion pathophysiology is important for optimal lesion formation and safe arrhythmia treatments. Objective Although others have described the presentation and outcomes of patients with CA injury after ablation, a review that consolidates the mechanisms of CA injury after RFA has yet to be presented in the cardiology literature. Methods We conducted an extensive literature search of studies published over the past 30 years that relate the biophysics of RFA with CA perfusion pathophysiology and injury. Results We present a review of the dynamic relationship between RFA and CA perfusion. We describe RFA lesion pathology, mechanisms of CA injury from RFA, and factors that influence lesion formation, such as convective cooling and the shadow effect. Conclusion We summarize methods to mitigate CA injury after RFA and propose new research avenues to optimize lesion formation and safe arrhythmia treatments when tissue is ablated in the vicinity of CAs.

Coronary anatomy has traditionally focused on ventricular circulation. This is largely due to the extent to which coronary artery disease contributes to ischemic heart disease through ventricular myocardial damage. Atrial fibrillation and other tachyarrhythmias that involve the atria, however, remain a major cause of morbidity and mortality. In order to increase mechanistic research and therapeutic interventional procedures for diseases of the atria, an optimal knowledge of atrial anatomy is necessary. While substantial clarity exists regarding the distribution of nerve terminals and the organization of muscle bundles, the anatomy of coronary atrial circulation remains understudied. Historically, the high anatomical variability of atrial coronary branches led to unstandardized nomenclature in the literature. In this review, we delineate the anatomic courses of key atrial coronary branches and their perfusion territories, clarify their nomenclature, and propose unifying anatomical concepts of atrial circulation that we believe to be critical to the success of modern electrophysiologic and surgical procedures.

Bisphosphonates are widely employed to decrease bone loss in disorders characterized by increased osteoclast-mediated bone resorption, such as senile osteoporosis.1 While generally well tolerated, side effects such as an acute inflammatory phase reaction, osteonecrosis of the jaw, gastro-intestinal disorders or hypocalcemia have been described.1 Also, contradictory reports of an association between atrial fibrillation (AF) and the use bisphosphonates has led to confusing statements and sent mixed messages to practitioners and patients.2 Details on these conflicting observations are summarized in previously published review articles.1-3 Interestingly, several hypotheses linking bisphosphonates to the onset of AF have been formulated: an acute increase in pro-inflammatory cytokines, disturbances in calcium homeostasis or extra-cellular matrix remodeling.2 To date, however, none of these premises have been tested, the mechanisms by which bisphosphonates may impact cardiac electrophysiology are unknown, and as of late 2008, the Food and Drug Administration failed to identify a clear association and concluded that no change in prescribing practices was warranted.1, 2 In this issue of the Journal of Cardiovascular Electrophysiology, Bonilla et al. present a multi-faceted investigation describing plausible mechanisms for bisphosphonates-induced cardiac arrhythmias. Their results have substantial mechanistic depth and, albeit provocative, put at question the previous status quo on an association between bisphosphonates and cardiac arrhythmias. The authors started their work with a clinical observation compatible, although inconclusively, with a bisphosphonate-induced arrhythmia. A 55 year old female having had a single dose of ibandronate-a commonly used bisphosphonate- experienced syncope and subsequently presented with QT/QTc interval prolongation which normalized following ibandronate discontinuation. Based upon this suspicious observation, the authors conducted a comprehensive basic and translational investigation which included a 3-month treatment of canines with ibandronate, subsequent cell electrophysiology-patch-clamp and intra-cellular calcium- measurements, and numerical simulations. The authors demonstrate clearly that ibandronate exerts a massive effect on myocyte electrophysiology. First the APD is about 30-40% prolonged with early after depolarizations arising significantly more after ibandronate perfusion. Also, the authors noticeably show that the repolarizing current Ito is reduced by ibandronate-both slope conductance and maximal density, but also that ibandronate-related APD changes are heavily dependent on the sarcoplasmic reticulum (SR) calcium-controlling receptor, the ryanodine receptor (RyR). When the RyR was blocked after ryanodine perfusion, or that the calcium was chelated with BAPTA, none of the APD changes described above were seen. Besides, ibandronate treatment caused a significant increase in calcium load and a decrease in calcium spark amplitude, while spark intensity was rebounding during washout. The latter observation could be an important insight as the pro-arrhythmic action may follow bisphosphonates withdrawal rather than associate with its use. Altogether, two seemingly independent mechanisms were probably at play: a decrease in repolarization reserve with a decreased Ito current, and RyR blocking action with increased SR load.In silico, an additional potentially critical finding was that the forward RyR inactivation rate may underlie bisphosphonate-related Ito current decrease and APD prolongation. Although the means by which the former is mechanistically related to the latter remain unclear, these original mechanisms are likely additive as both were needed to mimic experimental APD prolongation. Hence, this well-conducted study yields solid evidence that ibandronate-and presumably other bisphosphonates- adversely modulate cardiac myocyte electrophysiology. Nonetheless, it is uncertain whether these findings translate to the organ or the in vivo realities. As pointed out by the authors, compensatory mechanisms such as inter-cellular communication, a modulation of the autonomic nervous input, or an increased inflammation could sum up to a much lesser effect that the one seen in isolated cells. Still, the work presented by Bonilla et al. stands as a compelling mechanistic dataset which helps in appreciating bisphosphonates' impact on cardiac electrophysiology. This effort warrants further investigation to clarify cellular mechanisms, and to assess whether atrial myocytes are similarly sensitive to bisphosphonates. Also, this work is a call for clinical studies focused on a detailed analysis of the time period following bisphosphonates withdrawal. Altogether, Bonilla et al. observations are a strong scholarly incentive for a comprehensive research programaiming at elucidating the effects of bisphosphonates on the heart.

The authorshave implemented an isolated canine perfused right atrialpreparation—appended to a rim of right ventricular tissue—and recorded atrial and ventricular transmembrane actionpotentials and pseudo-electrograms before and after intra-coronary perfusion of various concentrations of WenxinKeli. Interestingly, Wenxin Keli produced effects more no-ticeable in atrial tissue than in ventricular tissue, as it causedaction potential duration (APD) shortening and postrepolar-ization refractoriness—which is a prolongation of effectiverefractory periods without APD prolongation—in an atrial-selective manner. In addition, Wenxin Keli produced agreater reduction in the maximum rate of rise of the actionpotential upstroke and a larger increase in the diastolicthreshold for excitation in atrial vs ventricular cells, sug-gestive of I

Background Photodynamic therapy (PDT) consists of generating exquisitely localized cell damage by laser illumination of a tissue previously perfused with photosensitizing substances. Our goal was to adapt this approach to achieve cell-specific cardiac ablation. Here, we present preliminary results demonstrating feasibility in vivo. Methods In vivo PDT ablation was performed in anesthetized rats after left lateral thoracotomy and exposure of the left atrium (Figure B). Then, a PDT-enabling nanoplatform—10-nm/8-arm PEG conjugated to chlorine (Ce6) and to the cardiac targeting peptide (CTP), as photosensitizer and targeting agent, respectively—was injected in the tail vein. After 15–60 minutes, 300-mW 671-nm laser light was directed toward the left atrium. Results Ce6 fluorescence intensity profile (Figure A) showed that PDT nanoplatform myocardial delivery and targeting were highly tissue specific. During in vivo PDT ablation, local left atrial appendages (LAA) electrogram amplitude was monitored as a surrogate indicator of ablation success. Before PDT nanoplatform injection and in sham experiments in which the PDT nanoplatform was not injected, LAA local electrogram amplitude did not change after laser illumination (13.1% ± 4.6%, P = .36, N=3). However, after PDT nanoplatform injection, laser illumination led to rapid myocardial ablation, and LAA electrogram local signal amplitude was reduced by 95% in nontargeted free Ce6 injected rats (88.3% ± 10.1%, P P Conclusions Our preliminary data strongly support the feasibility of nanoplatform-enabled and tissue-specific PDT ablation.

Background Ranolazine inhibits the peak Na+ current in the atria and has been shown to suppress paroxysmal atrial fibrillation (PxAF). However, the underlying mechanisms are not clear, and its antiarrhythmic efficacy in persistent AF (PsAF) is unknown. Methods We investigated the effects of ranolazine in Langendorff-perfused sheep hearts. PxAF was induced by burst pacing during acute stretch (12 mm H2O; N = 5). PsAF was induced in chronically implanted animals (single-chamber pacemaker, right atrial lead) by intermittent pacing (20 Hz) maintained for 6 months (N = 3). Epicardial and endocardial optical mapping of the left atrial appendage (LAA) and the posterior left atrium (PLA), respectively, was performed simultaneously. Following a control period of 50 minutes of AF, 10 μM ranolazine was perfused for 20 minutes. If sinus rhythm (SR) was not restored, the concentration of ranolazine was increased to 20 μM. LAA samples were taken for Western blot (WB) analysis to determine the expression of Na+ channel protein (NaV1.5) in PxAF vs PsAF. Results In PxAF, the baseline dominant frequency (DF) in the PLA was 10.1 ± 1.6 Hz. Ranolazine at 10 μM decreased DF to 7.2 ± 0.9 Hz (P = .008, N = 5) and terminated AF in all hearts after 15 ± 4 minutes. Ranolazine also significantly decreased the number of singularity points (SP) in PxAF (51.9 ± 11.9/cm2 to 29.5 ± 4.6/cm2, per 5 seconds, P = .005). AF could be reinduced in 4 5 hearts, but was nonsustained (median duration = 28 seconds). In PsAF, baseline DF in the PLA was 10.9 ± 2.9 Hz. Ranolazine 10 μM decreased DF to 7.2 ± 1.1 Hz (P = .05, N = 3) but did not terminate AF. Increasing concentration to 20 μM decreased DF to 5.8 ± 1.1 Hz (P = .019) but without reversal to SR. Ranolazine did not decrease the SP in PsAF, even at 20 μM (17.3 ± 3.6/cm2 to 10.7 ± 3.6/cm2, per 5 seconds, P = NS). WB analysis of LAA showed a 59.4% decrease in NaV1.5 in PsAF (N = 3) compared with PxAF (N = 3, P Conclusions Ranolazine exerts an antiarrhythmic effect in PxAF by reducing both DF and SP. In contrast, ranolazine did not terminate PsAF despite reducing DF. This is partly due to the lack of effect of ranolazine in altering the number of SP (representing wavebreaks), thus allowing AF to sustain, and may be related to electrical and/or structural remodeling of the atria occurring in PsAF.