Mavacamten decreases maximal force and Ca2+ sensitivity in the N47K-myosin regulatory light chain mouse model of hypertrophic cardiomyopathy.

Morbidity and mortality associated with heart disease is a growing threat to the global population, and novel therapies are needed. Mavacamten (formerly called MYK-461) is a small molecule that binds to cardiac myosin and inhibits myosin ATPase. Mavacamten is currently in clinical trials for the treatment of obstructive hypertrophic cardiomyopathy (HCM), and it may provide benefits for treating other forms of heart disease. We investigated the effect of mavacamten on cardiac muscle contraction in two transgenic mouse lines expressing the human isoform of cardiac myosin regulatory light chain (RLC) in their hearts. Control mice expressed wild-type RLC (WT-RLC), and HCM mice expressed the N47K RLC mutation. In the absence of mavacamten, skinned papillary muscle strips from WT-RLC mice produced greater isometric force than strips from N47K mice. Adding 0.3 µM mavacamten decreased maximal isometric force and reduced Ca2+ sensitivity of contraction for both genotypes, but this reduction in pCa50 was nearly twice as large for WT-RLC versus N47K. We also used stochastic length-perturbation analysis to characterize cross-bridge kinetics. The cross-bridge detachment rate was measured as a function of [MgATP] to determine the effect of mavacamten on myosin nucleotide handling rates. Mavacamten increased the MgADP release and MgATP binding rates for both genotypes, thereby contributing to faster cross-bridge detachment, which could speed up myocardial relaxation during diastole. Our data suggest that mavacamten reduces isometric tension and Ca2+ sensitivity of contraction via decreased strong cross-bridge binding. Mavacamten may become a useful therapy for patients with heart disease, including some forms of HCM.NEW & NOTEWORTHY Mavacamten is a pharmaceutical that binds to myosin, and it is under investigation as a therapy for some forms of heart disease. We show that mavacamten reduces isometric tension and Ca2+ sensitivity of contraction in skinned myocardial strips from a mouse model of hypertrophic cardiomyopathy that expresses the N47K mutation in cardiac myosin regulatory light chain. Mavacamten reduces contractility by decreasing strong cross-bridge binding, partially due to faster cross-bridge nucleotide handling rates that speed up myosin detachment.

The mechanism and prognosis of acute and late improvement in mitral regurgitation after cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) improves functional mitral regurgitation (MR); however, the mechanism and differences in acute and late improvement in MR are unclear. We aimed to evaluate the factors associated with the acute and late MR improvements and the prognosis of MR improvement after CRT. This retrospective study included 121 patients who underwent CRT implantation with full echocardiography assessment at baseline, 1 week, and 6 months after implantation. MR severity was classified into five grades (0: none to 4: severe). Two-dimensional speckle-tracking echocardiography with radial strain was used to assess dyssynchrony, and the time difference between the lateral and inferior segments at papillary muscle levels (TDlate-inf) was calculated. The MR improved 1 week and 6 months after CRT in 40 (33%) and 45 (37%) patients, respectively. On multivariate analyses, TDlate-inf (baseline-1 week) and SPWMD were independently associated with acute MR improvement. The %reduction in left ventricular end-systolic volume (LVESV) (baseline-6 months) and TDlate-inf (baseline-1 week) were independently correlated with late MR improvement. The patients with pre-MR grades 2-4 and improved MR after CRT showed significantly better prognosis in heart failure hospitalization. Cutoff values of ≥ 19.5 ms of the reduction of TDlate-inf and ≥ 30.8% of the %reduction of LVESV were significantly associated with the decrease in heart failure hospitalization. The improved interpapillary muscle activation time delay and volume reduction after CRT were associated with acute and late MR improvements. There may be different time course of recovery and distinct causes for late MR improvement.

Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain.

Myosin light chain 2 ( MYL2) gene encodes the myosin regulatory light chain (RLC) simultaneously in heart ventricles and in slow-twitch skeletal muscle. Using transgenic mice with cardiac-specific expression of the human R58Q-RLC mutant, we sought to determine whether the hypertrophic cardiomyopathy phenotype observed in papillary muscles (PMs) of R58Q mice is also manifested in slow-twitch soleus (SOL) muscles. Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force that was not observed in the fast-twitch extensor digitorum longus muscles of R58Q vs. wild-type-RLC mice, but mutant animals did not display gross muscle weakness in vivo. Consistent with SOL muscle abnormalities in R58Q vs. wild-type mice, myosin ATPase staining revealed a decreased proportion of fiber type I/type II only in SOL muscles but not in the extensor digitorum longus muscles. The similarities between SOL muscles and PMs of R58Q mice were further supported by quantitative proteomics. Differential regulation of proteins involved in energy metabolism, cell-cell interactions, and protein-protein signaling was concurrently observed in the hearts and SOL muscles of R58Q mice. In summary, even though R58Q expression was restricted to the heart of mice, functional similarities were clearly observed between the hearts and slow-twitch skeletal muscle, suggesting that MYL2 mutated models of hypertrophic cardiomyopathy may be useful research tools to study the molecular, structural, and energetic mechanisms of cardioskeletal myopathy associated with myosin RLC.-Kazmierczak, K., Liang, J., Yuan, C.-C., Yadav, S., Sitbon, Y. H., Walz, K., Ma, W., Irving, T. C., Cheah, J. X., Gomes, A. V., Szczesna-Cordary, D. Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain.

Multipolar mapping for catheter ablation of premature ventricular complexes originating from papillary muscles in the structurally normal heart: a case series.

BACKGROUND: Previous studies on radiofrequency catheter ablation of premature ventricular complexes (PVCs) arising from the left ventricle (LV) papillary muscles (PM) show a modest procedural success rate with higher recurrence rate. Our study sought to explore the utility of using a multipolar mapping with a steerable linear duodecapolar catheter for ablating the PM PVCs. METHODS: Detailed endocardial multipolar mapping was performed using a steerable linear duodecapolar catheter in 6 consecutive PM PVCs patients with structurally normal heart. The clinical features and procedural data as well as success rate were analysed. RESULTS: LV endocardial electroanatomic mapping was performed in all patients via a retrograde aortic approach using a duodecapolar mapping catheter. All patients displayed a PVC burden with 16.2 ± 5.4%. Duodecapolar catheter mapping demonstrated highly efficiency with an average procedure time (95.8 ± 7.4 min) and fluoroscopy time (14.2 ± 1.5 min). The mean number of ablation applications points was 6.8 ± 1.9 with an average overall ablation duration of 6.1 ± 3.0 min. The values of earliest activation time during mapping using duodecapolar catheter were 37.8 ± 7.2 ms. All patients demonstrated acute successful ablation, and the PVC burden in all patients after an average follow-up of 8.5 ± 2.0 months was only 0.7%. There were no complications during the procedures and after follow-up. CONCLUSIONS: Mapping and ablation of PM PVCs using a duodecapolar catheter facilitated the identification of earliest activation potentials and pace mapping, and demonstrated a high success rate during follow-up.

Intraventricular muscle bundle as a novel cause of left ventricular aneurysm.

BACKGROUND: There are a variety of causes of left ventricular aneurysm, but it is rarely due to a disturbance in intraventricular hemodynamics. To the best of our knowledge, there have been no reports of ventricular aneurysm at the left ventricular apex caused by an abnormal left ventricular muscle bundle. CASE PRESENTATION: We report two cases of patients with congenital abnormal left ventricular muscle bundles which caused disturbances in intraventricular hemodynamics. This process eventually led to a left ventricular aneurysm at the apex of the heart. In both cases, transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) indicated ventricular aneurysm formation at the apex of the left ventricle. There were also abnormal muscular bundles connecting the ventricular septum and the posterior wall of the left ventricle. The only differences between these two cases were the comorbidities and severity of symptoms. CONCLUSION: Ventricular aneurysm at the apex of the left ventricle is common. However, it is rare for a ventricular aneurysm to form due to intraventricular hemodynamic disturbances caused by an abnormal muscle bundle as opposed to that due to original ventricular wall damage, which is more common. There is currently a lack of relevant studies on the treatment and prognosis of such patients. Whether surgical resection of a ventricular aneurysm leads to a better prognosis remains uncertain.

Lipid Emulsion Restoration of Myocardial Contractions After Bupivacaine-Induced Asystole In Vitro: A Benefit of Long- and Medium-Chain Triglyceride Over Long-Chain Triglyceride.

BACKGROUND: The relative efficacies of a long- and medium-chain triglyceride (LCT/MCT) emulsion and an LCT emulsion for treatment of bupivacaine (BPV)-induced cardiac toxicity are poorly defined. METHODS: After inducing asystole by BPV, varied concentrations (1%-12%) of either LCT/MCT (Lipofundin; B. Braun, Melsungen, Germany) or LCT emulsion (Intralipid; Fresenius Kabi, Upsala, Sweden) were applied to observe the recovery of stimulated contractile responses and contractile forces in either a recirculating or washout condition for 60 minutes, using guinea pig papillary muscles. The recirculation condition was used to demonstrate BPV binding by lipid emulsion. The washout condition was used to determine whether the time-dependent recovery of contraction is due to their metabolic enhancement. Oxfenicine, an inhibitor of carnitine palmitoyltransferase I in heart mitochondria, was used to evaluate the effect of each lipid emulsion on mitochondrial metabolic inhibition by BPV. To examine the effect of the lipid emulsion alone on contractility, either lipid emulsion was examined. BPV concentrations in solution and myocardial tissues were measured. RESULTS: In the recirculating condition, LCT/MCT emulsions (2%-12%) restored regular stimulated contractile responses in all muscles. Eight percent and 12% LCT/MCT emulsions led to complete recovery of contractile forces after 30 minutes. Meanwhile, LCT emulsions (4%-12%) did not restore regular stimulated contractile responses in some muscles (6, 3, and 2 in 9 muscles each in 4%, 8%, and 12% emulsions, respectively). Partial recovery, approximately 60%, of contractile forces was observed with 8% and 12% LCT emulsions. In the washout experiments, after asystole, LCT/MCT emulsions (1%-12%) restored contractility to baseline levels earlier and greater than LCT emulsion. Partial recovery, approximately 60%, was observed with a high concentration of LCT emulsion (12%). In the oxfenicine-pretreated group, the contractile recovery was enhanced with LCT/MCT emulsion but showed no change with LCT emulsion. Contractile depression by 40% was observed with high concentrations of LCT emulsion alone (8% and 12%), whereas no depression or enhanced contraction was observed with LCT/MCT emulsion (1%-12%) alone. Both types of lipid emulsions (2%-12%) caused concentration-related reductions of tissue BPV levels; LCT/MCT emulsions reduced tissue BPV levels slightly greater than LCT emulsion in a recirculating condition. CONCLUSIONS: An LCT/MCT emulsion was more beneficial than an LCT emulsion in terms of local anesthetic-binding and metabolic enhancement for treating acute BPV toxicity. The metabolic benefit of MCT, combined with the local anesthetic-binding effect of LCT, in an LCT/MCT emulsion may improve contractile function better than an LCT emulsion in an isolated in vitro animal myocardium model.

Relations of Augmented Systolic Annular Expansion and Leaflet/Papillary Muscle Dynamics in Late-Systolic Mitral Valve Prolapse Evaluated by Echocardiography with a Speckle Tracking Analysis.

The mechanism of systolic annular expansion in mitral valve prolapse (MVP) is not clarified. Since annular expansion is systolic outward shift of MV leaflet/chorda tissue complex at superior and outer ends, annular expansion could be related to inward (superior) shift of the complex at another inferior and inner end of the papillary muscle (PM) tip and/or systolic lengthening of the tissue complex, especially MV leaflets.MV annulus systolic expansion, PMs' systolic superior shift, and MV leaflets' systolic lengthening were evaluated by echocardiography with a speckle tracking analysis in 25 normal subjects, 25 subjects with holo-systolic MVP and 20 subjects with late-systolic MVP.PMs' superior shift, MV leaflets' lengthening, MV annular area at the onset of systole and subsequent MV annulus expansion were significantly greater in late-systolic MVP than in holo-systolic MVP (4.6 ± 1.6 versus 1.5 ± 0.7 mm/m2, 2.5 ± 1.4 versus 0.6 ± 2.0 mm/m2, 6.8 ± 2.5 versus 5.7 ± 1.0 cm2/m2 and 1.6 ± 0.8 versus 0.1 ± 0.5 cm2/m2, P < 0.001, respectively). Multivariate analysis identified MV leaflets' lengthening and PMs' superior shift as independent factors associated with MV annular expansion.Conclusions: These results suggest that systolic MV annular expansion in MVP is related to abnormal MV leaflets' lengthening and PMs' superior shift.

Possible mechanism of late systolic mitral valve prolapse: systolic superior shift of leaflets secondary to annular dilatation that causes papillary muscle traction.

Progressive superior shift of the mitral valve (MV) during systole is associated with abnormal papillary muscle (PM) superior shift in late systolic MV prolapse (MVP). The causal relation of these superior shifts remains unclarified. We hypothesized that the MV superior shift is related to augmented MV superiorly pushing force by systolic left ventricular pressure due to MV annular dilatation, which can be corrected by surgical MV plasty, leading to postoperative disappearance of these superior shifts. In 35 controls, 28 patients with holosystolic MVP, and 28 patients with late systolic MVP, the MV coaptation depth from the MV annulus was measured at early and late systole by two-dimensional echocardiography. The PM tip superior shift was monitored by echocardiographic speckle tracking. MV superiorly pushing force was obtained as MV annular area × (systolic blood pressure - 10). Measurements were repeated after MV plasty in 14 patients with late systolic MVP. Compared with controls and patients with holosystolic MVP, MV and PM superior shifts and MV superiorly pushing force were greater in patients with late systolic MVP [1.3 (0.5) vs. 0.9 (0.6) vs. 3.9 (1.0) mm/m2, 1.3 (0.5) vs. 1.2 (1.0) vs. 3.3 (1.3) mm/m2, and 487 (90) vs. 606 (167) vs. 742 (177) mmHg·cm2·m-2, respectively, means (SD), P < 0.001]. MV superior shift was correlated with PM superior shift ( P < 0.001), which was further related to augmented MV superiorly pushing force ( P < 0.001). MV and PM superior shift disappeared after surgical MV plasty for late systolic MVP. These data suggest that MV annulus dilatation augmenting MV superiorly pushing force may promote secondary superior shift of the MV (equal to late systolic MVP) that causes subvalvular PM traction in patients with late systolic MVP. NEW & NOTEWORTHY Late systolic mitral valve prolapse (MVP) is associated with mitral valve (MV) and papillary muscle (PM) abnormal superior shifts during systole, but the causal relation remains unclarified. MV and PM superior shifts were correlated with augmented MV superiorly pushing force by annular dilatation and disappeared after surgical MV plasty with annulus size and MV superiorly pushing force reduction. This suggests that MV annulus dilatation may promote secondary superior shifts of the MV (late systolic MVP) that cause subvalvular PM traction.

Papillary muscle ventricular arrhythmias in patients with arrhythmic mitral valve prolapse: Electrophysiologic substrate and catheter ablation outcomes.

BACKGROUND: Mitral valve prolapse (MVP) is a common valve condition and has been associated with sudden cardiac death. Premature ventricular contractions (PVCs) from the papillary muscles (PMs) may play a role as triggers for ventricular fibrillation (VF) in these patients. OBJECTIVES: To characterize the electrophysiological substrate and outcomes of catheter ablation in patients with MVP and PM PVCs. METHODS: Of 597 patients undergoing ablation of ventricular arrhythmias during the period 2012-2015, we identified 25 patients with MVP and PVCs mapped to the PMs (64% female). PVC-triggered VF was the presentation in 4 patients and a fifth patient died suddenly during follow-up. The left ventricle ejection fraction (LVEF) was 50.5% ± 11.8% and PVC burden was 24.4% ± 13.1%. A cardiac magnetic resonance imaging was performed in nine cases and areas of late gadolinium enhancement were found in four of them. A detailed LV voltage map was performed in 11 patients, three of which exhibited bipolar voltage abnormalities. Complete PVC elimination was achieved in 19 (76%) patients and a significant reduction in PVC burden was observed in two (8%). In patients in which the ablation was successful, the PVC burden decreased from 20.4% ± 10.8% to 6.3% ± 9.5% (P = 0.001). In 5/6 patients with depressed LVEF and successful ablation, the LV function improved postablation. No significant differences were identified between patients with and without VF. CONCLUSIONS: PM PVCs are a source of VF in patients with MVP and can induce PVC-mediated cardiomyopathy that reverses after PVC suppression. Catheter ablation is highly successful with more than 80% PVC elimination or burden reduction.

In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice.

RATIONALE: Duchenne muscular dystrophy is a severe inherited form of muscular dystrophy caused by mutations in the reading frame of the dystrophin gene disrupting its protein expression. Dystrophic cardiomyopathy is a leading cause of death in Duchenne muscular dystrophy patients, and currently no effective treatment exists to halt its progression. Recent advancement in genome editing technologies offers a promising therapeutic approach in restoring dystrophin protein expression. However, the impact of this approach on Duchenne muscular dystrophy cardiac function has yet to be evaluated. Therefore, we assessed the therapeutic efficacy of CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing on dystrophin expression and cardiac function in mdx/Utr+/- mice after a single systemic delivery of recombinant adeno-associated virus. OBJECTIVE: To examine the efficiency and physiological impact of CRISPR-mediated genome editing on cardiac dystrophin expression and function in dystrophic mice. METHODS AND RESULTS: Here, we packaged SaCas9 (clustered regularly interspaced short palindromic repeat-associated 9 from Staphylococcus aureus) and guide RNA constructs into an adeno-associated virus vector and systemically delivered them to mdx/Utr+/- neonates. We showed that CRIPSR-mediated genome editing efficiently excised the mutant exon 23 in dystrophic mice, and immunofluorescence data supported the restoration of dystrophin protein expression in dystrophic cardiac muscles to a level approaching 40%. Moreover, there was a noted restoration in the architecture of cardiac muscle fibers and a reduction in the extent of fibrosis in dystrophin-deficient hearts. The contractility of cardiac papillary muscles was also restored in CRISPR-edited cardiac muscles compared with untreated controls. Furthermore, our targeted deep sequencing results confirmed that our adeno-associated virus-CRISPR/Cas9 strategy was very efficient in deleting the ≈23 kb of intervening genomic sequences. CONCLUSIONS: This study provides evidence for using CRISPR-based genome editing as a potential therapeutic approach for restoring dystrophic cardiomyopathy structurally and functionally.

Regularization-Free Strain Mapping in Three Dimensions, With Application to Cardiac Ultrasound.

Quantifying dynamic strain fields from time-resolved volumetric medical imaging and microscopy stacks is a pressing need for radiology and mechanobiology. A critical limitation of all existing techniques is regularization: because these volumetric images are inherently noisy, the current strain mapping techniques must impose either displacement regularization and smoothing that sacrifices spatial resolution, or material property assumptions that presuppose a material model, as in hyperelastic warping. Here, we present, validate, and apply the first three-dimensional (3D) method for estimating mechanical strain directly from raw 3D image stacks without either regularization or assumptions about material behavior. We apply the method to high-frequency ultrasound images of mouse hearts to diagnose myocardial infarction. We also apply the method to present the first ever in vivo quantification of elevated strain fields in the heart wall associated with the insertion of the chordae tendinae. The method shows promise for broad application to dynamic medical imaging modalities, including high-frequency ultrasound, tagged magnetic resonance imaging, and confocal fluorescence microscopy.

A Steam Pop Detected by Intracardiac Echocardiography During Catheter Ablation of the Left Ventricular Papillary Muscle.

A 60-year-old female with premature ventricular contractions (PVCs) originating from the bottom of the posteromedial papillary muscle of the left ventricle underwent radiofrequency catheter ablation (RFCA) using an irrigated-tip catheter. During ablation of the PVCs, a loud steam pop was observed. Intracardiac echocardiography (ICE) revealed a growing, hyperechogenic intramyocardial microbubble formation around the catheter tip. The formation disappeared slowly and completely, leaving an endocardial laceration without pericardial effusion. ICE imaging is valuable during a difficult RFCA procedure, because ICE reveals the exact anatomical position of the catheter and thus allows rapid evaluation of the occurrence of steam popping and any possible subsequent complication.

The tip of the muscle is a dominant location of ventricular ectopy originating from papillary muscles in the left ventricle.

INTRODUCTION: Frequent ventricular premature complexes (VPCs) may cause symptoms and/or lead to deterioration of LV systolic function. Although frequent VPCs may be abolished by catheter ablation, it may be challenging in case of their origin from the LV papillary muscles (PMs). Our collaborative study aimed to analyze in detail the site of origin and the outcome of ablation. METHODS: Consecutive 34 patients (males: 68%; aged 62 ± 12 years; LV ejection fraction: 50 ± 9%) undergoing catheter ablation of VPCs originating from PMs were included. All procedures were guided by intracardiac echocardiography. RESULTS: The size and shape of PMs were highly variable. The length of anterolateral and posteromedial PM was 23 ± 4 mm and 28 ± 7 mm, respectively. In about one-third of patients, the PM was formed by two distinctly separate heads. The ectopic foci were located on anterolateral, posteromedial or both PM in 35%, 56% and 9% of cases, respectively. Their location was found within the distal, mid, or proximal (basal) third of PM in the 67%, 19%, and 14%, respectively. A total of 86% of PM foci were acutely abolished and long-term success was achieved in 65% of patients. Absence of VPCs of other morphologies and a high burden of ectopic activity before ablation were associated with favorable clinical outcome. CONCLUSION: VPCs originate predominantly from the distal portion of the PM. This knowledge may facilitate the mapping in patients with infrequent ectopic beats. Intracardiac echocardiography is of crucial importance for navigation of the ablation catheter and for assessment of its stability at PM target sites.

Usefulness of pace mapping in catheter ablation of left ventricular papillary muscle ventricular arrhythmias with a preferential conduction.

INTRODUCTION: Preferential conduction from an origin to breakout sites can occur during ventricular arrhythmias (VAs) originating from the left ventricular papillary muscles (LVPMs). The purpose of this study was to investigate the incidence, electrophysiological characteristics, and relevance to radiofrequency catheter ablation (RFCA) of such a preferential conduction demonstrated by pace mapping. METHODS AND RESULTS: We studied 34 consecutive patients undergoing RFCA of 40 LVPM VAs. Among 78 QRS morphologies during these VAs, pace mapping was performed for 67 QRS morphologies during 37 VAs, and revealed VA-matched pace maps (M-PMs) with a latency for 14 QRS morphologies during 11 VAs (30%). Among 47 QRS morphologies with activation mapping, RFCA at the earliest activation site (EAS) was successful in 39, but not successful in 8 despite M-PMs with no latency. In these cases, RFCA was successful at remote sites of the M-PMs with latency (n = 6) and a site located between the EAS and site of that with latency (n = 1). Among the remaining 31 QRS morphologies with pace mapping only, RFCA was successful at M-PM sites with no latency in 17, and at M-PMs sites with latency in 7. In 3 of those 7 QRS morphologies, M-PMs were recorded at multiple remote sites, and RFCA was not successful at M-PM sites with no latency (n = 2) or a shorter latency (n = 1). CONCLUSIONS: When an M-PM with latency was recorded in LVPM VAs, RFCA at that site was highly successful. Attention should be paid to latency as well as the score during pace mapping of LVPM VAs.

Mechanistic subtypes of focal right ventricular tachycardia.

Idiopathic sustained focal right ventricular tachycardia (VT) is most frequently due to outflow tract (OT) tachycardia. This arrhythmia is recognized by its characteristic ECG pattern and sensitivity to adenosine. However, there are other forms of idiopathic, focal sustained VT that originate from the right ventricle (RV), which are less well appreciated and easily overlooked. This review will identify the characteristic features and electrophysiologic properties of these forms of RV VT, including those originating from the tricuspid annulus, right ventricular papillary muscles, and moderator band as well as variants of classic RVOT tachycardia and those due to microreentry in the presence of preclinical disease. Recognition of these subtypes of focal RV tachycardia should facilitate targeted therapy.

Imaging characteristics of papillary muscle site of origin of ventricular arrhythmias in patients with mitral valve prolapse.

BACKGROUND: Mitral valve prolapse has been associated with increased risk of ventricular arrhythmias. We aimed to examine whether certain cardiac imaging characteristics are associated with papillary muscle origin of ventricular arrhythmias in these patients. METHODS AND RESULTS: We screened electronic medical records of all patients documented to have mitral valve prolapse on either transthoracic echocardiogram (TTE) or cardiac magnetic resonance imaging (CMR) in our center, who also underwent an electrophysiologic study (EPS) between 2007 and 2016. Anterior and posterior mitral leaflet thickness and prolapsed distance were measured on TTE and late gadolinium enhancement (LGE) was assessed on CMR. Patients were categorized as papillary muscle positive (pap (+)) or negative (pap (-)) using EPS. Eighteen patients were included in this study. Of the 15 patients who underwent TTE, a significantly higher proportion of patients in the pap (+) group had an anterior to posterior leaflet prolapse ratio of >0.45 indicating more symmetric leaflet prolapse. There were no differences in anterior or posterior leaflet thickness or prolapse distance between the groups. Patients in the pap (+) group were more likely to be women. Of the 7 patients who underwent CMR, those who were pap (+) were more likely to have LGE in the region of the papillary muscles than those who were pap (-). CONCLUSION: Female gender, more symmetric bileaflet prolapse on TTE, and the presence of papillary muscle LGE on CMR may be associated with papillary muscle origin of ventricular arrhythmias in patients with mitral valve prolapse.

Surface electrocardiography characteristics and radiofrequency catheter ablation of idiopathic ventricular arrhythmias originating from the left infero-septal papillary muscles: differences from those originating from the left posterior fascicle.

Aims: Distinguishing between ventricular arrhythmias originating from the left ventricular infero-septal papillary muscles (PM) and those from the left posterior fascicle (LPF) by surface electrocardiography (ECG) is very difficult. This study aimed to report the ECG characteristics and radiofrequency catheter ablation of PM and LPF ventricular arrhythmias. Methods and results: A total of 127 patients underwent catheter ablation of idiopathic ventricular arrhythmias originating from the LPF (n = 106; 85 males; 10-70 years) or PM (n = 21; 14 males; 4-68 years) were studied. A three-dimensional electroanatomic system (3D-EAS) was used to aid ablation. PM ventricular arrhythmias had a longer QRS duration (154.4 ± 18.0 vs. 119.7 ± 12.6 ms, P < 0.001) than LPF ventricular arrhythmias. All 7 ventricular arrhythmias with QRS duration >160 ms originated from the PM, whereas all 87 ventricular arrhythmias with QRS duration <130 ms arose from the LPF. In 33 ventricular arrhythmias with QRS 130-160 ms, all 13 with Vi/Vt ≤ 0.85 originated from the PM, and 19 of 20 with Vi/Vt > 0.85 arose from the LPF. Of the 8 PM ventricular arrhythmias patients whose initial ablation was undertaken using a non-irrigated 4 mm-tip catheter, 1 failed and 6 recurred. However, of the remaining 13 ones using an irrigated catheter and the 3D-EAS, all succeeded and 2 recurred. No complications were noted in any patient. Conclusion: PM ventricular arrhythmias could be identified from LPF ventricular arrhythmias by calculation of QRS duration combined with Vi/Vt using ECG.

Comparison of robotic magnetic navigation-guided and manual catheter ablation of ventricular arrhythmias arising from the papillary muscles.

Aims: Due to the complex anatomy of the left ventricular (LV) and right ventricular (RV) papillary muscles (PMs), PM ventricular arrhythmias (VAs) can be challenging to target with ablation. We sought to compare the outcomes of robotic magnetic navigation-guided (RMN) ablation and manual ablation of VAs arising from the LV and RV PMs. Methods and results: We evaluated 35 consecutive patients (mean age 65 ± 12 years, 69% male) who underwent catheter ablation of 38 VAs originating from the LV and RV PMs as confirmed by intracardiac echocardiography. Catheter ablation was initially performed using RMN-guidance in 24 (69%) patients and manual guidance in 11 (31%) patients. Demographic and procedural data were recorded and compared between the two groups. The VA sites of origin were mapped to 20 (53%) anterolateral LV PMs, 14 (37%) posteromedial LV PMs, and 4 (11%) RV PMs Acute successful ablation was achieved for 20 (74%) VAs using RMN-guided ablation and 8 (73%) VAs using manual ablation (P = 1.000). Fluoroscopy times were significantly lower among patients undergoing RMN ablation compared to patients undergoing manual ablation [median 7.3, interquartile range (IQR) 3.9-18 vs. 24 (16-44) min; P = 0.005]. Retrograde transaortic approach was used in 1 (4%) RMN patients and 5 (46%) manual patients (P = 0.005). No procedural complications were seen in study patients. Conclusion: Use of an RMN-guided approach to target PM VAs results in comparable success rates seen with manual ablation but with lower fluoroscopy times and decreased use of transaortic retrograde access.

Effect of Antazoline on Electrophysiological Properties of Atrial Muscle and Conduction System of the Heart.

PURPOSE: Antazoline is a first-generation antihistaminic agent with additional anticholinergic properties and antiarrhythmic potential. Recent data shows its high effectiveness in sinus rhythm restoration among patients with paroxysmal atrial fibrillation. The effect of antazoline on electrophysiological parameters of the heart in vivo has not yet been examined. The aim of this study was to evaluate changes in electrophysiological parameters of the heart muscle and conduction system as a response to increasing doses of antazoline. METHODS: After successful ablation of supraventricular arrhythmias, the electrophysiological parameters: sinus rhythm cycle length (SRCL), AH, HV, QRS, QT, QTc intervals, Wenckebach point (WP), sinus node recovery period (SNRT), intra- (hRA-CSos) and interatrial conduction time (hRA-CSd), right and left atrium refractory period (RA-; LA-ERP), and atrioventricular node refractory period (AVN-ERP) were assessed initially and after 100, 200, and 300 mg of antazoline given intravenously. RESULTS: Fifteen patients (8 males, 19-72 years old) undergoing EPS and RF ablation were enrolled. After 100 mg bolus, a significant reduction in SRCL was noticed. After antazoline administration, significant prolongation of HV, QRS, QTc, hRA-CSos, hRA-CSd intervals, RA- and LA-ERP and reduction of SRCL were observed. After a total dose of 300 mg, QT interval prolonged significantly. Increasing the dose of antazoline had no impact on AH, Wenckebach point, AVN-ERP, and SNRT. CONCLUSION: Antazoline has an effect on electrophysiological parameters of the atrial muscle and has rapid onset of action. No negative effect on sinus node function and atrioventricular conduction in a unique property among antiarrhythmic drugs.

High-density mapping for catheter ablation of premature ventricular complexes originating from left ventricular papillary muscles: A case series.

PURPOSE: Ablation of premature ventricular complexes (PVCs) originating from left-sided papillary muscles is challenging. We tested a new approach by performing high-density mapping of PVC. METHODS AND RESULTS: We used a 20-pole deflectable spiral catheter during ablation procedures in four consecutive patients. Three presented with mitral valve prolapse, one with dilated cardiomyopathy. PVC burden was 24 ± 13%. The procedures lasted 182 ± 55.4 minutes, including 10 ± 3.2 minutes of radiofrequency. In all patients, mapping evidenced internal primary activation relative to the left ventricle shell (mean distance 21.3 ± 5.1 mm). Endocavitary prematurity was -38.3 ± 4.8 ms. Primary ablation success was achieved for all patients. CONCLUSIONS: High-density mapping of the papillary muscles in the left ventricle using a spiral catheter may be feasible. We identified the PVC foci away from the left ventricular shell. This consolidates the assumption for the origin of these ectopic beats at the junction between the chordae tendineae and the papillary muscles.