Journal: Circ Arrhythm Electrophysiol

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Abstract

Drug Interactions Affecting Antiarrhythmic Drug Use.

Mar PL, Horbal P, Chung MK, Dukes JW, ... Gopinathannair R, from the American Heart Association Electrocardiography and Arrhythmias Committee of the Council of Clinical Cardiology
Antiarrhythmic drugs (AAD) play an important role in the management of arrhythmias. Drug interactions involving AAD are common in clinical practice. As AADs have a narrow therapeutic window, both pharmacokinetic as well as pharmacodynamic interactions involving AAD can result in serious adverse drug reactions ranging from arrhythmia recurrence, failure of device-based therapy, and heart failure, to death. Pharmacokinetic drug interactions frequently involve the inhibition of key metabolic pathways, resulting in accumulation of a substrate drug. Additionally, over the past 2 decades, the P-gp (permeability glycoprotein) has been increasingly cited as a significant source of drug interactions. Pharmacodynamic drug interactions involving AADs commonly involve additive QT prolongation. Amiodarone, quinidine, and dofetilide are AADs with numerous and clinically significant drug interactions. Recent studies have also demonstrated increased morbidity and mortality with the use of digoxin and other AAD which interact with P-gp. QT prolongation is an important pharmacodynamic interaction involving mainly Vaughan-Williams class III AAD as many commonly used drug classes, such as macrolide antibiotics, fluoroquinolone antibiotics, antipsychotics, and antiemetics prolong the QT interval. Whenever possible, serious drug-drug interactions involving AAD should be avoided. If unavoidable, patients will require closer monitoring and the concomitant use of interacting agents should be minimized. Increasing awareness of drug interactions among clinicians will significantly improve patient safety for patients with arrhythmias.



Circ Arrhythm Electrophysiol: 02 May 2022:101161CIRCEP121007955; epub ahead of print
Mar PL, Horbal P, Chung MK, Dukes JW, ... Gopinathannair R, from the American Heart Association Electrocardiography and Arrhythmias Committee of the Council of Clinical Cardiology
Circ Arrhythm Electrophysiol: 02 May 2022:101161CIRCEP121007955; epub ahead of print | PMID: 35491871
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Abstract

Relationship Between Maximal Left Ventricular Wall Thickness and Sudden Cardiac Death in Childhood Onset Hypertrophic Cardiomyopathy.

Norrish G, Ding T, Field E, Cervi E, ... Kaski JP, ERN GUARD-HEART*
Background
Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort.
Methods
The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids).
Results
MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk.
Conclusions
In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.



Circ Arrhythm Electrophysiol: 02 May 2022:CIRCEP121010075; epub ahead of print
Norrish G, Ding T, Field E, Cervi E, ... Kaski JP, ERN GUARD-HEART*
Circ Arrhythm Electrophysiol: 02 May 2022:CIRCEP121010075; epub ahead of print | PMID: 35491873
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Abstract

New-Onset Atrial Fibrillation in Patients Hospitalized With COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Registry.

Rosenblatt AG, Ayers C, Rao A, Howell SJ, ... de Lemos JA, Das SR
Background
New-onset atrial fibrillation (AF) in patients hospitalized with COVID-19 has been reported and associated with poor clinical outcomes. We aimed to understand the incidence of and outcomes associated with new-onset AF in a diverse and representative US cohort of patients hospitalized with COVID-19.
Methods
We used data from the American Heart Association COVID-19 Cardiovascular Disease Registry. Patients were stratified by the presence versus absence of new-onset AF. The primary and secondary outcomes were in-hospital mortality and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, stroke, cardiogenic shock, and heart failure). The association of new-onset AF and the primary and secondary outcomes was evaluated using Cox proportional-hazards models for the primary time to event analyses.
Results
Of the first 30 999 patients from 120 institutions across the United States hospitalized with COVID-19, 27 851 had no history of AF. One thousand five hundred seventeen (5.4%) developed new-onset AF during their index hospitalization. New-onset AF was associated with higher rates of death (45.2% versus 11.9%) and MACE (23.8% versus 6.5%). The unadjusted hazard ratio for mortality was 1.99 (95% CI, 1.81-2.18) and for MACE was 2.23 (95% CI, 1.98-2.53) for patients with versus without new-onset AF. After adjusting for demographics, clinical comorbidities, and severity of disease, the associations with death (hazard ratio, 1.10 [95% CI, 0.99-1.23]) fully attenuated and MACE (hazard ratio, 1.31 [95% CI, 1.14-1.50]) partially attenuated.
Conclusions
New-onset AF was common (5.4%) among patients hospitalized with COVID-19. Almost half of patients with new-onset AF died during their index hospitalization. After multivariable adjustment for comorbidities and disease severity, new-onset AF was not statistically significantly associated with death, suggesting that new-onset AF in these patients may primarily be a marker of other adverse clinical factors rather than an independent driver of mortality. Causality between the MACE composites and AF needs to be further evaluated.



Circ Arrhythm Electrophysiol: 27 Apr 2022:101161CIRCEP121010666; epub ahead of print
Rosenblatt AG, Ayers C, Rao A, Howell SJ, ... de Lemos JA, Das SR
Circ Arrhythm Electrophysiol: 27 Apr 2022:101161CIRCEP121010666; epub ahead of print | PMID: 35475654
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Abstract

Intramural Needle Ablation for Refractory Premature Ventricular Contractions.

Dukkipati SR, Nakamura T, Nakajima I, Oates C, ... Stevenson WG, Reddy VY
Background
Frequent premature ventricular contractions (PVCs) are often amenable to catheter ablation. However, a deep intramural focus may lead to failure due to inability of standard ablation techniques to penetrate the focus. We sought to assess the efficacy and safety of infusion needle ablation (INA) for PVCs that are refractory to standard radiofrequency ablation.
Methods
Under 2 Food and Drug Administration approved protocols, INA was evaluated in patients with frequent PVCs that were refractory to standard ablation. Initial targets for ablation were selected by standard mapping techniques. INA was performed with a deflectable catheter equipped with an extendable/retractable needle at the tip that can be extended up to 12 mm into the myocardium and is capable of pacing and recording. After contrast injection for location assessment, radiofrequency ablation was performed with the needle tip using a temperature-controlled mode (maximum temperature 60 °C) with saline infusion from the needle. The primary end point was a decrease in PVC burden to <5000/24 hours at 6 months. The primary safety end point was incidence of procedure- or device-related serious adverse events.
Results
At 4 centers, 35 patients (age 55.3±16.9 years, 74.2% male) underwent INA. The baseline median PVC burden was 25.4% (interquartile range, 18.4%-33.9%) and mean left ventricular ejection fraction was 37.7±12.3%. Delivering 10.3±8.0 INA lesions/patient (91% had adjunctive standard radiofrequency ablation also) resulted in acute PVC elimination in 71.4%. After a mean follow-up of 156±109 days, the primary efficacy end point was met in 73.3%. The median PVC burden decreased to 0.8% (interquartile range, 0.1%-6.0%; P<0.001). The primary safety end point occurred in 14.3% consisting of 1 (2.9%) heart block, 1 (2.9%) femoral artery dissection, and 3 (8.6%) pericardial effusions (all treated percutaneously).
Conclusions
INA is effective for the elimination of frequent PVCs that are refractory to conventional ablation and is associated with an acceptable safety profile.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT01791543 and NCT03204981.



Circ Arrhythm Electrophysiol: 27 Apr 2022:101161CIRCEP121010020; epub ahead of print
Dukkipati SR, Nakamura T, Nakajima I, Oates C, ... Stevenson WG, Reddy VY
Circ Arrhythm Electrophysiol: 27 Apr 2022:101161CIRCEP121010020; epub ahead of print | PMID: 35476455
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Abstract

GENESIS: Gene-Specific Machine Learning Models for Variants of Uncertain Significance Found in Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome-Associated Genes.

Draelos RL, Ezekian JE, Zhuang F, Moya-Mendez ME, ... Henao R, Landstrom AP
Background
Cardiac channelopathies such as catecholaminergic polymorphic tachycardia and long QT syndrome predispose patients to fatal arrhythmias and sudden cardiac death. As genetic testing has become common in clinical practice, variants of uncertain significance (VUS) in genes associated with catecholaminergic polymorphic ventricular tachycardia and long QT syndrome are frequently found. The objective of this study was to predict pathogenicity of catecholaminergic polymorphic ventricular tachycardia-associated RYR2 VUS and long QT syndrome-associated VUS in KCNQ1, KCNH2, and SCN5A by developing gene-specific machine learning models and assessing them using cross-validation, cellular electrophysiological data, and clinical correlation.
Methods
The GENe-specific EnSemble grId Search framework was developed to identify high-performing machine learning models for RYR2, KCNQ1, KCNH2, and SCN5A using variant- and protein-specific inputs. Final models were applied to datasets of VUS identified from ClinVar and exome sequencing. Whole cell patch clamp and clinical correlation of selected VUS was performed.
Results
The GENe-specific EnSemble grId Search models outperformed alternative methods, with area under the receiver operating characteristics up to 0.87, average precisions up to 0.83, and calibration slopes as close to 1.0 (perfect) as 1.04. Blinded voltage-clamp analysis of HEK293T cells expressing 2 predicted pathogenic variants in KCNQ1 each revealed an ≈80% reduction of peak Kv7.1 current compared with WT. Normal Kv7.1 function was observed in KCNQ1-V241I HEK cells as predicted. Though predicted benign, loss of Kv7.1 function was observed for KCNQ1-V106D HEK cells. Clinical correlation of 9/10 variants supported model predictions.
Conclusions
Gene-specific machine learning models may have a role in post-genetic testing diagnostic analyses by providing high performance prediction of variant pathogenicity.



Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010326
Draelos RL, Ezekian JE, Zhuang F, Moya-Mendez ME, ... Henao R, Landstrom AP
Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010326 | PMID: 35357185
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Abstract

Electrocardiographic Findings, Arrhythmias, and Left Ventricular Involvement in Familial ST-Depression Syndrome.

Christensen AH, Vissing CR, Pietersen A, Tfelt-Hansen J, ... Olesen MS, Bundgaard H
Background
Familial ST-depression syndrome is an inherited disease characterized by persistent, nonischemic ST-deviations, and risk of arrhythmias and heart failure. We aimed at further characterizing the ECG, arrhythmias, and structural characteristics associated with this novel syndrome.
Methods
Retrospective analysis of data from consecutive families with familial ST-depression Syndrome in Denmark. ECG features, prevalence and type of arrhythmias, occurrence of systolic dysfunction, and medium-term outcome were analyzed.
Results
Forty affected individuals (43% men; mean age at diagnosis 49.1 years) from 14 apparently unrelated families with ≥2 affected members were included. Autosomal dominant inheritance was observed in all families. The ECG phenotype seemed to develop in prepuberty and the ST-deviations were persistent and most pronounced in leads V4/V5/II, respectively. Serial ECG analyses showed stable to slow progression of the ECG phenotype. Exercise accentuated the ST-deviations with a maximum difference between rest/stress (mean) of -117 μV in lead V5. During a mean follow-up of 9.3±7.1 years 5 (13%) patients developed sustained ventricular arrhythmias or (aborted) sudden cardiac death, 10 (25%) developed atrial fibrillation, 2 (5%) other supraventricular arrhythmias, and 10 (25%) were diagnosed with left ventricular ejection fraction ≤50%. The ventricular arrhythmias were polymorphic with relatively short-coupled premature ventricular contractions at onset (300-360 ms); no QT prolongation was observed. Seven patients had at least one catheter ablation; 5 for supraventricular arrhythmias and 2 for ventricular arrhythmias. Males experienced more arrhythmic end points than females (P<0.01).
Conclusions
The familial ST-depression ECG phenotype is stable to slowly progressive after medium-term follow-up. Clinically, both supra- and ventricular arrhythmias are common; as are some degree of left ventricular systolic dysfunction. Familial ST-depression represent a novel inherited cause of polymorphic ventricular tachycardia.



Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010688
Christensen AH, Vissing CR, Pietersen A, Tfelt-Hansen J, ... Olesen MS, Bundgaard H
Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010688 | PMID: 35357203
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Abstract

90 vs 50-Watt Radiofrequency Applications for Pulmonary Vein Isolation: Experimental and Clinical Findings.

Bortone A, Albenque JP, Ramirez FD, Haïssaguerre M, ... Jaïs P, Pambrun T
Background
Fifty-watt radiofrequency applications have proven to be safe and efficient for pulmonary vein isolation (PVI). However, as PV reconnection still occurs and ablation catheter instability significantly contributes to suboptimal lesion formation, a new ablation catheter capable of delivering 90 W for 4 seconds only has been developed with the aim of improving PVI outcomes. In this setting, we sought to determine whether 90 W applications create transmural lesions without collateral damage experimentally and whether they can safely improve PVI procedures clinically compared with 50 W settings.
Methods
Experimentally, individual lesions were created in vivo in the right atrium of 6 swine with 90 W-4 seconds applications using the SmartTouch-SF catheter in a power-controlled mode (3 animals) or the QDOT-MICRO catheter in a temperature-controlled mode (3 animals). Clinically, PVI was performed in a homogenous population of 150 consecutive paroxysmal atrial fibrillation patients using CARTO and the QDOT-MICRO catheter in a temperature-controlled mode (75 patients 50 W-ablation index-guided and 75 patients 90 W-4 seconds).
Results
Mostly, (94.9%) experimental lesions were transmural in the thin-walled right atrium of swine. However, collateral damage was observed with both catheters in 17.9% of lesions. Clinically, 90 W procedures had a lower first-pass PVI rate (49% versus 81%, P<10-4) and a higher acute PV reconnection rate (21% versus 5%, P=0.004) than 50 W procedures, whereas total procedural duration (62 versus 66 minutes, P=0.09), 1-year sinus rhythm maintenance (88% versus 90%, P=0.6) and safety (1 tamponade per group) were similar in both groups.
Conclusions
Experimentally, using the QDOT-MICRO catheter, 90 W-4 seconds lesions are mostly transmural in the thin-walled right atrium of swine (median depth 1.87 mm) with a moderate lesion diameter of 6.62 mm but retain the potential for collateral damage. Clinically, 90 W-4 seconds applications are associated with a lower first-pass PVI rate and a higher acute PV reconnection rate than 50 W applications but similar safety outcomes and effectiveness at 1 year.



Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010663
Bortone A, Albenque JP, Ramirez FD, Haïssaguerre M, ... Jaïs P, Pambrun T
Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010663 | PMID: 35363039
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Abstract

P Wave Parameters and Indices: A Critical Appraisal of Clinical Utility, Challenges, and Future Research-A Consensus Document Endorsed by the International Society of Electrocardiology and the International Society for Holter and Noninvasive Electrocardiology.

Chen LY, Ribeiro ALP, Platonov PG, Cygankiewicz I, ... Bayés-de-Luna A, Baranchuk A
Atrial cardiomyopathy, characterized by abnormalities in atrial structure and function, is associated with increased risk of adverse cardiovascular and neurocognitive outcomes, independent of atrial fibrillation. There exists a critical unmet need for a clinical tool that is cost-effective, easy to use, and that can diagnose atrial cardiomyopathy. P wave parameters (PWPs) reflect underlying atrial structure, size, and electrical activation; alterations in these factors manifest as abnormalities in PWPs that can be readily ascertained from a standard 12-lead ECG and potentially be used to aid clinical decision-making. PWPs include P wave duration, interatrial block, P wave terminal force in V1, P wave axis, P wave voltage, P wave area, and P wave dispersion. PWPs can be combined to yield an index (P wave index), such as the morphology-voltage-P-wave duration ECG risk score. Abnormal PWPs have been shown in population-based cohort studies to be independently associated with higher risks of atrial fibrillation, ischemic stroke, sudden cardiac death, and dementia. Additionally, PWPs, either individually or in combination (as a P wave index), have been reported to enhance prediction of atrial fibrillation or ischemic stroke. To facilitate translation of PWPs to routine clinical practice, additional work is needed to standardize measurement of PWPs (eg, via semiautomated or automated measurement), confirm their reliability and predictive value, leverage novel approaches (eg, wavelet analysis of P waves and machine learning algorithms), and finally, define the risk-benefit ratio of specific interventions in high-risk individuals. Our ultimate goal is to repurpose the ubiquitous 12-lead ECG to advance the study, diagnosis, and treatment of atrial cardiomyopathy, thus overcoming critical challenges in prevention of cardiovascular disease and dementia.



Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010435
Chen LY, Ribeiro ALP, Platonov PG, Cygankiewicz I, ... Bayés-de-Luna A, Baranchuk A
Circ Arrhythm Electrophysiol: 31 Mar 2022; 15:e010435 | PMID: 35333097
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Abstract

On the Electrophysiology and Mapping of Intramural Arrhythmic Focus.

Anderson RD, Rodriguez Padilla J, Joens C, Masse S, ... Vigmond E, Nanthakumar K
Background
Conventional mapping of focal ventricular arrhythmias relies on unipolar electrogram characteristics and early local activation times. Deep intramural foci are common and associated with high recurrence rates following catheter-based radiofrequency ablation. We assessed the accuracy of unipolar morphological patterns and mapping surface indices to predict the site and depth of ventricular arrhythmogenic focal sources.
Methods
An experimental beating-heart model used Langendorff-perfused, healthy swine hearts. A custom 56-pole electrode array catheter was positioned on the left ventricle. A plunge needle was placed perpendicular in the center of the grid to simulate arrhythmic foci at variable depths. Unipolar electrograms and local activation times were generated. Simulation models from 2 human hearts were also included with grids positioned simultaneously on the endocardium-epicardium from multiple left ventricular, septal, and outflow tract sites.
Results
A unipolar Q or QS complex lacks specificity for superficial arrhythmic foci, as this morphology pattern occupies a large surface area and is the predominant pattern as intramural depth increases without developing a R component. There is progressive displacement from the arrhythmic focus to the surface exit as intramural focus depth increases. A shorter total activation time over the overlying electrode array, larger surface area within initial 20 ms activation, and a dual surface breakout pattern all indicate a deep focus.
Conclusions
Displacement from the focal intramural origin to the exit site on the mapping surface could lead to erroneous lesion delivery strategies. Traditional unipolar electrogram features lack specificity to predict the intramural arrhythmic source; however, novel endocardial-epicardial mapping surface indices can be used to determine the depth of arrhythmic foci.



Circ Arrhythm Electrophysiol: 24 Mar 2022:CIRCEP121010384; epub ahead of print
Anderson RD, Rodriguez Padilla J, Joens C, Masse S, ... Vigmond E, Nanthakumar K
Circ Arrhythm Electrophysiol: 24 Mar 2022:CIRCEP121010384; epub ahead of print | PMID: 35323037
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Abstract

Electrophysiology and Arrhythmogenesis in the Human Right Ventricular Outflow Tract.

Aras K, Gams A, Faye R, Brennan J, ... Bernus O, Efimov IR
Background
Right ventricular outflow tract (RVOT) is a common source of ventricular tachycardia, which often requires ablation. However, the mechanisms underlying the RVOT\'s unique arrhythmia susceptibility remain poorly understood due to lack of detailed electrophysiological and molecular studies of the human RVOT.
Methods
We conducted optical mapping studies in 16 nondiseased donor human RVOT preparations subjected to pharmacologically induced adrenergic and cholinergic stimulation to evaluate susceptibility to arrhythmias and characterize arrhythmia dynamics.
Results
We found that under control conditions, RVOT has shorter action potential duration at 80% repolarization relative to the right ventricular apical region. Treatment with isoproterenol (100 nM) shortened action potential duration at 80% repolarization and increased incidence of premature ventricular contractions (P=0.003), whereas acetylcholine (100 μM) stimulation alone had no effect on action potential duration at 80% repolarization or premature ventricular contractions. However, acetylcholine treatment after isoproterenol stimulation reduced the incidence of premature ventricular contractions (P=0.034) and partially reversed action potential duration at 80% repolarization shortening (P=0.029). Immunolabeling of RVOT (n=4) confirmed the presence of cholinergic marker VAChT (vesicular acetylcholine transporter) in the region. Rapid pacing revealed RVOT susceptibility to both concordant and discordant alternans. Investigation into transmural arrhythmia dynamics showed that arrhythmia wave fronts and phase singularities (rotors) were relatively more organized in the endocardium than in the epicardium (P=0.006). Moreover, there was a weak but positive spatiotemporal autocorrelation between epicardial and endocardial arrhythmic wave fronts and rotors. Transcriptome analysis (n=10 hearts) suggests a trend that MAPK (mitogen-activated protein kinase) signaling, calcium signaling, and cGMP-PKG (protein kinase G) signaling are among the pathways that may be enriched in the male RVOT, whereas pathways of neurodegeneration may be enriched in the female RVOT.
Conclusions
Human RVOT electrophysiology is characterized by shorter action potential duration relative to the right ventricular apical region. Cholinergic right ventricular stimulation attenuates the arrhythmogenic effects of adrenergic stimulation, including increase in frequency of premature ventricular contractions and shortening of wavelength. Right ventricular arrhythmia is characterized by positive spatial-temporal autocorrelation between epicardial-endocardial arrhythmic wave fronts and rotors that are relatively more organized in the endocardium.



Circ Arrhythm Electrophysiol: 02 Mar 2022:CIRCEP121010630; epub ahead of print
Aras K, Gams A, Faye R, Brennan J, ... Bernus O, Efimov IR
Circ Arrhythm Electrophysiol: 02 Mar 2022:CIRCEP121010630; epub ahead of print | PMID: 35238622
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Abstract

Novel Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family.

Kato K, Isbell HM, Fressart V, Denjoy I, ... Shea MA, Guicheney P
Background
CaM (calmodulin), encoded by 3 separate genes (CALM1, CALM2, and CALM3), is a multifunctional Ca2+-binding protein involved in many signal transduction events including ion channel regulation. CaM variants may present with early-onset long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, or sudden cardiac death. Most reported variants occurred de novo. We identified a novel CALM3 variant, p.Asn138Lys (N138K), in a 4-generation family segregating with LQTS. The aim of this study was to elucidate its pathogenicity and to compare it with that of p.D130G-CaM-a variant associated with a severe LQTS phenotype.
Methods
We performed whole exome sequencing for a large, 4-generation family affected by LQTS. To assess the effect of the detected CALM3 variant, the intrinsic Ca2+-binding affinity was measured by stoichiometric Ca2+ titrations and equilibrium titrations. L-type Ca2+ and slow delayed rectifier potassium currents (ICaL and IKs) were recorded by whole-cell patch-clamp. Cav1.2 and Kv7.1 membrane expression were determined by optical fluorescence assays.
Results
We identified 14 p.N138K-CaM carriers in a family where 2 sudden deaths occurred in children. Several members were only mildly affected compared with CaM-LQTS patients to date described in literature. The intrinsic Ca2+-binding affinity of the CaM C-terminal domain was 10-fold lower for p.N138K-CaM compared with WT-CaM. ICaL inactivation was slowed in cells expressing p.N138K-CaM but less than in p.D130G-CaM cells. Unexpectedly, a larger IKs current density was observed in cells expressing p.N138K-CaM, but not for p.D130G-CaM, compared with WT-CaM.
Conclusions
The p.N138K CALM3 variant impairs Ca2+-binding affinity of CaM and ICaL inactivation but potentiates IKs. The variably expressed phenotype of this variant compared with previously published de novo LQTS-CaM variants is likely explained by a milder impairment of ICaL inactivation combined with IKs augmentation.



Circ Arrhythm Electrophysiol: 27 Feb 2022:CIRCEP121010572; epub ahead of print
Kato K, Isbell HM, Fressart V, Denjoy I, ... Shea MA, Guicheney P
Circ Arrhythm Electrophysiol: 27 Feb 2022:CIRCEP121010572; epub ahead of print | PMID: 35225649
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Abstract

Orthostatic Hypotension: Management of a Complex, But Common, Medical Problem.

Fedorowski A, Ricci F, Hamrefors V, Sandau KE, ... Gopinathannair R, Olshansky B
Orthostatic hypotension (OH), a common, often overlooked, disorder with many causes, is associated with debilitating symptoms, falls, syncope, cognitive impairment, and risk of death. Chronic OH, a cardinal sign of autonomic dysfunction, increases with advancing age and is commonly associated with neurodegenerative and autoimmune diseases, diabetes, hypertension, heart failure, and kidney failure. Management typically involves a multidisciplinary, patient-centered, approach to arrive at an appropriate underlying diagnosis that is causing OH, treating accompanying conditions, and providing individually tailored pharmacological and nonpharmacological treatment. We (1) propose a novel streamlined pathophysiological classification of OH; (2) review the relationship between the cardiovascular disease continuum and OH; (3) discuss OH-mediated end-organ damage; (4) provide diagnostic and therapeutic algorithms to guide clinical decision making and patient care; (5) identify current gaps in knowledge and try to define future research directions. Using a case-based learning approach, specific clinical scenarios are presented highlighting various presentations of OH to provide a practical guide to evaluate and manage patients who have OH.



Circ Arrhythm Electrophysiol: 24 Feb 2022:CIRCEP121010573; epub ahead of print
Fedorowski A, Ricci F, Hamrefors V, Sandau KE, ... Gopinathannair R, Olshansky B
Circ Arrhythm Electrophysiol: 24 Feb 2022:CIRCEP121010573; epub ahead of print | PMID: 35212554
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Abstract

Natriuretic Peptide Oligomers Cause Proarrhythmic Metabolic and Electrophysiological Effects in Atrial Myocytes.

Yang Z, Subati T, Kim K, Murphy MB, ... Barnett JV, Murray KT
Background
With aging, the human atrium invariably develops amyloid composed of ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide). Preamyloid oligomers are the primary cytotoxic species in amyloidosis, and they accumulate in the atrium during human hypertension and a murine hypertensive model of atrial fibrillation susceptibility. We tested the hypothesis that preamyloid oligomers derived from natriuretic peptides cause cytotoxic and electrophysiological effects in atrial cells that promote arrhythmia susceptibility and that oligomer formation is enhanced for a mutant form of ANP linked to familial atrial fibrillation.
Methods
Oligomerization was assessed by Western blot analysis. Bioenergic profiling was performed using the Seahorse platform. Mitochondrial dynamics were investigated with immunostaining and gene expression quantitated using RT quantitative polymerase chain reaction. Action potentials and ionic currents were recorded using patch-clamp methods and intracellular calcium measured using Fura-2.
Results
Oligomer formation was markedly accelerated for mutant ANP (mutANP) compared with WT (wild type) ANP. Oligomers derived from ANP, BNP, and mutANP suppressed mitochondrial function in atrial HL-1 cardiomyocytes, associated with increased superoxide generation and reduced biogenesis, while monomers had no effects. In hypertensive mice, atrial cardiomyocytes displayed reduced action potential duration and maximal dV/dT of phase 0, with an elevated resting membrane potential, compared with normotensive mice. Similar changes were observed when atrial cells were exposed to oligomers. mutANP monomers produced similar electrophysiological effects as mutANP oligomers, likely due to accelerated oligomer formation, while ANP and BNP monomers did not. Oligomers decreased Na+ current, inward rectifier K+ current, and L-type Ca++ current, while increasing sustained and transient outward K+ currents, to account for these effects.
Conclusions
These findings provide compelling evidence that natriuretic peptide oligomers are novel mediators of atrial arrhythmia susceptibility. Moreover, the accelerated oligomerization by mutANP supports a role for these mediators in the pathophysiology of this mutation in atrial fibrillation.



Circ Arrhythm Electrophysiol: 24 Feb 2022:CIRCEP121010636; epub ahead of print
Yang Z, Subati T, Kim K, Murphy MB, ... Barnett JV, Murray KT
Circ Arrhythm Electrophysiol: 24 Feb 2022:CIRCEP121010636; epub ahead of print | PMID: 35212578
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Abstract

Open-Label, Multicenter Study of Flecainide Acetate Oral Inhalation Solution for Acute Conversion of Recent-Onset, Symptomatic Atrial Fibrillation to Sinus Rhythm.

Crijns HJGM, Elvan A, Al-Windy N, Tuininga YS, ... Belardinelli L, INSTANT Investigators
Background
Oral and intravenous flecainide is recommended for cardioversion of atrial fibrillation. In this open-label, dose-escalation study, the feasibility of delivering flecainide via oral inhalation (flecainide acetate inhalation solution) for acute conversion was evaluated. We hypothesized that flecainide delivered by oral inhalation would quickly reach plasma concentrations sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation.
Methods
Patients (n=101) with symptomatic atrial fibrillation (for ≤48 hours) self administered flecainide acetate inhalation solution using a nebulizer (30 mg [n=10], 60 mg [n=22], 90 mg [n=21], 120 mg [n=19], and 120 mg in a formulation containing saccharin [n=29]). Electrocardiograms and flecainide plasma concentrations were obtained, cardiac rhythm using 4-hour Holter was monitored, and adverse events were recorded.
Results
Conversion rates increased with dose and with the maximum plasma concentrations of flecainide. At the highest dose, 48% of patients converted to sinus rhythm within 90 minutes from the start of inhalation. Among patients who achieved a maximum plasma concentration >200 ng/mL, the conversion rate within 90 minutes was 50%; for those who achieved a maximum plasma concentration <200 ng/mL, it was 24%. Conversion was rapid (median time to conversion of 8.1 minutes from the end of inhalation), and conversion led to symptom resolution in 86% of the responders. Adverse events were typically mild and transient and included: cough, throat pain, throat irritation; at the highest dose with the formulation containing saccharin, these adverse events were reported by 41%, 14%, and 3% of patients, respectively. Cardiac adverse events consistent with those observed with oral and intravenous flecainide were uncommon and included postconversion pauses (n=2), bradycardia (n=1), and atrial flutter with 1:1 atrioventricular conduction (n=1); none required treatment, and all resolved without sequelae.
Conclusions
Administration of flecainide via oral inhalation was shown to be safe and to yield plasma concentrations of flecainide sufficient to restore sinus rhythm in patients with recent-onset atrial fibrillation.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03539302.



Circ Arrhythm Electrophysiol: 23 Feb 2022:CIRCEP121010204; epub ahead of print
Crijns HJGM, Elvan A, Al-Windy N, Tuininga YS, ... Belardinelli L, INSTANT Investigators
Circ Arrhythm Electrophysiol: 23 Feb 2022:CIRCEP121010204; epub ahead of print | PMID: 35196871
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This program is still in alpha version.