Conduction system disease management in patients candidate and/or treated for the aortic valve disease: an Italian Survey promoted by Italian Association of Arrhythmology and Cardiac Pacing (AIAC).

BACKGROUND: Conduction system disorders represent a frequent complication in patients undergoing surgical (surgical aortic valve replacement, SAVR) or percutaneous (transcatheter aortic valve implantation, TAVI) aortic valve replacement. The purpose of this survey was to evaluate experienced operators approach in this clinical condition. METHODS: This survey was independently conducted by the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) and it consisted of 24 questions regarding the respondents' profile, the characteristics of participating centres, and conduction disease management in different scenarios. RESULTS: Fifty-five physicians from 55 Italian arrhythmia centres took part in the survey. Prophylactic pacemaker implantation is rare. In case of persistent complete atrioventricular block (AVB), 49% and 73% respondents wait less than one week before implanting a definitive pacemaker after SAVR and TAVI, respectively. In case of second degree AVB, the respondents wait some days more for definitive implantation. Respondents consider bundle branch blocks, in particular pre-existing left bundle branch block (LBBB), the worst prognostic factors for pacemaker implantation after TAVI. The implanted valve type is considered a relevant element to evaluate. In patients with new-onset LBBB and severe/moderate left ventricular systolic dysfunction, respondents would implant a biventricular pacemaker in 100/55% of cases, respectively. CONCLUSIONS: Waiting time before a definitive pacemaker implantation after aortic valve replacement has reduced compared to the past, and it is anticipated in TAVI vs. SAVR. Bundle branch blocks are considered the worse prognostic factor for pacemaker implantation after TAVI. The type of pacemaker implanted in new-onset LBBB patients without severe left ventricular systolic dysfunction is heterogeneous.

Association between cardiac conduction block and cardiovascular disease and all-cause mortality: The kailuan study.

BACKGROUND: Although bundle branch block and atrioventricular block are recognized to be association with cardiovascular disease (CVD) and mortality, the relationship between cardiac conduction block (CCB) and both CVD and all-cause mortality has yet to be explored. AIMS: To explore the relationship between CCB and CVD and all-cause mortality. METHODS AND RESULTS: We included 145,805 subjects (mean age 49.7 years, 81.2% males) from the kailuan study. CCB was diagnosed through a 12­lead electrocardiograph (ECG). Mortality and CVD events were ascertained through multiple sources, including a municipal social insurance institution, hospital records, death certificates, and regular active follow-ups. After a mean follow-up of 12.5 years, 18,301 cases developed all-cause mortality. After excluding 4443 subjects with CVD presence at baseline, 13,208 cases of CVD occurred among the 141,362 study subjects during follow-up. Compared with non-CCB group, the cumulative incidence of CVD and all-cause mortality for CCB group was 18.38% VS 12.14% and 33.45% VS 14.18%, respectively. The multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) with CCB group were 1.25(1.17-1.34) for CVD, and 1.31(1.25-1.38) for all-cause mortality. Additionally, there were generally stronger associations for CCB with all-cause mortality and CVD in younger participants compared with their older counterparts (Ps-interaction <0.001). CONCLUSION: CCB can increase the risk of CVD and all-cause mortality in the general population. Our findings highlight the importance of strategies for preventing CCB to reduce the risk of CVD and mortality.

Safety and efficacy of left bundle branch area pacing compared with right ventricular pacing in patients with bradyarrhythmia and conduction system disorders: Systematic review and meta-analysis.

BACKGROUND: Right Ventricular Pacing (RVP) may have detrimental effects in ventricular function. Left Bundle Branch Area Pacing (LBBAP) is a new pacing strategy that appears to have better results. The aim of this systematic review and meta-analysis is to compare the safety and efficacy of LBBAP vs RVP in patients with bradyarrhythmia and conduction system disorders. METHODS: MEDLINE, EMBASE and Pubmed databases were searched for studies comparing LBBAP with RVP. Outcomes were all-cause mortality, atrial fibrillation (AF) occurrence, heart failure hospitalizations (HFH) and complications. QRS duration, mechanical synchrony and LVEF changes were also assessed. Pairwise meta-analysis was conducted using random and fixed effects models. RESULTS: Twenty-five trials with 4250 patients (2127 LBBAP) were included in the analysis. LBBAP was associated with lower risk for HFH (RR:0.33, CI 95%:0.21 to 0.50; p < 0.001), all-cause mortality (RR:0.52 CI 95%:0.34 to 0.80; p = 0.003), and AF occurrence (RR:0.43 CI 95%:0.27 to 0.68; p < 0.001) than RVP. Lead related complications were not different between the two groups (p = 0.780). QRSd was shorter in the LBBAP group at follow-up (WMD: -32.20 msec, CI 95%: -40.70 to -23.71; p < 0.001) and LBBAP achieved better intraventricular mechanical synchrony than RVP (SMD: -1.77, CI 95%: -2.45 to -1.09; p < 0.001). LBBAP had similar pacing thresholds (p = 0.860) and higher R wave amplitudes (p = 0.009) than RVP. CONCLUSIONS: LBBAP has better clinical outcomes, preserves ventricular electrical and mechanical synchrony and has excellent pacing parameters, with no difference in complications compared to RVP.

Effect of acute CORticosteroids on conduction defects after Transcatheter Aortic Valve Implantation: the CORTAVI study.

AIMS: Conduction abnormalities, requiring a permanent pacemaker (PPM), are the most common electrical complications after transcatheter aortic valve implantation (TAVI). The exact mechanism for conduction system defects is not yet clear. The local inflammatory process and edema are thought to play a role in the development of electrical disorders. Corticosteroids are effective anti-inflammatory and antiedematous agents. We aim to investigate the potential protective effect of corticosteroids on conduction defects after TAVI. METHODS: This is a retrospective study of a single center. We analyzed 96 patients treated with TAVI. Thirty-two patients received oral prednisone 50 mg for 5 days after the procedure. This population was compared with the control group. All patients were followed up after 2 years. RESULTS: Of the 96 patients included, 32 (34%) were exposed to glucocorticoids after TAVI. No differences in age, preexisting right bundle branch block or left bundle branch block, or valve type were seen among patients exposed to glucocorticoids versus those who were unexposed. We observed no significant differences between the two groups in the overall frequency of new PPM implantations during hospitalization (12% vs. 17%, P  = 0.76). The incidence of atrioventricular block (AVB) (STx 9% vs. non-STx 9%, P  = 0.89), right bundle branch block (STx 6% vs. non-STx 11%, P  = 0.71), and left bundle branch block (STx 34% vs. non-STx 31%, P  = 0.9) was not significantly different between the STx and non-STx groups. At 2 years after TAVI, none of the patients had implanted PPM or had severe arrhythmias documented by 24-h Holter ECG or cardiac examination. CONCLUSION: Oral prednisone treatment does not appear to significantly reduce the incidence of AVB requiring acute PPM implantation after TAVI.

Incidence and management of atrioventricular conduction disorders in new-onset left bundle branch block after TAVI: A prospective multicenter study.

BACKGROUND: New-onset left bundle branch block (LBBB) is one of the most frequent complications after transcatheter aortic valve implantation (TAVI) and is associated with delayed high degree atrioventricular (AV) block. OBJECTIVES: The objectives of this study were to determine the incidence of AV block in such a population and to assess the performance and safety of a risk stratification algorithm on the basis of electrophysiology study (EPS) followed by implantation of a pacemaker or implantable loop recorder (ILR). METHODS: This was a prospective open-label study with 12-month follow-up. From June 8, 2015, to November 8, 2018, 183 TAVI recipients (mean age 82.3 ± 5.9 years) were included at 10 centers. New-onset LBBB after TAVI persisting for >24 hours was assessed by electrophysiology study during initial hospitalization. High-risk patients (His-ventricle interval ≥70 ms) were implanted with a dual-chamber pacemaker recording AV conduction disturbance episodes. Patients at lower risk were implanted with an ILR with automatic remote monitoring. RESULTS: A high-grade AV conduction disorder was identified in 56 patients (30.6%) at 12 months. Four subjects were symptomatic, all in the ILR group. No complications were associated with the stratification procedure. Patients with His-ventricle interval ≥70 ms displayed more high-grade AV conduction disorders (53.2% [25 of 47] vs 22.8% [31 of 136]; P < .001). In a multivariate analysis, His-ventricle interval ≥70 ms was independently associated with the occurrence of a high-grade conduction disorder (subdistribution hazard ratio 2.4; 95% confidence interval 1.2-4.8; P = .010). CONCLUSION: New-onset LBBB after TAVI was associated with high rates of high-grade AV conduction disturbances. The stratification algorithm provided safe and valuable aid to management decisions and reliable guidance on pacemaker implantation.

Bradykarde Herzrhythmusstörungen ­ neue Devices und Techniken.

Abnormalities of the sinus node, atrial tissue, atrioventricular node tissue, and specialized conduction system can all contribute to bradycardia. For this reason, the diagnosis and treatment of bradycardia have become challenging. In order to further optimize the assessment and treatment of patients with bradycardia, new guidelines on cardiac pacemaker therapy and cardiac resynchronization therapy were published by the European Society of Cardiology (ESC) last year. These include new recommendations for diagnostics, dealing with reflex syncope and treatment algorithms for syncope and bundle branch block. The use of leadless pacemakers is being discussed in selected and especially multimorbid patients as an alternative to conventional transvenous pacemaker implantation. Conduction system pacing as a physiological form of stimulation was included in the guidelines for the first time.

Monitoring conduction disturbances following TAVR: Feasibility study of early discharge using a novel telemetry patch.

INTRODUCTION: Despite the technological advances and increasing operator experience, the rate of permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) has not decreased over time. With a continuous downward trend in post-TAVR length of stay, prolonged home-monitoring may have a key role in detecting potentially serious conduction abnormalities after TAVR discharge. METHODS: In this study, the ZioPatch-AT monitor was used to detect conduction abnormalities after TAVR discharge. The cardiac monitoring device was systematically provided to all patients having pre-existing right bundle branch block or developing intra-/peri-procedural conduction disturbances, in the absence of guideline indication for PPI at discharge. RESULTS: From a total of 75 patients at high-risk of conduction disturbances, 8 (11%) of them underwent PPI and most of them (6/8) were detected before symptoms' occurrence. Paired analysis between baseline and discharge electrocardiograms detected a significant widening of the QRS in all patients; on the contrary, PR length was significantly increased only in the group experiencing HAVB after discharge (p < 0.01). CONCLUSIONS: In an early post-TAVR discharge era, 30-day outpatient cardiac rhythm monitoring is potentially a safe solution to allow timely recognition of new conduction disturbances requiring PPI.

Development of atrioventricular and intraventricular conduction disturbances in patients undergoing transcatheter aortic valve replacement with new generation self-expanding valves: A real world multicenter analysis.

BACKGROUND: High degree cardiac conduction disturbances (HDCD) remain a major complication after transcatheter aortic valve replacement (TAVR), especially with self-expandable valves (SEV). Our aim was to investigate peri-procedural and in-hospital modification of atrioventricular and intracardiac conduction associated to new generation SEV implantation, and the development of new HDCD resulting in permanent pacemaker implantation (PPM) in patients undergoing TAVR. METHODS AND RESULTS: Three-hundred forty-four consecutive patients with severe aortic stenosis who underwent TAVR with a new generation SEV [Evolut-R/Pro (n = 130), Acurate-neo (n = 79), Portico (n = 75) and Allegra (n = 60)] were included. An analysis of baseline, post-TAVR and pre-discharge ECG and procedural aspects were centrally performed. A significant increase in baseline PR interval (169.6 ± 28.2 ms) and QRS complex width (101.7 ± 25.9 ms) was noted immediately post-TAVR (188.04 ± 34.49; 129.55 ± 30.02 ms), with a partial in-hospital reversal (179.4 ± 30.1; 123.06 ± 30.94 ms), resulting in a net increase at hospital discharge of 12.6 ± 38.8 ms and 21.4 ± 31.6 ms (p < 0.001), respectively. The global incidence of new onset persistent HDCD at hospital discharge was 46.3%, with 17.7% of patients requiring PPM. Independent predictors of new onset HCDC at hospital discharge were valve recapture (OR: 2.8; 95% IC: 1.1-7.2, p = 0.033) and implantation depth ≥ 6 mm (OR: 1.9 05% IC 1.1-3.3, p = 0.015), while higher implantation (<3 mm (OR: 0.3, 95% IC 0.1-0.7, p = 0.014) and use of Acurate-Neo valve (OR: 0.4; 95% IC 0.2-0.8, p = 0.009) were protective factor. CONCLUSIONS: New generation self-expanding aortic valves were associated with a significant increase in PR and QRS interval at hospital discharge leading to a very high rate of HDCD. While valve recapture and implantation depth were independent predictors for the occurrence of HDCD, use of Accurate-Neo valve was a protective factor.

Management of conduction disorders after transcatheter aortic valve implantation: results of the EHRA survey.

Conduction disorders such as left bundle branch block (LBBB) are common after transcatheter aortic valve implantation (TAVI). Consensus regarding a reasonable strategy to manage conduction disturbances after TAVI has been elusive. The European Heart Rhythm Association (EHRA) conducted a survey to capture contemporary clinical practice for conduction disorders after TAVI. A 25-item online questionnaire was developed and distributed among the EHRA electrophysiology (EP) research network centres. Of 117 respondents, 44% were affiliated with university hospitals. A standardized management protocol for advanced conduction disorders such as LBBB or atrioventricular block (AVB) after TAVI was available in 63% of participating centres. Telemetry after TAVI was chosen as the most frequent management strategy for patients with new-onset or pre-existing LBBB (79% and 70%, respectively). Duration of telemetry in patients with new-onset LBBB varied, with a 48-h period being the most frequently chosen, but almost half monitoring continued for at least 72 h. Similarly, in patients undergoing EP study due to new-onset LBBB, the HV interval cut-off point leading to pacemaker implantation was heterogeneous among European centres, although an HV >75 ms threshold was the most common. Conduction system pacing was chosen as a preferred approach by 3.7% of respondents for patients with LBBB and normal left ventricular ejection fraction (LVEF), and by 5.6% for patients with LBBB and reduced LVEF. This survey suggests some heterogenity in the management of conduction disorders after TAVI across European centres. The risk stratification strategies vary substantially. Conduction system pacing in patients with LBBB after TAVI is still underused.

Reliable identification of cardiac conduction abnormalities in drug discovery using automated patch clamp II: Best practices for Nav1.5 peak current in a high throughput screening environment.

INTRODUCTION: For reliable identification of cardiac safety risk, compounds should be screened for activity on cardiac ion channels in addition to hERG, including NaV1.5 and CaV1.2. We identified different parameters that might affect IC50s of compounds on NaV1.5 peak and late currents recorded using automated patch clamp (APC) and suggest outlines for best practices. METHODS: APC instruments SyncroPatch 384 and Patchliner were used to record NaV1.5 peak and late current. Up to 24 CiPA compounds were used to investigate effects of voltage protocol, holding potential (-80 mV or - 95 mV) and temperature (23 ± 1 °C or 36 ± 1 °C) on IC50 values on hNaV1.5 overexpressed in HEK or CHO cells either as frozen cells or running cultures. RESULTS: The IC50s of 18 compounds on the NaV1.5 peak current recorded on the SyncroPatch 384 using the CiPA step-ramp protocol correlated well with the literature. The use of frozen or cultured cells did not affect IC50s but voltage protocol and holding potential did cause differences in IC50 values. Temperature can affect Vhalf of inactivation and also compound potency. A compound incubation time of 5-6 min was sufficient for most compounds, however slow acting compounds such as terfenadine required longer to reach maximum effect. DISCUSSION: We conclude that holding potential, voltage protocol and temperature can affect IC50 values and recommend the use of the CiPA step-ramp protocol at physiological temperature to record NaV1.5 peak and late currents for cardiac safety. Further recommendations include: a minimum compound incubation time of 5 min, a replicate number of 4 and the use of positive and negative controls for reliable IC50s.

Analysis of the shape of the T-wave in congenital long-QT syndrome type 3 by geometric morphometrics.

The characteristic shape of the T-wave in congenital long-QT syndrome type 3 (LQTS3) is considered a late-onset T-wave. We analyzed the difference in the shapes of the T-waves of V5 in the electrocardiograms (ECGs) of LQTS3 cases and normal subjects using generalized Procrustes analysis. The J and Q points of LQTS3 cases are shifted to the upper left compared to those of normal subjects. SdFmax is the point on the ECG where the second derivative is first maximized. SdFmax is the point where the change in the slope of the ascending limb of the T-wave is maximized. SdFmax in LQTS3 cases is shifted to the lower right compared to normal subjects. The interval from J to SdFmax in LQTS3 cases is expanded compared with that of normal subjects. From principal component analysis of the Procrustes mean shape of the T-wave landmarks, the second principal component shows a shift of SdFmax to the lower right. These results can quantitatively explain why the T-wave of LQTS3 cases looks like a late-onset T-wave. After being fitted to a multivariate logistic regression model, LQTS3 cases and normal subjects can be distinguished by the second independent component.

Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction.

BACKGROUND: Genetic variants in SCN10A, encoding the neuronal voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, encoding the major essential cardiac sodium channel NaV1.5. METHODS: The expression of SCN10A was investigated in mouse and human hearts. With the use of CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by genome-wide association studies single-nucleotide polymorphism mapping and expression quantitative trait loci analysis. RESULTS: We found that cardiomyocytes of the atria, sinoatrial node, and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (Scn10a-short). Transcription occurs from an intronic enhancer-promoter complex, whereas full-length Scn10a transcript was undetectable in the human and mouse heart. Expression quantitative trait loci analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, whereas the expression of Scn5a, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that noncoding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts NaV1.5-mediated sodium current and heart rhythm. CONCLUSIONS: Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that noncoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.

Conduction Disorders: The Value of Surface ECG.

PURPOSE OF REVIEW: The purpose of the current mini-review is to describe the importance of surface ECG for the diagnosis of conduction disorder. METHODS: The MEDLINE/PubMed database was used, with the keywords "ECG" and "conduction disorders"; over the past 10 years. Other documents were included because of their relevance. MAIN FINDINGS: Data on the anatomy and function of the cardiac electrical system have been described. Conduction disorders including sinus node dysfunction, atrioventricular blocks, intraventricular conduction disorders are exposed as to their epidemiology, etiology, presentation, anatomical site of impaired conduction of the electrical stimulus. The importance of ECG in patients with a cardiac implantable electronic device was also discussed, in addition to future perspectives. CONCLUSION: Surface ECG allows the diagnosis of atrioventricular and intraventricular conduction disorder and its anatomical block site most of the time, without the need for invasive tests such as electrophysiological study. Dysfunctions of cardiac implantable electronic devices can be diagnosed by ECG, as well as the prediction of response to cardiac resynchronization therapy.

Cardiac Emerinopathy: A Nonsyndromic Nuclear Envelopathy With Increased Risk of Thromboembolic Stroke Due to Progressive Atrial Standstill and Left Ventricular Noncompaction.

BACKGROUND: Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. METHODS: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). RESULTS: We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. CONCLUSIONS: Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.