Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.

Ablation of typical atrial flutter using mini electrode measurements for maximum voltage-guided ablation: A randomized, controlled trial.

BACKGROUND: Novel ablation catheters with mini electrode (ME) sensing have become available but their utility is unclear. We investigated whether ablation of the cavotricuspid isthmus (CTI) for atrial flutter (AFL) would be improved using ME signals. METHODS: Sixty-one patients (76% male, 63 ± 10 years) with CTI-dependent AFL underwent ablation using a maximum voltage-guided approach, randomized to either standard 8 mm non-irrigated catheter with bipolar signals or IntellaTip MiFi catheter using ME signals alone. RESULTS: Acute bidirectional block was achieved in 97%. Mean follow-up was 16.7 ± 10 months. The median number of ablation lesions was 13 in both groups (range 3-62 vs. 1-43, p = .85). No significant differences were observed in AFL recurrences (17% vs. 11%, p = .7), median procedure durations (97 min [interquartile range (IQR), 71-121] vs. 87 min [IQR, 72-107], p = .55) or fluoroscopy times (31 min [IQR, 21-52] vs. 38 min [IQR, 25-70], p = .56). Amplitudes of ME signals were on average 160% greater than blinded bipolar signals. In 23.7% of lesions where bipolar signals were difficult to interpret, 13.6% showed a clear ME signal. CONCLUSIONS: There was no difference in the effectiveness of CTI ablation guided by ME signals, compared with using bipolar signals from a standard 8 mm ablation catheter. While ME signal amplitudes were larger and sometimes present when the bipolar signal was unclear, this did not improve procedural characteristics or outcomes. The results suggest future research should focus on lesion integrity rather than signal sensing.

A simple maneuver to determine if septal accessory pathway ablation requires a left atrial approach.

INTRODUCTION: Septal accessory pathway (AP) ablation can be challenging due to the complex anatomy of the septal region. The decision to access the left atrium (LA) is often made after failure of ablation from the right. We sought to establish whether the difference between ventriculo-atrial (VA) time during right ventricular (RV) apical pacing versus the VA during tachycardia would help establish the successful site for ablation of septal APs. METHODS: Intracardiac electrograms of patients with orthodromic reciprocating tachycardia (ORT) using a septal AP with successful catheter ablation were reviewed. The ∆VA was the difference between the VA interval during RV apical pacing and the VA interval during ORT. The difference in the VA interval during right ventricular entrainment and ORT (StimA-VA) was also measured. RESULTS: The median ∆VA time was significantly less in patients with a septal AP ablated on the right side compared with patients with a septal AP ablated on the left side (12 ± 19 vs. 56 ± 10 ms, p < .001). The StimA-VA was significantly different between the two groups (22 ± 14 vs. 53 ± 9 ms, p < .001). The ∆VA and StimA-VA were always ≤ 40 ms in patients with non-decremental septal APs ablated from the right side and always greater than 40 ms in those with septal APs ablated from the left. CONCLUSION: ΔVA and StimA-VA values identified with RV apical pacing in the setting of ORT involving a septal AP predict when left atrial access will be necessary for successful ablation.

The evolution of gene-guided management of inherited arrhythmia syndromes: Peering beyond monogenic paradigms towards comprehensive genomic risk scores.

Inherited arrhythmia syndromes have traditionally been viewed as monogenic forms of disease whose pathophysiology is driven by a single highly penetrant rare genetic variant. Although an accurate depiction of a proportion of genetic variants, the variable penetrance frequently noted in genotype positive families and the presence of sporadic genotype negative cases have long highlighted a more nuanced truth being operative. Coupled with our more recent recognition that many rare variants implicated in inherited arrhythmia syndromes possess unexpectedly high allele frequencies within the general population, these observations have contributed to the realization that a spectrum of pathogenicity exists among clinically relevant genetic variants. Notably, variable mutation pathogenicity and corresponding variable degrees of penetrance emphasize a limitation of contemporary guidelines, which attempt to dichotomize genetic variants as pathogenic or benign. Recognition of the existence of low and intermediate penetrant variants insufficient to be causative for disease in isolation has served to emphasize the importance of additional genetic, clinical, and environmental factors in the pathogenesis of rare inherited arrhythmia syndromes. Despite being rare, it has also become increasingly evident that common genetic variants play critical roles in both heritable channelopathies and cardiomyopathies and in aggregate may even be the primary drivers in certain instances, such as genotype negative Brugada syndrome. Our growing realization that the genetic substrates of inherited arrhythmia syndromes have intricacies that extend beyond traditionally perceived monogenic paradigms has highlighted a potential value of leveraging more comprehensive genomic risk scores for predicting disease development and arrhythmic risk.

Advances in atrioventricular and interventricular optimization of cardiac resynchronization therapy - what's the gold standard?

INTRODUCTION: Cardiac resynchronization therapy (CRT) is one of the most important advances in heart failure management in the last twenty years. Approximately one-third of patients appear not to respond to therapy. Although there are a number of possible mechanisms for non-response, an important factor is suboptimal atrioventricular (AV) and interventricular (VV) timing intervals. There remains controversy over whether routinely optimizing intervals is necessary and there is no agreed gold standard methodology. Optimization has classically been performed using echocardiography which has limits related to resource use, time-cost and variable reproducibility. Newer optimization methods using device-based sensors and algorithms show promise in reducing heart-failure hospitalization compared with echocardiography. Areas covered: This review outlines the rationale for optimization, the principles of AV and VV optimization, the standard echocardiographic approach and newer device-based algorithms and the evidence base for their use. Expert commentary: The incremental gains of optimization are likely to be real, but small, compared to the overall improvement gained from cardiac resynchronization itself. At this time routine optimization may not be mandatory but should be performed where there is no response to CRT. Device-based optimization algorithms appear to be practical and in some cases, deliver superior clinical outcomes compared to echocardiography.

Elective Cardioversion in the Era of Novel Oral Anticoagulants - Does a Nurse Administered Verbal Questionnaire for Compliance Negate the Need for Routine Transoesophageal Echocardiography?

BACKGROUND: Anticoagulation prior to elective external direct current cardioversion (EDCCV) is mandatory. The inability to monitor compliance with novel oral anticoagulants (NOACs) raises a potential safety issue. We aimed to evaluate whether a structured, nurse-led assessment of compliance prior to EDCCV ensures safety without the need for routine transoesophageal echocardiography (TOE). METHODS: Data was prospectively collected on consecutive patients undergoing EDCCV during 2014-2015. All procedures were supervised by an electrophysiology clinical nurse consultant (EPCNC). Drug compliance was verbally assessed using a standardised questionnaire by the EPCNC. Novel oral anticoagulants compliance was required for a continuous period of 3 weeks prior to EDCCV; otherwise a TOE-guided EDDCV was performed. All patients had follow-up 30 days post-procedure. RESULTS: Three hundred and eleven cardioversions were performed on 256 patients in whom 154 (49.5%) were prescribed a NOAC (rivaroxaban (n=105; 68.2%), dabigatran (n=38; 24.7%), apixaban (n=11; 7.1%)). Median age was 63 years (24-94 yrs), mean CHADS2-Vasc score was 2.0±1.5 and 138 (89.6%) were outpatients. One hundred and twenty-nine (83.8%) EDCCV were for atrial fibrillation and 25 (16.2%) for atrial flutter. Sinus rhythm was achieved in 90.3% of cases. Fourteen patients (9%) assessed as non-compliant underwent TOE. 129 (83.8%) EDCCV were performed without prior TOE. No stroke or systemic embolism was identified in any patient treated with either warfarin or a NOAC. CONCLUSIONS: A standardised, verbal questionnaire can be administered to detect NOAC non-compliance in patients undergoing EDCCV. With appropriate compliance assessment a nurse-led EDCCV without routine TOE did not significantly compromise safety in this study group.

Cardiac Sarcoidosis, Left Ventricular Impairment and Chronic Right Ventricular Pacing: Pacing or Pathology?

BACKGROUND: Cardiac sarcoidosis (CS) is an uncommon and under-recognised disease which most frequently presents with atrioventricular (AV) block and may also present with ventricular arrhythmias and left ventricular (LV) systolic dysfunction. Because of its protean clinical manifestations, confirming a diagnosis of CS is often challenging. METHODS: We report two cases where patients presented with atrioventricular (AV) block without evidence of underlying myocardial disease, underwent chronic dual-chamber pacing, and presented several years later with severe LV systolic dysfunction. RESULTS: Both patients were referred for assessment of pacing-induced cardiomyopathy with a view to upgrading their device to cardiac resynchronisation therapy (CRT). Subsequent investigation revealed features consistent with CS and appropriate immunosuppressive therapy resulted in improvement in LV function avoiding the requirement for CRT. CONCLUSION: We present a review of the diagnosis of cardiac sarcoidosis, the importance of imaging modalities and current treatment recommendations.

Surface ECG and Fluoroscopy are Not Predictive of Right Ventricular Septal Lead Position Compared to Cardiac CT.

BACKGROUND: Controversy exists regarding the optimal lead position for chronic right ventricular (RV) pacing. Placing a lead at the RV septum relies upon fluoroscopy assisted by a surface 12-lead electrocardiogram (ECG). We compared the postimplant lead position determined by ECG-gated multidetector contrast-enhanced computed tomography (MDCT) with the position derived from the surface 12-lead ECG. METHODS: Eighteen patients with permanent RV leads were prospectively enrolled. Leads were placed in the RV septum (RVS) in 10 and the RV apex (RVA) in eight using fluoroscopy with anteroposterior and left anterior oblique 30° views. All patients underwent MDCT imaging and paced ECG analysis. ECG criteria were: QRS duration; QRS axis; positive or negative net QRS amplitude in leads I, aVL, V1, and V6; presence of notching in the inferior leads; and transition point in precordial leads at or after V4. RESULTS: Of the 10 leads implanted in the RVS, computed tomography (CT) imaging revealed seven to be at the anterior RV wall, two at the anteroseptal junction, and one in the true septum. For the eight RVA leads, four were anterior, two septal, and two anteroseptal. All leads implanted in the RVS met at least one ECG criteria (median 3, range 1-6). However, no criteria were specific for septal position as judged by MDCT. Mean QRS duration was 160 ± 24 ms in the RVS group compared with 168 ± 14 ms for RVA pacing (P = 0.38). CONCLUSIONS: We conclude that the surface ECG is not sufficiently accurate to determine RV septal lead tip position compared to cardiac CT.

Using the Surface ECG to Identify Right Ventricular Pacing Lead Position: A Cautionary Tale.

Chronic right ventricular (RV) apical pacing may lead to the development of heart failure in some patients. Although pacing of the RV septum has been proposed as an alternative, positioning a lead in the true septum has proven challenging. In addition to fluoroscopy at implant, it has been suggested that 12-lead surface electrocardiogram (ECG) can be used to determine septal lead position; however, studies show this may be inaccurate. We present a case where a change in the ECG QRS axis late after pacemaker insertion with an active fixation lead highlights the difficulties of ECG localization of pacing leads.