Results of comprehensive genetic testing in patients presenting to a multidisciplinary inherited heart disease clinic in India.

OBJECTIVES: This study aims to analyze the results of comprehensive genetic testing in patients presenting to a dedicated multidisciplinary inherited heart disease clinic in India. METHODS: All patients presenting to our clinic from August 2017 to October 2023 with a suspected inherited heart disease and consenting for genetic testing were included. The probands were grouped into familial cardiomyopathies namely hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM) and peripartum cardiomyopathy (PPCM), channelopathies namely congenital long QT syndrome (LQTS) and Brugada syndrome (BrS), and heritable connective tissue disorder namely Marfan Syndrome (MFS). Next generation sequencing (NGS) was used, and pre-test and post-test counseling were provided to probands and cascade screening offered to relatives. RESULTS: Mean age of the subjects (n = 77; 48 probands, 29 relatives) was 43 ± 18 years, 68 % male and 44 % symptomatic, with 36 HCM, 3 DCM, 3 ACM, 1 PPCM, 3 LQTS, 1 BrS and 1 MFS probands. The diagnostic yield of NGS-based genetic testing was 31 %; variants of uncertain significance (VUS) were identified in 54 %; and 15 % were genotype-negative. Twenty-nine relatives from 18 families with HCM (n = 12), DCM (n = 3), ACM (n = 2) and MFS (n = 1) underwent genetic testing. The genotype positive probands/relatives and VUS carriers with strong disease phenotype and/or high risk variant were advised periodic follow-up; the remaining probands/relatives were discharged from further clinical surveillance. CONCLUSIONS: Genetic testing guides treatment and follow-up of patients with inherited heart diseases and should be carried out in dedicated multidisciplinary clinics with expertise for counseling and cascade screening of family members.

Arrhythmogenic or dilated or desmoplakin cardiomyopathy? A challenging case managed by our multidisciplinary cardiogenetic team.

Arrhythmogenic cardiomyopathy (ACM), characterized by fibro or fibrofatty infiltration of the myocardium with a predominant arrhythmic presentation, is a genetically mediated cause of sudden cardiac death in the young and athletic individuals. We report a case of a severe form of biventricular ACM in a middle-aged man with a family history of cardiomyopathy-related young death. The proband was identified to harbor two novel mutations in the DES and DOLK genes and was managed comprehensively with a multidisciplinary team approach. This report reinforces the need for a dedicated cardiovascular genetics program as well as a population-specific genetic database in developing countries.

Clinical/electrophysiologic characteristics of infranodal Wenckebach in patients with indication for permanent ventricular pacing: A prospective study.

BACKGROUND: Infranodal Wenckebach is rare and not well characterized. OBJECTIVE: We prospectively studied clinical and electrophysiologic characteristics of patients with atrioventricular (AV) Wenckebach with an indication for permanent ventricular pacing. METHODS: During a 2-year period, all patients with an indication for permanent ventricular pacing underwent targeted preimplantation electrophysiologic study. Clinical and electrophysiologic characteristics at presentation and ventricular pacing percentage at 6-month follow-up were evaluated. RESULTS: A total of 163 patients (median age, 68 [interquartile range, 60-74] years; male, 59%; median QRS duration, 110 [90-130] ms; complete AV block in 123 [75.5%]) were included. AV Wenckebach was noted in 22 (13.4%) patients (median age, 70 [63-76.5] years; male, 54%; median QRS duration, 120 [110-140] ms) and classified as infranodal (12/163 [7.3%]) vs AV nodal (10/163 [6.1%]). Patients with infranodal Wenckebach (infrahisian in all), compared with AV nodal Wenckebach, demonstrated higher frequency with left ventricular ejection fraction ≤40% (41.7% vs 0%; P = .04), longer median HV interval (90 vs 49 ms; P = .005), lower frequency of isolated first-degree AV block (8.3% vs 60%; P = .02), higher frequency of right bundle branch block with left anterior fascicular block (75% vs 10%; P = .003), lesser PR increment at onset of AV Wenckebach (20.5 vs 80 ms; P = .002), and onset of 2:1 AV block at longer cycle lengths (91.7% vs 20%; P = .002). CONCLUSION: Of patients referred for pacemaker implantation, infranodal Wenckebach was present in 27.5% (11/40) without complete AV block. It was as frequent as AV nodal Wenckebach and associated with characteristic electrophysiologic findings.

Heart Failure with Mildly Reduced Ejection Fraction-A Phenotype Waiting to Be Explored.

Heart failure (HF) presents a significant global health challenge recognised by frequent hospitalisation and high mortality rates. The assessment of left ventricular (LV) ejection fraction (EF) plays a crucial role in diagnosing and predicting outcomes in HF, leading to its classification into preserved (HFpEF), reduced (HFrEF), and mildly reduced (HFmrEF) EF. HFmrEF shares features of both HFrEF and HFpEF but also exhibits distinct characteristics. Despite advancements, managing HFmrEF remains challenging due to its diverse presentation. Large-scale studies are needed to identify the predictors of clinical outcomes and treatment responses. Utilising biomarkers for phenotyping holds the potential for discovering new treatment targets. Given the uncertainty surrounding optimal management, individualised approaches are imperative for HFmrEF patients. This chapter examines HFmrEF, discusses the rationale for its re-classification, and elucidates HFmrEF's key attributes. Furthermore, it provides a comprehensive review of current treatment strategies for HFmrEF patients.

Correlation of extent of left ventricular endocardial unipolar low-voltage zones with ventricular tachycardia in nonischemic cardiomyopathy.

BACKGROUND: Endocardial electrogram (EGM) characteristics in nonischemic cardiomyopathy (NICM) have not been explored adequately for prognostication. OBJECTIVE: We aimed to study correlation of bipolar and unipolar EGM characteristics with left ventricular ejection fraction (LVEF) and ventricular tachycardia (VT) in NICM. METHODS: Electroanatomic mapping of the left ventricle was performed. EGM characteristics were correlated with LVEF. Differences between groups with and without VT and predictors of VT were studied. RESULTS: In 43 patients, unipolar EGM variables had better correlation with baseline LVEF than bipolar EGM variables: unipolar voltage (r = +0.36), peak negative unipolar voltage (r = -0.42), peak positive unipolar voltage (r = +0.38), and percentage area of unipolar low-voltage zone (LVZ; r = -0.41). Global mean unipolar voltage (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2-0.8), extent of unipolar LVZ (HR, 1.6; 95% CI, 1.1-2.3), and percentage area of unipolar LVZ (HR, 1.6; 95% CI, 1.1-2.3) were significant predictors of VT. For classification of patients with VT, extent of unipolar LVZ had an area under the curve of 0.82 (95% CI, 0.69-0.95; P < .001), and percentage area of unipolar LVZ had an area under the curve of 0.83 (95% CI, 0.71-0.96; P = .01). Cutoff of >3 segments for extent of unipolar LVZ had the best diagnostic accuracy (sensitivity, 90%; specificity, 67%) and cutoff of 33% for percentage area of unipolar LVZ had the best diagnostic accuracy (sensitivity, 95%; specificity, 60%) for VT. CONCLUSION: In NICM, extent and percentage area of unipolar LVZs are significant predictors of VT. Cutoffs of >3 segments of unipolar LVZ and >33% area of unipolar LVZ have good diagnostic accuracies for association with VT.

Characteristics of the phenotype of mixed cardiomyopathy in patients with implantable cardioverter-defibrillators.

BACKGROUND OR PURPOSE: The prognosis of m ixed cardiomyopathy (CMP) in patients with implanted cardioverter-defibrillators (ICDs) has not been investigated. We aim to study the demographic, clinical, device therapies and survival characteristics of mixed CMP in a cohort of patients implanted with a defibrillator. METHODS: The term mixed CMP was used to categorise patients with impaired left ventricular ejection fraction attributed to documented non-ischemic triggers with concomitant moderate coronary artery disease. This is a single center observational cohort of 526 patients with a mean follow-up of 8.7 ± 3.5 years. RESULTS: There were 42.5% patients with ischemic cardiomyopathy (ICM), 26.9% with non-ischemic cardiomyopathy (NICM) and 30.6% with mixed CMP. Mixed CMP, compared to NICM, was associated with higher mean age (69.1 ± 9.6 years), atrial fibrillation (55.3%) and greater incidence of comorbidities. The proportion of patients with mixed CMP receiving device shocks was 23.6%, compared to 18.4% in NICM and 27% in ICM. The VT cycle length recorded in mixed CMP (281.6 ± 43.1 ms) was comparable with ICM (282.5 ± 44 ms; p = 0.9) and lesser than NICM (297.7 ± 48.7 ms; p = 0.1). All-cause mortality in mixed CMP (21.1%) was similar to ICM (20.1%; p = 0.8) and higher than NICM (15.6%; p = 0.2). The Kaplan-Meier curves revealed hazards of 1.57 (95% CI: 0.91, 2.68) for mixed CMP compared to NICM. CONCLUSION: In a cohort of patients with ICD, the group with mixed CMP represents a phenotype predominantly comprised of the elderly with a higher incidence of comorbidities. Mixed CMP resembles ICM in terms of number of device shocks and VT cycle length. Trends of long-term prognosis of patients with mixed CMP are worse than NICM and similar to ICM.

Correlation of myocardial strain by CMR-feature tracking with substrate abnormalities detected by electro-anatomical mapping in patients with nonischemic cardiomyopathy.

BACKGROUND: Late gadolinium enhancement (LGE) detected by cardiac MRI (CMR) has low correlation with low voltage zones (LVZs) detected by electroanatomical mapping (EAM). We aim to study correlation of myocardial strain by CMR- Feature Tracking (FT) alongside LGE with LVZs detected by EAM. METHODS: Nineteen consecutive CMRs of patients with EAM were analyzed offline by CMR-FT. Peak value of circumferential strain (CS), longitudinal strain (LS), and LGE was measured in each segment of the left ventricle (17-segment model). The percentage of myocardial segments with CS and LS > -17% was determined. Percentage area of LGE-scar was calculated. Global and segment-wise bipolar and unipolar voltage was collected. Percentage area of bipolar LVZ (<1.5 mV) and unipolar LVZ (<8.3 mV) was calculated. RESULTS: Mean age was 62±11 years. Mean LVEF was 37±13%. Mean global CS was -11.8±5%. Mean global LS was -11.2±4%. LGE-scar was noted in 74% of the patients. Mean percentage area of LGE-scar was 5%. There was significant correlation between percentage abnormality detected by LS with percentage bipolar LVZ (r = +0.5, p = 0.03) and combined percentage CS+LS abnormality with percentage unipolar LVZ (r = +0.5, p = 0.02). Per-unit increase in CS increased the percentage area of unipolar LVZ by 2.09 (p = 0.07) and per-unit increase in LS increased the percentage area of unipolar LVZ by 2.49 (p = 0.06). The concordance rates between CS and LS to localize segments with bipolar/unipolar LVZ were 79% and 95% compared to 63% with LGE. CONCLUSIONS: Myocardial strain detected by CMR-FT has a better correlation with electrical low voltage zones than the conventional LGE.

Effect of Catheter Ablation Using Pulmonary Vein Isolation With vs Without Posterior Left Atrial Wall Isolation on Atrial Arrhythmia Recurrence in Patients With Persistent Atrial Fibrillation: The CAPLA Randomized Clinical Trial.

Importance: Pulmonary vein isolation (PVI) alone is less effective in patients with persistent atrial fibrillation (AF) compared with paroxysmal AF. The left atrial posterior wall may contribute to maintenance of persistent AF, and posterior wall isolation (PWI) is a common PVI adjunct. However, PWI has not been subjected to randomized comparison. Objective: To compare PVI with PWI vs PVI alone in patients with persistent AF undergoing first-time catheter ablation. Design, Setting, and Participants: Investigator initiated, multicenter, randomized clinical trial involving 11 centers in 3 countries (Australia, Canada, UK). Symptomatic patients with persistent AF were randomized 1:1 to either PVI with PWI or PVI alone. Patients were enrolled July 2018-March 2021, with 1-year follow-up completed March 2022. Interventions: The PVI with PWI group (n = 170) underwent wide antral pulmonary vein isolation followed by posterior wall isolation involving linear ablation at the roof and floor to achieve electrical isolation. The PVI-alone group (n = 168) underwent wide antral pulmonary vein isolation alone. Main Outcomes and Measures: Primary end point was freedom from any documented atrial arrhythmia of more than 30 seconds without antiarrhythmic medication at 12 months, after a single ablation procedure. The 23 secondary outcomes included freedom from atrial arrhythmia with/without antiarrhythmic medication after multiple procedures, freedom from symptomatic AF with/without antiarrhythmic medication after multiple procedures, AF burden between study groups at 12 months, procedural outcomes, and complications. Results: Among 338 patients randomized (median age, 65.6 [IQR, 13.1] years; 76.9% men), 330 (97.6%) completed the study. After 12 months, 89 patients (52.4%) assigned to PVI with PWI were free from recurrent atrial arrhythmia without antiarrhythmic medication after a single procedure, compared with 90 (53.6%) assigned to PVI alone (between-group difference, -1.2%; hazard ratio [HR], 0.99 [95% CI, 0.73-1.36]; P = .98). Of the secondary end points, 9 showed no significant difference, including freedom from atrial arrhythmia with/without antiarrhythmic medication after multiple procedures (58.2% for PVI with PWI vs 60.1% for PVI alone; HR, 1.10 [95% CI, 0.79-1.55]; P = .57), freedom from symptomatic AF with/without antiarrhythmic medication after multiple procedures (68.2% vs 72%; HR, 1.20 [95% CI, 0.80-1.78]; P = .36) or AF burden (0% [IQR, 0%-2.3%] vs 0% [IQR, 0%-2.8%], P = .47). Mean procedural times (142 [SD, 69] vs 121 [SD, 57] minutes, P < .001) and ablation times (34 [SD, 21] vs 28 [SD, 12] minutes, P < .001) were significantly shorter for PVI alone. There were 6 complications for PVI with PWI and 4 for PVI alone. Conclusions and Relevance: In patients undergoing first-time catheter ablation for persistent AF, the addition of PWI to PVI alone did not significantly improve freedom from atrial arrhythmia at 12 months compared with PVI alone. These findings do not support the empirical inclusion of PWI for ablation of persistent AF. Trial Registration: anzctr.org.au Identifier: ACTRN12616001436460.

Long-term mortality in heart failure with mid-range ejection fraction: systematic review and meta-analysis.

AIMS: Heart failure patients with mid-range ejection fraction (HFmrEF) have overlapping clinical features, compared with patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). We aim to perform a meta-analysis of studies reporting long-term outcomes in HFmrEF compared with HFrEF and HFpEF. METHODS AND RESULTS: Data from 18 eligible large-scale studies including 126 239 patients were pooled. Patients with HFmrEF had a lower risk of all-cause death than those with HFrEF [risk ratio (RR) = 0.92; 95% CI = 0.85-0.98; P < 0.001]. This significant difference was seen in the follow-up at 1, 2, and 3 years. Patients with HFmrEF had significantly lower risk of cardiovascular (CV) deaths than HFrEF (RR = 0.77; 95% CI = 0.65-0.92; P < 0.001). Subgroup analysis showed that studies recruiting >50% of males had higher risk of deaths with HFrEF (RR = 1.15; 95% CI = 1.04-1.26; P = 0.006). When compared with HFpEF, patients with HFmrEF had comparable risk of all-cause death (RR = 1.02; 95% CI = 0.96-1.09; P = 0.53). Similarly, there were no differences in the 1, 2, and 3 year deaths; CV and non-CV deaths were insignificant between HFmrEF and HFpEF. CONCLUSIONS: The results of the study support that HFmrEF has better prognosis than HFrEF but similar prognosis when compared with HFpEF. Gender disparity between studies seems to influence the results between HFmrEF and HFrEF. Transition in left ventricular ejection fraction (LVEF), which could not be addressed in the study, may play a decisive role in determining outcomes. PROSPERO review registration number CRD42021277107.

Computerized tomography image correlation of His bundle/deep septal pacing location and outcomes: an analysis from the Canberra HIs bundle/deep septal Pacing Study (CHIPS).

BACKGROUND: Localisation of the conduction system under fluoroscopy is not easy and the ideal location of the pacing leads in physiological pacing is still being debated. OBJECTIVE: The primary aim was to assess the lead locations using cardiac CT scan. Secondary aims were clinical outcomes including success and safety of the procedure and lead performance. METHODS: Of the 100 consecutive patients who received physiological pacing, 34 patients underwent follow-up cardiac CT scan. The four different types of pacing were identified as His bundle (HBP), para-Hisian, left bundle branch (LBBP), and deep septal pacing. RESULTS: Most patients had successful HBP via the right atrium (RA) (87.5%) as compared to the right ventricle (RV) (12.5%). Lower thresholds were observed when leads were placed within 2 mm of the junction of the membranous and muscular ventricular septum. Unlike HBP, LBBP was possible at a wide region of the septum and selective capture of individual fascicles was feasible. LBBP showed deeper penetration of leads into the septum, as compared to deep septal pacing (70% vs. 45%). Approximately, 80% of patients did not have an intra-ventricular portion of the membranous septum. CONCLUSIONS: The anterior part of the atrio-ventricular (AV) septum at the junction between the membranous and muscular septum via RA appeared to be the best target to successfully pace His bundle. LBBP was possible at a wide region of the septum and selective capture of individual fascicle was feasible. Adequate depth of penetration of lead was very important to capture the left bundle.

Catheter ablation for persistent atrial fibrillation: A multicenter randomized trial of pulmonary vein isolation (PVI) versus PVI with posterior left atrial wall isolation (PWI) - The CAPLA study.

BACKGROUND: The success of pulmonary vein isolation (PVI) is reduced in persistent AF (PsAF) compared to paroxysmal AF. Adjunctive ablation strategies have failed to show consistent incremental benefit over PVI alone in randomized studies. The left atrial posterior wall is a potential source of non-PV triggers and atrial substrate which may promote the initiation and maintenance of PsAF. Adding posterior wall isolation (PWI) to PVI had shown conflicting outcomes, with earlier studies confounded by methodological limitations. OBJECTIVES: To determine whether combining PWI with PVI significantly improves freedom from AF recurrence, compared to PVI alone, in patients with PsAF. METHODS: This is a multi-center, prospective, international randomized clinical trial. 338 patients with symptomatic PsAF refractory to anti-arrhythmic therapy (AAD) will be randomized to either PVI alone or PVI with PWI in a 1:1 ratio. PVI involves wide antral circumferential pulmonary vein (PV) isolation, utilizing contact force sensing ablation catheters. PWI involves the creation of a floor line connecting the inferior aspect of the PVs, and a roof line connecting the superior aspect of the PVs. Follow up is for a minimum of 12 months with rhythm monitoring via implantable cardiac device and/or loop monitor, or frequent intermittent monitoring with an ECG device. The primary outcome is freedom from any documented atrial arrhythmia of > 30 seconds off AAD at 12 months, after a single ablation procedure. CONCLUSIONS: This randomized study aims to determine the success and safety of adjunctive PWI to PVI in patients with persistent AF.

Utility of Intracardiac Echocardiography to Guide Transseptal Catheterization for Different Electrophysiology Procedures.

"Intracardiac echocardiography (ICE) has evolved into an indispensable tool in the armamentarium of cardiac electrophysiologists not only for understanding the internal cardiac anatomy but also for establishing transseptal access and for monitoring electrophysiology procedures. ICE aids in live monitoring of every step of the procedure including early detection of complications. Access to the left atrium through transseptal catheterization is a vital step to perform atrial fibrillation and accessory pathway ablations, ablation of left ventricular tachycardias, left atrial appendage closures, left ventricular endocardial electrode implantations for cardiac resynchronization therapies, and for selectively sampling the regions of interest during endomyocardial biopsies."

Cardiac resynchronization with His-CRT-D in a patient with severe heart failure and Scimitar syndrome.

Cardiac resynchronization therapy with His-bundle pacing is evolving rapidly as a viable cardiac device strategy for the treatment of severe chronic heart failure. The success of this technique in patients with congenital heart disease is facilitated by advanced integrated imaging modalities. We report a case of cardiac resynchronization therapy with His-bundle pacing with defibrillator for the management of a patient with heart failure with severely reduced ejection fraction, left bundle branch block, and congenital heart disease characterized by Scimitar syndrome with cardiac dextroposition. We highlight the contribution of integrated imaging modalities to guide accurate lead positioning.