Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Cryoablation of Papillary Muscles at Surgery for Malignant Ventricular Arrhythmias Due to Mitral Valve Prolapse.

BACKGROUND: Mitral valve prolapse (MVP) is relatively common condition and while generally benign a small subset of patient suffers from malignant ventricular arrhythmias (MVA) and sudden cardiac death (SCD). METHOD AND MATERIAL: We report three cases of mitral valve prolapse, mitral regurgitation and malignant ventricular arrhythmias refractory to medical therapy, who had surgical cryoablation at the time of surgery on the mitral valve. RESULTS: During a follow-up period ranging from 3 to 11 years all three patients have remained free of ventricular arrhythmias and cryoablation lesions targeting the base of the papillary muscles have not caused any detrimental effect on the valve function. CONCLUSION: Surgical cryoablation of papillary muscles as described in this article should be considered in MVP who suffer from MVA, aborted SCD or frequent ventricular ectopics likely to cause LV dysfunction.

Characteristic Histopathological Findings and Cardiac Arrest Rhythm in Isolated Mitral Valve Prolapse and Sudden Cardiac Death.

Background The association between mitral valve prolapse (MVP) and sudden death remains controversial. We aimed to describe histopathological changes in individuals with autopsy-determined isolated MVP (iMVP) and sudden death and document cardiac arrest rhythm. Methods and Results The Australian National Coronial Information System database was used to identify cases of iMVP between 2000 and 2018. Histopathological changes in iMVP and sudden death were compared with 2 control cohorts matched for age, sex, height, and weight (1 group with noncardiac death and 1 group with cardiac death). Data linkage with ambulance services provided cardiac arrest rhythm for iMVP cases. From 77 221 cardiovascular deaths in the National Coronial Information System database, there were 376 cases with MVP. Individual case review yielded 71 cases of iMVP. Mean age was 49±18 years, and 51% were women. Individuals with iMVP had higher cardiac mass (447 g versus 355 g; P<0.001) compared with noncardiac death, but similar cardiac mass (447 g versus 438 g; P=0.64) compared with cardiac death. Individuals with iMVP had larger mitral valve annulus compared with noncardiac death (121 versus 108 mm; P<0.001) and cardiac death (121 versus 110 mm; P=0.002), and more left ventricular fibrosis (79% versus 38%; P<0.001) compared with noncardiac death controls. In those with iMVP and witnessed cardiac arrest, 94% had ventricular fibrillation. Conclusions Individuals with iMVP and sudden death have increased cardiac mass, mitral annulus size, and left ventricular fibrosis compared with a matched cohort, with cardiac arrest caused by ventricular fibrillation. The histopathological changes in iMVP may provide the substrate necessary for development of malignant ventricular arrhythmias.

Arrhythmogenic Right Ventricular Cardiomyopathy: A Review of Living and Deceased Probands.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially life-threatening genetic cardiomyopathy with a spectrum of clinical presentations including sudden cardiac death (SCD). METHODS: Clinical and genetic data of 44 probands referred to a cardiac genetics clinic (2007-2017) who met 2010 Task Force Criteria (TFC) for ARVC diagnosis were included. RESULTS: Thirty-three (33) (75%) male, 20 (45%) were referred by the Victorian Institute of Forensic Medicine. Presentation that lead to diagnosis included ARVC-related SCD (n=19), SCD due to alternate cause of death (n=1), aborted cardiac arrest (n=6), stable symptomatic ventricular tachycardia (n=14), palpitations (n=3) and presyncope (n=1). Left ventricular involvement (50%) was more common in the SCD subgroup (84% vs 21%, p<0.001). Genetic testing (n=39) revealed a pathogenic mutation in 16 (commonest: plakophillin-2 (n=9)), a variant of uncertain significance (VUS) in 15, with no abnormality in eight. In the SCD subgroup, median age at death was 44.7 years and 74% were male. Genetic testing (n=16) in this subgroup revealed a pathogenic mutation in six patients (commonest: desmoplakin (n=4)). Comparison of the two commonest mutations (PKP2 and desmoplakin [DSP]) showed DSP mutation was more frequently associated with SCD (p<0.01) and LV involvement (p<0.001). Screening of 117 relatives has lead to ARVC diagnosis in 29 patients. CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy has a heterogeneous and often severe clinical presentation. Sudden cardiac death and aborted cardiac arrest (ACA) are common, demonstrating electrical abnormalities appear early in the ARVC phenotype. Left ventricular involvement was common and may reflect a worse prognosis. Genetic testing is essential in family screening and may be helpful in risk assessment. Desmoplakin mutation is associated with LV involvement and may be indicative of worse prognosis and increased risk of SCD. Genetic screening of proband family members in a specialised multidisciplinary clinic is essential in early diagnosis of affected family members.

Update on the Diagnosis and Management of Brugada Syndrome.

Brugada Syndrome (BrS) is an autosomal dominant channelopathy with variable penetrance affecting the sodium channel. It reduces the transport of sodium ions essential for proper generation of the cardiac action potential. The resulting inhomogeneous repolarisation in areas of the RV epicardium causes malignant ventricular arrhythmias. BrS is diagnosed by typical cove shaped ST elevation of > 2mm in ≥1 RV precordial lead V1, V2 occurring spontaneously or after provocative drug test with IV administration of Class 1 antiarrhythmic drug such as flecainide or ajmaline. The incidence of BrS is variable being higher in South East Asians and is generally quoted as 1:2000. It is responsible for up to 20% of sudden arrhythmic deaths in those without structural heart disease. Typical presentation is syncope or resuscitated sudden death and symptoms usually occur at night or at rest especially after a large meal. Fever is a common trigger, particularly in children. Genetic testing for BrS is a Class 2A indication and the yield has increased recently to nearly 40%. Genetic testing assists with family screening.

Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death and high yield in unexplained cardiac arrest syndromes.

BACKGROUND: It has been reported that cardiological screening and genetic evaluation in relatives of families with sudden unexplained death syndrome and unexplained cardiac arrest (UCA) may uncover a heritable etiology in a significant proportion of families. OBJECTIVE: To evaluate the yield of a comprehensive evaluation protocol of a large unselected cohort of consecutive families with autopsy-negative sudden unexplained death syndrome (termed sudden arrhythmic death syndrome [SADS]) and UCA. METHODS: We studied (1) 109 consecutive families (411 relatives) referred with 1 or more sudden deaths in the family and (2) 52 consecutive probands with UCA (91 relatives) referred by cardiologists between January 2007 and December 2012. A comprehensive cardiological screening was performed followed by targeted genetic evaluation if a clinical phenotype was proven or suspected. Diagnosis was made by a multidisciplinary team using published clinical criteria. RESULTS: A diagnosis was made in 19 of 109 families with SADS (yield 18%), with the majority having long QT syndrome (LQTS). Diagnosis varied according to proband age, with LQTS most common in the very young (≤20 years) and Brugada syndrome in the older age probands (≥40 years) (P = .03). In contrast, a diagnosis was made in 32 of 52 families with UCA (yield 62%), the majority of which had LQTS and Brugada syndrome. No clinical or circumstantial factors increased the likelihood of diagnosis in families with either SADS or UCA. CONCLUSIONS: In contrast to previously published series, a comprehensive strategy of cardiological evaluation and targeted genetic testing in more than 100 families with SADS was found to have a lower diagnostic yield (18%). Diagnostic yield in families with UCA was approximately 4 times higher (62%), which is consistent with the published literature.

Cardiac pacing: memories of a bygone era.

The first cardiac pacemaker implants occurred in the late 1950s and involved insertion of epicardial or epimyocardial leads and abdominal pulse generators. By the mid 1960s, cardiologists were making attempts to insert transvenous leads into the right ventricle. These early unipolar leads had large, polished, high polarization electrodes, no fixation device, and no lumen in which to place a stylet for lead positioning. The lead implantation procedures were usually long and the irradiation to both patient and operator excessive. Pulse generators were powered by zinc-mercury cells, which were large, unreliable, and prone to sudden output failure. Postoperative complications such as lead dislodgement, exit block, and premature power source failure were very common with most patients requiring further surgery within a year. Little has been written of this period and in particular the experiences of the operators, such that today's pacemaker implanters have virtually no knowledge of this bygone era. This historical report by four Australian cardiologists details the operative procedures and follow-up management of those original pacemaker recipients.

Scar-related right atrial macroreentrant tachycardia in patients without prior atrial surgery: electroanatomic characterization and ablation outcome.

BACKGROUND: Few descriptions of right atrial macroreentrant atrial tachycardia involving regions of spontaneous "scar" have been reported. OBJECTIVES: We describe the electrocardiographic, electrophysiologic, and electroanatomic characteristics of an unusual RA macroreentrant atrial tachycardia in eight patients with spontaneous RA scarring. METHODS: Eight of 286 patients with macroreentrant atrial tachycardia treated with radiofrequency ablation had RA spontaneous scarring and underwent conventional electrophysiologic studies and electroanatomic mapping. RESULTS: Eight patients (age 53 +/- 12 years) had symptoms for 58 +/- 62 months and had not responded to 2.5 +/- 0.8 antiarrhythmic drugs and 1.0 +/- 0.9 DC cardioversions. All patients had overall normal systolic function, and five had mild atrial enlargement. Scarring was present in the posterolateral wall extending from the crista terminalis toward the tricuspid annulus. The proportion of RA classified as scar was 31% +/- 14% (range 11%-46%). Stable circuits were around scar in seven patients, through a "channel" within the scar in four, and typical cavotricuspid isthmus-dependent flutter in five. Radiofrequency ablation sites included the cavotricuspid isthmus; between the inferior vena cava, superior vena cava, or crista terminalis and scar; or a channel in the scar. ECG morphology of the RA free wall tachycardias varied, depending upon whether cavotricuspid isthmus block was present. Radiofrequency ablation of all inducible circuits was successful in six patients and of all clinical circuits in seven. At follow-up of 20 +/- 13 months, six patients are free from macroreentrant atrial tachycardia, one has infrequent nonsustained macroreentrant atrial tachycardia, and one is controlled with previously ineffective medication. Five had sinus node dysfunction requiring permanent pacemaker implant. CONCLUSIONS: Extensive spontaneous scarring of the RA is an unusual cause of macroreentrant atrial tachycardias, both cavotricuspid isthmus dependent and independent in the same patient. Radiofrequency ablation is an effective treatment. Sinus node dysfunction requiring permanent pacemaker is common. The cause is unknown.

Electrophysiological and electrocardiographic characteristics of focal atrial tachycardia originating from the pulmonary veins: acute and long-term outcomes of radiofrequency ablation.

BACKGROUND: The objective of this study was to describe the electrophysiological characteristics, anatomic distribution, and long-term outcome after focal ablation (RFA) of pulmonary vein (PV) atrial tachycardia (AT). Both atrial fibrillation (AF) and AT may be due to a rapidly firing focus in the PVs. Whether these represent two aspects of the same process is unknown. METHODS AND RESULTS: Twenty-seven patients with 28 PV(16%) ATs of a consecutive series of 172 undergoing RFA for focal AT are reported. The mean age was 39+/-16 years, with symptoms for 9+/-14 years resistant to 1.7+/-0.8 medications. AT occurred spontaneously or with isoproterenol in all patients and was not inducible with PES in any. The distribution of PV ATs was right superior PV, 11; left superior PV, 11; left inferior PV, 5; and right inferior PV, 1; 26of 28 foci (93%) were ostial. RFA was successful in 28 of 28 PV ATs acutely. RFA was focal in 25 of 28, with PV isolation of a single target vein in 3. There were 4 recurrences at a mean of 3.3 months. Repeat RFA was performed in all 4 and successful in 3 of 4. All but one recurrence occurred from the same site. Long-term success was achieved in 26 of 27 (96%) patients at mean follow-up of 25+/-22 months. No patients have had subsequent development of AF or AT from a different site. CONCLUSIONS: PV AT has a distribution similar to PV AF, with a propensity to upper veins. However, the majority of foci are ostial, and only a small percentage occur from deep in the PV. Focal RFA is associated with high long-term success, with freedom from both AT from other sites and from AF. PV AT is a localized process and therefore may be different from PV AF.

Effect of chronic right atrial stretch on atrial electrical remodeling in patients with an atrial septal defect.

BACKGROUND: Adults with an atrial septal defect (ASD) frequently develop late atrial arrhythmias. We sought to characterize the pattern and persistence of atrial electrical remodeling caused by chronic right atrial (RA) stretch in this group. METHODS AND RESULTS: Thirteen ASD patients without atrial arrhythmia (42+/-10 years old; RA volume, 65+/-16 mL) and 17 normal control subjects (44+/-11 years old; RA volume, 38+/-8 mL) had electrophysiological study to measure (1) atrial effective refractory period (AERP) from the low lateral/high lateral/high septal RA and distal coronary sinus (CS), (2) dispersion of AERP, (3) lateral-RA and CS conduction time during constant pacing, (4) conduction delay across the crista terminalis measuring the number of crista catheter bipoles (0-10) recording discrete double potentials during pacing, (5) corrected sinus node recovery time, and (6) P-wave duration. After ASD closure (8.3+/-5.6 months), follow-up echo studies (n=12) and electrophysiological study (n=4) were performed. The low-lateral AERP, P-wave duration, sinus node recovery time, and extent of conduction delay across the crista terminalis were significantly greater in ASD patients. No differences were found for other measured electrophysiological study parameters. At follow-up, there was incomplete resolution of RA volume (47+/-12 mL; P<0.01 versus before surgery), a trend toward shortening of the AERP at the lateral RA and an increase at the distal CS and high septal RA, but persisting extensive, widely split crista double potentials. CONCLUSIONS: Chronic RA stretch because of ASD causes electrical remodeling with modest increases in RA ERP, conduction delay at the crista terminalis, and sinus node dysfunction. Conduction delay at the crista terminalis persists beyond ASD closure and may contribute to the long-term atrial arrhythmia substrate in this condition.