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.

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

BACKGROUND: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. METHODS: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Insights into sudden cardiac death: exploring the potential relevance of non-diagnostic autopsy findings.

AIMS: Unexplained sudden cardiac death (SCD) may be attributable to cardiogenetic disease. Presence or absence of autopsy anomalies detected following premature sudden death direct appropriate clinical evaluation of at-risk relatives towards inherited cardiomyopathies or primary arrhythmia syndromes, respectively. We investigated the relevance of non-diagnostic pathological abnormalities of indeterminate causality (uncertain) such as myocardial hypertrophy, fibrosis, or inflammatory infiltrates to SCD. METHODS AND RESULTS: At-risk relatives of unexplained SCD cases aged 1-64 years without prior cardiac disease (n = 98) with either normal and negative (40%, true sudden arrhythmic death syndrome; SADS) or isolated non-diagnostic (60%, uncertain sudden unexplained death; SUD) cardiac histological autopsy findings at a central forensic pathology unit were referred to the regional unexplained SCD clinic for clinical cardiac phenotyping. Uncertain SUD were older than true SADS cases (31.8 years vs. 21.1 years, P < 0.001). A cardiogenetic diagnosis was established in 24 families (24.5%) following investigation of 346 referred relatives. The proportions of uncertain SUD and true SADS explained by familial cardiogenetic diagnoses were similar (20% vs. 31%, P = 0.34, respectively), with primary arrhythmia syndromes predominating. Unexplained SCD cases were more likely than matched non-cardiac premature death controls to demonstrate at least one uncertain autopsy finding (P < 0.001). CONCLUSION: Primary arrhythmia syndromes predominate as familial cardiogenetic diagnoses amongst both uncertain SUD and true SADS cases. Non-diagnostic or uncertain histological findings associate with SUD, though cannot be attributed a causative status. At-risk relatives of uncertain SUD cases should be evaluated for phenotypic evidence of both ion channel disorders and cardiomyopathies.

Sudden Cardiac Death in Schizophrenia: A Review.

In patients with schizophrenia, cardiovascular disease accounts for nearly 50% of deaths and decreased life expectancy, and the incidence of sudden cardiac death is about four times higher than in the background population. While the majority of sudden deaths are due to ischaemic heart disease and its recognised risk factors, about 10% of sudden deaths are unexplained and are thought to be due to cardiac arrhythmias. This review discusses various factors that might contribute to this increased mortality, such as the effect of antipsychotic drugs on potassium and sodium channel function, increased incidence of Brugada pattern in patients with schizophrenia and the role of the autonomic nervous system. It stresses the control of traditional coronary risk factors and discusses various noninvasive tests to identify patients at risk. It also mentions the reported association for nonsynonymous genetic polymorphism rs10503929 within the neuregulin 1 gene (NRG1) and the minor allele C and its role in the risk of sudden cardiac death in schizophrenia.

A Prospective Study of Sudden Cardiac Death among Children and Young Adults.

BACKGROUND: Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults. METHODS: We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. RESULTS: A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. CONCLUSIONS: The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).

Channelopathies That Lead to Sudden Cardiac Death: Clinical and Genetic Aspects.

Forty per cent (40%) of sudden unexpected natural deaths in people under 35 years of age are associated with a negative autopsy, and the cardiac ion channelopathies are the prime suspects in such cases. Long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are the most commonly identified with genetic testing. The cellular action potential driving the heart cycle is shaped by a specific series of depolarising and repolarising ion currents mediated by ion channels. Alterations in any of these currents, and in the availability of intracellular free calcium, leaves the myocardium vulnerable to polymorphic ventricular tachycardia or ventricular fibrillation. Each channelopathy has its own electrocardiogram (ECG) signature, typical mode of presentation, and most commonly related gene. Long QT type 1 (gene, KCNQ1) and CPVT (gene, RyR2) typically present with cardiac events (ie syncope or cardiac arrest) during or immediately after exercise in young males; long QT type 2 (gene, KCNH2) after startle or during the night in adult females-particularly early post-partum, and long QT type 3 and Brugada syndrome (gene, SCN5A) during the night in young adult males. They are commonly misdiagnosed as seizure disorders. Fever-triggered cardiac events should also raise the suspicion of BrS. This review summarises genetics, cellular mechanisms, risk stratification and treatments. Beta blockers are the mainstay of treatment for long QT syndrome and CPVT, and flecainide is remarkably effective in CPVT. Brugada syndrome is genetically a more complex disease than the others, and risk stratification and management is more difficult.

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.

The Electrocardiographic Footprints of Wenckebach Block.

In 1899, Karel Frederik Wenckebach described a cardiac arrhythmia with periodic dropped beats now referred to as a Wenckebach sequence. This was later shown to be due to a block in the atrioventricular node, but today, we identify Wenckebach sequences throughout the heart with most being recognised on the surface electrocardiograph as characteristic footprints. This manuscript will revisit Wenckebach atrioventricular block, the typical features of which only occur in about 15% of cases, with the remainder atypical. Earlier reports regarded Wenckebach atrioventricular sequences as rare as they are only occasionally seen on the surface 12-lead electrocardiograph. Today, however, with the increased use of ambulatory Holter monitoring, Wenckebach atrioventricular sequences occur in 4-6% of all traces and are particularly common at night in the young. Most, but not all cases are benign and the clinical spectrum will be reviewed. Atypical Wenckebach atrioventricular sequences are a complex group which will be analysed in detail with a broad range of illustrations. Outside the atrioventricular conducting system, such as in the sinus node, Wenckebach sequences may not be obvious as they are partially hidden from the electrocardiographic tracing. However, by understanding the sequence footprints, clues are available in interpreting tracing with periodic pauses. Dual chamber paced rhythms may show Wenckebach sequences due to electronic control of the atrioventricular delay. Rarely exit blocks at the cellular level in the atrium, ventricle or at the pacing electrode-tissue interface can demonstrate Wenckebach sequences recognised on the surface electrocardiograph.

The Cardiac Genetics Clinic: a model for multidisciplinary genomic medicine.

OBJECTIVES: To describe patient characteristics, standard operating procedure, and uptake of genetic testing at the multidisciplinary Cardiac Genetics Clinic (CGC) at the Royal Melbourne Hospital during its first 6 years. DESIGN: Database exploration of referral diagnoses, sex, number of clinic visits and incidence of genetic testing in a population of individuals attending the CGC. SETTING: Tertiary referral hospital (Royal Melbourne Hospital) providing cardiac genetics services to the state of Victoria. PARTICIPANTS: All individuals initially attending the clinic between July 2007 and July 2013, either as the proband or as an at-risk family member. MAIN OUTCOME MEASURES: Classification of patients into diagnostic categories, number of probands and at-risk relatives assessed, incidence and outcomes of genetic testing. RESULTS: 1170 individuals were seen for the first time over the 6-year period; 57.5% made only one visit. The median age was 39 years. Most were encompassed within four broad diagnostic categories: cardiomyopathy (315 patients), aortopathy (303 patients), arrhythmia disorders (203 patients) and resuscitated cardiac arrest and/or family history of sudden cardiac death (341 patients); eight patients had "other" diagnoses. Genetic testing (mutation detection or predictive testing) was undertaken in 381 individuals (32.6%), and a pathogenic mutation was identified in 47.6% of tests, representing 15.3% of the total population. CONCLUSION: The CGC fulfils an important role in assisting clinicians and patients by reviewing genetic cardiac diagnoses. Clinical practice during the study period moved from a selected candidate gene approach to broader gene panel-based testing. This move to next-generation sequencing may increase the detection of mutations and variants of unknown significance. A major contribution by the clinic to the care of these individuals and their families is the provision (or negating) of a diagnosis, and of a plan for managing risks of predictable cardiac disease.

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.

Implantable cardioverter defibrillators (ICDs) in octogenarians.

Octogenarians are a growing section of the community. Implantable cardioverter defibrillator (ICD) implantations and replacements in this age group are becoming frequent. There are no randomised control trials or large observational studies of octogenarians and indications for ICD implantations are extrapolated from published primary and secondary prevention trials, where the age group has been in its sixties. About 75% of ICDs are implanted for primary prevention guided by patient's ejection fraction. Most patients who have ICDs do not have a clear idea about the function and limitation of ICDs. Patient education about ICDs is an important aspect which deserves consideration, particularly in this age group. The use of ICDs in octogenarians should be individualised and carefully scrutinised. It should take into consideration overall health status, symptom severity, co-morbidities and intermediate and long-term prognosis. There should be detailed discussion about patient preference and expectations. Physicians must provide a realistic appraisal of potential benefits and risks and address device management issues at end of life. This discussion should also take place when ICD replacement is considered.

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.

Low risk of major complications associated with pulmonary vein antral isolation for atrial fibrillation: results of 500 consecutive ablation procedures in patients with low prevalence of structural heart disease from a single center.

OBJECTIVES: To report the major complication rate associated with pulmonary vein antral isolation (PVAI) in a consecutive series of 500 patients from a single center. BACKGROUND: Catheter ablation for atrial fibrillation (AF) is an established procedure for refractory AF. However, the risk of major complications has been reported to range from 3.9% to 4.5% and continues to represent a cause for concern. We hypothesized that these studies may have overestimated the rate of major complications associated with PVAI in patients with a low prevalence of structural heart disease (SHD). METHODS: Data were prospectively collected from 500 consecutive AF ablation procedures on 424 patients (mean age 55 ± 11 years, 79% men, paroxysmal AF-80% and persistent AF-20%, CHADS2 scores of 0, 1, 2, 3 present in 64%, 28%, 7%, 1%, respectively), performed between July 2006 and September 2009. All procedures were performed under general anesthesia with intraoperative transesophageal echo. PVAI was performed using a nonfluoroscopic mapping system with an endpoint of PV isolation. Adjunctive left atrial ablation was performed in 21% of patients only. Major complications were defined from a compilation of those reported in 5 prior studies reporting complications. RESULTS: In 500 procedures, there were no instances of death, stroke/TIA, cardiac tamponade, atrioesophageal fistula, or PV stenosis. Major complications occurred in 4 procedures (0.8%): esophageal hematoma (TEE probe)--2; pharyngeal trauma--1; and retroperitoneal hematoma-1. CONCLUSIONS: AF ablation can be performed safely in young patients without structural heart disease with a low risk (<1%) of major complications when using a strategy of PVAI.

Long-term outcome following ablation of atrial flutter occurring late after atrial septal defect repair.

AIMS: In patients with surgical atrial septal defect (ASD) repair, late atrial flutters (AFLs), including cavotricuspid isthmus (CTI)-dependent and non-CTI-dependent scar-related flutter (AFL), are common. Radiofrequency ablation (RFA) of these arrhythmias has a high acute success rate. We aimed to characterize the long-term freedom from atrial arrhythmias in this population. METHODS: Twenty consecutive patients undergoing RFA for AFL late after ASD repair were included. Electrophysiological assessment included multipolar activation, entrainment, and electroanatomic mapping. Clinical, electrocardiograph, and Holter monitoring follow-up was conducted every 6 months. RESULTS: Mean age was 53 ± 13 years. Time from surgical repair to RFA was 29 ± 15 years. All patients had CTI-dependent AFL (20/20). There were 1.6 ± 0.7 arrhythmias per patient; other arrhythmias included non-CTI-dependent AFL (14), focal atrial tachycardia (two), and atrioventricular nodal reentry tachycardia (two) . Acute success was obtained in 100%. Five patients with recurrent AFL (three CTI dependent, two non-CTI dependent) at 13 ± 8 months had successful repeat RFA. At 3.2 ± 1.6 years follow-up since the last procedure, 90% of patients with successful RFA for AFL remained free of their clinical arrhythmia. However, 30% of the original 20 patients had documented atrial fibrillation (AF) 2.1 ± 1.6 years after the last procedure; five (25%) required AF intervention. One stroke (5%) occurred in the context of late AF. CONCLUSION: RFA of AFL occurring late after surgical ASD repair has a low long-term risk of recurrence, although 25% of patients required two procedures. However, there is a high late incidence of AF (30%), with an additional 25% of patients requiring intervention for AF.

Predictors of acute and long-term success of slow pathway ablation for atrioventricular nodal reentrant tachycardia: a single center series of 1,419 consecutive patients.

BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common mechanism of supraventricular tachycardia. Slow pathway (SP) ablation is the first-line treatment approach with a high acute success rate and a low risk of inadvertent complete atrioventricular (AV) block. However, there is still some uncertainty as to the most appropriate procedural endpoints and the impact of these on risk of recurrence. We report the acute and long-term results of SP ablation in a large single-center consecutive series and analyze predictors of acute success and late recurrence. METHODS: The study included 1,448 consecutive procedures in 1,419 patients with AVNRT (mean age 49 ± 17 years, 66% women) who underwent SP ablation using a combined electrophysiologic and anatomic approach. Univariate and multivariate analysis was performed for potential predictors of acute success and late recurrence. RESULTS: Acute success was achieved in 98.1%. Transient (first, second, or third degree) AV block occurred during the procedure in 20 (1.41%) patients. One patient (0.07%) had persistent first-degree and transient second-degree AV block after ablation and underwent pacemaker implant at day 21. Of the 1,391 patients with successful ablation, 22 patients (1.5%) developed AVNRT recurrence during a follow-up period of 63 ± 38 months. The only independent predictor of reduced procedural success was the presence of atypical AVNRT (hazard ratio 3.1, P = 0.04). Independent predictors of AVNRT recurrence were age <20 years and female gender (hazard ratios 14.1 and 3.7, respectively). No significant difference in the incidence of late recurrence was observed in patients with or without residual slow-pathway conduction, or according to use of isoproterenol testing or general anesthesia. However, patients with a single echo with recurrence had a significantly larger echo window (median 85 ms) than those without (median 30 ms, P = 0.01). CONCLUSIONS: This study demonstrates in a large consecutive single-center series that SP ablation using radiofrequency energy is a highly effective procedure with an extremely low risk of inadvertent AV block and a low recurrence rate. We found that single-AV nodal echo beats represented a procedural endpoint that did not predict AVNRT recurrence but that a large echo window is associated with recurrence. Recurrence rates in this series were higher in young women, possibly reflecting a more conservative approach to ablation in this age group.

Diagnosis and management of Brugada Syndrome.

Brugada Syndrome (BS) is a cardiac ion channel disorder linked to loss of function mutation in the SCN5A gene which affects the sodium current. The diagnosis is made on the ECG showing characteristic cove-shaped ST elevation in leads V(1) to V(3) in the absence of structural heart disease, electrolyte disturbance or ischaemia. This condition is genetically transmitted as an autosomal dominant syndrome with incomplete penetrance. It is responsible for 20% of all sudden deaths in those without structural heart disease. Diagnosis of BS can be difficult as the ECG changes are dynamic and variable. Genetic mutation in SCN5A gene is found in 25-30% of patients with Brugada Syndrome. Patients may present with syncope due to polymorphic VT or resuscitated sudden death in the third or fourth decade of life. Symptoms frequently occur at night or at rest and fever is a common trigger in children. Patients presenting with syncope or resuscitated sudden cardiac death should have an implantable defibrillator. Management of asymptomatic patients is controversial and risk stratification is required. www.brugadadrugs.org gives a list of drugs that should be avoided by patients suffering from BS.

Cardiac genetic investigation of young sudden unexplained death and resuscitated out of hospital cardiac arrest.

Nearly 30% of young sudden deaths have negative autopsies and these sudden unexplained deaths (SUDs) are presumed to be due to heritable cardiac arrhythmias attributed to cardiac ion channel disorders. Comprehensive cardiac and genetic testing of families of SUD is helpful in the detection of inherited cardiac genetic conditions. It frequently provides a clue to the cause of death in SUD victims and allows early diagnosis and opportunities to prevent SUD in other family members. Out of Hospital Cardiac Arrest (OHCA) victims and their families also require similar assessment, although the role of genetic testing in this group should be reserved to patients where a clinical diagnosis is established. A team approach with multidisciplinary specialised clinics and increased access to genetic analysis is very helpful in achieving these goals.

Systematic quantification of histologic ventricular fibrosis in isolated mitral valve prolapse and sudden cardiac death.

BACKGROUND: Cardiac fibrosis in mitral valve prolapse (MVP) is implicated in the development of sudden cardiac death (SCD); however, the pattern remains poorly characterized. OBJECTIVE: The purpose of this study was to systematically quantify left and right ventricular fibrosis in individuals with isolated MVP and SCD (iMVP-SCD), whereby other potential causes of death are excluded, compared to a control cohort. METHODS: Individuals with iMVP-SCD were identified from the Victorian Institute of Forensic Medicine, Australia, and matched for age, sex, and body mass index to control cases with noncardiac death. Cardiac tissue sections were analyzed to determine collagen deposition in the left ventricular free wall (anterior, lateral, and posterior portions), interventricular septum, and right ventricle. Within the iMVP-SCD cases, the endocardial-to-epicardial distribution of fibrosis within the left ventricle was specifically characterized. RESULTS: Seventeen cases with iMVP-SCD were matched 1:1 with 17 controls, yielding 149 samples and 1788 histologic regions. The iMVP-SCD group had increased left ventricular (anterior, lateral, and posterior; all P <.001) and interventricular septum fibrosis (P <.001), but similar amounts of right ventricular fibrosis (P = .62) compared to controls. In iMVP-SCD, left ventricular fibrosis was significantly higher in the lateral and posterior walls compared to the anterior wall and interventricular septum (all P <.001). Within the lateral and posterior walls, iMVP-SCD cases had a significant endocardial-to-epicardial gradient of cardiac fibrosis (P <.01) similar to other known conditions that cause cardiac remodeling. CONCLUSION: Our study indicates that nonuniform left ventricular remodeling with both localized and generalized left ventricular fibrosis is important in the pathogenesis of SCD in individuals with MVP.