Inflammation in the Pathogenesis of Arrhythmogenic Cardiomyopathy: Secondary Event or Active Driver?

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiac disease characterized by arrhythmia and progressive fibro-fatty replacement of the myocardium, which leads to heart failure and sudden cardiac death. Inflammation contributes to disease progression, and it is characterized by inflammatory cell infiltrates in the damaged myocardium and inflammatory mediators in the blood of ACM patients. However, the molecular basis of inflammatory process in ACM remains under investigated and it is unclear whether inflammation is a primary event leading to arrhythmia and myocardial damage or it is a secondary response triggered by cardiomyocyte death. Here, we provide an overview of the proposed players and triggers involved in inflammation in ACM, focusing on those studied using in vivo and in vitro models. Deepening current knowledge of inflammation-related mechanisms in ACM could help identifying novel therapeutic perspectives, such as anti-inflammatory therapy.

The role of ILR monitoring in patients with a family history of SADS, a view from real clinical practice

Background/Introduction Implantable Loop Recorder (ILR) device monitoring is an established method for long term heart rhythm monitoring in patients with inherited cardiac conditions. Many present with a family history of Sudden Arrhythmic Death Syndrome (SADS). The value of ILR findings in the investigation of SADS relatives has not been well documented. Purpose We aimed to evaluate the impact of ILR monitoring on the management plans of patients with a family history of SADS. Methods We performed a retrospective analysis of the ILR reports and electronic patient records of all patients at the inherited cardiac disease clinic with a family history of SADS and an ILR implanted. Patient demographics, ILR implant indication and specific changes to management plans were recorded and analysed using descriptive statistics. Results All 135 patients with ILR monitoring at the inherited cardiac disease clinic were screened and 87 patients (57.6% female, 41.7±14.0 years) with SADS relatives were included in the study. The mean follow up period was 657.9±392.3 days from ILR implant. Indications for ILR implantation included syncope (n=31, 15.7%), presyncope (45, 22.7%), palpitations (44, 22.2%), chest pain (9, 4.5%), short term heart rhythm monitor findings (6, 3.0%), ECG findings (6, 3.0%), asymptomatic indications (10, (5.1%) including patients with more than one relative with SADS, a family history of conduction disease or family history of long QT syndrome), and atypical symptoms (2 (1%) including seizures and sleep paralysis). Some patients had more than one indication for ILR at the time of implant. As a direct result of ILR monitoring, 43 (49.4%) patients had a change to their management plan. 6 specific definitions for management changes were used: Permanent pacemaker implantation (2, 2.3%), subsequent electrophysiology study (3, 3.5%), medication change (7, 8.1%), arrhythmia excluded as a cause for patient symptoms (26, 29.9%), prompted ILR implant in first degree relative (11, 12.6%) and ILR re-implant for further monitoring for premature conduction disease (1, 1.2%). Patients whose indication for ILR implant was palpitations had the highest likelihood for change of management with 27 changes associated with this indication, of which exclusion of arrhythmia as a cause for symptoms (15) was the most frequent outcome. The indications, syncope and presyncope both yield 21 management changes each. Conclusion The use of ILR devices in family relatives of patients with SADS provides information that may directly impact on patient management, with syncope providing the highest yield and reassurance the most common outcome in our cohort. ILR monitoring helped guide a wide range of other management strategies which included changes to medications and the need for further cardiac procedures. This data represented clinical practice in a niche patient cohort who are at risk for inherited cardiac conditions and associated arrhythmias. FUNDunding Acknowledgement Type of funding sources: None. Indication for ILR vs management change Indications for ILR implant

Diagnostic findings in relatives to victims of sudden unexplained death or non-autopsied possible sudden cardiac death

Introduction Sudden cardiac death (SCD) may be caused by several inherited cardiac diseases and screening and treatment of relatives may be lifesaving. Sudden unexplained death (SUD) victims have been autopsied, whereas non-autopsied possible SCD (pSCD) victims are only filtered on manner of death and medical records. Screening of relatives may identify an inherited cardiac disease. Purpose To assess the diagnostic yield at initial evaluation and during follow-up of relatives to SUD and pSCD victims. Furthermore, to evaluate the outcome in the relatives. Methods We retrospectively included first-degree relatives to SUD and pSCD victims referred to our tertiary center from 2005 to 2018. Probands with known antemortem inherited cardiac disease were excluded. Data from systematic screening and routine follow-up of the relatives were registered. Results We included 371 first-degree relatives from 187 families: 276 SUD relatives (age at initial evaluation 35±17 years, 54% men;) and 95 pSCD relatives (age at initial evaluation 40±15 years, 51% men). The diagnostic yield among SUD families was 18%, among pSCD families 13% (p>0.05 between groups). The diagnoses in SUD families were mainly channelopathies (68%), whereas the pSCD families were diagnosed with cardiomyopathies, channelopathies, and premature ischemic heart disease (Figure 1). The vast majority of diagnosed families (93%) were diagnosed at the initial evaluation and only two families were diagnosed during the mean follow-up of 5.4 years. During follow-up, 57 (15%) relatives had a cardiac-related hospitalization, 12 (3%) relatives had a cardiac device implanted, three (1%) relatives died of non-cardiac causes, and one (0.5%) relative had a myocardial infarction. There was no significant difference in cardiac event rates between the SUD and pSCD groups (all p>0.05). Conclusion One in 6–7 families with SUD or pSCD victims obtained a diagnosis based on screening of relatives; we mainly diagnosed channelopathies in SUD families and a broader spectrum of inherited cardiac disease in the pSCD families. The majority of affected relatives was diagnosed at the initial evaluation and clinical follow-up may not be warranted in all relatives with normal findings at initial screening. Figure 1. Family diagnoses in categories, n (%) Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Capital Regions Research Foundation and The A.P. Moeller Foundation.

Autopsy examination in sudden cardiac death: a current perspective on behalf of the Association for European Cardiovascular Pathology

In sudden cardiac death, an autopsy is an essential step in establishing a diagnosis of inherited cardiac disease and identifying families that require cardiac screening. To evaluate aspects of post-mortem practice in Europe, a questionnaire was designed and circulated to both clinical and forensic pathologists. There was a 48% response rate and information was obtained from 17 countries. The results showed a wide variety in the management of sudden cardiac death, with a general tendency towards a lack of thorough investigation. In up to 40% of cases, autopsies were not performed in subjects less than 50 years who may have died from cardiac disease. Reasons for this were lack of finance and lack of interest from police, legal authorities, and doctors. Only 50% of pathologists seem to follow a standard protocol for autopsy examination, apparently due to lack of expertise and/or training. When autopsies were performed, histology and toxicology were almost always taken, genetic studies were generally available and retention of the heart for specialist study was usually permitted. Our results suggest that although the standard of practice is appropriate in many centres, many more cases should have autopsies, especially in sudden deaths in subjects less than 50 years.

Inherited Cardiac Disease

Every year, thousands of people die or suffer chronic disability as the result of inherited diseases of the cardiovascular system. In many cases, diagnosis of inherited disease is delayed or missed owing to a lack of awareness, and an even greater number of relatives are exposed to unnecessary risk. This new edition of Inherited Cardiac Disease provides a comprehensive summary of the aetiology, presentation, and management of genetic disorders of the cardiovascular system. Fully updated to reflect the advances in molecular genetic technologies and the publication of national guidelines for the management of families with inherited cardiac diseases, it retains the first edition’s broad scope and applicability to all members of the multidisciplinary team, from specialists in cardiology and clinical genetics, to genetic counsellors, paediatricians, nurse specialists, and GPs who may come into contact with families presenting with inherited cardiac diseases. After chapters on the general principles of cardiovascular genetics, genetic testing and counselling, individual disorders are then examined in detail, each account featuring a clinical summary, diagnostic tests and special investigations, and treatments relevant to each inherited cardiac disease. Written in the succinct bullet-point style of the Oxford Specialist Handbooks, this new edition of Inherited Cardiac Disease delivers key information in an accessible manner, and is an invaluable guide to anyone who works with patients who are affected by inherited diseases of the cardiovascular system in their practice.

Introduction

This chapter sets out the rationale for the second edition of this Oxford Specialist Handbook in Inherited Cardiac Disease, with the aim to describe the basic principles of clinical genetics where relevant to cardiology practice, with the advances in sequencing technologies since the previous edition included to aid diagnosis.