Understanding Clinical and Genetic Complexities in Patients and Families with Inherited Heart Disease

Abstract

The inherited heart diseases are a diverse group of conditions with the shared complication of sudden cardiac death. This thesis sheds new light on clinical and genetic aspects of two poorly understood cohorts: (1) individuals who have suffered a sudden cardiac arrest or sudden cardiac death without an apparent cause on clinical investigations or autopsy and (2) patients with Brugada Syndrome. A range of study types (from cohort review to prospective clinical trial) and techniques (including genomic sequencing and deep phenotyping with cardiac magnetic resonance imaging and non-invasive electroanatomical mapping) are combined to investigate inherited heart disease in this thesis.

Chapter 1 introduces the inherited heart diseases and provides an overview of the basic principles of medical genetics. Chapters 2 and 3 review the scope of the problem of sudden cardiac arrest and sudden cardiac death in the young with a summary of the conditions implicated in these events and the key role of genetic testing. Chapters 4 and 5 reveal the importance of identifying concealed cardiomyopathy in sudden cardiac arrest survivors and sudden cardiac death victims and highlight how identifying concealed cardiomyopathy aids in the care of survivors and their families.

Chapter 6 reviews the challenges of caring for patients with Brugada syndrome. Chapters 7 and 8 investigate clinical aspects of this complex entity. Longitudinal imaging assessment revealed that structural abnormalities can emerge overtime (Chapter 7). A pilot study demonstrated that the electrophysiological effects of hydroquinidine can be detected on non-invasive assessment (Chapter 8).

This thesis highlights the importance of understanding the molecular drivers, recognising the varied clinical phenotypes, and identifying the arrhythmogenic substrate in the inherited heart diseases, with the ultimate goal to improve care of patients and their families with these complex conditions, and to prevent sudden cardiac death.