Stroke

Stroke is the third most common cause of death, and the most common cause of disability in developed countries. This chapter examines the genetics of stroke, and single gene causes (although stroke is often just one component of the phenotype). It then describes Anderson—Fabry disease, CADASIL, RVCL, autosomal-dominant porencephaly and infantile hemiparesis, hereditary cerebral haemorrhage with amyloidosis, Moya-Moya disease, sickle cell disease, and MELAS.

The heart and inherited haematological disorders

This chapter covers inherited haematological disorders. It explains the pathophysiology, genetics, and iron overload of thalassaemia; cardiac disease in both β‎ and α‎thalassaemia; the pathophysiology, genetics, and iron overload in haemochromatosis; the evaluation of patients; and finally the management of patients at risk of cardiac iron overload.

Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an inborn error of metabolism that leads to accumulation of low-density lipoprotein cholesterol (LDL-C) particles in the blood and premature coronary artery atherosclerosis. This chapter covers the clinical criteria for the diagnosis of FH, the genetics that underpins the condition, cascade testing, premature coronary heart disease, and treatment methods.

Mitochondrial cardiovascular diseases

This chapter begins by defining the mitochondrial genome, and the subsequent assessment of suspected mitochondrial DNA (mtDNA) disorders. The incidence and prevalence of cardiac involvement in mitochondrial disorders is covered, including the probably under-reporting of this. Different cardiovascular phenotypes associated with mitochondrial disease (arrhythmias, hypertrophic cardiomyopathy, Barth syndrome etc.) are all described, and then the clinical management of the diseases are explained. As there is no fixed treatment, pharmacological regimens to avoid, and other approaches are also included.

Inherited arrhythmias and conduction disorders

Long QT syndrome is primarily a disorder of repolarization with three principal ion channel currents accounting for the condition. Management revolves around optimization of beta blockade and avoidance of triggers with implantable cardiac defibrillators (ICD) recommended in high risk cases. Brugada syndrome is thought to be caused by Na channel mutations although the aetiology is not fully established. Controversy exists regarding optimal risk stratification approaches. Catecholaminergic polymorphic ventricular tachycardia is caused by abnormalities in calcium handling leading to bidirectional ventricular tachycardia/VF and can be managed using medication –principally beta blockers and occasionally sympathectomy with ICD in cardiac arrest survivors with specific caveats. Inherited conduction disorders should always be considered in patients presenting at a younger age with conduction disease paying specific attention to lamin mutations where an ICD will need to be considered.

Coronary artery disease and myocardial infarction

This chapter covers coronary artery disease (CAD) and myocardial infarction, starting with an introduction to the main causal and treatable risk factors for CAD and myocardial infarction, then goes on to discuss the Mendelian disorders associated with CAD (e.g. Tangier disease, sitosterolaemia, etc.) Association studies based on the candidate gene approach are discussed along with genomic studies, e.g. polygenic risk scores.

Cardiomyopathies

The chapter covers heart muscle diseases, starting from the classification and the importance of a cardiomyopathy-focused mindset for diagnostic work up. It goes on to examine genetics, diagnosis, common challenging differentials, and family screening in a number of specific cardiomyopathies in both adults and children. Management of specific cardiomyopathies is discussed in detail, including symptomatic and prognostic treatment with drugs, devices, and surgery, with focus on areas of ongoing debate, such as arrhythmic risk stratification and overlap between dilated and arrhythmogenic cardiomyopathy. In the final section it discusses the pathophysiology, diagnosis, and management of a distinct condition (and arguably not a cardiomyopathy), Takotsubo syndrome.

Marfan syndrome and related inherited disorders of connective tissue

The phenotype of inherited disorders of connective tissue is extensive and may involve multiple body systems. In most cases, the clinical picture is that of a progressive chronic disease with mild to severe dermatological, osteo-articular, ocular, and cardiovascular manifestations. The spectrum of cardiovascular manifestations is broad and may range from a mild structural abnormality (e.g. mitral incompetence) to life-threatening complications (e.g. aortic dissection). This chapter provides a general guide to diagnosis and management of cardiovascular manifestations in Marfan syndrome and related inherited disorders of connective tissue. Major conditions are discussed in detail and the interested reader is advised to consult online resources for information on other less common inherited connective tissue disorders

Genetic counselling

Genetic counselling is one of the major tools in managing inherited cardiac conditions (ICCs) including single gene disorders such as hypertrophic cardiomyopathy and long QT syndrome to multifactorial conditions such as coronary artery disease (CAD) and congenital heart disease (CHD). This chapter deals with genetic counselling for ICCs that are typically transmitted in a Mendelian fashion, for example cardiomyopathies, arrhythmias, Marfan syndrome, as well as inherited lipid disorders. Typically, a genetic counsellor works within a multidisciplinary team including cardiologists, clinical geneticists, nurses, social workers, and psychologists. This chapter covers the role of genetic counsellors, process, consent and confidentiality, communication, and outcomes.

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.