Childhood hypertrophic cardiomyopathy: characterising early phenotypes and disease progression to identify novel therapeutic targets

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that causes abnormal thickening of the heart muscle and is associated with an increased risk of sudden death in young individuals. Research over the last few decades has identified many of the genes responsible for causing HCM. However, its treatment has remained largely unchanged over the last 20-30 years and focussed on improving symptoms, screening family members who may be at risk of developing the condition, and preventing complications such as sudden death and stroke. Until now, very little attention has been paid to developing treatments to modify the underlying disease process, preventing the expression of disease in at risk individuals or halting its progression. In order to address this, it is essential to understand the early features of HCM and how it develops and progresses with time. In particular, it is important to understand the link between the gene changes that cause the condition, the mechanisms that result in heart muscle thickening, and how the condition manifests clinically.
There have been very few studies investigating the onset of HCM in children and its clinical progression. This study takes advantage of a unique cohort of children and adolescents with HCM studied at Great Ormond Street Hospital over the last 25 years, including new techniques of MRI imaging, to identify the earliest clinical features of HCM and how these progress over time.
Recently, we have identified new "biomarkers" (substances that can be identified in blood and urine samples and quantified to give information about biological processes) that are expressed in adults with HCM and correlate with clinical markers of disease severity. It is not known whether similar biomarkers are expressed in gene carriers who do not have clinical signs of HCM or in children with HCM. Over the last 3 years, we have set up a unique resource of blood and urine samples from children and teenagers with HCM (and other genetic heart diseases) that can be used to assess these and other new biomarkers.
In this study, we will use these unique resources to:
1) Identify the early clinical features of HCM in children and teenagers with HCM
2) Investigate whether children with HCM and those who carry HCM-causing gene mutations express similar biomarkers to adults with HCM and identify novel biomarkers of HCM expression and progression
3) Investigate new mechanisms of HCM development using new MRI imaging techniques, and explore whether inflammation also plays a role in the development of HCM in children
The results of this study will identify new markers of disease expression and progression in HCM and will lead to the development of new treatments for the condition.

Hypertrophic cardiomyopathy (HCM) is a clinically and genetically heterogeneous condition characterised by unexplained left ventricular hypertrophy. Although rare in childhood (estimated prevalence <3:100,000), HCM is a leading cause of sudden cardiac death (SCD). The aetiology of childhood HCM is heterogeneous, includes inborn errors of metabolism, neuromuscular disorders and malformation syndromes. Most cases, however, are caused by mutations in the cardiac sarcomere protein genes, inherited as an autosomal dominant trait with variable and age-related penetrance. The last 3-4 decades have seen significant advances in our understanding of the genetic basis of HCM, but clinical management remains largely unchanged and focussed on symptom palliation, family screening and prevention of disease-related complications such as SCD and stroke. To date, little attention has been paid to modification of the underlying disease process. Recently, there has been increasing interest in the potential for pharmacological therapy to prevent disease expression in pre-phenotypic mutation carriers, but pilot studies have been hampered by a lack of understanding of the underlying pathophysiological mechanisms of disease expression and progression. Animal studies using novel small molecules targeting actin-myosin binding have suggested that they may prevent the development of LVH in pre-phenotypic mutation carriers. However, a better understanding of the early features of HCM is essential before this approach can be translated into the clinic. One of the greatest challenges remains to understand the relationship between genotype, pathophysiology and clinical phenotype. This work takes advantage of a unique clinical cohort and bioresource and aims to use deep clinical and molecular phenotyping techniques to characterise the early clinical and biochemical phenotypic features of childhood HCM and investigate the pathophysiological mechanisms of clinical disease expression and progression.

The rationale of this project is to increase understanding of the development and progression of HCM, which can then be translated into therapeutic interventions of direct relevance to the quality of life and longevity of patients. The proposed work will impact and benefit a wide range of stakeholders.
For patients, the major impacts include empowerment through greater understanding of their disease and the development of new clinical tools that can be used to monitor disease progression and alert physicians to the need for closer surveillance. By identifying new peripheral markers of disease expression and progression, this study offers potentially affected relatives new biomarkers that could be used to identify preclinical disease and thereby direct clinical monitoring. The population prevalence of HCM is 1:500, meaning that at least 1 million people in Europe are affected. This study will be of significant benefit to the adult HCM population, with the development of therapies aimed at preventing disease progression that may result from further work informed by the findings in this study. Although the estimated prevalence of HCM in childhood is substantially lower (~3:100,000), this is highly likely to be an underestimate, as current screening guidelines do not recommend routine clinical or genetic screening below the age of 10-12 years. We have recently shown that clinically important disease can be detected in early childhood in a substantial proportion of families and this is likely to result in a change in international screening recommendations and the identification of an even larger population of patients with asymptomatic disease that could benefit from early pharmacological intervention to prevent disease progression.
For wider society, the major impact relates to the contribution of HCM to the sudden death of young and fit individuals, including children and elite athletes. An enhanced ability to detect preclinical disease using peripheral markers may be of value in preparticipation screening of athletes.
Greater understanding of the pathophysiological mechanisms of HCM disease development may offer insights into mechanisms of disease expression and progression in other settings such as heart failure. At present, there are no treatments aimed at preventing disease expression or halting progression. This work is likely to lead to the identification of novel therapeutic targets, with considerable potential for collaborations with the Pharma industry.
The research outcomes will not only benefit paediatric and adult cardiologists who manage HCM patients. Some of the findings will have a ground-breaking impact on cardiovascular genomic medicine as a whole, with a potential impact on clinicians and researchers across many fields of medicine.
At a local level, the proposed work aligns with the medium- and long-term strategies of the UCL ICS Centre for Heart Muscle Disease and the UCL ICS Department of Children's Cardiovascular Disease: the UCL Centre for Heart Muscle Disease Research has the following aims: (i) Delivery of new experimental medicine studies with clinical impact; (ii) Development of core translational activities designed to consolidate experimental personalised medicine in the field of Inherited Cardiovascular Disease; (iii) Enhanced support for major programmes of separately funded UCL discovery science. The key disease research themes underpinning the Centre's scientific strategy are: Stratified patient cohorts; Cardiac Imaging; Non-invasive and invasive electrophysiological phenotyping; Bioinformatics and computational modelling; Functional genomics; Biomarker discovery. The complimentary aims of the UCL ICS Department of Children's Cardiovascular Disease are to use novel data science and computational techniques to accomplish 3 main objectives: Better patient and disease characterisation, Better design of new therapies and Better evaluation and measurement of outcome.