Cardiovascular — Sub-theme 2: Inherited Cardiovascular Conditions (ICC)

Sub-theme leads: Prof Stefan Neubauer and Prof Hugh Watkins

Over the past five years, we have brought genetic testing for a range of Sudden Cardiac Death (SCD) syndromes into the NHS and established novel magnetic resonance imaging (MRI) methods with potential to improve diagnosis and management in cardiomyopathy. To further improve management of patients with Inherited Cardiovascular Conditions (ICCs), we are:

Exploiting new advances in genetic testing in Sudden Cardiac Death Syndromes.

Using a targeted sequencing approach has allowed introduction of a 13 gene Hypertrophic Cardiomyopathy (HCM) screen into our NHS lab (2011). This is now being validated, and we are seeking approval of the UK Genetic Testing Network for gene panels for the full range of SCD Syndromes (cardiomyopathies and channelopathies). This will increase testing output, speed-up turnaround, reduce cost and allow genetic differentiation of disorders that require different treatment.

The ICC sub-theme is also working on another approach (whole exome sequencing) which will become cheaper than the current method, thus permitting the surveying of a wider range of disease genes. To enable NHS uptake we are working to:

  • Produce a cost-effective semi-automated analysis pipeline.
  • Develop methods for evaluating “genetic variants of uncertain significance”. We will determine true prevalence and disease causing role using our ICC database (GenetICC) for family segregation data.
  • Explore ethical, legal and social implications of disease causing variant discovery in genes unaddressed by prior counselling.
  • Improve mechanisms for family cascade screening. As more testing is done in the NHS, more genetic variants will be revealed with implications for the wider family. We are focussing on connecting family data in the electronic patient record and addressing issues of confidentiality.

Disease gene discovery

The >2000 families we have screened provide unrivalled opportunities to identify novel disease genes, pathways and mechanisms.

Phenotyping with advanced imaging techniques

Multiparametric MR imaging in hypertrophic cardiomyopathy

Multiparametric MR imaging in hypertrophic cardiomyopathy
Clockwise from top left: T1 mapping; MR tagging; cine-MRI; Late gadolinium enhancement; Unpublished figure from OCMR

We are also studying large genotyped patient groups with cardiomyopathy to formally evaluate clinical utility of novel imaging tools and disease-modifying interventions. For example, we are contributing to leadership of an international study using highly detailed MR imaging to phenotype (characterise observable physical qualities) of HCM in 2500 patients, which will lead to improved clinical systems. We are testing novel imaging parameters, such as myocardial fibre structure, oxygenation and energetics, and their alteration in HCM. By studying large numbers of patients, we are establishing important genotype-phenotype correlations.

Our continuing physiological and mechanistic studies in HCM will enable us to test novel, disease-modifying therapies. As an example, our collaborative study giving HCM patients a drug previously used in the treatment of angina has demonstrated improvement in symptoms and myocardial energetics (Circulation 2010;122:1562), and we are now in the process of planning a multi-centre Phase III randomised clinical trial (RCT) powered for clinical end-points. We hope to extend this approach to other therapeutic agents.

Relevance of research to the health of patients and the public: Genetics testing in SCD syndromes and novel imaging biomarkers in HCM will improve diagnosis, therapeutic decision and genetic counselling. Novel disease-modifying therapies in HCM could have a major impact on improving prognosis.