Clinical Lectureship in Cardiology

The purpose of this research is to identify the inherited causes of cardiovascular disease. In particular, we aim to find the genetic differences that control heart and vessel function and cause abnormal heart rhythms, heart failure, abnormal heart muscle thickening and artery disease. This will help us find new ways to identify, treat and prevent these diseases.
For this study we have so far recruited nearly 2000 healthy adults. We used the latest MRI technology to scan them and to create individual 3D digital images of the beating heart. We also used state-of-the-art MRI techniques to obtain images of their blood vessels and blood flow. In addition, each volunteer had their blood pressure monitored over 24 hours, a heart tracing and some blood taken for genetic testing.
We will now use powerful computer programs to analyse these 3D scans with the genetic information we collected. This will be a much more accurate way of discovering what are the genetic and environment factors that lead to disease. We will start by studying variations in the gene titin. These are present in 1% of the population but it is not known why or how they cause heart failure in only some people.

Background and Aims

The genetic and environmental factors that define cardiovascular structure and function, particularly at the intersection between health and the earliest stages of disease, remain poorly characterised. Conventional cardiovascular imaging provides limited, semi-quantitative and global metrics of the heart leading to underpowered imaging-genetics studies. We have demonstrated that three-dimensional (3D) cardiac magnetic resonance (CMR) imaging with computational quantitative phenotyping provides methodological, statistical and scaling advantages for epidemiological and genetic studies of the heart. The aim of my research is to use state-of-the-art cardiovascular imaging and computational techniques to identify the common and rare genetic variants associated with cardiac hypertrophy and dysfunction in humans. Our research found that truncating variants in titin (TTNtv) are present in 15-20% of dilated cardiomyopathy cases and, surprisingly, in ~1% of the general population.

Methods

Volunteers without self-reported cardiovascular disease are being recruited prospectively via advertisement to the UK Digital Heart Project (https://digital-heart.org/). We excluded participants who had known cardiovascular or metabolic disease and standard safety contraindications to MR imaging were followed. This study was approved by a research ethics committee and all participants gave written informed consent. So far 1950 volunteers (55% females; 70% Caucasian; mean age 41 years, SD 13) have had CMR imaging performed on a 1.5T Philips Achieva system (Best, Netherlands). In addition to conventional cine balanced steady-state free precession (b-SSFP) imaging, a high-spatial resolution 3D b-SSFP cine sequence was used that captures the whole-heart phenotype in a single breath-hold (reconstructed voxel size 1.2 × 1.2 × 2 mm). A cardiac atlas-based software was developed to quantitatively analyse 2D and 3D phenotypes (eg, wall thickness and function) at over 46?000 points across the heart. Ambulatory 24 hour blood pressure (BP) / pulse wave velocity (PWV) monitoring was used to supplement standard BP and ECG measurements. Detailed social and family histories were collected and anthropometric variables measured. Blood samples were taken for genotyping, whole-exome sequencing and serum biochemistry. Associations between phenotypes, clinical variables and genotypes were studied with 3D regression models and Bayesian latent factor analysis.

Research plans

We are using high-resolution quantitative phenotyping combined with computational modelling and advanced statistical analysis to identify the genes and biological pathways that determine cardiovascular morphological and physiological features. Following on from encouraging preliminary data we will carry out a 3D genome-wide association study. In addition we will carry out a study to clarify the penetrance and pathogenicity of TTNtv in humans.