Clinical Lectureship in Cardiology

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

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.

Technical Summary

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.

Publications


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Corden B (2016) Relationship between body composition and left ventricular geometry using three dimensional cardiovascular magnetic resonance. in Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
Dawes TJ (2016) Moderate Physical Activity in Healthy Adults Is Associated With Cardiac Remodeling. in Circulation. Cardiovascular imaging
De Marvao A (2016) The Authors Reply. in JACC. Cardiovascular imaging
Quinlan M (2016) Exercise CMR: real-time assessment of cardiac performance with phase contrast imaging in Journal of Cardiovascular Magnetic Resonance
 
Description Starter Grant for Clinical Lecturers
Amount £30,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2016 
End 10/2019
 
Description Cardiac dysfunction in schizophrenia: a potential mechanism underlying the excess of cardiovascular disease in the disorder? 
Organisation Imperial College London (ICL)
Department Department of Life Sciences (encompassing Biology)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have helped design the pilot study and analysed the cardiac MRI data in a cohort of subjects with schizophrenia. I have contributed to the drafting of a grant application for a large longitudinal scan.
Collaborator Contribution Recruitment of patients, funding of scanning and expert knowledge of the mechanisms of anti-psychotic medications
Impact Grant application to the BMA Foundation for Medical Research.
Start Year 2017
 
Description UK Biobank 
Organisation UK Biobank
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution I am a co-researcher in Imperial College London's application for access to the UK Biobank data. We have obtained the first ~3000 cardiac MRI data sets from this large population study and are in the process of applying our automated image segmentation and machine learning analysis methods to these scans. We intend to use this cohort as replication cohort of some of our genetic findings in the UK Digital Heart project (n=2000) and as a discovery study (GWAS).
Collaborator Contribution Recruiting, deeply phenotyping and genotyping 100,000 subjects.
Impact Analysis still under way. Only pilot data available.
Start Year 2016
 
Description "Cardiomyopathies : a look at the future" conference (Florence, Italy) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was a member of the faculty for the "Cardiomyopathies: a look at the future" conference that took place in Florence in December 2016. The conference aimed to provide a comprehensive update on international cardiomyopathy research by presenting ongoing efforts in the fields of genetics and genomics, translational science and imaging. The program encouraged a close interaction among geneticists, biostatisticians, basic scientists, imaging specialists and clinicians, with ample time for discussion and a session reserved to young investigators ongoing research projects. Such design allowed for debate, maximised interaction and promoted networking.
Year(s) Of Engagement Activity 2016
URL http://ecm.mcrconference.it/sites/default/files/brochures/programma_152.pdf
 
Description Several newspapers and TV interviews as a result of a publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact As part of the publication of our paper: 'Titin-truncating variants affect heart function in disease cohorts and the general population' and with the help of Duke-NUS (Singapore), the BHF and the MRC press offices I produced a press release and gave multiple interviews to several media channels. Media coverage included:

Daily Mail (print and online)
Evening Standard (print and online)
The Guardian (print and online)
The Times (print)
The Daily Telegraph (print)
The Independent
The Sun
The Express
Channel 5 News (5pm)
BBC Radio 5 Live
It was picked up on Press Association which led to further regional online pieces.
Year(s) Of Engagement Activity 2016
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_21-11-2016-17-1-24