A North-South Partnership in Congenital Heart Disease (CHD)

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences

Abstract

Congenital heart disease (CHD) is the commonest birth malformation, affecting nearly 1% of liveborn children. It is also a major cause of miscarriage. In Western countries, the availability of open-heart surgery to correct even severe heart malformations has transformed the outlook for CHD patients. In the 1950s, only around 10% of children with a serious heart malformation lived to adulthood; the rate now is over 90%. By contrast, African countries face enormous challenges in managing children and adults with CHD, related both to lack of resources and lack of an African specific evidence base. Almost all research carried out into the causes, treatment and outcomes of CHD has been done in Western countries. We do not even know for certain such basic information as whether the rate at which CHD occurs is the same in African populations as it is in Western populations, and whether the range of CHD conditions encountered is similar. There may be particular risk factors for the development of CHD in certain African environments that, if they were known about, could be modified to reduce the risk of CHD occurring - but there is little or no African based research thus far into factors that may cause CHD. Regarding treatment, open heart surgery is not readily available in any African country, and there is limited resource to select the patients most likely to benefit from an operation, maximise their fitness for a procedure, and follow up complex cases following surgery. This results in major gaps in knowledge regarding how best to provide optimal outcomes for African CHD populations, within severe resource constraints that are unlikely to change rapidly.

This foundation project will establish a sustainable CHD research infrastructure at the University of Cape Town, South Africa, the leading educational institution on the African continent; and create a model that could be applied in other South African centres and collaborating African countries. We will invite adult and child patients who attend the CHD units in Cape Town, which are among the largest in South Africa, to participate in the project. We will establish a comprehensive database containing clinical information about the patients and their families, and we will request samples of blood or saliva to enable us to investigate the role of inherited factors (genes) in causing CHD. We aim to enrol at least 1200 patients in the two year period of the grant. The UK partner group at The University of Manchester is among the world leaders in studying the role of genes in CHD, so we will test in this African population the importance of genes we have already shown to be important in Western populations, as our first experiment. If the foundation project shows that it is feasible to enrol and conduct genetic studies in African CHD patients, we will be very well placed to search for particularly African genetic causes of CHD in future experiments. We will also carry out studies modelling the abnormal blood flow that occurs in CHD patients using powerful computers, to see if we can identify patterns that are useful in predicting outcomes for patients.

The patient database will also provide a unique resource for African researchers to address key questions about the causation of CHD beyond genetics; the rates at which particular heart malformations occur; and the outcomes for patients in an African context. We will request consent to keep in contact with all enrolled patients, which will enable us to study the effects of CHD throughout patients' lifecourse following the two-year Foundation Award. The resource will help African researchers to define the most important and feasible research topics for future study in the population they are serving. The research emerging from this registry will provide clear signposts on steps that can be taken to address the extremely different outcomes of CHD, which is now a highly treatable condition, between Western and African countries.

Technical Summary

Building on the existing clinical cardiovascular research expertise in Cape Town, we will create a comprehensive registry and database of both adult and child CHD patients, with capacity for the integration of genotypic data, and develop the infrastructure necessary for prospective follow-up. We will carry out detailed clinical and echocardiographic characterisation of all participants at enrolment. We will biobank samples from probands (and their parents where available) for DNA extraction and downstream 'omics analyses. We will obtain cardiac tissue from study participants who undergo a cardiac surgical procedure during the period of the study. We will aim to enrol at least 1200 patients. We will conduct focused candidate gene studies using next-generation sequencing panels to explore the contribution of rare variants in genes previously implicated in CHD risk in Europeans, in an African population. We will undertake patient specific studies to investigate the potential for computational fluid dynamics (CFD) modelling to contribute to personalised medicine in two CHD conditions: repaired tetralogy of Fallot (TOF) and coarctation of the aorta (CoA). Structural and flow data will be extracted from CT, echocardiography and serial cardiac MR scanning. We will identify the baseline haemodynamic features in each patient using standard flow derived metrics and map this to a detailed morphological characterisation of the geometry. The genetic and CFD study results will establish the feasibility of our approach and provide justification for a more substantial, and possibly pan-African, follow-on award. Establishment of the resource will provide a foundation for African researchers to address pressing questions regarding the lifecourse epidemiology and optimal treatment of CHD in an African context in future applications.

Planned Impact

The key areas of impact of this work include (1) advancement in scientific and health knowledge, (2) development of clinical, imaging and laboratory expertise, (3) addressing the contribution of CHD to adverse outcomes in maternal and child health, (4) delivering highly skilled people to the labor market, (5) engaging the public on the value of improved understanding of CHD and creating patient and family-informed and accountable research, (6) consolidating international and continental networks, and (7) direct improved patient benefit in a transitional country.

Establishment of the largest database of comprehensively phenotyped adult and child CHD patients on the African continent will enable epidemiological, clinical and genetic studies to be conducted to the benefit of patients and healthcare systems. Our findings will inform the development of health and social policy: in particular documenting the impact of late presentation and delayed referral to specialist care on prognosis and the occurrence of complications of CHD; and establishing the consequences of a CHD diagnosis for patients and their families. We will connect with local and national Ministers of Health in South Africa (building on already-established relationships with these directorates) to stimulate action on our findings demonstrating the contribution of CHD to adverse outcomes in maternal and child health. We will engage the patient and family CHD community to improve outcomes through better education and understanding.

We will have additional impact through training a cadre of CHD researchers and healthcare professionals in Southern Africa: physicians and surgeons, research nurses, cardiac clinical physiologists, and basic scientists. This will not only enhance the quality of care for patients enrolled in the study, but new knowledge and practices will be disseminated in the participating centres. Drs Mayosi, Zuhlke and Ntsekhe have leadership roles in the Pan African Society of Cardiology, SouthAfrica Heart and the African interventional cardiology meeting AfricaPCR, which will facilitate this. We will further the practice of evidence-based medicine in CHD care by adding substantially to the resource of high-quality African data on CHD epidemiology, management and outcomes.

We will investigate the role of genetics in the causation of CHD in Africa. By comparing and contrasting genetic variants in African and European ancestry populations, we will identify causal genes important to CHD risk. Patients will benefit from the increased knowledge about CHD risk as it may be possible, in some families, to explain the reason CHD has occurred and quantify its recurrence risk. Also, knowledge about how heart development can go wrong will inform our knowledge of normal mechanisms, and potentially inform approaches to regenerative medicine for other types of heart disease (such as heart failure). All laboratory genetic work will be carried out in Cape Town, with the Manchester team providing support as required. Bioinformatics analysis tasks will be shared, with a particular emphasis placed on capacity building at UCT.

Demonstrating the feasibility of collaboratively producing detailed anatomical and computational fluid dynamic models in CHD will potentially lead to novel approaches to risk stratification. It will also directly inform the efforts of our partners in developing percutaneously implantable valve devices suitable for use in LMICs, to address major causes of late morbidity in CHD, e.g. pulmonary valve stenosis/regurgitation following Tetralogy of Fallot repair. Should potentially patentable outputs result from this research, we will work with the Technology Transfer offices of UoM and UCT to ensure protection of intellectual property and support of entrepreneurial opportunities. In keeping with ODA goals, any exploitation of IP would be led from and chiefly to the benefit of the African partner.

Publications

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Owen B (2018) Structural modelling of the cardiovascular system. in Biomechanics and modeling in mechanobiology

 
Description MRC/DFID African Research Leader Award
Amount £700,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2019 
End 01/2024
 
Title The PROTEA Study Database 
Description A comprehensive database of phenotypic information on congenital heart disease patients at Red Cross Children's Hospital, Cape Town, and Groote Schuur Hospital, Cape Town. The database is implemented in Filemaker Pro software. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The great majority of patients passing through the Cape Town congenital service are now databased. There is great interest in the PROTEA database from colleagues in several sub-Saharan countries and from the Aswan Heart Centre, Magdi Yacoub Heart Foundation, Egypt. 
 
Description African Research Leader Award - Prof Liesl Zuhlke 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution UK PI for the award. Responsibility for mentorship of ARL Prof Zuhlke. Leading genetics aspects of CHD project that is part of the ARL
Collaborator Contribution Contribution to grant writing Expertise in genetic epidemiology of CHD BIoinformatics and data analysis expertise.
Impact Training for students Highly cited publication Infastructure development in South Africa Scientific capacity development in South Africa
Start Year 2019
 
Description Collaboration with Aswan Heart Institute 
Organisation Aswan Heart Center
Country Egypt 
Sector Hospitals 
PI Contribution Database generation, Protocol generation.
Collaborator Contribution Patients will be databased, samples for genetics will be collected. The partners will allot developer time to port our existing congenital heart disease database to an open source platform.
Impact None as yet.
Start Year 2017
 
Description PROTEA Study Inaugural Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The kickoff meeting for the PROTEA study involved professionals in congenital heart disease and genetics from the UK and South Africa, together with students and trainees. The meeting also involved charitable fundraisers for congenital heart disease research in South Africa, patients, and members of parent support groups, together with ethicists and public policymakers. The meeting enabled very useful exchange of ideas among these different stakeholder groups.
Year(s) Of Engagement Activity 2017