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An Integrated Cardiovascular System (ICVS):

Inherited Cardiac Disease A proposal for the UCLP Academic Health Sciences Network (AHSN) February 2013

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Collaborators University College London Hospitals NHS Foundation Trust Professor Perry Elliott (Clinical Lead) Professor William McKenna Dr Antonis Pantazis Dr Maite Tome-Esteban Dr Pier Lambiase Dr Martin Lowe (Clinical Lead Electrophysiology) Simon Waller (CNS) Linda Moss (CNS) Eileen Firman (CNS) Michael Baldini (CNS) Rebecca Hylands (Trials coordinator) Sharon Jenkins (Genetic counsellor) Demetra Georgiou (Genetic counsellor) Dr Bryan Mist (Physiologist) Shaughan Dickie (Databasing) Barts Health NHS Trust Dr Saidi Mohiddin (Clinical Lead) Neha Sekhri Ceri Davies Richard Schilling GOSH Dr Juan Pablo Kaski Dr Alessandro Giardini Sarah Mead-Regan (CNS) Michael Burch Matthew Fenton Sophie Neligan (CNS)

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Introduction

Diseases of the heart and blood vessels are major contributors to human morbidity and mortality. While the majority are the consequence of common disorders such as hypertension and coronary artery disease, a substantial proportion is caused by genetic disorders that, in aggregate, constitute a disease burden greater than many cancers. Recognition of this fact is important as conventional patient pathways neither provide access to the expert multidisciplinary teams required for the diagnosis and management of most inherited disorders nor cater for the needs of families of patients with inherited cardiovascular disease. Over the past decade, a number of reports have raised the profile of inherited cardiovascular conditions in the NHS. In March 2005, chapter eight of the national service framework (NSF) for coronary heart disease focussed on the issue of sudden cardiac death in young people and highlighted the high prevalence of inherited disorders in this group. A core aim of the document was to develop NHS systems that ‘identify family members at risk and provide personally tailored, sensitive and expert support, diagnosis, treatment, information and advice to close relatives’. It recommended that evaluation of families should take place “…in a dedicated clinic with staff who are trained in diagnosis, management and support and with genetic counselling and further testing available if appropriate.” In 2009, an informal cardiac genetics group commissioned the PHG Foundation to conduct a survey of Cardiac Genetics Services in the UK under the supervision of an expert Working Group. A questionnaire sent to all regional genetics centres identified twenty services caring for one or more inherited cardiovascular conditions. Respondents provided qualitative information about service configuration, operation and resourcing and quantitative data on activity levels. The survey demonstrated that the capacity of services in the UK is inadequate to meet current and future needs and that service provision is highly unequal in quality as well as quantity across the country. Services were found to be highly London-centred, but there was no evidence of overprovision of services within the capital nor was there any indication that the London services were compensating for the shortfall elsewhere in the UK. The report concluded: “Benefits from expert patient management for ICCs arise through the precise diagnosis of patients and affected relatives, which enables tailoring of advice and treatment to reduce risk; and that all patients with ICCs and their families should have access to specialist care from multidisciplinary teams with particular knowledge and experience in the diagnosis and management of these conditions. Such teams should include a balance of consultant cardiologists with subspecialist expertise in fields such as echocardiography, electrophysiology and paediatric cardiology, consultant geneticists, genetic counsellors, clinical laboratory scientists, specialist nurses and cardiac physiologists.”

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Epidemiology of Inherited Cardiovascular Disease The inherited cardiovascular conditions (ICCs) are a group of genetic disorders caused by mutations in genes encoding components of the contractile apparatus and electrical system of the heart or its vasculature. The five major categories of ICCs are:

Arrhythmia syndromes caused my mutations in cardiac ion channel genes that encode the proteins involved in generating the cardiac action potential. These include long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS) and early repolarization syndrome (ERS).

Cardiomyopathies caused by mutations in genes encoding proteins of the contractile apparatus and cytoskeleton of cardiac myocytes. These include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM) and left ventricular non-compaction (LVNC).

Aortopathies caused by mutations in genes encoding connective tissue proteins of the vasculature and other organs. These include Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS) and Loeys-Dietz syndrome (LDS).

Muscular dystrophies with cardiac involvement, including Emery-Dreifuss muscular dystrophy and myotonic dystrophy.

Familial hypercholesterolaemia (FH) and other disorders of cholesterol metabolism that cause premature coronary artery disease.

Collection of population level data for individual inherited cardiovascular diseases is difficult because there is no systematic approach to their identification or recording at a national level. Data collection is also hampered by the often subtle early manifestations of disease which can be difficult to distinguish from common multifactorial conditions. Nevertheless, it is possible from UK and World literature to estimate the number of prevalent cases of the major inherited cardiac conditions (Table 1). Using these data, we have estimated numbers of prevalent cases for the commonest inherited cardiovascular disorders in the population of six million people across North Central London, and North East London, South and West Hertfordshire, South Bedfordshire and South West and Mid Essex served by the UCLP AHSN. Accepting that these estimates must be interpreted cautiously, they are likely to represent a substantial underestimate of the true burden of inherited cardiovascular disease in adult and paediatric populations because most studies fail to account for disease in relatives and exclude other genetic conditions that have heart manifestations.

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Table 1: Estimates for numbers of people with commonest inherited cardiovascular disorders resident in the UCLP Network

Condition Population Prevalence Estimated prevalent cases UCLP AHSN

Hypertrophic Cardiomyopathy 1 in 500 12000

Familial Hypercholesterolaemia 1 in 500 12000

Arrhythmogenic right ventricular cardiomyopathy 1 in 1000 to 1 in 10,000 600-6000

Long QT syndrome 1 in 5000 1200

Dilated cardiomyopathy 1 in 2500 2400

Brugada Syndrome 1 in 5000 1200

Marfan Syndrome 1 in 5000 1200

Myotonic dystrophy 1 in 8,000 750

TOTAL 30,150-35,550

Current service provision for patients in UCLP AHSN 1. The Inherited Cardiovascular Disease Unit, UCL/UCLH The cardiomyopathy unit was established at St. George’s Hospital, London in 1988 and transferred to the Heart Hospital in April 2003. It has since evolved into the largest inherited cardiac conditions service in the UK. The multidisciplinary team comprises doctors, nurses and genetic counsellors with specific expertise in the diagnosis and management of inherited cardiomyopathies, familial arrhythmia syndromes, paediatric cardiology and cardiovascular imaging. Dedicated disease specific outpatient clinics operate at The Heart Hospital and Great Ormond Street Hospital. Data obtained from the study of patients and relatives is used to conduct clinical and basic research, supported by funding from national research agencies, cardiovascular charities and the European Commission. The inherited cardiac disease service at UCLH receives referrals from all over the United Kingdom, but 80% of patients are referred from PCTs in the South East and and South Central regions. The majority of referrals are from cardiologists seeking advice on diagnosis, treatment and genetic counselling, and from general practitioners responding to the diagnosis of a relative with cardiomyopathy or sudden cardiac death. The number and complexity of referrals has steadily increased over the past seven years (Figure One).

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Figure 1: Numbers of patients seen in The Heart Hospital Cardiomyopathy and Inherited arrhythmia clinics 2006-2011

The PHG survey (based on data for 2007/8) demonstrated that less than half of the patients seen at UCLH (39%) came from 31 PCTs within the London SHA. Comparative rates for services provided to new patients and total patients within a given region were calculated in relation to SHA populations and populations for Wales, Scotland and Northern Ireland. In this calculation, the figures for The Heart Hospital were allocated to the region from which patients were referred and only included in the London and SE Coast SHA when patients were referred from London or SE Coast SHAs. This gave a more accurate picture of the levels of service provision received by patients living in regions outside of London and also in London compared to other parts of the UK. The numbers of patients seen were much greater at The Heart Hospital compared to other London centres (the total number of patients seen is 5,628 at THH compared to 3,421 for all the other London services combined). Ideally, the data should have been corrected for other centres in London as a number of these also receive referrals from across the UK and so inflate the level of service provision received for patients from London and the SE Coast compared to other parts of the UK. However, these data were not available at the time of the report. 2. Barts Health NHS Trust (Formerly Barts and The London NHS Trust): The Heart Muscle Disease (HMD) clinical service at the London Chest Hospital (LCH) was set up in 2006 when a once monthly HCM clinic was developed. This was an initiative to provide for a clearly evident but unmet clinical need for local outpatients and to provide the cardiomyopathy expertise that is an essential component of a large complex tertiary acute cardiac service.

Service Growth From managing a cohort of 65 patients in 2006, a recent audit (August 2012) demonstrates that the service now manages nearly 1500 patients with hypertrophic cardiomyopathy (figure two). The audit, examining indices of care quality did not include the other ICCs managed by the service.

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A 2010 audit identified referral sources: 50% from other cardiac clinics; 23% were new HMD diagnoses following acute cardiac presentations; 20% following CMR imaging and only 7% through family screening. To support referral pathways, the HMD service generated clinical guidelines, contributes sessions to inpatient and CMR activity and developed a satellite clinic at Newham University Hospital – the local DGH for 15-20% of our patients. Figure 2: Number of HCM patients managed at LCH between 2006-2012.

3. Great Ormond Street Hospital/ICH The Inherited Cardiovascular Diseases service at GO was established in 2003, following the transfer of the cardiomyopathy service from St George’s Hospital to the Heart Hospital. Until June 2011, the service comprised a weekly cardiomyopathy clinic and a weekly special arrhythmia service. The service was restructured in 2011, and currently provides 2 weekly cardiomyopathy clinics, a dedicated inherited arrhythmia clinic and a new aortopathy clinic. The integrated service is based on a multidisciplinary team, including paediatric cardiologists with expertise in ICCs, paediatric cardiac specialist nurses, clinical psychologists, paediatric clinical physiologists and admin support staff. In addition, the team works closely with the North East Thames Regional Genetics Service, also based at GOSH, and specialist paediatric cardiac pathologists.

Clinical Activity Since the restructuring of the service in June 2011, the number of patients seen by the service has more than doubled (Figure 3):

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Figure 3: Clinic activity GOS inherited arrhythmia service (CMP=cardiomyopathy; SAS=sudden arrhythmia syndrome; MARF=Marfan Syndrome)

Approximately 70% patients referred to the service come from the GOSH Cardiac Network referral region in London and the East of England, but patients are referred from across the UK. Transition to adult services The process of transition from paediatric to adult cardiac services begins in early adolescence, and is carried out by the multidisciplinary team at GOSH, together with visiting adult ICC cardiologists from UCLH. Patients are transitioned at 16-18 years of age to the Heart Hospital, UCLH or BLT depending on where adult relatives are followed up. The process of transition is facilitated by joint multidisciplinary meetings at the Heart Hospital and BLT.

Clinical and research collaborations within UCLP ASHN

Specialised Cardiovascular Services The existing ICC teams work with a number of other services in across the UCLP network to provide support services to patients with inherited cardiac disease. These include the UCLH Grown Up Congenital Heart Disease Unit (High Risk Pregnancy and Marfan’s Disease Service), structural heart disease services, interventional cardiology, cardiothoracic surgery and electrophysiology.

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Rare Disease Units A rare disease is defined by the European Union as one affecting less than 5 in 10,000 of the general population. There are between 6,000 and 8,000 known rare diseases and it estimated that 1 in 17 of the population will be affected by a rare disease at some point in their lives, equating to approximately 3.5 million people in the UK. Over 350 rare disease cohorts exist across UCLP ranging from amyloidosis to severe combined immunodeficiency. Of the 60 nationally commissioned specialist services in England, over 30 of these are based within UCLP. The Inherited cardiac units at UCLH, GOS and BLT work with individual rare disease groups across UCLP to provide expert diagnosis and care for patients in whom cardiac disease is an important manifestation of their disease. Specific disease collaborations include:

Lysosomal Storage Disorders Royal Free Hospital/Queen Square GOS

Congenital Muscular Dystrophies Dubowitz Neuromuscular service, GOS Queen Square, UCLH

Muscle Channelopathies Queen Square, UCLH

Rare Mitochondrial Disorders Treatment Queen Square UCLH GOS

Ehlers-Danlos Syndrome Treatment (Northwick Park)

Patient Charities The ICC teams work very closely with the charitable sector to provide medical and educational support to patients and carers throughout the UK. Examples of joint initiatives include telemedicine links to support ICC clinics in Glasgow and Belfast (Cardiomyopathy Association) and the production of patient information booklets and videos that are distributed nationally (Cardiomyopathy Association and The British Heart Foundation). The ICC team also works with the Cardiomyopathy Association to organise annual national conferences aimed at practicing cardiologists, specialist registrars, nurses and general practitioners. There were approximately 200 attendees at the medical meeting in 2012.

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Proposal for a UCLP ASHN Inherited Cardiovascular Disease Service Establishment of a unified research and clinical network within the UCLP ASHN presents an opportunity to build a unique healthcare system for inherited cardiovascular conditions. Clinical services for Inherited Cardiac diseases will be provided according to principles that embrace the strategic goals of UCLP including an emphasis on standards of excellence for clinical practice, education and research.

A new care network for patients with ICC By virtue of the uncommon nature of individual inherited cardiac conditions and the geographic distribution of modern British families, specialist ICC services operate within large referral networks and collaborative clinical partnerships involving many clinical commissioning groups and national services. The challenge therefore is to provide the highest standards of care for all patients. We propose to consolidate the three existing referral centres (UCLH, BLT and GOS) into a UCLP Centre for Inherited Cardiovascular Disease by developing common operating procedures and informatics, multidisciplinary teams that work across sites, and joint appointments. This will create the largest centre of excellence for the diagnosis and management of inherited cardiovascular disease in the World and will form the basis for large scale research programmes. The fact that this involves a minimum of three hospital trusts means that this will, for the moment, be a virtual centre but future developments, including potential merger with Bart's and an imminent cardiac services review by UCLP for its 6.5 million population present opportunities for colocation of at least the adult services. We also propose a new strategy for delivery of ICC services at a local level. This is challenging as most patients are offered lifelong follow-up, yet may experience very long periods of clinical stability. In order to meet the need for the population served by UCLP, we propose a network in which the National Centre acts as a virtual hub for a number of satellite ICC Services. These will share personnel, clinical and research governance, standard operating procedures and informatics systems with the hub. All patients reviewed at the satellites will be registered centrally and will have access to the core ICC centres. Newly diagnosed outpatients and those attending for family screening may be seen exclusively at satellite clinics according to individual clinical needs and location, as defined in the SOPs. Elective inpatient stays and day-case attendances will almost always be in one of the central ICC centres.

Pilot Clinic We have recently gained experience in the delivery of ICC clinical care in sites more convenient for patients. A newly established clinic at Newham University Hospital (NUH), affiliated with the cardiomyopathy service at the London Chest Hospital (LCH) is led by a consultant cardiologist who also manages patients at LCH. The NUH clinic was initially

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focussed only on cardiomyopathy patients local to NUH that had been previously assessed at LCH. However, the NUH clinic rapidly attracted new referrals. Most diagnostic/prognostic assessments are readily provided at NUH; a minority of patients with predefined characteristics are referred to LCH, which also provides MDT services, advanced imaging (exercise echo, CT and CMR) and invasive investigation and management. In addition to improving patient access, capacity and flexibility is enhanced as the LCH clinic can dedicate more time to complex patients. The NUH service can provide urgent inpatient assessments, including anaesthetic advice, and respond to local emergencies.

Opportunities arising from the UCLP ASHN Inherited Cardiovascular Disease Service Enhanced Research Collaborations Clinical and translational research are major centralising forces. Large patient numbers, dedicated research personnel, specialised equipment and key partnerships are essential for most ICC research. A key component of our research strategy is the ambition to include all ICC patients in research projects including biobanking and large scale outcomes research. There are also synergies between the internationally recognised expertise in inherited cardiovascular disease at UCL and developing research programmes within the BLT NIHR Cardiovascular Biomedical Research Unit and the Heart Centre at Charterhouse Square. Opportunities for integrated research programmes relevant to the ICC theme include advanced cardiac imaging, cardiovascular genetics, stem cell biology, pharmacology, electrophysiology, cardiovascular epidemiology and large-scale trials of novel treatment strategies. The recent incorporation of the Institute of Cardiovascular Science (ICS) into the new Faculty of Population Health Sciences at UCL offers opportunities for outcomes research and health economic analysis, while the recently developed partnership between UCL and Yale University presents an unprecedented opportunity for genomic research.

Education and Training Increasing demand for inherited cardiac disease services over the next 5-10 years will generate a need for increased awareness and training for health care professionals. The union of existing services across UCLP ASHN will create a critical mass of clinical activity and expertise that can be used to support comprehensive quality training and education. A major function of the new Inherited Cardiovascular Disease Network will be the development of an educational programme based on regular courses, small group teaching and remote learning using state of the art telemedicine and conferencing facilities. This development will help to establish ICVD as new medical sub specialty by establishing national and international training programmes

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Wealth Creation Inherited cardiovascular diseases represent a substantial unmet need for therapeutic innovations. The scale of clinical activity that this proposal envisages provides a globally unique platform for the identification of novel therapeutic targets, randomised clinical trials and population scale outcomes research. Existing research pipelines in genomics, proteomics and outcomes research will be scaled up to support the basic science necessary in the translation of novel therapies into clinical practice. The inherited disease programme directly complements recent UCLP endorsed innovations such as the BHF Research Excellence bid for Centre for Therapeutic Innovation.