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Current Research Projects

Can we teach old drugs new tricks?

Heartbeat Trust researchers adopt drug repurposing strategies to develop novel cardiac therapies that can potentially be excelled to the clinic.

An exciting new project that focuses on the repurposing of FDA approved epigenetic based therapies for the treatment of diseases associated with cardiac hypertrophy has been funded by Enterprise Ireland. Aberrant hypertrophy of the heart is a key pathological component of the majority of cardiac diseases and is a result of myocyte hypertrophy and fibrotic collagen deposition. Currently there are no therapies on the market that directly target cardiac hypertrophy, and treatment of the most aggressive forms that obstruct the outflow tract usually entails alcoholic septal ablation of excess tissue (delivery through the coronary arteries), or invasive surgical intervention (myectomy). Therapeutic approaches for these pathologies at present target risk factors that drive the disease, and do not directly modify the heart and the underlying disease mechanisms. The initial focus of this project is on disease subsets of hypertrophic cardiomyopathies and the research will hopefully lead to a first-in-man for cardiac indication clinical trial.

This two year project will bring together a multi-disciplinary team of research scientists and clinicians within the Heartbeat Trust, UCD, St Vincent’s University Hospital, Tallaght Hospital, the Cleveland Clinic, Ohio. Dr. Chris Watson, principal investigator of this commercialisation project, stresses that “there are many challenges ahead but we are eager to take the project forward along the commercialisation road map to acquire additional pre-clinical, clinical, and drug formulation data that will strengthen our case for a first-in-man trail for cardiac indication with our repurposed epigenetically targeted therapy”.

Drug repurposing is an attractive mechanism that can reduce costs and timelines associated with developing new therapeutic strategies by minimising regulatory barriers of pre-clinical and clinical safety studies, accelerating the process of delivering academic drug leads to the clinic.

Targeting cardiac fibrosis for heart failure treatment

EU FP7 project proposes novel early detection and therapy of cardiac abnormalities

Heartbeat Trust Researchers form part of an international cluster grant, funded by the European Commission bringing together eleven European partners in six different countries from public research organisations and industry. The FP7 Consortium is called FIBRO-TAREGTS and has a primary objective to apply innovative research approaches to target cardiac fibrosis for heart failure treatment.

Cardiac fibrosis contributes to cardiac tissue stiffness. This adversely impacts the normal functioning of the heart and, over time, causes symptomatic heart failure with symptoms of breathlessness, congestion, oedema and fatigue. More than 6.5 million people suffer from heart failure in Europe. The incidence is increasing at an alarming rate because of an aging population and the outbreak of cardiovascular risk factors such as diabetes, obesity and high blood pressure. This serious, often irreversible, disease is the leading cause of hospitalisation for patients over the age of 65.

Early interventions targeting key mechanisms, including myocardial interstitial fibrosis, could slow down progression to and worsening of heart failure. The FIBRO-TARGETS project proposes an innovative approach to detect cardiac abnormalities early using circulating biomarkers of myocardial interstitial fibrosis. The initial objective for the consortium is to confirm the main biological mechanisms involved in myocardial interstitial fibrosis. They hope to experimentally validate new molecules and targeted therapeutic strategies that improve the quality of the cellular matrix and limit myocardial interstitial fibrosis. Finally, these targets could be used as biomarkers to predict, monitor and describe the response to myocardial interstitial fibrosis treatments.

Dr Chris Watson said, “Our research contribution to the project will involve heart failure phenotyping using a biomarker based approach (protein and miRNA) and monitoring changes in these novel MIF biotargets in response to anti-fibrotic therapy. Some of this work will be carried out in our STOP-HF patient population, a recently described novel longitudinal cohort with cardiovascular disease risk factors that has captured new onset heart failure progression in real time (Ledwidge et. al. JAMA 2013). We are excited to be involved in FIBRO-TARGETS as it builds on our current research investigating novel biomarkers and therapies for heart failure.”

HOMAGE: The Ageing Heart

 Heartbeat Trust Researchers are co-investigators within the European Commission funded Framework Programme 7 Project

HOMAGE (Heart OMics in AGEing) is a ‘bench to bedside’ project which aims to identify and validate specific biomarkers of heart failure in order to prevent the development of the disease affecting elderly population.

As more people survive into old age, the prevalence of heart failure, one of the most common and debilitating diseases in older people, will rise still further. Indeed, the prevalence of heart failure is increasing worldwide due to an ageing population as well as a rising trend of risk factors for heart disease such as diabetes, obesity and hypertension. Heart failure is a major cause of mortality and morbidity in the world and remains the most frequent cause of hospitalization for patients over 65 years old. Delaying or preventing heart failure will have great benefit to those at personal risk, their families, society and the economy. HOMAGE aims to provide a biomarker approach that will [1] help identify patients at high risk of developing heart failure before the onset of symptoms and [2]. subsets of patients who are more likely to respond to specifically targeted therapies (personalized medicine).

The Metabolic Road to Diastolic Heart Failure “MEDIA” programme of research

In 2012, the STOP HF Screening Programme began sharing our information with other specialist research centres throughout Europe in an effort to improve detection and prevention of Diastolic Heart Failure (DHF) in the at risk population. It is believed that a collaborative approach to research in this area will be the fastest and most effective way to improve care. This work was facilitated by the European Commission under the collaborative research project MEDIA:

As alluded to in the acronym MEDIA, the MEDIA project hypothesises that MEtabolic risk factors lead to DIAstolic heart failure. This hypothesis is based on the high prevalence (80%) of metabolic risk factors in diastolic heart failure patients and on the rising incidences of diastolic heart failure and of obesity or type 2 diabetes. The MEDIA project investigates how metabolic risk factors contribute to diastolic heart failure focusing on elastic properties of cardiomyocytes, myocardial collagen deposition, posttranslational modification of cytoskeletal proteins and epigenetic modifications. From better understanding of these underlying mechanisms new algorithms for diagnosis and treatment of diastolic heart failure will subsequently be developed.

The Diabetic Heart

Can we predict which patients with diabetes will develop cardiomyopathies?

The ‘Natural history of Diabetic Cardiomyopathy’ Project

The prevalence of heart failure is set to increase by 25% between now and 2030, with an associated 2.5 fold increase in medical costs. These concerning epidemiological trends are driven by many factors, including the epidemic of diabetes mellitus with data demonstrating up to a five-fold increase of incident heart failure among women and two-fold among men with diabetes. These findings highlight the need to focus on prevention of heart failure and in particular directing such prevention strategies at those with diabetes.

This longitudinal project plans to investigate the natural history of cardiac dysfunction (left ventricular diastolic dysfunction, LVDD) in a diabetic population, providing a basis for understanding the disease and its progression, and to develop an effective preventative strategy by improving our diagnostic and disease monitoring capacity.

This project will utilise the already established STOP HF screening programme database, an epidemiological intervention study focusing on the natural history of ventricular dysfunction in those at risk of heart failure. Four groups of participants will be compared in the ‘Natural History of Diabetic Cardiomyopathy’ project: [1]those with diabetes and LVDD, [2]those with diabetes and without LVDD, [3]those without diabetes and with LVDD, and [4]those without diabetes and without LVDD.

The prevalence and phenotype of each group will be compared at baseline, those who rapidly progress to severe disease, and those who develop progressive LVDD. A specific proteomic and microRNA footprint will be identified to provide novel diagnostic and therapeutic opportunities focusing on the diabetic patient with cardiac dysfunction. These will form the basis of the development of novel diagnostic tests that could be used in diabetes populations to help predict who is at higher risk of developing cardiac complications, and therefore enabling a more focused personalised patient care and intervention based strategy.