Investigating Myocardial Infarct Scars as a Focal Arrhythmogenic Substrate Using Advanced Computational Modelling Based-On High-Resolution Imaging

Although an increasing number of people survive heart attacks, the scar left in their heart muscle leaves them at an increased risk of developing lethal cardiac 'arrhythmias' (abnormal beating of the heart) following the initial attack. Little is known about the underlying processes linking the presence of scars to increased death from cardiac arrhythmias. Specifically, it is not well understood whether the scar is involved in the actual generation of the arrhythmia, or whether it just helps to stabilise an arrhythmic episode generated by another mechanism, unrelated to the scar itself. As a result, diagnosis and therapy planning is non-optimal for these patients, and the rate of sudden death due to arrhythmic events is still high within this population.

Current clinical tools can provide useful information regarding scars within patients who have suffered prior heart attacks. Clinical magnetic resonance (MR) imaging gives an important non-invasive means of analysing the location and shape of scars in patients. In addition, analysis of clinical electrocardiogram (ECG) recordings during arrhythmia can suggest not only the type of arrhythmia, but also the role the scar may play in such episodes. In particular, careful analysis of the shape of the ECG trace in the first few arrhythmic beats has suggested that, in many cases, the scar itself is highly likely to be the actual source of the ectopic activity responsible for generating the arrhythmia.

Basic science investigations have shown that the structure of the tissue in and around the scar is highly diverse, and that the functional electrical properties are also changed from that of the normal, healthy cardiac tissue. As such, how the scar may act to generate lethal arrhythmia is thought to involve highly complex processes, which are not yet well understood.

Our goal is to use computer modelling alongside high-resolution animal and clinical images to gain an in-depth understanding of the underlying processes involved in the generation of lethal arrhythmias directly from within cardiac scars.

By using high-resolution animal images of scars, we will generate exceptionally-detailed computational models to investigate how the interaction between structural and functional diversity within a scar may encourage the generation of arrhythmia. This will allow us to understand how the fine-scaled properties of the scar and surrounding tissue make it susceptible to arrhythmias, identifying key 'hot spot' regions which represent the most dangerous potential sources of arrhythmic activity.

We will then use this knowledge in comparison with patient MR and arrhythmia incidence data to make an important step towards translating these findings into the clinic, helping provide a mechanistic explanation of the underlying observed relationships uncovered in the clinical data.

Overall, the findings from this research will pave the way for improved of risk stratification in patients with cardiac scars, and the development of novel clinically-useful therapies targeting the scar as a source of arrhythmia generation. The potential beneficiaries from this research will be extensive due to the high incidence of heart attacks annually in the UK (124,000), and the significant risk posed by arrhythmia to individuals following a heart attack. Consequently, this work also has the potential to reduce the health and economic costs of associated death and illness.

Each year in the UK, over 125,000 people suffer from a heart attack, which, in the vast majority of cases, is a direct result of some form of coronary heart disease (CHD). Unfortunately, the incidence of CHD is expected to significantly rise in the coming decades due to an aging population as well increases in the incidence of diabetes and the obesity epidemic, all of which have known associative links with this disease.

Although advances in primary care have seen increases in survival rates following initial heart attacks, the heart tissue is often damaged by the attack, leaving a myocardial infarct scar. The presence of infarct scars have been directly linked to a significantly increased risk of sudden death due to cardiac arrhythmias. However, a fundamental lack of understanding of the physiological mechanisms at play in this population means that risk stratification and current treatment strategies for patients with infarct scars is highly non-optimal, accentuating the lethal arrhythmic risk. This proposal aims to foster a greater mechanistic understanding of the pathological processes underlying the genesis of arrhythmias in the setting of infarct scars and, ultimately helping to advance current therapeutic and risk assessment technologies, addressing the significant health and corresponding economic challenges associated with this condition.

As a direct result of this proposal, the following will directly benefit:

1. Scientific Research Community, by providing: (1) a shift in the current thinking regarding the therapeutic target and treatment strategies for these patients to focus more on the scar as a source of focal arrhythmogenesis; and, (2) essential understanding of the bioelectric behaviour of the scar substrate at the histo-anatomical level and how this can be represented within computational models for future research investigations.

2. Industrial Companies, through providing essential mechanistic understanding of the functioning of the scar as an arrhythmogenic substrate which will lead to the pursuit of novel catheter ablation, electrical device and pharmacological interventions targeting these arrhythmogenic processes.

In the longer-term, the outcomes of this proposal will benefit:

1. the Patient, by increasing survival rates and reducing morbidity through improved stratification of arrhythmogenic risk and development of more reliable and safer therapeutic technologies against arrhythmia episodes. This will help to address one of the key societal health challenges in coming decades due to the expected increase in CHD patients and at progressively younger ages.

2. the NHS, through reducing spending on follow-up treatments for patients suffering from incessant scar-related arrhythmias by optimising the frequency and efficiency of therapeutic interventions. Savings could include shorter and less frequent operation procedures, better selection of those patients requiring expensive electrical devices or drug therapies, and reduction in necessary primary care and mortality rates.

3. the Economy, through improving economic productivity of heart attack suffers by increasing their day-to-day well-being through reducing morbidity and risk. Due to the large number of heart attack suffers, and with the corresponding progressive decrease in the age of CHD patients, this could represent a significant long-term saving.