Experimental manipulation of indices of lesion severity in multi-vessel coronary artery disease: Quantitative exploration of collateral influences.

Coronary arteries are blood vessels on the surface of the heart supplying it with blood. Coronary artery disease (CAD) occurs when fatty deposits build up in the walls of these vessels, narrowing them like lime scale in a pipe. In advanced disease blood flow is decreased by multiple narrowings in more than one vessel (multi-vessel disease). The body responds by building new interconnections between the narrowed arteries. These interconnecting vessels are called collaterals. They provide a network that interacts with the diseased coronary arteries to provide an additional supply of blood to 'top-up' the otherwise sluggish blood flow. This complex pattern of disease occurs in multi-vessel disease and, given our aging population, is increasingly common.

When symptoms progress, restoration of blood flow is required. This is done by either squashing the fatty deposits open with a balloon and a metal meshwork (stenting) or by open-heart bypass surgery. Both of these techniques are potentially dangerous and expensive. They should only ever be performed to narrowed vessels severe enough to starve the heart muscle of oxygen (ischaemia). Over the last 20 years a system has been developed to categorise whether a narrowing is severe enough to treat. Narrowings can be categorised as either 'green light' (non ischaemic) or 'red light' (ischaemic). Ischaemic narrowings need to be stented or bypassed. This technique has revolutionised the treatment of coronary artery disease.

However, in complex multi-vessel disease with collaterals, there are situations when these categories can suddenly change. A narrowing initially classified as 'red' can become 'green' (i.e. doesn't require treatment) if a narrowing in another vessel is stented first. This is very important. In this example, the stenting of one narrowing has fixed two superficially unrelated problems, saving the patient from a further procedure that carries expense and risk. We still do not know enough about how this 'two-for-one' fixing takes place.

During this fellowship Dr. Christopher Cook, a heart specialist in training, will study exactly how flow in the coronary and collateral arteries interact and adapt. In particular, he will investigate how a change to blood flow in one vessel can have a knock-on effect on blood flow in another vessel. If we can better understand this process, we could transform our treatment of multi-vessel coronary artery disease. By avoiding unnecessary stenting and even bypass surgery, patient safety and economic benefits will be massive. Dr. Cook will be working with an internationally renowned research group to make this important exploration. This group already has a track record of scientific breakthroughs in the field of pressure and flow changes in coronary vessels. The group has state-of-the-art facilities to conduct this work and world-leading expertise and knowledge.

This is not a clinical trial. The project will be a series of safe and quick experiments conducted on patients with multi-vessel coronary artery disease. All patients will be undergoing the tests as part of their normal clinical work up. Pressure and flow measurements will be made within the diseased vessels to provide a wealth of data that can be analysed afterwards. The scientific group will be using validated techniques to see how these variables change in response to a sudden change in blood flow (as happens when a vessel is stented). The experiments have been meticulously designed to maximise the acquisition of data with minimal inconvenience and risk to participants.

In summary, this is an important and exciting research proposal into one of the most important diseases affecting man. By using data collected in humans the results are immediately applicable to real world medicine. This means discoveries can be incorporated into clinical practice quickly and efficiently to improve patient care.

Aims:
To test the hypothesis that collateral mediated changes in coronary flow pattern can alter the physiological severity of stenoses in multi-vessel coronary artery disease.

Objectives:
-To understand how 'two-for-one' stenting occurs (how the severity of a stenosis can be improved without a need for further stenting or bypass surgery).
-To quantify the role of the collateral circulation in this clinically important process.
-To incorporate an assessment of collateral function into the physiological diagnostic approach to patients with multi-vessel disease.

Methodology:
-40 patients with multi-vessel CAD (30-40% of all CAD patients) will be recruited over 2.5 years. All angiography will be clinically indicated.
-Patients will undergo baseline intracoronary pressure and velocity measurements using a 0.014" pressure and flow sensor tipped wire. Assessments will be made to all moderate-severe stenoses.
-One wire will be placed in one vessel (A) and a second wire in another vessel (B).
-An intracoronary balloon will be positioned over the wire in a proximal, non-diseased segment in (A). It will be inflated to low-pressure (to avoid endothelial damage) for 60-90 seconds to transiently occlude flow. Pressure and flow will be measured distally in (A).
-Pressure and flow will be measured simultaneously in (B) to provide data on collateral flow modulation between (A) and (B).
-Measurements during balloon occlusion will be compared to baseline to quantify flow redistribution in response to an acute change in antegrade flow in (A).
-The process will be repeated with hyperaemia to determine FFR and changes from baseline.
-Wave intensity analysis will be applied to determine the effect of hyperaemia on collaterals.

Scientific and medical opportunities:
Findings from this study will impact across the entire spectrum of the disease, with mechanistic insights that can be readily translated into improved clinical practice.

ACADEMIC BENEFICIARIES:

I aim to define physiological mechanisms for coronary flow adaptation and its role in the augmentation of stenosis severity. This has never been done before. This will fill a current knowledge gap in the field. I am proposing an entirely new way of thinking about and measuring the collateral circulation. This will generate significant academic interest and training in the use of intracoronary pressure and flow assessments. I am using a novel method that is a new way of investigating collaterals. The timescale for this impact is early and expected from Year 3 onwards.

ECONOMIC AND SOCIETAL BENEFICIARIES:

Government And Policy Makers:
In state funded healthcare systems, rationalisation of healthcare expenditure is essential. This research is aimed at the minimisation of expensive therapies such as coronary stenting and bypass surgery. Safe deferral to medical therapy is vastly more economical. By using established technologies in a novel fashion, expensive technology appraisals would not need to be commissioned. Overall, this makes a very attractive package for government and policy makers to increase the effectiveness of public services providing healthcare for aging populations. I envisage our findings would help shape health policy in the management of CAD. The timescale for this impact is late and expected after the PhD and refinement of the process is defined.

Industry:
I am proposing the novel application of quantifying the role of the collateral circulation in terms of the physiological severity of an epicardial vessel. This new utlisation of an existing technology substantially broadens the use of intracoronary pressure and flow wires.

In 2013 the European Society of Cardiology upgraded the physiological assessment of angiographically moderate-severe stenoses to the highest level of recommendation. There is forecast to be an explosion in the use of physiological techniques in the coronary catheter lab. However, there is currently no provision to deal with the effect of collaterals because there is no good method to assess their influence on stenosis severity. This work will provide valuable and much needed understanding of the quantification of collateral function in multi-vessel disease. The interest from industry in order to readily bring this knowledge to the clinical environment represents a strong impact factor for this research.

The Wider (Global) Public:
CAD is one of the most prevalent diseases in man and the WHO leading cause of death worldwide. The wider public is at significant risk of this disease. Insights from this research will directly improve their care. We have selected the most complex phenotype of CAD to investigate. This is relevant as populations age and medical management of CAD improves. More complex patterns of disease are now requiring revascularisation. Improvements in the treatment of multi-vessel CAD is therefore of strategic importance. The timescale for this impact is expected after the PhD and refinement of the diagnostic process is defined.

This research has global scope. As lesser economically developed countries adopt western lifestyles, the prevalence of diabetes, smoking and hypertension are increasing. The global burden of CAD is set to rise, making improvements in care ever more relevant. The timescale for this impact is late and expected after the PhD.

The UK:
This research proposal represents a leading UK research group with international recognition in the field of coronary haemodynamics. By expanding into the study of collaterals, this project will continue to promote the UK as a pioneer in this field. The work will be presented internationally, raising the research competitiveness of the UK on a worldwide stage. The timescale for this impact is early and expected from Year 2 onwards.