Characterising disease mechanisms and tailoring therapies for coronary microvascular dysfunction

Angina is the term used to describe chest pain that is caused by an imbalance between the supply and demand of blood supply to the heart. The coronary circulation supplies the heart muscle with its own blood supply, and is made up of large arteries (0.5-5mm in size, visible on an x-ray based test called an angiogram), and small arteries (the microvasculature, invisible on an angiogram). Narrowing of the large arteries is the most commonly recognized cause of angina but 40%-50% of patients with angina have no detectable narrowings. While some of these patients may have non-cardiac chest pain, up to 60% have coronary microvascular disease (CMD). CMD is associated with poor quality of life, adverse clinical outcomes and an increased cost to the healthcare and social system. Patients often do not receive a clear diagnosis and physicians have little guidance on the appropriate medical therapy to reduce symptom burden and improve quality of life. It is now possible to assess the microvasculature using special techniques during an angiogram and also using cardiac MRI scans. Using these approaches, our group has shown CMD is clearly associated with abnormalities that could lead to angina and that these techniques could be applied in almost all cardiac centres. Our previous research has also shown, for the first time, that not all CMD is the same and there are two distinct forms - those who already have abnormally elevated blood flow even at rest (and so have used up some of their reserve) and others who have normal blood flow at rest but lack capacity to increase blood flow in response to exercise and stress. These subtypes behave differently at rest and at exertion, but both lead to a supply-demand mismatch, which leads to the symptoms of angina.

During this study, Dr. Sinha, a heart specialist in training, will investigate why the different subtypes of CMD behave the way that they do using both invasive (coronary angiogram and Doppler flow studies) and non-invasive (cardiac magnetic resonance imaging) techniques. Our group has an established track record of invasively assessing coronary artery physiology both in the clinical and research setting. We will also use cardiac MRI to identify and utilise both known and novel markers of supply-demand mismatch. Our cardiac MRI unit is world renowned for its work on imaging markers of supply-demand mismatch in patients with angina. Dr. Amedeo Chiribiri, who is the lead of our MRI department, will kindly be co-supervising with the proposed project.

The final part of this study will involve investigating whether therapy stratified according to CMD subtype will improve symptoms and quality of life in patients with CMD. The proposed medications have a good safety profile and are mechanistically attractive options. Patients will take part in a randomised, blinded, crossover trial, whereupon they will be randomised into two groups using a computer software program. Patients will undergo a baseline assessment of their exercise capacity on a treadmill, measurement of blood tests that can identify supply-demand mismatch post-exertion, fill out questionnaires documenting their symptom burden, and carry portable devices that can monitor their level of activity (FitBit). Patients will be given the first medication to take for four weeks followed by another detailed assessment, as described above. Patients will then be given the second medication for four weeks followed by the final detailed assessment. Patients and the researcher will both be blinded to the medication being used.

In summary, this study will provide a better understanding of the microvascular changes that lead to the development of CMD. This knowledge can be used to develop novel therapeutic targets in the future. Our trial of stratified therapy according to subtypes will be the first of its kind in patients with CMD and has huge potential to identify medications that can improve patients' quality of life.

AIMS: Elucidate the pathogenesis of CMD subtypes and study the effects of subtype-stratified treatment on patients' exercise capacity and quality of life.

OBJECTIVES: 1. Investigate why patients with functional CMD have elevated basal coronary blood flow (CBF); 2. Investigate whether subtype-stratified treatment yields superior outcomes compared to empirical treatment regimens.

METHODOLOGY: According to our power calculations, 50 patients will need to be recruited to address the first objective and 78 patients for the second objective. 50 patients will undergo intracoronary physiology assessment during rest, bicycle exercise, peripheral infusion of adenosine, and intracoronary infusions of substance P followed by S-methyl-l-thiocitrulline (SMTC) or N(G)-monomethyl-l-arginine (L-NMMA). Adenosine is used to determine the coronary flow reserve and substance P tests endothelial function. CBF will be measured before and after the infusions of intracoronary vasoactive agents (substance P, SMTC and L-NMMA) to evaluate the microvascular response to these agents. The same 50 patients will undergo cardiac MRI to assess indirect and direct (blood oxygen level dependent) measures of myocardial ischaemia. These 50 patients, along with 28 patients already confirmed to have CMD on intracoronary assessment, will be invited to partake in a randomised, blinded, crossover trial investigating the effects of Ranolazine and Sildenafil on patients' exercise time, release of post-exertion cardiac biomarkers, angina-specific questionnaire scores and number of steps on a FitBit monitor. The primary outcome measure will be exercise duration on the exercise treadmill test.

SCIENTIFIC AND MEDICAL OPPORTUNITIES: Improving our understanding of the pathogenesis of CMD subtypes is important in order to develop novel therapies for patients with CMD. A subtype-stratified therapeutic approach is likely to improve patients' exercise capacity and quality of life.

Our proposed study is likely to benefit a large group of people. The following section describes this in more detail.

CONTEMPORARY ACADEMIC CARDIOLOGISTS
As mentioned in detail in the 'Academic Beneficiaries' section, our proposed study follows on from the robust and ground-breaking research already carried out by our group in patients with CMD. For the first time, we have shown that CMD is a heterogeneous condition comprising functional and structural components. These patient subgroups behave differently during rest and during exertion. Our proposed study aims to investigate the pathogenesis of the different subtypes in more detail. A better understanding of the underlying disease process will be a key piece of information for the academic Cardiac fraternity. It will form the foundation for future work looking at the associated risk factors, epidemiology and the natural history of this disease. It will also form the first step in the development of novel therapeutic agents specifically targeting the underlying pathology in each subtype. Our suggested therapeutic protocol is robust and comprehensive, taking into account both objective and patient-centric outcome measures. Therefore, not only are we trialing specific agents for specific subtypes, which in itself is a novel concept that can be built upon in future studies, but we have also developed a new study protocol that other groups researching CMD can utilise.

NATIONAL HEALTH SERVICE, POLICY MAKERS AND THE DEPARTMENT OF HEALTH
CMD is an extremely important condition for the NHS and department of health. It is associated with poor quality of life, adverse outcomes, links with heart failure with preserved ejection fraction, increased use of healthcare resources and increased cost to the social system. It affects a large proportion of patients complaining of chest pain and, given the current uncertainty regarding management of these patients, they present recurrently to both their primary and secondary care providers and undergo multiple non-invasive and invasive investigations to no avail. A better understanding of the underlying pathogenesis of CMD may lead to the development of non-invasive methods to diagnose and monitor CMD in the future. Furthermore, a better understanding of the pathogenesis of CMD will likely lead to the identification and/or development of novel therapeutic agents that can target the subtype-specific pathology. All in all, our proposed study is likely to bring us closer to an improved understanding and management of patients with CMD. This will certainly reduce the stressors on the healthcare and social services as outlined above.

BENEFIT TO PATIENTS
The group that stands to benefit the most from our research is our patient group. Most of the patients with CMD are currently misdiagnosed or discharged with false reassurance. These patients recurrently present to the healthcare service with worsening symptoms. We now know that CMD not only affects patients' quality of life but it also has an adverse impact on their overall outcome. A better understanding of the pathogenesis and the use of a stratified treatment strategy is likely to lead to the development of efficacious treatment with a favourable adverse effect profile that will be extremely beneficial for these patients.

Our CMD research unit has been involved with CMD patient groups both at a local and national level. As a result of this, and our ongoing commitment to carry out high quality research in this field, we have been invited to present our research findings at the first ever symposium on CMD organised by patients featuring world opinion leaders in CMD.