Coronary microvascular dysfunction and Dysregulated nNOS signalling as patho-mechanisms in Heart Failure with Preserved Ejection Fraction (HFpEF)
Lead Research Organisation:
King's College London
Department Name: Cardiovascular
Abstract
Heart Failure with Preserved Ejection Fraction (HFpEF) is a heart condition that severely affects patients' quality of life and can be fatal. In HFpEF, although the heart pumps with adequate strength, the heart muscle is unable to relax properly after each squeeze. This leads to accumulation of fluid and shortness of breath, which can be so severe that it requires admission to hospital.
We do not fully understand what causes the heart dysfunction that is seen in HFpEF. Perhaps because of this lack of understanding, there are only few proven medicines for HFpEF.
It has been suggested that abnormalities in the function of the tiny, microscopic arteries in the heart ("coronary microvascular dysfunction") may play a role in the development of HFpEF, as may abnormalities in the production of nitric oxide, a small molecule that has an important role in heart relaxation. It is thought that there may be too much nitric oxide produced within the heart due to abnormal increases in activity of a particular enzyme called neuronal nitric oxide synthase ('nNOS'). Across three studies, the proposed research will seek to explore in detail the relationship between coronary microvascular dysfunction and abnormal nitric oxide signalling with heart function in patients with HFpEF.
Patients with HFpEF often undergo hospital tests to check the heart arteries and to measure the pressures within the heart, a procedure called cardiac catheterisation. In Aim 1, we will perform measures of coronary microvascular function and heart function in patients with HFpEF during their cardiac catheterisation test. We will place special wires in the heart arteries and within the heart to measure the coronary microvascular function and heart function both at rest and during exercise. We have performed similar research procedures with many patients in previous research studies and we know that these techniques are safe. By combining the information from the heart arteries and from the heart function, this will allow us to understand how the coronary microvascular function affects heart function in HFpEF.
Aim 2 will also involve patients with HFpEF who are undergoing cardiac catheterisation tests. We will give patients a drug that is known to temporarily block the function of nNOS to see what the effect is on heart function both at rest and during exercise. The effect in patients with HFpEF will be compared with the effect in patients without HFpEF. The results of this study are important because if it confirmed that nNOS activity is abnormally high in HFpEF then new treatments could be designed to decrease nNOS activity and potentially improve heart relaxation in HFpEF.
In Aim 3 we will compile a database, or registry, of patients with HFpEF who have been assessed for coronary microvascular dysfunction. This will include the patients in Aims 1 and 2 but may also include any patient with HFpEF who has had scans such as heart ultrasound or MRI to assess for heart artery disease. We will record information on patients when we first meet them and then again after 1 year. This will give us important information as to whether patients with HFpEF and coronary microvascular dysfunction have worse symptoms and more hospitalisations that those without coronary microvascular dysfunction.
Overall, the results of the three studies should provide important information on the heart abnormalities that lead to HFpEF. It is hoped that the results may lead the way to new treatments for HFpEF that are targeted at the underlying abnormalities that cause HFpEF.
We do not fully understand what causes the heart dysfunction that is seen in HFpEF. Perhaps because of this lack of understanding, there are only few proven medicines for HFpEF.
It has been suggested that abnormalities in the function of the tiny, microscopic arteries in the heart ("coronary microvascular dysfunction") may play a role in the development of HFpEF, as may abnormalities in the production of nitric oxide, a small molecule that has an important role in heart relaxation. It is thought that there may be too much nitric oxide produced within the heart due to abnormal increases in activity of a particular enzyme called neuronal nitric oxide synthase ('nNOS'). Across three studies, the proposed research will seek to explore in detail the relationship between coronary microvascular dysfunction and abnormal nitric oxide signalling with heart function in patients with HFpEF.
Patients with HFpEF often undergo hospital tests to check the heart arteries and to measure the pressures within the heart, a procedure called cardiac catheterisation. In Aim 1, we will perform measures of coronary microvascular function and heart function in patients with HFpEF during their cardiac catheterisation test. We will place special wires in the heart arteries and within the heart to measure the coronary microvascular function and heart function both at rest and during exercise. We have performed similar research procedures with many patients in previous research studies and we know that these techniques are safe. By combining the information from the heart arteries and from the heart function, this will allow us to understand how the coronary microvascular function affects heart function in HFpEF.
Aim 2 will also involve patients with HFpEF who are undergoing cardiac catheterisation tests. We will give patients a drug that is known to temporarily block the function of nNOS to see what the effect is on heart function both at rest and during exercise. The effect in patients with HFpEF will be compared with the effect in patients without HFpEF. The results of this study are important because if it confirmed that nNOS activity is abnormally high in HFpEF then new treatments could be designed to decrease nNOS activity and potentially improve heart relaxation in HFpEF.
In Aim 3 we will compile a database, or registry, of patients with HFpEF who have been assessed for coronary microvascular dysfunction. This will include the patients in Aims 1 and 2 but may also include any patient with HFpEF who has had scans such as heart ultrasound or MRI to assess for heart artery disease. We will record information on patients when we first meet them and then again after 1 year. This will give us important information as to whether patients with HFpEF and coronary microvascular dysfunction have worse symptoms and more hospitalisations that those without coronary microvascular dysfunction.
Overall, the results of the three studies should provide important information on the heart abnormalities that lead to HFpEF. It is hoped that the results may lead the way to new treatments for HFpEF that are targeted at the underlying abnormalities that cause HFpEF.
Technical Summary
Heart failure with preserved ejection fraction (HFpEF) is a common cardiac condition with high rates of morbidity and mortality, but the underlying pathophysiology is poorly understood. Both coronary microvascular disease (CMD) and abnormalities in nitric oxide signalling are thought to play a key role. The overarching objective of this research is to produce data on the role of CMD and nitric oxide signalling (particularly myocardial nNOS) in the pathophysiology of HFpEF.
Hypotheses and Methods
1) In patients with HFpEF, the presence of CMD is associated with more severe abnormalities in LV diastolic function and exercise physiology. This hypothesis will be addressed by performing complex invasive haemodynamic studies in patients with HFpEF in the cardiac catheter laboratory. Coronary microvascular function will be assessed through gold-standard wire-based technology. LV function will be assessed using a conductance-manometry catheter to derive data in the pressure-volume plane. Supine exercise will be performed.
2) HFpEF is associated with dysregulation of myocardial nNOS function. This hypothesis will be address by measuring the effect of the specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) on measures of LV function during exercise in patients with HFpEF.
3) The presence of CMD portends adverse clinical outcomes in HFpEF and represents a distinct cluster within the overall heterogenous HFpEF population. To address this hypothesis, a prospective registry of HFpEF patients (all with assessment of coronary microvascular function) will be created. Patients will be followed up at 1 year for clinical outcomes.
Exploitation of results: The research will generate novel data on the role of CMD and nitric oxide signalling in HFpEF and has the potential to identify both CMD and abnormal myocardial nNOS signalling as potential therapeutic targets in HFpEF. This research would lead to further translational research and may lead to new therapies.
Hypotheses and Methods
1) In patients with HFpEF, the presence of CMD is associated with more severe abnormalities in LV diastolic function and exercise physiology. This hypothesis will be addressed by performing complex invasive haemodynamic studies in patients with HFpEF in the cardiac catheter laboratory. Coronary microvascular function will be assessed through gold-standard wire-based technology. LV function will be assessed using a conductance-manometry catheter to derive data in the pressure-volume plane. Supine exercise will be performed.
2) HFpEF is associated with dysregulation of myocardial nNOS function. This hypothesis will be address by measuring the effect of the specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) on measures of LV function during exercise in patients with HFpEF.
3) The presence of CMD portends adverse clinical outcomes in HFpEF and represents a distinct cluster within the overall heterogenous HFpEF population. To address this hypothesis, a prospective registry of HFpEF patients (all with assessment of coronary microvascular function) will be created. Patients will be followed up at 1 year for clinical outcomes.
Exploitation of results: The research will generate novel data on the role of CMD and nitric oxide signalling in HFpEF and has the potential to identify both CMD and abnormal myocardial nNOS signalling as potential therapeutic targets in HFpEF. This research would lead to further translational research and may lead to new therapies.
