Dr. Andrew Maree

Summary

Introduction: Heart-rate recovery time between 10 and 20 seconds post-orthostatic challenge (HRRT10-20) correlates with all-cause mortality and is a direct marker of autonomic function (McCrory et al, Circ Res.2016). Preliminary analysis of patients with severe symptomatic aortic stenosis (AS) shows impaired HRRT10-20 in this cohort who have a very high untreated mortality. Moderate AS is also associated with increased mortality but current practice is to wait until patients develop symptoms or severe AS. Hypothesis: Patients with moderate AS will have evidence of autonomic dysfunction when compared to age and sex matched controls and a lesser degree of autonomic dysfunction than patients with severe AS. Increased autonomic dysfunction may identify those at highest risk who should be considered for earlier valve replacement. Methods: Active project prospectively comparing patients with moderate aortic stenosis with age and sex matched controls.

Funding Agency

Royal City of Dublin Hospital Trust

Summary

We hypothesise that cardiovascular autonomic function improves following aortic valve replacement and represents a measurable predictor of procedural outcome and thereby mortality benefit. We also hypothesize that patients post transcatheter aortic valve implantation (TAVI) have comparable cardiovascular autonomic function outcomes to patients post surgical aortic valve replacement (SAVR). Ongoing research project with ethics approval and grant funding in place but pending completion therefore methodology withheld.

Funding Agency

Royal City of Dublin Hospital Trust

Project Type

Collaborative Clinical Research Study

Person Months

24

Summary

Ongoing research, enrolement completed and data analysis ongoing. Part published but final publication in preparation therefore methodology withheld.

Funding Agency

Royal City of Dublin Hospital Trust

Project Type

Collaborative Clinical Research Study

Person Months

24

Summary

Despite extensive research cardiovascular disease remains the leading cause of death in developed countries. Thus, its primary and secondary prevention remain a public health priority. Non-traumatic chest pain presentation to the accident and emergency department accounts for between 6-10% of patients' seen and management of these patients is challenging. An assay that detects patients with chest pain who are at risk of plaque rupture and in whom coronary thrombosis and myocardial injury have not yet occurred would provide for pre-emptive treatment and thereby also diminish the risk of progression to chronic cardiovascular disease would be extremely useful. This is the basis of our novel serum biomarker study. We will evaluate patients who present with chest pain and screen them for novel serum biomarkers of coronary plaque instability. We will also develop assays for measuring these proteins and ultimately develop a blood test that will identify patients at high risk of MI. The aim is that when a patient presents to A&E with chest pain a series of point of care serum marker assay will facilitate rapid stratification as cardiac or non-cardiac chest pain. This will allow for early treatment or discharge. We have been working with collaborators in Bristol who have developed a mouse model of atherosclerosis (Research Frontiers Programme funded by SFI). Using this ApoE mouse model of atherosclerosis and a protein array we have already identified a number of serum proteins (biomarkers) where changes in their levels predict plaque rupture. We collected serum from mice both before and after plaque rupture and analysed the levels of different proteins in the serum of these mice. Plaque rupture was determined by histological analysis of the brachiocephalic artery. We identified a number of novel proteins that were present at significantly high levels in the serum prior to plaque rupture and may be predictive of higher risk of rupture. A number of these proteins have never been shown to be associated with plaque rupture previously. Although we provided evidence that these serum proteins have the potential to act as biomarkers of plaque rupture we did so in an artificial animal model of plaque rupture and therefore needed to confirm that the same protein pattern occurred in humans. We therefore conducted a preliminary pilot study of 40 patients who presented with chest pain. We identified similar markers of plaque rupture in patients presenting with unstable angina. While these biomarker proteins were clearly expressed in mice we needed to confirm that the same proteins were expressed in humans. To achieve this we enrolled a small number of patients at Waterford Regional Hospital in 2013 and repeated the same protein biomarker assays confirming that these markers were present in human serum and detectable by ELISA.

Funding Agency

Royal City of Dublin Hospital Trust

Project Type

Collaborative Clinical Research Study

Person Months

24

Summary

B) Proteomic Analysis Many types of CVD have a platelet component in their pathogenesis. These include atherosclerosis leading to coronary artery disease (platelet secretion contributes to atherosclerosis, thrombotic events leading to myocardial infarction (platelets are central to thrombosis); and potentially atrial fibrillation leading to stroke (there is evidence of platelet activation in atrial fibrillation that may contribute to thrombosis leading to embolism and stroke. For this arm of our study we hypothesize that biomarkers may be identified in platelet samples that are associated with risk of developing various forms of CVD, or with suboptimal responses to antithrombotic therapy (bleeding, or continued risk of thrombosis). Furthermore, it is hypothesised that these markers are present chronically, not just at the time of acute events, and could be used to diagnose disease or predict treatment response. Proteomics offers a way to transform how platelets are analysed by determining the composition of platelet proteins and their changes upon stimulation and in disease. Proteomics can be used to explore the differences in protein profiles between different cardiovascular disease (CVD) populations, using information from multiple proteins to identify shared features of patient groups. Such a 'signature' of disease may have several future applications. Firstly, it may ultimately be used in the prediction of outcomes in CVD. Secondly, it may be used to monitor treatments of CVD, to determine if treatment normalises the signature. Thirdly, variations in the signature may identify subcategories and stratifications in CVD populations, and may be used to determine the type and extent of treatment suitable for individual patients. As part of a research and development programme in platelet biomarkers, Java Clinical Research in University College Dublin (UCD) has developed a method to analyse platelet samples for protein markers that may predict risk of thrombosis and response to antiplatelet drugs. Platelets are an excellent source of biomarkers for this, since they play a role in many types of CVD, including atherogenesis, thrombosis and bleeding. Furthermore, platelets are readily sampled from peripheral blood, and Java has developed streamlined methods to process and analyse them for biomarkers that reflect the donor's status and the impact of genetic variation, disease and drug treatment. The study was withdrawn due to closure of the Java Clinical Research in University College Dublin (UCD) and inability to perform proteomic analysis shortly after funding awarded.

Funding Agency

Royal City of Dublin Hospital Trust

Project Type

Collaborative Clinical Research Study

Person Months

6