AbstractDespite improvements in interventional and pharmacological therapy of atherosclerotic disease,it is still the leading cause of death in the developed world. Hence there is a need for further development of effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Atherosclerosis has long been identified as having an inflammatory component contributing to its pathogenesis, whilst the available therapy primarily targets hyperlipidaemia and prevention of thrombosis. Acknowledging a pleotropic anti-inflammatory effect to some therapies, such as acetyl salicylic acid and the statins, none of the currently approved medicines for management of either stable or complicated atherosclerosis has inflammation as a primary target. Monocytes, as representatives of the innate immune system, play a major role in the initiation, propagation and progression of atherosclerosis from a stable to an unstable state. Animal study data support a role of monocytes in acute coronary syndromes and in outcome post infarction; however, limited research has been done in humans.
In this thesis I describe for the first time in a large cohort of ST elevation myocardial infarction(STEMI) patients followed up for three years that total monocyte count, monocyte subset 1(Mon 1), and monocyte subset 2 (Mon 2) are predictive of major adverse cardiac events (MACE)post STEMI (including death, new diagnosis of heart failure, recurrent acute coronary syndrome). Both the inflammatory function of monocyte subsets (via assessment and quantification of IKK as a surrogate for the NFB inflammatory pathway activation) as well as the phagocytic activity of monocytes were studied in order to describe the mechanism through which monocytes affect their action. There was no significant difference in the NFB pathway activity between those patients who developed an adverse event and those who did not. Also NFB activity was not predictive of MACE. However the phagocytic activity of Mon 1 and Mon 2 were predictive of MACE suggesting that phagocytic activity of monocytes is the mechanism through which monocytes implement their action. Also this supports that the newly described monocytes subset 2 (Mon 2) is predominantly an inflammatory monocyte subset, not reparative as Mon 3.
Major adverse cardiac events were driven mainly by heart failure diagnosis and echocardiographic findings. Hence the association between ventricular remodelling and phenotypic and functional characterisation of monocytes subsets was studied in this thesis. Total monocyte count, Mon 1 and Mon 2 were again predictive of negative ventricular remodelling with increase in end systolic indexed volume of >15% at 6 months follow up echocardiogram post infarction. Subclinical parameters of systolic dysfunction, namely global longitudinal strain and global circumferential strain were also significantly correlated with total monocyte count as well as Mon 1 levels.
Given the above, I studied the effect of incorporating total monocyte count in Thrombolysis in Myocardial Infarction (TIMI) STEMI score to predict patient outcome at 30 days post infraction.C- statistics indicated improved prognostication of the TIMI STEMI model after incorporation of the total monocyte count into the model with improved area under the curve from 0.67 (for TIMI STEMI score), to area under the curve of 0.77 (TIMIMon score). This allows individual tailoring of secondary preventative therapy in order to improve patient outcome post infarction.Having described a potential mechanism through which the innate immune system affects outcome in STEMI patients, namely Mon1 and Mon2 through their phagocytic activity, the results from this thesis could be a stepping stone into targeted anti-inflammatory therapy in management of myocardial infarction.
|Date of Award||3 Jan 2017|
|Supervisor||Helen R Griffiths (Supervisor)|
- monocyte subpopulations
- ST-elevation myocardial infarction
- left ventricular remodelling
- immune system
- phagocytic activity
Monocyte subpopulations in patients following ST-elevation myocardial infarction : implications for post-infarction left ventricular remodelling and clinical outcomes
Ghattas, A. (Author). 3 Jan 2017
Student thesis: Doctoral Thesis › Doctor of Philosophy