Improving mechanistic understanding of left ventricular dysfunction and risk in stable coronary artery disease
File(s)
Author(s)
Jones, Richard
Type
Thesis
Abstract
Background: There remains a need for better mechanistic understanding of myocardial dysfunction and adverse clinical outcomes in patients with stable coronary artery disease (CAD).
Methods and Results:
i) Serial cardiovascular magnetic resonance (CMR) was performed on 43 patients undergoing coronary artery bypass grafting (CABG). Visual ischaemic burden (median: 18.0% [10.5-21.0] vs 42.0% [27.0-51.0], P<0.001) and global myocardial perfusion reserve (median: 2.40 [1.72-2.75] vs 1.71 [1.36-2.22], P=0.002) improved post-operatively. Change in patient-reported health status correlated with change in visual ischaemic burden.
ii) From 33 patients undergoing CABG, 63 left ventricular (LV) biopsies were acquired. The global myocardial ATP/ADP ratio was reduced in CAD patients as compared to donor tissue, with increased expression of oxidative phosphorylation genes encoding electron transport chain complexes. Paired analyses of biopsies obtained from LV segments with or without inducible ischaemia revealed no difference in the regional metabolic or single-cell transcriptomic landscape.
iii) The relevance of genetic and CMR features of dilated cardiomyopathy (DCM) in individuals with CAD was assessed. Rare variants in DCM-associated genes were associated with LV remodelling and outcomes in individuals with CAD in the UK Biobank. Non-infarct pattern myocardial scar in patients with CAD recruited to a London registry was associated with adverse remodelling but was not a predictor of outcome and had no rare genetic basis.
iv) Late gadolinium enhancement (LGE) quantification, alongside computational image analysis, was performed in 437 patients with CAD. Core infarct mass and peri-infarct zone mass were independently associated with sudden cardiac death (SCD), improving risk stratification beyond LV ejection fraction. Several shape-based scar microstructure features associated with SCD.
Conclusions: My results suggest that ischaemia has a global effect on the myocardium, with a potential role for targeting mitochondrial redox biology. Adverse cardiac remodelling in CAD is complex with ischaemic myocardial scar an important determinant of outcomes, particularly arrhythmic.
Methods and Results:
i) Serial cardiovascular magnetic resonance (CMR) was performed on 43 patients undergoing coronary artery bypass grafting (CABG). Visual ischaemic burden (median: 18.0% [10.5-21.0] vs 42.0% [27.0-51.0], P<0.001) and global myocardial perfusion reserve (median: 2.40 [1.72-2.75] vs 1.71 [1.36-2.22], P=0.002) improved post-operatively. Change in patient-reported health status correlated with change in visual ischaemic burden.
ii) From 33 patients undergoing CABG, 63 left ventricular (LV) biopsies were acquired. The global myocardial ATP/ADP ratio was reduced in CAD patients as compared to donor tissue, with increased expression of oxidative phosphorylation genes encoding electron transport chain complexes. Paired analyses of biopsies obtained from LV segments with or without inducible ischaemia revealed no difference in the regional metabolic or single-cell transcriptomic landscape.
iii) The relevance of genetic and CMR features of dilated cardiomyopathy (DCM) in individuals with CAD was assessed. Rare variants in DCM-associated genes were associated with LV remodelling and outcomes in individuals with CAD in the UK Biobank. Non-infarct pattern myocardial scar in patients with CAD recruited to a London registry was associated with adverse remodelling but was not a predictor of outcome and had no rare genetic basis.
iv) Late gadolinium enhancement (LGE) quantification, alongside computational image analysis, was performed in 437 patients with CAD. Core infarct mass and peri-infarct zone mass were independently associated with sudden cardiac death (SCD), improving risk stratification beyond LV ejection fraction. Several shape-based scar microstructure features associated with SCD.
Conclusions: My results suggest that ischaemia has a global effect on the myocardium, with a potential role for targeting mitochondrial redox biology. Adverse cardiac remodelling in CAD is complex with ischaemic myocardial scar an important determinant of outcomes, particularly arrhythmic.
Version
Open Access
Date Issued
2022-12-12
Date Awarded
01/07/2023
License URL
Advisor
Prasad, Sanjay
Vazir, Ali
Murphy, Mike
Halliday, Brian
Sponsor
National Heart and Lung Institute
Grant Number
WHCC P76228
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)