Novel approaches to risk stratification in common cardiovascular diseases using circulating and imaging biomarkers

© 2021 Jay Kumar Manohar RamchandCardiovascular disease (CVD) is a leading cause of morbidity and mortality. The number of individuals at risk of CVD complications continues to rise, making CVD preventative strategies an ongoing public health priority. Current risk-stratification approaches have limited predictive value, which poses a significant challenge in delivering preventative therapies. Therefore, finding new biomarkers for CVD is of interest and may improve the identification of individuals who would benefit most from preventative therapies. The main aim of this thesis was to identify novel approaches to risk stratification in common CVD states using circulating and imaging biomarkers. This thesis consists of four studies that evaluated: 1) The prognostic role of circulating angiotensin converting enzyme 2 (ACE2) in coronary artery disease (Chapter 3); 2) The role of circulating and myocardial ACE2 in aortic stenosis (Chapter 4); 3) The role of abnormal myocardial tissue characterisation using native T1 time, a cardiac magnetic resonance technique in aortic stenosis (Chapter 5); and 4) The role of opportunistic screening using cardiac computed tomography (CT) to identify markers of vascular disease such as coronary artery calcium and thoracic aortic dilation in atrial fibrillation (Chapter 6). The first study (Chapter 3) was a prospective evaluation of circulating ACE2 levels in patients with obstructive coronary artery disease. ACE2 is an integral membrane protein that degrades angiotensin II and has an emerging role as a circulating biomarker of CVD. Over a median follow up of 10.5 years, circulating ACE2 activity independently predicted the occurrence of major adverse cardiovascular events (MACE) [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.24–4.72]. The second study (Chapter 4) investigated the relationship between circulating ACE2 activity levels and all-cause mortality in patients with aortic stenosis. Additionally, the relationship between circulating ACE2 activity, myocardial ACE2 gene expression, and myocardial fibrosis were examined. Higher circulating ACE2 levels were associated with increased myocardial structural abnormalities such as increased LV mass index and increased LV volumes. Over a median follow-up of 5 years, elevated circulating ACE2 activity was an independent predictor of all-cause mortality with incremental prognostic value after adjustment for relevant clinical, imaging, and biochemical parameters (HR: 2.28; 95% CI: 1.03 to 5.06). In a subset of patients with myocardial tissue collection, increased circulating ACE2 was associated with reduced myocardial ACE2 gene expression and severe myocardial fibrosis. The third study (Chapter 5) investigated whether diffuse myocardial fibrosis characterised by greater native T1 times on cardiac magnetic resonance provides prognostic utility to predict MACE (all-cause mortality or heart failure hospitalisation) in patients severe AS being evaluated for transcatheter aortic valve replacement. Native T1 times were higher than previously reported values in healthy controls. Patients with higher T1 times were more likely to have evidence of myocardial decompensation demonstrated by higher NT-proBNP levels and lower left ventricular ejection fraction. Over a median follow-up of 3.1 years, increased native T1 time (HR:1.68; 95% CI:1.08 - 2.62) and age > 75 years (HR:1.82;1.01–3.28) were independent predictors of MACE. The fourth study (Chapter 6) investigated the prevalence of incidental vascular diseases, including thoracic aortic aneurysmal disease and coronary atherosclerosis, both important causes of cardiovascular mortality, in patients with atrial fibrillation. In a cross-sectional study of 1,000 consecutive patients with atrial fibrillation, one in five were found to have newly identified thoracic aortic aneurysmal disease on multidetector chest CT. A small proportion (1%) had significantly aneurysmal dimensions that approached surgical thresholds. Although two-thirds of the cohort had coronary calcification, 38% were not taking lipid-lowering therapy. The findings therefore represent an opportunity to substantially optimise preventative measures in AF. Overall, the findings of the thesis suggest that the circulating and imaging biomarkers evaluated in the above studies, provide incremental diagnostic and/or prognostic information in patients with CVD. The findings need confirmation in large independent cohorts before these biomarkers can be incorporated into risk stratification algorithms