It is well established that type 2 diabetes mellitus (T2DM) in isolation is associated with increased cardiovascular morbidity and mortality, even in the absence of coronary artery disease. However, despite epidemiological evidence showing increased morbidity and mortality when T2DM co-exists in states of acquired or inherited cardiac hypertrophy, such as severe aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) respectively, a more detailed assessment of the metabolic, structural, and functional phenotypic alterations associated with co-morbid T2DM in these common cardiovascular conditions remains to be established. Cardiac magnetic resonance (CMR) and phosphorus magnetic resonance spectroscopy (31P-MRS) are powerful tools which can aid the characterisation of the myocardial sequelae of these common co-morbidities.
The aims of this thesis were to use CMR and 31P-MRS to define the impact of co-morbid T2DM in severe AS and in HCM respectively, with regard to the alterations in myocardial phosphocreatine to ATP ratio (PCr/ATP) as a sensitive indicator of myocardial energetic state, perfusion, structure, and function.
To the best of my knowledge this thesis is the first to report that severe AS or HCM-associated abnormalities in myocardial PCr/ATP and in stress indices of myocardial perfusion including stress myocardial blood flow and myocardial perfusion reserve are exacerbated by T2DM comorbidity. Moreover, in a longitudinal cohort study this thesis is the first to report that while aortic valve replacement reverses myocardial abnormalities and limitations in exercise capacity in patients with severe AS alone, despite a similar degree of improvement in aortic valve gradient, the recovery in myocardial features were nevertheless undermined by T2DM comorbidity. In addition, in patients with HCM, the work in this thesis shows that despite matching for sarcomeric mutations and left ventricular mass, patients with T2DM comorbidity displayed a greater degree of fibrosis burden with higher scar percentage than patients with HCM alone.
This work has also demonstrated that the energetic impairment in T2DM seen with non-invasive imaging, translates to impairment in myocardial mitochondrial oxidative phosphorylation with use of high resolution respirometry technique on myocardial biopsy sample analysis. Additionally, a modified phosphorous spectroscopy technique is presented, with improved patient comfort and a higher degree of reproducibility, which might allow for the wider application of this technique.
In summary, the work in this thesis demonstrates the significant impact of T2DM on myocardial PCr/ATP, perfusion, and function in states of cardiac hypertrophy and demonstrates the potential for advanced MR imaging techniques to allow for improved patient risk stratification and a more refined approach to assessing and treating these common co-morbidities.
