Type 2 diabetes mellitus (T2D) is associated with an increased risk of heart failure and cardiovascular mortality even in the absence of coronary artery disease. Although the reasons for this are not clear, candidate mechanisms are impaired cardiac high energy phosphate metabolism and coronary microvascular dysfunction. Cardiac magnetic resonance imaging (CMR) and magnetic resonance spectroscopy (MRS) are powerful tools for the noninvasive assessment of the functional, structural and the metabolic status of the heart. The overarching aims of this thesis were to combine advanced CMR and MRS techniques to study disease mechanisms in asymptomatic patients with uncomplicated T2D who had no prior diagnosis of cardiovascular disease. In chapter 3, prospective longitudinal cardiac structural and functional changes were studied in T2D patients over a six-year follow-up period. In this study T2D patients who have not experienced any cardiovascular events and remained asymptomatic over the follow-up period showed significant reductions in cardiac size and biventricular systolic function over time. The work represented in chapter 4 showed that while T2D is associated with greater visceral adiposity in overweight patients, accumulation of visceral fat was evident even in T2D patients with a normal body weight at levels similar to overweight non-diabetic controls. Secondly, in T2D patients, all measures of adiposity strongly correlated with one another, and visceral adipose tissue, body mass index and waist circumference were each related to abnormalities in cardiac systolic and diastolic strain, and insulin resistance. Thirdly, myocardial stress perfusion was only reduced in overweight T2D participants, with no reduction in global stress myocardial blood flow or myocardial perfusion reserve index in the normal body weight T2D patients or in overweight healthy volunteers compared to normal body weight healthy volunteers. The work represented in Chapter 5 was set out to establish the links between myocardial perfusion, systolic and diastolic function and energetics in the healthy and the diabetic human heart, at rest and during pharmacological stress combining 31phosphorus-MRS (31P-MRS) and CMR techniques. It is well established that the diabetic heart is characterised by reductions in myocardial phosphocreatine to ATP ratio which is a sensitive indicator of myocardial energetic status that can be noninvasively measured in vivo using 31P-MRS. This reduction is among the earlier subclinical cardiac changes in T2D patients. This work showed that in response to dobutamine stress, patients with T2D as well as healthy volunteers and age-matched veteran athletes show decrements in myocardial energetics, similar increments in global longitudinal shortening and left ventricular ejection fraction (LVEF), but with a blunted increment in stress perfusion in T2D patients. This work also showed that rest and stress myocardial blood flow are is associated with rest and stress LVEF, while rest and stress energetics are associated with rest and stress diastolic parameters respectively, suggesting that diastolic function is a more energetically sensitive process than global systolic function. Chapter 6 was a randomised, phase-2, single centre, open-label, cross-over design mechanistic drug trial of glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide compared to peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone. T2D is characterized by dysregulated insulin secretion and resistance to insulin action. Both the insulin secretion and insulin resistance are amenable to pharmacological intervention. GLP-1 receptor activation promotes insulin secretion and causes weight loss. Pioglitazone is a peroxisome proliferator activated receptor gamma agonist which targets peripheral insulin sensitivity. This work was set out to compare the efficacies of two distinct glycaemic control strategies of targeting beta-cell dysfunction (liraglutide) or insulin resistance (pioglitazone) in improving subclinical cardiac energetic, structural, functional and perfusion alterations in T2D patients with no known prior cardiovascular disease. This randomised cross-over study showed that four months treatment with incretin mimetic liraglutide results in significant improvements in myocardial perfusion and energetics, while the insulin sensitiser pioglitazone shows no effect in modulation of these parameters. Both treatments led to improvements in insulin sensitivity. Pioglitazone results in significant increases in LV mass and an isolated improvement in rest diastolic function. In conclusion, the work in this thesis demonstrates the power of CMR and MRS in elucidating the changes in patients with T2D who are overweight/obese, and of studying biological effects of novel treatment agents on the heart.
