Non-ischemic cardiomyopathy is increasingly recognised in type 2 diabetes mellitus (T2DM). This appears to initially present as asymptomatic, subclinical diastolic dysfunction (DD) before progressively manifesting with symptoms such as dyspnoea and impaired exercise capacity. The aetiology is likely multi-factorial, secondary to a combination of microvascular disease, hyperglycaemia, inflammation, hyperlipidemia, autonomic dysfunction and neurohormonal abnormalities. Accumulating evidence suggests that diffuse, reactive myocardial fibrosis is an important underlying process in diabetic cardiomyopathy (DCM), although the exact causative mechanisms remain undefined.
Myocardial biopsy cannot be easily justified in asymptomatic subjects with T2DM on ethical and financial grounds. Hence, non-invasive methods to detect myocardial functional and structural abnormalities may provide important alternative means for identification of DCM. Early recognition could result in more timely institution of anti-fibrotic pharmacological or lifestyle therapies. Long-term this may have the potential to halt or even regress the fibrotic process. This thesis initially aims to outline the non-invasive methods by which diffuse myocardial fibrosis has been previously identified in several disease processes. Of these previously validated techniques, Chapter 2 outlines the methodologies selected for inclusion within the remainder of this thesis.
Chapter 3 addresses the impact of exercise on myocardial function by examining the correlates of the exercise response in T2DM. Myocardial dysfunction was sought at rest and after exercise in 167 subjects. Resting myocardial dysfunction was identified in 24 subjects and was associated with metabolic dysfunction, impaired exercise capacity and impaired longitudinal diastolic functional reserve index. Inducible myocardial dysfunction with exercise was detected in an additional 70 subjects and was associated with higher backscatter (cIB) and lower peak heart rate but not metabolic control. This abnormal stress response suggests myocardial fibrosis and cardiac autonomic neuropathy have an underlying role in DCM.
Chapter 4 examines the role of the end-systolic pressure-volume response (ESPVR), as a marker of contractile reserve, in the detection of subclinical DCM. 167 subjects underwent resting and exercise stress echocardiography. An impaired ESPVR was demonstrated in 83 subjects who were older and had features of resting subclinical DCM as well as impaired peak hemodynamic response and stress systolic function. Chapter 5 seeks to examine the relationship between different non-invasive measures of myocardial fibrosis in early DCM. 67 subjects underwent exercise stress echocardiography, T1 mapping with cardiac magnetic resonance imaging (CMR) and metabolic assessment. An association was found between DD on echo, post-contrast T1 values on CMR and metabolic disturbance. Thus, supporting that diffuse myocardial fibrosis is a contributor to early DCM and that metabolic derangement may be a causative factor.
Chapter 6 examines the relationship between myocardial dysfunction, metabolic derangement and pro-collagen biomarkers of types I and III collagen in T2DM. 390 asymptomatic subjects underwent clinical, echocardiographic and biochemical assessment, in addition to quantification of biomarkers of pro-collagen types I and III. After stratification for metabolic derangement; 53 (14%) had isolated T2DM, 67 (17%) had T2DM with isolated hypertension, 178 (45%) had T2DM with the metabolic syndrome and 92 (24%) had T2DM with the metabolic syndrome and end-organ involvement (microalbuminuria). Metabolic derangement was associated with worsening DD and increased myocardial signal intensity on cIB. A weak association was found with pro-collagen biomarkers, thereby suggesting a limited role of collagen turnover in DCM.
Chapter 7 explores the effect of spironolactone, as an anti-fibrotic agent, on echocardiographic parameters and pro-collagen biomarkers by assessing the response of functional and structural parameters to aldosterone antagonism in asymptomatic subjects with T2DM. Biochemical, anthropometric and echocardiographic data were measured in 225 subjects. Pro-collagen biomarkers were assayed from peripheral blood or urine to assess myocardial collagen turnover. DD without occult coronary artery disease was identified in 81 individuals. Of these, 49 subjects were randomized to spironolactone 25mg/day or placebo for 6 months. Aldosterone antagonism improved myocardial diastolic properties (peak E wave, E/A ratio) and myocardial structure (cIB), without significant changes in pro-collagen biomarkers.
Chapter 8 assesses the anti-fibrotic effect of spironolactone therapy on myocardial structure using T1 mapping and pro-collagen biomarkers. 60 asymptomatic subjects with T2DM and DD participated in post-contrast T1 mapping and pro-collagen biomarkers to determine myocardial collagen content. Subjects were randomized to spironolactone 25mg/day, exercise training or placebo for 6 months. Post-intervention, neither aldosterone antagonism nor exercise training had a significant impact on myocardial structure.
In conclusion, the findings of this thesis suggest that myocardial dysfunction manifests even in asymptomatic T2DM and is primarily attributable to DD. These abnormalities may be unmasked with exercise and are closely related to the degree of metabolic derangement. Intervention with spironolactone, as an antifibrotic agent, improves some parameters of diastolic function and cIB as a measure of myocardial structure; however, T1 mapping and pro-collagen biomarkers do not significantly change. This suggests that although myocardial fibrosis may play a partial role in DCM, it does not appear to be the main contributing factor causing myocardial dysfunction and may therefore not be an important therapeutic target.