Non-invasive cardiac imaging in the detection and assessment of subclinical diabetic heart disease

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This project aims to establish the prevalence of subclinical diabetic heart disease, its relationship to myocardial fibrosis on imaging and biochemical parameters and its response to antifibrotic therapy with spironolactone. MATERIALS & METHODS Patient Selection The patient cohort will compromise apparently healthy patients with type 2 diabetes mellitus (T2DM) and suboptimal control (glycosylated haemoglobin [HbA1c] > 7%) recruited from the hospital clinics and the community. Subjects with known macrovascular or microvascular complications of type two diabetes mellitus (T2DM), hypertensive, valvular or coronary disease or other significant co-morbidities such as arrhythmias, malignancy, psychiatric or renal disease will be excluded. Pregnant and breast feeding women will also be excluded. Study design 225 patients will be recruited and undergo initial screening with echocardiography and cardiac magnetic resonance imaging for evidence of diabetic heart disease. Based on past studies at our research centre, it is predicted that approximately one third of these participants will have evidence of subclinical myocardial dysfunction. Previous work with spironolactone and hypertensive heart disease in our group has shown a significant impact on myocardial properties in patient numbers of less than 30, so a proportionate reduction should be detectable from this study group even allowing for a 30% drop-out. There are no previous studies investigating myocardial fibrosis in type 2 diabetes mellitus (T2DM) with cardiac magnetic resonance imaging on which this study can be powered. Baseline measures on all subjects will include: body mass index, hip and waist circumference and resting haemodynamic parameters. Fasting blood samples will be collected to assess haematological parameters, renal and hepatic function, lipid profile, glucose, insulin, glycosylated haemoglobin (HbA1c) and brain natriuretic peptide (BNP) concentrations. Urine collection for albumin to creatinine ratio for detection of diabetic nephropathy will also be performed. Additional plasma, serum and urine will be stored for subsequent investigation of collagen biomarkers as surrogate measures of myocardial fibrosis. All study subjects will undergo a baseline transthoracic echocardiogram to assess for evidence of systolic or diastolic dysfunction using standard echocardiographic parameters. Tissue Doppler imaging (TDI)including tissue velocity, strain and strain rate will be employed to detect further subclinical abnormalities. All subjects will then undergo a standard treadmill exercise stress test before being reimaged at peak heart rate for evidence of inducible wall motion abnormalities (indicative of ischaemic heart disease) and with tissue Doppler imaging (TDI) for subtle myocardial dysfunction which is not otherwise apparent at rest. Those with inducible wall motion abnormalities will be excluded based on their likelihood to have ischaemic heart disease. Appropriate clinical follow-up will be arranged. Patients who are found to have evidence of subclinical myocardial dysfunction and a proportion of matched controls from the original patient group will then be further investigated with cardiac magnetic resonance imaging for evidence of underlying myocardial fibrosis. Patients with subclinical dysfunction will also be randomised to anti-fibrotic therapy with spironolactone (25 mg orally per day) or placebo for 6 months with the aim of reducing the extent and progression of myocardial collagen deposition. Throughout the intervention period, patients will receive 4 weekly follow-up to monitor for adverse events and compliance. Post-intervention, anthropometric measurements, biochemical markers and imaging with resting and exercise echocardiograms and cardiac magnetic resonance imaging will be repeated. PROJECTED OUTCOMES This work aims to highlight the importance of early detection and treatment of subclinical diabetic heart disease, which, if left unaddressed, may result in an epidemic of symptomatic diabetic heart disease in the future. We also hypothesize that anti-fibrotic therapy will have a favourable effect on myocardial function and exercise capacity.

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