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Background: Heart failure is a major cause of morbidity and mortality in diabetes mellitus, but its pathophysiology is poorly understood.
Aim: To determine the prevalence and determinants of subclinical cardiovascular dysfunction in adults with type 2 diabetes (T2D).
Plan: 518 asymptomatic adults (aged 18-75 years) with T2D will undergo comprehensive evaluation of cardiac structure and function using cardiac MRI (CMR) and spectroscopy, echocardiography, CT coronary calcium scoring, exercise tolerance testing and blood sampling. 75 controls will undergo the same evaluation.
Primary hypothesis: myocardial steatosis is an independent predictor of left ventricular global longitudinal strain. Secondary hypotheses: will assess whether CMR is more sensitive to detect early cardiac dysfunction than echocardiography and BNP, and whether cardiac dysfunction is related to peak oxygen consumption.
Expected value of results: This study will reveal the prevalence and determinants of cardiac dysfunction in T2D, and could provide targets for novel therapies.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Type 2 diabetics | Participants will be aged (≥18 and ≤75 years) with T2D and no prior history of cardiovascular disease. |
| |
| Healthy controls | Cases will be compared with age-, gender- and ethnicity-matched healthy controls. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cardiovascular magnetic resonance (CMR) imaging and magnetic resonance spectroscopy | Diagnostic Test | CMR scanning performed on a 3T MRI scanner. Standardised protocol incorporating cine functional assessment to determine LV mass, systolic function and left atrial volumes; global systolic strain and diastolic strain rates will be assessed by tagging and with tissue tracking analysis from cine images, adenosine rest and stress myocardial perfusion to assess reserve index and qualitative perfusion defects as previously described, aortic distensibility and pulse wave velocity to measure aortic stiffness, delayed contrast enhancement for assessment of LV fibrosis and evidence of previous myocardial infarction. Myocardial and liver triglyceride content will be assessed using the modified Hepafat® sequence or 1H MR spectroscopy at the inter ventricular septum. DIXON technique for the quantification of visceral adiposity and subcutaneous adipose tissue. |
| Measure | Description | Time Frame |
|---|---|---|
| Prevalence of early heart failure in type 2 diabetes | Proportion of participants with type 2 diabetes who have features of early heart failure | 5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Multivariate and independent predictors of LV systolic and diastolic function in type 2 diabetes | Multivariate and independent predictors of LV systolic and diastolic function in type 2 diabetes | 3 years |
| Sensitivity of CMR versus echocardiography and BNP for detecting subclinical cardiovascular dysfunction in type 2 diabetes |
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Inclusion Criteria:
Exclusion Criteria:
Importantly, patients with subclinical CAD, and other common comorbidities such as obesity and hypertension, will not be excluded from this study. This will enable us to evaluate the contribution of CAD to myocardial dysfunction in diabetes and ensures our study group is representative of the general population with diabetes. Similarly, as mild dyspnoea is extremely common and non-specific participants with mild dyspnoea will be included.
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Cases will be adults with stable type 2 diabetes and no past medical history of known cardiovascular disease.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Gerry P McCann, MD | Contact | 01162583402 | gpm12@le.ac.uk | |
| Gaurav S Gulsin, MBChB(Hons) | Contact | 01162583244 | gg149@leicester.ac.uk |
| Name | Affiliation | Role |
|---|---|---|
| Gerry P McCann, MD | University of Leicester | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Leicester | Recruiting | Leicester | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41663151 | Derived | Ayton SL, Aslam S, Dattani A, Yeo JL, Gulsin GS, Slomka PJ, Dey D, McCann GP, Singh A. Association of epicardial adipose tissue with markers of cardiac remodelling and clinical outcomes in asymptomatic aortic stenosis. Open Heart. 2026 Feb 9;13(1):e003804. doi: 10.1136/openhrt-2025-003804. | |
| 35643571 | Derived |
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Quantitative buffy coat and plasma samples will be stored for future potential biomarker and genotyping studies.
|
| Transthoracic echocardiography | Diagnostic Test | Comprehensive transthoracic echocardiography, including: tissue Doppler indices of diastolic filling and speckle tracking for systolic and diastolic strain/strain rate, exclusion of valvular abnormalities, assessment of LV size and function. |
|
| Computed tomography coronary artery calcium scoring | Diagnostic Test | Computed Tomography coronary calcium scoring to assess the presence of subclinical atherosclerosis and allow an estimate of atheroma burden in addition to epicardial adipose tissue characterisation and systolic strain. |
|
| Cardiopulmonary exercise testing | Diagnostic Test | Physician supervised incremental symptom limited cardiopulmonary exercise tolerance test with ECG and haemodynamic monitoring. |
|
| Manganese-enhanced magnetic resonance imaging (MEMRI) | Diagnostic Test | A subset of the participants will have cardiac MRI scanning with manganese-based contrast agent, lasting approximately 45-50 minutes. After localisers, baseline functions and native T1 maps have been acquired, Mangafodipir (0.1mL/kg) will be administered intravenously at 1ml/min, with additional T1 maps acquired every 2.5 min after administration of the contrast agent for up to 30 minutes. |
|
| Ambulatory blood pressure monitoring | Diagnostic Test | A 24-hour blood pressure monitor will be worn at the end of the visit to the following day. |
|
| Accelerometer watch | Diagnostic Test | Watch worn to collect free living physical activity data for 7 days. |
|
| Blood tests | Diagnostic Test | Collection of blood samples from each participant to characterise the participant's health status and to develop a proteomic signature of early heart failure. |
|
Sensitivity of CMR versus echocardiography and BNP for detecting subclinical cardiovascular dysfunction in type 2 diabetes |
| 3 years |
| Independent association of CMR measures with aerobic exercise capacity in type 2 diabetes | Independent association of CMR measures (LV systolic and diastolic strain and strain rates) with aerobic exercise capacity (peak VO2) in type 2 diabetes | 3 years |
| Differences in LV remodelling (indexed LV mass) between cases and controls | Differences in LV remodelling (indexed LV mass) between cases and controls | 3 years |
| Independent clinical and imaging predictors of major adverse cardiovascular and, in particular, heart failure events in the patients with type 2 diabetes | Independent clinical and imaging predictors of major adverse cardiovascular and, in particular, heart failure events in the patients with type 2 diabetes | 5 years |
| Differences in cardiac MRI and echo-derived systolic and diastolic strain and strain rates between cases and controls. | Differences in cardiac MRI and echo-derived systolic and diastolic strain and strain rates between cases and controls. | 3 years |
| Differences in coronary atheroma burden (CT coronary artery calcium score) between cases and controls | Differences in coronary atheroma burden (CT coronary artery calcium score) between cases and controls | 3 years |
| Differences in aerobic exercise capacity (peak V02) between cases and controls | Differences in aerobic exercise capacity (peak V02) between cases and controls | 3 years |
| Differences in myocardial perfusion reserve between cases and controls | Differences in myocardial perfusion reserve between cases and controls | 3 years |
| Differences in heart rate and blood pressure variability between cases and controls | Differences in heart rate and blood pressure variability between cases and controls | 3 years |
| Myocardial steatosis | Myocardial steatosis as an independent predictor of LV global longitudinal strain | 3 years |
| Myocardial calcium handling as assessed by manganese-enhanced magnetic resonance imaging (MEMRI) | Manganese influx constants calculated using Patlak modelling | 5 years |
| Proteomic signature | Proteomic analysis will be conducted to identify a proteomic signature of early heart failure in type 2 diabetes that will be externally validated | 5 years |
| Remission of type 2 diabetes | The phenotype of participants defined as in remission will be compared to active type 2 diabetes and healthy volunteers | 5 years |
| Yeo JL, Gulsin GS, Brady EM, Dattani A, Bilak JM, Marsh AM, Sian M, Athithan L, Parke KS, Wormleighton J, Graham-Brown MPM, Singh A, Arnold JR, Lawson C, Davies MJ, Xue H, Kellman P, McCann GP. Association of ambulatory blood pressure with coronary microvascular and cardiac dysfunction in asymptomatic type 2 diabetes. Cardiovasc Diabetol. 2022 May 28;21(1):85. doi: 10.1186/s12933-022-01528-2. |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D058065 | Diabetic Cardiomyopathies |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D009202 | Cardiomyopathies |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D048909 | Diabetes Complications |
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| ID | Term |
|---|---|
| D003952 | Diagnostic Imaging |
| D049268 | Positron-Emission Tomography |
| D004452 | Echocardiography |
| D005080 | Exercise Test |
| D018660 | Blood Pressure Monitoring, Ambulatory |
| D006403 | Hematologic Tests |
| ID | Term |
|---|---|
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D014055 | Tomography, Emission-Computed |
| D007090 | Image Interpretation, Computer-Assisted |
| D007089 | Image Enhancement |
| D010781 | Photography |
| D011877 | Radionuclide Imaging |
| D014054 | Tomography |
| D003947 | Diagnostic Techniques, Radioisotope |
| D057791 | Cardiac Imaging Techniques |
| D014463 | Ultrasonography |
| D006334 | Heart Function Tests |
| D003935 | Diagnostic Techniques, Cardiovascular |
| D012129 | Respiratory Function Tests |
| D003948 | Diagnostic Techniques, Respiratory System |
| D016552 | Ergometry |
| D008919 | Investigative Techniques |
| D001795 | Blood Pressure Determination |
| D018670 | Monitoring, Ambulatory |
| D008991 | Monitoring, Physiologic |
| D019411 | Clinical Laboratory Techniques |
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