Prevalence and Determinants of Subclinical Cardiovascular Dysfunction in Adults With Type 2 Diabetes Mellitus

Overview

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.

Interventions

• Diagnostic test Cardiovascular magnetic resonance (CMR) imaging and magnetic resonance spectroscopy
  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 stif
• Diagnostic test Transthoracic echocardiography
  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.
• Diagnostic test Computed tomography coronary artery calcium scoring
  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.
• Diagnostic test Cardiopulmonary exercise testing
  Physician supervised incremental symptom limited cardiopulmonary exercise tolerance test with ECG and haemodynamic monitoring.
• Diagnostic test Manganese-enhanced magnetic resonance imaging (MEMRI)
  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.
• Diagnostic test Ambulatory blood pressure monitoring
  A 24-hour blood pressure monitor will be worn at the end of the visit to the following day.
• Diagnostic test Accelerometer watch
  Watch worn to collect free living physical activity data for 7 days.
• Diagnostic test Blood tests
  Collection of blood samples from each participant to characterise the participant's health status and to develop a proteomic signature of early heart failure.

Primary outcome measures

• Prevalence of early heart failure in type 2 diabetes [Time frame: 5 years]

Secondary outcome measures (12)

• Multivariate and independent predictors of LV systolic and diastolic function in type 2 diabetes [Time frame: 3 years]
• Sensitivity of CMR versus echocardiography and BNP for detecting subclinical cardiovascular dysfunction in type 2 diabetes [Time frame: 3 years]
• Independent association of CMR measures with aerobic exercise capacity in type 2 diabetes [Time frame: 3 years]
• Differences in LV remodelling (indexed LV mass) between cases and controls [Time frame: 3 years]
• Independent clinical and imaging predictors of major adverse cardiovascular and, in particular, heart failure events in the patients with type 2 diabetes [Time frame: 5 years]
• Differences in cardiac MRI and echo-derived systolic and diastolic strain and strain rates between cases and controls. [Time frame: 3 years]
• Differences in coronary atheroma burden (CT coronary artery calcium score) between cases and controls [Time frame: 3 years]
• Differences in aerobic exercise capacity (peak V02) between cases and controls [Time frame: 3 years]
• Differences in myocardial perfusion reserve between cases and controls [Time frame: 3 years]
• Differences in heart rate and blood pressure variability between cases and controls [Time frame: 3 years]
• Myocardial steatosis [Time frame: 3 years]
• Myocardial calcium handling as assessed by manganese-enhanced magnetic resonance imaging (MEMRI) [Time frame: 5 years]

Eligibility criteria

Inclusion criteria

• Participant is willing and able to give informed consent for participation in the study.
• Male or Female, aged ≥18 and ≤75 years.
• Diagnosed with Stable type 2 diabetes (determined by: i) formal diagnosis in GP case records, ii) a record of diagnostic oral glucose tolerance test OR glycated haemoglobin level ≥6.5%).

Exclusion criteria

• Angina pectoris or limiting dyspnoea (>NYHA II),
• Major atherosclerotic disease: Symptomatic CAD, history of myocardial infarction, previous revascularisation, stroke/transient ischaemic attack or symptomatic peripheral vascular disease.
• Atrial fibrillation or flutter.
• Moderate or severe valvular heart disease.
• History of heart failure or cardiomyopathy.
• Type 1 diabetes mellitus (T1DM).
• Low fasting C-peptide levels suggestive of adult-onset T1DM.
• Stage III-V renal disease (estimated glomerular filtration rate ≤30ml/min/1.73m2).
• Absolute contraindications to CMR.

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

United Kingdom · 1 center

• University of Leicester — Leicester

Publications

• 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. PMID 41663151
• 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. PMID 35643571

Identifiers

NCT: NCT03132129 · 0580

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗