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

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies
• Intervention / Treatment: Diagnostic test: Cardiovascular magnetic resonance (CMR) imaging and magnetic resonance spectroscopy; Diagnostic test: Transthoracic echocardiography; Diagnostic test: Computed tomography coronary artery calcium scoring; Diagnostic test: Cardiopulmonary exercise testing; Diagnostic test: Manganese-enhanced magnetic resonance imaging (MEMRI); Diagnostic test: Ambulatory blood pressure monitoring; Diagnostic test: Accelerometer watch; Diagnostic test: Blood tests

• Study Type: Observational
• Enrollment (Estimated): 593

Contacts and Locations

• Study Contact: Name: Gerry P McCann, MD; Phone Number: 01162583402; Email: gpm12@le.ac.uk
• Study Contact Backup: Name: Gaurav S Gulsin, MBChB(Hons); Phone Number: 01162583244; Email: gg149@leicester.ac.uk

Study Locations

• United Kingdom
  • Leicester, United Kingdom
    • Recruiting
    • University of Leicester
    • Contact: Gaurav S Gulsin, MRCP(UK)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Cases will be adults with stable type 2 diabetes and no past medical history of known cardiovascular disease.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Type 2 diabetics; Participants will be aged (≥18 and ≤75 years) with T2D and no prior history of cardiovascular disease.	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 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.; 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.
Healthy controls; Cases will be compared with age-, gender- and ethnicity-matched healthy controls.	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 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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: University of Leicester
• Investigators: Principal Investigator: Gerry P McCann, MD, University of Leicester

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2017
• Primary Completion (Estimated): October 31, 2029
• Study Completion (Estimated): October 31, 2029

Study Registration Dates

• First Submitted: April 19, 2017
• First Submitted That Met QC Criteria: April 24, 2017
• First Posted (Actual): April 27, 2017

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Cardiovascular magnetic resonance; Diabetic cardiomyopathy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Cardiomyopathies; Diabetic Cardiomyopathies; Physiological Effects of Drugs; Trace Elements; Micronutrients; Calcium-Regulating Hormones and Agents; Calcium; Manganese
• Other Study ID Numbers: 0580

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No