Comparison of Differencens in VO2-max, Perfusion of the Heart and Brain and Cognitive Performance Between Patients with Type 2 Diabetes and Healthy Age Matched Controls.

Trial statusNot yet recruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age60+
SponsorUniversity Hospital Bispebjerg and Frederiksberg

About this trial

In the aging population, ischemic heart disease, stroke and dementia are increasingly prevalent. Diagnosis and treatment of the former two i.e., large-vessel coronary heart disease and endovascular thrombectomy of the brain in relation to stroke have improved significantly. Yet, the majority of elderly patients with ischemic heart disease do not have large-vessel heart disease and it seems that small vessel disease (SVD) may explain a large fraction of these cases as well as the cardiovascular morbidity in the elderly. Hence, the current development in diagnostics and treatments of ischemic heart disease does not address the most common subtype of ischemic disease seen in elderly patients.

It has been suggested that SVD is part of a multisystem disorder and several systematic reviews have addressed the hypothesis of a potential link between small vessel disease of the heart, brain, and kidneys. Cerebral SVD is prevalent in the aging population causing cognitive impairment, dementia, and an increased risk of stroke, and cerebral hypoperfusion is an acknowledged cause of vascular dementia and a possible cause of Alzheimer's disease. Further, cognitive impairment within multiple cognitive domains is highly prevalent in heart failure and is associated to an increased risk of dementia. The link between heart failure and dementia may be due to multisystem SVD, although a direct link between the two is possible.

Among other known risk factors such as age, hypertension, and female sex, diabetes is a major cause of SVD and is linked to coronary heart disease as well as cognitive impairment. The diagnosis of cerebral SVD relies on MRI detecting infarctions, haemorrhages, microbleeds and ischemic white matter changes, i.e. Fazekas score. In contrast, perfusion PET is used to image myocardial perfusion in patients with coronary SVD; and coronary SVD is recognized as a part of the pathophysiology in angina, coronary artery disease, and heart failure. Perfusion PET before and after adenosine-induced vasodilation allows for measuring, the myocardial flow reserve (MFR), i.e. perfusion capacity, which in the absence of regional perfusion defects, is a measure of coronary SVD. Prof. Eva Prescott have recently shown that reduced MFR obtained by 82Rb PET is a strong predictor of future microvascular events and all-cause mortality.

Exercise is well known to improve cognitive health but professor Carl-Johan Boraxbekk has shown that the effect on cognitive performance may be dependent on the initial cerebrovascular status, as patients with moderate to severe white matter changes did not improve after a 6 months physical activation intervention in contrast to patients with mild changes. Yet, it is possible to improve brain function in diabetic patients through either dietary or exercise interventions.

Systemic SVD is measured as cerebral SVD (reduced brain perfusion during acetazolamide-induced vasodilation) and coronary SVD (reduced heart perfusion during adenosine-induced vasodilation). The researchers anticipate that patients with type 2 dabetes have reduced perfusion capacity of the brain and heart correlating to reduced cognition and cardiorespiratory fitness (VO2-max).

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

Duration over 5 years

Moderate microalbuminuria

Non-proliferative diabetic retinopathy

Speaks and understands Danish (required for reliable cognitive testing)

Disqualifiers

Previous AMI, atrial fibrillation, significant cardiac valve disease, HFrEF (LVEF <45%), asthma.

Previous stroke or significant neurological disease including cognitive dysfunction.

Ongoing depression.

Hypothyroidism

Trial population

Patients with type 2 diabetes with increased risk of microvascular disease.

Trial design

Design model

Case-control

Time perspective

Cross-sectional

Treatments tested in this trial

  • PET

    Diagnostic test

    PET imaging will be performed with a Discovery 710 PET/CT scanner (GE Healthcare, Milwaukee, WI, USA). Four 5-minute PET recordings will be performed of each subject within a single scanning session of 70 min. Two consecutive 5-minute scans are conducted of the heart and brain in rest. \[15O\]H2O, is produced on-site (GENtrace, GE, Uppsala, Sweden), and 600 MBq \[15O\]H2O is intravenously injected by an automatic Hidex Radiowater Generator (Hidex, Turku, Finland). To induce heart vasodilation, adenosine is infused (140 g/kg/min) for 6 min and a scan of the heart is repeated. To induce brain vasodilation, 1 g of acetazolamide is infused over 5 min and 15 min later the brain is scanned. Myocardial perfusion is calculated using CarimasCE software version 1.3.1. (Turku, Finland). Cerebral perfusion is calculated using PMOD software (PMOD Technologies, Switzerland).

Treatment groups

72 Participants
are divided into 2 treatment groups
Group A: 48 patients with type 2 diabetes and increased risk of microvascular disease1 intervention
Group B: 24 healthy age-matched participants1 intervention

Trial outcomes

Primary outcomes

1

[15O]H2O PET assessment of the blood perfusion to the brain

We will use the scan to determine our primary outcome: Blood perfusion to the brain. Radioactive water (\[15O\]H2O) will be used as a PET-tracer since it follows the blood and is the gold standard tracer for PET-based blood perfusion measurements. We measure the blood perfusion of both the brain as the perfusion capacity, meaning the difference between blood perfusion to the organ at rest and the maximally possible perfusion. In the brain we use injection of diamox to stimualte maximal dilation of the cerebral arteries which corresponds to the maximally possible perfusion of the brain.

Time frame
From baseline testing to end of study, 6 months
2

[15O]H2O PET assessment of the blood perfusion of the heart

We will use the scan to determine our primary outcome: Blood perfusion to the heart. Radioactive water (\[15O\]H2O) will be used as a PET-tracer since it follows the blood and is the gold standard tracer for PET-based blood perfusion measurements. We measure the blood perfusion of both the heart as the perfusion capacity, meaning the difference between blood perfusion to the organ at rest and the maximally possible perfusion. In the heart we use injection of adenosin to stimualte maximal dilation of the coronary arteries which corresponds to the maximally possible perfusion of the heart.

Time frame
From baseline testing to end of study, 6 months

Secondary outcomes

1

Cognitive performance (CANTAB)

Testing of a broad range of cognitive functions. The test is tablet based and one of the most \"investigator-independent\" cognitive tests available. The test takes around 45 minutes to perform.

Time frame
From baseline testing to end of study, 6 months
2

Cognitive Performance (SCIP-D)

Assessed via SCIP-D in order to evaluate a broad range of cognitive areas in around 15-20 minutes. Both groups will undergo both tests. The primary investigator will receive learning in how to carry out the SCIP-D correctly. SCIP-D is a more clinically relevant test that can be used in a clinical setting to identify patients with cognitive dysfunction.

Time frame
From baseline testing to end of study, 6 months
3

Cardiorespiratory fitness (VO2-max)

Will be assessed as the maximal or peak oxygen consumption (VO2-max or VO2-peak) during a cardiopulmonal exercise test (CPET).

Time frame
From baseline testing to end of study, 6 months

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

University Hospital Bispebjerg and Frederiksberg

Lead sponsor

Danish Cardiovascular Academy

Collaborator

Bispebjerg Hospital

Collaborator

The Dagmar Marshall Foundation

Collaborator

Steno Diabetes Center Copenhagen

Collaborator

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