Cross-sectional cohort study to analyse the relation between advanced glycation end-products (AGEs) and diastolic function in patients with diabetes mellitus with and without chronic heart failure.

In patients with diabetes mellitus (DM) the risk of developing heart failure
(HF) is strongly increased. The prevalence of LV diastolic dysfunction in
asymptomatic patients with type 2 DM is significantly higher than in patients
without type 2 DM. In patients with systolic heart failure, diastolic function
and not systolic function was related to NYHA functional class. Patients with
DM also develop vascular dysfunction, which may further contribute to the
development of chronic HF (CHF). In patients with DM and CHF, symptoms seem to
be more severe compared to similar CHF patients without DM. One possible
explanation might be that patients with DM the levels of advanced glycation
end-products (AGEs) are increased compared to non-diabetic patients. AGEs are
modifications of protein, formed by oxidative or non-oxidative reactions. The
formation of AGEs affects the physiological properties of proteins in the
matrix, such as turnover and elasticity. AGEs also cause complex vascular,
myocardial, structural, and functional changes via the interaction with
AGE-receptors. In patients with diabetes, enhanced AGE accumulation is
associated with the development of diabetic complications. One of the diabetic
complications associated with AGE accumulation is the development of diabetic
cardiomyopathy. The first manifestation of diabetic cardiomyopathy is
asymptomatic diastolic dysfunction that progresses to systolic dysfunction.
In addition to the development of diabetic cardiomyopathy, patients with
diabetes also develop vascular dysfunctions. One explanation for this could be
that formation of AGE-crosslink results in increased arterial stiffening.

We hypothesize that patients with CHF and diabetes are more symptomatic and
have a more impaired diastolic and vascular function than patients with CHF
without diabetes, which is related to accumulation in tissue and serum AGEs.

Aim is to establish the relation between plasma and tissue AGE levels and the
severity of diastolic/vascular dysfunction and its relation with symptoms in
patients with type 2 DM with and without CHF, and in patients with CHF without
DM.

Primary Research Question
1. To establish the relation between plasma and tissue AGE levels and the
severity of diastolic and vascular dysfunction and symptoms in CHF patients
with DM compared with age-matched CHF patients without DM.

Secondary Research Questions
1. To establish AGE levels in patients with DM with and without CHF, and
patients with CHF without DM compared with age
matched normal controls.
2. To establish the relation between plasma and tissue AGE levels and the
severity of vascular dysfunction in CHF patients
with DM compared with age-matched CHF patients without diabetes and age
matched healthy controls.
3. To establish the relation between plasma and tissue AGE levels, diastolic
dysfunction and the severity of heart failure
measured as NYHA functional class and levels of NT-pro-BNP in CHF patients
with and without type 2 DM.
4. To establish the relation between vascular function and the severity of
heart failure measured as NYHA functional class
and levels of NT-pro-BNP in CHF patients with and without type 2 DM.
5. To establish the relation between plasma and tissue AGE levels on quality of
live (QoL) measured with the Minnesota
Living Heart Failure score.
6. To establish the relation between diastolic function and exercise capacity
measured in six minutes walk test (6MWT).

In this cross-sectional study we will include patients with type 2 DM with and
without CHF and patients with CHF without DM. In parallel a control group will
be included. Diabetic patients without CHF will be screened from patients
visiting the Internal Medicine outpatient clinic or Diabetes centre for routine
diabetes care. Patients with CHF with and without DM will be screened from the
Cardiology outpatient clinic. Control patients will be screened from the
partners of the patients included from both outpatient departments and Diabetes
centre.

Patients will be informed about the presence of this study by their treating
physician. Patients will be informed in writing about the purpose, the study
design, study duration, draw-backs and risks, and the consequences of
preliminary ending of the study. Patients will receive at least one week to
think about the participation to the current research. If they are willing to
participate, patients will be asked to sign written informed consent and are
scheduled for the study visit at the outpatient clinic followed by collection
of blood, an echocardiographic examination, Minnesota Living with Heart Failure
Questionnaire, 6 Minutes Walk Test, and non-invasive measurements of vascular
function. Patients will be studied in the morning after an overnight fast and
abstinence from tobacco, caffeine and alcohol and before any medication is
taken. At any time during the study patients are allowed to stop their
participation without any consequences. Medical care will resume normally.

Patients are scheduled for the study visit at the outpatient clinic where they
will be physically examined by the research physician and asked at the current
condition, followed by collection of blood, an echocardiographic examination,
Minnesota Living with Heart Failure questionnaire (MLHF), six-Minute Walk Test
(6MWT) and non-invasive measurements of vascular function. This will take about
2-2.5 hour.
All measurements except collection of blood are non-invasive and therefore have
a minimum risk of complications.