Heart failure with preserved ejection fraction (HFpEF), perfusion and metabolism

The prevalence of heart failure (HF) continues to rise exponentially worldwide,
primarily to be attributed to an increase in HFpEF (Heart Failure with
preserved Ejection Fraction). HF can be split evenly into HFpEF, formerly
classified as diastolic heart failure, and HFrEF (HF with reduced ejection
fraction) formerly classified as systolic heart failure. In the Netherlands,
approximately 70.000 patients suffer from HFpEF. HFpEF, is characterized by an
increased stiffness of the heart, and is associated with multiple
comorbidities, such as diabetes, hypertension and obesity. However, HFpEF is
more than just a complication of these comorbidities, and consequently requires
more than just treatment of these comorbidities. Typical heart failure
medications, proven to be successful in HFrEF, such as ace inhibitors and
beta-blockers have failed to improve quality of life or survival in HFpEF
patients. Currently, no evidence-based treatment can be offered for HFpEF,
resulting in poor quality of life, enormous costs and bad outcome. Therefore, a
better understanding of the underlying pathophysiology is essential in order to
find a treatment for these patients.
Low-grade inflammation, caused by multiple comorbidities, is suggested
to play a central role in HFpEF. It is thought that low-grade inflammation
causes fibrosis as well as endothelial dysfunction, which is known to be
present in these patients. Indeed, our previous research demonstrated the
inability of HFpEF patients to increase myocardial oxygen delivery during
exercise, suggesting impaired microvascular function. We therefore hypothesize
that peripheral/ generalized endothelial dysfunction results in coronary
microvascular dysfunction, accompanied by impaired myocardial microvascular
perfusion and impaired cardiac energy metabolism.

The objective is to assess whether myocardial microvascular perfusion and
myocardial energy metabolism is impaired in HFpEF patients. Additionally we
will evaluate whether endothelial dysfunction is associated with diminished
myocardial perfusion (e.g. coronary microvascular dysfunction) and impaired
myocardial metabolism. We will assess whether non-invasive CMR techniques are
valid compared to the gold-standard biopsy

This study is a prospective case-control study

Group I: HFpEF patients
Group II: controls

Duration: 2 separate days, no treatment intervention or follow-up.
Setting: MUMC+, outpatient clinic cardiology (day 1), radiology (day 2)

In this case control study patients will be assessed for endothelial function,
myocardial perfusion and myocardial metabolism.
Measurements will be performed based on standard study protocols. All
diagnostic test are routinely used in clinic, with the exception of the
non-invasive glycocalyx measurement. (for details see methods section) The
whole measurement programme will take place on three separate days and will
last approximately 5 hours (day 1) and 2 hours (day 2)

Overview Diagnostic tests
Day 1 Clinical assessment (standard clinical care)
- Echocardiography
- Holter
- 6MWT
- Lung function test
- Exercise test
- ApneaLink
- QoL questionnaires
- Lab

Day 2 Extra assessment as part of this study:
- CMR
- Glycocalyx measurement
- Biobank (METC 14-4-078)

Day 3 Extra assessment as part of this study:
- 31P-MRS (Skeletal Muscle Phosphorus Magnetic Resonance Spectroscopy)

Adenosin stress infusion
The use of adenosine infusion in these patients can be regarded as safe and
side effects are transient and generally well tolerated. Effects related to the
known pharmacology of adenosine are frequent, but usually harmless,
self-limiting and of short duration. Discontinuation of infusion may be
necessary if the effect is intolerable. Any side effect is rapidly reversed
with termination of adenosine infusion, within seconds.

Gadovist should not be used in patients with severe renal impairment
(Glomerular filtration rate (GFR) < 30 ml/min/1.73m2 because there have been
reports of nephrogenic systemic fibrosis associated with use of some
gadolinium-containing contrast agents in these patients, thus these patients
will be excluded from the study).


Heat-induced skin hyperaemic response
A method to measure skin microvascular endothelial function is the heat-induced
skin hyperaemic response. After an acclimatization period of 30 minutes,
microvascular measurements will be performed. Skin blood flow will be measured
with laser Doppler flowmetry before (baseline) and during 25 minutes of local
heating to 44° C with the heated LDF-probe.
This high temperature does not cause pain or disconfort.