Treating the compromised hearts of patients with Rheumatoid Arthritis * Can we repair the damage?

The most frequent cause of death in patients with chronic inflammatory joint
diseases (IJD), including rheumatoid arthritis (RA), is of cardiovascular (CV)
origin. The systemic inflammatory activity that underlies IJD is an important
risk factor for the development of CV disorders, as inflammation is pivotal in
the acceleration of atherosclerosis development, increasing the odds of
myocardial infarction, stroke and peripheral vascular disease. In addition,
chronic inflammation may lead to microvascular dysfunction, microvascular
rarefaction, interstitial fibrosis and stiff cardiomyocytes, decreasing the
ability of the cardiac muscle to contract and relax. This could result in
preclinical diastolic left ventricular (LV) dysfunction, which can progress to
heart failure (HF) with preserved ejection fraction (HFpEF).

Currently, HFpEF represents 50% of HF cases, but its prevalence is increasing
as a result of a growing awareness and diagnosis and due to changes in
population demographics. While mortality rates in patients with heart failure
with reduced ejection fraction (HFrEF) and HFpEF are comparable, unlike HFrEF
no therapy has yet been shown to improve survival and only diuretics can give
solely relief of symptoms. Furthermore, studies have repetitively shown a
strikingly high prevalence of HFpEF in patients with RA.

Accumulating evidence shows that systemic inflammatory disease activity in
general plays a pivotal role in development of cardiac dysfunction. In
addition, a recent case control study showed a 70% increase of relative risk of
developing heart failure in early onset (<1 year) RA patients compared to the
control group. This suggests that there is a relationship between systemic
inflammatory activity and cardiac dysfunction which is not solely related to
atherosclerosis formation as this is a slowly accelerating process.

We therefore hypothesize that diastolic LV function improves in RA patients
responding to anti-inflammatory treatment. Therefore, effective
anti-inflammatory treatment can reduce the risk of HFpEF, especially in
patients with a high cardiovascular risk profile.
Until now, therapy with biologics such as tumour necrosis factor (TNF) blockers
has shown to be the most effective anti-inflammatory treatment in RA.
Therefore, we expect that RA patients with high disease activity, in whom TNF
blocking therapy is initiated, will show the highest decrease in inflammatory
disease activity which can subsequently be related to diastolic LV function.
Our hypothesis is thus that diastolic LV function improves in RA patients
responding to anti-inflammatory treatment, as diastolic LV function is also
driven by systemic inflammatory processes.

A major challenge in diastolic LV dysfunction remains the debate regarding the
proper assessment and diagnostic approach. Currently transthoracic Doppler
echocardiography (TTE) is the primary way of non-invasive assessment of
diastolic LV function. However, the major drawback of this non-invasive
assessment is due to the low sensitivity of the detection of diastolic LV
dysfunction. This is explained by the fact that the hemodynamic derangements in
HFpEF-patients at rest, even in advanced stages are relatively mild and that
TTE is performed only at resting conditions, thus with a chance of missing
important diastolic LV dysfunction.

In this light, the Department of Cardiology, VUmc, recently developed
exercise-stress echocardiography (ESE), a highly sophisticated diagnostic tool,
in which echocardiography images are gained during treadmill exercise until
patients become symptomatic. The VUmc is currently one of the few medical
centers in Europe offering routine ESE for clinical and research practice.
For the proposed study we will include 50 RA patients that are eligible for
anti-inflammatory treatment with TNF blockers. At baseline, before the start of
anti-inflammatory treatment, ESE will be performed. After six months of
treatment, a second ESE will be performed. Patients will serve as own control
and echocardiographic parameters will be compared to baseline.

Primary Objective: To investigate diastolic LV dysfunction before and after 6
months anti-inflammatory treatment with TNF blockers in patients with RA,
assessed by exercise-stress echocardiography.
Secondary Objective: To investigate whether systolic LV function improves in
patients with RA during treatment with anti-inflammatory therapy with TNF
blockers resulting in lower disease activity.

A prospective cohort study in RA patients indicated for anti-TNF therapy who
undergo exercise-stress echocardiography before start and after 6 months
therapy.

We do not expect any severe risks as consequent of the study procedure. There
are some aspects to this protocol that may cause (some) discomfort to the
subjects. First, during exercise-stress echocardiography the subject has to
stay in fixed position in a semi-supine bicycle while cycling against
resistance. Second, the exercise-stress echocardiography can cause physical
strain as the workload is escalated in a stepwise fashion until the patient
reaches a heartrate of 100 bpm and at maximum exertion, while imagining is
performed. However, the patient has authority to stop at any moment if the
exertion causes too much discomfort. Third, In addition to the blood samples
acquired in clinical setting an additional 10ml of blood will be drawn.
Possible side effects from blood drawing include faintness, inflammation of the
vein, pain, bruising, or bleeding at the site of puncture. here is also a
slight possibility of infection. Fourth, when measuring blood pressure, the
inflation of the cuff may cause transient paraesthesia in the hand. This study
may improve our understanding of the role of inflammation on cardiac
dysfunction and the possible reversibility of cardiac dysfunction. Therefore
this study has potential to decrease the risk of development of heart failure
with preserved ejection fraction in RA patients.