Cardiac disease in Ankylosing Spondylitis

Increased cardiovascular mortality and cardiovascular morbidity
The overall mortality rate in AS patients is increased 60-90% compared with the
general population(1). This higher mortality rate is predominately caused by
increased cardiovascular (CV) risk(2,3). The cause of death in patients with AS
is mainly of circulatory origin, ranging in different studies from 17-40% of
total deaths(4). This increased mortality of circulatory origin is attributable
to both an increase in cardiac diseases such as valvular heart disease,
conduction disturbances and cardiomyopathies, and an increase in
atherosclerotic disease(2). It should be noted that, although most studies
indicate an increased cardiovascular risk in AS, in some studies this increased
risk was not found. A recent large retrospective database study from 2012 with
1686 AS-patients showed no significantly increased rate of myocardial
infarction (hazard ratio of 1.28). In addition, the incidence of stroke was
also not increased (hazard ratio of 1.0). Remarkably, the prevalence of risk
factors for myocardial infarction and stroke, such as diabetes and
hypertension, were increased compared with the control group in this study(5).

Cardiac disease
Valvular disease - Aortic valve involvement is often described in AS(6). A few
decades ago aortitis was a major complication in AS, but nowadays this is
rarely encountered. Nonetheless, the inflammation process in AS patients still
causes aortic cusp retraction and thereby aortic regurgitation (prevalence
ranging from 0% - 26%), although the exact mechanism of aortic valve
involvement is not fully understood(7). A proposed mechanism is that cellular
inflammation results in a marked fibroblastic reparative response, adventitial
thickening, focal destruction of the medial elastic tissue and intima
proliferation. Intimal proliferation of the vasa vasora leads to endarteritis
and then root dilatation. This process extends to the aortic annulus and
produces basal thickening and downward retraction of the cups. When
inflammation spreads, the mitral valve can also be affected(8,9).

Conduction disorders - Inflammation may extend into the ventricular septum,
affecting the endocardium and myocardium(10). Damage by inflammation leads to
fibrosis of the intraventricular septum causing conduction disturbances in up
to 30% of patient(11,12). Also atrioventricular nodal blood supply may be
impaired, contributing to these conduction disturbances(13). First-, second-,
and third-degree atrioventricular blocks appear to be common conduction
aberrations (14).

Cardiomyopathy - Systolic and diastolic dysfunction of the ventricles are both
found in AS patients, causing heart insufficiency and increase the risk for
stroke caused by arterial tromboembolism.(7,15,16). Left ventricular systolic
dysfunction is described less often than diastolic dysfunction (6,17).
Diastolic dysfunction is more relevant, as it preludes heart failure and is
seen in younger patients(18). Compared with systolic function, diastolic
function is difficult to define and therefore difficult to assess. Hence, most
studies use markers such as mitral inflow velocities (E and A waves)(19). The E
and A waves corresponds with early flow during LV relaxation and subsequent
contribution of atrial contraction, respectively. When diastolic function is
normal, E wave exceeds A wave. When relaxation is impaired, atrial contraction
contributes relatively more to ventricular filling (thus A>E). When LV
diastolic pressure increases to the point that atrial contraction contributes
little to filling, the E wave again becomes predominant, but with rapid
deceleration, first in a pseudo normal pattern and ultimately in a restrictive
pattern(20).

Atherosclerosis and AS
The inflammatory process also results in an increased atherosclerotic risk in
patients with AS, as it contributes to all stages of atherosclerosis.
Endothelial dysfunction, an early key event in atherosclerosis, is more evident
in AS patients than in healthy controls(21). Traditional CV risk factors such
as dyslipidemia, hypertension and smoking, are increased in AS, and may also
contribute to the atherosclerotic risk(3,22-26). Carotid intima media thickness
(cIMT) is a well established parameter for quantifying preclinical
atherosclerosis. A first meta-analysis of cIMTs revealed an increase in cIMT of
0.07 mm in 272 AS patients versus 195 matched controls, implying a 14%
increased cardiovascular risk(25).

Discussion
Some investigators advocate echocardiographic screening of every AS patient, to
find cardiac disease in an early stage, and adjusting treatment accordingly in
these patients(6). However, most studies only investigated limited number of
patients, and are contradictory in the observed prevalences of cardiac disease.
Moreover, the observed abnormalities varied. Therefore, the extent of these
cardiac diseases, and hence the necessity of routine echocardiographic
screening, is still not known. Studies with larger sample sizes are essential
to enable firm conclusions about cardiac manifestations in patients with AS.

Preparatory work
A systematic review of our group published in 2004 suggests an increased
cardiovascular risk in AS patients(27). Following this, a questionnaire-based
study in 593 AS patients was conducted, in which an increased prevalence of
myocardial infarction in comparison to the general population was
found[peters2010]. In a subsequent investigation we compared 59 AS patients
with controls and found that AS patients had a significantly increased cIMT
(0.62 ± 0.09mm) in comparison to the control subjects (0.57mm ± 0.09mm).
Finally, in a study of 15 AS patients and 12 controls we found that
TNF-blocking therapy improved the microvascular dysfunction and lipid profiles
in AS patients(28).

Hypothesis and objectives
Our primary goal is to investigate the prevalence of cardiac disease in AS
patients, based on the following hypothesis: the prevalence of cardiac disease,
such as valvular heart diseases, conduction disturbances and cardiomyopathies
in AS-patients is higher compared with patients without AS.

Methods
Echocardiography is an established non-invasive instrument to assess cardiac
function. In this study transthoracic echocardiography will be used for
assessment of left ventricular function and valvular heart disease. We will us
electrocardiography to screen for and investigate conduction disturbances.
We will screen AS patients between 50 and 75 years with cardiac echography and
electrocardiography. The primary outcome will be diastolic dysfunction.
Secondary outcomes will be to assess the prevalence of valvular heart diseases
and conduction disturbances, to assess cIMT thickness as a marker of
atherosclerosis and to assess left ventricular systolic function. As cardiac
disease is more prominent with older age, we will include subjects between 50
and 75 years and a matched control group will be included.
If cardiac abnormalities are found on TTE or ECG, we ask patients permission to
make a cardiac MRI. With a cardiac MRI we attempt to investigated the
pathogenesis of cardiac manifestations in AS patients. If a cardiac MRI is
made, we will draw one additional blood sample to assess hematocrit.

Primary objective:
To investigate left ventricular diastolic function in AS-patients compared with
osteoarthritis patients.

Secondary objectives:
To assess the prevalence of valvular heart diseases and conduction
disturbances.
To assess left ventricular systolic function.
To assess cIMT thickness

The study is cross sectional.

There are some aspects to this protocol that may cause (some) discomfort to the
subjects. First, the subjects have to remain fasted as indicated at the time of
blood collection and cIMT measurement. Second, the collection of blood may
cause some discomfort. Possible side effects from blood drawing include
faintness, inflammation of the vein, pain, bruising, or bleeding at the site of
puncture. There is also a slight possibility of infection. Third, during each
vascular measurement, namely IMT measurement and thoracic echography the
subject has to stay in a fixed position. Fourth, when measuring blood pressure,
the inflation of the cuff may cause transient paraesthesia in the hand.
Subjects have to visit the research centre one, two or three times. If possible
the visits will be combined.
In case of found abnormalities on ECG or TTE, we ask patients permission to
make a cardiac MRI. This cardiac MRI can be discomforting to the subjects.
First, patients have lay still in a fixed position for a prolonged period of
time in a small space. Second, a contrast fluid is used which has to be
administrated intravenously. This could cause faintness, inflammation of the
vein, pain, bruising, bleeding or infection at the site of puncture. If a
cardiac MRI is made, we will draw one additional blood sample to assess
hematocrit.