Examination of (handgrip) exercise to triggers coronary vasoconstriction in patients who are referred for a coronary function test

Patients with angina symptoms and no obstructive coronary artery disease
(ANOCA) pose a diagnostic and therapeutic challenge.
Up to 40% of patients undergoing a coronary angiogram for symptoms/signs of
ischemia (such as angina/chest pain) do not have obstructive atherosclerotic
coronary artery disease (CAD). However, angiography only concentrates on fixed
atherosclerotic disease in the epicardial vessels. In about half of the 40% of
patients without obstructive CAD, the mechanism underlying cardiac ischemia is
coronary vasomotor dysfunction. In coronary vasomotor dysfunction, ischemia is
caused by impaired coronary blood flow because of impaired endothelial and/or
non-endothelial coronary vasoreactivity resulting in the coronary epicardial or
microvasculature not dilating properly or even becoming vasospastic. We have
previously shown that the majority of patients with coronary vasomotor
dysfunction have vasospastic (epicardial and/or microvascular vasospasm)
angina, while a smaller part have co-existing or isolated microvascular
dysfunction. Furthermore, we have shown that vasospastic angina is associated
with underlying atherosclerotic disease as assessed by intracoronary imaging
(submitted).

Patients with vasomotor dysfunction often have episodes of chest pain leading
to frequent first aid visits and hospital admissions with associated high
health care costs. Moreover, it is associated with a worsened cardiovascular
prognosis. Patients are at an increased risk for long-term coronary ischemic
events. Therefore, in order to reduce complaints and health care costs, and
improve prognosis; and increased understanding of the underlying
pathophysiology, and subsequent adequate diagnosis and treatment are of
paramount importance.

With regards to coronary artery vasospasm, including the vasomotor dysfunction
endotypes epicardial and microvascular spasm, the abnormal coronary artery
responses, including increase of coronary vasomotor tone. This may occur
either in response to drugs, toxins or through (patho)physiological stimuli
including exercise.

During exercise sympathetic activity is increased which causes dilatation of
coronary vessels and thus an increase in myocardial blood flow. In this process
cardiac efferent adrenergic signals and release of various hormones play an
pivotal role. How the activation occurs exactly is not determined yet. In
patients with (partial) denudation of the endothelial layer coronary spasm
might occur. Accordingly, patients with suspected ANOCA may demonstrate
abnormal, vasoconstrictive responses of the coronary arteries to exercise
stimuli. Sueda et al. demonstrated that a third of patients with coronary
spastic angina had a positive treadmill exercise test. This might alternatively
be explained by non-spasm microvascular dysfunction, requiring different
treatment. This indicates that exercise might induce coronary spasm. However in
these patients only electrocardiogram and complaints were monitored. Also local
handgrip exercise, when performed at high intensity, is capable of activating
the sympathetic nervous system. Accordingly, also intensive local handgrip
exercise may provoke abnormal coronary artery responses. To our knowledge no
study yet have demonstrated epicardial spasm on angiography due to handgrip
exercise.

Hypothesis: We expect that high intensity handgrip exercise is a trigger for
epicardial and microvascular spasm in patients who have epicardial or
microvascular spasm during acetylcholine provocation test.

Main research question:
Does (handgrip) exercise provoke vasoconstrictive responses of the coronary
arteries in patients with suspected ANOCA with clinically indicated coronary
function test including acetylcholine provocation test?

Secondary objective, to explore whether handgrip exercise provokes coronary
spasm in patients with a normal acetylcholine response.

This is a prospective pilot study aiming to determine whether handgrip exercise
has coronary vasoconstrictive response in patients with proven coronary
epicardial spasm, as assessed by intracoronary acetylcholine provocation
testing.
The study protocol will add 5 minutes handgrip exercise to a standard invasive
investigation as described below.
Thirty patients will be included who have been planned for clinically indicated
invasive coronary vasoreactivity testing. This includes coronary angiography
(including 6 to 10 angiograms), acetylcholine spasm provocation testing
(including 5 angiograms), and thermodilution based assessment of coronary
microvascular dysfunction.
First, angiography will be performed to evaluate whether coronary obstruction
is present, if not, acetylcholine provocation testing and coronary physiology
measurements will be performed. Then the patients will perform 5 minute
handgrip exercise to evaluate exercise induced coronary spasm with two
additional angiograms (1 after the exercise and 1 after nitroglycerine if spasm
occurs).
Each week the Radboud university medical center performs 3 to 4 coronary
function tests CRT procedures. Considering a consent rate of 75% 3 study
procedures can be performed each week. Indicating an approximate study duration
of 10 weeks. There is no follow up connected to the study.

Number of subjects - This is a pilot study aiming to give a first indication of
the effect of exercise on coronary vasospasm. There is no sample size
calculation possible at this stage. We expect a maximum of 3 patients to drop
out during the assessments, based on a 90% completion rate.

Variables - The primary outcome is the presence of epicardial vasoconstriction
after handgrip test, as determined by angiography / electrocardiogram and
complaints.

There are no major risks associated with participation in the study for
patients in the short or long term. Patients will only be exposed to additional
X-rays due to one or two additional recordings of the left coronary artery,
depending on whether nitroglycerin will be administered. Furthermore, the
hospital visit will be extended by five minutes for the patients, which will
not give a drastic change to their day.