SELECTIVE INTRACORONARY HYPOTHERMIA IN PATIENTS WITH ST-ELEVATION MYOCARDIAL INFARCTION TO REDUCE INFARCT SIZE

In acute myocardial infarction, early restoration of epicardial and myocardial
blood flow is of paramount importance to limit infarction size and create
optimum conditions for favourable long-term outcome.
Currently, restoration of epicardial blood flow is preferably and effectively
obtained by primary percutaneous coronary intervention (PPCI). After opening
the occluded artery, however, the reperfusion process itself causes damage to
the myocardium, the so called *reperfusion injury*[6,7]. The phenomenon of
reperfusion injury is incompletely understood and currently there is no
established therapy for preventing it. Contributory factors are intramyocardial
edema with compression of the microvasculature, oxidative stress, calcium
overload, mitochondrial transition pore opening, micro embolization, neutrophil
plugging and hyper contracture. This results in myocardial stunning,
reperfusion arrhythmias and ongoing myocardial necrosis.
There is general agreement that a large part of the cell death caused by
myocardial reperfusion injury occurs during the first few minutes of
reperfusion, and that early treatment is required to prevent it.
Myocardial hypothermia may attenuate the pathological mechanisms mentioned
above. However, limited data are available on the beneficial effects of
hypothermia to protect the myocardium from reperfusion damage. In animals,
several studies demonstrated a protective effect of hypothermia on the
infarction area. This effect was only noted when hypothermia was established
before reperfusion. Hypothermia is therefore thought to attenuate several
damaging acute reperfusion processes such as oxidative stress, release of
cytokines and development of interstitial or cellular edema. Furthermore, it
has been shown that induced hypothermia resulted in increased ATP-preservation
in the ischemic myocardium compared to normothermia.
The intracoronary use of hypothermia by infused cold saline in pigs was
demonstrated to be safe by Otake et al[9]. In their study, saline of 4°C was
used without complications (such as vasospasm, hemodynamic instability or
bradycardia) and it even attenuated ventricular arrhythmia significantly.
Studies in humans, however, have not been able to confirm this effect, which is
believed to be mainly due to the fact that the therapeutic temperature could
not reached before reperfusion in the majority of patients or not achieved at
all. Furthermore, in these studies it was intended to induce total body
hypothermia, which in turn may lead to systemic reactions such as shivering and
enhanced adrenergic state often requiring sedatives, which may necessitate
artificial ventilation.

In fact, up to now any attempt to achieve therapeutic myocardial hypothermia in
humans with myocardial infarction, is fundamentally limited because of four
reasons:
1. Inability to cool the myocardium timely, i.e. before reperfusion
2. Inability to cool the diseased myocardium selectively
3. Inability to achieve an adequate decrease of temperature quick enough (i.e.
within minutes)
4. Inability to achieve an adequate decrease of temperature large enough (at
least 4°C below body temperature)

Consequently, every attempt to achieve effective hypothermia in ST-segment
myocardial infarction in humans has been severely hampered and was inadequate.

In the last two years, we have developed a methodology overcoming all of the
limitations mentioned above. At first, we have tested that methodology in
isolated beating pig hearts with coronary artery occlusion and next, we have
tested the safety and feasibility of this methodology in humans.
Therefore, the time has come to perform a proof-of-principle study in humans,
which is the subject of this protocol.

To evaluate the effectiveness of selective intracoronary hypothermia in
patients with anterior wall ST-elevation myocardial infarction to limit
reperfusion injury and to limit infarct size.

Patients will be randomized in a 1:1 fashion to either routine PPCI (control
group) or intra-coronary cooling (intervention group).

Additional procedures for the study in the intervention group
1) A normal pressure wire temperature will be positioned in the distal coronary
artery
2) Hypothermia is started during 10 min (induction phase).
3) Deflation of the balloon after 10 min of hypothermia while the cooling
continues.
4) Then the normal PCI is performed according the normal procedure.

ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The initial procedure will be the emergent coronary angiography identical to
the first part of a regular PPCI and implantation of stents. There are no
additional associated risks with that part of the procedure.
In patients eligible for the study and assigned to the hypothermia group, the
equipment and drugs used are not different from the standard equipment.
The procedure is prolonged by approximately 20 minutes, but the Ischemic time
is only prolonged by 10 minutes, thereby hypothesizing that this does not
significantly affects infarct size, especially with the potentially protective
effects of hypothermia in mind.
In the safety and feasibility study which has been performed in humans, no
adverse effects of the cooling were observed in anterior wall infarctions. In
none of the patients unexpected side effects such as hemodynamically
instability or arrhythmias were noted during the intracoronary hypothermia.
Finally and importantly, in the Catharina Hospital, except from the safety and
feasibility study for the hypothermia in STEMI patients, we have extensive
experience with saline infusion at room temperature in stable patients (n=53)
and patients with acute myocardial infarction (n=20).
The third phase of the procedure (i.e. placing the stent) and the further
treatment of the patients is not different from normal routine.