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JACC: HEART FAILURE
VOL. 3, NO. 11, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
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http://dx.doi.org/10.1016/j.jchf.2015.08.003
EDITORIAL COMMENT
Limiting Infarct Size in
ST-Segment Myocardial Infarction
The Holy Grail of Reperfusion Therapy*
Eric R. Bates, MD
A
cute thrombotic occlusion of a coronary ar-
device to reduce left ventricular wall stress before
tery usually produces myocardial ischemia
establishing myocardial reperfusion. Ten Yorkshire
that can result in myocardial infarction if
swine underwent 90-min balloon occlusion of the
reperfusion is not restored. Reperfusion injury from
mid left anterior descending artery: 5 were random-
reintroduction of blood and oxygen into the ischemic
ized to primary reperfusion for 120 min without me-
area at risk can result in additional myocyte cell death
chanical support before humane killing and 5 were
(1,2). Whereas early reperfusion therapy has been
treated with a left ventricular axial flow catheter
shown to reduce infarct size by decreasing ischemic
(Impella CP, Abiomed Inc., Danvers, Massachusetts)
injury time and results in lower morbidity and mor-
during an additional 60 min of ischemia time and
tality rates (3), little progress has been made in
during a similar 120-min reperfusion time before
decreasing the additional impact of reperfusion
humane killing. This swine model of ischemia–
injury on infarct size despite 3 decades of effort
reperfusion
(1,2,4). Although many interventions targeting reper-
experimental methodology to evaluate reperfusion
fusion injury have seemed promising in experimental
injury was uniquely sophisticated. Changes in left
studies, they have failed to reduce infarct size consis-
ventricular pressure–volume curves were assessed
tently or improve clinical outcome in clinical trials
using a conductance catheter system and left ven-
and have not been endorsed by clinical practice
tricular wall stress was evaluated by 3-dimensional
guideline committees as effective therapeutic strate-
echocardiography. Tissue protein levels were quan-
gies (5). Nevertheless, reperfusion injury is a popular
titated from sham-operated controls and infarct
pre-clinical research area and the enthusiasts remain
zones to measure cardioprotective signaling and
optimistic that a therapeutic breakthrough will even-
apoptosis
tually be achieved.
infarct size as a percent of left ventricular area were
injury
is
regulation.
well-established,
Apoptosis
and
but
the
myocardial
also measured.
SEE PAGE 873
As expected, the axial flow catheter reduced left
In this issue of JACC: Heart Failure, Kapur et al. (6)
ventricular wall stress and myocardial oxygen de-
evaluated the therapeutic benefit of mechanical pre-
mand. The authors demonstrated activation of a
conditioning on ischemic myocardium at risk for
“myocardial protection program” in the myocardial
infarction in a swine model of acute coronary occlu-
infarct zone with upregulation of a cardioprotective
sion
signaling system that decreased apoptosis and resul-
using
a
percutaneous
circulatory
support
ted in a 43% reduction in myocardial infarct size.
They concluded that mechanical preconditioning of
*Editorials published in JACC: Heart Failure reflect the views of the
the myocardium, despite an additional 1 hr of total
authors and do not necessarily represent the views of JACC: Heart Failure
ischemic time, may reduce infarct size and the sub-
or the American College of Cardiology.
From the Division of Cardiovascular Diseases, Department of Internal
Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
Dr. Bates has reported that he has no relationships relevant to the
contents of this paper to disclose.
sequent development of heart failure after STsegment elevation myocardial infarction (STEMI).
The authors are to be congratulated for conducting
an elegant pre-clinical physiology study and further
884
Bates
JACC: HEART FAILURE VOL. 3, NO. 11, 2015
NOVEMBER 2015:883–5
Limiting Infarct Size
elucidating an interesting molecular and cellular
1 h of symptom onset and that the mortality rate is
regulatory system. However, the clinical translation
only 1 percent if reperfusion is successful within this
of infarct size reduction with mechanical pre-
golden hour (9,10).
conditioning seen in this study is less obvious, espe-
Second, there are no compelling clinical data sup-
cially when one considers that the total ischemic time
porting the premise that left ventricular support de-
was relatively short by clinical standards and the
vices improve prognosis in STEMI. In the fibrinolytic
reduction in infarct size was quite large despite a
era of reperfusion, intra-aortic balloon pump (IABP)
longer ischemic time. Animal models are limited by
counterpulsation improved reperfusion rates and
the fact that abrupt balloon occlusion of a normal
decreased reocclusion rates during fibrinolysis, pre-
artery is different than thrombotic occlusion of an
sumably by augmenting diastolic coronary blood
inflamed atherosclerotic human artery with distal
flow. However, primary PCI with stenting and dual
embolization. Also, human infarct size is additionally
antiplatelet therapy produces high reperfusion rates
modulated by intermittent or persistent infarct artery
and low reocclusion rates, with no additional benefit
occlusion, collateral circulation, oxygen demand, and
gained with IABP counterpulsation in decreasing
microvascular reperfusion; and patients are hetero-
infarct size or mortality, even with cardiogenic shock
geneous, live in uncontrolled environments, have
(11,12). Nor is there any clinical evidence that higher
comorbidities, and are treated with medications that
systemic cardiac output, higher mean arterial pres-
may affect ischemic injury (4). In short, there are
sure, or lower pulmonary capillary wedge pressure
many conflicting clinical factors that might impact
obtained with the use of a percutaneous left ventric-
cardioprotective signaling pathways and make it very
ular support device improves clinical outcomes
difficult for a promising reperfusion injury therapy to
compared with IABP counterpulsation (13). Support
show
devices do increase bleeding complications, inflam-
clinical
benefit
outside
of
a
rigorously
controlled laboratory experiment, especially given
mation, and cost.
the success already achieved in decreasing the com-
So, although I applaud the investigators for con-
plications of myocardial ischemia with reperfusion
ducting an excellent pre-clinical study that demon-
therapy.
strates that left ventricular unloading activates
The theory behind the hypothesis of this study
cardioprotective signaling pathways in the infarct
that further reductions in ischemic time will not
zone that decrease infarct size in a large animal
improve clinical outcomes and that mechanical cir-
model,
culation can reduce infarct size are based on 2 major
conditioning with a percutaneous left ventricular
clinical assumptions that need to be challenged.
assist device will not translate into a successful
First, Kapur et al. (6) claim that recent data have
clinical strategy that reduces myocardial infarct
confirmed that “more rapid primary reperfusion does
size. Delaying reperfusion therapy for 1 h and
not improve clinical outcomes” in STEMI (6). The
routinely inserting an expensive percutaneous sup-
citation used to support the statement refers to a
port device before primary PCI is not a clinically
population-level analysis where recent decreases in
plausible strategy. Therefore, until the big break-
annual door-to-balloon time at the population level
through in reducing infarct size by decreasing
were not associated with a parallel decrease in mor-
reperfusion injury is attained, time to treatment
tality
(7).
However,
using
the
same
dataset,
will
I
would
remain
the
predict
most
that
mechanical
modifiable
variable
pre-
in
Nallamothu et al. demonstrated that shorter patient-
decreasing infarct size in STEMI. Current efforts to
specific
associated
decrease total ischemia time by earlier activation of
consistently at the individual level with lesser in-
emergency medical services, direct transport to a
hospital and 6-month mortality rates (8). The
hospital with PCI capability, prehospital activation of
discordance in the 2 analyses is explained by an
the
increasing mortality risk in the growing and changing
rapid performance of primary PCI remains the best
primary percutaneous coronary intervention (PCI)
strategy to decrease myocardial infarct size in
population that has resulted in the recent absence of
STEMI (14).
door-to-balloon
times
were
cardiac
catheterization
laboratory,
and
association between annual door-to-balloon time and
changes in mortality at the population level, despite
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
the consistent association between door-to-balloon
Eric R. Bates, CVC Cardiovascular Medicine, University
time and mortality at the patient level. In fact, it
of Michigan Medical Center, 1500 E. Medical Center
has been demonstrated that STEMI can be aborted
Drive, Ann Arbor, Michigan 48109-5869. E-mail: ebates
in 15% of patients if reperfusion is restored within
@umich.edu.
Bates
JACC: HEART FAILURE VOL. 3, NO. 11, 2015
NOVEMBER 2015:883–5
Limiting Infarct Size
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KEY WORDS myocardial infarct size,
myocardial infarction, reperfusion injury
885