Limiting Infarct Size in ST-Segment Myocardial Infarction

JACC: HEART FAILURE

VOL. 3, NO. 11, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER INC.

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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6. Kapur NK, Qiao X, Paruchuri V, et al. Mechanical pre-conditioning with acute circulatory support before reperfusion limits infarct size in acute myocardial infarction. J Am Coll Cardiol HF 2015;3: 873–82. 7. Menees DS, Peterson ED, Wang Y, et al. Doorto-balloon time and mortality among patients undergoing primary PCI. N Engl J Med 2013;369: 901–9. 8. Nallamothu BK, Normand SL, Wang Y, et al. Relation between door-to-balloon times and mortality after primary percutaneous coronary intervention over time: a retrospective study. Lancet 2015;385:1114–22.

10. Weaver WD, Cerqueira M, Hallstrom AP, et al. Prehospital-initiated vs hospital-initiated thrombolytic therapy. JAMA 1993;270:1211–6. 11. Patel MR, Smalling RW, Thiele H, et al. Intraaortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial. JAMA 2011;306:1329–37. 12. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287–96. 13. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J 2014;35:156–67.

9. Taher T, Fu Y, Wagner GS, et al. Aborted myocardial infarction in patients with ST-segment elevation: insights from the Assessment of the Safety and Efficacy of a New Thrombolytic

14. Bates ER, Jacobs AK. Time to treatment in patients with STEMI. N Engl J Med 2013:389–92.

Regimen-3 Trial Electrocardiographic substudy. J Am Coll Cardiol 2004;44:38–43.

KEY WORDS myocardial infarct size, myocardial infarction, reperfusion injury

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