Original Investigation
Transvalvular Ventricular Unloading Before Reperfusion in Acute Myocardial Infarction

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Abstract

Background

Myocardial damage due to acute ST-segment elevation myocardial infarction (STEMI) remains a significant global health problem. New approaches to limit myocardial infarct size and reduce progression to heart failure after STEMI are needed. Mechanically reducing left ventricular (LV) workload (LV unloading) before coronary reperfusion is emerging as a potential approach to reduce infarct size.

Objectives

Given the central importance of mitochondria in reperfusion injury, we hypothesized that compared with immediate reperfusion (IR), LV unloading before reperfusion improves myocardial energy substrate use and preserves mitochondrial structure and function.

Methods

To explore the effect of LV unloading duration on infarct size, we analyzed data from the STEMI-Door to Unload (STEMI-DTU) trial and then tested the effect of LV unloading on ischemia and reperfusion injury, cardiac metabolism, and mitochondrial function in swine models of acute myocardial infarction.

Results

The duration of LV unloading before reperfusion was inversely associated with infarct size in patients with large anterior STEMI. In preclinical models, LV unloading reduced the expression of hypoxia-sensitive proteins and myocardial damage due to ischemia alone. LV unloading with a transvalvular pump (TV-P) but not with venoarterial extracorporeal membrane oxygenation (ECMO) reduced infarct size. Using unbiased and blinded metabolic profiling, TV-P improved myocardial energy substrate use and preserved mitochondrial structure including cardiolipin content after reperfusion compared with IR or ECMO. Functional testing in mitochondria isolated from the infarct zone showed an intact mitochondrial structure including cardiolipin content, preserved activity of the electron transport chain including mitochondrial complex I, and reduced oxidative stress with TV-P–supported reperfusion but not with IR or ECMO.

Conclusions

These novel findings identify that transvalvular unloading limits ischemic injury before reperfusion, improves myocardial energy substrate use, and preserves mitochondrial structure and function after reperfusion.

Key Words

acute myocardial infarction
cardioprotection
circulatory support
mitochondria

Abbreviations and Acronyms

ATP
adenosine triphosphate
CI
mitochondrial complex I
CMR
cardiac magnetic resonance
ECMO
extracorporeal membrane oxygenation
ETC
electron transport chain
HIF-1α
hypoxia-inducible factor 1-alpha
IMM
inner mitochondrial membrane
IR
immediate reperfusion
LAD
left anterior descending
LV
left ventricular
PHD
prolyl hydroxylase domain
ROS
reactive oxygen species
STE
ST-segment elevation
STEMI
ST-segment elevation myocardial infarction
TV-P
transvalvular pump
U-DR
unloading and delayed reperfusion
U-IR
unloading and immediate reperfusion

Cited by (0)

This work was supported by a grant from the National Institutes of Health (R01HL139785-01 and R01HL133215-01) to Dr. Kapur and from Abiomed Inc. to Tufts Medical Center. Dr. Kapur has received institutional grant support and speaker/consulting honoraria from Abbott, Abiomed, Boston Scientific, LivaNova, Medtronic, MD Start, and Precardia. Dr. O’Neill has received consulting fees from Edwards and Abiomed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.

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