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Beyond Reperfusion: Acute Ventricular Unloading and Cardioprotection During Myocardial Infarction.

ABSTRACT: Heart failure is a major cause of morbidity and mortality around the world, and myocardial infarction is its leading cause. Myocardial infarction destroys viable myocardium, and this dead tissue is replaced by a non-contractile scar that results in impaired cardiac function and a significantly increased likelihood of the patient developing heart failure. Limiting infarct scar size has been the target of pre-clinical and clinical investigations for decades. However, beyond reperfusion, few therapies have translated into the clinic that limit its formation. New approaches are needed. This review will focus on new clinical and pre-clinical data demonstrating that acute ventricular unloading prior to reperfusion by means of percutaneous left ventricular support devices reduces ischemia-reperfusion injury and limits infarct scar size. Emphasis will be given to summarizing our current mechanistic understanding of this new therapeutic approach to treating myocardial infarction.

SUBMITTER: Curran J

PROVIDER: S-EPMC6497619 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Beyond Reperfusion: Acute Ventricular Unloading and Cardioprotection During Myocardial Infarction.

Curran Jerry J Burkhoff Daniel D Kloner Robert A RA

Journal of cardiovascular translational research 20190122 2

Heart failure is a major cause of morbidity and mortality around the world, and myocardial infarction is its leading cause. Myocardial infarction destroys viable myocardium, and this dead tissue is replaced by a non-contractile scar that results in impaired cardiac function and a significantly increased likelihood of the patient developing heart failure. Limiting infarct scar size has been the target of pre-clinical and clinical investigations for decades. However, beyond reperfusion, few therap ...[more]

PMID: 30671717

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Project description:BackgroundMyocardial 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.ObjectivesGiven 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.MethodsTo 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.ResultsThe 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.ConclusionsThese novel findings identify that transvalvular unloading limits ischemic injury before reperfusion, improves myocardial energy substrate use, and preserves mitochondrial structure and function after reperfusion.

Project description:BACKGROUND:Heart failure after an acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. We recently reported that activation of a transvalvular axial-flow pump in the left ventricle and delaying myocardial reperfusion, known as primary unloading, limits infarct size after AMI. The mechanisms underlying the cardioprotective benefit of primary unloading and whether the acute decrease in infarct size results in a durable reduction in LV scar and improves cardiac function remain unknown. OBJECTIVES:This study tested the importance of LV unloading before reperfusion, explored cardioprotective mechanisms, and determined the late-term impact of primary unloading on myocardial function. METHODS:Adult male swine were subjected to primary reperfusion or primary unloading after 90 min of percutaneous left anterior descending artery occlusion. RESULTS:Compared with primary reperfusion, 30 min of LV unloading was necessary and sufficient before reperfusion to limit infarct size 28 days after AMI. Compared with primary reperfusion, primary unloading increased expression of genes associated with cellular respiration and mitochondrial integrity within the infarct zone. Primary unloading for 30 min further reduced activity levels of proteases known to degrade the cardioprotective cytokine, stromal-derived factor (SDF)-1?, thereby increasing SDF-1? signaling via reperfusion injury salvage kinases, which limits apoptosis within the infarct zone. Inhibiting SDF-1? activity attenuated the cardioprotective effect of primary unloading. Twenty-eight days after AMI, primary unloading reduced LV scar size, improved cardiac function, and limited expression of biomarkers associated with heart failure and maladaptive remodeling. CONCLUSIONS:The authors report for the first time that first mechanically reducing LV work before coronary reperfusion with a transvalvular pump is necessary and sufficient to reduce infarct size and to activate a cardioprotective program that includes enhanced SDF-1? activity. Primary unloading further improved LV scar size and cardiac function 28 days after AMI.

Dataset Information

Beyond Reperfusion: Acute Ventricular Unloading and Cardioprotection During Myocardial Infarction.

Publications

Beyond Reperfusion: Acute Ventricular Unloading and Cardioprotection During Myocardial Infarction.

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