From bedside to bench and back again: translational studies of mechanical unloading of the left ventricle to promote recovery after acute myocardial infarction [version 1; referees: 2 approved]

Heart failure is a major cause of global morbidity and mortality. Acute myocardial infarction (AMI) is a primary cause of heart failure due in large part to residual myocardial damage despite timely reperfusion therapy. Since the 1970’s, multiple preclinical laboratories have tested whether reducing myocardial oxygen demand with a mechanical support pump can reduce infarct size in AMI. In the past decade, this hypothesis has been studied using contemporary circulatory support pumps. We will review the most recent series of preclinical studies in the field which led to the recently completed Door to Unload ST-segment Elevation Myocardial Infarction (DTU-STEMI) safety and feasibility pilot trial

Mechanical Left Ventricular Unloading to Reduce Infarct Size During Acute Myocardial Infarction: Insight from Preclinical and Clinical Studies

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality. Pioneering preclinical work reported by Peter Maroko and Eugene Braunwald in 1971 identified oxygen supply and demand are primary determinants of myocardial infarct size in the setting of a heart attack. Since the 1950s, advances in mechanical engineering led to the development of short-term circulatory support devices that range from pulsatile to continuous flow pumps. The primary objective of these pumps is to reduce native heart work, enhance coronary blood flow, and sustain systemic perfusion. Whether these pumps could reduce myocardial infarct size in the setting of AMI became an intense focus for preclinical investigation with variable animal models, experimental algorithms, and pump platforms being tested. In this review, we discuss the design of these preclinical studies and the evolution of mechanical support platforms and attempt to translate these experimental methods into clinical trials.status: publishe

Transvalvular Ventricular Unloading Before Reperfusion in Acute Myocardial Infarction

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