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

PHD2 is a regulator for glycolytic reprogramming in macrophages

The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM). Both showed typical features of anaerobic glycolysis, which were paralleled by increased pyruvate dehydrogenase kinase 1 (PDK1) protein levels and a decreased pyruvate dehydrogenase enzyme activity. Metabolic alterations were associated with an impaired cellular functionality. Inhibition of PDK1 or knockout of hypoxia-inducible factor 1α (HIF-1α) reversed the metabolic phenotype and impaired the functionality of the PHD2-deficient RAW cells and BMDM. Taking these results together, we identified a critical role of PHD2 for a reversible glycolytic reprogramming in macrophages with a direct impact on their function. We suggest that PHD2 serves as an adjustable switch to control macrophage behavior

TCT-812 Modified SCAI Classification for Cardiogenic Shock Is Associated With Increasing In-Hospital Mortality: A Report From the Cardiogenic Shock Working Group Registry

Background Cardiogenic shock (CS) mortality remains prohibitively high. A major limitation has been the lack of registry data available for analysis. The National Cardiogenic Shock Working Group Registry (NCSWGR) is a multicenter retrospective database of patients with CS. We now provide an interim update on the registry and tested whether a modified version of the recent SCAI shock classification (Figure) is associated with in-hospital mortality. Methods We performed an analysis of the NCSWGR from 2017 to 2019. SCAI shock classifications were used. Class C and D shock patients were subdivided into 2 groups. Class C1 did not require any pressors or device therapy. Class C2 required 1 device or drug intervention. Class D1 required \u3e1 drug but no device therapy. Class D2 required \u3e1 drug and device therapy or multiple devices. Results The NCSWGR contains data from 1,565 patients with CS obtained from 8 medical centers across the United States. CS was managed without device therapy (14%), intra-aortic balloon pump (IABP) alone (27%), Impella alone or in combination with IABP (21%), venoarterial extracorporeal membrane oxygenation (ECMO) alone or in combination with either IABP or Impella (16%), or other combination of drug or device therapy (22%). SCAI class distribution was 4% class A or B, 7% class C1, 24% class C2, 4% class D1, and 61% class D2. Patients in class E were excluded. In-hospital mortality increased according to SCAI class (Figure). Conclusion We report data from the largest retrospective multicenter registry of CS inclusive of hemodynamic variables. Our findings suggest that a modified version of the SCAI shock classifications may correlate with in-hospital mortality

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