Primary left ventricular unloading with delayed reperfusion in patients with anterior ST-elevation myocardial infarction: Rationale and design of the STEMI-DTU randomized pivotal trial.

BACKGROUND: Despite successful primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI), myocardial salvage is often suboptimal, resulting in large infarct size and increased rates of heart failure and mortality. Unloading of the left ventricle (LV) before primary PCI may reduce infarct size and improve prognosis. STUDY DESIGN AND OBJECTIVES: STEMI-DTU (NCT03947619) is a prospective, randomized, multicenter trial designed to compare mechanical LV unloading with the Impella CP device for 30 minutes prior to primary PCI to primary PCI alone without LV unloading. The trial aims to enroll approximately 668 subjects, with a potential sample size adaptation, with anterior STEMI with a primary end point of infarct size as a percent of LV mass evaluated by cardiac magnetic resonance at 3-5 days after PCI. The key secondary efficacy end point is a hierarchical composite of the 1-year rates of cardiovascular mortality, cardiogenic shock ≥24 hours after PCI, use of a surgical left ventricular assist device or heart transplant, heart failure, intra-cardiac defibrillator or chronic resynchronization therapy placement, and infarct size at 3 to 5 days post-PCI. The key secondary safety end point is Impella CP-related major bleeding or major vascular complications within 30 days. Clinical follow-up is planned for 5 years. CONCLUSIONS: STEMI-DTU is a large-scale, prospective, randomized trial evaluating whether mechanical unloading of the LV by the Impella CP prior to primary PCI reduces infarct size and improves prognosis in patients with STEMI compared to primary PCI alone without LV unloading.

Unloading the Left Ventricle Before Reperfusion in Patients With Anterior ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. METHODS: In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. RESULTS: All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53). CONCLUSIONS: We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270.

Left Ventricular Remodeling After Anterior-STEMI PCI: Imaging Observations in the Door-to-Unload (DTU) Pilot Trial.

OBJECTIVES: To determine the predictive value of cardiac magnetic resonance (CMR) and echocardiographic parameters on left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients without cardiogenic shock and treated with mechanical LV unloading followed by immediate or delayed percutaneous coronary intervention (PCI)-mediated reperfusion. BACKGROUND: In STEMI, infarct size (IS) directly correlates with major cardiovascular outcomes. Preclinical models demonstrate mechanical LV unloading before reperfusion reduces IS. The door-to-unload (DTU)-STEMI pilot trial evaluated the safety and feasibility of LV unloading and delayed reperfusion in patients with STEMI. METHODS: This multicenter, prospective, randomized, safety and feasibility trial evaluated patients with anterior STEMI randomized 1:1 to LV unloading with the Impella CP (Abiomed) followed by immediate reperfusion vs delayed reperfusion after 30 minutes of unloading. Patients were assessed by CMR at 3-5 days and 30 days post PCI. Echocardiographic evaluations were performed at 3-5 and 90 days post PCI. At 3-5 days post PCI, patients were compared based on IS as percentage of LV mass (group 1 ≤25%, group 2 >25%). Selection of IS threshold was performed post hoc. RESULTS: Fifty patients were enrolled from April 2017 to May 2018. At 90 days, group 1 (IS ≤25%) exhibited improved LV ejection fraction (from 53.1% to 58.9%; P=.001) and group 2 (IS >25%) demonstrated no improvement (from 37.6% to 39.1%; P=.55). LV end-diastolic volume and end-systolic volume were unchanged in group 1 and worsened in group 2. There was correlation between 3-5 day and 30-day CMR measurements of IS and 90-day echocardiography-derived LV ejection fraction. CONCLUSIONS: Immediate 3-5 day post-therapy IS by CMR correlates with 90-day echocardiographic LVEF and indices of remodeling. Patients with post-therapy IS >25% demonstrated evidence of adverse remodeling. Larger studies are needed to corroborate these findings with implications on patient management and prognosis.

Hysteretic device characteristics indicate cardiac contractile state for guiding mechanical circulatory support device use.

BACKGROUND: Acute heart failure and cardiogenic shock remain highly morbid conditions despite prompt medical therapy in critical care settings. Mechanical circulatory support (MCS) is a promising therapy for these patients, yet remains managed with open-loop control. Continuous measure of cardiac function would support and optimize MCS deployment and weaning. The nature of indwelling MCS provides a platform for attaining this information. This study investigates how hysteresis modeling derived from MCS device signals can be used to assess contractility changes to provide continuous indication of changing cardiac state. Load-dependent MCS devices vary their operation with cardiac state to yield a device-heart hysteretic interaction. Predicting and examining this hysteric relation provides insight into cardiac state and can be separated by cardiac cycle phases. Here, we demonstrate this by predicting hysteresis and using the systolic portion of the hysteresis loop to estimate changes in native contractility. This study quantified this measurement as the enclosed area of the systolic portion of the hysteresis loop and correlated it with other widely accepted contractility metrics in animal studies (n = 4) using acute interventions that alter inotropy, including a heart failure model. Clinical validation was performed in patients (n = 8) undergoing Impella support. RESULTS: Hysteresis is well estimated from device signals alone (r = 0.92, limits of agreement: - 0.18 to 0.18). Quantified systolic area was well correlated in animal studies with end-systolic pressure-volume relationship (r = 0.84), preload recruitable stroke work index (r = 0.77), and maximum slope of left ventricular pressure (dP/dtmax) (r = 0.95) across a range of inotropic conditions. Comparable results were seen in patients with dP/dtmax (r = 0.88). Diagnostic capability from ROC analysis yielded AUC measurements of 0.92 and 0.90 in animal and patients, respectively. CONCLUSIONS: Mechanical circulatory support hysteretic behavior can be well modeled using device signals and used to estimate contractility changes. Contractility estimate is correlated with other accepted metrics, captures temporal trends that elucidate changing cardiac state, and is able to accurately indicate changes in inotropy. Inherently available during MCS deployment, this measure will guide titration and inform need for further intervention.

Effects of a prolonged submersion on bone strength and metabolism in young healthy submariners.

Submariners taking part in prolonged missions are exposed to environmental factors that may adversely affect bone health. Among these, relatively high levels of CO(2), lack of sunlight exposure affecting vitamin D metabolism, limited physical activity, and altered dietary habits. The aims of this study were to examine the effect of a prolonged submersion (30 days) on changes in bone strength using quantitative bone speed of sound and in markers of bone metabolism that include bone turnover (BAP, PINP, TRAP5b, and CTx) and endocrine regulators (serum calcium, PTH, and 25[OH]D) in a group of 32 young healthy male submariners. The prolonged submersion led to increases in body weight and BMI and to a decrease in fitness level. There was a significant decrease in bone strength following the submersion. Speed of sound exhibited continued decline at 4 weeks after return to shore and returned to baseline levels at the 6-month follow-up. There was a significant increase in circulating calcium level. PTH and 25(OH)D levels decreased significantly. Significant decreases were observed in both TRAP5b and CTx levels, markers of bone resorption, as well as in N-terminal propeptide of type I collagen (PINP), a bone formation marker. Prolonged submersion led to a significant decrease in bone strength, accompanied by an overall decrease in bone metabolism. Bone strength was regained only 6 months after return to shore. Prevention and/or rehabilitation programs should be developed following periods of relative disuse even for young submariners. The effects of repeated prolonged submersions on bone health are yet to be determined.

Mechanical circulatory support device-heart hysteretic interaction can predict left ventricular end diastolic pressure.

The full potential of mechanical circulatory systems in the treatment of cardiogenic shock is impeded by the lack of accurate measures of cardiac function to guide clinicians in determining when to initiate and how to optimally titrate support. The left ventricular end diastolic pressure (LVEDP) is an established metric of cardiac function that refers to the pressure in the left ventricle at the end of ventricular filling and immediately before ventricular contraction. In clinical practice, LVEDP is typically only inferred from, and poorly correlates with, the pulmonary capillary wedge pressure (PCWP). We leveraged the position of an indwelling percutaneous ventricular assist device and advanced data analysis methods to obtain LVEDP from the hysteretic operating metrics of the device. We validated our hysteresis-derived LVEDP measurement using mock flow loops, an animal model of cardiac dysfunction, and data from a patient in cardiogenic shock to show greater measurement precision and correlation with actual pressures than traditional inferences via PCWP. Delineation of the nonlinear relationship between device and heart adds insight into the interaction between ventricular support devices and the native heart, paving the way for continuous assessment of underlying cardiac state, metrics of cardiac function, potential closed-loop automated control, and rational design of future innovations in mechanical circulatory support systems.

Underutilization of Coronary Artery Disease Testing Among Patients Hospitalized With New-Onset Heart Failure.

BACKGROUND: Although ischemic coronary artery disease (CAD) is the most common etiology of heart failure (HF), the extent to which patients with new-onset HF actually undergo an ischemic work-up and/or revascularization is not well defined. OBJECTIVES: This study sought to analyze the patterns of testing for ischemic CAD and revascularization in patients with new-onset HF. METHODS: This was a retrospective cohort study using Truven Health MarketScan Commercial and Medicare databases from 2010 to 2013. The occurrence of noninvasive and invasive ischemic CAD testing and revascularization procedures were examined among patients with new inpatient HF diagnoses during the index hospitalization and within 90 days of admission. RESULTS: Among 67,161 patients identified with new-onset HF during an inpatient hospitalization, only 17.5% underwent testing for ischemic CAD during the index hospitalization, increasing to 27.4% at 90 days. Among patients with new-onset HF, only 2.1% underwent revascularization during the index hospitalization for HF; by 90 days, the revascularization rate had increased to 4.3%. Of the tests performed for ischemic CAD, stress testing (nuclear stress testing or stress echocardiography) was performed in 7.9% of new-onset HF patients during the index hospitalization (14.6% within 90 days), whereas coronary angiography was performed in 11.1% of patients during the index hospitalization (16.5% within 90 days). In adjusted analyses, HF patients carrying a baseline diagnosis of CAD had greater odds of noninvasive ischemic testing (odds ratio: 1.25; 95% confidence interval: 1.17 to 1.33; p < 0.0001), as well as invasive ischemic testing (odds ratio: 1.93; 95% confidence interval: 1.83 to 2.05; p < 0.0001), at the index hospitalization than those without baseline CAD. CONCLUSIONS: The majority of patients hospitalized for new-onset HF did not receive testing for ischemic CAD either during hospitalization or within 90 days, which suggests significant underutilization of ischemic CAD assessment in new-onset HF patients.