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Reducing myocardial infarct size: challenges and future opportunities.

ABSTRACT: Despite prompt reperfusion by primary percutaneous coronary intervention (PPCI), the mortality and morbidity of patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) remain significant with 9% death and 10% heart failure at 1?year. In these patients, one important neglected therapeutic target is 'myocardial reperfusion injury', a term given to the cardiomyocyte death and microvascular dysfunction which occurs on reperfusing ischaemic myocardium. A number of cardioprotective therapies (both mechanical and pharmacological), which are known to target myocardial reperfusion injury, have been shown to reduce myocardial infarct (MI) size in small proof-of-concept clinical studies-however, being able to demonstrate improved clinical outcomes has been elusive. In this article, we review the challenges facing clinical cardioprotection research, and highlight future therapies for reducing MI size and preventing heart failure in patients presenting with STEMI at risk of myocardial reperfusion injury.

SUBMITTER: Bulluck H

PROVIDER: S-EPMC4789695 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Reducing myocardial infarct size: challenges and future opportunities.

Bulluck Heerajnarain H Yellon Derek M DM Hausenloy Derek J DJ

Heart (British Cardiac Society) 20151216 5

Despite prompt reperfusion by primary percutaneous coronary intervention (PPCI), the mortality and morbidity of patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) remain significant with 9% death and 10% heart failure at 1 year. In these patients, one important neglected therapeutic target is 'myocardial reperfusion injury', a term given to the cardiomyocyte death and microvascular dysfunction which occurs on reperfusing ischaemic myocardium. A number of cardiop ...[more]

PMID: 26674987

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Project description:BackgroundPerfluoropropane droplets formulated from commercial microbubbles exhibit different acoustic characteristics than their parent microbubbles, most likely from enhanced endothelial permeability. This enhanced permeability may permit delayed echo-enhancement imaging (DEEI) similar to delayed enhancement magnetic resonance imaging (DE-MRI). We hypothesized this would allow detection and quantification of myocardial scar.MethodsIn 15 pigs undergoing 90 minutes of left anterior descending ischemia by either balloon (n = 13) or thrombotic occlusion (n = 2), DE-MRI was performed at 2-24 days postocclusion. Delayed echo-enhancement imaging was performed at 2-4 minutes following an intravenous injection of 1 mL of 50% Definity (Lantheus Medical) compressed into 180 nm droplets; DEEI was attempted in all pigs with single-pulse harmonic imaging at 1.7 transmit/3.4 MHz receive. Myocardial defects observed with DEEI were quantified (percentage of infarct area) and compared with DE-MRI as well as postmortem staining. In six pigs, multipulse low-mechanical index (MI) fundamental nonlinear imaging (FNLI) with intermittent high-MI impulses was performed to determine whether droplet activation within the infarct zone was achievable with a longer pulse duration.ResultsThe range of infarct size area by DE-MRI ranged from 0% to 46% of total left ventricular area. Single-pulse harmonic imaging detected a contrast defect that correlated closely with infarct area by DE-MRI (r = 0.81, P = .0001). The FNLI high-MI impulses resulted in droplet activation in both the infarct and normal zones. Harmonic subtraction of the FNLI images resulted in infarct zone enhancement that also correlated closely with infarct size (r = 0.83; P = .04). Droplets were observed on postmortem transmission electron microscopy within myocytes of the infarct and remote normal zone.ConclusionIntravenously Definity nanodroplets can be utilized to detect and quantify infarct zone at the bedside using DEEI techniques.

Project description:BackgroundMedical training through specialization and even subspecialization has contributed significantly to clinical excellence in treating single acute conditions. However, the needs of complex patients go beyond single diseases, and there is a need to identify a group of generalists who are able to deliver cost-effective, holistic care to patients with multiple comorbidities and multi-faceted needs. Community hospitals (CHs) are a critical part of Singapore's shift toward a community-centric care model as the population ages. Community Hospitals of the Future ("CHoF") represent a series of emerging conversations around approaches to reimagine and redesign care delivery in a CH setting in response to changing care needs.MethodsAn environmental scan in the CH landscape using semi-structured interviews was conducted with 26 senior management, management, and working-level staff from seven community hospitals in Singapore. This environmental scan aims to understand the current barriers and future opportunities for CHs; to guide how CHs would have to shift in terms of (i) care delivery and resourcing, (ii) information flow, and (iii) financing; and to conceptualize CHoF to meet the changing care needs in Singapore.FindingsThe analysis of all transcripts revealed four broad sections of themes: (i) current care delivery in CHs, (ii) current challenges of CHs, (iii) future opportunities, and (iv) challenges in reimagining CHs. An emerging theme regarding the current key performance indicators used also surfaced. Resource limitations and financing structure of CH surfaced as limitations to expanding its capability. However, room for expansion of CH roles tapping on the current expertise were acknowledged and shared.ConclusionWith the current issues of (i) rapidly aging population, (ii) specialist-centric healthcare system, and (iii) fragmentation of care ecosystem, there is a need to further understand how CHoF can be modeled to better tackle them. Therefore, several important questions have been devised to land us in a microscopic view on how to develop CHoF in the right constructs. Demographic changes, patient segmentation, service and regulatory parameters, patient's perspective, care delivery, and financial levers (or lack of) are some of the categories that the interview questions looked into. Therefore, the data gathered would be used to guide and refine the concept of CHoF.

Project description:RationaleMetformin has been demonstrated to decrease infarct size (IS) and prevent postinfarction left ventricular (LV) remodeling in rodents when given intravenously at the time of reperfusion. It remains unclear whether similar cardioprotection can be achieved in a large animal model.ObjectiveThe objective of this study was to determine whether intravascular infusion of metformin at the time of reperfusion reduces myocardial IS in a porcine model of acute myocardial infarction.Methods and resultsIn a blinded and randomized preclinical study, closed-chest swine (n=20) were subjected to a 60-minute left anterior descending coronary artery occlusion to produce myocardial infarction. Contrast-enhanced computed tomography was performed during left anterior descending coronary artery occlusion to assess the ischemic area-at-risk. Animals were randomized to receive either metformin or vehicle as an initial intravenous bolus (5 mg/kg) 8 minutes before reperfusion, followed by a 15-minute left coronary artery infusion (1 mg/kg per minute) commencing with the onset of reperfusion. Echocardiography and computed tomographic imaging of LV function were performed 1 week later, at which time the heart was removed for postmortem pathological analysis of area-at-risk and IS (triphenyltetrazolium chloride). Baseline variables including hemodynamics and LV function were similar between groups. Peak circulating metformin concentrations of 374±35 µmol/L were achieved 15 minutes after reperfusion. There was no difference between the area-at-risk as a percent of LV mass by computed tomography (vehicle: 20.7%±1.1% versus metformin: 19.7%±1.3%; P=0.59) or postmortem pathology (22.4%±1.2% versus 20.2%±1.2%; P=0.21). IS relative to area-at-risk averaged 44.5%±5.0% in vehicle-treated versus 38.2%±6.8% in metformin-treated animals ( P=0.46). There was no difference in global function 7 days after myocardial infarction as assessed by echocardiography or computed tomographic ejection fraction (56.2%±2.6% versus 56.3%±2.4%; P=0.98).ConclusionsIn contrast to rodent hearts, postconditioning with high-dose metformin administered immediately before reperfusion does not reduce IS or improve LV function 7 days after myocardial infarction in swine. These results reinforce the importance of rigorously testing therapies in large animal models to facilitate clinical translation of novel cardioprotective therapies.

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Reducing myocardial infarct size: challenges and future opportunities.

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Reducing myocardial infarct size: challenges and future opportunities.

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