Ischemic heart disease (IHD) is a significant cause of morbidity and mortality in Western society. Although interventions such as thrombolysis and percutaneous coronary intervention (PCI) have proven efficacious in ischemia and reperfusion (IR) injury, the underlying pathologic process of IHD, laboratory studies suggest further protection is possible, and an expansive research effort is aimed at bringing new therapeutic options to the clinic. Mitochondrial dysfunction plays a key role in the pathogenesis of IR injury and cardiomyopathy (CM). However, despite promising mitochondria-targeted drugs emerging from the lab, very few have successfully completed clinical trials. As such, the mitochondrion is a potential untapped target for new IHD and CM therapies. Notably, there are a number of overlapping therapies for both these diseases, and as such novel therapeutic options for one condition may find use in the other. This review summarizes efforts to date in targeting mitochondria for IHD and CM therapy, and outlines emerging drug targets in this field.
Key PointsQuestionIn critically ill adult patients undergoing tracheal intubation, does intravenous infusion of a crystalloid solution as a 500-mL fluid bolus decrease the incidence of severely low blood pressure, cardiac arrest, or death (referred to as cardiovascular collapse) during or shortly after the procedure?FindingsIn this randomized clinical trial that included 1065 critically ill adults, the incidence of cardiovascular collapse was 21.0% with administration of a fluid bolus vs 18.2% without administration of a fluid bolus, a difference that was not statistically significant.MeaningAmong critically ill adults undergoing tracheal intubation, administration of a fluid bolus did not significantly decrease the incidence of cardiovascular collapse.
Rationale Tissue ischemia/reperfusion (IR) injury underlies several leading causes of death such as heart-attack and stroke. The lack of clinical therapies for IR injury may be partly due to the difficulty of adapting IR injury models to high-throughput screening (HTS). Objective To develop a model of IR injury that is both physiologically relevant and amenable to HTS. Methods and Results A micro-plate based respirometry apparatus was used. Controlling gas flow in the plate head space, coupled with the instrument’s mechanical systems, yielded a 24 well model of IR injury in which H9c2 cardiomyocytes were transiently trapped in a small volume, rendering them ischemic. Following initial validation with known protective molecules, the model was used to screen a 2000 molecule library, with post IR cell death as an endpoint. pO2 and pH monitoring in each well also afforded metabolic data. Ten protective, detrimental and inert molecules from the screen were subsequently tested in a Langendorff perfused heart model of IR injury, revealing strong correlations between the screening endpoint and both recovery of cardiac function (negative r2=0.66), and infarct size (positive, r2=0.62). Relationships between the effects of added molecules on cellular bioenergetics, and protection against IR injury, were also studied. Conclusion This novel cell-based assay can predict either protective or detrimental effects on IR injury in the intact heart. Its application may help identify therapeutic or harmful molecules.
Background: The prevalence, characteristics, and outcomes related to the ventilator-associated event(s) (VAE) in neurocritically ill patients are unknown and examined in this study. Methods:A retrospective study was performed on neurocritically ill patients at a 413-bed level 1 trauma and stroke center who received three or more days of mechanical ventilation to describe rates of VAE, describe characteristics of patients with VAE, and examine the association of VAE on ventilator days, mortality, length of stay, and discharge to home.Results: Over a 5-year period from 2014 through 2018, 855 neurocritically ill patients requiring mechanical ventilation were identified. A total of 147 VAEs occurred in 130 (15.2%) patients with an overall VAE rate of 13 per 1000 ventilator days and occurred across age, sex, BMI, and admission Glasgow Coma Scores. The average time from the start of ventilation to a VAE was 5 (range 3-48) days after initiation of mechanical ventilation. Using Centers for Disease Control and Prevention definitions, VAEs met criteria for a ventilator-associated condition in 58% of events (n = 85), infection-related VAE in 22% of events (n = 33), and possible ventilator-associated pneumonia in 20% of events (n = 29). A most common trigger for VAE was an increase in positive end-expiratory pressure (84%). Presence of a VAE was associated with an increase in duration of mechanical ventilation (17.4[IQR 20.5] vs. 7.9[8.9] days, p < 0.001, 95% CI 7.86-13.92), intensive care unit (ICU) length of stay (20.2[1.1] vs. 12.5[0.4] days, p < 0.001 95% CI 5.3-10.02), but not associated with in-patient mortality (34.1 vs. 31.3%. 95% CI 0.76-1.69) or discharge to home (12.7% vs. 16.3%, 95% 0.47-1.29).Conclusions: VAE are prevalent in the neurocritically ill. They result in an increased duration of mechanical ventilation and ICU length of stay, but may not be associated with in-hospital mortality or discharge to home.
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