Background Emerging evidence suggests that ‘adaptive’ induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction. Methods and Results Anesthetized pigs underwent 45 min of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS: an agent that purportedly up-regulates autophagy; 20 mg/kg) or saline at 10 min before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 min following CAPS treatment and assayed (by immunoblotting) for two proteins involved in autophagomsome formation: Beclin-1 and light chain (LC) 3B-II. To investigate whether the efficacy of CAPS was maintained with ‘delayed’ treatment, additional pigs received CAPS (20 mg/kg) at 30 min post-occlusion. Expression of Beclin-1 and LC3B-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5% and 41±4% in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline-controls (p<0.01 and p<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins. Conclusion Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS, and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.
Introduction The homeostatic intracellular repair response (HIR2) is an endogenous beneficial pathway that eliminates damaged mitochondria and dysfunctional proteins in response to stress. The underlying mechanism is adaptive autophagy. The purpose of this study was to determine whether the HIR2 response is activated in the heart in patients undergoing cardiac surgery and to assess whether it is associated with the duration of ischemic arrest and predicted surgical outcome. Methods Autophagy was assessed in 19 patients undergoing coronary artery bypass or valve surgery requiring cardiopulmonary bypass (CPB). Biopsies of the right atrial appendage obtained before initiation of CPB and after weaning from CPB were analyzed for autophagy by immunoblotting for LC3, Beclin-1, Atg5-12, and p62. Changes in p62, a marker of autophagic flux, were correlated with duration of ischemia and with the mortality/morbidity risk scores obtained from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (v2.73). Results Heart surgery was associated with a robust increase in autophagic flux indicated by depletion of LC3-I, LC3-II, Beclin-1, and Atg5-12; the magnitude of change for each of these factors correlated significantly with changes in the flux marker p62. Moreover, changes in p62 correlated directly with cross clamp time and inversely with the mortality/morbidity risk scores. Conclusion These findings are consistent with preclinical studies indicating that HIR2 is cardioprotective, and reveal that it is activated in patients in response to myocardial ischemic stress. Strategies designed to amplify HIR2 during conditions of cardiac stress may have therapeutic utility and represent an entirely new approach to myocardial protection in patients undergoing heart surgery.
ImportanceCancer screening deficits during the first year of the COVID-19 pandemic were found to persist into 2021. Cancer-related deaths over the next decade are projected to increase if these deficits are not addressed.ObjectiveTo assess whether participation in a nationwide quality improvement (QI) collaborative, Return-to-Screening, was associated with restoration of cancer screening.Design, Setting, and ParticipantsAccredited cancer programs electively enrolled in this QI study. Project-specific targets were established on the basis of differences in mean monthly screening test volumes (MTVs) between representative prepandemic (September 2019 and January 2020) and pandemic (September 2020 and January 2021) periods to restore prepandemic volumes and achieve a minimum of 10% increase in MTV. Local QI teams implemented evidence-based screening interventions from June to November 2021 (intervention period), iteratively adjusting interventions according to their MTVs and target. Interrupted time series analyses was used to identify the intervention effect. Data analysis was performed from January to April 2022.ExposuresCollaborative QI support included provision of a Return-to-Screening plan-do-study-act protocol, evidence-based screening interventions, QI education, programmatic coordination, and calculation of screening deficits and targets.Main Outcomes and MeasuresThe primary outcome was the proportion of QI projects reaching target MTV and counterfactual differences in the aggregate number of screening tests across time periods.ResultsOf 859 cancer screening QI projects (452 for breast cancer, 134 for colorectal cancer, 244 for lung cancer, and 29 for cervical cancer) conducted by 786 accredited cancer programs, 676 projects (79%) reached their target MTV. There were no hospital characteristics associated with increased likelihood of reaching target MTV except for disease site (lung vs breast, odds ratio, 2.8; 95% CI, 1.7 to 4.7). During the preintervention period (April to May 2021), there was a decrease in the mean MTV (slope, −13.1 tests per month; 95% CI, −23.1 to −3.2 tests per month). Interventions were associated with a significant immediate (slope, 101.0 tests per month; 95% CI, 49.1 to 153.0 tests per month) and sustained (slope, 36.3 tests per month; 95% CI, 5.3 to 67.3 tests per month) increase in MTVs relative to the preintervention trends. Additional screening tests were performed during the intervention period compared with the prepandemic period (170 748 tests), the pandemic period (210 450 tests), and the preintervention period (722 427 tests).Conclusions and RelevanceIn this QI study, participation in a national Return-to-Screening collaborative with a multifaceted QI intervention was associated with improvements in cancer screening. Future collaborative QI endeavors leveraging accreditation infrastructure may help address other gaps in cancer care.
Intracardiac myxomas have traditionally been divided into solid ovoid and soft papillary types based on a morphological appearance. Papillary myxomas given their friable nature are far more likely to cause embolic phenomenon and present with neurological symptoms, making it necessary to discriminate between these tumor subtypes. Papillary myxomas have also been demonstrated to be significantly less vascular than their ovoid counterparts in previous angiographic studies. We describe here for the first time, the application of transesophageal real time myocardial contrast echocardiography in a case of atrial papillary myxoma to assess tumor vascularity. (Echocardiography 2010;27:E46-E49).
Autophagy is an endogenous survival mechanism and adaptive response to cellular stress. We hypothesized that autophagy plays an important cardioprotective role in humans and would be accelerated during the ischemic stress of conventional heart surgery. In a prospective study to test this hypothesis, we measured key autophagy proteins (Beclin-1, Atg5-12, p62) in cardiac tissue from 5 patients undergoing cardiac surgery. Right atrial biopsies were obtained before and after cessation of cardiopulmonary bypass (CPB). In 4 of these patients, CPB was associated with a marked decrease in cardiac Beclin-1, Atg5-12, and p62. We believe that depletion of these factors, particularly p62, reflects a brisk increase in autophagic flux (Fig. 1). In one patient (#02), autophagic flux appeared to be impaired. This occurred in an aged patient with characteristics of metabolic syndrome (MetS) who had the highest predicted operative morbidity/mortality. While the number of patients studied is small and insufficient to reach any definitive conclusions, these preliminary data confirm the feasibility of studying autophagy in the human heart and suggest that ischemic stress during heart surgery is associated with a marked upregulation of autophagic flux. A better understanding of the role of autophagy could lead to the development of new cardioprotective strategies. [Figure 1: Changes in cardiac autophagy proteins in patients undergoing heart surgery before and after cross-clamping the aorta (after restoration of myocardial blood flow).]
Background: Previously we showed that the homeostatic intracellular repair response (HIR2) is activated in the hearts of patients undergoing cardiac surgery. Autophagy is a principal component of this beneficial response that clears fragile mitochondria and protein aggregates. Moreover, we have previously shown that mitochondrial elimination through autophagy (mitophagy) is a key element in ischemic preconditioning. Thus, an important mechanism of cardioprotection appears to involve the upregulation of autophagy which facilitates the clearance of vulnerable mitochondria to limit I/R injury. We hypothesized that this protective action leads to turnover of the existing mitochondrial population in the heart during the resolution of I/R injury. The purpose of this study was to examine if the mechanism of HIR2 extends to remodeling the existing mitochondrial population of the heart. Study Design: Autophagy and mitochondrial turnover were assessed in 10 patients undergoing coronary artery bypass or valve surgery requiring cardiopulmonary bypass. Biopsies of the right atrial appendage obtained before initiation and after weaning from cardiopulmonary bypass were processed to yield whole tissue lysates and mitochondria-enriched heavy membrane fractions. Samples were analyzed for autophagy by immunoblotting for LC3, Beclin-1, ATG5-12, and p62. Mitochondrial turnover was assessed by monitoring Tom70, Cox4, Drp1, p62 and Parkin in tissue lysates and heavy membrane fractions. Results: Heart surgery was associated with a robust increase in autophagy indicated by depletion of LC3, Beclin-1, ATG5-12 and p62, as well as the mitophagy and fission regulator Drp1. Parkin increased in the mitochondrial fraction after bypass. Surprisingly, post-bypass tissue lysates showed a marked increase in mitochondrial markers Tom70 and Cox4, suggesting mitochondrial biogenesis. Conclusions: These findings provide evidence for the first time in humans that coordinated mitophagy and biogenesis are part of the homeostatic response to I/R, pointing to the importance of studying this aspect of HIR2. Strategies designed to amplify HIR2 during cardiac stress may represent an entirely new approach to myocardial protection in patients undergoing heart surgery.
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