Mitochondria and Metabolism in Right Heart Failure

Heart failure (HF) is a clinically complex and heterogenous disease characterized by an inability of the heart to pump sufficient blood to the periphery. As such, it has historically been thought of and studied as a disease of the left ventricle (LV). While LV failure is the most common form of HF, it is the ability of the right heart to function that predicts survival in many clinical settings. Extrapolation of mechanisms of left HF to the right ventricle (RV) has yet to prove fruitful in identification of therapeutic approaches, in large part due to a lack of basic mechanistic understanding of the RV which is embryologically, anatomically, and physiologically distinct from the LV. The failing LV is characterized by mitochondrial dysfunction and a metabolic switch, both of which contribute to an energetically starved heart with poor contractile ability. These mechanisms, however, are far less described in the failing RV. The purpose of this chapter is to present the current literature examining the role of mitochondria and metabolism in the healthy right heart, treatments to target deficits in the failing RV, and to identify knowledge gaps for future research in this clinically important area

Long‐lived Snell dwarf mice display increased proteostatic mechanisms that are not dependent on decreased mTORC1 activity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111144/1/acel12329.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111144/2/acel12329-sup-0001-SuppInfo.pd

Outcomes in patients with gunshot wounds to the brain.

Introduction:Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. Methods:We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. Results:825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. Conclusion:We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. Level of evidence:Level II

Outcome in patients perceived as receiving excessive care across different ethical climates: a prospective study in 68 intensive care units in Europe and the USA

Purpose: Whether the quality of the ethical climate in the intensive care unit (ICU) improves the identification of patients receiving excessive care and affects patient outcomes is unknown. Methods: In this prospective observational study, perceptions of excessive care (PECs) by clinicians working in 68 ICUs in Europe and the USA were collected daily during a 28-day period. The quality of the ethical climate in the ICUs was assessed via a validated questionnaire. We compared the combined endpoint (death, not at home or poor quality of life at 1 year) of patients with PECs and the time from PECs until written treatment-limitation decisions (TLDs) and death across the four climates defined via cluster analysis. Results: Of the 4747 eligible clinicians, 2992 (63%) evaluated the ethical climate in their ICU. Of the 321 and 623 patients not admitted for monitoring only in ICUs with a good (n = 12, 18%) and poor (n = 24, 35%) climate, 36 (11%) and 74 (12%), respectively were identified with PECs by at least two clinicians. Of the 35 and 71 identified patients with an available combined endpoint, 100% (95% CI 90.0–1.00) and 85.9% (75.4–92.0) (P = 0.02) attained that endpoint. The risk of death (HR 1.88, 95% CI 1.20–2.92) or receiving a written TLD (HR 2.32, CI 1.11–4.85) in patients with PECs by at least two clinicians was higher in ICUs with a good climate than in those with a poor one. The differences between ICUs with an average climate, with (n = 12, 18%) or without (n = 20, 29%) nursing involvement at the end of life, and ICUs with a poor climate were less obvious but still in favour of the former. Conclusion: Enhancing the quality of the ethical climate in the ICU may improve both the identification of patients receiving excessive care and the decision-making process at the end of life

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

Impact of altitude on COVID-19 infection and death in the United States: A modeling and observational study.

BackgroundCOVID-19, the disease caused by SARS-CoV-2, has caused a pandemic, sparing few regions. However, limited reports suggest differing infection and death rates across geographic areas including populations that reside at higher elevations (HE). We aimed to determine if COVID-19 infection, death, and case mortality rates differed in higher versus low elevation (LE) U.S. counties.MethodsUsing publicly available geographic and COVID-19 data, we calculated per capita infection and death rates and case mortality in population density matched HE and LE U.S. counties. We also performed population-scale regression analysis to investigate the association between county elevation and COVID-19 infection rates.FindingsPopulation density matching of LA (2133m, n = 58) counties yielded significantly lower COVID-19 cases at HE versus LE (615 versus 905, p = 0.034). HE per capita deaths were significantly lower than LE (9.4 versus 19.5, p = 0.017). However, case mortality did not differ between HE and LE (1.78% versus 1.46%, p = 0.27). Regression analysis, adjusted for relevant covariates, demonstrated decreased COVID-19 infection rates by 12.82%, 12.01%, and 11.72% per 495m of county centroid elevation, for cases recorded over the previous 30, 90, and 120 days, respectively.ConclusionsThis population-adjusted, controlled analysis suggests that higher elevation attenuates infection and death. Ongoing work from our group aims to identify the environmental, biological, and social factors of residence at HE that impact infection, transmission, and pathogenesis of COVID-19 in an effort to harness these mechanisms for future public health and/or treatment interventions

Mechanisms and implications of sex differences in cardiac aging

Aging promotes structural and functional remodeling of the heart, even in the absence of external factors. There is growing clinical and experimental evidence supporting the existence of sex-specific patterns of cardiac aging, and in some cases, these sex differences emerge early in life. Despite efforts to identify sex-specific differences in cardiac aging, understanding how these differences are established and regulated remains limited. In addition to contributing to sex differences in age-related heart disease, sex differences also appear to underlie differential responses to cardiac stress such as adrenergic activation. Identifying the underlying mechanisms of sex-specific differences may facilitate the characterization of underlying heart disease phenotypes, with the ultimate goal of utilizing sex-specific therapeutic approaches for cardiac disease. The purpose of this review is to discuss the mechanisms and implications of sex-specific cardiac aging, how these changes render the heart more susceptible to disease, and how we can target age- and sex-specific differences to advance therapies for both male and female patients

The right ventricular fibroblast secretome drives cardiomyocyte dedifferentiation.

RationaleIn virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We've previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells.ObjectiveTo determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture.Methods and resultsBrief exposure (ConclusionsThese data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction