Sounding the Alarm: What Clinicians Need to Know about Physical, Emotional, and Cognitive Recovery After Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVE: We summarize the existing data on the occurrence of physical, emotional, and cognitive dysfunction associated with postintensive care syndrome (PICS) in adult survivors of venoarterial extracorporeal membrane oxygenation (VA-ECMO). DATA SOURCES: MEDLINE, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched. STUDY SELECTION: Peer-reviewed studies of adults receiving VA-ECMO for any reason with at least one measure of health-related quality of life outcomes or PICS at long-term follow-up of at least 6 months were included. DATA EXTRACTION: The participant demographics and baseline characteristics, in-hospital outcomes, long-term health outcomes, quality of life outcome measures, and prevalence of PICS were extracted. DATA SYNTHESIS: Twenty-seven studies met inclusion criteria encompassing 3,271 patients who were treated with VA-ECMO. The studies were limited to single- or two-center studies. Outcomes variables and follow-up time points evaluated were widely heterogeneous which limits comprehensive analysis of PICS after VA-ECMO. In general, the longer-term PICS-related outcomes of survivors of VA-ECMO were worse than the general population, and approaching that of patients with chronic disease. Available studies identified high rates of abnormal 6-minute walk distance, depression, anxiety, and posttraumatic stress disorder that persisted for years. Half or fewer survivors return to work years after discharge. Only 2 of 27 studies examined cognitive outcomes and no studies evaluated cognitive dysfunction within the first year of recovery. No studies evaluated the impact of targeted interventions on these outcomes. CONCLUSIONS: Survivors of VA-ECMO represent a population of critically ill patients at high risk for deficits in physical, emotional, and cognitive function related to PICS. This systematic review highlights the alarming reality that PICS and in particular, neurocognitive outcomes, in survivors of VA-ECMO are understudied, underrecognized, and thus likely undertreated. These results underscore the imperative that we look beyond survival to focus on understanding the burden of survivorship with the goal of optimizing recovery and outcomes after these life-saving interventions. Future prospective, multicenter, longitudinal studies in recovery after VA-ECMO are justified.

TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

Molecular and functional characteristics of megakaryocytes and platelets in aging.

PURPOSE OF REVIEW: Advances in medical care and preventive measures have contributed to increasing life expectancy. Therefore, it is critical to expand our understanding of the physiological and pathophysiological adaptations of the hematological system in aging. We highlight and review the findings from recent investigations aimed at understanding the effects of aging on megakaryocytes and platelets. RECENT FINDINGS: Biochemical and transcriptomic studies of megakaryocytes and platelets from older humans and mice have advanced our understanding of the molecular and functional characteristics of megakaryocytes and platelets during aging. These studies have led to the identification of metabolic and inflammatory pathways associated with the generation of hyperreactive platelets that may significantly contribute to the high incidence of thrombosis in aging. SUMMARY: By increasing our research efforts to understand and identify the characteristics of megakaryocytes and platelets in aging, we will increase our potential to develop novel therapies aimed at decreasing the incidence of aging-associated thrombosis. These efforts will also serve as a foundation to better understand the role of megakaryocytes and platelets in other age-related hematological conditions with high thrombotic risk such as clonal hematopoiesis of indeterminate potential and myeloproliferative neoplasms.

Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis.

While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis.

ABC Transporter Required for Intercellular Transfer of Developmental Signals in a Heterocystous Cyanobacterium.

UNLABELLED: In the filamentous cyanobacterium Anabaena, patS and hetN encode peptide-derived signals with many of the properties of morphogens. These signals regulate the formation of a periodic pattern of heterocysts by lateral inhibition of differentiation. Here we show that intercellular transfer of the patS- and hetN-dependent developmental signals from heterocysts to vegetative cells requires HetC, a predicted ATP-binding cassette transporter (ABC transporter). Relative to the wild type, in a hetC mutant differentiation resulted in a reduced number of heterocysts that were incapable of nitrogen fixation, but deletion of patS or hetN restored heterocyst number and function in a hetC background. These epistasis results suggest that HetC is necessary for conferring self-immunity to the inhibitors on differentiating cells. Nine hours after induction of differentiation, HetC was required for neither induction of transcription of patS nor intercellular transfer of the patS-encoded signal to neighboring cells. Conversely, in strains lacking HetC, the patS- and hetN-encoded signals were not transferred from heterocyst cells to adjacent vegetative cells. The results support a model in which the patS-dependent signal is initially transferred between vegetative cells in a HetC-independent fashion, but some time before morphological differentiation of heterocysts is complete, transfer of both signals transitions to a HetC-dependent process. IMPORTANCE: How chemical cues that regulate pattern formation in multicellular organisms move from one cell to another is a central question in developmental biology. In this study, we show that an ABC transporter, HetC, is necessary for transport of two developmental signals between different types of cells in a filamentous cyanobacterium. ABC transporters are found in organisms as diverse as bacteria and humans and, as the name implies, are often involved in the transport of molecules across a cellular membrane. The activity of HetC was shown to be required for signaling between heterocysts, which supply fixed nitrogen to the organism, and other cells, as well as for conferring immunity to self-signaling on developing heterocysts.

The RGSGR amino acid motif of the intercellular signalling protein, HetN, is required for patterning of heterocysts in Anabaena sp. strain PCC 7120.

Nitrogen-fixing heterocysts are arranged in a periodic pattern on filaments of the cyanobacterium Anabaena sp. strain PCC 7120 under conditions of limiting combined nitrogen. Patterning requires two inhibitors of heterocyst differentiation, PatS and HetN, which work at different stages of differentiation by laterally suppressing levels of an activator of differentiation, HetR, in cells adjacent to source cells. Here we show that the RGSGR sequence in the 287-amino-acid HetN protein, which is shared by PatS, is critical for patterning. Conservative substitutions in any of the five amino acids lowered the extent to which HetN inhibited differentiation when overproduced and altered the pattern of heterocysts in filaments with an otherwise wild-type genetic background. Conversely, substitution of amino acids comprising the putative catalytic triad of this predicted reductase had no effect on inhibition or patterning. Deletion of putative domains of HetN suggested that the RGSGR motif is the primary component of HetN required for both its inhibitory and patterning activity, and that localization to the cell envelope is not required for patterning of heterocysts. The intercellular signalling proteins PatS and HetN use the same amino acid motif to regulate different stages of heterocyst patterning.

STRAUMA: A Novel Alert System for a Combined Stroke and Trauma.

INTRODUCTION: Cerebrovascular accident (CVA) can lead to traumatic injury. While timely administration of tissue plasminogen activator (tPA) can be lifesaving in CVAs, it is contraindicated with active bleeding. A STRAUMA is a combined stroke and highest-level trauma activation for patients with suspected CVA and signs of trauma. The purpose of this study is to evaluate the impact of the STRAUMA activation on time to CT and patient outcomes. METHODS: A retrospective review was conducted on adult patients presenting to a Level 1 trauma and comprehensive stroke center with signs of CVA between 01/2019 and 09/2020. Patients who had a STRAUMA activation were compared to patients who had a stroke alert. RESULTS: Five hundred and eighty patients met the inclusion criteria. Of these, 111 had STRAUMA activations and 469 had stroke alerts. There were no differences in age, gender, or anticoagulation use. The STRAUMA group had a higher NIH stroke scale (NIHSS) (11 vs 5, P<.0001). The STRAUMA group had a longer time to CT (23.1 min vs 16.9 min, P<.0001) and a lower rate of tPA (13.5% vs 27.9%, P = .001). Time to tPA and thrombectomy were similar. The STRAUMA group had a 15% rate of traumatic injury with a median injury severity score of 9. Mortality was higher in the STRAUMA group (14.4% vs 6.0%, P = .003). Multivariable logistic regression identified NIHSS and time to CT as predictors of mortality. STRAUMA did not predict mortality. CONCLUSION: The novel STRAUMA activation allows for an evaluation of both stroke and trauma to facilitate safe and timely administration of lifesaving interventions.

Frozen Elephant Trunk for Acute Type A Dissection: Is Risk from Procedure or Patient Characteristics?

BACKGROUND: The initial goal of acute Type A aortic dissection (ATAAD) repair remains to get the patient off the table safely. More extensive repair is being pushed at the index operation with the frozen elephant trunk (FET) operation, but outcomes are suggested to be worse. However, we hypothesize that the risk associated with the FET in ATAAD is from the patient presenting factors rather than the operation itself. METHODS: A retrospective review of a single institution prospective database from 2015 to 2021 was performed. Two cohorts were created based on the indication for FET: evidence of radiographic malperfusion (n = 44) or clinical malperfusion (n = 31). Data were analyzed for preoperative characteristics, intraoperative characteristics, and postoperative outcomes. Statistical univariate analysis was performed with chi-square analysis and t-tests with significance determined at an alpha level of 0.05. RESULTS: Preoperative characteristics were similar in each group, independent of malperfusion markers. The intraoperative characteristics were similar, except the clinical malperfusion group had more packed red blood cells and cryoprecipitate given. The clinical malperfusion group had longer intensive care unit length of stay (p < 0.001), more postoperative strokes (p < 0.001), more reoperations (p <0.0001), and higher mortality rate (p = 0.0003). CONCLUSION: These data suggest that clinical malperfusion increases the risk of major complications and death. However, full arch replacement with FET in the absence of clinical malperfusion does not appear to add risk to the operation for ATAAD. Patients with increased risk of distal degeneration should be considered for more aggressive replacement to avoid subsequent arch replacement.

Noteworthy Cardiac Literature From 2021: Coronary Guideline Change Without New Data, Heart Transplant Donation After Cardiac Death, Covid Effects on Global Cardiac Surgery, and Attempt to Improve Dissection Remodeling.

Cardiac surgery continues to evolve. The last year has been notable for many reasons. The guidelines for coronary revascularization introduced significant discord. The pandemic continues to affect the care on a global scale. Advances in organ procurement and dissection care move forward with better understanding and better technology.

Ectopic expression of hetP can partially bypass the need for hetR in heterocyst differentiation by Anabaena sp. strain PCC 7120.

Differentiation of nitrogen-fixing cells, called heterocysts, by the cyanobacterium Anabaena sp. strain PCC 7120 requires HetR, which is considered the master regulator of heterocyst differentiation. In this study, ectopic expression of hetP from an inducible promoter was shown to partially bypass the need for hetR in heterocyst differentiation. A hetR-deletion strain with hetP expressed ectopically produced cells morphologically similar to heterocysts that produced exopolysaccharide and glycolipids specific to heterocysts, and nitrogenase activity was present under anaerobic conditions, as indicated by an acetylene reduction assay. Five potential transcription start points or transcript processing sites located at positions -727, -545, -208, -177 and -12 bp relative to the putative translational start site were identified in the promoter region of hetP. Relative levels of transcription and their location in filaments resembled that previously reported for HetR protein in various genetic backgrounds, and an inverted repeat sequence in the promoter of hetP was necessary for binding of HetR. Two of the three identified homologues of hetP found in PCC 7120 partially complemented a hetP-null mutant. Taken together, these results suggest that HetP functions directly downstream of HetR in the regulatory network responsible for heterocyst differentiation.

Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors.

The early events that drive myeloid oncogenesis are not well understood. Most studies focus on the cell-intrinsic genetic changes and how they impact cell fate decisions. We consider how chronic exposure to the proinflammatory cytokine, interleukin-1ß (IL-1ß), impacts Cebpa-knockout hematopoietic stem and progenitor cells (HSPCs) in competitive settings. Surprisingly, we found that Cebpa loss did not confer a hematopoietic cell-intrinsic competitive advantage; rather chronic IL-1ß exposure engendered potent selection for Cebpa loss. Chronic IL-1ß augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-knockout HSPCs are resistant to the prodifferentiative effects of chronic IL-1ß, and competitively expand. We further show that ectopic CEBPA expression reduces the fitness of established human acute myeloid leukemias, coinciding with increased differentiation. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention.

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress.

Hematopoietic stem cells (HSCs) are capable of entering the cell cycle to replenish the blood system in response to inflammatory cues; however, excessive proliferation in response to chronic inflammation can lead to either HSC attrition or expansion. The mechanism(s) that limit HSC proliferation and expansion triggered by inflammatory signals are poorly defined. Here, we show that long-term HSCs (HSCLT) rapidly repress protein synthesis and cell cycle genes following treatment with the proinflammatory cytokine interleukin (IL)-1. This gene program is associated with activation of the transcription factor PU.1 and direct PU.1 binding at repressed target genes. Notably, PU.1 is required to repress cell cycle and protein synthesis genes, and IL-1 exposure triggers aberrant protein synthesis and cell cycle activity in PU.1-deficient HSCs. These features are associated with expansion of phenotypic PU.1-deficient HSCs. Thus, we identify a PU.1-dependent mechanism triggered by innate immune stimulation that limits HSC proliferation and pool size. These findings provide insight into how HSCs maintain homeostasis during inflammatory stress.

A somatic evolutionary model of the dynamics of aneuploid cells during hematopoietic reconstitution.

Aneuploidy is a feature of many cancers. Recent studies demonstrate that in the hematopoietic stem and progenitor cell (HSPC) compartment aneuploid cells have reduced fitness and are efficiently purged from the bone marrow. However, early phases of hematopoietic reconstitution following bone marrow transplantation provide a window of opportunity whereby aneuploid cells rise in frequency, only to decline to basal levels thereafter. Here we demonstrate by Monte Carlo modeling that two mechanisms could underlie this aneuploidy peak: rapid expansion of the engrafted HSPC population and bone marrow microenvironment degradation caused by pre-transplantation radiation treatment. Both mechanisms reduce the strength of purifying selection acting in early post-transplantation bone marrow. We explore the contribution of other factors such as alterations in cell division rates that affect the strength of purifying selection, the balance of drift and selection imposed by the HSPC population size, and the mutation-selection balance dependent on the rate of aneuploidy generation per cell division. We propose a somatic evolutionary model for the dynamics of cells with aneuploidy or other fitness-reducing mutations during hematopoietic reconstitution following bone marrow transplantation. Similar alterations in the strength of purifying selection during cancer development could help explain the paradox of aneuploidy abundance in tumors despite somatic fitness costs.

Decoy fitness peaks, tumor suppression, and aging.

Recent reports by Martincorena et al and Yokoyama et al reveal unanticipated dynamics of somatic evolution in the esophageal epithelium, with clonal expansions apparently driven by mutations in Notch1 dominating the epithelium even in middle-aged individuals, far outpacing the prevalence of these mutations in esophageal cancers. We propose a model whereby the promotion of clonal expansions by mutations such as in Notch1 can limit more malignant somatic evolutionary trajectories until old ages.

Evolved Cellular Mechanisms to Respond to Genotoxic Insults: Implications for Radiation-Induced Hematologic Malignancies.

Human exposure to ionizing radiation is highly associated with adverse health effects, including reduced hematopoietic cell function and increased risk of carcinogenesis. The hematopoietic deficits manifest across blood cell types and persist for years after radiation exposure, suggesting a long-lived and multi-potent cellular reservoir for radiation-induced effects. As such, research has focused on identifying both the immediate and latent hematopoietic stem cell responses to radiation exposure. Radiation-associated effects on hematopoietic function and malignancy development have generally been attributed to the direct induction of mutations resulting from radiation-induced DNA damage. Other studies have illuminated the role of cellular programs that both limit and enhance radiation-induced tissue phenotypes and carcinogenesis. In this review, distinct but collaborative cellular responses to genotoxic insults are highlighted, with an emphasis on how these programmed responses impact hematopoietic cellular fitness and competition. These radiation-induced cellular programs include apoptosis, senescence and impaired self-renewal within the hematopoietic stem cell (HSC) pool. In the context of sporadic DNA damage to a cell, these cellular responses act in concert to restore tissue function and prevent selection for adaptive oncogenic mutations. But in the contexts of whole-tissue exposure or whole-body exposure to genotoxins, such as radiotherapy or chemotherapy, we propose that these programs can contribute to long-lasting tissue impairment and increased carcinogenesis.