Contemporary Trends of Clinical Outcomes in Primary Left Ventricular Assist Device Implantation and Postprocedure High-Risk Categories.

OBJECTIVE: We aimed to analyze trends of 30-day readmission and find high-risk patients associated with increased risk of mortality, resource use, and readmission after primary left ventricular assist device (LVAD) implantation. Limited data exist on the contemporary trends of readmission rates and patients at a higher risk of worse outcomes after LVAD implantation. METHODS AND RESULTS: This is a retrospective study of adults from the Nationwide Readmission Database who underwent primary durable LVAD implantation from 2010 to 2018. The main outcomes were 30-day readmission rates and their trends in patients with primary durable LVAD implantation from 2010 to 2018. This study also sought to identify patients at the highest risk for readmission, in-hospital mortality, and resource use. A total of 31,002 adults with primary durable LVAD implantation were included in the present analysis. Overall, 3808 patients (12.3%) died and 27,168 (87.6%) were discharged alive. Of those discharged alive, 8303 patients (30.6%) were readmitted within 30 days. The trend of 30-day all-cause readmission among LVAD implantation patients remained similar from 2010 to 2018 (P = .809). The in-hospital mortality rate during the index hospitalization decreased significantly (P = .014), and the mean cost of an index hospitalization increased (P = .031) during the study period. The patients with post-LVAD in-hospital cardiac, vascular, and thromboembolic complications (ie, high-risk patients) had the highest mortality, resource use, and readmission rates compared with patients without major complications. CONCLUSIONS: This study found that the readmission rates associated with LVAD implantation did not change from 2010 to 2018 and identified high-risk patients who may benefit from closer monitoring after primary LVAD implantation.

Acute Hemodynamic Effects of Sacubitril-Valsartan In Heart Failure Patients Receiving Intravenous Vasodilator and Inotropic Therapy.

BACKGROUND: Prior study has demonstrated that transitioning patients in acutely decompensated heart failure with a low cardiac output directly from intravenous (i.v.) vasoactive (ie, vasodilators or inotropes) drugs to sacubitril-valsartan (S/V) can be done safely with tolerance to the 1-month follow-up. Here, we further characterize the hemodynamic impact of S/V after patients have been optimized on vasoactive therapy. METHODS AND RESULTS: In a single-center, retrospective analysis, 25 patients with cardiac index of less than 2.2 L/min/m2 were admitted to the cardiac intensive care unit and newly initiated on angiotensin receptor-neprilysin inhibitor therapy with the guidance of invasive hemodynamic monitoring. Hemodynamic data were gathered and compared upon cardiac intensive care unit admission, after optimization with i.v. vasoactive therapy, and after S/V initiation and weaning off i.v. THERAPY: All patients who tolerated S/V (n = 20) were weaned off vasoactive medications before transfer out of cardiac intensive care unit. Patients maintained their significant improvement in cardiac index and reduction in SVR/PVR on transition from i.v. inotropic and vasodilator therapy to oral S/V. There was an increase in pulmonary artery pulsatility index with S/V therapy compared with the i.v. vasoactive phase of care. CONCLUSIONS: Patients in the cardiac intensive care unit can be successfully bridged from vasoactive i.v. therapy to oral S/V with sustained improvement in cardiac index garnered from vasoactive agents. We also observed improvement in the pulmonary artery pulsatility index and maintenance of left and right ventricular unloading with S/V. These encouraging findings merit further prospective study.

Extra-cardiac management of cardiogenic shock in the intensive care unit.

Cardiogenic shock (CS) is a heterogeneous clinical syndrome characterized by low cardiac output leading to end-organ hypoperfusion. Organ dysoxia ranging from transient organ injury to irreversible organ failure and death occurs across all CS etiologies but differing by incidence and type. Herein, we review the recognition and management of respiratory, renal and hepatic failure complicating CS. We also discuss unmet needs in the CS care pathway and future research priorities for generating evidence-based best practices for the management of extra-cardiac sequelae. The complexity of CS admitted to the contemporary cardiac intensive care unit demands a workforce skilled to care for these extra-cardiac critical illness complications with an appreciation for how cardio-systemic interactions influence critical illness outcomes in afflicted patients.

Temporal Trends of Enrollment by Sex and Race in Major Cardiovascular Randomized Clinical Trials.

Background: Women and racialized minorities continue to be underrepresented in cardiovascular (CV) trial outcomes data, despite comprising a significant global burden of CV disease. This study evaluated the impact of trial characteristics on the temporal enrollment of women and racialized minorities in prominent CV trials published in the period 1986-2023. Methods: MEDLINE was searched for CV trials published in The Lancet, the Journal of the American Medical Association, and the New England Journal of Medicine. Participant and investigator demographics, types of interventions, clinical indications, and funding sources were compared according to the enrollment of women or racialized minorities. Results: From 799 studies, including 4,071,921 patients, the enrollment of women and racialized minorities significantly increased from 1986 to 2023 (both P ≤ 0.001). Although the enrollment of women varied by trial indication, comprising 25.0% of coronary artery disease, 35.2% of noncoronary and/or vascular disease, 13.8% of heart failure, 17.0% of arrhythmia, and 28.7% of other CV trials (P ≤ 0.001), it did not differ by peer-reviewed vs industry funding. First authors who were women were more likely than first authors who were men to enroll significantly more women (P = 0.01). Conclusions: Active efforts to increase diverse enrollment, along with improved reporting, including of sex and race, in future CV trials may increase the generalizability of their findings and applicability to global populations.

Contexte: Les femmes et les groupes racisés demeurent sous-représentés dans les données de résultats d'essais cliniques sur les maladies cardiovasculaires (CV) malgré l'important fardeau global associé à ces maladies. Cette étude visait à évaluer l'effet des caractéristiques des essais sur la sélection temporelle des femmes et des membres de groupes racisés dans les essais portant principalement sur les maladies CV durant la période de 1986 à 2023. Méthodologie: La base de données MEDLINE a été consultée à la recherche d'essais sur les maladies CV publiés dans The Lancet, Journal of the American Medical Association et New England Journal of Medicine. Les données démographiques des participants et des chercheurs, les types d'interventions, les indications cliniques et les sources de financement ont été comparés en fonction de la sélection des femmes ou des membres de groupes racisés. Résultats: Dans 799 études cumulant 4 071 921 patients, la sélection des femmes et des membres de groupes racisés a augmenté significativement entre 1986 et 2023 (p ≤ 0,001 dans les deux cas). Bien que la sélection des femmes variait en fonction des indications des essais, soit 25,0 % dans les essais portant sur les coronaropathies, 35,2 % pour les maladies non coronariennes et/ou vasculaires, 13,8 % pour l'insuffisance cardiaque, 17,0 % pour l'arythmie et 28,7 % pour d'autres maladies CV (p ≤ 0,001), elle ne différait pas selon que les études étaient révisées par des pairs ou qu'elles étaient financées par l'industrie. Lorsqu'une femme était l'autrice principale, le nombre de femmes sélectionnées était susceptible d'être plus élevé que lorsque l'auteur principal était un homme (p = 0,01). Conclusions: Des efforts actifs pour diversifier davantage la sélection des participants et mieux rendre compte des différences, notamment en ce qui concerne le sexe et la race, pourraient élargir la portée des conclusions des futurs essais sur les maladies CV et leur application à l'ensemble de la population.

Understanding Etiologies of Cardiac Arrest: Seeking Definitional Clarity.

Cardiac arrest leading to death and sudden cardiac death (SCD) may refer implicitly to situations in which death is unexpected and primarily of cardiac cause. National and international societies have published differing definitions for the various terms relating to cardiac arrest and SCD. We highlight the controversies in defining SCD, including the lack of a universal definition, the heterogeneity in the operationalization of the term "sudden," and limitations of time-based systems of SCD classification. We discuss the importance of a standardized methodology for classifying cardiac arrest as recommended by the World Health Organization (WHO) that should include use of multisource evidence (eg, coroner, autopsy, and toxicology reports) for confirming or refuting a cardiac cause of arrest. We reveal how a universal definition of SCD has been incorrectly attributed to the WHO and how this has been perpetuated in the literature. We make the case that definitional clarity is essential to understanding epidemiology, evaluating novel treatments, forming international collaboration, and innovating public health prevention strategies. We propose a practical schema to categorize cardiac arrest events to describe and study this population more accurately.

Special Considerations in the Care of Women With Advanced Heart Failure.

Advanced heart failure (AHF) is associated with increased morbidity and mortality, and greater healthcare utilization. Recognition requires a thorough clinical assessment and appropriate risk stratification. There are persisting inequities in the allocation of AHF therapies. Women are less likely to be referred for evaluation of candidacy for heart transplantation or left ventricular assist device despite facing a higher risk of AHF-related mortality. Sex-specific risk factors influence progression to advanced disease and should be considered when evaluating women for advanced therapies. The purpose of this review is to discuss the role of sex hormones on the pathophysiology of AHF, describe the clinical presentation, diagnostic evaluation and definitive therapies of AHF in women with special attention to pregnancy, lactation, contraception and menopause. Future studies are needed to address areas of equipoise in the care of women with AHF.

Regional Differences in the Ghrelin-Growth Hormone Secretagogue Receptor Signalling System in Human Heart Disease.

BACKGROUND: The hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR) are expressed in myocardium. GHSR binding activates signalling pathways coupled to cardiomyocyte survival and contractility. These properties have made the ghrelin-GHSR axis a candidate for a biomarker of cardiac function. The dynamics of ghrelin-GHSR are altered significantly in late stages of heart failure (HF) and cardiomyopathy, when left ventricular (LV) function is failing. We examined the relationship of GHSR with ghrelin in cardiac tissue from patients with valvular disease with no detectable changes in LV function. METHODS: Biopsy samples from the left ventricle and left atrium were obtained from 25 patients with valvular disease (of whom 13 also had coronary artery disease) and preserved LV ejection fraction, and compared to control samples obtained via autopsy. Using quantitative confocal fluorescence microscopy, levels of GHSR were determined using [Dpr3(n-octanoyl),Lys19(sulfo-Cy5)]ghrelin(1-19), and immunofluorescence determined ghrelin, the heart failure marker natriuretic peptide type-B (BNP), and contractility marker sarcoplasmic reticulum ATPase pump (SERCA2a). RESULTS: A positive correlation between GHSR and ghrelin was apparent in only diseased tissue. Ghrelin and BNP significantly correlated in the left ventricle and strongly colocalized to the same intracellular compartment in diseased and control tissue. GHSR, ghrelin, and BNP all strongly and significantly correlated with SERCA2a in the left ventricle of diseased tissue only. CONCLUSIONS: Our results suggest that the dynamics of the myocardial ghrelin-GHSR axis is altered in cardiovascular disease in the absence of measurable changes in heart function, and might accompany a regional shift in endocrine programming.

CONTEXTE: L'hormone ghréline et son récepteur, le récepteur sécrétagogue de l'hormone de croissance (GHSR, de l'anglais growth hormone secretagogue receptor), sont exprimés dans le myocarde. La liaison au récepteur GHSR active les voies de signalisation associées à la survie et à la contractilité des cardiomyocytes. Ces propriétés font de l'axe ghréline-récepteur GHSR un bon candidat biomarqueur de la fonction cardiaque. En effet, la dynamique de cet axe est considérablement altérée aux stades avancés de l'insuffisance cardiaque et de la cardiomyopathie, lorsque la fonction ventriculaire gauche décline. Nous avons donc étudié la relation entre le récepteur GHSR et la ghréline dans le tissu cardiaque de patients présentant une valvulopathie sans changements détectables dans la fonction ventriculaire gauche. MÉTHODOLOGIE: Des échantillons de tissus du ventricule et de l'oreillette gauches ont été prélevés par biopsie chez 25 patients présentant une valvulopathie (dont 13 avaient aussi une coronaropathie) et une fraction d'éjection ventriculaire gauche préservée, puis comparés avec des échantillons témoins prélevés à l'autopsie. Les taux du récepteur GHSR ont été mesurés par microscopie en fluorescence confocale quantitative à l'aide de [Dpr3(n-octanoyl),Lys19(sulfo-Cy5)] ghréline(1-19); les taux de ghréline, de peptide natriurétique de type B (BNP, un marqueur de l'insuffisance cardiaque), et de pompe ATPase du réticulum sarcoplasmique (SERCA2a; un marqueur de la contractilité) ont quant à eux été mesurés par immunofluorescence. RÉSULTATS: Nous avons noté une corrélation positive entre le récepteur GHSR et la ghréline uniquement dans les tissus lésés. Il existe une corrélation significative entre les taux de ghréline et de BNP dans le ventricule gauche, les deux substances étant fortement localisées dans le même compartiment intracellulaire, tant dans les tissus malades que dans les tissus témoins. Le récepteur GHSR, la ghréline et le BNP sont tous fortement et significativement corrélés avec la SERCA2a SERCA2a dans le tissu ventriculaire gauche malade seulement. CONCLUSIONS: Nos résultats semblent indiquer que la dynamique de l'axe ghréline-récepteur GHSR dans le myocarde est altérée en cas de maladie cardiovasculaire même en l'absence de changements mesurables de la fonction cardiaque, et que cette altération pourrait être attribuable à une modification régionale de la programmation endocrinienne.

Cardiovascular Physicians, Scientists, and Trainees Balancing Work and Caregiving Responsibilities in the COVID-19 Era: Sex and Race-Based Inequities.

BACKGROUND: The ongoing COVID-19 pandemic has exposed a work-life (im)balance that has been present but not openly discussed in medicine, surgery, and science for decades. The pandemic has exposed inequities in existing institutional structure and policies concerning clinical workload, research productivity, and/or teaching excellence inadvertently privileging those who do not have significant caregiving responsibilities or those who have the resources to pay for their management. METHODS: We sought to identify the challenges facing multidisciplinary faculty and trainees with dependents, and highlight a number of possible strategies to address challenges in work-life (im)balance. RESULTS: To date, there are no Canadian-based data to quantify the physical and mental effect of COVID-19 on health care workers, multidisciplinary faculty, and trainees. As the pandemic evolves, formal strategies should be discussed with an intersectional lens to promote equity in the workforce, including (but not limited to): (1) the inclusion of broad representation (including equal representation of women and other marginalized persons) in institutional-based pandemic response and recovery planning and decision-making; (2) an evaluation (eg, institutional-led survey) of the effect of the pandemic on work-life balance; (3) the establishment of formal dialogue (eg, workshops, training, and media campaigns) to normalize coexistence of work and caregiving responsibilities and to remove stigma of gender roles; (4) a reevaluation of workload and promotion reviews; and (5) the development of formal mentorship programs to support faculty and trainees. CONCLUSIONS: We believe that a multistrategy approach needs to be considered by stakeholders (including policy-makers, institutions, and individuals) to create sustainable working conditions during and beyond this pandemic.

CONTEXTE: La pandémie de COVID-19 a mis en lumière le déséquilibre entre travail et vie personnelle qui règne depuis des décennies dans les milieux de la médecine, de la chirurgie et des sciences, mais dont on ne parlait pas ouvertement. La pandémie a en effet mis au jour des iniquités dans la structure et les politiques des établissements en matière de charge de travail clinique, de productivité de la recherche et d'excellence en enseignement, qui favorisent par inadvertance les personnes qui n'ont pas de responsabilités familiales importantes ou qui ont les ressources nécessaires pour leur prise en charge. MÉTHODOLOGIE: Nous avons tenté de cerner les difficultés auxquelles font face les enseignants multidisciplinaires et les stagiaires ayant des personnes à charge, et nous proposons un certain nombre de stratégies possibles pour faciliter la conciliation travail-vie personnelle. RÉSULTATS: À ce jour, il n'existe pas de données canadiennes permettant de quantifier les répercussions physiques et mentales de la pandémie de COVID-19 sur les travailleurs de la santé, les enseignants multidisciplinaires et les stagiaires. Au fil de l'évolution de la pandémie, il conviendrait de formuler des stratégies officielles à la lumière des commentaires d'intervenants des différents secteurs concernés, afin de promouvoir l'équilibre au sein des effectifs; ces stratégies pourraient notamment inclure ce qui suit (sans toutefois s'y limiter) : 1) l'inclusion d'une vaste représentation (y compris une représentation égale des femmes et des autres personnes marginalisées) pour la réponse à la pandémie dans les établissements, la planification du rétablissement et la prise de décisions; 2) une évaluation (p. ex. au moyen d'un sondage mené sous la direction des établissements) des répercussions de la pandémie sur la conciliation travail-vie personnelle; 3) l'établissement d'un dialogue formel (p. ex. ateliers, activités de formation et campagnes dans les médias) afin de normaliser la coexistence des responsabilités professionnelles et familiales et d'éliminer la stigmatisation associée aux rôles des sexes; 4) une réévaluation de la charge de travail et des promotions; et 5) la mise sur pied de programmes formels de mentorat pour soutenir les enseignants et les stagiaires. CONCLUSIONS: Nous croyons que les intervenants (décideurs, établissements et personnes) devraient envisager une approche multistratégie afin d'instaurer des conditions de travail viables pendant la pandémie et par la suite.

Mitral and tricuspid stenosis caused by light chain cardiac amyloid deposition.

Cardiac amyloidosis results in an infiltrative restrictive cardiomyopathy, with a number of characteristic features: biventricular hypertrophy, abnormal myocardial global longitudinal strain with relative apical sparing, biatrial dilation, and small pericardial effusion along with conduction abnormalities. Amyloid deposits leading to hemodynamically significant valvular heart disease are very rare. We describe a rare case of concomitant moderately severe tricuspid and mitral valve stenosis because of ongoing amyloid deposition in a patient with progressive multiple myeloma and fat pad biopsy-proven light chain amyloidosis. Worsening infiltrative cardiomyopathy and valvulopathy despite evidence-based chemotherapy and heart failure pharmacotherapy led to end-stage disease and death. Valvular involvement in cardiac amyloidosis requires early recognition of the underlying disease condition to guide directed medical therapy and prevent its progression. In this instance, valvuloplasty or valve replacement is not a viable option.

Sex, Gender, and Equity in Cardiovascular Medicine, Surgery, and Science in Canada: Challenges, Successes, and Opportunities for Change.

BACKGROUND: A previous review of sex, gender, and equity within cardiovascular (CV) medicine, surgery, and science in Canada has revealed parity during medical and graduate school training. The purpose of this study was to explore sex and gendered experiences within the Canadian CV landscape, and their impact on career training and progression. METHODS: An environmental scan was conducted of the Canadian CV landscape, which included an equity survey using Qualtrics software. RESULTS: The environmental scan revealed that women remain underrepresented within CV training programs as trainees (12%-30%), program directors (33%), in leadership roles at the divisional level (21%), and in other professional or career-related activities (< 30%). Our analysis also showed improvements of career engagement at these levels of women at over time. The thematic analysis of the equity survey responses (n = 71 respondents; 83% female; 9.7% response rate among female Canadian Cardiovascular Society members) identified the following themes reported within the socio-ecological framework: desire to report inequities vs staying the course (individual level); desire for social support and mentorship and challenges of dual responsibilities (interpersonal level); concerns over exclusionary cliques and desire for respect and opportunity (organizational level); and increasing awareness and actions to overcome institutional barriers and accountability (societal level). CONCLUSIONS: Although women face challenges and remain underrepresented in CV medicine, surgery, and science, this study highlights potential opportunities for improving access of female medical, surgical, and research trainees and professionals to specialized cardiovascular training, career advancement, leadership, and research.

CONTEXTE: Une étude antérieure portant sur le sexe, le genre et l'équité en médecine, chirurgie et sciences cardiovasculaires (CV) au Canada a révélé une parité au cours de la formation médicale et des études supérieures. L'objectif de cette étude était d'évaluer les expériences liées au sexe et au genre dans le paysage canadien du domaine CV, et leur impact sur la formation et la progression de carrière. MÉTHODES: Une analyse de l'environnement du paysage canadien dans le domaine CV a été réalisée, incluant une étude sur l'équité en utilisant le logiciel Qualtrics. RÉSULTATS: L'analyse de l'environnement a révélé que les femmes restent sous-représentées dans les programmes de formation du domaine CV que ce soit en tant que stagiaires (12 à 30 %), directrices de programme (33 %), dans les rôles de direction au niveau divisionnaire (21 %) et dans d'autres activités professionnelles ou associées à la carrière (< 30 %). Notre analyse a également montré une amélioration de l'engagement professionnel des femmes à ces niveaux au fil du temps. L'analyse thématique des réponses à l'enquête sur l'équité (n = 71 répondants; 83 % de femmes ; 9,7 % de taux de réponse parmi les membres féminins de la Société canadienne de cardiologie) a permis de dégager les thèmes suivants au sein du système socioécologique : désir de signaler les inégalités par rapport à la volonté de maintenir cap précis (au niveau individuel); désir de soutien social et de mentorat et défis liés à la double responsabilité (au niveau interpersonnel); préoccupations concernant les cliques exclusives et désir de respect et d'opportunité (au niveau organisationnel); et sensibilisation et actions accrues pour surmonter les obstacles institutionnels et les niveaux de responsabilité (au niveau sociétal). CONCLUSIONS: Bien que les femmes soient confrontées à des défis et restent sous-représentées dans les domaines de la médecine, de la chirurgie et des sciences CV, cette étude met en évidence les possibilités d'améliorer l'accès des stagiaires féminines et des professionnelles de la médecine, de la chirurgie et de la recherche à la formation spécialisée en cardiologie, à l'avancement de carrière, au rôle de direction et à la recherche.

Insulin action on glucose transporters through molecular switches, tracks and tethers.

Glucose entry into muscle cells is precisely regulated by insulin, through recruitment of GLUT4 (glucose transporter-4) to the membrane of muscle and fat cells. Work done over more than two decades has contributed to mapping the insulin signalling and GLUT4 vesicle trafficking events underpinning this response. In spite of this intensive scientific research, there are outstanding questions that continue to challenge us today. The present review summarizes the knowledge in the field, with emphasis on the latest breakthroughs in insulin signalling at the level of AS160 (Akt substrate of 160 kDa), TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) and their target Rab proteins; in vesicle trafficking at the level of vesicle mobilization, tethering, docking and fusion with the membrane; and in the participation of the cytoskeleton to achieve optimal temporal and spatial location of insulin-derived signals and GLUT4 vesicles.

Dynamics of the Ghrelin/Growth Hormone Secretagogue Receptor System in the Human Heart Before and After Cardiac Transplantation.

Currently, the early preclinical detection of left ventricular dysfunction is difficult because biomarkers are not specific for the cardiomyopathic process. The underlying molecular mechanisms leading to heart failure remain elusive, highlighting the need for identification of cardiac-specific markers. The growth hormone secretagogue receptor (GHSR) and its ligand ghrelin are present in cardiac tissue and are known to contribute to myocardial energetics. Here, we examined tissue ghrelin-GHSR levels as specific markers of cardiac dysfunction in patients who underwent cardiac transplantation. Samples of cardiac tissue were obtained from 10 patients undergoing cardiac transplant at the time of organ harvesting and during serial posttransplant biopsies. Quantitative fluorescence microscopy using a fluorescent ghrelin analog was used to measure levels of GHSR, and immunofluorescence was used to measure levels of ghrelin, B-type natriuretic peptide (BNP), and tissue markers of cardiomyocyte contractility and growth. GHSR and ghrelin expression levels were highly variable in the explanted heart, less in the grafted heart biopsies. GHSR and ghrelin were strongly positively correlated, and both markers were negatively correlated with left ventricular ejection fraction. Ghrelin had stronger positive correlations than BNP with the signaling markers for contractility and growth. These data suggest that GHSR-ghrelin have potential use as an integrated marker of cardiac dysfunction. Interestingly, tissue ghrelin appeared to be a more sensitive indicator than BNP to the biochemical processes that are characteristic of heart failure. This work allows for further use of ghrelin-GHSR to interrogate cardiac-specific biochemical mechanisms in preclinical stages of heart failure (HF).

Optimal Strategy and Timing of Left Ventricular Venting During Veno-Arterial Extracorporeal Life Support for Adults in Cardiogenic Shock: A Systematic Review and Meta-Analysis.

BACKGROUND: Veno-arterial extracorporeal life support (VA-ECLS) is widely used to treat refractory cardiogenic shock. However, increased left ventricular (LV) afterload in VA-ECLS can worsen pulmonary congestion and compromise myocardial recovery. Our objectives were to explore the efficacy, safety, and optimal timing of adjunctive LV venting strategies. METHODS: A systematic search was performed on Medline, EMBASE, PubMed, CDSR, CCRCT, CINAHL, ClinicalTrials.Gov, and WHO ICTRP from inception until January 2019 for all relevant studies, including LV venting. Data were analyzed for mortality and weaning from VA-ECLS on the basis of timing of LV venting, along with adverse complications. RESULTS: A total of 7995 patients were included from 62 observational studies, wherein 3458 patients had LV venting during VA-ECLS. LV venting significantly improved weaning from VA-ECLS (odds ratio, 0.62 [95% CI, 0.47-0.83]; P=0.001) and reduced short-term (30 day; risk ratio [RR], 0.86 [95% CI, 0.77-0.96]; P=0.008) but not in-hospital (RR, 0.92 [95% CI, 0.83-1.01] P=0.09) or long-term (6 months; RR, 0.96 [95% CI, 0.90-1.03]; P=0.27) mortality. Early (<12 hours; RR, 0.86 [95% CI, 0.75-0.99]; P=0.03) but not late (≥12 hours; RR, 0.99 [95% CI, 0.71-1.38]; P=0.93) LV venting significantly reduced short-term mortality. Patients with LV venting spent more time on VA-ECLS (3.6 versus 2.8 days, P<0.001), and mechanical ventilation (7.1 versus 4.6 days, P=0.013). With the exception of hemolysis (RR, 2.18 [95% CI, 1.58-3.01]; P<0.00001), overall adverse events did not differ. CONCLUSIONS: LV venting, especially if done early (<12 hours), appears to be associated with an increased success of weaning and reduced short-term mortality. Future studies are required to delineate the importance of any or early LV venting adjuncts on mortality and morbidity outcomes.

Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease.

BACKGROUND: Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. METHODS: We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. FINDINGS: We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermore, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. INTERPRETATION: We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel "seno-destructive" SMC phenotype could open new opportunities for managing BAV aortopathy. FUND: Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair.

Selective regulation of the perinuclear distribution of glucose transporter 4 (GLUT4) by insulin signals in muscle cells.

Insulin regulates glucose transporter 4 (GLUT4) availability at the surface of muscle and adipose cells. In L6 myoblasts, stably expressed GLUT4myc is detected mostly in a perinuclear region. In unstimulated cells, about half of perinuclear GLUT4myc colocalizes with the transferrin receptor (TfR). Insulin stimulation selectively decreased the perinuclear colocalization of GLUT4myc with TfR determined by 3D-reconstruction of fluorescence images. Perinuclear GLUT4myc adopted two main distributions defined morphometrically as 'conical' and 'concentric'. Insulin rapidly reduced the proportion of cells with conical in favor of concentric perinuclear GLUT4myc distributions in association with the gain in surface GLUT4myc. Upon removal of insulin, the GLUT4myc perinuclear distribution and surface levels reversed in parallel. In contrast, hypertonicity (which like insulin elevates surface GLUT4myc) did not elicit perinuclear GLUT4myc redistribution. Insulin also caused redistribution of perinuclear vesicle-associated membrane protein-2 (VAMP2), without alteration of perinuclear TfR and VAMP3. Inhibitory mutants of phosphatidylinositol-3 kinase (Deltap85) or Akt substrate AS160 (AS160-4P) prevented insulin-mediated perinuclear GLUT4myc redistribution. Tetanus toxin expression did not prevent the perinuclear GLUT4myc redistribution, suggesting that redistribution is independent of GLUT4myc fusion with the plasma membrane. We propose that insulin causes selective, dynamic relocalization of perinuclear GLUT4myc and VAMP2 and perinuclear GLUT4myc redistribution is a direct target of insulin-derived signals.

Dissecting GLUT4 traffic components in L6 myocytes by fluorescence-based, single-cell assays.

Postprandial blood glucose homeostasis is regulated by an insulin-stimulated increase in glucose transport into muscle and fat tissues via glucose transporter isoform 4 (GLUT4). In the basal state, this constitutively recycling membrane protein predominantly resides intracellularly. In order to achieve the insulin-stimulated increase in glucose flux, GLUT4 increases its cell surface abundance at the expense of preformed intracellular depots. By confocal microscopy of cultured L6 muscle cells stably expressing myc-tagged GLUT4 (L6-GLUT4myc), we can visualize the two arms of GLUT4 traffic: exocytosis (movement to the cell surface) and endocytosis (internalization from the cell surface).