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HeartMate 3 is the only durable left ventricular assist devices (LVAD) currently implanted in the United States. The purpose of this study was to develop a predictive model for 1 year mortality of HeartMate 3 implanted patients, comparing standard statistical techniques and machine learning algorithms. Adult patients registered in the Society of Thoracic Surgeons, Interagency Registry for Mechanically Assisted Circulatory Support (STS-INTERMACS) database, who received primary implant with a HeartMate 3 between January 1, 2017, and December 31, 2019, were included. Epidemiological, clinical, hemodynamic, and echocardiographic characteristics were analyzed. Standard logistic regression and machine learning (elastic net and neural network) were used to predict 1 year survival. A total of 3,853 patients were included. Of these, 493 (12.8%) died within 1 year after implantation. Standard logistic regression identified age, Model End Stage Liver Disease (MELD)-XI score, right arterial (RA) pressure, INTERMACS profile, heart rate, and etiology of heart failure (HF), as important predictor factors for 1 year mortality with an area under the curve (AUC): 0.72 (0.66-0.77). This predictive model was noninferior to the ones developed using the elastic net or neural network. Standard statistical techniques were noninferior to neural networks and elastic net in predicting 1 year survival after HeartMate 3 implantation. The benefit of using machine-learning algorithms in the prediction of outcomes may depend on the type of dataset used for analysis.
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Insuficiência Cardíaca , Coração Auxiliar , Adulto , Humanos , Estados Unidos , Estudos Retrospectivos , Insuficiência Cardíaca/cirurgia , Coração Auxiliar/efeitos adversos , Sistema de Registros , Resultado do TratamentoRESUMO
Cardiomyocytes in the adult human heart show a regenerative capacity, with an annual renewal rate around 0.5%. Whether this regenerative capacity of human cardiomyocytes is employed in heart failure has been controversial. Using retrospective 14C birth dating we analyzed cardiomyocyte renewal in patients with end-stage heart failure. We show that cardiomyocyte generation is minimal in end-stage heart failure patients at rates 18-50 times lower compared to the healthy heart. However, patients receiving left ventricle support device therapy, who showed significant functional and structural cardiac improvement, had a >6-fold increase in cardiomyocyte renewal relative to the healthy heart. Our findings reveal a substantial cardiomyocyte regeneration potential in human heart disease, which could be exploited therapeutically.
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INTRODUCTION: Acute kidney injury (AKI) in patients treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is associated with high mortality. The objective of this study was to investigate whether cytokine levels before the initiation of ECMO treatment could predict AKI. We also aimed to investigate the impact of AKI on 30-day and 1-year mortality. METHODS: Serum cytokine levels were analyzed in 100 consecutive VA-ECMO-treated patients at pre-cannulation, at 48 h post-cannulation, and at 8 days. Clinical data to establish the incidence and outcome of AKI after the start of ECMO was retrieved from the local ECMO registry. SETTING: The study was conducted at tertiary care, university hospital. Participants included 100 patients treated with VA-ECMO. INTERVENTIONS: The blood samples for cytokine analysis were collected before VA-ECMO treatment, at 48 h after VA-ECMO treatment was started, and at 8 days. RESULTS: Pre-cannulation serum IL-10 levels were significantly higher in patients who developed AKI (212 [38.9, 620.7]) versus those who did not (49.0 [11.9, 102.2]; p = 0.007), and the development of AKI can be predicted by pre-cannulation IL-10 levels (p = 0.025, OR = 1.2 [1.02-1.32]). The development of AKI during ECMO treatment is associated with increased 30-day mortality (p = 0.049) compared to patients who did not develop AKI and had a pre-cannulation estimated glomerular filtration rate ≥ 45 mL/min. The 1-year survival rate for patients with AKI who survived the first 30 days of ECMO treatment is comparable to that of patients without AKI. CONCLUSION: Increased pre-cannulation IL-10 levels are associated with the development of AKI during VA-ECMO support. AKI is associated with increased 30-day mortality compared to patients with no AKI and better renal function. However, patients with AKI who survive the first 30 days have a 1-year survival rate similar to those without AKI.
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Injúria Renal Aguda , Oxigenação por Membrana Extracorpórea , Humanos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Interleucina-10 , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Taxa de Sobrevida , Cateterismo , Estudos RetrospectivosRESUMO
PURPOSE: There is limited research on the use and outcomes of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment for massive pulmonary embolism (PE). This study compared VA-ECMO treatment for massive PE versus patients treated medically. MATERIALS AND METHODS: Patients diagnosed with massive PE at one hospital system were reviewed. VA-ECMO and non-ECMO groups were compared by t test and Chi-square. Mortality risk factors were identified by logistic regression. Survival was assessed by Kaplan Meier and propensity matching of groups. RESULTS: Ninety-two patients were included (22 VA-ECMO and 70 non-ECMO). Age (OR 1.08, 95% CI 1.03-1.13), arterial SBP (OR 0.97, 95% CI 0.94-0.99), albumin (OR 0.3, 95% CI 0.1-0.8), and phosphorus (OR 2.0, 95% CI 1.4-3.17) were independently associated with 30-day mortality. Alkaline phosphate (OR 1.03, 95% CI 1.01-1.05) and SOFA score (OR 1.3, 95% CI 1.06-1.51) were associated with 1-year mortality. Propensity matching showed no difference in 30-day (59% VA-ECMO versus 72% non-ECMO, p = 0.363) or 1-year survival (50% VA-ECMO versus 64% non-ECMO, p = 0.355). CONCLUSIONS: Patients treated with VA-ECMO for massive PE and medically treated patients have similar short- and long-term survival. Further research is needed to define clinical recommendations and benefits of intensive therapy such as VA-ECMO in this critically ill population.
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BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a key support modality for cardiogenic shock. The 2018 United Network for Organ Sharing (UNOS) heart transplant allocation algorithm prioritizes VA-ECMO patients. OBJECTIVE: To evaluate the role of VA-ECMO in bridging to advanced heart failure therapies. METHODS: We analyzed adult patients from the multicenter Extracorporeal Life Support Organization registry receiving VA-ECMO for cardiac support or resuscitation between 2016 and 2021 in the United States, comparing bridge-to-transplant (BTT) and non-BTT intent patients, as well as pre- vs post-2018 patients, on a wide range of demographic and clinical outcome predictors. RESULTS: Of 17,087 patients, 797 received left ventricular assist device (LVAD)/heart transplant, 7,931 died or had poor prognosis, and 8,359 had expected recovery at ECMO discontinuation. Patients supported with BTT intent had lower clinical acuity than non-BTT candidates and were more likely to receive LVAD/transplant. The proportion of patients who received VA-ECMO as BTT and received LVAD/transplant increased after 2018. Post-2018 BTT patients had significantly lower clinical acuity and higher likelihood of transplant than both post-2018 non-BTT patients and pre-2018 BTT patients. ECMO complications were associated with lower likelihood of transplant but were significantly less common post-2018 than pre-2018. CONCLUSIONS: After implementation of the 2018 UNOS allocation system, ECMO utilization as BTT or LVAD has increased, and the acuity of BTT intent patients cannulated for ECMO has decreased. There has not yet been an increase in more acute ECMO patients getting transplanted. This may partially explain the post-transplant outcomes of ECMO patients in the current era reported in UNOS.
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Oxigenação por Membrana Extracorpórea , Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Adulto , Humanos , Insuficiência Cardíaca/terapia , Choque Cardiogênico/terapia , Estudos RetrospectivosRESUMO
Endothelial dysfunction and impaired vasodilation are linked with adverse cardiovascular events. T lymphocytes expressing choline acetyltransferase (ChAT), the enzyme catalyzing biosynthesis of the vasorelaxant acetylcholine (ACh), regulate vasodilation and are integral to the cholinergic antiinflammatory pathway in an inflammatory reflex in mice. Here, we found that human T cell ChAT mRNA expression was induced by T cell activation involving the PI3K signaling cascade. Mechanistically, we identified that ChAT mRNA expression was induced following the attenuation of RE-1 Silencing Transcription factor REST-mediated methylation of the ChAT promoter, and that ChAT mRNA expression levels were up-regulated by GATA3 in human T cells. In functional experiments, T cell-derived ACh increased endothelial nitric oxide-synthase activity, promoted vasorelaxation, and reduced vascular endothelial activation and promoted barrier integrity by a cholinergic mechanism. Further, we observed that survival in a cohort of patients with severe circulatory failure correlated with their relative frequency of ChAT +CD4+ T cells in blood. These findings on ChAT+ human T cells provide a mechanism for cholinergic immune regulation of vascular endothelial function in human inflammation.
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Colina O-Acetiltransferase , Linfócitos T , Humanos , Camundongos , Animais , Linfócitos T/metabolismo , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Colinérgicos , Acetilcolina/metabolismo , RNA Mensageiro/metabolismoRESUMO
Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and shorter timelines than are needed to produce a new drug. To date, drug repurposing for cardiovascular indications has been opportunistic and driven by knowledge of disease mechanisms or serendipitous observation rather than by systematic endeavours to match an existing drug to a new indication. Innovations in two areas of personalized medicine - computational approaches to associate drug effects with disease signatures and predictive model systems to screen drugs for disease-modifying activities - support efforts that together create an efficient pipeline to systematically repurpose drugs to treat cardiovascular disease. Furthermore, new experimental strategies that guide the medicinal chemistry re-engineering of drugs could improve repurposing efforts by tailoring a medicine to its new indication. In this Review, we summarize the historical approach to repurposing and discuss the technological advances that have created a new landscape of opportunities.
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Doenças Cardiovasculares , Reposicionamento de Medicamentos , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Medicina de PrecisãoRESUMO
OBJECTIVES: To evaluate the use of temporary-permanent pacemaker (TPP) in patients with right bundle branch block (RBBB) undergoing transcatheter aortic valve replacement (TAVR). We also sought to identify key predictors of permanent pacemaker (PPM) within 30 days of TAVR in this population. BACKGROUND: RBBB is a well-recognized risk factor for PPM post TAVR. TPP provides stable transient pacing and reduces the need for critical care beds. METHODS: This is a retrospective chart review of 371 patients who underwent TAVR at our institution. All patients with pre-existing RBBB had TPP placed prior to TAVR (n = 37). The primary outcome was the need for critical care beds. Multivariate logistic regression analysis was performed to identify predictors of PPM within 30 days of TAVR. RESULTS: 67 patients required PPM within 30 days of TAVR, and 56 implanted before discharge. 51% (19 out of 37) of TPP group required PPM before discharge compared to 11% (37 out of 334) of No TPP (p < 0.001), yet TPP group spent significantly fewer hours in a critical care bed (19 vs 28 h, p = 0.01). Length of membranous septum (LMS) <8.49 mm was the strongest independent predictor of PPM within 30 days of TAVR (RAUC of 0.80, Sensitivity 0.7 and Specificity 0.8) and 98% of patients with LMS < 7 mm required PPM within 30 days. CONCLUSION: TPP-TAVR is a well-defined multidisciplinary protocol that reduces the need for critical care beds in patients with pre-existing RBBB referred for TAVR. Additionally, LMS is the strongest predictor of PPM implantation in this population. CONDENSED ABSTRACT (100 WORDS): This study evaluated the use of temporary-permanent pacemakers (TPP) in patients with right bundle branch block (RBBB) undergoing transcatheter aortic valve replacement (TAVR). TPP-TAVR provided stable pacing allowing for early mobilization and reduced the need for critical care beds. Multivariate logistic regression analysis identified length of membranous septum (LMS) <8.49 mm in patients with RBBB as the strongest independent predictor of PPM need within 30 days of TAVR. 98% of patients with RBBB and LMS < 7 mm required PPM at 30 days regardless of other characteristics including valve type and size.
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Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/etiologia , Bloqueio de Ramo/terapia , Estimulação Cardíaca Artificial/efeitos adversos , Humanos , Estudos Retrospectivos , Fatores de Risco , Substituição da Valva Aórtica Transcateter/efeitos adversos , Resultado do TratamentoRESUMO
Fewer ST-elevation myocardial infarctions (STEMIs) presentations and increased delays in care occurred during the COVID-19 pandemic in urban areas. Whether these associations occurred in a more rural population has not been previously reported. Our objective was to evaluate the impact of COVID-19 on time-to-presentation for STEMI in rural locations. Patients presenting to a large STEMI network spanning 27 facilities and 13 predominantly rural counties between January 1, 2016 and April 30, 2020 were included. Presentation delays, defined as time from symptom onset to arrival at the first medical facility, classified as ≥12 and ≥24 hours from symptom onset were compared among patients in the pre-COVID-19 and the early COVID-19 eras. To account for patient-level differences, 2:1 propensity score matching was performed using binary logistic regression. Among 1,286 patients with STEMI, 1,245 patients presented in the pre-COVID-19 era and 41 presented during the early COVID-19 era. Presentation delays ≥12 hours (19.5% vs 4.0%) and ≥24 hours (14.6% and 0.2%) were more common in COVID-19 than pre-COVID-19 cohorts (p <0.001 for both), despite a low COVID-19 prevalence. Similar results were seen in propensity-matched comparisons (≥12 hours: 19.5% vs 2.4%, p = 0.002; ≥24 hours 14.6% vs 0.0%, p = 0.001). In a predominantly rural STEMI population, delays in seeking medical care after symptom onset were markedly more frequent during the COVID-19 era, despite low COVID-19 prevalence. Considering delays in reperfusion have multiple adverse downstream consequences, these findings may have important implications in rural communities during future pandemic resurgences.
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COVID-19 , Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , COVID-19/epidemiologia , Humanos , Infarto do Miocárdio/epidemiologia , Pandemias , Intervenção Coronária Percutânea/métodos , Prevalência , População Rural , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologiaRESUMO
OBJECTIVES: The augmented inflammatory response to cardiac surgery is a recognized cause of postoperative acute kidney injury. The present study aimed to investigate the effects of preoperative cyclosporine treatment on cytokine production and delineate factors associated with postoperative kidney impairment. DESIGN: A randomized, double-blind, placebo-controlled, single-center study. SETTING: At a tertiary care, university hospital. PARTICIPANTS: Patients eligible for elective coronary artery bypass grafting surgery; 67 patients were enrolled. INTERVENTIONS: Patients were randomized to receive 2.5 mg/kg cyclosporine or placebo before surgery. Cytokine levels were measured after the induction of anesthesia and 4 hours after the end of cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Tissue-aggressive (interleukin [IL]-1ß, macrophage inflammatory protein [MIP]-1ß, granulocyte colony-stimulating factor [G-CSF], IL-6, IL-8, IL-17, MCP-1), as well tissue-lenient (IL-4) cytokines, were significantly elevated in response to surgery. Changes in cytokine levels were not affected by cyclosporine pretreatment. CONCLUSIONS: Elective coronary artery bypass grafting surgery with cardiopulmonary bypass triggers cytokine activation. This activation was not impacted by preoperative cyclosporine treatment.
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Ponte de Artéria Coronária , Ciclosporina , Ponte Cardiopulmonar , Ponte de Artéria Coronária/efeitos adversos , Ciclosporina/farmacologia , Citocinas/farmacologia , Humanos , Rim/fisiologiaRESUMO
PURPOSE: To evaluate the effect of the new heart transplant (HT) allocation system in left ventricular assist device (LVAD) supported patients listed as bridge to transplantation (BTT). METHODS: Adult patients who were listed for HT between October 18, 2016 and October 17, 2019, and were supported with an LVAD, enrolled in the UNOS database were included in this study. Patients were classified in the old or new system if they were listed or transplanted before or after October 18, 2018, respectively. RESULTS: A total of 3261 LVAD patients were listed for transplant. Of these, 2257 were classified in the old and 1004 in the new system. The cumulative incidence of death or removal from the transplant list due to worsening clinical status at 360-days after listing was lower in the new system (4% vs. 7%, P = .011). LVAD Patients listed in the new system had a lower frequency of transplantation within 360-days of listing (52% vs. 61%, P < .001). A total of 1843 LVAD patients were transplanted, 1004 patients in the old system and 839 patients in the new system. The post-transplant survival at 360 days was similar between old and new systems (92.3% vs. 90%, P = .08). However, LVAD patients transplanted in the new system had lower frequency of the combined endpoint, freedom of death or re-transplantation at 360 days (92.2% vs. 89.6%, P = .046). CONCLUSION: The new HT allocation system has affected the LVAD-BTT population significantly. On the waitlist, LVAD patients have a decreased cumulative frequency of transplantation and a concomitant decrease in death or delisting due to worsening status. In the new system, LVAD patients have a decreased survival free of re-transplantation at 360 days post-transplant.
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Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Adulto , Sobrevivência de Enxerto , Insuficiência Cardíaca/cirurgia , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Listas de EsperaRESUMO
Despite progressive improvements over the decades, the rich temporally resolved data in an echocardiogram remain underutilized. Human assessments reduce the complex patterns of cardiac wall motion, to a small list of measurements of heart function. All modern echocardiography artificial intelligence (AI) systems are similarly limited by design - automating measurements of the same reductionist metrics rather than utilizing the embedded wealth of data. This underutilization is most evident where clinical decision making is guided by subjective assessments of disease acuity. Predicting the likelihood of developing post-operative right ventricular failure (RV failure) in the setting of mechanical circulatory support is one such example. Here we describe a video AI system trained to predict post-operative RV failure using the full spatiotemporal density of information in pre-operative echocardiography. We achieve an AUC of 0.729, and show that this ML system significantly outperforms a team of human experts at the same task on independent evaluation.
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Aprendizado Profundo , Insuficiência Cardíaca/diagnóstico por imagem , Disfunção Ventricular Direita/cirurgia , Ecocardiografia , Coração/diagnóstico por imagem , Coração/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Período Pós-Operatório , Cuidados Pré-Operatórios , Estudos Retrospectivos , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Gravação em VídeoRESUMO
BACKGROUND: Multicenter data on long term survival following LVAD implantation that make use of contemporary definitions of RV failure are limited. Furthermore, traditional survival analyses censor patients who receive a bridge to heart transplant. Here we compare the outcomes of LVAD patients who develop post-operative RV failure accounting for the transitional probability of receiving an interim heart transplantation. METHODS: We use a retrospective cohort of LVAD patients sourced from multiple high-volume centers based in the United States. Five- and ten-year survival accounting for transition probabilities of receiving a heart transplant were calculated using a multi-state Aalen Johansen survival model. RESULTS: Of the 897 patients included in the study, 238 (26.5%) developed post-operative RV failure at index hospitalization. At 10 years the probability of death with post-op RV failure was 79.28% vs 61.70% in patients without (HR 2.10; 95% CI 1.72 - 2.57; p = < .001). Though not significant, patients with RV failure were less likely to be bridged to a heart transplant (HR 0.87, p = .4). Once transplanted the risk of death between both patient groups remained equivalent; the probability of death after a heart transplant was 3.97% in those with post-operative RV failure shortly after index LVAD implant, as compared to 14.71% in those without. CONCLUSIONS AND RELEVANCE: Long-term durable mechanical circulatory support is associated with significantly higher mortality in patients who develop post-operative RV failure. Improving outcomes may necessitate expeditious bridge to heart transplant wherever appropriate, along with critical reassessment of organ allocation policies.
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Insuficiência Cardíaca/mortalidade , Transplante de Coração , Ventrículos do Coração/diagnóstico por imagem , Coração Auxiliar/efeitos adversos , Complicações Pós-Operatórias/mortalidade , Disfunção Ventricular Direita/cirurgia , Função Ventricular Direita/fisiologia , Falha de Equipamento , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/cirurgia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Prognóstico , Reoperação , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos/epidemiologia , Disfunção Ventricular Direita/fisiopatologiaRESUMO
Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here, we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two patients with LQT1 with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterization of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay, and whole cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared with healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted norepinephrine. hiPSC-SNs at 60 ± 2.2 days in vitro had healthy resting membrane potentials (-60 ± 1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased norepinephrine release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarization, compared with age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared with heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together, our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes.NEW & NOTEWORTHY Here, we present the first study of patient-derived LQT1 sympathetic neurons that are norepinephrine secreting, and electrophysiologically functional, in vitro. Our data reveal a novel LQT1 sympathetic neuronal phenotype of increased neurotransmission and excitability. The identified sympathetic neuronal hyperactivity phenotype is of particular relevance as it could contribute to the mechanisms underlying sympathetically triggered arrhythmia in LQT1.
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Síndrome do QT Longo/fisiopatologia , Neurônios/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Potenciais de Ação/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Leucócitos Mononucleares/citologia , Técnicas de Patch-ClampRESUMO
PURPOSE OF REVIEW: Drug development has evolved over the years from being one-at-a-time to be massive screens in an industrial manner. Bringing a new therapeutic agent from concept to bedside can take a decade and cost billions of dollars-with most concepts failing along the way. Of the few compounds that make it to clinical testing, less than one out of eight make it to approval. This traditional drug development pipeline is challenging for prevalent diseases and makes the development of new therapeutics for rare diseases financially intractable. RECENT FINDINGS: Repurposing of drugs is an alternative to identify new applications for the thousands of compounds that have already been approved for clinical use. There is now a range of strategies for such efforts that leverage clinical data, pharmacologic data, and/or genomic or transcriptomic data. These strategies, together with examples, are detailed in this review. Drug repurposing bypasses the pre-clinical work and thereby opens up the opportunity to provide targeted treatment at a fraction of the cost that is accompanied with the development from ideation to full approval. Such an approach makes drug discovery for any disease process more efficient but holds particular promise for rare diseases for which there is little to no other viable drug development channel.
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Descoberta de Drogas , Reposicionamento de Medicamentos , Genômica , HumanosRESUMO
Historically, patients with restrictive (RCM) and hypertrophic cardiomyopathy (HCM) experienced longer wait-times for heart transplant (HT) and increased waitlist mortality. Recently, a new HT allocation system was implemented in the United States. We sought to determine the impact of the new HT system on RCM/HCM patients. Adult patients with RCM/HCM listed for HT between November 2015 and September 2019 were identified from the UNOS database. Patients were stratified into two groups: old system and new system. We identified 872 patients who met inclusion criteria. Of these, 608 and 264 were classified in the old and new system groups, respectively. The time in the waitlist was shorter (25 vs. 54 days, P < .001), with an increased frequency of HT in the new system (74% vs. 68%, P = .024). Patients who were transplanted in the new system had a longer ischemic time, increased use of temporary mechanical circulatory support and mechanical ventilation. There was no difference in posttransplant survival at 9 months (91.1% vs. 88.9%) (p = .4). We conclude that patients with RCM/HCM have benefited from the new HT allocation system, with increased access to HT without affecting short-term posttransplant survival.
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Cardiomiopatia Hipertrófica , Transplante de Coração , Transplantes , Adulto , Cardiomiopatia Hipertrófica/cirurgia , Bases de Dados Factuais , Transplante de Coração/efeitos adversos , Humanos , Estudos Retrospectivos , Estados Unidos/epidemiologia , Listas de EsperaRESUMO
Historically, adult congenital patients have longer waitlist time and worse outcomes on the heart transplant waitlist as well as poorer early post-transplant survival. A new heart transplantation allocation system was implemented in the United States on October 18, 2018. The effect of the new allocation system on adult congenital patients is unknown. Adult congenital patients listed for transplantation between November 1, 2015 and September 30, 2019 registered in the United Network for Organ Sharing were included in the study. October 18, 2018 was used as the limit to distribute listed and transplanted patients into old and new groups. A total of 399 patients were listed for heart transplant only, 284 in the old system and 115 in the new system. Clinical characteristics were similar between both groups. The cumulative incidence of poor outcome on the transplant list was similar in both groups (P = .23), but the cumulative incidence of transplant was higher in the new system group (P < .009) and was associated with a shorter waitlist time. The one-year post-transplant outcome was similar between old and new groups (P = .37). The new allocation system has benefited adult congenital patients with increased cumulative frequency of transplantation without worsening short-term survival after transplantation.
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Cardiopatias Congênitas , Insuficiência Cardíaca , Transplante de Coração , Adulto , Sobrevivência de Enxerto , Cardiopatias Congênitas/cirurgia , Humanos , Estudos Retrospectivos , Estados Unidos/epidemiologia , Listas de EsperaRESUMO
BACKGROUND: Historically, patients bridged on extracorporeal membrane oxygenation (ECMO) to heart transplantation (HT) have very high post-transplant mortality. In the new heart transplant allocation system, ECMO-supported patients have the highest priority for HT. However, data are lacking on the outcomes of these critically ill patients. We compared the waitlist and post-transplant outcomes of ECMO-supported patients in the new and old allocation systems. METHODS: Adult patients supported by ECMO at the time of listing or transplantation who were registered in the United Network for Organ Sharing database between November 1, 2015 and September 30, 2019 were included. Clinical characteristics, outcomes in the waitlist, and post-transplant survival were compared between the old and new systems. Cox Proportional and subdistribution hazard regression models were used to evaluate the variables contributing to the post-transplant and waitlist outcomes RESULTS: A total of 296 ECMO-supported patients were listed for HT. Of these, 191 were distributed to the old system, and 105 were distributed to the new system. Patients listed in the new system had a higher cumulative incidence of HT (p < 0.001) and lower incidence of death or removal (pâ¯=â¯0.001) from the transplant list than patients listed in the old system. The 6-month survival after transplantation was 74.6% and 90.6% for the old- and new-era patients, respectively (pâ¯=â¯0.002). Among ECMO-supported patients, being listed or transplanted on the new system was independently associated with improved outcomes in the waitlist and after transplantation. CONCLUSIONS: With the implementation of the new heart transplant allocation system, ECMO-supported patients have a shorter waitlist time, improved frequency of HT, and improved short-term post-transplant survival.