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1.
Ann Thorac Surg ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34592266

RESUMO

Atrioesophageal fistula (AEF) formation is a rare but formidable complication after catheter radiofrequency ablation (RFA) for atrial fibrillation. We present four patients who underwent urgent primary intracardiac repair of the left atrium via sternotomy with central cardiopulmonary bypass and early aortic cross-clamp, followed by repair of the esophagus. We believe that this approach represents the safest strategy for addressing this morbid and often fatal complication.

2.
ASAIO J ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34560718

RESUMO

Continuous-flow left ventricular assist devices (CF-LVAD) have been shown to enhance reverse remodeling and myocardial recovery in certain patients allowing for device removal. We sought to analyze the characteristics and describe outcomes of patients who underwent CF-LVAD explantation at a large academic center. We retrospectively identified all patients who underwent CF-LVAD explants due to recovery from 2006 to 2019. Patient baseline characteristics and data on pre- and postexplant evaluation were collected and analyzed. Of 421 patients who underwent CF-LVAD implantation, 13 underwent explantation (3.1%). Twelve HeartMate II and one HeartWare LVAD were explanted. All patients had nonischemic cardiomyopathy. Median time from heart failure diagnosis to LVAD implant was 12 months (interquartile range [IQR], 2-44) and the median time supported on LVAD was 22 months (IQR, 11-28). Two patients died within 30 days of explant. Three additional patients died during the follow-up period and all were noted to be nonadherent to medical therapy. After a mean follow-up duration of 5 years, overall survival was 52%. Mean pre-explant ejection fraction was 49%, which decreased at most recent follow-up to 32%. Mean pre-explant left ventricular internal diameter in diastole (LVIDD) was 4.37 cm and increased to 5.52 cm at most recent follow-up. Continuous-flow left ventricular assist device explantation is feasible and safe in select patients.

3.
J Am Coll Cardiol ; 78(1): 1-9, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-33945832

RESUMO

BACKGROUND: Transcatheter edge-to-edge (TEER) mitral repair may be complicated by residual or recurrent mitral regurgitation. An increasing need for surgical reintervention has been reported, but operative outcomes are ill defined. OBJECTIVES: This study evaluated national outcomes of mitral surgery after TEER. METHODS: The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database was used to identify 524 adults who underwent mitral surgery after TEER between July 2014 and June 2020. Emergencies (5.0%; n = 26), previous mitral surgery (5.3%; n = 28), or open implantation of transcatheter prostheses (1.5%; n = 8) were excluded. The primary outcome was 30-day or in-hospital mortality. RESULTS: In the study cohort of 463 patients, the median age was 76 years (interquartile range [IQR]: 67 to 81 years), median left ventricular ejection fraction was 57% (IQR: 48% to 62%), and 177 (38.2%) patients had degenerative disease. Major concomitant cardiac surgery was performed in 137 (29.4%) patients: in patients undergoing isolated mitral surgery, the median STS-predicted mortality was 6.5% (IQR: 3.9% to 10.5%), the observed mortality was 10.2% (n = 23 of 225), and the ratio of observed to expected mortality was 1.2 (95% confidence interval [CI]: 0.8 to 1.9). Predictors of mortality included urgent surgery (odds ratio [OR]: 2.4; 95% CI: 1.3 to 4.6), nondegenerative/unknown etiology (OR: 2.2; 95% CI: 1.1 to 4.5), creatinine of >2.0 mg/dl (OR: 3.8; 95% CI: 1.9 to 7.9) and age of >80 years (OR: 2.1; 95% CI: 1.1 to 4.4). In a volume outcomes analysis in an expanded cohort of 591 patients at 227 hospitals, operative mortality was 2.6% (n = 2 of 76) in 4 centers that performed >10 cases versus 12.4% (n = 64 of 515) in centers performing fewer (p = 0.01). The surgical repair rate after failed TEER was 4.8% (n = 22) and was 6.8% (n = 12) in degenerative disease. CONCLUSIONS: This study indicates that mitral repair is infrequently achieved after failed TEER, which may have implications for treatment choice in lower-risk and younger patients with degenerative disease. These findings should inform patient consent for TEER, clinical trial design, and clinical performance measures.


Assuntos
Cateterismo Cardíaco , Implante de Prótese de Valva Cardíaca , Anuloplastia da Valva Mitral/efeitos adversos , Insuficiência da Valva Mitral , Valva Mitral , Complicações Pós-Operatórias , Reoperação , Fatores Etários , Idoso , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/métodos , Feminino , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/métodos , Mortalidade Hospitalar , Humanos , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/patologia , Valva Mitral/cirurgia , Anuloplastia da Valva Mitral/métodos , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/mortalidade , Insuficiência da Valva Mitral/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Prognóstico , Recidiva , Reoperação/efeitos adversos , Reoperação/métodos , Reoperação/estatística & dados numéricos , Fatores de Risco , Estados Unidos
4.
Curr Heart Fail Rep ; 18(4): 240-251, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33956313

RESUMO

PURPOSE OF REVIEW: Cardiogenic shock represents a very challenging patient population due to the undifferentiated pathologies presenting as cardiogenic shock, difficult decision-making, prognostication, and ever-expanding support options. The role of cardiac surgeons on this team is evolving. RECENT FINDINGS: The implementation of a shock team is associated with improved outcomes in patients with cardiogenic shock. Early deployment of mechanical circulatory support devices may allow an opportunity to rescue these patients. Cardiothoracic surgeons are a critical component of the shock team who can deploy timely mechanical support and surgical intervention in selected patients for optimal outcomes.

5.
Elife ; 102021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33755016

RESUMO

SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines, yet is frequently mutated in human cancer. Here, we examine the role of SHP2 in the responses of breast cancer cells to EGF by monitoring phosphoproteome dynamics when SHP2 is allosterically inhibited by SHP099. The dynamics of phosphotyrosine abundance at more than 400 tyrosine residues reveal six distinct response signatures following SHP099 treatment and washout. Remarkably, in addition to newly identified substrate sites on proteins such as occludin, ARHGAP35, and PLCγ2, another class of sites shows reduced phosphotyrosine abundance upon SHP2 inhibition. Sites of decreased phospho-abundance are enriched on proteins with two nearby phosphotyrosine residues, which can be directly protected from dephosphorylation by the paired SH2 domains of SHP2 itself. These findings highlight the distinct roles of the scaffolding and catalytic activities of SHP2 in effecting a transmembrane signaling response.


Assuntos
Receptores ErbB/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteômica/métodos , Catálise , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Ocludina/metabolismo , Fosfolipase C gama/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Fosfotirosina/metabolismo , Piperidinas/metabolismo , Piperidinas/farmacologia , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Domínios de Homologia de src
6.
J Am Coll Cardiol ; 77(6): 713-724, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33573741

RESUMO

BACKGROUND: Whether to repair nonsevere tricuspid regurgitation (TR) during surgery for ischemic mitral valve regurgitation (IMR) remains uncertain. OBJECTIVES: The goal of this study was to investigate the incidence, predictors, and clinical significance of TR progression and presence of ≥moderate TR after IMR surgery. METHODS: Patients (n = 492) with untreated nonsevere TR within 2 prospectively randomized IMR trials were included. Key outcomes were TR progression (either progression by ≥2 grades, surgery for TR, or severe TR at 2 years) and presence of ≥moderate TR at 2 years. RESULTS: Patients' mean age was 66 ± 10 years (67% male), and TR distribution was 60% ≤trace, 31% mild, and 9% moderate. Among 2-year survivors, TR progression occurred in 20 (6%) of 325 patients. Baseline tricuspid annular diameter (TAD) was not predictive of TR progression. At 2 years, 37 (11%) of 323 patients had ≥moderate TR. Baseline TR grade, indexed TAD, and surgical ablation for atrial fibrillation were independent predictors of ≥moderate TR. However, TAD alone had poor discrimination (area under the curve, ≤0.65). Presence of ≥moderate TR at 2 years was higher in patients with MR recurrence (20% vs. 9%; p = 0.02) and a permanent pacemaker/defibrillator (19% vs. 9%; p = 0.01). Clinical event rates (composite of ≥1 New York Heart Association functional class increase, heart failure hospitalization, mitral valve surgery, and stroke) were higher in patients with TR progression (55% vs. 23%; p = 0.003) and ≥moderate TR at 2 years (38% vs. 22%; p = 0.04). CONCLUSIONS: After IMR surgery, progression of unrepaired nonsevere TR is uncommon. Baseline TAD is not predictive of TR progression and is poorly discriminative of ≥moderate TR at 2 years. TR progression and presence of ≥moderate TR are associated with clinical events. (Comparing the Effectiveness of a Mitral Valve Repair Procedure in Combination With Coronary Artery Bypass Grafting [CABG] Versus CABG Alone in People With Moderate Ischemic Mitral Regurgitation, NCT00806988; Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation, NCT00807040).


Assuntos
Progressão da Doença , Insuficiência da Valva Mitral/cirurgia , Isquemia Miocárdica/complicações , Insuficiência da Valva Tricúspide/epidemiologia , Idoso , Desfibriladores Implantáveis , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Masculino , Marca-Passo Artificial , Estudos Prospectivos , Recidiva , Índice de Gravidade de Doença , Acidente Vascular Cerebral/epidemiologia , Valva Tricúspide/diagnóstico por imagem
7.
Ann Thorac Surg ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33631158

RESUMO

BACKGROUND: We hypothesized that long-term clinical and echocardiographic recovery of the impaired ventricle from pressure (AS) and volume (AR) overload would be different following aortic valve replacement (AVR). METHODS: We compared the results of AVR in patients with a pre-operative ejection fraction (EF) of 0.35 or less due to AS, AR or mixed disease. We constructed a mixed-effects model of EF and left ventricular end diastolic diameter (LVEDD) to understand ventricular recovery over the short (in-hospital), intermediate (3-6 month) and longer (>24 months) terms. We sought to identify factors associated with clinical and echocardiographic recovery using multivariable analysis. RESULTS: Between July 2011 and 2017, 136 patients with pre-operative EF of 0.35 or less and severe AS (83), severe AR (18) or mixed AS and AR (35) underwent AVR. There were 2 early deaths in the AS group (1.5%). Survival at 1, 2 and 5 years did not differ between groups. Baseline EF did not differ between the groups but improved with markedly different trajectory and time course in AS, AR and mixed groups over time. LVEDD regressed in all patient cohorts, following a different pattern for AS and AR. Baseline EF and LVEDD predicted long term fate of the LV but did not determine survival. We identify factors associated with long term survival. CONCLUSIONS: The pattern of LV recovery appears to be early in AS and delayed in AR. Baseline clinical factors, rather than echocardiographic status of the LV, appear to determine late survival.

8.
Shock ; 56(2): 245-254, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33394972

RESUMO

INTRODUCTION: Lactic acidosis after cardiac surgery with cardiopulmonary bypass is common and associated with an increase in postoperative morbidity and mortality. A number of potential causes for an elevated lactate after cardiopulmonary bypass include cellular hypoxia, impaired tissue perfusion, ischemic-reperfusion injury, aerobic glycolysis, catecholamine infusions, and systemic inflammatory response after exposure to the artificial cardiopulmonary bypass circuit. Our goal was to examine the relationship between early abnormalities in microcirculatory convective blood flow and diffusive capacity and lactate kinetics during early resuscitation in the intensive care unit. We hypothesized that patients with impaired microcirculation after cardiac surgery would have a more severe postoperative hyperlactatemia, represented by the lactate time-integral of an arterial blood lactate concentration greater than 2.0 mmol/L. METHODS: We measured sublingual microcirculation using incident darkfield video microscopy in 50 subjects on intensive care unit admission after cardiac surgery. Serial measurements of systemic hemodynamics, blood gas, lactate, and catecholamine infusions were recorded each hour for the first 6 h after surgery. Lactate area under the curve (AUC) was calculated over the first 6 h. The lactate AUC was compared between subjects with normal and low perfused vessel density (PVD < 18 mm/mm2), high microcirculatory heterogeneity index (MHI > 0.4), and low vessel-by-vessel microvascular flow index (MFIv < 2.6). RESULTS: Thirteen (26%) patients had a low postoperative PVD, 20 patients (40%) had a high MHI, and 26 (52%) patients had a low MFIv. Patients with low perfused vessel density had higher lactate AUC compared with subjects with a normal PVD (22.3 [9.4-31.0] vs. 2.6 [0-8.8]; P < 0.0001). Patients with high microcirculatory heterogeneity had a higher lactate AUC compared with those with a normal MHI (2.5 [0.1-8.2] vs. 13.1 [3.7-31.1]; P < 0.001). We did not find a difference in lactate AUC when comparing high and low MFIv. CONCLUSION: Low perfused vessel density and high microcirculatory heterogeneity are associated with an increased intensity and duration of lactic acidosis after cardiac surgery with cardiopulmonary bypass.

9.
Am Heart J ; 232: 1-9, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33214129

RESUMO

BACKGROUND: Patients with atrial fibrillation (AF) who have undergone mitral valve repair are at risk for thromboembolic strokes. Prior to 2019, only vitamin K antagonists were recommended for patients with AF who had undergone mitral valve repair despite the introduction of direct oral anticoagulants (DOAC) in 2010. OBJECTIVE: To characterize the use of anticoagulants in patients with AF who underwent surgical mitral valve repair (sMVR) or transcatheter mitral valve repair (tMVR). METHODS: We performed a retrospective cohort analysis of patients with AF undergoing sMVR or tMVR between 04/2014 and 12/2018 using Optum's de-identified Clinformatics® Data Mart Database. We identified anticoagulants prescribed within 90 days of discharge from hospitalization. RESULTS: Overall, 1997 patients with AF underwent valve repair: 1560 underwent sMVR, and 437 underwent tMVR. The mean CHA2DS2-VASc score among all patients was 4.1 (SD 1.9). The overall use of anticoagulation was unchanged between 2014 (72.2%) and 2018 (70.0%) (P = .49). Among patients who underwent sMVR or tMVR between April 2014 and December 2018, the use of VKA therapy decreased from 62.9% to 32.1% (P < .01 for trend) and the use of DOACs increased from 12.4% to 37.3% (P < .01 for trend). CONCLUSIONS: Among patients with AF who underwent sMVR or tMVR between 2014 and 2018, roughly 30% of patients were not treated with any anticoagulant within 90 days of discharge, despite an elevated stroke risk in the cohort. The rate of DOAC use increased steadily over the study period but did not significantly increase the rate of overall anticoagulant use in this high-risk cohort.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Anuloplastia da Valva Mitral , Insuficiência da Valva Mitral/cirurgia , Acidente Vascular Cerebral/prevenção & controle , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Feminino , Fidelidade a Diretrizes , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/complicações , Cuidados Pós-Operatórios , Guias de Prática Clínica como Assunto , Acidente Vascular Cerebral/etiologia
10.
J Thorac Cardiovasc Surg ; 162(1): 155-164.e2, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32014329

RESUMO

OBJECTIVE: This study seeks to assess the safety of overlap in cardiac surgery. METHODS: Coarsened exact matching was used to assess the impact of overlap on outcomes among cardiac surgical interventions (n = 4463) over 2 years (2014-2016). Overlap was categorized as any, beginning, or end overlap. Study subjects were matched 1:1 on 11 variables, including Charlson comorbidity score, surgical costs, body mass index, length of postoperative hospitalization, and race, among others. Serious unanticipated events were studied, including readmission, unplanned return to the operating room, and mortality. RESULTS: A total of 984 patients had any overlap and were matched to similar patients without overlap (n = 1501). For beginning/end overlap, separate matched groups were created (n = 462, n = 329 patients, respectively). Among matched patients, any overlap did not predict unanticipated return to surgery at 30 or 90 days. Any overlap did not predict increased readmission, reoperation, or emergency department visits at 30 or 90 days. Overlap did not predict higher rates of death over follow-up. Beginning/end overlap had results similar to any overlap. CONCLUSIONS: Nonconcurrent, overlapping surgery is not associated with an increase in adverse outcomes in a large, matched cardiac surgery population.

11.
J Thorac Cardiovasc Surg ; 161(2): 666-678.e3, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-31973895

RESUMO

OBJECTIVES: There is limited evidence to guide the decision to proceed with weaning from venoarterial extracorporeal membrane oxygenation, and approximately 30% of patients weaned "successfully" do not survive to hospital discharge. We evaluated predictors of in-hospital mortality and midterm outcomes of patients successfully weaned from venoarterial extracorporeal membrane oxygenation after support for cardiogenic shock, surviving more than 24 hours after weaning, with the aim of improving patient selection for durable weaning. METHODS: We performed a retrospective analysis of 92 patients supported on venoarterial extracorporeal membrane oxygenation and successfully weaned between January 2013 and February 2018. Survival was estimated by the Kaplan-Meier method. Predictors of in-hospital mortality were identified using a Cox proportional hazards model and an Akaike information criterion-selected multivariate model. RESULTS: Overall survival at hospital discharge was 64.2%; survival was 54.6% 1 year after support and 51.4% 3 years after support. A history of diabetes, previous myocardial infarction, prolonged extracorporeal membrane oxygenation support, and hypoxemia at extracorporeal membrane oxygenation weaning were independent predictors of in-hospital mortality. At midterm follow-up, New York Heart Association class I heart function was observed in 53% of patients, class II in 19%, class III in 16%, and class IV in 12%. Average left ventricular ejection fraction was 46.5% ± 18.2%, and 50% of the patients had been readmitted to the hospital because of heart failure. CONCLUSIONS: Durable extracorporeal membrane oxygenation weaning with acceptable midterm functional status is obtainable in well-selected patients. Previous myocardial infarction, diabetes, prolonged extracorporeal membrane oxygenation support, and pulmonary dysfunction strongly predicted in-hospital mortality after venoarterial extracorporeal membrane oxygenation weaning. In this high-risk situation, other heart replacement therapies should be considered.


Assuntos
Oxigenação por Membrana Extracorpórea/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
12.
J Cardiothorac Vasc Anesth ; 35(7): 2144-2154, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33268279

RESUMO

Coronary artery bypass grafting is a highly efficacious mode of myocardial revascularization that reduces mortality from ischemic heart disease. The patient presenting after acute myocardial infarction in cardiogenic shock presents a unique challenge. Early revascularization is proven to reduce mortality, but many questions remain, including the optimal mode and extent of revascularization, the role of mechanical circulatory support, and which patients are candidates for surgical intervention. Unprecedented attention to the outcomes of cardiac surgery means decisions about the management of the acute myocardial infarction in cardiogenic shock patients are influenced by risk aversion. The authors here review this topic to arm the reader with a comprehensive understanding of the literature to better guide surgical decision-making and perioperative management.

13.
J Cardiothorac Vasc Anesth ; 35(1): 106-115, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32505603

RESUMO

OBJECTIVE: Resuscitation after cardiac surgery needs to address multiple pathophysiological processes that are associated with significant morbidity and mortality. Functional microcirculatory derangements despite normal systemic hemodynamics have been previously described but must be tied to clinical outcomes. The authors hypothesized that microcirculatory dysfunction after cardiac surgery would include impaired capillary blood flow and impaired diffusive capacity and that subjects with the lowest quartile of perfused vessel density would have an increased postoperative lactate level and acute organ injury scores. DESIGN: Prospective, observational study. SETTING: A single, tertiary university cardiovascular surgical intensive care unit. PARTICIPANTS: 25 adults undergoing elective cardiac surgery requiring cardiopulmonary bypass. INTERVENTION: Sublingual microcirculation was imaged using incident dark field microscopy before and 2 to 4 hours after surgery in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: Compared with baseline measurements, postoperative vessel-by-vessel microvascular flow index (2.9 [2.8-2.9] v 2.5 [2.4-2.7], p < 0.0001) and perfused vessel density were significantly impaired (20.7 [19.3-22.9] v 16.3 [12.8-17.9], p < 0.0001). The lowest quartile of perfused vessel density (<12.8 mm/mm2) was associated with a significantly increased postoperative lactate level (6.0 ± 2.9 v 1.8 ± 1.2, p < 0.05), peak lactate level (7.6 ± 2.8 v 2.8 ± 1.5, p = 0.03), and sequential organ failure assessment (SOFA) score at 24 and 48 hours. CONCLUSION: In patients undergoing cardiac surgery, there was a significant decrease in postoperative microcirculatory convective blood flow and diffusive capacity during early postoperative resuscitation. Severely impaired perfused vessel density, represented by the lowest quartile of distribution, is significantly related to hyperlactatemia and early organ injury.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Ácido Láctico , Adulto , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Hemodinâmica , Humanos , Microcirculação , Soalho Bucal , Estudos Prospectivos
14.
ESC Heart Fail ; 7(6): 3573-3581, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33263224

RESUMO

AIMS: Perioperative blood transfusions are common among patients undergoing left ventricular assist device (LVAD) implantation. The association between blood product transfusion at the time of LVAD implantation and mortality has not been described. METHODS AND RESULTS: This was a retrospective cohort study of all patients who underwent continuous flow LVAD implantation at a single, large, tertiary care, academic centre, from 2008 to 2014. We assessed used of packed red blood cells (pRBCs), platelets, and fresh frozen plasma (FFP). Outcomes of interest included all-cause mortality and acute right ventricular (RV) failure. Standard regression techniques were used to examine the association between blood product exposure and outcomes of interest. A total of 170 patients were included in this study (mean age: 56.5 ± 15.5 years, 79.4% men). Over a median follow-up period of 11.2 months, for every unit of pRBC transfused, the hazard for mortality increased by 4% [hazard ratio (HR) 1.04; 95% CI 1.02-1.07] and odds for acute RV failure increased by 10% (odds ratio 1.10; 95% CI 1.05-1.16). This association persisted for other blood products including platelets (HR for mortality per unit 1.20; 95% CI 1.08-1.32) and FFP (HR for mortality per unit 1.08; 95% CI 1.04-1.12). The most significant predictor of perioperative blood product exposure was a lower pre-implant haemoglobin. CONCLUSIONS: Perioperative blood transfusions among patients undergoing LVAD implantation were associated with a higher risk for all-cause mortality and acute RV failure. Of all blood products, FFP use was associated with worst outcomes. Future studies are needed to evaluate whether pre-implant interventions, such as intravenous iron supplementation, will improve the outcomes of LVAD candidates by decreasing need for transfusions.


Assuntos
Coração Auxiliar , Disfunção Ventricular Direita , Adulto , Idoso , Transfusão de Sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
15.
Ann Thorac Surg ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33227272

RESUMO

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) cause degradation of von Willebrand factor (VWF) multimers and bleeding. Multiple techniques exist to characterize VWF deficiency. However, a standard methodology has not been established in LVAD patients. Toward this goal, we evaluated 4 methods to quantify VWF multimers. METHODS: We collected paired blood samples from patients (n = 48) before and after 1 week of LVAD support. After 652 ± 59 days of support, patients were classified as bleeders (≥1 bleeding episode) or nonbleeders. VWF multimers were resolved with electrophoresis and immunoblotting, the gold-standard to evaluate VWF multimers. We evaluated 4 quantification methods. RESULTS: Each method demonstrated significant VWF degradation during LVAD support vs a paired, pre-LVAD sample (method 1, VWF length: 48 of 48 patients, -10% ± 1%, P < .0001; method 2, VWF density: 40 of 48, -34% (interquartile range, -46% to -8%), P < .0001; method 3, pre-LVAD to LVAD ratio: 46 of 48, 17 ± 5: 10 ± 1, P < .0001; method 4, LVAD/pre-LVAD index: 46 of 48, 57% (interquartile range, 50% to 73%), P < .0001). Bleeding occurred in 27 of 48 patients. Method 1 demonstrated significantly fewer VWF multimers in bleeders compared with nonbleeders (-11% ± 1% vs -8% ± 1%; P = .01). Other methods did not demonstrate this potentially important clinical relationship. CONCLUSIONS: A standardized methodology is needed to quantify VWF multimer degradation with mechanical circulatory support devices. Novel method 1 successfully quantified the patient-specific change in VWF multimer length during LVAD support and demonstrated a difference in VWF multimers between bleeders and nonbleeders. Adoption of consensus methodology will assist to standardize patient-specific bleeding risk, inform anticoagulation and antiplatelet therapy, and evaluate LVAD hemocompatibility.

16.
J Med Chem ; 63(22): 13578-13594, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32910655

RESUMO

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Antineoplásicos/uso terapêutico , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Macaca fascicularis , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ratos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
Perfusion ; : 267659120958153, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32940143

RESUMO

PURPOSE: We sought to assess the relationship of intraoperative perfusion parameters while on cardiopulmonary bypass, including oxygen delivery (DO2), to the need for ECMO following orthotopic heart transplantation (OHT). METHODS: We included all adult (>18 years old) OHTs performed at our institution since implementation of an electronic perfusion record (March 2019-February 2020). Multi-organ transplants were excluded. The primary outcome was the need for immediate venoarterial ECMO in the OR following OHT. Univariable statistics were computed across demographic, clinical, operative, and perfusion variables, including oxygen delivery (DO2) measured each minute. RESULTS: Fifty-three OHT were included with a median age of 54 years (interquartile range, 45-61). The primary outcome occurred in eight patients (15.1%). A significantly greater proportion of patients requiring ECMO had ischemic cardiomyopathy (50.0% (4/8) vs. 15.6% (7/45), p = 0.02) and had preoperative ventricular assist devices (37.5% (3/8) vs. 8.9% (4/45), p = 0.03). Median bypass times were longer in the ECMO group (217 vs. 147 minutes, p = 0.001). Phenylephrine doses were nonsignificantly higher in ECMO patients (4.1 vs. 1.9 mg, p = 0.10). No significant differences were observed in single-point median DO2 (275 vs. 294 mL O2/min/m2 BSA, p = 0.17) and nadir DO2 (226 vs. 222, p = 0.94), but increasing time and depth of DO2 below a threshold of 300 mL O2/min/m2 BSA (i.e. area over the DO2 curve (AOC) but below threshold) was significantly associated with the need for postoperative ECMO (p = 0.04). CONCLUSION: This is the first study to examine the relationship of perfusion parameters, including oxygen delivery, to outcomes following heart transplantation. We note that DO2 < 300-AOC was significantly associated with the need for postoperative ECMO following heart transplant. Further study will clarify whether potential DO2 differences in patients who require post-OHT ECMO reflect vasoplegia, or a more causative relationship which might be leveraged to improve outcomes.

18.
J Card Fail ; 26(10): 870-875, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32681883

RESUMO

BACKGROUND: Impella (Abiomed Inc, Danvers, MA) is a temporary mechanical support device positioned across the aortic valve, and can be used to support patient before LVAD implantation. There are no data on the incidence of aortic insufficiency (AI) in patients supported with Impella as a bridge to durable LVAD implantation. We sought to assess the incidence of AI in patients with Impella support as a bridge to durable left ventricular assist device (LVAD) implantation. METHODS: We reviewed all patients undergoing primary LVAD implantation at the University of Pennsylvania from January 2015 onward, comparing those supported with Impella as temporary mechanical support with those supported by either venoarterial extracorporeal life support or an intra-aortic balloon pump. We reviewed transthoracic echocardiography preoperatively, as well as at 1 week, 1, 3, 6, 9, and 12 months after LVAD implantation. RESULTS: A total of 215 echocardiograms were analyzed in 41 patients. Eleven patients were supported with Impella before LVAD implant-6 patients with Impella alone (5 with Impella CP, 1 with Impella 5.0) and 5 with Impella in conjunction with venoarterial extracorporeal life support (2 with Impella 2.5, 2 with Impella CP, and 1 with Impella 5.0). After LVAD implant, mild or moderate AI developed in 82% of patients supported with Impella (9 of 11) compared with 43% of those without Impella (13 of 30) (P = .038). CONCLUSIONS: Patients supported by Impella as a bridge to durable LVAD have a higher risk of developing AI. Further studies are needed to assess this risk as the use of the Impella increases.

19.
Eur J Cardiothorac Surg ; 58(5): 923-931, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32725134

RESUMO

OBJECTIVES: There has been increasing interest in using extracorporeal membrane oxygenation (ECMO) to rescue patients with pulmonary embolism (PE) in the advanced stages of respiratory or haemodynamic decompensation. We examined mid-term outcomes and risk factors for in-hospital mortality. METHODS: We conducted a retrospective study of 36 patients who required ECMO placement (32 veno-arterial ECMO, 4 veno-venous) following acute PE. Survival curves were estimated using the Kaplan-Meier method. Risk factors for in-hospital mortality were assessed by logistic regression analysis. Functional status and quality of life were assessed by phone questionnaire. RESULTS: Overall survival to hospital discharge was 44.4% (16/36). Two-year survival conditional to discharge was 94% (15/16). Two-year survival after veno-arterial ECMO was 39% (13/32). In patients supported with veno-venous ECMO, survival to discharge was 50%, and both patients were alive at follow-up. In univariable analysis, a history of recent surgery (P = 0.064), low left ventricular ejection fraction (P = 0.029), right ventricular dysfunction ≥ moderate at weaning (P = 0.083), on-going cardiopulmonary resuscitation at ECMO placement (P = 0.053) and elevated lactate at weaning (P = 0.002) were risk factors for in-hospital mortality. In multivariable analysis, recent surgery (P = 0.018) and low left ventricular ejection fraction at weaning (P = 0.013) were independent factors associated with in-hospital mortality. At a median follow-up of 23 months, 10 patients responded to our phone survey; all had acceptable functional status and quality of life. CONCLUSIONS: Massive acute PE requiring ECMO support is associated with high early mortality, but patients surviving to hospital discharge have excellent mid-term outcomes with acceptable functional status and quality of life. ECMO can provide a stable platform to administer other intervention with the potential to improve outcomes. Risk factors for in-hospital mortality after PE and veno-arterial ECMO support were identified.


Assuntos
Oxigenação por Membrana Extracorpórea , Embolia Pulmonar , Humanos , Embolia Pulmonar/complicações , Embolia Pulmonar/terapia , Qualidade de Vida , Estudos Retrospectivos , Choque Cardiogênico , Volume Sistólico , Função Ventricular Esquerda
20.
J Cardiothorac Surg ; 15(1): 161, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616001

RESUMO

BACKGROUND: High ischemic mitral regurgitation (IMR) recurrence rates continue to plague IMR repair with undersized ring annuloplasty. We have previously shown that pre-repair three-dimensional echocardiography (3DE) analysis is highly predictive of IMR recurrence. The objective of this study was to determine the quantitative change in 3DE annular and leaflet tethering parameters immediately after repair and to determine if intraoperative post-repair 3DE parameters would be able to predict IMR recurrence 6 months after repair. METHODS: Intraoperative pre- and post-repair transesophageal real-time 3DE was performed in 35 patients undergoing undersized ring annuloplasty for IMR. An advanced modeling algorhythm was used to assess 3D annular geometry and regional leaflet tethering. IMR recurrence (≥ grade 2) was assessed with transthoracic echocardiography 6 months after repair. RESULTS: Annuloplasty significantly reduced septolateral diameter, commissural width, annular area, and tethering volume and significantly increased all segmental tethering angles (except A2). Intraoperative post-repair annular geometry and leaflet tethering did not differ significantly between patients with recurrent IMR (n = 9) and patients with non-recurrent IMR (n = 26). No intraoperative post-repair predictors of IMR recurrence could be identified. CONCLUSIONS: Undersized ring annuloplasty changes mitral geometry acutely, exacerbates leaflet tethering, and generally fixes IMR acutely, but it does not always fix the delicate underlying chronic problem of continued left ventricular dilatation and remodeling. This may explain why pre-repair 3D valve geometry (which reflects chronic left ventricular remodeling) is highly predictive of recurrent IMR, whereas immediate post-repair 3D valve geometry (which does not completely reflect chronic left ventricular remodeling anymore) is not.


Assuntos
Insuficiência da Valva Mitral/cirurgia , Idoso , Ecocardiografia , Ecocardiografia Tridimensional , Feminino , Humanos , Masculino , Anuloplastia da Valva Mitral , Insuficiência da Valva Mitral/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico , Valor Preditivo dos Testes , Recidiva
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