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2.
Artigo em Inglês | MEDLINE | ID: mdl-34689984

RESUMO

OBJECTIVES: We examined for differences in pre-left ventricular assist device (LVAD) implantation myocardial transcriptome signatures among patients with different degrees of mitral regurgitation (MR). METHODS: Between January 2018 and October 2019, we collected left ventricular (LV) cores during durable LVAD implantation (n = 72). A retrospective chart review was performed. Total RNA was isolated from LV cores and used to construct cDNA sequence libraries. The libraries were sequenced with the NovaSeq system, and data were quantified using Kallisto. Gene Set Enrichment Analysis (GSEA) and Gene Ontology analyses were performed, with a false discovery rate <0.05 considered significant. RESULTS: Comparing patients with preoperative mild or less MR (n = 30) and those with moderate-severe MR (n = 42), the moderate-severe MR group weighted less (P = .004) and had more tricuspid valve repairs (P = .043), without differences in demographics or comorbidities. We then compared both groups with a group of human donor hearts without heart failure (n = 8). Compared with the donor hearts, there were 3985 differentially expressed genes (DEGs) for mild or less MR and 4587 DEGs for moderate-severe MR. Specifically altered genes included 448 DEGs for specific for mild or less MR and 1050 DEGs for moderate-severe MR. On GSEA, common regulated genes showed increased immune gene expression and reduced expression of contraction and energetic genes. Of the 1050 genes specific for moderate-severe MR, there were additional up-regulated genes related to inflammation and reduced expression of genes related to cellular proliferation. CONCLUSIONS: Patients undergoing durable LVAD implantation with moderate-severe MR had increased activation of genes related to inflammation and reduction of cellular proliferation genes. This may have important implications for myocardial recovery.

3.
ASAIO J ; 67(10): 1139-1147, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34570728

RESUMO

We examined cardiac features associated with residual mitral regurgitation (MR) following continuous-flow left ventricular assist device (cfLVAD) implant. From 2003 to 2017, 134 patients with severe MR underwent cfVLAD implant without mitral valve (MV) intervention. Echocardiographic (echo) assessment occurred pre-cfLVAD, early post-cfLVAD, and at last available echo. Ventricular and atrial volumes were calculated from established formulas and normalized to be predicted. Cluster analysis based on preoperative normalized left ventricular and atrial volumes, and MV height identified grades 1, 2, and 3 with progressively larger cardiac chamber sizes. Median early echo follow-up was 0.92 (0.55, 1.45) months and the last follow-up was 15.12 (5.28, 38.28) months. Mitral regurgitation improved early after cfLVAD by 2.10 ± 1.16 grades (p < 0.01). Mitral regurgitation severity at the last echocardiogram positively correlated with the preoperative left ventricular volume (p = 0.014, R = 0.212), left atrial volume (p = 0.007, R = 0.233), MV anteroposterior height (p = 0.032, R = 0.185), and MV mediolateral diameter (p = 0.043, R = 0.175). Morphologically, smaller grade 1 hearts were correlated with MR resolution at the late follow-up (p = 0.023). Late right ventricular failure (RVF) at the last clinical follow-up was less in grade 1 (4/48 [8.3%]) compared with grades 2 and 3 (26/86 [30.2%]), p = 0.004). Grade 1 cardiac dimensions correlates with improvement in severe MR and had less late RVF.


Assuntos
Coração Auxiliar , Insuficiência da Valva Mitral , Ecocardiografia , Coração Auxiliar/efeitos adversos , Humanos , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
4.
Eur Heart J ; 42(42): 4373-4385, 2021 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-34534287

RESUMO

AIMS: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance. METHODS AND RESULTS: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD. CONCLUSION: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.


Assuntos
Aneurisma Aórtico , Animais , Biomarcadores , Dissecação , Humanos , Metabolômica , Camundongos , Ácido Succínico
6.
Physiol Rep ; 9(17): e15004, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34435466

RESUMO

BACKGROUND: Dysfunction and inflammation of hearts subjected to cold ischemic preservation may differ between left and right ventricles, suggesting distinct strategies for amelioration. METHODS AND RESULTS: Explanted murine hearts subjected to cold ischemia for 0, 4, or 8 h in preservation solution were assessed for function during 60 min of warm perfusion and then analyzed for cell death and inflammation by immunohistochemistry and western blotting and total RNA sequencing. Increased cold ischemic times led to greater left ventricle (LV) dysfunction compared to right ventricle (RV). The LV experienced greater cell death assessed by TUNEL+ cells and cleaved caspase-3 expression (n = 4). While IL-6 protein levels were upregulated in both LV and RV, IL-1ß, TNFα, IL-10, and MyD88 were disproportionately increased in the LV. Inflammasome components (NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1) and products (cleaved IL-1ß and gasdermin D) were also more upregulated in the LV. Pathway analysis of RNA sequencing showed increased signaling related to tumor necrosis factor, interferon, and innate immunity with ex-vivo ischemia, but no significant differences were found between the LV and RV. Human donor hearts showed comparable inflammatory responses to cold ischemia with greater LV increases of TNFα, IL-10, and inflammasomes (n = 3). CONCLUSIONS: Mouse hearts subjected to cold ischemia showed time-dependent contractile dysfunction and increased cell death, inflammatory cytokine expression and inflammasome expression that are greater in the LV than RV. However, IL-6 protein elevations and altered transcriptional profiles were similar in both ventricles. Similar changes are observed in human hearts.

7.
J Card Surg ; 36(10): 3987-3988, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34232522
9.
J Card Surg ; 36(8): 2677-2684, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34018246

RESUMO

OBJECTIVE: Implantation of donor hearts with prolonged ischemic times is associated with worse survival. We sought to identify risk factors that modulate the effects of prolonged preservation. METHODS: Retrospective review of the United Network for Organ Sharing database (2000-2018) to identify transplants with >5 (n = 1526) or ≤5 h (n = 35,733) of donor heart preservation. In transplanted hearts preserved for >5 h, Cox-proportional hazards identify modifiers for survival. RESULTS: Compared to ≤5 h, transplanted patients with >5 h of preservation spent less time in status 1B (76 ± 160 vs. 85 ± 173 days, p = .027), more commonly had ischemic cardiomyopathy (42.3% vs. 38.3%, p = .002), and less commonly received a blood type O heart (45.4% vs. 50.8%, p < .001). Longer heart preservation time was associated with a higher incidence of postoperative stroke (4.5% vs. 2.5%, p < .001), and dialysis (16.4% vs. 10.6%, p < .001). Prolonged preservation was associated with a greater likelihood of death from primary graft dysfunction (2.8% vs. 1.5%, p < .001) but there was no difference in death from acute (2.0% vs. 1.7%, p = .402) or chronic rejection (2.0% vs. 1.9%, p = .618). In transplanted patients with >5 h of heart preservation, multivariable analysis identified greater mortality with ischemic cardiomyopathy etiology (hazard ratio [HR] = 1.36, p < 0.01), pre-transplant dialysis (HR = 1.84, p < .01), pre-transplant extracorporeal membrane oxygenation (ECMO, HR = 2.36, p = .09), and O blood type donor hearts (HR = 1.35, p < .01). CONCLUSION: Preservation time >5 h is associated with worse survival. This mortality risk is further amplified by preoperative dialysis and ECMO, ischemic cardiomyopathy etiology, and use of O blood type donor hearts.


Assuntos
Transplante de Coração , Sobrevivência de Enxerto , Humanos , Diálise Renal , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos
10.
J Card Surg ; 36(7): 2442-2451, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33896038

RESUMO

BACKGROUND: The opioid epidemic has seen a drastic increase in the incidence of drug-associated infective endocarditis (IE). No clinical tool exists to predict operative morbidity and mortality in patients undergoing surgery. METHODS: A multi-institutional database was reviewed between 2011 and 2018. Multivariate logistic regression was fitted in an automated stepwise fashion. The STratification risk analysis in OPerative management of drug-associated IE (STOP) score was constructed. Morbidity was defined as reintubation, prolonged ventilation, pneumonia, renal failure, dialysis, stroke, reoperation for bleeding, and a permanent pacemaker. Cross-validation provided an unbiased estimate of out-of-sample performance. RESULTS: A total of 1181 patients underwent surgery for drug-associated IE (median age, 39; interquartile range [IQR], 30-54, 386 women [32.7%], 341 reoperations for prosthetic valve endocarditis [28.9%], 316 patients with multivalve disease [26.8%]). Operative morbidity and mortality were 41.1% and 5.9%, respectively. Predictors of morbidity were dialysis (95% confidence interval [CI], 1.16-2.82), emergent intervention (1.83-4.73), multivalve procedure (1.01-1.98), causative organisms other than Streptococcus (1.09-2.02), and type of valve procedure performed [aortic valve procedure (1.07-2.15), mitral valve replacement (1.03-2.05), tricuspid valve replacement (1.21-2.60)]. Predictors of mortality were dialysis (1.29-5.74), active endocarditis (1.32-83), lung disease (1.25-5.43), emergent intervention (1.69-6.60), prosthetic valve endocarditis (1.24-3.69), aortic valve procedure (1.49-5.92) and multivalve disease (1.00-2.95). Variables maximizing explanatory power were translated into a scoring system. Each point increased odds of morbidity and mortality by 22.0% and 22.4% with an accuracy of 94.0% and 94.1%, respectively. CONCLUSION: Drug-related IE is associated with significant morbidity and mortality. An easily-applied risk stratification score may aid in clinical decision-making.


Assuntos
Endocardite Bacteriana , Endocardite , Próteses Valvulares Cardíacas , Preparações Farmacêuticas , Adulto , Endocardite/cirurgia , Endocardite Bacteriana/cirurgia , Feminino , Humanos , Diálise Renal , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento
11.
J Card Surg ; 36(6): 1843-1849, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33604994

RESUMO

OBJECTIVE: We examined for improvements in preoperative moderate mitral regurgitation following continuous-flow left ventricular assist device (cfLVAD) implantation. METHODS: From 2006 to 2020, 190 patients with moderate MR underwent cfVLAD implant without concomitant mitral valve (MV) surgery. Cardiac dimensions and contractility, as well as valve function, were assessed with an echocardiogram (echo) pre-cfLVAD, and at approximately 1 month post-cfLVAD. Outcomes were determined by retrospective chart review. RESULTS: Median echo follow-up was 0.94 (0.53, 1.38) months. Residual significant moderate or greater MR was present in 30/190 (15.8%) on follow-up. Patients with significant residual MR had larger preoperative left ventricular internal diameters in diastole (74.4 ± 8.7 vs. 71.1.0 ± 9.1 mm, p = .034). Significant residual MR was associated with higher preoperative mean pulmonary artery pressures (OR = 1.055, p = .035) and pulmonary capillary wedge pressures (OR = 1.060, p = .034). Significant residual MR on echo was not associated with any survival difference (p = .325). The 1, 5, and 10 year survival were 89.9%, 55.2%, and 34.2%, respectively. CONCLUSIONS: For patients with moderate MR undergoing LVAD implantation, the likelihood of significant residual MR is low and mitral intervention in this population is not recommended. However, select patients with larger preoperative left heart dimensions and pulmonary vascular pressures may be at risk for persistent residual MR.


Assuntos
Coração Auxiliar , Insuficiência da Valva Mitral , Humanos , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
13.
Artigo em Inglês | MEDLINE | ID: mdl-33558115

RESUMO

OBJECTIVE: The study objective was to determine the influence of allograft ischemic time on heart transplant outcomes among ABO donor organ types given limited prior reports of its survival impact. METHODS: We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous and categoric variables were analyzed by parametric and nonparametric testing. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables. RESULTS: By comparing allograft ischemic time less than 4 hours (n = 6579) with 4 hours or more (n = 25,875), the hazard ratios for death at 15 years after prolonged ischemic time (≥4 hours) for blood types O, A, B, and AB were 1.106 (P < .001), 1.062 (P < .001), 1.059 (P = .062), and 1.114 (P = .221), respectively. Unadjusted data demonstrated higher mortality for transplantation of O versus non-O donor hearts for ischemic time 4 hours or more (hazard ratio, 1.164; P < .001). After propensity matching, O donor hearts continued to have worse survival if preserved for 4 hours or more (hazard ratio, 1.137, P = .008), but not if ischemic time was less than 4 hours (hazard ratio, 1.042, P = .113). In a matched group with 4 hours or more of ischemic time, patients receiving O donor organs were more likely to experience death from primary graft dysfunction (2.5% vs 1.7%, P = .052) and chronic allograft rejection (1.9% vs 1.1%, P = .021). No difference in death from primary graft dysfunction or chronic allograft rejection was seen with less than 4 hours of ischemic time (P > .150). CONCLUSIONS: Compared with non-O donor hearts, transplantation with O donor hearts with ischemic time 4 hours or more leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when anticipating extended cold ischemic times.

14.
Sci Rep ; 11(1): 1139, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441956

RESUMO

To support point-of-care decision making by presenting outcomes of past treatment choices for cohorts of similar patients based on observational data from electronic health records (EHRs), a machine-learning precision cohort treatment option (PCTO) workflow consisting of (1) data extraction, (2) similarity model training, (3) precision cohort identification, and (4) treatment options analysis was developed. The similarity model is used to dynamically create a cohort of similar patients, to inform clinical decisions about an individual patient. The workflow was implemented using EHR data from a large health care provider for three different highly prevalent chronic diseases: hypertension (HTN), type 2 diabetes mellitus (T2DM), and hyperlipidemia (HL). A retrospective analysis demonstrated that treatment options with better outcomes were available for a majority of cases (75%, 74%, 85% for HTN, T2DM, HL, respectively). The models for HTN and T2DM were deployed in a pilot study with primary care physicians using it during clinic visits. A novel data-analytic workflow was developed to create patient-similarity models that dynamically generate personalized treatment insights at the point-of-care. By leveraging both knowledge-driven treatment guidelines and data-driven EHR data, physicians can incorporate real-world evidence in their medical decision-making process when considering treatment options for individual patients.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Hiperlipidemias/terapia , Hipertensão/terapia , Estudos de Coortes , Mineração de Dados , Registros Eletrônicos de Saúde , Humanos , Aprendizado de Máquina , Medicina de Precisão , Estudos Retrospectivos , Fluxo de Trabalho
16.
J Am Med Inform Assoc ; 28(3): 588-595, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33180897

RESUMO

OBJECTIVE: To present clinicians at the point-of-care with real-world data on the effectiveness of various treatment options in a precision cohort of patients closely matched to the index patient. MATERIALS AND METHODS: We developed disease-specific, machine-learning, patient-similarity models for hypertension (HTN), type II diabetes mellitus (T2DM), and hyperlipidemia (HL) using data on approximately 2.5 million patients in a large medical group practice. For each identified decision point, an encounter during which the patient's condition was not controlled, we compared the actual outcome of the treatment decision administered to that of the best-achieved outcome for similar patients in similar clinical situations. RESULTS: For the majority of decision points (66.8%, 59.0%, and 83.5% for HTN, T2DM, and HL, respectively), there were alternative treatment options administered to patients in the precision cohort that resulted in a significantly increased proportion of patients under control than the treatment option chosen for the index patient. The expected percentage of patients whose condition would have been controlled if the best-practice treatment option had been chosen would have been better than the actual percentage by: 36% (65.1% vs 48.0%, HTN), 68% (37.7% vs 22.5%, T2DM), and 138% (75.3% vs 31.7%, HL). CONCLUSION: Clinical guidelines are primarily based on the results of randomized controlled trials, which apply to a homogeneous subject population. Providing the effectiveness of various treatment options used in a precision cohort of patients similar to the index patient can provide complementary information to tailor guideline recommendations for individual patients and potentially improve outcomes.


Assuntos
Tomada de Decisões Assistida por Computador , Diabetes Mellitus Tipo 2/terapia , Hiperlipidemias/terapia , Hipertensão/terapia , Aprendizado de Máquina , Administração dos Cuidados ao Paciente/métodos , Guias de Prática Clínica como Assunto , Registros Eletrônicos de Saúde , Medicina Baseada em Evidências , Humanos , Resultado do Tratamento
19.
Circ Heart Fail ; 13(4): e006409, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32264717

RESUMO

BACKGROUND: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury. METHODS: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively. RESULTS: The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours. CONCLUSIONS: Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage.


Assuntos
Temperatura Baixa/efeitos adversos , Transplante de Coração , Ventrículos do Coração/metabolismo , Preservação de Órgãos , Disfunção Primária do Enxerto/genética , Transcriptoma , Apoptose/efeitos dos fármacos , Apoptose/genética , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Perfilação da Expressão Gênica , Glucose/farmacologia , Transplante de Coração/efeitos adversos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Humanos , Inflamação/genética , Inflamação/patologia , Manitol/farmacologia , Preservação de Órgãos/efeitos adversos , Soluções para Preservação de Órgãos/farmacologia , Cloreto de Potássio/farmacologia , Disfunção Primária do Enxerto/patologia , Disfunção Primária do Enxerto/prevenção & controle , Procaína/farmacologia , Fatores de Risco , Fatores de Tempo , Transcriptoma/efeitos dos fármacos
20.
Ann Thorac Surg ; 110(4): 1259-1264, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32105716

RESUMO

BACKGROUND: Aortic valve (AV) repair (AVr) using a central coaptation stitch or bioprosthetic AV replacement (AVR) are most commonly performed at the time of durable left ventricular assist device implant to address AV insufficiency (AI). METHODS: Prospective data collection on 46 patients undergoing left ventricular assist device implant from 2007 through 2018 who received concomitant AVr (n = 40) or AVR (n = 6) was retrospectively analyzed to assess freedom from recurrent aortic insufficiency. Paired Wilcoxon rank-sum test was used to compare echocardiographic findings. Mantel-Cox statistics were used to analyze survival. RESULTS: For AVr, central coaptation led to a mean decrease in AI severity by 2.1 ± 1.0 grades (P < .001). Three patients (7.5%) had recurrence of at least moderate AI by 3 years. In comparison, all patients in the AVR group had mild or less AI on subsequent follow-up. Success of AVr in downgrading AI severity was associated with a smaller aortic root diameter (P = .011) and sinotubular junction diameter (P = .003). An aortic root diameter greater than 3.5 cm was predictive of less improvement in AI severity compared with 3.5 cm or less (1.83 ± 1.03 versus 2.47 ± 0.80 grades of improvement; P = .038). Duration of cardiopulmonary bypass was 32 minutes longer and duration of aortic cross-clamp was 38 minutes longer for AVR versus AVr cohorts. No difference in 30-day (P = .418) or overall survival (P = .572) between the AVr and AVR groups was seen. CONCLUSIONS: Aortic valve repair for addressing AI has a recurrence rate of 7.5% at 3 years. Success in downgrading AI is more likely with a smaller aortic root. No difference in survival was observed between AVr and AVR.


Assuntos
Insuficiência da Valva Aórtica/cirurgia , Anuloplastia da Valva Cardíaca , Insuficiência Cardíaca/complicações , Implante de Prótese de Valva Cardíaca , Coração Auxiliar , Adulto , Idoso , Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/mortalidade , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
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