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AIMS: Vein grafts are used for many indications, including bypass graft surgery and arterio-venous fistula (AVF) formation. However, patency following vein grafting or AVF formation is suboptimal for various reasons, including thrombosis, neointimal hyperplasia and adverse remodeling. Recently, endothelial to mesenchymal transition (EndMT) was found to contribute to neointimal hyperplasia in mouse vein grafts. We aimed to evaluate the clinical potential of inhibiting EndMT, and developed the first dedicated preclinical model to study the efficacy of local EndMT inhibition immediately prior to AVF creation. METHODS AND RESULTS: We first undertook pilot studies to optimize the creation of a femoral AVF in pigs and verify that EndMT contributes to neointimal formation. We then developed a method to achieve local in vivo SMAD3 knockdown by dwelling a lentiviral construct containing SMAD3 shRNA in the femoral vein prior to AVF creation. Next, in Phase 1, 6 pigs were randomized to SMAD3 knockdown or control lentivirus to evaluate the effectiveness of SMAD3 knockdown and EndMT inhibition 8 days after AVF creation. In Phase 2, 16 pigs were randomized to SMAD3 knockdown or control lentivirus and were evaluated to assess longer-term effects on AVF diameter, patency and related measures at 30 days after AVF creation.In Phase 1, compared to controls, SMAD3 knockdown achieved a 75% reduction in the proportion of CD31+ endothelial cells co-expressing SMAD3 (p<0.001), and also a significant reduction in the extent of EndMT (p<0.05). In Phase 2, compared to controls, SMAD3 knockdown was associated with an increase in the minimum diameter of the venous limb of the AVF (1.56±1.66 versus 4.26±1.71mm, p<0.01) and a reduced degree of stenosis (p<0.01). Consistent with this, neointimal thickness was reduced in the SMAD3 knockdown group (0.88±0.51 versus 0.45±0.19mm, p<0.05). Furthermore, endothelial integrity (the proportion of luminal cells expressing endothelial markers) was improved in the SMAD3 knockdown group (p<0.05). CONCLUSIONS: EndMT inhibition in a preclinical AVF model by local SMAD3 knockdown using gene therapy led to reduced neointimal hyperplasia, increased endothelialization and a reduction in the degree of AVF stenosis. This provides important proof-of-concept to pursue this approach as a clinical strategy to improve the patency of AVFs and other vein grafts.
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OBJECTIVES: We sought to examine readmission rates and predictors of hospital readmission following TAVR in patients with ESRD. BACKGROUND: End-stage renal disease (ESRD) is associated with poor outcomes following transcatheter aortic valve replacement (TAVR). METHODS: We assessed index hospitalizations for TAVR from the National Readmissions Database from 2017 to 2018 and used propensity scores to match those with and without ESRD. We compared 90-day readmission for any cause or cardiovascular cause. Length of stay (LOS), mortality, and cost were assessed for index hospitalizations and 90-day readmissions. Multivariable logistic regression was performed to identify predictors of 90-day readmission. RESULTS: We identified 49,172 index hospitalizations for TAVR, including 1,219 patients with ESRD (2.5%). Patient with ESRD had higher rates of all-cause readmission (34.4% vs. 19.2%, HR 1.96, 95% CI 1.68-2.30, p<0.001) and cardiovascular readmission (13.2% vs. 7.7%, HR 1.85, 95% CI 1.44-2.38, p<0.001) at 90 days. During index hospitalization, patients with ESRD had longer length of stay (mean difference 1.9 days), increased hospital cost (mean difference $42,915), and increased in-hospital mortality (2.6% vs. 0.9%). Among those readmitted within 90 days, patients with ESRD had longer LOS and increased hospital charge, but similar in-hospital mortality. Diabetes (OR 1.86, 95% CI 1.31-2.64) and chronic pulmonary disease (OR 1.51, 95% CI 1.04-2.18) were independently associated with higher odds of 90-day readmission in patients with ESRD. CONCLUSION: Patients with ESRD undergoing TAVR have higher mortality and increased cost associated with their index hospitalization and are at increased risk of readmission within 90 days following TAVR.
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Estenose da Valva Aórtica , Falência Renal Crônica , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Readmissão do Paciente , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/cirurgia , Fatores de Tempo , Resultado do Tratamento , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Fatores de RiscoRESUMO
OBJECTIVES: We sought to examine the efficacy and safety of adding fibrinogen-guided low-dose multi-day Alteplase™ tissue plasminogen activator (tPA) in the management of intravascular hemolysis (IVH) in patients with the HeartMate II (HM-II) continuous flow (CF) left ventricular assist device (LVAD) who failed to achieve IVH resolution with conventional augmented anticoagulation (AAC). BACKGROUND: IVH in patients with LVAD is often treated with AAC, failing which pump exchange is considered. We hypothesized that a trial of low-dose tPA after failed AAC therapy could resolve IVH and prevent pump exchange in some patients. METHODS: We performed a retrospective study of 31 HM-II CF LVAD patients admitted to our center from January 2015 to January 2020 for IVH management who received tPA following failed AAC. Primary 6-month outcomes included successful IVH resolution, unsuccessful IVH resolution requiring pump exchange, gastrointestinal bleeding, ischemic and hemorrhagic cerebrovascular accident (CVA), and death. RESULTS: Thirty-one patients with IVH were treated with tPA following failed AAC. Successful resolution of IVH occurred in 22/31 (71%) patients. Pump exchange occurred in 9/31 (29%) patients. Gastrointestinal bleeding occurred in 7/31 (22.6%) patients. Ischemic CVA occurred in 6/31 (19.4%) patients. CONCLUSIONS: Management of IVH with administration of low-dose tPA after failed AAC is feasible and may prevent pump exchange in some patients.
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Insuficiência Cardíaca , Coração Auxiliar , Trombose , Anticoagulantes/efeitos adversos , Fibrinogênio/uso terapêutico , Hemorragia Gastrointestinal/etiologia , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Hemólise , Humanos , Estudos Retrospectivos , Trombose/prevenção & controle , Ativador de Plasminogênio Tecidual/efeitos adversosRESUMO
Endothelial dysfunction has been demonstrated in patients with Continuous Flow-Left Ventricular Assist Devices (CF-LVADs) but association with adverse events has not been shown. We used a noninvasive, operator-independent device called VENDYS® to assess vasodilatory function based on digital thermal measurements postrelease of a brachial artery occlusion in ambulatory patients with CF-LVAD (n = 56). Aortic valve opening and pulse perception were also documented before the test. Median duration of CF-LVAD support was 438 days. The VENDYS® test generates a vascular reactivity index (VRI). Outcomes for the CF-LVAD patients were compared between VRI < 1 and VRI ≥ 1. The bleeding events were driven primarily by a difference in neurologic bleeds. Multivariate analysis showed that VRI < 1 correlated with future bleeding events (HR: 5.56; P = 0.01). The C-statistic with the VRI dichotomized as above was 0.82. There was a trend toward a worse survival in patients with poor endothelial function. Endothelial vasodilatory dysfunction measured by a simple test utilizing digital thermal monitoring can predict adverse bleeding events in patients with CF-LVADs.
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Endotélio Vascular/fisiologia , Coração Auxiliar/efeitos adversos , Hemorragia/etiologia , Idoso , Estudos Transversais , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Vasodilatação/fisiologiaRESUMO
While Doppler and cuff blood pressure techniques are prevalent methods of assessing blood pressure in patients with continuous flow left ventricular assist devices, the impact of pulsatility on measurement is not well established. Retrospective chart analysis of clinical variables including pulse perception, blood pressure (Doppler and standard cuff), and aortic valve opening on echo at clinic visit were abstracted. Stable outpatients on continuous flow left ventricular assist devices support with concomitant portable echo assessment were included. Mean average difference was calculated and Pearson's correlation performed for all those patients who had both Doppler and cuff pressure obtained. In all, 74 Heartmate-II patients with a median time from implant of 380 days were analyzed. A pulse was perceived in 82% of patients with persistent aortic valve opening on portable echo and also in 30% of those who had a persistently closed aortic valve. The mean average difference between the Doppler and systolic cuff pressure was ~13 mmHg (r = 0.5, p = 0.004) when a pulse was present and ~11 mmHg when aortic valve was open (r = 0.68, p < 0.0001). Pulse presence seems to reflect aortic valve opening a majority of the time but not always. In the presence of a prominent pulse or persistent aortic valve opening, the Doppler pressure seems to be more reflective of a systolic pressure than mean perfusion pressure. Hence, assessment of pulsatility needs to be incorporated into blood pressure measurement methods for patients with continuous flow left ventricular assist devices.
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Determinação da Pressão Arterial/métodos , Insuficiência Cardíaca , Frequência Cardíaca , Coração Auxiliar/normas , Valva Aórtica/diagnóstico por imagem , Pressão Sanguínea/fisiologia , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ultrassonografia Doppler/métodosRESUMO
The new allocation criteria classify patients on veno-arterial extracorporeal membranous oxygenation (VA-ECMO) as the highest priority for receiving orthotopic heart transplantation (OHT) especially if they are considered not candidates for ventricular assist devices. The outcomes of patients who receive ventricular assist devices (VADs) after being listed for heart transplantation with VA-ECMO is unknown. We analyzed 355 patients listed for OHT with VA-ECMO from the United Network for Organ Sharing database from 2006 to 2014. Univariate and multivariate Cox proportional-hazards models were used to determine the contribution of prognostic variables to the outcome. Thirty-three patients (9.3%) received VADs (15 dischargeable, 7 non-dischargeable VADs). The VAD and non-VAD groups had similar listing characteristics except that the VAD group were more likely to have non-ischemic cardiomyopathy (48.5% vs. 25.2%), and less likely to be obese (6.1% vs. 25.2%) or have a history of prior organ transplant (3% vs. 31.1%). Patients who underwent VAD implantation had more days on the list (median 189 vs. 14 days) compared to the non-VAD group. Amongst the patients who had VADs, (25/33) 75.5% patients were subsequently transplanted with similar post-transplant survival compared to the non-VAD group (72% vs. 60.5%; p = 0.276). Predictors of one-year post-transplant mortality included panel reactive antibodies (PRA) class I ≥ 20%, recipient smoking history, increased serum creatinine and total bilirubin. Therefore, a small proportion of patients listed for transplantation with VA ECMO undergo VAD implantation. Their waitlist survival is better than non-VAD group but with similar post-transplant survival.
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Patients bridged to transplant (BTT) with continuous-flow left ventricular assist devices (CF-LVADs) have increased in the past decade. Decision support tools for these patients are limited. We developed a risk score to estimate prognosis and guide decision-making. We included heart transplant recipients bridged with CF-LVADs from the United Network for Organ Sharing (UNOS) database and divided them into development (2,522 patients) and validation cohorts (1,681 patients). Univariate and multivariate Cox proportional hazards models were performed. Variables that independently predicted outcomes (age, African American race, recipient body mass index [BMI], intravenous [IV] antibiotic use, pretransplant dialysis, and total bilirubin) were assigned weight using linear transformation, and risk scores were derived. Patients were grouped by predicted posttransplant mortality: low risk (≤ 38 points), medium risk (38-41 points), and high risk (≥ 42 points). We performed Cox proportional hazards analysis on wait-listed CF-LVAD patients who were not transplanted. Score significantly discriminated survival among the groups in the development cohort (6.7, 12.9, 20.7; p = 0.001), validation cohort (6.4, 10.1, 13.6; p < 0.001), and ambulatory cohort (6.4, 11.5, 17.2; p < 0.001). We derived a left ventricular assist device (LVAD) BTT risk score that effectively identifies CF-LVAD patients who are at higher risk for worse outcomes after heart transplant. This score may help physicians weigh the risks of transplantation in patients with CF-LVAD.
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Sistemas de Apoio a Decisões Clínicas , Insuficiência Cardíaca/terapia , Transplante de Coração , Coração Auxiliar , Adulto , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Transplante de Coração/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.IMPORTANCE Viruses are the most commonly identified causes of pneumonia and inflict unacceptable morbidity, despite currently available therapies. While lung epithelial cells are principal targets of respiratory viruses, they have also been recently shown to contribute importantly to therapeutically inducible antimicrobial responses. This work finds that lung cells can be stimulated to protect themselves against viral challenges, even in the absence of leukocytes, both reducing viral burden and improving survival. Further, it was found that the protection occurs via unexpected induction of reactive oxygen species (ROS) from spatially segregated sources without reliance on type I interferon signaling. Coordinated multisource ROS generation has not previously been described against viruses, nor has ROS generation been reported for epithelial cells against any pathogen. Thus, these findings extend the potential clinical applications for the strategy of inducible resistance to protect vulnerable people against viral infections and also provide new insights into the capacity of lung cells to protect against infections via novel ROS-dependent mechanisms.
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Células Epiteliais/imunologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/imunologia , Espécies Reativas de Oxigênio/imunologia , Animais , Células Epiteliais/virologia , Feminino , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/genética , Influenza Humana/virologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Toll-Like/genética , Receptores Toll-Like/imunologiaRESUMO
Tubulointerstitial injury is one of the hallmarks of renal disease. In particular, interstitial fibrosis has a prominent role in the development and progression of kidney injury. Collagen-producing fibroblasts are responsible for the ECM deposition. However, the origin of those activated fibroblasts is not clear. This chapter will discuss in detail the concept of epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT) in the context of fibrosis and kidney disease. In short, EMT and EndMT involve a change in cell shape, loss of polarity and increased motility associated with increased collagen production. Thus, providing a new source of fibroblasts. However, many controversies exist regarding the existence of EMT and EndMT in kidney disease, as well as its burden and role in disease development. The aim of this chapter is to provide an overview of the concepts and profibrotic pathways and to present the evidence that has been published in favor and against EMT and EndMT.
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Células Endoteliais/patologia , Transição Epitelial-Mesenquimal/fisiologia , Nefropatias/patologia , Animais , Fibrose , HumanosRESUMO
BACKGROUND: Anemia is common in patients with heart failure and is associated with adverse outcomes. Management of anemia in CF-LVAD patients is not well studied. Our purpose is to characterize and identify the etiology of anemia in CF-LVAD patients. Secondary objectives are to describe the effect of CF-LVAD on pre-existing anemia and assess its impact after CF-LVAD support. METHODS: Cross-sectional study from January to July 2015 of ambulatory patients supported with a CF-LVAD for at least 6-months that presented with hemoglobin <12 g/dL and no recent gastrointestinal bleeding. Patients were classified as iron-deficient and non-iron-deficient and compared. Additionally, a retrospective analysis of 116 consecutive patients who underwent CF-LVAD from 2008 to 2013 with reported hemoglobin at 6 months as outpatients were divided into anemic or non-anemic and compared. RESULTS: In our cross-sectional cohort, iron deficiency was the most common cause of anemia. Notably, 49% of the iron-deficient patients were already on iron supplementation. In our retrospective cohort, 59% of the patients were anemic after 6 months of support. Anemic patients were older, had lower albumin, higher brain natriuretic peptide (BNP), worse renal function and New York Heart Association (NYHA) class. Anemia had a HR of 3.16 (95%CI 1.38-7.26) to predict a composite of 1-year death and HF readmissions, as well as HF-readmissions alone. CONCLUSIONS: The most common cause of anemia in our study was iron-deficiency; almost half of the patients were iron deficient despite treatment, suggesting that oral iron may not be sufficient to reverse anemia. Anemia regardless of etiology was associated with adverse outcomes.
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Anemia/epidemiologia , Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Fatores Etários , Idoso , Anemia/tratamento farmacológico , Estudos Transversais , Feminino , Compostos Ferrosos/uso terapêutico , Insuficiência Cardíaca/epidemiologia , Hematínicos/uso terapêutico , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Estudos RetrospectivosRESUMO
Pulmonary hypertension (PH) is commonly present in patients with chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF) where it is classified as Group III PH by the World Health Organization (WHO). PH has been identified to be present in as much as 40% of patients with COPD or IPF and it is considered as one of the principal predictors of mortality in patients with COPD or IPF. However, despite the prevalence and fatal consequences of PH in the setting of chronic lung diseases, there are limited therapies available for patients with Group III PH, with lung transplantation remaining as the most viable option. This highlights our need to enhance our understanding of the molecular mechanisms that lead to the development of Group III PH. In this review we have chosen to focus on the current understating of PH in IPF, we will revisit the main mediators that have been shown to play a role in the development of the disease. We will also discuss the experimental models available to study PH associated with lung fibrosis and address the role of the right ventricle in IPF. Finally we will summarize the current available treatment options for Group III PH outside of lung transplantation.
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Hipertensão Pulmonar/etiologia , Fibrose Pulmonar Idiopática/complicações , Animais , Modelos Animais de Doenças , Epigênese Genética , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , PrevalênciaRESUMO
The model for end-stage liver disease (MELD) has been used as a predictor of mortality after left ventricular assist device (LVAD) placement. However, improvement or worsening of MELD and how those changes affect outcomes is unknown. We performed a retrospective analysis of 244 patients implanted with a continuous flow (CF) LVAD. Patients were dichotomized at admission into low- or high-risk categories using a cutoff of MELD ≥ 19, and they were reclassified at day of implant forming four groups: Group LL (low to low, remained low risk), LH (low to high, worsened to high risk), HH (high to high, remained high risk), and HL (high to low, improved to low risk). Patients who improved to a low risk (group HL) had the same 1 year survival as those that remained low risk (group LL; 80% vs. 77%; p = 0.6). However, patients who were initially classified as low risk and worsened to a high risk (group LH) had a survival that was worse than those that were consistently high risk (group HH; 55% vs. 10%; p = 0.01). Model for end-stage liver disease reclassification after adjusting for commonly attributed risk factors remained an independent predictor for mortality, including patients classified as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 1 and 2. In conclusion, our MELD score reclassification is an independent and powerful predictor of mortality in patients undergoing LVAD implantation.
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Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Adulto , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics.
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Hipertensão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Nanopartículas/administração & dosagem , Sirolimo/farmacologia , Administração Intravenosa , Animais , Modelos Animais de Doenças , Pulmão/patologia , Ratos , Ratos Sprague-Dawley , Sirolimo/administração & dosagemRESUMO
AIMS: Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure. METHODS AND RESULTS: In vitro cellular uptake and intracellular trafficking of MSVs was examined by scanning electron microscopy, confocal microscopy, time-lapse microscopy, and flow cytometry in cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. The MSVs were internalized within the first hours, and trafficked to perinuclear regions in all the cell lines. Cytotoxicity was investigated by annexin V and cell cycle assays. No significant evidence of toxicity was found. In vivo intravenous cardiac accumulation of MSVs was examined by high content fluorescence and confocal microscopy, with results showing increased accumulation of particles in failing hearts compared with normal hearts. Similar to observations in vitro, MSVs were able to associate, internalize, and traffic to the perinuclear region of cardiomyocytes in vivo. CONCLUSIONS: Results show that MSVs associate, internalize, and traffic in cardiovascular cells without any significant toxicity. Furthermore, MSVs accumulate in failing myocardium after intravenous administration, reaching intracellular regions of the cardiomyocytes. These findings represent a novel avenue to develop nanotechnology-based therapeutics and diagnostics in heart failure.