Publications by authors named "Michael A Solomon"

44 Publications

Epidemiology and outcomes of pulmonary hypertension in the cardiac intensive care unit.

Eur Heart J Acute Cardiovasc Care 2022 Jan 22. Epub 2022 Jan 22.

Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.

Aims: Pulmonary hypertension (PH) has been consistently associated with adverse outcomes in hospitalized patients. Limited epidemiologic data exist regarding PH in the cardiac intensive care unit (CICU) population. Here, we describe the prevalence, aetiology, and outcomes of PH in the CICU.

Methods And Results: Cardiac intensive care unit patients admitted from 2007 to 2018 who had right ventricular systolic pressure (RVSP) measured via transthoracic echocardiography near CICU admission were included. PH was defined as RVSP >35 mmHg, and moderate-to-severe PH as RVSP ≥50 mmHg. Predictors of in-hospital mortality were determined using multivariable logistic regression. Among 5042 patients (mean age 69.4 ± 14.8 years; 41% females), PH was present in 3085 (61%). The majority (68%) of patients with PH had left heart failure, and 29% had lung disease. In-hospital mortality occurred in 8.3% and was more frequent in patients with PH [10.9% vs. 4.2%, adjusted odds ratio (OR) 1.40, 95% confidence interval (CI) 1.03-1.92, P = 0.03], particularly patients with moderate-to-severe PH (14.4% vs. 6.2%, adjusted OR 1.65, 95% CI 1.27-2.14, P < 0.001). In-hospital mortality increased incrementally as a function of higher RVSP (adjusted 1.18 per 10 mmHg increase, 95% CI 1.09-1.28, P < 0.001). Patients with higher RVSP or moderate-to-severe PH had increased in-hospital mortality across admission diagnoses (all P < 0.05).

Conclusions: Pulmonary hypertension is very common in the CICU population and appears to be independently associated with a higher risk of death during hospitalization, although the strength of this association varies according to the underlying admission diagnosis. These data highlight the importance of PH in patients with cardiac critical illness.
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http://dx.doi.org/10.1093/ehjacc/zuab127DOI Listing
January 2022

Mineralocorticoid Receptor Antagonist Treatment of Established Pulmonary Arterial Hypertension Improves Interventricular Dependence in SU5416-Hypoxia Rat Model.

Am J Physiol Lung Cell Mol Physiol 2022 Jan 19. Epub 2022 Jan 19.

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, United States.

Treatment with mineralocorticoid receptor (MR) antagonists beginning at the outset of disease, or early thereafter, prevents pulmonary vascular remodeling in pre-clinical models of pulmonary arterial hypertension (PAH). However, the efficacy of MR blockade in established disease, a more clinically relevant condition, remains unknown. Therefore, we investigated the effectiveness of two MR antagonists, eplerenone (EPL) and spironolactone (SPL), after development of severe right ventricular (RV) dysfunction in the rat SU5416-hypoxia (SuHx) PAH model. Cardiac magnetic resonance imaging (MRI) in SuHx rats at the end of week 5, prior to study treatment, confirmed features of established disease including reduced RV ejection fraction, RV hypertrophy, pronounced septal flattening with impaired left ventricular filling and reduced cardiac index. Five weeks of treatment with either EPL or SPL improved left ventricular filling and prevented the further decline in cardiac index compared to placebo. Interventricular septal displacement was reduced by EPL while SPL effects were similar, but not significant. Although MR antagonists did not significantly reduce pulmonary artery pressure or vessel remodeling in SuHx rats with established disease, animals with higher drug levels had lower pulmonary pressures. Consistent with effects on cardiac function, EPL treatment tended to suppress MR and pro-inflammatory gene induction in the RV. In conclusion, MR antagonist treatment led to modest, but consistent beneficial effects on interventricular dependence after the onset of significant RV dysfunction in the SuHx PAH model. These results suggest that measures of RV structure and/or function may be useful endpoints in clinical trials of MR antagonists in PAH patients.
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http://dx.doi.org/10.1152/ajplung.00238.2021DOI Listing
January 2022

Higher levels of allograft injury in black patients early after heart transplantation.

J Heart Lung Transplant 2021 Dec 23. Epub 2021 Dec 23.

Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Laborarory of Applied Precision Omics (APO), Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Department of Medicine, Stanford University School of Medicine, Palo Alto, California. Electronic address:

Black patients suffer higher rates of antibody-mediated rejection and have worse long-term graft survival after heart transplantation. Donor-derived cell free DNA (ddcfDNA) is released into the blood following allograft injury. This study analyzed %ddcfDNA in 63 heart transplant recipients categorized by Black and non-Black race, during the first 200 days after transplant. Immediately after transplant, %ddcfDNA was higher for Black patients (mean [SE]: 8.3% [1.3%] vs 3.2% [1.2%], p = 0.001). In the first week post-transplant, the rate of decay in %ddcfDNA was similar (0.7% [0.68] vs 0.7% [0.11], p = 0.78), and values declined in both groups to a comparable plateau at 7 days post-transplant (0.46% [0.03] vs 0.45% [0.04], p = 0.78). The proportion of Black patients experiencing AMR was higher than non-Black patients (21% vs 9% [hazard ratio of 2.61 [95% confidence interval: 0.651-10.43], p = 0.18). Black patients were more likely to receive a race mismatched organ than non-Black patients (69% vs 35%, p = 0.01), which may explain the higher levels of early allograft injury.
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http://dx.doi.org/10.1016/j.healun.2021.12.006DOI Listing
December 2021

Direct pixel to pixel principal strain mapping from tagging MRI using end to end deep convolutional neural network (DeepStrain).

Sci Rep 2021 11 26;11(1):23021. Epub 2021 Nov 26.

Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, 10 Center Drive, Bldg. 10, CRC, Rm. 3-5340, Bethesda, MD, 20892, USA.

Regional soft tissue mechanical strain offers crucial insights into tissue's mechanical function and vital indicators for different related disorders. Tagging magnetic resonance imaging (tMRI) has been the standard method for assessing the mechanical characteristics of organs such as the heart, the liver, and the brain. However, constructing accurate artifact-free pixelwise strain maps at the native resolution of the tagged images has for decades been a challenging unsolved task. In this work, we developed an end-to-end deep-learning framework for pixel-to-pixel mapping of the two-dimensional Eulerian principal strains [Formula: see text] and [Formula: see text] directly from 1-1 spatial modulation of magnetization (SPAMM) tMRI at native image resolution using convolutional neural network (CNN). Four different deep learning conditional generative adversarial network (cGAN) approaches were examined. Validations were performed using Monte Carlo computational model simulations, and in-vivo datasets, and compared to the harmonic phase (HARP) method, a conventional and validated method for tMRI analysis, with six different filter settings. Principal strain maps of Monte Carlo tMRI simulations with various anatomical, functional, and imaging parameters demonstrate artifact-free solid agreements with the corresponding ground-truth maps. Correlations with the ground-truth strain maps were R = 0.90 and 0.92 for the best-proposed cGAN approach compared to R = 0.12 and 0.73 for the best HARP method for [Formula: see text] and [Formula: see text], respectively. The proposed cGAN approach's error was substantially lower than the error in the best HARP method at all strain ranges. In-vivo results are presented for both healthy subjects and patients with cardiac conditions (Pulmonary Hypertension). Strain maps, obtained directly from their corresponding tagged MR images, depict for the first time anatomical, functional, and temporal details at pixelwise native high resolution with unprecedented clarity. This work demonstrates the feasibility of using the deep learning cGAN for direct myocardial and liver Eulerian strain mapping from tMRI at native image resolution with minimal artifacts.
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http://dx.doi.org/10.1038/s41598-021-02279-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626490PMC
November 2021

Native-resolution myocardial principal Eulerian strain mapping using convolutional neural networks and Tagged Magnetic Resonance Imaging.

Comput Biol Med 2021 Nov 18:105041. Epub 2021 Nov 18.

Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Assessment of regional myocardial function at native pixel-level resolution can play a crucial role in recognizing the early signs of the decline in regional myocardial function. Extensive data processing in existing techniques limits the effective resolution and accuracy of the generated strain maps. The purpose of this study is to compute myocardial principal strain maps ε and ε from tagged MRI (tMRI) at the native image resolution using deep-learning local patch convolutional neural network (CNN) models (DeepStrain).

Methods: For network training, validation, and testing, realistic tMRI datasets were generated and consisted of 53,606 cine images simulating the heart, the liver, blood pool, and backgrounds, including ranges of shapes, positions, motion patterns, noise, and strain. In addition, 102 in-vivo image datasets from three healthy subjects, and three Pulmonary Arterial Hypertension patients, were acquired and used to assess the network's in-vivo performance. Four convolutional neural networks were trained for mapping input tagging patterns to corresponding ground-truth principal strains using different cost functions. Strain maps using harmonic phase analysis (HARP) were obtained with various spectral filtering settings for comparison. CNN and HARP strain maps were compared at the pixel level versus the ground-truth and versus the least-loss in-vivo maps using Pearson correlation coefficients (R) and the median error and Inter-Quartile Range (IQR) histograms.

Results: CNN-based local patch DeepStrain maps at a phantom resolution of 1.1mm × 1.1 mm and in-vivo resolution of 2.1mm × 1.6 mm were artifact-free with multiple fold improvement with ε ground-truth median error of 0.009(0.007) vs. 0.32(0.385) using HARP and ε ground-truth error of 0.016(0.021) vs. 0.181(0.08) using HARP. CNN-based strain maps showed substantially higher agreement with the ground-truth maps with correlation coefficients R > 0.91 for ε and ε compared to R < 0.21 and R < 0.82 for HARP-generated maps, respectively.

Conclusion: CNN-generated Eulerian strain mapping permits artifact-free visualization of myocardial function at the native image resolution.
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http://dx.doi.org/10.1016/j.compbiomed.2021.105041DOI Listing
November 2021

De Novo vs Acute-on-Chronic Presentations of Heart Failure-Related Cardiogenic Shock: Insights from the Critical Care Cardiology Trials Network Registry.

J Card Fail 2021 10;27(10):1073-1081

Levine Cardiac Intensive Care Unit, TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Heart failure-related cardiogenic shock (HF-CS) accounts for an increasing proportion of cases of CS in contemporary cardiac intensive care units. Whether the chronicity of HF identifies distinct clinical profiles of HF-CS is unknown.

Methods And Results: We evaluated admissions to cardiac intensive care units for HF-CS in 28 centers using data from the Critical Care Cardiology Trials Network registry (2017-2020). HF-CS was defined as CS due to ventricular failure in the absence of acute myocardial infarction and was classified as de novo vs acute-on-chronic based on the absence or presence of a prior diagnosis of HF, respectively. Clinical features, resource use, and outcomes were compared among groups. Of 1405 admissions with HF-CS, 370 had de novo HF-CS (26.3%), and 1035 had acute-on-chronic HF-CS (73.7%). Patients with de novo HF-CS had a lower prevalence of hypertension, diabetes, coronary artery disease, atrial fibrillation, and chronic kidney disease (all P < 0.01). Median Sequential Organ Failure Assessment (SOFA) scores were higher in those with de novo HF-CS (8; 25th-75th: 5-11) vs acute-on-chronic HF-CS (6; 25th-75th: 4-9, P < 0.01), as was the proportion of Society of Cardiovascular Angiography and Intervention (SCAI) shock stage E (46.1% vs 26.1%, P < 0.01). After adjustment for clinical covariates and preceding cardiac arrest, the risk of in-hospital mortality was higher in patients with de novo HF-CS than in those with acute-on-chronic HF-CS (adjusted hazard ratio 1.36, 95% confidence interval 1.05-1.75, P = 0.02).

Conclusions: Despite having fewer comorbidities, patients with de novo HF-CS had more severe shock presentations and worse in-hospital outcomes. Whether HF disease chronicity is associated with time-dependent compensatory adaptations, unique pathobiological features and responses to treatment in patients presenting with HF-CS warrants further investigation.
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http://dx.doi.org/10.1016/j.cardfail.2021.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514080PMC
October 2021

Pulmonary arterial hypertension patients display normal kinetics of clot formation using thrombelastography.

Pulm Circ 2021 Jul-Sep;11(3):20458940211022204. Epub 2021 Jun 24.

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Pulmonary arterial hypertension is characterized by endothelial dysfunction and microthrombi formation. The role of anticoagulation remains controversial, with studies demonstrating inconsistent effects on pulmonary arterial hypertension mortality. Clinical anticoagulation practices are currently heterogeneous, reflecting physician preference. This study uses thrombelastography and hematology markers to evaluate whether clot formation and fibrinolysis are abnormal in pulmonary arterial hypertension patients. Venous blood was collected from healthy volunteers ( = 20) and patients with pulmonary arterial hypertension ( = 20) on stable medical therapy for thrombelastography analysis. Individual thrombelastography parameters and a calculated coagulation index were used for comparison. In addition, hematologic markers, including fibrinogen, factor VIII activity, von Willebrand factor activity, von Willebrand factor antigen, and alpha2-antiplasmin, were measured in pulmonary arterial hypertension patients and compared to healthy volunteers. Between group differences were analyzed using t tests and linear mixed models, accounting for repeated measures when applicable. Although the degree of fibrinolysis (LY30) was significantly lower in pulmonary arterial hypertension patients compared to healthy volunteers (0.3% ± 0.6 1.3% ± 1.1,  = 0.04), all values were within the normal reference range (0-8%). All other thrombelastography parameters were not significantly different between pulmonary arterial hypertension patients and healthy volunteers ( ≥ 0.15 for all). Similarly, alpha2-antiplasmin activity levels were higher in pulmonary arterial hypertension patients compared to healthy volunteers (103.7% ± 13.6 82.6% ± 9.5,  < 0.0001), but all individual values were within the normal range (75-132%). There were no other significant differences in hematologic markers between pulmonary arterial hypertension patients and healthy volunteers ( ≥ 0.07 for all). Sub-group analysis comparing thrombelastography results in patients treated with or without prostacyclin pathway targeted therapies were also non-significant. In conclusion, treated pulmonary arterial hypertension patients do not demonstrate abnormal clotting kinetics or fibrinolysis by thrombelastography.
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http://dx.doi.org/10.1177/20458940211022204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237222PMC
June 2021

Advanced Respiratory Support in the Contemporary Cardiac ICU.

Crit Care Explor 2020 Sep 17;2(9):e0182. Epub 2020 Sep 17.

TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

The medical complexity and critical care needs of patients admitted to cardiac ICUs are increasing, and prospective studies examining the underlying cardiac and noncardiac diagnoses, the management strategies, and the prognosis of cardiac ICU patients with respiratory failure are needed.

Design: Prospective cohort study.

Setting: The Critical Care Cardiology Trials Network is a research collaborative of cardiac ICUs across the United States and Canada.

Patients: We included all medical cardiac ICU admissions at 25 cardiac ICUs during two consecutive months annually at each center from 2017 to 2019.

Measurements: We evaluated the use of advanced respiratory therapies including invasive mechanical ventilation, noninvasive ventilation, and high-flow nasal cannula versus no advanced respiratory support across admission diagnoses and the association with in-hospital mortality.

Main Results: Of 8,240 cardiac ICU admissions, 1,935 (23.5%) were treated with invasive mechanical ventilation, 573 (7.0%) with noninvasive ventilation, and 281 (3.4%) with high-flow nasal cannula. Admitting diagnoses among those with advanced respiratory support were diverse including general medical problems in patients with heart disease as well as primary cardiac problems. In-hospital mortality was higher in patients who received invasive mechanical ventilation (38.1%; adjusted odds ratio, 2.53; 2.02-3.16) and noninvasive ventilation or high-flow nasal cannula (8.8%; adjusted odds ratio, 2.25; 1.73-2.93) compared with patients without advanced respiratory support (4.6%). Reintubation rate was 7.6%. The most common variables associated with respiratory insufficiency included heart failure, infection, chronic obstructive pulmonary disease, and pulmonary vascular disease.

Conclusions: One-third of cardiac ICU admissions receive respiratory support with associated increased mortality. These data provide benchmarks for quality improvement ventures in the cardiac ICU, inform cardiac critical care training and staffing patterns, and serve as foundation for future studies aimed at improving outcomes.
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http://dx.doi.org/10.1097/CCE.0000000000000182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678799PMC
September 2020

Contemporary Management of Severe Acute Kidney Injury and Refractory Cardiorenal Syndrome: JACC Council Perspectives.

J Am Coll Cardiol 2020 09;76(9):1084-1101

Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland; Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Acute kidney injury (AKI) and cardiorenal syndrome (CRS) are increasingly prevalent in hospitalized patients with cardiovascular disease and remain associated with poor short- and long-term outcomes. There are no specific therapies to reduce mortality related to either AKI or CRS, apart from supportive care and volume status management. Acute renal replacement therapies (RRTs), including ultrafiltration, intermittent hemodialysis, and continuous RRT are used to manage complications of medically refractory AKI and CRS and may restore normal electrolyte, acid-base, and fluid balance before renal recovery. Patients who require acute RRT have a significant risk of mortality and long-term dialysis dependence, emphasizing the importance of appropriate patient selection. Despite the growing use of RRT in the cardiac intensive care unit, there are few resources for the cardiovascular specialist that integrate the epidemiology, diagnostic workup, and medical management of AKI and CRS with an overview of indications, multidisciplinary team management, and transition off of RRT.
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http://dx.doi.org/10.1016/j.jacc.2020.06.070DOI Listing
September 2020

COVID-19 and Disruptive Modifications to Cardiac Critical Care Delivery: JACC Review Topic of the Week.

J Am Coll Cardiol 2020 07 16;76(1):72-84. Epub 2020 Apr 16.

Department of Critical Care and Division of Cardiology, Department of Medicine, University of Alberta Hospital, Alberta, Canada. Electronic address: https://twitter.com/seanvandiepen.

The COVID-19 pandemic has presented a major unanticipated stress on the workforce, organizational structure, systems of care, and critical resource supplies. To ensure provider safety, to maximize efficiency, and to optimize patient outcomes, health systems need to be agile. Critical care cardiologists may be uniquely positioned to treat the numerous respiratory and cardiovascular complications of the SARS-CoV-2 and support clinicians without critical care training who may be suddenly asked to care for critically ill patients. This review draws upon the experiences of colleagues from heavily impacted regions of the United States and Europe, as well as lessons learned from military mass casualty medicine. This review offers pragmatic suggestions on how to implement scalable models for critical care delivery, cultivate educational tools for team training, and embrace technologies (e.g., telemedicine) to enable effective collaboration despite social distancing imperatives.
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http://dx.doi.org/10.1016/j.jacc.2020.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161519PMC
July 2020

Venoarterial Extracorporeal Membrane Oxygenation in Cardiogenic Shock: Lifeline of Modern Day CICU.

J Intensive Care Med 2021 Mar 13;36(3):290-303. Epub 2019 Dec 13.

Department of Cardiovascular Medicine, 12251The University of Kansas Health System, Kansas City, KS, USA.

Cardiogenic shock (CS) portends an extremely high mortality of nearly 50% during index hospitalization. Prompt diagnoses of CS, its underlying etiology, and efficient implementation of treatment modalities, including mechanical circulatory support (MCS), are critical especially in light of such high predicted mortality. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides the most comprehensive cardiopulmonary support in critically ill patients and hence has seen a steady increase in its utilization over the past decade. Hence, a good understanding of VA-ECMO, its role in treatment of CS, especially when compared with other temporary MCS devices, and its complications are vital for any critical care cardiologist. Our review of VA-ECMO aims to provide the same.
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http://dx.doi.org/10.1177/0885066619894541DOI Listing
March 2021

Clinical Practice Patterns in Temporary Mechanical Circulatory Support for Shock in the Critical Care Cardiology Trials Network (CCCTN) Registry.

Circ Heart Fail 2019 11 11;12(11):e006635. Epub 2019 Nov 11.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (A.P.C., C.B.G., L.K.N.).

Background: Temporary mechanical circulatory support (MCS) devices provide hemodynamic assistance for shock refractory to pharmacological treatment. Most registries have focused on single devices or specific etiologies of shock, limiting data regarding overall practice patterns with temporary MCS in cardiac intensive care units.

Methods: The CCCTN (Critical Care Cardiology Trials Network) is a multicenter network of tertiary CICUs in North America. Between September 2017 and September 2018, each center (n=16) contributed a 2-month snapshot of consecutive medical CICU admissions.

Results: Of the 270 admissions using temporary MCS, 33% had acute myocardial infarction-related cardiogenic shock (CS), 31% had CS not related to acute myocardial infarction, 11% had mixed shock, and 22% had an indication other than shock. Among all 585 admissions with CS or mixed shock, 34% used temporary MCS during the CICU stay with substantial variation between centers (range: 17%-50%). The most common temporary MCS devices were intraaortic balloon pumps (72%), Impella (17%), and veno-arterial extracorporeal membrane oxygenation (11%), although intraaortic balloon pump use also varied between centers (range: 40%-100%). Patients managed with intraaortic balloon pump versus other forms of MCS (advanced MCS) had lower Sequential Organ Failure Assessment scores and less severe metabolic derangements. Illness severity was similar at high- versus low-MCS utilizing centers and at centers with more advanced MCS use.

Conclusions: There is wide variation in the use of temporary MCS among patients with shock in tertiary CICUs. While hospital-level variation in temporary MCS device selection is not explained by differences in illness severity, patient-level variation appears to be related, at least in part, to illness severity.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008928PMC
November 2019

Meta-analysis of blood genome-wide expression profiling studies in pulmonary arterial hypertension.

Am J Physiol Lung Cell Mol Physiol 2020 01 16;318(1):L98-L111. Epub 2019 Oct 16.

Critical Care Medicine Department, Clinical Center, and National Institutes of Health, Bethesda, Maryland.

Inflammatory cell infiltrates are a prominent feature of aberrant vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that immune effector cells contribute to disease progression. Genome-wide blood expression profiling studies have attempted to better define this inflammatory component of PAH pathobiology but have been hampered by small sample sizes, methodological differences, and very little gene-level reproducibility. The current meta-analysis (seven studies; 156 PAH patients/110 healthy controls) was performed to assess the comparability of data across studies and to possibly derive a generalizable transcriptomic signature. Idiopathic (IPAH) compared with disease-associated PAH (APAH) displayed highly similar expression profiles with no differentially expressed genes, even after substantially relaxing selection stringency. In contrast, using a false discovery rate of ≤1% and < 40% (low-to-moderate heterogeneity across studies) both IPAH and APAH differed markedly from healthy controls with the combined PAH cohort yielding 1,269 differentially expressed, unique gene transcripts. Bioinformatic analyses, including gene-set enrichment, which uses all available data independent of gene selection thresholds, identified interferon, mammalian target of rapamycin/p70S6K, stress kinase, and Toll-like receptor signaling as enriched mechanisms within the PAH gene signature. Enriched biological functions and diseases included tumorigenesis, autoimmunity, antiviral response, and cell death consistent with prevailing theories of PAH pathogenesis. Although otherwise indistinguishable, APAH (predominantly PAH due to systemic sclerosis) had a somewhat stronger interferon profile than IPAH. Meta-analysis defined a robust and generalizable transcriptomic signature in the blood of PAH patients that can help inform the identification of biomarkers and therapeutic targets.
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http://dx.doi.org/10.1152/ajplung.00252.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985867PMC
January 2020

Demographics, Care Patterns, and Outcomes of Patients Admitted to Cardiac Intensive Care Units: The Critical Care Cardiology Trials Network Prospective North American Multicenter Registry of Cardiac Critical Illness.

JAMA Cardiol 2019 09;4(9):928-935

Clinical Center and Cardiology Branch, Critical Care Medicine Department, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Importance: Single-center and claims-based studies have described substantial changes in the landscape of care in the cardiac intensive care unit (CICU). Professional societies have recommended research to guide evidence-based CICU redesigns.

Objective: To characterize patients admitted to contemporary, advanced CICUs.

Design, Setting, And Participants: This study established the Critical Care Cardiology Trials Network (CCCTN), an investigator-initiated multicenter network of 16 advanced, tertiary CICUs in the United States and Canada. For 2 months in each CICU, data for consecutive admissions were submitted to the central data coordinating center (TIMI Study Group). The data were collected and analyzed between September 2017 and 2018.

Main Outcomes And Measures: Demographics, diagnoses, management, and outcomes.

Results: Of 3049 participants, 1132 (37.1%) were women, 797 (31.4%) were individuals of color, and the median age was 65 years (25th and 75th percentiles, 55-75 years). Between September 2017 and September 2018, 3310 admissions were included, among which 2557 (77.3%) were for primary cardiac problems, 337 (10.2%) for postprocedural care, 253 (7.7%) for mixed general and cardiac problems, and 163 (4.9%) for overflow from general medical ICUs. When restricted to the initial 2 months of medical CICU admissions for each site, the primary analysis population included 3049 admissions with a high burden of noncardiovascular comorbidities. The top 2 CICU admission diagnoses were acute coronary syndrome (969 [31.8%]) and heart failure (567 [18.6%]); however, the proportion of acute coronary syndrome was highly variable across centers (15%-57%). The primary indications for CICU care included respiratory insufficiency (814 [26.7%]), shock (643 [21.1%]), unstable arrhythmia (521 [17.1%]), and cardiac arrest (265 [8.7%]). Advanced CICU therapies or monitoring were required for 1776 patients (58.2%), including intravenous vasoactive medications (1105 [36.2%]), invasive hemodynamic monitoring (938 [30.8%]), and mechanical ventilation (652 [21.4%]). The overall CICU mortality rate was 8.3% (95% CI, 7.3%-9.3%). The CICU indications that were associated with the highest mortality rates were cardiac arrest (101 [38.1%]), cardiogenic shock (140 [30.6%]), and the need for renal replacement therapy (51 [34.5%]). Notably, patients admitted solely for postprocedural observation or frequent monitoring had a mortality rate of 0.2% to 0.4%.

Conclusions And Relevance: In a contemporary network of tertiary care CICUs, respiratory failure and shock predominated indications for admission and carried a poor prognosis. While patterns of practice varied considerably between centers, a substantial, low-risk population was identified. Multicenter collaborative networks, such as the CCCTN, could be used to help redesign cardiac critical care and to test new therapeutic strategies.
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http://dx.doi.org/10.1001/jamacardio.2019.2467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659157PMC
September 2019

Role of Critical Care Medicine Training in the Cardiovascular Intensive Care Unit: Survey Responses From Dual Certified Critical Care Cardiologists.

J Am Heart Assoc 2019 03;8(6):e011721

1 Critical Care Medicine Department National Institutes of Health Clinical Center Bethesda MD.

Background Cardiovascular intensive care units ( CICUs ) have evolved from coronary care wards into distinct units for critically ill patients with primary cardiac diseases, often suffering from illnesses that cross multiple disciplines. Mounting evidence has demonstrated improved survival with the incorporation of dedicated CICU providers with expertise in critical care medicine ( CCM ). This is the first study to systematically survey dual certified physicians in order to assess the relevance of CCM training to contemporary CICU care. Methods and Results Utilizing American Board of Internal Medicine data through 2014, 397 eligible physicians had obtained initial certification in both cardiovascular disease and CCM . A survey to delineate the role of critical care training in the CICU was provided to these physicians. Among those surveyed, 120 physicians (30%) responded. Dual certified physicians reported frequent use of their CCM skills in the CICU , highlighting ventilator management, multiorgan dysfunction management, end-of-life care, and airway management. The majority (85%) cited these skills as the reason CCM training should be prioritized by future CICU providers. Few (17%) agreed that general cardiology fellowship alone is currently sufficient to care for patients in the modern CICU . Furthermore, there was a consensus that there is an unmet need for cardiologists trained in CCM (70%) and that CICU s should adopt a level system similar to trauma centers (61%). Conclusions Citing specific skills acquired during CCM training, dual certified critical care cardiologists reported that their additional critical care experience was necessary in their practice to effectively deliver care in the modern CICU .
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http://dx.doi.org/10.1161/JAHA.118.011721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475069PMC
March 2019

Epidemiology of Shock in Contemporary Cardiac Intensive Care Units.

Circ Cardiovasc Qual Outcomes 2019 03;12(3):e005618

Critical Care Medicine Department, National Institutes of Health Clinical Center and Cardiovascular Branch, National Heart, Lung, and Blood Institute, of the National Institutes of Health, Bethesda, MD (M.A.S.).

Background Clinical investigations of shock in cardiac intensive care units (CICUs) have primarily focused on acute myocardial infarction (AMI) complicated by cardiogenic shock (AMICS). Few studies have evaluated the full spectrum of shock in contemporary CICUs. Methods and Results The Critical Care Cardiology Trials Network is a multicenter network of advanced CICUs in North America. Anytime between September 2017 and September 2018, each center (n=16) contributed a 2-month snap-shot of all consecutive medical admissions to the CICU. Data were submitted to the central coordinating center (TIMI Study Group, Boston, MA). Shock was defined as sustained systolic blood pressure <90 mm Hg with end-organ dysfunction ascribed to the hypotension. Shock type was classified by site investigators as cardiogenic, distributive, hypovolemic, or mixed. Among 3049 CICU admissions, 677 (22%) met clinical criteria for shock. Shock type was varied, with 66% assessed as cardiogenic shock (CS), 7% as distributive, 3% as hypovolemic, 20% as mixed, and 4% as unknown. Among patients with CS (n=450), 30% had AMICS, 18% had ischemic cardiomyopathy without AMI, 28% had nonischemic cardiomyopathy, and 17% had a cardiac cause other than primary myocardial dysfunction. Patients with mixed shock had cardiovascular comorbidities similar to patients with CS. The median CICU stay was 4.0 days (interquartile range [IQR], 2.5-8.1 days) for AMICS, 4.3 days (IQR, 2.1-8.5 days) for CS not related to AMI, and 5.8 days (IQR, 2.9-10.0 days) for mixed shock versus 1.9 days (IQR, 1.0-3.6) for patients without shock ( P<0.01 for each). Median Sequential Organ Failure Assessment scores were higher in patients with mixed shock (10; IQR, 6-13) versus AMICS (8; IQR, 5-11) or CS without AMI (7; IQR, 5-11; each P<0.01). In-hospital mortality rates were 36% (95% CI, 28%-45%), 31% (95% CI, 26%-36%), and 39% (95% CI, 31%-48%) in AMICS, CS without AMI, and mixed shock, respectively. Conclusions The epidemiology of shock in contemporary advanced CICUs is varied, and AMICS now represents less than one-third of all CS. Despite advanced therapies, mortality in CS and mixed shock remains high. Investigation of management strategies and new therapies to treat shock in the CICU should take this epidemiology into account.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.119.005618DOI Listing
March 2019

Positive Pressure Ventilation in the Cardiac Intensive Care Unit.

J Am Coll Cardiol 2018 09;72(13):1532-1553

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Contemporary cardiac intensive care units (CICUs) provide care for an aging and increasingly complex patient population. The medical complexity of this population is partly driven by an increased proportion of patients with respiratory failure needing noninvasive or invasive positive pressure ventilation (PPV). PPV often plays an important role in the management of patients with cardiogenic pulmonary edema, cardiogenic shock, or cardiac arrest, and those undergoing mechanical circulatory support. Noninvasive PPV, when appropriately applied to selected patients, may reduce the need for invasive mechanical PPV and improve survival. Invasive PPV can be lifesaving, but has both favorable and unfavorable interactions with left and right ventricular physiology and carries a risk of complications that influence CICU mortality. Effective implementation of PPV requires an understanding of the underlying cardiac and pulmonary pathophysiology. Cardiologists who practice in the CICU should be proficient with the indications, appropriate selection, potential cardiopulmonary interactions, and complications of PPV.
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http://dx.doi.org/10.1016/j.jacc.2018.06.074DOI Listing
September 2018

Pulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab.

BMC Pulm Med 2018 Jul 11;18(1):112. Epub 2018 Jul 11.

Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.

Background: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking.

Case Presentation: A 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD).

Conclusion: PTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes.
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http://dx.doi.org/10.1186/s12890-018-0681-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042377PMC
July 2018

Spironolactone-induced degradation of the TFIIH core complex XPB subunit suppresses NF-κB and AP-1 signalling.

Cardiovasc Res 2018 01;114(1):65-76

Critical Care Medicine Department, Clinical Center.

Aims: Spironolactone (SPL) improves endothelial dysfunction and survival in heart failure. Immune modulation, including poorly understood mineralocorticoid receptor (MR)-independent effects of SPL might contribute to these benefits and possibly be useful in other inflammatory cardiovascular diseases such as pulmonary arterial hypertension.

Methods And Results: Using human embryonic kidney cells (HEK 293) expressing specific nuclear receptors, SPL suppressed NF-κB and AP-1 reporter activity independent of MR and other recognized nuclear receptor partners. NF-κB and AP-1 DNA binding were not affected by SPL and protein synthesis blockade did not interfere with SPL-induced suppression of inflammatory signalling. In contrast, proteasome blockade to inhibit degradation of xeroderma pigmentosum group B complementing protein (XPB), a subunit of the general transcription factor TFIIH, or XPB overexpression both prevented SPL-mediated suppression of inflammation. Similar to HEK 293 cells, a proteasome inhibitor blocked XPB loss and SPL suppression of AP-1 induced target genes in human pulmonary artery endothelial cells (PAECs). Unlike SPL, eplerenone (EPL) did not cause XPB degradation and failed to similarly suppress inflammatory signalling. SPL combined with siRNA XPB knockdown further reduced XPB protein levels and had the greatest effect on PAEC inflammatory gene transcription. Using chromatin-immunoprecipitation, PAEC target gene susceptibility to SPL was associated with low basal RNA polymerase II (RNAPII) occupancy and TNFα-induced RNAPII and XPB recruitment. XP patient-derived fibroblasts carrying an N-terminal but not C-terminal XPB mutations were insensitive to both SPL-mediated XPB degradation and TNFα-induced target gene suppression. Importantly, SPL treatment decreased whole lung XPB protein levels in a monocrotaline rat model of pulmonary hypertension and reduced inflammatory markers in an observational cohort of PAH patients.

Conclusion: SPL has important anti-inflammatory effects independent of aldosterone and MR, not shared with EPL. Drug-induced, proteasome-dependent XPB degradation may be a useful therapeutic approach in cardiovascular diseases driven by inflammation.
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http://dx.doi.org/10.1093/cvr/cvx198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852512PMC
January 2018

Use of sacubitril/valsartan in acute decompensated heart failure: a case report.

ESC Heart Fail 2018 02 16;5(1):184-188. Epub 2017 Oct 16.

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Refractory heart failure typically requires costly long-term, continuous intravenous inodilator infusions while patients await mechanical circulatory support or cardiac transplantation. The combined angiotensin receptor blocker-neprilysin inhibitor, sacubitril/valsartan, is a novel therapy that can increase levels of endogenous vasoactive peptides. This therapy has been recommended as an alternative agent in patients with chronic heart failure with reduced ejection fraction and New York Heart Association class II-III symptoms. Here, we report a case of a patient with refractory stage D heart failure with reduced ejection fraction who was successfully weaned off continuous intravenous inodilator support using sacubitril/valsartan after prior failed attempts using standard therapies.
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http://dx.doi.org/10.1002/ehf2.12219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793985PMC
February 2018

Advanced Percutaneous Mechanical Circulatory Support Devices for Cardiogenic Shock.

Crit Care Med 2017 Nov;45(11):1922-1929

1Critical Care Medicine, National Institutes of Health Clinical Center, Bethesda, MD. 2Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.

Objectives: To review temporary percutaneous mechanical circulatory support devices for the treatment of cardiogenic shock, including current evidence, contraindications, complications, and future directions.

Data Sources: A MEDLINE search was conducted with MeSH terms: cardiogenic shock, percutaneous mechanical circulatory support, extracorporeal membrane oxygenation, Impella, and TandemHeart.

Study Selection: Selected publications included randomized controlled trial data and observational studies describing experience with percutaneous mechanical circulatory support in cardiogenic shock.

Data Extraction: Studies were chosen based on strength of association with and relevance to cardiogenic shock.

Data Synthesis: Until recently, there were few options if cardiogenic shock was refractory to vasopressors or intra-aortic balloon pump counterpulsation. Now, several percutaneous mechanical circulatory support devices, including Impella (Abiomed, Danvers, MA), TandemHeart (CardiacAssist, Pittsburgh, PA), and extracorporeal membrane oxygenation, are more accessible. Compared with intra-aortic balloon pump, Impella provides greater hemodynamic support but no reduction in mortality. Similarly, TandemHeart improves hemodynamic variables but not survival. Comparative studies have been underpowered for mortality because of small sample size. Veno-arterial extracorporeal membrane oxygenation offers the advantage of biventricular circulatory support and oxygenation, but there are significant vascular complications. Comparative studies with extracorporeal membrane oxygenation have not been completed. Despite lack of randomized controlled data, there has been a substantial increase in use of percutaneous mechanical circulatory support. Several ongoing prospective studies with larger sample sizes may provide answers, and newer devices may become smaller, easier to insert, and more effective.

Conclusions: Mortality from cardiogenic shock remains unacceptably high despite early coronary revascularization or other therapies. Although evidence is lacking and complications rates are high, improvements and experience with percutaneous mechanical circulatory support may offer the prospect of better outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000002676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640487PMC
November 2017

Organizational Structure, Staffing, Resources, and Educational Initiatives in Cardiac Intensive Care Units in the United States: An American Heart Association Acute Cardiac Care Committee and American College of Cardiology Critical Care Cardiology Working Group Cross-Sectional Survey.

Circ Cardiovasc Qual Outcomes 2017 08;10(8):e003864

From the Department of Critical Care and Division of Cardiology, University of Alberta, Edmonton, Canada (S.v.D.); Division of Cardiology, University of British Columbia, Vancouver, Canada (C.B.F.); Duke Clinical Research Institute, Durham, NC (C.B.G., A.S., L.K.N.); Brigham and Women's Hospital and Harvard Medical School, Boston, MA (D.A.M.); National, Heart, Lung, and Blood Institute and Clinical Center, National Institutes of Health, Bethesda, MD (M.A.S.); Rush University Medical Center, Chicago, IL (J.S.); Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Milton S. Hershey Medical Center, Penn State University, Hershey, PA (I.C.G.); Divisions of Cardiology and Pulmonary and Critical Care Medicine, University of North Carolina School of Medicine, Chapel Hill (J.N.K.); and University of Miami Miller School of Medicine, FL (M.G.C.).

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http://dx.doi.org/10.1161/CIRCOUTCOMES.117.003864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666693PMC
August 2017

Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation.

J Heart Lung Transplant 2017 Sep 20;36(9):1004-1012. Epub 2017 May 20.

Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland; Laboratory of Transplantation Genomics, National Heart, Lung, and Blood Institute, Bethesda, Maryland. Electronic address:

Background: Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts.

Methods: After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts.

Results: We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R > 0.99, p < 10), as well as across manual and automated platforms (slope = 0.80, R = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001).

Conclusions: The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation.
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http://dx.doi.org/10.1016/j.healun.2017.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988434PMC
September 2017

Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells.

Am J Physiol Lung Cell Mol Physiol 2016 Jan 20;310(2):L187-201. Epub 2015 Nov 20.

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.

A proliferative endothelial cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Bone morphogenetic protein type II receptor (BMPR2) loss-of-function is the most common cause of heritable PAH and has been closely linked to the formation of pathological plexiform lesions. Although some BMPR2 mutations leave ligand-dependent responses intact, the disruption of ligand-independent, noncanonical functions are universal among PAH-associated BMPR2 genotypes, but incompletely understood. This study examined the noncanonical signaling consequences of BMPR2 silencing in human pulmonary artery endothelial cells to identify potential therapeutic targets. BMPR2 siRNA silencing resulted in a proliferative, promigratory pulmonary artery endothelial cell phenotype and disruption of cytoskeletal architecture. Expression profiling closely reflected these phenotypic changes. Gene set enrichment and promoter analyses, as well as the differential expression of pathway components identified Ras/Raf/ERK signaling as an important consequence of BMPR2 silencing. Raf family members and ERK1/2 were constitutively activated after BMPR2 knockdown. Two Raf inhibitors, sorafenib and AZ628, and low-dose nintedanib, a triple receptor tyrosine kinase inhibitor upstream from Ras, reversed the abnormal proliferation and hypermotility of BMPR2 deficiency. Inhibition of dysregulated Ras/Raf/ERK signaling may be useful in reversing vascular remodeling in PAH.
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http://dx.doi.org/10.1152/ajplung.00303.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719048PMC
January 2016

Isolation of a circulating CD45-, CD34dim cell population and validation of their endothelial phenotype.

Thromb Haemost 2014 Oct 24;112(4):770-80. Epub 2014 Jul 24.

Michael A. Solomon, MD, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Building 10, Room 2C145, Bethesda, MD 20892-1662, USA, Tel.: +1 301 496 9320, Fax: +1 301 402 1213, E-mail:

Accurately detecting circulating endothelial cells (CECs) is important since their enumeration has been proposed as a biomarker to measure injury to the vascular endothelium. However, there is no single methodology for determining CECs in blood, making comparison across studies difficult. Many methods for detecting CECs rely on characteristic cell surface markers and cell viability indicators, but lack secondary validation. Here, a CEC population in healthy adult human subjects was identified by flow cytometry as CD45-, CD34dim that is comparable to a previously described CD45-, CD31bright population. In addition, nuclear staining with 7-aminoactinomycin D (7-AAD) was employed as a standard technique to exclude dead cells. Unexpectedly, the CD45-, CD34dim, 7-AAD- CECs lacked surface detectable CD146, a commonly used marker of CECs. Furthermore, light microscopy revealed this cell population to be composed primarily of large cells without a clearly defined nucleus. Nevertheless, immunostains still demonstrated the presence of the lectin Ulex europaeus and von Willebrand factor. Ultramicro analytical immunochemistry assays for the endothelial cell proteins CD31, CD34, CD62E, CD105, CD141, CD144 and vWF indicated these cells possess an endothelial phenotype. However, only a small amount of RNA, which was mostly degraded, could be isolated from these cells. Thus the majority of CECs in healthy individuals as defined by CD45-, CD34dim, and 7-AAD- have shed their CD146 surface marker and are senescent cells without an identifiable nucleus and lacking RNA of sufficient quantity and quality for transcriptomal analysis. This study highlights the importance of secondary validation of CEC identification.
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http://dx.doi.org/10.1160/TH14-01-0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988526PMC
October 2014
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