Publications by authors named "Charles Marboe"

97 Publications

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

Surveillance for disease progression of transthyretin amyloidosis after heart transplantation in the era of novel disease modifying therapies.

J Heart Lung Transplant 2021 Oct 25. Epub 2021 Oct 25.

Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, New York.

Background: Heart Transplantation (HT) is a rational therapy for advanced transthyretin cardiac amyloidosis (ATTR-CA), but the impact of ongoing amyloid deposition is not well defined. We evaluated a cohort of patients who underwent HT for ATTR-CA to determine the incidence of de novo or progression of post-HT ATTR deposition.

Methods: All patients who were followed post-HT for ATTR-CA at our center were included. Baseline demographics and post-HT manifestations of TTR deposition were collected. All patients completed the Composite Autonomic Symptom Score (COMPASS-31 quantifies autonomic symptoms, with a higher score [0-100] indicating more severe autonomic dysfunction) and Polyneuropathy Disability Score (PND, range from 0 [asymptomatic] to IV [confined to wheelchair/bed]) questionnaires.

Results: Twelve patients (5 wild-type, 7 variant [6 p.Val142Ile, 1 p.Thr80Ala]) were included. Mean age at HT was 64.6 (SD: 4.8) years, 83.3% male, and 50% Black. At a median of 4.0 years (IQR 2.4, 5.9) post-HT, 8 patients had symptoms of ATTR deposition (5 with gastrointestinal involvement, 4 orthopedic and 4 neurologic), with 4 patients having ≥2 body systems involved. There were no patients with recurrent cardiac involvement. Median COMPASS-31 score was 17.3 (IQR 11.3, 23.5) at 3.9 years (IQR 2.4, 5.9) post-HT. Four patients had a PND score of stage 1 (sensory disturbance), 1 patient was stage 2 (impaired walking) and 1 patient stage 3b (required a walking aid).

Conclusions: More than 50% of patients had evidence of progressive or de novo ATTR deposition post-HT, impairing quality of life despite a well-functioning cardiac allograft. These observations highlight an unmet need to establish the role of formal surveillance and treatment of TTR using TTR disease-modifying therapies, which may maintain or improve quality of life post-HT for ATTR-CA.
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http://dx.doi.org/10.1016/j.healun.2021.10.007DOI Listing
October 2021

Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19.

JCI Insight 2022 Jan 25;7(2). Epub 2022 Jan 25.

Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.

Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes - myocarditis and cardiac necrosis - have proved uncommon. To elucidate the pathophysiology of COVID-19-associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non-COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19-associated cardiac microthrombi.
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http://dx.doi.org/10.1172/jci.insight.154633DOI Listing
January 2022

Can lightning strike twice? Wild-type transthyretin cardiac amyloidosis associated with rare liver disease.

Oxf Med Case Reports 2021 Nov 25;2021(11):omab113. Epub 2021 Nov 25.

Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

Wild-type ATTR cardiac amyloidosis (ATTRwt-CA) is not as rare as previously thought to be. Patients with infiltrative cardiac amyloidosis often present with right-sided heart failure (HF) symptomatology. Clinically significant liver disease and cirrhosis has not been reported in ATTRwt-CA. We present two cases of ATTRwt-CA with right-sided HF and abnormal liver function tests initially thought to be secondary to congestive hepatopathy but found to have rare and unrelated liver disease. These cases highlight the importance of developing a broad differential diagnosis and leveraging a multidisciplinary team approach in evaluating patients for unusual causes of cirrhosis/other chronic liver diseases when ATTR cardiac amyloidosis patients present with congestive hepatopathy.
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http://dx.doi.org/10.1093/omcr/omab113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633595PMC
November 2021

Response by Shah et al to Letter Regarding Article, "Cell-Free DNA to Detect Heart Allograft Acute Rejection".

Circulation 2021 09 7;144(10):e198-e199. Epub 2021 Sep 7.

Genomic Research Alliance for Transplantation (GRAfT), Bethesda, MD (P.S., S.A-E., I.T., S.H., E.F., K.S., M.E.R., S.S.N., H.K., U.F., A.B., A.M., K.B., Y.Y., M.K.J., C.Marboe, G.J.B., H.A.V.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055697DOI Listing
September 2021

Transcriptomic heterogeneity of antibody mediated rejection after heart transplant with or without donor specific antibodies.

J Heart Lung Transplant 2021 11 8;40(11):1472-1480. Epub 2021 Jul 8.

Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York. Electronic address:

Background: Antibody mediated rejection (AMR) is an increasingly studied cause of graft failure after heart transplantation. AMR diagnosis previously required the detection of circulating donor specific antibodies (DSA); however, the most recent criteria only require pathological findings. This classification defined a subset of patients with AMR, yet without known antibodies. Here, we sought to evaluate differences in the transcriptome profile associated with different types of AMR.

Methods: RNA sequencing was used on endomyocardial biopsies to analyze and compare transcriptomic profiles associated with different subtypes of AMR defined by immunopathological and histopathological findings, as well as the presence or absence of DSA. Gene expression profiles were characterized for each diagnostic group.

Results: The most divergent gene expression profiles were observed between patients with or without DSA. AMR subtypes associated with DSA showed expression of signature genes involved in monocyte activation and response to interferon. There was also substantial difference between the transcriptomic profiles of AMR defined by histopathological and immunopathological findings, the latter being associated with expression of mucin genes. In contrast, there was no differential RNA expression between patients with pAMR1i without DSA and those without AMR. Likewise, no differential expression was observed between patients with pAMR1h with DSA and pAMR2.

Conclusions: Overall, our studies reveal different expression profiles in endomyocardial biopsies in relation to some key criteria used to diagnose AMR. These findings support the view that the diagnosis of AMR encompasses several phenotypes that may rely on distinct mechanisms of injury.
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http://dx.doi.org/10.1016/j.healun.2021.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571048PMC
November 2021

Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses.

bioRxiv 2021 Jul 27. Epub 2021 Jul 27.

Cardiac injury is associated with critical COVID-19, yet its etiology remains debated. To elucidate the pathogenic mechanisms of COVID-19-associated cardiac injury, we conducted a single-center prospective cohort study of 69 COVID-19 decedents. Of six cardiac histopathologic features, microthrombi was the most commonly detected (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi. Using single nuclei RNA-sequence analysis, we discovered an enrichment of pro-thrombotic/anti-fibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts relative to microthrombi-negative COVID-19. Non-COVID-19 non-failing hearts were used as reference controls. Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.
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http://dx.doi.org/10.1101/2021.07.27.453843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328056PMC
July 2021

Tale of a Black Heart!

Ann Thorac Surg 2021 Jun 17. Epub 2021 Jun 17.

Division of Cardiac, Thoracic & Vascular Surgery, Columbia University College of Physicians and Surgeons, New York. Electronic address:

Alkaptonuria is a rare condition of inborn error of metabolism. Association with aortic stenosis has been described; however, diagnosis at the time of valve replacement is infrequent. Recognition of this condition has potential management implications as the durability of prosthetic valves in such cases is unknown. We describe a case report which depicts these unique aspects.
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http://dx.doi.org/10.1016/j.athoracsur.2021.05.063DOI Listing
June 2021

Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study.

J Heart Lung Transplant 2021 08 24;40(8):822-830. Epub 2021 Apr 24.

Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, Maryland; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, Maryland; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, Maryland. Electronic address:

Background: Acute rejection, which includes antibody-mediated rejection and acute cellular rejection, is a risk factor for lung allograft loss. Lung transplant patients often undergo surveillance transbronchial biopsies to detect and treat acute rejection before irreversible chronic rejection develops. Limitations of this approach include its invasiveness and high interobserver variability. We tested the performance of percent donor-derived cell-free DNA (%ddcfDNA), a non-invasive blood test, to detect acute rejection.

Methods: This multicenter cohort study monitored 148 lung transplant subjects over a median of 19.6 months. We collected serial plasma samples contemporaneously with TBBx to measure %ddcfDNA. Clinical data was collected to adjudicate for acute rejection. The primary analysis consisted of computing the area-under-the-receiver-operating-characteristic-curve of %ddcfDNA to detect acute rejection. Secondary analysis determined %ddcfDNA rule-out thresholds for acute rejection.

Results: ddcfDNA levels were high after transplant surgery and decayed logarithmically. With acute rejection, ddcfDNA levels rose six-fold higher than controls. ddcfDNA levels also correlated with severity of lung function decline and histological grading of rejection. %ddcfDNA area-under-the-receiver-operating-characteristic-curve for acute rejection, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of <0.5% and <1.0% showed a negative predictive value of 96% and 90% for acute rejection, respectively. Histopathology detected one-third of episodes with ddcfDNA levels ≥1.0%, even though >90% of these events were coincident to clinical complications missed by histopathology.

Conclusions: This study demonstrates that %ddcfDNA reliably detects acute rejection and other clinical complications potentially missed by histopathology, lending support to its use as a non-invasive marker of allograft injury.
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http://dx.doi.org/10.1016/j.healun.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319066PMC
August 2021

A molecular single-cell lung atlas of lethal COVID-19.

Nature 2021 07 29;595(7865):114-119. Epub 2021 Apr 29.

Human Immune Monitoring Core, Columbia University Irving Medical Center, New York, NY, USA.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1 pathological fibroblasts contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.
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http://dx.doi.org/10.1038/s41586-021-03569-1DOI Listing
July 2021

A Rare Case of Cardiac Mesenchymal Hamartoma and Comprehensive Review of the Literature With Emphasis on Histopathology.

Int J Surg Pathol 2021 Oct 22;29(7):764-769. Epub 2021 Mar 22.

12286Rutgers/New Jersey Medical School, Newark, NJ, USA.

Hamartomas are primary, benign neoplastic lesions that most commonly derive from a single variably differentiated cell lineage. Here, we report an unusual case of a cardiac hamartoma. A 62-year-old woman presented with chest pain and palpitations. Serial imaging revealed a large slowly growing and highly vascularized left ventricular mass, which required surgical resection. Microscopically, the lesion was composed of nodular fibrovascular proliferation with haphazardly embedded muscle bundles and peripheral calcifications. Immunohistochemical studies revealed prominent muscle-specific actin positive and smooth muscle actin positive muscle fiber bundles within a disorganized fibrovascular stroma. This characterization is most consistent with cardiac mesenchymal hamartoma. Relevant differential diagnoses for this lesion include hamartoma of mature cardiac myocytes (HMCMs) and intramuscular hemangioma. The prominent smooth muscle differentiation of muscle bundles was incompatible with defining features of HMCM. Absence of S100-positive nerve and mature adipose cells distinguished this lesion from the recently defined, heterogeneous cardiac mesenchymal hamartoma. Forty-seven cases of cardiac hamartoma reported from 1970 to 2020 were reviewed to provide histopathologic context.
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http://dx.doi.org/10.1177/10668969211002264DOI Listing
October 2021

Longitudinal profiling of circulating miRNA during cardiac allograft rejection: a proof-of-concept study.

ESC Heart Fail 2021 06 13;8(3):1840-1849. Epub 2021 Mar 13.

Department of Medicine I, Division of Cardiology, University Hospital of Friedrich Schiller University Jena, Am Klinikum 1, Jena, 07747, Germany.

Aims: Allograft rejection following heart transplantation (HTx) is a serious complication even in the era of modern immunosuppressive regimens and causes up to a third of early deaths after HTx. Allograft rejection is mediated by a cascade of immune mechanisms leading to acute cellular rejection (ACR) and/or antibody-mediated rejection (AMR). The gold standard for monitoring allograft rejection is invasive endomyocardial biopsy that exposes patients to complications. Little is known about the potential of circulating miRNAs as biomarkers to detect cardiac allograft rejection. We here present a systematic analysis of circulating miRNAs as biomarkers and predictors for allograft rejection after HTx using next-generation small RNA sequencing.

Methods And Results: We used next-generation small RNA sequencing to investigate circulating miRNAs among HTx recipients (10 healthy controls, 10 heart failure patients, 13 ACR, and 10 AMR). MiRNA profiling was performed at different time points before, during, and after resolution of the rejection episode. We found three miRNAs with significantly increased serum levels in patients with biopsy-proven cardiac rejection when compared with patients without rejection: hsa-miR-139-5p, hsa-miR-151a-5p, and hsa-miR-186-5p. We identified miRNAs that may serve as potential predictors for the subsequent development of ACR: hsa-miR-29c-3p (ACR) and hsa-miR-486-5p (AMR). Overall, hsa-miR-486-5p was most strongly associated with acute rejection episodes.

Conclusions: Monitoring cardiac allograft rejection using circulating miRNAs might represent an alternative strategy to invasive endomyocardial biopsy.
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http://dx.doi.org/10.1002/ehf2.13238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120386PMC
June 2021

Cell-Free DNA to Detect Heart Allograft Acute Rejection.

Circulation 2021 03 13;143(12):1184-1197. Epub 2021 Jan 13.

Genomic Research Alliance for Transplantation, Bethesda, MD (S.A.-E., P.S., I.T., S.H., E.F., K.S., M.E.R., S.S.N., H.K., U.F., A.B., A.M., K.B., Y.Y., M.K.J., C.M., G.J.B., H.A.V.).

Background: After heart transplantation, endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive, and its conventional histological interpretation has limitations. This is a validation study to assess the performance of a sensitive blood biomarker-percent donor-derived cell-free DNA (%ddcfDNA)-for detection of AR in cardiac transplant recipients.

Methods: This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data were collected to define AR, its 2 phenotypes (acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range [IQR]) for AR, AMR, and ACR with controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.

Results: The study included 171 subjects with median posttransplant follow-up of 17.7 months (IQR, 12.1-23.6), with 1392 EMBx, and 1834 %ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (IQR, 0.03%-0.21%) by 28 days. Also, %ddcfDNA increased again with AR compared with control values (0.38% [IQR, 0.31-0.83%], versus 0.03% [IQR, 0.01-0.14%]; <0.001). The rise was detected 0.5 and 3.2 months before histopathologic diagnosis of ACR and AMR. The area under the receiver operator characteristic curve for AR was 0.92. A 0.25%ddcfDNA threshold had a negative predictive value for AR of 99% and would have safely eliminated 81% of EMBx. In addition, %ddcfDNA showed distinctive characteristics comparing AMR with ACR, including 5-fold higher levels (AMR ≥2, 1.68% [IQR, 0.49-2.79%] versus ACR grade ≥2R, 0.34% [IQR, 0.28-0.72%]), higher area under the receiver operator characteristic curve (0.95 versus 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.

Conclusions: We found that %ddcfDNA detected AR with a high area under the receiver operator characteristic curve and negative predictive value. Monitoring with ddcfDNA demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in patients with heart transplant and paves the way for a clinical utility study. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221834PMC
March 2021

T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy.

Am J Transplant 2021 04 26;21(4):1465-1476. Epub 2020 Oct 26.

Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, New York.

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor β chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4 and CD8 memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFβ) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.
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http://dx.doi.org/10.1111/ajt.16333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672660PMC
April 2021

Feasibility of near-infrared spectroscopy as a tool for anatomical mapping of the human epicardium.

Biomed Opt Express 2020 Aug 8;11(8):4099-4109. Epub 2020 Jul 8.

Department of Electrical Engineering, Columbia University, New York, NY 10027, USA.

Epicardial ablation is necessary for the treatment of ventricular tachycardias refractory to endocardial ablation due to arrhythmic substrates involving the epicardium. The human epicardium is composed of adipose tissue and coronary vasculature embedded on the surface and within the myocardium, which can complicate electroanatomical mapping, electrogram interpretation and ablation delivery. We propose using near-infrared spectroscopy (NIRS) to decipher adipose tissue from myocardial tissue within human hearts . Histological measurement of epicardial adipose thickness direct correlated (R = 0.884) with the adipose contrast index. These results demonstrate the potential of NIRS integrated catheters for mapping the spatial distribution of epicardial substrates and could aid in improving guidance during epicardial ablation interventions.
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http://dx.doi.org/10.1364/BOE.394294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449747PMC
August 2020

Isolated Immunoglobulin G4-Related Disease Myocarditis Treated With Heart Transplantation.

Circ Heart Fail 2020 12 8;13(12):e007204. Epub 2020 Sep 8.

Beth Israel Deaconess Medical Center, Boston, MA (J.E.D., N.P.).

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007204DOI Listing
December 2020

Forty Postmortem Examinations in COVID-19 Patients.

Am J Clin Pathol 2020 11;154(6):748-760

Department of Pathology and Cell Biology, Columbia University Irving Medical Center and the NewYork-Presbyterian Hospital, New York, NY.

Objectives: Although diffuse alveolar damage, a subtype of acute lung injury (ALI), is the most common microscopic pattern in coronavirus disease 2019 (COVID-19), other pathologic patterns have been described. The aim of the study was to review autopsies from COVID-19 decedents to evaluate the spectrum of pathology and correlate the results with clinical, laboratory, and radiologic findings.

Methods: A comprehensive and quantitative review from 40 postmortem examinations was performed. The microscopic patterns were categorized as follows: "major" when present in more than 50% of cases and "novel" if rarely or not previously described and unexpected clinically.

Results: Three major pulmonary patterns were identified: ALI in 29 (73%) of 40, intravascular fibrin or platelet-rich aggregates (IFPAs) in 36 (90%) of 40, and vascular congestion and hemangiomatosis-like change (VCHL) in 20 (50%) of 40. The absence of ALI (non-ALI) was novel and seen in 11 (27%) of 40. Compared with ALI decedents, those with non-ALI had a shorter hospitalization course (P = .02), chest radiographs with no or minimal consolidation (P = .01), and no pathologically confirmed cause of death (9/11). All non-ALI had VCHL and IFPAs, and clinically most had cardiac arrest.

Conclusions: Two distinct pulmonary phenotypic patterns-ALI and non-ALI-were noted. Non-ALI represents a rarely described phenotype. The cause of death in non-ALI is most likely COVID-19 related but requires additional corroboration.
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http://dx.doi.org/10.1093/ajcp/aqaa156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499554PMC
November 2020

Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs.

Nat Med 2020 07 13;26(7):1102-1113. Epub 2020 Jul 13.

Department of Biomedical Engineering, Columbia University, New York, NY, USA.

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.
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http://dx.doi.org/10.1038/s41591-020-0971-8DOI Listing
July 2020

Adrenal Vascular Changes in COVID-19 Autopsies.

Arch Pathol Lab Med 2020 10;144(10):1159-1160

Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.

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http://dx.doi.org/10.5858/arpa.2020-0248-LEDOI Listing
October 2020

The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited.

Am J Transplant 2020 12 28;20(12):3308-3318. Epub 2020 Jun 28.

Department of Pathology, Stanford University, Stanford, California, USA.

The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting, two main topics in cardiac transplant pathology were addressed: (a) Improvement of endomyocardial biopsy (EMB) accuracy for the diagnosis of rejection and other significant injury patterns, and (b) the orphaned lesion known as Quilty effect or nodular endocardial infiltrates. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate the histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from hematoxylin and eosin (H&E) stain to multiplex labeling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas was reviewed, and possible pathogenesis proposed, based on advances in immunology to explain conflicting data. The Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ.
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http://dx.doi.org/10.1111/ajt.16083DOI Listing
December 2020

Large and Uneven Bites in End-to-End Anastomosis of the Rat Femoral Artery.

J Reconstr Microsurg 2020 Sep 17;36(7):486-493. Epub 2020 Apr 17.

Department of Orthopedic Surgery, Columbia University Irving Medical Center, New York, New York.

Background:  Successful microvascular anastomosis depends on sutures that adequately oppose both cut vessel edges. Trainees tend to take oversized or uneven bite. To improve early microsurgical skill acquisition using the rat, this study tests the belief that such bites compromise early patency by applying exaggerated bites to end-to-end arterial anastomoses.

Methods:  Twelve Sprague-Dawley rats were randomly assigned to one of the four bite techniques to be applied to both femoral arteries (mean diameter, 0.8 mm). Large (L) and standard (S) bites measured 1.0 and 0.2 mm from the edge, respectively. Eight simple interrupted anastomoses were performed per bite technique, each labeled according to every proximal end bite size, followed by every distal end bite size: LL, LS, SL, and SS. Anastomosis time and blood flow rates were recorded and analyzed statistically. After sacrifice 5 days postoperation, anastomosis sections of each technique were examined histologically.

Results:  All 24 anastomoses (100%) maintained patency for 5 days. There was no statistical difference between all postoperative blood flow measurements at any given time. Anastomosis times using LL, LS, SL, and SS bite techniques were 41.6, 33.2, 34.8, and 25.5 minutes, respectively. Anastomosis time for the traditional bite technique (SS) was significantly shorter than all other bite techniques ( < 0.05). Histological examination of the harvested segments from each group revealed similar pathophysiological features.

Conclusion:  Oversized bites (1 mm), placed symmetrically and asymmetrically across the anastomosis, do not affect early patency in the rat femoral artery. A reduced reliance on conventional guidelines for suture bites appears acceptable during microarterial anastomoses if the goal is vessel patency. However, we believe clinical competence involves the ability to place small, even bites consistently and uniformly. During microsurgical training, the occasional large bite need not be replaced; however, the trainee should be encouraged to take standard bites.
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http://dx.doi.org/10.1055/s-0040-1709453DOI Listing
September 2020

Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation.

Am J Transplant 2020 09 26;20(9):2571-2580. Epub 2020 Apr 26.

Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, New York, USA.

Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor human leukocyte antigen (HLA) is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non-HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single-center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥ pAMR1 (n = 43) and non-AMR (n = 21) were tested for reactivity against a panel of 44 non-HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non-AMR (P = .002) and healthy controls (n = 94, P < .0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (P < .0001) and AMR patients with DSA and PRA > 10% were identified as the subgroup with significantly elevated responses. Reactivity to 4 antigens, vimentin, beta-tubulin, lamin A/C, and apolipoprotein L2, was significantly different between AMR and non-AMR patients. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non-HLA are associated with DSA-positive AMR although their specific role in mediating allograft injury is not yet understood.
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http://dx.doi.org/10.1111/ajt.15871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117249PMC
September 2020

Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine.

J Thorac Cardiovasc Surg 2020 04 17;159(4):1640-1653.e18. Epub 2019 Oct 17.

Department of Biomedical Engineering, Columbia University Medical Center, Columbia University, New York, NY; Departments of Thoracic and Cardiac Surgery, Vanderbilt University, Nashville, Tenn. Electronic address:

Objectives: Lung remains the least-utilized solid organ for transplantation. Efforts to recover donor lungs with reversible injuries using ex vivo perfusion systems are limited to <24 hours of support. Here, we demonstrate the feasibility of extending normothermic extracorporeal lung support to 4 days using cross-circulation with conscious swine.

Methods: A swine behavioral training program and custom enclosure were developed to enable multiday cross-circulation between extracorporeal lungs and recipient swine. Lungs were ventilated and perfused in a normothermic chamber for 4 days. Longitudinal analyses of extracorporeal lungs (ie, functional assessments, multiscale imaging, cytokine quantification, and cellular assays) and recipient swine (eg, vital signs and blood and tissue analyses) were performed.

Results: Throughout 4 days of normothermic support, extracorporeal lung function was maintained (arterial oxygen tension/inspired oxygen fraction >400 mm Hg; compliance >20 mL/cm HO), and recipient swine were hemodynamically stable (lactate <3 mmol/L; pH, 7.42 ± 0.05). Radiography revealed well-aerated lower lobes and consolidation in upper lobes of extracorporeal lungs, and bronchoscopy showed healthy airways without edema or secretions. In bronchoalveolar lavage fluid, granulocyte-macrophage colony-stimulating factor, interleukin (IL) 4, IL-6, and IL-10 levels increased less than 6-fold, whereas interferon gamma, IL-1α, IL-1β, IL-1ra, IL-2, IL-8, IL-12, IL-18, and tumor necrosis factor alpha levels decreased from baseline to day 4. Histologic evaluations confirmed an intact blood-gas barrier and outstanding preservation of airway and alveolar architecture. Cellular viability and metabolism in extracorporeal lungs were confirmed after 4 days.

Conclusions: We demonstrate feasibility of normothermic maintenance of extracorporeal lungs for 4 days by cross-circulation with conscious swine. Cross-circulation approaches could support the recovery of damaged lungs and enable organ bioengineering to improve transplant outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2019.09.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094131PMC
April 2020

Imaging of subendocardial adipose tissue and fiber orientation distributions in the human left atrium using optical coherence tomography.

J Cardiovasc Electrophysiol 2019 12 5;30(12):2950-2959. Epub 2019 Nov 5.

Department of Electrical Engineering, Columbia University, New York, NY.

Background: Optical coherence tomography (OCT) has the potential to provide real-time imaging guidance for atrial fibrillation ablation, with promising results for lesion monitoring. OCT can also offer high-resolution imaging of tissue composition, but there is insufficient cardiac OCT data to inform the use of OCT to reveal important tissue architecture of the human left atrium. Thus, the objective of this study was to define OCT imaging data throughout the human left atrium, focusing on the distribution of adipose tissue and fiber orientation as seen from the endocardium.

Methods And Results: Human hearts (n = 7) were acquired for imaging the left atrium with OCT. A spectral-domain OCT system with 1325 nm center wavelength, 6.5 μm axial resolution, 15 μm lateral resolution, and a maximum imaging depth of 2.51 mm in the air was used. Large-scale OCT image maps of human left atrial tissue were developed, with adipose thickness and fiber orientation extracted from the imaging data. OCT imaging showed scattered distributions of adipose tissue around the septal and pulmonary vein regions, up to a depth of about 0.43 mm from the endocardial surface. The total volume of adipose tissue detected by OCT over one left atrium ranged from 1.42 to 28.74 mm . Limited fiber orientation information primarily around the pulmonary veins and the septum could be identified.

Conclusion: OCT imaging could provide adjunctive information on the distribution of subendocardial adipose tissue, particularly around thin areas around the pulmonary veins and septal regions. Variations in OCT-detected tissue composition could potentially assist ablation guidance.
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http://dx.doi.org/10.1111/jce.14255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916589PMC
December 2019

Quadravalvular Noninfectious Endocarditis.

JACC Case Rep 2019 Oct 25;1(3):350-354. Epub 2019 Sep 25.

Division of Cardiology, Montefiore Medical Center, Bronx, New York.

Nonbacterial thrombotic endocarditis is characterized by sterile thrombi on cardiac valves. This report describes the case of nonbacterial endocarditis without pathologic findings of fibrin or platelet deposition. Quadrivalvular endocarditis was found to be due to immunoglobulin M heavy chain deposition. This was a case of nonbacterial, nonthrombotic quadrivalvular endocarditis, which was termed noninfective endocarditis. ().
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http://dx.doi.org/10.1016/j.jaccas.2019.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288629PMC
October 2019

Characterization of the human myocardium by optical coherence tomography.

J Biophotonics 2019 12 26;12(12):e201900094. Epub 2019 Aug 26.

Department of Electrical Engineering, Columbia University, New York, New York.

Imaging of cardiac tissue structure plays a critical role in the treatment and understanding of cardiovascular disease. Optical coherence tomography (OCT) offers the potential to provide valuable, high-resolution imaging of cardiac tissue. However, there is a lack of comprehensive OCT imaging data of the human heart, which could improve identification of structural substrates underlying cardiac abnormalities. The objective of this study was to provide qualitative and quantitative analysis of OCT image features throughout the human heart. Fifty human hearts were acquired, and tissues from all chambers were imaged with OCT. Histology was obtained to verify tissue composition. Statistical differences between OCT image features corresponding to different tissue types and chambers were estimated using analysis of variance. OCT imaging provided features that were able to distinguish structures such as thickened collagen, as well as adipose tissue and fibrotic myocardium. Statistically significant differences were found between atria and ventricles in attenuation coefficient, and between adipose and all other tissue types. This study provides an overview of OCT image features throughout the human heart, which can be used for guiding future applications such as OCT-integrated catheter-based treatments or ex vivo investigation of structural substrates.
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http://dx.doi.org/10.1002/jbio.201900094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456394PMC
December 2019

Optical coherence tomography imaging of cardiac substrates.

Quant Imaging Med Surg 2019 May;9(5):882-904

Columbia University Medical Center, New York, NY, USA.

Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Knowledge of a patient's heart structure will help to plan procedures, potentially identifying arrhythmia substrates, critical structures to avoid, detect transplant rejection, and reduce ambiguity when interpreting electrograms and functional measurements. Similarly, basic research of numerous cardiac diseases would greatly benefit from structural imaging at cellular scale. For both applications imaging on the scale of a myocyte is needed, which is approximately 100 µm × 10 µm. The use of optical coherence tomography (OCT) as a tool for characterizing cardiac tissue structure and function has been growing in the past two decades. We briefly review OCT principles and highlight important considerations when imaging cardiac muscle. In particular, image penetration, tissue birefringence, and light absorption by blood during imaging are important factors when imaging the heart with OCT. Within the article, we highlight applications of cardiac OCT imaging including imaging heart tissue structure in small animal models, quantification of myofiber organization, monitoring of radiofrequency ablation (RFA) lesion formation, structure-function analysis enabled by functional extensions of OCT and multimodal analysis and characterizing important substrates within the human heart. The review concludes with a summary and future outlook of OCT imaging the heart, which is promising with progress in optical catheter development, functional extensions of OCT, and real time image processing to enable dynamic imaging and real time tracking during therapeutic procedures.
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http://dx.doi.org/10.21037/qims.2019.05.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571187PMC
May 2019

Eosinophils, Lymphocytes, and Myocytes, Oh My: HIV-Associated Myocarditis.

Am J Med 2020 01 26;133(1):52-55. Epub 2019 Jun 26.

Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York.

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http://dx.doi.org/10.1016/j.amjmed.2019.05.055DOI Listing
January 2020
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