Charles Marboe - Academia.edu (original) (raw)

Papers by Charles Marboe

Research paper thumbnail of Regulation of Nitric Oxide Production in Human Coronary Microvessels and the Contribution of Local Kinin Formation

Circulation, Jul 1, 1996

Background The goal of this study was to define the regulation of nitric oxide release by coronar... more Background The goal of this study was to define the regulation of nitric oxide release by coronary microvessels from the failing and nonfailing human heart and to determine the role of local kinin production in the elaboration of nitric oxide by human coronary microvascular endothelium. Methods and Results Ten hearts from humans with end-stage heart failure and two hearts from patients without heart failure were harvested at the time of orthotopic cardiac transplantation. Microvessels were sieved and the production of nitrite was determined by the Griess reaction. Microvessels were incubated in the presence of agonists for nitric oxide production (acetylcholine and bradykinin), which caused dose-dependent increases in nitrite, a response that was blocked by N G -nitro- l -arginine methyl ester and receptor-specific antagonists (atropine and HOE 140, respectively). In addition, the production of nitrite by microvessels from the failing heart appeared to be less than that produced by microvessels from the nonfailing heart. Incubation with norepinephrine or the α 2 -adrenergic agonist BHT 920 also caused dose-dependent increases in nitrite production, which were blocked by the B 2 -receptor antagonist HOE 140. This implicated local kinin synthesis as an intermediate step in the production of nitric oxide in response to α 2 -adrenoceptor stimulation. The production of nitric oxide was also prevented by the addition of serine protease inhibitors, which blocked the action of local kallikrein, again suggesting a role for local kinin synthesis. Conclusions Our results indicate that nitric oxide is produced by human coronary microvessels, that nitric oxide production may be reduced but certainly not increased in microvessels from the failing human heart, and that there is active local kinin generation in these blood vessels.

Research paper thumbnail of A clinically relevant model of acute respiratory distress syndrome in human-size swine

Disease Models & Mechanisms

Despite over 30 years of intensive research for targeted therapies, treatment of acute respirator... more Despite over 30 years of intensive research for targeted therapies, treatment of acute respiratory distress syndrome (ARDS) remains supportive in nature. With mortality upwards of 30%, a high-fidelity pre-clinical model of ARDS, on which to test novel therapeutics, is urgently needed. We used the Yorkshire breed of swine to induce a reproducible model of ARDS in human-sized swine to allow the study of new therapeutics, from both mechanistic and clinical standpoints. For this, animals were anesthetized, intubated and mechanically ventilated, and pH-standardized gastric contents were delivered bronchoscopically, followed by intravenous infusion of Escherichia coli-derived lipopolysaccharide. Once the ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FIO2) had decreased to <150, the animals received standard ARDS treatment for up to 48 h. All swine developed moderate to severe ARDS. Chest radiographs taken at regular intervals showed significantly worse...

Research paper thumbnail of Absence of dense platelet granules and ceroid-laden macrophages: Investigating the diversity of clinical presentations in Hermansky-Pudlak syndrome

Human Pathology: Case Reports, 2021

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic disorder in which the proper fu... more Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic disorder in which the proper function of lysosome-related organelles (LROS) is impaired due to mutation in one of several well-characterized genes, including, but not limited to: HPS1, HPS3, and HPS4. Clinical manifestations include oculocutaneous albinism, nystagmus, platelet dysfunction, progressive pulmonary fibrosis, and granulomatous colitis. We present a case of a 28-year-old woman of Puerto Rican descent who required post-partum lung transplantation due to an inherited HPS1 mutation. The pathologies observed in HPS underline the mechanistic importance of LROS in a variety of tissue types and organ systems.

Research paper thumbnail of Forty Postmortem Examinations in COVID-19 Patients

American Journal of Clinical Pathology, 2020

ObjectivesAlthough diffuse alveolar damage, a subtype of acute lung injury (ALI), is the most com... more ObjectivesAlthough 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.MethodsA 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.ResultsThree 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, th...

Research paper thumbnail of T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy

American Journal of Transplantation, 2020

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clo... more 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.

Research paper thumbnail of Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation

American Journal of Transplantation, 2020

Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) di... more Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor 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=0.002) and healthy controls (n=94, p<0.0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (p<0.0001) and AMR patients with DSA and PRA>10% were identified as the subgroup with significantly elevated responses. Four antigens, vimentin, tubulin alpha 1B, lamin A/C and apolipoprotein L2, were significantly different between AMR and non-AMR. 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.

Research paper thumbnail of Quadravalvular Noninfectious Endocarditis

JACC: Case Reports, 2019

Nonbacterial thrombotic endocarditis is characterized by sterile thrombi on cardiac valves. This ... more 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.

Research paper thumbnail of Characterization of the human myocardium by optical coherence tomography

Journal of Biophotonics, 2019

Research paper thumbnail of Multicontrast endomyocardial imaging by single‐channel high‐resolution cross‐polarization optical coherence tomography

Journal of Biophotonics, 2018

A single‐channel high‐resolution cross‐polarization (CP) optical coherence tomography (OCT) syste... more A single‐channel high‐resolution cross‐polarization (CP) optical coherence tomography (OCT) system is presented for multicontrast imaging of human myocardium in one‐shot measurement. The intensity and functional contrasts, including the ratio between the cross‐ and co‐polarization channels as well as the cumulative retardation, are reconstructed from the CP‐OCT readout. By comparing the CP‐OCT results with histological analysis, it is shown that the system can successfully delineate microstructures in the myocardium and differentiate the fibrotic myocardium from normal or ablated myocardium based on the functional contrasts provided by the CP‐OCT system. The feasibility of using A‐line profiles from the 2 orthogonal polarization channels to identify fibrotic myocardium, normal myocardium and ablated lesion is also discussed.

Research paper thumbnail of Mapping the human pulmonary venoatrial junction with optical coherence tomography

Biomedical Optics Express, 2019

Imaging guidance provided by optical coherence tomography (OCT) could improve the outcomes of atr... more Imaging guidance provided by optical coherence tomography (OCT) could improve the outcomes of atrial fibrillation (AF) ablation by providing detailed structural information of the pulmonary veins, which are critical targets during ablation. In this study, stitched volumetric OCT images of venoatrial junctions from post-mortem human hearts were acquired and compared to histology. Image features corresponding to venous media and myocardial sleeves, as well as fiber orientation and fibrosis, were identified and found to vary between veins. Imaging of detailed tissue architecture could improve understanding of the AF structural substrate within the pulmonary veins and assist the guidance of ablation procedures.

Research paper thumbnail of Chemotherapy and its Effect on Testicular Morphology in Children

Journal of Urology, 1984

Bilateral testicular biopsies were performed on 25 boys between 4 and 16 years old with the diagn... more Bilateral testicular biopsies were performed on 25 boys between 4 and 16 years old with the diagnosis of acute lymphocytic leukemia after the induction of regression with vincristine and prednisone, followed by cyclic maintenance therapy with a combination of 6-mercaptopurine, methotrexate, L-asparaginase, cyclophosphamide and doxorubicin for 2 years. These drugs were given in accordance with children's cancer study group protocols. Only 3 boys had positive biopsies (12 per cent), although post-treatment testicular morphology was abnormal in the overwhelming majority. Interstitial fibrosis was present in 16 children (70 per cent), basement membrane thickening in 12 (50 per cent) and, most importantly, a reduction in the tubular fertility index of greater than 50 per cent in 20 (80 per cent). There was no relationship between the abnormal morphology encountered and the age of the patient when treated. Most of these changes may be reversible with time but only a biopsy at a later date can establish the long-term effects of treatment on testicular morphology and, perhaps, help to predict future fertility potential.

Research paper thumbnail of TCT-379 Feasibility of Endomyocardial Imaging Using Optical Coherence Tomography For the Diagnosis of Myocardial Disease

Journal of the American College of Cardiology, 2014

Background: Although acute abnormal findings (AAF) immediate after drug-eluting stent (DES) impla... more Background: Although acute abnormal findings (AAF) immediate after drug-eluting stent (DES) implantation such as stent malapposition, edge dissection, tissue protrusion and thrombus were frequently observed only by optical coherence tomography (OCT), relevant clinical implications have not yet to be evaluated systematically. We sought to evaluate long-term clinical outcomes of patients with AAF, compared with patients without AAF detected only by OCT after DES implantation. Methods: A total of 157 patients undergoing OCT analysis immediate after DES implantation were enrolled and divided into 2 groups [AAF group (n¼104) and non-AAF (n¼53)] according to presence or absence of at least 1 OCT-defined AAF as followings; thrombus (n¼37), malapposition (n¼62), tissue protrusion (n¼47) and edge dissection (n¼33). The primary end point was MACE [major advanced cardiovascular events; all-cause death, non-fatal myocardial infarction (MI), target vessel revascularization (TVR), or stent thrombosis], which was compared between the both groups. Demographic, clinical, lesional and procedural data were also analyzed between two groups. Quantification analysis of AAF was performed to define the correlation between severity of AAF and MACE. Results: Median follow-up duration was 24.7AE8.2 months. Baseline characteristics were statistically similar in two groups. The rate of MACE was not significantly different between the two groups (8.7% for AAF vs. 3.8% for non-AAF, P¼0.338), as well as each components of MACE; all-cause death (1.0% vs. 0%, p¼0.448), nonfatal MI (1.0% vs. 1.9%, p¼0.551), and TVR (2.9% vs. 0%, p¼0.551). In Cox regression analysis, there was no significant relationship with AAF and MACE (HR¼0.53, 95% CI, 0.096 to 2.923; p¼0.467). The severity of AAF also was not associated with the incidence of MACE. Conclusions: AAF immediate after DES implantation, such as edge dissection, tissue protrusion, malapposition and thrombus, detectable only on OCT, had no effect on long-term clinical outcomes , irrespective of its severity.

Research paper thumbnail of Monoclonal antibody identification of mononuclear cells in endomyocardial biopsy specimens from a patient with rheumatic carditis

Human Pathology, 1985

A 17-year-old woman with rheumatic carditis underwent endomyocardial biopsy both prior to and fol... more A 17-year-old woman with rheumatic carditis underwent endomyocardial biopsy both prior to and following treatment with prednisone and aspirin. Frozen sections from the endomyocardial biopsy specimens were studied with monoclonal antibodies by an indirect immunofluorescence technique to define the composition of the inflammatory infiltrate in the myocardium and to determine whether the composition of the infiltrate is distinctive and diagnostically useful. The specimen from the initial biopsy contained a heterogeneous infiltrate composed of T lymphocytes, macrophages, B lymphocytes, and mast cells. T lymphocytes predominated, and the ratio of T-helper to T-cytotoxic/suppressor cells was 2.0. Following treatment the overall cellularity of the infiltrate was diminished, but the infiltrate remained heterogeneous; T cells predominated, and the T-helper to T-cytotoxic/suppressor ratio was reversed, to 0.59. The composition of the inflammatory infiltrate in this case of rheumatic carditis distinguishes it immunologically from other &quot;idiopathic,&quot; presumably virus-associated, forms of myocarditis.

Research paper thumbnail of Findings of inflammation and possible autoimmunity in calcific aortic stenosis of unknown etiology in the geriatric population

Journal of Surgical Research, 2004

Research paper thumbnail of Gene Expression Profiles of Patients With Antibody-Mediated Rejection After Cardiac Transplantation

The Journal of Heart and Lung Transplantation, 2008

Research paper thumbnail of Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

Transplantation, 2012

Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading... more Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). Methods. We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades Q2R merged because of small numbers). Results. Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade Q2R by at least one were assigned this grade by both. Conclusion. The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade Q2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteriaVEMB based or otherwiseVthat correspond better with the pathophysiology of the transplanted heart.

Research paper thumbnail of Early Donor-Derived Cell-Free DNA Predicts Peak Allograft Function in Heart Transplant

The Journal of Heart and Lung Transplantation, 2020

Purpose: There is mounting evidence on the use of donor-derived cell-free DNA (dd-cfDNA) as a non... more Purpose: There is mounting evidence on the use of donor-derived cell-free DNA (dd-cfDNA) as a non-invasive tool to detect acute antibody and cellular mediated rejection. However the role of dd-cfDNA in detecting and monitoring cardiac allograft vasculopathy (CAV) in the absence of acute rejection remains unknown. We hypothesized that dd-cfDNA levels would correlate with the presence of CAV. Methods: 65 clinically stable heart transplant recipients ≥ 2 years post-transplant, with no rejection episodes in the preceding 6 months were enrolled. CAV was assessed by routine coronary angiogram and intravascular ultrasound. Patients were stratified by time since transplant (2-5, 5-10 and ≥ 10 years post transplant) and high versus low levels of dd-cfDNA defined as above and below the median. Significant CAV was defined as Stanford III-IV or angiographic disease. A targeted amplification, next generationsequencing assay (AlloSure Ò ; CareDx, Inc.) was used to detect dd-cfDNA. Results: Of 58 patients with known CAV status, 30 had high levels of ddcf-DNA (≥0.14%) and 28 had low levels (<0.14%). There was no difference in left ventricular ejection fraction between the groups but CAV was present in 63% of patients with high levels of ddcf-DNA compared to 36% in the low ddcf-DNA group (p 0.047). Donor-specific antibodies were present in 27% of the high ddcf-DNA group compared to 3.6% of the low ddcf-DNA group (p 0.026) (Table). There were no differences in the frequency of cellular and antibody medicated rejection episodes between the groups. Importantly, there were also no differences in time post-transplant between patients with high versus low ddcf-DNA. Conclusion: dd-cfDNA levels were associated with CAV in a cohort of stable transplant recipients >2 years post HT and thus might help to identify those in need for invasive assessment. Further studies should investigate if there is an association between dd-cfDNA levels and CAV severity and whether dd-cfDNA levels can predict CAV progression.

Research paper thumbnail of Real‐time optical spectroscopic monitoring of nonirrigated lesion progression within atrial and ventricular tissues

Journal of Biophotonics, 2018

Despite considerable advances in guidance of radiofrequency ablation (RFA) therapy for the treatm... more Despite considerable advances in guidance of radiofrequency ablation (RFA) therapy for the treatment of cardiac arrhythmias, success rates have been hampered by a lack of tools for precise intraoperative evaluation of lesion extent. Near-infrared spectroscopic (NIRS) techniques are sensitive to tissue structural and biomolecular properties, characteristics that are directly altered by RF treatment. In this work, a combined NIRS-RFA catheter is developed for real-time monitoring of tissue reflectance during RF energy delivery. An algorithm is proposed for processing NIR spectra to approximate non-irrigated lesion depth in both atrial and ventricular tissues. The probe optical geometry was designed to bias measurement influence toward absorption enabling enhanced sensitivity to changes in tissue composition. A set of parameters termed "lesion optical indices" are defined encapsulating spectral differences between ablated and unablated tissue. Utilizing these features, a model for real-time tissue spectra classification and lesion size estimation is presented. Experimental validation conducted within freshly excised porcine cardiac specimens showed strong concordance between algorithm estimates and post-hoc tissue assessment.

Research paper thumbnail of 78-P

Human Immunology, 2012

Aim To establish the impact of anti-HLA antibodies formed prior and/or following heart transplant... more Aim To establish the impact of anti-HLA antibodies formed prior and/or following heart transplantation in a cohort of 137 pediatric recipients, transplanted between January 2000 and December 2011. Methods Anti-HLA class I and class II antibodies were monitored by traditional CDC methods using donor and panel T and B lymphocytes and SPA for detection of DSA. Endomyocardial biopsies were performed by protocol and whenever rejection was suspected. Results The allograft survival was 89% at 10 years in patients who had no lymphocytotoxic antibodies either before or after transplantation, yet dropped to 55% in patients who developed anti-HLA class I antibodies (p Conclusions All AMR episodes occurring in patients from this study population have documented evidence of complement binding antibodies and C4d deposition in the graft, reinforcing the conclusion that an integrated study of pathologic, immunologic and functional changes is required for timely and effective treatment of AMR.

Research paper thumbnail of Higher levels of allograft injury in black patients early after heart transplantation

The Journal of Heart and Lung Transplantation, 2021

Research paper thumbnail of Regulation of Nitric Oxide Production in Human Coronary Microvessels and the Contribution of Local Kinin Formation

Circulation, Jul 1, 1996

Background The goal of this study was to define the regulation of nitric oxide release by coronar... more Background The goal of this study was to define the regulation of nitric oxide release by coronary microvessels from the failing and nonfailing human heart and to determine the role of local kinin production in the elaboration of nitric oxide by human coronary microvascular endothelium. Methods and Results Ten hearts from humans with end-stage heart failure and two hearts from patients without heart failure were harvested at the time of orthotopic cardiac transplantation. Microvessels were sieved and the production of nitrite was determined by the Griess reaction. Microvessels were incubated in the presence of agonists for nitric oxide production (acetylcholine and bradykinin), which caused dose-dependent increases in nitrite, a response that was blocked by N G -nitro- l -arginine methyl ester and receptor-specific antagonists (atropine and HOE 140, respectively). In addition, the production of nitrite by microvessels from the failing heart appeared to be less than that produced by microvessels from the nonfailing heart. Incubation with norepinephrine or the α 2 -adrenergic agonist BHT 920 also caused dose-dependent increases in nitrite production, which were blocked by the B 2 -receptor antagonist HOE 140. This implicated local kinin synthesis as an intermediate step in the production of nitric oxide in response to α 2 -adrenoceptor stimulation. The production of nitric oxide was also prevented by the addition of serine protease inhibitors, which blocked the action of local kallikrein, again suggesting a role for local kinin synthesis. Conclusions Our results indicate that nitric oxide is produced by human coronary microvessels, that nitric oxide production may be reduced but certainly not increased in microvessels from the failing human heart, and that there is active local kinin generation in these blood vessels.

Research paper thumbnail of A clinically relevant model of acute respiratory distress syndrome in human-size swine

Disease Models & Mechanisms

Despite over 30 years of intensive research for targeted therapies, treatment of acute respirator... more Despite over 30 years of intensive research for targeted therapies, treatment of acute respiratory distress syndrome (ARDS) remains supportive in nature. With mortality upwards of 30%, a high-fidelity pre-clinical model of ARDS, on which to test novel therapeutics, is urgently needed. We used the Yorkshire breed of swine to induce a reproducible model of ARDS in human-sized swine to allow the study of new therapeutics, from both mechanistic and clinical standpoints. For this, animals were anesthetized, intubated and mechanically ventilated, and pH-standardized gastric contents were delivered bronchoscopically, followed by intravenous infusion of Escherichia coli-derived lipopolysaccharide. Once the ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FIO2) had decreased to <150, the animals received standard ARDS treatment for up to 48 h. All swine developed moderate to severe ARDS. Chest radiographs taken at regular intervals showed significantly worse...

Research paper thumbnail of Absence of dense platelet granules and ceroid-laden macrophages: Investigating the diversity of clinical presentations in Hermansky-Pudlak syndrome

Human Pathology: Case Reports, 2021

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic disorder in which the proper fu... more Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic disorder in which the proper function of lysosome-related organelles (LROS) is impaired due to mutation in one of several well-characterized genes, including, but not limited to: HPS1, HPS3, and HPS4. Clinical manifestations include oculocutaneous albinism, nystagmus, platelet dysfunction, progressive pulmonary fibrosis, and granulomatous colitis. We present a case of a 28-year-old woman of Puerto Rican descent who required post-partum lung transplantation due to an inherited HPS1 mutation. The pathologies observed in HPS underline the mechanistic importance of LROS in a variety of tissue types and organ systems.

Research paper thumbnail of Forty Postmortem Examinations in COVID-19 Patients

American Journal of Clinical Pathology, 2020

ObjectivesAlthough diffuse alveolar damage, a subtype of acute lung injury (ALI), is the most com... more ObjectivesAlthough 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.MethodsA 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.ResultsThree 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, th...

Research paper thumbnail of T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy

American Journal of Transplantation, 2020

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clo... more 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.

Research paper thumbnail of Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation

American Journal of Transplantation, 2020

Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) di... more Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor 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=0.002) and healthy controls (n=94, p<0.0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (p<0.0001) and AMR patients with DSA and PRA>10% were identified as the subgroup with significantly elevated responses. Four antigens, vimentin, tubulin alpha 1B, lamin A/C and apolipoprotein L2, were significantly different between AMR and non-AMR. 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.

Research paper thumbnail of Quadravalvular Noninfectious Endocarditis

JACC: Case Reports, 2019

Nonbacterial thrombotic endocarditis is characterized by sterile thrombi on cardiac valves. This ... more 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.

Research paper thumbnail of Characterization of the human myocardium by optical coherence tomography

Journal of Biophotonics, 2019

Research paper thumbnail of Multicontrast endomyocardial imaging by single‐channel high‐resolution cross‐polarization optical coherence tomography

Journal of Biophotonics, 2018

A single‐channel high‐resolution cross‐polarization (CP) optical coherence tomography (OCT) syste... more A single‐channel high‐resolution cross‐polarization (CP) optical coherence tomography (OCT) system is presented for multicontrast imaging of human myocardium in one‐shot measurement. The intensity and functional contrasts, including the ratio between the cross‐ and co‐polarization channels as well as the cumulative retardation, are reconstructed from the CP‐OCT readout. By comparing the CP‐OCT results with histological analysis, it is shown that the system can successfully delineate microstructures in the myocardium and differentiate the fibrotic myocardium from normal or ablated myocardium based on the functional contrasts provided by the CP‐OCT system. The feasibility of using A‐line profiles from the 2 orthogonal polarization channels to identify fibrotic myocardium, normal myocardium and ablated lesion is also discussed.

Research paper thumbnail of Mapping the human pulmonary venoatrial junction with optical coherence tomography

Biomedical Optics Express, 2019

Imaging guidance provided by optical coherence tomography (OCT) could improve the outcomes of atr... more Imaging guidance provided by optical coherence tomography (OCT) could improve the outcomes of atrial fibrillation (AF) ablation by providing detailed structural information of the pulmonary veins, which are critical targets during ablation. In this study, stitched volumetric OCT images of venoatrial junctions from post-mortem human hearts were acquired and compared to histology. Image features corresponding to venous media and myocardial sleeves, as well as fiber orientation and fibrosis, were identified and found to vary between veins. Imaging of detailed tissue architecture could improve understanding of the AF structural substrate within the pulmonary veins and assist the guidance of ablation procedures.

Research paper thumbnail of Chemotherapy and its Effect on Testicular Morphology in Children

Journal of Urology, 1984

Bilateral testicular biopsies were performed on 25 boys between 4 and 16 years old with the diagn... more Bilateral testicular biopsies were performed on 25 boys between 4 and 16 years old with the diagnosis of acute lymphocytic leukemia after the induction of regression with vincristine and prednisone, followed by cyclic maintenance therapy with a combination of 6-mercaptopurine, methotrexate, L-asparaginase, cyclophosphamide and doxorubicin for 2 years. These drugs were given in accordance with children's cancer study group protocols. Only 3 boys had positive biopsies (12 per cent), although post-treatment testicular morphology was abnormal in the overwhelming majority. Interstitial fibrosis was present in 16 children (70 per cent), basement membrane thickening in 12 (50 per cent) and, most importantly, a reduction in the tubular fertility index of greater than 50 per cent in 20 (80 per cent). There was no relationship between the abnormal morphology encountered and the age of the patient when treated. Most of these changes may be reversible with time but only a biopsy at a later date can establish the long-term effects of treatment on testicular morphology and, perhaps, help to predict future fertility potential.

Research paper thumbnail of TCT-379 Feasibility of Endomyocardial Imaging Using Optical Coherence Tomography For the Diagnosis of Myocardial Disease

Journal of the American College of Cardiology, 2014

Background: Although acute abnormal findings (AAF) immediate after drug-eluting stent (DES) impla... more Background: Although acute abnormal findings (AAF) immediate after drug-eluting stent (DES) implantation such as stent malapposition, edge dissection, tissue protrusion and thrombus were frequently observed only by optical coherence tomography (OCT), relevant clinical implications have not yet to be evaluated systematically. We sought to evaluate long-term clinical outcomes of patients with AAF, compared with patients without AAF detected only by OCT after DES implantation. Methods: A total of 157 patients undergoing OCT analysis immediate after DES implantation were enrolled and divided into 2 groups [AAF group (n¼104) and non-AAF (n¼53)] according to presence or absence of at least 1 OCT-defined AAF as followings; thrombus (n¼37), malapposition (n¼62), tissue protrusion (n¼47) and edge dissection (n¼33). The primary end point was MACE [major advanced cardiovascular events; all-cause death, non-fatal myocardial infarction (MI), target vessel revascularization (TVR), or stent thrombosis], which was compared between the both groups. Demographic, clinical, lesional and procedural data were also analyzed between two groups. Quantification analysis of AAF was performed to define the correlation between severity of AAF and MACE. Results: Median follow-up duration was 24.7AE8.2 months. Baseline characteristics were statistically similar in two groups. The rate of MACE was not significantly different between the two groups (8.7% for AAF vs. 3.8% for non-AAF, P¼0.338), as well as each components of MACE; all-cause death (1.0% vs. 0%, p¼0.448), nonfatal MI (1.0% vs. 1.9%, p¼0.551), and TVR (2.9% vs. 0%, p¼0.551). In Cox regression analysis, there was no significant relationship with AAF and MACE (HR¼0.53, 95% CI, 0.096 to 2.923; p¼0.467). The severity of AAF also was not associated with the incidence of MACE. Conclusions: AAF immediate after DES implantation, such as edge dissection, tissue protrusion, malapposition and thrombus, detectable only on OCT, had no effect on long-term clinical outcomes , irrespective of its severity.

Research paper thumbnail of Monoclonal antibody identification of mononuclear cells in endomyocardial biopsy specimens from a patient with rheumatic carditis

Human Pathology, 1985

A 17-year-old woman with rheumatic carditis underwent endomyocardial biopsy both prior to and fol... more A 17-year-old woman with rheumatic carditis underwent endomyocardial biopsy both prior to and following treatment with prednisone and aspirin. Frozen sections from the endomyocardial biopsy specimens were studied with monoclonal antibodies by an indirect immunofluorescence technique to define the composition of the inflammatory infiltrate in the myocardium and to determine whether the composition of the infiltrate is distinctive and diagnostically useful. The specimen from the initial biopsy contained a heterogeneous infiltrate composed of T lymphocytes, macrophages, B lymphocytes, and mast cells. T lymphocytes predominated, and the ratio of T-helper to T-cytotoxic/suppressor cells was 2.0. Following treatment the overall cellularity of the infiltrate was diminished, but the infiltrate remained heterogeneous; T cells predominated, and the T-helper to T-cytotoxic/suppressor ratio was reversed, to 0.59. The composition of the inflammatory infiltrate in this case of rheumatic carditis distinguishes it immunologically from other &quot;idiopathic,&quot; presumably virus-associated, forms of myocarditis.

Research paper thumbnail of Findings of inflammation and possible autoimmunity in calcific aortic stenosis of unknown etiology in the geriatric population

Journal of Surgical Research, 2004

Research paper thumbnail of Gene Expression Profiles of Patients With Antibody-Mediated Rejection After Cardiac Transplantation

The Journal of Heart and Lung Transplantation, 2008

Research paper thumbnail of Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

Transplantation, 2012

Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading... more Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). Methods. We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades Q2R merged because of small numbers). Results. Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade Q2R by at least one were assigned this grade by both. Conclusion. The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade Q2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteriaVEMB based or otherwiseVthat correspond better with the pathophysiology of the transplanted heart.

Research paper thumbnail of Early Donor-Derived Cell-Free DNA Predicts Peak Allograft Function in Heart Transplant

The Journal of Heart and Lung Transplantation, 2020

Purpose: There is mounting evidence on the use of donor-derived cell-free DNA (dd-cfDNA) as a non... more Purpose: There is mounting evidence on the use of donor-derived cell-free DNA (dd-cfDNA) as a non-invasive tool to detect acute antibody and cellular mediated rejection. However the role of dd-cfDNA in detecting and monitoring cardiac allograft vasculopathy (CAV) in the absence of acute rejection remains unknown. We hypothesized that dd-cfDNA levels would correlate with the presence of CAV. Methods: 65 clinically stable heart transplant recipients ≥ 2 years post-transplant, with no rejection episodes in the preceding 6 months were enrolled. CAV was assessed by routine coronary angiogram and intravascular ultrasound. Patients were stratified by time since transplant (2-5, 5-10 and ≥ 10 years post transplant) and high versus low levels of dd-cfDNA defined as above and below the median. Significant CAV was defined as Stanford III-IV or angiographic disease. A targeted amplification, next generationsequencing assay (AlloSure Ò ; CareDx, Inc.) was used to detect dd-cfDNA. Results: Of 58 patients with known CAV status, 30 had high levels of ddcf-DNA (≥0.14%) and 28 had low levels (<0.14%). There was no difference in left ventricular ejection fraction between the groups but CAV was present in 63% of patients with high levels of ddcf-DNA compared to 36% in the low ddcf-DNA group (p 0.047). Donor-specific antibodies were present in 27% of the high ddcf-DNA group compared to 3.6% of the low ddcf-DNA group (p 0.026) (Table). There were no differences in the frequency of cellular and antibody medicated rejection episodes between the groups. Importantly, there were also no differences in time post-transplant between patients with high versus low ddcf-DNA. Conclusion: dd-cfDNA levels were associated with CAV in a cohort of stable transplant recipients >2 years post HT and thus might help to identify those in need for invasive assessment. Further studies should investigate if there is an association between dd-cfDNA levels and CAV severity and whether dd-cfDNA levels can predict CAV progression.

Research paper thumbnail of Real‐time optical spectroscopic monitoring of nonirrigated lesion progression within atrial and ventricular tissues

Journal of Biophotonics, 2018

Despite considerable advances in guidance of radiofrequency ablation (RFA) therapy for the treatm... more Despite considerable advances in guidance of radiofrequency ablation (RFA) therapy for the treatment of cardiac arrhythmias, success rates have been hampered by a lack of tools for precise intraoperative evaluation of lesion extent. Near-infrared spectroscopic (NIRS) techniques are sensitive to tissue structural and biomolecular properties, characteristics that are directly altered by RF treatment. In this work, a combined NIRS-RFA catheter is developed for real-time monitoring of tissue reflectance during RF energy delivery. An algorithm is proposed for processing NIR spectra to approximate non-irrigated lesion depth in both atrial and ventricular tissues. The probe optical geometry was designed to bias measurement influence toward absorption enabling enhanced sensitivity to changes in tissue composition. A set of parameters termed "lesion optical indices" are defined encapsulating spectral differences between ablated and unablated tissue. Utilizing these features, a model for real-time tissue spectra classification and lesion size estimation is presented. Experimental validation conducted within freshly excised porcine cardiac specimens showed strong concordance between algorithm estimates and post-hoc tissue assessment.

Research paper thumbnail of 78-P

Human Immunology, 2012

Aim To establish the impact of anti-HLA antibodies formed prior and/or following heart transplant... more Aim To establish the impact of anti-HLA antibodies formed prior and/or following heart transplantation in a cohort of 137 pediatric recipients, transplanted between January 2000 and December 2011. Methods Anti-HLA class I and class II antibodies were monitored by traditional CDC methods using donor and panel T and B lymphocytes and SPA for detection of DSA. Endomyocardial biopsies were performed by protocol and whenever rejection was suspected. Results The allograft survival was 89% at 10 years in patients who had no lymphocytotoxic antibodies either before or after transplantation, yet dropped to 55% in patients who developed anti-HLA class I antibodies (p Conclusions All AMR episodes occurring in patients from this study population have documented evidence of complement binding antibodies and C4d deposition in the graft, reinforcing the conclusion that an integrated study of pathologic, immunologic and functional changes is required for timely and effective treatment of AMR.

Research paper thumbnail of Higher levels of allograft injury in black patients early after heart transplantation

The Journal of Heart and Lung Transplantation, 2021