Benjamin S. Mantell

Cincinnati Children's Hospital Medical Center

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Linda J. Addonizio

Columbia University Irving Medical Center

Marc E. Richmond

Morgan Stanley Children's Hospital

Robert M. O’Doherty

University of Pittsburgh

Irene D. Lytrivi

Columbia University Irving Medical Center

Yoshifumi Naka

NewYork–Presbyterian Hospital

Emmanuel Zorn

Columbia University Irving Medical Center

James K. Kirklin

University of Alabama at Birmingham

Susan Restaino

Columbia University Irving Medical Center

Ian Sipula

University of Pittsburgh

Sarah B. See

Columbia University Irving Medical Center

Cooperative Institutions

Columbia University

Columbia University Irving Medical Center

University of Pittsburgh

Cincinnati Children's Hospital Medical Center

Morgan Stanley Children's Hospital

NewYork–Presbyterian Hospital

New York Hospital Queens

Presbyterian Hospital

University of Cincinnati

University of Pittsburgh Medical Center

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Association Between High Sensitivity Troponin Levels Following Pediatric Orthotopic Heart Transplantation and Intensive Care Unit Resource Utilization

Pediatric Cardiology (2024)

Adam M. Butensky Shyam Desai Michael P. DiLorenzo Irene D. Lytrivi Benjamin S. Mantell

Vascular surgery

Coronary care unit

10.1007/s00246-024-03424-w

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PPAR gamma agonist pioglitazone restores impaired mitochondrial biogenesis and function in insulin resistant C2C12 myotubes

The FASEB Journal (2006)

Ines Pagel Benjamin S. Mantell Michael N. Sack

Insulin resistance in skeletal muscle associates with dysregulation of mitochondrial function and downregulation of the nuclear regulators of mitochondrial biogenesis including peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) and nuclear respiratory factor 1 (NRF-1). These skeletal muscle metabolic and regulatory perturbations presage the development of type 2 diabetes (T2DM). As thiazolidinediones (TZD’s – PPARγ mediated insulin sensitizers) delay the development of T2DM we propose that TZD’s may reverse mitochondrial biogenesis dysregulation during insulin resistance. C2C12 myotubes were cultivated in medium containing low glucose (LG, 25mM) or high glucose + high insulin (HGI, 40mM/100nM). Vehicle or the TZD Pioglitazone (Pio, 50μM) was subsequently administred for 2 days. C2C12 cells treated with HGI exhibit attenuated insulin signaling in parallel with significant downregulation of PGC-1, NRF-1 and mtTFA (mitochondrial transcription factor A) gene expression versus LG conditions. This genomic profile is mirrored by significantly smaller mitochondria, reduced oxygen consumption, decreased mitochondrial membrane potential and diminished ATP content. Treatment with Pio partially restored insulin signaling and normalized gene expression of PGC-1, NRF-1 and mtTFA. Moreover, in Pio treated cells, oxygen consumption is normalized, as is ATP production. In conclusion, Pioglitazone-mediated normalization of the mitochondrial biogenesis program and associated mitochondrial respiration may provide a mechanism whereby this class of drug delays the development of T2DM. Funding – NIH Intramural Program.

TFAM

Pioglitazone

NRF1

10.1096/fasebj.20.4.a524-a

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Mechanisms of Antibody Mediated Rejection in the Absence of Donor Specific Antibodies

The Journal of Heart and Lung Transplantation (2019)

Sarah B. See Benjamin S. Mantell Kevin J. Clerkin Bryan Ray Rodica E. Vasilescu

Immunofluorescence

Panel reactive antibody

10.1016/j.healun.2019.01.630

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PGC-1α Integrates Insulin Signaling, Mitochondrial Regulation, and Bioenergetic Function in Skeletal Muscle

Journal of Biological Chemistry (2008)

Ines Pagel-Langenickel Jianjun Bao Joshua J. Joseph Daniel R. Schwartz Benjamin S. Mantell

The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1α. Overexpression of PGC-1α rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1α expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone up-regulates PGC-1α in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1α and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1α. Moreover, PGC-1α is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.

Bioenergetics

C2C12

Pioglitazone

10.1074/jbc.m800842200

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Citations (119)

Fate of Semilunar Valves From Discarded Hearts at the Time of Pediatric Heart Retransplantation

Pediatric Transplantation (2025)

Landon Arcadi Muhammad Faateh Muhammad Raees David L.S. Morales Benjamin S. Mantell

ABSTRACT Background Partial heart transplantation (PHT) is a novel procedure for children in need of a growing valve replacement option. One challenge is identifying suitable donor valves. Semilunar heart valves from patients receiving a retransplant may be a source, however their functionality and growth potential especially at the time of retransplant are unknown. We aimed to assess growth and function of these valves. Methods Data from patients undergoing a retransplant at a single institution were analyzed. Echocardiograms were compared following the primary transplant and immediately before retransplant to assess growth and valve function. Results Thirteen patients were included. Recipient and donor ages at the primary transplant were median (range): 2 years (0–13) and 3 years (0–40), respectively. The median time to retransplant was 11 years (2–21). There was an overall growth across all semilunar valve measurements; aortic valve annulus diameter (mean increase ± standard deviation): 0.2 ± 0.12 cm, aortic root: 0.29 ± 0.16 cm, and pulmonary valve annulus: 0.5 ± 0.34 cm; all p < 0.05. The growth rate of valves was higher in younger patients and showed a better correlation with graft age relative to recipient age: aortic valve annulus growth R 2 : 0.61 (graft age) versus 0.54 (recipient age); aortic root R 2 : 0.73 versus 0.57; pulmonary valve annulus R 2 : 0.94 versus 0.86. No patients had clinically significant regurgitation or stenosis on the latest echocardiogram. All except one patient's measurement had valve Z ‐scores within ±2 at retransplant. Conclusion Explanted hearts from patients undergoing retransplantation could be considered an additional source of semilunar valves for PHT. Valves from these hearts were found to function normally and grew in proportion with the recipient's body. Valves from younger donors/recipients demonstrated a more rapid growth rate.

Cardiac skeleton

Pulmonary valve

10.1111/petr.70022

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Dendritic Cells Promote Macrophage Infiltration and Comprise a Substantial Proportion of Obesity-Associated Increases in CD11c+ Cells in Adipose Tissue and Liver

Diabetes (2012)

Maja Stefanović-Račić Xiao Yang Michael S. Turner Benjamin S. Mantell Donna B. Stolz

Obesity-associated increases in adipose tissue (AT) CD11c(+) cells suggest that dendritic cells (DC), which are involved in the tissue recruitment and activation of macrophages, may play a role in determining AT and liver immunophenotype in obesity. This study addressed this hypothesis. With the use of flow cytometry, electron microscopy, and loss-and-gain of function approaches, the contribution of DC to the pattern of immune cell alterations and recruitment in obesity was assessed. In AT and liver there was a substantial, high-fat diet (HFD)-induced increase in DC. In AT, these increases were associated with crown-like structures, whereas in liver the increase in DC constituted an early and reversible response to diet. Notably, mice lacking DC had reduced AT and liver macrophages, whereas DC replacement in DC-null mice increased liver and AT macrophage populations. Furthermore, delivery of bone marrow-derived DC to lean wild-type mice increased AT and liver macrophage infiltration. Finally, mice lacking DC were resistant to the weight gain and metabolic abnormalities of an HFD. Together, these data demonstrate that DC are elevated in obesity, promote macrophage infiltration of AT and liver, contribute to the determination of tissue immunophenotype, and play a role in systemic metabolic responses to an HFD.

CD11c

Immunophenotyping

Adipose tissue macrophages

Infiltration (HVAC)

10.2337/db11-1523

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Citations (204)

Long-Term Survival in Pediatric Heart Transplantation: A 35-Year Single-Center Experience

The Journal of Heart and Lung Transplantation (2021)

Jing Wen Marc E. Richmond Sabrina Law T.M. Lee Irene D. Lytrivi

Single Center

10.1016/j.healun.2021.01.1822

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A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels

AJP Endocrinology and Metabolism (2008)

Maja Stefanović-Račić Germán Perdomo Benjamin S. Mantell Ian Sipula Nicholas F. Brown

Nonalcoholic fatty liver disease (NAFLD), hypertriglyceridemia, and elevated free fatty acids are present in the majority of patients with metabolic syndrome and type 2 diabetes mellitus and are strongly associated with hepatic insulin resistance. In the current study, we tested the hypothesis that an increased rate of fatty acid oxidation in liver would prevent the potentially harmful effects of fatty acid elevation, including hepatic triglyceride (TG) accumulation and elevated TG secretion. Primary rat hepatocytes were transduced with adenovirus encoding carnitine palmitoyltransferase 1a (Adv-CPT-1a) or control adenoviruses encoding either beta-galactosidase (Adv-beta-gal) or carnitine palmitoyltransferase 2 (Adv-CPT-2). Overexpression of CPT-1a increased the rate of beta-oxidation and ketogenesis by approximately 70%, whereas esterification of exogenous fatty acids and de novo lipogenesis were unchanged. Importantly, CPT-1a overexpression was accompanied by a 35% reduction in TG accumulation and a 60% decrease in TG secretion by hepatocytes. There were no changes in secretion of apolipoprotein B (apoB), suggesting the synthesis of smaller, less atherogenic VLDL particles. To evaluate the effect of increasing hepatic CPT-1a activity in vivo, we injected lean or obese male rats with Adv-CPT-1a, Adv-beta-gal, or Adv-CPT-2. Hepatic CPT-1a activity was increased by approximately 46%, and the rate of fatty acid oxidation was increased by approximately 44% in lean and approximately 36% in obese CPT-1a-overexpressing animals compared with Adv-CPT-2- or Adv-beta-gal-treated rats. Similar to observations in vitro, liver TG content was reduced by approximately 37% (lean) and approximately 69% (obese) by this in vivo intervention. We conclude that a moderate stimulation of fatty acid oxidation achieved by an increase in CPT-1a activity is sufficient to substantially reduce hepatic TG accumulation both in vitro and in vivo. Therefore, interventions that increase CPT-1a activity could have potential benefits in the treatment of NAFLD.

Lipogenesis

Carnitine palmitoyltransferase I

Ketogenesis

Steatosis

10.1152/ajpendo.00497.2007

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Citations (181)

Getting to Transplant Should Not Be the Goal

Journal of the American College of Cardiology (2024)

David L.S. Morales Benjamin S. Mantell

10.1016/j.jacc.2024.06.009

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Immune cell function assay and T lymphocyte counts lack association with rejection or infection in pediatric heart transplant recipients

Clinical Transplantation (2022)

Justin K. Chen David M. Salerno Heather Corbo Benjamin S. Mantell Marc E. Richmond

Abstract Introduction Immune cell function assay (ICFA) and CD3 lymphocyte counts have been considered to be useful in discerning the overall intensity of immunosuppression in pediatric orthotopic heart transplant (OHT) recipients. Methods The aim of this retrospective analysis was to evaluate trends of ICFA and CD3 lymphocyte counts and their association with adverse outcomes post‐OHT. Results A total of 381 ICFA and 493 CD3 laboratory values obtained in 78 patients within six months post‐OHT were analyzed. There were 14 patients treated for biopsy‐proven acute rejection, four of whom had ISHLT grade 2R/3A rejection. In patients with rejection versus those without, CD3 and ICFA values were 122 (IQR 74.5–308) cells/mm 2 and 224.5 (IQR 132–343.5) ng/ml compared to 231.8 (IQR 68–421) cells/m 2 and 191 (IQR 81.5–333) ng/mL ( p = NS for both). Twenty‐six patients had at least one detectable cytomegalovirus or Epstein‐Barr virus DNAemia within the study timeframe. In patients with viremia versus those without, CD3 and ICFA values were 278.5 (IQR 68–552) cells/mm 2 and 130 (IQR 48–284) ng/ml compared to 195 (IQR 74.5–402.5) cells/mm 2 and 212 (IQR 89–342) ng/ml ( p = NS for both). Conclusions No association was found between these immune markers and adverse outcomes. In the absence of larger pediatric studies justifying the role of these tests in identifying elevated risk profiles post OHT, we do not recommend their routine use.

Immunosuppression

Viremia

10.1111/ctr.14858

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Citations (2)