Vinicio de Jesus Perez MD

All Publications

• Safety, Feasibility, and Utility of Digital Mobile Six-Minute Walk Testing in Pulmonary Arterial Hypertension: The DynAMITE Study. medRxiv : the preprint server for health sciences Schütz, N., Glinskii, V., Anderson, R., Del Rosario, P., Hedlin, H., Lee, J., Hess, J., Van Wormer, S., Lopez, A., Hershman, S. G., De Jesus Perez, V., Zamanian, R. T. 2024

  Abstract

  Pulmonary arterial hypertension (PAH) is a life-threatening progressive cardiopulmonary disease associated with high morbidity and mortality. Changes in the six-minute walk test (6MWT) provide prognostic information and help guide treatment decisions for PAH. However, since 6MWT requires in-clinic visits, clinical interventions to address disease progression may be delayed. Wearable technologies could reduce this delay by allowing the performance of 6MWT in the community and delivering data to clinicians remotely.To perform a pilot study to determine the safety and feasibility of performing 6MWT in PAH outpatients using a wearable app-based tool.PAH patients recruited at Stanford University were provided an Apple Watch with an app to perform daily, self-administered 6MWT over 12 weeks. Bland-Altman plots and correlations were used to assess the agreement and reliability of in-clinic vs. app-based 6MWT data at the beginning and end of the 12-week trial.From 55 PAH participants, we collected 3,139 app-recorded walks during 979.7 patient-weeks of exposure. On average, participants performed 3±2.3 weekly walks. No serious adverse events were reported. App-derived walk distance was highly correlated ( r ≥ 0.9) to the baseline in-clinic 6MWD and showed excellent reliability (ICC=0.9). Correlation and agreement were significantly lower at the 12-week follow-up visit. App-derived metrics beyond 6MWD showed promising associations with disease status.App-based outpatient 6MWT is feasible, safe, reasonably accurate, likely clinically relevant, and reliable in PAH patients but long-term measurement stability may be a concern. App-derived digital measures beyond distance show promise for future applications.

  View details for DOI 10.1101/2024.08.08.24311687

  View details for PubMedID 39211883

  View details for PubMedCentralID PMC11361239

• C-type natriuretic peptide/cGMP/FoxO3 signaling attenuates hyperproliferation of pericytes from patients with pulmonary arterial hypertension. Communications biology Dabral, S., Noh, M., Werner, F., Krebes, L., Völker, K., Maier, C., Aleksic, I., Novoyatleva, T., Hadzic, S., Schermuly, R. T., Perez, V. i., Kuhn, M. 2024; 7 (1): 693

  Abstract

  Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary Arterial Hypertension (PAH). Augmented expression and action of growth factors trigger these pathological changes. Endogenous factors opposing such alterations are barely known. Here, we examine whether and how the endothelial hormone C-type natriuretic peptide (CNP), signaling through the cyclic guanosine monophosphate (cGMP) -producing guanylyl cyclase B (GC-B) receptor, attenuates the pericyte dysfunction observed in PAH. The results demonstrate that CNP/GC-B/cGMP signaling is preserved in lung pericytes from patients with PAH and prevents their growth factor-induced proliferation, migration, and transdifferentiation. The anti-proliferative effect of CNP is mediated by cGMP-dependent protein kinase I and inhibition of the Phosphoinositide 3-kinase (PI3K)/AKT pathway, ultimately leading to the nuclear stabilization and activation of the Forkhead Box O 3 (FoxO3) transcription factor. Augmentation of the CNP/GC-B/cGMP/FoxO3 signaling pathway might be a target for novel therapeutics in the field of PAH.

  View details for DOI 10.1038/s42003-024-06375-3

  View details for PubMedID 38844781

  View details for PubMedCentralID PMC11156916

• Constructing the Framework for Disease Modification in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Zamanian, R. T., Weatherald, J., Sweatt, A. J., Hemnes, A., Rashid, M., Psotka, M. A., Bogaard, H. J., de Jesus Perez, V. 2024

  View details for DOI 10.1164/rccm.202401-0089PP

  View details for PubMedID 38471030

• WNT7A deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension. The European respiratory journal Chakraborty, A., Nathan, A., Orcholski, M., Agarwal, S., Shamskhou, E. A., Auer, N., Mitra, A., Guardado, E. S., Swaminathan, G., Condon, D. F., Yu, J., McCarra, M., Juul, N. H., Mallory, A., Guzman-Hernandez, R. A., Yuan, K., Rojas, V., Crossno, J. T., Yung, L., Yu, P. B., Spencer, T., Winn, R. A., Frump, A., Karoor, V., Lahm, T., Hedlin, H., Fineman, J. R., Lafyatis, R., Knutsen, C. N., Alvira, C. M., Cornfield, D. N., de Jesus Perez, V. A. 2023

  Abstract

  INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis, but their role in PAH is incompletely understood. We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH.METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a-/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx).RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced VEGF-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signaling by facilitating Y1175 tyrosine phosphorylation in VEGFR2 through ROR2, a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a-/- mice under either chronic hypoxia and SuHx, global Wnt7a+/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodeling. Similar to PAH, Wnt7a+/- PMVECs exhibited insufficient angiogenic response to VEGF-A that improved with Wnt7a.CONCLUSIONS: Wnt7a promotes VEGF signaling in lung PMVECs and its loss is associated with insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.

  View details for DOI 10.1183/13993003.01625-2022

  View details for PubMedID 37024132

• Cardiopulmonary disease as sequelae of long-term COVID-19: Current perspectives and challenges. Frontiers in medicine Oliveira, R. K., Nyasulu, P. S., Iqbal, A. A., Hamdan Gul, M., Ferreira, E. V., Leclair, J. W., Htun, Z. M., Howard, L. S., Mocumbi, A. O., Bryant, A. J., Tamuzi, J. L., Avdeev, S., Petrosillo, N., Hassan, A., Butrous, G., de Jesus Perez, V. 2022; 9: 1041236

  Abstract

  COVID-19 infection primarily targets the lungs, which in severe cases progresses to cytokine storm, acute respiratory distress syndrome, multiorgan dysfunction, and shock. Survivors are now presenting evidence of cardiopulmonary sequelae such as persistent right ventricular dysfunction, chronic thrombosis, lung fibrosis, and pulmonary hypertension. This review will summarize the current knowledge on long-term cardiopulmonary sequelae of COVID-19 and provide a framework for approaching the diagnosis and management of these entities. We will also identify research priorities to address areas of uncertainty and improve the quality of care provided to these patients.

  View details for DOI 10.3389/fmed.2022.1041236

  View details for PubMedID 36530872

• Lung Pericytes in Pulmonary Vascular Physiology and Pathophysiology. Comprehensive Physiology Yuan, K., Agarwal, S., Chakraborty, A., Condon, D. F., Patel, H., Zhang, S., Huang, F., Mello, S. A., Kirk, O. I., Vasquez, R., de Jesus Perez, V. A. 2021; 11 (3): 2227-2247

  Abstract

  Pericytes are mesenchymal-derived mural cells localized within the basement membrane of pulmonary and systemic capillaries. Besides structural support, pericytes control vascular tone, produce extracellular matrix components, and cytokines responsible for promoting vascular homeostasis and angiogenesis. However, pericytes can also contribute to vascular pathology through the production of pro-inflammatory and pro-fibrotic cytokines, differentiation into myofibroblast-like cells, destruction of the extracellular matrix, and dissociation from the vessel wall. In the lung, pericytes are responsible for maintaining the integrity of the alveolar-capillary membrane and coordinating vascular repair in response to injury. Loss of pericyte communication with alveolar capillaries and a switch to a pro-inflammatory/pro-fibrotic phenotype are common features of lung disorders associated with vascular remodeling, inflammation, and fibrosis. In this article, we will address how to differentiate pericytes from other cells, discuss the molecular mechanisms that regulate the interactions of pericytes and endothelial cells in the pulmonary circulation, and the experimental tools currently used to study pericyte biology both in vivo and in vitro. We will also discuss evidence that links pericytes to the pathogenesis of clinically relevant lung disorders such as pulmonary hypertension, idiopathic lung fibrosis, sepsis, and SARS-COVID. Future studies dissecting the complex interactions of pericytes with other pulmonary cell populations will likely reveal critical insights into the origin of pulmonary diseases and offer opportunities to develop novel therapeutics to treat patients afflicted with these devastating disorders. © 2021 American Physiological Society. Compr Physiol 11:2227-2247, 2021.

  View details for DOI 10.1002/cphy.c200027

  View details for PubMedID 34190345

• Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension FRONTIERS IN MEDICINE Pienkos, S., Gallego, N., Condon, D. F., Cruz-Utrilla, A., Ochoa, N., Nevado, J., Arias, P., Agarwal, S., Patel, H., Chakraborty, A., Lapunzina, P., Escribano, P., Tenorio-Castano, J., de Jesus Perez, V. A., Spanish PAH Consortium 2021; 8: 625763

  Abstract

  Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear. TNIP2 and TRAF2 encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH. Methods: Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting. Results: We discovered a novel missense variant in the TNIP2 gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a de novo protein-truncating variant in the TRAF2. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h. Conclusions: We have identified two rare novel variants in TNIP2 and TRAF2 using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.

  View details for DOI 10.3389/fmed.2021.625763

  View details for Web of Science ID 000649921700001

  View details for PubMedID 33996849

  View details for PubMedCentralID PMC8119639

• Distinct Types of Plexiform Lesions Identified by Synchrotron-Based Phase Contrast Micro-CT. American journal of physiology. Lung cellular and molecular physiology Westoo, C., Norvik, C. C., Peruzzi, N., van der Have, O., Lovric, G., Jeremiasen, I., Tran, P., Mokso, R., de Jesus Perez, V. A., Brunnstrom, H., Bech, M., Galambos, C., Tran-Lundmark, K. 2021

  Abstract

  In pulmonary arterial hypertension, plexiform lesions are associated with severe arterial obstruction and right ventricular failure. Exploring their structure and position is crucial for understanding the interplay between hemodynamics and vascular remodeling. The aim of this research was to use synchrotron-based phase contrast micro-CT to study the three-dimensional structure of plexiform lesions. Archived paraffin-embedded tissue-samples from 14 patients with pulmonary arterial hypertension (13 idiopathic, 1 with known BMPR2-mutation) were imaged. Clinical data showed high median PVR (12,5 WU) and mPAP (68 mmHg). Vascular lesions with more than one lumen were defined as plexiform. Prior radiopaque dye injection in some samples facilitated 3D-rendering. Four distinct types of plexiform lesions were identified: (1) localized within or derived from monopodial branches (supernumerary arteries), often with connection to the vasa vasorum; (2) localized between pulmonary arteries and larger airways as a tortuous transformation of intrapulmonary bronchopulmonary anastomoses; (3) as spherical structures at unexpected abrupt ends of distal pulmonary arteries; and (4) as occluded pulmonary arteries with re-canalization. By appearance and localization, types 1-2 potentially relieve pressure via the bronchial circulation, as pulmonary arteries in these patients were almost invariably occluded distally. In addition, types 1-3 were often surrounded by dilated thin-walled vessels, often connected to pulmonary veins, peri-bronchial vessels or the vasa vasorum. Collaterals, by-passing completely occluded pulmonary arteries, were also observed to originate within plexiform lesions. In conclusion, synchrotron-based imaging revealed significant plexiform lesion heterogeneity, resulting in a novel classification. The four types likely have different effects on hemodynamics and disease progression.

  View details for DOI 10.1152/ajplung.00432.2020

  View details for PubMedID 33881927

• Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive IPAH and COVID-19 Infection. American journal of respiratory and critical care medicine Zamanian, R. T., Pollack, C. V., Gentile, M. A., Rashid, M., Fox, J. C., Mahaffey, K. W., de Jesus Perez, V. 2020

  View details for DOI 10.1164/rccm.202004-0937LE

  View details for PubMedID 32369396

• Mural Cell SDF1 Signaling is Associated with the Pathogenesis of Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology Yuan, K. n., Liu, Y. n., Zhang, Y. n., Nathan, A. n., Tian, W. n., Yu, J. n., Sweatt, A. J., Condon, D. n., Chakraborty, A. n., Agarwal, S. n., Auer, N. n., Zhang, S. n., Wu, J. C., Zamanian, R. T., Nicolls, M. R., de Jesus Perez, V. A. 2020

  Abstract

  Pulmonary artery smooth muscle cells (PASMCs) and pericytes are NG2+ mural cells that provide structural support to pulmonary arteries and capillaries. In pulmonary arterial hypertension (PAH), both mural cell types contribute to PA muscularization but whether similar mechanisms are responsible for their behavior is unknown.RNA-Seq was used to compare the gene profile of pericytes and PASMCs from PAH and healthy lungs. NG2-Cre-ER mice were used to generate NG2-selective reporter mice (NG2tdT) for cell lineage identification and tamoxifen-inducible mice for NG2-selective SDF1 knockout (SDF1NG2-KO).Hierarchical clustering of RNA-seq data demonstrated that the genetic profile of PAH pericytes and PASMCs is highly similar. Cellular lineage staining studies on NG2tdT mice in chronic hypoxia showed that similar to PAH, tdT+ cells accumulate in muscularized microvessels and demonstrate significant upregulation of SDF1, a chemokine involved in chemotaxis and angiogenesis. Compared to controls, SDF1NG2-KO mice in chronic hypoxia had reduced muscularization and lower abundance of NG2+ cells around microvessels. SDF1 stimulation in healthy pericytes induced greater contractility and impaired their capacity to establish endothelial-pericyte communications. In contrast, SDF1 knockdown reduced PAH pericyte contractility and improved their capacity to associate with vascular tubes in co-culture.SDF1 is upregulated in NG2+ mural cells and is associated with PA muscularization. Targeting SDF1 could help prevent and/or reverse muscularization in PAH.

  View details for DOI 10.1165/rcmb.2019-0401OC

  View details for PubMedID 32084325

• Long Noncoding RNA TYKRIL Plays a Role in Pulmonary Hypertension via the p53-Mediated Regulation of PDGFRβ. American journal of respiratory and critical care medicine Zehendner, C. M., Valasarajan, C. n., Werner, A. n., Boeckel, J. N., Bischoff, F. C., John, D. n., Weirick, T. n., Glaser, S. F., Rossbach, O. n., Jaé, N. n., Demolli, S. n., Khassafi, F. n., Yuan, K. n., de Jesus Perez, V. A., Michalik, K. M., Chen, W. n., Seeger, W. n., Guenther, A. n., Wasnick, R. M., Uchida, S. n., Zeiher, A. M., Dimmeler, S. n., Pullamsetti, S. S. 2020

  Abstract

  Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored.To elucidate the role of tyrosine kinase receptor inducing lncRNA (TYKRIL) as a regulator of p53/platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and to investigate its role in PAH.Using RNAseq data, TYKRIL was identified to be consistently upregulated in pericytes and pulmonary arterial smooth muscles cells (PASMCs) exposed to hypoxia and derived from IPAH patients. TYKRIL knockdown reversed the pro-proliferative (n=3) and anti-apoptotic (n=3) phenotype induced under hypoxic and IPAH conditions. Due to the poor species conservation of TYKRIL, ex-vivo studies were carried out in precision cut lung slices (PCLS) from PH patients. Knockdown of TYKRIL in PCLS decreased the vascular remodeling (n=5). The number of PCNA positive cells in the vessels were decreased and number of TUNEL positive cells in the vessels were increased in LNA treated group compared to control. Expression of PDGFRβ, a key player in PH, was found to strongly correlate with TYKRIL expression in the patient samples (n=12) and TYKRIL knockdown decreased PDGFRβ expression (n=3). Importantly, TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRβ by binding to the N-terminal of p53 and interfering with p53-p300 interaction that subsequently regulates p53 nuclear translocation.TYKRIL plays an important role in PAH by regulating the p53/PDGFRβ axis.

  View details for DOI 10.1164/rccm.201910-2041OC

  View details for PubMedID 32634060

• Perspectives on Cardiopulmonary Critical Care for COVID-19 Patients: From Members of the American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Journal of the American Heart Association Maron, B. A., Gladwin, M. T., Bonnet, S. n., De Jesus Perez, V. n., Perman, S. M., Yu, P. B., Ichinose, F. n. 2020: e017111

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), marks a global event that will permanently reshape implementation of intensive care medicine. As of June 4, 2020, there are 6,606,455 reported cases of COVID-19 including 388,556 fatalities spanning 215 countries and territories, although epidemiological data remain incomplete. Early autopsy reports emphasize proximal airway and distal airspace involvement, including alveolar epithelial inflammation and capillary thickening.

  View details for DOI 10.1161/JAHA.120.017111

  View details for PubMedID 32552164

• ANATOMIC, GENETIC AND FUNCTIONAL PROPERTIES OF THE RETINAL CIRCULATION IN PULMONARY HYPERTENSION Pulmonary Circulation Nickel, N. P., Shamskhou, E. A., Razeen, M., Condon, D., Messentier, L., Dubra, A., Liao, Y., Zamanian, R. T., Yuan, K., de Jesus Perez, V. A. 2020

  View details for DOI 10.1177/2045894020905508

• Loss of Endothelium-Derived Wnt5a Is Associated With Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension CIRCULATION Yuan, K., Shamskhou, E. A., Orcholski, M. E., Nathan, A., Reddy, S., Honda, H., Mani, V., Zeng, Y., Ozen, M. O., Wang, L., Demirci, U., Tian, W., Nicolls, M. R., Perez, V. 2019; 139 (14): 1710–24

  View details for DOI 10.1161/CIRCULATIONAHA.118.037642

  View details for Web of Science ID 000469320000018

• A Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration. Cell Das, S., Goldstone, A. B., Wang, H., Farry, J., D'Amato, G., Paulsen, M. J., Eskandari, A., Hironaka, C. E., Phansalkar, R., Sharma, B., Rhee, S., Shamskhou, E. A., Agalliu, D., de Jesus Perez, V., Woo, Y. J., Red-Horse, K. 2019

  Abstract

  Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.

  View details for PubMedID 30686582

• EXPRESS: Low-Grade Albuminuria in Pulmonary Arterial Hypertension. Pulmonary circulation Nickel, N. n., Perez, V. i., Fessel, J. P., Cogan, J. n., Hamid, R. n., West, J. D., de Caestecker, M. n., Yang, H. n., Zamanian, R. T., Austin, E. n. 2019: 2045894018824564

  View details for PubMedID 30632900

• Methamphetamine use association with pulmonary diseases: a retrospective investigation of hospital discharges in California from 2005 to 2011 European Respiratory Journal Open Research Tsai, H., Lee, J., Hedlin, H., Zamanian, R., de Jesus Perez, V. 2019

  View details for DOI 10.1183/23120541.00017-2019

• BEYOND THE LUNGS: SYSTEMIC MANIFESTATIONS OF PULMONARY ARTERIAL HYPERTENSION. American journal of respiratory and critical care medicine Nickel, N. P., Yuan, K. n., Dorfmuller, P. n., Provencher, S. n., Lai, Y. C., Bonnet, S. n., Austin, E. D., Koch, C. D., Morris, A. n., Perros, F. n., Montani, D. n., Zamanian, R. T., de Jesus Perez, V. A. 2019

  Abstract

  Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries resulting in right heart failure and death. Until recently, PAH was seen as a disease restricted to the pulmonary circulation. However, there is growing evidence that PAH patients also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. While some of these anomalies are partially due to right ventricular insufficiency, recent data support a mechanistic link to the genetic and molecular events behind PAH pathogenesis. This review will serve as an introduction to the major systemic findings in PAH and the evidence that supports a common mechanistic link with PAH pathophysiology. In addition, we will discuss recent studies describing morphological changes in systemic vessels and the possible role of bronchopulmonary anastomoses in the development of plexogenic arteriopathy. Based on available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury and systemic vascular dysfunction contribute to systemic manifestations in PAH. This concept not only opens exciting research possibilities, but also encourages clinicians to consider extrapulmonary manifestations in their management of PAH patients.

  View details for DOI 10.1164/rccm.201903-0656CI

  View details for PubMedID 31513751

• Hydrogel-based delivery of Il-10 improves treatment of bleomycin-induced lung fibrosis in mice. Biomaterials Shamskhou, E. A., Kratochvil, M. J., Orcholski, M. E., Nagy, N. n., Kaber, G. n., Steen, E. n., Balaji, S. n., Yuan, K. n., Keswani, S. n., Danielson, B. n., Gao, M. n., Medina, C. n., Nathan, A. n., Chakraborty, A. n., Bollyky, P. L., De Jesus Perez, V. A. 2019; 203: 52–62

  Abstract

  Idiopathic pulmonary fibrosis (IPF) is a life-threatening progressive lung disorder with limited therapeutic options. While interleukin-10 (IL-10) is a potent anti-inflammatory and anti-fibrotic cytokine, its utility in treating lung fibrosis has been limited by its short half-life. We describe an innovative hydrogel-based approach to deliver recombinant IL-10 to the lung for the prevention and reversal of pulmonary fibrosis in a mouse model of bleomycin-induced lung injury. Our studies show that a hyaluronan and heparin-based hydrogel system locally delivers IL-10 by capitalizing on the ability of heparin to reversibly bind IL-10 without bleeding or other complications. This formulation is significantly more effective than soluble IL-10 for both preventing and reducing collagen deposition in the lung parenchyma after 7 days of intratracheal administration. The anti-fibrotic effect of IL-10 in this system is dependent on suppression of TGF-β driven collagen production by lung fibroblasts and myofibroblasts. We conclude that hydrogel-based delivery of IL-10 to the lung is a promising therapy for fibrotic lung disorders.

  View details for PubMedID 30852423

• DRUG INDUCED PULMONARY ARTERIAL HYPERTENSION: A PRIMER FOR CLINICIANS AND SCIENTISTS. American journal of physiology. Lung cellular and molecular physiology Orcholski, M. E., Yuan, K. n., Rajasingh, C. n., Tsai, H. n., Shamskhou, E. A., Dhillon, N. K., Voelkel, N. F., Zamanian, R. T., de Jesus Perez, V. A. 2018

  Abstract

  Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) defined by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexigens, recreational stimulants, and more recently, several Food and Drug Administration (FDA)-approved medications. While the clinical manifestation, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of PAH, its clinical course can be unpredictable and to some degree dependent on removal of the offending agent. Since only a subset of individuals develop D-PAH, it is probable that genetic susceptibilities play a role in the pathogenesis, but the characterization of the genetic factors responsible for these susceptibilities remains rudimentary. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. The implementation of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate the identification of high-risk drugs and incentivize regulatory strategies to prevent further outbreaks of D-PAH. The goal for this review is to inform clinicians and scientists of the prevalence of D-PAH and to highlight the growing number of common drugs that have been associated with the disease.

  View details for PubMedID 29417823

• Health Disparities in Patients with Pulmonary Arterial Hypertension: A Blueprint for Action. An Official American Thoracic Society Statement. American journal of respiratory and critical care medicine Talwar, A., Garcia, J. G., Tsai, H., Moreno, M., Lahm, T., Zamanian, R. T., Machado, R., Kawut, S. M., Selej, M., Mathai, S., D'Anna, L. H., Sahni, S., Rodriquez, E. J., Channick, R., Fagan, K., Gray, M., Armstrong, J., Rodriguez Lopez, J., de Jesus Perez, V. 2017; 196 (8): e32-e47

  Abstract

  Health disparities have a major impact in the quality of life and clinical care received by minorities in the United States. Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder that affects children and adults and that, if untreated, results in premature death. The impact of health disparities in the diagnosis, treatment, and clinical outcome of patients with PAH has not been systematically investigated.The specific goals of this research statement were to conduct a critical review of the literature concerning health disparities in PAH, identify major research gaps and prioritize direction for future research.Literature searches from multiple reference databases were performed using medical subject headings and text words for pulmonary hypertension and health disparities. Members of the committee discussed the evidence and provided recommendations for future research.Few studies were found discussing the impact of health disparities in PAH. Using recent research statements focused on health disparities, the group identified six major study topics that would help address the contribution of health disparities to PAH. Representative studies in each topic were discussed and specific recommendations were made by the group concerning the most urgent questions to address in future research studies.At present, there are few studies that address health disparities in PAH. Given the potential adverse impact of health disparities, we recommend that research efforts be undertaken to address the topics discussed in the document. Awareness of health disparities will likely improve advocacy efforts, public health policy and the quality of care of vulnerable populations with PAH.

  View details for DOI 10.1164/rccm.201709-1821ST

  View details for PubMedID 29028375

• REDUCED CARBOXYLESTERASE 1 IS ASSOCIATED WITH ENDOTHELIAL INJURY IN METHAMPHETAMINE INDUCED PULMONARY ARTERIAL HYPERTENSION. American journal of physiology. Lung cellular and molecular physiology Orcholski, M. E., Khurshudyan, A., Shamskhou, E. A., Yuan, K., Chen, I. Y., Kodani, S. D., Morisseau, C., Hammock, B. D., Hong, E. M., Alexandrova, L., Alastalo, T., Berry, G., Zamanian, R. T., de Jesus Perez, V. A. 2017: ajplung 00453 2016-?

  Abstract

  Pulmonary arterial hypertension is a complication of methamphetamine use (METH-PAH) but the pathogenic mechanisms are unknown. Given that cytochrome P450 2D6 (CYP2D6) and carboxylesterase 1 (CES1) are involved in metabolism of METH and other amphetamine-like compounds, we postulated that loss of function variants could contribute to METH-PAH. While no difference in CYP2D6 expression was seen by lung immunofluorescence, CES1 expression was significantly reduced in endothelium of METH-PAH microvessels. Mass spectrometry analysis showed that healthy pulmonary microvascular endothelial cells (PMVECs) have the capacity to both internalize and metabolize METH. Furthermore, whole exome sequencing data from 18 METH-PAH patients revealed that 94.4% of METH-PAH patients were heterozygous carriers of a single nucleotide variant (SNV, rs115629050) predicted to reduce CES1 activity. PMVECs transfected with this CES1 variant demonstrated significantly higher rates of METH-induced apoptosis. METH exposure results in increased formation of reactive oxygen species (ROS) and a compensatory autophagy response. Compared to healthy cells, CES1-deficient PMVECs lack a robust autophagy response despite higher ROS, which correlates with increased apoptosis. We propose that reduced CES1 expression/activity could promote development of METH-PAH by increasing PMVEC apoptosis and small vessel loss.

  View details for DOI 10.1152/ajplung.00453.2016

  View details for PubMedID 28473326

• Drug induced Pulmonary Hypertension: The First 50 Years Advances in Pulmonary Hypertension de Jesus Perez, V. A. 2017; 15 (3): 133-137
• Features and Outcomes of Methamphetamine Associated Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Zamanian, R. T., Hedlin, H. n., Greuenwald, P. n., Wilson, D. M., Segal, J. I., Jorden, M. n., Kudelko, K. n., Liu, J. n., Hsi, A. n., Rupp, A. n., Sweatt, A. J., Tuder, R. n., Berry, G. J., Rabinovitch, M. n., Doyle, R. L., De Jesus Perez, V. n., Kawut, S. M. 2017

  Abstract

  While amphetamines are recognized as "likely" agents to cause drugs and toxins associated pulmonary arterial hypertension (PAH), (meth)amphetamine associated PAH (Meth-APAH) has not been well described.To prospectively characterize the clinical presentation, histopathology, and outcomes of Meth-APAH compared to those of idiopathic PAH (iPAH).We performed a prospective cohort study of Meth-APAH and iPAH patients presenting to the Stanford University Pulmonary Hypertension Program between 2003-2015. Clinical, pulmonary angiography, histopathology, and outcomes data were compared. We used data from the Healthcare Cost and Utilization Project to estimate the epidemiology of PAH in (meth)amphetamine abusers hospitalized in California.The study sample included 90 Meth-APAH and 97 iPAH patients. Meth-APAH patients were less likely to be female, but similar in age, body mass index, and six minute walk distance to iPAH patients. Meth-PAH patients reported more advanced heart failure symptoms, had significantly higher right atrial pressure (12.7±6.8 vs. 9.8±5.1 mmHg, p=0.001), and lower stroke volume index (22.2±7.1 vs 25.5±8.7 mL/m2, p=0.01). Event-free survival in Meth-APAH was 64.2%, 47.2%, and 25% at 2.5, 5, and 10 years respectively, representing more than double the risk of clinical worsening or death compared to iPAH (HR 2.04, 95% CI 1.28-3.25, p=0.003) independent of confounders. California data demonstrated a 2.6 fold increase in risk of PAH diagnosis in hospitalized (meth)amphetamine users.Meth-APAH is a severe and progressive form of PAH with poor outcomes. Future studies should focus on mechanisms of disease and potential therapeutic considerations.

  View details for PubMedID 28934596

• Increased Pyruvate Dehydrogenase Kinase 4 Expression in Lung Pericytes Is Associated with Reduced Endothelial-Pericyte Interactions and Small Vessel Loss in Pulmonary Arterial Hypertension. American journal of pathology Yuan, K., Shao, N., Hennigs, J. K., Discipulo, M., Orcholski, M. E., Shamskhou, E., Richter, A., Hu, X., Wu, J. C., de Jesus Perez, V. A. 2016; 186 (9): 2500-2514

  Abstract

  Reduced endothelial-pericyte interactions are linked to progressive small vessel loss in pulmonary arterial hypertension (PAH), but the molecular mechanisms underlying this disease remain poorly understood. To identify relevant gene candidates associated with aberrant pericyte behavior, we performed a transcriptome analysis of patient-derived donor control and PAH lung pericytes followed by functional genomics analysis. Compared with donor control cells, PAH pericytes had significant enrichment of genes involved in various metabolic processes, the top hit being PDK4, a gene coding for an enzyme that suppresses mitochondrial activity in favor of glycolysis. Given reports that link reduced mitochondrial activity with increased PAH cell proliferation, we hypothesized that increased PDK4 is associated with PAH pericyte hyperproliferation and reduced endothelial-pericyte interactions. We found that PDK4 gene and protein expression was significantly elevated in PAH pericytes and correlated with reduced mitochondrial metabolism, higher rates of glycolysis, and hyperproliferation. Importantly, reducing PDK4 levels restored mitochondrial metabolism, reduced cell proliferation, and improved endothelial-pericyte interactions. To our knowledge, this is the first study that documents significant differences in gene expression between human donor control and PAH lung pericytes and the link between mitochondrial dysfunction and aberrant endothelial-pericyte interactions in PAH. Comprehensive characterization of these candidate genes could provide novel therapeutic targets to improve endothelial-pericyte interactions and prevent small vessel loss in PAH.

  View details for DOI 10.1016/j.ajpath.2016.05.016

  View details for PubMedID 27456128

• Novel approaches to pulmonary arterial hypertension drug discovery. Expert opinion on drug discovery Sung, Y. K., Yuan, K., de Jesus Perez, V. A. 2016; 11 (4): 407-414

  Abstract

  Introduction Pulmonary arterial hypertension (PAH) is a rare disorder associated with abnormally elevated pulmonary pressures that, if untreated, leads to right heart failure and premature death. The goal of drug development for PAH is to develop effective therapies that halt, or ideally, reverse the obliterative vasculopathy that results in vessel loss and obstruction of blood flow to the lungs. Areas Covered This review summarizes the current approach to candidate discovery in PAH and discusses the currently available drug discovery methods that should be implemented to prioritize targets and obtain a comprehensive pharmacological profile of promising compounds with well-defined mechanisms. Expert opinion To improve the successful identification of leading drug candidates, it is necessary that traditional pre-clinical studies are combined with drug screening strategies that maximize the characterization of biological activity and identify relevant off-target effects that could hinder the clinical efficacy of the compound when tested in human subjects. A successful drug discovery strategy in PAH will require collaboration of clinician scientists with medicinal chemists and pharmacologists who can identify compounds with an adequate safety profile and biological activity against relevant disease mechanisms.

  View details for DOI 10.1517/17460441.2016.1153625

  View details for PubMedID 26901465

• PDGF-dependent ß-catenin activation is associated with abnormal pulmonary artery smooth muscle cell proliferation in pulmonary arterial hypertension. FEBS letters Takahashi, J., Orcholski, M., Yuan, K., de Jesus Perez, V. 2016; 590 (1): 101-109

  Abstract

  Pulmonary arterial hypertension (PAH) is characterized by excessive pulmonary arterial smooth muscle cells (PASMCs) growth, partially in response to PDGF-BB but whether this is dependent on β-catenin (βC) activation is unclear. Compared to healthy cells, PAH PASMCs demonstrate higher levels of proliferation both at baseline and with PDGF-BB that correlate with GSK3β dependent βC activation. We show that βC knockdown but not Wnt5a stimulation reduces PDGF-BB dependent growth and normalizes PAH PASMCs proliferation. These findings support that cross-talk between PDGF and Wnt signaling modulates PASMC proliferation and suggest that βC targeted therapies could treat abnormal vascular remodeling in PAH.

  View details for DOI 10.1002/1873-3468.12038

  View details for PubMedID 26787464

• Activation of the Wnt/Planar Cell Polarity Pathway Is Required for Pericyte Recruitment during Pulmonary Angiogenesis. American journal of pathology Yuan, K., Orcholski, M. E., Panaroni, C., Shuffle, E. M., Huang, N. F., Jiang, X., Tian, W., Vladar, E. K., Wang, L., Nicolls, M. R., Wu, J. Y., de Jesus Perez, V. A. 2015; 185 (1): 69-84

  Abstract

  Pericytes are perivascular cells localized to capillaries that promote vessel maturation, and their absence can contribute to vessel loss. Whether impaired endothelial-pericyte interaction contributes to small vessel loss in pulmonary arterial hypertension (PAH) is unclear. Using 3G5-specific, immunoglobulin G-coated magnetic beads, we isolated pericytes from the lungs of healthy subjects and PAH patients, followed by lineage validation. PAH pericytes seeded with healthy pulmonary microvascular endothelial cells failed to associate with endothelial tubes, resulting in smaller vascular networks compared to those with healthy pericytes. After the demonstration of abnormal polarization toward endothelium via live-imaging and wound-healing studies, we screened PAH pericytes for abnormalities in the Wnt/planar cell polarity (PCP) pathway, which has been shown to regulate cell motility and polarity in the pulmonary vasculature. PAH pericytes had reduced expression of frizzled 7 (Fzd7) and cdc42, genes crucial for Wnt/PCP activation. With simultaneous knockdown of Fzd7 and cdc42 in healthy pericytes in vitro and in a murine model of angiogenesis, motility and polarization toward pulmonary microvascular endothelial cells were reduced, whereas with restoration of both genes in PAH pericytes, endothelial-pericyte association was improved, with larger vascular networks. These studies suggest that the motility and polarity of pericytes during pulmonary angiogenesis are regulated by Wnt/PCP activation, which can be targeted to prevent vessel loss in PAH.

  View details for DOI 10.1016/j.ajpath.2014.09.013

  View details for PubMedID 25447046

• Molecular pathogenesis and current pathology of pulmonary hypertension. Heart failure reviews de Jesus Perez, V. A. 2015

  Abstract

  Following its initial description over a century ago, pulmonary arterial hypertension (PAH) continues to challenge researchers committed to understanding its pathobiology and finding a cure. The last two decades have seen major developments in our understanding of the genetics and molecular basis of PAH that drive cells within the pulmonary vascular wall to produce obstructive vascular lesions; presently, the field of PAH research has taken numerous approaches to dissect the complex amalgam of genetic, molecular and inflammatory pathways that interact to initiate and drive disease progression. In this review, we discuss the current understanding of PAH pathology and the role that genetic factors and environmental influences share in the development of vascular lesions and abnormal cell function. We also discuss how animal models can assist in elucidating gene function and the study of novel therapeutics, while at the same time addressing the limitations of the most commonly used rodent models. Novel experimental approaches based on application of next generation sequencing, bioinformatics and epigenetics research are also discussed as these are now being actively used to facilitate the discovery of novel gene mutations and mechanisms that regulate gene expression in PAH. Finally, we touch on recent discoveries concerning the role of inflammation and immunity in PAH pathobiology and how they are being targeted with immunomodulatory agents. We conclude that the field of PAH research is actively expanding and the major challenge in the coming years is to develop a unified theory that incorporates genetic and mechanistic data to address viable areas for disease modifying drugs that can target key processes that regulate the evolution of vascular pathology of PAH.

  View details for PubMedID 26694808

• Optical Coherence Tomography of Pulmonary Arterial Walls in Humans and Pigs (Sus scrofa domesticus). Comparative medicine Brunner, N. W., Zamanian, R. T., Ikeno, F., Mitsutake, Y., Connolly, A. J., Shuffle, E., Yuan, K., Orcholski, M., Lyons, J., de Jesus Perez, V. A. 2015; 65 (3): 217-224

  Abstract

  Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by progressive elevation of the pulmonary pressures that, in the absence of therapy, results in chronic right-heart failure and premature death. The vascular pathology of PAH is characterized by progressive loss of small (diameter, less than 50 μm) peripheral pulmonary arteries along with abnormal medial thickening, neointimal formation, and intraluminal narrowing of the remaining pulmonary arteries. Vascular pathology correlates with disease severity, given that hemodynamic effects and disease outcomes are worse in patients with advanced compared with lower-grade lesions. Novel imaging tools are urgently needed that demonstrate the extent of vascular remodeling in PAH patients during diagnosis and treatment monitoring. Optical coherence tomography (OCT) is a catheter-based intravascular imaging technique used to obtain high-resolution 2D and 3D cross-sectional images of coronary arteries, thus revealing the extent of vascular wall pathology due to diseases such as atherosclerosis and in-stent restenosis; its utility as a diagnostic tool in the assessment of the pulmonary circulation is unknown. Here we show that OCT provides high-definition images that capture the morphology of pulmonary arterial walls in explanted human lungs and during pulmonary arterial catheterization of an adult pig. We conclude that OCT may facilitate the evaluation of patients with PAH by disclosing the degree of wall remodeling present in pulmonary vessels. Future studies are warranted to determine whether this information complements the hemodynamic and functional assessments routinely performed in PAH patients, facilitates treatment selection, and improves estimates of prognosis and outcome.

  View details for PubMedID 26141446

• Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1 JOURNAL OF CLINICAL INVESTIGATION Ali, Z. A., Perez, V. D., Yuan, K., Orcholski, M., Pan, S., Qi, W., Chopra, G., Adams, C., Kojima, Y., Leeper, N. J., Qu, X., Zaleta-Rivera, K., Kato, K., Yamada, Y., Oguri, M., Kuchinsky, A., Hazen, S. L., Jukema, J. W., Ganesh, S. K., Nabe, E. G., Channon, K., Leon, M. B., Charest, A., Quertermous, T., Ashley, E. A. 2014; 124 (12): 5159-5174

  Abstract

  Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling.

  View details for DOI 10.1172/JCI77484

  View details for Web of Science ID 000345677200011

  View details for PubMedID 25401476

• Pumping it up! Angiogenesis and muscle deconditioning in pulmonary hypertension. American journal of respiratory and critical care medicine de Jesus Perez, V. A. 2014; 190 (3): 250-251

  View details for DOI 10.1164/rccm.201406-1163ED

  View details for PubMedID 25084260

• Targeting the Wnt signaling pathways in pulmonary arterial hypertension. Drug discovery today de Jesus Perez, V., Yuan, K., Alastalo, T., Spiekerkoetter, E., Rabinovitch, M. 2014; 19 (8): 1270-1276

  Abstract

  Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with elevated pulmonary pressures and right heart failure resulting from progressive loss and thickening of small pulmonary arteries. Despite their ability to improve symptoms, current therapies fail to prevent disease progression, leaving lung transplantation as the only therapy in end-stage PAH. To overcome the limitations of current therapies, there is an active search for disease-modifying agents capable of altering the natural history of, and improving clinical outcomes in, PAH. The Wnt signaling pathways have emerged as attractive treatment targets in PAH given their role in the preservation of pulmonary vascular homeostasis and the recent development of Wnt-specific compounds and biological therapies capable of modulating pathway activity. In this review, we summarize the literature describing the role of Wnt signaling in the pulmonary circulation and discuss promising advances in the field of Wnt therapeutics that could lead to novel clinical therapies capable of preventing and/or reversing pulmonary vascular pathology in patients with this devastating disease.

  View details for DOI 10.1016/j.drudis.2014.06.014

  View details for PubMedID 24955837

• Whole-Exome Sequencing Reveals TopBP1 as a Novel Gene in Idiopathic Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Perez, V. A., Yuan, K., Lyuksyutova, M. A., Dewey, F., Orcholski, M. E., Shuffle, E. M., Mathur, M., Yancy, L., Rojas, V., Li, C. G., Cao, A., Alastalo, T., Khazeni, N., Cimprich, K. A., Butte, A. J., Ashley, E., Zamanian, R. T. 2014; 189 (10): 1260-1272

  Abstract

  Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable and ∼15% of patients with IPAH, their low penetrance (∼20%) suggests that other unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole-exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH, but whether WES can also accelerate gene discovery in IPAH remains unknown.To determine whether WES can help identify novel gene modifiers in patients with IPAH.Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated patients with IPAH lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR.A total of nine genes were identified as high-priority candidates. Our top hit was topoisomerase DNA binding II binding protein 1 (TopBP1), a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from patients with IPAH. Although TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival.WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibility to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.

  View details for DOI 10.1164/rccm.201310-17490C

  View details for Web of Science ID 000336017200018

  View details for PubMedID 24702692

  View details for PubMedCentralID PMC4225850

• Loss-of BMPR2 is Associated With Abnormal DNA Repair in Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology Li, M., Vattulainen, S., Aho, J., Orcholski, M., Rojas, V., Yuan, K., Helenius, M., Taimen, P., Myllykangas, S., De Jesus Perez, V., Koskenvuo, J. W., Alastalo, T. P. 2014

  Abstract

  Rationale: Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic for pulmonary arterial hypertension (PAH). While a phenotypic switch in pulmonary endothelial cells (EC) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. Methods: Bioinfomatics approach, patient samples and in vitro experiments were utilized. Results: By combining a meta-analysis of human iPAH-associated gene-expression microarrays and a unique gene expression profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss-of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from iPAH patients and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control as excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified BRCA1 as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. Conclusions: We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.

  View details for DOI 10.1165/rcmb.2013-0349OC

  View details for PubMedID 24433082

• Loss of adenomatous poliposis coli-a3 integrin interaction promotes endothelial apoptosis in mice and humans. Circulation research de Jesus Perez, V. A., Yuan, K., Orcholski, M. E., Sawada, H., Zhao, M., Li, C. G., Tojais, N. F., Nickel, N., Rajagopalan, V., Spiekerkoetter, E., Wang, L., Dutta, R., Bernstein, D., Rabinovitch, M. 2012; 111 (12): 1551-1564

  Abstract

  Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins promote pulmonary angiogenesis by recruiting the Wnt/β-catenin pathway, we proposed that β-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH.This study aims to establish the role of β-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury.To assess the impact of β-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive β-catenin elevation. Surprisingly, hypoxic Apc(Min/+) mice displayed greater PH and small PA loss compared with control C57Bl6J littermates. PA endothelial cells isolated from Apc(Min/+) demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the α3 integrin, to stabilize focal adhesions and activate integrin-linked kinase-1 and phospho Akt. We found that PA endothelial cells from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin, and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC.We show that APC is integral to PA endothelial cells adhesion and survival and is reduced in PA endothelial cells from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.

  View details for DOI 10.1161/CIRCRESAHA.112.267849

  View details for PubMedID 23011394

  View details for PubMedCentralID PMC3821702

• BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways JOURNAL OF CELL BIOLOGY Perez, V. A., Ali, Z., Alastalo, T., Ikeno, F., Sawada, H., Lai, Y., Kleisli, T., Spiekerkoetter, E., Qu, X., Rubinos, L. H., Ashley, E., Amieva, M., Dedhar, S., Rabinovitch, M. 2011; 192 (1): 171-188

  Abstract

  We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)-β-catenin (βC) and Wnt-planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt-dependent manner, induces βC transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via α4-integrins. ILK-1 then induces the Wnt-PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1-mediated motility. Transfection of a Dvl mutant that binds βC without activating RhoA-Rac1 not only prevents BMP-2-mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent βC activity. Interfering with the Dvl-dependent Wnt-PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2-mediated tandem activation of Wnt-βC and Wnt-PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.

  View details for DOI 10.1083/jcb.201008060

  View details for PubMedID 21220513

• Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways JOURNAL OF CELL BIOLOGY Perez, V. A., Alastalo, T., Wu, J. C., Axelrod, J. D., Cooke, J. P., Amieva, M., Rabinovitch, M. 2009; 184 (1): 83-99

  Abstract

  Mutations in bone morphogenetic protein (BMP) receptor II (BMPRII) are associated with pulmonary artery endothelial cell (PAEC) apoptosis and the loss of small vessels seen in idiopathic pulmonary arterial hypertension. Given the low penetrance of BMPRII mutations, abnormalities in other converging signaling pathways may be necessary for disease development. We hypothesized that BMPRII supports normal PAEC function by recruiting Wingless (Wnt) signaling pathways to promote proliferation, survival, and motility. In this study, we report that BMP-2, via BMPRII-mediated inhibition of GSK3-beta, induces beta-catenin (beta-C) accumulation and transcriptional activity necessary for PAEC survival and proliferation. At the same time, BMP-2 mediates phosphorylated Smad1 (pSmad1) or, with loss of BMPRII, pSmad3-dependent recruitment of Disheveled (Dvl) to promote RhoA-Rac1 signaling necessary for motility. Finally, using an angiogenesis assay in severe combined immunodeficient mice, we demonstrate that both beta-C- and Dvl-mediated RhoA-Rac1 activation are necessary for vascular growth in vivo. These findings suggest that the recruitment of both canonical and noncanonical Wnt pathways is required in BMP-2-mediated angiogenesis.

  View details for DOI 10.1083/jcb.200806049

  View details for Web of Science ID 000262867000010

  View details for PubMedID 19139264

  View details for PubMedCentralID PMC2615088

• Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension. The Journal of experimental medicine Niihori, M., James, J., Varghese, M. V., McClain, N., Lawal, O. S., Philip, R. C., Baggett, B. K., Goncharov, D. A., de Jesus Perez, V., Goncharova, E. A., Rafikov, R., Rafikova, O. 2024; 221 (11)

  Abstract

  Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency.

  View details for DOI 10.1084/jem.20231568

  View details for PubMedID 39320470

• TAZ and RUNX2 awareness in pulmonary hypertension due to left heart disease. The European respiratory journal de Jesus Perez, V. A., Lai, Y. 2024; 64 (5)

  View details for DOI 10.1183/13993003.00905-2024

  View details for PubMedID 39542510

• Unraveling the role of HIF and epigenetic regulation in pulmonary arterial hypertension: implications for clinical research and its therapeutic approach. Frontiers in medicine Mitra, A., Yi, D., Dai, Z., de Jesus Perez, V. 2024; 11: 1460376

  Abstract

  Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with high pulmonary pressure, which ultimately leads to right heart failure and premature death. Emerging evidence suggests that both hypoxia and epigenetics play a pivotal role in the pathogenesis of PAH development. In this review article, we summarize the current developments in regulation of hypoxia inducible factor (HIF) isoforms in PAH vascular remodeling and the development of suitable animal models for discovery and testing of HIF pathway-targeting PAH therapeutics. In addition, we also discuss the epigenetic regulation of HIF-dependent isoforms in PAH and its therapeutic potential from a new perspective which highlights the importance of HIF isoform-specific targeting as a novel salutary strategy for PAH treatment.

  View details for DOI 10.3389/fmed.2024.1460376

  View details for PubMedID 39450110

  View details for PubMedCentralID PMC11499164

• Deciphering the Complexities of Pulmonary Hypertension: The Emergent Role of Single-Cell Omics. American journal of respiratory cell and molecular biology Rafikov, R., de Jesus Perez, V., Dekan, A., Kudryashova, T. V., Rafikova, O. 2024

  Abstract

  Expanding upon the critical advancements brought forth by single-cell omics in pulmonary hypertension (PH) research, this review delves deep into how these technologies have been piloted in a new era of understanding this complex disease. By leveraging the power of single cell transcriptomics (scRNA-seq), researchers can now dissect the complicated cellular ecosystem of the lungs, examining the key players such as endothelial cells, smooth muscle cells, pericytes, and immune cells, and their unique roles in the pathogenesis of PH. This more granular view is beyond the limitations of traditional bulk analysis, allowing for the identification of novel therapeutic targets previously obscured in the aggregated data. Connectome analysis based on single-cell omics of the cells involved in pathological changes can reveal a clearer picture of the cellular interactions and transitions in the cellular subtypes. Furthermore, the review acknowledges the challenges that lie ahead, including the need for enhancing the resolution of scRNA-seq to capture even finer details of cellular changes, overcoming logistical barriers in processing human tissue samples, and the necessity of integrating diverse omics approaches to fully comprehend the molecular underpinnings of PH. The promise of these single-cell technologies is immense, offering the potential for targeted drug development and the discovery of biomarkers for early diagnosis and disease monitoring. Through these advancements, the field moves closer to realizing the goal of precision medicine for patients with PH.

  View details for DOI 10.1165/rcmb.2024-0145PS

  View details for PubMedID 39141563

• VIEWING PULMONARY HYPERTENSION THROUGH A PEDIATRIC LENS. The European respiratory journal Agarwal, S., Fineman, J., Cornfield, D. N., Alvira, C. M., Zamanian, R. T., Goss, K., Yuan, K., Bonnet, S., Boucherat, O., Pullamsetti, S., Alcázar, M. A., Goncharova, E., Kudryashova, T. V., Nicolls, M. R., de Jesús Pérez, V. 2024

  View details for DOI 10.1183/13993003.01518-2023

  View details for PubMedID 38575157

• Precision Solutions: A Strategy to Improve Medical Care for Patients With Pulmonary Hypertension in Latin America. Chest Orozco-Levi, M., de Jesús Pérez, V. 2024; 165 (3): 669-672

  View details for DOI 10.1016/j.chest.2023.10.031

  View details for PubMedID 38461017

• Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension. bioRxiv : the preprint server for biology Liu, B., Yi, D., Li, S., Ramirez, K., Xia, X., Cao, Y., Zhao, H., Tripathi, A., Qiu, S., Kala, M., Rafikov, R., Gu, H., de Jesus Perez, V., Lemay, S. E., Glembotski, C. C., Knox, K. S., Bonnet, S., Kalinichenko, V. V., Fallon, M. B., Boucherat, O., Dai, Z. 2024

  Abstract

  Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Recent studies showed that FABP4 and FABP5 were expressed in ECs across multiple tissues and circulating FABP4 level was elevated in the PAH patients. However, the role of endothelial FABP4/5 in the pathogenesis of PAH remains undetermined.FABP4/5 expression was examined in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with idiopathic PAH (IPAH) and pulmonary hypertension (PH) rat models. Plasma proteome analysis was performed in human PAH samples. Echocardiography, hemodynamics, histology, and immunostaining were performed to evaluate the lung and heart PH phenotypes in Egln1 Tie2Cre (CKO) mice and Egln1 Tie2Cre /Fabp4-5 -/- (TKO) mice. Bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) analysis were performed to understand the cellular and molecular mechanisms of endothelial FABP4/5 mediated PAH pathogenesis.Both FABP4 and FABP5 were highly induced in ECs of CKO mice and PAECs from IPAH patients, and in whole lungs of PH rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of both Fabp4 and 5 in CKO mice caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure. Fabp4/5 deletion also normalized EC glycolysis, reduced ROS and HIF-2α expression, and decreased aberrant EC proliferation in CKO lungs.PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and hyperproliferation, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

  View details for DOI 10.1101/2024.02.11.579846

  View details for PubMedID 38370670

  View details for PubMedCentralID PMC10871348

• Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling. EMBO reports Kim, H., Liu, Y., Kim, J., Kim, Y., Klouda, T., Fisch, S., Baek, S. H., Liu, T., Dahlberg, S., Hu, C. J., Tian, W., Jiang, X., Kosmas, K., Christou, H. A., Korman, B. D., Vargas, S. O., Wu, J. C., Stenmark, K. R., Perez, V. d., Nicolls, M. R., Raby, B. A., Yuan, K. 2024

  Abstract

  Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.

  View details for DOI 10.1038/s44319-023-00054-w

  View details for PubMedID 38243138

  View details for PubMedCentralID 9199463

• Seven Additional Patients with SOX17 Related Pulmonary Arterial Hypertension and Review of the Literature. Genes Gallego-Zazo, N., Miranda-Alcaraz, L., Cruz-Utrilla, A., Del Cerro Marín, M. J., Álvarez-Fuente, M., Del Mar Rodríguez Vázquez Del Rey, M., Guillén Rodríguez, I., Becerra-Munoz, V. M., Moya-Bonora, A., Ochoa Parra, N., Parra, A., Pascual, P., Cazalla, M., Silván, C., Arias, P., Valverde, D., de Jesús-Pérez, V., Lapunzina, P., Escribano-Subías, P., Tenorio-Castano, J. 2023; 14 (10)

  Abstract

  Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. Here, we report seven additional patients with variants in SOX17 and a review of sixty previously described patients in the literature. Patients described in this study suffered with additional conditions including large septal defects, as described by other groups. Collectively, sixty-seven PAH patients have been reported so far with variants in SOX17, including missense and loss-of-function (LoF) variants. The majority of the loss-of-function variants found in SOX17 were detected in the last exon of the gene. Meanwhile, most missense variants were located within exon one, suggesting a probable tolerated change at the amino terminal part of the protein. In addition, we reported two idiopathic PAH patients presenting with the same variant previously detected in five patients by other studies, suggesting a possible hot spot. Research conducted on PAH associated with congenital heart disease (CHD) indicated that variants in SOX17 might be particularly prevalent in this subgroup, as two out of our seven additional patients presented with CHD. Further research is still necessary to clarify the precise association between the biological pathway of SOX17 and the development of PAH.

  View details for DOI 10.3390/genes14101965

  View details for PubMedID 37895315

  View details for PubMedCentralID PMC10606077

• Health Care Disparities in Pulmonary Arterial Hypertension. Clinics in chest medicine Bernardo, R. J., de Jesus Perez, V. A. 2023; 44 (3): 543-554

  Abstract

  The current approach for the management of pulmonary arterial hypertension (PAH) relies on data gathered from clinical trials and large registries. However, there is concern that minorities including Black, Indigenous, and People of Color are underrepresented in these trials and registries, making current data not generalizable to these groups of patients. Hence, it is important to discuss the significance of race/ethnicity and socioeconomic factors in patients with PAH. Here, we review the current knowledge on health care disparities in PAH. We also propose future steps in the global task of assuring justice and equality in access to pulmonary hypertension health care.

  View details for DOI 10.1016/j.ccm.2023.03.010

  View details for PubMedID 37517834

• Access to Medically Necessary Reproductive Care for Individuals with Pulmonary Hypertension. American journal of respiratory and critical care medicine Sonntag, E., Akgun, K. M., Bag, R., Rosensweig, E. B., Bernardo, R. J., Burnetti, C., Chybowski, A., de Jesus Perez, V. A., Diwan, J., Guthrie, K. M., Halscott, T., Lahm, T., Vaught, J., Ventetuolo, C. E., Hemnes, A. R. 2023

  View details for DOI 10.1164/rccm.202302-0230VP

  View details for PubMedID 37311249

• UnWNTing the Heart: Targeting WNT Signaling in Pulmonary Arterial Hypertension. Circulation research Goncharova, E. A., Kudryashova, T. V., de Jesus Perez, V. A., Rafikova, O. 2023; 132 (11): 1486-1488

  View details for DOI 10.1161/CIRCRESAHA.123.322912

  View details for PubMedID 37228239

• Effects of biomechanical and biochemical stimuli on angio- and vasculogenesis in a complex microvasculature-on-chip. iScience Ferrari, D., Sengupta, A., Heo, L., Petho, L., Michler, J., Geiser, T., de Jesus Perez, V. A., Kuebler, W. M., Zeinali, S., Guenat, O. T. 2023; 26 (3): 106198

  Abstract

  The endothelium of blood vessels is a vital organ that reacts differently to subtle changes in stiffness and mechanical forces exerted on its environment (extracellular matrix (ECM)). Upon alteration of these biomechanical cues, endothelial cells initiate signaling pathways that govern vascular remodeling. The emerging organs-on-chip technologies allow the mimicking of complex microvasculature networks, identifying the combined or singular effects of these biomechanical or biochemical stimuli. Here, we present a microvasculature-on-chip model to investigate the singular effect of ECM stiffness and mechanical cyclic stretch on vascular development. Following two different approaches for vascular growth, the effect of ECM stiffness on sprouting angiogenesis and the effect of cyclic stretch on endothelial vasculogenesis are studied. Our results indicate that ECM hydrogel stiffness controls the size of the patterned vasculature and the density of sprouting angiogenesis. RNA sequencing shows that the cellular response to stretching is characterized by the upregulation of certain genes such as ANGPTL4+5, PDE1A, and PLEC.

  View details for DOI 10.1016/j.isci.2023.106198

  View details for PubMedID 36879808

• Predictors and outcomes of acute pulmonary embolism in COVID-19; insights from US National COVID cohort collaborative. Respiratory research Gul, M. H., Htun, Z. M., de Jesus Perez, V., Suleman, M., Arshad, S., Imran, M., Vyasabattu, M., Wood, J. P., Anstead, M., Morris, P. E. 2023; 24 (1): 59

  Abstract

  OBJECTIVES: To investigate whether COVID-19 patients with pulmonary embolism had higher mortality and assess the utility of D-dimer in predicting acute pulmonary embolism.PATIENTS AND METHODS: Using the National Collaborative COVID-19 retrospective cohort, a cohort of hospitalized COVID-19 patients was studied to compare 90-day mortality and intubation outcomes in patients with and without pulmonary embolism in a multivariable cox regression analysis. The secondary measured outcomes in 1:4 propensity score-matched analysis included length of stay, chest pain incidence, heart rate, history of pulmonary embolism or DVT, and admission laboratory parameters.RESULTS: Among 31,500 hospitalized COVID-19 patients, 1117 (3.5%) patients were diagnosed with acute pulmonary embolism. Patients with acute pulmonary embolism were noted to have higher mortality (23.6% vs.12.8%; adjusted Hazard Ratio (aHR)=1.36, 95% CI [1.20-1.55]), and intubation rates (17.6% vs. 9.3%, aHR=1.38[1.18-1.61]). Pulmonary embolism patients had higher admission D-dimer FEU (Odds Ratio(OR)=1.13; 95%CI [1.1-1.15]). As the D-dimer value increased, the specificity, positive predictive value, and accuracy of the test increased; however, sensitivity decreased (AUC 0.70). At cut-off D-dimer FEU 1.8 mcg/ml, the test had clinical utility (accuracy 70%) in predicting pulmonary embolism. Patients with acute pulmonary embolism had a higher incidence of chest pain and history of pulmonary embolism or deep vein thrombosis.CONCLUSIONS: Acute pulmonary embolism is associated with worse mortality and morbidity outcomes in COVID-19. We present D-dimer as a predictive risk tool in the form of a clinical calculator for the diagnosis of acute pulmonary embolism in COVID-19.

  View details for DOI 10.1186/s12931-023-02369-7

  View details for PubMedID 36810085

• C-type natriuretic peptide-cGMP signalling attenuates hyperproliferation of lung pericytes from patients with Pulmonary Hypertension Dabral, S., Noh, M., Krebes, L., Abesser, M., Voelker, K., Novoyatleva, T., Schermuly, R., de Jesus Perez, V., Kuhn, M. BMC. 2023

  View details for Web of Science ID 000928017700034

• Decreasing ELK3 expression improves Bone Morphogenetic Protein Receptor 2 signaling and pulmonary vascular cell function in PAH. bioRxiv : the preprint server for biology Ali, M. K., Zhao, L., Perez, V. d., Nicolls, M. R., Spiekerkoetter, E. F. 2023

  Abstract

  ELK3 is upregulated in blood and pulmonary vascular cells of PAH patients and may play a significant role in PAH potentially through modulating BMPR2 signaling.

  View details for DOI 10.1101/2023.01.14.524023

  View details for PubMedID 36711443

  View details for PubMedCentralID PMC9882174

• Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities. PLoS pathogens Kumar, R., Aktay-Cetin, Ö., Craddock, V., Morales-Cano, D., Kosanovic, D., Cogolludo, A., Perez-Vizcaino, F., Avdeev, S., Kumar, A., Ram, A. K., Agarwal, S., Chakraborty, A., Savai, R., de Jesus Perez, V., Graham, B. B., Butrous, G., Dhillon, N. K. 2023; 19 (1): e1011063

  Abstract

  The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.

  View details for DOI 10.1371/journal.ppat.1011063

  View details for PubMedID 36634048

• The social and economic disadvantage in pulmonary hypertension: A work (still) in progress. Pulmonary circulation Bernardo, R. J., de Jesus Perez, V. 2023; 13 (1): e12196

  View details for DOI 10.1002/pul2.12196

  View details for PubMedID 36788943

• Editorial: Pulmonary hypertension in the modern era: Science and clinical practice, Volume II. Frontiers in medicine Bogaard, H. J., Goncharova, E. A., de Jesus Perez, V. A. 2023; 10: 1136157

  View details for DOI 10.3389/fmed.2023.1136157

  View details for PubMedID 36814774

• Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections. JCI insight Kratochvil, M. J., Kaber, G., Demirdjian, S., Cai, P. C., Burgener, E. B., Nagy, N., Barlow, G. L., Popescu, M., Nicolls, M. R., Ozawa, M. G., Regula, D. P., Pacheco-Navarro, A. E., Yang, S., de Jesus Perez, V. A., Karmouty-Quintana, H., Peters, A. M., Zhao, B., Buja, M. L., Johnson, P. Y., Vernon, R. B., Wight, T. N., Stanford COVID-19 Biobank Study Group, Milla, C. E., Rogers, A. J., Spakowitz, A. J., Heilshorn, S. C., Bollyky, P. L. 2022; 7 (12)

  Abstract

  Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors, with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observed increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor-stimulated gene-6 staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicated that increases in HA and DNA in COVID-19 respiratory secretion samples correlated with enhanced inflammatory burden and suggested that DNA and HA may be viable therapeutic targets in COVID-19 infection.

  View details for DOI 10.1172/jci.insight.152629

  View details for PubMedID 35730564

• Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. Circulation. Genomic and precision medicine De Jong, H. N., Dewey, F. E., Cordero, P., Victorio, R. A., Kirillova, A., Huang, Y., Madhvani, R., Seo, K., Werdich, A. A., Lan, F., Orcholski, M., Robert Liu, W., Erbilgin, A., Wheeler, M. T., Chen, R., Pan, S., Kim, Y. M., Bommakanti, K., Marcou, C. A., Martijn Bos, J., Haddad, F., Ackerman, M., Vasan, R. S., MacRae, C., Wu, J. C., de Jesus Perez, V., Snyder, M., Parikh, V. N., Ashley, E. A. 2022: 101161CIRCGEN121003563

  Abstract

  BACKGROUND: The study of hypertrophic cardiomyopathy (HCM)-a severe Mendelian disease-can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease.METHODS: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered shRNAs and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell-derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics.RESULTS: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio. Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell-derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil.CONCLUSIONS: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.

  View details for DOI 10.1161/CIRCGEN.121.003563

  View details for PubMedID 35671065

• An evidence appraisal of heart organoids in a dish and commensurability to human heart development in vivo. BMC cardiovascular disorders Thomas, D., de Jesus Perez, V. A., Sayed, N. 2022; 22 (1): 122

  Abstract

  Stem-cell derived in vitro cardiac models have provided profound insights into mechanisms in cardiac development and disease. Efficient differentiation of specific cardiac cell types from human pluripotent stem cells using a three-step Wnt signaling modulation has been one of the major discoveries that has enabled personalized cardiovascular disease modeling approaches. Generation of cardiac cell types follow key development stages during embryogenesis, they intuitively are excellent models to study cardiac tissue patterning in primitive cardiac structures. Here, we provide a brief overview of protocols that have laid the foundation for derivation of stem-cell derived three-dimensional cardiac models. Further this article highlights features and utility of the models to distinguish the advantages and trade-offs in modeling embryonic development and disease processes. Finally, we discuss the challenges in improving robustness in the current models and utilizing developmental principles to bring higher physiological relevance. In vitro human cardiac models are complimentary tools that allow mechanistic interrogation in a reductionist way. The unique advantage of utilizing patient specific stem cells and continued improvements in generating reliable organoid mimics of the heart will boost predictive power of these tools in basic and translational research.

  View details for DOI 10.1186/s12872-022-02543-7

  View details for PubMedID 35317745

• Health disparity is a global issue: Understanding Latin America PULMONARY CIRCULATION Gomberg-Maitland, M., Perez, V. 2022; 12 (1): e12049

  View details for DOI 10.1002/pul2.12049

  View details for Web of Science ID 000773548600001

  View details for PubMedID 35506086

  View details for PubMedCentralID PMC9052985

• Hispanic Ethnicity and Social Determinants of Health in Pulmonary Arterial Hypertension: The Pulmonary Hypertension Association Registry. Annals of the American Thoracic Society Bernardo, R. J., Lu, D., Ramirez, R. L., Hedlin, H., Kawut, S. M., Bull, T., De Marco, T., Ford, H. J., Grinnan, D., Klinger, J. R., McConnell, J. W., Berman-Rosenzweig, E., Shlobin, O. A., Zamanian, R. T., de Jesus Perez, V. A. 2022

  Abstract

  Rationale There is a noticeable underrepresentation of minorities in clinical trials and registries in pulmonary arterial hypertension (PAH). Prior studies evaluating the association between Hispanic ethnicity and clinical outcomes in patients with PAH have not assessed the socioeconomic profile of Hispanic individuals or the significance of social determinants of health in clinical outcomes. Objective To determine the association between Hispanic ethnicity, social determinants of health, and clinical outcomes in PAH. Methods Prospective cohort study of adult participants with PAH enrolled in the Pulmonary Hypertension Association Registry, a multicenter US-based registry of patients treated at Pulmonary Hypertension Care Centers. Participants were classified as Hispanics and non-Hispanic Whites, based on self-reported ethnicity. A comparison of baseline clinical and sociodemographic characteristics between groups was performed as well using absolute standardized differences (ASD). The primary outcome of the study was to assess transplant-free survival between Hispanics and non-Hispanic Whites. A Cox proportional hazards model was used for the multivariable analysis after adjusting for age, sex, PAH etiology, annual income, education level and health insurance. Results A total of 683 individuals were included, 98 (14.3%) of Hispanic ethnicity. Hispanic patients had impaired access to health care (31.6% vs. 12.9% Medicaid/uninsured; ASD 0.35), lower education level (72.6% vs. 94.0% high school graduates or higher; ASD 0.60) and lower annual income (32.0% vs. 17.4% with income <20,000 US dollars; ASD 0.47), as compared with non-Hispanic Whites. Hispanic patients had a higher frequency of ER visits and a higher number of hospitalizations, despite having similar disease severity (incidence rate ratio 1.452, 95% CI 1.326 - 1.590 and 1.428, 95% CI 1.292 - 1.577, respectively). While the unadjusted analysis showed a lower transplant/death hazard ratio for Hispanics (HR 0.47, 95% CI 0.24-0.94; p=0.032), there was no association between Hispanic ethnicity and outcome in the multivariable model after adjusting for social determinants of health and other covariates (HR 0.76, 95% CI 0.35-1.62; p=0.474). Conclusions Hispanic ethnicity was not associated with differences in survival after adjusting for social determinants of health and other factors. Social determinants of health are important to consider when assessing the association between ethnicity and outcomes in PAH.

  View details for DOI 10.1513/AnnalsATS.202109-1051OC

  View details for PubMedID 35239467

• Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective. Nature reviews. Cardiology Halawa, S., Pullamsetti, S. S., Bangham, C. R., Stenmark, K. R., Dorfmuller, P., Frid, M. G., Butrous, G., Morrell, N. W., de Jesus Perez, V. A., Stuart, D. I., O'Gallagher, K., Shah, A. M., Aguib, Y., Yacoub, M. H. 2021

  Abstract

  The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with severe hypoxia being the cause of death in the most critical cases. Coronavirus disease 2019 (COVID-19) is extremely heterogeneous in terms of severity, clinical phenotype and, importantly, global distribution. Although the majority of affected patients recover from the acute infection, many continue to suffer from late sequelae affecting various organs, including the lungs. The role of the pulmonary vascular system during the acute and chronic stages of COVID-19 has not been adequately studied. A thorough understanding of the origins and dynamic behaviour of the SARS-CoV-2 virus and the potential causes of heterogeneity in COVID-19 is essential for anticipating and treating the disease, in both the acute and the chronic stages, including the development of chronic pulmonary hypertension. Both COVID-19 and chronic pulmonary hypertension have assumed global dimensions, with potential complex interactions. In this Review, we present an update on the origins and behaviour of the SARS-CoV-2 virus and discuss the potential causes of the heterogeneity of COVID-19. In addition, we summarize the pathobiology of COVID-19, with an emphasis on the role of the pulmonary vasculature, both in the acute stage and in terms of the potential for developing chronic pulmonary hypertension. We hope that the information presented in this Review will help in the development of strategies for the prevention and treatment of the continuing COVID-19 pandemic.

  View details for DOI 10.1038/s41569-021-00640-2

  View details for PubMedID 34873286

• Recommended Reading from the Pulmonary and Critical Care Medicine Fellowship Program at Stanford University Medical Center. American journal of respiratory and critical care medicine Glinskii, V., Lyn, R., Thomas, C., de Jesus Perez, V. A. 2021

  View details for DOI 10.1164/rccm.202102-0462RR

  View details for PubMedID 34714222

• "NOVEL MECHANISMS TARGETED BY DRUG TRIALS IN PULMONARY ARTERIAL HYPERTENSION". Chest Condon, D. F., Agarwal, S., Chakraborty, A., Auer, N., Vazquez, R., Patel, H., Zamanian, R. T., de Jesus Perez, V. A., Condon, D. F. 2021

  Abstract

  Pulmonary arterial hypertension (PAH) is a rare disease associated with abnormally elevated pulmonary pressures and right heart failure resulting in high morbidity and mortality. While PAH prognosis has improved with the introduction of pulmonary vasodilators, disease progression remains a major problem. Given that available therapies are inadequate for preventing small vessel loss and obstruction, there is an active interest in identifying drugs capable of targeting angiogenesis and mechanisms involved in regulation of cell growth and fibrosis. Among the mechanisms linked to PAH pathogenesis, recent preclinical studies have identified promising compounds that are currently being tested in clinical trials. These drugs target seven of the major mechanisms associated with PAH pathogenesis: BMP signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. In this review, we will discuss the preclinical studies that led to prioritization of these mechanisms and will discuss recently completed and ongoing phase 2/3 trials using novel interventions such as sotatercept, anastrozole, rodatristat ethyl, tyrosine kinase inhibitors, and endothelial progenitor cells among others. We anticipate that the next generation of compounds will build upon the success of the current standard of care and improve clinical outcomes and quality of life of patients afflicted with PAH.

  View details for DOI 10.1016/j.chest.2021.10.010

  View details for PubMedID 34655569

• Prioritizing Equity and Diversity in Academic Medicine Faculty Recruitment and Retention JAMA HEALTH FORUM Ajayi, A. A., Rodriguez, F., de Jesus Perez, V. 2021; 2 (9)

  View details for DOI 10.1001/jamahealthforum.2021.2426

  View details for Web of Science ID 000837117200003

• CHK yourself, before you wreck yourself: targeting the DNA damage response in secondary pulmonary hypertension. Thorax Bryant, A., de Jesus Perez, V. 2021

  View details for DOI 10.1136/thoraxjnl-2021-217882

  View details for PubMedID 34417351

• Immunoprofiling of Nonarteritic Anterior Ischemic Optic Neuropathy. Translational vision science & technology Mesentier-Louro, L. A., Stell, L., Yan, Y., Montague, A. A., de Jesus Perez, V., Liao, Y. J. 2021; 10 (8): 17

  Abstract

  Purpose: Nonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy in those older than 50 years. There is no blood diagnostic test or efficient treatment for NAION. We investigated the suitability of blood inflammatory proteins as biomarkers and therapeutic targets of NAION.Methods: We conducted an exploratory, cross-sectional case-control study including 18 patients with NAION (n = 5 acute, and n = 13 chronic) and 9 controls. NAION was confirmed by clinical examination and optical coherence tomography. Subjects underwent peripheral blood collection; plasma was isolated within 2 hours and analyzed using a 76-plex array of cytokines, chemokines, and growth factors.Results: In acute NAION, there was increased peripapillary retinal thickness on optical coherence tomography consistent with optic disc edema. Plasma profiling revealed dramatic changes in inflammatory proteins in NAION. Statistical analysis generated a list of 20 top-ranked molecules in NAION, with 15% overlap in acute and chronic NAION. Principal component analysis, hierarchical clustering, and Spearman correlation generally segregated controls, acute and chronic NAION, with some overlap. Longitudinal data from one patient demonstrated an evolving inflammatory pattern from acute to chronic NAION. In acute NAION, Eotaxin-3, MCP-2, TPO, and TRAIL were the top biomarker candidates. In chronic NAION, IL-1alpha and CXCL10 emerged as the strongest therapeutic targets.Conclusions: Post-NAION inflammation occurs in both acute and chronic NAION. Statistical analysis of plasma profile changes generated a list of 20 potential biomarker and therapeutic targets of NAION.Translational Relevance: We identified blood molecular targets to improve NAION diagnosis and treatment.

  View details for DOI 10.1167/tvst.10.8.17

  View details for PubMedID 34264294

• Pulmonary Arterial Hypertension Secondary to Drugs and Toxins. Clinics in chest medicine Ramirez, R. L., Pienkos, S. M., de Jesus Perez, V., Zamanian, R. T. 2021; 42 (1): 19–38

  Abstract

  Pulmonary arterial hypertension secondary to drugs and toxins is an important subgroup of group 1 pulmonary hypertension associated with significant morbidity and mortality. Many drugs and toxins have emerged as risk factors for pulmonary arterial hypertension, which include anorexigens, illicit agents, and several US Food and Drug Administration-approved therapeutic medications. Drugs and toxins are classified as possible or definite risk factors for pulmonary arterial hypertension. This article reviews agents that have been implicated in the development of pulmonary arterial hypertension, their pathologic mechanisms, and methods to prevent the next deadly outbreak of drug- and toxin-induced pulmonary arterial hypertension.

  View details for DOI 10.1016/j.ccm.2020.11.008

  View details for PubMedID 33541612

• No Good Deed Goes Unpunished: Mitomycin-Induced Pulmonary Venoocclusive Disease and Cancer. Chest De Jesus Perez, V. A., Zamanian, R. T. 2021; 159 (3): 910–11

  View details for DOI 10.1016/j.chest.2020.10.060

  View details for PubMedID 33678275

• Editorial: Pulmonary Hypertension in the Modern Era: Science and Clinical Practice. Frontiers in medicine Goncharova, E. A., Bogaard, H. J., de Jesus Perez, V. A. 2021; 8: 785181

  View details for DOI 10.3389/fmed.2021.785181

  View details for PubMedID 34778329

  View details for PubMedCentralID PMC8581044

• Prescription Patterns for Pulmonary Vasodilators in the Treatment of Pulmonary Hypertension Associated With Chronic Lung Diseases: Insights From a Clinician Survey. Frontiers in medicine Thomas, C. A., Lee, J., Bernardo, R. J., Anderson, R. J., Glinskii, V., Sung, Y. K., Kudelko, K., Hedlin, H., Sweatt, A., Kawut, S. M., Raj, R., Zamanian, R. T., de Jesus Perez, V. 1800; 8: 764815

  Abstract

  Background: Pulmonary hypertension is a complication of chronic lung diseases (PH-CLD) associated with significant morbidity and mortality. Management guidelines for PH-CLD emphasize the treatment of the underlying lung disease, but the role of PH-targeted therapy remains controversial. We hypothesized that treatment approaches for PH-CLD would be variable across physicians depending on the type of CLD and the severity of PH. Methods and Results: Between May and July 2020, we conducted an online survey of PH experts asking for their preferred treatment approach in seven hypothetical cases of PH-CLD of varying severity. We assessed agreement amongst clinicians for initial therapy choice using Fleiss' kappa calculations. Over 90% of respondents agreed that they would treat cases of severe PH in the context of mild lung disease with some form of PH-targeted therapy. For cases of severe PH in the context of severe lung disease, over 70% of respondents agreed to use PH-targeted therapy. For mild PH and mild lung disease cases, <50% of respondents chose to start PH-specific therapy. There was overall poor agreement between respondents in the choice to use mono-, double or triple combination therapy with PH-specific agents in all cases. Conclusion: Although management guidelines discourage the routine use of PH-targeted therapies to treat PH-CLD patients, most physicians choose to treat patients with some form of PH-targeted therapy. The choice of therapy and treatment approach are variable and appear to be influenced by the severity of the PH and the underlying lung disease.

  View details for DOI 10.3389/fmed.2021.764815

  View details for PubMedID 34926507

• Hypoxia-induced inflammation: Profiling the first 24-hour posthypoxic plasma and central nervous system changes. PloS one Mesentier-Louro, L. A., Rangel, B. n., Stell, L. n., Shariati, M. A., Dalal, R. n., Nathan, A. n., Yuan, K. n., de Jesus Perez, V. n., Liao, Y. J. 2021; 16 (3): e0246681

  Abstract

  Central nervous system and visual dysfunction is an unfortunate consequence of systemic hypoxia in the setting of cardiopulmonary disease, including infection with SARS-CoV-2, high-altitude cerebral edema and retinopathy and other conditions. Hypoxia-induced inflammatory signaling may lead to retinal inflammation, gliosis and visual disturbances. We investigated the consequences of systemic hypoxia using serial retinal optical coherence tomography and by assessing the earliest changes within 24h after hypoxia by measuring a proteomics panel of 39 cytokines, chemokines and growth factors in the plasma and retina, as well as using retinal histology. We induced severe systemic hypoxia in adult C57BL/6 mice using a hypoxia chamber (10% O2) for 1 week and rapidly assessed measurements within 1h compared with 18h after hypoxia. Optical coherence tomography revealed retinal tissue edema at 18h after hypoxia. Hierarchical clustering of plasma and retinal immune molecules revealed obvious segregation of the 1h posthypoxia group away from that of controls. One hour after hypoxia, there were 10 significantly increased molecules in plasma and 4 in retina. Interleukin-1β and vascular endothelial growth factor were increased in both tissues. Concomitantly, there was significantly increased aquaporin-4, decreased Kir4.1, and increased gliosis in retinal histology. In summary, the immediate posthypoxic period is characterized by molecular changes consistent with systemic and retinal inflammation and retinal glial changes important in water transport, leading to tissue edema. This posthypoxic inflammation rapidly improves within 24h, consistent with the typically mild and transient visual disturbance in hypoxia, such as in high-altitude retinopathy. Given hypoxia increases risk of vision loss, more studies in at-risk patients, such as plasma immune profiling and in vivo retinal imaging, are needed in order to identify novel diagnostic or prognostic biomarkers of visual impairment in systemic hypoxia.

  View details for DOI 10.1371/journal.pone.0246681

  View details for PubMedID 33661927

• Puerto Rico Health System Resilience After Hurricane Maria: Implications for Disaster Preparedness in the COVID-19 Era. medRxiv : the preprint server for health sciences Rios, C., Ling, E., Rivera Gutierrez, R., Gonzalez, J., Bruce, J., Barry, M., de Jesus Perez, V. 2020

  Abstract

  Every year, Puerto Rico faces a hurricane season fraught with potentially catastrophic structural, emotional and health consequences. In 2017, Puerto Rico was hit by Hurricane Maria, the largest natural disaster to ever affect the island. Several studies have estimated the excess morbidity and mortality following Hurricane Maria in Puerto Rico, yet no study has comprehensively examined the underlying health system weaknesses contributing to the deleterious health outcomes.A qualitative case study was conducted to assess the ability of the UPR health system to provide patient care in response to Hurricane Maria. An established five key resilience framework and inductive analysis was used to identify factors that affected health system resilience. Thirteen Emergency Medicine Physicians, Family Medicine Physicians, and Hospital Administrators in a University of Puerto Rico (UPR) Community Hospital were interviewed as part of our study.Of the five key resiliency components, three domains were notably weak with respect to UPR resiliency. Prior to the Hurricane, key personnel at the UPR hospital were unaware of the limited capacity of back-up generators at hospitals and were ill-prepared to transfer ICU patients to appropriate hospitals. Post Hurricane, the hospital faced self-regulation challenges when triaging the provision of Hurricane-related emergency services with delivering core health services, in particular for patients with chronic conditions. Finally, during and after the Hurricane, integration of patient care coordination between the UPR hospital ambulances, neighboring hospitals, and national and state government was suboptimal. The two remaining resiliency factors, addressing diverse needs and system adaptiveness in a time of crisis, were seen as strengths.Hurricane Maria exposed weaknesses in the Puerto Rican health system, notably the lack of awareness about the limited capacity of backup generators, poor patient care coordination, and interruption of medical care for patients with chronic conditions. As in other countries, the current COVID epidemic is taxing the capacity of the Puerto Rico health system, which could increase the likelihood of another health system collapse should another hurricane hit the island. Therefore, a resilience framework is a useful tool to help health systems identify areas of improvement in preparation for possible natural disasters.

  View details for DOI 10.1101/2020.09.20.20198531

  View details for PubMedID 32995821

  View details for PubMedCentralID PMC7523162

• Hyaluronan is abundant in COVID-19 respiratory secretions. medRxiv : the preprint server for health sciences Kaber, G., Kratochvil, M. J., Burgener, E. B., Peltan, E. L., Barlow, G., Yang, S., Nicolls, M. R., de Jesus Perez, V., Rosser, J. I., Wardle, A. J., Kalinowski, A., Ozawa, M. G., Regula, D. P., Nagy, N., Heilshorn, S. C., Milla, C. E., Rogers, A. J., Bollyky, P. L. 2020

  Abstract

  COVID-19 respiratory infections are associated with copious, adherent respiratory secretions that prolong chronic ventilation and contribute to the morbidity and mortality caused by the disease. We hypothesized that hyaluronan, an extracellular matrix glycosaminoglycan produced at sites of active inflammation that promotes edema in other settings, might be a component of these secretions. To interrogate this, we examined the respiratory secretions collected from eight intubated patients with COVID-19, six control patients with cystic fibrosis (CF), a different respiratory disease also associated with thick adherent secretions, and eight healthy controls. In this sample set we found that hyaluronan content is increased approximately 20-fold in both CF and COVID-19 patients compared to healthy controls. The hyaluronan in COVID-19 samples was comprised of low-molecular weight fragments, the hyaluronan form most strongly linked with pro-inflammatory functions. Hyaluronan is similarly abundant in histologic sections from cadaveric lung tissue from COVID-19 patients. These findings implicate hyaluronan in the thick respiratory secretions characteristic of COVID-19 infection. Therapeutic strategies targeting hyaluronan should be investigated further for potential use in patients with COVID-19.

  View details for DOI 10.1101/2020.09.11.20191692

  View details for PubMedID 32935110

  View details for PubMedCentralID PMC7491514

• Pulmonary Vein Stenosis and Pulmonary Hypertension Following a Catheter-Based Radiofrequency Ablation for Atrial Fibrillation: A Case Report. The American journal of case reports Thomas, C. A., Cruz Morel, K. J., Viswanathan, M. N., de Jesus Perez, V. A. 2020; 21: e924709

  Abstract

  BACKGROUND Pulmonary vein (PV) stenosis is a rare condition characterized by progressive luminal size reduction of one or more pulmonary veins (PVs), which can increase postcapillary pressure resulting in shortness of breath, cough, hemoptysis, and pulmonary hypertension (PH). The diagnosis of PV stenosis requires a high degree of suspicion. PV stenosis is a rare but recognized complication of catheter-based radiofrequency ablation (RFA) for atrial fibrillation (AF). CASE REPORT We present a case of a 78-year-old man who underwent a surgical MAZE procedure followed by catheter-based RFA to treat AF. He subsequently developed shortness of breath, exercise limitation, and PH. The patient was ultimately diagnosed with PV stenosis, which was a sequela of the RFA and the cause of his PH. The patient was treated by stenting of his PV, with improvement in his exercise capacity and PH. Follow-up imaging showed improved pulmonary blood flow and reduced pulmonary pressures. CONCLUSIONS We conclude that PV stenosis should be high in the differential as the cause of dyspnea in patients with PH and a previous history of RFA for AF management. Early recognition and treatment can prevent complete occlusion of the affected PV and lead to an improvement in the patient's symptoms and quality of life.

  View details for DOI 10.12659/AJCR.924709

  View details for PubMedID 32844783

• THE CANCER HYPOTHESIS OF PULMONARY ARTERIAL HYPERTENSION: THE NEXT TEN YEARS. American journal of physiology. Lung cellular and molecular physiology Condon, D., Agarwal, S., Chakraborty, A., de Jesus Perez, V. A. 2020

  View details for DOI 10.1152/ajplung.00057.2020

  View details for PubMedID 32186209

• Systemic hypoxia led to little retinal neuronal loss and dramatic optic nerve glial response. Experimental eye research Mesentier Louro, L. A., Shariati, M. A., Dalal, R. n., Camargo, A. n., Kumar, V. n., Shamskhou, E. A., de Jesus Perez, V. n., Liao, Y. J. 2020: 107957

  Abstract

  Vision loss is a devastating consequence of systemic hypoxia, but the cellular mechanisms are unclear. We investigated the impact of acute hypoxia in the retina and optic nerve. We induced systemic hypoxia (10% O2) in 6-8w mice for 48 h and performed in vivo imaging using optical coherence tomography (OCT) at baseline and after 48 h to analyze structural changes in the retina and optic nerve. We analyzed glial cellular and molecular changes by histology and immunofluorescence and the impact of pretreatment with 4-phenylbutyric acid (4-PBA) in oligodendroglia survival. After 48 h hypoxia, we found no change in ganglion cell complex thickness and no loss of retinal ganglion cells. Despite this, there was significantly increased expression of CCAAT-enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum stress, in the retina and optic nerve. In addition, hypoxia induced obvious increase of GFAP expression in the anterior optic nerve, where it co-localized with CHOP, and significant loss of Olig2+ oligodendrocytes. Pretreatment with 4-PBA, which has been shown to reduce endoplasmic reticulum stress, rescued total Olig2+ oligodendrocytes and increased the pool of mature (CC-1+) but not of immature (PDGFRa+) oligodendrocytes. Consistent with a selective vulnerability of the retina and optic nerve in hypoxia, the most striking changes in the 48 h murine model of hypoxia were in glial cells in the optic nerve, including increased CHOP expression in the astrocytes and loss of oligodendrocytes. Our data support a model where glial dysfunction is among the earliest events in systemic hypoxia - suggesting that glia may be a novel target in treatment of hypoxia.

  View details for DOI 10.1016/j.exer.2020.107957

  View details for PubMedID 32032627

• Pulmonary Vascular Fellowship Training to Promote Excellence in PH Clinical Care: The Stanford Perspective. American College of Cardiology (acc.org) Kudelko, K., Zamanian, R., de Jesus Perez, V. 2020
• Drug- and toxin-induced pulmonary arterial hypertension: Current state of the literature Global Cardiology Science and Practice Ramirez III, R., Thomas, C., Anderson, R., Bernardo, R., Al-Motarreb, A., Al-Suwaidi, J., Zamnanian, R., de Jesus Perez, V. 2020; 2019 (3)

  View details for DOI 10.21542/gcsp.2019.19

• Hiding in Plain Sight: The Basement Membrane in Pulmonary Vascular Remodeling. American journal of respiratory cell and molecular biology Chakraborty, A. n., de Jesus Perez, V. A. 2020

  View details for DOI 10.1165/rcmb.2020-0100ED

  View details for PubMedID 32275838

• Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Karnes, J. H., Wiener, H. W., Schwantes-An, T. H., Natarajan, B. n., Sweatt, A. J., Chaturvedi, A. n., Arora, A. n., Batai, K. n., Nair, V. n., Steiner, H. E., Giles, J. B., Yu, J. n., Hosseini, M. n., Pauciulo, M. W., Lutz, K. A., Coleman, A. W., Feldman, J. n., Vanderpool, R. n., Tang, H. n., Garcia, J. G., Yuan, J. X., Kittles, R. n., de Jesus Perez, V. n., Zamanian, R. T., Rischard, F. n., Tiwari, H. K., Nichols, W. C., Benza, R. L., Desai, A. A. 2020

  Abstract

  Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Group 1 PAH patients were included from two national registries with genome-wide data and two local cohorts and further incorporated in a global meta-analysis. Hazard ratios (HRs) were calculated for transplant-free all-cause mortality in Hispanics with Non-Hispanic whites (NHWs) as the reference group. Odds ratios (ORs) for inpatient-specific mortality in PAH patients were also calculated for race/ethnic groups from an additional National Inpatient Sample (NIS) dataset, not included in the meta-analysis.After covariate adjustment, self-reported Hispanics (n=290) exhibited significantly reduced mortality versus NHWs (n=1970) after global meta-analysis (HR 0.60[0.41-0.87], p=0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR 0.48[0.23-1.01], p=0.053) in the two national registries. Finally, in the NIS, an inpatient mortality benefit was also observed for Hispanics (n=1524) versus NHWs (n=8829; OR 0.65[0.50-0.84], p=0.001). An inpatient mortality benefit was observed for Native Americans (n=185; OR 0.38[0.15-0.93], p=0.034).This study demonstrates a reproducible survival benefit for Hispanic Group 1 PAH patients in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

  View details for DOI 10.1164/rccm.201907-1447OC

  View details for PubMedID 31916850

• Portopulmonary Hypertension: From Bench to Bedside Frontiers in Medicine Thomas , C., Ginskii, V., de Jesus Perez, V., Sahay, S. 2020

  View details for DOI 10.3389/fmed.2020.569413

• Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension. The European respiratory journal Amsallem, M. n., Sweatt, A. J., Arthur Ataam, J. n., Guihaire, J. n., Lecerf, F. n., Lambert, M. n., Ghigna, M. R., Ali, M. K., Mao, Y. n., Fadel, E. n., Rabinovitch, M. n., de Jesus Perez, V. n., Spiekerkoetter, E. n., Mercier, O. n., Haddad, F. n., Zamanian, R. T. 2020

  Abstract

  No prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort) and 76 patients (validation cohort). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, New York Heart Association NYHA class and NT-proBNP] and Stanford score [RV end-systolic remodelling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Biomarkers expressions were measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant, or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk for heart failure who warrant closer follow-up and intensified therapy.

  View details for DOI 10.1183/13993003.02428-2020

  View details for PubMedID 33334941

• Clinical Differences and Outcomes between Methamphetamine-Associated and Idiopathic Pulmonary Arterial Hypertension in the PHAR. Annals of the American Thoracic Society Kolaitis, N. A., Zamanian, R. T., de Jesus Perez, V. A., Badesch, D. B., Benza, R. L., Burger, C. D., Chakinala, M. M., Elwing, J. M., Feldman, J. n., Lammi, M. R., Mathai, S. C., McConnell, J. W., Presberg, K. W., Robinson, J. C., Sager, J. n., Shlobin, O. A., Simon, M. A., Kawut, S. M., Glidden, D. V., Singer, J. P., De Marco, T. n. 2020

  Abstract

  Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH, and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH.To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the US, hemodynamics, health-related quality of life, PAH-specific treatment, and health care utilization.The Pulmonary Hypertension Association Registry is a US-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, six-minute walk distance, therapy, and health care utilization. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations.Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the Western US. The Meth-APAH group was younger, had a poorer socioeconomic status, and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater, 95%CI: 0.07 to 0.37), and worse PAH-specific (emPHasis-10) health-related quality of life (-5.4, 95%CI: -8.1 to -2.8). There was no difference in dual combination therapy, however, participants with Meth-APAH were less likely to be initiated on triple therapy (OR: 0.43, 95%CI 0.24 to 0.77) or parenteral therapy (OR: 0.10, 95%CI 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (IRR: 2.30, 95%CI 1.71 to 3.11) and more likely to be hospitalized (IRR: 1.42, 95%CI 1.10 to 1.83).Meth-APAH represents a unique clinical phenotype of PAH, most common in the Western US. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.

  View details for DOI 10.1513/AnnalsATS.202007-774OC

  View details for PubMedID 33064950

• Mechanics of right ventricular dysfunction in pulmonary arterial hypertension and heart failure with preserved ejection fraction. Cardiovascular diagnosis and therapy Bernardo, R. J., Haddad, F. n., Couture, E. J., Hansmann, G. n., de Jesus Perez, V. A., Denault, A. Y., de Man, F. S., Amsallem, M. n. 2020; 10 (5): 1580–1603

  Abstract

  Right ventricular (RV) dysfunction is the most important determinant of survival in patients with pulmonary hypertension (PH). The manifestations of RV dysfunction not only include changes in global RV systolic function but also abnormalities in the pattern of contraction and synchrony. The effects of PH on the right ventricle have been mainly studied in patients with pulmonary arterial hypertension (PAH). However, with the demographic shift towards an aging population, heart failure with preserved ejection fraction (HFpEF) has become an important etiology of PH in recent years. There are significant differences in RV mechanics, function and adaptation between patients with PAH and HFpEF (with or without PH), which are related to different patterns of remodeling and dysfunction. Due to the unique features of the RV chamber, its connection with the main pulmonary artery and the pulmonary circulation, an understanding of the mechanics of RV function and its clinical significance is mandatory for both entities. In this review, we describe the mechanics of the pressure overloaded right ventricle. We review the different mechanical components of RV dysfunction and ventricular dyssynchrony, followed by insights via analysis of pressure-volume loop, energetics and novel blood flow patterns, such as vortex imaging. We conduct an in-depth comparison of prevalence and characteristics of RV dysfunction in HFpEF and PAH, and summarize key outcome studies. Finally, we provide a perspective on needed and expected future work in the field of RV mechanics.

  View details for DOI 10.21037/cdt-20-479

  View details for PubMedID 33224775

  View details for PubMedCentralID PMC7666917

• Racial and ethnic disparities in PAH Pulmonary Hypertension: Controversial and Emerging Topics Cruz Morel, K., Talwar, A., de Jesus Perez, V. Springer Nature. 2020; 1st: 197–202

  View details for DOI 10.1007/978-3-030-52787-7

• In Defense of the Nucleus: NUDT1 and Oxidative DNA Damage in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Agarwal, S. n., de Jesus Perez, V. A. 2020

  View details for DOI 10.1164/rccm.202009-3706ED

  View details for PubMedID 33095993

• The 6th World Symposium on Pulmonary Hypertension: what's old is new. F1000Research Condon, D. F., Nickel, N. P., Anderson, R. n., Mirza, S. n., de Jesus Perez, V. A. 2019; 8

  Abstract

  In February 2018, the 6th World Symposium on Pulmonary Hypertension (WSPH) brought together experts from various disciplines to review the most relevant clinical and scientific advances in the field of PH over the last 5 years. Based on careful review and discussions by members of the different task forces, major revisions were made on the hemodynamic definition for various forms of PH and new genes were added to the list of genetic markers associated with pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease. In addition, the use of risk stratification tools was encouraged as a strategy to reduce one-year mortality risk in PAH patients through early implementation of PAH therapies. While members of the medical community are still debating some of the proposed changes, the new WSPH guidelines advocate early diagnosis and initiation of combination therapy to reduce mortality and improve quality of life in patients with PH.

  View details for DOI 10.12688/f1000research.18811.1

  View details for PubMedID 31249672

  View details for PubMedCentralID PMC6584967

• Diagnosis and Management of Pulmonary Hypertension in the Modern Era: Insights from the 6th World Symposium. Pulmonary therapy Thomas, C. A., Anderson, R. J., Condon, D. F., de Jesus Perez, V. A. 2019

  Abstract

  The past 20 years have seen major advances in the diagnosis and management of pulmonary hypertension, a disease associated with significant morbidity and mortality. The 6th World Symposium in Pulmonary Hypertension (WSPH) took place in February 2018 and attempted to consolidate the current knowledge in the field into practical recommendations to help prioritize an action plan to improve patient outcomes and identify future research directions. In this review, we will summarize the highlights of the 6th WSPH proceedings, including revisions to the hemodynamic definitions and classification of the various types of pulmonary hypertension, genetic advances, approaches to risk stratification, and updated treatment algorithms.

  View details for DOI 10.1007/s41030-019-00105-5

  View details for PubMedID 32048239

• EpiHope for the Treatment of Pulmonary Arterial Hypertension: Selective vs Non-selective BET Inhibition. American journal of respiratory and critical care medicine Pullamsetti, S. S., de Jesus Perez, V. A. 2019

  Abstract

  ...

  View details for DOI 10.1164/rccm.201906-1235LE

  View details for PubMedID 31419389

• Clinical Outcomes of Inferior Vena Cava Filter in Complicated Pulmonary Embolism Pulmonary Circulation Htun, Z. M., Gul, M. H., Rigdon, J., de Jesus Perez, V. A. 2019: 2045894019882636

  Abstract

  Background: Previous observational studies suggest that inferior vena cava filter placement in pulmonary embolism patients complicated with congestive heart failure, mechanical ventilation, and shock may have a mortality benefit. We sought to analyze the survival benefits of inferior vena cava filter in pulmonary embolism patients complicated with acute myocardial infarction, acute respiratory failure, shock, or requiring treatment with thrombolytics. Methods: This retrospective observational study used hospital discharge data from the National Inpatient Sample Data (NIS). ICD-9-CM coding was used to identify complicated pulmonary embolism patients (N = 254,465) in NIS from 2002 to 2014, including the subgroups of acute myocardial infarction, acute respiratory failure, shock, and thrombolytics. Inferior vena cava filter recipients were 1:1 propensity score-matched on age, sex, race, deep vein thrombosis, Elixhauser comorbidities, and other pulmonary embolism comorbidities (45 covariates) to non-inferior vena cava filter recipients in complicated pulmonary embolism patients and separately in each subgroup. Clinical outcomes were compared between the inferior vena cava filter group and the non-inferior vena cava filter group. Results: Mortality rate in complicated pulmonary embolism patients with inferior vena cava filter placement was lower (20.9% vs. 33%; NNT = 8.28, 95% confidence interval (CI) 7.91-8.69, E-value = 2.53) and in the subgroups; acute myocardial infarction (17.9% vs. 30.1%; NNT = 8.19, 95% CI 7.52-8.92, E-value = 2.76), acute respiratory failure (19.5% vs. 29.7%; NNT = 9.76, 95% CI 8.67-11.16, E-value = 2.38), shock (30.7% vs. 47.1%; NNT = 6.08, 95% CI 5.73-6.47, E-value = 2.43), and with the use of thrombolytics (7% vs. 12.9 %; NNT 17.1, 95% CI 14.88-20.12, E-value = 3.01) (p < 0.001 for all). Conclusion: Inferior vena cava filter placement in pulmonary embolism complicated with acute myocardial infarction, acute respiratory failure, shock, or requiring thrombolytic therapy was associated with reduced mortality.

  View details for DOI 10.1177/2045894019882636

  View details for PubMedCentralID PMC6868584

• Diagnosis and Management of Pulmonary Hypertension in the Modern Era: Insights from the 6th World Symposium Pulmonary Therapy Thomas, C., Anderson, R., Condon, D., de Jesus Perez, V. 2019: 1-14

  View details for DOI 10.6084/m9.figshare.10304645.

• New and Emerging Therapies for Pulmonary Arterial Hypertension. Annual review of medicine Spiekerkoetter, E. n., Kawut, S. M., de Jesus Perez, V. A. 2019; 70: 45–59

  Abstract

  Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.

  View details for PubMedID 30216732

• EXPRESS: Myocardial Bridge - An Unrecognized Cause of Chest Pain in Pulmonary Arterial Hypertension. Pulmonary circulation Rajmohan, D. n., Sung, Y. K., Kudelko, K. n., Perez, V. i., Haddad, F. n., Tremmel, J. n., Schnittger, I. n., Zamanian, R. T., Spiekerkoetter, E. F. 2019: 2045894019860738

  View details for DOI 10.1177/2045894019860738

  View details for PubMedID 31187693

• EMAPII: A Key Player in HIV-Nef Induced Pulmonary Vasculopathy. American journal of respiratory cell and molecular biology Shamskhou, E. A., Verghese, L., Yuan, K., De Jesus Perez, V. A. 2018

  View details for PubMedID 30376353

• Pulmonary Vascular Complications of Liver Disease. American journal of respiratory and critical care medicine Lam, K., de Jesus Perez, V. 2018; 198 (3): P5-P6

  View details for DOI 10.1164/rccm.1983P5

  View details for PubMedID 30067088

• Career Development of Young Physician-Scientists in the Cardiovascular Sciences: Perspective and Advice From the Early Career Committee of the Cardiopulmonary, Critical Care, and Resuscitation Council of the American Heart Association. Circulation research Agarwal, S. n., Spiekerkoetter, E. n., Austin, E. D., de Jesus Perez, V. n., Dezfulian, C. n., Maron, B. A., Ryan, J. J., Starks, M. A., Yu, P. B., Bonnet, S. n., Perman, S. M. 2018; 122 (10): 1330–33

  View details for PubMedID 29748361

• PH Roundtable: Pulmonary Hypertension Roundtable: Clinical Experiences With Drug- and Toxin-Related PH Advances in Pulmonary Hypertension Bartolome, S., Zamanian, R., de Jesus Perez, V., Chin, K. 2018; 17 (2): 80-85

  View details for DOI 10.21693/1933-088X-17.2.80

• Stimulants and Pulmonary Arterial Hypertension: An Update Advances in Pulmonary Hypertension Ramirez III, R., de Jesus Perez, V., Zamanian, R. 2018; 17 (2)
• Methamphetamine and the risk of pulmonary arterial hypertension. Current opinion in pulmonary medicine Ramirez, R. L., Perez, V. D., Zamanian, R. T. 2018

  Abstract

  Methamphetamine is a highly addictive drug originally developed for the treatment of neuropsychiatric disorders. At present, the epidemic rise of illicit methamphetamine use has increased the number of patients living with medical complications. Our group has recently identified a definite association between methamphetamine use and pulmonary arterial hypertension (PAH), a life-threatening disease characterized by occlusive vasculopathy and progressive right heart failure. This review will discuss the evidence that links methamphetamine with PAH and how to approach the diagnosis and management of methamphetamine-associated pulmonary arterial hypertension (Meth-APAH) patients in clinic.Compared with idiopathic (I) PAH, Meth-APAH patients present with worse functional status, right ventricular dysfunction, and exercise tolerance. Despite therapy, the 5-year survival of Meth-APAH patients is significantly lower compared with IPAH. Genetic studies suggest that loss of function variants in genes involved in drug detoxification can increase susceptibility for methamphetamine-related vascular injury and trigger occlusive vasculopathy.PAH patients undergoing diagnostic evaluation should be screened for a history of current or past methamphetamine use. Pharmacovigilance should be implemented to monitor patients being treated with methamphetamine for neuropsychiatric disorders (e.g., attention-deficit hyperactivity disorder). More studies will be needed to identify which susceptibility factors increase risk of PAH in methamphetamine users.

  View details for PubMedID 30036313

• Long-Term Right Ventricular Adaptation to Postnatal Hyperoxia: Too Much of a Good Thing? American journal of respiratory cell and molecular biology Perez, V. i. 2017; 56 (5): 559-560

  View details for DOI 10.1165/rcmb.2016-0429ED

  View details for PubMedID 28459383

• MicroRNA and Cardiovascular Disease 2016. BioMed research international Yuan, L. Q., de Jesus Perez, V., Liao, X. B., Król, M., Yeh, C. H. 2017; 2017: 3780513

  View details for DOI 10.1155/2017/3780513

  View details for PubMedID 28428960

  View details for PubMedCentralID PMC5385911

• fibroblast-specific STAT3 signaling. FASEB journal Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. 2017; 31 (3): 868-881

  Abstract

  The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but the mechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)-dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox-mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3 knockdown postnatal mice-plus syngeneic fibroblast cell-transplant models-we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10-induced HA synthesis for regenerative wound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signaling were intact, the antifibrotic repair phenotype that is induced by IL-10 overexpression was abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatory mechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative, HA-rich wound extracellular matrix may lead to the development of innovative therapies to attenuate postnatal fibrosis in organ systems or diseases in which dysregulated inflammation and HA intersect.-Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.

  View details for DOI 10.1096/fj.201600856R

  View details for PubMedID 27903619

• Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-β in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. Arteriosclerosis, thrombosis, and vascular biology Tojais, N. F., Cao, A. n., Lai, Y. J., Wang, L. n., Chen, P. I., Alcazar, M. A., de Jesus Perez, V. n., Hopper, R. K., Rhodes, C. J., Bill, M. A., Sakai, L. Y., Rabinovitch, M. n. 2017

  Abstract

  We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly.Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cell and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assemblies were impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblast stimulated with BMP4 or TGFβ1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension.Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

  View details for PubMedID 28619995

• Inducible pluripotent stem cells and pulmonary arterial hypertension: the future is now! Stem cell investigation Lopez, M. R., de Jesus Perez, V. n. 2017; 4: 53

  View details for PubMedID 28725649

  View details for PubMedCentralID PMC5503909

• EXPRESS: Endothelial Dysfunction in Pulmonary Arterial Hypertension: An Evolving Landscape (2017 Grover Conference Series). Pulmonary circulation Ranchoux, B., Harvey, L. D., Ayon, R. J., Babicheva, A., Bonnet, S., Chan, S. Y., Yuan, J., Perez, V. i. 2017: 2045893217752912

  View details for DOI 10.1177/2045893217752912

  View details for PubMedID 29283043

• The emerging role of angiogenesis in adaptive and maladaptive right ventricular remodeling in pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology Frump, A. L., Bonnet, S. n., de Jesus Perez, V. A., Lahm, T. n. 2017: ajplung.00374.2017

  Abstract

  Right ventricular (RV) function is the primary prognostic factor for both morbidity and mortality in pulmonary hypertension (PH). RV hypertrophy is initially an adaptive physiological response to increased overload; however, with persistent and/or progressive afterload increase, this response frequently transitions to more pathological maladaptive remodeling. The mechanisms and disease processes underlying this transition are mostly unknown. Angiogenesis has recently emerged as a major modifier of RV adaptation in the setting of pressure overload. A novel paradigm has emerged that suggests that angiogenesis and angiogenic signaling are required for RV adaptation to afterload increases, and that impaired and/or insufficient angiogenesis is a major driver of RV decompensation. Here we summarize our current understanding of the concepts of maladaptive and adaptive RV remodeling, discuss the current literature on angiogenesis in the adapted and failing RV, and identify potential therapeutic approaches targeting angiogenesis in RV failure.

  View details for PubMedID 29097426

• In Vivo Study of Human Endothelial-Pericyte Interaction Using the Matrix Gel Plug Assay in Mouse. Journal of visualized experiments : JoVE Yuan, K., Orcholski, M. E., Huang, N. F., de Jesus Perez, V. A. 2016

  Abstract

  Angiogenesis is the process by which new blood vessels are formed from existing vessels. New vessel growth requires coordinated endothelial cell proliferation, migration, and alignment to form tubular structures followed by recruitment of pericytes to provide mural support and facilitate vessel maturation. Current in vitro cell culture approaches cannot fully reproduce the complex biological environment where endothelial cells and pericytes interact to produce functional vessels. We present a novel application of the in vivo matrix gel plug assay to study endothelial-pericyte interactions and formation of functional blood vessels using severe combined immune deficiency mutation (SCID) mice. Briefly, matrix gel is mixed with a solution containing endothelial cells with or without pericytes followed by injection into the back of anesthetized SCID mice. After 14 days, the matrix gel plugs are removed, fixed and sectioned for histological analysis. The length, number, size and extent of pericyte coverage of mature vessels (defined by the presence of red blood cells in the lumen) can be quantified and compared between experimental groups using commercial statistical platforms. Beyond its use as an angiogenesis assay, this matrix gel plug assay can be used to conduct genetic studies and as a platform for drug discovery. In conclusion, this protocol will allow researchers to complement available in vitro assays for the study of endothelial-pericyte interactions and their relevance to either systemic or pulmonary angiogenesis.

  View details for DOI 10.3791/54617

  View details for PubMedID 28060266

• Modified High Molecular Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance. American journal of respiratory cell and molecular biology Gebe, J. A., Yadava, K., Ruppert, S. M., Marshall, P., Hill, P., Falk, B. A., Sweere, J. M., Han, H., Kaber, G., Medina, C., Mikecz, K., Ziegler, S. F., Balaji, S., Keswani, S. G., de Jesus Perez, V. A., Butte, M. J., Nadeau, K., Altemeier, W. A., Fanger, N., Bollyky, P. L. 2016: -?

  Abstract

  The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-κB signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.

  View details for PubMedID 27598620

• Novel signaling pathways in pulmonary arterial hypertension (2015 Grover Conference Series). Pulmonary circulation Awad, K. S., West, J. D., de Jesus Perez, V., Maclean, M. 2016; 6 (3): 285-294

  Abstract

  The proliferative endothelial and smooth muscle cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Mutations in bone morphogenetic protein type 2 receptor (BMPR2) have been identified as the most common genetic cause of PAH and females with BMPR2 mutations are 2.5 times as likely to develop heritable forms of PAH than males. Higher levels of estrogen have also been observed in males with PAH, implicating sex hormones in PAH pathogenesis. Recently, the estrogen metabolite 16α-OHE1 (hydroxyestrone) was implicated in the regulation of miR29, a microRNA involved in modulating energy metabolism. In females, decreased miR96 enhances serotonin's effect by upregulating the 5-hydroxytryptamine 1B (5HT1B) receptor. Because PAH is characterized as a quasi-malignant disease, likely due to BMPR2 loss of function, altered signaling pathways that sustain this cancer-like phenotype are being explored. Extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinases (MAPKs) play a critical role in proliferation and cell motility, and dysregulated MAPK signaling is observed in various experimental models of PAH. Wnt signaling pathways preserve pulmonary vascular homeostasis, and dysregulation of this pathway could contribute to limited vascular regeneration in response to injury. In this review, we take a closer look at sex, sex hormones, and the interplay between sex hormones and microRNA regulation. We also focus on MAPK and Wnt signaling pathways in the emergence of a proproliferative, antiapoptotic endothelial phenotype, which then orchestrates an angioproliferative process of vascular remodeling, with the hope of developing novel therapies that could reverse the phenotype.

  View details for DOI 10.1086/688034

  View details for PubMedID 27683605

• Loss of PPAR? in endothelial cells leads to impaired angiogenesis. Journal of cell science Vattulainen-Collanus, S., Akinrinade, O., Li, M., Koskenvuo, M., Li, C. G., Rao, S. P., de Jesus Perez, V., Yuan, K., Sawada, H., Koskenvuo, J. W., Alvira, C., Rabinovitch, M., Alastalo, T. 2016; 129 (4): 693-705

  Abstract

  Tie2 promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPARγ) in mice leads to osteopetrosis and pulmonary arterial hypertension. Vascular disease is associated with loss of PPARγ in pulmonary microvascular endothelial cells (PMVEC), we evaluated the role of PPARγ in PMVEC functions, such as angiogenesis and migration. The role of PPARγ in angiogenesis was evaluated in Tie2CrePPARγ(flox/flox) and wild type (WT) mice, and in mouse and human PMVECs. RNA-sequencing and bioinformatic approaches were utilized to reveal angiogenesis-associated targets for PPARγ. Tie2CrePPARγ(flox/flox) mice showed an impaired angiogenic capacity. Analysis of endothelial progenitor-like cells using bone marrow transplantation combined with evaluation of isolated PMVECs revealed that loss of PPARγ attenuates the migration and angiogenic capacity of mature PMVECs. PPARγ-deficient human PMVECs showed a similar migration defect in culture. Bioinformatic and experimental analyses revealed E2F1 as a novel target of PPARγ in the regulation of PMVEC migration. Disruption of the PPARγ-E2F1 axis was associated with a dysregulated Wnt pathway related to the GSK3β interaction protein. In conclusion, PPARγ plays an important role in sustaining angiogenic potential in mature PMVECs through E2F1-mediated gene regulation.

  View details for DOI 10.1242/jcs.169011

  View details for PubMedID 26743080

• Recent advances in the management of pulmonary arterial hypertension. F1000Research Tsai, H., Sung, Y. K., de Jesus Perez, V. 2016; 5: 2755-?

  Abstract

  Over the past 20 years, there has been an explosion in the development of therapeutics to treat pulmonary arterial hypertension (PAH), a rare but life-threatening disorder associated with progressive elevation of pulmonary pressures and severe right heart failure. Recently, the field has seen the introduction of riociguat, a soluble guanylate cyclase stimulator, a new endothelin receptor antagonist (macitentan), and oral prostanoids (treprostinil and selexipag). Besides new drugs, there have been significant advances in defining the role of upfront combination therapy in treatment-naïve patients as well as proposed methods to deliver systemic prostanoids by use of implantable pumps. In this review, we will touch upon the most important developments in PAH therapeutics over the last three years and how these have changed the guidelines for the treatment of PAH. These exciting developments herald a new era in the treatment of PAH which will be punctuated by the use of more clinically relevant endpoints in clinical research trials and a novel treatment paradigm that may involve upfront double- or triple-combination therapy. We anticipate that the future will make use of these strategies to test the efficacy of upcoming new drugs that aspire to reduce disease progression and improve survival in patients afflicted with this devastating disease.

  View details for PubMedID 27990270

• First among Equals: Nerve Growth Factor in the Pathogenesis of Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine de Jesus Perez, V. A. 2015; 192 (3): 274-275

  View details for DOI 10.1164/rccm.201504-0807ED

  View details for PubMedID 26230231

• Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension. Cardiovascular research Chang, Y., Tseng, C., Tannenberg, P., Eriksson, L., Yuan, K., de Jesus Perez, V. A., Lundberg, J., Lengquist, M., Botusan, I. R., Catrina, S., Tran, P., Hedin, U., Tran-Lundmark, K. 2015; 107 (1): 20-31

  Abstract

  Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study, we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH.In normoxia, Hspg2(Δ3/Δ3) mice, deficient in perlecan HS, had reduced pericytes and muscularization of intra-acinar vessels. Pulmonary angiography revealed a peripheral perfusion defect. Despite these abnormalities, right ventricular systolic pressure (RVSP) and myocardial mass remained normal. After 4 weeks of hypoxia, increases in the proportion of muscularized vessels, RVSP, and right ventricular hypertrophy were significantly less in Hspg2(Δ3/Δ3) compared with wild type. The early phase of hypoxia induced a significantly lower increase in fibroblast growth factor receptor-1 (FGFR1) protein level and receptor phosphorylation, and reduced pulmonary artery smooth muscle cell (PASMC) proliferation in Hspg2(Δ3/Δ3). At 4 weeks, FGF2 mRNA and protein were also significantly reduced in Hspg2(Δ3/Δ3) lungs. Ligand and carbohydrate engagement assay showed that perlecan HS is required for HS-FGF2-FGFR1 ternary complex formation. In vitro, proliferation assays showed that PASMC proliferation is reduced by selective FGFR1 inhibition. PASMC adhesion to fibronectin was higher in Hspg2(Δ3/Δ3) compared with wild type.Perlecan HS chains are important for normal vascular arborization and recruitment of pericytes to pulmonary vessels. Perlecan HS deficiency also attenuates hypoxia-induced PH, where the underlying mechanisms involve impaired FGF2/FGFR1 interaction, inhibition of PASMC growth, and altered cell-matrix interactions.

  View details for DOI 10.1093/cvr/cvv143

  View details for PubMedID 25952902

• Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection AMERICAN JOURNAL OF TRANSPLANTATION Jiang, X., Nguyen, T. T., Tian, W., Sung, Y. K., Yuan, K., Qian, J., Rajadas, J., Sallenave, J., Nickel, N. P., Perez, V. d., RABINOVITCH, M., Nicolls, M. R. 2015; 15 (7): 1768-1781

  Abstract

  The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling.

  View details for DOI 10.1111/ajt.13189

  View details for Web of Science ID 000356494300013

  View details for PubMedID 25727073

• Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension. JACC. Cardiovascular imaging Haddad, F., Spruijt, O. A., Denault, A. Y., Mercier, O., Brunner, N., Furman, D., Fadel, E., Bogaard, H. J., Schnittger, I., Vrtovec, B., Wu, J. C., de Jesus Perez, V., Vonk-Noordegraaf, A., Zamanian, R. T. 2015; 8 (6): 627-638

  Abstract

  This study sought to determine whether a simple score combining indexes of right ventricular (RV) function and right atrial (RA) size would offer good discrimination of outcome in patients with pulmonary arterial hypertension (PAH).Identifying a simple score of outcome could simplify risk stratification of patients with PAH and potentially lead to improved tailored monitoring or therapy.We recruited patients from both Stanford University (derivation cohort) and VU University Medical Center (validation cohort). The composite endpoint for the study was death or lung transplantation. A Cox proportional hazard with bootstrap CI adjustment model was used to determine independent correlates of death or transplantation. A predictive score was developed using the beta coefficients of the multivariable models.For the derivation cohort (n = 95), the majority of patients were female (79%), average age was 43 ± 11 years, mean pulmonary arterial pressure was 54 ± 14 mm Hg, and pulmonary vascular resistance index was 25 ± 12 Wood units m(2). Over an average follow-up of 5 years, the composite endpoint occurred in 34 patients, including 26 deaths and 8 patients requiring lung transplant. On multivariable analysis, RV systolic dysfunction grade (hazard ratio [HR]: 3.4 per grade; 95% confidence interval [CI]: 2.0 to 7.8; p < 0.001), severe RA enlargement (HR: 3.0; 95% CI: 1.3 to 8.1; p = 0.009), and systemic blood pressure <110 mm Hg (HR: 3.3; 95% CI: 1.5 to 9.4; p < 0.001) were independently associated with outcome. A right heart (RH) score constructed on the basis of these 3 parameters compared favorably with the National Institutes of Health survival equation (0.88; 95% CI: 0.79 to 0.94 vs. 0.60; 95% CI: 0.49 to 0.71; p < 0.001) but was not statistically different than the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) score c-statistic of 0.80 (95% CI: 0.69 to 0.88) with p = 0.097. In the validation cohort (n = 87), the RH score remained the strongest independent correlate of outcome.In patients with prevalent PAH, a simple RH score may offer good discrimination of long-term outcome.

  View details for DOI 10.1016/j.jcmg.2014.12.029

  View details for PubMedID 25981508

• Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension. American journal of physiology. Lung cellular and molecular physiology Helenius, M. H., Vattulainen, S., Orcholski, M., Aho, J., Komulainen, A., Taimen, P., Wang, L., de Jesus Perez, V. A., Koskenvuo, J. W., Alastalo, T. 2015; 308 (10): L1046-57

  Abstract

  Endothelial cell (EC) dysfunction plays a role in the pathobiology of occlusive vasculopathy in pulmonary arterial hypertension (PAH). Purinergic signalling pathways, which consists of extracellular nucleotide and nucleoside mediated cell signalling through specific receptors, are known to be important regulators of vascular tone and remodelling. Therefore, we hypothesized that abnormalities in the vascular purinergic microenvironment are associated with PAH. Enzymatic clearance is crucial to terminate unnecessary cell activation; one of the most abundantly expressed enzyme on EC surface is E-NTPDase1/CD39, which hydrolyses ATP and ADP to AMP. We used histological samples from patients and healthy donors, radioisotope labelled substrates to measure ecto-enzyme activity, and a variety of in vitro approaches to study the role of CD39 in PAH. Immunohistochemistry on human idiopathic PAH patients' lungs demonstrated that CD39 was significantly down-regulated in the endothelium of diseased small arteries. Similarly, CD39 expression and activity were decreased in cultured pulmonary ECs from IPAH patients. Suppression of CD39 in vitro resulted in EC phenotypic switch that gave rise to apoptosis resistant pulmonary arterial endothelial cells, and promoted a microenvironment that induced vascular smooth muscle cell migration. We also identified that the ATP receptor P2Y11 is essential for ATP-mediated EC survival. Furthermore, we report that apelin, a known regulator of pulmonary vascular homeostasis, can potentiate the activity of CD39 both in vitro and in vivo. We conclude that sustained attenuation of CD39 activity through ATP accumulation is tightly linked to vascular dysfunction and remodelling in PAH and could represent a novel target for therapy.

  View details for DOI 10.1152/ajplung.00340.2014

  View details for PubMedID 25820525

• MicroRNA and Cardiovascular Disease BIOMED RESEARCH INTERNATIONAL Liao, X., Perez, V. A., Krol, M., Yeh, C., Yuan, L. 2015

  View details for DOI 10.1155/2015/734380

  View details for Web of Science ID 000358880300001

  View details for PubMedID 26266261

• Current Clinical Management of Pulmonary Arterial Hypertension CIRCULATION RESEARCH Zamanian, R. T., Kudelko, K. T., Sung, Y. K., Perez, V. D., Liu, J., Spiekerkoetter, E. 2014; 115 (1): 131-147

  Abstract

  During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.

  View details for DOI 10.1161/CIRCRESAHA.115.303827

  View details for Web of Science ID 000337738900016

• Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery. Pulmonary circulation Brunner, N., de Jesus Perez, V. A., Richter, A., Haddad, F., Denault, A., Rojas, V., Yuan, K., Orcholski, M., Liao, X. 2014; 4 (1): 10-24

  Abstract

  Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population.

  View details for DOI 10.1086/674885

  View details for PubMedID 25006417

• Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. journal of experimental medicine Sawada, H., Saito, T., Nickel, N. P., Alastalo, T., Glotzbach, J. P., Chan, R., Haghighat, L., Fuchs, G., Januszyk, M., Cao, A., Lai, Y., Perez, V. d., Kim, Y., Wang, L., Chen, P., Spiekerkoetter, E., Mitani, Y., Gurtner, G. C., Sarnow, P., Rabinovitch, M. 2014; 211 (2): 263-280

  Abstract

  Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.

  View details for DOI 10.1084/jem.20111741

  View details for PubMedID 24446489

• FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. journal of clinical investigation Spiekerkoetter, E., Tian, X., Cai, J., Hopper, R. K., Sudheendra, D., Li, C. G., El-Bizri, N., Sawada, H., Haghighat, R., Chan, R., Haghighat, L., de Jesus Perez, V., Wang, L., Reddy, S., Zhao, M., Bernstein, D., Solow-Cordero, D. E., Beachy, P. A., Wandless, T. J., ten Dijke, P., Rabinovitch, M. 2013; 123 (8): 3600-3613

  Abstract

  Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

  View details for DOI 10.1172/JCI65592

  View details for PubMedID 23867624

• Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus. Journal of molecular medicine (Berlin, Germany) Jiang, X., Hsu, J. L., Tian, W., Yuan, K., Olcholski, M., de Jesus Perez, V., Semenza, G. L., Nicolls, M. R. 2013

  Abstract

  Microvascular ischemia and infections are associated with the development of chronic rejection following lung transplantation. The von Hippel-Lindau protein (VHL) controls protein levels of hypoxia-inducible factors (HIFs), regulates vascular repair, and improves tissue perfusion. Here, we studied the role of VHL in microvascular repair by orthotopically transplanting tracheas into mice with VHL haplodeficiency in Tie2 lineage cells. We showed that VHL haplodeficiency prolonged airway microvascular perfusion and promoted tissue blood flow through the production of the angiogenic factors, SDF-1 and angiopoietin 1. VHL-haplodeficient pulmonary endothelial cells exhibited increased angiogenic activity, resistance to serum deprivation-induced cell death, and enhanced microvascular repair. By contrast, in recipient mice with HIF-1α deficiency in Tie2 lineage cells, microvascular repair was significantly diminished and suggested that recipient-derived HIF-1α normally participates in the repair of alloimmune-mediated microvascular damage. To evaluate the translational impact of our findings, we compared VHL-haplodeficient mice with wild-type controls using a model of Aspergillus airway infection. In 83 % of the VHL-haplodeficient recipients, Aspergillus fumigatus was noninvasive in contrast to 75 % of wild-type mice in which the mold was deeply invasive. Our study demonstrated that stabilization of HIF-1α in angiogenic cells, through Tie2 cell VHL haplodeficiency, promoted airway microvascular regeneration and vascular normalization and thereby minimized tissue ischemia and hypoxia. By also mitigating the virulence of A. fumigatus, a common pathogen and itself a risk factor for the development of lung transplant rejection, the selective enhancement of HIF-1α expression has the prospect of offering several novel therapeutic effects to transplant recipients.Microvascular loss and prolonged ischemia occurs with acute rejection. Von Hippel-Lindau (VHL) protein controls hypoxia inducible factors (HIFs). In tracheal allografts, VHL haplodeficient Tie2 cells promote neovascularization. Reduced transplant ischemia limits Aspergillus invasion.

  View details for DOI 10.1007/s00109-013-1063-8

  View details for PubMedID 23797537

• MiR-133a modulates osteogenic differentiation of vascular smooth muscle cells. Endocrinology Liao, X. B., Zhang, Z. Y., Yuan, K., Liu, Y., Feng, X., Cui, R. R., Hu, Y. R., Yuan, Z. S., Gu, L., Li, S. J., Mao, D. A., Lu, Q., Zhou, X. M., de Jesus Perez, V. A., Yuan, L. Q. 2013

  Abstract

  Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease and peripheral vascular disease. A hallmark of this pathological process is the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with β-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression and mineralized nodule formation. Conversely, the knockdown of miR-133a using a miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion and Runx2 expression. Runx2 was identified as a direct target of miR-133a by co-transfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3`-UTR sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2 knockdown cells, and the inhibition of osteogenic differentiation by pre-miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.

  View details for DOI 10.1210/en.2012-2236

  View details for PubMedID 23798596

• Understanding the pharmacokinetics of oral treprostinil in patients with pulmonary arterial hypertension. Journal of cardiovascular pharmacology de Jesus Perez, V. A. 2013; 61 (6): 471-473

  View details for DOI 10.1097/FJC.0b013e318294980e

  View details for PubMedID 23575261

• MicroRNAs: promising therapeutic targets for the treatment of pulmonary arterial hypertension. Expert opinion on therapeutic targets Yuan, K., Orcholski, M., Tian, X., Liao, X., de Jesus Perez, V. A. 2013; 17 (5): 557-564

  Abstract

  MicroRNAs (miRNAs) are small noncoding RNAs that not only regulate gene expression during normal development but can also be active players in several diseases. To date, several studies have demonstrated a possible role for specific miRNAs in the regulation of pulmonary vascular homeostasis suggesting that novel therapeutic agents which target these modulators of gene expression could serve to treat pulmonary arterial hypertension (PAH). AREAS COVERED: The characterization of miRNA-mediated gene modulation in the pulmonary circulation is expanding very rapidly. This review summarizes current relevant findings on the role of miRNAs in the pathogenesis of PAH and expands on the potential use of agents that target these molecules as future disease-modifying therapies. EXPERT OPINION: Further understanding of miRNA biology and function in the pulmonary circulation will serve to further enhance our understanding of their contribution to the pathogenesis of PAH. The implementation of a systems biology approach will help accelerate the discovery of miRNAs that influence angiogenesis and cellular responses to vascular injury. Experimental characterization of these miRNAs using in vitro and in vivo methods will be required to validate the biological roles of these miRNAs prior to the consideration of their use as therapeutic targets in future clinical trials.

  View details for DOI 10.1517/14728222.2013.765863

  View details for PubMedID 23379818

• A case of recurrent pericardial constriction presenting with severe pulmonary hypertension Pulmonary Circulation Nathan Brunner, Krithika Ramachandran, Kristina T. Kudelko, Yon K. Sung, Edda Spiekerkoetter, Phillip C. Yang, Roham T. Zamanian, Vinicio de Jesus Perez 2013; 3 (2): 436-439
• Effectiveness of YouTube as a Source of Medical Information on Heart Transplantation. Interactive journal of medical research Chen, H., Hu, Z., Zheng, X., Yuan, Z., Xu, Z., Yuan, L., Perez, V. A., Yuan, K., Orcholski, M., Liao, X. 2013; 2 (2)

  Abstract

  In this digital era, there is a growing tendency to use the popular Internet site YouTube as a new electronic-learning (e-learning) means for continuing medical education. Heart transplantation (HTx) remains the most viable option for patients with end-stage heart failure or severe coronary artery disease. There are plenty of freely accessible YouTube videos providing medical information about HTx.The aim of the present study is to determine the effectiveness of YouTube as an e-learning source on HTx.In order to carry out this study, YouTube was searched for videos uploaded containing surgical-related information using the four keywords: (1) "heart transplantation", (2) "cardiac transplantation", (3) "heart transplantation operation", and (4) "cardiac transplantation operation". Only videos in English (with comments or subtitles in English language) were included. Two experienced cardiac surgeons watched each video (N=1800) and classified them as useful, misleading, or recipients videos based on the HTx-relevant information. The kappa statistic was used to measure interobserver variability. Data was analyzed according to six types of YouTube characteristics including "total viewership", "duration", "source", "days since upload", "scores" given by the viewers, and specialized information contents of the videos.A total of 342/1800 (19.00%) videos had relevant information about HTx. Of these 342 videos, 215 (62.8%) videos had useful information about specialized knowledge, 7/342 (2.0%) were found to be misleading, and 120/342 (35.1%) only concerned recipients' individual issues. Useful videos had 56.09% of total viewership share (2,175,845/3,878,890), whereas misleading had 35.47% (1,375,673/3,878,890). Independent user channel videos accounted for a smaller proportion (19% in total numbers) but might have a wider impact on Web viewers, with the highest mean views/day (mean 39, SD 107) among four kinds of channels to distribute HTx-related information.YouTube videos on HTx benefit medical professionals by providing a substantial amount of information. However, it is a time-consuming course to find high-quality videos. More authoritative videos by trusted sources should be posted for dissemination of reliable information. With an improvement of ranking system and content providers in future, YouTube, as a freely accessible outlet, will help to meet the huge informational needs of medical staffs and promote medical education on HTx.

  View details for DOI 10.2196/ijmr.2669

  View details for PubMedID 24263225

  View details for PubMedCentralID PMC3841345

• Safety and efficacy of transition from systemic prostanoids to inhaled treprostinil in pulmonary arterial hypertension. American journal of cardiology de Jesus Perez, V. A., Rosenzweig, E., Rubin, L. J., Poch, D., Bajwa, A., Park, M., Jain, M., Bourge, R. C., Kudelko, K., Spiekerkoetter, E., Liu, J., Hsi, A., Zamanian, R. T. 2012; 110 (10): 1546-1550

  Abstract

  Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.

  View details for DOI 10.1016/j.amjcard.2012.07.012

  View details for PubMedID 22853986

• The Intersection of Genes and Environment Development of Pulmonary Arterial Hypertension in a Patient With Hereditary Hemorrhagic Telangiectasia and Stimulant Exposure CHEST Ayala, E., Kudelko, K. T., Haddad, F., Zamanian, R. T., Perez, V. d. 2012; 141 (6): 1598-1600

  Abstract

  Pulmonary arterial hypertension (PAH) is a rare complication of hereditary hemorrhagic telangiectasia (HHT). The triggers that promote the development of PAH in HHT remain poorly understood. We present the case of a 45-year-old woman with decompensated right-sided heart failure secondary to newly diagnosed PAH. The clinical diagnosis of HHT was confirmed on the basis of recurrent spontaneous epistaxis, multiple typical mucocutaneous telangiectasia, and the presence of pulmonary arteriovenous malformation. There was also a suggestive family history. The patient was discovered to have active and extensive stimulant abuse in addition to HHT. We concluded that there may be a temporal relationship between exposure to stimulants and development of PAH in a host with underlying gene mutation. This case highlights the paradigm of PAH development after environmental exposure in a genetically susceptible host.

  View details for DOI 10.1378/chest.11-1402

  View details for Web of Science ID 000305039300054

  View details for PubMedID 22670022

  View details for PubMedCentralID PMC3367481

• Diagnosis and management of pulmonary hypertension associated with left ventricular diastolic dysfunction Pulmonary Circulation de Jesus Perez, V., Haddad, F, Zamanian RT 2012; 2 (2): 163
• Development of a recurrent pleural effusion in a patient with pulmonary arterial hypertension treated with imatinib Case Reports in Clinical Medicine Olga M. Fortenko, Lana Melendres-Groves, Alice Richter, Xiaobo Liao, Edda Spiekerkoetter, Roham Zamanian, Vinicio A. De Jesus Perez 2012; 1 (2): 38-41
• Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699

  Abstract

  Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure).By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5-7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m2; OR, 2.7; 95% CI, 1.2-6.3), hyponatremia (serum sodium ≤136 mEq/L; OR, 3.6; 95% CI, 1.7-7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation.These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

  View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

  View details for PubMedID 21908586

• Pulmonary Hypertension Associated With Left Heart Disease: Characteristics, Emerging Concepts, and Treatment Strategies PROGRESS IN CARDIOVASCULAR DISEASES Haddad, F., Kudelko, K., Mercier, O., Vrtovec, B., Zamanian, R. T., Perez, V. D. 2011; 54 (2): 154-167

  Abstract

  Left heart disease (LHD) represents the most common causes of pulmonary hypertension (PH). Whether caused by systolic or diastolic dysfunction or valvular heart disease, a hallmark of PH associated with LHD is elevated left atrial pressure. In all cases, the increase in left atrial pressure causes a passive increase in pulmonary pressure. In some patients, a superimposed active component caused by pulmonary arterial vasoconstriction and vascular remodeling may lead to a further increase in pulmonary arterial pressure. When present, PH is associated with a worse prognosis in patients with LHD. In addition to local abnormalities in nitric oxide and endothelin production, gene modifiers such as serotonin polymorphisms may be associated with the pathogenesis of PH in LHD. Optimizing heart failure regimens and corrective valve surgery represent the cornerstone of the treatment of PH in LHD. Recent studies suggest that sildenafil, a phosphodiesterase-5 inhibitor, is a promising agent in the treatment of PH in LHD. Unloading the left ventricle with circulatory support may also reverse severe PH in patients with end-stage heart failure allowing candidacy to heart transplantation.

  View details for DOI 10.1016/j.pcad.2011.06.003

  View details for Web of Science ID 000294880400009

  View details for PubMedID 21875514

• Disruption of PPAR gamma/beta-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival JOURNAL OF CLINICAL INVESTIGATION Alastalo, T., Li, M., Perez, V. D., Pham, D., Sawada, H., Wang, J. K., Koskenvuo, M., Wang, L., Freeman, B. A., Chang, H. Y., Rabinovitch, M. 2011; 121 (9): 3735-3746

  Abstract

  Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with pulmonary arterial hypertension (PAH) can impair pulmonary arterial EC (PAEC) function. This can adversely affect EC survival and promote SMC proliferation. We hypothesized that interventions to normalize expression of genes that are targets of BMPR2 signaling could restore PAEC function and prevent or reverse PAH. Here we have characterized, in human PAECs, a BMPR2-mediated transcriptional complex between PPARγ and β-catenin and shown that disruption of this complex impaired BMP-mediated PAEC survival. Using whole genome-wide ChIP-Chip promoter analysis and gene expression microarrays, we delineated PPARγ/β-catenin-dependent transcription of target genes including APLN, which encodes apelin. We documented reduced PAEC expression of apelin in PAH patients versus controls. In cell culture experiments, we showed that apelin-deficient PAECs were prone to apoptosis and promoted pulmonary arterial SMC (PASMC) proliferation. Conversely, we established that apelin, like BMPR2 ligands, suppressed proliferation and induced apoptosis of PASMCs. Consistent with these functions, administration of apelin reversed PAH in mice with reduced production of apelin resulting from deletion of PPARγ in ECs. Taken together, our findings suggest that apelin could be effective in treating PAH by rescuing BMPR2 and PAEC dysfunction.

  View details for DOI 10.1172/JCI43382

  View details for PubMedID 21821917

• Incidence, Correlates, and Consequences of Acute Kidney Injury in Patients With Pulmonary Arterial Hypertension Hospitalized With Acute Right-Side Heart Failure JOURNAL OF CARDIAC FAILURE Haddad, F., Fuh, E., Peterson, T., Skhiri, M., Kudelko, K. T., Perez, V. D., Winkelmayer, W. C., Doyle, R. L., Chertow, G. M., Zamanian, R. T. 2011; 17 (7): 533-539

  Abstract

  Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH).We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8-8.5), high central venous pressure (OR 1.8, 95% CI 1.1-2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1-8.8). AKI was strongly associated with 30-day mortality after acute right-side heart failure hospitalization (OR 5.3, 95% CI 2.2-13.2).AKI is relatively common in patients with PAH and associated with a short-term risk of death.

  View details for DOI 10.1016/j.cardfail.2011.03.003

  View details for PubMedID 21703524

• Chronic Thromboembolic Pulmonary Hypertension NEW ENGLAND JOURNAL OF MEDICINE Perez, V. A., Zamanian, R. T. 2011; 364 (17): 1677-1677

  View details for Web of Science ID 000289940400022

  View details for PubMedID 21524224

• Disruption of the Apelin-APJ System Worsens Hypoxia-Induced Pulmonary Hypertension ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Chandra, S. M., Razavi, H., Kim, J., Agrawal, R., Kundu, R. K., Perez, V. D., Zamanian, R. T., Quertermous, T., Chun, H. J. 2011; 31 (4): 814-U212

  Abstract

  The G-protein-coupled receptor APJ and its ligand apelin are highly expressed in the pulmonary vasculature, but their function in this vascular bed is unclear. We hypothesized that disruption of apelin signaling would lead to worsening of the vascular remodeling associated with pulmonary hypertension (PH).We found that apelin-null mice developed more severe PH compared with wild-type mice when exposed to chronic hypoxia. Micro-computed tomography of the pulmonary arteries demonstrated significant pruning of the microvasculature in the apelin-null mice. Apelin-null mice had a significant reduction of serum nitrate levels. This was secondary to downregulation of endothelial nitric oxide synthase (eNOS), which was associated with reduced expression of Kruppel-like factor 2 (KLF2), a known regulator of eNOS expression. In vitro knockdown studies targeting apelin in human pulmonary artery endothelial cells demonstrated decreased eNOS and KLF2 expression, as well as impaired phosphorylation of AMP-activated kinase and eNOS. Moreover, serum apelin levels of patients with PH were significantly lower than those of controls.These data demonstrate that disruption of apelin signaling can exacerbate PH mediated by decreased activation of AMP-activated kinase and eNOS, and they identify this pathway as a potentially important therapeutic target for treatment of this refractory human disease.

  View details for DOI 10.1161/ATVBAHA.110.219980

  View details for PubMedID 21233449

• Making Sense of the Estrogen Paradox in Pulmonary Arterial Hypertension American Journal of Respiratory and Critical Care Medicine vinicio de jesus perez 2011; 184: 629
• Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead. International journal of clinical practice. Supplement de Jesus Perez, V., Kudelko, K., Snook, S., Zamanian, R. T. 2011: 8-10

  Abstract

  Since the identification of the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs and toxins nearly fifty years ago, the expanding landscape of available pharmaceuticals and illicit drugs is further fueling this association. While some causative agents in drugs and toxins associated PAH (D&T-APAH) have been identified, little is known about the exact biology and clinical implications of the disease. In this review, we discuss the historical evidence that links PAH with exposure to anorexinogens, cocaine, and methamphetamines and concentrate on what is known about potential pathogenesis, clinical manifestations, and current management. We conclude that future research should focus on studies looking at clinical outcome and susceptibility factors.

  View details for DOI 10.1111/j.1742-1241.2010.02606.x

  View details for PubMedID 21176010

• Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay. journal of heart and lung transplantation Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., de Jesus Perez, V. 2010; 29 (9): 1071-1075

  Abstract

  We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

  View details for DOI 10.1016/j.healun.2010.04.023

  View details for PubMedID 20627625

  View details for PubMedCentralID PMC2926193

• Cholinergic Modulation of Angiogenesis: Role of the 7 Nicotinic Acetylcholine Receptor JOURNAL OF CELLULAR BIOCHEMISTRY Wu, J. C., Chruscinski, A., Perez, V. A., Singh, H., Pitsiouni, M., Rabinovitch, M., Utz, P. J., Cooke, J. P. 2009; 108 (2): 433-446

  Abstract

  Pathological angiogenesis contributes to tobacco-related diseases such as malignancy, atherosclerosis and age-related macular degeneration. Nicotine acts on endothelial nicotinic acetylcholine receptors (nAChRs) to activate endothelial cells and to augment pathological angiogenesis. In the current study, we studied nAChR subunits involved in these actions. We detected mRNA for all mammalian nAChR subunits except alpha(2), alpha(4), gamma, and delta in four different types of ECs. Using siRNA methodology, we found that the alpha(7) nAChR plays a dominant role in nicotine-induced cell signaling (assessed by intracellular calcium and NO imaging, and studies of protein expression and phosphorylation), as well as nicotine-activated EC functions (proliferation, survival, migration, and tube formation). The alpha(9) and alpha(7) nAChRs have opposing effects on nicotine-induced cell proliferation and survival. Our studies reveal a critical role for the alpha(7) nAChR in mediating the effects of nicotine on the endothelium. Other subunits play a modulatory role. These findings may have therapeutic implications for diseases characterized by pathological angiogenesis.

  View details for DOI 10.1002/jcb.22270

  View details for Web of Science ID 000270438000012

  View details for PubMedID 19623583

  View details for PubMedCentralID PMC3140170

• S100A4 and Bone Morphogenetic Protein-2 Codependently Induce Vascular Smooth Muscle Cell Migration via Phospho-Extracellular Signal-Regulated Kinase and Chloride Intracellular Channel 4 CIRCULATION RESEARCH Spiekerkoetter, E., Guignabert, C., Perez, V. D., Alastalo, T., Powers, J. M., Wang, L., Lawrie, A., Ambartsumian, N., Schmidt, A., Berryman, M., Ashley, R. H., Rabinovitch, M. 2009; 105 (7): 639-U37

  Abstract

  S100A4/Mts1 is implicated in motility of human pulmonary artery smooth muscle cells (hPASMCs), through an interaction with the RAGE (receptor for advanced glycation end products).We hypothesized that S100A4/Mts1-mediated hPASMC motility might be enhanced by loss of function of bone morphogenetic protein (BMP) receptor (BMPR)II, observed in pulmonary arterial hypertension.Both S100A4/Mts1 (500 ng/mL) and BMP-2 (10 ng/mL) induce migration of hPASMCs in a novel codependent manner, in that the response to either ligand is lost with anti-RAGE or BMPRII short interference (si)RNA. Phosphorylation of extracellular signal-regulated kinase is induced by both ligands and is required for motility by inducing matrix metalloproteinase 2 activity, but phospho-extracellular signal-regulated kinase 1/2 is blocked by anti-RAGE and not by BMPRII short interference RNA. In contrast, BMPRII short interference RNA, but not anti-RAGE, reduces expression of intracellular chloride channel (CLIC)4, a scaffolding molecule necessary for motility in response to S100A4/Mts1 or BMP-2. Reduced CLIC4 expression does not interfere with S100A4/Mts1 internalization or its interaction with myosin heavy chain IIA, but does alter alignment of myosin heavy chain IIA and actin filaments creating the appearance of vacuoles. This abnormality is associated with reduced peripheral distribution and/or delayed activation of RhoA and Rac1, small GTPases required for retraction and extension of lamellipodia in motile cells.Our studies demonstrate how a single ligand (BMP-2 or S100A4/Mts1) can recruit multiple cell surface receptors to relay signals that coordinate events culminating in a functional response, ie, cell motility. We speculate that this carefully controlled process limits signals from multiple ligands, but could be subverted in disease.

  View details for DOI 10.1161/CIRCRESAHA.109.205120

  View details for Web of Science ID 000270150800006

  View details for PubMedID 19713532

  View details for PubMedCentralID PMC2818124

• Angina Associated With Left Main Coronary Artery Compression in Pulmonary Hypertension JOURNAL OF HEART AND LUNG TRANSPLANTATION Perez, V. A., Haddad, F., Vagelos, R. H., Fearon, W., Feinstein, J., Zamanian, R. T. 2009; 28 (5): 527-530

  Abstract

  Chest pain is a common complaint in patients with pulmonary arterial hypertension (PAH). Left main coronary artery (LMCA) compression by an enlarged pulmonary artery trunk (PAT) has been associated with angina, but appropriate diagnostic and treatment approaches remain poorly defined. We present two cases of angina caused by LMCA compression from an enlarged pulmonary artery, one of which also presented with new, severe left ventricular systolic dysfunction attributed to myocardial ischemia. Diagnosis of LMCA stenosis was made via coronary angiography followed by computed tomography-gated coronary angiography (CT-CA), which confirmed pulmonary artery enlargement as the source of extrinsic compression. Restoring LMCA patency with percutaneous intervention and/or aggressive treatment of pulmonary hypertension led to significant improvement in angina, cardiac function and quality of life. Given the negative impact on cardiac function, prompt diagnosis and treatment of extrinsic LMCA compression should be considered a priority.

  View details for DOI 10.1016/j.healun.2008.12.008

  View details for PubMedID 19416787

• An antiproliferative BMP-2/PPAR gamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension JOURNAL OF CLINICAL INVESTIGATION Hansmann, G., de Jesus Perez, V. A., Alastalo, T., Alvira, C. M., Guignabert, C., Bekker, J. M., Schellong, S., Urashima, T., Wang, L., Morrell, N. W., Rabinovitch, M. 2008; 118 (5): 1846-1857

  Abstract

  Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPARgamma and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB-induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPARgamma that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARgamma agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient-derived BMP-RII mutant PASMCs, a PPARgamma antagonist, and PASMCs isolated from PPARgamma- and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARgamma, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARgamma in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPARgamma-mediated events could protect against PAH, and PPARgamma agonists may reverse PAH in patients with or without BMP-RII dysfunction.

  View details for DOI 10.1172/JCI32503

  View details for PubMedID 18382765

• Coexistence of Primary adenocarcinoma of the lung and Tsukamurella pneumonia: a case report and review of the literature Journal of Medical Case Reports de Jesus Perez, V., Swigris J, Ruoss, S 2008; 207 (2)
• Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation CIRCULATION Hansmann, G., Wagner, R. A., Schellong, S., Perez, V. A., Urashima, T., Wang, L., Sheikh, A. Y., Suen, R. S., Stewart, D. J., Rabinovitch, M. 2007; 115 (10): 1275-1284

  Abstract

  Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator-activated receptor-gamma in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE-/-) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-gamma agonist (eg, rosiglitazone).We report that apoE-/- mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE-/- were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE-/- mice were insulin resistant and had more severe PAH than female apoE-/- mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE-/- mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE-/- or C57Bl/6 control mice.We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-gamma activation can reverse PAH in an animal model.

  View details for DOI 10.1161/CIRCULATIONAHA.106.663120

  View details for Web of Science ID 000244864100017

  View details for PubMedID 17339547