Browsing by Author "Rajagopal, Sudarshan"
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Item Open Access Assessing right atrial function in pulmonary hypertension: window to the soul of the right heart?(American journal of physiology. Heart and circulatory physiology, 2020-01) Alenezi, Fawaz; Rajagopal, Sudarshan; Kutty, ShelbyItem Open Access Beta-Arrestins and Receptor Signaling in the Vascular Endothelium.(Biomolecules, 2020-12-23) Lee, Claudia; Viswanathan, Gayathri; Choi, Issac; Jassal, Chanpreet; Kohlmann, Taylor; Rajagopal, SudarshanThe vascular endothelium is the innermost layer of blood vessels and is a key regulator of vascular tone. Endothelial function is controlled by receptor signaling through G protein-coupled receptors, receptor tyrosine kinases and receptor serine-threonine kinases. The β-arrestins, multifunctional adapter proteins, have the potential to regulate all of these receptor families, although it is unclear as to whether they serve to integrate signaling across all of these different axes. Notably, the β-arrestins have been shown to regulate signaling by a number of receptors important in endothelial function, such as chemokine receptors and receptors for vasoactive substances such as angiotensin II, endothelin-1 and prostaglandins. β-arrestin-mediated signaling pathways have been shown to play central roles in pathways that control vasodilation, cell proliferation, migration, and immune function. At this time, the physiological impact of this signaling has not been studied in detail, but a deeper understanding of it could lead to the development of novel therapies for the treatment of vascular disease.Item Open Access Biased agonism at chemokine receptors.(Cellular signalling, 2021-02) Eiger, Dylan Scott; Boldizsar, Noelia; Honeycutt, Christopher Cole; Gardner, Julia; Rajagopal, SudarshanIn the human chemokine system, interactions between the approximately 50 known endogenous chemokine ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological processes including immune cell activation and homeostasis, development, angiogenesis, and neuromodulation. CKRs are a family of G protein-coupled receptors (GPCR), which represent the most common and versatile class of receptors in the human genome and the targets of approximately one third of all Food and Drug Administration-approved drugs. Chemokines and CKRs bind with significant promiscuity, as most CKRs can be activated by multiple chemokines and most chemokines can activate multiple CKRs. While these ligand-receptor interactions were previously regarded as redundant, it is now appreciated that many chemokine:CKR interactions display biased agonism, the phenomenon in which different ligands binding to the same receptor signal through different pathways with different efficacies, leading to distinct biological effects. Notably, these biased responses can be modulated through changes in ligand, receptor, and or the specific cellular context (system). In this review, we explore the biochemical mechanisms, functional consequences, and therapeutic potential of biased agonism in the chemokine system. An enhanced understanding of biased agonism in the chemokine system may prove transformative in the understanding of the mechanisms and consequences of biased signaling across all GPCR subtypes and aid in the development of biased pharmaceuticals with increased therapeutic efficacy and safer side effect profiles.Item Open Access Biased agonists of the chemokine receptor CXCR3 differentially signal through Gαi:β-arrestin complexes.(Science signaling, 2022-03-22) Zheng, Kevin; Smith, Jeffrey S; Eiger, Dylan S; Warman, Anmol; Choi, Issac; Honeycutt, Christopher C; Boldizsar, Noelia; Gundry, Jaimee N; Pack, Thomas F; Inoue, Asuka; Caron, Marc G; Rajagopal, SudarshanG protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and signal through the proximal effectors, G proteins and β-arrestins, to influence nearly every biological process. The G protein and β-arrestin signaling pathways have largely been considered separable; however, direct interactions between Gα proteins and β-arrestins have been described that appear to be part of a distinct GPCR signaling pathway. Within these complexes, Gαi/o, but not other Gα protein subtypes, directly interacts with β-arrestin, regardless of the canonical Gα protein that is coupled to the GPCR. Here, we report that the endogenous biased chemokine agonists of CXCR3 (CXCL9, CXCL10, and CXCL11), together with two small-molecule biased agonists, differentially formed Gαi:β-arrestin complexes. Formation of the Gαi:β-arrestin complexes did not correlate well with either G protein activation or β-arrestin recruitment. β-arrestin biosensors demonstrated that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We also found that Gαi:β-arrestin complexes did not couple to the mitogen-activated protein kinase ERK, as is observed with other receptors such as the V2 vasopressin receptor, but did couple with the clathrin adaptor protein AP-2, which suggests context-dependent signaling by these complexes. These findings reinforce the notion that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of the spectrum of biased agonism.Item Open Access Clinical and echocardiographic predictors of mortality in acute pulmonary embolism.(Cardiovasc Ultrasound, 2016-10-28) Dahhan, Talal; Siddiqui, Irfan; Tapson, Victor F; Velazquez, Eric J; Sun, Stephanie; Davenport, Clemontina A; Samad, Zainab; Rajagopal, SudarshanPURPOSE: The aim of this study was to evaluate the utility of adding quantitative assessments of cardiac function from echocardiography to clinical factors in predicting the outcome of patients with acute pulmonary embolism (PE). METHODS: Patients with a diagnosis of acute PE, based on a positive ventilation perfusion scan or computed tomography (CT) chest angiogram, were identified using the Duke University Hospital Database. Of these, 69 had echocardiograms within 24-48 h of the diagnosis that were suitable for offline analysis. Clinical features that were analyzed included age, gender, body mass index, vital signs and comorbidities. Echocardiographic parameters that were analyzed included left ventricular (LV) ejection fraction (EF), regional, free wall and global RV speckle-tracking strain, RV fraction area change (RVFAC), Tricuspid Annular Plane Systolic Excursion (TAPSE), pulmonary artery acceleration time (PAAT) and RV myocardial performance (Tei) index. Univariable and multivariable regression statistical analysis models were used. RESULTS: Out of 69 patients with acute PE, the median age was 55 and 48 % were female. The median body mass index (BMI) was 27 kg/m(2). Twenty-nine percent of the cohort had a history of cancer, with a significant increase in cancer prevalence in non-survivors (57 % vs 29 %, p = 0.02). Clinical parameters including heart rate, respiratory rate, troponin T level, active malignancy, hypertension and COPD were higher among non-survivors when compared to survivors (p ≤ 0.05). Using univariable analysis, NYHA class III symptoms, hypoxemia on presentation, tachycardia, tachypnea, elevation in Troponin T, absence of hypertension, active malignancy and chronic obstructive pulmonary disease (COPD) were increased in non-survivors compared to survivors (p ≤ 0.05). In multivariable models, RV Tei Index, global and free (lateral) wall RVLS were found to be negatively associated with survival probability after adjusting for age, gender and systolic blood pressure (p ≤ 0.05). CONCLUSION: The addition of echocardiographic assessment of RV function to clinical parameters improved the prediction of outcomes for patients with acute PE. Larger studies are needed to validate these findings.Item Open Access Clinical Features and Outcomes of Patients with Sarcoidosis-associated Pulmonary Hypertension.(Scientific reports, 2019-03-11) Parikh, Kishan S; Dahhan, Talal; Nicholl, Leigh; Ruopp, Nicole; Pomann, Gina-Maria; Fortin, Terry; Tapson, Victor F; Rajagopal, SudarshanThe presence of pulmonary hypertension (PH) significantly worsens outcomes in patients with advanced sarcoidosis, but its optimal management is unknown. We aimed to characterize a large sarcoidosis-associated pulmonary hypertension (SAPH) cohort to better understand patient characteristics, clinical outcomes, and management strategies including treatment with PH therapies. Patients at Duke University Medical Center with biopsy-proven sarcoidosis and SAPH confirmed by right heart catheterization (RHC) were identified from 1990-2010. Subjects were followed for up to 11 years and assessed for differences by treatment strategy for their SAPH, including those who were not treated with PH-specific therapies. Our primary outcomes of interest were change in 6-minute walk distance (6MWD) and change in N-terminal pro-brain natriuretic peptide (NT-proBNP) by after therapy. We included 95 patients (76% women, 86% African American) with SAPH. Overall, 70% of patients had stage IV pulmonary sarcoidosis, and 77% had functional class III/IV symptoms. Median NT-proBNP value was elevated (910 pg/mL), and right ventricular dysfunction was moderate/severe in 55% of patients. Median values for mean pulmonary artery pressure (49 mmHg) and pulmonary vascular resistance (8.5 Woods units) were consistent with severe pulmonary hypertension. The mortality rate over median 3-year follow-up was 32%. Those who experienced a clinical event and those who did not had similar overall echocardiographic findings, hemodynamics, 6MWD and NT-proBNP at baseline, and unadjusted analysis showed that only follow-up NT-proBNP was associated with all-cause hospitalization or mortality. A sign test to evaluate the difference between NT-Pro-BNP before and after PH therapy produced evidence that a significant difference existed between the median pre- and post-NT-Pro-BNP (-387.0 (IQR: -1373.0-109), p = 0.0495). Use of PH-specific therapy may be helpful in selected patients with SAPH and pre-capillary pulmonary vascular disease. Prospective trials are needed to characterize responses to PH-specific therapy in this subset of patients with SAPH.Item Open Access Diverse Cardiopulmonary Diseases are Associated with Distinct Xenon MRI Signatures.(The European respiratory journal, 2019-10-16) Wang, Ziyi; Bier, Elianna A; Swaminathan, Aparna; Parikh, Kishan; Nouls, John; He, Mu; Mammarappallil, Joseph G; Luo, Sheng; Driehuys, Bastiaan; Rajagopal, SudarshanBACKGROUND:As an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129Xenon MR imaging and spectroscopy to identify patterns of regional gas transfer impairment and hemodynamics that are uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF), and pulmonary arterial hypertension (PAH). METHODS:Healthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6), and PAH (n=10) underwent 129Xe gas transfer imaging and dynamic spectroscopy. For each patient, 3D maps were generated to depict ventilation, barrier uptake (129Xe dissolved in interstitial tissue), and red blood cell (RBC) transfer (129Xe dissolved in RBCs). Dynamic 129Xe spectroscopy was used to quantify cardiogenic oscillations in the RBC signal amplitude and frequency shift. RESULTS:Compared to healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (p≤0.01, p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared to all other groups (p≤0.02, p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared to all other groups (p≤0.007) and increased RBC amplitude and shift oscillations compared to healthy volunteers (p=0.007, p≤0.01). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02, p=0.005) compared to healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01). CONCLUSION:COPD, IPF, LHF, and PAH each exhibit unique 129Xe MR imaging and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and hemodynamics at the alveolar-capillary level.Item Open Access Echocardiography to Screen for Pulmonary Hypertension in CKD(Kidney International Reports, 2020-12-01) Edmonston, Daniel L; Rajagopal, Sudarshan; Wolf, Myles© 2020 International Society of Nephrology Introduction: Pulmonary hypertension (PH) is a common yet incompletely understood complication of chronic kidney disease (CKD). Although transthoracic echocardiogram is commonly used to noninvasively estimate PH, it has not been validated in a CKD population. We investigated the utility of this diagnostic tool for CKD-associated PH in a large right heart catheterization (RHC) cohort. Methods: We reviewed RHC and echocardiography data in 4036 patients (1714 with CKD) obtained between 2011 and 2014 at a single center. We used multivariate regression to determine the associations of echocardiography measurements with PH, and evaluated whether estimated glomerular filtration rate (eGFR) modified these associations. Using internal validation, we sequentially added measurements to predictive models and analyzed the incremental predictive performance using the change in the area under the receiver operating characteristic curve (ΔAUC) and net reclassification improvement. Results: The echocardiography measurements most strongly associated with the diagnosis of PH included tricuspid regurgitant velocity (TRV), tricuspid annular plane systolic excursion (TAPSE), right atrial pressure, diastolic dysfunction, and right ventricular function. Among these measurements, eGFR significantly modified the associations of TAPSE and diastolic dysfunction with the diagnosis of PH. The model consisting of a combination of TRV, right atrial pressure, and TAPSE most accurately predicted the diagnosis of PH in a CKD population (AUC 0.82). Conclusions: The optimal model to predict PH diagnosis included TRV, right atrial pressure, and TAPSE. Since TAPSE more strongly associated with PH in the CKD population, these findings support a CKD-specific approach to the development of noninvasive screening algorithms for PH.Item Open Access Evaluation and Management of Pulmonary Hypertension in Noncardiac Surgery: A Scientific Statement From the American Heart Association.(Circulation, 2023-04) Rajagopal, Sudarshan; Ruetzler, Kurt; Ghadimi, Kamrouz; Horn, Evelyn M; Kelava, Marta; Kudelko, Kristina T; Moreno-Duarte, Ingrid; Preston, Ioana; Rose Bovino, Leonie L; Smilowitz, Nathaniel R; Vaidya, Anjali; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, and the Council on Cardiovascular and Stroke NursingPulmonary hypertension, defined as an elevation in blood pressure in the pulmonary arteries, is associated with an increased risk of death. The prevalence of pulmonary hypertension is increasing, with an aging population, a rising prevalence of heart and lung disease, and improved pulmonary hypertension survival with targeted therapies. Patients with pulmonary hypertension frequently require noncardiac surgery, although pulmonary hypertension is associated with excess perioperative morbidity and death. This scientific statement provides guidance on the evaluation and management of pulmonary hypertension in patients undergoing noncardiac surgery. We advocate for a multistep process focused on (1) classification of pulmonary hypertension group to define the underlying pathology; (2) preoperative risk assessment that will guide surgical decision-making; (3) pulmonary hypertension optimization before surgery to reduce perioperative risk; (4) intraoperative management of pulmonary hypertension to avoid right ventricular dysfunction and to maintain cardiac output; and (5) postoperative management of pulmonary hypertension to ensure recovery from surgery. Last, this scientific statement highlights the paucity of evidence to support perioperative pulmonary hypertension management and identifies areas of uncertainty and opportunities for future investigation.Item Open Access Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.(Journal of cardiovascular pharmacology, 2020-04) Parikh, Kishan S; Doerfler, Sean; Shelburne, Nicholas; Kennedy, Karla; Whitson, Jordan; Dahhan, Talal; Fortin, Terry; Rajagopal, SudarshanParenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 μg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.Item Open Access How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways(Cellular Signalling, 2019-02) Rajarathnam, Krishna; Schnoor, Michael; Richardson, Ricardo M; Rajagopal, Sudarshan© 2018 Elsevier Inc. Chemokines play crucial roles in combating microbial infection and initiating tissue repair by recruiting neutrophils in a timely and coordinated manner. In humans, no less than seven chemokines (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8) and two receptors (CXCR1 and CXCR2) mediate neutrophil functions but in a context dependent manner. Neutrophil-activating chemokines reversibly exist as monomers and dimers, and their receptor binding triggers conformational changes that are coupled to G-protein and β-arrestin signaling pathways. G-protein signaling activates a variety of effectors including Ca2+ channels and phospholipase C. β-arrestin serves as a multifunctional adaptor and is coupled to several signaling hubs including MAP kinase and tyrosine kinase pathways. Both G-protein and β-arrestin signaling pathways play important non-overlapping roles in neutrophil trafficking and activation. Functional studies have established many similarities but distinct differences for a given chemokine and between chemokines at the level of monomer vs. dimer, CXCR1 vs. CXCR2 activation, and G-protein vs. β-arrestin pathways. We propose that two forms of the ligand binding two receptors and activating two signaling pathways enables fine-tuned neutrophil function compared to a single form, a single receptor, or a single pathway. We summarize the current knowledge on the molecular mechanisms by which chemokine monomers/dimers activate CXCR1/CXCR2 and how these interactions trigger G-protein/β-arrestin-coupled signaling pathways. We also discuss current challenges and knowledge gaps, and likely advances in the near future that will lead to a better understanding of the relationship between the chemokine-CXCR1/CXCR2-G-protein/β-arrestin axis and neutrophil function.Item Open Access Identification of potent pyrazole based APELIN receptor (APJ) agonists(Bioorganic and Medicinal Chemistry, 2020-01-01) Narayanan, Sanju; Vasukuttan, Vineetha; Rajagopal, Sudarshan; Maitra, Rangan; Runyon, Scott P© 2019 Elsevier Ltd The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly attractive target for pulmonary and cardiometabolic diseases. Small molecule regulators of this receptor with good drug-like properties are needed. Recently, we discovered a novel pyrazole based small molecule agonist 8 of the apelin receptor (EC50 = 21.5 µM, Ki = 5.2 µM) through focused screening which was further optimized to initial lead 9 (EC50 = 0.800 µM, Ki = 1.3 µM). In our efforts to synthesize more potent agonists and to explore the structural features important for apelin receptor agonism, we carried out structural modifications at N1 of the pyrazole core as well as the amino acid side-chain of 9. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC50 values of <100 nM. Recruitment of β-arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β-arrestin recruitment. These compounds may be suitable as tools for in vivo studies of apelin receptor function.Item Open Access Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.(Circulation, 2023-07) Ghadimi, Kamrouz; Cappiello, Jhaymie L; Wright, Mary Cooter; Levy, Jerrold H; Bryner, Benjamin S; DeVore, Adam D; Schroder, Jacob N; Patel, Chetan B; Rajagopal, Sudarshan; Shah, Svati H; Milano, Carmelo A; INSPIRE-FLO InvestigatorsBackground
Right ventricular failure (RVF) is a leading driver of morbidity and mortality after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy.Methods
In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and mortality at 30 days, 90 days, and 1 year after surgery.Results
Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes.Conclusions
Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO.Registration
URL: https://www.Clinicaltrials
gov; Unique identifier: NCT03081052.Item Embargo Mechanisms of Biased Signaling at the Chemokine Receptor CXCR3(2023) Eiger, Dylan ScottG protein-coupled receptors (GPCRs) are the most common transmembrane receptors in the human genome and the target of approximately one-third of all approved drugs. GPCRs interact with many transducers like G proteins and β-arrestins. Some GPCRs preferentially activate specific signaling transducers over others, leading to unique signaling profiles – a phenomenon called biased signaling. The chemokine system, a subfamily of GPCRs, serves as an endogenous example of biased signaling where over 50 different chemokines and 20 receptors interact promiscuously. While previous research has shown that chemokines which activate the same receptor can produce different physiologic responses, the mechanisms underlying these findings remain unclear. Using the three endogenous chemokines of the chemokine receptor CXCR3, we investigated two mechanisms underlying biased signaling at GPCRs. First, using mass spectrometry and cell-based assays, we determined that the chemokines induce different amounts and patterns of GPCR phosphorylation which direct CXCR3 engagement with different transducers. Second, we determined that biased signaling is dependent on the specific location of CXCR3, and subcellular signaling regulates inflammation in a mouse model of contact hypersensitivity. Together, we conclude that differential receptor phosphorylation and subcellular signaling are two mechanisms underlying the biased signaling observed at GPCRs.
Item Open Access MEF2 and the Right Ventricle: From Development to Disease.(Frontiers in cardiovascular medicine, 2019-01) Clapham, Katharine R; Singh, Inderjit; Capuano, Isabella S; Rajagopal, Sudarshan; Chun, Hyung JPulmonary arterial hypertension is a progressive and ultimately life-limiting disease in which survival is closely linked to right ventricular function. The right ventricle remains relatively understudied, as it is known to have key developmental and structural differences from the left ventricle. Here, we will highlight what is known about the right ventricle in normal physiology and in the disease state of pulmonary arterial hypertension. Specifically, we will explore the role of the family of MEF2 (myocyte enhancer factor 2) transcription factors in right ventricular development, its response to increased afterload, and in the endothelial dysfunction that characterizes pulmonary arterial hypertension. Finally, we will turn to review potentially novel therapeutic strategies targeting these pathways.Item Open Access Monitoring Pulmonary Arterial Hypertension Using an Implantable Hemodynamic Sensor.(Chest, 2019-06-29) Benza, Raymond L; Doyle, Mark; Lasorda, David; Parikh, Kishan S; Correa-Jaque, Priscilla; Badie, Nima; Ginn, Greg; Airhart, Sophia; Franco, Veronica; Kanwar, Manreet K; Murali, Srinivas; Raina, Amresh; Agarwal, Rahul; Rajagopal, Sudarshan; White, Jason; Biederman, RobertBACKGROUND:Pulmonary arterial hypertension (PAH) is a chronic disease that ultimately progresses to right-sided heart failure (HF) and death. Close monitoring of pulmonary artery pressure (PAP) and right ventricular (RV) function allows clinicians to appropriately guide therapy. However, the burden of commonly used methods to assess RV hemodynamics, such as right heart catheterization, precludes frequent monitoring. The CardioMEMS HF System (Abbott) is an ambulatory implantable hemodynamic monitor, previously only used in patients with New York Heart Association (NYHA) class III HF. In this study, we evaluate the feasibility and early safety of monitoring patients with PAH and right-sided HF using the CardioMEMS HF System. METHODS:The CardioMEMS HF sensors were implanted in 26 patients with PAH with NYHA class III or IV right-sided HF (51.3 ± 18.3 years of age, 92% women, 81% NYHA class III). PAH therapy was tracked using a minimum of weekly reviews of CardioMEMS HF daily hemodynamic measurements. Safety, functional response, and hemodynamic response were tracked up to 4 years with in-clinic follow-ups. RESULTS:The CardioMEMS HF System was safely used to monitor PAH therapy, with no device-related serious adverse events observed and a single preimplant serious adverse event. Significant PAP reduction and cardiac output elevation were observed as early as 1 month postimplant using trends of CardioMEMS HF data, coupled with significant NYHA class and quality of life improvements within 1 year. CONCLUSIONS:The CardioMEMS HF System provided useful information to monitor PAH therapy, and demonstrated short- and long-term safety. Larger clinical trials are needed before its widespread use to guide therapy in patients with severe PAH with right-sided HF.Item Open Access Nasally Inhaled Nitric Oxide for Sudden Right-Sided Heart Failure in the Intensive Care Unit: NO Time Like the Present.(Journal of cardiothoracic and vascular anesthesia, 2019-03) Ghadimi, Kamrouz; Rajagopal, SudarshanItem Open Access Overcoming Confounding to Characterize the Effects of Calcium Channel Blockers.(Function (Oxford, England), 2023-01) Rajagopal, Sudarshan; Rosenberg, Paul BItem Open Access Pathogen evasion of chemokine response through suppression of CXCL10(2019-02-22) Antonia, Alejandro; Alvarez, Monica; Trahair, Esme; Gibbs, Kyle; Pittman, Kelly; Barnes, Alyson; Smith, Jeffrey; Smith, Jeffrey; Rajagopal, Sudarshan; Thompson, Will; Reinhardt, Lee; Ko, DennisAbstract Clearance of intracellular pathogens, such as Leishmania ( L. ) major , depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial functions, including T cell recruitment. Infection with L. major in a human monocyte cell line induced robust CXCL10 transcription without increasing extracellular CXCL10 protein concentrations. We found that this transcriptionally independent suppression of CXCL10 is mediated by the virulence factor and protease, glycoprotein-63 ( gp63) . Specifically, GP63 cleaves CXCL10 after amino acid A81 at the base of a C-terminal alpha-helix. Cytokine cleavage by GP63 demonstrated specificity, as GP63 cleaved CXCL10 and its homologues, which all bind the CXCR3 receptor, but not distantly related chemokines, such as CXCL8 and CCL22. Further characterization demonstrated that CXCL10 cleavage activity by GP63 was produced by both extracellular promastigotes and intracellular amastigotes. Crucially, CXCL10 cleavage impaired T cell chemotaxis in vitro , indicating that cleaved CXCL10 cannot signal through CXCR3. Ultimately, we propose CXCL10 suppression is a convergent mechanism of immune evasion, as Salmonella enterica and Chlamydia trachomatis also suppress CXCL10. This commonality suggests that counteracting CXCL10 suppression may provide a generalizable therapeutic strategy against intracellular pathogens. Importance Leishmaniasis, an infectious disease that annually affects over one million people, is caused by intracellular parasites that have evolved to evade the host’s attempts to eliminate the parasite. Cutaneous leishmaniasis results in disfiguring skin lesions if the host immune system does not appropriately respond to infection. A family of molecules called chemokines coordinate recruitment of the immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that Leishmania (L.) major employs to suppress host chemokines: an L. major protease cleaves chemokines known to recruit T cells that fight off infection. We observe that other common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica , reduce levels of the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival.Item Open Access Physiological Functions of Biased Signaling at the Chemokine Receptor CXCR3(2019) Smith, JeffreyG protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and one of the most common drug targets. It is now well-established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, G protein receptor kinases, and beta-arrestins. Certain ligands can preferentially activate certain signaling cascades while inhibiting others, a phenomenon referred to as biased signaling. While biased signaling is observed in many ex-vivo assays, the physiological relevance of biased signaling is not well established. Using the chemokine receptor CXCR3, a receptor that regulates T cell function, and its endogenous chemokines CXCL9, CXCL10, and CXCL11, I established that endogenous biased signaling exists at CXCR3. After identifying small molecule biased CXCR3 agonists using cell-based assays, I utilized human samples and mouse models of T cell movement and inflammation to determine that differential activation of either the G protein or beta-arrestin signaling pathways downstream of CXCR3 produces distinct functional differences. I identified that beta-arrestin regulated-Akt signaling appears critical for full efficacy chemotaxis. I conclude that biased signaling at CXCR3 produces distinct physiological responses.