Franz Rischard

Interests

Research

Exercise physiologyRVPA couplingFunctional imaging of the RV and pulmonary vasculatureClinical trialsPulmonary vascular phenotypingPersonalized medicine in pulmonary hypertension

Teaching

Pulmonary physiologyExercise physiologyPulmonary vascular and right ventricular imaging

Courses

Scholarly Contributions

Journals/Publications

• Ahmed, M., Zaghloul, N., Zimmerman, P., Casanova, N. G., Sun, X., Song, J. H., Hernon, V. R., Sammani, S., Rischard, F., Rafikova, O., Rafikov, R., Makino, A., Kempf, C. L., Camp, S. M., Wang, J., Desai, A. A., Lussier, Y., Yuan, J. X., & Garcia, J. G. (2022). Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb. Pulmonary circulation, 11(4), 20458940211059712.
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  Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothelial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Hemodynamic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (three weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPT mice were exposed to 10% hypoxia (three weeks). Biochemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (right ventricular systolic pressure, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF- were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPT KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.
• Maestas, T., Hansen, L. M., Vanderpool, R. R., Desai, A. A., Airhart, S., Knapp, S. M., Cohen, A., Feldman, J., & Rischard, F. P. (2022). Right ventricular afterload predicts long-term transition from parenteral to oral treprostinil in pulmonary arterial hypertension. Pulmonary circulation, 8(4), 2045894018797270.
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  Despite the increasing trends, reports on long-term follow-up are limited on transitioning from parenteral to oral treprostinil therapy in patients with pulmonary arterial hypertension (PAH). We investigated both the effectiveness of parenteral to oral treprostinil transition and the characteristics associated with transition failure over a duration of two years. The study included 37 Group I functional class I and II patients with PAH on combination therapy. Patients were excluded if cardiac index ≤2.2 L/min/m, right atrial pressure ≥11 mmHg, or 6-min walk distance ≤250 m. Patients were categorized as successful (Transition) or unsuccessful (Transition) transition based on clinical stability, or a parenteral comparator (Parenteral) if they remained on parenteral therapy (no transition). All patients underwent two right heart catheterizations, one at enrollment and a second post transition. Of 24 total transition patients, 46% were classified as Transition. Transition occurred on average 577 days post transition. Both Transition and Transition had similar hemodynamics at diagnosis and treprostinil dose before and after transition. Before transition, the pulmonary vascular resistance (PVR) was significantly higher in the Transition (6.7 ± 2 WU) vs. Transition group (3.5 ± 1.5 WU). At follow-up catheterization, the Transition group demonstrated further increases in PVR, greater than the Parenteral group, without recovery despite "rescue" therapy in the Transition group. A pre-transition PVR of 4.16 WU discriminated the Transition from the Transition group. While a subset of PAH patients on combination therapy may be safely transitioned from parenteral to oral treprostinil, caution should be exercised in patients with elevated baseline PVR to avoid irreversible destabilization.
• Nathan, S. D., Tapson, V. F., Elwing, J., Rischard, F., Mehta, J., Shapiro, S., Shen, E., Deng, C., Smith, P., & Waxman, A. (2022). Efficacy of Inhaled Treprostinil on Multiple Disease Progression Events in Patients with Pulmonary Hypertension due to Parenchymal Lung Disease in the INCREASE Trial. American journal of respiratory and critical care medicine, 205(2), 198-207.
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  The INCREASE study of inhaled treprostinil met its primary endpoint of change in 6-minute-walk distance at Week 16. In addition, there were significantly fewer clinical worsening events in patients receiving inhaled treprostinil. However, the incidence of multiple events in the same patient is unknown. This analysis evaluated the effect of continued treatment with inhaled treprostinil on the frequency and impact of multiple disease progression events. Patients enrolled in INCREASE were analyzed for disease progression events, defined as at least 15% decline in 6-minute-walk distance, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, at least 10% decline in forced vital capacity, or death during the duration of the 16-week study. In total, 147 disease progression events occurred in the inhaled treprostinil group (89/163 patients, 55%) compared with 215 events (109/163 patients, 67%) in the placebo group ( = 0.018). There was a lower incidence of each disease progression component in the inhaled treprostinil group: 6-minute-walk distance decline (45 vs. 64 events), lung disease exacerbation (48 vs. 72 events), FVC decline (19 vs. 33), cardiopulmonary hospitalization (23 vs. 33 events), and death (10 vs. 12). Fewer patients receiving inhaled treprostinil had multiple progression events compared with those receiving the placebo (35 vs. 58, 22% vs. 36%;  = 0.005). Patients who received inhaled treprostinil were significantly less likely to experience further disease progression events after an initial event compared with patients receiving placebo. These results support the continuation of inhaled treprostinil despite the occurrence of disease progression in clinical practice.
• Romanoski, C. E., Qi, X., Sangam, S., Vanderpool, R. R., Stearman, R. S., Conklin, A., Gonzalez-Garay, M., Rischard, F., Ayon, R. J., Wang, J., Simonson, T., Babicheva, A., Shi, Y., Tang, H., Makino, A., Kanthi, Y., Geraci, M. W., Garcia, J. G., Yuan, J. X., & Desai, A. A. (2022). Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes. Pulmonary circulation, 10(4), 2045894020968531.
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  Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.
• Rosenkranz, S., Feldman, J., McLaughlin, V. V., Rischard, F., Lange, T. J., White, R. J., Peacock, A. J., Gerhardt, F., Ebrahimi, R., Brooks, G., Satler, C., Frantz, R. P., & , A. S. (2022). Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. Respiratory medicine, 10(1), 35-46.
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  Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH.
• Smith, P., Shapiro, S., Rischard, F., Nathan, S. D., Tapson, V. F., Elwing, J., Mehta, J., Shen, E., Deng, C., & Waxman, A. (2022). Efficacy of Inhaled Treprostinil on Multiple Disease Progression Events in Patients with Pulmonary Hypertension due to Parenchymal Lung Disease in the INCREASE Trial. American Journal of Respiratory and Critical Care Medicine, 205(2), 198-207. doi:10.1164/rccm.202107-1766oc
• Vanderpool, R. R., Tedford, R. J., Rischard, F. P., Insel, M., Hunter, K. S., Garcia, J. G., & Bedrick, E. J. (2022). The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension.. Chest, 161(4), 1048-1059. doi:10.1016/j.chest.2021.09.040
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  Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy..Does RV adaptation predict therapeutic response over time?.We evaluated 52 incident treatment-naive patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 months), and follow-up 2 (∼18 months). All patients received goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I or II was not achieved. On the basis of their therapeutic response, patients were evaluated at follow-up 1 as nonresponders (died) or as responders, and again at follow-up 2 as super-responders (low risk) or partial responders (high/intermediate risk). Multiparametric risk was based on a simplified European Respiratory Society/European Society of Cardiology guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean ± SD or as OR (95% CI)..Nine patients (17%) were nonresponders. PAH-directed therapy improved the European Respiratory Society low-risk score from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was nonsignificantly higher in responders (0.9 ± 0.4) vs nonresponders (0.6 ± 0.4; P = .09) but could not be used to predict super-responder status at follow-up 2 (OR, 1.40 [95% CI, 0.28-7.0]; P = .84). Baseline RV ejection fraction and change in Eed were successfully used to predict super-responder status at follow-up 2 (OR, 1.15 [95% CI, 1.0-1.27]; P = .009 and OR, 0.29 [95% CI, 0.86-0.96]; P = .04, respectively)..In patients with advanced PAH, RV-pulmonary arterial coupling could not discriminate irreversible RV failure (nonresponders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RV ejection fraction were the best predictors of therapeutic response.
• Vizza, C. D., Vigo, B., Vanderpool, R., Valli, G., Sciomer, S., Rischard, F., Rinaldo, R., Papa, S., Palange, P., Manzi, G., Insel, M., Howard, L., Giudice, F. L., Garcia, J. G., Fedele, F., & Badagliacca, R. (2022). Incremental value of cardiopulmonary exercise testing in intermediate-risk pulmonary arterial hypertension.. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. doi:10.1016/j.healun.2022.02.021
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  Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing in this setting remains undefined..Two independent cohorts with idiopathic PAH at intermediate risk were used to develop (n = 124) and externally validate (n = 143) the prognostic model. Cross-validation on the overall population was used to strengthen the results of the analysis. Risk assessment was based on the simplified version of the ESC/ERS guidelines score. Discrimination and calibration were assessed..A risk score was constructed based on the beta-coefficient of the cross-validated model, including the stroke volume index (SVI) and the peak oxygen uptake (VO2 peak). Patients were grouped based on cutoff values of the risk score allowing the highest discrimination in the overall cohort. Group 1, score ≤2 (101 patients) with VO2 peak ≥14 ml/kg/min and SVI >30 ml/m2; Group 2, score between 2 and 5 (112 patients) with VO2 peak between 9 and 14 ml/kg/min, and SVI between 20 and 50 ml/m2; Group 3, score >5 (46 patients) with VO2 peak
• Badagliacca, R., Papa, S., & Rischard, F. (2021). Multidimensional assessment and cluster analysis for idiopathic pulmonary arterial hypertension phenotyping. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 40(2), 166-167.
• Garcia, J. G., Vanderpool, R., Vizza, C. D., Vigo, B., Valli, G., Sciomer, S., Rischard, F., Rinaldo, R., Papa, S., Palange, P., Manzi, G., Insel, M., Howard, L., Giudice, F. L., Fedele, F., & Badagliacca, R. (2021). 150 Incremental value of cardiopulmonary exercise testing in intermediate-risk pulmonary arterial hypertension. European Heart Journal Supplements, 23(Supplement_G). doi:10.1093/eurheartj/suab133.015
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  Abstract Aims Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status despite targeted-therapy, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing (CPET) in this setting remains undefined. Methods and results Two independent cohorts with idiopathic PAH at intermediate risk were used to develop (n = 124) and externally validate (n = 143) the prognostic model. Risk assessment was based on the simplified version of the ESC/ERS guidelines score. The same definition of clinical worsening (CW) was used for both cohorts. Discrimination and calibration were assessed. Seventy-four derivation cohort patients experienced CW (51.2%) during a median of 34 months. Stroke volume index (SVI) and 6-min walk-distance (6MWD) were independent predictors of CW. With addition of CPET variables, SVI and VO2 peak independently improved the power of the prognostic model, determined by the integrated discrimination integral (IDI) index. ROC-derived cut-off values for SVI and VO2 peak were 34 and 14 ml/kg/min, respectively. Forty-eight validation cohort patients experienced CW (33.5%) during a median of 27 months follow-up. Different combinations of cut-off values of SVI and VO2 peak defined three meaningful groups showing good discrimination and calibration. The event-free survival rates at 1, 2, and 3 years were, respectively, 96%, 89%, and 89% for high SVI/high VO2 peak combination; 85%, 73%, and 61% for high SVI/low VO2 peak; and 80%, 70%, and 56% for low SVI/low VO2 peak. Conclusions Combinations of VO2 peak and SVI during follow-up is important in the prognostication of intermediate-risk prevalent patients with idiopathic PAH.
• Harris, D. T., Badowski, M., Jernigan, B., Sprissler, R., Edwards, T., Cohen, R., Paul, S., Merchant, N., Weinkauf, C. C., Bime, C., Erickson, H. E., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., Campion, J., , Chopra, M., et al. (2021). SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus. Biomedicines, 9(5).
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Jellis, C. L., Park, M. M., Abidov, A., Borlaug, B. A., Brittain, E. L., Frantz, R., Hassoun, P. M., Horn, E. M., Jaber, W. A., Jiwon, K., Karas, M. G., Kwon, D., Leopold, J. A., Maron, B., Mathai, S. C., Mehra, R., Rischard, F., Rosenzweig, E. B., Tang, W. H., , Vanderpool, R., et al. (2021). Comprehensive echocardiographic evaluation of the right heart in patients with pulmonary vascular diseases: the PVDOMICS experience. European heart journal. Cardiovascular Imaging.
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  There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease.
• Kariotis, S., Jammeh, E., Swietlik, E. M., Pickworth, J. A., Rhodes, C. J., Otero, P., Wharton, J., Iremonger, J., Dunning, M. J., Pandya, D., Mascarenhas, T. S., Errington, N., Thompson, A. A., Romanoski, C. E., Rischard, F., Garcia, J. G., Yuan, J. X., An, T. S., Desai, A. A., , Coghlan, G., et al. (2021). Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood. Nature communications, 12(1), 7104.
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  Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.
• Leopold, J. A., Kawut, S. M., Aldred, M. A., Archer, S. L., Benza, R. L., Bristow, M. R., Brittain, E. L., Chesler, N., DeMan, F. S., Erzurum, S. C., Gladwin, M. T., Hassoun, P. M., Hemnes, A. R., Lahm, T., Lima, J. A., Loscalzo, J., Maron, B. A., Rosa, L. M., Newman, J. H., , Redline, S., et al. (2021). Diagnosis and Treatment of Right Heart Failure in Pulmonary Vascular Diseases: A National Heart, Lung, and Blood Institute Workshop. Circulation. Heart failure, 14(6).
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  Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.
• Lussier, Y., Desai, A. A., Wang, J., Makino, A., Rafikov, R., Rafikova, O., Rischard, F., Sammani, S., Song, J. H., Sun, X., Casanova, N. G., Zaghloul, N., Ahmed, M., Zimmerman, P., Hernon, V. R., Kempf, C. L., Camp, S. M., Yuan, J. X., & Garcia, J. G. (2021). Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT‐neutralizing mAb. Pulmonary Circulation, 11(4), 1-14. doi:10.1177/20458940211059712
• Rahaghi, F. F., Allen, R. P., Balasubramanian, V. P., Chakinala, M. M., Elwing, J. M., Feldman, J., Leary, P. J., Rischard, F., Safdar, Z., Sood, N., & Oudiz, R. J. (2021). An expert panel delphi consensus statement on patient selection and management for transitioning between oral and inhaled treprostinil. Pulmonary pharmacology & therapeutics, 66, 101979.
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  Treprostinil, a prostacyclin analogue used in the treatment of pulmonary arterial hypertension (PAH), is available for administration by parenteral, oral, or inhaled routes. Transitioning between routes may be beneficial for appropriate patients; however, there is little published data on transitions between oral and inhaled treprostinil. We used a modified Delphi process to develop expert consensus recommendations on transitions between these formulations. Three questionnaires were used to develop statements about relevant aspects of transition management, which the panelists rated, using a Likert scale, from -5 (strongly disagree) to +5 (strongly agree). Eleven physicians with expertise in PAH treatment modalities, participated in the panel. Of the 492 statements evaluated, consensus was reached on 215 (43.7%). Key consensus recommendations included (1) accurately defining successful transition, as stable or improved PAH with good tolerability and adherence, and (2) patients with stable, low-risk PAH showing insufficient response or tolerability to their existing treprostinil therapy (and due to restrictions in up titration of dosing), as appropriate candidates for transitions between treprostinil formulations. Panelists did not reach consensus for an overall strategy for performing these transitions, mainly because of variability in their practice parameters. Consensus was also achieved on recommendations for adverse event management, including reassurance, administration of oral treprostinil 3 times daily with food, and dosing inhaled treprostinil at intervals ≥3 hours apart. The Delphi process aided in developing expert consensus recommendations that may provide clinically useful guidance for transitioning between treprostinil formulations. However, additional data from centers with high volumes of PAH patients undergoing treprostinil transitions would be optimal for defining more complete and robust strategies to facilitate successful transition.
• Rischard, F., Acharya, T., Insel, M., & Stroud, S. (2021). Abstract 9677: Therapeutic Improvements in Pulmonary Arterial Hypertension Are Related to Cardiopulmonary Function but Not Skeletal Muscle Oxygen Extraction. Circulation, 144(Suppl_1). doi:10.1161/circ.144.suppl_1.9677
• Rischard, F., Hassoun, P. M., Leopold, J. A., Kawut, S. M., Aldred, M. A., Archer, S. L., Benza, R. L., Bristow, M. R., Brittain, E. L., Chesler, N., DeMan, F. S., Erzurum, S. C., Gladwin, M. T., Hemnes, A. R., Lahm, T., Lima, J. A., Loscalzo, J., Maron, B. A., Mercer Rosa, L., , Newman, J. H., et al. (2021). Diagnosis and Treatment of Right Heart Failure in Pulmonary Vascular Diseases: A National Heart, Lung, and Blood Institute Workshop. Circulation: Heart Failure, 14(6). doi:10.1161/circheartfailure.120.007975
• Vanderpool, R. R., Hunter, K. S., Insel, M., Garcia, J. G., Bedrick, E. J., Tedford, R. J., & Rischard, F. P. (2021). The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension. Chest.
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  Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy.
• Badagliacca, R., Rischard, F., Papa, S., Kubba, S., Vanderpool, R., Yuan, J. X., Garcia, J. G., Airhart, S., Poscia, R., Pezzuto, B., Manzi, G., Miotti, C., Luongo, F., Scoccia, G., Sciomer, S., Torre, R., Fedele, F., & Vizza, C. D. (2020). Clinical implications of idiopathic pulmonary arterial hypertension phenotypes defined by cluster analysis. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 39(4), 310-320.
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  >Despite advances in drug development, life expectancy in idiopathic pulmonary arterial hypertension (IPAH) remains unacceptable. Contemporary IPAH characterization is based on criteria that may not adequately capture disease heterogeneity and may be proposed as a possible explanation for why patient outcome is still unfavorable. The aim of this study was to apply cluster analysis to improve phenotyping of patients with IPAH and analyze long-term clinical outcome of derived clusters.
• Chen, Y., Lu, W., Yang, K., Duan, X., Li, M., Chen, X., Zhang, J., Kuang, M., Liu, S., Wu, X., Zou, G., Liu, C., Hong, C., He, W., Liao, J., Hou, C., Zhang, Z., Zheng, Q., Chen, J., , Zhang, N., et al. (2020). Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension. British journal of pharmacology, 177(12), 2743-2764.
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  Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH).
• Hassoun, P. M., Hassoun, P. M., Tang, W., Tang, W., Rosenzweig, E. B., Rosenzweig, E. B., Rischard, F., Rischard, F., Radeva, M., Radeva, M., Leopold, J. A., Leopold, J. A., Horn, E. M., Horn, E. M., Hemnes, A. R., Hemnes, A. R., Frantz, R. P., & Frantz, R. P. (2020). Abstract 15800: Inter-race and Ethnicity Comparisons in Pulmonary Hypertension From the Pulmonary Vascular Phenomics (PVDOMICS) Program. Circulation, 142. doi:10.1161/circ.142.suppl_3.15800
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  Intro: Recent World Symposium of Pulmonary Hypertension (WSPH) Group 1 data indicate significant racial and ethnic disparities in disease severity and mortality. It is unclear if these differences ...
• Janowski, A. M., Vanderpool, R. R., Rischard, F., Ravellette, K. S., & Garcia, J. G. (2020). Abstract 17308: Unsupervised K-means Clustering to Identify Signatures of Right Ventricle Dysfunction in Patients With Pulmonary Hypertension. Circulation, 142. doi:10.1161/circ.142.suppl_3.17308
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  Introduction: Right ventricular (RV) function is a determinant of mortality in patients with pulmonary hypertension but current assessments are based on individual variables. Unsupervised k-means c...
• Karnes, J. H., Wiener, H. W., Schwantes-An, T. H., Natarajan, B., Sweatt, A. J., Chaturvedi, A., Arora, A., Batai, K., Nair, V., Steiner, H. E., Giles, J. B., Yu, J., Hosseini, M., Pauciulo, M. W., Lutz, K. A., Coleman, A. W., Feldman, J., Vanderpool, R., Tang, H., , Garcia, J. G., et al. (2020). Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine, 201(11), 1407-1415.
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  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. Patients with Group 1 PAH 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) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis. After covariate adjustment, self-reported Hispanic patients ( = 290) exhibited significantly reduced mortality versus NHW patients ( = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87];  = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01];  = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients ( = 1,524) versus NHW patients ( = 8,829; OR, 0.65 [95% CI, 0.50-0.84];  = 0.001). An inpatient mortality benefit was observed for Native American patients ( = 185; OR, 0.38 [95% CI, 0.15-0.93];  = 0.034). This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., Aini, T. E., Rischard, F., , Campion, J., et al. (2020). Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure. medRxiv : the preprint server for health sciences.
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  We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., , Campion, J., et al. (2020). Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity. Immunity, 53(5), 925-933.e4.
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  We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
• Rischard, F. (2019). Tools of the Trade: How Do You Perform and Interpret an Exercise Test?. Advances in Pulmonary Hypertension Official Journal of the Pulmonary Hypertension Association, 2(18), 47-55.
• Rosenzweig, E. B., Rischard, F., Leopold, J. A., Larive, A. B., Jacob, M., Horn, E. M., Hemnes, A. R., Hassoun, P. M., Frantz, R. P., Rosenzweig, E. B., Rischard, F., Leopold, J. A., Larive, A. B., Jacob, M., Horn, E. M., Hemnes, A. R., Hassoun, P. M., & Frantz, R. P. (2020). Abstract 17272: Frequency of Acute Vasodilator Response in Incident and Prevalent Patients With Pulmonary Arterial Hypertension (Group 1): Results From the Pulmonary Vascular Disease Omics (PVDOMICS) Study. Circulation, 142(Suppl_3). doi:10.1161/circ.142.suppl_3.17272
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  Introduction: The prevalence of acute vasodilator response (AVR) to inhaled NO (defined as a reduction in mPAP ≥ 10 mmHg with an absolute value of mPAP ≤ 40 mmHg with increased/unchanged CO) is rep...
• Rosenzweig, E. B., Rosenzweig, E. B., Rischard, F., Rischard, F., Leopold, J. A., Leopold, J. A., Larive, B., Larive, B., Horn, E. M., Horn, E. M., Hemnes, A. R., Hemnes, A. R., Hassoun, P. M., Hassoun, P. M., Frantz, R. P., Frantz, R. P., Finet, E., & Finet, E. (2020). Abstract 15433: The Left Atrium and Pulmonary Vascular Disease in PVDOMICS Cohorts. Circulation, 142. doi:10.1161/circ.142.suppl_3.15433
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  Left atrial (LA) size and function is recognized as a cumulative index of pulmonary capillary wedge pressure (PCWP) and an index of left heart disease (LHD). While anticipated that LA features cont...
• Rosenzweig, E. B., Rosenzweig, E. B., Rischard, F., Rischard, F., Leopold, J. A., Leopold, J. A., Larive, B., Larive, B., Jacob, M., Jacob, M., Horn, E. M., Horn, E. M., Hemnes, A. R., Hemnes, A. R., Hassoun, P. M., Hassoun, P. M., Frantz, R. P., & Frantz, R. P. (2020). Abstract 14817: Assessing the Burden of Cardiovascular Risk Factors and Disease Across PVDOMICS Cohorts. Circulation, 142. doi:10.1161/circ.142.suppl_3.14817
• Seckeler, M. D., Bliss, A., Rischard, F., & Klewer, S. E. (2020). Early bioprosthetic tricuspid valve stenosis due to size mismatch in Ebstein anomaly-Successful transcatheter treatment. Journal of cardiac surgery, 35(11), 3138-3140.
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  Patients with congenital heart disease are surviving well into adulthood thanks to advances in medical and clinical care. We present a patient with Ebstein anomaly who underwent surgical tricuspid valve replacement and suffered early valve stenosis due to her unique anatomy. This case highlights the importance of the "unnatural" anatomy that can be encounter in this challenging patient population.
• Seckeler, M., Rischard, F., Dobson, C., Boyer, P. J., & Strah, D. (2020). Improvement in ventilation-perfusion mismatch after percutaneous recanalization of near-atretic pulmonary artery due to non-small cell lung cancer. Current Problems in Cancer: Case Reports. doi:doi.org/10.1016/j.cpccr.2020.100025
• Sun, X., Sun, B. L., Babicheva, A., Vanderpool, R., Oita, R. C., Casanova, N., Tang, H., Gupta, A., Lynn, H., Gupta, G., Rischard, F., Sammani, S., Kempf, C. L., Moreno-Vinasco, L., Ahmed, M., Camp, S. M., Wang, J., Desai, A. A., Yuan, J. X., & Garcia, J. G. (2020). Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling. Transcriptional Regulation by SOX and HIF-2α. American journal of respiratory cell and molecular biology, 63(1), 92-103.
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  We previously demonstrated involvement of (nicotinamide phosphoribosyltransferase) in pulmonary arterial hypertension (PAH) and now examine regulation and extracellular NAMPT's (eNAMPT's) role in PAH vascular remodeling. transcription and protein expression in human lung endothelial cells were assessed in response to PAH-relevant stimuli (PDGF [platelet-derived growth factor], VEGF [vascular endothelial growth factor], TGF-β1 [transforming growth factor-β1], and hypoxia). Endothelial-to-mesenchymal transition was detected by SNAI1 (snail family transcriptional repressor 1) and PECAM1 (platelet endothelial cell adhesion molecule 1) immunofluorescence. An eNAMPT-neutralizing polyclonal antibody was tested in a PAH model of monocrotaline challenge in rats. Plasma eNAMPT concentrations, significantly increased in patients with idiopathic pulmonary arterial hypertension, were highly correlated with indices of PAH severity. eNAMPT increased endothelial-to-mesenchymal transition, and each PAH stimulus significantly increased endothelial cell promoter activity involving transcription factors STAT5 (signal transducer and activator of transcription 5), SOX18 (SRY-box transcription factor 18), and SOX17 (SRY-box transcription factor 17), a PAH candidate gene newly defined by genome-wide association study. The hypoxia-induced transcription factor HIF-2α (hypoxia-inducible factor-2α) also potently regulated promoter activity, and HIF-2α binding sites were identified between -628 bp and -328 bp. The PHD2 (prolyl hydroxylase domain-containing protein 2) inhibitor FG-4592 significantly increased promoter activity and protein expression in an HIF-2α-dependent manner. Finally, the eNAMPT-neutralizing polyclonal antibody significantly reduced monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-κB activation. eNAMPT is a novel and attractive therapeutic target essential to PAH vascular remodeling.
• Tang, W. H., Rosenzweig, E. B., Rischard, F., Leopold, J. A., Larive, A. B., Horn, E. M., Hemnes, A. R., Hassoun, P. M., & Frantz, R. P. (2020). ACUTE VASOREACTIVITY TESTING DURING RIGHT HEART CATHETERIZATION IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: RESULTS FROM THE PULMONARY VASCULAR DISEASE OMICS PROJECT. Chest, 158(4), A2154-A2155. doi:10.1016/j.chest.2020.08.1856
• Tang, W. H., Rosenzweig, E. B., Rischard, F., Leopold, J. A., Larive, A. B., Horn, E. M., Hemnes, A. R., Hassoun, P. M., & Frantz, R. P. (2020). ACUTE VASOREACTIVITY TESTING DURING RIGHT HEART CATHETERIZATION IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: RESULTS FROM THE PULMONARY VASCULAR DISEASE OMICS PROJECT. Chest, 158(4). doi:10.1016/j.chest.2020.08.1856
• Tang, W., Tang, W., Rosenzweig, E. B., Rosenzweig, E. B., Rischard, F., Rischard, F., Radeva, M., Radeva, M., Leopold, J. A., Leopold, J. A., Horn, E. M., Horn, E. M., Hemnes, A. R., Hemnes, A. R., Hassoun, P. M., Hassoun, P. M., Frantz, R. P., & Frantz, R. P. (2020). Abstract 15029: Atrial Arrhythmias and Pulmonary Hypertension Across Wsph Groups. Circulation, 142. doi:10.1161/circ.142.suppl_3.15029
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  Introduction: Previous reports have shown that atrial and ventricular arrhythmias (VA) are common in all forms of pulmonary hypertension (PH) with prevalence of supraventricular arrhythmias ranging...
• Rischard, F. (2018). Right Ventricular mass/volume in PHA: A double edged sword?. European Respiratory Journal. doi:10.1183/13993003
• Vanderpool, R. R., Puri, R., Osorio, A., Wickstrom, K., Desai, A., Black, S., Garcia, J. G., Yuan, J., & Rischard, F. (2019). EXPRESS: Surfing the Right Ventricular Pressure Waveform: Methods to assess Global, Systolic and Diastolic RV Function from a Clinical Right Heart Catheterization. Pulmonary circulation, 2045894019850993.
• Kubba, S., Vanderpool, R., Wickstrom, K., Rosado-toro, J., Rischard, F., Janardhanan, R., & Airhart, S. (2018). Abstract 17250: Underestimation of RV Volume by 3D Echocardiography in Patients With Severe PAH. Circulation, 138(Suppl_1). doi:10.1161/circ.138.suppl_1.17250
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  Background: Right ventricular (RV) volume is a significant predictor of mortality in pulmonary arterial hypertension (PAH). RV volume measured by 3D echocardiography (3DE) an attractive imaging modality because it is faster and cheaper than cardiac MRIs. However, newer semi-automated speckle tracking 3DE has not been validated against cardiac MRI (CMR) in patients with severe PAH and dilated RVs. This study investigated the feasibility of 3DE to measure RV volumes in a prevalent cohort of patients with severe PAH. Methods: Patients with severe PAH with a 3DE and CMR within 30 days were included. RV endocardial contours were performed using TomTec 4D RV analysis© for 3DE and Circle Cardiovascular Imaging 42© for CMR. Results: Patients (n = 11) had severe PAH as classified as having high sPAP (66.4±5.0 mmHg), and reduced RV ejection fraction as measured by CMR (37.7±2.9%). In two patients, 3DE was not obtainable due to suboptimal definition of ventricular walls. In the remaining patients, there were systematic underestimation of volumes by 3DE (EDV bias: -71.5 LOA: 63.7; ESV -58.7: LOA: 72.7) and appears to be volume dependent (Fig 1A ). Lack of agreement seemed to possibly be related to extrapolation of poorly defined lateral wall RV endocardium by 3DE in patients with a large right ventricle (Fig 1B). Conclusion: Lack of agreement between CMR and 3DE derived RV volumes suggests the need for further validation of 3DE in patients with severe PAH.
• Naeije, R., Saggar, R., Badesch, D., Rajagopalan, S., Gargani, L., Rischard, F., Ferrara, F., Marra, A. M., D' Alto, M., Bull, T. M., Saggar, R., Grünig, E., & Bossone, E. (2018). Exercise-Induced Pulmonary Hypertension: Translating Pathophysiological Concepts Into Clinical Practice. Chest, 154(1), 10-15.
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  Exercise stress testing of the pulmonary circulation for the diagnosis of latent or early-stage pulmonary hypertension (PH) is gaining acceptance. There is emerging consensus to define exercise-induced PH by a mean pulmonary artery pressure > 30 mm Hg at a cardiac output < 10 L/min and a total pulmonary vascular resistance> 3 Wood units at maximum exercise, in the absence of PH at rest. Exercise-induced PH has been reported in association with a bone morphogenetic receptor-2 gene mutation, in systemic sclerosis, in left heart conditions, in chronic lung diseases, and in chronic pulmonary thromboembolism. Exercise-induced PH is a cause of decreased exercise capacity, may precede the development of manifest PH in a proportion of patients, and is associated with a decreased life expectancy. Exercise stress testing of the pulmonary circulation has to be dynamic and rely on measurements of the components of the pulmonary vascular equation during, not after exercise. Noninvasive imaging measurements may be sufficiently accurate in experienced hands, but suffer from lack of precision, so that invasive measurements are required for individual decision-making. Exercise-induced PH is caused either by pulmonary vasoconstriction, pulmonary vascular remodeling, or by increased upstream transmission of pulmonary venous pressure. This differential diagnosis is clinical. Left heart disease as a cause of exercise-induced PH can be further ascertained by a pulmonary artery wedge pressure above or below 20 mm Hg at a cardiac output < 10 L/min or a pulmonary artery wedge pressure-flow relationship above or below 2 mm Hg/L/min during exercise.
• Tang, H., Wu, K., Wang, J., Vinjamuri, S., Gu, Y., Song, S., Wang, Z., Zhang, Q., Balistrieri, A., Ayon, R. J., Rischard, F., Vanderpool, R., Chen, J., Zhou, G., Desai, A. A., Black, S. M., Garcia, J. G., Yuan, J. X., & Makino, A. (2018). Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension. JACC. Basic to translational science, 3(6), 744-762.
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  Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.
• Whitaker, M. E., Nair, V., Sinari, S., Dherange, P. A., Natarajan, B., Trutter, L., Brittain, E. L., Hemnes, A. R., Austin, E. D., Patel, K., Black, S. M., Garcia, J. G., Yuan Md PhD, J. X., Vanderpool, R. R., Rischard, F., Makino, A., Bedrick, E. J., & Desai, A. A. (2018). Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension. The American journal of medicine, 131(6), 702.e7-702.e13.
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  Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction.
• Hemnes, A. R., Beck, G. J., Newman, J. H., Abidov, A., Aldred, M. A., Barnard, J., Berman Rosenzweig, E., Borlaug, B. A., Chung, W. K., Comhair, S. A., Erzurum, S. C., Frantz, R. P., Gray, M. P., Grunig, G., Hassoun, P. M., Hill, N. S., Horn, E. M., Hu, B., Lempel, J. K., , Maron, B. A., et al. (2017). PVDOMICS: A Multi-Center Study to Improve Understanding of Pulmonary Vascular Disease Through Phenomics. Circulation research, 121(10), 1136-1139.
• Newman, J. H., Rich, S., Abman, S. H., Alexander, J. H., Barnard, J., Beck, G. J., Benza, R. L., Bull, T. M., Chan, S. Y., Chun, H. J., Doogan, D., Dupuis, J., Erzurum, S. C., Frantz, R. P., Geraci, M., Gillies, H., Gladwin, M., Gray, M. P., Hemnes, A. R., , Herbst, R. S., et al. (2017). Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report. American journal of respiratory and critical care medicine, 195(12), 1661-1670.
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  The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched "Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics" (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.
• Rischard, F., Mathai, S. C., Newman, J. H., Rich, S., Abman, S. H., Alexander, J. H., Barnard, J., Beck, G. J., Benza, R. L., Bull, T. M., Chan, S. Y., Chun, H. J., Doogan, D., Dupuis, J., Erzurum, S. C., Frantz, R. P., Geraci, M., Gillies, H., Gladwin, M., , Gray, M. P., et al. (2017). Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI–Cardiovascular Medical Research and Education Fund Workshop Report. American Journal of Respiratory and Critical Care Medicine, 195(12), 1661-1670. doi:10.1164/rccm.201701-0150ws
• Song, S., Ayon, R. J., Yamamura, A., Yamamura, H., Dash, S., Babicheva, A., Tang, H., Sun, X., Cordery, A. G., Khalpey, Z. I., Black, S., Desai, A., Rischard, F., Mcdermott, K. M., Garcia, J. G., Makino, A., & Yuan, J. (2017). Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. American journal of physiology. Lung cellular and molecular physiology, 312(3), L309-L325.
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  Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that a capsaicin-induced increase in [Ca2+]cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs from healthy donors. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23 to 43°C, or decreasing the extracellular pH value from 7.4 to 5.9 enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca2+]cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing the extracellular osmotic pressure from 310 to 200 mOsmol/l also increased [Ca2+]cyt, and the hypo-osmolarity-induced rise in [Ca2+]cyt was greater in IPAH PASMCs than in healthy PASMCs. Inhibition of TRPV1 (with 5'-IRTX or capsazepine) or knockdown of TRPV1 (with short hairpin RNA) attenuated capsaicin-, acidity-, and osmotic stretch-mediated [Ca2+]cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca2+]cyt, and capsaicin-induced CREB phosphorylation were significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMC proliferation. Taken together, the capsaicin-mediated [Ca2+]cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca2+ influx and excessive PASMC proliferation in patients with IPAH.
• Tang, H., Babicheva, A., McDermott, K. M., Gu, Y., Ayon, R. J., Song, S., Wang, Z., Gupta, A., Zhou, T., Sun, X., Dash, S., Wang, Z., Balistrieri, A., Zheng, Q. Y., Cordery, A. G., Desai, A. A., Rischard, F., Khalpey, Z., Wang, J., , Black, S. M., et al. (2017). Endothelial HIF-2α Contributes to Severe Pulmonary Hypertension by Inducing Endothelial-to-Mesenchymal Transition. American journal of physiology. Lung cellular and molecular physiology, ajplung000962017.
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  Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration contributes to the elevated PVR in patients with IPAH. Here we report that increased HIF-2α in lung vascular endothelial cells (LVEC) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVEC from IPAH patients and PH animals compared with controls. LVEC from IPAH patients had a higher level of HIF-2α than that from normals, while HIF-1α was upregulated in IPAH-PASMC. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), was involved in the enhanced EndMT and upregulated SNAI1/2 in IPAH-LVEC. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1/SNAI2 expression in IPAH-LVEC. Mice with EC-specific knockout (KO) of the PHD2 gene, egln1 (egln1EC-/-), developed severe PH under normoxic conditions; while Snai1/2 and EndMT were increased in LVEC of egln1EC-/- mice. EC-specific KO of the HIF-2α gene, hif2a, prevented mice from developing hypoxia-induced PH, whereas EC-specific deletion of the HIF-1α gene, hif1a, or SMC-specific deletion of hif2a, negligibly affected the development of PH. Also, hypoxia (48-72 hrs) increased HIF-1α in normal human PASMC and HIF-2α in normal human LVEC. These data indicate that increased HIF-2α in LVEC plays a pathogenic role in the development of PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and remodeling.
• Vanderpool, R. R., Desai, A. A., Knapp, S. M., Simon, M. A., Abidov, A., Yuan, J. X., Garcia, J. G., Hansen, L. M., Knoper, S. R., Naeije, R., & Rischard, F. P. (2017). How prostacyclin therapy improves right ventricular function in pulmonary arterial hypertension. The European respiratory journal, 50(2).
• Vanderpool, R. R., Tang, H., Rischard, F., & Yuan, J. X. (2017). Is p38 MAPK a Dark Force in Right Ventricular Hypertrophy and Failure in Pulmonary Arterial Hypertension?. American journal of respiratory cell and molecular biology, 57(5), 506-508.
• Chakinala, M. M., Feldman, J. P., Rischard, F., Mathier, M., Broderick, M., Leedom, N., Laliberte, K., & White, R. J. (2016). Transition from parenteral to oral treprostinil in pulmonary arterial hypertension. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.
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  Parenteral prostanoids are effective treatment for pulmonary arterial hypertension, but long-term pump infusion systems have significant delivery-related safety and convenience limitations.
• Oudiz, R., Agarwal, M., Rischard, F., & De Marco, T. (2016). An advanced protocol-driven transition from parenteral prostanoids to inhaled trepostinil in pulmonary arterial hypertension. Pulmonary circulation, 6(4), 532-538.
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  Patients with pulmonary arterial hypertension (PAH) often require parenteral prostanoids to improve symptoms and signs of PAH. Complications of parenteral prostanoids-such as catheter-related infections and intolerable adverse effects-may develop, prompting transition to inhaled prostanoids. We report a prospective, protocol-driven transition from parenteral prostanoids to inhaled prostanoids with monitoring of exercise gas exchange and acute hemodynamics. Three PAH centers recruited patients transitioning from parenteral prostanoids to inhaled trepostinil. Rigid inclusion criteria were used, including parenteral prostanoid dose < 30 ng/kg/min, New York Heart Association functional class (FC) < 3, and pulmonary vascular resistance (PVR) < 6 Wood units. Of the 9 patients meeting initial inclusion criteria, 3 were excluded. In the remaining patients, the parenteral prostanoid was reduced and the inhaled prostanoid was increased over 24-36 hours with continuous hemodynamic monitoring. Exercise capacity and FC were measured at baseline and weeks 1, 4, and 12. All patients were successfully weaned from parenteral prostanoids. An acute PVR decrease was seen with most inhaled prostanoid doses, but PVR varied throughout the transition. Patients tolerated inhaled prostanoids for 9-12 breaths 4 times a day with no treatment-limiting adverse events. At week 12, FC was unchanged, and all patients continued to receive inhaled prostanoids without serious adverse events or additional PAH therapy. In 5 of 6 patients, 6-minute walk distance and peak [Formula: see text] were within 10% of baseline. Using a strict transition protocol and rigid patient selection criteria, the parenteral prostanoid to inhaled prostanoid transition appeared safe and well tolerated and did not result in clinical deterioration over 12 weeks. Hemodynamic variability noted acutely during transition in our study did not adversely affect successful transition. (Trial registration: ClinicalTrials.gov identifier: NCT01268553).
• Rischard, F., Oudiz, R., Agarwal, M., & De Marco, T. (2016). An Advanced Protocol‐Driven Transition from Parenteral Prostanoids to Inhaled Trepostinil in Pulmonary Arterial Hypertension. Pulmonary Circulation, 6(4), 532-538. doi:10.1086/688711
• Song, S., Ayon, R. J., Yamamura, A., Yamamura, H., Dash, S., Babicheva, A., Tang, H., Sun, X., Cordery, A. G., Khalpey, Z. I., Black, S. M., Desai, A. A., Rischard, F., McDermott, K. M., Garcia, J. G., Makino, A., & Yuan, J. X. (2016). Capsaicin-induced Ca2+ Signaling is Enhanced via Upregulated TRPV1 Channels in Pulmonary Artery Smooth Muscle Cells from Patients with Idiopathic PAH. American journal of physiology. Lung cellular and molecular physiology, ajplung.00357.2016.
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  Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that capsaicin-induced increase in [Ca2+]cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23ºC to 43ºC, or decreasing extracellular pH value from 7.4 to 5.9, enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43ºC)-mediated enhancement of capsaicin-induced [Ca2+]cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing extracellular osmotic pressure from 310 to 200 mOsmol/L also increased [Ca2+]cyt and the hypoosmolarity-induced rise in [Ca2+]cyt was greater in IPAH PASMCs than in normal PASMCs. Inhibition of TRPV1 (with 5'-IRTX or capsazepine) or knockdown of TRPV1 (with shRNA) attenuated capsaicin-, acidity- and osmotic stretch-mediated [Ca2+]cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca2+]cyt; the capsaicin-induced CREB phosphorylation was significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMCs proliferation. Taken together, the capsaicin-mediated [Ca2+]cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism contributing to the augmented Ca2+ influx and excessive PASMCs proliferation in IPAH patients.
• Tang, H., Yamamura, A., Yamamura, H., Song, S., Fraidenburg, D. R., Chen, J., Gu, Y., Pohl, N. M., Zhou, T., Jiménez-Pérez, L., Ayon, R. J., Desai, A. A., Goltzman, D., Rischard, F., Khalpey, Z., Black, S. M., Garcia, J. G., Makino, A., & Yuan, J. X. (2016). Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology, 310(9), L846-59.
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  An increase in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. Previously, we demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) and animals with experimental pulmonary hypertension (PH) were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca(2+) influx in PASMC and the implication of CaSR in the development of PH remain elusive. Here, we report that CaSR functionally interacts with TRPC6 to regulate [Ca(2+)]cyt in PASMC. Downregulation of CaSR or TRPC6 with siRNA inhibited Ca(2+)-induced [Ca(2+)]cyt increase in IPAH-PASMC (in which CaSR is upregulated), whereas overexpression of CaSR or TRPC6 enhanced Ca(2+)-induced [Ca(2+)]cyt increase in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, whereas blockade of CaSR in IPAH-PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice (casr(-/-)) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction. These data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development and progression of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension.
• Vanderpool, R. R., Rischard, F., Naeije, R., Hunter, K., & Simon, M. A. (2016). Simple functional imaging of the right ventricle in pulmonary hypertension: Can right ventricular ejection fraction be improved?. International journal of cardiology, 223, 93-94.
• Abidov, A., & Rischard, F. (2015). Quantitative Right Ventricular Function in Pulmonary Arterial Hypertension: A Quest for a More Reliable Metric. Echocardiography (Mount Kisco, N.Y.).
• Bernardo, R., Dalabih, M., Jenkins, I., Hansen, L., Knoper, S., & Rischard, F. (2015). 18. Increased Afterload And Stroke Work During Exercise Does Not Amplify Resting Ventriculo-Vascular Uncoupling In Patients With Pulmonary Arterial Hypertension On Therapy.. American Journal of Respiratory and Critical Care Medicine.
• Dalabih, M. R., Bernardo, R. J., Hansen, L., Tafich-Rios, C. A., & Rischard, F. (2015). 17. Invasive Cardiopulmonary Exercise Testing Characterizes a Unique Phenotype of Patients with Interstitial Lung Disease and Pulmonary Hypertension Similar to Patients with Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., Bernardo, R., Vanderpool, R., Abidov, A., Jenkins, I., Simon, M. A., Hansen, L., Knoper, S., & Champion, H. C. (2015). Right ventricular (RV) morphometric and ventriculo-vascular (VV) coupling patterns in patients with advanced pulmonary arterial hypertension (PAH) undergoing parenteral treprostinil therapy.. European Resp Journal.
• Rischard, F., Jenkins, I., Raz, Y., Hansen, L., Knoper, S., Thomson, J., Hobson, N., & Hunter, K. S. (2015). 19. RV Stroke Work Index Better Predicts Early Right Ventricular Uncoupling, Mortality, And Treatment Response Than Traditional Metrics Of Right Ventricular Function In Patients With Advanced Treatment Naive Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., Vanderpool, R., Jenkins, I., Colombo, J., Lax, D., & Seckler, M. D. (2015). Selective Pulmonary Vasodilation Improves Ventriculo-vascular Coupling and Gas Exchange in a Patient with Unrepaired Single Ventricle Physiology. Pulmonary Circulation, 407-411.
• Rischard, F., Vanderpool, R., Jenkins, I., Dalabih, M., Colombo, J., Lax, D., & Seckeler, M. (2015). Selective pulmonary vasodilation improves ventriculovascular coupling and gas exchange in a patient with unrepaired single-ventricle physiology. Pulmonary circulation, 5(2), 407-11.
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  We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology.
• Dalabih, M., Rischard, F., & Mosier, J. M. (2014). What's new: the management of acute right ventricular decompensation of chronic pulmonary hypertension. Intensive care medicine, 40(12), 1930-3.
• Hansen, L., Rischard, F., & Knoper, S. (2014). Safety, Tolerability, and Efficacy of Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension. Journal of Heart and Lung Transplantation, S309, 33.
• Rischard, F., Champion, H. C., Jenkins, R., Hansen, L., Knoper, S., & Waxman, A. (2014). Right ventriculo-arterial coupling in patients with pulmonary arterial hypertension undergoing rapid dose escalation of treprostinil. Journal of Heart and Lung Transplantation, 33.
• Rischard, F., & McKean, T. (1998). Ischemia and ischemic preconditioning in the buffer-perfused pigeon heart. Comparative biochemistry and physiology. Part C, Pharmacology, toxicology & endocrinology, 119(1), 59-65.
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  Isolated pigeon hearts were perfused with Krebs-Henseleit bicarbonate buffer with 1.25 mM Ca++ at a pressure of 60 cm H2O and paced at 210 beats per min. After an equilibration perfusion of 30 min, hearts were subjected to 10 min global ischemia and then reperfused for 30 min. Left ventricular +dP/dtmax, systolic, and end diastolic pressures differed significantly from baseline values during reperfusion as did the release of lactate dehydrogenase (LDH). When the hearts were preconditioned by interruption of flow for two 2.5-min intervals, followed by 10 min of ischemia and then reperfusion, the short periods of ischemia, followed by reperfusion, protected the hearts against the longer bout of ischemia as evidenced by significant differences between the left ventricular (LV) pressure, +dP/dtmax, LV end diastolic pressure and LDH values obtained from the hearts of control vs. preconditioned hearts. Substitution of 1 microM adenosine for the preconditioning ischemia also resulted in the preconditioning response. Ischemic preconditioning (IP) was not blocked by addition of 100 microM 8-(-p-sulfophenyl) theophylline, an adenosine receptor antagonist. Therefore, isolated, perfused bird hearts can be preconditioned, and the mechanism may involve adenosine receptors, although their activation is not necessary for i.p. to occur. Factors in addition to adenosine are likely involved.

Proceedings Publications

• Rischard, F., Chatterjee, A., Insel, M., Kubba, S., Habib, N., Sher, N., Tandon, A., & Seckeler, M. (2022). To Drain or Not to Drain: Hemodynamic Characterization of Tamponade in PAH. In American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., Kubba, S., Uhland, C., Insel, M., & Stroud, S. (2022). Oxygen Utilization as a Primary Mediator of Age-Related Functional Decline in Pulmonary Arterial Hypertension. In American Journal of Respiratory and Critical Care Medicine.
• Rischard, F. P., Radeva, M., Pvdo, G. A., & Highland, K. B. (2020). Concurrent Heart or Lung Disease Significantly Lowers the Six Minute Walk Distance in World Symposium of Pulmonary Hypertension Group 1 Pulmonary Arterial Hypertension. In B55. POT POURRI OF THE TOP CLINICAL STUDIES IN PULMONARY HYPERTENSION.
• Airhart, S., Desai, A. A., Garcia, J. G., Vanderpool, R. R., Yuan, J. X., Vanderpool, R., Rischard, F. P., Puri, R., Lizarraga, A., Hansen, L., Erickson, H., Desai, A. A., & Airhart, S. (2019). Additive Effect of Sleep Disordered Breathing on the Severity of Pulmonary Vascular Disease in Patients with Pulmonary Arterial Hypertension. In C52. USE YOUR ILLUSION II: CLINICAL RESEARCH IN PAH.

Presentations

• Habib, N., Sher, A., Tandon, S., Kubba, S., Insel, M., Chatterjee, A., Seckeler, M., & Rischard, F. (2022, May). To Drain or Not to Drain: Hemodynamic Charcterization of Tamponade in Pulmonary Arterial Hypertension. American Thoracic Society 2022. San Francisco, CA.
• Rischard, F., Kubba, S., Stroud, S. C., Insel, M., & Uhland, C. (2022, May). Oxygen Utilization as a Primary Mediator of Age-Related Functional Decline in Pulmonary Arterial Hypertension. American Thoracic Society 2022. San Francisco, CA.
• Vanderpool, R., Rischard, F., & Seckeler, M. (2020, September). Long-term hemodynamic benefits after ‘treat-to-close’ for intracardiac shunts and pulmonary hypertension. European Respiratory Society International Congress 2020. Vienna, Austria.
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  Virtual event due to COVID-19 pandemic
• Rischard, F., Desai, A., Garcia, J. G., & Yuan, J. (2017, May). Right ventriculo-arterial physiologic and morphologic phenotyping in Hispanic and non-Hispanic cohorts (PVDOMICS). American Thoracic Society Conference. Washington, D.C.: American Thoracic Society.
• Vanderpool, R., Knapp, S. M., Honkanen, I., Wickstrom, K., Desai, A., Bernardo, R., Rischard, F., Vanderpool, R., Knapp, S. M., Honkanen, I., Wickstrom, K., Desai, A., Bernardo, R., & Rischard, F. (2017, January). Feasibility of determining right ventricular diastolic stiffness from a standard right heart catheterization. Pulmonary Vascular Research Institute Annual Conference. MIami, FL: Pulmonary Vascular Research Institute.
• Vanderpool, R., Vanderpool, R., Knapp, S. M., Knapp, S. M., Honkanen, I., Honkanen, I., Wickstrom, K., Wickstrom, K., Desai, A., Desai, A., Bernardo, R., Bernardo, R., Rischard, F., & Rischard, F. (2017, May). Resting right ventricular diastolic function and pulmonary arterial compliance associate with right ventricular contractile reserve in patients with pulmonary arterial hypertension.. American Thoracic Society Conference. Washington, D.C.: American Thoracic Society.
• Rischard, F. (2015, December). Pulmonary Vascular Disease in Connective Tissue Disorders. Rheumatology Grand Rounds. Tucson, AZ.
• Agarwal, M. I., De Marco, T., Rischard, F., & Oudiz, R. J. (2014, October). Protocol-Driven Transition from Parenteral Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension (PAH). Chest (Oral presentation). Austin, TX.
• Rischard, F. (2014, August). Pulmonary Hypertension. Pulmonary/Critical Care Didactics. Tucson, AZ: The University of Arizona.
• Rischard, F. (2014, June). Right ventriculo-arterial coupling in patients with pulmonary arterial hypertension undergoing rapid dose escalation of treprostinil. Pulmonary Hypertension Association International Conference. Indianapolis, IN.
• Rischard, F. (2014, October). Ventriculo-vascular coupling. Southwest Pulmonary Arterial Hypertension Symposium. Phoenix, AZ.
• Rischard, F. (2015, October). Types of Pulmonary Hypertension-Classifications and New Information. PHA On-the Road Conference. Phoenix, AZ.
• Rischard, F. (2013, February). Advanced Pulmonary Hemodynamics. College of Medicine, Cardiology. Tucson, AZ: The University of Arizona.
• Rischard, F. (2013, September). Pulmonary Hypertension. Pulmonary/Critical Care Didactics. Tucson, AZ: The University of Arizona.
• Rischard, F. (2014, August). Exercise catheterization. PHRN Conference. Washington, DC.
• Rischard, F. (2012, February). Advanced Pulmonary Hemodynamics. Pulmonary/Critical Care Didactics. Tucson, AZ: The University of Arizona.
• Rischard, F. (2012, September). Assessing Volume Responsiveness in the ICU. Pulmonary/Critical Care Didactics. Tucson, AZ: The University of Arizona.
• Rischard, F. (2011, December). Pulmonary Vascular Physiology and Pathophysiology. Pulmonary/Critical Care Didactics. Tucson, AZ: The University of Arizona.
• Rischard, F. (2011, October). Pulmonary Hypertension Diagnosis and Therapy. Pulmonary/Critical Care Didactics. Tucson, AZ: The University of Arizona.
• Rischard, F. (2014, October). Clinical applications of exercise catheterization. Southwest Pulmonary Arterial Hypertension Symposium. Phoenix, AZ.
• Rischard, F. (2009, Spring). Pulmonary hypertension and current therapy. 18th Annual Southwestern Conference on Medicine. Tucson, az.
• Rischard, F. (2009, Spring). Pulmonary hypertension and current therapy. 19th Annual Southwestern Conference on Medicine. Tucson, AZ.

Poster Presentations

• Rischard, F., Vanderpool, R., Janardhanan, R., Desai, A., Rosado-Toro, J., Wickstrom, K., Airhart, S., & Kubba, S. (2019, May). The Inaccuracy of Right Ventricular 3d Echocardiography Is Accentuated by Disease Severity in Pulmonary Arterial Hypertension. American Thoracic Society 2019. Dallas, TX.
• Rischard, F., Yuan, J., Garcia, J., Naeije, R., Janardhanan, R., Kubba, S., Hansen, L., Lizarraga, A., Erickson, H., Airhart, S., Puri, R., Holmathchi, J., & Vanderpool, R. (2019, May). Ratio of Stroke Volume to End-Systolic Volume Predicts Change in Right Ventricular Ejection Fraction in Patients with Pulmonary Arterial Hypertension. American Thoracic Society 2019. Dallas, TX.
• Vanderpool, R., Rischard, F., Yuan, J., Airhart, S., Kubba, S., & Keeley Ravellette, K. (2019, April). Increased Pulmonary Vascular Impedance in Patients with Severe Pulmonary Arterial Hypertension. Experimental Biology 2019. Orlando, FL.
• Vizza, C., Fedele, F., Torre, R., Sciomer, S., Manzi, G., Pezzuto, B., Poscia, R., Airhart, S., Garcia, J., Yuan, J., Vanderpool, R., Kubba, S., Papa, S., Rischard, F., & Badagliacca, R. (2019, April). Clinical Implications of Idiopathic Pulmonary Arterial Hypertension Phenotypes Defined by Cluster Analysis. International Society for Heart and Lung Transplantation 2019. Orlando, FL.
• Rischard, F., Vanderpool, R., Janardhanan, R., Rosado-Toro, J., Wickstrom, K., Airhart, S., & Kubba, S. (2018, spring). Underestimation of RV Volume by 3D Echocardiography in Patients With Severe PAH. American Heart Association Annual Scientific Session 2018. Chicago, IL.
• Seckeler, M., Rischard, F., Stout, J., Seckeler, M., Rischard, F., Stout, J., Seckeler, M., Rischard, F., & Stout, J. (2018, April). Use of a New Predictive Equation for Oxygen Consumption in Adults With Pulmonary Hypertension Undergoing Cardiac Catheterization. The Society for Cardiovascular Angiography and Interventions 2018 Scientific Sessions. San Diego, CA.
• Servin, F., Rosado, J. A., Janardhanan, R., Yuan, J., Rischard, F., & Vanderpool, R. (2018, Summer). Assessment of Pulmonary Arterial Structure and its Association with Right Ventricular Function in Pulmonary Arterial Hypertension. Biomechanics, Bioengineering and Biotransport Conference. Seven Springs, PA.
• Bernardo, R., Wickstrom, K., Desai, A., Nair, V., Vanderpool, R., Rischard, F., Bernardo, R., Wickstrom, K., Desai, A., Nair, V., Vanderpool, R., Rischard, F., Bernardo, R., Wickstrom, K., Desai, A., Nair, V., Vanderpool, R. R., Rischard, F., Bernardo, R., , Wickstrom, K., et al. (2017, September). Echocardiographic measures of right ventricular function poorly correlate with changes in contractility and coupling in treatment naïve patients with pulmonary artery hypertension before and after therapy.. European Respiratory Society Congress. Milan, Italy: European Respiratory Society.
• Bernardo, R., Wickstrom, K., Honkanen, I., Desai, A., Vanderpool, R., Rischard, F., Bernardo, R., Wickstrom, K., Honkanen, I., Desai, A., Vanderpool, R., & Rischard, F. (2017, January). Eccentric right ventricular remodeling is beneficial in pulmonary arterial hypertension patients responding to Treprostinil. Annual Pulmonary Vascular Research Institute (PVRI) World Congress. Miami, F: Pulmonary Vascular Research Institute.
• Gupta, A., Lynn, H. D., Nair, V., Gupta, G., Cordery, A., Patel, K., Kadakia, A., Knox, K., Larson, B., Duarte, J., Rischard, F., Garcia, J. G., Yuan, J., & Desai, A. (2017, May). Exome sequencing reveals a novel SNP in UCHL1 in pulmonary arterial hypertension.. American Thoracic Society Conference.. Washington, D.C.: American Thoracic Society.
• Hansen, L., Maestas, T., Knapp, S., Erickson, H., Desai, A., & Rischard, F. (2017, May). long-term transition from parenteral to oral treprostinil: Associations with baseline RV afterload but not function. American Thoracic Society Conference. Washington, D.C.: American Thoracic Society.
• Nair, V., Whitaker, M. E., Sinari, S., Natarajan, B., Trutter, L., Dherange, P., Brittain, E. L., Hemnes, A. R., Austin, E. D., Patel, K., Kadakia, A., Rischard, F., Garcia, J. G., Yuan, J., Makino, A., Black, S., Bedrick, E. J., & Desai, A. (2017, May). Effects of diabetes mellitus on pulmonary vascular stiffness and right ventricular remodeling. American Thoracic Society Conference. Washington, D.C.: American Thoracic Society.
• Natarajan, B., Nair, V., Dhrange, P., Whitaker, M., Riaz, I., Shewale, A., Yarlagadda, V., Patel, K., Knox, K., Khalpey, Z. I., Suryanarayana, P., Black, S., Garcia, J. G., Rischard, F., Yuan, J., & Desai, A. (2017, June). Hispanic disparities in PAH: Multi-modality validation of increased susceptibility to right ventricular dysfunction. Arizona Chapter of American College of Cardiology. Phoenix, AZ: Arizona Chapter of American College of Cardiology.
• Rosado-Toro, J. A., Avery, R., Altbach, M. I., Rischard, F., & Vanderpool, R. R. (2017, November). Feasibility of MRI-RHC based pressure volume loops in control and PAH patients. AHA Annual Conference. Anahaim, CA: American Heart Association.
• Vanderpool, R. R., Knapp, S. M., Honkanen, I., Wickstrom, K., Desai, A., Bernardo, R., & Rischard, F. (2017, May). Resting right ventricular diastolic function and pulmonary arterial compliance associate with right ventricular contractile reserve in patients with pulmonary arterial hypertension. American Thoracic Society Conference. Washington, D.C.: American Thoracic Society.
• Abidov, A., Pahuja, M., Desai, A., Bernardo, R., Dingell, J. D., & Rischard, F. (2016, November). The effects of interventricular uncoupling pulmonary arterial hypertension 0n MRI-derived metrics 0f right and left ventricular volumes and function: Comparison with invasive hemodynamics. Society of Cardiovascular Magnetic Resonance Scientific Session. Los Angeles, C: Society of Cardiovascular Magnetic Resonanc.
• Natarajan, B., Nair, V., Dherange, P., Whitaker, M., Riaz, I., Shewale, A., Yarlagadda, V., Patel, K., Knox, K. S., Khalpey, Z. I., Suryanarayana, P., Black, S., Garcia, J. G., Rischard, F., Yuan, J., & Desai, A. (2016, November). Hispanic disparities in PAH: Multi-modality validation of increased susceptibility to right ventricular dysfunction.. American Heart Association Scientific Sessions;. New Orleans, L: American Heart Association.
• Whitaker, M. E., Nair, V., Sinari, S., Natarajan, B., Trutter, L., Aystin, E. D., Hemnes, A. R., Brittain, E. L., Dherange, P., Patel, K., Rischard, F., Yuan, J., Makino, A., Bedrick, E. J., & Desai, A. (2016, November). Effects of insulin resistance on pulmonary vascular stiffness and right ventricular remodeling.. American College of Physicians - Arizona Chapter Scientific Meeting. Phoenix, AZ: American College of Physicians - Arizona Chapter Scientific Meeting.
• Bernardo, R., Vanderpool, R., Abidov, A., Jenkins, I., Simon, M. A., Hansen, L., Knoper, S., Champion, H. C., & Rischard, F. (2015, January). A concentric hypertrophic right ventricular phenotype in advanced pulmonary arterial hypertension is associated with increased ventriculo-vascular stiffening and impaired treatment response to parenteral treprostinil. 8th Pulmonary Vascular Research Institute Annual World Congress. Guangzhou, China.
• Dherange, P., Nair, V., Irbaz Bin Riaz, F., Shewale, A., Whitaker, M. E., Yarlagadda, V., Chinthammit, C., Knox, K. S., Khalpey, Z. I., Suryanarayana, P., Rischard, F., Hansen, L., Yuan, J., Garcia, J. G., & Desai, A. (2015, August). Disparities in pulmonary arterial hypertension: Effects of Hispanic ethnicity on susceptibility to right ventricular dysfunction. 2015 American College of Physicians Meeting (ACP). Phoenix, AZ: American College of Physicians.
• Dherange, P., Nair, V., Riaz, I. B., Shewale, A., Whitaker, M. E., Yarlagadda, V., Rischard, F., Hansen, L., & Desai, A. (2015, April). Referral patterns in pulmonary hypertension: A single center experience. 2015 CHEST Conference. Montreal, Quebec, Canada: American College of Chest Physicians.
• Rischard, F., Vanderpool, R., Jenkins, I., Simon, M. A., Hansen, L., Knoper, S., & Champion, H. C. (2015, January). The prospective relationship of traditional metrics of RV function to right ventriculo-vascular coupling in patients with advanced pulmonary arterial hypertension undergoing titration of parenteral treprostinil. 8th Pulmonary Vascular Research Institute Annual World Congress. Guangzhou, China.
• Rischard, F., Vanderpool, R., Champion, H., Simon, M., Rischard, M., Jenkins, I., Knoper, S., Hansen, L., & Waxman, A. (2014, September). Afterload Reduction Governs Improvement in RV Systolic Function and Ventriculo-Arterial Adaptation in Patients with Pulmonary Arterial Hypertension(PAH) Undergoing Rapid Dose Escalation of Tresprostinil. Afterload Reduction Governs Improvement in RV Systolic Function and Ventriculo-Arterial Adaptation in Patients with Pulmonary Arterial Hypertension(PAH) Undergoing Rapid Dose Escalation of Tresprostinil. Munich, Germany.
• Rischard, F., & Knoper, S. (2013, September). Surrogate Markers of Right Ventricular Adaptation Better Predict Long-term Survival in Patients with Pulmonary Arterial Hypertension On Therapy Than Traditional Prognostic Variables. European Respiratory Society Meeting. Barcelona, Spain.
• Rischard, F., Quan, S., Knoper, S., & Bloom, J. (2006, October 2006). Association between right heart enlargement and restrictive lung pattern in patients with pulmonary arterial hypertension. Chest 2006: 72nd Annual International Scientific Assembly of the American College of Chest Physicians. Salt Lake City, UT.

Others

• Dalabih, M., & Rischard, F. (2014, May). Right Ventricular Pulsatile Loading Is Increased By Exercise in Patients with Resting and Exercise-Associated Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., Champion, H. C., Vanderpool, R., Jenkins, I., Hansen, L., Hunter, K. S., Knoper, S., & Waxman, A. (2014, May). Prospective evaluation of surrogate measures of ventriculo-arterial coupling in patients with pulmonary arterial hypertension undergoing rapid dose escalation of treprostinil. American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., Champion, H. C., Vanderpool, R., Jenkins, I., Hansen, L., Knoper, S., & Waxman, A. (2014, May). Pulsatile unloading of the right ventricle results in significant afterload reduction in patients with pulmonary arterial hypertension undergoing rapid dose escalation of treprostinil. American Journal of Respiratory and Critical Care Medicine.
• White, R. J., Rischard, F., Chakinala, M., Howell, M., Laliberte, K., & Feldman, J. (2014, Spring). Safety and Tolerability of Transitioning from Parenteral Treprostinil to Oral Treprostinil in Patients with Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine.
• Dalabih, M., Sam, A., & Rischard, F. (2013, May). Characterization Of patients With Exercise-Associated Pulmonary Arterial Hypertension Responding To Therapy. American Journal of Respiratory and Critical Care Medicine.
• Rischard, F., & Knoper, S. (2013, May). Surrogate Markers Of Right Ventricular Adaptation Better Predict Survival Than Does TAPSE In Patients With PAH Responding To Therapy. American Journal of Respiratory and Critical Care Medicine.
• Saggar, R., Rischard, F., White, R. J., Mathier, M., Elwing, J., Allen, R., Peterson, L., Anerson, C., Laliberte, K., & Saggar, R. (2013, May). Effect Of Oral Treprostinil On Hemodynamics During Exercise In Patients With Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine.
• Vo, T., Knox, K. S., Rischard, F., & Hansen, L. (2012, Spring). Treprostinil Induced Platelet Dysfunction and Massive Hemoptysis in Idiopathic Pulmonary Hypertension Patient. American Journal of Respiratory and Critical Care Medicine.