Dr. Roham Zamanian specializes in the treatment of pulmonary hypertension, right heart failure, and pulmonary embolism. He has more than 13 years of sub-specialty experience in pulmonary vascular diseases. Dr. Zamanian is considered one of the leading national experts in clinical trials and drug development for pulmonary hypertension.

Clinical Focus

  • Pulmonary Hypertension
  • pulmonary vascular diseases
  • pulmonary embolism
  • right heart failure
  • Pulmonology (Lung) and Critical Care
  • Pulmonary Disease

Academic Appointments

Administrative Appointments

  • Director, Adult Pulmonary Hypertension Service, Vera Moulton Wall Center for Pulmonary Vascular Disease (2007 - Present)
  • Clinical Director, VMWC Pulmonary Hypertension Database, Vera Moulton Wall Center for Pulmonary Vascular Disease (2006 - Present)

Honors & Awards

  • Howard Huges Summer Fellowship, Harvard School of Medicine (1992 & 1993)
  • Ralph Waldo Gerard Award for Outstanding Researcher, University of California, Irvine School of Biological Sciences (1994)
  • Excellence in Research Award, University of California, Irvine School of Biological Sciences (1995)
  • Case Presentation Award, ACCP - Chest 2000 (2000)
  • Resident Research Presentation Award, Univ of Calif, Irvine Medical Center - Dept of Medicine (2001)
  • Fellow of the Year, Univ of Califronia, Irvine Medical Center (2002-2003)
  • Young Investigator Career Development Award, Entelligence Actelion Young Investigators Program (2006-2007)
  • Faculty Teaching Award, Dept of Medicine, Stanford (2007)
  • Fellow of the American College of Chest Physicians, American College of Chest Physicians (2008)

Professional Education

  • Board Certification: Pulmonary Disease, American Board of Internal Medicine (2006)
  • Medical Education:University of California Irvine (1999) CA
  • Fellowship:Stanford University School of Medicine (2006) CA
  • Fellowship:Stanford University School of Medicine (2005) CA
  • Fellowship:University of Irvine Medical Center (2003) CA
  • Residency:University of Irvine Medical Center (2002) CA
  • Internship:University of Irvine Medical Center (2000) CA
  • Super-Fellowship, Stanford University, Pulmonary Vascular Disease (2006)
  • Fellowship, Stanford University, Pulmonary & Critical Care (2005)
  • Fellowship, UCI Medical Center, Pulmonary & Critical Care (2003)
  • Residency, UCI Medical Center, Internal Medicine (2002)
  • MD, University of California, Irvine, Medicine (1999)
  • BS, University of California, Irvine, Biological Sciences (1994)

Community and International Work

  • Blue Lips Foundation



    Ongoing Project


    Opportunities for Student Involvement


  • PHaware

    Populations Served

    Pulmonary Hypertension Patients



    Ongoing Project


    Opportunities for Student Involvement


  • Member PHA Scientific Leadership Council

    Partnering Organization(s)

    Pulmonary Hypertension Association



    Ongoing Project


    Opportunities for Student Involvement



  • Edda Spiekerkoetter, Marlene Rabinovitch, Roham Zamanian. "United StatesFK506 for treatment of PAH", Leland Stanford Junior University

Current Research and Scholarly Interests

1. Development and evaluation of prognostic and diagnostic integral biomarkers in PAH.

2. Prevalence and Treatment of Insulin Resistance in PAH.

3. Role of inflammation and proteomic signature in PAH

4. Development of novel therapeutics (bench to bedside) including FK506 & Elastase Inhibition in PAH.

5. Assessment of Vasoreactivity (gain and loss) in pulmonary arterial hypertension

6. Assessment of microvascular function in PAH.

2016-17 Courses

Stanford Advisees

All Publications

  • Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clinical and experimental rheumatology Chung, L., Fairchild, R. M., Furst, D. E., Li, S., Alkassab, F., Bolster, M. B., Csuka, M. E., Derk, C. T., Domsic, R. T., Fischer, A., Frech, T., Gomberg-Maitland, M., Gordon, J. K., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Hant, F., Silver, R., Simms, R., Varga, J., Steen, V. D., Zamanian, R. T. 2016: -?


    To assess the utility of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in detecting and monitoring pulmonary hypertension (PH) in systemic sclerosis (SSc).PHAROS is a multicenter prospective cohort of SSc patients at high risk for developing pulmonary arterial hypertension (SSc-AR-PAH) or with a definitive diagnosis of SSc-PH. We evaluated 1) the sensitivity and specificity of BNP≥64 and NT-proBNP≥210 pg/mL for the detection of SSc-PAH and/ or SSc-PH in the SSc-AR-PAH population; 2) baseline and longitudinal BNP and NT-proBNP levels as predictors of progression to SSc-PAH and/or SSc-PH; 3) baseline BNP≥180, NT-proBNP≥553 pg/mL, and longitudinal changes in BNP and NT-proBNP as predictors of mortality in SSc-PH diagnosed patients.172 SSc-PH and 157 SSc-AR- PAH patients had natriuretic peptide levels available. Median BNP and NT-proBNP were significantly higher in the SSc-PH versus SSc-AR-PAH group. The sensitivity and specificity for SSc-PAH detection using baseline BNP≥64 pg/mL was 71% and 59%; and for NT-proBNP≥210 pg/mL, 73% and 78%. NT-proBNP showed stronger correlations with haemodynamic indicators of right ventricular dysfunction than BNP. Baseline creatinine, RVSP > 40 mmHg, and FVC%:DLco% ratio ≥1.8 were associated with progression from SSc-AR-PAH to SSc-PH but no association with individual or combined baseline BNP and NT-proBNP levels was observed. Baseline and follow-up BNP or NT-proBNP levels were not predictive of death, however, a composite BNP/NT-proBNP group predicted mortality (HR 3.81 (2.08-6.99), p<.0001).NT-proBNP may be more useful than BNP in the detection and monitoring of PAH in SSc patients, but additional studies are necessary.

    View details for PubMedID 27908301

  • An observational study of inhaled-treprostinil respiratory-related safety in patients with pulmonary arterial hypertension. Pulmonary circulation Zamanian, R. T., Levine, D. J., Bourge, R. C., De Souza, S. A., Rosenzweig, E. B., Alnuaimat, H., Burger, C., Mathai, S. C., Leedom, N., DeAngelis, K., Lim, A., De Marco, T. 2016; 6 (3): 329-337


    Inhaled treprostinil (Tyvaso) has been shown to be a safe and effective addition to pulmonary arterial hypertension (PAH) oral therapies; however, the respiratory-related safety profile of inhaled treprostinil required further elucidation in the setting of routine clinical care. The objectives of this study were to characterize respiratory-related adverse events (AEs) associated with current or recent treatment with inhaled treprostinil and to compare the incidence of respiratory-related AEs in PAH patients treated with inhaled treprostinil with that in patients treated with other Food and Drug Administration (FDA)-approved PAH therapies. This was a long-term, prospective, observational study. All respiratory-related AEs were recorded during the study. The number of PAH patients enrolled was 1,333, 666 treated with inhaled treprostinil and 667 controls (treated with an FDA-approved PAH therapy other than inhaled treprostinil), for a total of 958 and 1,094 patient-years of exposure, respectively. In the inhaled-treprostinil group, 1,281 respiratory-related AEs were reported in 403 patients (61%), and in the control group, 1,295 respiratory-related AEs were reported in 388 patients (58%). Cough, throat irritation, nasal discomfort, and hemoptysis were the most common respiratory-related AEs (occurring in ≥2% of patients in either treatment group) that demonstrated a higher number of events per patient-year of exposure in the inhaled-treprostinil group than in the control group (risk ratio [95% confidence interval]: 1.487 [1.172-1.887], 3.777 [2.050-6.956], 2.039 [1.072-3.879], and 1.957 [1.024-3.741], respectively). Overall, inhaled treprostinil was well tolerated by PAH patients in routine clinical care, with respiratory-related AEs consistent with the known safety profile (trial registration: identifier: NCT01266265).

    View details for DOI 10.1086/688059

    View details for PubMedID 27683610

  • Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program CIRCULATION Maron, B. A., Hess, E., Maddox, T. M., Opotowsky, A. R., Tedford, R. J., Lahm, T., Joynt, K. E., Kass, D. J., Stephens, T., Stanislawski, M. A., Swenson, E. R., Goldstein, R. H., Leopold, J. A., Zamanian, R. T., Elwing, J. M., Plomondon, M. E., Grunwald, G. K., Baron, A. E., Rumsfeld, J. S., Choudhary, G. 2016; 133 (13): 1240-1248


    Pulmonary hypertension (PH) is associated with increased morbidity across the cardiopulmonary disease spectrum. Based primarily on expert consensus opinion, PH is defined by a mean pulmonary artery pressure (mPAP) ≥25 mm Hg. Although mPAP levels below this threshold are common among populations at risk for PH, the relevance of mPAP <25 mm Hg to clinical outcome is unknown.We analyzed retrospectively all US veterans undergoing right heart catheterization (2007-2012) in the Veterans Affairs healthcare system (n=21 727; 908-day median follow-up). Cox proportional hazards models were used to evaluate the association between mPAP and outcomes of all-cause mortality and hospitalization, adjusted for clinical covariates. When treating mPAP as a continuous variable, the mortality hazard increased beginning at 19 mm Hg (hazard ratio [HR]=1.183; 95% confidence interval [CI], 1.004-1.393) relative to 10 mm Hg. Therefore, patients were stratified into 3 groups: (1) referent (≤18 mm Hg; n=4 207); (2) borderline PH (19-24 mm Hg; n=5 030); and (3) PH (≥25 mm Hg; n=12 490). The adjusted mortality hazard was increased for borderline PH (HR=1.23; 95% CI, 1.12-1.36; P<0.0001) and PH (HR=2.16; 95% CI, 1.96-2.38; P<0.0001) compared with the referent group. The adjusted hazard for hospitalization was also increased in borderline PH (HR=1.07; 95% CI, 1.01-1.12; P=0.0149) and PH (HR=1.15; 95% CI, 1.09-1.22; P<0.0001). The borderline PH cohort remained at increased risk for mortality after excluding the following high-risk subgroups: (1) patients with pulmonary artery wedge pressure >15 mm Hg; (2) pulmonary vascular resistance ≥3.0 Wood units; or (3) inpatient status at the time of right heart catheterization.These data illustrate a continuum of risk according to mPAP level and that borderline PH is associated with increased mortality and hospitalization. Future investigations are needed to test the generalizability of our findings to other populations and study the effect of treatment on outcome in borderline PH.

    View details for DOI 10.1161/CIRCULATIONAHA.115.020207

    View details for Web of Science ID 000372852800004

    View details for PubMedID 26873944

  • Leukotriene B-4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension HYPERTENSION Qian, J., Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Shuffle, E. M., Tu, A. B., Valenzuela, A., Jiang, S., Zamanian, R. T., Fiorentino, D. F., Voelkel, N. F., Peters-Golden, M., Stenmark, K. R., Chung, L., Rabinovitch, M., Nicolls, M. R. 2015; 66 (6): 1227-1239


    A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

    View details for DOI 10.1161/HYPERTENSIONAHA.115.06370

    View details for Web of Science ID 000364481400021

    View details for PubMedID 26558820

    View details for PubMedCentralID PMC4646718

  • Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Hassoun, P. M., Zamanian, R. T., Damico, R., Lechtzin, N., Khair, R., Kolb, T. M., Tedford, R. J., Hulme, O. L., Housten, T., Pisanello, C., Sato, T., Pullins, E. H., Corona-Villalobos, C. P., Zimmerman, S. L., Gashouta, M. A., Minai, O. A., Torres, F., Girgis, R. E., Chin, K., Mathai, S. C. 2015; 192 (9): 1102-1110

    View details for DOI 10.1164/rccm.201507-1398OC

    View details for Web of Science ID 000364333500015

    View details for PubMedID 26360334

  • RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rhodes, C. J., Im, H., Cao, A., Hennigs, J. K., Wang, L., Sa, S., Chen, P., Nickel, N. P., Miyagawa, K., Hopper, R. K., Tojais, N. F., Li, C. G., Gu, M., Spiekerkoetter, E., Xian, Z., Chen, R., Zhao, M., Kaschwich, M., del Rosario, P. A., Bernstein, D., Zamanian, R. T., Wu, J. C., Snyder, M. P., Rabinovitch, M. 2015; 192 (3): 356-366


    Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.RNA sequencing was utilized to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension vs. controls and to assess the functional significance of major differentially expressed transcripts.The endothelial transcriptomes from seven control and six idiopathic pulmonary arterial hypertension patients' lungs were analyzed. Differentially expressed genes were related to BMPR2 signaling. Those downregulated were assessed for function in cultured cells, and in a transgenic mouse.Fold-differences in ten genes were significant (p<0.05), four increased and six decreased in patients vs.No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated six/ten patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2 regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2 and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration and tube formation. In mice null for the EFNA1 receptor, EphA2, vs. controls, VEGF receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy and loss of small arteries.The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

    View details for DOI 10.1164/rccm.201408-1528OC

    View details for Web of Science ID 000359178500017

    View details for PubMedID 26030479

  • Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Spiekerkoetter, E., Sung, Y. K., Sudheendra, D., Bill, M., Aldred, M. A., van de Veerdonk, M. C., Vonk Noordegraaf, A., Long-Boyle, J., Dash, R., Yang, P. C., Lawrie, A., Swift, A. J., Rabinovitch, M., Zamanian, R. T. 2015; 192 (2): 254-257

    View details for DOI 10.1164/rccm.201411-2061LE

    View details for PubMedID 26177174

  • Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nickel, N. P., Spiekerkoetter, E., Gu, M., Li, C. G., Li, H., Kaschwich, M., Diebold, I., Hennigs, J. K., Kim, K., Miyagawa, K., Wang, L., Cao, A., Sa, S., Jiang, X., Stockstill, R. W., Nicolls, M. R., Zamanian, R. T., Bland, R. D., Rabinovitch, M. 2015; 191 (11): 1273-1286


    Pulmonary arterial hypertension is characterized by endothelial cell dysfunction, impaired BMPR2 signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates the development of hypoxic pulmonary hypertension in mice, but its potential to improve endothelial cell function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown.To assess elafin-mediated regression of pulmonary vascular pathology in rats with pulmonary hypertension induced by VEGF receptor blockade and hypoxia (Sugen/Hypoxia), and in lung explants from pulmonary hypertension patients. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells from controls and patients, and to elucidate the underlying mechanism. Methods, Measurements and Main Results: In Sugen/Hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a product of BMPR2 signaling. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and in lung organ culture elafin decreased neointimal lesions. In normal and patient pulmonary artery endothelial cells, elafin enhanced survival and promoted angiogenesis by increasing pSMAD dependent and independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of caveolin-1 on endothelial surfaces.Elafin reverses obliterative changes in rat and human pulmonary arteries via elastase inhibition and caveolin-1 dependent amplification of BMPR2 signaling.

    View details for DOI 10.1164/rccm.201412-2291OC

    View details for Web of Science ID 000356105000014

    View details for PubMedID 25853696

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

    View details for DOI 10.1016/j.jcmg.2014.12.029

    View details for Web of Science ID 000356560600001

    View details for PubMedID 25981508

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


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

    View details for DOI 10.1016/j.jcmg.2014.12.029

    View details for PubMedID 25981508

  • Single- vs double-lung transplantation in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis since the implementation of lung allocation based on medical need. JAMA Schaffer, J. M., Singh, S. K., Reitz, B. A., Zamanian, R. T., Mallidi, H. R. 2015; 313 (9): 936-948


    Outcomes of single- and double-lung transplantation have not been rigorously assessed since the allocation of donor lungs according to medical need as quantified by the Lung Allocation Score, which began in 2005.To compare outcomes in single- and double-lung transplant recipients since the Lung Allocation Score was implemented.In this exploratory analysis, adults with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) who underwent lung transplantation in the United States between May 4, 2005, and December 31, 2012, were identified in the United Network for Organ Sharing thoracic registry, with follow-up to December 31, 2012. Posttransplantation graft survival was assessed with Kaplan-Meier analysis. Propensity scores were used to control for treatment selection bias. A multivariable flexible parametric prognostic model was used to characterize the time-varying hazard associated with single- vs double-lung transplantation.Single- or double-lung transplantation.Composite of posttransplant death and graft failure (retransplantation).Patients with IPF (n = 4134, of whom 2010 underwent single-lung and 2124 underwent double-lung transplantation) or COPD (n = 3174, of whom 1299 underwent single-lung and 1875 underwent double-lung transplantation) were identified as having undergone lung transplantation since May 2005. Median follow-up was 23.5 months. Of the patients with IPF, 1380 (33.4%) died and 115 (2.8%) underwent retransplantation; of the patients with COPD, 1138 (34.0%) died and 59 (1.9%) underwent retransplantation. After confounders were controlled for with propensity score analysis, double-lung transplants were associated with better graft survival in patients with IPF (adjusted median survival, 65.2 months [interquartile range {IQR}, 21.4-91.3 months] vs 50.4 months [IQR, 17.0-87.5 months]; P < .001) but not in patients with COPD (adjusted median survival, 67.7 months [IQR, 25.2-89.6 months] vs 64.0 months [IQR, 25.2-88.7 months]; P = .23). The interaction between diagnosis type (COPD or IPF) and graft failure was significant (P = .049). Double-lung transplants had a time-varying association with graft survival; a decreased instantaneous late hazard for death or graft failure among patients with IPF was noted at 1 year and persisted at 5 years postoperatively (instantaneous hazard at 5 years, hazard ratio, 0.67 [95% CI, 0.52-0.84] in patients with IPF and 0.89 [95% CI, 0.71-1.13] in patients with COPD).In an exploratory analysis of registry data since implementation of a medical need-based lung allocation system, double-lung transplantation was associated with better graft survival than single-lung transplantation in patients with IPF. In patients with COPD, there was no survival difference between single- and double-lung transplant recipients at 5 years.

    View details for DOI 10.1001/jama.2015.1175

    View details for PubMedID 25734735

  • Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest Chung, L., Farber, H. W., Benza, R., Miller, D. P., Parsons, L., Hassoun, P. M., McGoon, M., Nicolls, M. R., Zamanian, R. T. 2014; 146 (6): 1494-1504


    Background:Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population. Methods:The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations. Results:Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4±2.7% and 51.2±4.0%, respectively, compared with 80.9±2.7% and 76.4±4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ≤110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group. Conclusions:Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment. Registered #NCT00370214.Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population.The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations.Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4±2.7% and 51.2±4.0%, respectively, compared with 80.9±2.7% and 76.4±4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ≤110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group.Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive #NCT00370214.

    View details for DOI 10.1378/chest.13-3014

    View details for PubMedID 24992469

  • Impact of insulin resistance on ventricular function in pulmonary arterial hypertension. journal of heart and lung transplantation Brunner, N. W., Skhiri, M., Fortenko, O., Hsi, A., Haddad, F., Khazeni, N., Zamanian, R. T. 2014; 33 (7): 721-726


    Insulin resistance (IR) is an independent prognostic marker in pulmonary arterial hypertension (PAH), although the mechanism by which it engenders risk is unknown. We prospectively investigated the clinical, laboratory, hemodynamic, and echocardiographic characteristics of insulin-sensitive (IS) and IR patients with PAH.This was a prospective cohort study including well-phenotyped patients with PAH proven at cardiac catheterization. Patients were classified as IS or IR on the basis of the well-validated triglyceride/high-density lipoprotein-cholesterol ratio. Clinical, laboratory, and hemodynamic characteristics were compared between cohorts. Distance walked on the 6-minute walk test (6MWT) and echocardiograms were compared between IS and IR for the sub-set of patients that had these tests within 1 month of cardiac catheterization.Of the 111 PAH patients enrolled, 59 were IS, 25 were IR, and 27 were classified as indeterminate. Mean age was 45.8 ± 15.0 years. IR was associated with worse New York Heart Association class (p = 0.02). There were no differences in hemodynamics, biomarkers, 6MWT distance, or parameters of right ventricular function (i.e., tricuspid annular plane systolic excursion, myocardial performance index, and fractional area change) between groups. Despite similar systemic vascular resistance, parameters of left ventricular diastolic function were more favorable for IS vs IR, including mitral inflow E wave velocity (82 ± 17 vs 64 ± 19 msec, p = 0.02), E/A ratio (1.2 ± 0.4 vs 0.8 ± 0.2, p = 0.01), and lateral mitral valve E' velocity (13.9 ± 3.5 vs 10.4 ± 2.2 msec, p = 0.01).IR is associated with worse functional class and diastology compared with IS in PAH, although other prognostic parameters are similar.

    View details for DOI 10.1016/j.healun.2014.02.016

    View details for PubMedID 24819985

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


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

    View details for DOI 10.1161/CIRCRESAHA.115.303827

    View details for Web of Science ID 000337738900016

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


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

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

    View details for Web of Science ID 000336017200018

    View details for PubMedID 24702692

    View details for PubMedCentralID PMC4225850

  • Blocking Macrophage Leukotriene B-4 Prevents Endothelial Injury and Reverses Pulmonary Hypertension SCIENCE TRANSLATIONAL MEDICINE Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Qian, J., Dhillon, G., Gera, L., Farkas, L., Rabinovitch, M., Zamanian, R. T., Inayathullah, M., Fridlib, M., Rajadas, J., Peters-Golden, M., Voelkel, N. F., Nicolls, M. R. 2013; 5 (200)
  • Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Science translational medicine Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Qian, J., Dhillon, G., Gera, L., Farkas, L., Rabinovitch, M., Zamanian, R. T., Inayathullah, M., Fridlib, M., Rajadas, J., Peters-Golden, M., Voelkel, N. F., Nicolls, M. R. 2013; 5 (200): 200ra117-?


    Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.

    View details for DOI 10.1126/scitranslmed.3006674

    View details for PubMedID 23986401

  • Functional Class Improvement and 3-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry CHEST Barst, R. J., Chung, L., Zamanian, R. T., Turner, M., Mcgoon, M. D. 2013; 144 (1): 160-168


    ABSTRACT OBJECTIVE: New York Heart Association/World Health Organization functional class (FC) is associated with outcomes in pulmonary arterial hypertension (PAH). We assessed whether patients with PAH who improve from FC III to FC I/II have improved survival versus patients who remain at FC III or worsen to FC IV. METHODS: Patients aged ≥19 years with FC III PAH from the REVEAL Registry (N=982) were categorized as improved, unchanged, or worsened according to their change in FC from enrollment to first follow-up assessment within 1 year of enrollment. Kaplan-Meier estimates of 3-year survival from first follow-up and changes in 6-minute walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by etiology (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly and previously diagnosed [diagnostic right heart catheterization within or ≥3 months of enrollment, respectively]). RESULTS: Overall, 27% of patients improved FC. Survival was better in patients whose FC improved (84%±2%; n=263) versus those who remained unchanged (66%±2%; n=645) or worsened (29%±6%; n=74) (all P<.001). Survival was also better in patient subgroups whose FC improved versus those who remained unchanged (idiopathic/familial [P<.001], CTD-associated PAH [P=.009], whether newly [P=.004] or previously diagnosed [P<.001]. 6MWD improvements were greater in patients whose FC improved versus those who remained unchanged in the overall (P<.001) and CTD (P=.028) cohorts. CONCLUSION: Patients with PAH who improve from FC III to I/II, whether newly or previously diagnosed and regardless of PAH etiology, have better survival versus patients who remain FC Registration Number: NCT00370214.

    View details for DOI 10.1378/chest.12-2417

    View details for Web of Science ID 000321605500026

    View details for PubMedID 23429998

  • Transplantation for Idiopathic Pulmonary Arterial Hypertension Improvement in the Lung Allocation Score Era CIRCULATION Schaffer, J. M., Singh, S. K., Joyce, D. L., Reitz, B. A., Robbins, R. C., Zamanian, R. T., Mallidi, H. R. 2013; 127 (25): 2503-2513


    BACKGROUND: Lung transplant (LUT) and heart-lung transplant (HLT) represent surgical options for treating medically refractory idiopathic pulmonary arterial hypertension (IPAH). The effect of the lung allocation score (LAS) on waitlist and transplant outcomes in IPAH patients is poorly described. METHODS AND RESULTS: Adults diagnosed with IPAH and listed for transplant in the 80 months before and after the LAS algorithm was implemented (N=1430) were identified in the United Network for Organ Sharing thoracic registry. Patients were stratified by organ listed and pre- and post-LAS era. The cumulative incidences of transplant and mortality for waitlisted patients in both eras were appraised with competing outcomes analysis. Post-transplant survival was assessed with the Kaplan-Meier method. These analyses were repeated in propensity-matched subgroups. Cox proportional hazards analysis evaluated the effect of pre-listing and pre-transplant characteristics on mortality. We found that post-LAS-era patients had significantly worse comorbidities; nevertheless, both LUT and HLT candidates in this era enjoyed lower waitlist mortality and a higher incidence of transplant in our unmatched and propensity-matched analyses. On multivariable analysis, HLT and double-lung transplant (DLT) were associated with improved survival from the time of waitlisting, as was being listed at a medium-to-high-volume institution. Donor/recipient gender matching predicted post-transplant survival. CONCLUSIONS: The incidence of transplant has increased while waitlist mortality has decreased in IPAH patients waitlisted for transplant in the post-LAS era. Both HLT and DLT are predictive of survival in transplant candidates with IPAH, as is being listed at a medium-to-high-volume institution. Donor/recipient gender-matching is associated with better post-transplant survival.

    View details for DOI 10.1161/CIRCULATIONAHA.112.001080

    View details for Web of Science ID 000320916900014

    View details for PubMedID 23697910

  • Safety and Efficacy of Transition from Systemic Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension AMERICAN JOURNAL OF CARDIOLOGY Perez, V. A., Rosenzweig, E., Rubin, L. J., Poch, D., Bajwa, A., Park, M., Jain, M., Bourge, R. C., Kudelko, K., Spiekerkoetter, E., Liu, J., Hsi, A., Zamanian, R. T. 2012; 110 (10): 1546-1550
  • Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699


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

    View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

    View details for Web of Science ID 000297166100008

    View details for PubMedID 21908586

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


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

    View details for DOI 10.1016/j.cardfail.2011.03.003

    View details for Web of Science ID 000292368500002

    View details for PubMedID 21703524

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

    View details for Web of Science ID 000289940400022

    View details for PubMedID 21524224

  • Characterization of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension From REVEAL Identifying Systemic Sclerosis as a Unique Phenotype CHEST Chung, L., Liu, J., Parsons, L., Hassoun, P. M., McGoon, M., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. 2010; 138 (6): 1383-1394


    REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH).All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA).Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH).Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco, and poorest survival of all CTD-APAH; No.: NCT00370214; URL:

    View details for DOI 10.1378/chest.10-0260

    View details for Web of Science ID 000285494000017

    View details for PubMedID 20507945

    View details for PubMedCentralID PMC3621419

  • Worldwide Physician Education and Training in Pulmonary Hypertension Pulmonary Vascular Disease: The Global Perspective CHEST Elliott, C. G., Barst, R. J., Seeger, W., Porres-Aguilar, M., Brown, L. M., Zamanian, R. T., Rubin, L. J. 2010; 137 (6): 85S-94S


    Pulmonary hypertension (PH) affects > 25 million individuals worldwide and causes premature disability and death for many. The diagnosis and treatment of PH have advanced dramatically through the development of a clearly defined diagnostic classification, an evidence-based treatment algorithm for adults with pulmonary arterial hypertension using life-saving medications, and life-saving surgical procedures. However, worldwide education and training of physicians has lagged behind advances in the management of PH. Expertise in the diagnosis and management of PH is uncommon, even though physicians receive training on PH during their graduate and postgraduate education. Advances in worldwide physician education and training in PH will require substantial organization and work. Organizations working in this field will need to work collaboratively to maximize funding for education and to optimize the achievement of educational goals. Political, economic, and cultural barriers must be identified and overcome as part of any strategic plan. Global education should include training objectives for generalist, non-PH specialist, and PH specialist physicians.

    View details for DOI 10.1378/chest.09-2816

    View details for Web of Science ID 000278561500011

    View details for PubMedID 20522584

  • PPAR gamma Activation: A Potential Treatment for Pulmonary Hypertension SCIENCE TRANSLATIONAL MEDICINE Hansmann, G., Zamanian, R. T. 2009; 1 (12)


    The pathobiology of pulmonary arterial hypertension (PAH) involves multiple molecular pathways and environmental modifiers and is characterized by progressive obliteration of pulmonary arterioles, leading to increased pulmonary vascular resistance (PVR), right heart failure, and death in approximately 40 to 60% of patients 5 years after diagnosis. There is emerging evidence that many key genes involved in PAH development are targets of the insulin-sensitizing transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), and that pharmacological PPARgamma activation would lead to their beneficial induction or repression and subsequent antiproliferative, anti-inflammatory, proapoptotic, and direct vasodilatory effects in the vasculature. PPARgamma acts downstream of bone morphogenetic protein receptor II (BMP-RII), which is the cell surface receptor that is mutated or dysfunctional in many forms of PAH. Because our recent clinical observations indicate that insulin resistance may be an environmental risk factor or disease modifier ("second hit"), we suggest that PPARgamma-activating agents might be beneficial in the future treatment of both insulin-resistant and insulin-sensitive PAH patients with or without BMP-RII mutations.

    View details for DOI 10.1126/scitranslmed.3000267

    View details for Web of Science ID 000277263200003

    View details for PubMedID 20371457

  • Insulin resistance in pulmonary arterial hypertension EUROPEAN RESPIRATORY JOURNAL Zamanian, R. T., Hansmann, G., Snook, S., Lilienfeld, D., Rappaport, K. M., Reaven, G. M., RABINOVITCH, M., Doyle, R. L. 2009; 33 (2): 318-324


    Although obesity, dyslipidemia and insulin resistance (IR) are well known risk factors for systemic cardiovascular disease, their impact on pulmonary arterial hypertension (PAH) is unknown. The present authors' previous studies indicate that IR may be a risk factor for PAH. The current study has investigated the prevalence of IR in PAH and explored its relationship with disease severity. Clinical data and fasting blood samples were evaluated in 81 nondiabetic PAH females. In total, 967 National Health and Nutrition Examination Surveys (NHANES) females served as controls. The fasting triglyceride to high-density lipoprotein cholesterol ratio was used as a surrogate of insulin sensitivity. While body mass index was similar in NHANES versus PAH females (28.6 versus 28.7 kg.m(-2)), PAH females were more likely to have IR (45.7 versus 21.5%) and less likely to be insulin sensitive (IS; 43.2 versus 57.8%). PAH females mostly (82.7%) had New York Heart Association (NYHA) class II and III symptoms. Aetiology, NYHA class, 6-min walk-distance and haemodynamics did not differ between IR and IS PAH groups. However, the presence of IR and a higher NYHA class was associated with poorer 6-months event-free survival (58 versus 79%). Insulin resistance appears to be more common in pulmonary arterial hypertension females than in the general population, and may be a novel risk factor or disease modifier that might impact on survival.

    View details for DOI 10.1183/09031936.00000508

    View details for Web of Science ID 000263709300014

    View details for PubMedID 19047320

  • Surrogate and combined end points in pulmonary arterial hypertension. Proceedings of the American Thoracic Society Ventetuolo, C. E., Benza, R. L., Peacock, A. J., Zamanian, R. T., Badesch, D. B., Kawut, S. M. 2008; 5 (5): 617-622


    Pulmonary arterial hypertension is a rare and often devastating disease, although various effective therapies are now available. Clinical trials have used hemodynamic, cardiac imaging, laboratory, and exercise measurements as surrogate and intermediate end points in pulmonary arterial hypertension. Yet, based on the current literature, it is difficult to surmise which of these (if any) have been definitively validated. In addition, investigators have advocated the use of combined clinical end points in future clinical trials. The dependence of clinical trials and clinical management on such end points warrants a review of their use.

    View details for DOI 10.1513/pats.200803-029SK

    View details for PubMedID 18625754

  • Management strategies for patients with pulmonary hypertension in the intensive care unit CRITICAL CARE MEDICINE Zamanian, R. T., Haddad, F., Doyle, R. L., Weinacker, A. B. 2007; 35 (9): 2037-2050


    Pulmonary hypertension may be encountered in the intensive care unit in patients with critical illnesses such as acute respiratory distress syndrome, left ventricular dysfunction, and pulmonary embolism, as well as after cardiothoracic surgery. Pulmonary hypertension also may be encountered in patients with preexisting pulmonary vascular, lung, liver, or cardiac diseases. The intensive care unit management of patients can prove extremely challenging, particularly when they become hemodynamically unstable. The objective of this review is to discuss the pathogenesis and physiology of pulmonary hypertension and the utility of various diagnostic tools, and to provide recommendations regarding the use of vasopressors and pulmonary vasodilators in intensive care.We undertook a comprehensive review of the literature regarding the management of pulmonary hypertension in the setting of critical illness. We performed a MEDLINE search of articles published from January 1970 to March 2007. Medical subject headings and keywords searched and cross-referenced with each other were: pulmonary hypertension, vasopressor agents, therapeutics, critical illness, intensive care, right ventricular failure, mitral stenosis, prostacyclin, nitric oxide, sildenafil, dopamine, dobutamine, phenylephrine, isoproterenol, and vasopressin. Both human and animal studies related to pulmonary hypertension were reviewed.Pulmonary hypertension presents a particular challenge in critically ill patients, because typical therapies such as volume resuscitation and mechanical ventilation may worsen hemodynamics in patients with pulmonary hypertension and right ventricular failure. Patients with decompensated pulmonary hypertension, including those with pulmonary hypertension associated with cardiothoracic surgery, require therapy for right ventricular failure. Very few human studies have addressed the use of vasopressors and pulmonary vasodilators in these patients, but the use of dobutamine, milrinone, inhaled nitric oxide, and intravenous prostacyclin have the greatest support in the literature. Treatment of pulmonary hypertension resulting from critical illness or chronic lung diseases should address the primary cause of hemodynamic deterioration, and pulmonary vasodilators usually are not necessary.

    View details for DOI 10.1097/01.CCM.0000280433.74246.9E

    View details for Web of Science ID 000249038700005

    View details for PubMedID 17855818

  • Left Atrium Maximal Axial Cross-Sectional Area is a Specific Computed Tomographic Imaging Biomarker of World Health Organization Group 2 Pulmonary Hypertension. Journal of thoracic imaging Jivraj, K., Bedayat, A., Sung, Y. K., Zamanian, R. T., Haddad, F., Leung, A. N., Rosenberg, J., Guo, H. H. 2017; 32 (2): 121-126


    Left heart disease is associated with left atrial enlargement and is a common cause of pulmonary hypertension (PH). We investigated the relationship between left atrium maximal axial cross-sectional area (LA-MACSA), as measured on chest computed tomography (CT), and PH due to left heart disease (World Health Organization group 2) in patients with right heart catheterization-proven PH.A total of 165 patients with PH who had undergone right heart catheterization with pulmonary artery pressure and pulmonary capillary wedge pressure (PCWP) measurements and nongated chest CTs were included. LA-MACSA, LA anterior-posterior, and LA transverse measurements were independently obtained using the hand-drawn region-of-interest and distance measurement tools on standard PACS by 2 blinded cardiothoracic radiologists. Nonparametric statistical analyses and receiver operating characteristic curve were performed.Forty-three patients had group 2 PH (PCWP>15 mm Hg), and 122 had nongroup 2 PH (PCWP≤15 mm Hg). Median LA-MACSA was significantly different between the group 2 PH and nongroup 2 PH patients (2312 vs. 1762 mm, P<0.001). Interobserver concordance correlation for LA-MACSA was high at 0.91 (P<0.001). At a threshold of 2400 mm, LA-MACSA demonstrated 93% specificity for classifying group 2 PH (area under the curve, 0.73; P<0.001).LA-MACSA is a readily obtainable and reproducible measurement of left atrial enlargement on CT and can distinguish between group 2 and nongroup 2 PH with high specificity.

    View details for DOI 10.1097/RTI.0000000000000252

    View details for PubMedID 28009778

  • Investigating the value of right heart echocardiographic metrics for detection of pulmonary hypertension in patients with advanced lung disease. The international journal of cardiovascular imaging Amsallem, M., Boulate, D., Kooreman, Z., Zamanian, R. T., Fadel, G., Schnittger, I., Fadel, E., McConnell, M. V., Dhillon, G., Mercier, O., Haddad, F. 2017


    This study determined whether novel right heart echocardiography metrics help to detect pulmonary hypertension (PH) in patients with advanced lung disease (ALD). We reviewed echocardiography and catheterization data of 192 patients from the Stanford ALD registry and echocardiograms of 50 healthy controls. Accuracy of echocardiographic right heart metrics to detect PH was assessed using logistic regression and area under the ROC curves (AUC) analysis. Patients were divided into a derivation (n = 92) and validation cohort (n = 100). Experimental validation was assessed in a piglet model of mild PH followed longitudinally. Tricuspid regurgitation (TR) was not interpretable in 52% of patients. In the derivation cohort, right atrial maximal volume index (RAVI), ventricular end-systolic area index (RVESAI), free-wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) differentiated patients with and without PH; 20% of patients without PH had moderate to severe RV enlargement by RVESAI. On multivariate analysis, RAVI and TAPSE were independently associated with PH (AUC = 0.77, p < 0.001), which was confirmed in the validation cohort (0.78, p < 0.001). Presence of right heart metrics abnormalities did not improve detection of PH in patients with interpretable TR (p > 0.05) and provided moderate detection value in patients without TR. Only two patients with more severe PH (mean pulmonary pressure 35 and 36 mmHg) were missed. The animal model confirmed that right heart enlargement discriminated best pigs with PH from shams. This study highlights the frequency of right heart enlargement and dysfunction in ALD irrespectively from presence of PH, therefore limiting their use for detection of PH.

    View details for DOI 10.1007/s10554-017-1069-3

    View details for PubMedID 28120156

  • Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2016; 29 (2): 93-102
  • Prognostic utility of right atrial emptying fractions in pulmonary arterial hypertension. Pulmonary circulation Brunner, N. W., Haddad, F., Kobayashi, Y., Hsi, A., Swiston, J. R., Gin, K. G., Zamanian, R. T. 2015; 5 (3): 473-480


    Although left atrial function has been extensively studied in patients with heart failure, the determinants and clinical correlates of impaired right atrial (RA) function have been poorly studied. We investigated measures of RA function in pulmonary arterial hypertension (PAH). We identified all treatment-naive patients with World Health Organization category 1 PAH seen at our center during 2000-2011 who had right heart catheterization and 6-minute walk test (6MWT) within 1 month of initial echocardiographic examination. Atrial size was measured using the monoplane area-length method, and atrial function was quantified using total, passive, and active RA emptying fractions (RAEFs). We compared measures of RAEF with known prognostic clinical, echocardiographic, and hemodynamic parameters. For the subset of patients with follow-up echocardiographic examination/6MWT within 6-18 months, we investigated the change in RAEF. In an exploratory analysis, we investigated the association between RAEF and mortality. Our population consisted of 39 patients with treatment-naive (incident) PAH, 30 of whom had follow-up testing. The mean total, passive, and active RAEFs were 24.4% ± 15.1%, 8.5% ± 6.9%, and 17.6% ± 13.9%, respectively. Total and active RAEFs correlated with tricuspid annular plane systolic excursion (P = 0.004 and P = 0.005) and cardiac output (P = 0.02 and P = 0.01). The change in active RAEF correlated with change in 6-minute walk distance (P = 0.02). In our Cox regression analysis, low active and total RAEF were associated with mortality, with hazard ratios of 5.6 (95% confidence interval [CI], 1.2-26.2; P = 0.03) and 4.2 (95% CI, 1.1-15.5; P = 0.03), respectively. Passive RAEF was poorly reproducible and not associated with outcome. Measures of RAEF appear to have prognostic importance in PAH and warrant further study.

    View details for DOI 10.1086/682218

    View details for PubMedID 26401248

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


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

    View details for PubMedID 26141446

  • Septal curvature is marker of hemodynamic, anatomical, and electromechanical ventricular interdependence in patients with pulmonary arterial hypertension. Echocardiography (Mount Kisco, N.Y.) Haddad, F., Guihaire, J., Skhiri, M., Denault, A. Y., Mercier, O., Al-Halabi, S., Vrtovec, B., Fadel, E., Zamanian, R. T., Schnittger, I. 2014; 31 (6): 699-707


    The objective of this study was to determine the factors independently associated with septal curvature in patients with pulmonary arterial hypertension (PAH).Eighty-five consecutive patients with PAH who had an echocardiogram and a right heart catheterization within 24 hours of each others were included in the study. Septal curvature was assessed at the mid-papillary level using the eccentricity index (EI). Marked early systolic septal anterior motion was defined as a change in EI > 0.2 between end-diastole and early systole. Inter-ventricular mechanical delay was calculated as the percent time difference between right ventricular (RV) to left ventricular (LV) end-ejection time normalized for the RR interval.Average age was 45 ± 11 years and the majority of patients were women (75%). Mean right atrial pressure was 11 ± 7 mmHg, mean PAP was 52 ± 13 mmHg, relative RV area 1.8 ± 0.9, and RV fractional area change 24 ± 8%. End-diastolic EI was 1.6 ± 0.4 and systolic EI was 2.5 ± 0.8. On multivariate analysis relative pulmonary pressure, relative RV area, and inter-ventricular mechanical delay were independently associated with systolic EI (R(2)  = 0.72, P < 0.001). Independent determinants of diastolic EI included relative RV area and mean PAP (R(2)  = 0.69, P < 0.001). A systolic EI >1.08 differentiated patients with PAH from healthy controls with an AUC = 0.99. Patients with early systolic septal anterior motion (44% of subjects) had lower exercise capacity, more extensive ventricular remodeling, and worst ventricular function.Septal curvature is a useful marker of structural, hemodynamic, and electromechanical ventricular interdependence in PAH.

    View details for DOI 10.1111/echo.12468

    View details for PubMedID 24372843

  • Erythropoietin upregulation in pulmonary arterial hypertension. Pulmonary circulation Karamanian, V. A., Harhay, M., Grant, G. R., Palevsky, H. I., Grizzle, W. E., Zamanian, R. T., Ihida-Stansbury, K., Taichman, D. B., Kawut, S. M., Jones, P. L. 2014; 4 (2): 269-279


    The pathophysiologic alterations of patients with pulmonary arterial hypertension (PAH) are diverse. We aimed to determine novel pathogenic pathways from circulating proteins in patients with PAH. Multianalyte profiling (MAP) was used to measure 90 specifically selected antigens in the plasma of 113 PAH patients and 51 control patients. Erythropoietin (EPO) functional activity was assessed via in vitro pulmonary artery endothelial cell networking and smooth muscle cell proliferation assays. Fifty-eight patients had idiopathic PAH, whereas 55 had other forms of PAH; 5 had heritable PAH, 18 had connective tissue disease (15 with scleroderma and 3 with lupus erythematosis), 13 had portopulmonary hypertension, 6 had PAH associated with drugs or toxins, and 5 had congenital heart disease. The plasma-antigen profile of PAH revealed increased levels of several novel biomarkers, including EPO. Immune quantitative and histochemical studies revealed that EPO not only was significantly elevated in the plasma of PAH patients but also promoted pulmonary artery endothelial cell network formation and smooth muscle cell proliferation. MAP is a hypothesis-generating approach to identifying novel pathophysiologic pathways in PAH. EPO is upregulated in the circulation and lungs of patients with PAH and may affect endothelial and smooth muscle cell proliferation.

    View details for DOI 10.1086/675990

    View details for PubMedID 25006446

  • Response to letter regarding article, "transplantation for idiopathic pulmonary arterial hypertension: improvement in the lung allocation score era". Circulation Schaffer, J. M., Singh, S. K., Joyce, D. L., Reitz, B. A., Robbins, R. C., Zamanian, R. T., Mallidi, H. R. 2014; 129 (16)

    View details for DOI 10.1161/CIRCULATIONAHA.113.007272

    View details for PubMedID 24753555

  • Relationship between Echocardiographic and Magnetic Resonance Derived Measures of Right Ventricular Size and Function in Patients with Pulmonary Hypertension. Journal of the American Society of Echocardiography Shiran, H., Zamanian, R. T., McConnell, M. V., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Wu, J. C., Haddad, F., Yang, P. C. 2014; 27 (4): 405-412


    Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated.Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction (RVEF) were compared.The average age was 42 ± 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes (111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI. There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area (by TTE imaging) and RV end-diastolic volume (by MRI), R(2) = 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R(2) = 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R(2) = 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of 0.97 (P < .001). An RV end-diastolic area index of 18 cm(2)/m(2) provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001).Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal.

    View details for DOI 10.1016/j.echo.2013.12.011

    View details for PubMedID 24444659

  • A case of recurrent pericardial constriction presenting with severe pulmonary hypertension. Pulmonary circulation Brunner, N. W., Ramachandran, K., Kudelko, K. T., Sung, Y. K., Spiekerkoetter, E., Yang, P. C., Zamanian, R. T., Perez, V. d. 2013; 3 (2): 436-439


    Chronic constrictive pericarditis (CP) is a relatively rare condition in which the pericardium becomes fibrotic and noncompliant, eventually resulting in heart failure due to impaired ventricular filling. The only curative treatment is pericardiectomy. Classically, CP does not usually cause severe pulmonary hypertension. When attempting to differentiate CP from restrictive cardiomyopathy, the presence of severely elevated pulmonary arterial pressure is used as a diagnostic criterion ruling against CP. We present a case of proven recurrent pericardial constriction following pericardiectomy presenting with severe pulmonary hypertension.

    View details for DOI 10.4103/2045-8932.114780

    View details for PubMedID 24015347

  • RIGHT ATRIAL EMPTYING FRACTIONS ARE ASSOCIATED WITH SURVIVAL IN PULMONARY ARTERIAL HYPERTENSION 62nd Annual Scientific Session of the American-College-of-Cardiology Brunner, N. W., Haddad, F., Swiston, J. R., Gin, K., Tsang, T. S., Zamanian, R. T. ELSEVIER SCIENCE INC. 2013: E896–E896
  • IMPROVEMENT IN RIGHT ATRIAL FUNCTION IS ASSOCIATED WITH IMPROVED FUNCTIONAL CAPACITY IN PULMONARY ARTERIAL HYPERTENSION 62nd Annual Scientific Session of the American-College-of-Cardiology Brunner, N. W., Haddad, F., Swiston, J. R., Gin, K., Tsang, T. S., Zamanian, R. T. ELSEVIER SCIENCE INC. 2013: E1246–E1246
  • Pulmonary Arterial Hypertension: New Insights Into the Optimal Role of Current and Emerging Prostacyclin Therapies AMERICAN JOURNAL OF CARDIOLOGY Waxman, A. B., Zamanian, R. T. 2013; 111 (5): 1A-16A


    Pulmonary arterial hypertension (PAH), which is a subset of pulmonary hypertension, is a group of diseases distinguished by vascular remodeling of the small pulmonary arteries with associated elevated pulmonary arterial pressure and right ventricular failure. This progressive and sometimes fatal disease occurs as an idiopathic disease or as a component of other disease states. Estimates of the incidence of PAH have varied from 5 to 52 cases/1 million population. Symptoms begin with shortness of breath with exertion and progress to dyspnea with normal activities and, finally, dyspnea at rest. Untreated patients with PAH have a 1-, 3-, and 5-year survival rate of 68%, 48%, and 34%, respectively. Treated, the survival rates improve to 91% to 97% after 1 year and 84% to 91% after 2 years. The current definition of PAH consists of 3 specific hemodynamic assessments confirmed by right heart catheterization findings. One of several important pathophysiologic mechanisms involved in PAH is pulmonary vascular remodeling, which is caused by endothelial and smooth muscle cell hyperproliferation. This is coincident with overexpression of the vasoconstrictor endothelin-1 and a reduction in the vasodilators nitric oxide and prostacyclin, which further impedes proper vasomotor tone, among other effects. Prostacyclin therapies augment the decreased prostacyclin levels in patients with PAH. The currently approved prostacyclins for the treatment of PAH include epoprostenol, iloprost, and treprostinil. Among the 3 medications, the delivery options include intravenous infusion, subcutaneous infusion, and inhaled formulations. Epoprostenol has been shown to have a positive effect on survival in patients with PAH. All prostacyclins have demonstrated improvements in functional class, exercise tolerance, and hemodynamics in patients with PAH. Intravenously and subcutaneously administered formulations of prostacyclins require continuous infusion pump administration, which presents clinical challenges for both the patient and the care provider. Dosing must be individualized and also presents a clinical challenge. Inhaled formulations seem efficacious in moderately symptomatic patients with PAH and might be appropriate when combined with an oral medication. Combination therapies are commonly used in clinical practice, with the decision to do so based on randomized controlled trial data and case study evidence. The present report provides an overview of PAH, the scientific rationale for treatment with prostacyclin therapy, and the benefits and risks of prostacyclin therapy, both as monotherapy and combined with other medications approved for the treatment of PAH.

    View details for DOI 10.1016/j.amjcard.2012.12.002

    View details for Web of Science ID 000315666900001

    View details for PubMedID 23414683

  • A preliminary study investigating the quantification of beat-to-beat in seismocardiogram signals. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Inan, O. T., Pandia, K., Giovangrandi, L., Zamanian, R. T., Kovacs, G. T. 2013; 2013: 7286-7289


    Ballistocardiography and seismocardiography are both non-invasive mechanical measurements of the vibrations of the body in response to the heartbeat. The ballistocardiogram (BCG) signal represents the movements of the whole body in response to cardiac ejection of blood into the vasculature; the seismocardiogram (SCG) corresponds to local vibrations of the chest wall associated with sub-audible tissue and blood movement and audio frequency heart-valve closure dynamics. This paper focuses on methods for quantifying "signal consistency"--a quantitative measure of how morphologically similar each heartbeat in a patient's recording is compared to the ensemble average taken over the recording. Before comparing each beat to the average, known physiological sources of inconsistency--such as respiratory amplitude and timing variability--are removed, then the remaining inconsistency is quantified. Previously described methods for BCG signals are expanded to fit the high-frequency (> 20 Hz) components of the SCG. The use of this method in future work could help enable proactive management of heart disease in extra-clinical settings.

    View details for DOI 10.1109/EMBC.2013.6611240

    View details for PubMedID 24111427

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


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

    View details for DOI 10.1016/j.amjcard.2012.07.012

    View details for PubMedID 22853986

  • Airway Management and Perioperative Decision Making in the Patient With Severe Pulmonary Hypertension Who Requires Emergency Noncardiac Surgery JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Maxwell, B. G., Pearl, R. G., Kudelko, K. T., Zamanian, R. T., Hill, C. C. 2012; 26 (5): 940-944

    View details for DOI 10.1053/j.jvca.2012.06.018

    View details for Web of Science ID 000309020900031

    View details for PubMedID 22943790

  • Diagnosis and management of pulmonary hypertension associated with left ventricular diastolic dysfunction. Pulmonary circulation Perez, V. A., Haddad, F., Zamanian, R. T. 2012; 2 (2): 163-169


    Pulmonary hypertension (PH) is commonly seen in patients who present with left ventricular diastolic dysfunction (LVDD) and is considered a marker of poor prognosis. While PH in this setting is thought to result from pulmonary venous congestion, there is a subset of patients in which pulmonary pressures fail to improve with appropriate management of diastolic heart failure and go on to develop a clinical picture similar to that of patients with pulmonary arterial hypertension (PAH). Despite the utility of Doppler echocardiography and exercise testing in the initial evaluation of patients with suspected PH-LVDD, the diagnosis can only be confirmed using right heart catheterization. Management of PH-LVDD centers on both optimizing fluid management and afterload reduction to reducing left ventricular diastolic pressures and also increase pulmonary venous return. To date, there is no clear evidence that addition of PH-specific drugs can improve clinical outcomes, and their use should only be considered in the setting of clinical trials. In conclusion, PH-LVDD remains a challenging clinical entity that complicates the management of left ventricular dysfunction and significantly contributes to its morbidity and mortality. Determination of the optimal diagnostic and treatment strategies for this form of PH should be the goal of future studies.

    View details for DOI 10.4103/2045-8932.97598

    View details for PubMedID 22837857

  • Design and validation of an endothelial progenitor cell capture chip and its application in patients with pulmonary arterial hypertension JOURNAL OF MOLECULAR MEDICINE-JMM Hansmann, G., Plouffe, B. D., Hatch, A., von Gise, A., Sallmon, H., Zamanian, R. T., Murthy, S. K. 2011; 89 (10): 971-983


    The number of circulating endothelial progenitor cells (EPCs) inversely correlates with cardiovascular risk and clinical outcome, and thus has been proposed as a valuable biomarker for risk assessment, disease progression, and response to therapy. However, current strategies for isolation of these rare cells are limited to complex, laborious approaches. The goal of this study was the design and validation of a disposable microfluidic platform capable of selectively capturing and enumerating EPCs directly from human whole blood in healthy and diseased subjects, eliminating sample preprocessing. We then applied the "EPC capture chip" clinically and determined EPC numbers in blood from patients with pulmonary arterial hypertension (PAH). Blood was collected in tubes and injected into polymeric microfluidic chips containing microcolumns pre-coated with anti-CD34 antibody. Captured cells were immunofluorescently stained for the expression of stem and endothelial antigens, identified and counted. The EPC capture chip was validated with conventional flow cytometry counts (r = 0.83). The inter- and intra-day reliability of the microfluidic devices was confirmed at different time points in triplicates over 1-5 months. In a cohort of 43 patients with three forms of PAH (idiopathic/heritable, drug-induced, and connective tissue disease), EPC numbers are ≈50% lower in PAH subjects vs. matched controls and inversely related to two potential disease modifiers: body mass index and postmenopausal status. The EPC capture chip (5 × 30 × 0.05 mm(3)) requires only 200 μL of human blood and has the strong potential to serve as a rapid bedside test for the screening and monitoring of patients with PAH and other proliferative cardiovascular, pulmonary, malignant, and neurodegenerative diseases.

    View details for DOI 10.1007/s00109-011-0779-6

    View details for Web of Science ID 000294823900004

    View details for PubMedID 21735044

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


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

    View details for DOI 10.1016/j.pcad.2011.06.003

    View details for Web of Science ID 000294880400009

    View details for PubMedID 21875514

  • Survival in Pulmonary Hypertension Registries The Importance of Incident Cases Response CHEST Chung, L., Liu, J., Parsons, L. S., Hassoun, P. M., McGoon, M. D., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. 2011; 139 (6): 1548-1549
  • Disruption of the Apelin-APJ System Worsens Hypoxia-Induced Pulmonary Hypertension ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Chandra, S. M., Razavi, H., Kim, J., Agrawal, R., Kundu, R. K., Perez, V. D., Zamanian, R. T., Quertermous, T., Chun, H. J. 2011; 31 (4): 814-U212


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

    View details for DOI 10.1161/ATVBAHA.110.219980

    View details for Web of Science ID 000288437800017

    View details for PubMedID 21233449

  • Colonic ulceration as an unusual manifestation of vasculopathy in systemic sclerosis RHEUMATOLOGY Kao, L., Myer, P., Nguyen, L., Zamanian, R. T., Chung, L. 2011; 50 (3): 626-628

    View details for DOI 10.1093/rheumatology/keq276

    View details for Web of Science ID 000287745600030

    View details for PubMedID 21172924

  • Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead. International journal of clinical practice. Supplement de Jesus Perez, V., Kudelko, K., Snook, S., Zamanian, R. T. 2011: 8-10


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

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

    View details for PubMedID 21176010

  • Right ventricular failure: a novel era of targeted therapy. Current heart failure reports Banerjee, D., Haddad, F., Zamanian, R. T., Nagendran, J. 2010; 7 (4): 202-211


    There now is strong evidence to recognize the pivotal role of the right ventricle (RV) in heart disease and to establish it as a unique and separate entity than the left ventricle (LV). Here, we summarize the differences between the two ventricles, the diagnosis of RV failure, and the management of acute and chronic RV failure. We review the indices derived by echocardiography used to measure RV function, and novel biomarkers that may play a role diagnosing and prognosticating in RV-specific disease. There are new novel therapies that specifically target the RV in disease. For example, phosphodiesterase type 5 inhibitors improve contractility of the hypertrophied RV while sparing the normal LV in pulmonary arterial hypertension. The metabolism of the hypertrophied RV is another area for therapeutic exploitation by metabolic modulation. We also suggest future potential molecular targets that may be unique to the RV because they are upregulated in RV hypertrophy greater than in LV hypertrophy.

    View details for DOI 10.1007/s11897-010-0031-7

    View details for PubMedID 20890792

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


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

    View details for DOI 10.1016/j.healun.2010.04.023

    View details for PubMedID 20627625

    View details for PubMedCentralID PMC2926193

  • Epoprostenol-associated pneumonitis: Diagnostic use of a T-cell proliferation assay JOURNAL OF HEART AND LUNG TRANSPLANTATION Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., Perez, V. D. 2010; 29 (9): 1071-1075
  • ERG evaluation of daily, high-dose sildenafil usage Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Zoumalan, C. I., Zamanian, R. T., Doyle, R. L., Marmor, M. F. SPRINGER. 2009: 225–31


    Sildenafil can cause transient, mild ERG changes in healthy individuals taking large single doses. Although the drug was originally intended for intermittent use in erectile dysfunction, it has now been approved for chronic use in subjects with pulmonary arterial hypertension (PAH). The purpose of our study is to investigate possible ERG changes in subjects using large doses of sildenafil on a chronic daily basis.We examined five subjects with PAH taking sildenafil daily for 1-4 years. Full-field electroretinogram (ERG), multifocal ERG (mfERG), and color testing were performed. Three of the subjects returned on a later date for challenge off and on the medication.On chronic daily sildenafil, color vision testing was normal, and ERG and mfERG amplitudes were normal; however, cone implicit times on drug were modestly lengthened. There were no consistent full-field ERG changes when off the drug, but the mfERG showed a small amplitude increase and implicit time decrease, which returned 1 h after re-dosing.There was a modest lengthening of cone implicit time on chronic daily doses of sildenafil and a hint that some of these changes may be reversible in the short term. It does not appear that chronic sildenafil usage at these dosage levels is seriously toxic or threatening to vision.

    View details for DOI 10.1007/s10633-008-9148-3

    View details for Web of Science ID 000266261000006

    View details for PubMedID 18818963

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


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

    View details for DOI 10.1016/j.healun.2008.12.008

    View details for Web of Science ID 000266171400021

    View details for PubMedID 19416787

  • Progressive dyspnea after CABG: Complication of retained epicardial pacing wires ANNALS OF THORACIC SURGERY Horng, G. S., Ashley, E., Balsam, L., Reitz, B., Zamanian, R. T. 2008; 86 (4): 1352-1354


    We report a case of progressive dyspnea and recurrent pneumonia after uneventful coronary artery bypass graft surgery caused by migration of retained epicardial pacing wires into the right upper lobe of the lung. Removal of the wires by open thoracotomy resulted in significant improvement in dyspnea and near complete resolution of the bronchiectasis and consolidation.

    View details for DOI 10.1016/j.athoracsur.2008.03.013

    View details for Web of Science ID 000259848000044

    View details for PubMedID 18805194

  • Effectiveness and cost effectiveness of thrombolysis in patients with acute pulmonary embolism CURRENT OPINION IN PULMONARY MEDICINE Zamanian, R. T., Gould, M. K. 2008; 14 (5): 422-426


    Acute pulmonary embolism is a common, life-threatening, cardiopulmonary disorder with a high mortality rate within the first 3 months of diagnosis. As prompt anticoagulation is the mainstay of therapy in patients with pulmonary embolism, the clinical utility and cost effectiveness of systemic thrombolysis is debated.Pulmonary embolism with cardiogenic shock and hypotension is characterized as 'massive' in nature and an accepted indication for thrombolysis, although catheter-directed embolectomy with or without local lytic therapy is preferred in centers with appropriate experience. Acute right ventricular dysfunction is a poor prognostic indicator in patients with pulmonary embolism. The most recent randomized controlled trial of systemic thrombolysis in patients with submassive pulmonary embolism and right ventricular dysfunction found that, compared with heparin alone, alteplase and heparin reduced the risk of clinical deterioration requiring treatment escalation, but did not reduce the risk of death. Subsequently, a formal cost effectiveness concluded that alteplase and heparin was slightly less effective and marginally more expensive than heparin alone in this patient population.Current evidence does not support the use of thrombolytic agents in most hemodynamically stable patients with right ventricular dysfunction. However, improved methods of risk stratification may help to identify subgroups of patients at high risk of death that might benefit from systemic thrombolysis.

    View details for Web of Science ID 000258982100010

    View details for PubMedID 18664972

  • Chloride intracellular channel 4 (CLIC4), a novel downstream target of bone morphogenetic protein receptor II (BMPR-II) in human pulmonary artery smooth muscle cell (PASMC) migration 78th Annual Scientific Session of the American-Heart-Association Spiekerkoetter, E., Wang, L. L., Zamanian, R., Ambartsumian, N., Schmidt, A. M., Lukanidin, E., RABINOVITCH, M. LIPPINCOTT WILLIAMS & WILKINS. 2005: U210–U210
  • CT angiography of pulmonary artery aneurysms in Hughes-Stovin syndrome AMERICAN JOURNAL OF ROENTGENOLOGY Ketchum, E. S., Zamanian, R. T., Fleischmann, D. 2005; 185 (2): 330-332

    View details for Web of Science ID 000230738500008

    View details for PubMedID 16037501

  • Surgical and interventional therapies for pulmonary arterial hypertension SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Olsson, J. K., Zamanian, R. T., Feinstein, J. A., Doyle, R. L. 2005; 26 (4): 417-428


    Surgical and interventional therapies for pulmonary arterial hypertension (PAH) in appropriately selected patients have the potential to dramatically improve or, in some cases, cure PAH. These include atrial septostomy, a palliative procedure or bridge to transplantation in patients with refractory right heart failure, pulmonary thromboendarterectomy for pulmonary hypertension associated with chronic thromboembolic disease, and closure of congenital systemic-pulmonary shunts in patients with PAH but without significant pulmonary vascular disease. Lung transplantation should be considered for patients with all forms of PAH who demonstrate advanced or progressive disease.

    View details for Web of Science ID 000231671900010

    View details for PubMedID 16121319

  • Regulative response of the cranial neural tube after neural fold ablation: Spatiotemporal nature of neural crest regeneration and up-regulation of Slug DEVELOPMENT Sechrist, J., Nieto, M. A., Zamanian, R. T., BRONNERFRASER, M. 1995; 121 (12): 4103-4115


    After unilateral ablation of the avian cranial neural folds, the remaining neuroepithelial cells are able to replace the missing neural crest population (Scherson et al., 1993). Here, we characterize the cellular and molecular nature of this regulative response by defining: (1) the time and location of neural crest cell production by the neuroepithelium; (2) rostrocaudal axial differences in the regulative response; and (3) the onset of expression of Slug, a transcription factor present in premigratory and migrating neural crest cells. Using DiI and HNK-1 antibody labeling techniques, we find that neural crest regeneration occurs only after apposition of the remaining neuroepithelium with the epidermis, suggesting that the developmental mechanism underlying regeneration of the neural crest may recapitulate initial generation of the neural crest. The regulative response occurs maximally at the 3-5 somite stage, and slowly declines thereafter. Surprisingly, there are profound regional differences in the regenerative ability. Whereas a robust regulation occurs in the caudal midbrain/hindbrain, the caudal forebrain/rostral midbrain regenerates neural crest to a much lesser extent. After neural fold removal in the hindbrain, regenerated neural crest cells migrate in a segmental pattern analogous to that seen in unablated embryos; a decrease in regulative response appears to occur with increasing depth of the ablation. Up-regulation of Slug appears to be an early response after ablation, with Slug transcripts detectable proximal to the ablated region 5-8 hours after surgery and prior to emergence of neural crest cells. Both bilateral and unilateral ablations yield substantial numbers of neural crest cells, though the former recover less rapidly and have greater deficits in neural crest-derived structures than the latter. These experiments demonstrate that the regulative ability of the cranial neuroepithelium to form neural crest depends on the time, location and extent of neural fold ablation.

    View details for Web of Science ID A1995TM47800019

    View details for PubMedID 8575311