Bio

Clinical Focus


  • Pulmonary Hypertension
  • Pulmonary Disease
  • Pulmonology (Lung) and Critical Care

Academic Appointments


Administrative Appointments


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

Honors & Awards


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

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


  • Member PHA SLC

    Partnering Organization(s)

    Pulmonary Hypertension Association

    Location

    US

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


1. The Utility of S100A4/Mts1 as a Biomarker in Pulmonary Arterial Hypertension (PAH).

2. Prevalence and Treatment of Insulin Resistance in PAH.

3. The Effect of EGF-Receptor Blockade and Elastase Inhibitor on Pulmonary Arteries of Patients with PAH.

4. Characterization of Pulmonary Arteries in Patients with Idiopathic and Secondary PAH by Wedge Angiography.

5. The Optimal Angle for Angiographic Evaluation of the Left Pulmonary Artery in Patients with PAH.

Clinical Trials


  • A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil), 2 FDA Approved Pulmonary Hypertension Medications Recruiting

    The Study Hypothesis: Aggressive, upfront, dual therapy for treatment-naïve NYHA I/II/III PAH is superior to a traditional "step-up" approach. The study will evaluate: 1. Impact of dual, upfront, therapy on cardiovascular parameters in PAH as gauged by cardiac magnetic resonance imaging (cMRI) at 24 weeks and event free survival at outcome at 48 weeks. 2. Value of novel biomarkers (NT-pro BNP, Mts1/S100A4, and insulin resistance) and cutting-edge imaging technologies (cardiac MRI) as newer endpoints for clinical trials in PAH. 3. Utility of longer clinical trial design with the use of combined clinical events as time to clinical worsening surrogate

    View full details

  • FK506 (Tacrolimus) in Pulmonary Arterial Hypertension Recruiting

    Mutations in bone morphogenetic protein receptor 2 (BMPR2) are present in >80% of familial and ~20% of sporadic pulmonary arterial hypertension (PAH) patients. Furthermore dysfunctional BMP signaling is a general feature of pulmonary hypertension even in non-familial PAH. We therefore hypothesized that increasing BMP signaling might prevent and reverse the disease. We screened > 3500 FDA approved drugs for their propensity to increase BMP signaling and found FK506 (Tacrolimus) to be a strong activator of BMP signaling. Tacrolimus restored normal function of pulmonary artery endothelial cells, prevented and reversed experimental PAH in mice and rats. Given that Tacrolimus is already FDA approved with a known side-effect profile, it is an ideal candidate drug to use in patients with pulmonary arterial hypertension. The aims of our trial are: 1. Establish the Safety of FK506 in patients with PAH. 2. Evaluate the Efficacy of FK506 in PAH 3. Identify ideal candidates for future FK506 phase III clinical trial.

    View full details

  • Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH) Recruiting

    Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a serious, life-threatening manifestation of systemic sclerosis (SSc), an autoimmune disease of the connective tissue characterized by scarring (fibrosis) and atrophy of the skin, joints and tendons, skeletal muscles, and internal organs, and immunological disturbances. One-year survival for patients with SSc-PAH ranges from 50-81%. There is currently no cure for SSc-PAH and treatment is limited to vasodilator therapy used in all forms of PAH. In recent studies, immunotherapy was shown to be effective in treating SSc-interstitial lung disease, another serious, life-threatening manifestation of SSc. In addition, there are compelling pre-clinical data and anecdotal clinical reports that suggest modulation of the immune system may be an effective strategy for treating SSc-PAH. To test this approach, this trial will determine if rituximab, an immunotherapy, has a marked beneficial effect on clinical disease progression, with minimal toxicity, in patients with SSc-PAH when compared to placebo.

    View full details

  • Study of Incidence of Respiratory Tract AEs in Patients Treated With Tyvaso® Compared to Other FDA Approved PAH Therapies Recruiting

    A surveillance of respiratory tract related adverse events in patients treated with Tyvaso®(treprostinil) Inhalation Solution versus other FDA approved therapies

    View full details

Teaching

2013-14 Courses


Publications

Journal Articles


  • 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)
  • 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

    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 III.ClinicalTrials.gov 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

    Abstract

    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

  • Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699

    Abstract

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

    View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

    View details for 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

    Abstract

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

    View details for DOI 10.1016/j.cardfail.2011.03.003

    View details for 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

    Abstract

    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 subgroups. Trial registry: ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov.

    View details for DOI 10.1378/chest.10-0260

    View details for Web of Science ID 000285494000017

    View details for PubMedID 20507945

  • 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

    Abstract

    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)

    Abstract

    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

    Abstract

    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

    Abstract

    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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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. 2013

    Abstract

    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

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

    Abstract

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

    View details for DOI 10.1016/j.amjcard.2012.07.012

    View details for PubMedID 22853986

  • 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

    Abstract

    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

    Abstract

    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 ?L 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

    Abstract

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

    View details for DOI 10.1016/j.pcad.2011.06.003

    View details for Web of Science ID 000294880400009

    View details for PubMedID 21875514

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

    Abstract

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

    View details for DOI 10.1161/ATVBAHA.110.219980

    View details for 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

    Abstract

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

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

    View details for PubMedID 21176010

  • 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

    Abstract

    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., Perez, V. D. 2010; 29 (9): 1071-1075

    Abstract

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

    View details for DOI 10.1016/j.healun.2010.04.023

    View details for Web of Science ID 000281494800016

  • ERG evaluation of daily, high-dose sildenafil usage DOCUMENTA OPHTHALMOLOGICA Zoumalan, C. I., Zamanian, R. T., Doyle, R. L., Marmor, M. F. 2009; 118 (3): 225-231

    Abstract

    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

    Abstract

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

    View details for DOI 10.1016/j.healun.2008.12.008

    View details for 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

    Abstract

    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

    Abstract

    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

  • 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

    Abstract

    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

    Abstract

    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

Stanford Medicine Resources: