`Appl. No. 12/591,200
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`IN THE UNITED STATES PATENTAND TRADEMARKOFFICE
`
`Applicant:
`
`Horst OLSCHEWSKI et al.
`
`Title:
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`TREPROSTINIL ADMINISTRATION BY INHALATION
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`Appl. No.:
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`12/591,200
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`Filing Date:
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`11/12/2009
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`Examiner:
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`Sara Elizabeth Townsley
`
`Art Unit:
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`1629
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`Confirmation
`Number:
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`4093
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`DECLARATION UNDER 37 C.F.R,§ 1.132 OF DR. ROHAM T. ZAMANIAN
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`I, Dr. Roham T. Zamanian, hereby declare:
`
`1.
`
`I received a Bachelor of Science and a Doctor of Medicine from the University of
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`California, Irvine, where [ also completed my internship, residency, and a fellowship in
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`pulmonary medicine and critical care.
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`I completed a second fellowship in pulmonary
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`medicine and critical care at Stanford University Medical Center where I am now an
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`Associate Professor of Medicine and Director of the Adult Pulmonary Hypertension
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`Program.
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`2.
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`I am board certified in both internal and pulmonary medicine and have served as an
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`investigator in a numberofclinical trials of pulmonary hypertension drug trials, which are
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`listed in the attached CV. See EXHIBIT 1.
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`3.
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`Myresearch focuses on strategies for management of pulmonary hypertension, and I have
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`a numberof publications in these areas — listed in the attached CV. See EXHIBIT 1.
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`4828-2691-8182.1
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`IPR2021-00406
`United Therapeutics EX2086
`Page 1 of 113
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`IPR2021-00406
`United Therapeutics EX2086
`Page 1 of 113
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`[am a paid consultant for United Therapeutics, the assignee of the above-identified patent
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`application, in connection with this matter. My compensation does not depend on the
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`content of my opinions or the disposition of this application.
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`Prior to consulting for United Therapeutics, I was a principal investigatorin the “Aspire”
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`registry comparing the incidence of respiratory tract adverse events in patients treated
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`with United Therapeutics’ product — Tyvaso® — with other FDA approved pulmonary
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`hypertension therapies. Stanford University has also recerved compensation from United
`
`Therapeutics for my work as an investigator on the Confront and Freedom M trails.
`
`The Cited References
`
`I amfamiliar with the Office Action dated October 10, 2014 in U.S. Patent Application
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`No. 12/591,200 as well as the disclosure and claims of the subject application.
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`I am also
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`familiar with the references cited in the Office Action.
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`I understand the claims of U.S. Patent Application No. 12/591,200 are directed to a
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`methodoftreating pulmonary hypertension comprising administering by inhalation to a
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`human in need thereof a therapeutically effective single event dose of an inhalable
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`formulation with a pulsed ultrasonic nebulizer, wherein said therapeutically effective
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`single event dose comprises from 15 ug to 90 ug of treprostinil or a pharmaceutically
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`acceptable salt thereof, said therapeutically effective single event dose is inhaled in 18
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`or less breaths by the human
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`I have reviewed US 2004/0265238 (Chaudry) and U.S. Patent No. 6,357,671 (Cewers)
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`cited in the Office Action, in addition to further references pertinent in the art regarding
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`inhaled pulmonary hypertension treatment — specifically those references cited herein and
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`attached as EXHIBITS2-7,
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`Chaudry broadly relates to inhalable formulations for treating pulmonary hypertension
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`and methods of using the same, see, e.g. title. Among the list of hypertension reducing
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`4828-269} -8182.1
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`agents included the extensive list of paragraphs [0022]-[0027] are treprostinil and
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`iloprost. Both compounds are cited among examples of vasodilators in paragraph [0026]
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`that may ostensibly be used interchangeably with any other compounddisclosed in the
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`paragraph.
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`10,
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`An exemplary embodimentof the claimed invention comprising treprostinil is FDA
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`approved for use with pulmonary hypertension and available on the market as Tyvaso®,
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`An inhalable formulation fortreating pulmonary hypertension containing iloprost,
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`Ventavis®, is also FDA approved and currently available on the market.
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`11.
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`Contrary to the disclosure of Chaudry, Tyvaso® is not interchangeable with Ventavis®;
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`rather, based on myclinical experience and the surroundingliterature, Tyvaso® is
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`preferable to Ventavis®,
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`IL.
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`Skepticism and long-felt need prior to Tyvaso®
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`12.
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`As of May 15, 2006, the results of the Aerosolized Iloprost Randomized Study (ATR)
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`documenting the effects of inhaled iloprost had been public about three and a half years,
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`and Ventavis® had only been on the market for about one and a half years. See
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`Olschewski et al. N Engl. J. Med. 2002;347(5):322-329 (EXHIBIT 2), FDA Listing of
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`Priority NDA and BLA Approvals in 2004 (EXHIBIT3); see also Lee et al. J. Int. Med.
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`2005;258:199-215 (EXHIBIT 4).
`
`13,
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`Clinicians were largely still of the opinion that intravenous administration of a
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`prostacyclin analog was preferable to inhaled delivery. Thus, there was concern that the
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`adoption Ventavis® could be happening too rapidly without a full understanding of the
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`side effects.
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`14,
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`Further, adoption of Ventavis® posed a numberof issues. For instance, Ventavis®
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`required administration 6-9 times daily, which was considered challenging for patients to
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`implement. Moreover, clinicians remained concerned about the lack of nocturnal dosing
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`and physiologic impact of withdrawalduring the night and early morning hours. There
`were concerns on how to address the interaction between the patient and the nebulizer and
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`how to administer the therapy if the patient was either altered in mental status or
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`intubated in the intensive care unit.
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`As of May 15, 2006, clinicians would not have arrived at a methodoftreatment using
`inhaled treprostinil according to the present claims. There was too much uncertainty as to
`the effects of inhaled iloprost to speculate the potential effects of anotherinhaled
`formulation comprising a prostacyclin analog. Indeed, the medical community remained
`convinced that intravenous administration was preferable to inhalable therapeutics.
`
`Moreover,at that time, the pharmacodynamicsof inhaled treprostinil would have been
`unpredictable; thus, precluding the ability to arrive at dosing regimens such as those
`claimed. Factors such as half-life, drug-drug interactions, and adverse events could not
`be predicted based on the then available formulationsof treprostinil.
`
`Forat least these reasons, the benefits of inhaled treprostinil — such as thoselisted in the
`specification of the pending application at, for example, paragraphs [0081] to [0088] and
`in Figures 6, 10, and 11(discussed in detail below) — would not have been contemplated
`or expected as of May 15, 2006.
`
`15.
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`16.
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`17.
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`II.
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`Commercial success of Tyvaso®
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`18.
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`Interestingly, once Tyvaso® entered the market, it was clinically preferred to Ventavis®,
`Asindicated by the graph below,afterits entry onto the market, Tyvaso® rapidly
`increased its market share, while the share held by Ventavis® rapidly decreased.
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`US Inhaled Prostacyclin Market Share
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`100 per
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`80
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`Share 20
`%Market
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`60
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`40
`
`eauVontavis
`oomTYVaSO
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`Sept.
`2009
`
`Sept.
`2010
`
`Sept.
`2011
`
`Sept.
`2012
`
`Sept.
`2013
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`19,
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`I believe the tradeoff in market share results from the clinical advantages that Tyvaso®
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`has over Ventavis®.
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`A. Tyvaso® requires less frequent administration.
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`20,
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`21.
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`22.
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`23,
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`24.
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`Because of the pharmacodynamic differences between iloprost and treprostinil, Tyvaso®
`does not need to be administered as frequently as Ventavis®, leading to higher patient
`
`compliance.
`
`Ventavis® (inhaled iloprost) has a half-life between 20-25 min. As a result, Ventavis®
`needs to be used 6-9 times a day, as frequent as every 2 hours.
`
`In contrast, Tyvaso® (inhaled treprostinil) has a much longer half-life wheninhaled by
`human subjects suffering from pulmonary hypertension. This allows Tyvaso® to be
`administered markedly less frequently — about | to 4 times a day.
`
`In myclinical practice, | have found that patients are more likely to comply with a
`regimenthat requires less frequent administrations; thus, Tyvaso® has been preferable.
`
`Furthermore,the fact that Ventavis® has a shorthalf-life results in periods where patients
`may be off-medication while asleep unless they wake up to take a dose of the drug.
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`Nocturnal hypoxemia is a common symptom ofpatients with pulmonary hypertension,
`_ thus, periods where a patient is off-medication and asleep present face less risk if
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`Tyvaso® is prescribed instead of Ventavis®.
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`B, The pulsed ultrasonic nebulizer used with Tyvaso® is preferred by
`patients.
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`95.
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`The differences in the devices used to administer each drug also results in higher patient
`
`preference and compliance with Tyvaso®.
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`26.
`
`27.
`
` Ventavis® employs an adaptive aerosol delivery (AAD) nebulizer. See Ventavis®
`Patient Brochure (EXHIBIT 5). Such a device adjusts the dose amountto the volume of
`the breath the patient takes in. Thus, the duration of use of the deviceis dependent on the
`patient’s breathing. This can lead to the time engagement required to deliver the drug
`ranging from 10-20 min, depending on the AAD device. Each time the patient uses the
`device, the patient has to load in the drug. Once the dose is delivered, the patient has to
`take apart the device, remove the mesh, and then clean the mesh in distilled water. Each
`use of Ventavis® is, thus, a time-intensive process.
`
` Incontrast, Tyvaso® employsa pulsed ultrasonic nebulizer, as indicated in the pending
`claims. See Tyvaso® Patient Brochure (EXHIBIT 6). With this device, the dose is a
`fixed bolus dose per breath; thus, the dosing is based on breath number,e.g. 18 breaths or
`less as claimed. Id; see also Specification at paragraphs [0040], [0070], and [0078].
`Unlike the Ventavis® device, this device is filled once a day; nothing in the way of
`cleaning or disassembly is done with the device until the end of the day.
`
`28.
`
`In myclinical practice, I have found that this results in a better patient experience and,
`thus, higher patient compliance.
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`HI.
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`Unexpected Results
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`29,
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`30,
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`31.
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`32,
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`33.
`
`The results of the studies disclosed in the present application demonstrate that aerosolized
`terprostinil administered according to the instant claims has a dose dependent and longer
`pharmacokinetic effect than would be expected based oniloprost.
`
`Asnoted in paragraph [0081], while the maximumeffect of aerosoloized iloprost and
`treprostinil on pulmonary vascular resistance (PVR) was comparable, treatment with
`treprostinil achieved this maximumeffect much soonerandlasted for a longer duration
`comparedto treatment with iloprost. Further, while iloprost is known to reduce systemic
`arterial pressure (SAP), Figure 6C demonstrates that administration of treprostinil does
`
`not result in this same reduction of SAP.
`
`Regardless of pulse numberin which dose was administered, administration of
`aerosolized treprostinil resulted in no significant effect on SAP. Of particular clinical
`interest is the high reduction of PVR achieved in a three-pulse administration of 15 pg of
`treprostinil, which appears to have the most modest impact on SAP based on Figures 10
`
`and 11.
`
`These data suggest thattreprostinil is far morepulmonary selective than iloprost: a result
`that would have been unexpected as of May15,2006. See Whittle Biochem. Pharmacol.
`2012: 84:68-75 (a post-filing article describing potential mechanistic differences that may
`explain this difference in effect, EXHIBIT 7).
`
`IV.
`
`Conclusion
`
`Although not expected as of May 15, 2006, Tyvaso® is clinically superiorto Ventavis®
`and preferred to Ventavis® forat least the above mentioned reasons. Further, the claimed
`method employinginhaled treprostinil results in unexpected benefits for treatment of
`
`pulmonary hypertension.
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`34,
`
`I further declare that all statements made herein of my own knowledge are true and that
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`all statements made on information and belief are believed to be true, and further, that
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`these statements were made with the knowledge that willful false statements and the like
`so made are punishable byfine or imprisonment, or both, underSection 1001 of Title 18
`of the United States Code, and that such willful false statements may jeopardize the
`
`validity of the application or any patent issuing thereon.
`
`Signed this
`
`du
`4 ~ day of
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`November
`
`, 2015,
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`
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`A. BIOGRAPHICAL INFORMATION
`Roham T. Zamanian, M.D.
`Division of Pulmonary & Critical Care Medicine
`Stanford University Medical Center
`300 Pasteur Dr, Room H3143
`Stanford, CA 94305
`
`EXHIBIT 1
`
`B. ACADEMIC HISTORY
`1. Colleges and Universities Attended
`1989 - 1994
`Bachelor of Science, Biological Sciences
`University of California, Irvine
`
`1995 - 1999
`
`1999 - 2002
`
`2002 - 2003
`
`2003 - 2005
`
`2004 - 2006
`
`Doctor of Medicine
`University of California, Irvine College of Medicine
`
`Internship and Residency, Internal Medicine
`University of California, Irvine Medical Center (UCIMC)
`
`Pulmonary & Critical Care Fellowship
`Division of Pulmonary & Critical Care Medicine
`University of California, Irvine Medical Center
`
`Pulmonary & Critical Care Fellowship
`Division of Pulmonary & Critical Care Medicine
`Stanford University Medical Center
`
`eBay Advanced Fellowship in Pulmonary Vascular Disease
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University Medical Center
`
`2. Undergraduate and Medical School Awards and Activities
`* Dean’s Honor List (1990-1994)
`* The Campuswide Honors Program (1990-1994)
`* Howard Hughes SummerFellow, Harvard School of Medicine (1991, 1992)
`* UCI Undergraduate Excellence in Research Award (1994)
`* Ralph Waldo Gerard Award for Outstanding Researcher (1994)
`
`3.
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`Internship, Residency, and Fellowship Training and Awards
`* Intern of the year, UCIMC Dept of Medicine (1999-2000)
`* Case Presentation Award, American College of Chest Physicians (2000)
`* Departmentof Internal Medicine Research Presentation Award, UCIMC (2001)
`* Fellow of the Year, UCIMC Dept of Medicine (2002-2003)
`* Entelligence Young Investigator’s Career Development Award (2006)
`* American College of Chest Physicians Fellow (2007)
`* Stanford University, Dept. of Medicine, Division of PCCM Teaching Award (2007)
`
`4. Board Certification
`* 2003 American Board of Internal Medicine - Internal Medicine
`* 2006 American Board of Internal Medicine - Pulmonary
`
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`C. STANFORD UNIVERSITY EMPLOYMENTHISTORY
`7/1/2006-8/1/2007—Instructor of Medicine
`Division of Pulmonary & Critical Care Medicine
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University Schoo! of Medicine
`
`8/1/2007-7/1/2008
`
`7/1/2008-11/2014
`
`11/2014-Present
`
`Acting Assistant Professor of Medicine
`Division of Pulmonary andCritical Care Medicine
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University School of Medicine
`
`Assistant Professor of Medicine
`Division of Pulmonary and Critical Care Medicine
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University School of Medicine
`
`Associate Professor of Medicine
`Division of Pulmonary and Critical Care Medicine
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University School of Medicine
`
`2/1/2009-6/30/2012
`
`Secondary Affiliation in Division of Immunology
`Stanford University School of Medicine
`
`06/2006-Present
`
`Director, Adult PH Cardiac Catheterization Laboratory
`Adult Pulmonary Hypertension Clinical Service
`Division of Pulmonary & Critical Care Medicine
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University School of Medicine
`
`01/2007-Present
`
`Clinical Manager, VMWCClinical Database
`Vera Mouiton Wall Center for Pulmonary Vascular Disease
`Stanford University School of Medicine
`
`10/2007 - Present
`
`Director, Adult Pulmonary Hypertension Clinical Service
`Division of Pulmonary & Critical Care Medicine
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University School of Medicine
`
`09/2013 — 09/2018
`
`Junior Faculty Scholar Award
`Vera Moulton Wall Center for Pulmonary Vascular Disease
`Stanford University School of Medicine
`
`D. PUBLIC AND PROFESSIONAL SERVICE
`1. Society Membership & Leadership
`* Pulmonary Hypertension Association — Scientific Leadership Council
`-
`The PHCC Committee — Chair Task Force #2 (funding & sustainability)
`-
`The Insurance and Advocacy Committee (member)
`International Right Heart Failure Foundation Scientific Working Group (member).
`+
`* Pulmonary Vascular Research Institute — Fellow
`
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`* American Thoracic Society
`- American College of Chest Physicians - Fellow
`*
`International Society for Heart and Lung Transplantation
`
`2. Editorship
`American Thoracic Society Pulmonary Circulation — Pulmonary Hypertension Journal Club
`(2007-201 1)
`
`3. AdHoc Reviewer
`« Lancet
`Circulation
`Journal of the Amercian College of Cardiology
`American Journal of Respiratory & Critical Care Medine
`European Respiratory Journal
`CHEST
`Journal of Cardiac Failure
`International Journal of Rheumatology
`Biomarkers
`* Lung
`« American Heart Journal
`
`4. Clinicai Trial Committee Memberships
`
`* ASCO1 — Steering Committee Member.
`Rituximab for Scleroderma Associated PulmonaryArterial Hypertension.
`NIH/NIAID (2010-present)
`
`* SYMPHONY — Steering Committee Member.
`A Study of Macitentan in Pulmonary arterial HypertensiON to validate PAH-SYMPACT.
`Actelion (2012-present)
`
`* CMREF Ranolazine — Chair, Data and Safety Monitor Board.
`A Randomized, Double-blind, Placebo controlled, Multi-center study to Assess the Effect
`of Ranolazine on Outcomes and Right Heart Function in PAH.
`Cardiovascular Medical Research Education Fund & Gilead Sciences (2013-present)
`
`» Pfizer #A1481324 — Member, Revatio Clinical Endpoint Adjudication Committee.
`A Multinational Multicenter Study to Assess the Effects of Oral Sildenafil on Mortality in
`Aduits with PAH. (2014 — Present)
`
`5. Grant Review / Study Sections
`
`* Pulmonary VA Merit Grant Reviewer(2012)
`* VA Merit Grant Pulmonary Board External Referee for William S. Middleton Memorial
`Veterans Hospital (2014)
`
`E. GRANTS & AWARDS
`
`Completed:
`
`Study:
`
`The VISION Trial - A Randomized, Double-blind, Placebo-Controlled Study to
`Evaluate the Safety and Efficacy of the Addition of Inhaled Iloprost in Patients with
`Pulmonary Arterial Hypertension (PAH) Receiving Oral Sildenafil.
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`Co-PI for a multi-site trial at Stanford (PI - Ramona Doyle)
`Role:
`industry-initiated multi-institutional trial
`Type:
`industry (Actelion Pharmaceutical)
`Sponsor:
`Subjects: Total 67, Stanford 2
`Clinicaltrial.gov #: NCT00302211
`
`Study:
`
`Effect of Pioglitazone versus Bosentan on Metabolic Profiles and Outcomesof
`Insulin Resistant Patients with Pulmonary Arterial Hypertension
`Senior Investigator for the overall study
`Role:
`Investigator-initiated single institutionaltrial
`Type:
`Sponsor: Industry (Actelion Pharmaceutical)
`Subjects: Stanford 2
`Clinicaltrial.gov #: NCT00825266
`
`Study:
`
`The REVEAL Registry — Registry to Evaluate Early and Long-Term Pulmonary
`Arterial Hypertension Disease Characterization and Management
`Principal investigator for a multi-site trial at Stanford
`Role:
`Industry-initiated multi-institutionaltrial
`Type:
`Industry (Actelion Pharmaceutical)
`Sponsor:
`Subjects: Total 3500, Stanford 52
`Clinicaltrial.gov #: NCT00370214
`
`Study:
`
`Open Label Extension of the FREEDOM-CTrial - An International, Multicenter,
`Randomized, Double-blind, Placebo- Controlled Comparison of the Efficacy and
`Safety of Oral UT-15C Sustained Release Tablets in Combination with an
`Endothelin Receptor Antagonists and/or a Phosphodiestrase-5 Inhibitor in Subjects
`with Pulmonary Arterial Hypertension.
`Principal investigator for a multi-site trial at Stanford
`Role:
`Industry-initiated muiti-institutional trial
`Type:
`Industry (United Therapeutics Pharmaceutical)
`Sponsor:
`Subjects: Total 900, Stanford 3
`Clinicaltrial.gov #: NCT01027949
`
`Study:
`
`The PROSPECTRegistry — Registry to Evaluate Room Temperature Stable
`Epoprostenol.
`Principal investigator for a multi-site trial at Stanford
`Role:
`industry-initiated multi-institutional trial
`Type:
`Industry (Actelion Pharmaceutical)
`Sponsor:
`Subjects: Total 200, Stanford 7
`Clinicaltrial.gov #: Pending
`
`Current:
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`Proteomics of Inflammation, Immunity and Pulmonary Arterial Hypertension
`Grant:
`Source: National institutes of Health / The National Heart, Lung, and Blood Institute
`Dates:
`08/2010 ~ 08/2015; Enrolling.
`Role:
`Human Core Director, (P! — Gary Nolan)
`
`Elafin Therapy for Lung Diseases
`Grant:
`Source: National Institutes of Health / National Heart Lung and BloodInstitute (PAR-09-185)
`Dates:
`08/2011 — 08/2015; Enrolling.
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`Role:
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`Human Core Co-Director, (PI ~ Marlene Rabinovitch)
`
`Grant:
`
`iPSC Derived Endothelial Cells as Surrogates using Pulmonary Hypertension as a
`Prototype Disease
`Source: NIH/ National Heart Lung and Blood Institute (1U01HL107393-01)
`Dates:
`07/2011 — 06/2016; Enrolling.
`Role:
`Co-Investigator, (Pl — Marlene Rabinovitch)
`
`Grant:
`Source:
`Dates:
`Role:
`
`Stanford PAH Transplant and Preparation Center
`Continuing Medical Research and Education Fund (CMREF UL1RR024986)
`04/2006 — 03/2015; Enrolling.
`CO-PI, (Pl — Marlene Rabinovitch)
`
`Study:
`
`Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension
`with a Monoclonal Antibody to CD20 (Rituximab)
`Co-investigator for the overall study
`Role:
`Cooperative group clinicaltrial
`Type:
`Sponsor: National Institutes of Child Health and Human Development — (U19 Al 056362)
`Subjects: Total 27, Stanford 6 (Goal 80)
`Clinicaltrial.gov #: NCT01086540
`
`Study:
`
`CONFRONTPAH — A 48-week Study of the Effect of Dual Therapy (inhaled
`Treprostinil and Tadafafil) Versus Mono-therapy (Tadalafil), 2 FDA Approved
`Pulmonary Hypertension Medications.
`Senior Investigator for the overall study
`Role:
`investigator-initiated multi-institutionaltrial
`Type:
`Industry (United Therapeutics Pharmaceutical)
`Sponsor:
`Subjects: Total 21, Stanford 11 (Goal 30)
`Clinicaltrial.gov #: NCT01305252
`
`Study:
`
`Study of Incidence of Respiratory Tract Adverse Events in Patients Treated With
`Tyvaso® Compared to Other FDA Approved Pulmonary Arterial Hypertension (PAH)
`Therapies (Aspire)
`Principal investigator for a multi-site trial at Stanford
`Role:
`industry-initiated multi-institutionaltrial
`Type:
`Industry (United Therapeutics Pharmaceutical)
`Sponsor:
`Subjects: Total 1320, Stanford 42
`Clinicaltrial.gov #: NCT01266265
`
`Study:
`
`TrANSFORM PAH -— PhaseII Study of Safety, Tolerability, and Efficacy of FK-506
`(Tacrolimus) in Pulmonary Arterial Hypertension.
`Co-Senior Investigator for the overall study
`Role:
`Investigator-initiated single-center trial
`Type:
`Sponsor: University (Vera Moulton Wall Center & SPARK @ Stanford University)
`Subjects: Total 24, Goal 40
`Clinicaltrial.gov #: NCT01647945
`
`Study:
`
`SYMPHONY — A multi-center, open-label, single-arm, Phase 3b study of macitentan
`in patients with Pulmonary Arterial Hypertension to psychometrically validate the
`PAH-SYMPACTinstrument
`investigator & Steering Committee Member
`Role:
`Investigator-initiated single-center trial
`Type:
`Sponsor: Actelion Pharmaceuticals US, Inc.
`Subjects: Total 275, Stanford (pending)
`
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`Clinicaltrial.gov #: NCT01841762
`
`F. PUBLICATIONS[53 total: 47 published; 2 in press; 4 submitted]
`
`Peer-Reviewed[51 total; 45 published; 2 in press; 4 submitted]
`
`J Sechrist, MA Nieto, RT Zamanian, M Bronner-Fraser. Regulative Response of the
`1.
`Cranial Neural Tube after Neural Fold Ablation: Spatiotemporal Nature of Neural Crest
`Regeneration and up-regulation of S/ug. Development 1995 121, 4103-4115 (1995).
`
`J Olsson, RT Zamanian. Toxicity of Local Anesthetics in the Emergency Department.
`2.
`emedicine (Emergency Medicine) Online. 2005 www.emedicine.com
`
`J Olsson, RT Zamanian, JA Feinstein, RL Doyle. Surgical Strategies for Management
`3.
`of Pulmonary Arterial Hypertension. Semin Respir Crit Care Med. 2005 Aug; 26(4):417-28.
`
`4. E Ketchum, RT Zamanian, D Fleischmann. CT-Angiography of Pulmonary Artery
`Thrombi and Aneurysms in Hughes-Stovin Syndrome. Am J Roentgenol. 2005 Aug;
`185(2):330-2.
`
`5. RT Zamanian, F Haddad, RL Doyle, A Weinacker. ManagementStrategies for Patients
`with Pulmonary Hypertension in the Intensive Care Unit. Critical Care Medicine, 2007 Sep;
`35(9):2037-50.
`
`6. Cl Zoumalan, RT Zamanian, RL Doyle, MF Marmor. ERG evaluation of daily, high-dose
`sildenafil usage. Doc Ophthalmol, 2009 Jun;118(3):225-31. Epub 2008 Sept 26.
`
`7. GS Horng, E Ashley, L Balsam, B Reitz, RT Zamanian. Progressive dyspnea after
`CABG: Complication of Retained Epicardial Pacing Wires. Ann Thorac Surg, 2008
`Oct;86(4):1352-4.
`
`8. RT Zamanian, M Gould. Effectiveness and cost effectiveness of thrombolysis in
`patients with acute pulmonary embolism. Curr Opin Pulm Med, 2008 Sep;14(5):422-6.
`
`9. CE Ventetuolo, RL Benza, AJ Peacock, RT Zamanian, DB Badesch, SM Kawut.
`Surrogate and combined end points in pulmonary arterial hypertension. Proc Am Thorac
`Soc. 2008 Jul 15;5(5):617-22.
`
`10. RT Zamanian, G Hansmann, S Snook, D Lilienfeld, K Rappaport, M Rabinovitch, G
`Reaven, RL Doyle.
`Insulin Resistance in Pulmonary Arterial Hypertension. Eur Respir J.
`2009 Feb;33(2):318-24. Epub 2008 Dec 1.
`
`11. VA de Jesus Perez, F Haddad, RH Vagelos, W Fearon, J Feinstein, RT Zamanian.
`Angina associated with left main coronary artery compression in pulmonary hypertension. J
`Heart Lung Transplant. 2009 May;28(5):527-30. Epub 2009 Feb 20.
`
`12. Haddad F, Zamanian RT, Beraud AS, Schnittger |, Feinstein J, Peterson T, Yang P,
`Doyle RL, Rosenthal D. A Novel Non-invasive Method of Estimating Pulmonary Vascular
`Resistance in Patients With Pulmonary Arterial Hypertension.
`J Am Soc Echocardiogr
`2009;22:523-529.
`
`Page 14 of 113
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`Page 14 of 113
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`13. G Hansmann, RT Zamanian. PPARy Activation: A Novel Treatment for Pulmonary
`Arterial Hypertensions. Sci Transi Med. 2009 Dec 23;1(12):12ps14..
`
`14. Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, Miller DP, Nicolls
`MR, Zamanian RT. Characterization of connective tissue disease-associated pulmonary
`arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype.
`Chest. 2010 Dec;138(6):1383-94. Epub 2010 May 27.
`
`15. Elliott CG, Barst RJ, Seeger W, Porres-Aguilar M, Brown LM, Zamanian RT, Rubin LJ.
`Worldwide physician education and training in pulmonary hypertension: pulmonary vascular
`disease: the global perspective. Chest. 2010 Jun;137(6 Suppl):85S-94S.
`
`16. Kudelko KT, Nadeau K, Leung AN, Liu J, Haddad F, Zamanian RT, De Jesus Perez V.
`Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay.
`J
`Heart Lung Transplant. 2010 Sep;29(9):1071-5. Epub 2010 Jun 8.
`
`17. Banerjee D, Haddad F, Zamanian RT, Nagendran J. Right ventricular failure: a novel
`era of targeted therapy. Curr Heart Fail Rep. 2010 Dec;7(4):202-11.
`
`18. Kao L, Myer P, Nguyen L, Zamanian RT, Chung L. Colonic ulceration as an unusual
`manifestation of vasculopathy in
`systemic sclerosis. Rheumatology (Oxford). 2011
`Mar;50(3):626-8. Epub 2010 Dec 20.
`
`19. de Jesus Perez V, Kudelko K, Snook S, Zamanian RT. Drugs and toxins-associated
`pulmonary arterial hypertension: lessons learned and challenges ahead.
`Int J Clin Pract
`Suppl. 2011 Jan;(169):8-10. doi: 10.1111/).1742-1241.2010.02606.
`
`20. Chandra SM, Razavi H, Kim J, Agrawal R, Kundu RK, de Jesus Perez V, Zamanian
`RT, Quertermous T, Chun HJ. Disruption of the apelin-APJ system worsens hypoxia-
`induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):814-20.
`Epub 2011 Jan 13.
`
`21. Perez VA, Zamanian RT. Chronic thromboembolic pulmonary hypertension. N Engi J
`Med. 2011 Apr 28;364(17):1677.
`
`22. Haddad F, Fuh E, Peterson T, Skhiri M, Kudelko KT, De Jesus Perez V, Winkelmayer
`WC, Doyle RL, Chertow GM, Zamanian RT.
`Incidence, correlates, and consequences of
`acute kidneyinjury in patients with pulmonary arterial hypertension hospitalized with acute
`right-side heart failure. J Card Fail. 2011 Jul;17(7):533-9. Epub 2011 Apr 22.
`
`23. Hansmann G, Plouffe BD, Hatch A, von Gise A, Sallmon H, Zamanian RT, Murthy SK.
`Design and validation of an endothelial progenitor cell capture chip and its application in
`patients with pulmonaryarterial hypertension. J Mo/ Med (Berl). 2011 Jul 7.
`24. Haddad F, Kudelko K, Mercier O, Vrtovec B, Zamanian RT, de Jesus Perez V.
`Pulmonary hypertension associated with left heart disease: characteristics, emerging
`concepts, and treatment strategies. Prog Cardiovasc Dis. 2011 Sep-Oct;54(2):154-67.
`
`25. Haddad F, Peterson T, Fuh E, Kudelko K, de Jesus Perez V, Skhiri M, Vageios R,
`Schnittger |, Denault AY, David R, Doyle R, Zamanian RT. Characteristics and Outcome
`following Hospitalization for Acute Right Heart Failure in patients with Pulmonary Arterial
`Hypertension. Circ Heart Fail 2011 Nov:4(6):692-9. Epub 2011 Sep 9.
`
`Page 15 of 113
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`Page 15 of 113
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`26. Ayala E, Kudelko KT, Haddad F, Zamanian RT, De Jesus Perez V. The Intersection of
`Genes and Environment: Development of Pulmonary Arterial Hypertension in a patient with
`Hereditary Hemorrhagic Telangiectasia
`and
`Stimulant Exposure. CHEST 2012
`Jun; 141(6):1598-600.
`
`27. Maxweil BG, Pearl RG, Kudelko KT, Zamanian RT, Hill CC. Airway Management and
`Perioperative Decision Making in the Patient With Severe Pulmonary Hypertension Who
`Requires Emergency Noncardiac Surgery.
`J Cardiothorac Vasc Anesth.
`2012
`Oct;26(5):940-4.
`
`28. Perez VA, Rosenzweig E, Rubin LJ, Poch D, Bajwa A, Park M, Jain M, Bourge RC,
`Kudelko K, Spiekerkoetter E, Liu J, Hsi A, Zamanian RT. Safety and Efficacy of Transition
`from Systemic Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension. Am
`J Cardiol. 2012 Nov 15;110(10):1546-50. [Epub ahead ofprint]
`
`29. Perez VA, Haddad F, Zamanian RT. Diagnosis and management of pulmonary
`hypertension associated with left ventricular diastolic dysfunction.
`Pulm Circ. 2012
`Apr;2(2):163-9.
`
`Functional Class
`30. Barst RJ, Chung L, Zamanian RT, Turner M, McGoon M._
`Improvement and Three-Year Survival Outcomes in Patients With Pulmonary Arterial
`Hypertension in the REVEAL Registry. CHEST 2013 Jul;144(1):160-8.
`
`31. Waxman AB, Zamanian RT. Pulmonary Arterial Hypertension: New insights into the
`optimal
`role of current and emerging prostacyclin therapies.
`Am J Cardiol. 2013
`Mar4;111(5Suppl):1A-16A.
`
`32. Schaffer JM, Singh SK, Joyce DL, Reitz BA, Robbins RC, Zamanian RT, Mallidi HR.
`Transplantation for Idiopathic Pulmonary Artery Hypertension in the Lung Allocation Score
`Era. Circulation 2013 Jun 25;127(25):2503-13. Epub 2013 May 22. [Epub aheadofprint).
`
`33. Tian W, Jiang X, Tamosiuniene R, Sung YK, Qian J, Dhillon G, Gera L, Farkas L,
`Rabinovitch M, Zamanian RT, Inayathuilah M, Fridlib M, Rajadas J, Peters-Golden M,
`Voelkel NF, Nicolls MR. Blocking macrophage leukotriene b4 prevents endothelial injury
`and reverses pulmonary hypertension. Sci Trans! Med. 2013 Aug 28;5(200):200ra117.
`
`34. Malhotra R, Paskin-Flerlage S, Zamanian RT, Zimmerman P, Schmidt JW, Deng DY,
`Southwood M, Spencer R, Lai CS, Parker W, Channick RN, Morrell NW, Elliott CG, Yu PB.
`Circulating angiogenic modulatory factors predict survival and functional class in pulmonary
`arterial hypertension. Pulm Circ. 2013 Apr;3(2):369-80.
`
`35. Brunner NW, Ramachandran K, Kudelko KT, Sung YK, Spiekerkoetter E, Yang PC,
`Zamanian RT, Perez Vde J. A case of recurrent pericardial constriction presenting with
`severe pulmonary hypertension. Pulm Circ. 2013 Apr;3(2):436-9.
`
`36. Inan OT, Pandia K, Giovangrandi L, Zamanian RT, Kovacs GT. A preliminary study
`investigating the quantification of beat-to-beat
`in seismocardiogram signals. Conf Proc
`IEEE Eng MedBiol Soc. 2013;2013:7286-9.
`
`Page 16 of 113
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`Page 16 of 113
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`37. Mehra MR, Park MH, Landzberg MJ, Lala A, Waxman AB; International Right Heart
`Failure Foundation Scientific Working Group (Zamanian RT). Right heart failure: toward a
`common language. J Heart Lung Transplant. 2014 Feb;33(2):123-6
`
`38. Haddad F, Guihaire J, Skhiri M, Denault AY, Mercier O, Al-Halabi S, Vrtovec B, Fadel
`E, Zamanian RT, Schnittger |. Septal Curvature Is Marker of Hemodynamic, Anatomical,
`and Electromechanical Ventricular Interdependence in Patients with Pulmonary Arterial
`Hypertension. Echocardiography. 2013 Dec 23. [Epub aheadofprint]
`
`39. Shiran H, Zamanian RT, McConnell MV, Liang DH, Dash R, Heidary S, Sudini NL, Wu
`JC, Haddad F, Yang PC. Relationship between Echocardiographic and Magnetic
`Resonance Derived Measures of Right Ventricular Size and Function in Patients with
`Pulmonary Hypertension. J Am Soc Echocardiogr.