The overall goal of my clinical research and bench laboratory is to provide better care to patients with a rare disease of the lung blood vessels, pulmonary arterial hypertension (PAH). Our nationally accredited PHA Comprehensive Care Center provides evaluation and therapy for patients from all over New York and central PA, and we use the full complement of approved PAH therapies. We also contribute actively to clinical research in hopes of better therapies with drugs that are already available and those yet to be approved. I serve as leadership on steering committees and DSMB for global clinical trials in this deadly disease.

In my laboratory, we do experiments in animals and cells in an attempt to discover entirely new ways to treat this deadly disease.

Because echocardiograms often estimate pulmonary hypertension in patients with obstructive sleep apnea and heart failure, much of my clinical practice and expertise is focused in these two common problems.

The URMC Pulmonary Hypertension group also includes my partner Dan Lachant, MD; three full time RN's, Karen Frutiger, Ali Theuer and new comer Cyndi MacDonald; a full time administrator, Jocelyn Dixon; two research technicians, Deb Haight and Jackie Bruno; and a post-doctoral research associate, Allison Light.

Professional Background

I am a scarlet and grey bleeding Ohio State Buckeye who still has a special drawer for OSU sweatshirts and the like. I earned my MD and PhD degrees while in an NIH funded Medical Scientist Training Program at the University of Pittsburgh under the expert mentorship of Ian Reynolds. My thesis studies demonstrated that mitochondria were critical buffers of glutamate stimulated calcium loads and further that mitochondrial depolarization was an important consequence after pathologic neuronal stimulation.

I moved to Rochester in 1997 to begin residency training in internal medicine and stayed to complete training in pulmonary and critical care. Mark Taubman mentored my early scientific career in the lab studying rat models of pulmonary hypertension and a potential pathogenic role for tissue factor, the protease which initiates blood coagulation. I still have a strong interest in bench studies of the pulmonary vasculature, but more recently I have enjoyed leadership roles in phase 2 and 3 clinical trials for PAH drug development.

Faculty Appointments

Professor - Department of Medicine, Pulmonary Diseases and Critical Care (SMD)

Professor - Department of Pediatrics, Cardiology (SMD) - Joint

Professor - Department of Pharmacology and Physiology (SMD) - Joint

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PHA Accredited Centers

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Credentials

Residency & Fellowship

Fellowship, Pulmonary and Critical Care Medicine, University of Rochester Medical Center. 2000 - 2003

Residency, Internal Medicine, University of Rochester Medical Center. 1998 - 2000

Internship, Internal Medicine, University of Rochester Medical Center. 1997 - 1998

Education

MD | University of Pittsburgh School of Medicine. 1997

Awards

Parker B. Francis Fellowship in Pulmonary Biology, Francis Family Foundation 2005 - 2007

Buswell Fellowship, Department of Medicine, University of Rochester SMD 2003 - 2005

NIH Training Grant Multi-Disciplinary Training & Pulmonary Research, University of Rochester SMD 2001 - 2004

Alpha Omega Alpha, University of Pittsburgh 1996

NIH Medical Scientist Training Program, University of Pittsburgh 1990 - 1997

Phi Beta Kappa, Ohio State University 1990

Research

The University of Rochester is a nationally accredited PHA Comprehensive Care Center, and we provide evaluations for patients with echo estimated pulmonary hypertension. We take care of ~300 patients with WHO Group 1 classified Pulmonary Arterial Hypertension. I was a lead enroller and study author in the labeling trials for tadalafil (PHIRST), oral treprostinil (Freedom-M), and the initial combination Ambition study. I chair the Freedom-EV steering committee and am leading the ongoing global development efforts for oral treprostinil in WHO Group 1. We participated actively in the Reveal registry, and I am associate medical director for Bill Nichols' NIH funded PAH Biobank. We are the lead nationwide enrollers for the NIH funded study of rituxan in scleroderma PAH, and we are making active contributions to Reata's studies of bardoxolone. We use subcutaneous treprostinil (Remodulin, more than 150 patients over the years), inhaled Tyvaso, ambrisentan, tadalafil, macitentan, selexipag, and riociguat in combinations best tailored to a particular patient's needs. We provide a strong link to surgical centers at Massachusetts General and Allegheny General for our patients with chronic thromboembolic pulmonary hypertension.

I am grateful for the opportunity to serve as steering committee leadership in drug development projects with United Therapeutics (oral treprostinil) and PhaseBio (VIP analogue PB1046). I also serve as a consultant providing development advice to Reata, Gilead, Bayer, and Celtaxsys. I chair the DSMB for the first randomized, placebo-controlled trial of genetically-modified, endothelial progenitor cells led by colleagues in Canada (sponsor, Northern Therapeutics).

The overall goal of my bench laboratory is to do better preclinical testing of potential novel treatment options for pulmonary arterial hypertension. Our current approach is with a rat model that recapitulates the histopathology, severe hemodynamic alterations, and right ventricular heart failure seen in advanced human disease. This rat model employs pneumonectomy (promotes contralateral lung growth) and endothelial injury (low dose monocrotaline) to cause lethal pulmonary hypertension in about 4 weeks. Our animals die earlier with a more severe phenotype, and we presented the first report of proliferative, plexiform-like lesions in 2004. We have developed a novel CT angiography to assess for vascular pruning during disease progression, and we have become expert at evaluating RV size and function with echo. We have also utilized telemetry techniques to measure pressure in awake, behaving animals. Our main recent contribution has been to establish a model severe enough that we can test new therapy approaches in animals treated with today's FDA approved agents. We believe that this sort of preclinical testing will provide the best evidence to move compounds into the clinic. Deb Haight, LVT, leads the lab work.

We hypothesize that tissue factor (the membrane bound glycoprotein which initiates coagulation) is an important contributor to disease progression, and we are actively testing small molecule inhibitors of tissue factor and thrombin as novel therapies in this devastating disease.

Patents

Treatment of Pulmonary Hypertension Using An Agent that Inhibits a Tissue Factor Pathway

Issue date: October 22, 2013

Patent #: 8,563,511

Country: United States