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Research News

 

Pitt Researchers Show Potential and Limitations of Working with Big Data in Annals of Internal Medicine

A team of Pitt and UPMC investigators used diagnosis codes from administrative data to identify a large cohort of patients with heart failure. In this study, all hospital encounters with heart failure between 2008 and 2015 were assigned an ICD-9 heart failure code. These were further stratified into three categories: heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and heart failure of unspecified type. Lead author Dr. Ahmad Masri notes that "using over 20,000 unique encounters of heart failure patients, we found that heart failure coding shifted over time from heart failure of unspecified type toward heart failure with reduced and preserved ejection fraction. While this suggests that coding became more precise and accurate, it also reveals the limitations in using administrative data alone to evaluate our patients."

Senior author Dr. Suresh Mulukutla, says, "In the era of big data, there's a natural excitement to use administrative coding data for analysis, but we must recognize that coding data may change over time and it must be used cautiously. However, our team works closely with the cutting-edge UPMC Clinical Analytics program, led by Dr. Oscar Marroquin, to combine administrative data with clinical and outcome data, with vast potential to better define our patient populations so that we can understand our data and develop effective pathways to deliver patient-centric care."


 
 

Lung Transplant Can Be Performed Safely in Patients with Coronary Artery Disease

A team of UPMC researchers found that patients with coronary disease can safely undergo lung transplantation, according to a peer-reviewed article in Clinical Transplantation. Of 656 lung transplant recipients in the study, 324 had documented coronary disease, including 106 with obstructive coronary disease; however, outcomes in the patients with coronary disease, even obstructive coronary disease, were not significantly different than outcomes in patients with no trace of coronary disease. “There is a perception that patients with coronary artery disease are poor candidates for a lung transplant,” according to cardiologist Suresh Mulukutla, MD. “Our data suggest that these patients are able to safely undergo lung transplant with reasonably good outcomes, even if they have advanced coronary disease that requires coronary intervention.”


 
 

Arrival of Delphine Gomez, PhD Completes Recent VMI/HVI Faculty Recruitment Effort

Delphine Gomez, PhD has joined the group of new VMI/HVI faculty members on the recently-renovated 17th floor of the Biomedical Science Tower.  Following her arrival in February, Dr. Gomez has focused on setting up her laboratory, recruiting lab members, and learning the ins and outs of conducting research at Pitt.  Dr. Gomez comes from the University of Virginia Robert M. Berne Cardiovascular Research Center where she completed her postdoctoral fellowship in 2015.  Prior to that, she completed her Bachelor, Master, and Doctoral degrees at University Paris 7, France.  Her current research projects include:  control of smooth muscle cell differentiation and lineage memory; epigenetics/smooth muscle cell plasticity and atherosclerosis; and epigenetic and inflammation in atherosclerosis.  She holds an AHA Scientific Development Grant and has publications in prominent journals such as Circulation Research and Nature Medicine.  She plans to apply for more grants soon and looks forward to collaborating with her colleagues in the VMI and HVI.        


 
 

Endowed Chair in Amyloidosis and Heart Failure Will Drive New Research Program in VMI

The Pittsburgh Foundation and the University of Pittsburgh have agreed to fund the Richard S. Caliguiri Endowed Chair in Amyloidosis and Heart Failure.  The endowment will allow the VMI to recruit a distinguished amyloidosis investigator who will lead basic science research efforts focused on amyloidosis causes and interventions. 


Initial funding for the chair will come from two funds within the Pittsburgh Foundation:  the Richard S. Caliguiri Fund and the Simeon M. and Katherine Reed Jones Fund.  The Caliguiri Fund was established by the family of the late Richard S. Caliguiri who served as Pittsburgh’s mayor from 1977 until 1988 when he died of amyloidosis at the age of 56.  It is very important to the Caliguiri family that all funds raised go to research conducted in Pittsburgh.  Proceeds from the annual City of Pittsburgh Great Race also benefit the Caliguiri fund.  The Simeon M. and Katherine Reed Jones Fund, which supports research for heart disease, will also contribute a significant amount of money to the endowed chair.  Once annual donations from the two funds total $1 million, Pitt will match with a $1 million contribution.  

To celebrate the establishment of the chair and learn more about the research capabilities at Pitt, the Caliguiri family and current Pittsburgh mayor Bill Peduto toured the VMI and met with researchers and physicians in March.  Dr. Gladwin led the tour and explained the how the incoming amyloidosis investigator will benefit from Pitt’s strong, collaborative heart and vascular research environment and UPMC’s technology to perform advanced, non-invasive imaging scans that show build-up of amyloid proteins in the heart.


 
 

Collaborative Agreement with Bayer Spurs Major Sickle Cell Clinical Trial Study in VMI

In keeping with its strategic goal to partner with industry for translational hemostasis and vascular biology research, the VMI has launched several projects under Pitt’s master collaboration agreement with Bayer.  

The goal of this major new initiative is to advance translational research and therapies for heart, lung, and blood diseases.  Led by a joint steering committee comprised of representatives from both Bayer and Pitt, the collaboration focuses on pre-clinical and early phase clinical trials for drug development and big data analysis, including real-world evidence studies.

Through this collaboration, Bayer has funded several real-world evidence studies led by Pitt scientists as well as a nation-wide sickle cell disease clinical trial initiated and led by VMI Principal Investigator Gregory Kato, MD.  Ten hospitals across the country are currently recruiting or planning to recruit participants for this large phase 2 clinical trial that will assess in patients with sickle cell disease the safety, tolerability, and efficacy of riociguat, a drug currently approved to treat pulmonary hypertension.  The double-blind study will focus on changes in participants’ pain experience and physical function capabilities after twelve weeks in the study.  Dr. Kato is excited to combine the support of Bayer with the VMI’s sickle cell disease research expertise to expedite the development of new therapeutic interventions for patients with this severe disease with limited treatment options.  

As it continues to develop, this partnership will aim to bring together our distinguished scientists with Bayer’s clinical disease experts to better understand patient needs, and to develop novel therapies for heart, lung and blood diseases.


 
 

VMI Researchers Uncover Molecular Origins of Pulmonary Hypertension to Help Speed Treatment

VMI investigators Elena Goncharova, PhD, and Stephen Chan, MD, PhD, study how pulmonary hypertension develops in order to design better therapeutic interventions to prevent, regress, or cure this devastating cardiopulmonary disease.  During the past year, both investigators have made remarkable discoveries in the molecular pathways that cause remodeling of pulmonary vascular tissue and limit blood flow between the heart and lungs.  These discoveries will help identify drug targets that are likely to stop or significantly slow the disease progression.

Dr. Goncharova and her laboratory discovered a new mechanism that drives pathogenic proliferation and impairs apoptosis of vascular smooth muscle cells in small pulmonary arteries. They found that HIPPO, a key growth suppressor cassette that prevents organ overgrowth, is dysfunctional in small pulmonary arteries of patients with pulmonary arterial hypertension. This results in activation of transcriptional co-activators Yap and Taz, unleash other pro-proliferative pro-survival signaling pathways and increases cell proliferation and survival. The researchers identified ILK1 as a key molecule that “locks” HIPPO in inactive state and showed that pharmacological inhibition of ILK1 restores HIPPO function and stops the cyclical process of molecular activations that causes dangerous cell proliferation and apoptosis resistance in pulmonary hypertension patients’ arteries.  Selective ILK inhibitors can now be further explored as a promising strategy for therapeutic intervention to reverse pulmonary hypertension.

Dr. Chan and his laboratory discovered a novel link between pulmonary vessel wall stiffening and the way that these blood vessels create energy and biomass. Dr. Chan’s group found that this link is primarily controlled by the activation of YAP and TAZ which in turn control an enzyme called glutaminase.  Activation of glutaminase sets in motion a metabolic process that ends in dangerous cell proliferation in the arteries of pulmonary hypertension patients.  The Chan lab identified the YAP inhibitor verteporfin and the glutaminase inhibitor CB-839 as therapeutic drug candidates when used, either singly or together, can impede the molecular pathways driving this deadly disease.        

VISIT the Center for Pulmonary Vascular Biology and Medicine website to learn more about the exciting discoveries and innovations in PH research happening in the VMI.


 
 

Gladwin Lab Develops Potential Carbon Monoxide Antidote

VMI Director Mark Gladwin, MD and his lab have engineered a carbon monoxide-scavenging protein that reverses carbon monoxide (CO) poisoning in mice.  This protein, or a similar one, may lead to the creation of the first antidote in humans to the often deadly poisoning.

When inhaled, CO binds to hemoglobin in blood, preventing oxygen from being adequately circulated throughout the body.  CO also inhibits the process of respiration in mitochondria, which is crucial to cellular function and survival.  Current treatments for CO poisoning attempt to replace CO in blood with oxygen as quickly as possible. They are only moderately effective.  CO exposure results in debilitating effects on the body and the brain, including cognitive deficits that can persist months or years after a poisoning event.  The poisoning is responsible for more than 50,000 emergency room visits in the United States annually, and is one of the leading global causes of poisoning death. 

Gladwin and his team discovered that neuroglobin (Ngb), a hemoglobin-like protein present in the brain, binds CO with an unusually high affinity. The team engineered a mutant version of the protein, called Ngb H64Q, that is 1,200 times faster at forcing CO to release itself from being bound to hemoglobin than just air alone.  

When tested in a mouse model of CO poisoning, they found that Ngb H64Q was significantly better at removing CO from hemoglobin than existing treatments.  Importantly, CO bound to Ngb H64Q was detected in the urine of mice shortly after treatment, which indicated that the rodents were able to excrete the antidote from the body without any major toxic effects.  Researchers plan to scale up their safety and efficacy testing in animal models and hope to advance to clinical trials within the next few years.

Related publication:
Azarov I, Wang L, Rose JJ, Xu Q, Huang XN, Belanger A, Wang Y, Guo L, Liu C, Ucer KB, McTiernan CF, O'Donnell CP, Shiva S, Tejero J, Kim-Shapiro DB, Gladwin MT. (2016) Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning. Sci Transl Med. 8(368):368ra173. PMID 27928027. PMC5206801. DOI 10.1126/scitranslmed.aah6571.