Novel Molecular Target to Prevent Scarring of the Lung Blood Vessels Identified

Study identifies cancer protein as a target for treating fibrosis of the lung arteries with direct implications for patients with pulmonary arterial hypertension

Pulmonary arterial hypertension, a severe form of cardiopulmonary disease in which the arteries that transport blood from the heart to the lungs become thickened, constricted, and scarred, is a disease for which there is no cure. Investigators from Brigham and Women’s Hospital are unraveling the molecular mechanisms that may control PAH’s development and progression in an effort toward finding treatments that can halt the disease’s advancement. In a paper published this week in Science Translational Medicine, researchers share results from a study that identifies the cancer protein NEDD9 as a critical player in disease development, with potential therapeutic implications for patients with PAH.

“Our work identifies as a novel molecular target to prevent fibrosis in lung arteries, which can lead to early right-sided heart failure and death,” said corresponding author Bradley Maron, MD, a cardiologist and vascular biologist at BWH. “Our data provide an alternative mechanism that may account for the variability in fibrosis observed across subgroups of patients with PAH.”

In PAH, fibrosis is an important cause of damage to pulmonary arteries, which increases strain on the heart and leads to perpetual shortness of breath. In the past, researchers had theorized that one pathway acted as a “master switch” to globally control fibrosis but new evidence suggests that the development of fibrosis may be more complicated and more specific to different kinds of tissue. To better understand which genes and proteins may influence scarring specifically in the lung arteries, the Brigham research team used network medicine – a method of mapping relationships between proteins, pathways and more. Through this approach, the researchers discovered that the cancer protein NEDD9 is a critical mediator of vascular fibrosis in lung blood vessels.

They went on to identify a specific amino acid residue in NEDD9 that controls lung artery fibrosis. In patients with PAH, increased oxidant stress modifies this NEDD9 amino acid to cause lung artery fibrosis. The team also showed that the lung artery endothelium, previously regarded largely as a bystander in vascular fibrosis, contributes to this problem.

At the heart of the research team’s findings is NEDD9, which their data suggest mediates fibrotic vascular remodeling. The authors note that this has potential therapeutic relevance for PAH patients. While a therapy that targets this protein has not yet been developed, because of its role in cancer, several studies have put NEDD9 forward as an important therapeutic target for future drug discovery efforts.

Funding for this work was provided by the National Institutes of Health (NIH 1K08HL11207-01A1, NIH R56HL131787, NIH 1R01HL139613-01, NIH K08HL128802, NIH 1F32HL139019-01, NIH 5T32HL007633-32, NIH/NHLBI 1U01HL125215-01, R37 HL061795, HL108630, U54 HL119145, PPG HL048743, NHLBI F32HL131228, NIH/MIAMS K24 AR063120, R01 ARO70470, NIH 5R01-HL131910, NIH GM065204, NIH R01HL114839); American Heart Association (AHA 15GRNT25080016); Pulmonary Hypertension Association, CMREF, Klarman Foundation at Brigham and Women’s Hospital, and Systemic Sclerosis Foundation;

Paper cited: Samokhin, A et al. “NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension” Science Translational Medicine DOI: 10.1126/scitranslmed. aap7294

 

Double-Checking Diabetes Medications May Reduce Re-Hospitalizations

New study suggests that medication reconciliation programs can reduce risks

Clinicians may take upwards of 15 minutes to double-check a patient’s medication list in an electronic health record system, but according to a new study, this reconciliation process may be well worth the time for diabetes patients. In a paper to be published in the Diabetes Care journal, Brigham and Women’s Hospital physician Alexander Turchin, MD, MS, and his colleagues assessed medication reconciliation programs at BWH and Massachusetts General Hospital, and found that they seem to be working.

“Lists of medications often don’t match what the patient is actually taking,” said Turchin. “Data entry errors, as well as medications prescribed by other practitioners that we’re unaware of, can cause those discrepancies.” These discrepancies can lead to medication errors like omissions, duplications, improper doses and drug interactions that can sometimes have serious health consequences.

It’s not fully understood how common these discrepancies are. But two studies cited in the paper put the chance at 53.6 percent in 2005 – the same year that the Joint Commission first emphasized medication reconciliation as a national goal – and 41.3 percent in 2008. In one 2014 study cited, four out of five referral letters for 300 patients at a certain diabetes center each contained at least one medication discrepancy.

Diabetes patients are especially at risk for adverse reactions caused by improper dosages and pairings of medications. Incorrect dosing of medications like insulins and sulfonylureas can easily lead to low blood sugar – a dangerous complication that can result in seizures, loss of consciousness or even death.

To study whether medication reconciliation affected health outcomes for diabetes patients, Turchin and his team pulled patient records from January 2000 through June 2014. They examined the instances of medical reconciliation – when a clinician confirmed that a patient’s medications were correct – and the patient’s subsequent hospital visits in six-month periods. Patients typically took between one and two diabetes medications and visited primary care four times per assessment period. Turchin and his team found that clinicians reconciled diabetes medications in 67 percent of assessment periods, and that reconciliation of outpatient diabetes medications was associated with fewer subsequent hospitalizations and emergency room visits. They did not find the same correlation with reconciliation of non-diabetes medications the patients were on.

Extrapolating these findings, reconciling diabetes medications could save up to $6.7 billion annually – 8 percent of the total annual cost of hospitalizations of diabetes patients in the U.S. – and prevent rare but serious adverse reactions for patients.

“Our results suggest that reconciling diabetes medications could improve patient outcomes and decrease health care costs,” Turchin said.

This study was funded by the Patient-Centered Outcomes Research Institute.

Paper cited: Turchin A et al.  “Ambulatory Medication Reconciliation and Frequency of Hospitalizations and Emergency Department Visits in Patients with Diabetes.” Diabetes Care. DOI: 10.2337/dc17-1260