Mouse Model Developed to Study
Right Ventricular Recovery in Pulmonary Arterial Hypertension
By Amanda Chase, PhD
January 29, 2020
There are about 500-1000 new cases of pulmonary arterial hypertension (PAH) in the US each year, primarily women aged 30-60. PAH is characterized by a high blood pressure in the lungs, specifically the pulmonary arteries that carry blood from the right side of the heart (right ventricle, RV) to the lungs. While the RV pumps venous blood with low oxygen content to the lungs to pick up more oxygen, the left side of the heart receives blood from the lungs with high oxygen content to be pumped through the body. In PAH, due to a high pressure and resistance in the lung vessels, the ability to pump blood from the RV through the lungs is impaired, requiring the RV to pump against an increased afterload. Eventually this causes the RV to be overworked, leading to muscle weakening and right heart failure. From patients having received a lung transplantation for PAH, we have learned that the right ventricle has an amazing ability to recover after the excess pulmonary pressure is relieved, yet it is not known whether this is also true when its function is severely impaired. Some institutions prefer a heart-lung over a lung transplantation alone out of fear that the RV might not recover well enough in end-stage PAH and RV failure.
To study the capability of the RV to adapt to an increased, animal models mimicking right ventricular afterload have been developed. One method is to place a band around the pulmonary artery to restrict the blood flow and increase the resistance. This method is called pulmonary artery banding (PAB). Yet, to study the recovery of the RV to a reduced afterload, particularly in small animal models such as mice and rats, no good model existed up until now. Surgical removal of the band weeks after placement is not possible due to the development of scar tissue and a high mortality rate in the animals.
A team of researchers, led by Edda Spiekerkoetter, MD, Associate Professor of Medicine at Stanford University Medical Center and member of the Cardiovascular Institute, as well as her postdoctoral research fellow, Mario Boehm, PhD, sought to address this lack of a mouse model to study RV recovery by establishing a novel mouse model of “de-banding”. Their findings were recently published in the European Society of Cardiology journal. The team used the pre-clinical mouse model of surgical PAB and developed a reversal technique they termed “de-PAB”. Namely, they used absorbable sutures to allow studies on gradual right ventricular recovery from pressure overload. Using this novel mouse model, they were able to identify key molecular components responsible for the functional recovery of the right ventricle, allowing them to determine the order and timing of reverse remodeling, or recovery, events. Importantly, they were able to show that right ventricle dysfunction, RV fibrosis, and capillary rarefaction is completely reversible after the pressure overload is removed. Their mouse model provides the basis for future mechanistic studies on the recovery of the right ventricle, addressing the unknowns that could, eventually, lead to fewer heart-lung transplants in favor of lung transplants. Furthermore, their work shows that the right ventricle has self-healing properties, which opens the door to better understand beneficial pathways in the RV that might be therapeutically exploited to improve RV recovery in PAH.