Tremendous progress in the use of vasodilators, endothelin receptor blockers and nitric oxide activators has improved the quality of life and the survival of patients with pulmonary arterial hypertension (PAH), but morbidity and mortality remain high, said Marlene Rabinovitch, MD, FAHA, during the Distinguished Scientist Lecture on Tuesday.
Rabinovitch, the Dwight and Vera Dunlevie Professor of Pediatric Cardiology at the Stanford University School of Medicine said that at best there’s a 65 percent five-year survival rate followed by rapid attrition.
“Additionally, there’s an increasing number of conditions in which PAH is recognized as a serious complication that negatively impacts survival,” she said. “So, along with congenital heart disease, we now see PAH with heart failure and preserved ejection fraction, as well as reduced ejection fraction with metabolic syndrome.”
Rabinovitch discussed her research exploring the fundamental mechanisms responsible for the loss and obliteration of blood vessels that cause PAH.
“In addition to lung disease, there’s also increasing recognition of the adverse impact of PAH in sickle cell disease, and there’s virtually an epidemic of PAH related to substance abuse,” she said. “Worldwide attempts to eradicate HIV and schistosomiasis, for example, still face PAH as a complication, and treatments of scleroderma and liver disease are further challenged by the presence of this complication.”
The most insidious presentation of PAH, Rabinovitch said, is the idiopathic form because there is no underlying condition to provide a clue to its presence, and the symptomatology is also vague. She noted that PAH affects females more than males, frequently in the third to fifth decade of life, but also in infants and children. Its incidence is similar to a rare disease, but about 15 percent of cases are familial.
Rabinovitch said research has identified that a BMPR2 receptor mutation is present in approximately 70 percent of familial PAH cases and 20 percent of sporadic PAH cases, adding that further studies identified reduced BMPR2 expression in all forms of pulmonary arterial hypertension. The challenge for researchers, she said, became one of relating the dysfunction of this receptor to the pathological features of PAH and to what was already understood from laboratory studies.
“The genetic basis of idiopathic pulmonary arterial hypertension has given us important clues to the pathways that are perturbed that not only target the lung vasculature but are also relevant to systemic vascular disease,” she said.
Recent studies have shown that loss of BMPR2 not only induces apoptosis of endothelial cells, but also can be responsible for their transition to smooth muscle-like cells. As a consequence, in addition to losing their ability to proliferate, they lose their important function as a tight barrier, and they take on pro-inflammatory properties.
“Loss of BMPR2 recruits inflammatory cells, such as neutrophils, that release increased elastase, degrading poorly assembled elastic fibers,” Rabinovitch said. “Emerging therapies, such as elafin and FK506, repress inflammation and improve BMPR2 functions. Induced pluripotent stem cells also may prove to be useful in developing patient-specific treatments.”