BWH Clinical & Research News

A Multi-Pronged Approach to Understand and Treat Pulmonary Hypertension and Chronic Lung Disease in Infants

Helen Christou, MD

For Helen Christou, MD, neonatologist in the Neonatal Intensive Care Unit (NICU), research was not a lifelong dream. Originally from Cyprus, she was clinically trained in Greece and never planned to conduct research, in favor of spending more time with patients. But over the past 23 years of her career, she has made important contributions that helped to advance the field’s understanding of pulmonary hypertension and bronchopulmonary dysplasia (BPD) through her work currently funded by the National Institutes of Health (NIH).

Pulmonary hypertension is a life-threatening form of high blood pressure in the lungs caused by constriction and narrowing of the arteries, requiring the heart to work harder to pump blood, which can lead to heart failure and death. It affects infants, children and adults and causes shortness of breath and bluish skin color (cyanosis). When pulmonary hypertension affects infants right after they are born, it is called persistent pulmonary hypertension of the newborn (PPHN). Full-term, newborn infants who should be able to bond with their families can suddenly become so sick that they need to be cared for in the NICU and often must be placed on lung bypass to survive.

During her fellowship at Boston Children’s Hospital in the early 1990s, Christou had the opportunity to witness firsthand the impact of a novel therapy for PPHN. Prior to its discovery, PPHN was untreatable, causing disability and death in otherwise healthy, full-term newborns. The therapy was inhaled nitric oxide, which is the current standard of care for the condition. As a clinical fellow in Neonatology and with the guidance of her mentors, Christou worked on one of the early clinical trials of inhaled nitric oxide for PPHN. It was her first exposure to research.

Witnessing History Unfold

In 1992, nitric oxide was recognized as the “molecule of the year” by Science and in 1998, three researchers were awarded the Nobel Prize for its discovery. “Inhaled nitric oxide revolutionized care for these babies,” Christou said, recalling when the therapy was approved by the FDA in 2000. “A series of important discoveries in the lab and the contributions of many researchers in the clinical setting led to this medical breakthrough. These were very exciting times to be in this field.”

Her firsthand involvement in the translational process of bringing nitric oxide to clinical practice deeply moved and influenced Christou. “Being a part of such a compelling example of the value of neonatal research was a transformational experience and it drove me to pursue a career in research,” said Christou. “The neonatal period is critical for lifelong health, and I thought I could make a real impact on clinical outcomes and patient care.”

Another common breathing problem in infants is BPD, a form of chronic lung disease that occurs when infants are born prematurely or require a ventilator during their first few weeks of life. It can lead to coughing, wheezing, asthma, developmental problems, and sometimes pulmonary hypertension and death. BPD and associated pulmonary hypertension are difficult to treat because pulmonary arteries are not just constricted, but are anatomically remodeled. Inhaled nitric oxide is ineffective because there is thickening, caused by excessive tissue around the lumen, which restricts blood flow to the lungs.

According to Christou, the lungs are one of the last organs to develop in utero. There are five stages of lung development, and when a baby is born extremely prematurely (around 24 weeks), the third stage has barely been completed. “The first four stages must occur in the womb, so when a fetus is delivered pre-term, the lungs are suddenly exposed to a new environment, and development is disrupted,” said Christou. Oxygen and pressure from ventilators leads to scarring and chronic lung disease, such as BPD, which can later develop into pulmonary hypertension.

Discovering a New Way to Fight Pulmonary Hypertension

Through a series of studies, Christou and her team have identified a novel intervention that restores pulmonary blood vessel architecture in three different pre-clinical models of pulmonary hypertension. She and her team have found that when they induce mild metabolic acidosis, blood vessel muscle cells do not proliferate and migrate, decreasing vessel narrowing and causing a protective effect in animals with pulmonary hypertension. “More importantly, the blood vessels are better able to relax in response to nitric oxide,” said Christou, whose studies have shown that acidosis reverses anatomical abnormalities, thus preventing and reversing pulmonary hypertension.

“It’s a privilege to be part of a team that welcomes a new life. As clinicians, we have to be very aware of the responsibility we have beyond the initial neonatal course, to help infants establish a healthy life.”

Christou’s idea to study acidosis was novel and counter-intuitive. Because maintaining a pH balance is favored and acidosis is generally seen as negative, it was difficult for her to secure funding. But she continued to carefully design and carry out her studies. “I was a new investigator with a bold idea in the worst funding climate for scientific research in decades,” recalled Christou, whose work was funded by the NIH in 2014.

Today, Christou’s focus is on understanding additional mechanisms by which acidosis is beneficial in pulmonary hypertension and identifying the subset of patients, likely adults at first, who may be optimally responsive to this novel intervention. Because pulmonary hypertension can be either due to constriction of pulmonary arteries or more substantial architectural changes, her aim is to find a group of patients who suffer from the latter. When she identifies potential subjects for a clinical trial, she plans to use an existing drug that induces metabolic acidosis and proved to work in preclinical models. “The benefit of using an approved drug is that we already know its safety profile and dosing,” said Christou. “The process would be much faster, making it translationally feasible within my lifetime. It’s very exciting.”

Employing A Multi-Pronged Approach

Christou and her team are investigating several other avenues for minimizing lung injury and optimizing outcomes in infants. Through their studies on vitamin D, which has been shown to have positive effects in the lung architecture, they are exploring whether Vitamin D deficiency may increases the risk of BPD in premature infants. In 2012, Christou published a paper in Pediatric Research demonstrating that preterm babies have lower levels of vitamin D. However, a direct relationship to BPD has not yet been established. Christou is currently carrying out research to determine whether a lack of vitamin D is an independent risk factor in chronic lung disease; if is shown to be, she will design and conduct an intervention involving the supplementation of vitamin D.

Another area of active study is identifying biomarkers for certain morbidities associated with prematurity. It is well-established that babies born preterm or with low birth weight are at increased risk for a host of morbidities, including hypertension, obesity and diabetes. Christou and her team of collaborators are working to identify novel biomarkers that are associated with patterns of fetal growth and early neonatal growth and can be used as predictors for these morbidities. This line of work will have important implications for the nutritional care of preterm and at-risk infants.

“We are using a multi-pronged approach to address pulmonary hypertension, chronic lung disease and other morbidities in infants,” said Christou. “The more we can learn about these various elements, the more we can help patients and families.”

Complementing Research with Clinical Practice and Education

From left to right: Newborn Medicine researchers Zoe Michael, MD; Hannes Hudalla, MD; and Helen Christou, MD.

In addition to her role as principal investigator, Christou is also a clinician and educator. She practices as a neonatologist, leading the health care team in the care of critically ill and convalescent infants and supervising the training of pediatric residents and neonatal fellows.

She counsels expectant parents of high risk infants and attends high risk deliveries on a regular basis to provide specialized care from the very first moments after birth. “It’s a privilege to be part of a team that welcomes a new life,” said Christou. “As clinicians, we have to be very aware of the responsibility we have beyond the initial neonatal course, to help infants establish a healthy life.”

As director of the Harvard Neonatal-Perinatal Medicine Fellowship program, which encompasses four training sites and 18 fellows, Christou aims to lead by example to train the next generation of physician-scientists. According to Christou, it’s not easy for physicians to balance everything on their plate and also conduct their own research. That’s why she aims to be a role model and a mentor to younger physician-scientists – both to inspire them and to help retain them.

“Being able to practice all three—clinical care, research and teaching—gives me a sense of purpose,” said Christou. “They complement each other well. I have a unique ability to learn about clinical needs, bring them to the lab to ask the pertinent questions and then bring solutions back to patients.”