Cases of pulmonary hypertension continue to rise in the US, but new pharmaceuticals and improved cardiorespiratory diagnostic tools offer hope to the thousands of Americans afflicted by the disease.

By Phyllis Hanlon

According to the Centers for Disease Control (CDC), pulmonary hypertension (PH), elevated pressure in the blood vessels leading from the heart to the lungs, may occur in individuals of any age, gender or ethnicity and is often associated with lung and heart disease. Accurate statistics for prevalence are hard to pinpoint as the disease is often under- and misdiagnosed. Survival rates for pulmonary hypertension have also not been specifically identified; some experts cite a seven-year survival rate, while most researchers point out that confounding factors will impact survival.

In 2010, the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension (PAH) Disease Management (REVEAL)1 identified some key survival predictors and created a management reference tool for clinicians. The registry collected data from 2,716 patients with PAH to assess one-year predictors. Findings indicated that etiology of PAH, gender, functional class, exercise tolerance and right ventricular functioning are key predictors.

Treatment Goals

Clinicians commonly base treatment goals and outcome measures on the New York Heart Association (NYHA) Functional Classification, which has been updated several times since its inception in 1928, most recently in 1994.  The classification divides patients into four different categories depending on limitations during physical activity on normal breathing, various degrees of shortness of breath and/or angina pain. However, the system is subjective and differs from one clinician to another.2 In spite of its limitations, the NYHA FC may still be “a simple, reproducible, and clinically important assessment tool and prognostic measure in PAH patients, both at the time of diagnosis and at follow-up during PAH treatment,” according to Vallerie V. McLaughlin, MD and colleagues who conducted a study3 on the treatment goals of pulmonary hypertension.

One of the most widely used diagnostic tests is the 6-minute walk distance (6MWD) test, which, according to the study, “has been used as the primary endpoint for almost all pivotal clinical trials of PAH treatments.” Although the test is key in establishing prognosis at baseline and at follow-up, it does have certain limitations, including “the learning effect, day-to-day variation, and impact of demographic characteristics and comorbidities.”

Additionally, the 6MWD may fail to detect important changes in patients with early stage PAH but relatively high 6MWD at baseline, referred to as “the ceiling effect.” Moreover, the study authors question distance measures correlated to exercise capacity and right heart function and associated with PAH survival rates. Currently, the 6MWD goal is >380 m; the study authors recommend increasing this figure to 380 to 440 m, which might be a better therapeutic goal.

Another noninvasive diagnostic tool is cardiopulmonary exercise testing, “an integrative approach to assessing cardiac function, gas exchange, and muscular physiology.” Victor F. Tapson, MD, director, Venous Thromboembolism and Pulmonary Vascular Disease Research Program; director, clinical research, Women’s Guild Lung Institute; associate director, Pulmonary and Critical Care at Cedars-Sinai Medical Center in Los Angeles and co-author of the above-mentioned study, explained that cardiopulmonary testing is not one of the typical diagnostic tools used. “[But] if we can’t explain a reason, we will do a cardiopulmonary exercise test, which might give us a better idea than the six-minute walk test,” he said.

In recent years, the use of biomarkers has increased understanding of numerous medical conditions and biological processes, leading to more targeted treatment plans. When treating PAH, B-type natriuretic peptide (BNP), troponin, uric acid, C-reactive protein (CRP) and partial arterial pressure of carbon dioxide (PaCO2) measures offer prognostic implications at baseline and at follow-up. Tapson pointed out that BNP would usually be elevated if pulmonary hypertension were present.

The study also cited echocardiography as another widely used diagnostic tool for determining the presence of PAH. “An echocardiogram is a pivotal test. It helps establish right ventricular size and function. We conduct these tests up front to determine cause and severity. In a patient with suspected pulmonary embolism, it might confirm that [diagnosis],” Tapson said, adding though that the test is not helpful for patients with mild PAH.

Tapson cited other tests that are typically administered to help clinicians discern the cause of pulmonary hypertension. “We also do a right heart catheterization to get the hemodynamic status. This is the gold standard,” he said, noting that the test is invasive and carries some risk for certain patient populations. The study reported also that hemodynamic measures depict the physiological state at one point in time with the body at rest in a supine position, but does not capture changes related to activity.

Pulmonary function testing (PFTs) and ventilation perfusion (V-Q) and CT scans also assist in the diagnostic process.

Blocking Pathways 

Most studies on treatment options for pulmonary hypertension focus on dilating blood vessels while ignoring the inflammatory response surrounding those blood vessels. In 2013, Mark Nicolls, MD, division chief of pulmonary and critical care medicine at Stanford University as well as a staff physician at the Veterans Affairs Palo Alto Health Care System, served as senior author of a study published in Science Translational Medicine4  that examined the inflammation-producing pathway in pulmonary hypertension.

In this animal study, the authors demonstrated how an inflammatory mediator, leukotriene B4 (LTB4) causes pulmonary endothelium damage and breaks down the pulmonary smooth muscle homeostasis, eventually causing pulmonary hypertension. “Because current medications only temporarily release the symptom of PH, without solving the root of the disease – vascular remodeling characterized by endothelium injury and smooth muscle hyper-proliferation – there is still a huge unmet medical need for this fatal disease. We wanted to test drugs that block different eicosanoid pathways, including the LTB4 signaling, and hoped that we would be able to find a potential treatment for PH,” said Wen Tian, PhD, a research associate in Nicolls laboratory.

“We tested Zileuton, a 5-lipoxygenase inhibitor, MK886, an antagonist of 5-lipoxygeanse activation protein, knowing both 5-lipoxygenase, 5-lipoxygeanse activation is protein that is upstream of LTB4. Zileuton and MK886 doesn’t reduce right ventricular systolic pressure, an index for PH. However, we do see dramatic beneficial effect in terms of survival,” Tian added. “We also tested Montelukast, an asthma drug that works on the paralleling pathway, CysLT signaling and found it to be ineffective. Eventually, we found that treatments using a drug that either blocks LTB4 synthesis, i.e., Bestatin, or the receptor activity is able to reduce the right ventricular systolic pressure by 80%, close to the control level, and promote survival of the animal.”

For a large subset of PAH patients, inflammation plays a major pathogenic role, according to Tian. “In the last few years, our group has discovered that inflammation actually precedes pulmonary pressure changes and we also determined a special protective role for Tregs [regulatory T cells] in limiting inflammation following pulmonary vascular injury,” she said. “I did my PhD studying eicosanoid biology. I found it extremely interesting that LTB4 released by macrophages is a key mediator in millions of inflammatory diseases, such as diabetes, MI, cancer, COPD, etcetera. When I first joined Mark’s group a couple of years ago, I discovered that it might play a role in PAH under immune dysregulated conditions. And after years of research, I am very lucky to discover that LTB4 is of great pathogenic importance in PAH.”

Tian noted that Bestatin (ubenimex) is clinically safe and has been used in Japan as a chemotherapy adjuvant for more than 30 years. “An IND application for Bestatin use in PAH was submitted to the FDA and Phase II/III trials using Bestatin to treat IPAH (idiopathic pulmonary arterial hypertension) and connective tissue disease associated with PAH (CTD-PAH) is anticipated for early in 2016,” she said.

Comorbid Conditions

PH often presents with other medical conditions, such as gastro-esophageal reflux, obstructive sleep apnea, bronchopulmonary dysplasia, scleroderma and COPD. Tapson indicated that patients with scleroderma may develop PH associated with their underlying condition and some of the usual tests might be administered in this situation to rule out the presence of blood clots. “We have had some patients with positive lung scans that have had blood clots,” he said.

AdrianoTonelli, MD from the Department of Pulmonary, Allergy and Critical Care Medicine in the Respiratory Institute at the Cleveland Clinic, reported that pulmonary hypertension is prevalent in patients with advanced COPD. These patients will undergo the usual battery of tests, including a basic echocardiogram to look for congestive heart disease, a VQ scan to determine if there are clots in the lungs, heart catheterization to rule out connective tissue disease and a thorough history and physical examination.

In cases where the COPD is not severe, a patient’s pulmonary hypertension most likely can be attributed to another cause. “If the patient’s COPD is mild and there is not a lot of emphysema, we would have to find other reasons for the cause of the pulmonary hypertension,” Tonelli said.

Tonelli asserted that no clear answers present as viable treatment options. “There are few studies to show the benefits of treating pulmonary hypertension in this population. The studies that exist are usually more of a retrospective study and have a small sample size.” Nevertheless, some patients begin treating with sildenafil, a phosphodiesterase-5 (PDE5) inhibitor to increase hemodynamics, although Tonelli pointed out that this medication may worsen oxygenation. “It may violate other channels connecting to other tissue. It’s a challenge to treat,” he said. Inhaled and subcutaneous medications are also not effective treatment options for use in COPD patients with PH.

A 2015 study,5 which Tonelli coauthored, indicated that patients with severe COPD and PH “have a shorter expected survival and should be considered for transplant.” A retrospective data review of 4,930 patients on a lung transplant list who had right heart catheterization found that 30% had precapillary PH and 17% more had postcapillary PH; both carry an increased risk of death. The study also noted the 3-year mortality rate for patients with COPD and severe PH was 67%; those with less severe PH had a 45% mortality rate.

Although lung transplantation is recommended as the optimal treatment, Tonelli noted that some alternative therapies can impact quality of life. He suggested rehabilitation and keeping active by walking farther and practicing good breathing techniques. Tonelli also encourages those who require oxygen to comply. “Some patients feel using oxygen would make them sicker. Not so,” he said. “Sufficient oxygen makes the vessels in the lung dilate, reducing pressure.”

Lisa Brown-Hoff, BS, RRT, NPS, NRP instructor at MedStar SiTEL (Simulation Training and Education Lab), reported that pulmonary hypertension can also affect the neonatal intensive care unit (NICU). She said one to two babies per l,000 live births will develop persistent pulmonary hypertension, also known as persistent fetal circulation (PPHN). “Within 12 to 24 hours [after delivery] you might see the baby having work of breathing, grunting and respiratory distress,” she said. “We start the baby on Vapotherm high flow nasal cannula and pre- and post-ductal pulse oximetry. This will give us a heads up the baby might have PPHN. We’ll confirm [the diagnosis] with an echocardiogram.”

A neonate might develop PPHN due to meconium aspiration, congenital heart defects, diaphragmatic hernia or an idiopathic cause. “We do a blood gas analysis to monitor the baby,” said Brown-Hoff.

The first line of defense for neonates is always noninvasive but may include conventional ventilation, inhaled nitric oxide, and, as a last resort, ECMO. “We focus on those first 10 minutes of life and do everything to resuscitate the baby,” Brown-Hoff said.

A Paradigm Shift

New research has examined the combination use of ambrisentan plus tadalafil as an initial therapy for patients who had received no prior treatment. The AMBITION study6 comprised 500 subjects with World Health Organization functional class II or III symptoms of pulmonary hypertension with no previous therapy. The combination therapy (10 mg ambrisentan and 40 mg tadalafil) group had 253 subjects; the ambrisentan (10 mg ambrisentan plus placebo) monotherapy group, 126; and the tadalafil (40 mg tadalafil plus placebo) monotherapy group, 121. At week 24, the combination therapy group showed favorable results in three areas: greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than the monotherapy groups combined, higher patient satisfaction with clinical response and improvement in the 6-minute walk distance.

Tapson cited this study as a “paradigm shifter.” He said, “Typically we start treating pulmonary hypertension with one drug and wait to see the results. Then three months later, we might add another drug.” The authors of this study have presented a new way of treating pulmonary hypertension, which reflects more closely the way patients with cancer are treated, ie, with a cocktail of pharmaceutical agents concurrently. “This study suggests we give several drugs at the same time or closer together and gives us a jump on treatment,” he added.

In October, the Food and Drug Administration approved this combination therapy as an up-front treatment to delay progression of pulmonary arterial hypertension.


Phyllis Hanlon is a contributing writer to RT. For further information, contact [email protected].


  1. Benza RL, Miller DP, Gomberg-Maitland M et al. “Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).” Circulation. 2010 Jul 13; 122(2):164-72. doi.10.1161/CIRCULATIONAHA. 109.898122. Epub 2010 Jun 28.
  2. Raphael C, Briscoe C, Davies J et al. “Limitations of the New York Heart Association functional classification system and self?reported walking distances in chronic heart failure.” Heart. 2007 Apr; 93(4): 476–482. doi: 10.1136/hrt.2006.089656.
  3. McLaughlin VV, Gain SP, Howard LS et al. “Treatment goals of pulmonary hypertension.” JACC 2013: Vol. 62, No. 25, Suppl D. doi: 10./1016/j.jacc.2013.10.034.
  4. Tian W, Jiang X, Tamosiuniene R et al. “Blocking macrophage leukotriene B4 prevents endothelial injury and reverses pulmonary hypertension.” Science Translational Medicine  28 Aug 2013: Vol. 5, Issue 200, pp. 200ra117. doi: 10.1126/scitranslmed.3006674.
  5. Lane CR, Tonelli AR. “Lung transplantation in chronic obstructive pulmonary disease: patient selection and special considerations.” International Journal of COPD. 2015:10; 1-10.
  6. Galiè N, Barberà JA, Frost AE et al. “Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension.” N Engl J Med. 2015 Aug 27;373(99):834-44.doi: 10.1056/NEJMoa1413687.