During the first meeting of the World Symposium on Pulmonary Hypertension (WSPH) in 1973, experts agreed on a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg as the hemodynamic threshold for diagnosing PH.1 Nonetheless, attendees regarded this as an arbitrarily defined cutoff and acknowledged the need for additional research to elucidate the parameters of normal pulmonary circulation, according to a review published in Current Opinion in Pulmonary Medicine.2

After much debate among experts, refinement of the overall definition and classification of PH and pulmonary arterial hypertension (PAH), and accumulation of substantial evidence in this area over the past several decades, the 6th WSPH Task Force on Hemodynamic Definitions and Clinical Classification recently proposed reducing the diagnostic mPAP threshold from 25 mm Hg or above to more than 20 mm Hg for all PH groups.3

“This proposed change was based on evidence demonstrating that the upper limit of normal for mPAP in healthy adults is 20.6 mm Hg as well as a strong association of mildly elevated mPAPs (21-24 mm Hg) with increased mortality across diverse [PH] populations,” the review authors wrote.2


Continue Reading

However, it is unclear whether this increase in mortality can be attributed to PH in patients with these borderline mPAPs and whether the lower values are “representative of pulmonary vascular remodeling that warrants therapeutic intervention….” Therefore, some clinicians remain skeptical about the utility of the definition change in clinical practice.

To glean perspectives from experts in the field, we interviewed Timothy M. Fernandes, MD, MPH, pulmonologist and associate clinical professor of medicine in the department of pulmonary and critical care medicine at the University of California San Diego School of Medicine; and Paul M. Hassoun, MD, professor of medicine in the division of pulmonary and critical care medicine at the Johns Hopkins University School of Medicine, and director of the pulmonary hypertension program at Johns Hopkins Hospital in Baltimore.

What are your thoughts about the 6th WSPH proposal to lower the mPAP threshold to define PH from 25 mm Hg or above to more than 20 mm Hg?

Dr Fernandes: It is important to note that this change only represents one part of the 3-part definition. In addition to having an mPAP higher than 20 mm Hg, patients must also have both a pulmonary capillary wedge pressure less than 15 mm Hg and a pulmonary vascular resistance (PVR) greater than 3 Wood units.

For this new lower mPAP threshold to result in the reclassification of patients to a diagnosis of PAH, those with an mPAP of 20 to 24 mm Hg must also have a very low wedge pressure, a very low cardiac output, or both. It is exceedingly rare, therefore, that the new definition has significantly increased the population labeled as WHO [World Health Organization] group I PAH. 

Dr Hassoun: The new definition makes sense, as a pressure of 20 mm Hg would be 2 standard deviations above a PAP in a normal individual, meaning that very few normal individuals have pressures that reach 20 mm Hg. By keeping a PVR greater than 3 Wood units in the definition, we ensure that we do not include patients who have, for instance, a high PAP from high cardiac output or other causes.

What are the clinical implications of adopting this new definition?

Dr Fernandes: Patients with PAH frequently see a delay from the onset of symptoms to PAH diagnosis of more than 2.5 years.4 Many other more common diagnoses are considered before PAH is identified. As such, patients with mild cases of PAH who would meet this lower mPAP threshold do not frequently come to the attention of PAH experts. There are emerging data that even lower PVR thresholds may also see an increase in mortality from PH.2 Taken together with the delays in diagnoses seen, these lower thresholds should be a clarion call for the PAH community to identify these mild patients sooner.

Dr Hassoun: This will have little clinical implication for patients in group I of the classification, particularly patients with idiopathic PAH, who typically present with already severe PH — meaning their PAP is way above 20 or 25 mm Hg. If we look at any PH registry, we will find very few patients with idiopathic PAH who have an mPAP less than 25 mm Hg.

However, some patients with predisposing diseases, such as connective tissue disease (CTD; also group I) or chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD; group III), may be diagnosed at an earlier stage with the new definition and receive earlier treatment. This is specifically important for patients with CTD, a population at risk of developing PAH who may benefit from early treatment.   

What are remaining questions and research needs pertaining to this topic?

Dr Fernandes: We need more research into the implications of this definition change. Several groups of patients at risk for WHO group I PAH, such as those with CTDs like scleroderma, may benefit from intensive screening programs to identify these patients earlier. Determining whether these new definitions should suffice or if there is a role for invasive exercise testing to elicit a pulmonary hypertensive response and rule out exercise limitation due to left heart disease is needed. 

While previous research clearly shows increasing mortality once the mPAP is less than 20 mm Hg, these studies were mostly based on non-WHO group I patients. More rigorous phenotyping of these patients to tease out those with heart failure with preserved ejection fraction who have been diuresed to euvolemia from those who truly represent earlier presentations of WHO group I PAH is warranted. 

Finally, these patients with lower mPAP (20-24 mm Hg) were never included in any of the previous large randomized controlled trials of PAH therapies. There are retrospective data in patients with scleroderma-related PAH that demonstrated improved survival compared to historical control individuals, but this data are subject to lead time bias.2 The effects of PAH therapy in these patients with a mPAP of 20 to 24 mm Hg needs rigorous study in randomized controlled trials to assess the effects on functional status, morbidity, and mortality.

Dr Hassoun: There are several questions that remain to be answered. Will patients with mild disease (mPAP between 20-25 mm Hg) benefit from early treatment? How many of these patients will develop full blown PH over the next few years if left untreated?

In summary, the new definition will allow us to treat patients at risk earlier compared to the old definition, assuming the FDA [US Food and Drug Administration] will accept the approval of PAH drugs for this group of patients. It will make no real difference for patients with idiopathic PAH who, when they present to us, already have advanced disease.

References

1. Hatano S, Strasser T, eds. Primary pulmonary hypertension: report on a WHO meeting, Geneva, 15-17 October 1973. Geneva: World Health Organization; 1975.

2. Brusca SB, Zou Y, Elinoff JM. How low should we go? Potential benefits and ramifications of the pulmonary hypertension hemodynamic definitions proposed by the 6th World Symposium. Curr Opin Pulm Med. 2020;26(5):384-390.

3. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. doi:10.1183/13993003.01913-2018

4. Weatherald J, Humbert M. The ‘great wait’ for diagnosis in pulmonary arterial hypertension. Editorial. Respirology. 2020;25(8):790-792. doi:10.1111/resp.13814