Mechanistic subtypes of IPAH revealed

By Eleanor McDermid, Senior medwireNews Reporter

Researchers have provided evidence for distinct processes underlying vasodilator-responsive and nonresponsive idiopathic pulmonary arterial hypertension (IPAH).

Patients with vasodilator-responsive IPAH are able to recruit functional capillary surface area (FCSA) in response to increased blood flow, whereas nonresponsive patients are not, report David Langleben (McGill University, Montreal, Quebec, Canada) and co-workers.

Their findings are based on data from 14 patients, two of whom responded to acute challenge with intravenous epoprostenol.

In an editorial accompanying the study in the Annals of Internal Medicine, Evan Brittain and Anna Hemnes (Vanderbilt University Medical Center Nashville, Tennessee, USA) say: “Research rarely warrants publication based on findings in only 2 patients. Such work must necessarily show a new discovery or unveil a previously unknown aspect of a disease.”

But they say the findings provide “the strongest evidence to date” that patients with vasodilator-responsive IPAH have reversible vasoconstriction, whereas nonresponsive patients have “irreversible vascular obliteration”.

Prior to vasodilator challenge, the responsive patients had a FCSA (normalised to body surface area) that was in line with normal values and significantly larger than in nonresponsive patients, at an average of 3406 versus 1027 mL/min per m². The team measured FCSA using the activity of pulmonary capillary, endothelium-bound, angiotensin-converting enzyme (PCEB-ACE) as a proxy for perfused pulmonary CSA.

During challenge, responsive patients’ FCSA “increased dramatically”, to a peak measurement of 4989 mL/min per m², compared with just 1103 mL/min per m² in the nonresponsive group.

The single-pass, transpulmonary metabolism and hydrolysis of the hemodynamically inactive PCEB-ACE substrate ³H-Benzoyl-Phe-Ala-Pro did not change in responsive patients during vasodilator challenge, indicating that these patients “accommodate the increased cardiac output by true microvascular recruitment and not distention”, say the researchers.

But these measures decreased significantly in nonresponders, suggesting that the increased blood flow is accommodated in the “remaining patent and already maximally recruited” blood vessels. This, says the team, explains why a reduction in pulmonary vascular resistance, caused by increased blood flow, does not necessarily indicate a benefit for patients.

However, in their editorial, Brittain and Hemnes note that further study of vasoresponsive IPAH patients may reveal approaches to help nonresponders. They say that the study shows “how phenotyping in a rare subset can have an impact far beyond those 2 patients.”

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