Idiopathic PA hypertension responds variably to vasodilators

By Will Boggs MD

NEW YORK (Reuters Health) - Patients with idiopathic pulmonary arterial hypertension (IPAH) show different vascular responses to acute vasodilator challenge, according to a small study in Canada.

"Not all patients with seeming IPAH are alike," Dr. David Langleben, of McGill University, Montreal, Quebec, told Reuters Health by email. "The acute vasodilator responders are a truly distinct group. This group should probably be a separate subcategory in the classification of IPAH."

Only about 5% to 10% of patients with IPAH respond to an acute vasodilator challenge with a reduction in mean pulmonary arterial pressure (mPAP), and these patients generally improve clinically with long-term, high-dose calcium-channel blockers.

The lung normally accommodates increased blood flow by increasing capillary surface area (CSA), but histological abnormalities in IPAH obstruct luminal flow in precapillary microvessels and thereby reduce perfusion of the distal capillary microvasculature.

Dr. Langleben and Dr. Stylianos E. Organos from Attikon Hospital, Athens, Greece, proposed that IPAH patients who respond to acute vasodilator challenge would have increased pulmonary vascular resistance based on vascular tone, rather than cellular obstruction, so that CSA could be recruited during the challenge.

Their test of this hypothesis is reported in a letter in the January 20 Annals of Internal Medicine.

All 14 patients with IPAH showed decreases in pulmonary vascular resistance in response to acute vasodilator challenge, but only two had a reduction in mPAP.

A dozen nonresponders had a low functional CSA at baseline that did not increase at peak vasodilator dose. The two who did respond, however, had higher baseline functional CSA than the nonresponders, and their functional CSA increased by 40% to 50% at peak vasodilator dose.

"Nonresponders generally have a severe reduction in perfused lung microvasculature at rest, and it doesn't improve during the acute vasodilator challenge, whereas the responders recruit microvasculature," Dr. Langleben explained.

"This suggests that the upstream pulmonary arteriolar obstruction to flow is from cellular luminal narrowing in the nonresponders, while the pre-vasodilator increased pulmonary vascular resistance in the responders is likely due to vasoconstriction, without cellular proliferation."

"We have assumed that all IPAH represents a severely restricted lung bed, with till now no hope of normalization with therapy," Dr. Langleben said. "The responders are patients who, given the right therapy, manifest an essentially normal amount of perfused lung bed. This offers hope that the lung may be recoverable despite, at times, severe pre-treatment hemodynamics."

"The technique we used is a very powerful research tool, but it is arduous to perform and requires meticulous sample collection and processing," Dr. Langleben added. "It can provide tremendous insights into lung perfusion in disease and health, but it will never be anything other than a research tool. That being said, it is already, in preliminary studies beyond the present one, showing tremendous potential in helping understand lung microvascular recruitment in exercise, and in disease states, as well as the effects of therapies on improving vascular perfusion."

Dr. Evan Brittain and Dr. Anna R. Hemnes of Vanderbilt University Medical Center, Nashville, Tennessee, wrote an editorial related to this report. Dr. Brittain told Reuters Health by email, "These findings provide the strongest evidence to date that the small subset of patients who meet contemporary criteria for acute vasodilator responsiveness may in fact have a different disease than nonresponders with IPAH."

"One implication for management is that a reduction of PVR without a fall in mPAP after vasodilator exposure is not associated with capillary recruitment and therefore unlikely to benefit the patient," he explained. "This is a mechanistic validation of the clinical observation made by Sitbon and colleagues several years ago."

Dr. Olivier Sitbon, of Hopital Universitaire de Bicetre, La Kremlin-Bicetre, France, told Reuters Health by email, "We know for a long time that the vast majority of patients with PAH do not display acute pulmonary vasoreactivity. The minority of vasoreactive patients (<10%), i.e., those who are able to respond to long-term calcium antagonists, are easily detected with an acute vasodilator test using inhaled nitric oxide or i.v. prostacyclin."

"This report helps physicians to understand why responders and nonresponders have different phenotypes and probably different diseases," he said. "However, this does not impact the management of these patients."

Dr. Langleben agreed: "Right now, the management of the patients will not change. The responders should be given high-dose calcium channel blockers, while the nonresponders should receive the usual therapies for PAH. But, knowing that the pathophysiology is different, we should search for different genetic causes."

SOURCE: http://bit.ly/181xy9d and http://bit.ly/1ynBXNv

Ann Intern Med 2015.

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