In pulmonary arterial hypertension (PAH), the acute pulmonary vasodilator response to inhaled nitric oxide (iNO) is routinely assessed once, at diagnostic right heart catheterization, mainly to identify candidates for calcium channel blocker therapy. A single-center retrospective study of 54 PAH patients who each underwent two catheterizations with iNO challenge (Tooba, Almoushref and Tonelli, Lung 2020) found that group-level vasoreactivity did not change substantially over a median 24.5 months, but with wide patient-to-patient variability, a less pronounced fall in mean pulmonary artery pressure at the second test, an association between improved reactivity and phosphodiesterase-5 inhibitor exposure, and no survival association of any vasoreactivity measure. Its own stated unknown is whether the response to the acute pulmonary vasoreactivity test changes over time and determines prognosis. Around that question, later literature has engaged but not settled: (1) what accounts for the variability in repeat iNO responsiveness — treatment effects on pulmonary vascular physiology, underlying disease heterogeneity, or both — and whether PAH subtype or treatment pathway modifies the trajectory; (2) whether the repeat-test response or its change carries independent prognostic information — a question on which existing studies directly conflict; and, as the motivating clinical application, (3) whether any patient subgroup or response threshold exists for which serial vasoreactivity testing would change treatment selection or risk stratification. Together these ask one thing: whether repeat iNO vasoreactivity testing has clinical value and, if so, in whom and how it should be used.

Background

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary microvasculature, defined at invasive hemodynamic assessment by an elevated mean pulmonary artery pressure (mPAP) together with a normal pulmonary artery wedge pressure and an elevated pulmonary vascular resistance (PVR, expressed in Wood units, a resistance index derived from pressure and flow measurements). The reference standard for diagnosis is right heart catheterization (RHC), the placement of a catheter in the pulmonary artery allowing direct pressure measurement and cardiac output determination. During RHC, an acute vasoreactivity test (AVT) is commonly performed: the patient inhales nitric oxide (iNO, typically 40 ppm for 5 minutes), a rapidly acting selective pulmonary vasodilator, and the change in mPAP, PVR, and cardiac output is recorded; the source study assessed this hemodynamic response by absolute or percentage change in mPAP or PVR. A positive AVT by the widely used (Sitbon) criteria is a fall in mPAP of at least 10 mmHg reaching a value of 40 mmHg or below with an unchanged or increased cardiac output. Positive AVT is required before treating idiopathic, heritable, or drug/toxin-associated PAH with high-dose calcium channel blockers (CCBs), because a small subgroup of such 'vasoresponders' has excellent long-term outcome on CCBs alone. The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) pulmonary hypertension guidelines recommend AVT only at diagnostic RHC in these PAH subtypes; repeat (serial) AVT is not part of any recommended follow-up protocol. Modern PAH therapy otherwise consists of drugs targeting three pathways — endothelin receptor antagonists, prostacyclin analogues, and phosphodiesterase-5 (PDE5) inhibitors, which raise pulmonary vascular cyclic GMP and are themselves mild pulmonary vasodilators — used alone or in combination. Whether the acute iNO response is a stable trait of a patient's pulmonary vasculature or changes under disease progression and these therapies was, until the source study, essentially unexamined in adults. Tooba, Almoushref, and Tonelli (Lung 2020; first presented as a CHEST 2019 meeting abstract) retrospectively studied 54 PAH patients who underwent two RHCs with iNO challenge a median of 24.5 months apart. They reported that only the fall in mPAP during iNO was less pronounced at the second test (−8.6±8.1 versus −12.3±13.8 mmHg, p=0.02), that 8 of 54 patients met positive-test criteria at the first RHC but only 1 at the second, that greater reactivity at the second RHC was associated with PDE5 inhibitor use at the first RHC (56% versus 27%, p=0.04) and with more PAH-specific medications by the second RHC (2.3 versus 1.8, p=0.03), and that neither absolute nor percentage changes in mPAP or PVR during iNO at either catheterization, nor the change between catheterizations, predicted survival in Cox analysis. The study was small, single-center, retrospective, applied a 1 mmHg threshold to dichotomize 'increased' reactivity (within typical hemodynamic measurement error), performed no correction for multiple comparisons across four endpoints, and its Cox model rested on few events — so its null survival finding is fragile. Its own framing — that whether the vasoreactivity response changes over time and determines prognosis 'remains unknown' — defines the open question addressed here.

Problem Statement

Determine whether repeat inhaled nitric oxide (iNO) vasoreactivity testing during right heart catheterization has clinical value in adult pulmonary arterial hypertension (PAH) — in the source study's own framing, whether the response to the acute pulmonary vasoreactivity test changes over time and determines prognosis. Concretely: (1) establish whether the acute pulmonary vascular response to iNO (absolute and percentage change in mean pulmonary artery pressure and pulmonary vascular resistance) changes systematically over time between catheterizations under modern PAH therapy, and characterize the wide patient-to-patient variability in repeat responsiveness, including the two treatment-related associations reported by the source study (phosphodiesterase-5 inhibitor exposure at the first catheterization and the number of PAH-specific medications by the second); and (2) establish whether the repeat-test response, or its change from the first test, carries independent prognostic information for survival or other clinical outcomes after adjustment for established prognostic factors — resolving the direct conflict between the source study's null finding and the positive follow-up study of Ishii et al. 2023. The problem is answered for adult PAH populations as encountered in clinical cohorts; pediatric pulmonary hypertension constitutes supporting but distinct evidence. Two further questions remain open as interpretive context and motivating application: whether the observed variability reflects treatment effects on pulmonary vascular physiology or underlying disease heterogeneity, and whether PAH subtype or treatment pathway modifies the trajectory; and whether any identifiable patient subgroup or response threshold exists for which serial vasoreactivity testing would change treatment selection or risk stratification (for example, escalation of PAH-specific therapy, calcium channel blocker withdrawal, or transplant referral timing).

References

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