Finet, Emanuel

Abstract Rationale: Although guidelines recommend the use of provocative testing to diagnose pulmonary venous hypertension (PVH) that is unapparent at normal resting right heart catheterization (RHC), the incremental value of provocative testing is unknown. We aim to evaluate the incremental diagnostic capability of inhaled nitric oxide (iNO), fluid challenge (FC) or invasive cardiopulmonary exercise testing (iCPET) to unmask PVH using previously defined hemodynamic cutoffs. Methods: We included subjects from the NHLBI-funded Pulmonary Vascular Disease Phenomics (PVDOMICS) study. Our analysis included patients with World Symposium on Pulmonary Hypertension (WSPH) Group 2 disease (G2PH) and G2PH comparators (WSPH Group 2 phenotype without a diagnosis of PH) as determined by the PI or adjudication panel. We then applied a protocol-driven provocative approach based on the feasibility of modalities available in most catheterization labs. Using a pulmonary capillary wedge pressure (PCWP) cutoff of >15, frequencies were identified for subjects based on resting PCWP and with iNO. Frequencies were also identified for: those who received FC with a PCWP cutoff of ≥18 or those who received iCPET with PCWP cutoff of >20 (upright) or >25 (supine). Results: There were 419 subjects identified with WSPH Group 2 disease (Figure). Roughly half were found to have a PCWP >15 during resting RHC (N = 207). Of the remaining subjects with a resting PCWP ≤15 (N = 150), 42 subjects were found to have a PCWP >15 with iNO administration (40.0%). Of the remaining 63 subjects with PCWP ≤15 following iNO administration, nearly half (N = 26, 48.0%) demonstrated a PCWP ≥18 following FC while 8 subjects (14.8%) demonstrated an elevated PCWP following iCPET. Conclusions: There is a high proportion of G2PH patients (∼35%) who appear hemodynamically similar to precapillary PH at rest. Inhaled nitric oxide vasodilatory challenge unmasks G2PH in many patients. In situations where iNO does not disclose the G2PH phenotype, provocation with FC or iCPET can be useful as a supplementary provocative maneuver. Future directions will focus on agnostically assessing the utility of provocation based on grouping subjects by resting hemodynamics as well as assessing the use of provocation in other forms of PH.

Left atrial (LA) size and function is recognized as a cumulative index of pulmonary capillary wedge pressure (PCWP) and an index of left heart disease (LHD). While anticipated that LA features contribute to LHD-associated pulmonary hypertension (PH), we hypothesized that LA abnormalities (LAA) may exist in other WSPH groups. Therefore, we examined LA structure and function in the PVDOMICS cohorts. PVDOMICS enrolled 1097 total subjects with PH (mPA > 25 mmHg) and at-risk disease comparators (mPA<25 mmHg) for each of the WSPH groups. Patients with WSPH Groups 1, 3, 4, and 5 [non-Group 2] (n=618) were younger (56.2 ± 14.5 vs 60.1 ± 12.7 yrs, p<.02) and had less hypertension (38.6% vs 51.5 %, p<.02) than their non-Group 2 comparators (n=204). They also had less hypertension, diabetes, and a lower BMI than WSPH Group 2 (n=145), whereas WSPH Group 2 and its comparator Group 2 (n=130) were similar. LA area by echo was greater in WSPH Group 2 compared to non-Group 2 (22.8 ± 6.6 vs 16.9 ± 5.0 cm 2 , p<.02), in the comparator Group 2 vs. non-Group 2 comparators (22.7 ± 7.9 vs 16.4 ± 4.7 cm 2 , p<.02) but similar between WSPH group 2 and its comparator. MRI LA ejection fraction was lowest in Group 2 (33.2 ± 17.7%) and comparator Group 2 (38.9 ±16.7%, p=ns), significantly lower than WSPH non-Group 2 (45.9 ±14.7%, p<.02) which was lower than comparator non-Group 2 (50.9 14.6%, p<.02) which was lower than normal controls (n=96) (58.4 ±1.7%, p<.02). At right heart catheterization, whereas mPA pressures were similar between WSPH non-Group 2 and Group 2, resting PCW (11.1± 5.3 vs 20.3 5.6 mm Hg, p<0.02) was lower in WSPH non-Group 2 , PVR was higher (5.5[3.3, 8.7] vs. 3.7[7.2, 5.7] WU, p<0.02), and cardiac output was higher (5.4 ± 1.9 vs. 4.9 ± 1.6 L/min, p<0.02). Following a fluid challenge, PCW remained lower (14.9 ± 5.8 vs 20.7 ± 4.5 mm Hg, p<0.02) and PVR higher (5.2[3.1, 7.8] vs. 3.2[2.3, 5.5] WU, p<0.02). PCW and PVR at rest were lower in the comparator non-Group 2 vs WSPH non-Group 2 (8.9 ± 4.1 vs 11.1± 5.3 mm Hg, p<.02) and 1.7[1.2, 2.3] vs 5.5[3.3, 8.7] WU, p<.02. Thus, while LAA are most notable in WSPH and comparator Group 2’s, LAA differ between WSPH non-Group 2 and its non-Group 2 comparators. The role of LAA as predictors of PH outcomes remains to be determined.