Parenchymal Lung Disease in PAH Patients Managed with Prostacyclin Agonists

Abstracts S355 2Service

de Pneumologie, Hôpital Kremlin Bicètre, Paris, France; 3Service de Pneumologie, Hôpital Avicenne, Bobigny, France. Purpose: Clinical and particularly pathologic features in end stage pulmonary sarcoidosis (ESPS) are not well defined. Only anecdotal reports have suggested similarities with usual interstitial pneumonia (UIP). We hypothesized that characteristics in ESPS were distinct. Methods: Twenty-four patients who had a diagnosis of pulmonary sarcoidosis and underwent lung or heart and lung transplantation were included. Clinical characteristics at baseline, histopathology of explanted lungs and survival in ESPS patients were analyzed and compared to 20 and 22 lung transplanted patients with UIP and pulmonary langerhans cell histiocytosis (PLCH) respectively. Results: 5 (21%), 1 (5%) and 7 (35%) patients had heart and lungs transplantation among ESPS, UIP and PLCH candidates respectively. Pulmonary hypertension (PH) was diagnosed in 21 (84%), 9 (41%) and 18 (90%) in ESPS, UIP and PLCH patients respectively and significantly more severe in ESPS and PLCH groups. Similiarities of histopathology between groups included atheroma in large pulmonary artery, medial artery hypertrophy and capillary hemangiomatosis. However granulomatous arteritis was only found in the ESPS group. No significant differences in long-term outcome and survival were found among groups. Conclusion: Patients with ESPS referred for lung transplantation are more likely to have severe PH related to multifocal lesions of the pulmonary arterial vacular bed including granulomatous specific injuries. However, compared to controls, these specificities are not associated with a worse post transplant outcome. 9( 88) An Analysis of Mechanism of Hypoxia in Chronic Thromboembolic Pulmonary Hypertension S. Minatsuki , H. Maki, M. Hatano, I. Komuro.  Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan. Purpose: In chronic thromboembolic pulmonary hypertension (CTEPH), residual hypoxia remains to be a limitation of physical activity, despite hemodynamic status improved. However, the precise mechanism of hypoxia and the medical contribution to the hypoxia have not been fully clarified. The purpose of our study was to clarify the determinants of hypoxia in CTEPH. Methods: We retrospectively analyzed patients with CTEPH who had measured hemodynamic status, respiratory function, and dead space ratio. Patients, who received medical intervention, were measured these parameters before and after treatment. We excluded chronic lung disease. Results: In overall twenty-eight patients (19 female, 64±12 years), arterial oxygen saturation (SaO2) was 91.2±3.6% and dead space ratio (DSR) was 0.63±0.05. As far SaO2, %functional residual capacity (%FRC), mean pulmonary arterial pressure (mPAP) and DSR were significantly correlated (r=  0.53, 0.62, 0.44, p< 0.05, respectively). Fifteen in 28 received medical intervention (7 patients were treated by balloon pulmonary angioplasty only, 2 by riociguat only, and 6 by combination of the two treatments). By improvement of mPAP (38.6±9.4 vs 25.2±2.8 mmHg, p< 0.05), SaO2 and DSR were significantly improved (90.5±3.6 vs 93.9±1.9%, 0.64±0.5 vs 0.58±0.5, p< 0.05, respectively). However %FRC was not improved. Furthermore, abnormality of SaO2 and DSR were persisting despite adequate hemodynamic improvement. Conclusion: Current therapy can improve hypoxia in CTEPH. It also improves DSR by correcting ventilation-perfusion imbalance. However, it is not enough to restore normal blood oxygenation level. It is possible that correcting %FRC is one of clue of the normalization of hypoxia in CTEPH. 9( 89) Exercise CMR Can Evaluate RV Function and Hemodynamics in Patients with Pulmonary Arterial Hypertension: A Pilot Study E.W. Pollock , S. Raman, V. Franco.  The Ohio State University, Columbus, OH.

Purpose: Pulmonary arterial hypertension (PAH) is characterized by elevated lung pressures, which leads to vascular remodeling, high pulmonary vascular resistance, severe right ventricular (RV) failure and death. Cardiac magnetic resonance (CMR) is considered the gold standard for RV functional and morphological assessment. Exercise capacity provides additional prognostic information in PAH. The aim of the study was to assess RV reserve using a novel treadmill exercise stress CMR protocol in PAH patients. Methods: Patients were included if: ≥  18 years of age and had a clinicallyindicated CMR for evaluation of their mild to moderate PAH. Exclusion criteria included: Inability to exercise; atrial fibrillation; currently receiving IV or SQ prostacyclin; allergy to gadolinium; and significant renal insufficiency (GFR <  30 mL/min/1.73 m2). This study was approved by the IRB at our institution. We used a MRI-compatible in-room treadmill. We collected baseline demographics, right heart catheterization data, exercise stress testing, and CMR data. The CMR protocol lasted 45-60 minutes and consisted of obtaining localizers and traditional cardiac cine images followed by a treadmill exercise stress test. Immediately after the stress test, stress CMR was obtained. Subjects then recovered and additional recovery and delayedenhancement imaging were obtained. Results: 9 patients completed stress testing and 6 had an adequate stress test (85% of predicted heart rate). 3 patients stopped exercise prior to achieving target heart rates. Only 5 patients followed similar CMR protocols and data obtained from these patients included right and left ventricular volumes and ejection fractions at rest and post-exercise. Resting RVEF ranged 36-84% and stress RVEF ranged 28-67%. For 3 patients, the resting to stress EF decreased. One patient had an increase in RVEF and another had relatively no change in EF although RV volumes increased. Conclusion: We have successfully demonstrated for the first time the feasibility and safety of combining treadmill exercise stress and CMR in PAH patients. These pilot data suggest the potential utility of exercise stress CMR to evaluate RV functional reserve in patients with PAH. Further studies are needed. 9( 90) Parenchymal Lung Disease in PAH Patients Managed with Prostacyclin Agonists N.A. Weir , O.A. Shlobin, D. Brown, S.D. Nathan, S. Ahmad, C. King, A. Brown.  Inova Advanced Lung Disease & Transplant, Fairfax, VA. Purpose: PAH is a progressive vasculopathy involving the pulmonary circulation resulting in right heart failure. Prostacyclin agonists are primarily used in advanced disease. The initial evaluation of PAH involves imaging to exclude parenchymal lung disease. We have observed a subset of patients on prostacyclin agonists with abnormal findings on chest CT scans. We report on our cohort of patients on prostacyclin agonists who demonstrate atypical parenchymal findings in the absence of underlying ILD. Methods: A retrospective analysis of WHO group 1 PAH patients seen in our program from to 2000 to 2015 was performed. Patients receiving prostacyclin agonist therapy with CT chest imaging available for review were included. The most recent images for each patient were reviewed and scored for presence of abnormal findings. Results: The final cohort included 36 patients. 17/36 (47%) had IPAH, 9/36 (25%) familial, anorexigen, HIV or POPH, and 10/36 (28%) CTD related PAH. The mean age was 52 and 89% were female. Fifty percent (18/36) had evidence of micronodules, while only 11/36 (31%) had underlying ILD. Only 4/36 CT scans (11%) had no abnormalities other than enlarged pulmonary arteries. A common finding was mosaic attenuation (6/36) and in those, V/Q scans were low probability or normal. Another common CT finding was ground glass opacities (14/36). Bronchoscopy was performed in 3/36 and lung biopsy in 2/36 patients. Findings were consistent with PAH and in one case resulted in significant complications. Conclusion: Lung imaging is not completely normal in PAH patients receiving prostacyclin therapy. Parenchymal abnormalities may be associated with PAH or vasodilator therapy, rather than true ILD. Severe PAH patients are at increased risk of invasive procedures making evaluation with bronchoscopy or surgical lung biopsy unnecessary and possibly harmful. Further study of abnormal chest imaging in larger prospective trials or patient registries would be helpful in establishing the true prevalence of these parenchymal changes.

S356

The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016

Table 1

Table: Mean (SD) or Median (IQR)

Type of PAH

Duration prostacyclin therapy, months †

IPAH (N= 17)

58.3

CTD PAH (N= 10)

56.4

Other Group 1 PAH 20.4 (N= 9)

FVC, LFVC Mode prostacyclin percent predicted‡ therapy ⃰ 12 IV2 2.95, 85.4% oral1 SQ 7 IV1 oral1 2.21, 66.8% inhaled1 SQ 4 IV4 2.3,83.6% inhaled

Presence of Underlying Micronodules ILD 9 (53%)

1 (6%)

3 (30%)

6 (60%)

6 (66%)

4 (44%)

9( 91) Phenotypic Differences in Pulmonary Hypertension Due to Left Heart Disease (PHLHD) and Reversibility with Left Ventricular Assist Devices (LVAD) S. Lim , N. Howell, A. Ranasinghe, J. Mascaro.  University Hospital Birmingham, Birmingham, United Kingdom. Purpose: LVAD can effectively improve left-sided filling pressure and even reverse fixed and disproportionate PHLHD, based on pulmonary vascular resistance (PVR) measurements. Diastolic pressure gradient (DPG) > 7 mmHg may be a specific hemodynamic marker of pulmonary vascular disease. We hypothesised that there are persistent pulmonary vascular abnormalities despite improvements in PVR with LVAD in patients with baseline DPG> 7 mmHg. Methods: Retrospective single centre study of consecutive LVAD implanted in patients with PHLHD (precluded heart transplantation) as bridge to candidacy/transplantation. PHLHD was defined as mean pulmonary artery (PA) pressure > 25 mmHg with PA wedge pressure (PAWP) > 15 mmHg. Right heart catheter study was performed at baseline and 6 months post-implant. DPG = PA diastolic pressure-PAWP. PA capacitance (CPA) = stroke volume/ PA pulse pressure; PVR =  (mean PA pressure-PAWP)/cardiac output (CO). PA time constant (RC)= CPA ×PVR. Results: 15 patients were included (Age:52±12 years, ischemic: 7 (47%), ejection fraction: 15 (3)%, all INTERMACS 3/4). LVAD improved pulmonary hemodynamics in all patients [TABLE]. RC increased in all patients but the increase was minimal in the 4 patients with baseline DPG>  7 mmHg (2.3±0.3 vs 0.14±0.14, p7 mmHg [squares in FIGURE]. Conclusion: Baseline DPG> 7 mmHg identifies a PHLHD phenotype with persistent pulmonary vascular disease (limited change in RC), despite significant improvement in CO and PAWP with LVAD. 

PA systolic pressure Post-VAD PASP PA diastolic pressure Post-VAD PADP Mean PA pressure Post-VAD mean PAP PA wedge pressure Post-VAD PAWP Cardiac output Post-VAD CO PVR Post-VAD PVR CPA Post-VAD CPA RC time Post-VAD RC time

DPG

DPG> 7

p

68±5 31±4 31±2 16±4 41 (40-50) 24 (18-28) 28 (27-33) 15 (8-16) 3.6±0.5 5.4±0.7 4.7 (3.7-5.2) 1.6 (1.4-1.6) 1.3 (1.0-1.4) 4.6 (4.3-5.8) 5.2 (5.0-5.5) 7.5 (7.1-7.6)

94±28 43±17 41±10 17±7 54 (53-77) 24 (21-33) 31 (28-38) 13 (12-16) 3.8±0.7 5.2±0.6 6.0 (4.5-9.9) 2.4 (2.2-2.8) 1.0 (0.8-1.2) 2.3 (2.2-3.1) 5.5 (5.4-5.8) 5.7 (5.6-5.9)

0.013 0.023 0.002 0.72 0.138 0.661 0.571 0.489 0.576 0.728 0.226 0.006 0.138 0.001 0.226 0.001

9( 92) Tricuspid Regurgitation Is Associated with Pulmonary Hemodynamics and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension But Does Not Alter the Geometry of Right Ventricular Contraction J. Po , T. Meeran, R. Davey, R. Benza, A. Raina.  Allegheny General Hospital, Pittsburgh, PA. Purpose: Longitudinal contraction comprises the majority of overall right ventricular (RV) function in pulmonary arterial hypertension (PAH). Measures of longitudinal contraction such as tricuspid annular plane systolic excursion (TAPSE) are impaired in patients with PAH and RV dysfunction and may improve after decrease in RV afterload with PAH therapy. We hypothesized that significant tricuspid regurgitation (TR) may alter the geometry of RV contraction by effectively providing a low afterload release, leading to an overestimate of RV function by longitudinal measures in patients with TR. Methods: We retrospectively evaluated patients with WHO Group I PAH from 2011 to 2014 who had transthoracic echocardiograms (TTE), cardiac MRI and right heart catheterization at our center within 6 months. Tricuspid regurgitation on TTE was evaluated by qualitative and quantitative analysis. Echocardiographic, hemodynamic and MRI variables were compared between patients with mild or less TR vs. those with moderate or greater TR. Results: Fifty seven patients (mean age 55 years, 52% idiopathic, 35% connective tissue associated) were included. Twenty patients (36%) had moderate or severe TR. Patients with significant TR had higher mean PA pressure (52 vs. 42 mmHg, P= 0.005) and PVR (11 vs. 7 WU, P= 0.015) as well as larger right ventricular (RVEDD 50 vs. 42 mm, P= 0.001) and right atrial (RA) area 24 vs 18 cm2, P= 0.001) dimensions. TAPSE was lower in subjects with TR (16 vs 20 mm, P= 0.02) as was tissue Doppler S’ (12 vs 10 cm/s, p= 0.09) and RV ejection fraction (42 vs 48%, P= 0.04). However, the ratio of RV ejection fraction to TAPSE was similar between patients with and without TR (RVEF/TAPSE 2.9 vs 3.1, P= 0.43). The correlation between TAPSE and RVEF was stronger in patients without TR (R= 0.7 vs R= 0.55), but this difference was not significant. Conclusion: Tricuspid regurgitation is associated with higher PA pressures, PVR and larger right heart dimensions in PAH. Though RV ejection fraction and TAPSE are lower in patients with TR, the presence of TR does not significantly alter the contractile pattern of the RV, such that longitudinal measures remain valid in the quantitative assessment of RV function in PAH. 9( 93) A Coding Polymorphism in PFAS (The Gene Encoding Phosphoribosylformylglycinamidine Synthase) Is a Determinant of Prostacyclin Dose V. Thomeas ,1 M.L. Maitland,1 R.L. Benza,2 M. Tamari,3 E.R. Gamazon,4 A. Konkashbaev,4 H. Wheeler,5 T. Hirota,3 M. Kubo,3 N.J. Cox,4 M. Gomberg-Maitland.1  1University of Chicago, Chicago, IL; 2Allegheny