ABSTRACT
Pulmonary hypertension (PH) and right ventricular (RV) dysfunction increase mortality in multivessel pediatric pulmonary vein stenosis (PVS). Pulmonary vasodilator use is limited in PVS due to the perceived risk of pulmonary edema. We aimed to describe our experience with pulmonary vasodilators in PVS and to assess changes in RV function and hemodynamics over time. Children with multi‐vessel PVS (≥ 2 veins), mean pulmonary artery pressure > 20 mmHg, indexed pulmonary vascular resistance > 3 iWU, without single ventricle physiology, treated with pulmonary vasodilators from 2014 to 2024 were included in a single center, retrospective case series. RV systolic function was quantified by tricuspid annular plane systolic excursion (TAPSE), fractional area change (RVFAC), and longitudinal and free wall strain (RVLS, RVFWS). A four‐point PVS severity score was calculated from angiographic data. RV function and hemodynamics were compared from baseline to the most recent by Wilcoxon rank sum tests, controlling for change in PVS severity score. Thirty‐one patients (median (IQR) gestational age 27.1 (26.0, 35.9) weeks, birth weight 770 (540, 1900) grams) met the inclusion criteria. Median follow‐up was 27.0 (10.5, 71.5) months. Most (65%) had Group 3, lung disease‐related PH. One patient developed pulmonary edema requiring medication discontinuation. TAPSE, RVFAC, RVLS, and RVFWS improved significantly (p < 0.01 for all), independent of change in PVS severity score. Survivors demonstrated improved RV function compared to non‐survivors. Hemodynamics were unchanged. Pulmonary vasodilators may improve RV function in patients with PVS and PH in a rigorous surveillance program. The impact of improved RV function on mortality in PVS deserves further study.
Keywords: cardiac catheterization, echocardiogram, pulmonary hypertension, pulmonary vein stenosis, right ventricle
1. Introduction
Multivessel pulmonary vein stenosis (PVS) is a progressive condition characterized by stenosis or atresia of two or more lobar pulmonary veins, often resulting in pulmonary hypertension (PH) and right ventricular (RV) failure [1, 2]. Traditionally, PH due to PVS has been characterized as World Symposium of PH “Group 2” left heart disease‐related PH (LHD‐PH) [3, 4]. In Group 2 PH, elevated post‐capillary pressure from PVS, mitral or aortic valve disease, or left ventricular systolic or diastolic dysfunction causes elevated pulmonary artery pressure. Current guidelines do not recommend treatment of patients with Group 2 PH with pulmonary vasodilators [5, 6, 7], because of concern for potential pulmonary edema in patients with elevated post‐capillary pressure. However, the applicability of these guidelines to infants and children with PH and PVS is uncertain, and to our knowledge, the use of pulmonary vasodilators has not been well studied in PVS. This may be due to the relative rarity of PVS and co‐morbid conditions, including congenital heart disease and bronchopulmonary dysplasia (BPD). But patients with PH and co‐morbid conditions often overlap into other PH diagnostic categories, and their PH may be due to a substrate that might benefit from pulmonary vasodilator therapy.
Recently, a new category of LHD‐PH called “combined pre‐ and post‐capillary PH (CpcPH)” has been defined [4, 8]. In CpcPH, pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance are all elevated, highlighting the arterial vascular disease that can develop from backward transmission of increased hydrostatic pressure from post‐capillary venous obstruction [6, 9, 10]. Pediatric patients with PVS may have Cpc‐PH. While adult studies on pulmonary vasodilator use in CpcPH, have shown mixed results [11, 12, 13, 14, 15, 16], there is a scarcity of data on the use of pulmonary vasodilators in infants and children with PVS with both arterial and venous disease.
As our center's comprehensive PVS treatment program includes multi‐modal surgical and catheter‐based approaches, anti‐proliferative pharmacotherapy, and selective use of pulmonary vasodilators in patients with elevated pulmonary artery pressure and/or pulmonary vascular resistance, we performed a retrospective case series of patients with multi‐vessel PVS to describe this experience and provide preliminary data for future studies, specifically detailing, (1) adverse events potentially related to pulmonary vasodilators and (2) changes in quantitative measures of RV function, hemodynamics, and PVS severity in treated patients, while also exploring the question of whether these changes vary across the spectrum of PVS severity.
2. Methods
2.1. Study Design and Population
This was a retrospective single‐center case series including patients ages 0–18 years with: (1) multi‐vessel PVS (≥ 2 veins) diagnosed by cardiac catheterization, (2) hemodynamic criteria for PH with mean pulmonary artery pressure (mPAP) > 20 mmHg and indexed pulmonary vascular resistance (PVRi) > 3 indexed Wood units at baseline, (3) at least 2 cardiac catheterizations at The Children's Hospital of Philadelphia (CHOP), (4) pulmonary vasodilator treatment primarily managed by the CHOP Pulmonary Hypertension Team, and (5) PVS/PH treatment between 2014 and 2024. This series included patients with both isolated pre‐capillary PH (mPAP > 20 mmHg, pulmonary capillary wedge pressure ≤ 15 mmHg, and PVRi > 3 indexed Wood units) and those with CpcPH (mPAP > 20 mmHg, pulmonary capillary wedge pressure > 15 mmHg, and PVRi > 3 indexed Wood units). PH treatment included one or more of the following medications: sildenafil, tadalafil, bosentan, ambrisentan, treprostinil (intravenous, subcutaneous, or inhaled), or selexipag for any length of time, consistent with our center's practice to initiate sildenafil monotherapy at first PAH diagnosis, to add bosentan if there is still evidence of PAH at the following cardiac catheterization, and to reserve treprostinil for patients with right heart failure. Potential subjects undergoing surgical single ventricle palliation were excluded as the cardiac catheterization‐derived diagnostic criteria for single ventricle pulmonary hypertensive vascular disease are different than those for biventricular circulation and the treatment effect of pulmonary vasodilators may be different.
2.2. Study Measures
Demographic and clinical data were extracted from the medical record. The World Symposium of PH classification that best represented the patient's PH was confirmed by an investigator with PH expertise (CMA). Clinical notes were reviewed for medication side effects, including pulmonary edema, systemic hypotension, transaminitis, or other side effects resulting in discontinuation of pulmonary vasodilators. Age at PH diagnosis was represented by age at pulmonary vasodilator initiation. Cardiac catheterization reports, echocardiograms (echos), and PVS severity score were reviewed at baseline (prior or closest to pulmonary vasodilator initiation) and at the most recent assessment. Echos closest to the time of cardiac catheterization were used for this study. Cardiac catheterization reports were reviewed for right and left heart pressures, pulmonary and systemic blood flow, and pulmonary and systemic vascular resistances. Pulmonary vascular resistance was calculated as the difference between mean pulmonary artery pressure and left atrial pressure (when available; if not pulmonary capillary wedge pressure was substituted) divided by pulmonary blood flow and indexed to body surface area. At our center, acute vasoreactivity testing (AVT) is typically performed with fractional inspired oxygen concentration of 1.0 and inhaled nitric oxide of 40 parts per million if determined to be useful by the interventional cardiology team. If AVT was performed for patients in this cohort, a positive result was defined by the Sitbon criteria—a decrease in mPAP of at least 10 mmHg, reaching an absolute mPAP of 40 mmHg or less, with either an increased or unchanged cardiac index [17].
Clinically indicated echos were performed using standard pediatric views with 3‐8 MHz transducers on Phillips IE33 or EPIQ machines (Phillips, Andover, MA, USA) in accordance with our laboratory's comprehensive PH and RV function protocol. Quantitative analyses for RV systolic function included tricuspid annular plane systolic excursion (TAPSE) and TAPSE Z‐score [18, 19], RV fractional area change (RVFAC), and RV longitudinal and free wall strain (RVLS and RVFWS). Two pediatric cardiac sonographers (Y.W. and D.A.), blinded to clinical characteristics, obtained offline measures of RV function for any studies that did not originally include those analyses or those in which the tracings were considered inaccurate in the opinion of the sonographer. RVFAC was calculated as the end‐diastolic RV area minus the end‐systolic RV area divided by the end‐diastolic RV area [20]. RVFAC incorporates the longitudinal shortening of the right ventricle and the radial motion of the RV free wall towards the ventricular septum. RVLS and RVFWS were measured from apical 4‐chamber view using the vendor package with adjustment of the auto‐tracings or offline using TomTec software (Image Arena 4.6; Munich, Germany). By convention, strain is reported as a negative number, with a greater absolute value indicating better systolic function [21].
A published four‐point PVS severity score was calculated from cardiac or computed tomography angiography (CTA) [22]. Each pulmonary vein was scored 0–3. Common pulmonary veins were scored and multiplied by 2. Each patient has a potential score ranging from 0 to 11. PVS was defined as unilateral versus bilateral based on the anatomy of affected veins. Change in PVS severity score was defined as “improved” if there was a negative difference between the most recent and baseline score (i.e., most recent PVS severity score—baseline PVS severity score < 0); “no change” if there was no difference between the most recent and baseline score; and “worsened” if there was a positive difference between the most recent and baseline score (i.e., most recent PVS severity score—baseline PVS severity score > 0).
2.3. Statistical Analyses
Demographic and clinical characteristics were summarized by standard descriptive statistics. Continuous variables are presented as median and interquartile range (IQR). Categorical parameters are described as frequency (N) and percentage (%). Hemodynamic data, echo parameters, PVS severity scores, and PVS sidedness were compared at baseline and the most recent follow up using paired Wilcoxon rank sum tests. Change in hemodynamic data and echo parameters were compared when the change in PVS severity score and progression in PVS sidedness were held constant by paired Wilcoxon rank sum tests.
3. Results
Thirty‐one patients met the inclusion criteria (Figure 1, Table 1). Patients were 61% male with median (IQR) gestational age of 27.1 (26.0, 35.9) weeks and birth weight of 770 (540, 1900) grams. Most patients (65%) were WSPH classification group 3, lung disease‐related PH, of which most had BPD. Simple congenital heart disease, including atrial and ventricular septal defects and patent ductus arteriosus was present in 61%, while 10% of patients had complex congenital heart disease.
Figure 1.
Flow chart depicting generation of study sample.
Table 1.
Cohort characteristics.
| N = 31 | |
|---|---|
| Gender | |
| Female | 12 (39%) |
| Male | 19 (61%) |
| Race | |
| White | 14 (45%) |
| Black | 8 (26%) |
| Not specified | 9 (29%) |
| Ethnicity | |
| Hispanic/Latino | 7 (23%) |
| Non‐Hispanic/Latino | 23 (74%) |
| Unknown | 1 (3%) |
| Gestational age, weeks | 27.1 (26.0, 35.9) |
| Birthweight, grams | 770 (540, 1900) |
| Primary WSPH classification | |
| Group 1 PAH (IPAH, HPAH, CHD) | 5 (16%) |
| Group 2 PH (isolated PVS) | 4 (13%) |
| Group 3 PH (BPD, CDH, other developmental lung disease) | 20 (65%) |
| Group 4 CTEPH | 1 (3%) |
| Group 5 segmental PH, sickle cell disease, or other | 1 (3%) |
| Associated diagnoses | |
| Bronchopulmonary dysplasia | 19 (61%) |
| Simple CHD (ASD, VSD, PDA) | 19 (61%) |
| Complex CHD (CAVC, TOF, DORV, TGA, etc.) | 3 (10%) |
| Genetic diagnosis | 5 (16%) |
Note: n (%) or median (IQR).
Abbreviations: ASD, atrial septal defect; BPD, bronchopulmonary dysplasia; CAVC, complete atrioventricular canal defect; CDH, congenital diaphragmatic hernia; CHD, congenital heart disease. CTEPH; chronic thromboembolic pulmonary hypertension; DORV, double outlet right ventricle; IPAH, idiopathic pulmonary arterial hypertension; HPAH, heritable pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; PDA, patent ductus arteriosus; PH, pulmonary hypertension; PVS, pulmonary vein stenosis; TOF, tetralogy of Fallot; TGA, transposition of the great arteries; VSD, ventricular septal defect; WSPH, World Symposium of Pulmonary Hypertension.
Table 2 demonstrates the pulmonary vasodilators used in the cohort. Twelve patients (39%) were already being treated with a pulmonary vasodilator at the time of baseline PVS cath. Nearly all (97%) patients received sildenafil during their course, while many were later transitioned to tadalafil. About one‐third of the cohort was treated with an endothelin receptor antagonist, bosentan or ambrisentan. Twenty‐nine percent of patients were treated with intravenous or subcutaneous treprostinil. While nearly half (45%) of patients were treated with monotherapy, 35% of patients received dual therapy, and 19% of patients were treated with triple therapy. At the last follow‐up, patients had been treated with pulmonary vasodilators for 24.1 (7.8, 51.6) months. Pulmonary vasodilators were stopped in 17 (55%) of patients during the observation period. Medication discontinuation was due to PH improvement in 16 patients, while one patient developed pulmonary edema requiring discontinuation. No other adverse effects from pulmonary vasodilators were documented in the records. Overall survival was 77%. All deceased patients (n = 7) were on pulmonary vasodilators at the time of death.
Table 2.
PAH medications.
| N = 31 | |
|---|---|
| Age at pulmonary vasodilator medication start, months | 5.1 (3.2, 11.7) |
| On PH medications at baseline PVS cath | 12 (39%) |
| Length of treatment, months | 24.1 (7.8, 51.6) |
| Medications received | |
| Sildenafil | 30 (97%) |
| Tadalafil | 12 (39%) |
| Bosentan | 12 (39%) |
| Ambrisentan | 11 (35%) |
| Treprostinil (IV or SQ) | 9 (29%) |
| Selexipag | 1 (3.2%) |
| Number of pulmonary vasodilators | |
| 1 | 14 (45%) |
| 2 | 11 (35%) |
| 3 | 6 (19%) |
| Medication discontinuation | 17 (55%) |
| Reason for discontinuation | |
| Clinical improvement | 16 (52%) |
| Pulmonary edema | 1 (3%) |
Note: n (%) or median (IQR).
Abbreviations: IV, intravenous; PH, pulmonary hypertension; PVS, pulmonary vein stenosis; SQ, subcutaneous.
Table 3 demonstrates our approach to the severity of the PVS in this cohort. Patients were treated with a combination of balloon angioplasty, stent angioplasty, and surgical repair. Fifty‐two percent of patients were treated with sirolimus as anti‐proliferative treatment to prevent re‐stenosis.
Table 3.
PVS treatment approach.
| N = 31 | |
|---|---|
| Number of patients with PVS surgery | 5 (16%) |
| Number of interventional PVS cardiac catheterizations per patient | 3 (2, 6) |
| Number of affected veins with stents per patient | |
| 0 | 15 (48%) |
| 1 | 8 (26%) |
| 2 | 4 (13%) |
| 3 | 4 (13%) |
| Number of affected veins with balloon dilation angioplasty only per patient | |
| 0 | 4 (13%) |
| 1 | 6 (19%) |
| 2 | 12 (39%) |
| 3 | 8 (26%) |
| 4 | 1 (3%) |
| Treatment with sirolimus | 16 (52%) |
Note: n (%) or median (IQR).
Abbreviation: PVS, pulmonary vein stenosis.
Baseline and most recent echocardiographic parameters, hemodynamic data, and PVS severity score are demonstrated in Table 4. Median follow‐up from first cardiac catheterization to last clinical encounter was 27.0 (10.5, 71.5) months. At baseline, 14 patients (45% of the cohort) underwent AVT, of which 2 (14% of those with testing) had a positive response. At the most recent cardiac catheterization, 6 patients (19% of cohort) underwent AVT, of which 1 (17% of those with testing) had a positive response. TAPSE, RVFAC, RVLS, and RVFWS improved significantly (p < 0.01 for all) from baseline to most recent echo, with a decrease in TAPSE Z‐score (Figure 2). On average, PVS progressed with an increase in severity score from 4 to 5 (p = 0.002). Hemodynamics were unchanged other than pulmonary blood flow, which decreased from baseline to the most recent cardiac catheterization. However, there was a small net left to right shunt on average in the cohort at baseline, and pulmonary blood decreased to mirror the cardiac index at the most recent cardiac catheterization. There were no differences in mPAP or PVRi from baseline to the most recent cardiac catheterization.
Table 4.
Change in echocardiographic parameters, hemodynamic data, and PVS severity/sidedness from baseline to the most recent cardiac catheterization.
| Baseline N = 31 | Most recent N = 31 | p value | |
|---|---|---|---|
| Echocardiographic parameters | |||
| TAPSE, cm | 0.95 (0.71, 1.10) | 1.21 (1.10, 1.60) | 0.001 |
| TAPSE Z‐score | −0.98 (−2.64, 1.86) | −2.31 (−4.40, 0.37) | 0.051 |
| RVFAC, % | 27.5 (24.8, 33.6) | 42.0 (35.7, 46.2) | < 0.001 |
| RVLS, % | −17.75 (−20.70, −13.05) | −25.00 (−26.30, −22.80) | < 0.001 |
| RVFWS, % | −21.10 (−24.25, −17.25) | −29.00 (−30.85, −26.10) | < 0.001 |
| Hemodynamic data | |||
| Age at cath, months | 5.6 (3.4, 9.4) | 27.6 (9.3, 60.3) | n/a |
| Mean RA, mm Hg | 7 (4, 8) | 6 (4, 8) | 0.618 |
| RV systolic, mm Hg | 57 (50, 70) | 47 (35, 59) | 0.099 |
| RV EDP, mm Hg | 8 (7, 10) | 8 (6, 10) | 0.560 |
| Mean PA, mm Hg | 36 (29, 47) | 30 (23, 40) | 0.161 |
| PCWP, mm Hg | 12 (8, 16) | 13 (10, 17) | 0.198 |
| Mean LA, mm Hg | 8 (6, 10) | 10 (8, 12) | 0.067 |
| Aortic, systolic, mm Hg | 71 (65, 90) | 80 (73, 85) | 0.616 |
| Aortic, diastolic, mm Hg | 39 (35, 43) | 42 (39, 49) | 0.383 |
| Aortic, mean, mm Hg | 53 (46, 62) | 56 (53, 64) | 0.386 |
| Qp, L/min/m2 | 5.3 (4.1, 6.7) | 4.1 (3.7, 5.5) | 0.011 |
| Qs or CI, L/min/m2 | 4.7 (3.9, 5.6) | 4.1 (3.7, 5.1) | 0.361 |
| PVRi, iWU | 4.1 (3.2, 8.0) | 3.9 (2.5, 7.8) | 0.284 |
| SVRi, iWU | 13.8 (10.0, 16.5) | 13.0 (7.8, 15.0) | 0.586 |
| PVS severity and sidedness | |||
| Severity score | 4.00 (3.00, 5.00) | 5.00 (3.00, 6.00) | 0.002 |
| Sidedness | 0.2 | ||
| Bilateral | 18/30 (60%) | 23/31 (74%) | |
| Unilateral | 12/30 (40%) | 8/31 (26%) | |
| Median (IQR) | |||
Abbreviations: CI, cardiac index; EDP, end diastolic pressure; FAC, fractional area change; FWS, free wall strain; iWU, indexed Wood unit; LA, left atrial; LS, longitudinal strain; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; PVRi, indexed pulmonary vascular resistance; QP, pulmonary blood flow; Qs, systemic blood flow; RA, right atrial; RV, right ventricular; SVRi, systemic vascular resistance; TAPSE, tricuspid annular plane systolic excursion.
Figure 2.
Change in RV FAC from baseline to the most recent is shown for a survivor (images A and B) and a non‐survivor (images C and D). At the most recent assessment, radial and longitudinal RV contraction are evident in the survivor, while the non‐survivor demonstrates longitudinal RV contraction but poor radial compensation.
When change in PVS severity score was controlled, improvements in TAPSE, RVFAC, RVLS, and RVFWS persisted (Table 5). TAPSE, RVFAC, and RVFWS improved both in patients with improved and with worsened PVS severity scores. RVLS improved in all patients regardless of improved, worsened, or unchanged PVS severity score. Changes in TAPSE Z‐score did not differ based on changes in PVS severity. Pulmonary capillary wedge pressure increased with worsened PVS severity score (p < 0.05). No other hemodynamic measures changed with PVS severity score.
Table 5.
Change in echocardiographic parameters and hemodynamic data from baseline to the most recent cardiac catheterization, controlling for change in PVS severity score.
| Improved | Worsened | No change | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Characteristic | Baseline N = 5 | Most recent N = 5 | p value | Baseline N = 18 | Most recent N = 18 | p value | Baseline N = 8 | Most recent N = 8 | p value |
| TAPSE, cm | 1.0 (0.9, 1.0) | 1.6 (1.4, 1.8) | 0.012 | 0.9 (0.8, 1.2) | 1.2 (1.1, 1.6) | 0.020 | 1.0 (0.6, 1.1) | 1.2 (1.1, 1.4) | 0.065 |
| Unknown | 0 | 0 | 1 | 2 | 0 | 0 | |||
| TAPSE Z‐Score | −0.68 (−2.20, 0.30) |
1.18 (0.93, 1.31) |
0.421 |
−1.63 (−2.54, 0.16) |
−2.95 (−4.91, −1.25) |
0.113 |
1.28 (−5.12, 3.09) |
−2.48 (−5.06, −0.21) |
0.328 |
| Unknown | 0 | 0 | 1 | 2 | 0 | 0 | |||
| RVFAC, % | 29.5 (26.5, 30.3) | 44.6 (41.6, 47.9) | 0.008 | 27.1 (22.6, 37.7) | 38.0 (30.8, 46.2) | 0.018 | 27.9 (22.6, 32.4) | 43.3 (32.5, 46.0) | 0.050 |
| Unknown | 0 | 0 | 2 | 2 | 0 | 0 | |||
| RVLS, % |
−15.45 (−18.40, −12.05) |
−26.80 (−27.40, −26.40) |
0.016 |
−18.15 (−22.55, −16.15) |
−24.15 (−25.65, −21.70) |
0.003 |
−17.40 (−19.35, −12.60) |
−25.20 (−26.25, −21.35) |
0.015 |
| Unknown | 1 | 0 | 2 | 2 | 0 | 0 | |||
| RVFWS, % |
−19.10 (−20.15, −16.60) |
−31.10 (−35.20, −28.75) |
0.029 |
−21.80 (−27.25, −17.95) |
−29.05 (−31.50, −24.75) |
0.006 |
−21.95 (−22.60, −16.15) |
−28.15 (−29.65, −23.40) |
0.083 |
| Unknown | 1 | 1 | 2 | 2 | 0 | 0 | |||
| Mean RA, mm Hg | 7 (5, 7) | 7 (5, 8) | 0.915 | 7 (4, 9) | 6 (4, 8) | 0.973 | 7 (5, 8) | 6 (5, 8) | 0.709 |
| Unknown | 0 | 0 | 0 | 1 | 0 | 0 | |||
| RV systolic, mm Hg | 45 (38, 55) | 43 (28, 50) | 0.623 | 60 (53, 70) | 53 (41, 68) | 0.283 | 50 (44, 82) | 40 (34, 49) | 0.112 |
| Unknown | 1 | 0 | 0 | 1 | |||||
| RV EDP, mm Hg | 9 (8, 15) | 8 (6, 11) | 0.532 | 8 (6, 11) | 7 (6, 10) | 0.947 | 7 (7, 9) | 9 (6, 10) | 0.872 |
| Unknown | 1 | 0 | 0 | 1 | |||||
| Mean PA, mm Hg | 28 (28, 36) | 25 (19, 34) | 0.402 | 37 (30, 47) | 34 (24, 53) | 0.438 | 40 (25, 47) | 27 (23, 33) | 0.103 |
| Unknown | 0 | 0 | 0 | 0 | 0 | 0 | |||
| PCWP, mm Hg | 12 (7, 17) | 10 (10, 11) | 0.802 | 10 (8, 14) | 15 (10, 19) | 0.043 | 20 (15, 21) | 13 (8, 15) | 0.061 |
| Unknown | 1 | 0 | 8 | 4 | 3 | 1 | |||
| Mean LA, mm Hg | 8 (7, 10) | 9 (8, 10) | 0.752 | 8 (6, 11) | 10 (9, 12) | 0.081 | 6 (6, 8) | 12 (6, 14) | 0.271 |
| Unknown | 0 | 0 | 2 | 5 | 3 | 1 | |||
|
Aortic, systolic, mm Hg |
74 (63, 93) | 78 (77, 80) | 0.623 | 71 (62, 89) | 82 (70, 90) | 0.528 | 77 (65, 90) | 80 (75, 84) | 0.748 |
| Unknown | 1 | 0 | 6 | 2 | 4 | 2 | |||
|
Aortic, diastolic, mm Hg |
38 (36, 45) | 45 (41, 49) | 0.387 | 39 (35, 45) | 41 (37, 49) | 0.528 | 42 (38, 43) | 44 (39, 48) | 0.285 |
| Unknown | 1 | 0 | 6 | 2 | 4 | 2 | |||
|
Aortic, mean, mm Hg |
50 (44, 64) | 56 (53, 63) | 0.556 | 52 (47, 62) | 57 (53, 66) | 0.329 | 56 (45, 62) | 57 (53, 61) | 0.669 |
| Unknown | 1 | 0 | 6 | 2 | 4 | 2 | |||
| Qp, L/min/m2 | 5.6 (4.8, 10.9) | 6.0 (4.3, 7.1) | 0.690 | 5.1 (3.7, 7.0) | 4.0 (3.7, 4.7) | 0.169 | 5.3 (4.5, 5.7) | 4.4 (3.9, 5.3) | 0.153 |
| Unknown | 0 | 0 | 3 | 0 | 2 | 1 | |||
| Qs or CI, L/min/m2 | 4.8 (4.7, 5.6) | 4.0 (3.8, 4.3) | 0.151 | 4.2 (3.5, 5.3) | 4.0 (3.7, 5.1) | 0.931 | 5.3 (4.5, 5.7) | 4.4 (3.9, 5.3) | 0.153 |
| Unknown | 0 | 0 | 2 | 0 | 2 | 1 | |||
| PVRi, iWU | 3.30 (3.10, 4.40) | 2.50 (2.10, 3.80) | 0.548 | 5.50 (3.20, 8.10) | 5.80 (3.10, 10.00) | 0.877 | 4.10 (3.40, 7.90) | 3.45 (2.50, 5.25) | 0.385 |
| Unknown | 0 | 0 | 1 | 1 | 1 | 0 | |||
| SVRi, iWU | NA (NA, NA) | NA (NA, NA) | 14.7 (10.8, 16.5) | 13.0 (7.8, 15.0) | 0.352 | 10.0 (10.0, 10.0) | NA (NA, NA) | ||
| Unknown | 5 | 5 | 12 | 11 | 7 | 8 | |||
Note: Median (IQR).
Abbreviations: CI, cardiac index; EDP, end diastolic pressure; FAC, fractional area change; FWS, free wall strain; iWU, indexed Wood unit; LA, left atrial; LS, longitudinal strain; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; PVRi, indexed pulmonary vascular resistance; QP, pulmonary blood flow; Qs, systemic blood flow; RA, right atrial; RV, right ventricular; SVRi, systemic vascular resistance; TAPSE, tricuspid annular plane systolic excursion.
Similar findings were demonstrated when controlling for PVS progression from unilateral to bilateral disease (Table 6). TAPSE, RVFAC, RVGS, and RVFWS improved in patients with stable disease (i.e., no progression in sidedness). Changes in TAPSE Z‐score were similar regardless of disease progression.
Table 6.
Change in echocardiographic parameters and hemodynamic data, controlling for progression in PVS from unilateral to bilateral disease.
| Progression from unilateral to bilateral a | No change | |||||
|---|---|---|---|---|---|---|
| Characteristic | Baseline N = 5 | Most recent N = 5 | p value | Baseline N = 25 | Most recent N = 25 | p value |
| TAPSE, cm | 1.0 (0.9, 1.1) | 1.3 (1.1, 1.4) | 0.171 | 1.0 (0.7, 1.1) | 1.2 (1.1, 1.6) | < 0.001 |
| Unknown | 0 | 1 | 1 | 0 | ||
| TAPSE Z‐Score | −1.66 (−2.33, −0.28) | −3.23 (−4.58, −1.50) | 0.286 | −0.73 (−3.00, 2.21) | −1.93 (−4.09, 0.93) | 0.246 |
| Unknown | 0 | 1 | 1 | 0 | ||
| RVFAC, % | 28.9 (26.6, 36.5) | 42.2 (36.6, 46.1) | 0.059 | 28.5 (24.8, 34.6) | 42.2 (36.6, 47.0) | < 0.001 |
| Unknown | 1 | 1 | 1 | 1 | ||
| RVLS, % | −18.75 (−21.20, −17.95) | −22.80 (−24.75, −19.00) | 0.486 | −17.70 (−21.30, −12.70) | −25.35 (−26.45, −23.45) | < 0.001 |
| Unknown | 1 | 1 | 2 | 1 | ||
| RVFWS, % | −22.20 (−25.10, −21.20) | −30.45 (−30.80, −25.45) | 0.191 | −20.90 (−24.40, −16.50) | −28.50 (−32.10, −26.30) | < 0.001 |
| Unknown | 1 | 1 | 2 | 2 | ||
| Mean RA, mm Hg | 9 (8, 12) | 6 (4, 8) | 0.211 | 6 (4, 7) | 6 (5, 8) | 0.688 |
| Unknown | 0 | 1 | 0 | 0 | ||
| RV systolic, mm Hg | 55 (50, 59) | 51 (43, 53) | 0.548 | 57 (49, 72) | 47 (34, 65) | 0.087 |
| Unknown | 0 | 0 | 1 | 1 | ||
| RV EDP, mm Hg | 8 (8, 13) | 9 (6, 9) | 0.523 | 8 (6, 10) | 7 (6, 10) | 0.950 |
| Unknown | 0 | 0 | 1 | 1 | ||
| Mean PA, mm Hg | 36 (30, 41) | 32 (23, 40) | 0.530 | 36 (28, 44) | 30 (23, 39) | 0.214 |
| Unknown | 0 | 0 | 0 | 0 | ||
| PCWP, mm Hg | 15 (11, 23) | 19 (6, 20) | > 0.999 | 11 (8, 15) | 13 (10, 15) | 0.456 |
| Unknown | 1 | 2 | 10 | 3 | ||
| Mean LA, mm Hg | 13 (11, 13) | 12 (11, 13) | > 0.999 | 7 (6, 8) | 9 (8, 12) | 0.010 |
| Unknown | 1 | 1 | 4 | 5 | ||
| Aortic, systolic, mm Hg | 69 (63, 82) | 71 (69, 73) | 0.805 | 69 (64, 89) | 80 (76, 85) | 0.139 |
| Unknown | 1 | 0 | 10 | 4 | ||
| Aortic, diastolic, mm Hg | 35 (35, 37) | 42 (34, 43) | 0.621 | 40 (37, 43) | 42 (39, 48) | 0.334 |
| Unknown | 1 | 0 | 10 | 4 | ||
| Aortic, mean, mm Hg | 49 (46, 54) | 53 (48, 55) | 0.556 | 54 (45, 64) | 58 (53, 63) | 0.183 |
| Unknown | 1 | 0 | 10 | 4 | ||
| Qp, L/min/m2 | 5.6 (5.5, 10.1) | 4.7 (4.1, 5.3) | 0.099 | 4.9 (3.8, 6.7) | 4.1 (3.8, 5.6) | 0.132 |
| Unknown | 2 | 0 | 3 | 1 | ||
| Qs or CI, L/min/m2 | 5.6 (5.5, 7.5) | 4.7 (4.1, 5.3) | 0.084 | 4.6 (3.8, 5.1) | 4.0 (3.8, 4.9) | 0.373 |
| Unknown | 1 | 0 | 3 | 1 | ||
| PVRi, iWU | 4.1 (3.8, 5.6) | 3.3 (2.1, 7.8) | 0.730 | 4.2 (3.0, 8.1) | 3.9 (2.6, 5.9) | 0.741 |
| Unknown | 1 | 0 | 1 | 1 | ||
| SVRi, iWU | 16.5 (16.5, 16.5) | 7.8 (7.8, 7.8) | > 0.999 | 10.8 (10.0, 13.8) | 14.0 (9.2, 15.0) | 0.927 |
| Unknown | 4 | 4 | 20 | 19 | ||
Note: Median (IQR).
Abbreviations: CI, cardiac index; EDP, end diastolic pressure; FAC, fractional area change; FWS, free wall strain; iWU, indexed Wood unit; LA, left atrial; LS, longitudinal strain; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; PVRi, indexed pulmonary vascular resistance; QP, pulmonary blood flow; Qs, systemic blood flow; RA, right atrial; RV, right ventricular; SVRi, systemic vascular resistance; TAPSE, tricuspid annular plane systolic excursion.
aSidedness could not be determined at baseline in one patient due to insufficient imaging.
Survivors (n = 24) demonstrated greater improvements in TAPSE, RVFAC, RVLS, and RVFWS from baseline to most recent echo compared to non‐survivors (n = 7) (Table 7). There were no statistically significant differences in the most recent echo findings between survivors and non‐survivors, although the higher RVFAC in survivors may be a clinically meaningful change.
Table 7.
Change in echocardiographic parameters stratified by survivor status.
| Alive | Deceased | ||||||
|---|---|---|---|---|---|---|---|
| Characteristic | Baseline N = 24 | Most recent N = 24 | p value a | Baseline N = 7 | Most recent N = 7 | p value a | p value b |
| TAPSE, cm | 1.0 (0.7, 1.2) | 1.3 (1.1, 1.7) | < 0.001 | 0.9 (0.7, 1.1) | 1.2 (1.0, 1.4) | 0.197 | 0.168 |
| Unknown | 1 | 0 | 0 | 1 | |||
| TAPSE Z‐Score | −0.68 (−2.64, 1.86) | −2.31 (−4.91, 0.37) | 0.115 | −2.33 (−3.35, 3.18) | −2.30 (−3.66, 1.31) | 0.836 | 0.422 |
| Unknown | 1 | 0 | 0 | 1 | |||
| RVFAC, % | 29.5 (24.8, 33.6) | 44.5 (37.4, 47.9) | < 0.001 | 25.8 (24.8, 39.4) | 34.5 (30.4, 41.6) | 0.180 | 0.090 |
| Unknown | 1 | 1 | 1 | 1 | |||
| RVLS, % | −17.9 (−20.1, −12.5) | −25.0 (−26.3, −22.8) | < 0.001 | −17.8 (−22.2, −15.0) | −24.7 (−26.5, −20.6) | 0.065 | 0.896 |
| Unknown | 2 | 1 | 1 | 1 | |||
| RVFWS, % | −21.1 (−23.1, −14.8) | −29.6 (−30.8, −27.1) | < 0.001 | −22.2 (−24.4, −19.8) | −26.1 (−34.2, −20.8) | 0.149 | 0.595 |
| Unknown | 2 | 2 | 1 | 1 | |||
Note: Median (IQR).
Abbreviations: FAC, fractional area change; FWS, free wall strain; LS, longitudinal strain; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion.
a p value for comparison between baseline and most recent echo findings in patients in the alive or deceased subgroup.
b p value for comparison of most recent echo findings in alive vs. deceased patients.
4. Discussion
In this selected retrospective single‐center case series, patients with PVS and PH treated with pulmonary vasodilators in the setting of a rigorous PVS surveillance and treatment protocol experienced few adverse events requiring medication discontinuation. Quantitative measures of RV systolic function by echocardiogram improved with pulmonary vasodilators plus treatment of recurrent or progressive PVS. Improvements in RV function were demonstrated across the range of PVS severity and were significantly greater in survivors. These preliminary data can inform future multi‐center studies of optimal patient selection, treatment timing, and long‐term outcomes in patients with PVS and PH treated with pulmonary vasodilators.
These findings demonstrate for the first time the potential benefit of pulmonary vasodilators in PVS, perhaps without the anticipated adverse events. While the prognosis for children with PVS remains suboptimal, recent trends suggest an improvement in 3‐year survival to 70% [23, 24, 25] compared with 49% in historical series [26, 27]. As PH is a risk factor for mortality in PVS, some improvement in survival may be attributable to PH treatment plus aggressive medical, surgical, or catheter‐based therapies for PVS. Widespread use of pulmonary vasodilators in PVS has been limited due to concern for pulmonary edema from increased pulmonary blood flow with fixed obstruction. However, only 1 patient in our series developed pulmonary edema requiring pulmonary vasodilator discontinuation very early in their treatment course. The low reported number of side effects in our sample suggests that these medications can be used in combination with an aggressive PVS treatment and surveillance protocol, but should be tested in larger series. Physiologically, one hypothesis of treatment success is that flow distribution to segments of the lung with unobstructed or less stenotic veins is optimized, avoiding pulmonary edema. This may be why patients with stable unilateral disease had improved RV function in our series.
The goals of pulmonary vasodilator therapy in PH are to maintain RV function, improve patient symptoms and functional status, and prevent RV failure. In a single‐center series of patients with PVS, mortality increased as RV pressure increased from sub‐systemic to supra‐systemic values both at initial and at last cardiac catheterization [28]. Mortality also increased as qualitative RV systolic function worsened in this study and another single‐center study [29]. The echocardiographic measures—TAPSE, FAC, and longitudinal and free wall strain (myocardial deformation)—that we studied in this series are associated with survival in other forms of PH, including Group 1 pre‐capillary PAH (idiopathic, heritable, congenital heart disease‐associated forms) and Group 3 lung disease‐related PH (due to BPD and congenital diaphragmatic hernia) [30, 31, 32, 33, 34]. Our study is the first to demonstrate improvements in these measures of RV function in patients with PVS treated with pulmonary vasodilators plus various PVS therapies, even when the PVS severity score increased. The data suggested that survivors demonstrated greater improvements in RV function compared to non‐survivors. This should be studied further in larger sample sizes.
Adult data on pulmonary vasodilator therapy in acquired LHD‐PH highlights the need for further study of PH in the setting of post‐capillary obstruction, like multivessel PVS. Randomized trials and metanalyses in LHD‐PH have shown no benefit, and some have suggested harm in using these agents [11, 12, 13, 16]. Single‐center studies of adults with Cpc‐PH treated with pulmonary vasodilators to target the arterial component demonstrate some improvement in clinical parameters [15] but possibly with increased mortality [14]. However, the variable severity of post‐capillary PH within each lobe of the lung (depending on the severity of PVS in each vein) separates pediatric intraluminal PVS from adult LHD‐PH where all lung segments experience the same left atrial hypertension [35] and may explain a different response to pulmonary vasodilators in children with PH and PVS compared to adults with LHD‐PH. Despite mixed data, pulmonary vasodilators are often trialed in both adult and pediatric practice. In a survey of practice patterns regarding LHD‐PH among pediatric PH providers, 75% said they would treat LHD‐PH to support the RV and delay irreversible pulmonary vascular disease, but only if there was a pre‐capillary component [36]. However, when asked when they considered pulmonary vasodilators to be contraindicated, nearly half of the respondents reported PVS. These real‐world responses demonstrate that further research is needed into the use of these medications in PH in the setting of PVS, especially as we found rare medication‐related adverse events.
Our study provides preliminary data for several areas of future study. First, optimal patient selection for pulmonary vasodilator therapy is challenging since pediatric patients with PVS rarely present with “isolated” PVS. Increased awareness of PVS associated with BPD—chronic lung disease of prematurity—has contributed to interest in using pulmonary vasodilators in these patients who also have risk factors for pulmonary arterial hypertension, vascular hypoplasia, and parenchymal lung disease [2]. Future studies should consider phenotypic subtypes of PVS that may benefit from pulmonary vasodilator therapy. Second, the mechanism of improved RV function in these patients deserves further attention. We demonstrated significant improvements in global function measured by RVFAC and RVLS and segmental free wall deformation measured by RVFWS with treatment, but smaller improvements in TAPSE, which did not correspond to a detectable change in TAPSE Z‐score. These findings should be studied further to determine whether compensatory improvement in radial RV function outweighs improvement in longitudinal RV function (measured by TAPSE) in PVS patients [37]. Finally, the role of acute vasoreactivity testing to guide therapy in pediatric PH and PVS deserves future attention. In our study, the percentage of patients with a positive response to AVT was lower than a prior report of patients with segmental pulmonary vascular disease [38], possibly since many patients had already been started on pulmonary vasodilators due to concern for other types of PH at the time of baseline PVS catheterization, affecting the response to AVT.
Our study has some important limitations. First, inference about causality is limited in a case series. RV function may improve with aggressive management of progressive or recurrent PVS, independent of pulmonary vasodilator treatment. Second, the retrospective nature of the study may have resulted in missing some medication adverse events that could have been carefully assessed in a prospective study. Third, both the lack of response to AVT and the lack of improvement in hemodynamics by cardiac catheterization with treatment may be due to the number of patients on pulmonary vasodilators at baseline PVS catheterization. Fourth, while this is the largest cohort to date to examine this question, the sample size is fixed, and type II error and unmeasured confounding are inevitably possible. We did not examine the results by era or include a control group of untreated patients. While PVS severity worsened from baseline to the most recent cardiac catheterization, this may not reflect current outcomes, as anecdotally, more patients seem to stabilize with the current management approaches. Patients treated in the last 5 years may have different outcomes compared to those from the beginning of the observation period, as there have been several additions to our routine management of PVS that have likely improved outcomes. These include aggressive catheter‐based interventions, improved echo protocols with quantitative measures of RV function, anti‐proliferative treatment with sirolimus, and treatment with pulmonary vasodilators. Comparing outcomes in multivessel PVS patients with and without pulmonary vasodilator treatment would not be a valid comparison, as insufficient sample size would limit the power to control for the multiple other factors that impact outcomes. Finally, the small sample size did not permit subgroup analyses comparing patients with isolated pre‐capillary PH versus Cpc‐PH or in those treated with sirolimus. Different hemodynamic phenotypes or treatment strategies may respond differently to pulmonary vasodilators.
In conclusion, pediatric patients with multivessel PVS and PH treated with pulmonary vasodilators may experience less pulmonary edema than anticipated. RV function may improve when these medications are used within a comprehensive follow‐up PVS treatment program. Future studies are needed to understand the mechanism of improved RV function and impact on mortality in PVS. The preferred echocardiographic method with which to follow these patients should include more than one plane of RV shortening.
Author Contributions
C.M.A. designed and executed the study and wrote the manuscript. K.B. performed data collection. A.M. performed statistical analyses. Y.W. and D.A. performed echocardiographic analyses. D.F.B., L.M.R., and M.L.O. interpreted study findings and edited the manuscript. R.C. contributed to the study design and edited the manuscript.
Ethics Statement
The Children's Hospital of Philadelphia Institutional Review Board determined the study met exemption criteria per 45 CFR 46.104(d) 4(iii).
Conflicts of Interest
The authors declare no conflicts of interest.
Guarantor
Catherine M. Avitabile, MD.
Acknowledgments
Funding source: NIH K23HL150337 to C.M.A. 100% of the project support was from federal funding. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- 1. Nasr V. G., Callahan R., Wichner Z., Odegard K. C., and DiNardo J. A., “Intraluminal Pulmonary Vein Stenosis in Children: A ‘New’ Lesion,” Anesthesia & Analgesia 129, no. 1 (July 2019): 27–40, 10.1213/ANE.0000000000003924. [DOI] [PubMed] [Google Scholar]
- 2. Vanderlaan R. D., “Improving Outcomes in Pulmonary Vein Stenosis: Novel Pursuits and Paradigm Shifts,” Seminars in Thoracic and Cardiovascular Surgery: Pediatric Cardiac Surgery Annual 27 (2024): 92–99, 10.1053/j.pcsu.2024.01.003. [DOI] [PubMed] [Google Scholar]
- 3. Rosenzweig E. B., Abman S. H., Adatia I., et al., “Paediatric Pulmonary Arterial Hypertension: Updates on Definition, Classification, Diagnostics and Management,” European Respiratory Journal 53, no. 1 (January 2019): 1801916, 10.1183/13993003.01916-2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Ivy D., Rosenzweig E. B., Abman S. H., et al., “Embracing the Challenges of Neonatal and Paediatric Pulmonary Hypertension,” European Respiratory Journal 64, no. 4 (October 2024): 2401345, 10.1183/13993003.01345-2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.(a)Abman S. H., Hansmann G., Archer S. L., et al.,American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension Guidelines From the American Heart Association and American Thoracic Society,” Circulation 132, no. 21 (2015): 2037–2099, 10.1161/CIR.0000000000000329. [DOI] [PubMed] [Google Scholar]; (b)Erratum in: Circulation 133, no. 4 (January 2016): e368, 10.1161/CIR.0000000000000363. [DOI]
- 6. Vachiéry J. L., Tedford R. J., Rosenkranz S., et al., “Pulmonary Hypertension Due to Left Heart Disease,” European Respiratory Journal 53, no. 1 (January 2019): 1801897, 10.1183/13993003.01897-2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Galiè N., McLaughlin V. V., Rubin L. J., and Simonneau G., “An Overview of the 6th World Symposium on Pulmonary Hypertension,” European Respiratory Journal 53, no. 1 (January 2019): 1802148, 10.1183/13993003.02148-2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Galiè N., Humbert M., Vachiery J. L., et al., “2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT),” European Respiratory Journal 46 (2015): 903–975, 10.1183/13993003.01032‐2015. [DOI] [PubMed] [Google Scholar]; (b)Erratum in: European Respiratory Journal 46, no. 6 (December 2015) 1855–1856, 10.1183/13993003.51032‐2015. [DOI] [PubMed]
- 9. Rosenkranz S., Gibbs J. S., Wachter R., et al., “Left Ventricular Heart Failure and Pulmonary Hypertension,” European Heart Journal 37, no. 12 (2016): 942–954, 10.1093/eurheartj/ehv512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Al‐Omary M. S., Sugito S., Boyle A. J., Sverdlov A. L., and Collins N. J., “Pulmonary Hypertension Due to Left Heart Disease: Diagnosis, Pathophysiology, and Therapy,” Hypertension 75, no. 6 (June 2020): 1397–1408, 10.1161/HYPERTENSIONAHA.119.14330. [DOI] [PubMed] [Google Scholar]
- 11. Cao J. Y., Wales K. M., Cordina R., Lau E. M. T., and Celermajer D. S., “Pulmonary Vasodilator Therapies Are of No Benefit in Pulmonary Hypertension Due to Left Heart Disease: A Meta‐Analysis,” International Journal of Cardiology 273 (December 2018): 213–220, 10.1016/j.ijcard.2018.09.043. [DOI] [PubMed] [Google Scholar]
- 12. Kido K. and Coons J. C., “Efficacy and Safety of the Use of Pulmonary Arterial Hypertension Pharmacotherapy in Patients With Pulmonary Hypertension Secondary to Left Heart Disease: A Systematic Review,” Pharmacotherapy: Journal of Human Pharmacology and Drug Therapy 39, no. 9 (September 2019): 929–945, 10.1002/phar.2314. [DOI] [PubMed] [Google Scholar]
- 13. Opitz C. F., Hoeper M. M., Gibbs J. S. R., et al., “Pre‐Capillary, Combined, and Post‐Capillary Pulmonary Hypertension,” Journal of the American College of Cardiology 68, no. 4 (July 2016): 368–378, 10.1016/j.jacc.2016.05.047. [DOI] [PubMed] [Google Scholar]
- 14. Moghaddam N., Swiston J. R., Tsang M. Y. C., Levy R., Lee L., and Brunner N. W., “Impact of Targeted Pulmonary Arterial Hypertension Therapy in Patients With Combined Post‐ and Precapillary Pulmonary Hypertension,” American Heart Journal 235 (May 2021): 74–81, 10.1016/j.ahj.2021.01.003. [DOI] [PubMed] [Google Scholar]
- 15. Belyavskiy E., Ovchinnikov A., Potekhina A., Ageev F., and Edelmann F., “Phosphodiesterase 5 Inhibitor Sildenafil in Patients With Heart Failure With Preserved Ejection Fraction and Combined Pre‐ and Postcapillary Pulmonary Hypertension: A Randomized Open‐Label Pilot Study,” BMC Cardiovascular Disorders 20, no. 1 (September 2020): 408, 10.1186/s12872-020-01671-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.(a)Hoeper M. M., Oerke B., Wissmüller M., et al., “Tadalafil for Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: A Randomized Controlled Phase 3 Study,” Circulation 150, no. 8 (2024): 600–610, 10.1161/CIRCULATIONAHA.124.069340. [DOI] [PubMed] [Google Scholar]; (b)Erratum in: Circulation 151, no. 11 (March 2025): e763, 10.1161/CIR.0000000000001321. [DOI]
- 17. Sitbon O., Humbert M., Jaïs X., et al., “Long‐Term Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension,” Circulation 111, no. 23 (June 2005): 3105–3111, 10.1161/CIRCULATIONAHA.104.488486. [DOI] [PubMed] [Google Scholar]
- 18. Sluysmans T. and Colan S. D., “Structural Measurements and Adjustment For Growth,” in Echocardiography in Pediatric and Congenital Heart Disease., eds. Lai W. W., Cohen M. S., Geva T., and Mertens L. (Wiley‐Blackwell, 2009), chapter 5. [Google Scholar]
- 19. Colan S. D., “Normal Echocardiographic Values for Cardiovascular Structures,” in Echocardiography in Pediatric and Congenital Heart Disease, eds. Lai W. W, Cohen M. S., Geva T., and Mertens L. (Wiley‐Blackwell, 2009), 765–785, Appendix I. [Google Scholar]
- 20. Koestenberger M., Friedberg M. K., Nestaas E., Michel‐Behnke I., and Hansmann G., “Transthoracic Echocardiography in the Evaluation of Pediatric Pulmonary Hypertension and Ventricular Dysfunction,” Pulmonary Circulation 6, no. 1 (March 2016): 15–29, 10.1086/685051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Levy P. T., Sanchez Mejia A. A., Machefsky A., Fowler S., Holland M. R., and Singh G. K., “Normal Ranges of Right Ventricular Systolic and Diastolic Strain Measures in Children: A Systematic Review and Meta‐Analysis,” Journal of the American Society of Echocardiography 27, no. 5 (May 2014): 549–560.e3, e3, 10.1016/j.echo.2014.01.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Callahan R., Gauvreau K., Keochakian M., et al., “Predicting Outcomes in Pediatric Intraluminal Pulmonary Vein Stenosis Using a Comprehensive Standardized Catheterization Assessment: A Prospective Study,” Circulations: Cardiovascular Interventions 18 (2025): e015002, 10.1161/CIRCINTERVENTIONS.124.015002. [DOI] [PubMed] [Google Scholar]
- 23. Callahan R., Kieran M. W., Baird C. W., et al., “Adjunct Targeted Biologic Inhibition Agents to Treat Aggressive Multivessel Intraluminal Pediatric Pulmonary Vein Stenosis,” Journal of Pediatrics 198 (July 2018): 29–35.e5, 10.1016/j.jpeds.2018.01.029. [DOI] [PubMed] [Google Scholar]
- 24. Patel J. D., Briones M., Mandhani M., et al., “Systemic Sirolimus Therapy for Infants and Children With Pulmonary Vein Stenosis,” Journal of the American College of Cardiology 77, no. 22 (June 2021): 2807–2818, 10.1016/j.jacc.2021.04.013. [DOI] [PubMed] [Google Scholar]
- 25. Kalfa D., Belli E., Bacha E., et al., “Primary Pulmonary Vein Stenosis: Outcomes, Risk Factors, and Severity Score in a Multicentric Study,” Annals of Thoracic Surgery 104, no. 1 (July 2017): 182–189, 10.1016/j.athoracsur.2017.03.022. [DOI] [PubMed] [Google Scholar]
- 26. Seale A. N., Webber S. A., Uemura H., et al., “Pulmonary Vein Stenosis: The UK, Ireland and Sweden Collaborative Study,” Heart 95, no. 23 (December 2009): 1944–1949, 10.1136/hrt.2008.161356. [DOI] [PubMed] [Google Scholar]
- 27. Viola N., Alghamdi A. A., Perrin D. G., Wilson G. J., Coles J. G., and Caldarone C. A., “Primary Pulmonary Vein Stenosis: The Impact of Sutureless Repair on Survival,” Journal of Thoracic and Cardiovascular Surgery 142, no. 2 (August 2011): 344–350, 10.1016/j.jtcvs.2010.12.004. [DOI] [PubMed] [Google Scholar]
- 28. Sykes M. C., Ireland C., McSweeney J. E., Rosenholm E., Andren K. G., and Kulik T. J., “The Impact of Right Ventricular Pressure and Function on Survival in Patients With Pulmonary Vein Stenosis,” Pulmonary Circulation 8, no. 2 (April/June 2018): 1–6, 10.1177/2045894018776894. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.(a)Takajo D., Critser P. J., Cash M., Magness M., and Hirsch R., “Mortality Patterns in Pediatric Pulmonary Vein Stenosis: Insights Into Right Ventricular Systolic Pressure Associations,” Journal of the American Heart Association 14, no. 2 (2025): e037908, 10.1161/JAHA.124.037908. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b)Erratum in: Journal of American Heart Association 18, no. 14 (March 2025): e035037, 10.1161/JAHA.124.035037. [DOI]
- 30. Ploegstra M. J., Roofthooft M. T., Douwes J. M., et al., “Echocardiography in Pediatric Pulmonary Arterial Hypertension: Early Study on Assessing Disease Severity and Predicting Outcome,” Circulation: Cardiovascular Imaging 8, no. 1 (December 2014): e000878, 10.1161/CIRCIMAGING.113.000878. [DOI] [PubMed] [Google Scholar]
- 31. Bitterman Y., Hauck A., Manlhiot C., et al., “Serial Assessment of Tricuspid Annular Plane Systolic Excursion Is Associated With Death or Lung Transplant in Children With Pulmonary Arterial Hypertension,” Journal of the American Society of Echocardiography 34, no. 12 (December 2021): 1320–1322, 10.1016/j.echo.2021.08.015. [DOI] [PubMed] [Google Scholar]
- 32. Okumura K., Humpl T., Dragulescu A., Mertens L., and Friedberg M. K., “Longitudinal Assessment of Right Ventricular Myocardial Strain in Relation to Transplant‐Free Survival in Children With Idiopathic Pulmonary Hypertension,” Journal of the American Society of Echocardiography 27, no. 12 (December 2014): 1344–1351, 10.1016/j.echo.2014.09.002. [DOI] [PubMed] [Google Scholar]
- 33. Altit G., Bhombal S., Feinstein J., Hopper R. K., and Tacy T. A., “Diminished Right Ventricular Function at Diagnosis of Pulmonary Hypertension Is Associated With Mortality in Bronchopulmonary Dysplasia,” Pulmonary Circulation 9, no. 3 (October 2019): 1–11, 10.1177/2045894019878598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Avitabile C. M., Wang Y., Zhang X., et al., “Right Ventricular Strain, Brain Natriuretic Peptide, and Mortality in Congenital Diaphragmatic Hernia,” Annals of the American Thoracic Society 17, no. 11 (November 2020): 1431–1439, 10.1513/AnnalsATS.201910-767OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Sokoliuk V., DiNardo J. A., and Brown M. L., “Never Say Never: The Use of Nitric Oxide in Patients With Obstructed Pulmonary Veins: A Case Report,” A&A Practice 12, no. 6 (March 2019): 205–207, 10.1213/XAA.0000000000000885. [DOI] [PubMed] [Google Scholar]
- 36. Nawaytou H., Fineman J. R., Moledina S., Ivy D., Abman S. H., and Del Cerro M. J., “Practice Patterns of Pulmonary Hypertension Secondary to Left Heart Disease Among Pediatric Pulmonary Hypertension Providers,” Pulmonary Circulation 11, no. 1 (February 2021): 1–8, 10.1177/2045894021991446. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Kind T., Mauritz G. J., Marcus J. T., van de Veerdonk M., Westerhof N., and Vonk‐Noordegraaf A., “Right Ventricular Ejection Fraction Is Better Reflected by Transverse Rather Than Longitudinal Wall Motion in Pulmonary Hypertension,” Journal of Cardiovascular Magnetic Resonance 12, no. 1 (June 2010): 35, 10.1186/1532-429X-12-35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Domingo L., Magdo H. S., and Day R. W., “Acute Pulmonary Vasodilator Testing and Long‐Term Clinical Course in Segmental Pulmonary Vascular Disease,” Pediatric Cardiology 39, no. 3 (March 2018): 501–508, 10.1007/s00246-017-1780-9. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.