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Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension.

ABSTRACT: Pulmonary hypertension (PH) causes significant morbidity and mortality in children due to right ventricular (RV) failure. We sought to determine the effect of prostacyclin analogues on RV function assessed by echocardiography in children with PH. We conducted a retrospective cohort study of children with PH treated with a prostacyclin analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at our center. Data were collected before initiation of treatment (baseline) and at 1-3 and 6-12 months after. Protocolized echocardiogram measurements including tricuspid annular plane systolic excursion (TAPSE) and RV global longitudinal strain were made with blinding to clinical information. Forty-nine individuals (65% female), aged 0-29 years at the time of prostacyclin initiation were included. Disease types included pulmonary arterial hypertension (idiopathic [35%], heritable [2%], and congenital heart disease-associated [18%]), developmental lung disease (43%), and chronic thromboembolic PH (2%). Participants received intravenous (IV) epoprostenol (14%) and IV/subcutaneous (SQ) (67%) or inhaled (18%) treprostinil. Over the study period, prostacyclin analogues were associated with improvement in TAPSE ( P?=?0.007), RV strain ( P?

SUBMITTER: Hopper RK

PROVIDER: S-EPMC5843105 | biostudies-literature | 2018 Apr-Jun

REPOSITORIES: biostudies-literature

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Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension.

Hopper Rachel K RK Wang Yan Y DeMatteo Valerie V Santo Ashley A Kawut Steven M SM Elci Okan U OU Hanna Brian D BD Mercer-Rosa Laura L

Pulmonary circulation 20180226 2

Pulmonary hypertension (PH) causes significant morbidity and mortality in children due to right ventricular (RV) failure. We sought to determine the effect of prostacyclin analogues on RV function assessed by echocardiography in children with PH. We conducted a retrospective cohort study of children with PH treated with a prostacyclin analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at our center. Data were collected before initiation of treatment (baseline) and at 1- ...[more]

PMID: 29480089

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Project description:Right ventricular (RV) pressure overload has a vastly different clinical course in children with idiopathic pulmonary arterial hypertension (iPAH) than in children with pulmonary stenosis (PS). While RV function is well recognized as a key prognostic factor in iPAH, adverse ventricular-ventricular interactions and LV dysfunction are less well characterized and the pathophysiology is incompletely understood. We compared ventricular-ventricular interactions as hypothesized drivers of biventricular dysfunction in pediatric iPAH versus PS Eighteen iPAH, 16 PS patients and 18 age- and size-matched controls were retrospectively studied. Cardiac cycle events were measured by M-mode and Doppler echocardiography. Measurements were compared between groups using ANOVA with post hoc Dunnet's or ANCOVA including RV systolic pressure (RVSP; iPAH 96.8 ± 25.4 mmHg vs. PS 75.4 ± 18.9 mmHg; P = 0.011) as a covariate. RV-free wall thickening was prolonged in iPAH versus PS, extending beyond pulmonary valve closure (638 ± 76 msec vs. 562 ± 76 msec vs. 473 ± 59 msec controls). LV and RV isovolumetric relaxation were prolonged in iPAH (P < 0.001; LV 102.8 ± 24.1 msec vs. 63.1 ± 13.7 msec; RV 95 [61-165] vs. 28 [0-43]), associated with adverse septal kinetics; characterized by rightward displacement in early systole and leftward displacement in late RV systole (i.e., early LV diastole). Early LV diastolic filling was decreased in iPAH (73 ± 15.9 vs. PS 87.4 ± 14.4 vs. controls 95.8 ± 12.5 cm/sec; P = 0.004). Prolonged RVFW thickening, prolonged RVFW isovolumetric times, and profound septal dyskinesia are associated with interventricular mechanical discoordination and decreased early LV filling in pediatric iPAH much more than PS These adverse mechanics affect systolic and diastolic biventricular efficiency in iPAH and may form the basis for worse clinical outcomes. We used clinically derived data to study the pathophysiology of ventricular-ventricular interactions in right ventricular pressure overload, demonstrating distinct differences between pediatric pulmonary arterial hypertension (iPAH) and pulmonary stenosis (PS). Altered timing of right ventricular free wall contraction and profound septal dyskinesia are associated with interventricular mechanical discoordination and decreased early LV filling in iPAH much more than PS These adverse mechanics affect systolic and diastolic biventricular efficiency, independent of right ventricular systolic pressure.

Project description:Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR). Optimizing treatment strategies and timing for transplant remains challenging. Thus, a quantitative measure to predict disease progression would be greatly beneficial in treatment planning. We devised a novel method to assess right ventricular (RV) stroke work (RVSW) as a potential biomarker of the failing heart that correlates with clinical worsening. Pediatric patients with idiopathic PAH or PAH secondary to congenital heart disease who had serial, temporally matched cardiac catheterization and magnetic resonance imaging (MRI) data were included. RV and PA hemodynamics were numerically determined by using a lumped parameter (circuit analogy) model to create pressure-volume (P-V) loops. The model was tuned using optimization techniques to match MRI and catheterization derived RV volumes and pressures for each time point. RVSW was calculated from the corresponding P-V loop and indexed by ejection fraction and body surface area (RVSWEF) to compare across patients. Seventeen patients (8 boys; median age = 9.4 years; age range = 4.4-16.3 years) were enrolled. Nine were clinically stable; the others had clinical worsening between the time of their initial matched studies and their most recent follow-up (mean time = 3.9 years; range = 1.1-8.0 years). RVSWEF and the ratio of pulmonary to systemic resistance (Rp:Rs) values were found to have more significant associations with clinical worsening within one, two, and five years following the measurements, when compared with PVR index (PVRI). A receiver operating characteristic analysis showed RVSWEF outperforms PVRI, Rp:Rs and ejection fraction for predicting clinical worsening. RVSWEF correlates with clinical worsening in pediatric PAH, shows promising results towards predicting adverse outcomes, and may serve as an indicator of future clinical worsening.

Project description:Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague-Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure-volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.

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Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension.

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Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension.

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