Pharmacologic Management of Segmental Pulmonary Hypertension in Children After Unifocalization and Pulmonary Artery Reconstruction: Initial Experience

Abstract

Segmental pulmonary hypertension (PH) in congenital heart disease remains poorly understood with data limited to case studies. We performed a retrospective, single center study in children treated with PH medications after unifocalization/pulmonary artery reconstruction for major aortopulmonary collaterals (MAPCA). Drug response was determined by hemodynamic changes across at least two cardiac catheterizations. Mechanical properties of the segmental arteries were quantified by distensibility, stiffness, and augmentation indices. Twenty-five patients were included (8 surgical shunt, 17 complete repair), with 76% considered responsive to PH medications based on the relative decrease in maximum segmental mean pulmonary artery pressure (mPAP). At a median duration of 14 months (Q1-Q3 9.5-29), mPAP decreased from 33 mmHg (28-38) to 23 mmHg (21-32) (p < 0.001) with no significant change in blood flow distribution by lung perfusion scintigraphy. Subgroup analysis demonstrated a trend towards a larger percent decrease in mPAP of 35% (18-45) on dual therapy compared to 23% (Q1-Q3 3-36) on monotherapy (p = 0.16). In repaired patients, arterial distensibility at initial catheterization correlated with residual elevation in mPAP at follow-up (R ² 0.687, p < 0.001), with distensibility < 1.7%/mmHg associated with treatment failure. Among the lowest distensibility values were patients with JAG1 mutations, and among patients with extended follow-up, progressive increase in mPAP was identified only in those with hereditary PH-associated mutations. Children with segmental PH following pulmonary artery reconstruction can be successfully treated with PH medications. Although treatment efficacy may be limited in patients with high vascular stiffness and those with pathologic vascular mutations.

Keywords: MAPCA; Tetralogy of Fallot; congenital heart disease; genetics; vascular stiffness.

Figure 1

Flow Diagram of patient screening for study inclusion Primary Interval encompasses the time between first and second cardiac catheterizations. Secondary Interval is between the second and third catheterizations for a smaller number of patients with extended follow‐up. Of eight shunt patients at the start of the study, seven underwent repair following treatment, two of whom had a third catheterization.

Figure 2

Maximum segmental mean pulmonary artery pressure (mPAP) at initial and follow‐up cardiac catheterization. (A) Box plot of mPAP at Cath 1, 2 and 3 of the entire cohort following targeted PH treatment. (B) Parallel plot of mPAP at Cath 1, 2, and 3, differentiated by genetic mutation category. Left panel includes patients with mutations not‐associated with vascular dysfunction such as 22q11 deletion, those with normal genetic testing, or those without genetic testing. Right panel includes patients with vascular related mutations including JAG1 due to its association with macrovascular disease, and mutations in BMPR2 and KDR associated with hereditary pulmonary arterial hypertension (HPAH). Lines in blue represent shunted patients.

Figure 3

Change in maximum segmental mean pulmonary artery pressure (mPAP) by surgical stage Patients highlighted in red are those identified as non‐responders to medical therapy based on study criteria with a considerably higher proportion of non‐responders in the repair group. HPAH = hereditary pulmonary arterial hypertension.

Figure 4

Change in relative perfusion to the single lung with the lowest initial percent flow before and after treatment over the primary interval, separated by surgical stage (N = 19). LPS = lung perfusion scintigraphy.

Figure 5

Correlation by linear regression between distensibility measured at initial cardiac catheterization with (Top) mean pulmonary artery pressure (mPAP) and (Bottom) transpulmonary gradient (TPG) measured at follow‐up catheterization.

Figure 6

Box plot including individual observations depicting the percent change in maximum segmental mean pulmonary artery pressure (mPAP) over the primary interval between monotherapy and combination therapy among an adjusted subgroup.