Pediatric Pulmonary Hypertension in Left-Sided Heart Disease

INTRODUCTION

Pulmonary hypertension (PH) is a rare disease in children and is associated with significant morbidity and mortality.¹ Data from various registries have shown that 6th World Symposium of Pulmonary Hypertension (WSPH) group I and group III are the commonest forms; however, group II PH in pediatric patients has achieved increasing recognition in the two more recent WSPH classifications of PH.^2,3 PH from left-sided heart disease (group II PH) results when left heart pathology transmits passive hydrostatic pressure to the pulmonary vascular tree, first to the post–alveolar-capillary pulmonary venous system and then to the pre–alveolar-capillary pulmonary arterial system.^4,5

Although epidemiologic data in pediatric patients are limited, group II PH is becoming increasingly common, accounting for 5% to 14% of cases of pediatric PH.^2,5,6 While left ventricular (LV) systolic dysfunction is the primary cause of PH in adults, pediatric group II PH can be secondary to obstruction at any level of the left heart, including pathology of the pulmonary veins or the mitral or left atrioventricular valve (LAVV), LV systolic or diastolic dysfunction, or LV outflow tract ­obstruction.^7,8 These lesions can occur in isolation or in combination with each other, such as in Shone complex, and can progress and worsen over time.⁹

Group II PH can be further subdivided into two categories: postcapillary PH and combined precapillary and postcapillary PH (Cpc-PH).⁸ Elevations in left-sided pressures lead to distension and endothelial disruption of the post–alveolar-capillary vasculature, resulting in remodeling, including smooth muscle proliferation and intimal and medial thickening.⁸ The pulmonary veins, which normally lack a significant muscular medial layer, develop histologic features resembling pulmonary arterioles. This vascular remodeling helps mitigate the backward transmission of elevated left-sided pressures, at the expense of increased resistance to the left atrium (LA) leading to increased mean pulmonary artery (mPA) pressure and so-called postcapillary PH. Cpc-PH occurs with chronic elevations in left-sided pressures, which, if not adequately addressed, results in the remodeling of the pulmonary arterial system, including hypertrophy, fibrosis, thrombosis, and an increase in resistance in the pulmonary vasculature.¹⁰

Both isolated group II PH and Cpc-PH share common hemodynamic definitions reflective of the underlying pathophysiology, including mPA pressure of ≥20 mm Hg and pulmonary capillary wedge pressure (PCWP) of ≥15 mm Hg. Cpc-PH is further differentiated from isolated postcapillary PH by hemodynamic measurements reflective of increased pulmonary vascular resistance, either a transpulmonary gradient (TPG) of ≥7 mm Hg or an indexed pulmonary vascular resistance (PVRi) of ≥3 Wood units · m² (WU m²).² Given the high prevalence of group II PH in adult populations, the most recent European Society of Cardiology/Respiratory Society adult guidelines have lowered the threshold for the diagnosis of Cpc-PH to a PVR of >2 WU; however, these criteria have not yet been adopted for pediatric populations.¹¹

GENERAL APPROACH

Evaluation and management of group II PH are largely dependent on the underlying etiology of left heart disease, and much of the current understanding of this physiology comes from experience in adult populations with left heart failure and either a preserved or reduced ejection fraction. The use of pulmonary vasodilators in adult as well as pediatric group II PH varies by center without a single unifying strategy, and treatment is considered off-label due to the lack of supporting data. Central to the management of pediatric group II PH is the timely identification and surveillance of the underlying lesion and the reduction of the hydrostatic pressure in the alveolar capillary bed while monitoring for signs of worsening pulmonary edema.

Echocardiography

Echocardiography can be pivotal in the diagnosis of group II PH. A complete and thorough anatomic assessment is essential to evaluate all lesions contributing to group II PH.^2,3,12 Echocardiographic assessment, including color Doppler, can be used to evaluate for LAVV stenosis or regurgitation, aortic stenosis (AS), aortic hypoplasia, or coarctation of aorta (CoA). Each echocardiogram for a patient with concern for PH should include a thorough evaluation of all four pulmonary veins as pulmonary vein stenosis (PVS) has a variable onset and can be progressive. Qualitative and quantitative function assessments, including LV strain measurements, are necessary to evaluate for LV systolic dysfunction. Diastolic function may be difficult to fully assess using echocardiography but can be supported by abnormalities of left atrial size, tissue Doppler velocity of the LAVV lateral annulus, and/or pulsed-wave Doppler profile of the LAVV inflow.¹⁵

Echocardiography can provide an estimate of right ventricular (RV) and pulmonary artery pressure with a combination of the interventricular septal position, tricuspid regurgitation jet, and pulmonary regurgitation jet, as well as evaluating for RV systolic dysfunction.³ A comprehensive list of echocardiographic parameters as part of group II PH assessment is included in Table 1.

Table 1. Echocardiographic Parameters and Measurements Included as Part of the Evaluation of Pediatric Group II Pulmonary Hypertension

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PULMONARY VEIN STENOSIS

PVS is an emerging cause of both left-sided obstructive disease and PH with increased survival of infants born extremely preterm.²³ PVS can be either primary, affecting normally draining pulmonary veins, or secondary to anomalous pulmonary venous return that has been surgically repaired, with stenosis at the anastomosis site or in the distal veins. The underlying pathobiology of primary PVS is poorly understood and is likely multifactorial with known associations with prematurity and comorbid conditions, including bronchopulmonary dysplasia and necrotizing enterocolitis.^23,24

Primary PVS is a heterogeneous disease characterized by neointimal proliferation at the area of stenosis. Disease can range from discrete stenosis at the venoatrial junction to diffuse hypoplasia of the extrapulmonary pulmonary veins. PVS can involve one or more pulmonary veins and is often progressive, needing recurrent interventions, with high morbidity and mortality rates.^23–25 Due to its progressive nature, early identification using echocardiography is key. Computed tomography (CT) can be used to further evaluate the extent and location of vein stenosis or evidence of obliteration or atresia. Noninvasive imaging can underestimate pressure gradients, and cardiac catheterization is the gold standard for diagnosis. Catheterization can identify stenoses with angiography, directly measure pressure gradients, and allow for balloon angioplasty with or without stent placement.

Medications, including the mTOR inhibitor sirolimus, have been shown to slow the progression of the disease as well as improve rates of in-stent stenosis and neointimal proliferation.²⁶ Current surgical approaches for repair, including the so-called “sutureless repair,” have led to improvements in rates of restenosis and mortality.²⁵ Current management strategies with frequent surveillance catheterizations and interventions every 6 to 8 weeks have improved long-term outcomes; however, mortality rates 5 years from diagnosis remain as high as 40%.²⁷

COR TRIATRIATUM SINISTER

Cor triatriatum sinister is a rare congenital anomaly whereby an accessory membrane separates the LA into two chambers: a posterior chamber that receives blood flow from the pulmonary veins and an anterior chamber that drains across the LAVV into the LV. Restriction across this membrane prevents effective inflow into the LA and, if not addressed, can progress to group II PH. In severe cases, presentation can be early; however, in some cases, symptomatology can be vague, and diagnosis can be delayed well into adulthood.²⁸ Echocardiography is used to accurately make the diagnosis, and definitive treatment involves surgical resection of the intra-atrial membrane and is associated with favorable long-term outcomes with low rates of restenosis.

LEFT ATRIOVENTRICULAR VALVE OR MITRAL STENOSIS

Stenosis of the LAVV can occur in isolation or in combination with additional left-sided obstructive lesions, such as in Shone complex. LAVV stenosis can either be congenital or occur following repair of the LAVV.²⁹ These patients can develop group II PH with symptoms of pulmonary vascular congestion, hypoxia, or even syncope. Postrepair, there can be persistent PH, and overzealous vasodilator therapy may result in pulmonary vascular congestion and pulmonary edema.³⁰ Echocardiography can estimate mean pressure gradients across the LAVV, which can be further delineated by cardiac catheterization. Surgical repair by either valvuloplasty or valve replacement can have an effective result in lowering mPA pressure, with favorable outcomes.³¹

SHONE COMPLEX

Shone complex is a constellation of left-sided obstructive lesions, including LAVV stenosis with a supramitral ring, parachute LAVV, subaortic or aortic valve stenosis, and CoA. The extent and location of obstruction can be variable, and the degree of LAVV stenosis is one of the primary predictors of disease prognosis.⁹ Compared to isolated congenital LAVV stenosis, the concomitant LV outflow tract obstruction seen in Shone complex, combined with a potentially hypoplastic or noncompliant LV, further exacerbates left-sided disease and increases the risk of group II PH. Additional reoperations and reinterventions also carry a risk of worsening diastolic dysfunction on what can often already be a dysfunctional LV. PH in Shone complex is a risk factor for reintervention and worsened outcomes.³²

Repair is typically staged, with repairs of the aortic arch occurring earlier in infancy and delaying intervention on the LAVV until the patient reaches a favorable size for LAVV intervention. Close surveillance is needed to identify recurrent or worsening obstructive lesions and the development of atrial arrhythmias.

LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC DYSFUNCTION

LV dysfunction is the most common form of PH in adults and is becoming an increasingly recognized cause in pediatric patients.³ LV dysfunction can be either systolic, diastolic, or a combination of the two. It can be secondary to dilated or restrictive cardiomyopathy or myocarditis, or it can occur following surgical repair of congenital heart disease.^2,3

Echocardiography should be used for both qualitative and quantitative assessments of LV function. Careful assessment for reversible causes of LV dysfunction, such as coronary anomalies, should be performed. LV diastolic dysfunction leading to PH should be further evaluated using cardiac catheterization prior to therapy.^12,16 Catheterization allows for measurements of the PCWP and LV end-diastolic pressure and direct measurements of the cardiac index and PVRi. In patients with severe dysfunction requiring heart transplantation, a lowered PVRi following acute vasodilator testing can inform transplant candidacy and prognosis.³³

Treatment of group II PH and LV dysfunction with pulmonary vasodilators has been studied in both animal models and adult clinical trials, but data are limited for pediatric patients. Sildenafil can promote LV remodeling in heart failure as well as improvements in LV systolic and diastolic performance.³⁴ Sildenafil has been associated with improvements in echocardiographic indices of PH in adults with LV dysfunction and is largely tolerated in pediatric patients when administered with careful, in-hospital titration.³⁵ Despite these findings, clinical trials show conflicting results for sildenafil with respect to its impact on clinical status, quality of life, or symptomatology.^18–20 The guanylate cyclase stimulator riociguat has also demonstrated improved hemodynamics in heart failure, without any difference in clinical symptoms.³⁶ Given the conflicting evidence and potential for harm, current guidelines recommend against the use of pulmonary vasodilator therapy in group II PH from LV dysfunction, and any use in pediatric populations is considered off-label.¹¹ In patients with severe LV dysfunction, ventricular assist devices have been utilized to decompress the left heart, either as a bridge to heart transplantation or as destination therapy.³⁷

AORTIC STENOSIS

AS is an uncommon cause of group II PH in children and is typically a late finding from decompensated heart failure. AS can be congenital, secondary to a bicuspid or even unicuspid aortic valve, or acquired secondary to rheumatic heart disease.³⁸ While clinically significant PH is uncommon, congenital AS is associated with remodeling and arterialization of the pulmonary venous vasculature, both in utero and in the early neonatal period.³ This is likely due to changes in LV compliance in the setting of increased afterload, which can significantly improve following successful aortic valve intervention.³⁹ Balloon aortic valvuloplasty is often an initial transcatheter option for the treatment of congenital AS; however, in patients with more severe or long-standing disease, surgery with aortic valve repair or replacement is indicated.³⁸

CONCLUSION

The management of group II PH can be extremely challenging due to the wide array of contributing left-sided lesions that lead to it. Management is directed toward correcting the left-sided lesions, treating volume overload with diuretics, and, in very select cases, targeted PH therapy. While the importance of reducing left-sided pressures and the underlying left-sided lesion is well known, an individualized approach is vital to appropriately manage each patient with group II PH.