Sage Journals: Discover world-class research

Abstract

The many types of pulmonary hypertension (PH) are so protean in their biological origin, histological expression, and natural history that it is difficult to create a summary picture of the disease, or to easily compare and contrast characteristics of one type of PH with another. For newcomers to the field, however, such a picture would facilitate a broad understanding of PH. In this paper, we suggest that four characteristics are fundamental to describing the nature of various types of PH, and that taken together they define a number of patterns of PH expression. These characteristics are histopathology, developmental origin, associated clinical conditions, and potential for resolution. The “snapshot” is a way to concisely display the ways that these signal characteristics intersect in select specific types of PH, and is an effort to summarize these patterns in a way that facilitates a “big picture” comprehension of this disease.

Keywords

pulmonary hypertension (PH)review development characteristics

Introduction

Pulmonary hypertension (PH) is a disease of striking variety in its clinical and biological features,^1–3 much more so than systemic hypertension, which shows much less variability in the histopathology, fewer associated conditions, and developmental links.⁴ One catalogue of its many origins and associated conditions includes 113 types of PH, and this list will surely accrete with time.⁵ Existing classification schemes bring some order to this tangle,^2,5 but do not incorporate certain key characteristics of PH, nor emphasize the distinct patterns of PH expression—i.e. the ways that PH can be (e.g. rooted in early development versus late developing; idiopathic versus with associated cause; self-resolving versus progressive). The notion which underlies the summary diagram (“snapshot”) offered here is that there are four characteristics which are fundamental to describing the nature of various types of PH, and that taken together they define a number of patterns of PH expression (Table 1 and Fig. 1). These characteristics are histopathology, developmental origin, associated clinical conditions, and potential for resolution. They relate to the pathobiology of the disease, and two are also of major clinical importance (associated clinical conditions and potential for resolution). The snapshot is a way to concisely display the ways that these signal characteristics intersect in select specific types of PH, and is an effort to economically summarize these patterns in a way that facilitates a “big picture” comprehension of this disease, especially for those new to the field (Fig. 2). The snapshot does not aspire to be the I Ching of PH: it is sharply focused on concisely displaying these four key PH characteristics and is not a comprehensive survey of the field. It is based on observations in humans and little incorporates information developed from experimental models. The sheer quantity of such material prevents its inclusion, its application to human disease is often unclear,⁶ and since only fragments of pathological pathways have been thus far discerned their inclusion seems premature.

Table 1.

Summary of the characteristics which constitute the pattern of PH expression.

Characteristic	Comments
Histopathology	Six histopathological types described
Developmental origin	Four developmental phases described: 1. Fetal (D1) 2. Neonatal transition (D2) 3. Developmental (D3) 4. Post-developmental (PD)
Associated clinical conditions	Diseases (e.g. portal hypertension) or physiological abnormality (e.g. pulmonary venous hypertension) associated with increased risk of PH
Potential for resolution	Potential for pulmonary artery pressure to reduce to or nearly to normal spontaneously, or after a brief period of therapy, or after the inciting stimulus is removed

Fig. 1.

For each type of PH, four characteristics are used to describe the pattern of PH expression.

Fig. 2.

PH snapshot. The background color for the various types of PH (leftward most column) denotes the histopathology, while the color in the columns specifying the developmental period indicates whether the type of PH is potentially reversible.

Definitions and assumptions

Histopathological types

The nature of various types of PH is revealed in part by their microarchitecture, which we divide into histopathological types 1–6.⁷ Types T1–3 are derived from the standard approach to classifying pathological changes, where the architecture of small pulmonary arteries (PAs) and pulmonary veins (PV) is emphasized. Admittedly, these descriptions are incomplete, e.g. the number of PAs is seldom included in histological reports, although a reduction in their number is a component of many types of PH,^8–10 some structural features (e.g. pulmonary artery–systemic shunt pathways¹¹ and adventitial thickness¹²) are not described, and detailed cellular and molecular characterization of the pathology^7,13 is too sparsely reported to be included in the snapshot. Other types of microvascular pathology may need to be added in the future as more is learned (e.g. vascular remodeling with cavopulmonary circulations¹⁴). Perhaps most important, and as demonstrated in the snapshot, histopathology may correlate poorly with clinical outcome and often does not discriminate between very different types of PH.

T4–6 vasculopathies are relatively rare, encountered mostly in pediatrics, and usually receive little attention in PH reviews but are included because any broad overview of PH ought to include all well-characterized varieties of vascular disease, at least those which occur with some frequency. And these exotic vasculopathies may provide insights regarding more commonly encountered types of PH.

Specific histopathological types are:

T1: distal extension of smooth muscle and medial hypertrophy in small (<100 um) PAs but no intimal or higher grade lesions.¹²

T2: increased medial smooth muscle plus intimal hyperplasia and occlusion, ± higher grade lesions (“plexiform arteriopathy”).¹²

T3: vasculopathy with intimal occlusion of small PVs playing a major role (pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis [PVOD/PCH, referred to as PVOD here). Exuberant alveolar capillary proliferation also occurs, and T2 lesions in small PAs, although not plexiform lesions.^2,12,15

T4: stenosis of large pulmonary veins (pulmonary vein stenosis [PVS]). PVS is mostly a pediatric disease and when observed in adults is generally due to factors iatrogenic or external to the PV.^16,17 Leaving aside those forms of this disease, PVS is observed in four settings: following surgical manipulation of anomalously connected PV;^18,19 in ex-premature infants, often with bronchopulmonary dysplasia;^20,21 with congenital heart lesions without abnormally-connected PV or manipulation of them; and with no obvious associated factors.^16,20,22 (A possible link between PVS and other abnormalities, e.g. necrotizing enterocolitis, has been suggested but not proven.)

This vasculopathy has variable expression, ranging from a single discrete area of narrowing of the PV at its junction with the left atrium to diffuse narrowing extending deep into the lung.^23–25 The PVs are narrowed/obstructed by intimal and medial myofibroblast proliferation and deposition of carboxylated and sulfated acid mucoploysaccharides.^24,26–28 There is also T2 pathological remodeling of small PVs and PAs.^22,28 Whether this arterial and small vein remodeling is due to mechanical forces (pulmonary venous hypertension and/or increased pressure and flow [↑P+Q] in unobstructed segments of the lung) or rather reflects a pan-vascular pathology (or both) is unknown. Since anywhere from one to four veins may be affected, this disease is unlike most other pulmonary vasculopathies, where PVs are more uniformly involved.

T5: pulmonary vasculopathy involving narrowing/occlusion of large PAs (peripheral pulmonary stenosis [PPS]). The morphology is variable and can include discrete areas of narrowing in the central PAs, multiple narrowings in lobar and elastic PAs (often but not always at branching points), occlusion of elastic PAs, and diffuse narrowing of lobar and smaller PAs. Post-stenotic areas of PA dilation are also seen. This vasculopathy is observed in a variety of settings, especially Williams syndrome, non-Williams heritable PPS, Alagille’s syndrome, congenital rubella syndrome, moyamoya disease, idiopathic PPS, and with a variety of congenital cardiac malformations.²⁹

Descriptions of the histopathology of PA stenosis or hypoplasia are somewhat variable.³⁰ Intimal thickening, fibromyxomatous or cellular,^30–34 is the most consistent finding. Also observed is medial hyperplasia,^30,35 paucity or fragmentation of medial elastic fibers and mosaic pattern of medial elements,^{30,31,33–36} and dilation with medial atrophy distal to areas of narrowing.^31,33 Hypoplasia of central PAs, with normal intima, media, and adventitia, has also been observed.³⁰ Since “non-protected” (by large PA stenosis) regions of the vascular bed are often pathologically remodeled (T2 histopathology), presumably due to ↑P+Q, PH is due to both large and small PA pathology.^32,37

The variability in macroscopic and microscopic expression is perhaps not surprising, since different gene mutations (with different cognate proteins) are linked with associated conditions—William’s syndrome (ELN³⁸), Alagille’s syndrome (JAG 1³⁹), and moyamoya (RNF213, BRCC3/MTCP1, GUCY1A3⁴⁰). Indeed, one group found that large PA architecture with PPS subtly differs depending upon the associated condition (Williams, non-Williams, and non-syndromic arteriopathy versus Alagille’s versus moyamoya).⁴¹ For most of the reports cited above, no information is provided regarding any associated diagnoses, so the histological findings cannot be related to a particular variety of PPS, although one report of patients consistent with William’s syndrome described a “mosaic” pattern of elastic tissue in the media.³⁵

T6: PH associated with disordered vascular architecture due to abnormal development in utero. This type of vasculopathy displays an abnormal spatial arrangement of small PAs and/or veins, although there are features of T1/T2 vasculopathy as well. Two examples are well-described:

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD): malpositioned PV run with the arteries (sometimes in the same adventitial sheath) and bronchi, and there is medial hypertrophy of small PAs with distal extension of smooth muscle, a decreased number of capillaries, thickened alveolar septa with a thickened air-capillary interface, and alveoli and bronchioles are abnormal in shape and number.^42–44

Pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (ToF/PA): pulmonary perfusion is provided in two ways, by central PAs supplied with blood from one or more major aortopulmonary collateral arteries (MAPCAs) ± a patent ductus arteriosus, and directly by MAPCAs, which ramify into small PAs with similar structure (albeit smaller diameter) as normal vessels.⁴⁵ The central PAs are smaller in diameter than normal PAs and abnormally distributed. The MAPCAs are prone to develop intimal thickening and occlusive cushions anywhere along their course, limiting or interrupting perfusion to the segment(s) of the lung so supplied. And when MAPCAs do not narrow, T1/T2 vascular disease develops in the distal vessels due to ↑P+Q.^45–48

Developmental origin

Developmental events clearly underlie a few types of PH (e.g. ACD), but their significance is likely more general; appreciating how development goes awry may also inform our understanding of PH originating in the fully-developed circulation⁷ and suggest avenues for reconstructing the pathologically remodeled vascular bed. For the snapshot, PH can originate during one or more of four phases: fetal (D1); transitional (D2); developmental (D3); or post-development (PD). Fetal development confers abnormal pulmonary vascular structure of fetal origin. In utero events, which increase the risk of post-natal PH but are not necessary for it to develop (e.g. chorioamnionitis),^49–51 are not considered, nor is developmental programming, as the latter is too little understood at this time to permit inclusion. The fetal–neonatal transition—the rapid and radical in reduction of pulmonary vascular resistance (PVR) immediately after birth—is a critical physiological/structural developmental milestone.^52–55 The developmental phase is difficult to define precisely as lung development starts in utero but continues well after birth.⁵⁶ No sharp line separates the developing from the developed lung. Alveoli and supernumerary arteries increase in number until approximately eight years of age, but the most rapid vascular growth occurs earlier: alveoli and conventional PAs multiply most rapidly in the first 18 post-natal months, while for intra-acinar arteries rapid growth continues until about four years of age.^56,57 For the snapshot, the first four years are therefore considered the developmental phase, recognizing that growth continues beyond that time (post-developmental phase, for purposes of the snapshot).

Several types of PH develop in the first few years of life, but it is unclear exactly how the fact of development per se influences the pulmonary vasculopathy in these situations. For example, could incomplete resolution of fetal PVR be the origin of idiopathic PH in a four-month-old? Do ↑P+Q cardiac shunting defects cause more (or less) severe alteration of the pulmonary circulation because they impact the developing lung? Studies finding fewer small PAs in patients with cardiac shunts, not explained by intimal proliferation, are consistent with the notion that ↑P+Q impedes small PA development,^9,58,59 but since essentially all our experience with this hemodynamic alteration originates in the developing organism, it is hard to confirm this. Also, with some types of disordered development (e.g. congenital diaphragmatic hernia [CDH] and bronchopulmonary dysplasia [BPD]) PH often resolves in the first few years, indicating that impaired early development is not always permanent. Indeed, it seems likely that resolution of some types of PH (e.g. CDH) is actually facilitated by ongoing development.

Associated clinical conditions

A major preoccupation for the field has been arranging into categories PH associated with other medical conditions—indeed, that is the main feature of the Nice classification. Since, with few exceptions (e.g. ↑P+Q), PH occurs in only a minority (usually very small) of individuals with a PH-associated illness, be it other organ system disease, toxins, infections, environmental factors, or gene mutation, these conditions are actually risk-modifying, not causative factors,^2,60 which require interaction with other elements to culminate in PH. The clinical importance of this taxonomy is obvious, but associated conditions are incorporated into the snapshot for a second reason as well: connecting PH with associated illnesses has, and will, help us better understand the pathobiology of PH. An obvious example is pathological remodeling due to ↑P+Q (almost always due to congenital cardiac malformations).⁶¹ Though its mechanism(s) is unclear, it is certain that these mechanical factors are powerful stimuli for remodeling, a fact which was revealed when early investigators considered the effects of congenital cardiac defects on the lung’s circulation. And its relevance extends well beyond cardiac disease since these mechanical factors presumably operate with any type of pulmonary vasculopathy with uneven distribution of Q and P, as noted below.

The approach used here is similar to that used in the Nice classification insofar as select disease entities associated with PH (e.g. portopulmonary hypertension [POPH]) are incorporated, but it differs in one respect. Physiological perturbations (↑P+Q, pulmonary venous hypertension, alveolar hypoxia) are included rather than their cognate clinical conditions (e.g. congenital septal defects, left heart disease, lung disease), because specifying the responsible biological abnormality identifies the presumed proximate cause of the PH.

Potential for resolution

Types of PH for which PA pressure falls to normal, or nearly so, spontaneously, after a brief period of therapy (e.g. persistent pulmonary hypertension of the newborn [PPHN]) or after the inciting stimulus is removed (e.g. surgical relief of pulmonary venous hypertension via mitral valve intervention), are considered to have high potential for resolution. Since nearly any type of PH can rarely and unpredictably resolve,⁶² the likelihood of this needs to be specified, and we regard ≥ ∼50% odds of resolution as sufficient to qualify for high potential. “Resolution” does not necessarily imply completely normal PAP or PVR. While there are ample hemodynamic data on most types of PH upon first diagnosis, follow-up catheter-derived information is limited for most varieties, and since available echocardiographic data do not specify the exact PAP, mildly elevated PAP may escape detection. Nor does it imply that the pulmonary circulation is functionally normal. Even if normal at rest, PAP may increase abnormally with exercise⁶³ and/or the lung may be hyper-reactive to vasoconstrictive stimuli. Nor does it necessarily indicate complete histological normalization. For example, with mitral stenosis, even patients with biopsy-proven intimal fibrosis before relief of the stenosis show marked reduction in PAP after repair⁶⁴ and the same has been described with intracardiac shunts operated early on,⁹ but it seems unlikely that the intimal lesions disappear completely. This definition therefore lacks biological rigor and could be misleading insofar as it might seem to imply a completely normal clinical phenotype. But it does distinguish progressive PH from more benign varieties, including the potential for a pulmonary circulation compatible with treatment-free, symptom-free existence.

What the snapshot does not do

It does not include all types of PH, rather only those varieties—somewhat arbitrarily chosen—which represent particular intersections of properties and for which there is sufficient information to adequately characterize the PH. The snapshot is not a comprehensive classification scheme, nor an alternative to or replacement for existing taxonomies.^2,5 That said, the distinct combinations of snapshot characteristics could be affixed to any type of PH and it so characterized, e.g. idiopathic PH would be T2, D2–PD, irreversible; POPH would be T2, D3–PD, portopulmonary, reversible.

It does not incorporate notions of “treatability”. (i) Therapeutic approaches are rapidly evolving and FDA-approved targeted PH therapy has oozed across Nice categories (e.g. riociguat for class IV PH). And even where consensus indications for targeted therapy are lacking (e.g. Nice groups 2 and 3), this may attest to a lack of trials utilizing suitable patients rather than the lack of biological effect.^2,65 (ii) It is usually unclear what the clinical effectiveness of a drug (generally measured with functional criteria only partly influenced by the state of the pulmonary vascular bed) tells us about the nature of the PH being treated. Targeted PH therapy may have salutary effects on organ function other than the lung (e.g. the effect of PDE5 inhibitors on ventricular function) which account for a significant fraction of their benefit.

The snapshot does not take into account acute reactivity to vasodilators. This is an important characteristic for individual patients since it separates patients within a type (especially idiopathic pulmonary arterial hypertension) with respect to response to therapy and survival.^66,67 But it is of little utility in distinguishing between different types of PH since it is observed in some patients with many different types of PH. Indeed, it is possible that reactivity is usually present in the earliest stages in most or all forms of PH. And reactivity is usually lost,^66,67 which complicates trying to incorporate it into a summary classification.

Transient PH is not incorporated into the snapshot since in most or all types of PH (and the healthy pulmonary circulation, for that matter), PVR can acutely and reversibly increase with provocation (e.g. alveolar hypoxia).

The snapshot will not have long-term value without modification and enhancement. As more is learned of the developmental origins of pulmonary vascular disease, as better ways of defining its histopathology are developed, and as detailed mechanistic pictures of the various types of PH are uncovered this information will need to be incorporated into updated snapshots.

What the snapshot does do

It summarizes how many of the various types of PH are similar, and differ, with respect to the four important characteristics addressed here. It therefore provides a fairly broad but concise overview of this arena, to our knowledge one not previously available.

The field is currently focused mostly on idiopathic and other types of persistent PH, but the snapshot emphasizes the fact that many types of PH are reversible, at least if inciting causes can be eliminated, including those associated with T2 histopathology. The potential for favorable remodeling (even if this cannot be effected as often as we would like) is thus emphasized and gives reason for optimism for eventual development of definitive therapies.

The snapshot draws attention to forms of vasculopathy little discussed in major reviews (e.g. T4 and T5) and emphasizes how dynamic the pulmonary vascular bed can be (where developmental changes can greatly alter the characteristics of the lesser circulation). We hope that this stimulates new ways of thinking about the biology of pulmonary vascular remodeling and perhaps even new ideas for research.

Types of PH: rationale for assignment of characteristics

Idiopathic persistent pulmonary hypertension of the newborn (PPHN)

There are many conditions associated with severe PH in the neonate, but this summary focuses on the idiopathic variety, where the chest X-ray is normal (although there are often associated perinatal complications).^52,68

Histopathology: T1. Distal extension of smooth muscle into normally non-muscular arteries, increased thickness of small arteries, and increased adventitial thickness are the typical findings.^69–71 Two case reports also described loss of small PAs, one with idiopathic PPHN⁷¹ and another with PPHN clearly associated with premature ductal restriction.⁷²

Developmental origin: D1–2 (origin and resolution). It is unclear what fraction of idiopathic PPHN has fetal origins as distinct from being purely a reflection of a disordered transition. The authors of three histological studies suggested that the magnitude of wall thickening and distal extension in small PAs suggest that the disease originated in utero.^69,70,73 But the number of histological observations are relatively few and the patients, who died, may not reflect the disease in the vast majority who survive. It is also possible that the distal extension of smooth muscle occurred post-natally.⁷¹ More to the point, since the high PVR usually substantially resolves within a few days, it is hard not to think of PPHN as being due to delayed transition, even if set up in utero.⁵² The one clear exception is PPHN due to premature constriction of the ductus arteriosus,⁷⁴ and therefore fetal origin is also assigned.

Potential for resolution: High. We are aware of no data regarding early (neonatal) survival or PH over the long term for idiopathic PPHN per se in the modern (ECMO and iNO) era, but since early survival of PPHN patients as a class (excepting CDH) is ∼90%^75,76 and very few patients have echocardiographically detectable PH on longer-term follow-up,^77,78 it is clear that PH usually (if not invariably⁷⁹) resolves in these patients.

Congenital diaphragmatic hernia (CDH)

Histopathology: T1. Post-mortem examinations have shown, in addition to bilateral lung hypoplasia, a reduction in the number of airway generations and alveoli, reduction in the size and number of small PAs, with increased wall thickness and extension of muscle into smaller arteries than normal.^80–82

Developmental origin: D1–3 (resolution in D3). The vascular architectural abnormalities are clearly of fetal origin, but marked pulmonary vasoconstriction, which may resolve, in the early neonatal period^83,84 indicates that an abnormal transition can also play an important role.

Potential for resolution: High. While persistent and occasionally severe PH has been described a few years after CDH repair,^85,86 the vast majority of survivors (including those requiring extracorporeal membrane oxygenator support adjacent to repair) have non-detectable or only mild elevation in RV pressure.^87–92 (The fraction of non-survivors having refractory disease prior to demise is surely much greater, but given an overall survival rate of ∼75%,⁸⁷ only a relatively small percent of the population of patients with CDH develops suffers from refractory PH.⁹¹) It is possible that mildly increased PAP is under-diagnosed in these patients, but the many outcome reports making little or no mention of PH (e.g. Ssemakula,⁹³ Davis,⁹⁴ Vanano,⁹⁵ Muratore,⁹⁶ Bagolan⁹⁷) suggest that clinically appreciable PH in this setting is very uncommon.

Pulmonary venous hypertension (PVH)

Histopathology: T2. Arterial medial hypertrophy, longitudinal smooth muscle bundles, and intimal thickening and fibrosis, sometimes so severe as to obstruct the lumen of small PAs, have been described even in children, but higher grade lesions are not observed.^13,64,98 Pulmonary veins are affected as well, with the media (hypertrophy, fibrosis, “arterialization”) and intima (fibrosis and longitudinal smooth muscle cells) both involved.^85,99

Developmental origin: D1, D3, PD. Thickening of pulmonary veins with congenital lesions causing pulmonary venous obstruction has been observed at a few days of age;^100–102 hypoplasia of small PAs is also described.^103,104 Vascular changes also develop in the developing and mature lung.¹⁰⁵

Potential for resolution: High. The great majority of patients who develop PH due to PVH outside the neonatal period have substantial or complete resolution of PH with relief of PVH.⁶¹ There are few data regarding patients with PVH since birth, however, and it is possible that the potential for resolution is less favorable if persisting for years.¹⁰⁶

Bronchopulmonary dysplasia (BPD)

Histopathology: T1. Available histological information largely concerns patients with the “old” BPD, so it is possible that the micro-architecture of “new” BPD may differ. Not all patients evince arterial changes, but those who do show distal extension of smooth muscle, medial hypertrophy, and increased adventitial thickness.^107–112 Swollen or “chunky” endothelial cells, which encroach on the PA lumen, are also described,^107,110,111 but endothelial proliferation is seldom observed (<12%^109,111,112). T1 is therefore assigned as the pathological type, recognizing that a few patients may develop higher grade vasculopathy. Abnormal alveolar capillaries are also described,^113,114 but whether this contributes to increased PVR is unclear, especially when one considers that these patients can manifest both “reactivity” to vasodilators¹¹⁵ and a tendency to markedly increase PAP with viral and other insults. A reduced number of small arteries⁸ likely also contributes to increased PVR.

Developmental origin: D3 (origin and resolution).^8,116

Potential for resolution: High. The precise likelihood of resolution of PH in these patients is unknown, but published reports indicate that it is very likely greater than 50%.^21,117–119

Chronic alveolar hypoxia due to residence at high altitude

Alveolar hypoxia is a component of multiple disorders, e.g. chronic lung disease, but in these cases PH may be partly due to stimuli other than hypoxia per se (e.g. inflammation). We therefore focus on relatively “pure” alveolar hypoxia—that which attends residence at high altitude.

Histopathology: T1. Distal extension of smooth muscle, longitudinal muscle bundles, and (generally mild) medial hypertrophy are typically described.^120–122

Developmental origin: D3, PD.^123–126

Potential for resolution: High. Relocation to low altitude results in near or complete resolution of PH in the great majority.^127–131

Portopulmonary hypertension (POPH)

Histopathology: T2.^132,133

Developmental origin: D3, PD. PH due to portosystemic venous shunts is rare but well-described in infants and children.^134–137 But POPH is far more often diagnosed in adults, without apparent origin in early pulmonary vascular development.

Potential for resolution: High. How often is POPH reversed when its putative cause (portal hypertension) is eliminated by a liver transplant (LT)? Only case reports and small series are available, often with scanty hemodynamic follow-up. Some reports suggest relatively few patients show resolution of POPH after LT.^138–140 But three groups with extensive experience reported that targeted PH medications were discontinued in at least 50% of their patients with pre-LT POPH ^141–143 (although neither PAP or PVR post-LT were documented for most of the patients). Other small series and case reports show a substantial resolution of POPH, including documentation of RV systolic pressure ± PVR,^144–146 but with too few patients to determine the probability of resolution. Michael Krowka estimated that in ∼50% of patients, pre-LT prostacyclin can be discontinued with normal pulmonary hemodynamics after transplant.¹⁴⁷ The precise mechanism(s) driving improvement in pulmonary hemodynamics after LT remain elusive, although immunosuppressive regimens and the reduction of circulating factors derived from the removed diseased liver may both contribute. Intriguingly, the immunosuppressive medication tacrolimus is under investigation as a therapeutic for PAH, which while it may relate to an immune modifying role is being investigated currently more so due to its potential ability to increase molecular BMPR2 expression in PAH cases.¹⁴⁸ It should be appreciated that many cases of POPH resolution involve only mildly increased PVR,^{142–144,146,149,150} far lower than in other forms of reversible PH; a reduction in PVR from 3 or 4 WU to 2 WU does not imply much of a change in the architecture of the vascular bed. But the fact that POPH patients, prior to LT, often show a marked response to relatively low dose epoprostanol^{140,149,151,152} suggests that there is less fixed reduction of the vascular bed with POPH than with some other varieties of PH.

↑P+Q

We make no effort to grapple with congenital cardiac defects as a class, as PH-associated conditions, because besides altered P+Q, there are other confusing (e.g. PH with small septal defects) and perplexing factors involved (e.g. propensity for early vascular disease with d-TGA, not explained by hemodynamics^153–155). We focus instead on the physiologic abnormality of simultaneously ↑P+Q, with large (pressure unrestrictive) ventricular septal defect (VSD) and patent ductus arteriosus (PDA), being the archetypical types of these malformations.⁶¹ Indeed, there are very few clinical situations where these two hydrodynamic abnormalities occur in concert except with congenital cardiac malformations. Exactly how high is high, with respect to P and Q provoking vascular disease, is unclear but presumably varies somewhat from patient to patient. Most patients who develop vascular obstructive disease with a VSD have a pulmonary to systemic flow ratio > 2 prior to developing the vascular changes, and two reports suggest that fixed vascular changes are very unusual, at least in childhood, with mean PAP < 50 mmHg,⁶¹ although it should not be assumed that PAP near that value is reliably “safe.”

We refer specifically to greatly ↑P+Q, not to increased Q with low PAP; pre-tricuspid left-to-right shunts, which typically initially increase Q without much increasing P, can cause PH, but its likelihood and rate of development are much less than for ↑P+Q suffered from birth.⁶¹ We focus on ↑P+Q because it is a well-defined stimulus, the major factor driving development of vascular disease in many cardiac malformations, and because of its broader significance. This stimulus likely plays a role in many—maybe all—types of PH: in T2 PH there are highly narrowed or obstructed PAs as well as unobstructed vessels;^10,12 ↑P+Q in the unobstructed vessels likely leads to secondary pathological remodeling in these previously unaffected arteries.

Histopathology: T2. Patients with ↑P+Q initially develop T1 histopathology, but with time have a high likelihood of developing plexiform arteriopathy.^9,12,156,157

Developmental origin: D2–3, PD. Paul Wood thought that patients with Eisenmenger’s physiology had never experienced the normal early post-natal decline in PVR,¹⁵⁸ but it is clear that initially low PVR can increase with time, as does the risk of fixed/progressive vascular disease.^159,160 The snapshot acknowledges that high PVR may occasionally have its origin in the transition, but that irreversible remodeling is far more likely to develop in the developmental period or later. (PH caused by ↑P+Q in utero due to premature constriction of the ductus arteriosus is classified under PPHN.)

Potential for resolution: High/low. With a large VSD or PDA even greatly increased PVR can be much reduced or even normalize after repair of the defect if it is closed in the first year or two of life, but in other cases PVR will remain high or increase after repair, especially if closed later.^161–168 The snapshot confers this by indicating early potential for resolution which subsequently declines.

Peripheral pulmonary artery stenosis (PPS)

As noted above, PPS is associated with a number of systemic conditions, and different types of PPS may differ significantly in important characteristics. PPS with William’s syndrome is probably the best characterized in terms of hemodynamics and natural history.

Histopathology: T5, T2.

Developmental origin: D1, D3, PD. PPS associated with William’s syndrome has been documented in patients aged < 5 weeks,^169,170 and PPS of undefined association shortly after birth^36,171 indicating likely in utero development, but progression can occur later.^41,171,172

Potential for resolution: High for William’s syndrome but unclear for other types of PPS. Multiple reports suggest that substantial reduction of PH in infancy and childhood occurs in a majority of patients with Williams-related PPS although complete resolution is unusual and progression occurs in some cases.^{38,41,171–175} The potential for resolution for PPS associated with other conditions is likely much less, but longitudinal information is sparse. The snapshot indicates this by using both pink and light green to indicate the potential for resolution.

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD)

Histopathology: T6.

Developmental origin: D1.⁴³

Potential for resolution: Low. It is widely agreed that this disorder is essentially never reversible,^43,176 although it appears that there may be rare variants which do not result in early death.^177,178

Tetralogy of Fallot with pulmonary atresia and MAPCAs

Histopathology: T6.

Developmental origin: D1, D3, PD. The architecture of the central PAs/MAPCAs develops in utero, but T1/T2 disease can occur in the early developmental period and later, as noted above.⁴⁵

Potential for resolution: Low. In the unoperated patient, this type of pulmonary vasculopathy eventually causes reduced and maldistributed pulmonary blood flow due to narrowing of MAPCAs and vascular disease in ↑P+Q segments.

Pulmonary vein stenosis (PVS)

Histopathology: T4, T2.

Developmental origin: D1, D3, PD. PVS has been described in newborns,^23–25 indicating this disease can develop in utero. But it is unknown whether hypoplasia of the veins versus intimal hyperplasia (or both) cause PV narrowing in utero; we know of only one report of histology in a (one-day-old) neonate,²⁴ which implied that focal PV narrowing at the left atrial junction was due to fibrous intimal thickening. But intimal and medial changes have been described in patients as young as two months,^26,27 indicating that intimal hyperplasia surely can occur at least that early. It is conceivable that all PVS originates in the fetus and then progresses, but this seems unlikely: (1) Breinholt¹⁷⁹ described ten patients with no evidence of PVS (by echocardiography) who subsequently manifested the disease; (2) there are multiple reports of PVS presenting after the age of three years;^24,179–181 and (3) PVS developing after surgical correction of anomalously connected PV^18,19 is certainly a post-natal event. Prenatal and early developmental phase is therefore assigned, with most PVS developing after birth.

Potential for resolution: Low. Patients with one or two stenotic veins may be clinically stable indefinitely, presumably because only a tolerable fraction of the pulmonary circulation is affected, but the authors know of no reports of spontaneous resolution of the disease. When three or more veins are involved, progression of stenosis is almost always relentless.^{16,23,179,180}

Idiopathic pulmonary arterial hypertension (including heritable forms)

Histopathology: T2.¹²

Developmental origin: D2 (possible), D3, PD.^182,183 There are a few reports of infants with signs/symptoms of PH in the early neonatal period in whom unremitting and ultimately fatal PH is diagnosed weeks or months later,^184,185 and patients with apparently idiopathic PH as young as one month of age are included in one study.¹⁸² Since these and a few other reports suggest that incomplete fall of fetal PVR may account for a few cases of idiopathic PH, possible D2 origin is indicated.

Potential for resolution: Low.^183,186

Connective tissue disease (CTD) associated PH

Histopathology: T2/T3.^12,187,188 In addition to T2 pathological changes, a substantial fraction of patients with CTD of different types have PVOD-like small PV involvement.

Developmental origin: D3, PD.^188–190

Potential for resolution: Low.¹⁹¹

Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis spectrum disease (PVOD)

Histopathology: T3.

Developmental origin: PD.^192,193 So few cases of PVOD presenting in the developmental period have been described^193,194 (save those secondary to medical therapy) that it seems appropriate to assign post-developmental origin of the disease.

Potential for resolution: Low.^15,193

Toxin-associated PH

Histopathology: T2 (aminorex and fenfluramine^195,196).

Developmental origin: D3, PD. Many drugs have been reported as possible or definite risk factors for PH, with appetite suppressants being among the best characterized examples of the latter.^2,15 Aside from chemotherapy for malignancy in children,¹⁹⁷ the best-described cases of toxin-associated PH have occurred in adults, although diazoxide has been associated with PH in infants.^198–200

Potential for resolution: Low/high. Resolution of PH is very unlikely with aminorex and fenfluramine.^196,201 On the other hand, diazoxide-associated PH in infants appears to be reversible, although available information is very limited.^198–200 Dasatinib-related PH usually substantially improves (or completely abates) following cessation of the drug, although the best available information suggests that PAP usually remains elevated, at least for a few months.²⁰²

Summary

When various types of PH are thought of as having distinctive patterns of expression, and these patterns are graphically displayed, several PH features perhaps not widely appreciated become readily apparent:

While the field is currently focused heavily on idiopathic pulmonary arterial hypertension and other types of persistent PH (e.g. CTD, and CLD), many types of PH are largely reversible if inciting causes can be eliminated, indicating that the pulmonary circulation’s capacity for favorable remodeling is perhaps greater than often perceived.

Abnormal pulmonary blood vessels can take many histopathological forms, and with only a few exceptions (pulmonary venous hypertension being the most striking) reversible PH is associated with histopathology largely limited to increased medial smooth muscle.

Pulmonary vascular pathology can originate at any time of life, from early fetal life to late in adulthood. The potential for PH resolution is not tightly linked to any developmental period—early, and late, developmental origins are associated with types of PH which do, and do not, resolve.

Footnotes

Conflict of interest

The author(s) declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Yuan J-JG, Garcia JGN, Hales CA, et al. (eds). Textbook of Pulmonary Vascular Disease. New York: Springer, 2011.

Galie

Humbert

Vachiery

. 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). Eur Heart J 2016; 37: 67–119.

Abman

Hansmann

Archer

. Pediatric Pulmonary Hypertension: Guidelines from the American Heart Association and American Thoracic Society. Circulation 2015; 132: 2037–2099.

Black

Elliott

. Hypertension: A Companion to Braunwald’s Heart Disease, 2nd ed. Philadelphia, PA: Elsevier, 2013.

Cerro

Abman

Diaz

. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ 2011; 1: 286–298.

Stenmark

Meyrick

Galie

. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 2009; 297: L1013–1032.

Tuder

Abman

Braun

. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009; 54: S3–9.

Mourani

Abman

. Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Curr Opin Pediatr 2013; 25: 329–337.

Rabinovitch

Keane

Norwood

. Vascular structure in lung tissue obtained at biopsy correlated with pulmonary hemodynamic findings after repair of congenital heart defects. Circulation 1984; 69: 655–667.

10.

Yaginuma

Mohri

Takahashi

. Distribution of arterial lesions and collateral pathways in the pulmonary hypertension of congenital heart disease: a computer aided reconstruction study. Thorax 1990; 45: 586–590.

11.

Galambos

Sims-Lucas

Ali

. Intrapulmonary vascular shunt pathways in alveolar capillary dysplasia with misalignment of pulmonary veins. Thorax 2015; 70: 84–85.

12.

Stacher

Graham

Hunt

. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 261–272.

13.

Hunt

Bethea

Liu

. Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease. Am J Physiol Lung Cell Mol Physiol 2013; 305: L725–736.

14.

Ridderbos

Wolff

Timmer

. Adverse pulmonary vascular remodeling in the Fontan circulation. J Heart Lung Transplant 2015; 34: 404–413.

15.

Montani

Lau

Dorfmuller

. Pulmonary veno-occlusive disease. Eur Respir J 2016; 47: 1518–1534.

16.

Latson

Prieto

. Congenital and acquired pulmonary vein stenosis. Circulation 2007; 115: 103–108.

17.

Booher

Bach

. Acquired pulmonary vein stenosis: one problem, two mechanisms. J Am Soc Echocardiogr 2010; 23. 904.e1–3.

18.

Caldarone

Najm

Kadletz

. Relentless pulmonary vein stenosis after repair of total anomalous pulmonary venous drainage. Ann Thorac Surg 1998; 66: 1514–1520.

19.

Devaney

Chang

Ohye

. Management of congenital and acquired pulmonary vein stenosis. Ann Thor Surg 2006; 81: 992–995. discussion 5–6.

20.

Drossner

Kim

Maher

. Pulmonary vein stenosis: prematurity and associated conditions. Pediatrics 2008; 122: e656–661.

21.

del Cerro

Sabate Rotes

Carton

. Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes. Pediatr Pulmonol 2014; 49: 49–59.

22.

Pogoriler

Kulik

Casey

. Lung pathology in pediatric pulmonary vein stenosis. Pediatr Dev Pathol 2016; 19: 219–229.

23.

Driscoll

Hesslein

Mullins

. Congenital stenosis of individual pulmonary veins: clinical spectrum and unsuccessful treatment by transvenous balloon dilation. Am J Cardiol 1982; 49: 1767–1772.

24.

Bini

Cleveland

Ceballos

. Congenital pulmonary vein stenosis. Am J Cardiol 1984; 54: 369–375.

25.

Fong

Anderson

Park

. Morphologic features of stenosis of the pulmonary veins. Am J Cardiol 1988; 62: 1136–1138.

26.

Sadr

Tan

Kieran

. Mechanism of pulmonary vein stenosis in infants with normally connected veins. Am J Cardiol 2000; 86: 577–579. A10.

27.

Riedlinger

Juraszek

Jenkins

. Pulmonary vein stenosis: expression of receptor tyrosine kinases by lesional cells. Cardiovasc Pathol 2006; 15: 91–99.

28.

Sun

Doyle

Ringel

. Pulmonary vein stenosis. Hum Pathol 1995; 26: 880–886.

29.

Trivedi

Benson

. Interventional strategies in the management of peripheral pulmonary artery stenosis. J Interv Cardiol 2003; 16: 171–188.

30.

Edwards

Lucas

Jr Lock

. Morphologic changes in the pulmonary arteries after percutaneous balloon angioplasty for pulmonary arterial stenosis. Circulation 1985; 71: 195–201.

31.

Franch

Gay

Jr . Congenital stenosis of the pulmonary artery branches. A classification, with postmortem findings in two cases. Am J Med 1963; 35: 512–529.

32.

de Vries

Nikkels

van der Laag

. Moyamoya and extracranial vascular involvement: fibromuscular dysplasia? A report of two children. Neuropediatrics 2003; 34: 318–321.

33.

Kreutzer

Landzberg

Preminger

. Isolated peripheral pulmonary artery stenoses in the adult. Circulation 1996; 93: 1417–1423.

34.

MacMahon

Lee

Stone

. Congenital segmental coarctation of pulmonary arteries. (An anatomic study). Am J Pathol 1967; 50: 15–26.

35.

Blieden

Lucas

Jr Carter

. A developmental complex including supravalvular stenosis of the aorta and pulmonary trunk. Circulation 1974; 49: 585–590.

36.

Salisbury

Keeling

. Peripheral pulmonary artery stenosis. Arch Dis Child 1978; 53: 428–430.

37.

Ulrich

Fischler

Pfammatter

. Multiple peripheral pulmonary artery stenoses in adults: a rare cause of severe pulmonary hypertension necessitating lung transplantation. J Heart Lung Transplant 2005; 24: 1984–1987.

38.

Collins

2nd . Cardiovascular disease in Williams syndrome. Circulation 2013; 127: 2125–2134.

39.

Grochowski

Loomes

Spinner

. Jagged1 (JAG1): Structure, expression, and disease associations. Gene 2016; 576: 381–384.

40.

Guey

Tournier-Lasserve

Herve

. Moyamoya disease and syndromes: from genetics to clinical management. Appl Clin Genet 2015; 8: 49–68.

41.

Morray

Bergersen

Lock

. Occult progressive pulmonary arterial occlusion associated with right ventricular hypertension in patients with systemic arteriopathy. Congenit Heart Dis 2015; 10: E60–67.

42.

Wagenvoort

. Misalignment of lung vessels: a syndrome causing persistent neonatal pulmonary hypertension. Hum Pathol 1986; 17: 727–730.

43.

Bishop

Stankiewicz

Steinhorn

. Alveolar capillary dysplasia. Am J Respir Crit Care Med 2011; 184: 172–179.

44.

Cullinane

Cox

Silver

. Persistent pulmonary hypertension of the newborn due to alveolar capillary dysplasia. Pediatr Pathol 1992; 12: 499–514.

45.

Haworth

Macartney

. Growth and development of pulmonary circulation in pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries. Br Heart J 1980; 44: 14–24.

46.

Barboza

Siyahian

. Tetralogy of Fallot: aorto-pulmonary collaterals and pulmonary arteries have distinctly different transcriptomes. Pediatr Res 2014; 76: 341–346.

47.

Rabinovitch

Herrera-deLeon

Castaneda

. Growth and development of the pulmonary vascular bed in patients with tetralogy of Fallot with or without pulmonary atresia. Circulation 1981; 64: 1234–1249.

48.

Haworth

. Collateral arteries in pulmonary atresia with ventricular septal defect. A precarious blood supply. Br Heart J 1980; 44: 5–13.

49.

Jobe

. What is BPD in 2012 and what will BPD become? Early Hum Dev 2012; 88(Suppl. 2): S27–28.

50.

Collaco

Romer

Stuart

. Frontiers in pulmonary hypertension in infants and children with bronchopulmonary dysplasia. Pediatr Pulmonol 2012; 47: 1042–1053.

51.

Berkelhamer

Mestan

Steinhorn

. Pulmonary hypertension in bronchopulmonary dysplasia. Semin Perinatol 2013; 37: 124–131.

52.

Steinhorn

. Diagnosis and treatment of pulmonary hypertension in infancy. Early Hum Dev 2013; 89: 865–874.

53.

Cabral

Belik

. Persistent pulmonary hypertension of the newborn: recent advances in pathophysiology and treatment. J Pediatr (Rio J) 2013; 89: 226–242.

54.

Hall

Gorenflo

Reader

. Neonatal pulmonary hypertension prevents reorganisation of the pulmonary arterial smooth muscle cytoskeleton after birth. J Anat 2000; 196(Pt 3): 391–403.

55.

Fediuk

Dakshinamurti

. A role for actin polymerization in persistent pulmonary hypertension of the newborn. Can J Physiol Pharmacol 2015; 93: 185–194.

56.

Hislop AARL

Growth and Development of the Respiratory System-Anatomical Development . In: Davis

(ed). Scientific Foundations of Paediatrics, Philadelphia, PA: Saunders, 1974, pp. 214–254.

57.

Haworth

Hislop

. Pulmonary vascular development: normal values of peripheral vascular structure. Am J Cardiol 1983; 52: 578–583.

58.

Haworth

Sauer

Buhlmeyer

. Development of the pulmonary circulation in ventricular septal defect: a quantitative structural study. Am J Cardiol 1977; 40: 781–788.

59.

Rabinovitch

Haworth

Castaneda

. Lung biopsy in congenital heart disease: a morphometric approach to pulmonary vascular disease. Circulation 1978; 58: 1107–1122.

60.

Tuder

Archer

Dorfmuller

. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D4–12.

61.

Kulik

. Pulmonary blood flow and pulmonary hypertension: Is the pulmonary circulation flowophobic or flowophilic? Pulm Circ 2012; 2: 327–339.

62.

Epting

Wolfe

Abman

. Reversal of pulmonary hypertension associated with plexiform lesions in congenital heart disease: a case report. Pediatr Cardiol 2002; 23: 182–185.

63.

Maron

Redwood

Hirshfeld

Jr . Postoperative assessment of patients with ventricular septal defect and pulmonary hypertension. Response to intense upright exercise. Circulation 1973; 48: 864–874.

64.

Haworth

Hall

Panja

. Peripheral pulmonary vascular and airway abnormalities in adolescents with rheumatic mitral stenosis. Int J Cardiol 1988; 18: 405–416.

65.

Han

Bach

Hagan

. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013; 143: 1699–1708.

66.

Sitbon

Humbert

Jais

. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105–3111.

67.

Yung

Widlitz

Rosenzweig

. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation 2004; 110: 660–665.

68.

Drummond

Peckham

Fox

. The clinical profile of the newborn with persistent pulmonary hypertension. Observations in 19 affected neonates. Clin Pediatr 1977; 16: 335–341.

69.

Murphy

Rabinovitch

Goldstein

. The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr 1981; 98: 962–967.

70.

Haworth

Reid

. Persistent fetal circulation: Newly recognized structural features. J Pediatr 1976; 88: 614–620.

71.

McKenzie

Haworth

. Occlusion of peripheral pulmonary vascular bed in a baby with idiopathic persistent fetal circulation. Br Heart J 1981; 46: 675–678.

72.

Levin

Fixler

Morriss

. Morphologic analysis of the pulmonary vascular bed in infants exposed in utero to prostaglandin synthetase inhibitors. J Pediatr 1978; 92: 478–483.

73.

Ohara

Ogata

Tezuka

. Histological study of pulmonary vasculature in fatal cases of persistent pulmonary hypertension of the newborn. Tohoku J Exp Med 1991; 164: 59–66.

74.

Gewillig

Brown

De Catte

. Premature foetal closure of the arterial duct: clinical presentations and outcome. Eur Heart J 2009; 30: 1530–1536.

75.

Konduri

Solimano

Sokol

. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics 2004; 113: 559–564.

76.

Bendapudi

Rao

Greenough

. Diagnosis and management of persistent pulmonary hypertension of the newborn. Paediatr Respir Rev 2015; 16: 157–161.

77.

Rosenberg

Kennaugh

Moreland

. Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. J Pediatr 1997; 131: 70–75.

78.

Gothberg

Edberg

Tang

. Residual pulmonary hypertension in children after treatment with inhaled nitric oxide: a follow-up study regarding cardiopulmonary and neurological symptoms. Acta Paediatr 2000; 89: 1414–1419.

79.

Berger

Beghetti

Humpl

. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet 2012; 379: 537–546.

80.

Geggel

Reid

. The structural basis of PPHN. Clin Perinatol 1984; 11: 525–549.

81.

Beals

Schloo

Vacanti

. Pulmonary growth and remodeling in infants with high-risk congenital diaphragmatic hernia. J Pediatr Surg 1992; 27: 997–1001. discussion -2.

82.

Shehata

Sharma

van der Staak

. Remodeling of pulmonary arteries in human congenital diaphragmatic hernia with or without extracorporeal membrane oxygenation. J Pediatr Surg 2000; 35: 208–215.

83.

Haugen

Linker

Eik-Nes

. Congenital diaphragmatic hernia: determination of the optimal time for operation by echocardiographic monitoring of the pulmonary arterial pressure. J Pediatr Surg 1991; 26: 560–562.

84.

Mohseni-Bod

Bohn

. Pulmonary hypertension in congenital diaphragmatic hernia. Semin Pediatr Surg 2007; 16: 126–133.

85.

Kinsella

Ivy

Abman

. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol 2005; 29: 123–128.

86.

Schwartz

Bernbaum

Rychik

. Pulmonary hypertension in children following extracorporeal membrane oxygenation therapy and repair of congenital diaphragmatic hernia. J Perinatol 1999; 19: 220–226.

87.

Wynn

Krishnan

Aspelund

. Outcomes of congenital diaphragmatic hernia in the modern era of management. J Pediatr 2013; 163: 114–119 e1.

88.

Trachsel

Selvadurai

Adatia

. Resting and exercise cardiorespiratory function in survivors of congenital diaphragmatic hernia. Pediatr Pulmonol 2006; 41: 522–529.

89.

Iocono

Cilley

Mauger

. Postnatal pulmonary hypertension after repair of congenital diaphragmatic hernia: predicting risk and outcome. J Pediatr Surg 1999; 34: 349–353.

90.

Van Meurs

Robbins

Reed

. Congenital diaphragmatic hernia: long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr 1993; 122: 893–899.

91.

Dillon

Cilley

Mauger

. The relationship of pulmonary artery pressure and survival in congenital diaphragmatic hernia. J Pediatr Surg 2004; 39: 307–312. discussion -12.

92.

Zussman

Bagby

Benson

. Pulmonary vascular resistance in repaired congenital diaphragmatic hernia vs. age-matched controls. Pediatr Res 2012; 71: 697–700.

93.

Ssemakula

Stewart

Goldsmith

. Survival of patients with congenital diaphragmatic hernia during the ECMO era: an 11-year experience. J Pediatr Surg 1997; 32: 1683–1689.

94.

Davis

Firmin

Manktelow

. Long-term outcome following extracorporeal membrane oxygenation for congenital diaphragmatic hernia: the UK experience. J Pediatr 2004; 144: 309–315.

95.

Vanamo

Rintala

Sovijarvi

. Long-term pulmonary sequelae in survivors of congenital diaphragmatic defects. J Pediatr Surg 1996; 31: 1096–1099. discussion 9–100.

96.

Muratore

Kharasch

Lund

. Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg 2001; 36: 133–140.

97.

Bagolan

Morini

. Long-term follow up of infants with congenital diaphragmatic hernia. Semin Pediatr Surg 2007; 16: 134–144.

98.

Wagenvoort CA. Pulmonary Venous Hypertension. In: Pathology of Pulmonary Hypertension. New York, NY: John Wiley & Sons, 1977, pp. 183–195.

99.

Wagenvoort CA. Pulmonary Venous Hypertension. In: Pathology of Pulmonary Hypertension. New York, NY: John Wiley & Sons, 1977, pp. 195–199.

100.

Rychik

Rome

Collins

. The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome. J Am Coll Cardiol 1999; 34: 554–560.

101.

Graziano

Heidelberger

Ensing

. The influence of a restrictive atrial septal defect on pulmonary vascular morphology in patients with hypoplastic left heart syndrome. Pediatr Cardiol 2002; 23: 146–151.

102.

D’Souza

Vergales

Jayakumar

. Hypoplastic left heart syndrome and pulmonary veno-occlusive disease in an infant. Pediatr Cardiol 2013; 34: 1949–1951.

103.

Maeda

Yamaki

Kado

. Hypoplasia of the small pulmonary arteries in hypoplastic left heart syndrome with restrictive atrial septal defect. Circulation 2004; 110: II139–146.

104.

Maeda

Yamaki

Yokota

. Hypoplasia of the small pulmonary arteries in total anomalous pulmonary venous connection with obstructed pulmonary venous drainage. J Thorac Cardiovasc Surg 2004; 127: 448–456.

105.

Kulik

. Pulmonary hypertension caused by pulmonary venous hypertension. Pulm Circ 2014; 4: 581–595.

106.

Kulik

Harris

McElhinney

. The impact of pulmonary venous hypertension on the pulmonary circulation in the young. Congenit Heart Dis 2011; 6: 603–607.

107.

Bonikos

Bensch

Northway

Jr . Bronchopulmonary dysplasia: the pulmonary pathologic sequel of necrotizing bronchiolitis and pulmonary fibrosis. Hum Pathol 1976; 7: 643–666.

108.

Tomashefski

Jr Oppermann

Vawter

. Bronchopulmonary dysplasia: a morphometric study with emphasis on the pulmonary vasculature. Pediatr Pathol 1984; 2: 469–487.

109.

Stocker

. Pathologic features of long-standing “healed” bronchopulmonary dysplasia: a study of 28 3- to 40-month-old infants. Hum Pathol 1986; 17: 943–961.

110.

Chambers

van Velzen

. Ventilator-related pathology in the extremely immature lung. Pathology 1989; 21: 79–83.

111.

Hislop

Haworth

. Pulmonary vascular damage and the development of cor pulmonale following hyaline membrane disease. Pediatr Pulmonol 1990; 9: 152–161.

112.

Bush

Busst

Knight

. Changes in pulmonary circulation in severe bronchopulmonary dysplasia. Arch Dis Child 1990; 65: 739–745.

113.

Coalson

. Pathology of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 179–184.

114.

De Paepe

Mao

Powell

. Growth of pulmonary microvasculature in ventilated preterm infants. Am J Respir Crit Care Med 2006; 173: 204–211.

115.

Mourani

Ivy

Gao

. Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia. Am J Respir Crit Care Med 2004; 170: 1006–1013.

116.

Thebaud

Abman

. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med 2007; 175: 978–985.

117.

Mourani

Sontag

Younoszai

. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 2015; 191: 87–95.

118.

Joshi

Wilson

Kotecha

. Cardiovascular function in children who had chronic lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed 2014; 99: F373–379.

119.

Poon

Edwards

Kotecha

. Long term cardiovascular consequences of chronic lung disease of prematurity. Paediatr Respir Rev 2013; 14: 242–249.

120.

Arias-Stella

Saldana

. The terminal portion of the pulmonary arterial tree in people native to high altitudes. Circulation 1963; 28: 915–925.

121.

Heath

Smith

Rios Dalenz

. Small pulmonary arteries in some natives of La Paz, Bolivia. Thorax 1981; 36: 599–604.

122.

Heath

Williams

Rios-Dalenz

. Small pulmonary arterial vessels of Aymara Indians from the Bolivian Andes. Histopathology 1990; 16: 565–571.

123.

Penaloza

Arias-Stella

. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation 2007; 115: 1132–1146.

124.

Vogel

Weaver

Rose

. Pulmonary hypertension on exertion in normal man living at 10,150 feet (Leadville, Colorado). Med Thorac 1962; 19: 461–477.

125.

Sime

Banchero

Penaloza

. Pulmonary hypertension in children born and living at high altitudes. Am J Cardiol 1963; 11: 143–149.

126.

Miao

. High altitude heart disease in children in Tibet. High Alt Med Biol 2002; 3: 323–325.

127.

Sime

Penaloza

Ruiz

. Bradycardia, increased cardiac output, and reversal of pulmonary hypertension in altitude natives living at sea level. Br Heart J 1971; 33: 647–657.

128.

Banchero

Cruz

. Hemodynamic changes in the Andean native after two years at sea level. Aerosp Med 1970; 41: 849–853.

129.

Grover

Vogel

Voigt

. Reversal of high altitude pulmonary hypertension. Am J Cardiol 1966; 18: 928–932.

130.

Penaloza

Sime

. Chronic cor pulmonale due to loss of altitude acclimatization (chronic mountain sickness). Am J Med 1971; 50: 728–743.

131.

Anand

Malhotra

Chandrashekhar

. Adult subacute mountain sickness–a syndrome of congestive heart failure in man at very high altitude. Lancet 1990; 335: 561–565.

132.

Edwards

Weir

Edwards

. Coexistent pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987; 10: 1233–1238.

133.

Krowka

Pathology and Management of Portopulmonary Hypertension. In: Yuan

J-J

Garcia

JGN

Hales

(eds). Textbook of Pulmonary Vascular Disease, Rochester, MN: Springer Science+Business Medica LLC, 2011. p. 1024.

134.

Ohno

Muneuchi

Ihara

. Pulmonary hypertension in patients with congenital portosystemic venous shunt: a previously unrecognized association. Pediatrics 2008; 121: e892–899.

135.

Ersch

Banziger

Braegger

. An infant with pulmonary hypertension due to a congenital porto-caval shunt. Eur J Pediatr 2002; 161: 660–662.

136.

Law

Mack

Sokol

. Cardiopulmonary manifestations of portovenous shunts from congenital absence of the portal vein: pulmonary hypertension and pulmonary vascular dilatation. Pediatr Transplant 2011; 15: E162–168.

137.

Franchi-Abella

Branchereau

Lambert

. Complications of congenital portosystemic shunts in children: therapeutic options and outcomes. J Pediatr Gastroenterol Nutr 2010; 51: 322–330.

138.

Rafanan

Maurer

Mehta

. Progressive portopulmonary hypertension after liver transplantation treated with epoprostenol. Chest 2000; 118: 1497–1500.

139.

Ramsay

Simpson

Nguyen

. Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 1997; 3: 494–500.

140.

Khaderi

Khan

Safdar

. Long-term follow-up of portopulmonary hypertension patients after liver transplantation. Liver Transplant 2014; 20: 724–7.

141.

Safdar

Bartolome

Sussman

. Portopulmonary hypertension: an update. Liver Transplant 2012; 18: 881–891.

142.

Swanson

Wiesner

Nyberg

. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am J Transplant 2008; 8: 2445–2453.

143.

Ashfaq

Chinnakotla

Rogers

. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am J Transplant 2007; 7: 1258–1264.

144.

Bandara

Gordon

Sarwar

. Successful outcomes following living donor liver transplantation for portopulmonary hypertension. Liver Transplant 2010; 16: 983–989.

145.

Uchiyama

Soejima

Taketomi

. Successful adult-to-adult living donor liver transplantation in a patient with moderate to severe portopulmonary hypertension. Liver Transplant 2006; 12: 481–484.

146.

Ogawa

Hori

Doi

. Living-donor liver transplantation for moderate or severe porto-pulmonary hypertension accompanied by pulmonary arterial hypertension: a single-centre experience over 2 decades in Japan. J Hepatobiliary Pancreat Sci 2012; 19: 638–649.

147.

Krowka

Pathology and Management of Portopulmonary Hypertension. In: Yuan

J-J

Garcia

JGN

Hales

(eds). Textbook of Pulmonary Vascular Disease, Rochester, MN: Springer Science+Business Medica LLC, 2011. p. 1028.

148.

Spiekerkoetter

Sung

Sudheendra

. Low-dose FK506 (Tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 192: 254–257.

149.

Hollatz

Musat

Westphal

. Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension. Liver Transplant 2012; 18: 686–695.

150.

Sussman

Kaza

Barshes

. Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series. Am J Transplant 2006; 6: 2177–2182.

151.

Fix

Bass

De Marco

. Long-term follow-up of portopulmonary hypertension: effect of treatment with epoprostenol. Liver Transplant 2007; 13: 875–885.

152.

Tan

Markowitz

Montgomery

. Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol. Liver Transplant 2001; 7: 745–749.

153.

Ferencz

. Transposition of the great vessels. Pathophysiologic considerations based upon a study of the lungs. Circulation 1966; 33: 232–241.

154.

Lakier

Stanger

Heymann

. Early onset of pulmonary vascular obstruction in patients with aortopulmonary transposition and intact ventricular septum. Circulation 1975; 51: 875–880.

155.

Cordina

Celermajer

. Late-onset pulmonary arterial hypertension after a successful atrial or arterial switch procedure for transposition of the great arteries. Pediatr Cardiol 2010; 31: 238–241.

156.

Hislop

Haworth

Shinebourne

. Quantitative structural analysis of pulmonary vessels in isolated ventricular septal defect in infancy. Br Heart J 1975; 37: 1014–1021.

157.

Haworth

. Pulmonary vascular disease in ventricular septal defect: structural and functional correlations in lung biopsies from 85 patients, with outcome of intracardiac repair. J Pathol 1987; 152: 157–168.

158.

Wood

. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J 1958; 2: 755–762.

159.

Hoffman

Rudolph

. The natural history of ventricular septal defects in infancy. Am J Cardiol 1965; 16: 634–653.

160.

Keith

Rose

Collins

. Ventricular septal defect. Incidence, morbidity, and mortality in various age groups. Br Heart J 1971; 33(Suppl.): 81–87.

161.

Grosse-Brockhoff

Loogen

. Ventricular septal defect. Circulation 1968; 38: 13–20.

162.

Neutze

Ishikawa

Clarkson

. Assessment and follow-up of patients with ventricular septal defect and elevated pulmonary vascular resistance. Am J Cardiol 1989; 63: 327–331.

163.

Ikawa

Shimazaki

Nakano

. Pulmonary vascular resistance during exercise late after repair of large ventricular septal defects. Relation to age at the time of repair. J Thorac Cardiovasc Surg 1995; 109: 1218–1224.

164.

Hallidie-Smith

Hollman

Cleland

. Effects of surgical closure of ventricular septal defects upon pulmonary vascular disease. Br Heart J 1969; 31: 246–260.

165.

Castaneda

Zamora

Nicoloff

. High-pressure, high-resistance ventricular septal defect. Surgical results of closure through right atrium. Ann Thor Surg 1971; 12: 29–38.

166.

Braunwald

. The effects of surgical abolition of left-to-right shunts on the pulmonary vascular dynamics of patients with pulmonary hypertension. Circulation 1962; 26: 1270–1278.

167.

DuShane

Krongard

Ritter

The fate of raised pulmonary vascular resistance after surgery in ventricular septal defect. In: Rowe

Kidd

GSC

(eds). The Child with Congenital Heart Disease After Surgery, Mount Kisco, NY: Futura Publishing Company, 1976, pp. 299–312.

168.

Yeager

Freed

Keane

. Primary surgical closure of ventricular septal defect in the first year of life: results in 128 infants. J Am Coll Cardiol 1984; 3: 1269–1276.

169.

Pham

Moller

Hills

. Cardiac catheterization and operative outcomes from a multicenter consortium for children with Williams syndrome. Pediatr Cardiol 2009; 30: 9–14.

170.

Zalzstein

Moes

Musewe

. Spectrum of cardiovascular anomalies in Williams-Beuren syndrome. Pediatr Cardiol 1991; 12: 219–223.

171.

Wren

Oslizlok

Bull

. Natural history of supravalvular aortic stenosis and pulmonary artery stenosis. J Am Coll Cardiol 1990; 15: 1625–1630.

172.

Kececioglu

Kotthoff

Vogt

. Williams-Beuren syndrome: a 30-year follow-up of natural and postoperative course. Eur Heart J 1993; 14: 1458–1464.

173.

Giddins

Finley

Nanton

. The natural course of supravalvar aortic stenosis and peripheral pulmonary artery stenosis in Williams’s syndrome. Br Heart J 1989; 62: 315–319.

174.

Kim

Yoo

Choi

. Natural course of supravalvar aortic stenosis and peripheral pulmonary arterial stenosis in Williams’ syndrome. Cardiol Young 1999; 9: 37–41.

175.

Miyamura

Watanabe

Tatebe

. Spontaneous regression of peripheral pulmonary artery stenosis in Williams syndrome. Jpn Circ J 1996; 60: 311–314.

176.

Michalsky

Arca

Groenman

. Alveolar capillary dysplasia: a logical approach to a fatal disease. J Pediatr Surg 2005; 40: 1100–1105.

177.

Marshall

Silva

English

. Misplaced pulmonary arteries in an adult patient with pulmonary hypertension. Br J Radiol 2010; 83: e5–9.

178.

Ito

Akimoto

Cho

. A late presenter and long-term survivor of alveolar capillary dysplasia with misalignment of the pulmonary veins. Eur J Pediatr 2015; 174: 1123–1126.

179.

Breinholt

Hawkins

Minich

. Pulmonary vein stenosis with normal connection: associated cardiac abnormalities and variable outcome. Ann Thor Surg 1999; 68: 164–168.

180.

Holt

Moller

Larson

. Primary pulmonary vein stenosis. Am J Cardiol 2007; 99: 568–572.

181.

Song

Bae

Jeong

. Clinical characteristics and prognostic factors of primary pulmonary vein stenosis or atresia in children. Ann Thor Surg 2013; 95: 229–234.

182.

Fraisse

Jais

Schleich

. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis 2010; 103: 66–74.

183.

Moledina

Hislop

Foster

. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart 2010; 96: 1401–1406.

184.

Raine

Hislop

Redington

. Fatal persistent pulmonary hypertension presenting late in the neonatal period. Arch Dis Child 1991; 66: 398–402.

185.

Burnell

Joseph

Lees

. Progressive pulmonary hypertension in newborn infants. A report of two cases with no identifiable respiratory or cardiac disease. Am J Dis Child 1972; 123: 167–170.

186.

Sandoval

Bauerle

Palomar

. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation 1994; 89: 1733–1744.

187.

Dorfmuller

Humbert

Perros

. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol 2007; 38: 893–902.

188.

Gunther

Jais

Maitre

. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64: 2995–3005.

189.

Morse

Barst

Whitman

3rd . Isolated pulmonary hypertension in the grandchild of a kindred with scleroderma (systemic sclerosis): “neonatal scleroderma”? J Rheumatol 1989; 16: 1536–1541.

190.

Kimura

Weiss

Haroldson

. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2013; 65: 745–752.

191.

Sobanski

Launay

Hachulla

. Current approaches to the treatment of systemic-sclerosis-associated pulmonary arterial hypertension (SSc-PAH). Curr Rheumatol Rep 2016; 18: 10.

192.

Montani

Achouh

Dorfmuller

. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008; 87: 220–233.

193.

Woerner

Cutz

Yoo

. Pulmonary venoocclusive disease in childhood. Chest 2014; 146: 167–174.

194.

Wagenvoort

Losekoot

Mulder

. Pulmonary veno-occlusive disease of presumably intrauterine origin. Thorax 1971; 26: 429–434.

195.

Brenot

Herve

Petitpretz

. Primary pulmonary hypertension and fenfluramine use. Br Heart J 1993; 70: 537–541.

196.

Montani

Seferian

Savale

. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev 2013; 22: 244–250.

197.

Bouillon

Moride

Bensouda-Grimaldi

Pulmonary arterial hypertension secondary to anorexigens and other drugs and toxins. In: Yuan

J-J

Garcia

JGN

Hales

(eds). Textbook of Pulmonary Vascular Disease, New York, NY: Springer Science+Business Medica, LLC, 2011, pp. 1043–1060.

198.

Nebesio

Hoover

Caldwell

. Development of pulmonary hypertension in an infant treated with diazoxide. J Pediatr Endocrinol Metab 2007; 20: 939–944.

199.

FDA warns of pulmonary hypertension in infants treated with diazoxide. 2015. Available at: http://www.fda.gove/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm455125.htm.

200.

Dehdashtian

. Reversible pulmonary hypertension in an infant treated with diazoxide. Asia Pac J Med Toxicol 2014; 3: 84–86.

201.

Souza

Humbert

Sztrymf

. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J 2008; 31: 343–348.

202.

Montani

Bergot

Gunther

. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125: 2128–2137.

Pulmonary hypertension’s variegated landscape: a snapshot

Abstract

Keywords

Introduction

Definitions and assumptions

Histopathological types

Developmental origin

Associated clinical conditions

Potential for resolution

What the snapshot does not do

What the snapshot does do

Types of PH: rationale for assignment of characteristics

Idiopathic persistent pulmonary hypertension of the newborn (PPHN)

Congenital diaphragmatic hernia (CDH)

Pulmonary venous hypertension (PVH)

Bronchopulmonary dysplasia (BPD)

Chronic alveolar hypoxia due to residence at high altitude

Portopulmonary hypertension (POPH)

↑P+Q

Peripheral pulmonary artery stenosis (PPS)

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD)

Tetralogy of Fallot with pulmonary atresia and MAPCAs

Pulmonary vein stenosis (PVS)

Idiopathic pulmonary arterial hypertension (including heritable forms)

Connective tissue disease (CTD) associated PH

Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis spectrum disease (PVOD)

Toxin-associated PH

Summary

Footnotes

Conflict of interest

Funding

References