Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension.

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Prostanoids in pediatric pulmonary hypertension: clinical response, time-to-effect, and dose-response.

For pediatric pulmonary arterial hypertension (PAH) patients treated with parenteral prostanoids, response predictors, and the dose-effect relationship are ill defined. We determined the following: (1) which pulmonary vascular hemodynamic variable, after initiating prostanoids, best correlates with a significant clinical response; (2) the time interval after treatment when if no pulmonary hemodynamic improvement has occurred, none is ever likely to; and (3) the relationship between the prostanoid dose and its hemodynamic effects. This is a retrospective cohort study of 31 pediatric patients with Group 1 PAH treated with parenteral prostanoids. We found the following: (1) A fall in mean pulmonary arterial pressure (mPAP) of ≥25% predicted freedom from adverse clinical events with 80.7% accuracy and was also associated with improved functional class. (2) Thirty-three percent of patients who avoided an adverse clinical event demonstrated a ≥25% reduction in mPAP after 1 year of treatment, and 65% by 2 years. (3) Lower mPAP was seldom seen with doses of epoprostenol >60 ng/kg/min (100 ng/kg/min for treprostinil). Cardiac index was positively correlated with the dose of epoprostenol but not treprostinil; cardiac index >4 l/min/m2 was seen at modest as well as high doses. We conclude that a ≥25% fall in mPAP on prostanoids indicates a positive clinical response which, if validated in other studies, may be useful for patient management or clinical trials. Some patients take more than 2 years for this change. Exceptionally high doses were generally not more effective than lower, although we could not determine whether lower doses would have been as effective.

Improving Safety of Intravenous Prostacyclin Administration to Pediatric Patients With Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension is a rare, life-threatening disease with limited therapeutic options and no definitive cure. Continuous intravenous prostacyclin therapy is indicated for treatment of severe disease. These medications have a narrow therapeutic index and a brief half-life; therefore, administration errors can be lethal. OBJECTIVE: To reduce medication errors through an inpatient program to improve, standardize, and disseminate continuous intravenous prostacyclin therapy practice guidelines. METHODS: Data were collected from the electronic safety reporting system of a single hospital to determine the number and types of continuous intravenous prostacyclin therapy errors that were reported over an 8-year period. A clinical database and hospital pharmacy records were used to determine the number of days on which hospitalized pediatric patients received the therapy. INTERVENTIONS: A nursing-directed quality improvement initiative to enhance the safety of continuous intravenous prostacyclin therapy for pediatric patients was begun in January 2009. Efforts to improve safety fell into 4 domains: policy, process, education, and hospital-wide safety initiatives. RESULTS: The number of therapy errors per 1000 patient days fell from 19.28 in 2009 to 5.95 in 2016. Chi-square analysis was used to compare the result for 2009 with that for each subsequent year, with P values of .66, .35, .16, .09, .03, .12, and .25 found for 2010 through 2016, respectively. CONCLUSIONS: The trend in reduction of continuous intravenous prostacyclin therapy errors suggests that proactive processes to standardize its administration, emphasizing both policy and education, reduce medication errors and increase patient safety.

Pulmonary Artery Banding in Post-tricuspid Congenital Cardiac Shunting Defects with High Pulmonary Vascular Resistance.

Reports of "treat and repair" of cardiac shunting lesions with inoperably high pulmonary vascular resistance (PVR) mostly concern pre-tricuspid defects; post-tricuspid lesions are different. We report our experience with pulmonary artery (PA) banding ± targeted pulmonary hypertension medications in five patients with a large VSD and inoperably high PVR, and review previous reports of PA banding with post-tricuspid defects. Three of our 5 patients had mean PAP > 50 mmHg after banding and no or only a transient fall in PVR. Two patients had mean PAP < 50 mmHg and lower PVR after banding; they had closure of their VSDs but have since had a progressive increase in PVR (follow-up after closure, 3.5 and 7.7 years). Previous reports have also documented difficulty in achieving sufficient band gradient. Of previously reported patients, only one became operable only after banding and targeted therapy, and was repaired; follow-up after repair was short-term (16 months). Our and previous experience demonstrate the difficulty in placing a PA band sufficiently tight to substantially reduce PA pressure. Reported attempts to "treat and repair" post-tricuspid defects are few and have met with limited success, and we found that PVR may increase significantly over time after repair. But more information is needed. Accurate interpretation of experience with "treat and repair" requires: careful characterization of the pulmonary circulation prior to "treating"; considering spontaneously reversible factors at pre-treatment catheterization before ascribing reduction in PVR to medical therapy; and long-term observation of PVR in patients who have had defect closure.

Systemic Ventricular Dysfunction Between Stage One and Stage Two Palliation.

Infants with a single ventricle can develop systemic ventricular dysfunction (SVD) after stage 1 operation, but available information is sparse. We reviewed our patients having Norwood, Sano, or hybrid procedures to better understand this problem. We conducted a retrospective, case-controlled cohort study of 267 patients having stage1 operation, examining outcomes between stages 1 and 2 (survival and subsequent cardiac surgeries), predictor variables, and histology of hearts explanted at transplantation. SVD developed in 32 (12%) patients and resolved in 13 (41%); mean age of onset was 3.0 ± 1.63 months; median = 2.79. SVD was not associated with cardiac anatomy, type of stage 1 procedure, weight, coronary abnormality, or atrioventricular valve regurgitation. The mean age of resolution = 12.1 ± 9.6 months; median = 6.3, and resolution may have been more likely with a systemic LV than RV (p = 0.067). Outcomes for the entire SVD group were less favorable than for those without, but patients with resolution of SVD had outcomes at least as good those without SVD. Myocardial histology (n = 4) suggested chronic ischemia. The risk of SVD after stage 1, while low, may be a fundamental feature of this patient population. SVD occurs with either a systemic RV or LV, although patients with a systemic LV may be more likely to have resolution than those with an RV. We identified no predictor variables, but histologic findings suggest chronic ischemia may be involved. Given the low incidence of SVD, multi-center studies will be required to better define predictors of onset and resolution.

The impact of right ventricular pressure and function on survival in patients with pulmonary vein stenosis.

Pulmonary vein stenosis (PVS) is associated with pulmonary hypertension (PH), but there is little information regarding the impact of PH on right ventricular (RV) systolic function and survival. We conducted a retrospective cohort study of our patients to explore this and other aspects of pulmonary hemodynamics with PVS. RV function was assessed using qualitative two-dimensional echocardiography. The ratio of systolic pulmonary artery (PA) and aortic pressures (PA:Ao) at cardiac catheterization reflected pulmonary hemodynamics. Reactivity testing employed inhaled nitric oxide + 100% fiO2, or 100% fiO2 only; "reactivity" was a ≥ 20% decrease in PA:Ao. There were 105 PVS patients, although not all had data at every time point. (1) The mean PA:Ao at first cardiac catheterization (n = 77) was 0.79 ± 0.36; at last catheterization (n = 54), PA:Ao = 0.69 ± 0.30; 90% had systolic PAP > one-half systemic. Survival was shorter with PA:Ao > 0.5. (2) Differences in survival relative to RV dysfunction on the first echocardiogram were not significant, although they were using the last echocardiogram. (3) The magnitude of RV dysfunction was positively correlated with PA:Ao. (4) Balloon dilation of PV acutely decreased PA:Ao (-0.13 ± 0.37, P = 0.03 [n = 40 patients]). 5. Of 20 patients tested, 13 were acutely reactive to vasodilators. PH is a major feature of PVS. Reduced RV function and PA:Ao appear to be predictors of survival. Given the importance of PH in this disease, clinical studies of PVS treatments should include measures of PAP and RV function as important variables of interest.

Pulmonary hypertension's variegated landscape: a snapshot.

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.

Duration of Mechanical Ventilation and Perioperative Care Quality After Neonatal Cardiac Operations.

BACKGROUND: This study was conducted to determine whether the duration of mechanical ventilation (DOMV) could be used to benchmark the overall quality of care after neonatal congenital heart operations. METHODS: Children aged younger than 30 days undergoing cardiac operations were reviewed. Technical adequacy was assessed using the Technical Performance Score (TPS), a previously validated tool for determining the adequacy of a palliative or corrective surgical procedure that uses echocardiography criteria and need for unplanned reintervention to determine technical adequacy. Preoperative risk factors and postoperative complications were determined using The Society of Thoracic Surgeons Congenital Heart Surgery Database definitions. Surgical complexity was assessed using The Society of Thoracic Surgeons-European Association of Cardio-Thoracic Surgery (STAT) Mortality Categories. We explored associations between preoperative risk factors, STAT category, TPS, and postoperative complications with DOMV. RESULTS: Of 601 patients studied, 49 were not included in the multivariable analysis due to a STAT nonclassifiable operation or unmeasured TPS, or both. Multiple risk factors were associated with longer DOMV, including weight (p = 0.005), The Society of Thoracic Surgeons Congenital Heart Surgery Database preoperative factors (p = 0.005), STAT mortality category (p < 0.001), TPS (p < 0.001), and The Society of Thoracic Surgeons Congenital Heart Surgery Database-defined complications (p < 0.001). Multivariable regression showed that preoperative factors increased DOMV by 1.23 days (p = 0.01), class 3 TPS by 2.16 days (p < 0.001), and postoperative complications by 2.03 days (p < 0.001), with adjusted R2 = 0.42. CONCLUSIONS: Neonates with major residual lesions and postoperative complications have prolonged DOMV. DOMV may reflect the quality of care after congenital heart operations.

Association of Extracorporeal Membrane Oxygenation Support Adequacy and Residual Lesions With Outcomes in Neonates Supported After Cardiac Surgery.

OBJECTIVES: There is a paucity of data regarding the impact of extracorporeal membrane oxygenation support, adequacy of surgical repair, and timing of intervention for residual structural lesions in neonates cannulated to extracorporeal membrane oxygenation after cardiac surgery. Our goal was to determine how these factors were associated with survival. DESIGN: Retrospective study. SETTING: Cardiovascular ICU. SUBJECTS: Neonates (≤ 28 d old) with congenital heart disease cannulated to extracorporeal membrane oxygenation after cardiac surgery during 2006-2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-four neonates were cannulated to venoarterial extracorporeal membrane oxygenation after cardiac surgery. Survival to discharge was 50%. There was no difference in survival based on surgical complexity and those with single or biventricular congenital heart disease. Prematurity (≤ 36 wk gestation; odds ratio, 2.33; p = 0.01), preextracorporeal membrane oxygenation pH less than or equal to 7.17 (odds ratio, 2.01; p = 0.04), need for inotrope support during extracorporeal membrane oxygenation (odds ratio, 3.99; p = 0.03), and extracorporeal membrane oxygenation duration greater than 168 hours (odds ratio, 2.04; p = 0.04) were all associated with increased mortality. Although preextracorporeal membrane oxygenation lactate was not significantly different between survivors and nonsurvivors, unresolved lactic acidosis greater than or equal to 72 hours after cannulation (odds ratio, 2.77; p = 0.002) was associated with increased mortality. Finally, many patients (n = 70; 83%) were noted to have residual lesions after cardiac surgery, and time to diagnosis or correction of residual lesions was significantly shorter in survivors (1 vs 2 d; p = 0.02). CONCLUSIONS: Our data suggest that clearance of lactate is an important therapeutic target for patients cannulated to extracorporeal membrane oxygenation. In addition, timely identification of residual lesions and expedient interventions on those lesions may improve survival.

Lung Pathology in Pediatric Pulmonary Vein Stenosis.

Pulmonary vein stenosis is a rare progressive narrowing of the extrapulmonary pulmonary veins, presenting predominantly in infancy and virtually always lethal. It typically arises following repair of congenital heart disease, particularly anomalous pulmonary venous return. Histologic characterization of pediatric pulmonary vein stenosis, not previously well described, may provide insight into the disease pathobiology. We retrieved archival lung specimens (biopsy, explant, or autopsy) from patients with pediatric pulmonary vein stenosis. Medical records were reviewed. Microscopic examination included hematoxylin and eosin (H&E)-stained slides, and for a subset of patients, elastic, trichrome, smooth-muscle actin, and D2-40. Groups with different clinical disease features were compared using Fisher's exact test. A total of 33 patients (median age, 7 months) had available tissue and 52% had congenital heart disease; 18% were premature. Within the lungs, interlobular septal veins showed thickened muscular coats (in 58%), proliferation/tortuosity (in 6%), and fibromyxoid intimal proliferation (in 3%). Associated arterial hypertensive changes were seen in 30 (91%). The one patient with intrapulmonary venous fibromyxoid intimal proliferation was the only patient with apparent primary familial disease. Lymphangiectasia and arterial medial hypertrophy were histologic features that correlated with clinical grouping. We conclude that in pediatric pulmonary vein stenosis, intrapulmonary pulmonary veins commonly show muscular thickening, best interpreted as venous hypertensive remodeling. Fibromyxoid intimal proliferation resembling that of the extrapulmonary pulmonary veins is uncommon. Awareness of intrapulmonary features in various clinical subtypes of pulmonary vein stenosis may be diagnostically and therapeutically informative considering that current catheter-based and surgical therapy is directed at the extrapulmonary component of pulmonary vein stenosis.

Central venous line complications with chronic ambulatory infusion of prostacyclin analogues in pediatric patients with pulmonary arterial hypertension.

Chronic infusion of prostacyclin (PGI2) via a Broviac central venous line (CVL) is attended by risk of CVL-related complications, but we know of only one report regarding CVL-associated bloodstream infection (BSI) with PGI2 in children and none regarding other complications. We conducted a retrospective cohort study involving pediatric patients with pulmonary hypertension treated with chronic intravenous infusion of PGI2 at Boston Children's Hospital and determined the rate (per 1,000 line-days) of various CVL-related complications. We also determined how often complications necessitated line replacement and hospitalization, time to replacement of CVLs, and interpatient variability in the incidence of complications. From 1999 until 2014, 26 patients meeting follow-up criteria had PGI2 infusion, representing 43,855 line-days; mean follow-up was 56 months (range, 1.4-161 months). The CVL complication rates (per 1,000 line-days) were as follows: CVL-BSI, 0.25; superficial line infection, 0.48; impaired integrity, 0.59; occlusion, 0.09; and malposition, 0.32. The total complication rate was 1.73 cases per 1,000 line-days. All CVL-BSI and malposition cases were treated with CVL removal and replacement. Of CVLs with impaired integrity, 23 could be repaired and 3 required replacement. Six of 21 superficial CVL infections required replacement of the CVL. Three of 4 occluded CVLs were replaced. CVL complications occasioned 65 hospitalizations. There was marked interpatient variability in the rate of complications, much but not all of which appeared to be related to duration of CVL placement. We conclude that non-BSI complications are very significant and that efforts to teach and emphasize other aspects of line care are therefore very important.

Quality of life and parental adjustment in pediatric pulmonary hypertension.

BACKGROUND: This study examines the impact of pulmonary hypertension (PH) on the quality of life (QoL) of affected youth, as well as the relationships among PH disease severity, parental adjustment variables, and family relational functioning. METHODS: Subjects were 47 eligible parents of children with PH aged 2 to 18 years who were evaluated at Boston Children's Hospital. Measures of patient QoL and of parental stress, coping, and adjustment were administered to the caregivers. Clinicians rated illness severity and family relational functioning. RESULTS: Youth with PH scored significantly lower than healthy norms on a measure of parent-reported QoL (total, psychosocial, and physical QoL, each P < .0001). The parents reported encountering stressful events more frequently than published norms of parents of children with cancer (P < .0001). Thirty-four percent of parents of children with PH met criteria for presumed psychiatric diagnosis, and they reported using psychologic coping strategies significantly more often than a normative sample. A summary parental stress measure correlated inversely with child QoL, an effect that held true even after controlling for disease severity (P = .03). CONCLUSIONS: PH takes a major toll on children and their families. Decreased QoL among youth with PH was significantly associated with high levels of parental stress, over and above the effect of illness severity. These findings suggest that interventions to better support the caretakers of affected children and adolescents should accompany medical treatment advances so as to improve QoL for patients facing pediatric PH.

Pulmonary hypertension caused by pulmonary venous hypertension.

The effect of pulmonary venous hypertension (PVH) on the pulmonary circulation is extraordinarily variable, ranging from no impact on pulmonary vascular resistance (PVR) to a marked increase. The reasons for this are unknown. Both acutely reversible pulmonary vasoconstriction and pathological remodeling (especially medial hypertrophy and intimal hyperplasia) account for increased PVR when present. The mechanisms involved in vasoconstriction and remodeling are not clearly defined, but increased wall stress, especially in small pulmonary arteries, presumably plays an important role. Myogenic contraction may account for increased vascular tone and also indirectly stimulate remodeling of the vessel wall. Increased wall stress may also directly cause smooth muscle growth, migration, and intimal hyperplasia. Even long-standing and severe pulmonary hypertension (PH) usually abates with elimination of PVH, but PVH-PH is an important clinical problem, especially because PVH due to left ventricular noncompliance lacks definitive therapy. The role of targeted PH therapy in patients with PVH-PH is unclear at this time. Most prospective studies indicate that these medications are not helpful or worse, but there is ample reason to think that a subset of patients with PVH-PH may benefit from phosphodiesterase inhibitors or other agents. A different approach to evaluating possible pharmacologic therapy for PVH-PH may be required to better define its possible utility.

Pulmonary blood flow and pulmonary hypertension: Is the pulmonary circulation flowophobic or flowophilic?

Increased pulmonary blood flow (PBF) is widely thought to provoke pulmonary vascular obstructive disease (PVO), but the impact of wall shear stress in the lung is actually poorly defined. We examined information from patients having cardiac lesions which impact the pulmonary circulation in distinct ways, as well as experimental studies, asking how altered hemodynamics impact the risk of developing PVO. Our results are as follows: (1) with atrial septal defect (ASD; increased PBF but low PAP), shear stress may be increased but there is little tendency to develop PVO; (2) with normal PBF but increased pulmonary vascular resistance (PVR; mitral valve disease) shear stress may also be increased but risk of PVO still low; (3) with high PVR and PBF (e.g., large ventricular septal defect), wall shear stress is markedly increased and the likelihood of developing PVO is much higher than with high PBF or PAP only; and (4) with ASD, experimental and clinical observations suggest that increased PBF plus another stimulus (e.g., endothelial inflammation) may be required for PVO. We conclude that modestly increased wall shear stress (e.g., ASD) infrequently provokes PVO, and likely requires other factors to be harmful. Likewise, increased PAP seldom causes PVO. Markedly increased wall shear stress may greatly increase the likelihood of PVO, but we cannot discriminate its effect from the combined effects of increased PAP and PBF. Finally, the age of onset of increased PAP may critically impact the risk of PVO. Some implications of these observations for future investigations are discussed.

Dynamic evolution of practice guidelines: analysis of deviations from assessment and management plans.

OBJECTIVE: A Standardized Clinical Assessment and Management Plan (SCAMP) standardizes the care of patients with a predefined diagnosis while actively inviting and collecting data on clinician deviations (DEVs) from its recommendations. For 3 different pediatric cardiac diagnoses managed by SCAMPs, we determined the frequency of, types of, and reasons for DEVs, which are considered to be a valuable source of information and innovation. METHODS: DEVs were collected as part of SCAMP implementation. DEVs were reviewed by the SCAMP committee chairperson and by a separate protocol deviation committee; they were characterized as either justifiable (J), possibly justifiable (PJ), or not justifiable (NJ). RESULTS: We analyzed 415 patients, 484 clinic encounters, and 216 DEVs. Eighty-six (39.8%) of the DEVs were J, 21 (9.7%) were PJ, and 109 (50.4%) were NJ. The percentage of NJ DEVs relative to the number of opportunities for DEV was 4.1%. J and PJ DEVs were mostly due to management of unrelated conditions (11% overall) or special circumstances (22% overall). NJ DEVs primarily involved follow-up intervals (66%) and deleted tests (24%). The reason for deviating from SCAMP recommendations was not given for 31% of DEVs, even though such information was requested. CONCLUSIONS: The overall low rate of NJ DEV suggests that practitioners generally accept SCAMP recommendations, but improved capture of practitioners' reasons for deviating from those recommendations is needed. This analysis revealed multiple opportunities for improving patient care, suggesting that this process can be useful in both promulgating sound practice and evolving improved approaches to patient management.

The impact of pulmonary venous hypertension on the pulmonary circulation in the young.

OBJECTIVE AND DESIGN: Pulmonary venous hypertension is a well-characterized cause of pulmonary hypertension in adults, but little is known regarding the relationship between left atrial pressure and pulmonary arteriolar resistance in the young. Also, in adults relief of pulmonary venous hypertension results in a marked fall in pulmonary arteriolar resistance, but this could be different in children because vascular changes are more severe in young patients than adults with mitral stenosis. We inspected records of children at Children's Hospital Boston having mitral balloon valvuloplasty, and patients ≤5 years old having mitral valve replacement, to determine (1) the relationship between left atrial pressure and pulmonary arterial pressure and resistance (n = 94 children, median age 17.8 months) and (2) how pulmonary arteriolar resistance changes after mitral valve replacement. RESULTS: The average indexed pulmonary arteriolar resistance was 7.8 ± 5.9 units and was unrelated to age but was positively related to left atrial pressure. There was great variability in pulmonary arteriolar resistance for any given left atrial pressure. Pulmonary arterial pressure (n = 16) and pulmonary arterial resistance (n = 9) were measured before and after mitral valve replacement (median = 29.4 months old). Despite preoperative indexed pulmonary arterial resistance of ≥5 units in 11 of 15 patients, postoperative pulmonary arterial pressure was substantially lower in all save three, and two patients with high pulmonary arterial pressure still had high left atrial pressure postoperatively (25 mmHg). CONCLUSIONS: We conclude that in young children, as in adults, pulmonary arterial resistance generally falls greatly with reduction in left atrial pressure.

Pulmonary arterial hypertension: what the large pulmonary arteries tell us.

The morphology of the large intrapulmonary arteries (PAs) in pulmonary hypertension (PH) has received limited attention. Dilation, pruning, abrupt tapering, and tortuosity of PAs occur, but whether different patients have distinct PA phenotypes is unknown. Pulmonary arteriograms from 41 pediatric patients with PH were blindly reviewed by four experts who assigned each angiogram one of three designations: straight (S), tortuous (T), or ambiguous (A). Hemodynamic variables and outcomes were compared to the phenotypes. Thirty patients were either T (19) or S (11); 11 were A. The phenotypes were not associated with age. Tortuous patients had higher PA pressure and resistance than the S group and less likely to react to inhaled nitric oxide than S patients (p < 0.05). Clinical outcomes were similar for the three groups. Thus, in PH patients two subtypes of PA morphology can often be discerned, a reflection of variability in PA tortuosity. These morphological subtypes have differing hemodynamic characteristics. The mechanism(s) underlying these differences is unknown, but neither hydrodynamic factors nor duration of PH are fully explanatory. Because PA morphology might reveal information regarding the biology of pathological remodeling, it might prove enlightening to assess the large PA phenotype in future studies of PH.