Pulmonary Circulation

Right ventricular failure (RVF) is the most important prognostic factor for both morbidity and mortality in pulmonary arterial hypertension (PAH), but also occurs in numerous other common diseases and conditions, including left ventricle dysfunction. RVF remains understudied compared with left ventricular failure (LVF). However, right and left ventricles have many differences at the morphological level or the embryologic origin, and respond differently to pressure overload. Therefore, knowledge from the left ventricle cannot be extrapolated to the right ventricle. Few studies have focused on the right ventricle and have permitted to increase our knowledge on the right ventricular-specific mechanisms driving decompensation. Here we review basic principles such as mechanisms accounting for right ventricle hypertrophy, dysfunction, and transition toward failure, with a focus on epigenetics, inflammatory, and metabolic processes.

Within the cohort of patients suffering from idiopathic pulmonary arterial hypertension (IPAH) is a group that responds dramatically (VR-PAH) to an acute vasodilator challenge and that has excellent long-term hemodynamic improvement and prognosis on high dose calcium channel blockers compared with vasodilator non-responders (VN-PAH). For the purposes of diagnosing VR-PAH, there is to date no test to replace the acute vasodilator challenge. However, recent studies have identified markers that may aid in the identification of VR-PAH, including peripheral blood lymphocyte RNA expression levels of desmogelin-2 and Ras homolog gene family member Q, and plasma levels of provirus integration site for Moloney murine leukemia virus. Genome wide-array studies of peripheral blood DNA have demonstrated differences in disease specific genetic variants between VR-PAH and NR-PAH, with particular convergence on cytoskeletal function pathways and Wnt signaling pathways. These studies offer hope for future non-invasive identification of VR-PAH, and insights into pathogenesis that may lead to novel therapies. Examination of the degree of pulmonary microvascular perfusion in PAH has offered additional insights. During the acute vasodilator challenge, VR-PAH patients demonstrate true vasodilation with recruitment and increased perfusion of the capillary bed, while VN-PAH patients are unable to recruit vasculature. In the very few reports of lung histology, VR-PAH has more medial thickening in the precapillary arterioles, while VN-PAH has the classic histology of PAH, including intimal thickening. VR-PAH is a disorder with a phenotype distinct from VN-PAH and other types of PAH, and should be considered separately in the classification of PAH.

Therapies that target the prostacyclin pathway are considered effective, yet are complex to dose and may cause dose-limiting side effects for patients with pulmonary arterial hypertension (PAH). Careful side effect management and the ability to discern side effects from worsening disease are essential in order for patients to continue, and benefit from, prostacyclin therapy. This manuscript was developed through a collaborative effort of allied health providers with extensive experience in managing patients with PAH who are treated with medications that target the prostacyclin pathway. This article provides an overview of individual prostacyclin pathway therapies approved in the United States, side effects most commonly associated with these therapies, and practical suggestions for side effect management. Most patients will experience significant side effects on prostacyclin therapy. Creating a proactive and careful side effect management program will increase the likelihood that patients are able to stay on therapy and receive the benefits afforded by prostacyclin therapy.

Pulmonary arterial hypertension (PAH) affects the physical and emotional wellbeing of patients. More information is needed regarding mental problems and preferences for support. Qualitative interviews were used to explore mental problems and preference for support of PAH patients. Additionally, a survey was used to assess the presence of mental problems (Problem List), distress (Distress Thermometer) and the need for mental support. In 24 semi-structured interviews, the following problem themes were identified: energy balance; loss of abilities; feeling misunderstood; and handling of worries and emotions. Need for support was based on an interplay between resilience to psychological distress, additional life problems, age, disease status, attitude towards professional help, and experienced support from significant others. The results from the survey highlight the need for professional support, as 50.8% of the 67 patients who completed the survey would consider support when offered, specifically when offered by a pulmonary hypertension (PH) professional. Younger age (odds ratio [OR] = 0.97, P = 0.04), depression (OR = 11.435, P = 0.001) and possibly anxiety (OR = 3.831, P = 0.069) were related to need for support. In conclusion, many patients with PAH are in need of mental support, which should be offered by a PH professional and tailored to phase of the disease and personal characteristics.

Increased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability. Fine PM induced time-dependent activation of cytoskeletal machinery with increases in myosin light chain (MLC) phosphorylation and EC barrier disruption measured by transendothelial electrical resistance (TER), events attenuated by the Rho-dependent kinase (ROCK) inhibitor Y-27632 or the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC). Both Y-27632 and NAC prevented PM-induced stress fiber formation and phospho-MLC accumulation in human lung ECs. PM promotes rapid accumulation of Rho-GTP. This event is attenuated by NAC or knockdown of RhoA (siRNA). Consistent with ROCK activation, PM induced phosphorylation of myosin light chain phosphatase (MYPT) at Thr850, a post-translational modification known to inhibit phosphatase activity. Furthermore, PM activates the guanine nucleotide exchange factor (GEF) for Rho, p115, with p115 translocation to the cell periphery, in a ROS-dependent manner. Together these results demonstrate that fine PM induces EC cytoskeleton rearrangement via Rho-dependent pathways that are dependent upon the generation of oxidative stress. As the disruption of vascular integrity further contributes to cardiopulmonary physiologic derangements, these findings provide pharmacologic targets for prevention of PM-induced cardiopulmonary toxicity.

Pulmonary arterial hypertension (PAH) is associated with metabolic derangements including insulin resistance, although their effects on the cardiopulmonary disease are unclear. We hypothesized that insulin resistance promotes pulmonary hypertension (PH) development and mutations in type 2 bone morphogenetic protein receptor (BMPR2) cause cellular insulin resistance. Using a BMPR2 transgenic murine model of PAH and two models of inducible diabetes mellitus, we explored the impact of hyperglycemia and/or hyperinsulinemia on development and severity of PH. We assessed insulin signaling and insulin-mediated glucose uptake in human endothelial cells with and without mutations in BMPR2. PH developed in control mice fed a Western diet and PH in BMPR2 mutant mice was increased by Western diet. Pulmonary artery pressure correlated strongly with fasting plasma insulin but not glucose. Reactive oxygen species were increased in lungs of insulin-resistant animals. BMPR2 mutation impaired insulin-mediated endothelial glucose uptake via reduced glucose transporter translocation despite intact insulin signaling. Experimental hyperinsulinemia is strongly associated with PH in both control and BMPR2-mutant mice, though to a greater degree in those with BMPR2 mutation. Human pulmonary endothelial cells with BMPR2 mutation have evidence of reduced glucose uptake due to impaired glucose transporter translocation. These experiments support a role for hyperinsulinemia in pulmonary vascular disease.

In patients with Eisenmenger syndrome, life expectancy is usually longer than in patients with other forms of pulmonary arterial hypertension (PAH). We conducted a cohort study in which patients were followed over a long period of time in an attempt to identify potential predictors of clinical outcomes. Sixty-seven treatment-naïve patients were enrolled (age range = 12–60 years; median age = 33 years). Baseline demographic, diagnostic, and functional parameters, plasma levels of endothelial dysfunction markers, and treatment-related data were tested for possible correlations with event-free survival. Patients were started on oral PAH drugs at the beginning of follow-up (n = 23), during follow-up (n = 33), or remained untreated (n = 11). The duration of follow-up was 0.54–9.89 years (median = 7.13 years), with an overall survival rate of 82% and an event-free survival rate of 70%. The estimated mean for event-free survival time was 7.71 years (95% confidence interval [CI] = 6.86–8.55 years). Of the 16 variables that were analyzed, the duration of exposure to PAH drugs was identified as an independent protective factor (hazard ratio [HR] = 0.25 for quartiles, 95% CI = 0.14–0.47, P < 0.001). The initial functional class (HR = 3.07; 95% CI = 1.01–9.34; P = 0.048), the severity of right ventricular dysfunction (HR = 2.51 [mild, moderate or severe dysfunction]; 95% CI = 1.22–5.19; P = 0.013) and plasma von Willebrand factor concentration (HR = 1.74 for quartiles; 95% CI = 1.07–2.83; P = 0.026) were identified as risk factors. The length of exposure to oral PAH therapies influences survival favorably in Eisenmenger patients. This may be of interest for communities where access to medications is restricted.

Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.

Borderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP’s in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP <25 mmHg and pulmonary arterial wedge pressure ≤15 mmHg (n = 312) were stratified by mPAP < 13, 13–16, 17–20, and 21–24 mmHg. Those with ePH (n = 35) were compared with resting precapillary pulmonary hypertension (rPH; n = 16) and to those with normal hemodynamics (non-PH; n = 224). ePH prevalence was 6%, 8%, and 27% for resting mPAP 13–16, 17–20, and 21–24 mmHg, respectively. Within each of these resting mPAP epochs, ePH negatively impacted exercise capacity compared with non-PH (peak oxygen uptake 70 ± 16% versus 92 ± 19% predicted, P < 0.01; 72 ± 13% versus 86 ± 17% predicted, P < 0.05; and 64 ± 15% versus 82 ± 19% predicted, P < 0.001, respectively). Overall, ePH and rPH had similar functional limitation (peak oxygen uptake 67 ± 15% versus 68 ± 17% predicted, P > 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 ± 599 mL/min versus 1756 ± 720 mL/min versus 2482 ± 875 mL/min, respectively; P < 0.05), associated with chronotropic incompetence, increased right ventricular afterload and signs of right ventricular/pulmonary vascular uncoupling. In conclusion, ePH is most frequently found in borderline mPAP, reducing exercise capacity in a manner similar to rPH. When borderline mPAP is identified at RHC, evaluation of the pulmonary circulation under the stress of exercise is warranted.

We hypothesized that K_PA, a harmonic oscillator kinematics-derived spring constant parameter of the pulmonary artery pressure (PAP) profile, reflects PA compliance in pediatric patients. In this prospective study of 33 children (age range = 0.5–20 years) with various cardiac diseases, we assessed the novel parameter designated as K_PA calculated using the pressure phase plane and the equation K_PA = (dP/dt_max)²/([Pmax – Pmin])/2)², where dP/dt_max is the peak derivative of PAP, and Pmax – Pmin is the difference between the minimum and maximum PAP. PA compliance was also calculated using two conventional methods: systolic PA compliance (sPAC) was expressed as the stroke volume/Pmax – Pmin; and diastolic PA compliance (dPAC) was determined according to a two-element Windkessel model of PA diastolic pressure decay. In addition, data were recorded during abdominal compression to determine the influence of preload on K_PA. A significant correlation was observed between K_PA and sPAC (r = 0.52, P = 0.0018), but not dPAC. Significant correlations were also seen with the time constant (τ) of diastolic PAP (r = −0.51, P = 0.0026) and the pulmonary vascular resistance index (r = −0.39, P = 0.0242). No significant difference in K_PA was seen between before and after abdominal compression. K_PA had a higher intraclass correlation coefficient than other compliance and resistance parameters for both intra-observer and inter-observer variability (0.998 and 0.997, respectively). These results suggest that K_PA can provide insight into the underlying mechanisms and facilitate the quantification of PA compliance.

Pulmonary hypertension (PH) is common in patients with chronic kidney disease (CKD) and associated with increased mortality but the hemodynamic profiles, clinical risk factors, and outcomes have not been well characterized. Our objective was to define the hemodynamic profile and related risk factors for PH in CKD patients. We extracted clinical and hemodynamic data from Vanderbilt’s de-identified electronic medical record on all patients undergoing right heart catheterization during 1998–2014. CKD (stages III–V) was defined by estimated glomerular filtration rate thresholds. PH was defined as mean pulmonary pressure ≥ 25 mmHg and categorized into pre-capillary and post-capillary according to consensus recommendations. In total, 4635 patients underwent catheterization: 1873 (40%) had CKD; 1518 (33%) stage 3, 230 (5%) stage 4, and 125 (3%) stage 5. PH was present in 1267 (68%) of these patients. Post-capillary (n = 965, 76%) was the predominant PH phenotype among CKD patients versus 302 (24%) for pre-capillary (P < 0.001). CKD was independently associated with pulmonary hypertension (odds ratio = 1.4, 95% confidence interval = 1.18–1.65). Mortality among CKD patients rose with worsening stage and was significantly increased by PH status. PH is common and independently associated with mortality among CKD patients referred for right heart catheterization. Post-capillary was the most common etiology of PH. These data suggest that PH is an important prognostic co-morbidity among CKD patients and that CKD itself may have a role in the development of pulmonary vascular disease in some patients.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) require lifelong anticoagulation therapy. However, the bleeding risk and recurrence of venous thromboembolism (VTE) in CTEPH patients who are administered warfarin have not been adequately evaluated. The purpose of this study was to evaluate the risk of clinically relevant bleeding, recurrent VTE, and clinical worsening in patients with CTEPH who were administered warfarin.

The clinical records of 72 patients with CTEPH who regularly visited our institution and were administered warfarin were retrospectively reviewed between 1 January 2011 and 31 December 2015. We investigated the incidence of clinically relevant bleeding events, recurrent VTE, and hospitalization for the deterioration of pulmonary hypertension or right heart failure (RHF) during the observation period.

The mean observation period for the 72 patients was 3.60 ± 1.60 person-years. Clinically relevant bleeding, RHF, and recurrent VTE occurred in 21 (29.2%), eight (11.1%), and three (4.2%) of 72 patients, respectively, and the incidence rates for these events were 8.1%/person-year, 3.1%/person-year, and 1.2%/person-year, respectively. The incidence rates for the major and non-major bleeding events were 5.0%/person-year and 3.9%/person-year, respectively. The incidence of clinically relevant bleeding events was 20.8%/person-year during medical treatment with a soluble guanylate cyclase stimulator. One of 35 patients (2.9%) during the post-pulmonary endarterectomy period experienced hemoptysis during observation period (> 6 months after pulmonary endarterectomy). No bleeding events occurred during the post-balloon pulmonary angioplasty period.

In conclusion, warfarin effectively prevents VTE recurrence in CTEPH patients, but its effects may be associated with a considerable bleeding risk.

Anticoagulants are widely used in patients with pulmonary arterial hypertension (PAH) to prolong survival. However, there is a lack of robust evidence demonstrating the benefits of anticoagulants in PAH patients and very little is known about the complications of their use in this population. The objective of this study is to compare the safety of routine administration of oral anticoagulants between PAH patients who were and were not treated with oral anticoagulants. This observational, retrospective cohort study included consecutive patients with confirmed PAH from two centers: Brigham and Women’s Hospital in Boston and Hospital Universitario La Paz in Madrid from January 2009 to August 2015. The study group comprised patients who received therapeutic anticoagulation; patients who had never received anticoagulants were placed in the control group. Of the 201 included patients, 60.2% were treated with oral anticoagulants and 39.8% were not treated. The hazard ratio for major bleeding was 2.7 (95% confidence interval [CI] = 1.1–6.8; P = 0.036). The incidence rate for the anticoagulation group was 4.7 per 100 patient-years (95% CI = 2.5–8.0). The most frequent major hemorrhage was gastrointestinal bleeding with 24 cases (72.7%). Prior bleeding, poor anticoagulation, HAS-BLED score ≥3, diabetes, and number of medications were factors that increased the risk of major bleeding in patients using anticoagulants. The harmful effects of anticoagulants could outweigh the benefits in PAH patients. Therefore, anticoagulants should be prescribed on a case-by-case basis and should not be systematically recommended.

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug–drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH.

Portopulmonary hypertension (PoPH) is defined by the combination of portal hypertension and precapillary pulmonary arterial hypertension (PAH). Very little is known about this process in pediatric patients but prognosis is generally poor. We review our institutional experience and report on five patients with pediatric PoPH. The median age of PoPH diagnosis was six years and PAH was 14 years. PAH diagnosis was made by echocardiogram in all patients, four of whom also had cardiac catheterization. The median mean pulmonary artery pressure (mPAP) was 48.5 mmHg (interquartile range [IQR] = 46–60) with a median pulmonary vascular resistance index (PVRi) of 9 WU*M² (IQR = 8–22). All were acute pulmonary vasodilator testing non-responsive. All patients received targeted therapies. Three of five patients (60%) died despite an evidence-based approach to care. Of those who died, timing from the PoPH diagnosis to death ranged from three days to three years. Based upon our limited experience, PoPH is a disorder with significant mortality in childhood and challenges in treatment. Future research, focused on screening and early targeted treatment strategies, may alter the current dismal prognosis for these children.

Hypercapnic acidosis (HCA) has beneficial effects in experimental models of lung injury by attenuating inflammation and decreasing pulmonary edema. However, HCA increases pulmonary vascular pressure that will increase fluid filtration and worsen edema development. To reconcile these disparate effects, we tested the hypothesis that HCA inhibits endothelial mechanotransduction and protects against pressure-dependent increases in the whole lung filtration coefficient (K_f). Isolated perfused rat lung preparation was used to measure whole lung filtration coefficient (K_f) at two levels of left atrial pressure (P_LA = 7.5 versus 15 cm H₂O) and at low tidal volume (LV_t) versus standard tidal volume (STV_t) ventilation. The ratio of K_f2/K_f1 was used as the index of whole lung permeability. Double occlusion pressure, pulmonary artery pressure, pulmonary capillary pressures, and zonal characteristics (ZC) were measured to assess effects of HCA on hemodynamics and their relationship to K_f2/K_f1. An increase in P_LA2 from 7.5 to 15 cm H₂O resulted in a 4.9-fold increase in K_f2/K_f1 during LV_t and a 4.8-fold increase during STV_t. During LV_t, HCA reduced K_f2/K_f1 by 2.7-fold and reduced STV_t K_f2/K_f1 by 5.2-fold. Analysis of pulmonary hemodynamics revealed no significant differences in filtration forces in response to HCA. HCA interferes with lung vascular mechanotransduction and prevents pressure-dependent increases in whole lung filtration coefficient. These results contribute to a further understanding of the lung protective effects of HCA.

Leptin (a neuroendocrine peptide that enhances metabolism and acts on the hypothalamus to suppress appetite) and adiponectin (a protein that has insulin-sensitizing, anti-inflammatory, and antiproliferative properties) are involved in the pathobiology of pulmonary arterial hypertension (PAH). We hypothesized that plasma leptin and adiponectin as well as the leptin/adiponectin ratio are abnormal in PAH patients and their levels track with disease severity and functional changes during follow-up. We tested this hypothesis in a cohort of patients included in the 16-week, international, multicenter, double-blind, placebo-controlled FREEDOM-C2 study. Blood was collected at baseline and week 16 in 178 out of 310 randomized patients with PAH. Baseline plasma leptin and adiponectin concentrations were 25 ± 31 ng/mL and 7.8 ± 6.1 ug/mL, respectively. Leptin, adiponectin, and leptin/adiponectin (mean ± SD) changes at 16 week were of small magnitude. Leptin at baseline was significantly associated with older age, higher BMI, higher Borg dyspnea index, and lower NT-pro BNP. Women had higher levels of leptin than men (30.5 ± 33.2 versus 7.2 ± 6.4 ng/mL), even when adjusting for background therapy and etiology (linear regression: β = 21.8, P < 0.001). Adiponectin was negatively associated with BMI and positively associated with NT-pro BNP. Changes in leptin, adiponectin, and leptin/adiponectin ratio adjusted for weight at 16 weeks did not predict functional class, distance walk in 6 min or survival at one, two, three, or four years. Plasma leptin and adiponectin at baseline and their change at 16-week do not appear to significantly impact prognosis in PAH.

Macrophage migration inhibitory factor (MIF) and 22 a priori selected biomarkers were measured from pulmonary arterial hypertension (PAH) patients. Significant positive correlations were found between MIF and several angiogenic factors suggesting a possible MIF regulation role in PAH angiogenesis and pathobiology, but simultaneously highlighting the biomarkers profiling complexity in PAH.

Left main coronary artery (LMCA) disease due to external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity. Here, we describe a 52-year-old woman with pulmonary arterial hypertension (PAH) and anteroseptal old myocardial infarction (OMI). The cause of the OMI was external compression of the LMCA by the dilated MPA and aneurysm of the left coronary sinus of Valsalva. The patient’s sister (aged 56 years) had also been diagnosed with PAH and both women had a novel heterozygous splicing mutation, IVS2-2A > G (c.374-2A > G in NM_001456), in the filamin A (FLNA) gene. To our knowledge, this is the first report of HPAH which is likely to be due to FLNA mutation and compression of the LMCA between a dilated MPA and aneurysm of the left coronary sinus of Valsalva.

Patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-PAH-CTD) such as systemic sclerosis (SSc) have a poorer response to treatment and increased mortality compared with patients with idiopathic PAH. Current treatment options for PAH-CTD include prostanoids, phosphodiesterase type-5 inhibitors (PDE-5i), endothelin receptor antagonists, and the soluble guanylate cyclase stimulator riociguat. In this case series, we describe three patients with PAH-CTD related to limited scleroderma who were switched from a PDE-5i to riociguat due to insufficient clinical response. The switch to riociguat was associated with an improvement in respiratory and hemodynamic parameters and a favorable tolerability profile. These cases demonstrate that switching to riociguat is a therapeutic option in patients with PAH-CTD who have not achieved a satisfactory clinical response to a PDE-5i.

Pulmonary arterial hypertension (PAH) is a frequent complication of congenital heart disease as a consequence of altered pulmonary hemodynamics with increased pulmonary blood flow and pressure. The development of pulmonary vascular disease (PVD) in this patient population is an important concern in determining operative strategy. Early, definitive surgical repair, when possible, is the best therapy to prevent and treat PVD. However, this is not possible in some patients because they either presented late, after the development of PVD, or they have complex lesions not amenable to one-step surgical correction, including patients with single ventricle physiology, who have a continuing risk of developing PVD. These patients represent an important, high-risk subgroup and many have been considered inoperable. We present a case series of two patients with complex congenital heart disease and advanced PVD who successfully underwent a treat and repair strategy with aggressive PAH therapies before surgical correction. Both patients had normalization of pulmonary vascular resistance prior to surgical correction. Caution is warranted in applying this strategy broadly and long-term follow-up for these patients is crucial. However, this treat and repair strategy may allow for favorable outcomes among some patients who previously had no therapeutic options.