Pulmonary Circulation

The development of pulmonary hypertension is a poor prognostic sign in patients with obstructive sleep apnea (OSA) and affects both mortality and quality of life. Although pulmonary hypertension in OSA is traditionally viewed as a result of apneas and intermittent hypoxia during sleep, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressure. Human data show that pulmonary hypertension in the setting of OSA is, in large part, due to left heart dysfunction with either preserved or diminished ejection fraction. Longstanding increased left heart filling pressures eventually lead to pulmonary venous hypertension. The combination of hypoxic pulmonary vasoconstriction and pulmonary venous hypertension with abnormal production of mediators will result in vascular cell proliferation and aberrant vascular remodeling leading to pulmonary hypertension. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest shared mechanisms. The majority of patients with OSA do not receive a diagnosis and are undertreated. Appreciating the high prevalence and understanding the mechanisms of pulmonary hypertension in OSA would lead to better recognition and management of the condition.

Intracellular pH (pH_i) homeostasis is key to the functioning of vascular smooth muscle cells, including pulmonary artery smooth muscle cells (PASMCs). Sodium-hydrogen exchange (NHE) is an important contributor to pH_i control in PASMCs. In this review, we examine the role of NHE in PASMC function, in both physiologic and pathologic conditions. In particular, we focus on the contribution of NHE to the PASMC response to hypoxia, considering both acute hypoxic pulmonary vasoconstriction and the development of pulmonary vascular remodeling and pulmonary hypertension in response to chronic hypoxia. Hypoxic pulmonary hypertension remains a disease with limited therapeutic options. Thus, this review explores past efforts at disrupting NHE signaling and discusses the therapeutic potential that such efforts may have in the field of pulmonary hypertension.

Increased peripheral resistance of small distal pulmonary arteries is a hallmark signature of pulmonary hypertension (PH) and is believed to be the consequence of enhanced vasoconstriction to agonists, thickening of the arterial wall due to remodeling, and increased thrombosis. The elevation in arterial tone in PH is attributable, at least in part, to smooth muscle cells of PH patients being more depolarized and displaying higher intracellular Ca²⁺ levels than cells from normal subjects. It is now clear that downregulation of voltage-dependent K⁺ channels (e.g., Kv1.5) and increased expression and activity of voltage-dependent (Cav1.2) and voltage-independent (e.g., canonical and vanilloid transient receptor potential [TRPC and TRPV]) Ca²⁺ channels play an important role in the functional remodeling of pulmonary arteries in PH. This review focuses on an anion-permeable channel that is now considered a novel excitatory mechanism in the systemic and pulmonary circulations. It is permeable to Cl⁻ and is activated by a rise in intracellular Ca²⁺ concentration (Ca²⁺-activated Cl⁻ channel, or CaCC). The first section outlines the biophysical and pharmacological properties of the channel and ends with a description of the molecular candidate genes postulated to encode for CaCCs, with particular emphasis on the bestrophin and the newly discovered TMEM16 and anoctamin families of genes. The second section provides a review of the various sources of Ca²⁺ activating CaCCs, which include stimulation by mobilization from intracellular Ca²⁺ stores and Ca²⁺ entry through voltage-dependent and voltage-independent Ca²⁺ channels. The third and final section summarizes recent findings that suggest a potentially important role for CaCCs and the gene TMEM16A in PH.

Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease in which an increase in pulmonary vascular resistance leads to increased afterload on the right ventricle (RV), causing right heart failure and death. Our understanding of the pathophysiology of RV dysfunction in PAH is limited but is constantly improving. Increasing evidence suggests that in PAH RV dysfunction is associated with various components of metabolic syndrome, such as insulin resistance, hyperglycemia, and dyslipidemia. The relationship between RV dysfunction and fatty acid/glucose metabolites is multifaceted, and in PAH it is characterized by a shift in utilization of energy sources toward increased glucose utilization and reduced fatty acid consumption. RV dysfunction may be caused by maladaptive fatty acid metabolism resulting from an increase in fatty acid uptake by fatty acid transporter molecule CD36 and an imbalance between glucose and fatty acid oxidation in mitochondria. This leads to lipid accumulation in the form of triglycerides, diacylglycerol, and ceramides in the cytoplasm, hallmarks of lipotoxicity. Current interventions in animal models focus on improving RV dysfunction through altering fatty acid oxidation rates and limiting lipid accumulation, but more specific and effective therapies may be available in the coming years based on current research. In conclusion, a deeper understanding of the complex mechanisms of the metabolic remodeling of the RV will aid in the development of targeted treatments for RV failure in PAH.

Our previous work has shown that the increased lung endothelial permeability response to 14,15-epoxyeicosatrienoic acid (14,15-EET) in rat lung requires Ca²⁺ entry via vanilloid type-4 transient receptor potential (TRPV4) channels. Recent studies suggest that activation of TRPV4 channels in systemic vascular endothelium prolongs agonist-induced hyperpolarization and amplifies Ca²⁺ entry by activating Ca²⁺-activated K⁺ (K_Ca) channels, resulting in vessel relaxation. Activation of endothelial K_Ca channels thus has potential to increase the electrochemical driving force for Ca²⁺ influx via TRPV4 channels and to amplify permeability responses to TRPV4 activation in lung. To examine this hypothesis, we used Western blot analysis, electrophysiological recordings, and isolated-lung permeability measurements to document expression of TRPV4 and K_Ca channels and the potential for functional coupling. The results show that rat pulmonary microvascular endothelial cells express TRPV4 and 3 K_Ca channels of different conductances: large (BK), intermediate (IK), and small (SK3). However, TRPV4 channel activity modulates the IK and SK3, but not the BK, channel current density. Furthermore, the TRPV4-mediated permeability response to 14,15-EET in mouse lung is significantly attenuated by pharmacologic blockade of IK and SK3, but not BK, channels. Collectively, this functional coupling suggests that endothelial TRPV4 channels in rodent lung likely form signaling microdomains with IK and SK3 channels and that the integrated response dictates the extent of lung endothelial injury caused by 14,15-EET.

Compliance (C) and resistance (R) maintain a unique, inverse relationship in the pulmonary circulation, resulting in a constant characteristic time τ = RC that has been observed in healthy subjects as well as patients with pulmonary arterial hypertension (PAH). However, little is known about the dependence of right ventricular (RV) function on the coupled changes in R and C in the context of this inverse relationship. We hypothesized three simple dependencies of RV ejection fraction (RVEF) on R and C. The first model (linear-R) assumes a linear RVEF-R relation; the second (linear-C) assumes a linear RVEF-C relation; and the third one combines the former two in a mixed linear model. We found that the linear-R model and the mixed linear model are in good agreement with clinical evidence. A conclusive validation of these models will require more clinical data. Longitudinal data in particular are needed to identify the time course of ventricular-vascular impairment in PAH. Simple models like the ones we present here, once validated, will advance our understanding of the mechanisms of RV failure, which could improve strategies to manage RV dysfunction in PAH.

Riociguat is the first oral soluble guanylate cyclase stimulator shown to improve pulmonary hemodynamics in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH). This pilot study assessed the impact of a single dose of riociguat on hemodynamics, gas exchange, and lung function in patients with PH associated with chronic obstructive pulmonary disease (COPD). Adults with COPD-associated borderline or manifest PH (pulmonary vascular resistance > 270 dyn·s·cm⁻⁵, mean pulmonary artery pressure ≥ 23 mmHg, ratio of forced expiratory volume in 1 second [FEV₁] to forced vital capacity < 70%, and partial pressure of oxygen and carbon dioxide in arterial blood > 50 and ≤ 55 mmHg, respectively) received riociguat 1 or 2.5 mg during right heart catheterization. Twenty-two patients completed the study (11 men, 11 women, aged 56–82 years; 1-mg group: n = 10 [mean FEV₁: 43.1%]; 2.5-mg group: n = 12 [mean FEV₁: 41.2%]). Riociguat caused significant improvements (P < 0.01) from baseline in mean pulmonary artery pressure (1 mg: −3.60 mmHg [–11.44%]; 2.5 mg: −4.83 mmHg [–14.76%]) and pulmonary vascular resistance (1 mg: −58.32 dyn·s·cm⁻⁵ [–15.35%]; 2.5 mg: −123.8 dyn·s·cm⁻⁵ [–32.96%]). No relevant changes in lung function or gas exchange were observed. Single doses of riociguat were well tolerated and showed promising hemodynamic effects without untoward effects on gas exchange or lung function in patients with COPD-associated PH. Placebo-controlled studies of chronic treatment with riociguat are warranted.

Vasoreactivity testing with inhaled NO is recommended for pulmonary arterial hypertension (PAH) because of its therapeutic and prognostic value. Sildenafil has acute pulmonary vasodilating properties, but its diagnostic and prognostic impact in PAH is unknown. Our objective was to compare acute vasodilating responses to sildenafil and those to NO during right heart catheterization and also their prognostic values in patients with PAH. Ninety-nine patients with idiopathic PAH and 99 with associated PAH underwent vasoreactivity testing with NO and sildenafil. Only mild adverse effects of sildenafil, in the form of hypotension, were observed, at a rate of 4.5%. The acute responder rate was 8.1% for NO and 11.6% for sildenafil. The NO-induced response in mean pulmonary arterial pressure and cardiac output correlated with the response to sildenafil. Thirteen patients were long-term responders to calcium channel blockers (CCBs), and 3 of them were correctly identified by acute vasoreactivity test with both drugs. The specificity of the vasoreactivity test for identifying long-term CCB responders was 88.9% for NO and 85.1% for sildenafil testing. A trend toward better survival was found in sildenafil and NO responders, compared with nonresponders. Use of sildenafil for vasoreactivity testing is safe. Sildenafil may be useful as alternative vasoreactivity-testing agent, identifying the same number of long-term CCB responders as NO. However, NO seems to be a more ideal testing drug because of its pharmacologic properties. Moreover, sildenafil vasoreactivity testing might contribute to an improved estimate of prognosis among patients with PAH.

This study sought to determine the prevalence of coronary artery–pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to correlate their presence with the degree of clot burden. CTEPH is a treatable cause of severe pulmonary hypertension and right heart failure. Bronchopulmonary collateral vessels have been used as a supplementary diagnostic and prognostic tool for this disease. Coronary artery–pulmonary artery collaterals in this population have not been described. The coronary angiograms of 300 consecutive patients with CTEPH evaluated for pulmonary thromboendarterectomy (PTE) between January 1, 2007, and May 1, 2014, were examined. Of these patients, 259 (50% male; mean age, 58.3 ± 10.6 years) had cineangiographic images deemed adequate to definitively assess for the presence of coronary artery–pulmonary artery collaterals and were included in the final analyses. Pulmonary angiogram reports were reviewed for extent of pulmonary artery obstruction. The coronary angiograms of 259 age- and sex-matched control patients were also examined. Among 259 CTEPH patients with definitive imaging, 34 coronary artery–pulmonary artery collaterals were found in 28 patients (10.8%), versus 1 coronary artery–pulmonary artery collateral among control subjects (0.4%; P < 0.001). Compared with CTEPH patients without collaterals, patients with collaterals had a significantly higher prevalence of total occlusion of their right or left main pulmonary artery (P < 0.001) or lobar arteries (P < 0.001). In conclusion, the prevalence of coronary artery–pulmonary artery collaterals in CTEPH patients undergoing coronary angiography for possible PTE is approximately 11%. These vessels are associated with more severe pulmonary artery occlusion.

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.

Patients with scleroderma (SSc)–associated pulmonary arterial hypertension (PAH) have worse survival than patients with idiopathic PAH (IPAH). We hypothesized that the right ventricle (RV) adapts differently in SSc-PAH versus IPAH. We used cardiac magnetic resonance imaging (cMRI) and hemodynamic characteristics to assess the relationship between RV morphology and RV load in patients with SSc-PAH and IPAH. In 53 patients with PAH (35 with SSc-PAH and 18 with IPAH) diagnosed by right heart catheterization (RHC), we examined cMRIs obtained within 48 hours of RHC and compared RV morphology between groups. Regression analysis was used to assess the association between diagnosis (IPAH vs. SSc-PAH) and RV measurements after adjusting for age, sex, race, body mass index (BMI), left ventricular (LV) mass, and RV load. There were no significant differences in unadjusted comparisons of cMRI measurements between the two groups. Univariable regression showed RV mass index (RVMI) was linearly associated with measures of RV load in both the overall cohort and within each group. Multivariable linear regression models revealed a significant interaction between disease type and RVMI adjusting for pulmonary vascular resistance (PVR), age, sex, race, BMI, and LV mass. This model showed a decreased slope in the relationship between RVMI and PVR in the SSc-PAH group compared with the IPAH group. RVMI varies linearly with measures of RV load. After adjusting for multiple potential confounders, patients with SSc-PAH demonstrated significantly less RV hypertrophy with increasing PVR than patients with IPAH. This difference in adaptive hypertrophy may in part explain previously observed decreased contractility and poorer survival in SSc-PAH.

Asthma is increasingly recognized as a heterogeneous disease influenced by complex genetic and environmental contributions. Myosin light chain kinase (MLCK; gene symbol, MYLK), especially the nonmuscle isoform nmMLCK, is a cytoskeleton protein known to be related to human asthma susceptibility and severity, findings confirmed in preclinical models of asthmatic inflammation. In this study, we define the central capacity for a nmMLCK-influenced gene signature in human peripheral blood mononuclear cells to predict human asthma severity and exacerbation status. We refined this signature from a list of nmMLCK-influenced genes identified in lung tissues of nmMLCK knockout mice exposed to inflammatory stimuli (ventilator-induced lung injury), with subsequent identification of nmMLCK-influenced genes in a list of human asthma severity–related genes expressed in blood. The enriched nmMLCK-influenced gene signature successfully predicted human asthma severity and exacerbation status in both discovery and validation human asthma cohorts. These findings validate the central role played by nmMLCK in asthma susceptibility, severity, and exacerbation and further provide novel gene signatures as effective asthma biomarkers for severity, exacerbation, and prognosis.

There are few data on the epidemiology of pulmonary hypertension (PH)–related hospitalizations in children in the United States. Our aim was to determine hospital mortality, length of hospitalization, and hospital charges pertaining to PH-related hospitalizations and also the effects of codiagnoses and comorbidities. A retrospective review of the Kids’ Inpatient Database during the years 2000, 2003, 2006, and 2009 was analyzed for patients ≤20 years of age with a diagnosis of PH by ICD-9 (International Classification of Diseases, Ninth Revision) codes, along with associated diagnoses and comorbidities. Descriptive statistics, including Rao-Scott χ ² , ANOVA, and logistic regression models, were utilized on weighted values with survey analysis procedures. The number of PH-related hospital admissions is rising, from an estimated 7,331 (95% confidence interval [CI]: 5,556–9,106) in 2000 to 10,792 (95% CI: 8,568–13,016) in 2009. While infant age and congenital heart disease were most commonly associated with PH-related hospitalizations, they were not associated with mortality. Overall mortality for PH-related hospitalizations was greater than that for hospitalizations not associated with PH, 5.7% versus 0.4% (odds ratio: 16.22 [95% CI: 14.78%–17.8%], P < 0.001), but mortality is decreasing over time. Sepsis, respiratory failure, acute renal failure, hepatic insufficiency, arrhythmias, and the use of extracorporeal membrane oxygenation are associated with mortality. The number of PH-related hospitalizations is increasing in the United States. The demographics of PH in this study are evolving. Despite the increasing prevalence, mortality is improving.

A frequently used end point of clinical outcomes in patients with pulmonary arterial hypertension (PAH) is the 6-minute walk distance. Furthermore, some data suggest that mild to moderate exercise as an intervention in stable PAH is beneficial. Some of these questions have been recapitulated in the monocrotaline and hypoxia animal models of pulmonary hypertension. However, mild exercise and walk distance as end points have not been rigorously examined in the severe progressive Sugen 5416/hypoxia/normoxia (Su/Hx/Nx) animal model of PAH at each stage of worsening disease. Our hypothesis was that animals that were preselected as runners would have increased walk times and improved right ventricle/left ventricle plus septum (RV/LV+S) ratios, echocardiography, and histology compared with nonexercised Su/Hx/Nx animals. We examined four groups of rats: Su/Hx/Nx sedentary, Su/Hx/Nx exercised, control sedentary, and control exercised. Echocardiography was performed at 5, 8, and 13 weeks to assess right ventricular inner diameter in diastole and left ventricular eccentricity index. We found no difference between exercised and sedentary Su/Hx/Nx rats, and both were worsened compared with controls. Rats were euthanized at 13 weeks, and we found that neither RV/LV+S nor the occurrence of occlusive lesions were influenced by exercise. Most interesting, however, was that despite progressive PAH development, exercised Su/Hx/Nx rats showed no decrease in time or distance for treadmill exercise. In all, our data suggest that, despite severe PAH development, Su/Hx/Nx rats retain the same treadmill exercise capacity as control animals.

Pulmonary hypertension (PH) is a frequent complication of left heart disease and parenchymal lung disease, and it portends increased mortality. A growing number of medications are approved for the treatment of World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH). However, they are not well studied in PH of other etiologies (WHO groups 2–5). We sought to assess treatment approaches used by PAH referral centers in this diverse group of patients. We developed a semiquantitative online survey designed to evaluate the use of PAH-approved therapy by pulmonary vascular disease centers in the United States for management of non–group 1 PH. Thirty of 50 centers completed the survey. Almost all centers (93%) reported using PAH therapy for patients with non–group 1 PH, including 77% with group 2 PH and 80% with group 3 PH. Elevated transpulmonary gradient or pulmonary vascular resistance and the presence of right ventricular (RV) dysfunction were commonly cited as supporting use of PAH therapy in patients with PH secondary to left heart disease. For patients with PH and concomitant parenchymal lung disease, degree of pulmonary function impairment and RV dysfunction were most important in influencing use of PAH therapy. In conclusion, pulmonary vascular disease treatment centers use PAH-approved therapy for patients with WHO group 2–5 PH, mostly relying on hemodynamics and assessment of RV function to identify candidates for therapy. Clinical trials designed to test the efficacy of PAH therapy in PH due to left heart and lung disease are needed, as clinical practice has extended beyond the evidence for these etiologies of PH.

We aimed to characterize and estimate survival rates in patients diagnosed with pulmonary arterial hypertension (PAH) in western Denmark in the modern management era. All incident cases of PAH were consecutively enrolled in our single-center prospective cohort study between January 2000 and March 2012. A total of 134 patients fulfilling the inclusion criteria were followed up from first diagnostic right heart catheterization to either death or the end of the study. Kaplan-Meier survival analysis was used to estimate 1-, 3-, and 5-year survival rates with 95% confidence intervals (CIs). Survival in the total cohort was 86.4% (95% CI, 79.3%–91.2%) after 1 year, 72.9% (95% CI, 64.1%–79.9%) after 3 years, and 65.4% (95% CI, 55.8%–73.4%) after 5 years. Significantly better survival was seen in the group of patients with PAH associated with congenital heart disease than in the group of patients with idiopathic PAH, heritable PAH, connective tissue disease, HIV infection, and portal hypertension. In conclusion, survival rates in the Danish PAH population were similar to or slightly better than survival rates estimated in other modern registries. However, PAH remains a fatal disease, despite modern targeted therapies.

Left ventricular diastolic dysfunction is a well-described complication of systemic hypertension. However, less is known regarding the effect of chronic pressure overload on right ventricular (RV) diastolic function. We hypothesized that pulmonary hypertension (PHT) is associated with abnormal RV early relaxation and that this would be best shown by invasive pressure measurement. Twenty-five patients undergoing right heart catheterization for investigation of breathlessness and/or suspected PHT were studied. In addition to standard measurements, RV pressure was sampled with a high-fidelity micromanometer, and RV pressure/time curves were analyzed. Patients were divided into a PHT group and a non-PHT group on the basis of a derived mean pulmonary artery systolic pressure of 25 mmHg. Eleven patients were classified to the PHT group. This group had significantly higher RV minimum diastolic pressure (5.1 ± 6.6 vs. −0.1 ± 3.3 mmHg, P = 0.03) and RV end-diastolic pressure (RVEDP; 11.0 ± 6.3 vs. 3.8 ± 3.7 mmHg, P = 0.004), and RV τ was significantly prolonged (53 ± 32 vs. 31 ± 13 ms, P = 0.04). There were strong correlations between RV τ and RV minimum diastolic pressure (r = 0.93, P < 0.0001) and between RV τ and RVEDP (r = 0.87, P < 0.0001). There was a trend toward increased RV contractility (end-systolic elastance) in the PHT group (0.73 ± 0.21 vs. 0.52 ± 0.21 mmHg/mL, P = 0.07) and a correlation between RV systolic pressure and first derivative of maximum pressure change (r = 0.58, P = 0.003). Stroke volumes were similar. Invasive measures of RV early relaxation are abnormal in patients with PHT, whereas measured contractility is static or increasing, which suggests that diastolic dysfunction may precede systolic dysfunction. Furthermore, there is a strong association between measures of RV relaxation and RV filling pressures.

The Pulmonary Hypertension Association (PHA) is a patient advocacy organization seeking to find ways to prevent, improve treatment for, and cure pulmonary hypertension (PH) and to provide hope for the PH community through support, education, research, advocacy, and awareness. Many patients involved with PHA are also involved in various PH-specific research studies; however, the patient expectations and priorities for PH-specific research are currently unknown or not well examined. Our objective was to identify the current modes of study entry, priorities within research, and expectations over the course of study involvement for patient constituents of PHA. A 29-question online survey was designed by PHA and disseminated to the PHA patient constituency on its Facebook page through a post on November 29, 2012. Responses were collected on SurveyMonkey through December 10, 2012. Respondents were divided into parallel survey tracks, depending on whether the respondent indicated previous participation in research studies. These two cohorts of individuals were analyzed and, where appropriate, compared with tests of association. A total of 234 respondents were included in the final data analysis, with 95 (40.6%) reporting previous participation in research studies. These respondents reported an overall positive experience in their research studies (64.9% very good, 21.3% good, 12.8% neutral, 1.1% bad). Of the respondents with previous research study participation, 91.1% indicated that receipt of the study outcome after participation would positively influence their decision to participate in future research; despite this, only 41.17% reported receiving information of this sort after their participation. Research participation is a strong interest of PHA patient constituents; clear and consistent communication from the research team is an expectation of many participants. Despite this expectation, 58.83% of respondents indicated they did not receive communication from the research team after participation. This offers an opportunity not only to improve participants’ experiences but also to increase the likelihood of future study participation.

Although there are many studies focusing on the molecular pathways underlying lung vascular morphogenesis, the extracellular matrix (ECM)–dependent regulation of mesenchymal cell differentiation in vascular smooth muscle development needs better understanding. In this study, we demonstrate that the paired related homeobox gene transcription factor Prx1 maintains the elastic ECM properties, which are essential for vascular smooth muscle precursor cell differentiation. We have found that Prx1^null mouse lungs exhibit defective vascular smooth muscle development, downregulated elastic ECM expression, and compromised transforming growth factor (TGF)–β localization and signaling. Further characterization of ECM properties using decellularized lung ECM scaffolds derived from Prx1 mice demonstrated that Prx1 is required to maintain lung ECM stiffness. The results of cell culture using stiffness-controlled 2-D and 3-D synthetic substrates confirmed that Prx1-dependent ECM stiffness is essential for promotion of smooth muscle precursor differentiation for effective TGF-β stimulation. Supporting these results, both decellularized Prx1^null lung ECM and Prx1^WT (wild type) ECM scaffolds with blocked TGF-β failed to support mesenchymal cell to 3-D smooth muscle cell differentiation. These results suggest a novel ECM-dependent regulatory pathway of lung vascular development wherein Prx1 regulates lung vascular smooth muscle precursor development by coordinating the ECM biophysical and biochemical properties.

Patients with end-stage renal disease (ESRD) with arteriovenous dialysis access (AVDA) can develop symptoms of heart failure and pulmonary hypertension (PH). We report on 5 patients with ESRD and AVDA who presented with shortness of breath, heart failure, and PH. All patients had partial or complete closure of AVDA and were reevaluated after AVDA revision. All 5 subjects had clinical and echocardiographic evidence of heart failure, hypertensive heart disease, left ventricular diastolic dysfunction, and PH at baseline. After complete closure (n = 4) or partial banding (n = 1) of AVDA, mean New York Heart Association class improved from 3.4 ± 0.4 to 1.8 ± 0.4 (P = 0.016). Mean 6-minute walk distance improved from 236 ± 115 to 366 ± 51 m (P = 0.021). Serial echocardiography revealed a decrease in the right ventricle: left ventricle ratio from 1.12 ± 0.17 to 0.8 ± 0.06 (P = 0.005) and improved diastolic dysfunction parameters. On right heart catheterization before definitive AVDA revision, acute manual fistula or graft occlusion led to an average decrease in cardiac output of 1.1 L/min with no other changes in hemodynamics: 9.88 ± 2.2 to 8.71 ± 2.2 L/min (P = 0.059). However, the average decrease in cardiac output after definitive revision of the AVDA (mean, 90 days) was 4.0 L/min with marked improvements in biventricular filling pressures and pulmonary artery pressure. In patients with ESRD and AVDA presenting with heart failure and PH, revision or closure of AVDA can markedly improve dyspnea as well as the clinical, echocardiographic, and hemodynamic manifestations of heart failure and PH.

We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology.