Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide.

Introduction: Riociguat, an oral soluble guanylate cyclase stimulator, has been approved for use in adults with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension. However, there is limited data on its therapeutic use in children. Case Presentation: We report the case of two infants with severe suprasystemic pulmonary hypertension who were successfully treated with riociguat after failure to wean off inhaled nitric oxide (iNO) despite combination PAH therapy. Case 1 is a 6-month-old term male with TBX4 deletion who presented with severe hypoxemic respiratory failure and severe PAH immediately after birth. Initial cardiac catheterization showed PVRi 15.5 WU*m2. Marked hypoxemia and PAH persisted despite aggressive therapy with sildenafil, bosentan, intravenous treprostinil, and milrinone. The infant required high doses of inhaled nitric oxide (60 ppm) and manifested significant post-ductal hypoxemia and hemodynamic instability with any attempt at weaning. After discontinuation of sildenafil, initiation, and very slow uptitration of riociguat, the patient was able to maintain hemodynamic stability and wean from nitric oxide over 6 weeks with persistently severe but not worsened pulmonary hypertension. Case 2 is a 4-month-old term male with compound heterozygous SLC25A26 mutation and severe pulmonary hypertension. Initial cardiac catheterization showed PVRi 28.2 WU*m2. After uptitration of sildenafil, bosentan, and IV treprostinil, serial echocardiograms continued to demonstrate near-systemic pulmonary hypertension. He failed multiple attempts to wean off typical doses of iNO (10-20 ppm) over the following weeks with tachypnea, hypoxemia, and worsening pulmonary hypertension on echocardiogram despite continued aggressive combination targeted therapy. After a 24-h sildenafil washout, he was initiated and uptitrated on riociguat with concomitant, successful wean of nitric oxide over one week that was well tolerated. No serious adverse effects in the titration period were observed. Conclusion: Riociguat may be considered as an adjuvant therapeutic agent in selected children with severe PAH who are poorly responsive to sildenafil therapy and unable to wean from iNO.

Right ventricular-vascular coupling ratio in pediatric pulmonary arterial hypertension: A comparison between cardiac magnetic resonance and right heart catheterization measurements.

BACKGROUND: In pulmonary arterial hypertension (PAH), right ventricular (RV) failure is the main cause of mortality. Non-invasive estimation of ventricular-vascular coupling ratio (VVCR), describing contractile response to afterload, could be a valuable tool for monitoring clinical course in children with PAH. This study aimed to test two hypotheses: VVCR by cardiac magnetic resonance (VVCRCMR) correlates with conventional VVCR by right heart catheterization (VVCRRHC) and both correlate with disease severity. METHODS AND RESULTS: Twenty-seven patients diagnosed with idiopathic and associated PAH without post-tricuspid shunt, who underwent RHC and CMR within 17 days at two specialized centers for pediatric PAH were retrospectively studied. Clinical functional status and hemodynamic data were collected. Median age at time of MRI was 14.3 years (IQR: 11.1-16.8), median PVRi 7.6 WU × m2 (IQR: 4.1-12.2), median mPAP 40 mm Hg (IQR: 28-55) and median WHO-FC 2 (IQR: 2-3). VVCRCMR, defined as stroke volume/end-systolic volume ratio was compared to VVCRRHC by single-beat pressure method using correlation and Bland-Altman plots. VVCRCMR and VVCRRHC showed a strong correlation (r = 0.83, p < 0.001). VVCRCMR and VVCRRHC both correlated with clinical measures of disease severity (pulmonary vascular resistance index [PVRi], mean pulmonary artery pressure [mPAP], mean right atrial pressure [mRAP], and World Health Organization functional class [WHO-FC]; all p ≤ 0.02). CONCLUSIONS: Non-invasively measured VVCRCMR is feasible in pediatric PAH and comparable to invasively assessed VVCRRHC. Both correlate with functional and hemodynamic measures of disease severity. The role of VVCR assessed by CMR and RHC in clinical decision-making and follow-up in pediatric PAH warrants further clinical investigation.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension).

BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

Circulating fibrocytes are increased in children and young adults with pulmonary hypertension.

Chronic inflammation is an important component of the fibroproliferative changes that characterise pulmonary hypertensive vasculopathy. Fibrocytes contribute to tissue remodelling in settings of chronic inflammation, including animal models of pulmonary hypertension (PH). We sought to determine whether circulating fibrocytes were increased in children and young adults with PH. 26 individuals with PH and 10 with normal cardiac anatomy were studied. Fresh blood was analysed by flow cytometry for fibrocytes expressing CD45 and procollagen. Fibrocyte numbers were correlated to clinical and haemodynamic parameters, and circulating CC chemokine ligand (CCL)2 and CXC chemokine ligand (CXCL)12 levels. We found an enrichment of circulating fibrocytes among those with PH. No differences in fibrocytes were observed among those with idiopathic versus secondary PH. Higher fibrocytes correlated to increasing mean pulmonary artery pressure and age, but not to length or type of treatment. Immunofluorescence analysis confirmed flow sorting specificity. Differences in plasma levels of CCL2 or CXCL12, which could mobilise fibrocytes from the bone marrow, were not found. We conclude that circulating fibrocytes are significantly increased in individuals with PH compared with controls. We speculate that these cells might play important roles in vascular remodelling in children and young adults with pulmonary hypertension.

Pulmonary arterial hypertension: a comparison between children and adults.

The characteristics of pulmonary arterial hypertension (PAH), including pathology, symptoms, diagnosis and treatment are reviewed in children and adults. The histopathology seen in adults is also observed in children, although children have more medial hypertrophy at presentation. Both populations have vascular and endothelial dysfunction. Several unique disease states are present in children, as lung growth abnormalities contribute to pulmonary hypertension. Although both children and adults present at diagnosis with elevations in pulmonary vascular resistance and pulmonary artery pressure, children have less heart failure. Dyspnoea on exertion is the most frequent symptom in children and adults with PAH, but heart failure with oedema occurs more frequently in adults. However, in idiopathic PAH, syncope is more common in children. Haemodynamic assessment remains the gold standard for diagnosis, but the definition of vasoreactivity in adults may not apply to young children. Targeted PAH therapies approved for adults are associated with clinically meaningful effects in paediatric observational studies; children now survive as long as adults with current treatment guidelines. In conclusion, there are more similarities than differences in the characteristics of PAH in children and adults, resulting in guidelines recommending similar diagnostic and therapeutic algorithms in children (based on expert opinion) and adults (evidence-based).

Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome).

We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions,

Pulmonary arterial hypertension in children: Diagnostic work-up and challenges.

The diagnostic evaluation of a pediatric patient with suspected pulmonary arterial hypertension (PAH) is extensive but essential, given the rapid progression of the disease if left undiagnosed and untreated. The major goals of performing a complete diagnostic work-up are to confirm the diagnosis of PAH, assess disease severity, rule out associated diseases, and begin to formulate an individualized treatment plan for the pediatric patient with pulmonary hypertension. This article will provide a comprehensive review of the diagnostic work-up of the child with suspected PAH as well as a review of some of the challenges faced when assessing a child for PAH.

Non-congenital heart disease associated pediatric pulmonary arterial hypertension.

Recognition of causes of pulmonary hypertension other than congenital heart disease is increasing in children. Diagnosis and treatment of any underlying cause of pulmonary hypertension is crucial for optimal management of pulmonary hypertension. This article discusses the available knowledge regarding several disorders associated with pulmonary hypertension in children: idiopathic pulmonary arterial hypertension (IPAH), pulmonary capillary hemangiomatosis, pulmonary veno-occlusive disease, hemoglobinopathies, hepatopulmonary syndrome, portopulmonary hypertension and HIV. Three classes of drugs have been extensively studied for the treatment of IPAH in adults: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase inhibitors (Sildenafil, tadalafil). These medications have been used in treatment of children with pulmonary arterial hypertension, although randomized clinical trial data is lacking. As pulmonary vasodilator therapy in certain diseases may be associated with adverse outcomes, further study of these medications is needed before widespread use is encouraged.

Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension.

Intravenous prostanoids are the backbone of therapy for advanced pulmonary arterial hypertension (PAH) and have improved long-term outcome and quality of life. Currently, two prostanoids are approved by the US Food and Drug administration for parenteral administration: epoprostenol (Flolan) and treprostinil (Remodulin). Chronic intravenous therapy presents considerable challenges for patients and caregivers who must learn sterile preparation of the medication, operation of the pump, and care of the central venous catheter. Patients are routinely counseled and advised regarding the risks of CR-BSIs and catheter care before central line insertion. Central line infections as well as bacteremia are well documented risks of chronic intravenous therapy and may significantly contribute to morbidity and mortality. Recent reports have suggested a possible increase in CR-BSI; therefore, the Scientific Leadership Council of the Pulmonary Hypertension Association decided to provide guidelines for good clinical practice regarding catheter care. Although data exits regarding patients with central venous catheters and the risk of blood stream infections in patients with cancer or other disorders, there is little data regarding the special needs of patients with pulmonary arterial hypertension requiring central venous access. These guidelines are extrapolated from the diverse body of literature regarding central venous catheter care.

Stiffening of the Extrapulmonary Arteries From Rats in Chronic Hypoxic Pulmonary Hypertension.

Changes in the compliance properties of large blood vessels are critical determinants of ventricular afterload and ultimately dysfunction. Little is known of the mechanical properties of large vessels exhibiting pulmonary hypertension, particularly the trunk and right main artery. We initiated a study to investigate the influence of chronic hypoxic pulmonary hypertension on the mechanical properties of the extrapulmonary arteries of rats. One group of animals was housed at the equivalent of 5000 m elevation for three weeks and the other held at ambient conditions of ~1600 m. The two groups were matched in age and gender. The animals exposed to hypobaric hypoxia exhibited signs of pulmonary hypertension, as evidenced by an increase in the RV/(LV+S) heart weight ratio. The extrapulmonary arteries of the hypoxic animals were also thicker than those of the control population. Histological examination revealed increased thickness of the media and additional deposits of collagen in the adventitia. The mechanical properties of the trunk, and the right and left main pulmonary arteries were assessed; at a representative pressure (7 kPa), the two populations exhibited different quantities of stretch for each section. At higher pressures we noted less deformation among the arteries from hypoxic animals as compared with controls. A four-parameter constitutive model was employed to fit and analyze the data. We conclude that chronic hypoxic pulmonary hypertension is associated with a stiffening of all the extrapulmonary arteries.

Comparison of mechanical behavior among the extrapulmonary arteries from rats.

Results of comparative tests on pulmonary arteries from untreated Long-Evans rats are presented from three sections of the artery: the trunk, and the right and left main extrapulmonary arteries. Analyses were conducted looking for mechanical differences between the flow (longitudinal) and circumferential directions, between the right and left main arteries, and between each of the mains and the trunk. The mechanical properties of rat pulmonary arteries were obtained with a bubble inflation technique. A flat disk of rat pulmonary artery was constrained at the periphery and inflated, and the geometry of the resulting bubble of material recorded from six different angles. To analyze the data, the area under the stress-strain curve was calculated for each test and orientation. This area, related to the strain-energy density, was calculated at stress equal to 200kPa, for the purpose of statistical comparison. The mean values for the area show that the trunk is less compliant than the main arteries; this difference is supported by histological evidence. When comparing the circumferential and longitudinal properties of the arteries, differences are found for the trunk and left main arteries, but with opposite orientations being more compliant. The mean values for the two orientations for the right main artery are statistically identical. There was indication of significant difference in mechanical properties between the trunk and the main arteries. The left main artery in the circumferential orientation is highly compliant and appears to strongly influence the likelihood that significant differences will exist when included in a statistical population. These data show that each section of the extrapulmonary arterial system should not be expected to behave identically, and they provide the baseline mechanical behavior of the pulmonary artery from normotensive rats.

A microstructural hyperelastic model of pulmonary arteries under normo- and hypertensive conditions.

This work represents the first application of a statistical mechanics based microstructural orthotropic hyperelastic model to pulmonary artery mechanics under normotensive and hypertensive conditions. The model provides an analogy between the entangled network of long molecular chains and the structural protein framework seen in the medial layer, and relates the mechanical response at macro-level to the deformation (entropy change) of individual molecular chains at the micro-level. A finite element approach was adopted to implement the model. Material parameters were determined via comparing model output to measured pressure-stretch results from normotensive and hypertensive trunks and branches obtained from a rat model of pulmonary arterial hypertension. Results from this initial study show that this model appears reasonable for the study of hyperelastic and anisotropic pulmonary artery mechanics. Typical tangent modulus values ranged from 200 to 800 kPa for normotensive arteries-this increased to beyond 1 MPa for hypertensive vessels. Our study also provokes the hypothesis that increase of cross-linking density may be one mechanism by which the pulmonary artery stiffens in hypertension.

Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence.

We report a 17-month-old female patient with a rare cause of cardiomyopathy secondary to accumulation of amylopectin-like material (fibrillar glycogen) isolated to the heart. Evidence of amylopectinosis isolated to cardiac myocytes in this patient was demonstrated by histology and electron microscopy. Glycogen content, glycogen branching enzyme (GBE) activity, as well as phosphofructokinase enzyme activities measured in liver, skeletal muscle, fibroblasts and ex-transplanted heart tissue were all in the normal to lower normal ranges. Normal skeletal muscle and liver tissue histology and GBE activity, normal GBE activity in skin fibroblasts, plus normal GBE gene sequence in this patient exclude the classical branching enzyme deficiency (type IV GSD). We believe that this is an as yet uncharacterized and novel phenotype of GSD associated with cardiomyopathy, in which there is an imbalance in the regulation of glycogen metabolism limited to the heart.

Comparison of strength properties of normotensive and hypertensive rat pulmonary arteries.

A series of tests were conducted to quantify the difference in the mechanical properties of normo- and hypertensive pulmonary arteries. A bubble-test design was employed to measure the biaxial properties of a segment of artery. The test results compare the properties at multiple orientations of the trunk, right, and left pulmonary arteries from normal (Control) and monocrotaline-treated male Long-Evans wild rats that ranged in age from 8 to 17 weeks old, along with some preliminary results from hypoxic Long-Evans knock-out rats. Data show little difference between the stress-strain relationship of the control pulmonary arteries and that of the monocrotaline-treated pulmonary arteries. However, the preliminary results from the hypoxic pulmonary arteries show that the arterial material strains less before the onset of strain-stiffening behavior. The longitudinal orientation exhibits strain stiffening at lower strains than does the circumferential orientation. The differences between the left and right main arteries are minor. The trunk consistently demonstrates less stiffening in the region of larger strains for all conditions.

Neonatal aortic arch thrombosis masquerading as coarctation of the aorta.

We report two neonates with thrombosis of the aortic arch and isthmus diagnosed by echocardiography. Neonatal transient protein C deficiency was present in one patient and the other patient had severe perinatal asphyxia. Both patients presented with markedly reduced left ventricular function and severe aortic obstruction. In one infant, the thrombus was successfully removed surgically, and the second infant died due to serious complications of perinatal asphyxia.

Improved pretransplant management of infants with hypoplastic left heart syndrome enables discharge to home while waiting for transplantation.

For infants whose families select primary transplantation for hypoplastic left heart syndrome (HLHS), the waiting time averages 3 months. Given the relative shortage of organs, the morbidity and mortality of these patients have been high. Therefore, pretransplant management is critical to improve the number of patients who survive to transplantation. This series shows our evolving management for these children, with an emphasis on nonintensive care. Fifty-two infants with HLHS were listed for primary transplantation at our institution during a 6-year period. The management was aimed at manipulating the pulmonary and systemic blood flows by low-dose continuous infusion of prostaglandin E1 (PGE1), early use of inhaled nitrogen, delayed opening of the atrial septum, and discharge to home with PGE1 infusion for continuing care when the child was on room air and growing. Almost all of the children (46/ 52) required nitrogen therapy with initial FiO2 of 0.16-0.17. Patients were weaned off nitrogen by 5 to 6 weeks of age. One fourth of the children needed atrial septal opening, typically at 2 or 3 months of age. Seventeen (32.7%) of the infants were able to spend at least some of their waiting time at home. Forty-five of the 52 children (86.5%) survived to receipt of a donor heart. Newborns with HLHS whose families select primary transplantation as their surgical option can be managed with a minimally invasive approach until receipt of a donor heart with an improvement in mortality rate.

An Experimental Method for Measuring Mechanical Properties of Rat Pulmonary Arteries Verified With Latex.

This paper describes a test method for measuring the mechanical properties of small, nonlinear membrane samples from a rat model for pulmonary hypertension. The size and nonlinearity of the pulmonary artery samples poses a challenge for developing a test method that will generate quality, reproducible data in the pressure range experienced by the hypertensive pulmonary artery. The experimental method described here has sufficient precision to yield a combined relative standard uncertainty of 4 %. The method is calibrated against 75 µm thick latex and the data agree well with the neo-Hookian model.

Development of a noninvasive ultrasound color M-mode means of estimating pulmonary vascular resistance in pediatric pulmonary hypertension: mathematical analysis, in vitro validation, and preliminary clinical studies.

BACKGROUND: Accurate determination of pulmonary vascular resistance (PVR) is an important component in the evaluation and treatment of pediatric patients with pulmonary hypertension. We developed a novel technique, based on the concept of flow propagation, to estimate PVR noninvasively. The hypothesis is that changes in PVR cause changes in the velocity propagation (Vel(prop)) within the main pulmonary artery and that Vel(prop) can be quantified using color M-mode imaging. METHODS AND RESULTS: We tested the hypothesis using mathematical modeling, in vitro experiments, and preliminary clinical studies. The mathematical model showed that pressure and velocity tracings are closely correlated in time and that 6 to 18 ms time resolution was needed to resolve propagation times within typical main pulmonary artery lengths (2 to 5 cm). The in vitro experiments demonstrated that it was feasible to use color M-mode to measure Vel(prop) and that Vel(prop) correlated well with downstream resistance [y=(-1.01x)+22.77; R=0.96]. The method was then evaluated on patients undergoing acute pulmonary reactivity testing (n=22 measurements). Good correlation between Vel(prop) and PVR was found [y=(-1.71x)+26.0; R=0.90; SEE=2.41]. CONCLUSION: This newly developed method promises to be useful in the noninvasive evaluation of adults and children with pulmonary hypertension.

Role of inducible nitric oxide synthase in the pulmonary vascular response to birth-related stimuli in the ovine fetus.

To determine whether type II nitric oxide synthase (NOS II) contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) at birth, we studied the effects of selective NOS II antagonists N-(3-aminomethyl) benzylacetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselective NOS antagonist, nitro-L-arginine (L-NA), during mechanical ventilation with low FIO(2) (<10%), high FIO(2) (100%), and inhaled NO (20 ppm) in 23 near-term fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (P<0.05). In control animals, ventilation with low and high FIO(2) decreased PVR by 62% and 85%, respectively. Treatment with AG and 1400W attenuated the fall in PVR by 50% during ventilation with low and high FIO(2) (control versus treatment, P<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high FIO(2) to a similar degree as the NOS II antagonists. To test the selectivity of the NOS II antagonists, we studied the effects of acetylcholine and inhaled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not after treatment with nonselective NOS blockade with L-NA. In contrast, the response to inhaled NO was similar between treatment groups. We conclude that selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II activity contributes to NO-mediated pulmonary vasodilation at birth. We additionally speculate that stimulation of the airway epithelium by rhythmic distension and increased FIO(2) may activate NOS II release at birth.