San Francisco, March 27–29, 2014
Address correspondence to Dr. Jeffrey Fineman, UCSF Benioff Children's Hospital, 513 Parnassus Avenue, HSE-1418, Box 1346, San Francisco, California 94143-1346, USA
. 2014 Sep;4(3):527–530. doi: 10.1086/677368
Pulm Circ. 2014;4(3):527–530.
The automatic detection of the first (S1) and second (S2) heart sounds is difficult, and previous algorithms are imprecise. We sought to develop a wavelet-based algorithm for the detection of S1 and S2 in subjects with and without pulmonary artery hypertension (PAH). Heart sounds were recorded at the second left intercostal space and the apex with a digital stethoscope, simultaneously with pulmonary artery pressure (PAP). We used MATLAB software to develop a Daubechies wavelet algorithm for the automatic detection of S1 and S2 using the wavelet coefficient “D6,” based on power spectral analysis. We compared our algorithm with 4 other Daubechies wavelet–based algorithms (Liang, Kumar, Wang, and Zhong). We annotated S1 and S2 from aural and visual inspection of the phonocardiographic tracing by 2 trained cardiologists and the observation that in all subjects systole was shorter than diastole. We studied 22 subjects, (9 M, median age 6 years, range: 0.25–19 years). Eleven subjects had a mean PAP of less than 25 mmHg. Eleven subjects had mean PAP of at least 25 mmHg. All subjects had a PA wedge pressure of less than 15 mmHg. The sensitivity (SE) and positive predictivity (+P) of our algorithm were 69.84% and 67.87%, respectively. In comparison, the SE and +P of the Liang algorithm were 58.9% and 41.8%, those of the Kumar 18.8% and 11.9%, those of the Wang 49.8% and 44.8%, and those of the Zhong 42.6% and 52%. Our algorithm demonstrated robustness up to a signal-to-noise ratio (SNR) of 10 dB. For all the algorithms, detection errors arose from low-amplitude peaks, fast heart rates, low SNR, and fixed thresholds. Our algorithm for the detection of S1 and S2 improves the performance of existing Daubechies-based algorithms and justifies the wavelet coefficient “D6” usage through power spectral analysis. In addition, the robustness despite ambient noise may improve clinical performance.
Pulm Circ. 2014;4(3):527–530.
High inspired oxygen concentration (Fio2), either alone or with inhaled nitric oxide, is used for acute pulmonary vasodilator testing (AVT) in children, especially to assess operability of children with congenital systemic-to-pulmonary shunt lesions. Even if Vo2 is measured at baseline, it is assumed usually that Vo2 does not change with hyperoxia. We sought to compare the Vo2 calculated from cardiac output (CO) measured with thermodilution (TD) in room air and hyperoxia. We reviewed retrospectively the hemodynamic data obtained in children with pulmonary hypertension (PH) without intra- or extracardiac shunts who underwent cardiac catheterization between 2009 and 2014 and CO measured by TD in room air and hyperoxia. The Vo2 was calculated using the modified Fick equation CO = Vo2/(arterial-venous oxygen content difference). In hyperoxia, dissolved oxygen was included in the calculation. Data were available in 17 subjects (median age: 8.5 years [range: 1–18 years], median weight: 35 kg [range: 6–95 kg], and median body surface area: 1 m2 [range: 0.36–1.84 m2]). After 15 minutes of ventilation with Fio2 ≥ 0.85, calculated Vo2 increased from 156 ± 42 to 179 ± 54 mL/min/m2 (P < 0.0001), a change of 13% ± 11%, mean aortic pressure increased from 62 ± 11 to 67 ± 11 mmHg (P = 0.03), the systemic vascular resistance index increased from 25 ± 26 to 29 ± 31 WU/m2 (P = 0.04), and pulmonary artery wedge pressure increased from 12 ± 9 to 13 ± 10 mmHg (P = 0.001). There was no change in mean pulmonary artery pressure (from 41 ± 17 to 36 ± 16 mmHg; P = 0.1), pulmonary vascular resistance index (PVRI; from 15 ± 18 to 14 ± 19 WU/m2; P = 0.16), or cardiac index (from 3.5 ± 1.2 to 3.4 ± 1.3; P = 0.5). The Vo2 increased significantly during hyperoxia in children with PH. If Vo2 is assumed to remain constant during hyperoxic AVT, this may introduce errors in the calculation of pulmonary blood flow and PVRI if the direct Fick equation is used. Our results suggest that a prospective reevaluation of hyperoxia during AVT is required because the errors that may be introduced by the change in Vo2 and the increase in SVRI maybe be important in decision making, especially in children with borderline PVRI being considered for shunt closure.
Pulm Circ. 2014;4(3):527–530.
Portopulmonary hypertension (PPH) and hepatopulmonary syndrome (HPS) are risk factors for adverse outcomes after liver transplantation in adults. We sought to determine the incidence of PPH and HPS in children referred for liver transplantation. We reviewed the clinical findings, electrocardiograms (EKG), and echocardiograms in children referred for liver transplantation. Between 2010 and 2013, 41 patients were evaluated (median age: 7 months, range: 1–156 months, 23 males). Indications for liver transplantation were biliary atresia (n = 18; 44%), metabolic disease (n = 7; 17%), total parental nutrition–induced cholestasis (n = 6; 15%), and miscellaneous liver disease (n = 10; 24%). PPH was not detected by echocardiography. Contrast echocardiography revealed HPS in 4 cases (10%; right-to-left shunt confirmed by radionuclide scan in 3 of the 4), but only 2 patients (aged 7 and 11 years) had severe cyanosis (right-to-left shunt quantified at 17%–20%). Congenital cardiac anomalies were seen in 6 (15%), including patent ductus arteriosus (n = 2), muscular ventricular septal defect, interrupted inferior vena cava with azygous continuation and left ventricular noncompaction, bicuspid aortic valve, and supravalvar pulmonary stenosis. Septal hypertrophy was diagnosed by EKG in 16 (39%) of 41 patients and by echocardiography in 9 (22%) of 41. Twenty-two of the 41 underwent liver transplantation, with 3 deaths. After liver transplantation, resolution of septal hypertrophy was confirmed in 2 of 9 patients and right-to-left shunt in 3 of 4. One patient with PAVM died after liver transplant. In our series of young children undergoing evaluation for liver transplantation, PPH was not detected by echocardiography. HPS was detected in 7%–10% and regressed after liver transplantation. PPH was rare in young children with end-stage liver disease, but septal hypertrophy, congenital cardiac disease, and HPS were detected more frequently.
Pulm Circ. 2014;4(3):527–530.
We studied digital stethoscope recordings in children undergoing simultaneous catheterization of the pulmonary artery (PA) to determine whether heart sound intensity would be useful in the diagnosis of pulmonary artery hypertension (PAH). Heart sounds were recorded and stored in *.wav mono audio format. We performed recordings for 20 seconds, with sampling frequencies of 4,000 Hz at the second left intercostal space (second LICS) and the cardiac apex. Signals were analyzed and optimized with MATLAB 2010b. We annotated events representing the first (S1) and second (S2) heart sounds and the aortic (A2) and pulmonary (P2) components of S2. We calculated the intensity (I) of the extracted event area (x) as follows: 
, where n is the total number of heart sound samples in the extracted event and k is A2, P2, S1, or S2. We defined PAH as mean PA pressure (mPAp) of at least 25 mmHg and PA wedge pressure (PAWp) higher than 15 mmHg. We studied 22 subjects (median age 6 years [0.25–19 years], 13 female), 11 with PAH (mPAp median: 55 mmHg [range: 25–97 mmHg]) and 11 without PAH (mPAp median: 15 mmHg [range: 8–24 mmHg]). The P2/A2 (P = 0.0001) and P2/S2 (P = 0.0001) intensity ratios were significantly different between subjects with and without PAH. There was a linear correlation (r > 0.7) between the P2/S2 and P2/A2 intensity ratios and mPAp. We found that the P2/A2 and P2/S2 intensity ratios discriminate between children with and without PAH. These findings may be useful in the development of an acoustic device to diagnose PAH.
Pulm Circ. 2014;4(3):527–530.
Bronchopulmonary dysplasia (BPD) is a major cause of morbidity and mortality for preterm infants and may be associated with subsequent pulmonary hypertension (PH). Endothelin-1 (ET-1) has been implicated in the pathobiology of PH, with elevated levels found in term infants with PPHN and CDH. Longitudinal changes in ET-1 levels, the role of ET-1 in the development of BPD, and levels of ET-1 in premature infants remain to be elucidated. We evaluated serial ET-1 levels to determine whether a relationship exists with the development of PH in premature infants with and without BPD. We performed a prospective study of infants born at less than 30 weeks gestational age (GA) without major anomalies or congenital infection. Plasma ET-1 levels were drawn at less than 1 week of age and every 4 weeks until 36 weeks postmenstrual age (PMA), when an echocardiogram was performed for PH. ET-1 levels were measured by ELISA, and echos were scored for PH by masked pediatric cardiologists with a standardized tool. Twenty-eight infants (mean GA 27 ± 2 weeks) were enrolled. ET-1 levels peaked at 29–32 weeks PMA (<29 weeks: 27.1 ± 17.5 pg/mL; 29–32 weeks: 45.0 ± 21.9 pg/mL; 32–36 weeks: 35.7±12.6 pg/mL; P > 0.1). Seventy percent (7/10) of infants with BPD, versus 50% (7/14) of those without BPD, had ET-1 levels higher than 30.0 pg/mL at 36 weeks PMA. Peak levels for infants with BPD (46.7 ± 25.1 pg/mL) were higher than those for infants without BPD (43.2 ± 18.5 pg/mL), but the difference was not statistically significant (P > 0.1). None of the infants had PH by echo. In this small cohort of preterm infants, ET-1 levels were substantially higher than those reported for term infants with CDH (19–27 pg/mL) and closer to those for infants with PPHN (70 pg/mL). A larger, prospective study with follow-up beyond 36 weeks PMA is needed to investigate whether ET-1 levels and their postnatal trajectory correlate with the development of BPD or with increased risk for later respiratory morbidities, such as PH.
Pulm Circ. 2014;4(3):527–530.
Identification of a lung/vascular-specific pulmonary hypertension (PH) biomarker would aid in risk stratification and noninvasive monitoring of therapeutic efficacy. Our aim was to identify PH biomarkers via proteomic analysis of PH and control lungs, followed by complementary techniques to demonstrate alteration in PH lungs and plasma. Homogenized lung extract, from the Pulmonary Hypertension Breakout Initiative (PHBI) biorepository, from end-stage PH patients (idiopathic PAH = 5, PAH-associated with congenital heart disease = 5, control = 5) was analyzed by nonbiased, high-resolution mass spectrometry (Orbitrap Elite). Selection of lead biomarkers was by biological feasibility and spectral counting with more-than-2-fold or less-than-0.5-fold change between PH and control. Lung Western blot, immunohistochemistry (IHC), and ELISA were performed on PHBI homogenized lung, paraffin-embedded lung, and plasma, respectively, from adult PAH patients and controls. Data were analyzed by one-way ANOVA and the Kruskal-Wallis test. Eight hundred sixty nonredundant lung proteins were identified (APAH = 620, IPAH = 688, control = 688); 38 proteins were more than 2-fold up or less than 0.5-fold down in PH versus control lung. Periostin (IPAH: 7.5-fold; APAH: 9.5-fold) and matrix metalloproteinase 9 (MMP9; IPAH and APAH: both ≪0.5 fold) were identified as promising lead biomarkers. Western blot revealed elevated periostin, while MMP9 decreased in PH versus control lung. Periostin IHC localized to alveolar endothelial cells. ELISA assay showed increased periostin in PH versus control plasma (n = 17, PH median: 9,738 ng/mL, control median 1,433 ng/mL, P = 0.0502). Periostin and MMP9 have reciprocal expression in PH lung. Periostin is predominately endothelially expressed, with circulating periostin a promising new PH biomarker. MMPs play a significant role in PH pathogenesis. Future studies will include larger sample sets, including pediatric patients, and will evaluate additional potential PH biomarkers generated from proteomic lung analysis.
Pulm Circ. 2014;4(3):527–530.
Pulmonary hypertension (PH) complicates 25% of bronchopulmonary dysplasia (BPD) infants. Superoxide dismustase-2 (SOD2) is an endogenous mitochondrial antioxidant, and SOD2 overexpression has been shown to protect against acute lung injury in adult mice. We sought to determine the role of SOD2 in neonatal lung disease and PH. C57Bl/6 mice and isogenic SOD2+/+ and SOD2−/+ mice were placed in 21% (control) or 75% O2 (BPD) after birth for 14 days to induce PH. On day 14, pups were euthanized, and lungs were harvested. RVH was assessed by Fulton’s index (right ventricle/(left ventricle + septum weight)). Lungs were inflation fixed with 4% formalin; medial wall thickness (MWT) was assessed. PASMCs isolated from isogenic SOD2−/+ and SOD2+/+ mice were placed in 21% or 95% O2 for 24 hours. Lung and PASMC SOD2 expression was analyzed by Western blot. Lung and PASMC SOD2 activity was measured by commercial SOD assay. PASMC ROS was studied with mitochondrially targeted RoGFP and flow cytometry. BPD lungs have increased SOD2 expression (1.9 ± 0.3–fold vs. control) but unchanged SOD2 activity. SOD2−/+ PASMCs have decreased expression and activity at baseline (0.43 ± 0.1–fold and 0.7 ± 0.1–fold vs. SOD2+/+ PASMCs, respectively). SOD2+/+ and SOD2−/+ PASMCs increased SOD2 expression (2.4 ± 0.5–fold and 1.1 ± 0.3–fold vs. SOD2+/+ in 21% O2) but not activity in hyperoxia. SOD2−/+ PASMCs had increased mitochondrial ROS versus SOD2+/+ PASMCs at baseline and in hyperoxia (P < 0.05). Both SOD2+/+ and SOD2−/+ BPD pups developed RVH and increased MWT after 14 days of hyperoxia, but there was no difference between SOD2−/+ and SOD2+/+ mice. Neonatal mice respond to hyperoxia by inducing SOD2 expression, but not activity, in both lungs and isolated PASMCs. Interestingly, heterozygous SOD2 mice develop hyperoxia-induced RVH and vascular remodeling that is no worse than that in isogenic wild-type mice. Thus, we hypothesize that even partial SOD2 expression and activity are sufficient to prevent worsening of BPD-associated PH.
Pulm Circ. 2014;4(3):527–530.
Pulmonary arterial hypertension (PAH) is a complex disease that lacks adequate therapies. Recognition that endothelial and smooth muscle cell hyperproliferation contributes to the pathophysiology has drawn parallels to malignancy and has helped develop an emerging “quasi-neoplastic” model for the vascular changes seen in PAH. One important aspect is a shared alteration in metabolism. Similar to the Warburg effect in cancer biology, smooth muscle and endothelial cell glycolytic flux is frequently upregulated and mitochondrial respiration reduced in the setting of PAH, despite the presence of adequate oxygen. We hypothesize that in a large-animal model of increased pulmonary blood flow and PAH, smooth muscle cells from the central pulmonary arteries will exhibit metabolic alterations similar to the Warburg effect. Near-term fetal lambs underwent surgical placement of an aortopulmonary anastomosis, resulting in a postnatal increase in pulmonary blood flow. Primary smooth muscle cells (PASMCs) from the central PAs of control and shunt animals were derived, and their proliferation rates were assessed. Extracellular flux analysis (Seahorse Biosciences) was used to measure cellular oxygen consumption and extracellular acidification rates (an indirect measure of glycolytic flux). As predicted, PASMCs derived from shunted lambs exhibited faster growth (P < 0.001) and a 55% decrease in oxygen consumption rate compared to controls (P < 0.001). Interestingly, they also exhibited a 59% decrease in extracellular acidification rates (P < 0.001), indicating decreased glycolytic flux. Additionally, these cells were hyperresponsive to hypoxia, exhibiting greater HIF-1
protein accumulation at 2% O2. PASMCs from lambs with increased pulmonary blood flow and PAH have a phenotype of hyperproliferation and altered metabolism. The low rates of both oxygen consumption and glycolytic flux diverge from the expected Warburg metabolism and suggest that decreased mitochondrial oxygen consumption precedes increased glycolytic flux in early-stage PAH.
Pulm Circ. 2014;4(3):527–530.
Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease that, if left untreated, can lead to right ventricular failure and possibly death. Several effective therapies are now available to treat pulmonary hypertension, including phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and prostacyclin analogs, by the subcutaneous, intravenous, or inhaled route. In 2009, the FDA approved treprostinil (Tyvaso) for oral inhalation in adults with PAH, administered 4 times daily with a target dose of 9 breaths per treatment session. To date, there is no literature on the use of Tyvaso in patients with artificial airways. The acute pharmacodynamic effects, safety, and tolerability of Tyvaso via tracheostomy have not yet been described or studied. A 20-year-old male was admitted to our hospital with PAH secondary to systemic sclerosis. Prior to admission, his pulmonary hypertension was successfully managed with the use of tadalafil, ambrisentan, and inhaled Tyvaso. As a result of respiratory failure from vocal cord paralysis, he underwent an emergent tracheotomy. The delivery of inhaled Tyvaso through a tracheostomy tube was explored. Two Airlife straight intubation adapter pieces and 6 inches of the Airlife corrugated blue tubing were used to connect the Tyvaso Inhalation System to his artificial airway. Posttracheostomy, the patient continued his ability to self-administer the medication. His World Health Organization functional classification, brain natriuretic peptide levels, and echocardiograms were not significantly different when Tyvaso was administered via tracheostomy, compared with oral administration. The feasibility of delivering inhaled treprostinil via the Tyvaso Inhalation System through a tracheostomy proved successful in this patient. He continued the use of Tyvaso through his tracheostomy until he was able to occlude his tracheostomy and inhale the treprostinil orally. Further investigation is warranted regarding safety and the actual delivered dose to patients with PAH when delivered through an artificial airway.
Pulm Circ. 2014;4(3):527–530.
Treatment options for pulmonary hypertension associated with pulmonary venous obstruction may be limited and may be associated with high morbidity and mortality. We describe a case of the use of low-dose inhaled nitric oxide (NO) as a treatment of severe hypoxemia in the setting of pulmonary venous hypertension in a patient with uncorrected congenital pulmonary vein stenosis. A 9-month-old female infant with cri-du-chat syndrome, atrial and ventricular septal defects, patent ductus arteriosus, pulmonary hypertension, and chronic respiratory insufficiency requiring ventilation via a tracheostomy was admitted with fever and hypoxemia. She developed worsening pulmonary edema within 8 hours of initiation of NO therapy and was later found to have stenosis of multiple pulmonary veins. NO was weaned, but hypoxemia worsened. She was treated for 2 weeks with low-dose NO (≤1 ppm) and diuretic therapy to prevent fluid overload, which allowed for weaning from high–positive pressure ventilation settings. She later underwent successful stenting of multiple pulmonary veins and eventual discharge, off NO and on lower–positive pressure ventilation settings. Although caution is warranted in the use of pulmonary vasodilators in the setting of pulmonary venous hypertension, we suggest that a strategy including low-dose NO, vigilant monitoring for pulmonary edema, and meticulous attention to fluid balance may be helpful.
Pulm Circ. 2014;4(3):527–530.
QRS complex duration may reflect right ventricular (RV) size and dysfunction. Increased RV size and dysfunction predict a poor outcome in children with pulmonary hypertensive vascular disease (PHVD). We investigated the association of QRS duration with pulmonary vascular hemodynamics and outcome in children with PHVD. We reviewed the clinical data of children with PHVD who had an ECG recorded within 1 week of cardiac catheterization between 2009 and 2013. We excluded patients with congenital heart disease. The QRS duration was measured in lead V1 using the TM ECGvue application (Philips, Netherlands). Pulmonary artery (PA) pressures were measured directly, and pulmonary vascular resistance (PVRI) and pulmonary capacitance index (PACI) were calculated using measured oxygen consumption. Thirty-two patients (17 males), with a median age of 4 years (range: 3 months to 17 years) and a median weight of 13.9 kg (range: 3.3–77 kg), underwent 46 cardiac catheterizations. Diagnoses included idiopathic pulmonary arterial hypertension (58%), left heart disease (14%), and bronchopulmonary dysplasia (28%). There were 4 deaths due to right heart failure, and one patient required lung transplantation. One patient with good right ventricular function but hemoptysis from bronchial collaterals died of complications after embolization. Mean QRS duration was 85 ± 17 ms (upper limit of normal for age range: 75–85 ms). QRS duration longer than 93 ms predicted death or lung transplantation due to right heart failure (sensitivity: 100%, specificity: 68%) and PACI of less than 0.7 mL/mmHg/m2 (sensitivity: 70%, specificity: 75%). The mean PA pressure was 43 ± 18 mmHg, PVRI was 9.6 ± 6 WU/m2, and PACI was 1.13 ± 0.8 mL/mmHg/m2. QRS duration correlated with the systolic PA pressure (r = +0.26, P = 0.03), mean PA pressure (r = +0.26, P = 0.03), and PVRI (r = +0.3, P = 0.006) and negatively with the PACI (r = −0.45, P < 0.001). In children with PHVD, a QRS duration of longer than 93 ms predicts death from right heart failure with 100% sensitivity. A QRS of longer than 93 ms may be a useful, easily obtainable, noninvasive indicator of children who require close follow-up and further evaluation.
Pulm Circ. 2014;4(3):527–530.
We report the effectiveness and tolerability of subcutaneous (subQ) treprostinil as an add-on therapy in children with pulmonary arterial hypertension (PAH). Children with PAH with clinical worsening despite treatment with combination oral therapies were started on subQ treprostinil after detailed clinical evaluation and cardiac catheterization. Treprostinil doses were increased rapidly until symptomatic improvement was reported. All the children were followed regularly, with assessment of functional class (FC), N terminal–Pro brain natriuretic peptide (NT-ProBNP), 6-minute walk test (6MWT), and cardiac catheterization. Between 2010 and 2013, 7 children (median age: 13 years [range: 5–18 years], median weight: 17 kg [8–46 kg], 4 males) reached criteria to start subQ treprostinil therapy. After 23 months (range: 5–30 months) of follow-up, the median treprostinil dose was 64 ng/kg/min (range: 40–276 ng/kg/min). All follow-up parameters improved significantly (P < 0.05). Median FC (III [II–IV] vs. II [II–IV], 6MWTd (336 [0–551] vs. 418 m [300–815 m]), NT-ProBNP (141 [37.9–901] vs. 22.8 pg/mL [6.8–253 pg/mL]), mean PA pressure (67 [31–100] vs. 41 mmHg [40–60 mmHg]), PVRI (14.6 [6.8–40] vs. 8.1 WU/m2 [7–9.3 WU/m2]). One patient died following embolization therapy for hemoptysis. One patient was transitioned to intravenous prostacyclin and died on ECMO. SubQ sites lasted 40 days (range: 7–60 days). Parents managed site changes at home. Site pain was minimal, worst 1–2 days after site change, and resolved by day 4–5. No patient discontinued therapy because of site pain. Subcutaneous treprostinil in children with an inadequate response to combination oral therapies is well tolerated and results in significant improvement in FC, 6MWT, NT-ProBNP, mean PA pressure, and PVRI.