Rapid genome diagnosis of alveolar capillary dysplasia leading to treatment in a child with respiratory and cardiac failure.

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

Evaluation of methemoglobin as an intravascular contrast agent: T1 relaxation time effect in a rabbit model.

OBJECTIVE: Alternative contrast agents for MRI are needed for individuals who may respond adversely to gadolinium, and need an intravascular agent for specific indications. One potential contrast agent is intracellular methemoglobin, a paramagnetic molecule that is normally present in small amounts in red blood cells. An animal model was used to determine whether methemoglobin modulation with intravenous sodium nitrite transiently changes the T1 relaxation of blood. METHODS: Four adult New Zealand white rabbits were treated with 30 mg intravenous sodium nitrite. 3D TOF and 3D MPRAGE images were acquired before (baseline) and after methemoglobin modulation. T1 of blood was measured with 2D ss EPl acquisitions with inversion recovery preparation performed at two-minute intervals up to 30 min. T1 maps were calculated by fitting the signal recovery curve within major blood vessels. RESULTS: Baseline T1 was 1758 ± 53 ms in carotid arteries and 1716 ± 41 ms in jugular veins. Sodium nitrite significantly changed intravascular T1 relaxation. The mean minimum value of T1 was 1126 ± 28 ms in carotid arteries 8 to 10 min after the injection of sodium nitrite. The mean minimum value of T1 was 1171 ± 52 ms in jugular veins 10 to 14 min after the injection of sodium nitrite. Arterial and venous T1 recovered to baseline after a period of 30 min. CONCLUSION: Methemoglobin modulation produces intravascular contrast on T1-weighted MRI in vivo. Additional studies are needed to safely optimize methemoglobin modulation and sequence parameters for maximal tissue contrast.

Comparison of Methemoglobin, Deoxyhemoglobin, and Ferrous Nitrosyl Hemoglobin as Potential MRI Contrast Agents.

Gadolinium-based contrast agents (GBCAs) are in widespread use to enhance magnetic resonance imaging for evaluating vascular pathology. However, safety concerns and limitations regarding the use of GBCAs has led to an increased interest in alternative contrast agents. Previously, methemoglobin (metHb) and oxygen-free hemoglobin (HHb) have been shown to increase the T1-weighted signal intensity of blood, which is associated with a decrease in the T1 parameter and an enhanced contrast of the image. Thus, a lower T1 value compared to the baseline value is favorable for imaging. However, it is unknown as to whether metHb or HHb would be a stronger and more appropriate contrast agent and to what extent the T1-weighted signal is affected by concentration. This study evaluated T1-weighted images of blood samples over a range of metHb and HHb concentrations, as well as ferrous nitrosyl hemoglobin (HbIINO) concentrations. Comparison of T1 values from a baseline value of ~ 1500 ms showed that metHb is the strongest contrast agent (T1 ~ 950 ms at 20% metHb) and that HHb is a relatively weak contrast agent (T1 ~ 1450 ms at 20% HHb). This study showed for the first time that HbIINO can provide a contrast effect, although not as strong as metHb but stronger than HHb (T1 estimated as 1250 ms at 20% HbIINO). With metHb providing a viable contrast between 10 and 20%, metHb has the potential to be a safe and effective contrast agent since it can be naturally converted back to hemoglobin.

Rapid Formation of Methemoglobin via Nitric Oxide Delivery for Potential Use as an MRI Contrast Agent.

Contrast-enhanced magnetic resonance angiography is a vital tool for evaluating vascular pathology. However, concerns about the limitations and safety of gadolinium-based contrast agents have led to an interest in alternative agents. Methemoglobin (metHb) increases the T1-weighted signal intensity of the magnetic resonance image of blood and could provide a safe and effective alternative. MetHb can be produced by the reaction of nitric oxide (NO) gas with oxyhemoglobin followed by natural conversion back to hemoglobin by cytochrome b5 reductase. Since rapid production of metHb via NO has not been studied, the effectiveness of producing metHb via NO delivery to blood was evaluated using a hollow-fiber module. MetHb production began immediately and > 90% conversion was achieved within 10 min. MetHb remained stable for at least 90 min when NO delivery was removed following metHb formation. Comparison of experimental data for metHb formation with model predictions showed that only a fraction of the NO delivered was utilized for metHb production, suggesting an additional fast reaction of NO with other blood constituents. Directly delivering NO to blood for the rapid formation of metHb provides a potential platform for producing metHb as an alternative contrast agent.

Acute vasodilator testing following Fontan palliation: an opportunity to guide precision care?

BACKGROUND: Pulmonary vasodilators improve the functional capacity of some patients with pulmonary arterial hypertension. However, pulmonary vasodilators frequently fail to improve unequivocal endpoints of efficacy in patients with lower pulmonary arterial pressures who have been palliated with a Fontan procedure. OBJECTIVE: Haemodynamic measurements and the results of acute vasodilator testing in a subset of patients were reviewed to determine whether some patients acutely respond more favourably to sildenafil and might be candidates for precision care with a phosphodiesterase V inhibitor long term. MATERIALS AND METHODS: Heart catheterisation was performed in 11 patients with a Fontan procedure. Haemodynamic measurements were performed before and after treatment with intravenous sildenafil (mean 0.14, range 0.05-0.20 mg/kg). Results (mean ± standard deviation) were compared by paired and unpaired t-tests to identify statistically significant changes. RESULTS: Sildenafil was acutely associated with changes in mean pulmonary arterial pressure, transpulmonary gradient, indexed blood flow, and indexed vascular resistance. Changes in mean pulmonary arterial pressure were greater for patients with a mean pulmonary arterial pressure greater than 14 mmHg compared to patients with a lower mean pulmonary arterial pressure. Changes in transpulmonary gradient were greater for patients with a transpulmonary gradient greater than 5 mmHg compared to patients with a lower transpulmonary gradient. CONCLUSION: Sildenafil acutely decreases mean pulmonary arterial pressure and transpulmonary gradient and causes greater acute changes in patients with higher mean pulmonary arterial pressures and transpulmonary gradients. Haemodynamic measurements and vasodilator testing might help to guide precision care following Fontan palliation.

A Long-Term Survivor With Alveolar Capillary Dysplasia.

A patient with alveolar capillary dysplasia has survived more than 56 months with medical therapy. Intrauterine exposure to metformin potentially modified the severity of disease. In combination with other agents, endothelin receptor antagonists and amlodipine have been key medications in lowering pulmonary arterial pressure and managing right heart failure. (Level of Difficulty: Beginner.).

Acute vasodilator testing: An opportunity to advance the precision care of pulmonary hypertension.

The pulmonary arterial pressure of a child with severe pulmonary arterial hypertension immediately normalized while breathing nitric oxide during heart catheterization at 8 years of age. Her acute pulmonary vascular response to nitric oxide has persisted throughout her life. Her acute response to other medications has been similar to her long-term response to medications in the same class. Acute vasodilator testing with inhaled nitric oxide and other medications may be an opportunity to refine study design and advance precision care for patients with pulmonary hypertension.

Oral treprostinil use in children: a multicenter, observational experience.

Pulmonary arterial hypertension is a progressive, incurable disease that occurs in adults and children alike. Therapeutic options for children are limited and infrequently described, including newer agents such as treprostinil, an oral prostanoid. Herein, we describe the pooled pediatric experience in 28 patients from four pediatric pulmonary hypertension programs over two years. This descriptive, observational study describes the various methods of initiation of oral treprostinil in both prostanoid-naïve patients and those transitioning from parenteral or inhaled prostanoids. The youngest patient was four years old and the smallest weighed 16 kg. We describe adverse reactions and their management. Most patients in this study (27/28) were able to successfully initiate therapy. However, gastrointestinal adverse reactions were common; half of the patients started on this therapy had discontinued it within the two-year study period.

Methemoglobin Modulation as an Intravascular Contrast Agent for Magnetic Resonance Imaging: Proof of Concept.

Objective: The aim of this feasibility study was to investigate methemoglobin modulation in vivo as a potential magnetic resonance imaging (MRI) gadolinium based contrast agent (GBCA) alternative. Recently, gadolinium tissue deposition was identified and safety concerns were raised after adverse effects were discovered in canines and humans. Because of this, alternative contrast agents are warranted. One potential alternative is methemoglobinemia induction, which can create T1-weighted signal in vitro. Canines with hereditary methemoglobinemia represent a unique opportunity to investigate methemoglobin modulation. Our objective was to determine if methemoglobinemia could create high intravascular T1-signal in vivo with reversal using methylene blue. Methods: To accomplish this study, a 1.5-year-old male-castrated mixed breed canine with hereditary methemoglobinemia underwent 3T-MRI/MRA with T1-weighted sequences including 3D-T1-weighted Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) and 3D-Time-Of-Flight (TOF). Images were acquired during baseline methemoglobinemia and rescued using intravenous methylene blue (1 mg/kg). Intravascular T1-signal was compared between baseline methemoglobinemia and post-methylene blue. N = 10 separate T1-signal measurements were acquired for each vascular structure, normalized to muscle. Significance was determined using paired two-tailed t-tests and threshold alpha = 0.05. Fold-change was also calculated using the ratio of T1-signal between methemoglobinemia and post-methylene blue states. Results: At baseline, methemoglobin levels measured 19.5% and decreased to 4.9% after methylene blue. On 3D-T1-weighted MPRAGE, visible signal change was present in internal vertebral venous plexus (IVVP, 1.34 ± 0.09 vs. 0.83 ± 0.05, p < 0.001, 1.62 ± 0.06-fold) and external jugular veins (1.54 ± 0.07 vs. 0.87 ± 0.06, p < 0.001, 1.78 ± 0.10-fold). There was also significant change in ventral spinal arterial signal (1.21 ± 0.11 vs. 0.79 ± 0.07, p < 0.001, 1.54 ± 0.16-fold) but not in carotid arteries (2.12 ± 0.10 vs. 2.16 ± 0.11, p = 0.07, 0.98 ± 0.03-fold). On 3D-TOF, visible signal change was in IVVP (1.64 ± 0.14 vs. 1.09 ± 0.11, p < 0.001, 1.50 ± 0.11-fold) and there was moderate change in external jugular vein signal (1.51 ± 0.13 vs. 1.19 ± 0.08, p < 0.001, 1.27 ± 0.07-fold). There were also small but significant differences in ventral spinal arterial signal (2.00 ± 0.12 vs. 1.78 ± 0.10, p = 0.002, 1.13 ± 0.10-fold) but not carotid arteries (2.03 ± 0.17 vs. 1.99 ± 0.17, p = 0.15, 1.02 ± 0.04-fold). Conclusion: Methemoglobin modulation produces intravascular contrast on T1-weighted MRI in vivo. Additional studies are warranted to optimize methemoglobinemia induction, sequence parameters for maximal tissue contrast, and safety parameters prior to clinical implementation.

Acute Pulmonary Vasodilator Testing and Long-Term Clinical Course in Segmental Pulmonary Vascular Disease.

Results of acute pulmonary vasodilator testing (AVT) and the outcome of medical therapy have not been described in patients with segmental pulmonary vascular disease (SPVD). We sought to compare the pulmonary vasodilatory effects of oxygen, oxygen with nitric oxide, and diltiazem, and to describe the clinical course of patients with SPVD and pulmonary hypertension. A retrospective review of 16 patients with pulmonary hypertension and SPVD involving 2-3 major lung segments who underwent AVT between January 2000 and December 2015 was performed. Baseline hemodynamic measurements were obtained with patients breathing ≤ 30% oxygen. AVT was performed using 100% oxygen, 100% oxygen with 20 ppm nitric oxide, 21-35% oxygen, and 21-35% oxygen with intravenous diltiazem. The events associated with their long-term care were described. Nine of 16 patients were acutely responsive during AVT using the Sitbon criteria. The change in mean pulmonary artery pressure with oxygen or oxygen with nitric oxide (19 ± 12 mmHg) was significantly greater than the change with diltiazem (7 ± 5 mmHg). Pulmonary vasodilator therapy was initiated or escalated after AVT in 12 patients. Five patients subsequently experienced a decrease in mean pulmonary artery pressure or normalization in B-type natriuretic peptide. Three patients experienced adverse events associated with therapy. The actuarial survival was 94% over a period of 1-20 years. This study suggests that AVT can be used to identify patients with SPVD who are reactive to oxygen, oxygen with nitric oxide, and diltiazem. Clinical improvement was temporally associated with pulmonary vasodilator therapy in some patients with few adverse effects.

Selective pulmonary artery occlusion to treat hemoptysis associated with pulmonary venous obstruction.

Hemoptysis may occur in patients with pulmonary venous obstruction and prominent decompressing vessels in the airways adjacent to the affected pulmonary veins. The options for treatment of hemoptysis are limited, particularly when efforts to alleviate pulmonary venous obstruction have failed. Here we describe a patient with hemoptysis associated with stenosis of the central left upper pulmonary vein and occlusion of the central left lower pulmonary vein. The left upper pulmonary vein was dilated with balloon catheters and a vascular plug was placed in the left lower pulmonary artery. Vascular engorgement regressed in the left bronchus and hemoptysis has not recurred for 4 years despite recurrence of left upper pulmonary vein stenosis. Selective occlusion of branch pulmonary arteries may be an effective option for the treatment of hemoptysis from bleeding in lung segments with inoperable pulmonary venous obstruction.

Pulmonary veno-occlusive disease: Two children with gradual disease progression.

Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis are rare forms of pulmonary vascular disease. We report two cases of affected children who had evidence of pulmonary hypertension 3-5 years before developing radiographic findings of pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. Both patients experienced a moderate decrease in pulmonary arterial pressure during acute vasodilator testing. Both patients experienced an improvement in six-minute walk performance without an increase in pulmonary edema when treated with targeted therapy for pulmonary hypertension. In some patients, pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis may progress slowly over a period of months to years. A favorable acute vasodilator response may identify patients who will tolerate, and demonstrate transient clinical improvement with, medical therapy.

Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.

Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema.

Outcome following augmentation of superior cavopulmonary blood flow with an arteriovenous fistula.

BACKGROUND: Axillary or brachial arteriovenous fistulae are occasionally created to improve systemic oxygen saturation in patients with functionally univentricular circulation after superior cavopulmonary anastomosis. Different techniques of fistula construction may account for the conflicting results. We sought to determine the impact of axillary arteriovenous fistula on systemic oxygen saturation and survival before subsequent palliation or heart transplantation. METHODS: Medical records of patients who underwent a side-to-side anastomosis between an adjacent axillary artery and vein for cyanosis after superior cavopulmonary anastomosis between 1991 and 2010 were reviewed. RESULTS: The median age (n = 23) at the time of fistula creation was 54 months (4-278 months). There was no operative mortality. The median duration of fistula patency was 48 months (1-174 months). Oxygen saturation improved from 71% ± 10% preoperatively to 84% ± 4% early (P < .05) and 81% ± 4% long term after the arteriovenous fistula (P < .05). Twelve patients underwent additional surgery (total cavopulmonary anastomosis 6, partial biventricular repair 2, and heart transplantation 4) after an interval of 10 to 141 months. Six patients are alive with a patent fistula without subsequent interventions after an interval of 48 to 174 months. Two patients with spontaneous closure or device closure of the fistula are alive after an interval of 76 to 80 months without subsequent interventions. Three deaths occurred with a patent fistula without subsequent interventions after an interval of 1 to 84 months. CONCLUSIONS: Systemic oxygen saturation improved with creation of an axillary arteriovenous fistula after superior cavopulmonary anastomosis. The fistula extended the duration of this stage of palliation without precluding the option for additional palliation or heart transplantation.

Comparison between the Acute Pulmonary Vascular Effects of Oxygen with Nitric Oxide and Sildenafil.

OBJECTIVE: Right heart catheterization is performed in patients with pulmonary arterial hypertension to determine the severity of disease and their pulmonary vascular reactivity. The acute pulmonary vascular effect of inhaled nitric oxide is frequently used to identify patients who will respond favorably to long-term vasodilator therapy. This study sought to determine whether the acute pulmonary vascular effects of oxygen with nitric oxide and intravenous sildenafil are similar. METHODS: A retrospective, descriptive study of 13 individuals with pulmonary hypertension who underwent heart catheterization and acute vasodilator testing was performed. The hemodynamic measurements during five phases (21-53% oxygen, 100% oxygen, 100% oxygen with 20 ppm nitric oxide, 21-51% oxygen, and 21-51% oxygen with 0.05-0.29 mg/kg intravenous sildenafil) of the procedures were compared using analysis of variance. A linear regression analysis and a Bland Altman plot were used to compare the percent change in mean pulmonary arterial pressure and the percent change in pulmonary vascular resistance from baseline with oxygen and nitric oxide, and from baseline with sildenafil. RESULTS: Mean pulmonary arterial pressure and pulmonary vascular resistance acutely decreased with 100% oxygen with nitric oxide and 21-51% oxygen with sildenafil. Pulmonary blood flow during sildenafil was greater than pulmonary blood flow during 100% oxygen and 100% oxygen with nitric oxide. The pH, right atrial pressure, and left atrial pressure did not change during the five phase of heart catheterization. Mean pulmonary arterial pressure (millimeter of mercury, mean ± standard error of the mean) was 38 ± 4 during 21-53% oxygen, 32 ± 3 during 100% oxygen, 29 ± 2 during 100% oxygen with nitric oxide, 37 ± 3 during 21-51% oxygen, and 32 ± 2 during 21-51% oxygen with sildenafil. There was not a significant correlation between the percent change in pulmonary vascular resistance from baseline with oxygen and nitric oxide, and from baseline with sildenafil (r (2) = 0.011, p = 0.738). The Bland Altman analysis demonstrated statistical agreement between the effects of oxygen with nitric oxide and sildenafil. However, differences were large enough to limit the interchangeable use of these vasodilators in a clinical setting. CONCLUSION: Oxygen with nitric oxide and sildenafil decreased pulmonary vascular resistance. However, the pulmonary vascular effects of oxygen and nitric oxide do not reliably predict the acute response to sildenafil. Additional studies are needed to determine whether the acute response to sildenafil can be used to predict the long-term response to treatment with an oral phosphodiesterase V inhibitor.

Lifetime cardiac reinterventions following the Fontan procedure.

Patients with single ventricle physiology face significant morbidity and mortality following the Fontan procedure resulting in the need for additional cardiac reinterventions. Online patient education resources provide limited information on the reinterventions performed in single ventricle patients following the Fontan procedure. We sought to determine cardiac surgical and percutaneous reintervention rates and factors affecting reinterventions following the Fontan procedure. Databases from a single tertiary care center were retrospectively reviewed for all patients who underwent a Fontan procedure between 1978 and 2002. The number and type of cardiac surgical and percutaneous interventions following the Fontan procedure were determined, and relationships between need for reintervention and clinical variables were sought. A total of 91 patients (55 males) underwent the Fontan procedure at a median age of 5.50 years (IQR: 3.33-9.50 years). Median age at last follow-up, death, or transplant was 21.89 years (IQR: 10.87-25.51 years). Following the Fontan procedure, 60 (66%) patients required an additional 144 median sternotomies and 61 (67%) required 139 percutaneous cardiac interventions. Pacemaker system placement/replacement was the most common intervention following the Fontan procedure. The median time to first cardiac surgery following the Fontan was 1.96 years (IQR: 0.06-8.42 years) while the median time to the first percutaneous intervention was 7.63 years (IQR: 0.65-15.89 years). Families of single ventricle patients should be counseled on the likelihood of requiring additional cardiac interventions following the Fontan procedure.

Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice.

Current paediatric pulmonary hypertension (PH) diagnostic algorithms include some testing specifically for paediatrics, but it is unclear if this is used in clinical practice. We describe the current diagnostic workup of the TOPP (Tracking Outcomes and Practice in Paediatric Pulmonary hypertension) registry for suspected PH. We investigated 456 patients enrolled until February 2010. The majority had ECGs (94%), echocardiograms (96%) and/or chest radiographs (89%) performed and these were the noninvasive tests most frequently used for evaluation of suspected PH. No patient had all three tests considered normal, suggesting the potential for the combined use to rule out PH. For evaluation of complications associated with heart catheterisation (HC) we analysed a total of 908 HCs reported until February 2012. Of these, 554 were at diagnosis and 354 in follow-up. Complications were reported in 5.9% with five deaths considered related to HC, suggesting a higher rate of HC complications compared to adult studies. However, current recommendations support HC in paediatric PH. A proper application of the risk/benefit ratio for HC requires further data. Most children did not undergo the diagnostic workup currently recommended for adults, which highlights either incomplete awareness of current guidelines and/or challenges their appropriateness for children.

Living at altitude adversely affects survival among patients with a Fontan procedure.

OBJECTIVES: This study sought to determine whether survival in this cohort of patients was adversely affected by increased residential altitude. BACKGROUND: The success of the Fontan procedure depends in large part on low pulmonary vascular resistance (PVR). Factors that increase PVR, including an increase in residential altitude, may adversely affect long-term outcome. Higher altitude has been shown to affect functional well-being in patients with a Fontan circulation. METHODS: Databases from a tertiary cardiac care center in the Intermountain West (elevation 5,000 feet) were analyzed for patients born with single-ventricle anatomy who would now be of adult age. Complete data were then collected on all identified patients who subsequently underwent the Fontan operation. Correlates of, and time to, adverse outcome, defined as death, cardiac transplantation, or clinical decompensation requiring a move to sea level, were determined. RESULTS: Of 149 patients with single-ventricle anatomy, 103 underwent the Fontan procedure, with 70 surviving to adulthood at moderate altitude. Adverse outcome occurred in 55, with death in 24 (23%), cardiac transplantation in 18 (17%), and clinical decompensation requiring move to sea level in 13 (13%). There was no relationship between type, age at, or era of Fontan procedure and long-term outcome. Correlates of long-term, transplant-free survival at moderate altitude included lower residential altitude (4,296 vs. 4,637 feet, p < 0.001), and lower pulmonary artery pressures before the Fontan procedure (13 vs. 15 mm Hg, p = 0.01), and after (14 vs. 18 mm Hg, p = 0.01). CONCLUSIONS: Long-term outcome after the Fontan procedure is adversely impacted by higher residential altitude.