Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.
Adverse drug events; Pediatrics; Pulmonary; hypertension
New evidence of increased phosphodiesterase-5 (PDE-5) in hypertrophied human myocardium suggests that sildenafil, a selective PDE-5 inhibitor, may improve muscle contraction and therefore improve ventricular function. The purpose of this study was to compare ventricular function as assessed by echocardiography in 10 surgically palliated single-ventricle patients at baseline and again after a single dose of sildenafil. The velocity time integral of the ventricular outflow tract was increased 2 h after sildenafil administration (p = 0.01), thus suggesting an improvement in cardiac output.
Congenital heart disease; Fontan; Pediatric; Univentricular heart
Cardiac development is comprised of a series of morphological events tightly controlled both spatially and temporally. The molecular pathways controlling early cardiac differentiation are poorly understood, but Wnt signaling is emerging as a critical pathway for multiple aspects of early cardiovascular development. The Wnt pathway plays multiple roles in regulating cellular behavior including proliferation, differentiation, cell migration, and cell polarity. Recent data have demonstrated that Wnt activity is important for early precardiac mesoderm differentiation but must be inhibited in subsequent steps for cardiomyocyte differentiation to proceed. Given the important role that Wnt signaling plays in both the differentiation of cardiomyocytes from pluripotential stem cells and tissue regeneration in general, an increased understanding of this pathway is likely to enhance our knowledge about both cardiovascular development and reparative mechanisms.
Cardiac development; Progenitor; Wnt
The vertebrate heart is innervated by the sympathetic and parasympathetic components of the peripheral autonomic nervous system, which regulates its contractile rate and force. Understanding the mechanisms controlling sympathetic neuronal growth, differentiation, and innervation of the heart may provide insight into the etiology of cardiac arrhythmogenesis. In this review, we provide an overview of the cell signaling pathways and transcriptional effectors that regulate both the noradrenergic gene program during sympathetic neurogenesis and regional nerve density during cardiac innervation. We detail recent studies exploring transcriptional regulation of the bHLH transcription factor Hand1 in developing sympathetic neurons, and discuss how the Hand1 sympathetic neuron-specific cis-regulatory element may be further utilized to assess the contribution of altered sympathetic innervation to human cardiac disease.
sympathetic nervous system; neural crest
As a major cardiac voltage-gated sodium channel isoform in the heart, Nav1.5 channel is essential for the cardiac action potential initiation and the subsequent propagation throughout the heart. Mutations of Nav1.5 have been linked to a variety of cardiac disease such as long QT syndrome (LQTs), Brugada syndrome, cardiac conduction defect, atrial fibrillation and dilated cardiomyopathy. Mutagenesis approach and heterologous expression systems are most frequently used to study the function of this channel. This review is primarily focused on recent findings on Nav1.5 mutations that are associated with type 3 long QT syndrome (LQT3) in particular. Understanding the functional changes of the Nav1.5 mutation may offer critical insight into the mechanism of long QT3 syndrome. In addition, this review will provide the updated information on the current progress of using various experimental model systems to study primarily the long QT3 syndrome.
Cardiac sodium channel; cardiac arrhythmia; sodium channel mutation
Cardiac calsequestrin (Casq2) is the major Ca2+ binding protein in the sarcoplasmic reticulum which is the principle Ca2+ storage organelle of cardiac muscle. Over the last decade, experimental studies have provided new concepts on the role of Casq2 in the regulation of cardiac muscle Ca2+ handling. Furthermore, mutations in the gene encoding for cardiac calsequestrin, CASQ2, cause a rare but severe form of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Here, we review the physiology of Casq2 in cardiac Ca2+ handling and discuss pathophysiological mechanisms that lead to CPVT caused by CASQ2 mutations. We also describe the clinical aspects of CPVT and provide an update of its contemporary clinical management.
Specifically, FK506-binding proteins 12 (FKBP12) and 12.6 (FKBP12.6) are cis–trans peptidyl prolyl isomerases that are expressed in the heart. Both FKBP12 and FKBP12.6 were previously known to interact with ryanodine receptors in striated muscles. Although FKBP12 is abundantly present in the heart, its function in the heart is largely uncertain. Recently, by generating FKBP12 transgenic overexpression and cardiac-restricted knockout mice, we showed that FKBP12 is critically important in regulating trans-sarcolemmal ionic currents, predominately the voltage-gated Na+ current, INa, but it appears to be less important for regulating cardiac ryanodine receptor function. Similar genetic approaches also confirm the role of FKBP12.6 in regulating cardiac ryanodine receptors. The current study demonstrated that FKBP12 and FKBP12.6 have very different physiologic functions in the heart.
FK506-binding protein; Cardiac function; Arrhythmia; Voltage-gated sodium channel; Ryanodine receptor; Calcium release
Protein complex of the cardiac junctional sarcoplasmic reticulum (SR) membrane formed by type 2 ryanodine receptor, junction, triadin, and calsequestrin is responsible for controlling SR calcium (Ca) release. Increased intracellular calcium (Cai) activates the electrogenic sodium–Ca exchanger current, which is known to be important in afterdepolarization and triggered activities (TAs). Using optical-mapping techniques, it is possible to simultaneously map membrane potential (Vm) and Cai transient in Langendorff-perfused rabbit ventricles to better define the mechanisms by which Vm and Cai interactions cause early afterdepolarizations (EADs). Phase 3 EAD is dependent on heterogeneously prolonged action potential duration (APD). Electrotonic currents that flow between a persistently depolarized region and its recovered neighbors underlies the mechanisms of phase 3 EADs and TAs. In contrast, “late phase-3 EAD” is induced by APD shortening, not APD prolongation. In failing ventricles, upregulation of apamin-sensitive Ca-activated potassium (K) channels (IKAS) causes APD shortening after fibrillation-defibrillation episodes. Shortened APD in the presence of large Cai transients generates late-phase 3 EADs and recurrent spontaneous ventricular fibrillation. The latter findings suggest that IKAS may be a novel antiarrhythmic targets in patients with heart failure and electrical storms.
Triggered activity; After depolarization; Ventricular fibrillation; Calcium dynamics; Optical mapping
Although the adult mammalian myocardium exhibits a limited ability to undergo regenerative growth, its intrinsic renewal rate is insufficient to compensate for myocyte loss during cardiac disease. Transplantation of donor cardiomyocytes or cardiomyogenic stem cells is considered a promising strategy to reconstitute cardiac mass, provided the engrafted cells functionally integrate with host myocardium and actively contribute to its contractile force. We have previously developed a two-photon fluorescence microscopy-based assay that allows in situ screening of donor cell function following their intracardiac delivery. Here we review the techniques and summarize its application for quantitation of the extent to which a variety of donor cell types stably and functionally couple with the recipient myocardium.
Cellular transplantation; myocardial regeneration; intracellular calcium regulation; two-photon fluorescence microscopy
Recently published optical mapping studies in larger mammals, including human, have identified functionally discrete sino-atrial exit pathways of activation. This is in line with earlier mapping studies in dog and human but in contrast with findings in mouse and rabbit, where a propagation wavefront pattern of activation has been described. It underpins the complex 3D organization of the cardiac pacemaking and conduction system in larger species, where sinoatrial and atrioventricular nodal physiology both demonstrate identifiable activation pathways, which coincide with anatomical landmarks and histological architecture. So that, in addition to muscle fiber orientation and cell coupling, these intrinsic factors act to determine excitation pathways. This complex 3D organization increases the effect of source-to-sink mismatch both by greater variability of the space constant of tissue and by the 3D projection of this effect in all directions. Mathematical modeling provides a means to study these interactions and newer models should incorporate these additional factors and their effect in the 3D structure of large mammal physiology.
Cardiac conduction system; Sinoatrial node; Atrioventricular node; Computer simulation
Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-β appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-β on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-β measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-β on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642–1,896]; median 1,386 pg/ml [range 868–1,913]) compared with others without PDA (median 1,334 pg/ml [range 760–2,064]; median 1,712 pg/ml [range 1,014–2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-β levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-β was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83–1.17; day 7 OR 0.88, 95 % CI 0.74–1.04) on adjusted analyses. Our results suggest that blood spot TGF-β alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment.
Transforming growth factor; Patent ductus arteriosus; Preterm; Neonate
Infants with CHD have delayed brain maturation and alterations in brain volume. Brain metrics is a simple measurement technique that can be used to evaluate brain growth. This study used brain metrics to test the hypothesis that alterations in brain size persist at three months of age and that infants with CHD have slower rates of brain growth than control infants.
Fifty-seven infants with CHD underwent serial brain magnetic resonance imaging (MRI). To evaluate brain growth across the first three months of life, brain metrics were undertaken on 19 tissue and fluid spaces on MRIs performed pre-operatively and at three months of age.
Pre-operatively, infants with CHD have smaller frontal, parietal, cerebellar and brainstem measures (p<0.001). At three months of age, alterations persisted in all measures except the cerebellum. There was no difference between control and CHD infants in brain growth. However, the cerebellum trended towards greater growth in infants with CHD. Somatic growth was the primary factor that related to brain growth. Presence of focal white matter lesions pre- and post-operatively did not relate to alterations in brain size or growth.
Although infants with CHD have persistent alterations in brain size at three months of age, rates of brain growth are similar to that of healthy term infants. Somatic growth was the primary predictor of brain growth, emphasizing the importance of optimal weight gain in this population.
Congenital heart disease; Brain; Magnetic resonance imaging; Growth
The study aim was to define the clinical manifestations and long-term outcome of pediatric patients living at altitude with isolated pulmonary artery of ductal origin. This was a retrospective cohort study of 17 consecutive cases of isolated pulmonary artery of ductal origin at a single center. All patients lived at modest altitude (median, range; 2050 m, 1700–3050 m). Fifteen children (88%) were symptomatic at presentation. High altitude pulmonary edema was present in 2 patients (12%) at diagnosis and only 1 patient had episodes of hemoptysis during follow-up. Fourteen patients (82%) demonstrated evidence of pulmonary arterial hypertension (PAH). Among 14 patients with PAH, 11 patients had surgical interventions. PAH resolved in 5 of 11 patients (45%) undergoing surgical rehabilitation. One patient died during follow-up and 7 patients are receiving oral vasodilator therapies due to residual PAH; 14 patients remained asymptomatic. Our study showed that early intervention in patients with isolated pulmonary artery of ductal origin at modest altitude can potentially rehabilitate the isolated pulmonary artery and reverse the PAH. Whether surgery is indicated for patients with this disorder in the absence of PAH is unknown.
isolated pulmonary artery of ductal origin; unilateral absence of pulmonary artery; altitude; high altitude pulmonary edema; pulmonary arterial hypertension
Our objective was to investigate the safety, tolerability, and effects of tadalafil in children with pulmonary arterial hypertension after transition from sildenafil or receiving tadalafil as initial therapy. Thirty three pediatric patients with pulmonary arterial hypertension were retrospectively evaluated. Twenty nine of 33 patients were switched from sildenafil to tadalafil. The main reason for changing from sildenafil was once daily dosing. The average dose of sildenafil and tadalafil were 3.4+/−1.1 mg/kg/day and 1.0+/−0.4 mg/kg/day, respectively. In 14 of 29 patients undergoing repeat catheterization, statistically significant improvements were observed following transition from sildenafil to tadalafil, in mean pulmonary arterial pressure (mmHg) (53.2+/−18.3 versus 47.4+/−13.7, p<0.05) and pulmonary vascular resistance index (unitsxm2) (12.2+/−7.0 versus 10.6+/−7.2, p<0.05). In 4 patients treated with tadalafil as initial therapy, clinical improvement was noted. Side effect profiles were similar in patients who had transitioned from sildenafil to tadalafil and included headache, nausea, myalgia, nasal congestion, flushing, and allergic reaction. Two patients discontinued tadalafil due to migraine or an allergic reaction. One patient on sildenafil had no break through syncope after transition to tadalafil. Tadalafil can be safely used in pediatric patients with pulmonary arterial hypertension and may prevent disease progression.
tadalafil; sildenafil; phosphodiesterase type 5 inhibitor; safety; tolerability; children
Basic helix–loop–helix (bHLH) transcription factors control developmental decisions for a wide range of embryonic cell types. Hand1 and Hand2 are closely related bHLH proteins that control cardiac, craniofacial, and limb development. Within the developing heart, Hand1 expression becomes restricted predominantly to the left ventricle, whereas Hand2 becomes restricted predominantly to the left ventricle, for which findings have shown each Hand factor to be necessary for normal chamber formation. Forced overexpression of Hand1 throughout the early developing heart induces abnormal interventricular septal development, with resulting pathogenesis of congenital heart defects. To investigate the potential transcriptional mechanisms involved in heart morphogenesis by Hand2, this study used a replacement targeting approach to knock Hand2 into the Hand1 locus and ectopically express one copy of Hand2 within the endogenous Hand1 expression domain in the developing hearts of transgenic mice. The findings show that high-percentage Hand1Hand2 chimeras die at birth and exhibit a range of congenital heart defects. These findings suggest that Hand factors may act via unique transcriptional mechanisms mediated by bHLH factor partner choice, supporting the notion that alterations of Hand factor stoichiometry may be as deleterious to normal heart morphogenesis as Hand factor loss of function.
bHLH transcription factors; Chimeras; Congenital heart defects
Each year, tens of thousands of children undergo cardiopulmonary bypass (CPB) to correct congenital heart defects. Although necessary for surgery, CPB involves stopping the heart and exposing it to ischemic conditions. On reoxygenation, the heart can experience effects similar to that of acute myocardial infarction. Although much is known about adult injury, little is known about the effects of global ischemia on newborn ventricles. We studied newborn (2 to 4 days old) and adult (>8 weeks old) rabbit hearts subjected to ischemia–reperfusion (30 min of ischemia and 60 min of reperfusion). Our data demonstrated chamber- and age-specific changes in oxidative stress. During ischemia, hydrogen peroxide (H2O2) increased in both right-ventricular (RV) and left-ventricular (LV) myocytes of the newborn, although only the RV change was significant. In contrast, there was no significant increase in H2O2 in either RV or LV myocytes of adults. There was a fivefold increase in H2O2 formation in newborn RV myocytes compared with adults (P = 0.006). In whole-heart tissue, superoxide dismutase activity increased from sham versus ischemia in the left ventricle of both adult and newborn hearts, but it was increased only in the right ventricle of the newborn heart. Catalase activity was significantly increased after ischemia in both adult ventricles, whereas no increase was seen in newborn compared with sham hearts. In addition, catalase levels in newborns were significantly lower, indicating less scavenging potential. Nanoparticle-encapsulated ebselen, given as an intracardiac injection into the right or left ventricle of newborn hearts, significantly increased functional recovery of developed pressure only in the right ventricle, indicating the potential for localized antioxidant therapy during and after pediatric surgical procedures.
Ischemia–reperfusion; Oxidative stress; Catalase; Hydrogen peroxide
Plastic bronchitis (PB) is a rare disease that often occurs in patients with congenital heart disease (CHD) who have undergone staged single ventricle palliation. It is characterized by the formation of rubbery “casts” in the airways. PB treatment frequently includes inhaled tPA. However, the efficacy of tPA to reduce cast burden is unknown. This is further complicated by our lack of knowledge of cast composition. We obtained spontaneously expectorated PB casts from children (n=4) with CHD and one adult patient with idiopathic PB. Pathological assessment was made from paraffin-preserved samples. Casts were treated with phosphate-buffered saline (PBS) or tPA. Cast response to tPA was assessed by changes in cast weight and the production of fibrin D-dimer. Independent of dose, tPA reduced cast weight compared with PBS-treatment (p=0.001) and increased D-dimer levels. Histological staining showed that PB casts from all patients were comprised of fibrin and contained notable numbers of lymphocytes. Cast composition did not change over time. Collectively, these data support that in our PB patients, casts are comprised of fibrin and are responsive to tPA treatment. This makes inhaled tPA a potentially viable option for symptomatic relief of PB while we work to unravel the complexity of PB pathogenesis.
congential heart disease; Fontan physiology; pulmonary drug delivery
Debilitating cardiomyocyte loss underlies the progression to heart failure. Although there have been significant advances in treatment, current therapies are intended to improve or preserve heart function rather than regenerate lost myocardium. A major hurdle in implementing a cell-based regenerative therapy is the inefficient differentiation of cardiomyocytes from either endogenous or exogenous stem cell sources. Moreover, cardiomyocytes that develop in human embryonic stem cell (hESC) or human-induced pluripotent stem cell (hIPSC) cultures are comparatively immature, even after prolonged culture, and differences in their calcium handling, ion channel, and force generation properties relative to adult cardiomyocytes raise concerns of improper integration and function after transplantation. Thus, the discovery of natural and novel small molecule synthetic regulators of differentiation and maturation would accelerate the development of stem-cell-based myocardial therapies. Here, we document recent advances in defining natural signaling pathways that direct the multistep cardiomyogenic differentiation program and the development of small molecules that might be used to enhance differentiation as well as the potential characteristics of lead candidates for pharmaceutical stimulation of endogenous myocardial replacement.
Cardiomyocyte; Embryonic stem cell; Chemical screening
Pulmonary arteriovenous malformations (PAVMs) are a common source of morbidity after bidirectional superior cavopulmonary anastomosis (Glenn). The diversion of hepatic venous effluent away from the pulmonary circulation after Glenn appears to play a significant role in the pathogenesis of PAVMs. Although the liver is known to produce factors that regulate vascular development, specific hepatic inhibitors of angiogenesis have not been described in the post-Glenn population. Endostatin, produced from its precursor collagen XVIII, is a potent inhibitor of angiogenesis produced by the liver. This study aimed to investigate the hypothesis that endostatin levels decrease in patients after Glenn. Levels of endostatin and its precursor, long-type collagen XVIII, were determined by enzyme-linked immunoassay and immunoprecipitation, respectively, for serum samples from 38 patients undergoing Glenn, total cavopulmonary anastomosis (Fontan), or biventricular repair of cardiac defects. Samples were obtained before surgery and 24 h afterward. In patients undergoing a bidirectional Glenn procedure, endostatin levels decreased after surgery (n = 17; 4.42 vs 3.34 ng/ml; p < 0.001), and long type-collagen XVIII levels increased by 200 % (n = 10; p = 0.0001). However, endostatin levels did not change after surgery in patients undergoing Fontan (n = 13) or biventricular repair (n = 8). In patients undergoing Fontan, long-type collagen XVIII increased by 18 % (p < 0.01), whereas in control subjects, the levels were unchanged. These data suggest that the diversion of hepatic blood flow away from the pulmonary circulation in patients after the Glenn procedure inhibits endostatin production from collagen XVIII, resulting in decreased circulating serum endostatin levels. A decrease in endostatin may promote angiogenesis. The mechanism whereby the pulmonary circulation processes endostatin and its potential role in the pathogenesis of PAVMs warrant further study.
Angiogenesis inhibitor; Cardiac repair; Collagen XVIII; Congenital heart disease; Endostatin; Pulmonary arteriovenous malformations
Infants with hypoplastic left heart syndrome (HLHS) represent a high-risk population when they present for noncardiac surgery. To assist clinicians in the care of these infants, we present our experience of 36 HLHS patients who underwent abdominal surgery after stage I palliation. We reviewed patients with HLHS who underwent gastrostomy and/or fundoplication after stage I palliation during an 18-month period. We assessed the impact of preoperative echocardiographic predictors and regional anesthesia on use of intraoperative inotropes, extubation in the OR, perioperative instability, postoperative escalation of care, and length of hospital and intensive care unit stay. Of 39 abdominal operations, all but 2 were performed with open laparotomy. There was a positive association between regional anesthesia and instability during induction. Escalation of respiratory care occurred in 9 (23.1%) cases, and escalation of hemodynamic care occurred in 6 (15.4%) cases. Neoaortic valve insufficiency was associated with increased length of stay, and ventricular outflow obstruction was associated with escalation of hemodynamic care. Extubation in the OR was successful in 31 cases (79.5%). In-hospital death occurred in 1 patient (2.7%). HLHS infants often undergo abdominal surgery, but intraoperative instability and need for escalation of care is common. Specific echocardiographic findings were associated with length of stay and escalation of care. Regional anesthesia was associated with transient intraoperative instability but not with other adverse outcomes.
Hypoplastic left heart syndrome; Abdominal surgery; Fundoplication; Gastrostomy
Single-ventricle congenital heart disease (SVCHD) requires multiple palliative surgical procedures that leave visible surgical scars and physical deficits, which can alter body-image and self-esteem. This study aimed to compare sex and age differences in body-image, self-esteem, and body mass index (BMI) in adolescents and adults with SVCHD after surgical palliation with those of a healthy control group. Using a comparative, cross-sectional design, 54 adolescent and adult (26 male and 28 female) patients, age 15–50 years, with SVCHD were compared with 66 age-matched healthy controls. Body-image and self-esteem were measured using the Multidimensional Body-Self Relations Questionnaire–Appearance Scale and Rosenberg Self-Esteem Scale. Height and weight were collected from retrospective chart review, and BMI was calculated. Female adolescents and adult patients with SVCHD reported lower body image compared with males patients with SVCHD and healthy controls (p = 0.003). Specific areas of concern were face (p = 0.002), upper torso or chest (p = 0.002), and muscle tone (p = 0.001). Patients with SVCHD who were <21 years of age had lower body image compared with healthy controls (p = 0.006). Self-esteem was comparable for both patients with SVCHD and healthy peers. There were no sex differences in BMI; BMI was higher in subjects >21 years of age (p = 0.01). Despite the similarities observed in self-esteem between the two groups, female patients with SVCHD <21 years of age reported lower perceived body-image. Our findings support the need to recognize poor psychological adjustment related to low self-esteem in patients with SVCHD; female patients warrant increased scrutiny. Strategies to help patients with SVCHD cope with nonmodifiable aspects of body-image during the difficult adolescent–to–young adult years may potentially enhance self-esteem and decrease psychological distress.
Body-image; Self-esteem; Body mass index; Single-ventricle congenital heart disease