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Introduction Pediatric patients with cardiomyopathies are at risk for sudden death and may need implantable cardioverter defibrillators (ICD’s), but given their small size and duration of use, children are at increased risk for complications associated with ICD use. The subcutaneous ICD presents a favorable option for children without pacing indications. Unfortunately, initial pediatric studies have demonstrated a high complication rate, likely due to the 3-incision technique employed. Material and methods Patients with ICD but no pacing indication were retrospectively reviewed after implantation of subcutaneous ICD via the two-incision technique. In half of the patients, 10-J impedance test was also performed to compare with impedance obtained after defibrillation threshold testing with 65-J. Results Twelve patients were included. The median age was 14 years (range 10–16 years) with eight males included (72.7%). The median weight was 55 kg (range 29 kg–75.1 kg). Follow-up had a median of 11.5 months (range 2–27 months). The median body mass index was 18.4 kg/m squared (range 15.5–27.9 kg/m squared). One patient suffered a minor complication after tearing off the incisional adhesive strips early and required a non-invasive repair in clinic. Shock impedance had a median of 55 J (range 48–68 J). There was one appropriate shock/charge and no inappropriate shocks during follow-up. Conclusion The two-incision, intermuscular technique appears to have a lower acute complication rate than prior reports, in our cohort of 12 pediatric patients.

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. Methods and Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10−5; U.S. cohort, P = 2.2×10−13). Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.

Background: In the pediatric population, conventional transvenous and epicardial pacemaker systems carry complications such as lead distortion due to growth/activity, in addition to other lead/pocket complications. Materials & methods: A retrospective review of pediatric leadless pacing at the University of Minnesota Masonic Children’s Hospital from 2018 to 2020 was performed. Rationale for pacing, demographics of patients, thresholds and longevity of devices were recorded. Results: Seven leadless pacemaker insertions and one removal were performed successfully, in patients weighing between 19 kg and 58 kg. Three patients had Micra implantation via internal jugular vein. One pericardial effusion occurred perioperatively in a 19 kg patient with baseline thrombocytopenia, sideroblastic anemia and Pearson Marrow Pancreas syndrome. Conclusion: Leadless pacemaker implantation/early retrieval is feasible in pediatric patients.

Background Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. Methods This 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. Results The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. Conclusions Laronidase seemed to improve growth in participants

The mammalian heart has a limited regenerative capacity and typically progresses to heart failure following injury. Here, we defined a hedgehog (HH)-Gli1-Mycn network for cardiomyocyte proliferation and heart regeneration from amphibians to mammals. Using a genome-wide screen, we verified that HH signaling was essential for heart regeneration in the injured newt. Next, pharmacological and genetic loss- and gain-of-function of HH signaling demonstrated the essential requirement for HH signaling in the neonatal, adolescent, and adult mouse heart regeneration, and in the proliferation of hiPSC-derived cardiomyocytes. Fate-mapping and molecular biological studies revealed that HH signaling, via a HH-Gli1-Mycn network, contributed to heart regeneration by inducing proliferation of pre-existing cardiomyocytes and not by de novo cardiomyogenesis. Further, Mycn mRNA transfection experiments recapitulated the effects of HH signaling and promoted adult cardiomyocyte proliferation. These studies defined an evolutionarily conserved function of HH signaling that may serve as a platform for human regenerative therapies., Due to the limited proliferation capacity of adult mammalian cardiomyocytes, the human heart has negligible regenerative capacity after injury. Here the authors show that a Hedgehog-Gli1-Mycn signaling cascade regulates cardiomyocyte proliferation and cardiac regeneration from amphibians to mammals.

Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome—a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose—is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome ≥9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children.

BackgroundHigh-dose aspirin (HDA) is used with intravenous immunoglobulin (IVIg) in Kawasaki disease (KD). Practice regarding HDA varies, and it is unclear whether HDA duration affects the long-term course.MethodsWe retrospectively studied KD patients at our hospital for over 10 years. Patients were categorized as having received HDA for 0, 1-7, or >7 days. Primary outcome was the maximum coronary Z-score at diagnosis and follow-up; secondary outcomes included inflammatory markers.ResultsOne hundred and three patients had HDA duration documented, of which 35 patients had coronary artery abnormalities (CAAs) at diagnosis. There was no difference in demographics or inflammatory markers between the HDA groups, and no difference in HDA duration between patients with or without CAAs. Seventeen patients received no HDA; they had longer illness and defervescence duration before diagnosis, and were less likely to receive IVIg. For CAAs, multivariate regression revealed that HDA duration did not predict the coronary Z-score at 9-15 months. Higher Z-score at diagnosis was associated with higher Z-score at 9-15 months.ConclusionThe only factor associated with coronary Z-score at 9-15 months was the Z-score at diagnosis. At our institution, longer illness and defervescence duration and the lack of IVIg administration were associated with not administering HDA. HDA duration did not affect the clinically relevant outcomes, particularly CAA persistence.

Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM performed between 1974 and 2014. The most prevalent IEM in our cohort were X-linked adrenoleukodystrophy (ALD; 37.3%), Hurler syndrome (35.1%), and metachromatic leukodystrophy (MLD; 10.2%). Conditional on surviving ≥2 years after BMT, the overall survival for the entire cohort was 85.5 ± 2.4% at 10 years and 73.5 ± 3.7% at 20 years. The cohort had a 29-fold increased risk of late death compared with an age- and sex-matched cohort from the general US population (95% CI, 22- to 38-fold). The increased relative mortality was highest in the 2- to 5-year period after BMT (standardized mortality ratio [SMR], 207; 95% confidence interval [CI], 130 to 308) and declined with increasing time from BMT, but remained elevated for ≥21 years after BMT (SMR, 9; 95% CI, 4 to 18). Sequelae from the progression of primary disease were the most common causes of late mortality in this cohort (76%). The use of T cell-depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our findings demonstrate relatively favorable overall survival in ≥2-year survivors of allogeneic BMT for IEM, although primary disease progression continues to be responsible for the majority of late deaths.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a “structural vascular age” of at least 40 years old.

Due to their specialized location, stem and progenitor cells are often exposed to oxidative stress. Although ATP-binding cassette transporter subfamily G member 2 (Abcg2)-expressing cells have been implicated in cardiac protective mechanisms involving oxidative stress, there remains a lack of understanding regarding the behavior of cardiac Abcg2-expressing cells when exposed to ROS. The aim of the present study was to characterize the response of the cardiac Abcg2 lineage to oxidative stress. In vitro analysis demonstrated that the antioxidant program regulated by Abcg2 is dependent on a functional transporter. Delivery of paraquat dichloride (PQ), a systemic oxidative stress-inducing agent, to mice confirmed that Abcg2 provides a survival benefit. When exposed to PQ, reporter mice showed an increase in the Abcg2 lineage. Transcriptional and immunohistochemical analysis of Abcg2 lineage-positive cells revealed an enhanced vascular commitment after stress. Finally, preconditioning with PQ demonstrated a reduction in scar size and an increase in angiogenesis after permanent left coronary artery ligation. In conclusion, the data suggest that Abcg2 plays a cytoprotective role in response to in vivo oxidative stress. The contribution of the Abcg2 lineage to the vasculature in the heart is increased after PQ delivery.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients.The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls.MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory.A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (± SD) cIMT (0.56 ± 0.05 mm) compared to controls (0.44 ± 0.04 mm; adjusted p0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14 ± 0.09 mm(2)/mmHg versus 0.16 ± 0.05 mm(2)/mmHg; adjusted p=0.019), and higher cIEM (1362 ± 877 mmHg versus 942 ± 396 mmHg; adjusted p0.001). cCSD in MPS patients was lower than that of controls (29.7 ± 16.4% versus 32.0 ± 8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients.Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.

Mucopolysaccharidosis type I (MPS IH) is a lysosomal storage disease (LSD) caused by inactivating mutations to the alpha-L-iduronidase (IDUA) gene. Treatment focuses on IDUA enzyme replacement and currently employed methods can be non-uniform in their efficacy particularly for the cardiac and craniofacial pathology. Therefore, we undertook efforts to better define the pathological cascade accounting for treatment refractory manifestations and demonstrate a role for the renin angiotensin system (RAS) using the IDUA−/− mouse model. Perturbation of the RAS in the aorta was more profound in male animals suggesting a causative role in the observed gender dimorphism and angiotensin receptor blockade (ARB) resulted in improved cardiac function. Further, we show the ability of losartan to prevent shortening of the snout, a common craniofacial anomaly in IDUA−/− mice. These data show a key role for the RAS in MPS associated pathology and support the inclusion of losartan as an augmentation to current therapies.

Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrome is a multisystem disorder caused by galactosamine-6-sulfatase deficiency. Skeletal manifestations, including short stature, skeletal dysplasia, cervical instability, and joint destruction, are known to be associated with this condition. Due to the severity of these skeletal manifestations, the non-skeletal manifestations are frequently overlooked despite their significant contribution to disease progression and impact on quality of life. This review provides detailed information regarding the non-skeletal manifestations and suggests long-term assessment guidelines. The visual, auditory, digestive, cardiovascular, and respiratory systems are addressed and overall quality of life as measured by endurance and other functional abilities is discussed. Impairments such as corneal clouding, astigmatism, glaucoma, hearing loss, hernias, hepatomegaly, dental abnormalities, cardiac valve thickening and regurgitation, obstructive sleep apnea, tracheomalacia, restrictive and obstructive respiratory compromise, and muscular weakness are discussed. Increased awareness of these non-skeletal features is needed to improve patient care. Electronic supplementary material The online version of this article (doi:10.1007/s10545-012-9459-0) contains supplementary material, which is available to authorized users.

Increased longevity and metabolic correction following syngeneic BMT in a murine model of mucopolysaccharidosis type I

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality. The clinical examination of individuals with MPS is often difficult due to physical and, sometimes, intellectual patient limitations. The absence of precordial murmurs does not exclude the presence of cardiac disease. Echocardiography and electrocardiography are key diagnostic techniques for evaluation of valves, ventricular dimensions and function, which are recommended on a regular basis. The optimal technique for evaluation of coronary artery involvement remains unsettled. Standard medical and surgical techniques can be modified for MPS patients, and systemic therapies such as hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) may alter overall disease progression with regression of ventricular hypertrophy and maintenance of ventricular function. Cardiac valve disease is usually unresponsive or, at best, stabilized, although ERT within the first few months of life may prevent valve involvement, a fact that emphasizes the importance of early diagnosis and treatment in MPS.

Allogeneic transplantation remains the standard of care for patients with Hurler syndrome. As enzyme replacement therapy (ERT) has become available, controversy has emerged in regards to whether the use of enzyme in the peri-transplant period is appropriate. An analysis was performed on 74 patients with Hurler syndrome transplanted at the University of Minnesota between 1990 and 2003, before our use of ERT associated with transplant, with the intention of determining if patients at higher risk during the transplant can be identified based on evaluations and events before transplantation. Age, the presence of hydrocephalus, a history of cardiovascular issues or upper airway obstruction before transplant was not associated with significant differences in survival. In contrast, patients who had a history of lower airway disease, including reactive airway disease or bronchiolitis, or a history of pneumonia, had a significantly inferior outcome based on OS. The risk for serious respiratory complications was also assessed by evaluating the incidence of intubation. Overall, 31% of these patients were intubated. The risk of intubation was higher in older patients and in those with a history of lower airway disease. These findings have implications for the care of patients with high-risk features.

Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a uniformly lethal autosomal recessive storage disease caused by absence of the enzyme alpha-l-iduronidase (IDUA), which is involved in lysosomal degradation of sulfated glycosaminoglycans (GAGs). Cardiomyopathy and valvar insufficiency occur as GAGs accumulate in the myocardium, spongiosa of cardiac valves, and myointima of coronary arteries. Here we report the functional, biochemical, and morphologic cardiac findings in the MPS I mouse. We compare the cardiac functional and histopathological findings in the mouse to human MPS I. In MPS I mice, we have noted aortic insufficiency, increased left ventricular size, and decreased ventricular function. Aortic and mitral valves are thickened and the aortic root is dilated. However, murine MPS I is not identical to human MPS I. Myointimal proliferation of epicardial coronary arteries is unique to human MPS I, whereas dilation of aortic root appears unique to murine MPS I. Despite the differences between murine and human MPS I, the murine model provides reliable in vivo outcome parameters, such as thickened and insufficient aortic valves and depressed cardiac function that can be followed to assess the impact of therapeutic interventions in preclinical studies in Hurler syndrome.

Background: In contrast to adult mammalian heart, lower vertebrates such as newt exhibit a dramatic capacity for regeneration in response to injury. Understanding the underlying mechanisms and signaling pathways in newt could form the basis for regenerative therapies in mammals. In the present study, we explored the role of hedgehog (HH) signaling during cardiac regeneration. Methods and Results: To investigate cardiac regeneration (CR) in vivo, we performed ventricular resection studies in adult newt heart. Whole mount and histochemical studies revealed CR within 30 d of resection injury. Functional assessment by echocardiographic analysis showed improved ejection fraction from 22 ± 5% at 4 d to 42 ± 3% at 30 d of regeneration relative to control (60 ± 3%). Gene clustering and qRT-PCR analysis at 7d post injury indicated enrichment of hedgehog (HH) signaling factors including Shh and ptch1 by 3- and 2-fold respectively, suggesting a critical requirement of HH signaling at early stages of CR. We determined HH signaling is essential as pharmacological inhibition of the HH pathway resulted in complete ablation of CR. Using EdU-labeling and immunohistochemical analyses, we showed that HH signaling regulates proliferation of both epicardial and myocardial cells, as inhibition of the HH pathway reduced EdU-positive nuclei from 15 ± 2% to 5 ± 3%. In contrast, qRT-PCR analysis from murine hearts postnatal day (P) 2 to P14, showed reduced levels of HH signaling factors and cell-cycle associated mRNAs by 3.5-fold with concomitant increase of p21 by 2-fold. This implies HH signals are required for the proliferative process. Consistent with the newt studies, activation of HH in murine neonatal ventricular cardiomyocytes (NVCM) promoted cardiomyocyte proliferation, increasing positive nuclei from 10 ± 2% to 25 ± 3%, while inhibition of HH signaling reduced positivity to 6 ± 3%. qRT-PCR analysis established that activation of HH signaling in NVCM resulted in up regulation of transcripts associated with cardiomyocyte proliferation. Conclusion: These data indicated that HH signaling pathways modulate cardiomyocyte proliferation providing potential therapeutic targets for achieving mammalian cardiac regeneration.

Objectives This study sought to compare the effectiveness and safety of an angiotensin converting enzyme inhibitor (ACE-I) (lisinopril) vs. an angiotensin receptor blocker (ARB) (losartan) for the treatment of cardiomyopathy (CM) in boys with Duchenne muscular dystrophy (DMD). Background Development of CM is universal in boys with DMD. ACE-I and ARB have both been suggested as effective treatment options. ARBs have been associated with skeletal muscle regeneration in a mouse model of DMD. The question of which, if either, is more effective for CM treatment in DMD remains. The purpose of this multicenter double-blind prospective study was to compare efficacy and safety of lisinopril versus losartan in the treatment of newly diagnosed CM in boys with DMD. Methods Echocardiographic technician inter- and intraobserver variability were tested on 2 separate days on 2 different boys with DMD CM. Results were compared with paired t-testing. Twenty-two boys with newly diagnosed DMD CM (echocardiographic ejection fraction (EF) 10% EF drop. Three boys in the aCE-I group had 3 visits, due to study funding termination. Two were withdrawn because of low EF. All their data are included in the analysis for as long as they remained in the study. Mean EF's were similar at baseline (47.5%- ACE-I, 48.4%- ARB). After 1 year each group significantly improved to 54.6% and 55.2% respectively (p=.02). There was no difference between the 2 treatment groups at 1 year. Conclusions Inter-observer and intra-observer reliability studies showed no differences between echocardiographers on serial examinations. EF improved equally in the two groups. There is no therapeutic difference in EF improvement between lisinopril and losartan over the one-year duration for treatment of boys with DMD-related CM. Trial registration ClinicalTrials.gov NCT01982695.

Background . Open-lung biopsy is uncommon in children. Modern indications and outcomes are unknown. Methods . This is a retrospective review of 64 open-lung biopsies (58 patients) from 1976 to 1996. Open-lung biopsies were used to grade vasculopathy in 8 patients (12% of 64) with pulmonary hypertension and in 10 patients (16% of 64) with combined pulmonary hypertension and lung parenchymal disease. Forty-six biopsies (72%) were obtained to diagnose parenchymal disease. Comparisons were made between biopsies performed from 1976 to 1989 and from 1990 to 1996. Results . In the period 1990 to 1996, there were significantly more infants ( p = 0.03), comorbid disease ( p = 0.009), extracorporeal membrane oxygenation support ( p −4 ), and ventilator dependence ( p = 0.05) and significantly less immunocompromise ( p = 0.04). A definitive diagnosis was made in 43 of 64 cases (67%) and altered workup in 63 of 64 cases (98%). No correlation existed between Heath-Edwards grade of microangiopathy and catheterization data. Definitive diagnosis was most strongly associated with a nonimmunocompromised patient ( p −4 ). Although only one death (1.5%) was related to open-lung biopsy, the procedure was associated with a 30% inhospital mortality rate and an 11% morbidity rate. Of the 19 deaths, 1 patient died from the procedure, 13 died from their diseases, and 5 had support withdrawn. Death was associated with preoperative ventilator dependence ( p −4 ) and extracorporeal membrane oxygenation ( p = 0.007). Conclusions . Pediatric open-lung biopsy commonly alters the diagnostic workup (98%). It is recommended for children who have been supported for 2 weeks by extracorporeal membrane oxygenation and for those with combined pulmonary hypertension and parenchymal lung disease. It is less useful in immunocompromised children.

Objective To evaluate the efficacy and safety of two dose levels of galsulfase (Naglazyme®) in infants with MPS VI. Study design This was a phase 4, multicenter, multinational, open-label, two-dose level study. Subjects were randomized 1:1 to receive weekly infusions of 1.0 or 2.0 mg/kg of galsulfase for a minimum of 52 weeks. Progression of skeletal dysplasia was determined by monitoring physical appearance, radiographic changes, and growth. Urinary glycosaminoglycan (GAG) levels, gross and fine motor function, cardiac function, vision, hearing, and health resource utilization were evaluated. Safety assessments were performed. Results Four infants (aged 3.3–12.7 months) participated in the study. Galsulfase was well tolerated at 1.0 and 2.0 mg/kg/week dose levels with no drug-related serious adverse events. Two subjects experienced a total of four possible treatment-related adverse events which were all considered mild. Length and weight remained within age-expected norms. Skeletal abnormalities continued to progress in all subjects. High baseline urinary GAG levels (mean: 870 μg/mg creatinine) decreased by approximately 70 %; these reduced levels were maintained (mean: 220 μg/mg creatinine at week 52) despite the development of anti-galsulfase antibodies. Hearing, cardiac function, hepatosplenomegaly, and facial dysmorphism stabilized or improved, but corneal clouding progressed. There was no clear difference in safety or efficacy between the two doses. Conclusions Galsulfase at two dose levels was safe and well tolerated in infants. Normal growth was maintained but skeletal abnormalities continued to progress. Urinary GAG levels decreased with treatment. Early initiation of galsulfase may prevent or slow progression of some disease manifestations. Electronic supplementary material The online version of this article (doi:10.1007/s10545-013-9654-7) contains supplementary material, which is available to authorized users.

EF-hand proteins are ubiquitous in cell signaling. Parvalbumin (Parv), the archetypal EF-hand protein, is a high-affinity Ca(2+) buffer in many biological systems. Given the centrality of Ca(2+) signaling in health and disease, EF-hand motifs designed to have new biological activities may have widespread utility. Here, an EF-hand motif substitution that had been presumed to destroy EF-hand function, that of glutamine for glutamate at position 12 of the second cation binding loop domain of Parv (ParvE101Q), markedly inverted relative cation affinities: Mg(2+) affinity increased, whereas Ca(2+) affinity decreased, forming a new ultra-delayed Ca(2+) buffer with favorable properties for promoting cardiac relaxation. In therapeutic testing, expression of ParvE101Q fully reversed the severe myocyte intrinsic contractile defect inherent to expression of native Parv and corrected abnormal myocardial relaxation in diastolic dysfunction disease models in vitro and in vivo. Strategic design of new EF-hand motif domains to modulate intracellular Ca(2+) signaling could benefit many biological systems with abnormal Ca(2+) handling, including the diseased heart.

This paper provides a detailed overview and discussion of anaesthesia in patients with mucopolysaccharidosis (MPS), the evaluation of risk factors in these patients and their anaesthetic management, including emergency airway issues. MPS represents a group of rare lysosomal storage disorders associated with an array of clinical manifestations. The high prevalence of airway obstruction and restrictive pulmonary disease in combination with cardiovascular manifestations poses a high anaesthetic risk to these patients. Typical anaesthetic problems include airway obstruction after induction or extubation, intubation difficulties or failure [can’t intubate, can’t ventilate (CICV)], possible emergency tracheostomy and cardiovascular and cervical spine issues. Because of the high anaesthetic risk, the benefits of a procedure in patients with MPS should always be balanced against the associated risks. Therefore, careful evaluation of anaesthetic risk factors should be made before the procedure, involving evaluation of airways and cardiorespiratory and cervical spine problems. In addition, information on the specific type of MPS, prior history of anaesthesia, presence of cervical instability and range of motion of the temporomandibular joint are important and may be pivotal to prevent complications during anaesthesia. Knowledge of these risk factors allows the anaesthetist to anticipate potential problems that may arise during or after the procedure. Anaesthesia in MPS patients should be preferably done by an experienced (paediatric) anaesthetist, supported by a multidisciplinary team (ear, nose, throat surgeon and intensive care team), with access to all necessary equipment and support. Electronic supplementary material The online version of this article (doi:10.1007/s10545-012-9563-1) contains supplementary material, which is available to authorized users.

Serious cardiac valve disease and left ventricular hypertrophy occur in most untreated older children with severe mucopolysaccharidosis type I. Although it is assumed that early intervention prevents these processes, evaluation of cardiac findings in these infants has not yet been reported.We reviewed echocardiograms of 13 untreated infants1 year of age with severe mucopolysaccharidosis type I who had undergone evaluation for hematopoietic cell transplantation. We recorded left ventricular chamber dimensions, septal and posterior wall thicknesses, ventricular function, and aortic sinus diameters. We evaluated mitral and aortic valves for increased thickness, regurgitation, and stenosis.Average age (7M, 6F) was 221 (range 25-347) days. Left ventricular chamber dimension was ≥2 SD of normal in 3/13; wall thicknesses were ≥2 SD of normal in 2/13 infants. Systolic function was normal. Mitral valves were thickened in all infants; mitral regurgitation was present in 9/13, but significant in only three infants. Aortic valves were thickened in 10/13, but no infant had significant aortic regurgitation. Neither mitral nor aortic stenosis occurred. Aortic roots were dilated to ≥2 SD of normal in 5/13.Characteristic cardiac features of severe mucopolysaccharidosis type I can be seen in infancy. Mitral and aortic valve thickening are nearly universally present, even in the youngest infants. In 20-30 % of infants, other abnormalities such as left ventricular dilation, increased wall thickness, and mild mitral/aortic regurgitation may occur. Aortic root dilation is a frequent finding. Early intervention with enzyme replacement therapy may minimize the incidence and severity of cardiac findings in these infants.Serious cardiac valve disease and left ventricular hypertrophy occur in most untreated older children with severe mucopolysaccharidosis type I. Although it is assumed that early intervention prevents these processes, evaluation of cardiac findings in these infants has not yet been reported. In our study of 13 infants with severe untreated MPS I1 year of age, mitral and aortic valve thickening was nearly universally present and aortic root dilation was frequent. Despite this, we found a lower incidence of left ventricular hypertrophy and both a lower incidence and milder expression of mitral and aortic valve dysfunction than previously reported in older children. These findings suggest that earlier intervention, including neonatal screening, may be of benefit to children with severe MPS I.

Although coronary artery pathology is a prominent feature of mucopolysaccharidosis (MPS), it may be underestimated by coronary angiography because of its diffuse nature. It is also generally assumed that cardiovascular risk is increased in MPS and reduced following hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT), but this has never been formally evaluated. Non-invasive methods of assessing vascular endothelial function may provide a measure of cardiovascular risk in MPS. We evaluated endothelial function, using digital reactive hyperemia, in youth with MPS and in healthy controls.Digital reactive hyperemic index (RHI) was measured in 12 children and adolescents (age 10.3 ± 3.9 years old; 11 boys) with treated MPS and nine age- and gender-matched (11.4 ± 4.0; 8 boys) healthy controls. An independent t-test was used to compare RHI between individuals with MPS and controls.Children and adolescents with MPS (MPS type II: N = 5; type I: N = 4; type VI: N = 3) whether treated by HSCT (N = 4) or ERT (N = 8) had significantly lower RHI compared to controls (MPS 1.22 ± 0.19 vs. controls 1.46 ± 0.32, p 0.05).These preliminary findings suggest that children and adolescents with treated MPS have significantly poorer endothelial function when compared to healthy controls. Further investigation into the utility of endothelial function for risk stratification and the long term implications of reduced endothelial function in MPS is warranted.

The mitogen activated protein kinase (MAPK) signaling pathway regulates multiple events leading to heart failure including ventricular remodeling, contractility, hypertrophy, apoptosis, and fibrosis. The regulation of conserved intrinsic inhibitors of this pathway is poorly understood. We recently identified an up-regulation of Sprouty1 (Spry1) in a targeted approach for novel inhibitors of the MAPK signaling pathway in failing human hearts following reverse remodeling. The goal of this study was to test the hypothesis that up-regulated expression of Spry1 in cardiac myocytes would be sufficient to inhibit ERK1/2 activation and tissue remodeling. We established a murine model with up-regulated Spry1 expression in cardiac myocytes using the alpha-myosin heavy chain promoter (alpha-MHC). Heart weight and cardiac myocyte morphology were unchanged in adult male alpha-MHC-Spry1 mice compared to control mice. Ventricular function of alpha-MHC-Spry1 mice was unaltered at 8 weeks or 1 year of age. These findings were consistent with the lack of an effect of Spry1 on ERK1/2 activity. In summary, targeted up-regulation of Spry1 in cardiac myocytes is not sufficient to alter cell or tissue remodeling consistent with the lack of an effect on ERK1/2 activity.

Objective Multipotent adult progenitor cells (MAPCs) are adult stem cells derived from bone marrow. We investigated the capacity of MAPCs to aid in tissue healing after myocardial ischemia in mice with different levels of immune competence. Methods Adult murine C57BL/6 MAPCs were labeled with firefly luciferase and DsRed2 fluorescent protein and injected into the myocardium of immunocompetent C57BL/6 or T-, B- and natural killer–cell severe combined immunodeficient C57BL/6 Rag2/IL-2Rγc −/− mice at the time of myocardial infarction (MI). Mice were sequentially analyzed using in vivo whole body bioluminescent imaging for MAPC persistence and high-resolution ultrasound biomicroscopy to assess cardiac function. Results Luciferase signals emitted from donor MAPCs were significantly higher in Rag2/IL-2Rγc −/− mice compared with C57BL/6 recipients of labeled MAPCs. At 100, 200, and 365 days after MI, left ventricular contractile function was significantly improved (and normalized) in C57BL/6 MAPC recipients. In contrast, despite a greater degree of MAPC persistence compared with C57BL/6 recipients, no cardiac improvement occurred in Rag2/IL-2Rγc −/− recipients of MAPCs. The improved cardiac contractile performance in response to syngeneic MAPC infusion correlated with a prominent increase of vascular density in infarcted and peri-infarcted myocardium, which was dependent upon host immune competency. Conclusion These data indicate that immune competence of the recipient modulates the therapeutic impact of the adult nonhematopoietic stem cells infused after acute MI injury and that a more vigorous immune response is advantageous for therapeutic myocardial repair after MI.

I-cell disease or mucolipidosis type II, a rare inherited storage disorder of lysosomal enzyme localization, is characterized by dysostosis multiplex, progressive severe psychomotor retardation and death by 5-8 years from congestive heart failure and recurrent pulmonary infections. A 19-month old girl with I-cell disease received a bone marrow transplant (BMT) from an HLA-identical carrier brother. At the age of 7 years, 5 years after BMT, she has no history of respiratory infections. Her cardiac function remains normal with a shortening fraction of 47%, and she continues to gain neurodevelopmental milestones, albeit at a very slow rate. Musculoskeletal deformities have worsened despite BMT. This is the first report describing neurodevelopmental gains and prevention of cardiopulmonary complications in I-cell disease after BMT.

Staged repair of interrupted aortic arch and ventricular septal defect was carried out in 20 infants from 1979 through 1990. Among the important associated cardiac defects were transposition of the great arteries, truncus arteriosus, and anomalous origin of the right pulmonary artery. The first stage, usually consisting of the placement of an 8- or 10-mm polytetrafluoroethylene graft, pulmonary artery banding, and ligation of the patent ductus arteriosus, resulted in 20 survivors (100%) There were two interim deaths (10%) before the second stage of ventricular septal defect closure and pulmonary artery band removal, which had 15 survivors (83%, 15/18). Because the major morbidity and mortality early in this experience could be traced to leaving the pulmonary artery band on too long, early removal (within 2 to 3 months) was begun. Since 1985, 8 (100%) of 8 infants have survived both stages and are now doing well. Because of the relatively large polytetrafluoroethylene graft, only 1 child (aged 9 years) has experienced substantial late aortic arch obstruction and undergone placement of an 18-mm Dacron graft without difficulty. Of interest is the finding that in only 1 (5%) of the 20 patients has major (greater than or equal to 40-mm Hg gradient) left ventricular outflow tract obstruction developed. In summary, the staged repair of interrupted aortic arch with ventricular septal defect has become very reliable despite the condition of the infant or major associated cardiac anomalies and can be recommended for infants at high risk for primary repair. More long-term information will be needed to determine which approach will be the best choice for the majority of infants.

Cardiac transplantation has only recently become an accepted therapeutic modality for children and adolescents with end-stage cardiomyopathy. Long-term survival, the incidence of rejection, and the incidence of infection are still being defined. From 1985 to 1989, 21 children aged 6 months to 19 years (average age, 11.2 years) underwent cardiac transplantation at our institutions. Eighteen survived the operative period and have been followed for 5 to 49 months (average follow-up, 24 months). All operative survivors have received tripledrug immunosuppression consisting of cyclosporine, azathioprine, and prednisone. During follow-up, 7 patients have been treated on 12 occasions for rejection as documented by endomyocardial biopsy. Eight (67%) of the 12 episodes of rejection occurred in the presence of subtherapeutic cyclosporine levels. Two of the 7 patients treated for rejection have subsequently died of ongoing cardiac rejection and arrhythmia. There have been no perioperative or late deaths from infection. Bacterial sepsis was identified and treated twice during follow-up, viral infections on five occasions, and fungal infection once. Actuarial 1-year survival and 3-year survival of the 18 operative survivors are 94% and 78%, respectively. In the first 7 months after cardiac transplantation, 73% of patients were free from rejection and 83% were free from serious bloodborne infection. We conclude that (1) the incidence of rejection and infection is low with tripledrug immunosuppression; (2) rejection episodes occur must commonly within the first year after cardiac transplantation but can occur late; (3) rejection can often be associated with subtherapeutic cyclosporine levels; (4) major bacterial infection can occur in association with a common disease process but appears to respond to standard antibiotic therapy; and (5) viral infections have been well tolerated by the patients.

Infants with pulmonary atresia and intact ventricular septum pose a difficult clinical problem. Pulmonary valvotomy has been widely recommended for relief of the right ventricular obstruction, and most infants also have had an aortopulmonary shunt placed to ensure pulmonary blood flow. We have evolved a different approach that includes placement of a right ventricular outflow tract patch initially and continuation of prostaglandin E, infusion postoperatively until the need for a shunt can be determined. We report here our management of 15 neonates with this diagnosis and suprasystemic right ventricular pressures. All of the infants were placed on a regimen of prostaglandin E1 before the operation to improve pulmonary blood flow, and all had an outflow patch placed early in life. Satisfactory postoperative right ventricular function, which would allow both outflow patching and ductus ligation, could be confidently predicted in only two of the 15 patients. For nine of the 15 an outflow patch was placed and prostaglandin was infused postoperatively to provide pulmonary blood flow until right ventricular function became adequate. Early in the series, three other infants were judged to need an aortopulmonary shunt in addition to decompression by an outflow patch, and one infant had only a shunt placed. Postoperatively, adequate pulmonary blood flow was present in all, and 11 of the 15 (73%) survived. Three of the deaths (average 2.8 days) after the outflow patch operation probably resulted from premature cessation of the prostaglandin infusion. One neonate with an outflow patch and a shunt died of myocardial ischemia because of coronary artery steal through right ventricular sinusoids. One late death occurred suddenly in the child with only a shunt, presumably because of an arrhythmia. The remaining survivors (10/15, 67%) are alive and have had complete repair. Study of these patients has also revealed that the definition of adequate right ventricular size needs to be more liberal. Five of the 10 surviving patients had a residual atrial septal defect with a right-to-left shunt at the ages of 1 to 3 years, but balloon occlusion of the atrial septal defect during cardiac catheterization revealed that the right ventricle in these patients was functionally adequate. These five children subsequently underwent closure of the atrial septal defect, and in two the aortopulmonary shunt was also taken down. In summary, correction was achieved in all survivors, in contrast to reported studies in which many patients are living with shunts. Certain unifying treatment principles have emerged: (1) outflow patching can be performed in the neonatal period with good results, maximizing the potential for right ventricular growth. (2) Pulmonary blood flow can usually be assured postoperatively with infusion of prostaglandin E1. With time, right ventricular function often improves and the necessity for placement of an aortopulmonary shunt can be assessed more impartially. (3) A shunt seems to be needed only infrequently. (4) In cases of apparently inadequate size of the right ventricle on follow-up, right ventricular function can be assessed during cardiac catheterization by balloon occlusion of the atrial septal defect. If occlusion is tolerated, right ventricular function will be satisfactory after closure of the atrial septal defect.

Surgical repair of type B interruption of the aortic arch and ventricular septal defect (VSD) in the newborn period is difficult and the optimal approach is controversial. We report here our early and late results using a two-staged approach in the repair of these lesions in seven consecutive neonates whose weights ranged from 2.9 to 3.8 kg and who were all less than 21 days of age. Each underwent aortic arch reconstruction off cardiopulmonary bypass with placement of a large (6 to 10 mm) polytetrafluoroethylene (PTFE) graft and pulmonary artery banding for interruption of the aortic arch (six) or extreme hypoplasia (one) of the arch. All seven (100%) survived the first-stage operation. No significant (greater than 10 mm Hg) conduit gradient was found in the seven patients studied 3 to 18 months postoperatively. One death occurred in a patient at 1 year of age with severe subaortic stenosis. Six patients subsequently underwent closure of VSD and removal of a pulmonary artery band, with five survivors (83%). The operative death occurred in an infant in whom pulmonary hypertension developed from an inadequate pulmonary artery band. One late death occurred at home when a tracheostomy tube, required because of severe tracheomalacia, became plugged. The long-term survival rate for completion of both stages is 57%. We conclude: (1) Aortic arch reconstruction and pulmonary artery banding can be reliably performed even in critically ill infants, and the 8 or 10 mm grafts should be adequate for several years. (2) Significant subaortic stenosis occurred in only one patient. (3) Pulmonary artery banding was the greatest source of difficulty, and distortion of the pulmonary arteries, inadequate banding, and compression of the trachea were all seen. Therefore, the staged repair will provide good results with this complex anomaly, and most of the problems associated with this approach may be eliminated by early second-stage repair.

Correlative angiographic-anatomical studies in 19 cases of pulmonary atresia with infarct ventricular septum showed the following relations between the angiographic appearance of the pulmonary valve and the morphology of the right ventricle. (1) Doming of the pulmonary valve was associated with a nearly normal-sized right ventricle and a wide infundibulum patent to the level of the pulmonary valve. (2) A fixed valve was associated either with (a) pronounced hypoplasia of the ventricular changer and stenosis of the infundibulum or (b) less commonly, a massive right ventricle and Ebstein's malformation of the tricuspid valve. (3) An intermediate type valve was associated with a small right ventricle and a small infundibulum which was, however, patent to the level of the pulmonary valve. It is suggested that the configuration of the pulmonary valve is a result of haemodynamic stresses placed upon it. These stresses, in turn, are determined by the morphological nature of the right ventricle. Thus, the nature of the pulmonary valve as seen angiographically may ve used as an index of right ventricular morphology.

The mucopolysaccharidoses are a group of inherited metabolic diseases caused by deficiencies in enzymes involved in the sequential degradation of glycosaminoglycans (GAGs) leading to substrate accumulation in various tissues and organs. GAG accumulation can cause growth retardation and progressive damage to respiratory, cardiovascular, musculoskeletal, nervous, gastrointestinal, auditory, and visual systems. In the past, few people with severe phenotypic mucopolysaccharidosis (MPS) reached adulthood. However, better methods for diagnosis, multi-disciplinary care, and new therapies have extended lifespan, leading to an increasing number of patients surviving beyond childhood. The growing number of adult MPS patients poses significant challenges for clinicians who may not be familiar with the clinical manifestations of MPS. In addition, as new interventions have changed the natural history of these disorders, it is difficult to anticipate both the impact on life expectancy and other complications that may occur as these patients age. Because the MPS disorders are multi-organ diseases, their management requires a coordinated multi-disciplinary approach. Here we discuss the unique pattern of medical issues and multi-organ involvement in adult patients with MPS and identify the challenges that are associated with management of MPS. This review is based on information from an expert investigator meeting with MPS specialists held October 2–4, 2014 in Dublin, Ireland, as well as on current literature searches focusing on MPS and adults.