Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. METHODS: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. RESULTS: In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. CONCLUSIONS: Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

Elevated Heart Rate and Survival in Children With Dilated Cardiomyopathy: A Multicenter Study From the Pediatric Cardiomyopathy Registry.

Background In adults with heart failure, elevated heart rate is associated with lower survival. We determined whether an elevated heart rate was associated with an increased risk of death or heart transplant in children with dilated cardiomyopathy. Methods and Results The study is an analysis of the Pediatric Cardiomyopathy Registry and includes baseline data, annual follow-up, and censoring events (transplant or death) in 557 children (51% male, median age 1.8 years) with dilated cardiomyopathy diagnosed between 1994 and 2011. An elevated heart rate was defined as 2 or more SDs above the mean heart rate of children, adjusted for age. The primary outcomes were heart transplant and death. Heart rate was elevated in 192 children (34%), who were older (median age, 2.3 versus 0.9 years; P<0.001), more likely to have heart failure symptoms (83% versus 67%; P<0.001), had worse ventricular function (median fractional shortening z score, -9.7 versus -9.1; P=0.02), and were more often receiving anticongestive therapies (96% versus 86%; P<0.001) than were children with a normal heart rate. Controlling for age, ventricular function, and cardiac medications, an elevated heart rate was independently associated with death (adjusted hazard ratio [HR] 2.6; P<0.001) and with death or transplant (adjusted HR 1.5; P=0.01). Conclusions In children with dilated cardiomyopathy, elevated heart rate was associated with an increased risk of death and cardiac transplant. Further study is warranted into the association of elevated heart rate and disease severity in children with dilated cardiomyopathy and as a potential target of therapy.

Cardiac Biomarkers in Pediatric Cardiomyopathy: Study Design and Recruitment Results from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. STUDY DESIGN: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. RESULTS: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. CONCLUSION: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. CLINICAL TRIAL REGISTRATION NCT01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1.

A randomized controlled laboratory study on the long-term effects of methylphenidate on cardiovascular function and structure in rhesus monkeys.

BACKGROUND: Whether long-term methylphenidate (MPH) results in any changes in cardiovascular function or structure can only be properly addressed through a randomized trial using an animal model which permits elevated dosing over an extended period of time. METHODS: We studied 28 male rhesus monkeys (Macaca mulatta) approximately 7 years of age that had been randomly assigned to one of three MPH dosages: vehicle control (0 mg/kg, b.i.d., n = 9), low dose (2.5 mg/kg, b.i.d., n = 9), or high dose (12.5 mg/kg, b.i.d., n = 10). Dosage groups were compared on serum cardiovascular and inflammatory biomarkers, electrocardiograms (ECGs), echocardiograms, myocardial biopsies, and clinical pathology parameters following 5 years of uninterrupted dosing. RESULTS: With the exception of serum myoglobin, there were no statistical differences or apparent dose-response trends in clinical pathology, cardiac inflammatory biomarkers, ECGs, echocardiograms, or myocardial biopsies. The high-dose MPH group had a lower serum myoglobin concentration (979 ng/mL) than either the low-dose group (1882 ng/mL) or the control group (2182 ng/mL). The dose response was inversely proportional to dosage (P = .0006). CONCLUSIONS: Although the findings cannot be directly generalized to humans, chronic MPH exposure is unlikely to be associated with increased cardiovascular risk in healthy children.

Pediatric Cardiomyopathies.

Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1 to 1.5 per 100 000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of comorbidities, such as atherosclerosis, hypertension, renal dysfunction, and diabetes mellitus; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, cause, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphological and clinical manifestations, their outcomes differ significantly. Within 2 years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a 2-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting that treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies and highlights key areas where additional research is required. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02549664 and NCT01912534.

The Safety of Ingested Caffeine: A Comprehensive Review.

Caffeine is the most widely consumed psychoactive drug in the world. Natural sources of caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to promote arousal, alertness, energy, and elevated mood. Over the past decade, the introduction of new caffeine-containing food products, as well as changes in consumption patterns of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies about the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to the negative effects of caffeine consumption: pregnant and lactating women, children and adolescents, young adults, and people with underlying heart or other health conditions, such as mental illness. Here, we review the research into the safety and safe doses of ingested caffeine in healthy and in vulnerable populations. We report that, for healthy adults, caffeine consumption is relatively safe, but that for some vulnerable populations, caffeine consumption could be harmful, including impairments in cardiovascular function, sleep, and substance use. We also identified several gaps in the literature on which we based recommendations for the future of caffeine research.

The Benefits and Challenges of Preconsent in a Multisite, Pediatric Sickle Cell Intervention Trial.

Enrollment of patients in sickle cell intervention trials has been challenging due to difficulty in obtaining consent from a legal guardian and lack of collaboration between emergency medicine and hematology. We utilized education and preconsent in a pediatric multisite sickle cell intervention trial to overcome these challenges. Overall, 48 patients were enrolled after being preconsented. Variable Institutional Review Board policies related to preconsent validity and its allowable duration decreased the advantages of preconsent at some sites. The utility of preconsent for future intervention trials largely depends on local Institutional Review Board policies. Preeducation may also benefit the consent process, regardless of site differences.

Lessons learned from the Pediatric Cardiomyopathy Registry (PCMR) Study Group.

Cardiomyopathy is a rare disorder of the heart muscle, affecting 1.13 cases per 100,000 children, from birth to 18 years of age. Cardiomyopathy is the leading cause of heart transplantation in children over the age of 1. The Pediatric Cardiomyopathy Registry funded in 1994 by the National Heart, Lung, and Blood Institute was established to examine the epidemiology of the disease in children below 18 years of age. More than 3500 children across the United States and Canada have been enrolled in the Pediatric Cardiomyopathy Registry, which has followed-up these patients until death, heart transplantation, or loss to follow-up. The Pediatric Cardiomyopathy Registry has provided the most in-depth illustration of this disease regarding its aetiology, clinical course, associated risk factors, and patient outcomes. Data from the registry have helped in guiding the clinical management of cardiomyopathy in children under 18 years of age; however, questions still remain regarding the most clinically effective diagnostic and treatment approaches for these patients. Future directions of the registry include the use of next-generation whole-exome sequencing and cardiac biomarkers to identify aetiology-specific treatments and improve diagnostic strategies. This article provides a brief synopsis of the work carried out by the Pediatric Cardiomyopathy Registry since its inception, including the current knowledge on the aetiologies, outcomes, and treatments of cardiomyopathy in children.

Reduction of copper and metallothionein in toxic milk mice by tetrathiomolybdate, but not deferiprone.

Copper is both essential for life and toxic. Aberrant regulation of copper at the level of intracellular transport has been associated with inherited diseases, including Wilson's disease (WND) in humans. WND results in accumulation of copper and the copper and zinc-binding protein metallothionein (MT) in liver and other tissues, liver degeneration, and neurological dysfunction. The toxic milk (TX) mutation in mice results in a phenotype that mimics human WND, and TX has been proposed to be a model of the disease. We characterized TX mice as a model of altered metal ion and MT levels during development, and after treatment with the metal ion chelators tetrathiomolybdate (TTM) and deferiprone (L1). We report that hepatic, renal and brain copper and MT are elevated in TX mice at 3 and 12 months of age. Zinc was significantly higher in TX mouse liver, but not brain and kidney, at both time points. Nodules appeared spontaneously in TX mouse livers at 8-12 months that maintained high copper levels, but with more normal morphology and decreased MT levels. Treatment of TX mice with TTM significantly reduced elevated hepatic copper and MT. Transient increases in blood and kidney copper accompanied TTM treatment and indicated that renal excretion was a significant route of removal. Treatment with L1, on the other hand, had no effect on liver or kidney copper and MT, but resulted in increased brain copper and MT levels. These data indicate that TTM, but not L1, may be useful in treating diseases of copper overload including WND.