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Cancer diagnostics and therapies have improved steadily over the last few decades, markedly increasing life expectancy for patients at all ages. However, conventional and newer anti-neoplastic therapies can cause short- and long-term cardiotoxicity. The clinical implications of this cardiotoxicity become more important with the increasing use of cardiotoxic drugs. The implications are especially serious among patients predisposed to adverse cardiac effects, such as youth, the elderly, those with cardiovascular comorbidities, and those receiving additional chemotherapies or thoracic radiation. However, the optimal strategy for preventing and managing chemotherapy-induced cardiotoxicity remains unknown. The routine use of neurohormonal antagonists for cardioprotection is not currently justified, given the marginal benefits and associated adverse events, particularly with long-term use. The only United States Food and Drug Administration and European Medicines Agency approved treatment for preventing anthracycline-related cardiomyopathy is dexrazoxane. We advocate administering dexrazoxane during cancer treatment to limit the cardiotoxic effects of anthracycline chemotherapy.

This study shows that myocardial fibrosis is an early characteristic of hypertrophic cardiomyopathy caused by sarcomere mutations. The C-terminal propeptide of procollagen type I was shown to be a serum biomarker of early myocardial fibrosis. Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomere proteins. 1 , 2 With a prevalence of approximately 1 case per 500 persons in the general population, hypertrophic cardiomyopathy is the most common monogenic cardiac disorder. 3 The clinical diagnosis depends on the identification of unexplained left ventricular hypertrophy, but this finding is present only in persons with established disease and is typically absent in childhood. 4 In contrast, genetic diagnosis identifies pathogenic sarcomere mutations in persons at any age, including mutation carriers with overt hypertrophic cardiomyopathy and mutation carriers without hypertrophy who are at high risk for the development of disease. Studying . . .

Background International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework. Methods We compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases. Results Analysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives. Conclusions When found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.

Treatment of children with hypertrophic cardiomyopathy might be improved if the risk of death or heart transplantation could be predicted by risk factors present at the time of diagnosis. We analysed data from the Pediatric Cardiomyopathy Registry, which collected longitudinal data for 1085 children with hypertrophic cardiomyopathy from 1990 to 2009. Our goal was to understand how patient factors measured at diagnosis predicted the subsequent risk of the primary outcome of death or heart transplantation. The Kaplan-Meier method was used to calculate time-to-event rates from time of diagnosis to the earlier of heart transplantation or death for children in each subgroup. Cox proportional-hazards regression was used to identify univariable and multivariable predictors of death or heart transplantation within each causal subgroup. The poorest outcomes were recorded for the 69 children with pure hypertrophic cardiomyopathy with inborn errors of metabolism, for whom the estimated rate of death or heart transplantation was 57% (95% CI 44–69) at 2 years. Children with mixed functional phenotypes also did poorly, with rates of death or heart transplantation of 45% (95% CI 32–58) at 2 years for the 69 children with mixed hypertrophic and dilated cardiomyopathy and 38% (95% CI 25–51) at 2 years for the 58 children with mixed hypertrophic and restrictive cardiomyopathy. For children diagnosed with hypertrophic cardiomyopathy at younger than 1 year, the rate of death or transplantation was 21% (95% CI 16–27) at 2 years. For children diagnosed with hypertrophic cardiomyopathy and a malformation syndrome, the rate of death or transplantation was 23% (95% CI 12–34) at 2 years. Excellent outcomes were reported for the 407 children who were diagnosed with idiopathic hypertrophic cardiomyopathy at age 1 year or older, with a rate of death or heart transplantation of 3% (95% CI 1–5) at 2 years. The risk factors for poor outcomes varied according to hypertrophic cardiomyopathy subgroup, but they generally included young age, low weight, presence of congestive heart failure, lower left ventricular fractional shortening, or higher left ventricular end-diastolic posterior wall thickness or end-diastolic ventricular septal thickness at the time of cardiomyopathy diagnosis. For all hypertrophic cardiomyopathy subgroups, the risk of death or heart transplantation was significantly increased when two or more risk factors were present and also as the number of risk factors increased. In children with hypertrophic cardiomyopathy, the risk of death or heart transplantation was greatest for those who presented as infants or with inborn errors of metabolism or with mixed hypertrophic and dilated or restrictive cardiomyopathy. Risk stratification by subgroup of cardiomyopathy, by characteristics such as low weight, congestive heart failure, or abnormal echocardiographic findings, and by the presence of multiple risk factors allows for more informed clinical decision making and prognosis at the time of diagnosis. US National Institutes of Health and Children's Cardiomyopathy Foundation.

Studies of cardiomyopathy in children with Noonan syndrome (NS) have been primarily small case series or cross-sectional studies with small or no comparison groups. We used the Pediatric Cardiomyopathy Registry database to compare the survival experience of children with NS and hypertrophic cardiomyopathy (HCM) with children with idiopathic or familial HCM and to identify clinical and echocardiographic predictors of clinical outcomes. Longitudinal data in 74 children with NS and HCM and 792 children with idiopathic or familial isolated HCM were compared. Children with NS were diagnosed with HCM before 6 months old more often (51%) than children with HCM (28%) and were more likely to present with congestive heart failure (CHF) (24% vs 9%). The NS cohort had lower crude survival than the group with other HCM (P = .03), but survival did not differ after adjustment for CHF and age at diagnosis. Within the NS cohort (1-year survival 78%), a diagnosis of HCM before age 6 months with CHF resulted in 31% 1-year survival. Lower height-for-age z score (hazard ratio 0.26, P = .005) in place of CHF and lower left ventricular fractional shortening z score (hazard ratio 0.79, P = .04) also independently predicted mortality. Patients with NS with HCM have a worse risk profile at presentation compared with other children with HCM, resulting in significant early mortality (22% at 1 year). Decreased height-for-age and lower, although still supranormal, left ventricular fractional shortening z score are independent predictors of mortality in patients with NS with HCM. Such patients should have an aggressive therapeutic approach including potential listing for cardiac transplantation.

The aim of this study was to evaluate whether left ventricular (LV) systolic strain in children and young adults with congenital aortic stenosis (AS) and preserved ejection fraction was different from normal subjects and to determine whether any alterations in strain were related to myocardial fibrosis. In this retrospective study, 29 patients with congenital AS with a median age of 15.3 years (range 1.7 to 23.7), highest lifetime AS peak Doppler gradient of 73 mm Hg (22 to 110), most recent AS peak Doppler gradient of 49 mm Hg (0 to 90), and ejection fraction of 65 (55 to 79) were included. Strain was measured using 2-dimensional speckle-tracking echocardiography. Cardiac magnetic resonance was used to identify focal fibrosis by late gadolinium enhancement (LGE) and diffuse fibrosis by calculating the extracellular volume fraction (ECV) from T1 measurements. Compared to age-matched controls (n = 29), patients with AS had reduced LV longitudinal (17.0 ± 3.0% vs 20.6 ± 2.2%, p <0.001) and radial strain (28.8 ± 8.6% vs 34.9 ± 8.5%, p = 0.01), and similar circumferential strain (26.2 ± 5.9% vs 26.4 ± 3.9%, p = 0.79). Median ECV in patients with AS was 0.27 (0.22 to 0.38) and was not significantly correlated with systolic strain. Patients with LGE (n = 7) had lower longitudinal strain than those without LGE (n = 21; 15.0 ± 2.2 vs 17.7 ± 3.1, p = 0.036). In conclusion, in this cohort of children and young adults with congenital AS and preserved ejection fraction, longitudinal and radial strain were reduced, and decreased longitudinal strain was associated with LGE but not ECV.

Children with Kawasaki disease are at risk for the development of coronary-artery aneurysms. Standard therapy for this disorder includes intravenous immune globulin and aspirin. This study shows that, as compared with placebo, the addition of a single pulsed dose of intravenous methylprednisolone has no further beneficial effect over that of standard therapy and therefore cannot be recommended for routine treatment. This study shows that the addition of a single pulsed dose of intravenous methylprednisolone has no further beneficial effect over that of standard therapy and therefore cannot be recommended for routine treatment. The standard of care for children with acute Kawasaki disease is treatment with high-dose intravenous immune globulin and aspirin. 1 Despite receiving high-dose intravenous immune globulin within the first 10 days of illness, approximately 5% of children with Kawasaki disease have subsequent coronary aneurysms and 1% have giant aneurysms, as classified on the basis of criteria of the Japanese Ministry of Health. 2 – 4 Moreover, when coronary-artery dimensions are adjusted for body-surface area, a far greater proportion of children with Kawasaki disease have coronary-artery dilation than would be detected with the use of unadjusted dimensions. 5 The role of corticosteroids in the primary . . .

Impaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH). Seventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15). LA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both). LA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis.

Cardiomyopathy in children is a serious disorder that often results in cardiac transplantation or death. This study was based on a 1996–1999 registry of cases in New England and in Texas, Oklahoma, and Arkansas. The overall annual incidence was 1.13 cases per 100,000 children, but the incidence was much higher among infants than in other age groups. Dilated and hypertrophic cardiomyopathies predominated. The incidence was higher in boys than in girls and in blacks than in whites. Cardiomyopathy is a very serious disorder in children, and nearly 40 percent of children who present with symptomatic cardiomyopathy receive a heart transplant or die within the first two years. 1 The time to transplantation or death for children with cardiomyopathy has not improved during the past 35 years, and the outcomes in the most economically advanced nations are no better than those in developing nations. 2 – 4 The cardiomyopathies have an associated cost of nearly $200 million per year in adults and children in the United States alone. 5 , 6 The percentage of children with cardiomyopathy who receive a heart transplant has . . .

The aim of this study was to determine in pediatric Duchenne (DMD) and Becker muscular dystrophy (BMD) or other dilated cardiomyopathies (ODCM) whether outcomes differ by diagnosis. Children with dilated cardiomyopathy are treated as a single undifferentiated group. This cohort study of 128 children with DMD, 15 with BMD, and 312 with ODCM uses outcome measures of left ventricular (LV) size and function, death, heart transplant, and death or transplant. At cardiomyopathy diagnosis, the DMD and BMD groups had similar mean ages (14.4 and 14.6 years), prevalence of congestive heart failure (CHF) (30% and 33%), and LV fractional shortening (FS) Z-scores (median, −5.2 for DMD and −6.7 for BMD). The BMD group had more severe mitral regurgitation ( P = .05) and a higher mean LV end-diastolic dimension Z-score than the DMD group (2.9 ± 1.5 vs 1.2 ± 1.9, P = .002). Duchenne muscular dystrophy group survival was lower than in BMD or ODCM groups ( P = .06) at 5 years (57%, 100%, and 71%, respectively). In BMD, 25% received cardiac transplants within 0.4 years of cardiomyopathy diagnosis. The combined DMD and BMD group had less LV dilation and a closer-to-normal LV FS at cardiomyopathy diagnosis than the ODCM group. After 2 years, LV dilation increased, and LV FS did not change in the combined DMD and BMD group; for ODCM patients, LV dilation did not progress, and LV FS improved. Children with DMD and cardiomyopathy have a higher mortality. Becker muscular dystrophy has a high heart transplantation rate in the 5 years after diagnosis of cardiomyopathy. Serial echocardiography demonstrates a different disease course for DMD and BMD patients compared with ODCM patients.