Obesity Predisposes Anthracycline-Treated Survivors of Childhood and Adolescent Cancers to Subclinical Cardiac Dysfunction.

Anthracyclines are effective chemotherapeutics used in approximately 60% of pediatric cancer cases but have a well-documented risk of cardiotoxicity. Existing cardiotoxicity risk calculators do not include cardiovascular risk factors present at the time of diagnosis. The goal of this study is to leverage the advanced sensitivity of strain echocardiography to identify pre-existing risk factors for early subclinical cardiac dysfunction among anthracycline-exposed pediatric patients. We identified 115 pediatric patients with cancer who were treated with an anthracycline between 2013 and 2019. Peak longitudinal left ventricular strain was retroactively calculated on 495 surveillance echocardiograms via the TOMTEC AutoSTRAIN software. Cox proportional hazards models were employed to identify risk factors for abnormal longitudinal strain (> - 16%) following anthracycline treatment. High anthracycline dose (≥ 250 mg/m2 doxorubicin equivalents) and obesity at the time of diagnosis (BMI > 95th percentile-for-age) were both significant predictors of abnormal strain with hazard ratios of 2.79, 95% CI (1.07-7.25), and 3.85, 95% CI (1.42-10.48), respectively. Among pediatric cancer survivors, patients who are obese at the time of diagnosis are at an increased risk of sub-clinical cardiac dysfunction following anthracycline exposure. Future studies should explore the incidence of symptomatic cardiomyopathy 10-15 years post-treatment among patients with early subclinical cardiac dysfunction.

Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.

BACKGROUND: TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing. METHODS: Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed. RESULTS: Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance. CONCLUSIONS: Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.

Metabolic rate and hypoxia tolerance are affected by group interactions and sex in the fruit fly (Drosophila melanogaster): new data and a literature survey.

Population density and associated behavioral adjustments are potentially important in regulating physiological performance in many animals. In r-selected species like the fruit fly (Drosophila), where population density rapidly shifts in unpredictable and unstable environments, density-dependent physiological adjustments may aid survival of individuals living in a social environment. Yet, how population density (and associated social behaviors) affects physiological functions like metabolism is poorly understood in insects. Additionally, insects often show marked sexual dimorphism (larger females). Thus, in this study on D. melanogaster, we characterized the effects of fly density and sex on both mass-specific routine oxygen consumption (V̇O2) and hypoxia tolerance (PCrit). Females had significantly lower routine V̇O2 (∼4 µl O2 mg-1 h-1) than males (∼6 µl O2 mg-1 h-1) at an average fly density of 28 flies·respirometer chamber-1 However, V̇O2 was inversely related to fly density in males, with V̇O2 ranging from 4 to 11 µl O2 mg-1 h-1 at a density of 10 and 40 flies·chamber-1, respectively (r2=0.58, P<0.001). Female flies showed a similar but less pronounced effect, with a V̇O2 of 4 and 7 µl O2 mg-1 h-1 at a density of 10 and 40 flies·chamber-1, respectively (r2=0.43, P<0.001). PCrit (∼5.5 to 7.5 kPa) varied significantly with density in male (r2=0.50, P<0.01) but not female (r2=0.02, P>0.5) flies, with higher fly densities having a lower PCrit An extensive survey of the literature on metabolism in fruit flies indicates that not all studies control for, or even report on, fly density and gender, both of which may affect metabolic measurements.