Mutations in the human Filamin A ( FLNA ) gene disrupt neuronal migration to the cerebral cortex and cause cardiovascular defects. Complete loss of Flna in mice results in embryonic lethality with severe cardiac structural defects involving ventricles, atria, and outflow tracts, as well as widespread aberrant vascular patterning. Despite these widespread developmental defects, migration and motility of many cell types does not appear to be affected. Instead, Flna-null embryos display abnormal epithelial and endothelial organization and aberrant adherens junctions in developing blood vessels, heart, brain, and other tissues. Essential roles for FLNA in intercellular junctions provide a mechanism for the diverse developmental defects seen in patients with FLNA mutations.

Although important advances have been made in curing childhood cancer in the last several decades, long-term survivors face considerable morbidity and mortality because of late effects from their initial anticancer therapy. By 30 years after treatment, the cumulative mortality from treatment-related medical illness actually exceeds that of mortality from cancer recurrence. Cardiovascular disease, in particular, is a leading threat to the well-being of adult survivors of childhood cancers. Unfortunately, the mechanisms of these late cardiac effects are understudied and poorly understood. This article reviews cardiotoxicity associated with 2 major anticancer regimens used in treating childhood cancer patients: anthracycline treatment and radiation therapy. The known pathophysiology and clinical cardiac risk factors that further predispose these patients to late-onset cardiac events are discussed. Basic and translational research is urgently needed to clarify pathophysiologic mechanisms of late cardiac effects and to develop therapies to improve both long-term survival and quality of life of adults cured of pediatric cancers.

The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in 56 single cardiomyocytes from 12 individuals (aged from 0.4 to 82 years). Cardiomyocyte sSNVs accumulate with age at rates that are faster than in many dividing cell types and nondividing neurons. Cardiomyocyte sSNVs show distinctive mutational signatures that implicate failed nucleotide excision repair and base excision repair of oxidative DNA damage, and defective mismatch repair. Since age-accumulated sSNVs create many damaging mutations that disrupt gene functions, polyploidization in cardiomyocytes may provide a mechanism of genetic compensation to minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction.