dilated cardiomyopathy ͉ heart failure ͉ calcium cycling ͉ mutation ͉ phosphorylation

In human disease and experimental animal models, depressed Ca2+ handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca2+-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy

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IntroductionIn the face of unremitting hemodynamic stress, "adaptive" cardiac hypertrophy inevitably progresses to ventricular dilation and clinical heart failure, which affects an estimated 5 million Americans and has a mortality rate of approximately 50% in 4 years (1). A nearly universal characteristic of hypertrophied and failing myocardium is depressed sarcoplasmic reticulum (SR) Ca 2+ cycling, caused by decreased expression of the cardiac SR Ca 2+ ATPase (SERCA2a), by a relative overabundance of the SERCA2a inhibitory protein phospholamban (PLN), or by both (2, 3). Recent experimental successes have generated enthusiasm for treating heart failure by restoring SR Ca 2+ cycling, either through adenoviral-mediated myocardial-targeted expression of SERCA2a itself (4) or through antisense suppression (5) or genetic ablation of PLN (6), to relieve SERCA2a from endogenous inhibition. The common result of each approach is enhanced SR Ca 2+ cycling, which has improved energetics, survival, and cardiac function at the cellular, organ, and intact animal levels. Furthermore, there is no compromise in exercise performance or longevity in the case of PLN ablation (7,8).To date, PLN ablation or inhibition has improved SR Ca 2+ cycling and/or contractile function in transgenic Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca 2+ cycling. Normalization of Ca 2+ cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Gαq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C MUT ) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca 2+ transients and enhanced unloaded fractional shortening with no change in SR Ca 2+ pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Gαq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Gαq pathway or MyBP-C mutations.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

The objectives for the treatment of Wilms tumor in both the Children's Oncology Group (COG) and the International Society of Paediatric Oncology (SIOP) have focused on improving cure rates and minimizing toxicity by limiting the use of radiation and doxorubicin. Although the timing of surgery is different in COG (upfront surgery) and SIOP (upfront chemotherapy with delayed surgery), both are effective strategies and have the same survival. Fewer patients are treated with radiotherapy in the SIOP trials but with higher doses. The prognostic significance of biological markers such as 1q gain and clinical outcomes with novel radiation techniques such as intensity modulated radiation therapy will be determined in upcoming clinical trials. A closer collaboration between COG and SIOP could help promote research and improve the clinical outcomes of children with Wilms tumor.

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