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Mechanical unloading of the rat heart increases both protein synthesis and protein degradation. The transcriptional mechanism underlying increased protein synthesis during atrophic remodeling is not known. The aim of this study was to identify transcriptional regulators and the gene expression profile regulating protein synthesis in the unloaded rat heart and in the unloaded failing human heart. We measured DNA binding activity, transcript levels, and protein expression of transcriptional regulators of protein synthesis in a model of atrophic remodeling induced by heterotopic transplantation of the rat heart (duration 1 and 7 days). Using microarray analysis and quantitative RT-polymerase chain reaction, we found an increase in c-myc-regulated gene expression including an induction of ribosomal subunit messenger RNA's (RPS 10, RPL 21) and rRNA (18S). Consistent with the gene expression profile, DNA binding activity of c-myc and the nuclear protein concentration of its coactivator, upstream binding factor (UBF), increased in the atrophied heart whereas protein levels of the c-myc inhibitor MAD1 decreased. We found the same increase of ribosomal subunit messenger RNA and rRNA in 21 paired samples of failing human hearts obtained before and after left ventricular assist device treatment (mean duration: 157+/-31 days). In summary, mechanical unloading increases c-myc activity and c-myc-regulated gene expression in the rat heart. Changes in transcript levels of genes regulating ribosomal biogenesis in the unloaded rat heart resemble those found in the unloaded failing human heart. We concluded c-myc and c-myc-regulated gene expression are transcriptional regulators of protein synthesis during atrophic remodeling of the heart.

The authors used brain natriuretic peptide (BNP) as a reliable marker to identify nonresponders to cardiac resynchronization therapy (CRT) in patients with advanced heart failure. The study included 70 patients with left ventricular dysfunction (mean ejection fraction, 21+/-4%) and left bundle branch block (QRS duration, 164+/-25 milliseconds) treated with CRT. The authors reviewed data on New York Heart Association functional class, baseline ejection fraction, sodium, creatinine, QRS duration, and BNP levels 3 months before and after CRT therapy. The authors compared results of 42 patients who survived (973+/-192 days) after CRT implantation (responders) to those of 28 patients (nonresponders) who either expired (n=21) or underwent heart transplantation (n=5) or left ventricular assist device implantation (n=2) after an average of 371+/-220 days. Mean BNP levels after 3 months of CRT decreased in responders from 758+/-611 pg/mL to 479+/-451 pg/mL (P=.044), while in nonresponders there was increase in BNP levels from 1191+/-466 pg/mL to 1611+/-1583; P=.046. A rise in BNP levels was associated with poor response (death or need for transplantation or left ventricular assist device and impaired long-term outcome), which makes it a good predictor to identify such patients.

Although the relationship between antipsychotic medication, particularly second-generation antipsychotics (SGAs), and metabolic disturbance is increasingly accepted, there is an important, but little recognised, potential interaction between this and the other important serious adverse effect of neuroleptic malignant syndrome (NMS). We report a case of a 35-year old female who developed new onset type II diabetes mellitus with hyperosmolar hyperglycaemic coma and acute renal failure following treatment with a SGA for a first manic episode. The history is strongly suggestive of concurrent NMS. This case raises important questions about non-ketotic, hyperosmolar diabetic coma with antipsychotics, the possible association between hyperglycaemia and hyperthermia, and the direction of causality in this, the recognition of either syndrome when they co-exist and management issues in such patients. These questions are considered in the context of currently available literature.