A b s t r a c tIntroduction: Wilson's disease (WD) is a rare genetic disorder that leads to impairments in copper metabolism. Patients principally exhibit liver and neuropsychiatric symptoms, but because copper also accumulates in all body organs, other (typically milder) clinical symptoms can occur. To date, cardiac involvement has not been thoroughly investigated in patients with WD. This study aimed to evaluate heart structure and function in patients with WD with commonly available diagnostic methods. Material and methods: We compared 125 WD patients with an age-and sex-matched control group. Patients with WD were grouped according to their dominant symptoms -neurologic or hepatic. All subjects underwent clinical, electrocardiographic (ECG), and echocardiographic examinations. Results: All subjects had sinus rhythm on electrocardiography. The only ECG parameter that differed between patients with WD and the control group was the QRS prolongation (92.0 vs. 86.4 ms; p < 0.05). On echocardiography patients with WD exhibited more hypertrophy in the left ventricle than controls (posterior wall in diastole: 1.0 vs. 0.93; p < 0.01) and the left ventricle hypertrophy was more pronounced in the neurologic than in the hepatic subgroup (1.05 vs. 0.96 cm; p < 0.01). Left ventricular systolic function was similar in the WD and the control group (ejection fraction: 67.5% vs. 67.7%). On tissue Doppler echocardiography patients with WD demonstrated slowing of myocardial relaxation, which was more evident in the neurologic group. Conclusions: Heart involvement in WD was manifested mainly by mild left ventricular hypertrophy and subclinical changes in diastolic function, particularly in the patients with the neurologic form of disease.

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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.

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