Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.

Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.

[Patient survival, a change in methods, and hospitalization in CAPD abd hemodialysis]. / Patientenüberleben, Methodenwechsel und Hospitalisierung bei CAPD und Hämodialyse.

UNLABELLED: BACKGROUND AND OBJECTIVE OF STUDY: Continuous ambulatory peritoneal dialysis (CAPD) still plays a minor role in Germany compared with haemodialysis (HD) in the management of terminal renal failure. An investigation was undertaken to compare mortality rate, change of dialysing method as well as number and duration of hospital stays of patient undergoing CAPD or HD at a nephrological centre. PATIENTS AND METHODS: All 166 patients in terminal renal failure (except those with a malignancy) admitted between January 1987 and December 1992 were included (63 women and 103 men, aged 19-84 years). The choice between the two dialysis methods was made by the patients after detailed information had been given. Taking into account basic disease and any secondary illness as well as age and sex, survival time, any change of dialysing method and hospitalisation details were prospectively analysed for the two dialysing methods. RESULTS: After 4 years there were no significant differences in mortality rate between the two methods (HD 37%, CAPD 29%). The Cox model revealed no influence of various parameters on the mortality rate of the two methods. However, cumulative patients survival was significantly decreased by arterio-sclerotic disease (P < 0.05; probability of survival after 4 years was 53% and 73%, respectively, for HD and 57% and 77% for CAPD). Similarly, age > or = 60 years at onset of dialysis significantly lowered probability of survival (after 4 years of dialysis, 53% vs 70% for HD, 45% vs 80% for CAPD: P < 0.05). But there were no significant differences between the two methods with respect to these two factors. After 4 years, "method survival" was more common with HD (94%) than CAPD (64%), P < 0.05). In particular diabetics had a significantly lower "method survival" after 4 years than non-diabetics (29% vs 74%). There was no significant difference between the two methods regarding number and duration of hospital stays. CONCLUSIONS: These data show that, in a nephrological centre with long experience in both methods of dialysis, CAPD is an equal alternative to HD.