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.

Targeting S100A1 in heart failure.

Heart failure (HF) is the common endpoint of many cardiovascular diseases with a 1-year survival rate of about 50% in advanced stages. Despite increasing survival rates in the past years, current standard therapeutic strategies are far away from being optimal. For this reason, the concept of cardiac gene therapy for the treatment of HF holds great potential to improve disease progression, as it specifically targets key pathologies of diseased cardiomyocytes (CM). The small calcium (Ca(2+))-binding protein S100A1 presents a promising target for cardiac gene therapy, as it has been identified as a central regulator of cardiac performance and the Ca(2+)-driven network within CM. S100A1 was shown to regulate sarcoplasmic reticulum, sarcomere and mitochondrial function by modulating target protein activity. Furthermore, deranged S100A1 expression has been linked to HF in human ischemic and dilated cardiomyopathies as well as in various HF animal models. Proof-of-concept studies in small and large animal models as wells as in human failing CM could demonstrate feasibility and efficacy of S100A1 genetically targeted therapy. This review summarizes the developmental steps of S100A1 gene therapy for the implementation into first human clinical trials.

Gene therapy targets in heart failure: the path to translation.

Heart failure (HF) is the common end point of cardiac diseases. Despite the optimization of therapeutic strategies and the consequent overall reduction in HF-related mortality, the key underlying intracellular signal transduction abnormalities have not been addressed directly. In this regard, the gaps in modern HF therapy include derangement of ß-adrenergic receptor (ß-AR) signaling, Ca(2+) disbalances, cardiac myocyte death, diastolic dysfunction, and monogenetic cardiomyopathies. In this review we discuss the potential of gene therapy to fill these gaps and rectify abnormalities in intracellular signaling. We also examine current vector technology and currently available vector-delivery strategies, and we delineate promising gene therapy structures. Finally, we analyze potential limitations related to the transfer of successful preclinical gene therapy approaches to HF treatment in the clinic, as well as impending strategies aimed at overcoming these limitations.

Heavy metals in fish from the Barents Sea (summer 1994).

To assess the significance of metals in biota of the Barents Sea, preliminary information is presented for the concentrations of Cd, Pb, Hg, Ni, Cu and Zn in liver and muscle tissues of 15 marine fish species collected in the summer of 1994. Lead and Ni concentrations are below limits of detection (< 0.3 and 1.0 mg kg-1 dry wt.) in all tissues, as is Cd in muscle (< 0.10 mg kg-1). Generally, most of our results are within the reported literature range for various Arctic marine systems, especially regarding some commercially important species like cod and redfish, indicating that metal levels are not elevated. However, the interspecific variability is substantial and some remarkably high Cd levels (2.4 and 8.1 mg kg-1 dry wt.) in livers of Anarhichas species (catfish) and Raja fyllae (round skate) point to the problem of a general 'cadmium-anomaly' in polar marine waters, previously inferred from reported results for various pelagic and benthic invertebrates.

Trace metals in field samples of zooplankton from the Fram Strait and the Greenland Sea.

Trace metals (Cd, Pb, Ni, Cu, Zn and Hg) were evaluated in 14 zooplankton taxa collected on cruise ARK IX/Ib of RV 'Polarstern' to the Fram Strait and the Greenland Sea in March and April 1993. We found a substantial interspecific heterogeneity, e.g. with rather low Cd concentrations in calanoid copepods (0.1-0.7 mg kg-1, dry wt.) but remarkably high levels in the decapod Hymenodora glacialis (7-9 mg kg-1) and in the amphipods Themisto abyssorum and T. libellula (24-34 kg-1). In general, Pb was low (< 1 mg kg-1), while some enhanced Ni concentrations were found in the ostracod Conchoecia borealis (66-86 mg kg-1). A comparison to world-wide reported data on marine crustaceans did not reveal any suggestions on increased metal availabilities in both areas investigated, although one might expect a transport of some metals from Siberian rivers across the pole by the Transpolar Ice Drift Stream. However, more information on accumulation strategies of zooplankton under winter and summer conditions is necessary before a full assessment of metals in Arctic waters will be possible.