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Aortic valve stenosis is the most prevalent, clinically significant valvular disorder in adult patients. Surgical valve replacement is the standard therapy for patients with symptomatic and severe aortic stenosis; however, many patients are suboptimal candidates for surgery due to age and co-morbidities. The development of transcatheter aortic valve implantation (TAVI) has broadened the therapeutic options, especially in high-risk patients. The first randomized study comparing surgical valve replacement with TAVI in operable high-risk patients show similar mortality and reduction in symptoms after a 2-year follow-up. These data support the use of this technique in high-risk patients with severe aortic stenosis.

S100A1, a Ca superset2+-binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been shown to enhance cardiac contractile performance by regulating both sarcoplasmic reticulum (SR) Ca superset2+-handling and myofibrillar Ca superset2+-responsiveness. In cardiac disease, the expression of S100A1 is dynamically altered as it is significantly down-regulated in end stage human heart failure (HF), and it is up-regulated in compensated hypertrophy. Therefore, the delivery of a transgene encoding for S100A1 to the myocardium might be an attractive strategy for improving cardiac function in HF by replacing lost endogenous S100A1. In this study we sought to test whether exogenous S100A1 gene delivery to alter global cardiac function is feasible in the normal rabbit heart. An adenoviral S100A1 transgene (AdvS100A1) also containing the green fluorescent protein (GFP) was delivered using an intracoronary injection method with a dose of 5 x 10 superset11 total virus particles (tvp) (n = 8). Rabbits treated with either a GFP-only adenovirus (AdvGFP) or saline were used as control groups (n = 11 each). Seven days after global myocardial in vivo gene delivery hemodynamic parameters were assessed. S100A1 overexpression as a result of the intracoronary delivery of AdvS100A1 significantly increased left ventricular (LV) +dP/dt subsetmax, -dP/dt subsetmin and systolic ejection pressure (SEP) compared to both control groups after administration of isoproterenol (0.1, 0.5 and 1.0 microg/kgBW/min), while contractile parameters remained unchanged under basal conditions. These results demonstrate that global myocardial in vivo gene delivery is possible and that myocardial S100A1 overexpression can increase cardiac performance. Therefore, substitution of down-regulated S100A1 protein expression levels may represent a potential therapeutic strategy for improving the cardiac performance of the failing heart.

S100A1, a Ca(2+) binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been found to colocalize with the sarcoplasmic reticulum (SR) and the contractile filaments in cardiac tissue. Because S100A1 is known to modulate SR Ca(2+) handling in skeletal muscle, we sought to investigate the specific role of S100A1 in the regulation of myocardial contractility. To address this issue, we investigated contractile properties of adult cardiomyocytes as well as of engineered heart tissue after S100A1 adenoviral gene transfer. S100A1 gene transfer resulted in a significant increase of unloaded shortening and isometric contraction in isolated cardiomyocytes and engineered heart tissues, respectively. Analysis of intracellular Ca(2+) cycling in S100A1-overexpressing cardiomyocytes revealed a significant increase in cytosolic Ca(2+) transients, whereas in functional studies on saponin-permeabilized adult cardiomyocytes, the addition of S100A1 protein significantly enhanced SR Ca(2+) uptake. Moreover, in Triton-skinned ventricular trabeculae, S100A1 protein significantly decreased myofibrillar Ca(2+) sensitivity ([EC(50%)]) and Ca(2+) cooperativity, whereas maximal isometric force remained unchanged. Our data suggest that S100A1 effects are cAMP independent because cellular cAMP levels and protein kinase A-dependent phosphorylation of phospholamban were not altered, and carbachol failed to suppress S100A1 actions. These results show that S100A1 overexpression enhances cardiac contractile performance and establish the concept of S100A1 as a regulator of myocardial contractility. S100A1 thus improves cardiac contractile performance both by regulating SR Ca(2+) handling and myofibrillar Ca(2+) responsiveness.