Heart Rate Reduction Induced by the If Current Inhibitor Ivabradine Improves Diastolic Function and Attenuates Cardiac Tissue Hypoxia

International audienceAims: Enhanced heart rate (HR) is a compensatory mechanism in chronic heart failure (CHF), preserving cardiac output, but at the cost of increased left ventricular (LV) oxygen consumption and impaired diastolic function. The HR reduction (HRR) induced by the If current inhibitor ivabradine prevents LV systolic dysfunction in CHF, but whether HRR improves LV diastolic function is unknown. Methods: LV diastolic function and remodeling were assessed in rats with CHF after coronary ligation after long-term (90 days, starting 7 days after ligation) and delayed short-term (4 days, starting 93 days after ligation) ivabradine treatment (10 mg$kg −1$d −1). Results: Long-and short-term HRR reduced LV end-diastolic pressure, LV relaxation, and LV end-diastolic pressure-volume relation. Simultaneously, LV hypoxia-inducible factor-1a expression was reduced. Long-term and, to a more marked extent, short-term HRR increased endothelial cell proliferation, associated after long-term HRR with the prevention of CHF-related LV capillary rarefaction. Long-term and, to a lesser extent, short-term HRR increased endothe-lial nitric oxide synthase expression, associated after long-term HRR with improved nitric oxide-dependent coronary vasodilatation. Conclusions: Long-term HRR induced by ivabradine improves diastolic LV function probably involving attenuated hypoxia, reduced remodeling, and/or preserved nitric oxide bioavailability, resulting from processes triggered early after HRR initiation: angiogenesis and/or preservation of endothelial nitric oxide synthase expression

In Vitro and Ex Vivo Evaluation of Smart Infra-Red Fluorescent Caspase-3 Probes for Molecular Imaging of Cardiovascular Apoptosis

International audiencePURPOSE:The aim of this paper is to develop new optical bioprobes for the imaging of apoptosis.PROCEDURE:We developed quenched near-infrared probes which become fluorescent upon cleavage by caspase-3, the key regulatory enzyme of apoptosis.RESULTS:Probes were shown to be selectively cleaved by recombinant caspase-3. Apoptosis of cultured endothelial cells was associated with an increased fluorescent signal for the cleaved probes, which colocalized with caspase-3 and was reduced by the addition of a caspase-3 inhibitor. Flow cytometry demonstrated a similar profile between the cleaved probes and annexin V. Ex vivo experiments showed that sections of hearts obtained from mice treated with the proapoptotic drug doxorubicin displayed an increase in the fluorescent signal for the cleaved probes, which was reduced by a caspase-3 inhibitor.CONCLUSION:We demonstrated the capacity of these novel probes to detect apoptosis by optical imaging in vitro and ex vivo