Abstract
Ivabradine can reduce heart rate through inhibition of the current I(f) by still unexplored mechanisms. In a porcine model of ischemia reperfusion (IR), we found that treatment with 0.3 mg/kg Ivabradine increased plasma release of microvesicles (MVs) over Placebo, as detected by flow cytometry of plasma isolated from pigs 7 days after IR, in which a tenfold increase of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) containing (both high and low-glycosylated) MVs, was detected in response to Ivabradine. The source of MVs was investigated, finding a 37% decrease of CD31+ endothelial cell derived MVs, while CD41+ platelet MVs remained unchanged. By contrast, Ivabradine induced the release of HCN4+ (mostly cardiac) MVs. While no differences respect to EMMPRIN as a cargo component were found in endothelial and platelet derived MVs, Ivabradine induced a significant release of EMMPRIN+/HCN4+ MVs by day 7 after IR. To test the role of EMMPRIN+ cardiac MVs (EMCMV), H9c2 cell monolayers were incubated for 24 h with 107 EMCMVs, reducing apoptosis, and increasing 2 times cell proliferation and 1.5 times cell migration. The in vivo contribution of Ivabradine-induced plasma MVs was also tested, in which 108 MVs isolated from the plasma of pigs treated with Ivabradine or Placebo 7 days after IR, were injected in pigs under IR, finding a significant cardiac protection by increasing left ventricle ejection fraction and a significant reduction of the necrotic area. In conclusion ivabradine induces cardiac protection by increasing at least the release of EMMPRIN containing cardiac microvesicles.
Highlights
Coronary artery disease (CAD) and chronic heart failure (CHF) are two leading causes of death worldwide
Animals subjected to ischemia reperfusion (IR) and treated with 0.3 mg/kg Ivabradine (Figure 1A), had lower heart rate, and better stroke and left ventricle ejection fraction, as previously described [4,5]
The recent findings on blood released microvesicles (MVs) in response to acute myocardial infarction [10], led us to investigate whether Ivabradine may have an effect in the amount and/or composition of MV release, with the criteria of restricting events gated between 0.22 μm and 1 μm (Figure 1B)
Summary
Coronary artery disease (CAD) and chronic heart failure (CHF) are two leading causes of death worldwide. In attempting to restore adequate tissue perfusion, alterations on blood pressure and heart rate seriously increases myocardial oxygen [1] and compromises ventricular filling efficiency by shortening diastolic duration [2]. Beta-blocker administration was efficiently proved to reduce heart rate, undesired side effects like negative inotropic stimulation, highlighted the need of finding new pharmacological alternatives. Several clinical trials have proved the benefits of using the Funny I(f ) current inhibitor Ivabradine for the treatment of CAD and CHD, including the SHIFT study (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), in which Ivabradine has been shown to reduce re-hospitalization and mortality rates in patients with CHF and reduced left ventricular ejection fraction (LVEF) [3]. The contribution of Ivabradine in acute heart failure (AHF) was recently reported, confirming the effectiveness against dobutamine-induced tachycardia, and improving the hemodynamic parameters immediately after Acute Myocardial Infarction (AMI) and long-term [4,5], but the underlying molecular mechanisms are yet to be investigated
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