The Biological Effects of Ivabradine in Cardiovascular Disease

Abstract

A large number of studies in healthy and asymptomatic subjects, as well as patients with already established cardiovascular disease (CAD) have demonstrated that heart rate (HR) is a very important and major independent cardiovascular risk factor for prognosis. Lowering heart rate reduces cardiac work, thereby diminishing myocardial oxygen demand. Several experimental studies in animals, including dogs and pigs, have clarified the beneficial effects of ivabradine associated with HR lowering. Ivabradine is a selective inhibitor of the hyperpolarisation activated cyclic-nucleotide-gated funny current (If) involved in pacemaker generation and responsiveness of the sino-atrial node (SAN), which result in HR reduction with no other apparent direct cardiovascular effects. Several studies show that ivabradine substantially and significantly reduces major risks associated with heart failure when added to guideline-based and evidence-based treatment. However the biological effect of ivabradine have yet to be studied. This effects can appear directly on myocardium or on a systemic level improving endothelial function and modulating immune cell migration. Indeed ivabradine is an 'open-channel' blocker of human hyperpolarization-activated cyclic nucleotide gated channels of type-4 (hHCN4), and a 'closed-channel' blocker of mouse HCN1 channels in a dose-dependent manner. At endothelial level ivabradine decreased monocyte chemotactin protein-1 mRNA expression and exerted a potent anti-oxidative effect through reduction of vascular NADPH oxidase activity. Finally, on an immune level, ivabradine inhibits the chemokine-induced migration of CD4-positive lymphocytes. In this review, we discuss the biological effects of ivabradine and highlight its effects on CAD.

The NF-kB regulates the SHP-1 expression in monocytes in congestive heart failure

“…As shown in Figure 1A-C, the monocytes from pretreatment patients showed the activation of the TAK-1 and of the IKKbeta by phosphorylation on these sites, whereas un-phosphorylated TAK-1 and IKKbeta levels did not change after treatment. As expected, the level of pIkBalpha (Ser-32) is higher in pre-treated patients CCL5 -1.8±0.6 (1) −2.1±0.4 (3) CD14 -1.8±0.5 (1) −1.7±0.3 (4) ITGAM -2±0.6 (1) −2.3±0.5 (4) CCR1 -2.8±0.7 (2) −3.8±0.9 (3) NFKBIA 2.5±0.6 (1) 2.2±0.2 (3) PTPN6 1.9±0.6 (2) 2.4±0.3 (4) TNFAIP3 3±0.9 (1) 3.6±1.1 (3) CCL5 Protein 3., (1) FDR: 0%, (2) FDR: 0.1% (n=11); (3) p<.01, (4) p<.05 (n=50) © 1996-2017 with conventional drugs, whereas the WB analysis for un-phosphorylated IkBalpha protein confirmed an up-regulation of the mRNA reported through Microarray analysis as well as the qPCR analysis after therapy. As a post-translational modification of the NF-kB (p65) affecting its transcriptional activities, we performed further studies to determine the phosphorylation of the p65 at Ser-536 by the WB, using specific phospho-p65 antibody on nuclear protein extracts.…”

“…Heart Failure (HF) is one of the most common pathological condition in the Western World having the highest impact on survival and on the quality of life of patients. Although there have been significant progress that have reduced the mortality rate of the disease or delayed its progression and made way for quality of life considered acceptable, the prognosis of HF remains poor (1)(2)(3). Progression of HF is a result of compensatory mechanisms and modulation of T cells and complement system, and activation of a variety of pro-inflammatory cytokines, such as Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-6 (4)(5)(6)(7)(8).…”

A Novel Biological Role of α-Mangostin in Modulating Inflammatory Response Through the Activation of SIRT-1 Signaling Pathway

“…Inflammation is a major condition associated with various diseases and is a natural host defensive response to invading pathogens and tissue injury with the involvement of phagocytic cells such as macrophages, mast cells, dendritic cells, granulocytes, and innate lymphocytes (Speranza et al, ; Pesce et al, ). In many cases, inflammation is demonstrated to be an important contributor to diseases such as cancer, diabetes, and cardiovascular diseases (Speranza et al, ; Khuda‐Bukhsh et al, ). The Silent Information Regulator‐1 (Sirtuin1, SIRT‐1), a member of NAD + dependent class III histone deacetylase, has been shown to be involved in a variety of pathophysiological processes, such as inflammation, the modulation of cell growth and metabolism, and carcinogenesis.…”

Inflammation and cardiac dysfunction during sepsis, muscular dystrophy, and myocarditis

“…These effects can improve endothelial function, modulate immune cells and enhance a long-term adaptation in calcium handling. [ 120 ] In a dystrophy case report, ivabradine normalizes sinus tachycardia and heart failure in Becker’s muscular dystrophy patients with dilated cardiomyopathy and reduces arrhythmic events and left ventricular remodeling. [ 121 ]…”