Table 7.

Effects of ivabradine on inflammation and oxidative stress in patients with heart failure and animal studies.

Subjects	Dose of Ivabradine	Findings	Reference
Patients with cardiomyopathy (n = 33)	5 mg b.i.d. for 3 months and 7.5 mg b.i.d. for 3 months	↓ TNFα, ↔ IL-6 ↔ hsCRP	[32]
Patients with cardiomyopathy (n = 33)	5 mg b.i.d. for 3 months and 7.5 mg b.i.d. for 3 months	↔ sST2, ↓ GDF-15 ↓ H-FABP, ↔ suPAR	[124]
Patients with HF (n = 10)	5 mg b.i.d. and titrated to 7.5 mg b.i.d. for 6 months	↓ IL-6, ↓ TNFα	[34]
Diabetic cardiomyopathy in mice	20 mg/kg/d (p.o.) for 12 weeks	↓ Heart TNF-α mRNA and protein ↓ Heart IL-1β mRNA and protein ↓ Heart IL-6 mRNA and protein ↓ p-JNK, ↓ p-38	[13]
High-glucose-treated rat primary ventricular cardiac fibroblasts	10–40 µM	All concentrations: ↓ p-JNK protein ↓ p-p38 protein ↓ cell proliferation	[56]
Diastolic-dysfunction-induced HF in diabetic mice	20 mg/kg/d in drinking water for 4 weeks	↓ p-JNK protein ↓ p-p38 protein	[56]
LAD coronary-artery-ligated- induced cardiac remodeling in rats	10 mg/kg/d (i.g.) for 7 days	↓ TNFα ↓ IL-1β ↓ IL-6	[67]
Hypertension-induced cardiac remodeling in SHR	1 mg/kg/d (i.p.) for 14 days	↓ Number of inflammatory nuclei	[70]
Myocardial I/R-induced cardiac remodeling in pigs	0.3 mg/kg for 7 days	↑ de-expression of heart CyPA ↓ plasma CyPA protein ↑ cardiac CyPA protein ↔ heart CyPA mRNA ↑ CyPA-LG-EMMPRIN protein ↔ CyPA degradation	[71]
Hyperthyroid cardiomyopathy in rats	10 mg/kg/d (p.o.) for 28 days	↔ cardiac inflammation	[73]
High-glucose-induced apoptosis in cardiomyocytes	1–40 μM (pretreatment)	5–40 μM: ↓ p-IKKα/β protein ↔ IKKβ protein ↓ p-IκBα protein ↑ t-IκBα protein ↑ cyto NF-κB protein ↓ nuclear NF-κB protein	[107]
Diabetic cardiomyopathy in mice	20 and 40 mg/kg in drinking water for 12 weeks	Both doses: ↓ p-IKKα/β protein ↔ IKKβ protein ↓ p-IκBα protein ↑ t-IκBα protein ↑ cyto NF-κB protein ↓ nuclear NF-κB protein	[107]
Abdominal-aorta- constriction-induced chronic heart failure in rats	10 mg/kg/d (p.o.) for 12 weeks	↑ SOD protein	[12]

b.i.d., twice daily; cyto, cytoplasmic; CyPA, cyclophilin A; LG-EMMPRIN, low-glycosylated extracellular matrix metalloproteinase inducer; GDF-15, growth-differentiation factor-15; H-FABP, heart-type fatty acid binding protein; hsCRP, high-soluble C-reactive protein; i.g., intragastric; IL-1β, interleukin 1β; IL-6, interleukin 6; i.p., intraperitoneum; NF-κB, nuclear factor kappa-B; p-IκBα, phospho-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α; t-IκBα, total inhibitor of nuclear factor kappa-B kinase subunit α/β; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α; p-IKKα/β, inhibitor of nuclear factor kappa-B kinase subunit α/β; p-JNK, phosphorylated c-Jun N-terminal kinase; p.o., per oral; p-p38, phosphorylated p38; SOD, superoxide dismutase; sST2, soluble suppression of tumorigenicity; suPAR, soluble urokinase plasminogen activator receptor; TNFα, tumor necrosis factor α; ↔, no difference; ↓, reduced; ↑, increased.