Table 5.

Effects of ivabradine on interstitial fibrosis in experimental heart failure.

Models	Dose and Duration of Ivabradine	Findings	Reference
Experimental HFpEF in mice	10 mg/kg/d (low) and 20 mg/kg/d (high) (p.o.) for 4 weeks	High dose: ↓ LV fibrotic area	[58]
Experimental HFrEF in mice	10 mg/kg/d and 20 mg/kg/d (p.o.) for 8 weeks	High dose: ↓ LV fibrotic area ↓ LV α-SMA protein ↓ LV CTGF protein ↓ LV Col-1 and Col-3 protein ↓ LV TGF-β1 protein ↓ LV TGFR2 protein ↓ LV pSmad2/3 protein Low dose: ↓ LV fibrotic area ↓ LV α-SMA protein ↓ LV CTGF protein ↓ LV Col-1 and Col-3 protein ↓ LV TGF-β1 protein ↓ LV TGFR2 protein ↓ LV pSmad2/3 protein	[58]
Ang II-induced primary ventricular fibroblast proliferation	3 and 10 µM	Both concentrations: ↓ fibroblast proliferation rate ↓ α-SMA protein ↓ CTGF protein ↓ Col-1 and Col-3 protein ↓ TGF-β1 protein ↓ TGFR2 protein ↓ pSmad2/3 protein	[58]
Cardiogenic-shock-induced cardiac remodeling in pigs	0.3 mg/kg (i.v. bolus)	↓ MMP-9 protein ↔ EMMPRIN mRNA ↓ EMMPRIN protein ↑ EMMPRIN+Cav3 colonization	[74]
Isoproterenol-induced HF in rats	10 mg/kg/d (p.o.) for 14 days	↓ serum MMP-9	[55]
Hyperthyroid cardiomyopathy in rats	10 mg/kg/d (p.o.) for 28 days	↔ cardiac fibrosis	[73]
Myocardial I/R-induced cardiac remodeling in pigs	0.3 mg/kg for 7 days	↓ MMP-9 protein	[71]
Diastolic-dysfunction-induced HF in diabetic mice	20 mg/kg/d in drinking water for 4 weeks	↓ α-SMA protein ↓ Collagen 1 protein ↓ Collagen 3 protein ↓ TIMP2 protein ↑ MMP2 protein	[56]
High-glucose-treated rat primary ventricular cardiac fibroblasts	10–40 µM	All concentrations: ↓ Collagen 1 protein ↓ Collagen 3 protein ↓ α-SMA protein ↓ TIMP2 protein ↓ MMP2 protein	[56]
Diabetic cardiomyopathy in mice	20 and 40 mg/kg/d in drinking for 12 weeks	Both doses: ↓ collagen	[106]
Transverse-aortic-constriction- induced cardiac hypertrophy in mice	10, 20, 40, and 80 mg/kg/d (i.g.) for 4 weeks	All doses: ↓ Col 1 mRNA ↓ Col 3 mRNA ↓ PI3K protein ↓ mTORC1 ↔ mTORC2 ↓ Akt ↓ p-Akt ↓ p-p70S6K1	[15]
Diabetic cardiomyopathy in mice	20 mg/kg/d (p.o.) for 12 weeks	↓ Col 1 protein ↓ Col 3 protein	[13]
SU5416+Hypoxia-induced cardiac remodeling in rats	10 mg/kg/d (p.o.) for 3 weeks	↓ RV collagen area ↓ RV collagen I/III protein ratio ↓ RVTGF-β1 protein ↓ RV pSMAD2/Smad2,3 protein ↓ RV pSMAD3/Smad2,3 protein ↓ RV CTGF protein	[72]
RV pressure-loaded-induced cardiac remodeling in rats	10 mg/kg/d (p.o.) for 3 weeks	↓ RV collagen area ↓ RV collagen I/III protein ratio ↓ RVTGF-β1 protein ↓ RV pSMAD2/Smad2,3 protein ↓ RV pSMAD3/Smad2,3 protein ↓ RV CTGF protein	[72]
Pulmonary-hypertension-induced cardiac remodeling in rats	10 mg/kg/d (p.o.) for 3 weeks	↓ RV collagen area ↓ RV collagen I/III protein ratio ↓ RVTGF-β1 protein ↓ RV pSMAD2/Smad2,3 protein ↓ RV pSMAD3/Smad2,3 protein ↓ RV CTGF protein	[72]
Experimental hypertension-induced cardiac remodeling in SHR	10 mg/kg/d in drinking water for 6 weeks	↓ LV collagen ↓ LV hydroxyproline	[53]
Experimental hypertension-induced cardiac remodeling in rats	10 mg/kg/d in drinking water for 4 weeks	↔ LV hydroxyproline	[62]
Isoproterenol-induced HF in rats	10 mg/kg/d (p.o.) for 6 weeks	↓ LV hydroxyproline ↓ LV collagen	[54]
LAD coronary-artery-ligated- induced cardiac remodeling in rats	6–8 mg/kg/d (i.p.) for 4 weeks	↓ LV collagen ↓ LV TGF-β protein ↔ LV VEGF-A protein ↔ LV bradykinin protein	[66]
Severe post-MI chronic HF in rats	10 mg/kg/d in drinking water for 3 months	↓ collagen volume fraction	[63]
Hypertension-induced HF in rats	10 mg/kg/d in drinking water for 10 weeks	↔ LV Col 1a1 gene ↔ RA Col 1a1 gene ↔ LA Col 1a1 gene	[11]
Abdominal-aorta-constriction- induced chronic heart failure in rats	10 mg/kg/d (p.o.) for 12 weeks	↓ CTGF protein ↓ TGF-β1 gene ↓ COL-1 gene	[12]

Akt, protein kinase; Cav3, caveolin 3; Col 1, collagen 1; Col 3, collagen 3; CTGF, connective tissue growth factor; EMMPRIN, extracellular matrix metalloproteinase inducer; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; i.g., intragastric; i.p., intraperitoneum; i.v., intravenous; LV, left ventricle; MMP, matrix metalloproteinase; mTORC, mammalian target of rapamycin complex; p-Akt, phosphorylated protein kinase; p.o., per oral; PI3K, phosphatidylinositol 3-kinase; p-p70S6K1, phosphorylated protein S6 kinase beta-1; α-SMA, α-smooth muscle actin; SU5416, a tyrosine kinase inhibitor; TGF-β1, transforming growth factor β1; TGFR2, transforming growth factor receptor 2; pSmad (or pSMAD), phosphorylated small mothers against decapentaplegic; TIMP, tissue inhibitor of metalloproteinase; VEGF-A, vascular endothelial growth factor A; ↔, no difference; ↓, reduced; ↑, increased.