Table 3.

Effects of ivabradine on cardiac function in animal studies.

Models	Dose and Duration of Ivabradine	Findings	Reference
Surface ECG recordings and transesophageal electrophysiological study in female C57BL/10 mice	Single dose of 10 mg/kg (i.p.)	↓ HR ↑ QRS duration ↔ QR duration ↑ QT1 intervals ↑ QT2-P intervals ↑ S2Q2 intervals	[50]
Chronic-hypertension-induced cardiac hypertrophy in pigs	1 mg/kg/d infusion for 28 days	↓ HR, ↑ SV, ↑ LVEDP ↑ LV twist, ↔ LV twisting rate ↑ LV untwisting rate ↑ LV untwisting velocity at MVO ↔ LV apical rotation ↑ LV basal rotation ↑ untwist during isovolumic relaxation time	[51]
Experimental chronic- hypertension-induced cardiac remodeling in pigs	1 mg/kg (i.v. bolus, single)	↓ HR, ↔ CO ↔ dp/dtmax, ↔ LV pressure ↑ LV end-diastole internal diameter ↑ LV end-systole internal diameter ↑ LV relaxation filling ↑ LV early filling ↑ LV peak early filling rate	[52]
Experimental hypertension- induced cardiac remodeling in SHR	10 mg/kg/d in drinking water for 6 weeks	↓ HR, ↔ SBP, ↑ LVEF ↑ LVFS, ↓ E/A, ↓ E/Em	[53]
Isoproterenol-induced heart failure in rats	10 mg/kg/d (p.o.) for 6 weeks	↓ HR	[54]
Isoproterenol-induced heart failure in rats	10 mg/kg/d (p.o.) for 14 days	↓ HR	[55]
Diastolic-dysfunction-induced heart failure in diabetic mice	20 mg/kg/d in drinking water for 4 weeks	↓ HR, ↑ E/A, ↓ EDT ↑ −dp/dtmin, ↓ Tau, ↓ IVRT	[56]
Diabetic cardiomyopathy in mice	20 mg/kg/d (p.o.) for 12 weeks	↓ HR, ↑ LVEF	[13]
Myocardial I/R-induced cardiac remodeling in rats	10 mg/kg/d (p.o.) for 28 days	↓ HR, ↑ LVFS ↑ LVEF, ↑ delta LVEF	[57]
Experimental HFpEF in mice	10 mg/kg/d (low) and 20 mg/kg/d (high) (p.o.) for 4 weeks	High dose: ↓ HR, ↓ LVEDP, ↔ LVEF ↓ LV −dp/dtmax, ↔ LV +dp/dtmax, ↓ EDT, ↔ LVFS, ↓ IVRT Low dose: ↓ HR	[58]
Experimental HFrEF in mice	10 mg/kg/d and 20 mg/kg/d (p.o.) for 8 weeks	High dose: ↓ HR, ↓ LVEDP, ↓ IVRT ↓ LV −dp/dtmax ↑ LV +dp/dtmax ↓ EDT, ↑ LVEF, ↑ LVFS Low dose: ↓ HR	[58]
Post-MI-induced heart failure in rats	10 mg/kg/min (via osmotic pump) for 2 weeks	↓ HR, ↑ CO, ↑ SV, ↔ LVEF ↔ LV +dp/dt ↔ LV −dp/dt ↔ LVEDP	[59]
Myocardial I/R-induced cardiac remodeling in pigs	0.3 mg/kg (i.v.)	↓ HR, ↑ SV, ↓ CO, ↑ CVP ↔ MAP ↔ systemic arterial pressure ↔ pulmonary arterial pressure	[60]
Hypertension-induced heart failure in rats	10 mg/kg/d in drinking water for 10 weeks	↓ HR, ↔ SBP, ↓ E/A, ↓ E/E′ ↑ LVFS, ↑ LVEF	[11]
MI-induced cardiac remodeling in rats	10 mg/kg/d in drinking water for 8 weeks	↓ HR, ↑ LVEF, ↓ LVEDP ↑ LVDP, ↑ LV +dp/dt ↑ LV −dp/dt ↓ LV diastolic wall stress	[61]
Experimental hypertension- induced cardiac remodeling in rats	10 mg/kg/d in drinking water for 4 weeks	↓ HR, ↓ SBP, ↑ LVEF ↑ LVFS	[62]
Severe post-MI chronic HF in rats	10 mg/kg/d in drinking water for 3 months	↓ HR, ↑ LVEF, ↓ LVEDP ↓ LVEDV, ↓ LVESV ↑ SV, ↔ CO	[63]
Abdominal-aorta- constriction-induced chronic heart failure in rats	10 mg/kg/d (p.o.) for 12 weeks	↓ LVEDP, ↑ LV +dp/dt ↓ L V −dp/dt	[12]
Open chest with LV post- ischemia dysfunction in pigs	Bolus infusion of 0.5 mg/kg	↓ HR, ↑ SV, ↔ CO ↑ diastolic filling time ↔ MAP, cardiac efficiency	[64]
Chronic ischemic heart failure in diabetic rats	10 mg/kg/d (i.p.) for 7 weeks	↓ HR, ↑ LVFS, ↓ LVEDP	[65]
LAD coronary-artery- ligated-induced cardiac remodeling in rats	10 mg/kg/d in drinking water for 90 days	↓ HR, ↑ LVEF, ↔ LVEDV ↔ LVESV	[14]
LAD coronary-artery- ligated-induced cardiac remodeling in rats	6–8 mg/kg/d (i.p.) for 4 weeks	↓ HR, ↑ SV, ↔ LVEDV ↔ LVESV, ↓ LVEDV/LV mass ↑ LVEF, ↓ LVEDP ↑ LV coronary reserve ↔ coronary conductance	[66]
LAD coronary-artery- ligated-induced cardiac remodeling in rats	10 mg/kg/d (i.g.) for 7 days	↑ LVSP, ↓ LVEDP ↑ +dp/dtmax, ↓ −dp/dtmax	[67]
Doxorubicin-induced LV dysfunction in rats	10 mg/kg (i.p.), alternate days for 2 weeks	↓ HR, ↔ MAP, ↑ +dp/dtmax ↑ Tau, ↑ SDNN, ↓ LF ↔ HF, ↓ LF/HF, ↑ RMSSD ↑ Total power	[68]
Pulmonary-arterial- hypertension-induced heart failure in rats	10 mg/kg/d (p.o.) for 3 weeks	↔ HR, ↑ RV S′, ↑ LV E’ ↓ RV fractional area ↓ RV IVCT, ↓ LV IVCT ↓ Time to mitral valve opening ↓ Time to RV peak radial motion ↓ Time to maximum LVSB ↓ Time to maximum TAPSE ↓ Time to tricuspid valve opening ↓ RV Tau (τ)	[69]
Hypertension-induced cardiac remodeling in SHR	1 mg/kg/d (i.p.) for 14 days	↓ HR, ↓ SBP, ↓ DBP, ↓ MAP	[70]
Transverse-aortic- constriction-induced cardiac hypertrophy in mice	10, 20, 40, and 80 mg/kg/d (i.g.) for 4 weeks	All doses: ↓ HR, ↓ LV Vols, ↑ LVEF ↑ LVFS 10 and 20 mg/kg/d: ↓ LV Vold	[15]
Myocardial I/R-induced cardiac remodeling in pigs	0.3 mg/kg for 7 days	↑ LVEF	[71]
Pulmonary-hypertension- induced cardiac remodeling in rats	10 mg/kg/d (p.o.) for 3 weeks	↓ HR, ↓ RV longitudinal ↑ RV S′, ↓ RV S:D ratio ↓ RV TDI-MPI, ↓ TDI IVRT ↓ RDI IVRT/R-R, ↑ SV, ↑ CO ↑ RV +dp/dt, ↓ RV −dp/dt ↓ RV Tau	[72]
RV pressure-loaded-induced cardiac remodeling in rats	10 mg/kg/d (p.o.) for 3 weeks	↓ HR, ↑ FAC, ↑ TAPSE ↓ RV MPI, ↓ RV S:D ratio ↓ RV longitudinal ↓ RV TDI-MPI, ↓ TDI IVRT ↓ RDI IVRT/R-R, ↑ SV, ↑ CO ↓ RV EDP, ↑ RV +dp/dt ↓ RV −dp/dt, ↓ RV Ees ↓ RV Tau	[72]
SU5416+Hypoxia-induced cardiac remodeling in rats	10 mg/kg/d (p.o.) for 3 weeks	↓ HR, ↑ FAC, ↑ TAPSE ↓ RV MPI, ↓ RV TDI-MPI ↓ TDI IVCT, ↓ TDI IVRT ↓ RDI IVRT/R-R, ↑ SV, ↑ CO ↓ RV EDP, ↓ RV Ees, ↓ RV EDPVR, ↓ RV Tau	[72]
Hyperthyroid cardiomyopathy in rats	10 mg/kg/d (p.o.) for 28 days	↓ HR, ↓ EDT, ↑ Ea, ↓ E/Ea ↓ Scirc, ↓ SRcirc, ↓ Slong ↑ SRlong, ↑ Srad, ↑ SRrad	[73]
Cardiogenic-shock-induced cardiac remodeling in pigs	0.3 mg/kg (i.v. bolus)	↓ HR, ↑ SV, ↑ LVEF	[74]

A, late diastolic mitral inflow velocity; CO, cardiac output; CVP, central venous pressure; DBP, diastolic blood pressure; ECG, electrocardiogram; +dp/dt_max, maximal rate of rise of left ventricular pressure; −dp/dt_max, maximal rate of fall of left ventricular pressure; E, early diastolic mitral inflow velocity; E′, early diastolic mitral annular velocity; E_a, peak early diastolic mitral annular velocity; E/A, early-to-late diastolic mitral inflow velocity; ECG, electrocardiogram; EDP, end-diastolic pressure; EDPVR, end-diastolic pressure–volume relation; EDT, E peak deceleration time; Ees, left ventricular end-systolic elastance; Em, the maximal velocity of early diastolic wall movement wave at the level of mitral annulus; FAC, fractional area change; HF, power in high-frequency range; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; i.p., intraperitoneum; I/R, ischemia/reperfusion; i.v., intravenous; IVCT, isovolumic contraction time; IVRT, isovolumetric relaxation time; LF, power in low-frequency range; LV, left ventricle; LAD, left anterior descending; LVEDP, left ventricular end-diastolic pressure; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVFS, left ventricular fractional shortening; LVSB, early diastolic left ventricular septal bowing; LVSP, left ventricular systolic pressure; MAP, mean arterial pressure; MI, myocardial infarction; MPI, myocardial performance index; MVO, mitral valve opening; p.o., per oral; RMSSD, square root of the mean squared differences of successive normal-to-normal intervals; RV, right ventricle; R-R, electrocardiogram R wave to R wave interval; S′, systolic tissue wave velocity; S_circ, circumferential strain; SBP, systolic blood pressure; SR_circ, circumferential strain rate; S_long, longitudinal strain; SR_long, longitudinal strain rate; S_rad, radial strain; SR_rad, radial strain rate; SBP, systolic blood pressure; S:D, ratio of systolic duration to diastolic duration; SDNN, standard deviation of all normal-to-normal intervals; SHR, spontaneous hypertensive rats; SU5416, a tyrosine kinase inhibitor; SV, stroke volume; TAPSE, tricuspid annular plane systolic excursion; Tau, relaxation time constant; TDI, tissue Doppler imaging; Vold, volume in diastole; Vols, volume in systole; ↔, no difference; ↓, reduced; ↑, increased.