Table 2.

Summary of selected preclinical studies with S/V in cardiac disorders.

Animal model	Dose/duration	Main molecular mechanism(s) and effects	Cardiac and hemodynamic effects	Ref.
post-MI (LAD ligation) in SD rats	68 mg/kg daily, 4 weeks	Reduction of fibrosis rate in peri-infarct and remote myocardium	Reduction of HW, hypertrophy and fibrosis, LV remodeling, LVEDd; improvement of LV function and EF	[133]
MHD in C57BL/6J mice	100 mg/kg daily, 16 weeks	Reduction of fibrosis, hypertrophy, and collagen production in heart; reduction of myocardial oxidative stress	Reduction of total wall thickness, LV mass, LVEDP, E/Em; improvement of E/A ratio, Em, RPP	[134]
ISO-exposed Wistar rats	60 mg/kg daily, 1 week	Reduction of cardiac interstitial fibrosis and expression of TGF-$\beta$1, Col1a1, Ccl2	Reduction of serum NT-proBNP, SBP; attenuation of the LVEDP and Dp/dt max increase	[135]
MI (LAD-ligation) in SD rats	68 mg/kg daily, 4 weeks	Inhibition of myocardial fibroblast proliferation and collagen synthesis through downregulation of TGF-$\beta$1/Smads signaling	Reduction of LVEDd, LVEDs, IVSd, LVPWd; increase of EF, FS	[136]
HFrEF in diabetic C57BL/6J mice	60 mg/kg daily, 4 weeks	Reduction of LV fibrosis; decreased expression of TGF-$\beta$, ANP	Reduction of serum NT-proBNP, HW/BW; improvement of EF, SV, CO, SW	[137]
HFpEF in Dahl/SS rats	68 mg/kg daily, 4 weeks	Inhibition of cardiac fibrosis by suppressing the TGF-$\beta$1/Smad3 signaling pathway	Reduction of serum NT-proBNP, SBP, LV/BW, (Wet lung-Dry lung)/BW, LA/BW, IVSd, LVPWd, LA; correction of LV mass, E/A and E/E′; improvement of EF, FS, LV DD	[138]
DOX-exposed Wistar rats	68 mg/kg daily, 4–6 weeks	Altered extracellular matrix remodeling secondary to a reduction in myocardial MMP activity	Preservation of EF and FS	[139]
HFpEF in ZSF1 obese rats	60 mg/kg daily, 12 weeks	Reduction of perivascular fibrosis, decrease of Collagen I and III, ANP and BNP expressions, decrease of MMP-2 activity, increase of cGMP levels and phosphor-titin levels	Reduction of serum NT-proBNP, HW, LVESP, LVEDP, and LV stiffness, MAP in aorta, RV volume capacity; improvement of DD, EF and endothelial-dependent vasodilation in carotid arteries	[140]
Debanding surgery in C57BL/6 J mice with aortic banding	60 mg/kg daily, 4 weeks	Inhibition of NF-κB-mediated NLRP3 inflammasome activation	Reduction of HW/BW, LV mass, LVESd; improvement of EF, FS	[141]
MI (LAD ligation) in C57BL/6J mice	20 mg/kg daily, 4 weeks	Suppression of pro-inflammatory cytokines and ECM degradation by macrophages	Reduction of rate of death due to LV rupture, LVEDd, LVESd, plasma aldosterone, aldosterone/cGMP ratio; increase of survival rate, FS, plasma cGMP levels	[142]
TAC in C57Bl6/J mice	57 mg/kg twice daily, 4 weeks	Inhibition of Rho signaling via stabilization of ANF-induced PKG signaling	Reduction of SBP, LV mass, systolic and diastolic internal dimensions and volumes; improvement of EF, FS; preservation of E/E’ values	[143]
Post MI (LAD ligation) in SD rats	60 mg/kg daily, 4 weeks	Reduction of cardiomyocyte hypertrophy, cardiac fibrosis and collagen I expression in the non-infarct and border zone, expressions of ANP, $\beta$MHC, and TIMP2	Reduction of HW, LV weight, LA weight, lung weight, LV filling pressures, LVESV, LVEDP, LVPW thickness, LV diastolic wall strain, LV compliance; improvement of EF, FS, ESPV relationship; preservation of dP/dt max and dP/dt min normalized to LVEDV	[144]
TAC in C57BL/6 mice	60 mg/kg daily, 4 weeks	Inhibition of inflammatory response in blood and heart tissues, reduction of cardiac fibrosis and hypertrophy, improvement of ventricular remodeling	Reduction of LVEDs, LVEDd, LVPWs, LVPWd, IVSs, IVSd, LV mass; improvement of EF, FS	[145]
Post-TAC in C57BL/6 mice	60 mg/kg daily, 4 weeks	Reduction of cardiac fibrosis and preservation of cardiomyocyte morphology	Reduction of LA, EF, IVSd, LVPWd, LVEDd, LVESd	[146]
AF rabbit model	10 mg/kg twice daily, 3 weeks	Attenuation of atrial electrical and structural remodeling probably via calcineurin/NFAT pathway, preservation of cardiomyocyte morphology	Reduction of serum NT-proBNP, AF incidence; preservation of rapid pacing-induced atria and RV enlargement	[147]
diabetic CMP in C57BL/6 mice	60 mg/kg daily 16 weeks	Inhibition the HG- or diabetes-induced JNK/p38MAPK phosphorylation and NF-kB nuclear translocation; decrease of apoptosis, oxidative stress, fibrosis, collagen I, and collagen III levels	Reduction of serum NT-proBNP; improvement of LV contractility and diastolic function	[148]
MI (LAD ligation) in SD rats	68 mg/kg daily, 1 week	Inhibition of TAK1/JNK signalling cascade; reduction of interstitial fibrosis, collagen volume fraction, serum levels of inflammatory factors (IL‑1 $\beta$ and IL‑18) and ROS accumulation and downregulate the expression levels of NLRP3; downregulation of pro-caspase-l, pro-IL-l$\beta$ and pro-IL-18 expression	Reduction of myocardial injury and improved ventricular remodeling	[149]
EAM in BALB/c mice	20 mg/kg daily, 2 weeks	Inhibition of Th17 cell differentiation (independent from the NLRP3 inflammasome pathway); Reduction of inflammatory markers	Reduction of HW/BW, pathological scores of heart sections and cTnT	[150]
MCT-induced PH and Hypoxia-induced PH in SD rats	68 mg/kg daily, 2 weeks	Increase of ANP and CNP; Restoration of the down-regulated NPRs protein expression, preservation of cGMP content of lung tissues; decrease of IL-1$\beta$, IL-6, and TNF-$\alpha$ concentrations in blood	Reduction of MAP, mPAP, PVR, RV weight to LV + S weight ratio, pulmonary artery wall thickness, fully muscularization of pulmonary arterioles and improved non-muscular arterioles	[151]
DOX-induced dilatative CMP in Balb/c mice	60 mg/kg daily, 4 weeks	Preservation of mitochondrial function via reduced activity of fission protein Drp1; reduction of myocardial hypertrophy, fibrosis and cell size, apoptosis and cardiomyocyte contractile dysfunction	Reduction of serum NT-proBNP, HW/BW; improvement in HW/TL, EF, LVEDd, LVESd	[152]
TAC-induced pressure overload HF In C57BL/6	20 mg/kg daily, 4 weeks	Anti-hypertrophic effect by ameliorating oxidative stress via the Sirt3/MnSOD pathway; reduction of cardiac hypertrophy, fibrosis, ANP, BNP, $\beta$-MHC, myocardial ROS and myocardial apoptosis	Reduction of HW/BW, LW/BW, HW/TL; improvement of EF, FS and hypertrophy contractile dysfunction	[153]
HF by I/R injury (LAD ligation) in SHR	68 mg/kg daily, 4 or 6 weeks	Reduction of extension of infarct border zone, collagen volume fraction, collagen I and collagen III expressions, TIMP2, TGF-$\beta$; improved endothelium-independent vascular reactivity and vascular compliance; increased circulating plasma and myocardial NO levels and PKG protein levels	Reduction of serum NT-proBNP, LVEDd, LVESd, LVEDP; improvement of EF	[154]

Abbreviations: AF, atrial fibrillation; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; BW, body weight; Ccl2, C motif chemokine ligand 2; cGMP, cyclic guanosine monophosphate; CMP, cardiomyopathy; CNP, C-type natriuretic peptide; CO, cardiac output; Col1a1, collagen type 1 alpha 1; cTnT, cardiac Troponin T; DBP, diastolic blood pressure; DD, diastolic dysfunction; DOX, doxorubicin; EAM, experimental autoimmune myocarditis; ECM, extracellular matrix; EF, ejection fraction; ESPV, end-systolic pressure volume relationship; FS, fractional shortening; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HW, heart weight; HW/TL, heart weight/tibial length; IL, interleukin; ISO, isoproterenol; IVSd, interventricular septum thickness at the end of diastole; IVST, intraventricular septum thickness; LA, left atrial internal dimensions; LAD, left anterior descending artery; LV, left ventricle; LVEDd, left ventricle end-diastolic diameter; LVEDP, left ventricle end-diastolic pressure; LVEDV, left ventricle end-diastolic volume; LVESd, left ventricle end-systolic diameter; LVESP, left ventricle end-systolic pressure; LVESV, left ventricle end-systolic volume; LVPWd, left ventricular posterior wall thickness at the end of diastole; LVPWs, left ventricular posterior wall thickness at the end of systole; LVSP, left ventricle systolic pressure; MAP, mean arterial pressure; MCT, monocrotaline; $\beta$MHC, $\beta$ myosin heavy chain; MI, myocardial infarction; MMP, matrix metalloproteinase; mPAP, mean pulmonary arterial pressure; NT-proBNP, N-terminal pro b-type natriuretic peptide; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; ref., references; RPP, heart rate x developed pressure; RV, right ventricle; SBP, systolic blood pressure; SD, Sprague Dawley; SV, stroke volume; SW, stroke work; TAC, transverse aortic constriction; TIMP, tissue inhibitor of metalloproteinases; TGF-$\beta$, transforming growth factor-beta; TNF-$\alpha$, tumour necrosis factor-$\alpha$.