2,3,7,8-Tetrachlorodibenzo-p-dioxin19969063Zordoky, 2010in vitroH9c21, 5, 10, 20 nm48h

No decrease in cell viability at 1 - 20 nM (98% compared to control). Significant induction of the hypertrophic marker ANP by 2.5-fold and BNP by 3-fold.

2,3,7,8-tetrachlorodibenzo-p-dioxin15635151Antkiewicz, 2005in vivoZebrafish1 ppb1h exposure, up to 96 hpf.

Pericardial effusion, altered looping, reduced blood flow at 72h. Ventricles became more compact, elongation of atria. Functional deficits in the developing hearts, including blood regurgitation and ventricular standstill at 120h. Sig. reduction in heart tissue volume, and in the total number of CMs.

3,3',4,4',5-pentachlorobiphenyl18660518Grimes, 2008in vivoZebrafish7.5 μg/L24h exposure, up to 72hpf

Reduced cell number and size in ventricular myocardium. Severely dysmorphic heart with a reduced bulbus arteriosus and abnormal atrioventricular and outflow valve formation in 90% of embryos.

3,3',5,5'-tetrabromobisphenol A24596333Yang, 2015in vivoZebrafish0.05, 0.1, 0.5, 1 mg/L96h

Malformation, blood flow disorders, pericardial effusion, and spawn coagulation rates increased, survival decreased significantly after exposure to 0.5 and 1.0 mg. Induced ROS production dose-dependently. Cardiomyocyte apoptosis and induced expression of P53, Bax, and Caspase9. Bcl2 was down-regulated.

4-Fluoroamphetamine31526813Zwartsen, 2019in vitrohiPSC-CMs0.01, 0.1, 1, 10, 100, 300, 1000 μM2-30 min, 24h

Decreased the spike amplitude at 100 μM. Decreased beat rate at 300 µM. Prolonged FPDc concentration-dependently. No sig. effect on cell viability.

5-fluorouracil25034007Eskandari, 2014in vitroARVMs15 µM1-3h

Reduced cell viability (65-75% of control), and 2-fold increase in ROS formation after 3h at 15 µM. Sig. reduced GSH/GSSG. Induced mitochondrial membrane potential (MMP) collapse. Sig. increase in caspase 3 activity.

5-fluorouracil30634681Oliveira, 2019in vitroH9c20.13 - 5 µM24h, 48h

Reduced cell viability at 48h: 5 µM (89.52 ± 5.38%), 2.5 µM (91.69 ± 5.43%), 1 µM (95.00 ± 6.51%) and 0.5 μM (93.89 ± 5.19%) compared to control (100%).

5-fluorouracil30862114Mendes, 2019in vitroH9c250 µM48h

Reduced cell viability, both in MTT assay (93.7 ± 4.4%) and in NR uptake assay (86.6 ± 5.4%) compared to control (100%).

5-fluorouracil24704391Lamberti, 2014in vitroH9c2400 µM72h

Reduced cell viability to 50%. Increased Tbars and NO2- levels.

5-fluorouracil25671635Focaccetti, 2015in vitroHCMs10 nM to 1mM96h

10 μM or higher concentrations exerted cytostatic effects, lower concentrations of 5-FU did not influence cell proliferation significantly. >1 μM significantly compromised cell membrane integrity. dose- and time-dependent generation of ROS in low doses (<10 µM). Dose dependent statistically significant increase in the percentage of senescent cells compared to control.

5-fluorouracil1580574Millart, 1992in and ex vivoRat perfused heart1 mg/L for 80 minutes. 50 mg/kg.80 mins (perf.) or 5 days

No differences in contractility. Consistent increase in oxygen consumption associated with a decrease in the fractional extraction of oxygen. Pretreatment of rats led to decrease in inotropism. Mean coronary flow was consistently increased, CK Leakage did not differ.

5-fluorouracil35101590Li, 2022in vivoMice15, 30, 60 mg/kg7 days

5-FU-induced cardiotoxicity was related with iron transport, oxidative stress and ferritinophagy in vivo: Impaired LV function with decrease of EF, FS, CO. LVID and LVAW was increased. Increased LDH and CK blood levels. MDA levels (lipid peroxidation) were 8-22 fold higher. Increased Fe2+ and decreased GSH. Lower GPX4 expression. Smaller, crumpled and broken mitochondria. Protein level of Nrf2, NQO1 and GPX4 was downregulated while the protein levels of p53 were upregulated. Decreased expression of LC3.

5-fluorouracil35101590Li, 2022in vitroH9c22.5, 5, 10 µM48h

Reduced cell viability under 50% at doses >5 µM. Increased Fe2+ levels. Increased ROS levels. Reduced mito activity. Protein expression levels of Nrf2, NQO1, LC3, GPX4 were inhibited, p53 and TfR were elevated.

Aconitine30233701Zhang, 2018in vitrohiPSC-CMs0.125, 0.25, 0.5, 1, 2, 4, 8 µM2h, 6h, 24h

Reduced cell viability (% of control): 2h: ±90% at 8 µM. 6h: ±70% at 8 µM. 24h: ±70% at 0.25 µM, ±30% at 4 µM. Increased beating rate within 30 min: 3.7-fold at 0.25 µM, 7.3-fold at 3.0 µM. Increased caspase-3 and 9

Aconitine30410440Ma, 2018in vitroH9c20.01 - 50 μM24h

Reduced cell viability dose dependent (IC50 32 µM). Sig. increase of the MDA level at 10 µM, increased ROS, LC3-II, Beclin-1-mRNA, cleaved caspase-3, and [Ca2+]i. Decreased ΔΨ causing membrane depolarization. Increased mRNA expression levels of DHPR, SCN5A and RyR2.

Aconitine31657084Peng, 2020in vitroH9c20 - 100 µM12, 24, 36, 48, 72, 96h

Reduced cell viability and increased ROS at 1 µM (24h). Increased TNFα, FADD, and cytochrome C and the cleavage of caspase-3 and -8. Decreased Bcl-2. Stimulation of RIPK and NLRP3, caspase 1 and IL-1B cleavage.

Aconitine31975431Li, 2020in vivoZebrafish2, 8 µM12, 24, 36, 48h

Sig. decreased heart rate at low dose, inhibition of contraction. Bioinformatics relates cardiotoxicity to regulation of Ca2+ signals and the p38 mitogen-activated protein kinase (MAPK) signalling pathway. 8 μm sig. increased the expression levels of cacna1c, RYR2, ATP2a2b, p38, caspase 3, Bax, and TnC at 12h, but decreased at 36 and 48h.

Aconitine31975431Li, 2020in vitroH9c21.5, 4.5 mM30m

[Ca2+]i oscillation. Decreased expression levels of TnT and Bcl-2, increased caspase 3 and Bax dose dependently.

Aconitine34369901Zhao, 2021in vitroH9c20 - 100 µM24h

Reduced cell viability (% of control): ± 90% at 5uM, ±80% at 10 µM, dose dependent decrease. Increased LDH release, CK-MB levels, and AST activity. Increased production of NO. Increased ROS and [Ca2+]i. Upregulated Bax and Cleaved-caspase-3 and downregulated expression of Bcl-2. SOD, Na+/K+-ATPase, and Ca2+-ATPase levels were significantly decreased (P < 0.01) and MDA production was markedly increased.

Aconitine24840785Sun, 2014in vivoRats1,46 mg/kg/day for 10 days3 or 6 days after last dose

Ventricular tc and premature beats. Severe myocardial damage. RyR and NCX protein levels increased. SERCA decreased. upregulated P53, BAX, caspase-9, and caspase-3, downregulated BCL-2. Ca2+ overload through activation of L-type Ca2+ channels, causing arrhythmia. Apoptotic development via activation of P38 MAPK.

Aconitine24840785Sun, 2014in vitroARVMs1 µM0 - 7 min

Normal rhythm and diastolic function of ARVMs were disrupted by aconitine in 7 min in a time-dependent manner. Increased resting Ca2 + ratio, amplitude of Ca2 + ratio and amplitude/resting calcium in 4 min after 1 μM

Aconitine24840785Sun, 2014in vitroNRVMs0.01, 0.04, 0.16, and 0.64 μM10h

Reduced cell viability (% of control): 4 ± 3.76%, 87 ± 2.21%, 79 ± 2.43%, and 71 ± 5.64% with 0.01, 0.04, 0.16, and 0.64 μM aconitine, respectively. LDH levels increased to 422.98 ± 31.76, 485.39 ± 52.60, 539.06 ± 27.27, and 624.93 ± 14.31 U/L with 0.01, 0.04, 0.16, and 0.64 μM aconitine, respectively. CK content 2-fold increase, AST 1.4 fold.

Aconitine18779382Wang, 2008in vitroH9c21, 3, 10 µM0-15 s

Dose dependent inhibition of IKur.

Aconitine34520828Wang, 2022in vitroH9c23.125–400 μM24h

Reduced cell viability, sig. => 50 µM (% of control): ±90% at 50 µM, ±50% at 400 µM. Dose dependent release of LDH. Autophagosome activation. increased ROS. Aconitine induces autophagy by activating AMPK/ULK1 signalling pathway.

Amitriptyline32219715Aygun, 2020in vivoRats100 mg/kgsingle dose

Sig. increased heartbeat, QRS Complex duration, T wave duration, QT interval duration, and elevated ST segment amplitude. 457% increase in cardiac damaged tissue, 303% plasma cTnT level compared to control

Amitriptyline18845675Chopra, 2009in vitroMouse VCMs0 - 300 µM0 - 2h

AMT increased the rate of spontaneous Ca2+ releases and decreased the SR Ca2+ content. Intracellular [AMT] were approximately 5-fold higher than extracellular [AMT]. Activation of RyR2 channels and increased SR Ca2+ leak may contribute to AMT's proarrhythmic and cardiotoxic effects

Amitriptyline29239964Tsujikawa, 2018in vivoGuinea pigs15 mg/kg15 min

Depression of mean arterial pressure (mean difference 19 mmHg) and prolongation of QRS duration (-12 ms).

Amitriptyline27994924Hocaoglu, 2016ex vivoRat perfused heart55 µM1h

The amitriptyline infusion significantly decreased LVDP, dp/dtmax and heart rate (HR) and significantly prolonged QRS duration.

Amphetamine31526813Zwartsen, 2019in vitrohiPSC-CMs0.01, 0.1, 1, 10, 100, 300, 1000 μM2-30 min, 24h

Decreased spike amplitude at 100 μM. Decreased beat rate at 300 µM. Prolonged FPDc concentration-dependently. No sig. effect on cell viability.

Amsacrine3838387Kim, 1985in vivoRats3 - 12 mg/m2Weekly, 13 weeks

Elevations of total serum creatine phosphokinase, creatine phosphokinase-MB fraction, aspartate aminotransferase, and lactate dehydrogenase levels at 12 mg/m2, suggesting myocardial damage; however, there was no associated pathologic evidence of cardiotoxicity.

Amsacrine3839172Merkin, 1985ex vivoRat perfused heart1.5 - 2.5 µg/mLPerfusion

Acute moderate negative inotropic effect. 90% effect (25% decrease in developed force compared to the control) was observed at drug concentration of 1.5 μg/ml. The refractory period (as measured by stimuli of twice diastolic threshold intensity) increased progressively as the drug concentration was increased (up to 2.5 μg/ml).

Arsenic trioxide23161055Vineetha, 2013in vitroH9c25, 7.5 and 10 μMAnalysis 48h after single dose

Reduction in cell viability: 10% at 5 µM, 23% at 7.5 µM, 35% at 10 µM reduction compared to controls.

Arsenic trioxide34037972Vineetha, 2021in vitroH9c25 µMAnalysis 24h after single dose

ATO caused Ca2+ overload resulting in elevated expression of calcineurin and its downstream transcriptional effector NFATc causing the release of cytokines such as IL-2, IL-6, MCP-1, IFN-γ, and TNF-α

Arsenic trioxide29867492Zhang, 2021in vitroH9c22.5, 5, 10 μM24h

Mitochondrial dysfunction: mito structural damage, abnormal mPTP opening, increased ROS production, decreased ATP content.

Arsenic trioxide26815588Khoei, 2016in vitroH9c20.5, 1, 2 µM24h, 48h, 72h

Reduced cell viability compared to control (MTT-assay). 0.5uM: 80% at 24h, 70% at 48h, 60% at 72h. 1uM: 70% at 24h, 60% at 48h, 50% at 72h. 2uM: 50% at 24h, 45% at 48h, 40% at 72h. ROS generation increase up to 150% at 2uM. DNA synthesis reduced to 20% compared to control at 2uM. Caspase-3 150% at 2uM. Sig increase in apoptosis markers BAX and PUMA at 2uM. Sig decrease in NF-kB (70%) at 2 µM.

Arsenic trioxide30717322Wang, 2019in vitroARVMs100 µM20 minutes

Sig. increased sarcomere-shortening amplitude, ±dL/dt, TR90 and TPS, severely impaired cardiomyocyte contractile function, increase in resting Ca2+ ratio, Ca2+ transient amplitudes, ±d [Ca2+]/dtmax, the time to 50% peak [Ca2+]i, and the [Ca2+]i transient decay rate, reduced SERCA, SERCA2a and PLB activity compared to controls.

Arsenic trioxide26886836Varghese, 2017in vitroH9c210 µM24h

Reduced cell viability (MTT, 80% ), increased LDH release (160%), sig. increased lipid peroxidation and cellular Ca2+ levels. Sig. Alterations in ∆Ψm (JC-1 staining).

Arsenic trioxide28092839Yu, 2017in vitroH9c24 µM24h

Reduced cell viability (MTT, 79%), cell injury deteriorated at ATO dosing >4 µM. At 4 µM, reduction in the activities of SOD, CAT, and GSH-Px, therefore induction of oxidative stress. Sig. increase in caspase 3, 8 and 9. Sig. reduction in the Bcl-2/Bax protein ratio. Sig. reduction in p-Akt/Akt ratio.

Arsenic trioxide18346055Zhao, 2008in vitroH9c22 - 10 µM24h

Reduced cell viability (MTT, 70% at 10 µM), increased LDH release (only sig. at 10 µM). 10 µM dosing induced necrosis, lower doses did not. Dose dependent increase in ROS levels and [Ca2+]i.

Arsenic trioxide30090381Zhang, 2016in vitroARVMs25, 50, 100 µM0 - 20 min

Abnormal cardiomyocyte contraction in a dose-dependent and time-dependent manner. Increased amplitude of sarcomere shortening, -dL/dtmax and +dL/dtmax, TR90, and time-to-peak shortening. Intracellular imbalance of calcium homeostasis. Inhibition of SERCA2a, activation of ER stress.

Arsenic trioxide29297235Vineetha, 2018in vitroH9c210 µM48h

Sig. reduction in total antioxidant capacity, increased [Ca2+]i, reduction in MMP, increased ROS production. Decrease in Nrf2 and Bcl2 gene expression.

Arsenic trioxide32096187Chen, 2020in vitroH9c210 µM24h, 48h, 72h

Sig. reduced cell viability in time dependent manner.

Arsenic trioxide28391263Zhang, 2017in vitroH9c22.5, 5, 10, 20, and 40 µM24h

Reduced cell viability to 70% at 2.5 µM, 57.92% ± 2.86% at 10 µM, 30% at 40 µM. Sig. increased LDH at 10 µM. Sig. decreased ΔΨm at 10 µM. Decreased SOD, CAT, and GSH-Px activities at 10 µM. Up-regulated caspase-3 and caspase-9 expression levels, decreased Bcl-2 protein expression and increased Bax protein expression. Cyt-c release.

Arsenic trioxide23201927Wang, 2013in vitroH9c22, 4, 6, 8, and 10 μM24h

Reduced cell viability in concentration dependent manner to 38.92 ± 0.36% at 10 µM. Sig increased LDH, PI staining (necrosis), caspase-3 activity (200% at 10 µM), and ROS levels (250% at 10 µM compared to control levels). Downregulation of Bcl-2 and Bcl-xl, upregulation of Bax.

Arsenic trioxide19203718Raghu, 2009in vitroRat CMs (freshly isolated)30, 60 and 90 µM24h, 48h, 72h

ATO exposure caused alteration in mitochondrial integrity, generation of ROS, calcium overload and apoptosis in cardiac cells in dose- and duration-dependent manner.

Arsenic trioxide28094846Kopljar, 2017in vitrohiPSC-CMs1, 3, 10 µM4h, 12h, 24h, 48h, 72h

Significantly decreased beat area, beat rate and contraction velocity (starting from 4 to 12 h) at a concentration of 10 μM. At 3 μM, there was a trend towards a decreased CV at 72h. Modest increase in FABP3 at 72 h, accompanied by a decrease in NT-proBNP

Arsenic trioxide16597375Saad, 2006in vivoRats5 mg/kg/day10 days

Sig. increases in serum CK-MB, GPx, LDH and AST. Reduced GSH content, increased MDA and total NOx.

Atropine29123207Perera, 2017in vitroMouse VCMs10 nm0-1s

Positive inotropic and chronotropic effects. 10 nM potentiated the β-AR-induced cAMP response. Inhibition of cAMP-specific phosphodiesterase PDE4, leading to increased [cAMP]i, leading to elevated heart rate and increased contractility.

Azidothymidine33161113Zhao, 2020in vitroNRVMs50 µM0, 6, 12, 24, 36h

Reduced cell viability (to 0.8 at 36h) and MMP in time dependent manner. Increased Cle-casp-3, cyt-c, apaf-1. Decreased p-bad, bcl-2.

Azidothymidine21461578Gao, 2011in vitroHCMs1, 3, 10, 30, 100 µM48h

Cell apoptosis and necrosis in a dose-dependent manner. Elevation of caspase-3 and -7 activity, PARP activity. Sig. increased ROS.

Azidothymidine9895221Szabados, 1999in vivoRats50 mg/kg/day, 2 weeks3 days - 6 months

RR, PR and QT intervals prolonged sig. after 1 wk. Mitochondrial structure distortion. Increased ROS formation (235% - 328%) in heart muscle tissue, significant (2.56-fold) increase in TBA, increased carbonyl content. Activation of PARP, decrease in NAD+. Free ATP/ADP decreased 4-fold.

Azidothymidine1715447Lewis, 1991ex vivoRat perfused heart0.2 to 1.0 mg/mL; 29 to 102 mg/kg/day21, 35, or 49 days

Marked and widespread cardiac mitochondrial swelling with fractured and disrupted cristae after 35 days of 1 mg/ml. Mitochondrial cytochrome b mRNA expression was depressed.

Berberine29233041Zhang, 2018in vitroNRCMs0.03 - 10 µM24h

Beating rate and amplitude were totally inhibited at 10 µM. Irregular beating occurred at 0.3, 1.0, and 3.0 μM (1.5h).

Beta-naphtoflavone19969063Zordoky, 2010in vitroH9c210, 20, 30, 50 µM48h

No decrease in cell viability up to 10 µM. 20 - 50 µM decreased cell viability in dose dependent manner. Significant induction of the hypertrophic marker ANP by 2-fold and BNP by 4-fold. Sig. induction of CYP1A1, CYP1B1, CYP2E1 and CYP2J3

Bisphenol A32144343Reventun, 2020in vivoMice0-50 mg/kg per day4, 8, 16 weeks

Increased BP, HR, sig. prolonged QT interval and PR segment suggesting first degree AV block. Sig. impairment of contractility (decreased EF and FS). IVSd increased, cardiac hypertrophy. Hearts sig. enlarged. Perivascular fibrosis sig. increased after 8 weeks. Sig. increased TNF-a, CCL-2, -7, -12. Cardiac interstitial edema with sig. disarranged myocardial fibers, increased vascular permeability and leakage. Increased RIP 3 (necroptosis). Increased CamKII phosphorylation.

Bisphenol A32144343Reventun, 2020in vitroMAECs, H9c20 -100 µM24, 48, 72h

No effect on H9c2 cells. Reduced cell viability in MAECs time and dose dependently, increased RIP 3, leading to necroptosis in aortic endothelial cells.

Bisphenol A34419494Hyun, 2021in vitrohiPSC-CMs0 - 100 µM24h

No sig. effect on cell viability or LDH. Sig. decrease in amplitude and field potential duration (±70% of control) at 30 µM. Decreased APA, dV/dtmax, APD50, and APD90 in a dose-dependent manner, suggesting effects on Na, Ca and K channels. Dose-dependent reduction of calcium transient frequency, intracellular calcium peak, beating rate, and amplitude of cardiac contraction.

Bisphenol A33986332Kofron, 2021in vitro3D cardiac microtissue1, 10, 100, 1000 nM20 minutes

Sig. increase in APD metrics at 1 nM, but shortened APD metrics at higher concentrations.

Bisphenol A31830493Cheng, 2020in vitrohESC-CMs1000, 200, 8 ng/mL72h

No effect on cell viability. Proliferation of cells was sig. enhanced. At 8 ng: sig. increased relative mitochondria number and cell area, sig. decreased mitochondrial area and ATP production, sig. reduction in MMP. Increased mitochondrial length and cells with fragmented mitochondria. Increased [Ca2+]c.

Bisphenol A25572651Jiang, 2015in vivoRats50 µg/kg per day24 and 48 weeks

Myocardial hypertrophy, cardiomyocyte enlargement, impairment of cardiac function at 48w. Sig. reduced ATP production, dissipated MMP, declined mitochondrial respiratory complex activity at 24w. Decreased mitochondrial function, followed by cardiomyopathy. Decreased expression and hypermethylation of PGC-1a in heart tissue.

Bisphenol A24140712Gao, 2013in vitroARVMs1 nM5 min

Increased spontaneous excitation after repeated pacing. Increased frequency of Ca2+ sparks, spontaneous release of Ca2+ from the SR through RyRs. Increased contractility. Functional analysis showed that PKA but not CAMKII activation contributed to sarcoplasmic reticulum Ca2+ leak.

Bisphenol A31713131Amin, 2019in vivoRats30 mg/kg per day4 weeks

Sig. increase in mean values of serum copeptin level, histopathological changes in the form of dilated congested blood vessels and extensive collagen fiber deposition in the myocardium. Sig. increased TLR2 immunoreactions and DNA damage.

Bisphenol A31126002Lombo, 2019in vivoZebrafish2000 and 4000 μg/L24h

30% of exposed embryo displayed cardiac malformations. Overexpression of hand2, a crucial factor for cardiomyocyte differentiation, increased the expression of oestrogen receptor (esr2b), promoted an overexpression of a histone acetyltransferase (kat6a) and also caused an increase in histone acetylation, both mechanisms being able to act in synergy.

Bisphenol AF32408210Gu, 2020in vitroHCMs0.02, 0.2, 2, 20, 100, 200 mg/L24h

Sig. reduced cell viability at 20 mg and above. Sig. decrease in CAT and SOD activity accompanied by an increase in MDA levels. Sig. increased [ROS]i. Elevation in apoptosis rate. Sig. decreased MMP.

Bisphenol AF31981723Yang, 2020in vitrohESC-CMs0, 8, 200 and 1000 ng/mL48h

Cardiomyocyte hypertrophy due to increased production of reactive nitrogen species (RNS) via increased endothelial NO synthase (eNOS). Upregulation of mRNA levels of MYH7, Gata4, Mef2c, PLCB1, IP3R, and CAM.

Bisphenol F34023961Cheng, 2022in vitrohESC-CMs7 (35 nM), 140, 700, 140, 2800, and 5600 ng/mL48h

Increased [Ca2+]c, which was most noticeable at low dose (35 nM) rather than at higher doses. At 35 nM, altered morphological parameters of mitochondria and sig. decreases in ATP production, representing CM hypertrophy. Enhanced calcineurin (Cn) activity and induced abnormal mitochondrial fission via the CnAβ-DRP1 signalling pathway. Excessive Ca2+ influx by disrupted L-type Ca2+ channel.

Bortezomib20519734Nowis, 2010in vivoRats0.2mg/kg3 times/week for 1 to 3 weeks

Left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction

Bortezomib20519734Nowis, 2010in vitroH9c22.5, 5, 10, 20, 40 nM24h

Reduced cell viability in a time- and dose-dependent manner observed at 5 - 10 nM concentrations.

Cadmium (Cd2+)34255886Haverinen, 2021in vitroRainbow trout CMs10, 20, and 100 µM5 min

Altered ventricular APs in complex manner. Shortened ADP10, prolonged ADP50 and ADP90. Cd2+ reduced the density and slowed the kinetics of the Na+ current (INa) but left the inward rectifier K+ current (IK1) intact. Strong Cd2+-induced inhibition of the L-type calcium (Ca2+) current (ICaL).

Cadmium chloride29993192Shen, 2018in vitrohESC-CMs0.1 - 100 µM24h

Sig. reduced cell viability in dose dependent manner to ±50% at 100 µM. Sig. increased caspase-3 activity and ROS levels at 30 µM, increased apoptosis, cardiac sarcomeric disorganization, altered action potential profile and cardiac arrhythmias. Activated MAPK signalling pathway, suppression of P38 MAPK.

Cadmium chloride33581611Zhao, 2021in vivoSwine20 mg/kg diet40 days

Myocardial conc. of CdCl2 was 0.147±0.011 mg/kg, 8.6-fold higher than control group. Apoptotic cells increased up to 4.1 fold. Activation of AHR, CAR and PXR, contributing to production of ROS. Restrained antioxidant capacity, causing oxidative stress. MAPK pathway including JNK, ERK and p38 was activated, triggering mitochondrial pathway apoptosis in myocardium.

Cadmium chloride33626375Zhao, 2021in vivoSwine20 mg/kg diet40 days

Necrotic cell death and ion homeostasis imbalance in swine myocardium. Increased LXA4 content, inhibition of FPR2 expression, activated TGF-β pathway and suppressed Nrf2 pathway. Activation of the NF-κB pathway. Increased expressions of necroptosis related-genes TNF-α, TNFR1, RIP1, RIP3 and MLKL.

Cadmium chloride26182376Chen, 2015in vitroARVMs1 and 100 µM4 or 12h

Increased mRNA levels of Grp78, Atf4 and Atf6 leading to dramatic endoplasmic reticulum (ER) stress and impaired energy homoeostasis. Inhibition of protein kinase B (AKT)/mTOR pathway.

Cadmium chloride26462792Nazimabashir, 2015in vivoRats5 mg/kg per day4 weeks

Sig. Increased cTnT & I, CK-MB, AST, ALT, ALP, and plasma TC, TG, PL and FFA. Increased oxidative stress, impaired mito function. TNF-α, NO, IL-6 and NF-κB subunit were increased sig. Expression of cytochrome C, caspase-3 were sig. Upregulated. Decreased Bcl-2 with increased Bax. Sig. decreased Nrf2. Degeneration and disruption of cardiac myofibers, wide cardiac fibrils spaces, cardiac inflammation and necrosis. Swelling of heart mitochondria with loss of cristae, irregular shape and sizes, vacuolization.

Cadmium chloride9882592Limaye, 1999in vitroNRCMs0.05 - 1 µM0 - 60 min

Reduced cell viability sig. at 0.1 µM, beating stopped at 0.5 µM.

Carbachol19159405Hussain, 2009in vivo/ vitroRat cardiac muscle10 µMUnclear

Carbachol (10 µM) evoked a positive inotropic response only in muscles from rats with heart failure (not in healthy rat muscle)

Carbachol2790382Jakob, 1989in vitrohuman atrial heart muscle10 µM30 min

Carbachol evoked transient decreases of action potential duration and force of contraction in atrial heart tissue

Chrysene17112560Incardona, 2006in vivoZebrafish22 µMExp. between 6 and 72 hpf

Strong CYP1A induction (22-fold increase of mRNA), but no biological effects.

Cocaine33668403Verma, 2021in vitroH9c20.1 - 10, 50, 100 µg/mL72h

Reduced cell viability dose dependent. Increased ERK1-p44 and ERK2-p42 in first 24h. Dynamic remodelling of cytoskeleton, with changes in key cytoskeletal proteins (ERM,VASP) involved in mediating direct actin and plasma membrane/actin interactions.

Cocaine18952886Fan, 2009in vivoMice15, 20, 25, 30 mg/kg, 3/day14 days, 30 min after last injection

Sig. increased phosphorylated ERK1/2, p38 MAPK, and JNK (2.5-fold), increased p47phox (3.2-fold), Nox2 (2.34-fold). Sig. increased levels of ROS.

Cocaine18952886Fan, 2009in vitroH9c20-100 µM24h

Increased ROS production (5 µM 1.8-fold, 25uM 3-fold). Increased Nox2. Severe myocyte damage and cell death. Sig. increased ERK1/2 and p47phox.

Cocaine12808488Henning, 2003in vitroARVMs0.1 - 10 µM72h

1 µM increased myocyte protein content by 28±2%, caused a 45% increase in PKC ratio change.

Cocaine16891908Henning, 2006in vitroARVMs0.1 - 10 µM1, 10, 30, 60, 240, 480, or 1440 minutes

Translocation of CaMKII from cardiomyocyte soluble to particulate fractions (1 µM, 240 min). Increased total CM protein content by 29.2±3% at 5 µM, 20.5±3% at 1 µM. Increased B-MHC expression by 93% at 5 and 63% at 1 µM. Potentiation of peak calcium current. Increased [Ca2+]i 6-fold at highest dose.

Cocaine16382175Lattanzio, 2005in vitroH9c20.1 - 10 mM2-5 mins

Sig. Increased ROS production, MMP depolarization, [Ca2+]i increase.

Cocaine16382175Lattanzio, 2005in vivoRabbits2mg/kg30m

At 1 min after cocaine, the +MAX dP/dt had decreased, an indication of an impairment in the rate of contraction. At 5 min the MAX dP/dt had decreased, an indication of a reduction in the rate of relaxation.

Cocaine8792843Yuan, 1996in vitroNRCMs10^-5 - 10^-3 M3 - 72h

Dose and time dependent increase in LDH leakage, decrease in ATP, reduced MMP.

Cocaine8792843Yuan, 2000in vitroNRCMs10^-5 - 10^-3 M6, 12, 24h

Dose and time dependent increase in LDH leakage. Sig. decreased the mitochondrial respiratory control ratio at highest dose.

Cocaine9455993Besse, 1997in vivoRats40 mg/kg per day30m, 1, 2, 4h, 14-28 days

Left ventricular hypertrophy after 28d, 20% increase in the left to right ventricular weight ratio. T3 and T4 sig. decreased. Atrial natriuretic factor (ANF) increased, also in ventricular tissue.

Cocaine1566279Welder, 1992in vitroARCMs10^-9 - 10^-3 M1, 4, 24h

Morphological alterations included vacuolization, granulation and pseudopodia formation at 1h to highest doses. For all time points, the two highest doses sig. depressed contractility and induced LDH release.

Cocaine20702336Welder, 1988in vitroNRCMs10^-7 - 10^-3 M24h

Decrease in beating activity at 1h for highest doses 10^-5 -10^-3 M. Similar results were obtained at 24h. Morphological alterations at 10^-3 M. Vacuoles at 1h were replaced by dark granules within 24h. LDH release was sig. elevated at 10^-3 M for 24h.

Cocaine8776273Bai, 1996in vitroRat VCMs50, 100, 150 µM0 - 90 sec

Sig. decreased peak intracellular Ca2+ and cell-contraction rate in a dose-dependent manner. The K0.5 for the reduction of peak intracellular Ca2+ was 157.5 μM (calc.).

Cocaine31526813Zwartsen, 2019in vitrohiPSC-CMs0.01, 0.1, 1, 10, 30, 100 μM2-30 min, 24h

≥10 μM: beat rate and spike amplitude decreased by 44% and 51%, respectively, and the FPD(c) was prolonged ≥2-fold. ≥30 μM: quiescence, resulting in loss of signal from electrodes. No sig. effect on cell viability.

Cresyl diphenyl phosphate (CDP)25661707Du, 2015in vivoZebrafish0.10, 0.50, 1.0 mg/L72 hpf

Sig. Reduced heart rate at 0.1 mg. Pericardium edema and SV-BA distance extension, decreased number of cardiac muscle cells and thinner walls of ventricle and atrium at 0.1 mg. Disturbed expressions of transcriptional regulators, especially downregulation of BMP4, NKX2-5 and TBX5.

Daunorubicin26279420Wu, 2015in vitroH9c21 µM24h

Reduced cell viability (70.9 ± 2.6%) at 1 µM compared to control. Cell shrinkage, rounding, membrane blebbing. Degradation of cTnl and B-Tubulin. Increase in Annexin V from 3 to 21% vs control. Caspase-3 increase. Disturbance of MMP leading to cyt-c release and subsequent caspase-3 and 9 activation. Activation of ERKs (ratio of P-ERK to ERK was increased by 248%). Increases in phosphorylated ERK1/2, p53, and Bax protein content and decreased Bcl-2.

Daunorubicin21046361Vavrova, 2011in vivoRabbits3mg/kgWeekly, 10 weeks

Heart failure evident from decreased left ventricular ejection fraction and release of cardiac troponins to circulation. GPx activity in cardiac tissue sig. increased.

Daunorubicin21046361Vavrova, 2011in vitroH9c20.1 - 10 µM24h

Significant dose dependent toxicity. TC50: 0.48 µM. Loss of MMP (ΔΨm, JC-1 staining) at 1 µM. Decrease in GSH (40%) at 1 µM.

Daunorubicin17587482Adamcova, 2007in vitroNRVMs0.1 - 3 µM72h

Reduced cell viability (IC50 0.55 µM). Significant increase in LDH, cTnT and cTnI

Daunorubicin17587482Adamcova, 2007in vivoRabbits3mg/kgWeekly, 10 weeks

Reduced left ventricular fractional shortening (FS). Sig. increase in cardiac troponin cTnT and cTnI

Daunorubicin16444662Mojzisova, 2006in vitroRat CMs (freshly isolated)40 µg/mL24h, 48h

Reduced cell viability (38.6 ± 8.1% at 24h and 9.7 ± 4.1% at 48h). Increased LDH enzyme activity by 2-fold compared to control.

Daunorubicin18803248Mojzisova, 2009in vitroH9c240 µg/mL24h, 48h

Reduced cell viability (36.8 ± 7.3% at 24h and 19.8 ± 5.8% at 48h). Decreased Annexin V− (intact cell marker, 54.2 ± 7.4% compared to 98% in control cells). Increased Annexin V+ (early apoptosis marker, 45.4 ± 6.1% compared to 2.9 ± 0.5% in control cells).

Daunorubicin8808986Cusack, 1996in vitroAdult and old rat CMs (freshly isolated)175 µM210 min

Daunorubicin-induced decline in contractility (DS and dS/dt) was greater in old (24 - 28 months) compared to adult (6-9 months) myocardium (p < .02). Similarly, cardiac relaxation (90% relaxation time) was more impaired by daunorubicin in older preparations (p < 01).

Daunorubicin29039532Li, 2017in vitroH9c21 µM24h

Reduced cell viability (MTT, ±50%). Sig. decrease in p-Akt/Akt ratio. Sig. increase in cleaved caspase-3/caspase-3 ratio. Sig. increase in [Ca2+]i.

Daunorubicin35596909Cejas, 2022in vitrohiPSC-CMs5 µM14h

Reduced cell viability (down to 30.41 ± 19.73%).

Decabrominated diphenyl ether30802833Jing, 2019in vivoRats5, 50 and 500 mg/kg per day28 days

congestion of intermuscular capillaries. At 500mg: severe fiber disruption with focal haemorrhagic areas between the muscle bundles, and nuclear condensation or dissolution and myocyte swelling. Sig. increased CK and LDH at 50 mg. Dose-dependent increase of ET-1 level. Increased TNF-a, IL-1B, IL-6, SOD, GSH-Px, MDA.

Decabromodiphenyl ethane30802833Jing, 2019in vivoRats5, 50 and 500 mg/kg per day28 days

No histological changes up to 50 mg. At 500 mg: congestion of intermuscular capillaries with mild disruption. No alteration of CK activity, sig. Increased LDH at 500 mg. Dose-dependent increase of ET-1 level. Increased TNF-a, IL-1B, IL-6, SOD, GSH-Px, MDA.

Di(2-ethylhexyl)phthalate 22672789Posnack, 2012in vitroNRCMs50-100 μg/mL72h

Metabolic remodelling: upregulation of genes associated with fatty acid transport, esterification, mitochondrial import, and β-oxidation. Increased myocyte fatty acid-substrate utilization, oxygen consumption, mitochondrial mass, PPARα protein expression, and extracellular acidosis.

Di(2-ethylhexyl)phthalate 29377175Tang, 2018in vivoPregnant mice250, 500, 1000 mg/kg per dayE6.5 to E14.5

Increased fetal cardiac development malformations (septal defects, ventricular myocardium noncompaction and cardiac hypoplasia) resulting from the inhibition of cardiac GATA4/Mef2c/Chf1 expression via PPARγ activation.

Dieldrin28385952Slade, 2017in vivoZebrafish0.03, 0.15 or 1.8 µg/g feed21d

Activation of Akt/mTOR signalling and downregulation of lysosomal genes, participating in autophagy. Transcriptomics: fos and jun (cell proliferation regulators) were sig. dysregulated. Ace was increased 2-fold, oxytocin decreased 2-fold. Kcnj11l and kcnh2a increased. Increased IL-6, TNF-A. Decreased NF-kB, Ras.

Doxorubicin28300219Zhao, 2017in vitrohiPSC-CMs1 nm - 100 µM48h

Reduced cell viability (IC50 3.5 µM). Increased caspase-3 and DNA fragmentation. Release of cTnI. Dose-dependent increase in TNFR1, Fas, DR4, and DR5 at 450 nM. Increased caspase-3, 8 and FADD. TNF-related apoptosis inducing ligand (TRAIL) increase. Decrease in beating rate and amplitude.

Doxorubicin26537877Chaudhari, 2016in vitrohiPSC-CMs156 nm48h, 144h

Reduced cell viability at 144h (±80%) but not at 48h indicating time dependent effect. Repeated doxorubicin exposure (144h) resulted in long-term arrhythmic beating in hiPSC-CMs. 84 genes related to cardiac functions, stress and apoptosis were deregulated sig.

Doxorubicin21590773Budde, 2011in vivoMice20 mg/kg single dose i.p.1, 3 and 5 days after injection

impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points. enhancement in P-gp protein expression levels of 180 ± 18% in doxorubicin-treated mice. significant upregulation of abcb1a (162 ± 15% of control) and abcb1b (418 ± 110% of control) mRNA transcripts after 3 days

Doxorubicin21590773Budde, 2011in vitroHL-110 - 1000 nM24h, 48h

doxorubicin concentrations up to 333 nmol/L did not significantly alter the viability of adherent HL-1 cells.

Doxorubicin34775319He, 2021in vitroNRCMs, H9c21 µM48h

Reduced cell viability to 40% for NRCMs and H9c2. Sig. Increase in LDH (±10-fold compared to control). iron content of the Dox-treated group was significantly increased. PTGS2 expression was significantly increased, while GPX4 expression was decreased. mitochondria in Dox-treated NRCMs were severely distorted, with decreased cristae. expression of LC3/P62 slightly increased/decreased in NRCMs and H9C2 cells.

Doxorubicin29133306Gupta, 2018in vitrohiPSC-CMs0.1 µM72h

Qki deletion in cardiomyocytes increased their sensitivity to doxorubicin, whereas overexpression inhibited doxorubicin-induced apoptosis. Mechanistically, Qki inhibits doxorubicin-mediated cardiotoxicity via regulating cardiac circular RNAs.

Doxorubicin34525346Magdy, 2021in vitrohiPSC-CMs0.01 - 100 µM72h

SNP (rs2229774) in retinoic acid receptor-γ (RARG) is statistically associated with increased risk of anthracycline-induced cardiotoxicity. The hiPSC-CMs from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. The mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway.

Doxorubicin34207549Adamczyk, 2021in vitroH9c2, hiPSC-CMs5, 10 µM90 min

Reduced cell viability (% of control): [H9c2: ±85% at 5uM, ±80% at 10 µM] [hiPSC-CMs: ±75% at 5 µM, ±65% at 10 µM]. Increased ROS production (±2-2.5 fold increase at 5-10 µM in H9c2, ±2-3 fold increase at 5-10 µM in hiPSC-CMs compared to controls). Significant increase in caspase 3/7 activity.

Doxorubicin32487993Arai, 2020in vitro3D cardiac microtissue10 µM24h, 72h

Contractile force and beating rate of the cardiac constructs were evaluated by analysing changes in the movement of the needle tip and decreased dramatically 24h following DOX addition. Contraction of the cardiac construct completely ceased at 72h after DOX treatment

Doxorubicin28421296Chaudhari, 2017in vitrohiPSC-CMs156 nM48h, 144h

Impaired mitochondrial metabolism. Single exposure to DOX (48h) did not show alteration in the basal level of extracellular metabolites while repeated exposure to DOX (144h) caused reduction in the utilization of pyruvate and acetate, accumulation of formate, increased LDH release and reduced ATP levels compared to control culture medium.

Doxorubicin31231550McSweeney, 2019in vitrohiPSC-CMs100, 500 nM. 1.5, 5 µM.48h

Dose and time dependent decrease in cellular index: 0.75 at 500 nM, 0.55 at 1.5 µM, 0.45 at 5 µM (48h) compared to control (1.0 at 48h). No change at 100 nM. Further experiments were performed at 150 µM. Over a thousand genes were significantly dysregulated after 48h, mostly downregulation of genes pertained to cell cycle progression and cell division.

Doxorubicin32075047Zhang, 2020in vitrohiPSC-CMs, AC16, H9c21 µM24h

H9c2: dose dependent decrease in cell number, nuclear area, nuclear intensity, cell area, and an increase in calcium intensity and mitochondrial intensity (log curves available, EC50/IC50 all around 1 µM). 1 µM was selected for further experiments. Annexin V-was significantly increased at 1 μM Dox for 6h in AC16. Decreased rates of beating and amplitude, sig. upregulation of pro-BNP and IL6 in hiPSC-CMs, sig. downregulation of HDAC1, GATA4, and CTnI at 1uM Doxo.

Doxorubicin31106979Cui, 2019in vitrohiPSC-CMs2.5 µM24h

Maturation decreased the cytotoxicity of DOX: day 30 hiPSC-CMs showed significantly reduced cell viability vs. day 60 group. DOX leads to more ROS in day 60 CMS due to increase in mitochondria. Higher concentration of topoisomerase IIa in day 30 CMs, which leads to more DNA damage.

Doxorubicin26842497Chaudhari, 2016in vitrohiPSC-CMs156 nM48h, 144h

DOX in a range from 39 to 156 nM did not show a significant release of the cytotoxicity marker LDH compared to controls. DOX induced early deregulation of 14 miRNAs (10 up-regulated and 4 down-regulated) and persistent up-regulation of 5 miRNAs. Genes involved in cardiac contractile function.

Doxorubicin28456566Louisse, 2017in vitrohiPSC-CMs150, 300 nM. 6, 12 µM.Various

No effects on the beating rate and FPD at 6μm. Full stop of electrical act. and beating at 12μM, no effects on mitochondrial density and superoxide. Reduced cell survival and slightly altered mitochondrial membrane potential and mitochondrial calcium levels at 150 to 300 nM. Data available in sup.

Doxorubicin32185414Karhu, 2020in vitrohiPSC-CMs100, 300 nM. 1, 3 µM.0 - 21 days

Reduced cell viability (<50%) at 1 and 3 µM, while 14-day treatment with 100 nM induced only 26% reduction in viability. Decreased DNA content. 4-day exposure to 100 nM induced a 3.1-fold increase (P < 0.001) in the percentage of cardiomyocytes positive for proBNP. 14 day exposure to 100 nM induced a 3.1-fold increase (P = 0.001) in the percentage of cells with active caspase-3/7.

Doxorubicin28967302Takeda, 2017in vitrohiPSC-CMs0.1, 1, 2, 5, 10 µM24h

Sig. increase in LDH release: 5 μM (145% ± 48%) and 10 μM (228% ± 97%). Reduced viability: 2 μM (88.4% ± 13%), 5 μM (75.3% ± 9.0%), and 10 μM (58.3% ± 10%)

Doxorubicin28094846Kopljar, 2017in vitrohiPSC-CMs1, 3, 10 µM4h, 12h, 24h, 48h, 72h

Affected beat rate, beat area, and contraction velocity at 1 μM with higher concentrations eventually leading to beating arrest. Strong increase in FABP3 and cTnI levels at each time point. Down-regulation of TNNI3, GJA1 and GJC1

Doxorubicin34536182Atum, 2022in vitrohiPSC-CMs2 µM24h

Reduced cell viability (±40%). Reduced total NO level (±50%). Increased ROS production (H2O2, ±175%). Decreased expression of UCP2 mRNA and eNOS mRNA. Increased expression of miR-24.

Doxorubicin34931757Berecz, 2022in vitrohiPSC-CMs0, 1, 3, 10 µM48h

Activation of caspase 3/7, mitochondrial depolarization, and nuclear fragmentation were increased in concentration-dependent manner. However, necrosis (TO-PRO-3) was only induced in up to 7% of hiPSC-CMs in response to 3 μM doxorubicin.

Doxorubicin30634681Oliveira, 2019in vitroH9c20.13 - 5 µM24h, 48h

Reduced cell viability at 48h (1 µM: 71.93 ± 10.49%, 2.5 µM: 68.10 ± 7.89% and 5 μM: 67.95 ± 8.01%) compared to control (100%). Significant impairment of lysosomal neutral red uptake. DOX 1 µM reduced mitochondrial membrane potential to 34.10 ± 10.48% at 48h.

Doxorubicin30862114Mendes, 2019in vitroH9c21 µM48h

Reduced cell viability, both in MTT assay (50.2 ± 3.8%) and in NR uptake assay (31.3 ± 9.3%) compared to control (100%).

Doxorubicin29913208Damiani, 2018in vitroH9c20.1, 1 µM24h

Reduced cell viability (% of control): ±75% at 0.1 µM, ±50% at 1 µM. 1 µM induced sig. necrosis. Reduced ATP by half (1 µM). Decreased MMP. Increased ROS at 0.1 µM.

Doxorubicin26660439Hasinoff, 2016in vitroNRVMs0 - 100 µM6h, 24h, 48h, 72h

After 6h, MMP was reduced sig. (90% of control) at 0.05 µM. 15% LDH increase over control at 0.8 µM (72h)

Doxorubicin32336319Ryu, 2020in vivo/ vitroRats, NRCMs, hESC-CMs2x 15 mg/kg, 5 µM24h

Damaged myocytes with cell shrinkage, nuclear pyknosis, karyolysis, densed cyto-plasm, and vacuolation in rat hearts. Deterioration of α-actinin-2 arrangement. Increased apoptotic index by 10% in rats, 60-80% in NRCMs, 50-60% in hESC-CMs. Increase of oxidative stress indicators and gene levels of β-MHC, ANP, BNP, Spp1, IL-1β, IL-6, TLR2, TLR4, TNF-α, Bax/Bcl-2, and Casp9 and p53.

Endosulfan32344260Wei, 2020in vitroAC-160, 1.25, 2.5, 5, 10, 20, 40 μg/mL24h

Reduced cell viability (±, % of control): 90% at 2.5, 80% at 5, 70% at 10, 60% at 20, 30% at 40 ug/ml. Sig. increased ROS levels at 5 ug., decreased ATP levels, suppression of COX IV. BCL-2 downregulated at 1.25 ug. Elevated cyt-c, caspase-3 at 1.25, caspase-9 at 5 ug. Decreased expression of PI3K, p-Akt and p-Foxo3a, increased Bim.

Endosulfan32344260Wei, 2020in vivoRats1, 5 and 10 mg/kg21 days

Myocardial cellular degeneration, sig. at 5 mg. Necrosis at 10 mg. cTnI were sig. higher at 5 and 10 mg groups, and the hFABP level elevated at 10 mg. Sig. elevated AST (but not ALT) at 10 mg.

Endosulfan15337585Kalender, 2004in vivoRats2 mg/kg per day6 weeks

SOD, GPx, CAT activities and MDA level increased in the endosulfan-treated group heart tissue. Cytoplasmic edema and swelling and vacuolization of mitochondria.

Endosulfan23758152Ozmen, 2013in vivoRabbits1 mg/kg per day6 weeks

Microscopic haemorrhages, single-cell necrosis, inflammatory reactions, and fibrotic changes in the myocardium. Sig. Caspase-3 immunoreactivity.

Endosulfan19086562Jalili, 2007in vivoRats2 mg/kg per day28 days

Myocardial haemorrhages with interstitial oedema. Diapedesis of leukocytes. Myocardium degeneration, granulation of myofibrils with pyknotic nuclei. Thickening of arterial walls.

Endosulfan28273598Wei, 2017in vivoRats1, 5, 10 mg/kg per day21 days

Injury of cardiac tissue with impaired mitochondria integrity and elevated 8-OHdG expression in myocardial cells. Increased expressions of Fas, FasL, Caspase-8, Cleaved Caspase-8, Caspase-3 and Cleaved Caspase-3 in cardiac tissue.

Endosulfan28273598Wei, 2017in vitroHUVECs1, 6, 12 μg/mL 24h

DNA damage and activated DNA damage response signalling pathway (ATM/Chk2 and ATR/Chk1) and consequent cell cycle checkpoint. Apoptosis through death receptor pathway resulting from oxidative stress.

Endosulfan1702244Anand, 1990in vivoRabbits2.5 and 5.0 mg/kg2/week, 12 months

Rise in blood pressure and heart rate. Increases in PR, QT and RR intervals. Extensive myocardial damage with marked degeneration of muscle fibers vacuolization and leucocytic infiltration. Sig. increase of 11-hydroxycortisone at all time intervals.

Hexabromocyclododecane26476318Wu, 2016in vivoZebrafish0, 2, 20, 200 nM72h

cardiac hypertrophy. Sig. increased deposition of collagen (2-fold at 20 nM). Sig. increased ventricular wall thickness at 20 nM. Sig. Increased ANP and BNP at 200 nM. Decreased Ca2+ accumulation in cytoplasm. Increased SR uptake of Ca2+. Downregulation of miR-1 (regulator of cardiac hypertrophy).

Hexabromocyclododecane26476318Wu, 2016in vitroH9c2200 nM24h

Upregulation of Nkx2.5, downregulation of miRNA-1. Disordered Ca2+ handling. Imbalance of Ryr2, Serca2a and Ncx1 expression, inducing Ca2+ overload in the sarcoplasmic reticulum and high Ca2+-ATPase activities.

Idarubicin34787021Zhang, 2021in vitroHL-1 1, 3, 5, 7, 9 µM24h

Reduced cell viability (±90% at 1 µM, ±75% at 3 µM, ±60% at 5 µM, ±50% at 7 µM, ±30% at 9 µM) compared to control (100%). Increased ROS production. Increased level of intracellular MDA, LDH and NOS, but sig. reduced SOD, CAT, and GSH. Upregulated Bax–Bcl-2 ratio, caspase-3, caspase-7, and caspase-9 (all doses).

Idarubicin32629160Gossmann, 2020in vitrohiPSC-CMs10, 100 nM. 1, 10 µM1 to 5 days

Reduced beating amplitude (10 nM: ±60% at day 5. 100nM: ±60% at day 3. 1 µM: ±60% at day 1. 10 µM: 0% at day 1) compared and normalized to control (100%).

Idarubicin12426639Kalender, 2002in vivoRats5 mg kg weekly8 weeks

Atrial contractility of heart tissue was significantly decreased in the idarubicin-treated group compared to control (P<0.01). QT duration significantly increased. SOD and GSHPx activity was decreased, CAT and MDA activity was significantly increased.

Imatinib28964914Savi, 2018in vivoRats50, 100 mg/kg 3 times per week3 weeks

dose-dependent LV dysfunction, dose-dependent increase in wall thickness-to-chamber radius ratio. structural composition of IM treated hearts was unaffected. dose-dependent reduction of both arteriolar and capillary density.

Imatinib28964914Savi, 2018in vitroCardiac progenitor cells5 µM6h, 24h

Small pro-apoptotic effect. Slight increase in DNA degradation that peaked at 24h after exposure, corresponding to nearly 70% increase in tail intensity. Significant damage at DNA level (yH2AX stain, 2-fold increase in DNA fragmentation).

Imatinib28315715Chambers, 2017in vitroH9c250 µM24h

LD50: 26.2 μM ± 7.1 μM. At 50 µM: increased cyt-c, cleaved caspase 3, 7 and 9, 2.5-fold increase in ROS production, elevated lipid peroxidation, 3-fold incr. in protein carbonyls. At 12h: reduced respiration, decrease (15–20%) in ATP levels. Increased ΔΨm and ER stress.

Imatinib34136360Kobara, 2021in vitroNRCMs1, 5, 10 µM6h

10 µM significantly increased the level of LC3-II expression by 2.5-fold. increased beclin 1, Cathepsin D. increased acridine orange-stained mature autolysosome expression. Increased ROS levels, caspase-3 activity at 10 µM.

Imatinib34136360Kobara, 2021in vivoMice50, 200 mg/kg/day5 weeks

200 mg: dilatation of the left ventricle (LV) and reduced LV fractional shortening. Apoptosis and LC3-II expression in cardiac tissue were increased.

Imatinib30910525Burke, 2019in vitroRat cardiact fibroblasts3, 10 µM24h, 48h

Reduced viability in a concentration-dependent manner. Significantly reduced CF proliferation from 35.5 ± 3.2% in control to 23.0 ± 5.5% for 3 μM and to 9.4 ± 2.5% for 10 μM. Increased mRNA expression of TGFB1 7-fold, IL6 6-fold, and IL1B 7-fold and reduced PDGFD 15-fold at 10 µM.

Imatinib24504921Maharsy, 2014in vivoMice200 mg/kg/day5 weeks

Reduction in the mitral valve mean gradient due to impaired cardiac relaxation. Reduced LV posterior wall thickness (LVPW). 3-fold increase in TUNEL-positive nuclei. Myocyte-specific up-regulation of GATA4 or Bcl-2 protected against toxicity

Imatinib22641616Hu, 2012in vitroNRCMs0 - 100 µM24h

Cardiomyocyte dysfunction through disruption of autophagy and induction of ER stress, independent of c-Abl inhibition.

Imatinib16862153Kerkela, 2006in vivoMice50, 100, 200 mg/kg/d3 or 6 weeks

200 mg for 5 weeks: enhanced Ca2+-induced opening of the MPTP. 30% increase in number of mitochondria. Deterioration in contractile function and moderate left ventricular dilation after 3–4 weeks of treatment

Imatinib16862153Kerkela, 2006in vitroNRVMs2, 5, 10 µM24h

Reduced Δψm, increased cyt-c release, reduced ATP and ATP/ADP ratio, increased caspase 3, 7 activity. Loss of sarcolemmal integrity (necrotic cell death). upregulation and cleavage of PKCδ. Increased phosphorylation of eIF2α

Imatinib22843568Rana, 2012in vitrohiPSC-CMs0.01 - 100 µMUnclear

Reduced cell viability and oxygen consumption rate to 5% at 100 µM.

Imatinib25505575Herman, 2014in vivoRats50, 100, 200 mg/kg/day28 days

Myofibrillar loss, cytoplasmic vacuolization, and necrosis at all doses. Severity of the alterations was dose-related with mean lesion scores (based on a scale of 0–3) of 1.2 (50 mg), 2.1 (100 mg) and 2.9 (200 mg). Increases in cTnI, cTnT, and FABP3 levels were noted primarily in 200 mg.

Imatinib16597375Saad, 2006in vivoRats30 mg/kg/day10 days

Sig. increases in serum CK-MB, GPx, LDH and AST. Sig. increase of cardiac GSH and MDA.

Imatinib34973290Song, 2021in vivoMice25, 50, 100 mg/kg14 days

High dose groups: sig. increased serum CK, LDH and AST. Dose-dependent decrease of GSH and increase of tissue iron and MDA. Sig. increased cardiac lipid accumulation (1.8-fold at 25, 2.4-fold at 50 and 5.6-fold at 100 mg). Sig. decreased GPX4 expression.

Imatinib34973290Song, 2021in vitroH9c210, 20, 40 µM24h

Reduced cell viability (81.9% at 10, 59.4% at 20 and 33.1% at 40 µM). Destroyed MMP in dose dependent manner. Increased cellular ROS and iron levels. Downregulation of Nrf2, NQO1, HO-1, GPX4 and FTH1, and upregulation of P53 and TfR expression. Ferroptosis.

Imatinib35216404Bouitbir, 2022in vitroH9c21 to 100 µM24h

Inhibited Complex I (CI)- and CIII- linked respiration. Mitochondrial superoxide accumulation and decreased cellular GSH. Caspase 3/7 activation increased. Impaired function of enzyme complexes of the ETS

Imatinib35710779Smith, 2022in vitroCardiac progenitor cells1, 5, 10, 100 µM24h, 7 days

Reduced viability; 24h: 1uM 100%, 10 µM 90%, 100 µM 50%. 7 days: 1 µM 90%, 3 µM 70%, 5uM 60%. cells in S/G2/M phases reduced from 50.3 ± 5.1% in control cells to 29.3 ± 4.3% with 10 µM. Nkx2.5 expression was reduced 3 fold after 7 days.

Lead (Pb2+)23391631Ansari, 2013in vitroH9c225, 50, and 100 μM24h

Pb2+ was not cytotoxic, viability >90%. Increased β-MHC, α-MHC, and CYP1A1 mRNA. Resveratrol, an AhR antagonist, could sig. inhibit toxicity. Cardiotoxicity through AhR/CYP1A1-mediated mechanism.

Lead chloride28836190Mattos, 2017ex vivoGuinea pig hearts1-200 μM5-10 min

Acute exposure had a negative inotropic effect and increased diastolic tension. Decreased amplitude of the contractile force.

Lead chloride28836190Mattos, 2017in vitroGuinea pig CMs1-200 μM5-10 min

Extracellular lead blocked currents through Cav1.2 channels with IC50 of 18 µM, diminished their activation, and enhanced their fast inactivation, negatively affecting their gating currents.

Lead nitrate23391631Ansari, 2013in vivoRats25, 50 and 100 mg/kg per day3 days

Sig. cardiotoxicity and heart failure as evidenced by increase cardiac enzymes, LDH, AST, CK, and changes in histopathology at 100 mg. Decreased heart-BW ratio 35% at 100 mg. Induction of B-MHC and BNP while reduction of a-MHC mRNA and protein levels dose-dependently.

Lindane23458197Padma, 2013in vivoRats100 mg/kg per day30 days, fu 1 year

Sig. elevated CK and LDH. Myocardial tissue had inflammatory cells and separated muscle fibers. Sig. increase in TBARS. Sig. decreased SOD, CAT, GPx, and GST. Sig. increase in Ca2+ATPase activity, sig. decrease in Na2+/K+ ATPase and Mg2+ ATPase activities.

Lindane1702244Anand, 1990in vivoRabbits2.5 and 5.0 mg/kg2/week, 12 months

Rise in blood pressure and heart rate. Increases in PR, QT and RR intervals. Extensive myocardial damage with marked degeneration of muscle fibers vacuolization and leucocytic infiltration. Sig. increase of 11-hydroxycortisone at all time intervals.

Lindane16127354Ananya, 2005in vivoRats1.5 and 7 mg/kg per day21 days

Sig. increased myocardial TBARS, sig. decreased GSH. Increased SOD and catalase activities at 7 mg. Interstitial edema in the myocardium at 1.5 mg. Loss of integrity of the myofibrils, Z-band disruption, and mitochondrial damage.

Loperamide30597669Olofinsan, 2019in vivoRats1.5, 3, 6 mg/kg/day7 days

Dose-dependent increase in aspartate aminotransferase, LDH, creatine kinase-MB, and serum concentration of cardiac troponin I, total homocysteine, and nitric oxide. 50% decrease in antioxidant enzymes activity at 6 mg. Cardiotoxic through oxidative stress, lipid peroxidation, and DNA fragmentation.

Loperamide33125619Wolfes, 2021in vitroRabbit heart perfusion0.2, 0.35, 0.5 µM0-1s

Sig. increase in QT interval, APD90, and ventricular tachycardia (VT) episodes.

Lovastatin14678744Rabkin, 2003in vitroChicken embryo CMs10, 50, 100 µM24h

Concentration-dependent increase in apoptotic cell death and 100 μM lovastatin showed over a 4-fold increase in apoptosis through the mevalonate pathway. Caspase-2 and 3 were implicated.

Lovastatin17158337Hauck, 2006in vivo/ vitroRats, NRVMs20 mg/kg/day14 days

Recruitment of forkhead box FoxO3a transcription factor to p21 promoter, mediating activation of the p21 gene. Stimulation of protein kinase B/Akt kinase activity, and Akt-dependent phosphorylation forces p21 in the cytoplasm, where it inhibits Rho-kinases contributing to the suppression of cardiomyocyte hypertrophy.

MDMA31526813Zwartsen, 2019in vitrohiPSC-CMs0.01, 0.1, 1, 10, 100, 300, 1000 μM2-30 min, 24h

Decreased the spike amplitude at 100 μM. Also, at 0.1 μM MDMA, yet not at higher concentrations, an increase in spike amplitude was seen. 10 µM increased the beat rate by 20%. Decreased beat rate at 300 µM. Prolonged FPDc concentration-dependently. Sig. decreased cell viability only at 1000 µM.

Mitomycin C8763838Pritsos, 1996in vivoMice0, 5, 10, 20 mg/kg, 1 or 2 injections48h after treatment

Decreased heart tissue ATP to 40% of control (single and double, all doses).

Mitoxantrone32894303Costa, 2020in vitroHL-10.1, 1, 10 µM2, 4, 6, 12, 24, 48h

Decreased cell viability in conc./time dependent manner. Earliest effects at 6h (10 µM). At 24h: 10 µM (46.3 ± 8.7%), 1 µM (58.5 ± 10.4%), 0.1 µM (77.1 ± 12.6%). At 48h, viability was decreased dramatically. Increased GSH and caspase 9, 8, 3. Decreased proteasomal chymotrypsin-like activity in a conc./time dependent manner.

Mitoxantrone29913208Damiani, 2018in vitroH9c20.1, 1 µM24h

Reduced cell viability (% of control): ±75% at 0.1 µM, ±40% at 1 µM. 1 µM induced sig. necrosis. Reduced ATP by half (1 µM). Decrease MMP. Increased ROS at 0.1 µM.

Mitoxantrone23545721Rossato, 2013in vitroH9c2100 nM, 1 µM24h

Reduced cell viability (% of control): 69 ± 5% (100nM), 63 ± 7 % (1 µM)

Mitoxantrone24046265Rossato, 2013in vitroH9c210, 100 nM, 1, 5, 10, 50, 100 μM24, 48, 72, 96h

Reduced cell viability in conc./time dependent manner (% of control): 24h: ±80% at 10 µM, ±20% at 50 µM. 96h: ±80% at 1uM, ±30% at 5 µM. =>100 nM caused incr. in caspase-3 activity after 24h. ROS 96h (% of control): 137 ± 46.7% at 100 nM and 141 ± 56.9 % at 1 μM. At 96h, sig. decrease in GSH (100 nM). Change in MPP and sig. increase in [Ca2+]i.

Mitoxantrone23261645Schweikart, 2013in vitrohiPSC-CMs0.1, 1, 3, 10, 30 µM1h, 12h, 24h, 72h

Decrease in beat rate at 30 μM at 1h, at both 10 μM at 6h, and at 0.1 µM at >24h. Beating stopped at >3 µM after 24h. Dose- and time-dependent decrease in beat amplitude. Mitochondrial staining was reduced but increased MMP.

Mitoxantrone26660439Hasinoff, 2016in vitroNRVMs0 - 100 µM24h, 48h, 72h

15% LDH increase over control at 1 µM (72h), dose response plot available.

Mitoxantrone24096626Rossato, 2014in vivoRats7.5 mg/kg22 and 48 days

Treatment at day 20. Decrease of CK levels in MTX22 group when compared to MTX48 group and control group. Only in MTX48 group: cardiac relative mass higher, ATP lower.

Mono(2-ethylhexyl)phthalate33029813Wang, 2021in vitroAC-160 - 120 µM24h

Reduced cell viability (sig. at 60 µM, 20% decrease, at 100 µM 50% decrease) and MMP, whereas it increased LDH leakage (sig. at 60 µM), production of ROS, and apoptosis.

Nifedipine32336319Ryu, 2020in vivo/ vitroRats, NRCMs, hESC-CMs2x 100 mg/kg, 50 µM24h

0-20% increase in apoptotic index in rats, NRCMs, hESC-CMs (not stat sig.). Increase of oxidative stress indicators and gene levels of β-MHC, ANP, BNP, Spp1, IL-1β, IL-6, TLR2, TLR4, TNF-α, Bax/Bcl-2, and Casp9 and p53.

Nifedipine31526813Zwartsen, 2019in vitrohiPSC-CMs3, 10, 30 nM2-30 min, 24h

Sig. reduced FPDc (−11 ± 3.3%) at 30 nM, but no sig. effect on beat rate, spike amplitude or the number/percentage of active wells and electrodes. No sig. effect on cell viability.

Nifedipine33109927Vinagre, 2021in vitrohiPSC-CMs0.01, 0.03, 0.1, 0.3 µM30 min exposure, 20s recording

Concentration-dependent decreased amplitude, contraction and relaxation time, APD (APD30 and APD90)

Nifedipine27184445Dempsey, 2016in vitrohiPSC-CMs0 - 1 µMUnclear

Decreased CT amplitude. 0.01 µM: 20% decrease in AP50 and AP90, 20% increase in AP rise time, 20% decrease in Ca2+ amplitude. 0.3 µM: Ca2+ flux stops. 1 µM: stopped beating.

Nifedipine31079550Lam, 2019in vitrohiPSC-CMs433 nM (C ther.)30 mins, 14 days

Reductions in beating rate and contraction velocities. Persistent blockade of L-type calcium current. Upregulation of gene S100A8.

Nifedipine29274391Goineau, 2017in vitrohiPSC-CMs0.01, 0.03, 0.1, 0.3 and 1 μM5 min

Concentration-dependently shortened FPDcF, minimum effective concentration was 0.03 µM

Nifedipine20034863Braam, 2010in vitrohESC-CMs1 nm - 100 µM2 min

Dose-dependent shortening of the FPD, which was initiated at 10 nM and saturated at 1 μM

Paclitaxel17400210Pentassuglia, 2007in vitroARVMs0–15 μM48h

Slightly decreased cell viability at concentrations ≤ 6 μM, higher doses resulted in a sig. increase of myofibrillar damage. No effect on mitochondrial respiration. No increase in LDH. Reduced basal phosphorylation of Erk1/2 (0.7 fold) and Akt (0.5 fold ). Mild oxidative stress.

Perfluorooctane sulfonamide (PFOSA)35652794Chen, 2022in vivoZebrafish0.01, 0.1, 1, 10, and 100 μg/L120 hpf

Abnormal cardiac morphology, disordered heartbeat signals, as well as reduced heart rate and cardiac output. Effects could be prevented by AHR antagonist and were alleviated by ahr2 knockdown, indicating sig. role for AhR activation pathway in PFOSA cardiotoxicity.

Perfluorooctane sulfonate (PFOS)15737613Harada, 2005in vitroGuinea pig VMs1, 10, 20, 100 µMUnclear

Sig. decreased the rate of spike, action potential duration, and peak potential at doses over 10 µM. Increased the voltage-activated peak amplitude of I(CaL), and shifted the half-activation and inactivation voltages of I(CaL) to hyperpolarization.

Perfluorooctane sulfonate (PFOS)32861759Liu, 2020in vitromESC-CMs40 µM3 - 7 days

Induced swelling of mitochondria and autophagosome accumulation at 40 μM. Increased levels of LC3-II, p62, and ubiquitinated proteins. Induced an increase of LC3 and p62 localization into mitochondria, indicating that mitophagy degradation was impaired. Dysfunction of lysosomes. ATP depletion and reduced MMP.

Perfluorooctane sulfonate (PFOS)32088431Yang, 2020in vitrohESC-CMs0.1, 1, 10, 30, and 60 μM0 - 12 days

48h treatments did not lead to any obvious cell death at concentrations 60μM, only for doses > 180 μM. Inhibited cardiac differentiation and promoted epicardial specification via upregulation of the WNT signalling pathway.

Perfluorooctane sulfonate (PFOS)28288859Tang, 2017in vitromESC-CMs40 µM3 - 7 days

Expression of L-type Ca2+ channel (LTCC) was decreased, interrupting [Ca 2+]c transient amplitude. Mitochondrial swelling. MMP was decreased and ATP production lowered. Increased EGFR phosphorylation, activated Rictor signalling, destroying the mitochondria-associated endoplasmic reticulum membrane (MAM)

Perfluorooctane sulfonate (PFOS)34815766Xu, 2022in vivoRats1 and 10 mg/kg every other day14 days

Sig. Increased heart to body weight ratio at 10 mg. Sig. Increased expression of myocardial injury markers, such as cTn-T, LDH, CK and CK-MB. Cardiac fibrosis and myocardial hypertrophy at 10 mg. Sig. upregulation of p53, Bax, IL-1B, TNF-a.

Perfluorooctanoic acid (PFOA)31445018Lv, 2019in vitroChicken embryo CMs1, 10, 30 or 100 μg/mL24, 48, 72h

Reduced cell viability at 24h, 15.6% at 30 ug and 17.0% at 100 μg/ml. 48h: 1, 10, 30 and 100 μg/ml, 19.2%, 30.7%, 51.7%, 53.0%, respectively. Silencing of PPARa alleviated cytotoxicity. Sig. higher [Ca2+]i levels.

Perfluorooctanoic acid (PFOA)22273728Jiang, 2012in vivoChicken embryo heart0, 0.5, 1 and 2 mg/kg eggD19, 2 days prior to hatch

Alteration of multiple cardiac structural and functional parameters. Reduced left ventricular wall thickness, altered left ventricular volume, heart rate, stroke volume, and ejection fraction.

Perfluorooctanoic acid (PFOA)26098785Jiang, 2016in vitroChicken embryo CMs2 mg/kg of egg in ovo, 0 to 100 µg/mL in vitro1 or 36h

Decreased viability at 1h of exposure to 100 and 36h of exposure to 75 and 100 µg/mL in vitro. Decreases in time to maximum departure velocity and cell length at peak contraction, reduction in the 50% relaxation time. Decreased cardiomyocytes axial length. Sig increased ROS generation.

Perfluorooctanoic acid (PFOA)31037826Salimi, 2019in vivoMice1, 10, and 20 mg/kg per dayD5 - D9 of gestation.

Assessment on D15 of gestation. Thickening of endometrium (20% in group 20 mg/kg). Sig. increased mitochondrial swelling and ROS generation, sig. decreased MMP in heart mitochondria.

Perfluorooctanoic acid (PFOA)28934691Zhao, 2017in vivoChicken2 mg/kg egg in ovoUnclear

Significant elevation of heart rate and thinning of right ventricular wall thickness. PPARa silencing sig. increased right ventricular wall thickness of PFOA treated animals.

Permethrin34224971Feriani, 2021in vivoRats5 mg/kg/day12 weeks

Decreased R amplitude, ST segment elevation, marked increase in heart rate with auricular flutter, indicating onset of myocardial infarction. Sig. higher plasma TC, TG, LDL-C, decrease in HDL-C. Sig. higher AST, CK-MB, LD, CRP and cTn-T. Sig. higher TNF-a and IL-6. Sig. lower CAT, SOD, GPx, GSH. Upregulation of Caspase-3, Bax, NF-KB. High cardiac TGF-B1 expression. Cardiac fibrosis.

Permethrin23806482Vadhana, 2013in vivoRats34.05 mg/kg, per day, 21 days500 days

1.62-fold increase in Nrf2 mRNA level. Decreased heart surface area (296.59 ± 8.09 vs control group (320.86 ± 4.93, mm2). Intracellular calcium influx increased 4.33-fold.

Permethrin20574784Vadhana, 2010in vitroRat CMs5, 10, 20 µM1h

5, 10, and 20μM reduced cell viability 1.02, 6.12 and 5.1%. Oxidative damage to purine bases. Sig. DNA damage.

Phenanthrene31237719Vehniainen, 2019in vitroRainbow trout CMs0.3, 1.0, 10, and 30 µMUnclear

Shortened APD0 at 30 µM. Increased +dV/dt at 1 µM and accelerated –dV/dt at 10 µM. Modulation of cardiac INa, ICaL, and IKr currents

Phenanthrene32738692Rigaud, 2020in vivoRainbow trout100 µg/L1, 3, 7, 14 days

No detectable deformities or growth retardation. Sig. alteration of cacng7a (subunit of L-type Ca2+ channel). Altered key genes linked to the respiratory electron transport chain, as well as to oxygen and iron metabolism.

Phenanthrene33523501McGruer, 2021in vivoZebrafish12 or 15 µM6 to 72 hpf

Pericardial edema and bradycardia. Sig. alteration of genes fdft1 and hmgcra (cholesterol biosynthetic pathway). 2-dimensional yolk area was sig. increased, suggesting that lipid transport from the yolk to the developing embryo was impaired.

Phenanthrene32957295Zheng, 2020in vivoMedaka0, 2, 10, 50, and 250 μg/L28 days exposure

Exposure =>10 ug decreased survival rate. 2, 10, and 50 μg/L caused yolk sac edema and pericardial edema, accompanied by dysregulation of fgf8, bmp4, smyd1, ATPase and gata4 genes.

Phenanthrene31499312Ainerua, 2020in vitroBrown trout VCMs5, 15 or 25 μM30 min

Prolongation of QT interval (±8.6%) and MAPD (±13.2%). Sig. reduced trabecular force generation by ±24% at 15 μM and above, suggesting reduced cellular Ca2+ cycling. Reduction (±39%) in the intracellular Ca2+ transient amplitude. Reduced repolarising delayed rectifier K+ current (±70%).

Phenanthrene28570901Cypher, 2017in vivoZebrafish0, 1, 100, and 1000 μg/LExposure between 24 and 72-96 hpf

Decrease in heart rate (58%), cardiac output (80%), and arterial red blood cell velocity (84%) compared to control (100%) at 1000 ug. Effects are exacerbated by simultaneous exposure to hypoxia.

Phenanthrene26830171Huang, 2016in vivoRats0.5, 5, 50 μg/kg per day, 21 days6 weeks

Increased heart weight and CM size dose-dependently, indicating cardiac hypertrophy. Increased deposition of collagen in the heart sections.

Phenanthrene26830171Huang, 2016in vitroH9c20.05–50 nM12, 24h

No inhibitory effect on cell viability. Sig. enlargement of cell size (2-fold) at 50 nM. Increased protein synthesis (2-fold). CM hypertrophy. Increased mRNA levels of ANP, BNP and c-Myc. Sig. reduced levels of miR-133a (regulator of CM hypertrophy). Increased CdC42, RhoA, DNMT1, DNMT3a and DNMT3b. Increased DNA methylation, leading to reduced miRNA-133a and hypertrophy phenotype.

Phenanthrene23948075Zhang, 2013in vivoZebrafish0.05, 0.5, 5, 50 nM72hpf

Sig. increased interbeat variation (arrhythmia) at 5 and 50 nM.

Phenanthrene23948075Zhang, 2013in vitroH9c20.05, 0.5, 5, 50 nM72h

Disordered Ca(2+) handling characterized by impaired SR Ca(2+) uptake, and obvious Ca(2+) accumulation in the cytoplasm. Sig. decreased mRNA level of the SERCA2a Ca(2+) pump. Both the mRNA and protein levels of TBX5, a direct regulator of SERCA2a, were sig. decreased

Phenylephrine29339422Sun, 2019in vitroNRVMs50 µM6, 12, 24h

Cardiomyocyte hypertrophy was induced. Level of ANGPTL4 was increased at 6 and 12 h after PE treatment and then gradually declined over the next 12 h

Phenylephrine29128355Romano, 2017in vitroNRCMs100 µM48h

Cardiomyocyte hypertrophy was induced. Sig. cell size increase over control.

Phenylephrine32898528Li, 2020in vitrohESC-CMs25, 50 µM48h

Decreases of mitochondrial respiration, ATP, ATP synthetase and mitochondrial membrane potential. 50 µM increased the surface area of cardiomyocytes 2.7 fold. Downregulation of G6PD. Hypertrophic marker genes (ANP, BNP and β-MHC) were significantly elevated (50 µM)

Phenylephrine27940402Ji, 2017in vitroNRCMs100 µM48h

Increased size of cardiomyocytes: almost twice as large as control. Expression of ANP and BNP were enhanced. Sig. up-regulation of CaMKIIδ, STIM1. Peak amplitude of Ca2+ current in the SOCE was higher. Increased amplitude of Ca2+ release-activated currents

Phenylephrine34790705Fang, 2021in vitroNRVMs50 µM48h

Hypertrophy. Sig. reduced intracellular Zinc concentration, SLC39A2 is involved. Slc39a2 knockdown sig. potentiated PE-induced cell size enlargement.

Phenylephrine29862242Gao, 2018in vitroNRVMs50 µM48h

Hypertrophy. Reduced PPARγ and PGC1-α. Increased ANP and BNP, CM size.

Phenylephrine27161004Zhang, 2016in vitroNRVMs50 µM48h

Hypertrophy. Obvious enlargement of cardiomyocytes as measured by cell surface labelled with α-actinin. ANP, BNP, and MYH7, were increased. Protein/DNA ratio was elevated. miR-199a-5p was upregulated.

Phenylephrine34384564Sunagawa, 2021in vitroNRCMs30 µM48h

Increases in transcriptions of atrial naturistic factor (ANF) and brain naturistic peptide (BNP), markers of cardiomyocyte hypertrophy. PE induced acetylation of histone H3K9

Phenylephrine17287366Prasad, 2007in vitroNRCMs20 µM3-7 days

Hypertrophic enlargement. 69 ± 16% enhancement of overall protein expression. ANF was increased 2.97 ± 1.13- and 11.69 ± 1.95-fold after 3- or 7-day exposure to PE. SERCA2 transcription was reduced to 0.62 ± 0.24 and 0.44 ± 0.13 after 3- or 7-day.

Phenylephrine27094368Shen, 2016in vitroNRCMs100 µM24h

PE increased the surface area of cardiomyocytes (±2.5-fold) and elevated the expression of hypertrophy marker genes (ANF ±2-fold, BNP ±2-fold, B-MHC 1.5-fold). Decreased protein expression of SIRT6, elevated p300

Phenylephrine34914791Peng, 2021in vitroMouse VCMs100 µM48h

Enlargement of cells, increased ANP. Level of p-JNK was significantly increased, histone H3K9ac hyperacetylation. PCAF-HAT and MEF2A expression significantly increased. [Ca2+]i was clearly increased. LVAWT and LVPWT increased in vivo.

Phenylephrine28194469Peng, 2017in vivoMouse perfused heart20 mg/kg/day30 days, fu 1 year

Left ventricular hypertrophy, sig. increased heart to body weight ratio (1.5-fold). Increased HAT activity 1.6-fold, sig. increased p300, PCAF, SRC1, H3K9ac. mRNA-expression of MEF2A, Cx43, ANP, BNP, cTnT, and β-MHC were consistently higher. Sig. increase in left ventricular pressure and diastolic pressure. Survival rate 15%, HF incidence 90% after 1 year.

Phenylephrine28497371Dong, 2017in vitroNRCMs50 µM48h

Expression of Sestrin 2 declined to 60% of control. Sig. increased ANP and cell surface area. MAPKs (including ERK1/2, JNK 1/2 and p38) and mTOR (including its downstream effector p70S6K) were significantly activated at 30 min

Phenylephrine25449040Dong, 2015in vitroNRVMs10 µM3 days

Sig. increase in cell surface area from 789±91 µm2 to 1201±140 µm2. Increased protein expression of ANP 2-fold. 2-fold and around 1.7-fold increases of RhoA and ROCK activity. Increased [ROS]i 3.14-fold. MDA 1.65-fold.

Phenylephrine22818713Anestopoulos, 2013in vitroH9c2100 µM24h

Sig. increase in cell area, ANP, ERK1/2 activity and pAkt.

Phenylephrine15452191Gan, 2005in vitroNRCMs10 µM24h

Increased cell size (35%) and ANP. Increased ERK phosphorylation. Rapid c-Fos induction during first 30 m. Expression of G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold and upregulation of Na/H exchange isoform 1 (NHE1) expression.

Phenylephrine31163678Chaanine, 2019in vitroARCMs10 µM2h

Mitochondrial fission, fragmentation, mitophagy, and vascular degeneration.

Phenylephrine29110214Zhao, 2018in vitroNRCMs50 µM48h

Downregulation of miR-223, upregulation of STIM1.

Phenylephrine29901150Liu, 2018in vitroNRCMs10 µM48h

Sig. reduced ATP concentration (4.9±0.5 vs 9.1±0.7 nmol/mg). MMP sig. decreased (50% of control). Sig. increase in ROS (162% of control). CPT-2, Acadm, ANP decreased.

Phenylephrine16690042Kleiner, 2006in vitroNRCMs10 µM30m, 1, 3h

Transcript levels c-Jun and c-Fos were rapidly and markedly increased, JunD decreased.

Phenylephrine25770146Zhong, 2015in vitroNRVMs10 µM24h

Hypertrophic phenotype in NRVM characterized by increased cell-surface area and robust accumulation of ANP. Phosphorylation of ERK1/2 and GATA4 followed by nuclear translocation of the ANKRD1/ERK/GATA4 complex.

Phenylephrine15276029Kemp, 2004in vitroNRVMs100 µM1h

Expression of three clones (C208, C53 (CTGF) and C64) was increased. Increased CTGF mRNA 2.25 ± 0.27-fold.

Phenylephrine19966059Pang, 2009in vitroNRVMs10 µM6, 24h

Sig. hypertrophy (cell size and ANP). Sig. increased gene and protein expression of adenosine A1, A2a, and A3 receptors. Sig. increased production of adenosine, sig. upregulation in expression levels of equilibrative nucleoside transporter 1.

Phenylephrine25636810Huang, 2015in vitroNRCMs20 µM24h

Increased cell surface area and free fatty acid content, increased ERK1/2 phosphorylation, decreased expression of PPARα, decreased expression and activity of SCAD and decreased levels of ATP.

Phenylephrine35468773Qian, 2022in vitroNRCMs, AMCMs50 µM24h

Enhanced phosphorylation level of CaMKII, MEK, ERK1/2, PLN and RyR2. Increased Ca2+ spark frequency.

Pyrene32738692Rigaud, 2020in vivoRainbow trout32 μg/L1, 3, 7, 14 days

No detectable deformities or growth retardation. Sig. alteration of genes involved in the generation of the AP: cacna1i, kcna10a, kcnh8 and kcnj9. Altered key genes linked to the respiratory electron transport chain, as well as to oxygen and iron metabolism.

Pyrene17112560Incardona, 2006in vivoZebrafish25 µMExp. between 6 and 72 hpf

Strong CYP1A induction (12-fold increase of mRNA). Reduced peripheral circulation, anaemia, pericardial edema that evolves into yolk sac edema

Retene31237719Vehniainen, 2019in vitroRainbow trout CMs0.1, 1.0, and 10 µMUnclear

Shortened APD50 and APD0 at 1 µM. Augmented AP amplitude at 10 µM and increased overshoot at 1 µM. Modulation of cardiac INa, ICaL, and IKr currents.

Retene32738692Rigaud, 2020in vivoRainbow trout32 μg/L1, 3, 7, 14 days

No detectable deformities or growth retardation. Dysregulation of genes related to cardiac ion channels, calcium homeostasis and muscle contraction: sig. alteration of genes related to actin filaments (fscn2b and actn3b), myosin filaments (myha, myhc4, myhz1.1, myhz1.2 and myhz2) and the troponin complex (tnni1c, tnni2a.4, tnnt1 and tpma).

Retene26667672Vehniainen, 2016in vivoRainbow trout32 μg/L1, 3, 7, 14 days

Retene up- or down-regulated 122 genes. The largest Gene Ontology groups were signal transduction, transcription, apoptosis, cell growth, cytoskeleton, cell adhesion/mobility, cardiovascular development, xenobiotic metabolism, protein metabolism, lipid metabolism and transport, and amino acid metabolism.

Retene21040984Scott, 2011in vivoZebrafish12.5 μg/mL24, 36, 48 and 72 hpf

At 36h: pericardial edema and reduced blood flow, reduced layer of cardiac jelly in the atrium and reduced diastolic filling. Mechanism of retene toxicity is AhR2-mediated and CYP1A-independent.

Rofecoxib32111102Brenner, 2020in vivoRats5.12 mg/kg/day28 days

Rofecoxib treatment increased the mortality rate in the ischemia/reperfusion (I/R) group in vivo (OR = 7.8) due to its proarrhythmic effect via increased APD during I/R. Reduced infarct size. Increased viability of CMs in normoxia and in simulated ischemia/reperfusion injury.

Rosiglitazone24449420He, 2014ex vivoMouse perfused heart1, 3, 10, 30 µM2h

Myocardial energy deficiency and mitochondrial dysfunction. 10-30μM decreased [PCr], [ATP], ΔGATP, oxidation rates of glucose and palmitate, mitochondrial respiration rate and complex 1 and 4. Increased ROS and cardiac contractile dysfunction independent of PPARy.

Rosiglitazone24249632Mishra, 2014in vitroH9c250, 60 µM24h

Dose dependent reduction in cell viability. Sig. ROS increase. Increase in the expression of NOX-2 (4-fold), MMP-2 (6-fold), MMP-9 (64-fold), p40phox (4.8-fold), p47phox (6.6-fold), xanthine oxidase (162-fold). Increased iNOS (70-250 fold), nNOS (100-250 fold). Increased SOD, catalase, GR, GST and GPx. Cardiotoxicity mediated through HO1-nrf2-PKCδ Pathway.

Rosiglitazone24249632Mishra, 2014in vivoMice10 mg/kg/day10 days

Increased serum CK-MB, tissue cTnT, and iNOS expression. Increased SOD (2-fold), catalase (6-fold), GR (2-fold), GST (5-fold), GPX (7-fold). Global gene expression studies also showed the perturbation of oxidative phosphorylation, fat cell differentiation, and electron transport chain upon treatment in vivo.

Rosiglitazone28822817Pharaon, 2017in vitroNRCMs0.5, 1, 2, 5, 10, 50 and 100 μM12, 24, 48 and 72h

10 μM 48h sig. increased BNP (1.6 fold), 50 μM (1.5 fold) and 100 μM (1.6 fold). After 72h, 10 μM and 100 μM sig. increased BNP (1.4 and 1.8 fold). At 72h, 100 µM: increased surface area (1.6-fold), increased ANP (2.2 fold), increased phosphorylation of p38-MAPK (1.4 fold) and histone H3 (1.9 fold).

Sibutramine33389602Alyu, 2021in vitroARVMs10 µM3h

Sig. prolongation of APD25, APD50, reduction of amplitude, inhibition of RMP values. Inhibition of K+ current in a dose dependent manner. The mRNA levels of fast (Kv4.2 and Kv4.3) and slow (Kv1.4 and Kv2.1) components of K+-channels were decreased sig. Decreased resting basal Ca2+. ROS levels markedly increased.

Tebuconazole32980069Othmene, 2020in vivoRats0.9, 9, 27 and 45 mg/kg28 days

MDA, PC, AOPP, GPx, GR and GSSG levels increased, while GSH and GSH/GSSG ratio decreased. SOD and CAT initially increased at 0.9, 9 and 27 mg and then decreased at 45 mg. Increased SOD1, CAT and HSP70 protein levels. Myocardial tissue damage: leucocytic infiltration, haemorrhage congestion of cardiac blood vessels and cytoplasmic vacuolization.

Tebuconazole32006631Othmene, 2020in vivoRats0.9, 9, 27 mg/kg28 days

Increased relative weight at 9 and 27 mg (14.73% and 26.09%). Inhibition of cardiac AChE activity at 0.9, 9, 27 mg (12.52%, 28.18% and 42.93%). Sig. elevated activity of CPK and LDH, T-CHOL, TG, and LDL-C and decreased significantly HDL-C levels. Sig. increase in p53, upregulation of Bax, downregulation of Bcl-2, overexpression of cyt-c, caspase-9 and -3. Increased DNA damage and PCEMN. Increased myocardial fibrotic content at 9 and 27 mg (12 and 15%).

Tebuconazole32798748Othmene, 2020in vitroH9c220-120 µM, 60 µM24h

Dose-dependent cell death: 95% at 120, 80% at 100, 70% at 80, 50% at 60, 35% at 40, 20% at 20 µM. DNA damage: 2.48 and 4.65 fold at 30 and 60 µM. Sig. upregulation of p53, p21, Bax. Downregulation of Bcl2. Increased active forms of caspase-9 and -3. Cleavage of PARP. Increased ROS and MDA.

Tebuconazole35202779Miranda, 2022ex vivoMouse perfused heart0.3, 3, 30, and 300 μMUnclear

ECG abnormalities: increased QT and QTc interval, reduced intrinsic frequency. Changes in P duration, PR interval, decreased heart rate. Atrioventricular block. Elimination of electric activity at 300 µM.

Tebuconazole35202779Miranda, 2022in vitroMouse VCMs30 µMUnclear

Prolongation of APR. No effect on AP potential amplitude and resting membrane potential. Reduced the peak amplitude of ICa,L in a concentration-dependent manner. Increased total Ca2+ load, sarcomere shortening and calcium transient.

Telmisartan23073892Kim, 2012ex vivoRat perfused heart3, 10, 30, and 100 μM3h

Dose dependent MI: infarct size was 10% (10 μM), 20% (30 μM), and 65% (100 μM) of the total heart area. 30 μM sig. altered cardiac performance, hypercontractile LV with bradycardia and cardiac arrhythmia. Reduced heart rate (48% of control), average coronary flow rate (50%), higher LV developed pressure (169.4 ± 8.8%). LV internal dimension at end systole was sig. decreased. Increased cytosolic Ca2+ and Na+, no effect on Ca2+ currents but delayed inactivation of voltage-gated Na+ currents. Prolonged APD.

Tetrabromobisphenol A25846749Wu, 2016in vivoZebrafish0.1, 0.4, 0.7, 1 mg/L8 days

Dose-response alteration of hatching rate, survival rate, malformation rate, growth rate. Heart impairment. Decreased activities of Cu/Zn-SOD, CAT, GPx at 0.4 mg. Apoptotic cells mainly accumulated in the brain, heart, and tail, indicating possible TBBPA-induced brain, cardiac, and blood circulation system impairment.

Tetrabromobisphenol A24596333Yang, 2015in vivoZebrafish0.5, 1 mg/L24 - 96h

Malformation, blood flow disorders, pericardial edema, and spawn coagulation rates increased, whereas survival decreased significantly. Dose-dependent increase of ROS production. CM apoptosis. Increased P53, Bax, and Caspase9. Downregulation of Bcl-2. Alteration of cardiac genes: Tbx1, Raldh2, and Bmp2b.

Tributyltin30690233Pereira, 2019ex vivoMouse perfused heart1 nM to 10 mM5 min

Depressed cardiac contractility and relaxation in papillary muscle and intact whole heart. Increased cytosolic, mitochondrial ROS production and decreased mitochondrial membrane potential.

Tributyltin30690233Pereira, 2019in vitroMouse VCMs100 nM5 min

Depressed Ca2+ transient peaks and the rates of twitch [Ca2+]i decline. Higher concentrations led to cell death. Sig. reduced SR Ca2+ content via RyR leak. Increased cytosolic ROS production after 5 min. Decreased MMP.

Tributyltin22852845Santos, 2012ex vivoRat perfused heart100 ng/kg per day15 days

Sig. increased the baseline coronary perfusion pressure and impaired vasodilation. Sig. decreased serum 17β-oestradiol levels accompanied by a significant rise in serum progesterone levels. Elevated collagen in heart. Increased coronary perfusion pressure and incidence of cardiac hypertrophy.

Triphenyl phosphate (TPhP)25661707Du, 2015in vivoZebrafish0.10, 0.50, 1.0 mg/L72 hpf

Sig. Reduced heart rate at 0.5 mg. Pericardium edema and SV-BA distance extension, decreased number of cardiac muscle cells and thinner walls of ventricle and atrium at 0.5 mg. Disturbed expressions of transcriptional regulators, especially downregulation of BMP4, NKX2-5 and TBX5.

Tris (2-butoxyethyl) phosphate (TBOEP)33069947Xiong, 2021in vivoZebrafish20, 200, 1000 and 2000 µg/LExp. Between 2 - 120 hpf

No effect <20 ug. Sig. apoptosis in heart region. Increased oxidative stress. Heart rate declined at 1000 ug. Expression of dvl3, axin1 and axin2 was increased while the transcriptional abundance of β-catenin, pkc, wnt11, fzd, nkx2.5 and sox9b was downregulated.

Tris-(1,3-dichloro-2-propyl) phosphate (TDCPP)30685670Zhong, 2019in vivoZebrafish300 and 500 μg/L72hpf

Impeded growth of micro- and macrovessels. Decreased HR. mRNA levels of Vegfa, Vegfr1, Vegfr2 and Vegfa inducer Hifa dose-dependently decreased. mRNA levels of the Nrf2 and its target genes Sod1, Sod2, Gclm and Txn were reduced.

Tris-(1,3-dichloro-2-propyl) phosphate (TDCPP)30685670Zhong, 2019in vitroHUVECs10 - 200 µM24h

Increased cell proliferation induced by VEGF was suppressed by TDCPP exposure in a dose-dependent manner. repression of Nrf2 expression and activity. Application of a potent Nrf2 activator enhanced VEGF and protected against defective vascular development in zebrafish.

Verapamil24840785Sun, 2014in vitroARVMs10 µM0 - 7 min

Sarcomeric contractile function decreased continually. decreased the resting Ca2 + ratio, amplitude of Ca2 + ratio and amplitude/resting calcium

Verapamil27184445Dempsey, 2016in vitrohiPSC-CMs0 - 1 µMUnclear

Decreased CT amplitude. 0.1 µM: 20% decrease in AP50 and AP90, 20% increase in AP rise time, 20% decrease in Ca2+ amplitude. 1 µM: stopped beating, Ca2+ flux stops.

Verapamil31079550Lam, 2019in vitrohiPSC-CMs813 nM (C ther.)30 mins, 14 days

Reductions in beating rate and contraction velocities. Set of cardiac contraction-related genes were significantly downregulated (myofibril and sarcomeric structure–related pathways).

Verapamil29274391Goineau, 2017in vitrohiPSC-CMs3, 10, 30, 100 and 300 nM5 min

Concentration-dependently shortened FPDcF, minimum effective concentration was 30 nM

Verapamil11581079Hill, 2001ex vivoRat left ventricular muscle31 to 1020 nM15m

510 nM produced consistent reduction in developed tension of 52.9±3.2%.