_id Chemical PMID Author, year Study type Species Dose range Dosing/incubation timing Summary of findings 1 2,3,7,8-Tetrachlorodibenzo-p-dioxin 19969063 Zordoky, 2010 in vitro H9c2 1, 5, 10, 20 nm 48h 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 2,3,7,8-tetrachlorodibenzo-p-dioxin 15635151 Antkiewicz, 2005 in vivo Zebrafish 1 ppb 1h 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 3,3',4,4',5-pentachlorobiphenyl 18660518 Grimes, 2008 in vivo Zebrafish 7.5 μg/L 24h 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. 4 3,3',5,5'-tetrabromobisphenol A 24596333 Yang, 2015 in vivo Zebrafish 0.05, 0.1, 0.5, 1 mg/L 96h 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. 5 4-Fluoroamphetamine 31526813 Zwartsen, 2019 in vitro hiPSC-CMs 0.01, 0.1, 1, 10, 100, 300, 1000 μM 2-30 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. 6 5-fluorouracil 25034007 Eskandari, 2014 in vitro ARVMs 15 µM 1-3h 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. 7 5-fluorouracil 30634681 Oliveira, 2019 in vitro H9c2 0.13 - 5 µM 24h, 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%). 8 5-fluorouracil 30862114 Mendes, 2019 in vitro H9c2 50 µM 48h Reduced cell viability, both in MTT assay (93.7 ± 4.4%) and in NR uptake assay (86.6 ± 5.4%) compared to control (100%). 9 5-fluorouracil 24704391 Lamberti, 2014 in vitro H9c2 400 µM 72h Reduced cell viability to 50%. Increased Tbars and NO2- levels. 10 5-fluorouracil 25671635 Focaccetti, 2015 in vitro HCMs 10 nM to 1mM 96h 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. 11 5-fluorouracil 1580574 Millart, 1992 in and ex vivo Rat perfused heart 1 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. 12 5-fluorouracil 35101590 Li, 2022 in vivo Mice 15, 30, 60 mg/kg 7 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. 13 5-fluorouracil 35101590 Li, 2022 in vitro H9c2 2.5, 5, 10 µM 48h 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. 14 Aconitine 30233701 Zhang, 2018 in vitro hiPSC-CMs 0.125, 0.25, 0.5, 1, 2, 4, 8 µM 2h, 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 15 Aconitine 30410440 Ma, 2018 in vitro H9c2 0.01 - 50 μM 24h 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. 16 Aconitine 31657084 Peng, 2020 in vitro H9c2 0 - 100 µM 12, 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. 17 Aconitine 31975431 Li, 2020 in vivo Zebrafish 2, 8 µM 12, 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. 18 Aconitine 31975431 Li, 2020 in vitro H9c2 1.5, 4.5 mM 30m [Ca2+]i oscillation. Decreased expression levels of TnT and Bcl-2, increased caspase 3 and Bax dose dependently. 19 Aconitine 34369901 Zhao, 2021 in vitro H9c2 0 - 100 µM 24h 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. 20 Aconitine 24840785 Sun, 2014 in vivo Rats 1,46 mg/kg/day for 10 days 3 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. 21 Aconitine 24840785 Sun, 2014 in vitro ARVMs 1 µM 0 - 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 22 Aconitine 24840785 Sun, 2014 in vitro NRVMs 0.01, 0.04, 0.16, and 0.64 μM 10h 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. 23 Aconitine 18779382 Wang, 2008 in vitro H9c2 1, 3, 10 µM 0-15 s Dose dependent inhibition of IKur. 24 Aconitine 34520828 Wang, 2022 in vitro H9c2 3.125–400 μM 24h 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. 25 Amitriptyline 32219715 Aygun, 2020 in vivo Rats 100 mg/kg single 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 26 Amitriptyline 18845675 Chopra, 2009 in vitro Mouse VCMs 0 - 300 µM 0 - 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 27 Amitriptyline 29239964 Tsujikawa, 2018 in vivo Guinea pigs 15 mg/kg 15 min Depression of mean arterial pressure (mean difference 19 mmHg) and prolongation of QRS duration (-12 ms). 28 Amitriptyline 27994924 Hocaoglu, 2016 ex vivo Rat perfused heart 55 µM 1h The amitriptyline infusion significantly decreased LVDP, dp/dtmax and heart rate (HR) and significantly prolonged QRS duration. 29 Amphetamine 31526813 Zwartsen, 2019 in vitro hiPSC-CMs 0.01, 0.1, 1, 10, 100, 300, 1000 μM 2-30 min, 24h Decreased spike amplitude at 100 μM. Decreased beat rate at 300 µM. Prolonged FPDc concentration-dependently. No sig. effect on cell viability. 30 Amsacrine 3838387 Kim, 1985 in vivo Rats 3 - 12 mg/m2 Weekly, 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. 31 Amsacrine 3839172 Merkin, 1985 ex vivo Rat perfused heart 1.5 - 2.5 µg/mL Perfusion 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). 32 Arsenic trioxide 23161055 Vineetha, 2013 in vitro H9c2 5, 7.5 and 10 μM Analysis 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. 33 Arsenic trioxide 34037972 Vineetha, 2021 in vitro H9c2 5 µM Analysis 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 34 Arsenic trioxide 29867492 Zhang, 2021 in vitro H9c2 2.5, 5, 10 μM 24h Mitochondrial dysfunction: mito structural damage, abnormal mPTP opening, increased ROS production, decreased ATP content. 35 Arsenic trioxide 26815588 Khoei, 2016 in vitro H9c2 0.5, 1, 2 µM 24h, 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. 36 Arsenic trioxide 30717322 Wang, 2019 in vitro ARVMs 100 µM 20 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. 37 Arsenic trioxide 26886836 Varghese, 2017 in vitro H9c2 10 µM 24h Reduced cell viability (MTT, 80% ), increased LDH release (160%), sig. increased lipid peroxidation and cellular Ca2+ levels. Sig. Alterations in ∆Ψm (JC-1 staining). 38 Arsenic trioxide 28092839 Yu, 2017 in vitro H9c2 4 µM 24h 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. 39 Arsenic trioxide 18346055 Zhao, 2008 in vitro H9c2 2 - 10 µM 24h 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. 40 Arsenic trioxide 30090381 Zhang, 2016 in vitro ARVMs 25, 50, 100 µM 0 - 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. 41 Arsenic trioxide 29297235 Vineetha, 2018 in vitro H9c2 10 µM 48h Sig. reduction in total antioxidant capacity, increased [Ca2+]i, reduction in MMP, increased ROS production. Decrease in Nrf2 and Bcl2 gene expression. 42 Arsenic trioxide 32096187 Chen, 2020 in vitro H9c2 10 µM 24h, 48h, 72h Sig. reduced cell viability in time dependent manner. 43 Arsenic trioxide 28391263 Zhang, 2017 in vitro H9c2 2.5, 5, 10, 20, and 40 µM 24h 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. 44 Arsenic trioxide 23201927 Wang, 2013 in vitro H9c2 2, 4, 6, 8, and 10 μM 24h 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. 45 Arsenic trioxide 19203718 Raghu, 2009 in vitro Rat CMs (freshly isolated) 30, 60 and 90 µM 24h, 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. 46 Arsenic trioxide 28094846 Kopljar, 2017 in vitro hiPSC-CMs 1, 3, 10 µM 4h, 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 47 Arsenic trioxide 16597375 Saad, 2006 in vivo Rats 5 mg/kg/day 10 days Sig. increases in serum CK-MB, GPx, LDH and AST. Reduced GSH content, increased MDA and total NOx. 48 Atropine 29123207 Perera, 2017 in vitro Mouse VCMs 10 nm 0-1s 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. 49 Azidothymidine 33161113 Zhao, 2020 in vitro NRVMs 50 µM 0, 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. 50 Azidothymidine 21461578 Gao, 2011 in vitro HCMs 1, 3, 10, 30, 100 µM 48h Cell apoptosis and necrosis in a dose-dependent manner. Elevation of caspase-3 and -7 activity, PARP activity. Sig. increased ROS. 51 Azidothymidine 9895221 Szabados, 1999 in vivo Rats 50 mg/kg/day, 2 weeks 3 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. 52 Azidothymidine 1715447 Lewis, 1991 ex vivo Rat perfused heart 0.2 to 1.0 mg/mL; 29 to 102 mg/kg/day 21, 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. 53 Berberine 29233041 Zhang, 2018 in vitro NRCMs 0.03 - 10 µM 24h Beating rate and amplitude were totally inhibited at 10 µM. Irregular beating occurred at 0.3, 1.0, and 3.0 μM (1.5h). 54 Beta-naphtoflavone 19969063 Zordoky, 2010 in vitro H9c2 10, 20, 30, 50 µM 48h 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 55 Bisphenol A 32144343 Reventun, 2020 in vivo Mice 0-50 mg/kg per day 4, 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. 56 Bisphenol A 32144343 Reventun, 2020 in vitro MAECs, H9c2 0 -100 µM 24, 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. 57 Bisphenol A 34419494 Hyun, 2021 in vitro hiPSC-CMs 0 - 100 µM 24h 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. 58 Bisphenol A 33986332 Kofron, 2021 in vitro 3D cardiac microtissue 1, 10, 100, 1000 nM 20 minutes Sig. increase in APD metrics at 1 nM, but shortened APD metrics at higher concentrations. 59 Bisphenol A 31830493 Cheng, 2020 in vitro hESC-CMs 1000, 200, 8 ng/mL 72h 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. 60 Bisphenol A 25572651 Jiang, 2015 in vivo Rats 50 µg/kg per day 24 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. 61 Bisphenol A 24140712 Gao, 2013 in vitro ARVMs 1 nM 5 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. 62 Bisphenol A 31713131 Amin, 2019 in vivo Rats 30 mg/kg per day 4 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. 63 Bisphenol A 31126002 Lombo, 2019 in vivo Zebrafish 2000 and 4000 μg/L 24h 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. 64 Bisphenol AF 32408210 Gu, 2020 in vitro HCMs 0.02, 0.2, 2, 20, 100, 200 mg/L 24h 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. 65 Bisphenol AF 31981723 Yang, 2020 in vitro hESC-CMs 0, 8, 200 and 1000 ng/mL 48h 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. 66 Bisphenol F 34023961 Cheng, 2022 in vitro hESC-CMs 7 (35 nM), 140, 700, 140, 2800, and 5600 ng/mL 48h 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. 67 Bortezomib 20519734 Nowis, 2010 in vivo Rats 0.2mg/kg 3 times/week for 1 to 3 weeks Left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction 68 Bortezomib 20519734 Nowis, 2010 in vitro H9c2 2.5, 5, 10, 20, 40 nM 24h Reduced cell viability in a time- and dose-dependent manner observed at 5 - 10 nM concentrations. 69 Cadmium (Cd2+) 34255886 Haverinen, 2021 in vitro Rainbow trout CMs 10, 20, and 100 µM 5 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). 70 Cadmium chloride 29993192 Shen, 2018 in vitro hESC-CMs 0.1 - 100 µM 24h 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. 71 Cadmium chloride 33581611 Zhao, 2021 in vivo Swine 20 mg/kg diet 40 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. 72 Cadmium chloride 33626375 Zhao, 2021 in vivo Swine 20 mg/kg diet 40 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. 73 Cadmium chloride 26182376 Chen, 2015 in vitro ARVMs 1 and 100 µM 4 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. 74 Cadmium chloride 26462792 Nazimabashir, 2015 in vivo Rats 5 mg/kg per day 4 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. 75 Cadmium chloride 9882592 Limaye, 1999 in vitro NRCMs 0.05 - 1 µM 0 - 60 min Reduced cell viability sig. at 0.1 µM, beating stopped at 0.5 µM. 76 Carbachol 19159405 Hussain, 2009 in vivo/ vitro Rat cardiac muscle 10 µM Unclear Carbachol (10 µM) evoked a positive inotropic response only in muscles from rats with heart failure (not in healthy rat muscle) 77 Carbachol 2790382 Jakob, 1989 in vitro human atrial heart muscle 10 µM 30 min Carbachol evoked transient decreases of action potential duration and force of contraction in atrial heart tissue 78 Chrysene 17112560 Incardona, 2006 in vivo Zebrafish 22 µM Exp. between 6 and 72 hpf Strong CYP1A induction (22-fold increase of mRNA), but no biological effects. 79 Cocaine 33668403 Verma, 2021 in vitro H9c2 0.1 - 10, 50, 100 µg/mL 72h 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. 80 Cocaine 18952886 Fan, 2009 in vivo Mice 15, 20, 25, 30 mg/kg, 3/day 14 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. 81 Cocaine 18952886 Fan, 2009 in vitro H9c2 0-100 µM 24h 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. 82 Cocaine 12808488 Henning, 2003 in vitro ARVMs 0.1 - 10 µM 72h 1 µM increased myocyte protein content by 28±2%, caused a 45% increase in PKC ratio change. 83 Cocaine 16891908 Henning, 2006 in vitro ARVMs 0.1 - 10 µM 1, 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. 84 Cocaine 16382175 Lattanzio, 2005 in vitro H9c2 0.1 - 10 mM 2-5 mins Sig. Increased ROS production, MMP depolarization, [Ca2+]i increase. 85 Cocaine 16382175 Lattanzio, 2005 in vivo Rabbits 2mg/kg 30m 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. 86 Cocaine 8792843 Yuan, 1996 in vitro NRCMs 10^-5 - 10^-3 M 3 - 72h Dose and time dependent increase in LDH leakage, decrease in ATP, reduced MMP. 87 Cocaine 8792843 Yuan, 2000 in vitro NRCMs 10^-5 - 10^-3 M 6, 12, 24h Dose and time dependent increase in LDH leakage. Sig. decreased the mitochondrial respiratory control ratio at highest dose. 88 Cocaine 9455993 Besse, 1997 in vivo Rats 40 mg/kg per day 30m, 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. 89 Cocaine 1566279 Welder, 1992 in vitro ARCMs 10^-9 - 10^-3 M 1, 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. 90 Cocaine 20702336 Welder, 1988 in vitro NRCMs 10^-7 - 10^-3 M 24h 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. 91 Cocaine 8776273 Bai, 1996 in vitro Rat VCMs 50, 100, 150 µM 0 - 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.). 92 Cocaine 31526813 Zwartsen, 2019 in vitro hiPSC-CMs 0.01, 0.1, 1, 10, 30, 100 μM 2-30 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. 93 Cresyl diphenyl phosphate (CDP) 25661707 Du, 2015 in vivo Zebrafish 0.10, 0.50, 1.0 mg/L 72 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. 94 Daunorubicin 26279420 Wu, 2015 in vitro H9c2 1 µM 24h 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. 95 Daunorubicin 21046361 Vavrova, 2011 in vivo Rabbits 3mg/kg Weekly, 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. 96 Daunorubicin 21046361 Vavrova, 2011 in vitro H9c2 0.1 - 10 µM 24h 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. 97 Daunorubicin 17587482 Adamcova, 2007 in vitro NRVMs 0.1 - 3 µM 72h Reduced cell viability (IC50 0.55 µM). Significant increase in LDH, cTnT and cTnI 98 Daunorubicin 17587482 Adamcova, 2007 in vivo Rabbits 3mg/kg Weekly, 10 weeks Reduced left ventricular fractional shortening (FS). Sig. increase in cardiac troponin cTnT and cTnI 99 Daunorubicin 16444662 Mojzisova, 2006 in vitro Rat CMs (freshly isolated) 40 µg/mL 24h, 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. 100 Daunorubicin 18803248 Mojzisova, 2009 in vitro H9c2 40 µg/mL 24h, 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). 101 Daunorubicin 8808986 Cusack, 1996 in vitro Adult and old rat CMs (freshly isolated) 175 µM 210 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). 102 Daunorubicin 29039532 Li, 2017 in vitro H9c2 1 µM 24h 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. 103 Daunorubicin 35596909 Cejas, 2022 in vitro hiPSC-CMs 5 µM 14h Reduced cell viability (down to 30.41 ± 19.73%). 104 Decabrominated diphenyl ether 30802833 Jing, 2019 in vivo Rats 5, 50 and 500 mg/kg per day 28 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. 105 Decabromodiphenyl ethane 30802833 Jing, 2019 in vivo Rats 5, 50 and 500 mg/kg per day 28 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. 106 Di(2-ethylhexyl)phthalate 22672789 Posnack, 2012 in vitro NRCMs 50-100 μg/mL 72h 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. 107 Di(2-ethylhexyl)phthalate 29377175 Tang, 2018 in vivo Pregnant mice 250, 500, 1000 mg/kg per day E6.5 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. 108 Dieldrin 28385952 Slade, 2017 in vivo Zebrafish 0.03, 0.15 or 1.8 µg/g feed 21d 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. 109 Doxorubicin 28300219 Zhao, 2017 in vitro hiPSC-CMs 1 nm - 100 µM 48h 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. 110 Doxorubicin 26537877 Chaudhari, 2016 in vitro hiPSC-CMs 156 nm 48h, 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. 111 Doxorubicin 21590773 Budde, 2011 in vivo Mice 20 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 112 Doxorubicin 21590773 Budde, 2011 in vitro HL-1 10 - 1000 nM 24h, 48h doxorubicin concentrations up to 333 nmol/L did not significantly alter the viability of adherent HL-1 cells. 113 Doxorubicin 34775319 He, 2021 in vitro NRCMs, H9c2 1 µM 48h 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. 114 Doxorubicin 29133306 Gupta, 2018 in vitro hiPSC-CMs 0.1 µM 72h 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. 115 Doxorubicin 34525346 Magdy, 2021 in vitro hiPSC-CMs 0.01 - 100 µM 72h 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. 116 Doxorubicin 34207549 Adamczyk, 2021 in vitro H9c2, hiPSC-CMs 5, 10 µM 90 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. 117 Doxorubicin 32487993 Arai, 2020 in vitro 3D cardiac microtissue 10 µM 24h, 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 118 Doxorubicin 28421296 Chaudhari, 2017 in vitro hiPSC-CMs 156 nM 48h, 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. 119 Doxorubicin 31231550 McSweeney, 2019 in vitro hiPSC-CMs 100, 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. 120 Doxorubicin 32075047 Zhang, 2020 in vitro hiPSC-CMs, AC16, H9c2 1 µM 24h 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. 121 Doxorubicin 31106979 Cui, 2019 in vitro hiPSC-CMs 2.5 µM 24h 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. 122 Doxorubicin 26842497 Chaudhari, 2016 in vitro hiPSC-CMs 156 nM 48h, 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. 123 Doxorubicin 28456566 Louisse, 2017 in vitro hiPSC-CMs 150, 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. 124 Doxorubicin 32185414 Karhu, 2020 in vitro hiPSC-CMs 100, 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. 125 Doxorubicin 28967302 Takeda, 2017 in vitro hiPSC-CMs 0.1, 1, 2, 5, 10 µM 24h 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%) 126 Doxorubicin 28094846 Kopljar, 2017 in vitro hiPSC-CMs 1, 3, 10 µM 4h, 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 127 Doxorubicin 34536182 Atum, 2022 in vitro hiPSC-CMs 2 µM 24h 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. 128 Doxorubicin 34931757 Berecz, 2022 in vitro hiPSC-CMs 0, 1, 3, 10 µM 48h 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. 129 Doxorubicin 30634681 Oliveira, 2019 in vitro H9c2 0.13 - 5 µM 24h, 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. 130 Doxorubicin 30862114 Mendes, 2019 in vitro H9c2 1 µM 48h Reduced cell viability, both in MTT assay (50.2 ± 3.8%) and in NR uptake assay (31.3 ± 9.3%) compared to control (100%). 131 Doxorubicin 29913208 Damiani, 2018 in vitro H9c2 0.1, 1 µM 24h 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. 132 Doxorubicin 26660439 Hasinoff, 2016 in vitro NRVMs 0 - 100 µM 6h, 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) 133 Doxorubicin 32336319 Ryu, 2020 in vivo/ vitro Rats, NRCMs, hESC-CMs 2x 15 mg/kg, 5 µM 24h 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. 134 Endosulfan 32344260 Wei, 2020 in vitro AC-16 0, 1.25, 2.5, 5, 10, 20, 40 μg/mL 24h 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. 135 Endosulfan 32344260 Wei, 2020 in vivo Rats 1, 5 and 10 mg/kg 21 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. 136 Endosulfan 15337585 Kalender, 2004 in vivo Rats 2 mg/kg per day 6 weeks SOD, GPx, CAT activities and MDA level increased in the endosulfan-treated group heart tissue. Cytoplasmic edema and swelling and vacuolization of mitochondria. 137 Endosulfan 23758152 Ozmen, 2013 in vivo Rabbits 1 mg/kg per day 6 weeks Microscopic haemorrhages, single-cell necrosis, inflammatory reactions, and fibrotic changes in the myocardium. Sig. Caspase-3 immunoreactivity. 138 Endosulfan 19086562 Jalili, 2007 in vivo Rats 2 mg/kg per day 28 days Myocardial haemorrhages with interstitial oedema. Diapedesis of leukocytes. Myocardium degeneration, granulation of myofibrils with pyknotic nuclei. Thickening of arterial walls. 139 Endosulfan 28273598 Wei, 2017 in vivo Rats 1, 5, 10 mg/kg per day 21 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. 140 Endosulfan 28273598 Wei, 2017 in vitro HUVECs 1, 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. 141 Endosulfan 1702244 Anand, 1990 in vivo Rabbits 2.5 and 5.0 mg/kg 2/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. 142 Hexabromocyclododecane 26476318 Wu, 2016 in vivo Zebrafish 0, 2, 20, 200 nM 72h 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). 143 Hexabromocyclododecane 26476318 Wu, 2016 in vitro H9c2 200 nM 24h 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. 144 Idarubicin 34787021 Zhang, 2021 in vitro HL-1 1, 3, 5, 7, 9 µM 24h 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). 145 Idarubicin 32629160 Gossmann, 2020 in vitro hiPSC-CMs 10, 100 nM. 1, 10 µM 1 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%). 146 Idarubicin 12426639 Kalender, 2002 in vivo Rats 5 mg kg weekly 8 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. 147 Imatinib 28964914 Savi, 2018 in vivo Rats 50, 100 mg/kg 3 times per week 3 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. 148 Imatinib 28964914 Savi, 2018 in vitro Cardiac progenitor cells 5 µM 6h, 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). 149 Imatinib 28315715 Chambers, 2017 in vitro H9c2 50 µM 24h 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. 150 Imatinib 34136360 Kobara, 2021 in vitro NRCMs 1, 5, 10 µM 6h 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. 151 Imatinib 34136360 Kobara, 2021 in vivo Mice 50, 200 mg/kg/day 5 weeks 200 mg: dilatation of the left ventricle (LV) and reduced LV fractional shortening. Apoptosis and LC3-II expression in cardiac tissue were increased. 152 Imatinib 30910525 Burke, 2019 in vitro Rat cardiact fibroblasts 3, 10 µM 24h, 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. 153 Imatinib 24504921 Maharsy, 2014 in vivo Mice 200 mg/kg/day 5 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 154 Imatinib 22641616 Hu, 2012 in vitro NRCMs 0 - 100 µM 24h Cardiomyocyte dysfunction through disruption of autophagy and induction of ER stress, independent of c-Abl inhibition. 155 Imatinib 16862153 Kerkela, 2006 in vivo Mice 50, 100, 200 mg/kg/d 3 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 156 Imatinib 16862153 Kerkela, 2006 in vitro NRVMs 2, 5, 10 µM 24h 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 157 Imatinib 22843568 Rana, 2012 in vitro hiPSC-CMs 0.01 - 100 µM Unclear Reduced cell viability and oxygen consumption rate to 5% at 100 µM. 158 Imatinib 25505575 Herman, 2014 in vivo Rats 50, 100, 200 mg/kg/day 28 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. 159 Imatinib 16597375 Saad, 2006 in vivo Rats 30 mg/kg/day 10 days Sig. increases in serum CK-MB, GPx, LDH and AST. Sig. increase of cardiac GSH and MDA. 160 Imatinib 34973290 Song, 2021 in vivo Mice 25, 50, 100 mg/kg 14 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. 161 Imatinib 34973290 Song, 2021 in vitro H9c2 10, 20, 40 µM 24h 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. 162 Imatinib 35216404 Bouitbir, 2022 in vitro H9c2 1 to 100 µM 24h 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 163 Imatinib 35710779 Smith, 2022 in vitro Cardiac progenitor cells 1, 5, 10, 100 µM 24h, 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. 164 Lead (Pb2+) 23391631 Ansari, 2013 in vitro H9c2 25, 50, and 100 μM 24h 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. 165 Lead chloride 28836190 Mattos, 2017 ex vivo Guinea pig hearts 1-200 μM 5-10 min Acute exposure had a negative inotropic effect and increased diastolic tension. Decreased amplitude of the contractile force. 166 Lead chloride 28836190 Mattos, 2017 in vitro Guinea pig CMs 1-200 μM 5-10 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. 167 Lead nitrate 23391631 Ansari, 2013 in vivo Rats 25, 50 and 100 mg/kg per day 3 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. 168 Lindane 23458197 Padma, 2013 in vivo Rats 100 mg/kg per day 30 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. 169 Lindane 1702244 Anand, 1990 in vivo Rabbits 2.5 and 5.0 mg/kg 2/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. 170 Lindane 16127354 Ananya, 2005 in vivo Rats 1.5 and 7 mg/kg per day 21 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. 171 Loperamide 30597669 Olofinsan, 2019 in vivo Rats 1.5, 3, 6 mg/kg/day 7 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. 172 Loperamide 33125619 Wolfes, 2021 in vitro Rabbit heart perfusion 0.2, 0.35, 0.5 µM 0-1s Sig. increase in QT interval, APD90, and ventricular tachycardia (VT) episodes. 173 Lovastatin 14678744 Rabkin, 2003 in vitro Chicken embryo CMs 10, 50, 100 µM 24h 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. 174 Lovastatin 17158337 Hauck, 2006 in vivo/ vitro Rats, NRVMs 20 mg/kg/day 14 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. 175 MDMA 31526813 Zwartsen, 2019 in vitro hiPSC-CMs 0.01, 0.1, 1, 10, 100, 300, 1000 μM 2-30 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. 176 Mitomycin C 8763838 Pritsos, 1996 in vivo Mice 0, 5, 10, 20 mg/kg, 1 or 2 injections 48h after treatment Decreased heart tissue ATP to 40% of control (single and double, all doses). 177 Mitoxantrone 32894303 Costa, 2020 in vitro HL-1 0.1, 1, 10 µM 2, 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. 178 Mitoxantrone 29913208 Damiani, 2018 in vitro H9c2 0.1, 1 µM 24h 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. 179 Mitoxantrone 23545721 Rossato, 2013 in vitro H9c2 100 nM, 1 µM 24h Reduced cell viability (% of control): 69 ± 5% (100nM), 63 ± 7 % (1 µM) 180 Mitoxantrone 24046265 Rossato, 2013 in vitro H9c2 10, 100 nM, 1, 5, 10, 50, 100 μM 24, 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. 181 Mitoxantrone 23261645 Schweikart, 2013 in vitro hiPSC-CMs 0.1, 1, 3, 10, 30 µM 1h, 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. 182 Mitoxantrone 26660439 Hasinoff, 2016 in vitro NRVMs 0 - 100 µM 24h, 48h, 72h 15% LDH increase over control at 1 µM (72h), dose response plot available. 183 Mitoxantrone 24096626 Rossato, 2014 in vivo Rats 7.5 mg/kg 22 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. 184 Mono(2-ethylhexyl)phthalate 33029813 Wang, 2021 in vitro AC-16 0 - 120 µM 24h 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. 185 Nifedipine 32336319 Ryu, 2020 in vivo/ vitro Rats, NRCMs, hESC-CMs 2x 100 mg/kg, 50 µM 24h 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. 186 Nifedipine 31526813 Zwartsen, 2019 in vitro hiPSC-CMs 3, 10, 30 nM 2-30 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. 187 Nifedipine 33109927 Vinagre, 2021 in vitro hiPSC-CMs 0.01, 0.03, 0.1, 0.3 µM 30 min exposure, 20s recording Concentration-dependent decreased amplitude, contraction and relaxation time, APD (APD30 and APD90) 188 Nifedipine 27184445 Dempsey, 2016 in vitro hiPSC-CMs 0 - 1 µM Unclear 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. 189 Nifedipine 31079550 Lam, 2019 in vitro hiPSC-CMs 433 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. 190 Nifedipine 29274391 Goineau, 2017 in vitro hiPSC-CMs 0.01, 0.03, 0.1, 0.3 and 1 μM 5 min Concentration-dependently shortened FPDcF, minimum effective concentration was 0.03 µM 191 Nifedipine 20034863 Braam, 2010 in vitro hESC-CMs 1 nm - 100 µM 2 min Dose-dependent shortening of the FPD, which was initiated at 10 nM and saturated at 1 μM 192 Paclitaxel 17400210 Pentassuglia, 2007 in vitro ARVMs 0–15 μM 48h 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. 193 Perfluorooctane sulfonamide (PFOSA) 35652794 Chen, 2022 in vivo Zebrafish 0.01, 0.1, 1, 10, and 100 μg/L 120 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. 194 Perfluorooctane sulfonate (PFOS) 15737613 Harada, 2005 in vitro Guinea pig VMs 1, 10, 20, 100 µM Unclear 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. 195 Perfluorooctane sulfonate (PFOS) 32861759 Liu, 2020 in vitro mESC-CMs 40 µM 3 - 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. 196 Perfluorooctane sulfonate (PFOS) 32088431 Yang, 2020 in vitro hESC-CMs 0.1, 1, 10, 30, and 60 μM 0 - 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. 197 Perfluorooctane sulfonate (PFOS) 28288859 Tang, 2017 in vitro mESC-CMs 40 µM 3 - 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) 198 Perfluorooctane sulfonate (PFOS) 34815766 Xu, 2022 in vivo Rats 1 and 10 mg/kg every other day 14 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. 199 Perfluorooctanoic acid (PFOA) 31445018 Lv, 2019 in vitro Chicken embryo CMs 1, 10, 30 or 100 μg/mL 24, 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. 200 Perfluorooctanoic acid (PFOA) 22273728 Jiang, 2012 in vivo Chicken embryo heart 0, 0.5, 1 and 2 mg/kg egg D19, 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. 201 Perfluorooctanoic acid (PFOA) 26098785 Jiang, 2016 in vitro Chicken embryo CMs 2 mg/kg of egg in ovo, 0 to 100 µg/mL in vitro 1 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. 202 Perfluorooctanoic acid (PFOA) 31037826 Salimi, 2019 in vivo Mice 1, 10, and 20 mg/kg per day D5 - 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. 203 Perfluorooctanoic acid (PFOA) 28934691 Zhao, 2017 in vivo Chicken 2 mg/kg egg in ovo Unclear Significant elevation of heart rate and thinning of right ventricular wall thickness. PPARa silencing sig. increased right ventricular wall thickness of PFOA treated animals. 204 Permethrin 34224971 Feriani, 2021 in vivo Rats 5 mg/kg/day 12 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. 205 Permethrin 23806482 Vadhana, 2013 in vivo Rats 34.05 mg/kg, per day, 21 days 500 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. 206 Permethrin 20574784 Vadhana, 2010 in vitro Rat CMs 5, 10, 20 µM 1h 5, 10, and 20μM reduced cell viability 1.02, 6.12 and 5.1%. Oxidative damage to purine bases. Sig. DNA damage. 207 Phenanthrene 31237719 Vehniainen, 2019 in vitro Rainbow trout CMs 0.3, 1.0, 10, and 30 µM Unclear 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 208 Phenanthrene 32738692 Rigaud, 2020 in vivo Rainbow trout 100 µg/L 1, 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. 209 Phenanthrene 33523501 McGruer, 2021 in vivo Zebrafish 12 or 15 µM 6 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. 210 Phenanthrene 32957295 Zheng, 2020 in vivo Medaka 0, 2, 10, 50, and 250 μg/L 28 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. 211 Phenanthrene 31499312 Ainerua, 2020 in vitro Brown trout VCMs 5, 15 or 25 μM 30 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%). 212 Phenanthrene 28570901 Cypher, 2017 in vivo Zebrafish 0, 1, 100, and 1000 μg/L Exposure 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. 213 Phenanthrene 26830171 Huang, 2016 in vivo Rats 0.5, 5, 50 μg/kg per day, 21 days 6 weeks Increased heart weight and CM size dose-dependently, indicating cardiac hypertrophy. Increased deposition of collagen in the heart sections. 214 Phenanthrene 26830171 Huang, 2016 in vitro H9c2 0.05–50 nM 12, 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. 215 Phenanthrene 23948075 Zhang, 2013 in vivo Zebrafish 0.05, 0.5, 5, 50 nM 72hpf Sig. increased interbeat variation (arrhythmia) at 5 and 50 nM. 216 Phenanthrene 23948075 Zhang, 2013 in vitro H9c2 0.05, 0.5, 5, 50 nM 72h 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 217 Phenylephrine 29339422 Sun, 2019 in vitro NRVMs 50 µM 6, 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 218 Phenylephrine 29128355 Romano, 2017 in vitro NRCMs 100 µM 48h Cardiomyocyte hypertrophy was induced. Sig. cell size increase over control. 219 Phenylephrine 32898528 Li, 2020 in vitro hESC-CMs 25, 50 µM 48h 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) 220 Phenylephrine 27940402 Ji, 2017 in vitro NRCMs 100 µM 48h 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 221 Phenylephrine 34790705 Fang, 2021 in vitro NRVMs 50 µM 48h Hypertrophy. Sig. reduced intracellular Zinc concentration, SLC39A2 is involved. Slc39a2 knockdown sig. potentiated PE-induced cell size enlargement. 222 Phenylephrine 29862242 Gao, 2018 in vitro NRVMs 50 µM 48h Hypertrophy. Reduced PPARγ and PGC1-α. Increased ANP and BNP, CM size. 223 Phenylephrine 27161004 Zhang, 2016 in vitro NRVMs 50 µM 48h 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. 224 Phenylephrine 34384564 Sunagawa, 2021 in vitro NRCMs 30 µM 48h Increases in transcriptions of atrial naturistic factor (ANF) and brain naturistic peptide (BNP), markers of cardiomyocyte hypertrophy. PE induced acetylation of histone H3K9 225 Phenylephrine 17287366 Prasad, 2007 in vitro NRCMs 20 µM 3-7 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. 226 Phenylephrine 27094368 Shen, 2016 in vitro NRCMs 100 µM 24h 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 227 Phenylephrine 34914791 Peng, 2021 in vitro Mouse VCMs 100 µM 48h 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. 228 Phenylephrine 28194469 Peng, 2017 in vivo Mouse perfused heart 20 mg/kg/day 30 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. 229 Phenylephrine 28497371 Dong, 2017 in vitro NRCMs 50 µM 48h 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 230 Phenylephrine 25449040 Dong, 2015 in vitro NRVMs 10 µM 3 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. 231 Phenylephrine 22818713 Anestopoulos, 2013 in vitro H9c2 100 µM 24h Sig. increase in cell area, ANP, ERK1/2 activity and pAkt. 232 Phenylephrine 15452191 Gan, 2005 in vitro NRCMs 10 µM 24h 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. 233 Phenylephrine 31163678 Chaanine, 2019 in vitro ARCMs 10 µM 2h Mitochondrial fission, fragmentation, mitophagy, and vascular degeneration. 234 Phenylephrine 29110214 Zhao, 2018 in vitro NRCMs 50 µM 48h Downregulation of miR-223, upregulation of STIM1. 235 Phenylephrine 29901150 Liu, 2018 in vitro NRCMs 10 µM 48h 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. 236 Phenylephrine 16690042 Kleiner, 2006 in vitro NRCMs 10 µM 30m, 1, 3h Transcript levels c-Jun and c-Fos were rapidly and markedly increased, JunD decreased. 237 Phenylephrine 25770146 Zhong, 2015 in vitro NRVMs 10 µM 24h 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. 238 Phenylephrine 15276029 Kemp, 2004 in vitro NRVMs 100 µM 1h Expression of three clones (C208, C53 (CTGF) and C64) was increased. Increased CTGF mRNA 2.25 ± 0.27-fold. 239 Phenylephrine 19966059 Pang, 2009 in vitro NRVMs 10 µM 6, 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. 240 Phenylephrine 25636810 Huang, 2015 in vitro NRCMs 20 µM 24h 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. 241 Phenylephrine 35468773 Qian, 2022 in vitro NRCMs, AMCMs 50 µM 24h Enhanced phosphorylation level of CaMKII, MEK, ERK1/2, PLN and RyR2. Increased Ca2+ spark frequency. 242 Pyrene 32738692 Rigaud, 2020 in vivo Rainbow trout 32 μg/L 1, 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. 243 Pyrene 17112560 Incardona, 2006 in vivo Zebrafish 25 µM Exp. 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 244 Retene 31237719 Vehniainen, 2019 in vitro Rainbow trout CMs 0.1, 1.0, and 10 µM Unclear 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. 245 Retene 32738692 Rigaud, 2020 in vivo Rainbow trout 32 μg/L 1, 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). 246 Retene 26667672 Vehniainen, 2016 in vivo Rainbow trout 32 μg/L 1, 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. 247 Retene 21040984 Scott, 2011 in vivo Zebrafish 12.5 μg/mL 24, 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. 248 Rofecoxib 32111102 Brenner, 2020 in vivo Rats 5.12 mg/kg/day 28 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. 249 Rosiglitazone 24449420 He, 2014 ex vivo Mouse perfused heart 1, 3, 10, 30 µM 2h 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. 250 Rosiglitazone 24249632 Mishra, 2014 in vitro H9c2 50, 60 µM 24h 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. 251 Rosiglitazone 24249632 Mishra, 2014 in vivo Mice 10 mg/kg/day 10 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. 252 Rosiglitazone 28822817 Pharaon, 2017 in vitro NRCMs 0.5, 1, 2, 5, 10, 50 and 100 μM 12, 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). 253 Sibutramine 33389602 Alyu, 2021 in vitro ARVMs 10 µM 3h 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. 254 Tebuconazole 32980069 Othmene, 2020 in vivo Rats 0.9, 9, 27 and 45 mg/kg 28 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. 255 Tebuconazole 32006631 Othmene, 2020 in vivo Rats 0.9, 9, 27 mg/kg 28 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%). 256 Tebuconazole 32798748 Othmene, 2020 in vitro H9c2 20-120 µM, 60 µM 24h 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. 257 Tebuconazole 35202779 Miranda, 2022 ex vivo Mouse perfused heart 0.3, 3, 30, and 300 μM Unclear 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. 258 Tebuconazole 35202779 Miranda, 2022 in vitro Mouse VCMs 30 µM Unclear 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. 259 Telmisartan 23073892 Kim, 2012 ex vivo Rat perfused heart 3, 10, 30, and 100 μM 3h 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. 260 Tetrabromobisphenol A 25846749 Wu, 2016 in vivo Zebrafish 0.1, 0.4, 0.7, 1 mg/L 8 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. 261 Tetrabromobisphenol A 24596333 Yang, 2015 in vivo Zebrafish 0.5, 1 mg/L 24 - 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. 262 Tributyltin 30690233 Pereira, 2019 ex vivo Mouse perfused heart 1 nM to 10 mM 5 min Depressed cardiac contractility and relaxation in papillary muscle and intact whole heart. Increased cytosolic, mitochondrial ROS production and decreased mitochondrial membrane potential. 263 Tributyltin 30690233 Pereira, 2019 in vitro Mouse VCMs 100 nM 5 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. 264 Tributyltin 22852845 Santos, 2012 ex vivo Rat perfused heart 100 ng/kg per day 15 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. 265 Triphenyl phosphate (TPhP) 25661707 Du, 2015 in vivo Zebrafish 0.10, 0.50, 1.0 mg/L 72 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. 266 Tris (2-butoxyethyl) phosphate (TBOEP) 33069947 Xiong, 2021 in vivo Zebrafish 20, 200, 1000 and 2000 µg/L Exp. 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. 267 Tris-(1,3-dichloro-2-propyl) phosphate (TDCPP) 30685670 Zhong, 2019 in vivo Zebrafish 300 and 500 μg/L 72hpf 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. 268 Tris-(1,3-dichloro-2-propyl) phosphate (TDCPP) 30685670 Zhong, 2019 in vitro HUVECs 10 - 200 µM 24h 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. 269 Verapamil 24840785 Sun, 2014 in vitro ARVMs 10 µM 0 - 7 min Sarcomeric contractile function decreased continually. decreased the resting Ca2 + ratio, amplitude of Ca2 + ratio and amplitude/resting calcium 270 Verapamil 27184445 Dempsey, 2016 in vitro hiPSC-CMs 0 - 1 µM Unclear 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. 271 Verapamil 31079550 Lam, 2019 in vitro hiPSC-CMs 813 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). 272 Verapamil 29274391 Goineau, 2017 in vitro hiPSC-CMs 3, 10, 30, 100 and 300 nM 5 min Concentration-dependently shortened FPDcF, minimum effective concentration was 30 nM 273 Verapamil 11581079 Hill, 2001 ex vivo Rat left ventricular muscle 31 to 1020 nM 15m 510 nM produced consistent reduction in developed tension of 52.9±3.2%.