Table 3.

Key characteristics (KCs) of cardiovascular toxicants applied to two classic cardiotoxic drugs and the chemotherapeutic agent arsenic trioxide.

KC	Evidence for each KC for doxorubicin (human–animal–in vitro)	Evidence for each KC for fenfluramine (human–animal–in vitro)	Evidence for each KC for arsenic trioxide (human–animal–in vitro)
Mainly cardiac
1. Impairs regulation of cardiac excitability	QTc prolongation in humans and monkeys unrelated to potassium channel (hERG) inhibition (Engwall et al. 2021; Nousiainen et al. 1999).	—	QTc prolongation in humans with animal and in vitro evidence of potassium channel (hERG) inhibition (Alexandre et al. 2018; Dennis et al. 2007).
2. Impairs cardiac contractility and relaxation	Alters calcium homeostasis by inducing calcium leakage from the sarcoplasmic reticulum (Nebigil and Désaubry 2018).	—	Clinically relevant concentrations of arsenic trioxide causes intracellular calcium overload from damaged mitochondria (Varga et al. 2015).
3. Induces cardiomyocyte injury and death	Induces cardiomyocyte apoptosis, necrosis, necroptosis, and autophagy in cardiac cells and mice, which lead to injury and cell death (Ma et al. 2020).	—	Induces cardiomyocyte apoptosis and death in animal and cell culture models (Varga et al. 2015).
4. Induces proliferation of valve stroma	—	In vitro activation of $5{\text{-HT}}_{2\mathrm{B}}$ receptors; dose-dependent valve leaflet fibroplasia and thickening in mice, rats, and humans; development of valvular cardiac disease in clinical studies (Elangbam et al. 2008; Elangbam 2010; Fitzgerald et al. 2000; Reid et al. 2013; Roth 2007; Rothman et al. 2000; Taylor et al. 2007).	—
Mainly vascular
5. Impacts endothelial and vascular function	—	—	—
6. Alters hemostasis	—	—	—
7. Causes dyslipidemia	—	—	—
Both cardiac and vascular
8. Impairs mitochondrial function	Promotes mitochondrial fission, inhibits mitochondrial fusion, and impairs mitochondrial function in several ways, including decreasing the oxygen consumption rate and altering mitochondrial membrane potential (Osataphan et al. 2020).	—	Pro-apoptotic effect of arsenic trioxide in ventricular cardiomyocytes shown to be associated with Parkin-dependent ubiquitin proteasome activation and loss of mitochondrial membrane potential (Varga et al. 2015).
9. Modifies autonomic nervous system activity	—	—	—
10. Induces oxidative stress	Induces ROS and decreases superoxide dismutase‐2 in cardiac tissues (Osataphan et al. 2020).	—	—
11. Causes inflammation	Induces markers of inflammation in vivo, as reviewed by Prathumsap et al. (2020).	—	Chronic environmental exposures are associated with elevated circulating inflammatory markers in humans (Cosselman et al. 2015; Wu et al. 2014). Leads to vascular inflammation, endothelial dysfunction and atherosclerosis development in animals (Cosselman et al. 2015; States et al. 2009).
12. Alters hormone signaling	—	—	—

Note: Details are provided for those KCs that we for cancer treatments and cardiovascular toxicity of the European Society of Cardiology considered to have the strongest evidence for each agent (e.g., a combination of data from human epidemiological/clinical studies, in vivo animal studies and in vitro studies). —, Other KCs; $5{\text{-HT}}_{2\mathrm{B}}$, 5-HT subtype 2B; hERG, ether-à-go-go-related gene; QTc, corrected QT interval; ROS, reactive oxygen species; RyR2, ryanodine receptors.