Key Characteristics of Cardiovascular Toxicants

Abstract

Background: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches.

Objectives: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them.

Methods: An expert working group was convened to discuss mechanisms associated with CV toxicity.

Results: The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1-4 below), the vascular system (5-7), or both (8-12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling.

Discussion: These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM $\le 2.5\mu m$ in aerodynamic diameter (${\mathrm{PM}}_{2.5}$)] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321.

Figure 1.

Utility of the key characteristics (KCs) of cardiovascular toxicants in research, drug discovery, hazard assessment, and clinical practice. An illustration of how the KCs could be used in different areas and how translation of the resulting information could lead to accelerated research, inform better regulatory decisions, improve clinical practice, and ultimately prevent CVD. Note: CV, cardiovascular; CVD, cardiovascular disease; NAM, novel assessment methodologies.

Figure 2.

Key characteristics (KCs) associated with cardiac and vascular dysfunction. A summary of how different KCs of cardiovascular toxicant could affect (A) the heart and (B) the vasculature in both the acute and chronic setting. Some of the detailed mechanisms are given, as well as some clinical end points. Note: ANS, autonomic nervous system; AVN, avascular necrosis; CCS, cardiac conduction system; ${\mathrm{CO}}_2$, carbon dioxide; ${\mathrm{H}}^{+}$, hydrogen ion; ${\mathrm{K}}^{+}$, potassium ion; ${\mathrm{O}}_2$, oxygen; SAN, sinoatrial node.

Figure 3.

Key characteristics (KCs) associated with ${\mathrm{PM}}_{2.5}$ toxicity. A summary of how different KCs of fine particulate air pollution (${\mathrm{PM}}_{2.5}$) could affect the heart and the vasculature. Some of the detailed mechanisms are given, as well as some clinical end points. Note: ${\mathrm{H}}_2{\mathrm{O}}_2$, hydrogen peroxide; ${\text{OH}}^{•}$, hydroxide; ${\mathrm{O}}_2$^•−, reactive oxygen species; ${\text{ONOO}}^{–}$, peroxynitrite; ${\mathrm{PM}}_{2.5}$, particulate matter $\le 2.5\mathrm{\mu }\mathrm{m}$ in aerodynamic diameter (fine particulate matter).

Figure 4.

Key characteristics (KCs) associated with doxorubicin cardiotoxicity. A summary of how different KCs of doxorubicin could affect the heart and the vasculature. Some detailed mechanisms are given, as well as some clinical outcomes. Note: APAF1, apoptotic protease activating factor 1; Bad, Bcl-2-associated agonist of cell death; Bax, Bcl-associated X; BclXL, B-cell lymphoma-extra large; ${\mathrm{Ca}}^{2+}$ calcium ion; CASP3, caspase 3; CASP9, caspase 9; CytoC, cytochrome complex; ECG, electrocardiogram; eNOS, endothelial nitric oxide synthase; ER, estrogen receptor; ${\mathrm{Fe}}^{2+}$, iron ion; LV, left ventricular; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; Topo II, topoisomerase II; UPS, ubiquitin-proteasome system.