Linking Pollutants and Therapeutics to Heart Health: Key Characteristics of Cardiovascular Toxicants.

Categorizing chemicals that affect human health according to their key characteristics (KCs) has proven useful for carcinogens,1 endocrine-disrupting chemicals,2 and reproductive toxicants.3,4 The term “key characteristics” refers to shared properties of chemicals that are known to cause a particular human health outcome. The KC concept has been applied by researchers, regulatory agencies, and bodies such as the International Agency for Research on Cancer to better understand disease mechanisms and to help prioritize the development of new in vitro or in vivo chemical testing assays.5,6 The authors of a commentary recently published in Environmental Health Perspectives extend this work to chemicals with cardiovascular toxicity.7

By understanding the key characteristics of cardiovascular toxicants, researchers and regulators can better identify chemicals that may contribute to cardiovascular diseases as well as assess their mechanisms of action. Image: © iStock/andresr.

A diverse panel of 19 experts identified and grouped cardiovascular toxicants based on mechanistic similarities between therapeutics and environmental chemicals, such as air pollutants, arsenic, and lead. “We used textbook lists of drugs and chemicals that cause cardiovascular toxicity and also made a list of probable mechanisms,” says Martyn Smith, a professor of toxicology at the University of California, Berkeley, and the commentary’s senior author. “Since we typically have a better understanding of drug mechanisms, we wanted to apply that information to environmental pollutants that affect the cardiovascular system in similar ways.”

The panel identified 12 KCs, which they divided into three groups: those that primarily affect cardiac tissue (KC1–KC4), those that primarily affect vascular tissue (KC5–KC7), and those that affect both tissue types (KC8–KC12). The first group includes “KC1: impairs regulation of cardiac excitability,” which describes disruptions of ion channels that balance cardiac excitation and contraction. Abnormal ion channel activity can lead to cardiac arrhythmias and sudden cardiac death.7 Antiarrhythmic drugs8 and the environmental chemical bisphenol A9 are example compounds with KC1.

The second group includes “KC5: impacts endothelial and vascular function,” which describes damage to endothelial or smooth muscle cells in blood vessels. Impairments in these cells, which ensure proper blood flow and nutrient delivery to all organs, may result in atherosclerotic disease, hypertension, myocardial infarction, or other conditions.10 Chemicals with KC5 include antihypertensive drugs,11 arsenic,12 cadmium,13 and organophosphate pesticides.14

The third group includes “KC8: impairs mitochondrial function.” As the cell’s power factories, mitochondria regulate several important processes in both heart and vascular tissue. Their impairment may reduce energy metabolism, increase oxidative stress, or disturb ion channel function. Drugs with KC8 include anthracyclines,15 a class of cancer chemotherapeutic agents. Environmental chemicals with similar features include fine particulate matter ()16 and nitrogen dioxide.17

Matthew Campen, a professor of environmental health at the University of New Mexico, who was not involved in this project, says it makes sense to treat cardiac and vascular tissue both separately and together. “The cardiac muscle is exquisitely protected from many harmful impacts, [whereas] the blood vessels have received chronic insults from different toxicants for most of human history,” he explains.

Campen also appreciates that the KCs are broad enough to capture viruses, other nonchemical agents, and indirect mechanisms involving other organs. For example, kidney disease may contribute to cardiovascular disorders when the impaired ability to remove toxicants causes their accumulation in blood vessels.18

For Ana Navas-Acien, a professor of environmental health sciences at Columbia University, highlighting the shared KCs of therapeutics and environmental toxicants is especially important for the project’s diverse target audiences of epidemiologists, physicians, and basic, pharmaceutical, and regulatory scientists. “Drinking low levels of arsenic in your daily water is comparable to swallowing a daily pill of arsenic to treat certain diseases [i.e., African sleeping sickness and a rare form of leukemia],” says Navas-Acien, who was not involved in the project. “This helps people understand that some chemicals in the environment function exactly like drugs.”

, which exhibits seven KCs,7 illustrates the evolution of environmental cardiology,19,20,21 adds Navas-Acien. Early reports of acute cardiac events requiring hospitalization on days with high exposures to were followed by studies of chronic low-level exposures.22 A 2016 longitudinal study,23 for example, associated and nitrogen oxide exposures with coronary artery calcification as a marker of increased cardiovascular risk. “Cardiologists are beginning to recognize that air pollution and other environmental hazards can increase risk as much as smoking, lack of physical activity, and other lifestyle factors,” says Navas-Acien.

Air pollution also affects the lungs, brain, and other organs.24 Similarly, arsenic is a reproductive and cardiovascular toxicant and a carcinogen.25 This, says Smith, illustrates that some KCs apply to multiple systems, whereas others describe organ-specific pathways.

“KCs provide a systematic framework for improving our understanding of disease mechanisms,” adds Smith. That, he hopes, will benefit both drug development and efforts to reduce human exposure to environmental hazards.