Environmental Cardiology: Getting to the Heart of the Matter

Bob Weinhold

Environ Health Perspect. 2004;112(15) 

In This Article

Fingering the Villains

Given the evidence so far, fine particulates appear to be one of the primary environmental villains linked with CVD, and are drawing much of the research interest. One of the first major developments was publication of findings from the Six Cities Study in the 9 December 1993 New England Journal of Medicine. The study, by Harvard environmental epidemiologist Douglas Dockery, Pope, and six others, found a significant link between ambient urban air pollution, especially fine particulates, and increased deaths caused by cardiopulmonary disease, along with increases in lung cancer. In January 2004, Circulation published a study by Pope and others covering more than half a million people over 16 years, which found that fine particulates were more strongly linked with deaths from cardiovascular causes than with deaths from respiratory causes. The pattern of cardiovascular deaths was consistent with evidence that mechanistic pathways linking exposure and death included pulmonary and systemic inflammation, accelerated atherosclerosis (hardening of the arteries), and changes in cardiac autonomic function (as measured by changes in heart rate variability).

In addition to particulates, dozens of other substances have been identified as playing some role in CVD. The other five EPA "criteria" air pollutants (ozone, carbon monoxide, nitrogen oxides, sulfur dioxide, and lead) have some evidence linking them with CVD, as do at least 17 of the 87 drinking water contaminants monitored by the EPA. At least 8 of the 116 contaminants in people tracked so far in the CDC's ongoing biomonitoring project have CVD links. Pat Mastin, chief of the NIEHS Cellular, Organ, and Systems Pathobiology Branch, points out that several occupational exposures also have been associated with CVD, including exposures to vinyl chloride (used to produce polyvinyl chloride and industrial solvents), carbon monoxide (a common exhaust gas), and allylamine (used in ion exchange resins, pharmaceuticals, and water-soluble polymers).

According to Mastin, arsenic has been linked in Asia with a condition known as black foot disease, so named because of the gangrene caused by severe disease in the blood vessels. In addition, he says, areas of the United States have high drinking water concentrations of arsenic, and there is evidence for a link between arsenic exposure and ischemic heart disease and hypertension in such areas. And there are more than 50 other substances, including many heavy metals, solvents, and a few pesticides, that have been implicated in CVD by other sources.

The research conducted so far has found many tangible indicators of cardiovascular system effects, including atherosclerosis; vasoconstriction; and changes in heart rate variability, blood pressure, coagulation, platelet activation, endothelial cells, and the clotting protein fibrinogen. Those changes have been linked with serious outcomes such as ischemic heart disease, congestive heart failure, acute myocardial infarction, malignant ventricular arrhythmias, plaque vulnerability, acute thrombosis, stroke, and hypertension.

The difficult job of figuring out exactly how various chemicals cause these problems has just begun. Many pathways are under investigation. On the top of the list for some is the systemic inflammation caused by some chemicals. "In the end, it's all going to be tied to inflammation," Cascio says.

Pope, who agrees inflammation is a key element, has another prime suspect. "There's simply a lot of evidence that there's a role for [effects on] autonomic function," he says.

Cellular changes, such as alterations in ion channel function, cell proliferation, signal transduction pathways, and cell signaling, also are under scrutiny. For instance, research by Armando Meyer and colleagues published in the February 2004 EHP found that the insecticide chlorpyrifos affects cell signaling cascades critical to cardiac homeostasis.

Problems may be caused not just by a chemical, but by its metabolites. In a study reported in the September 2004 issue of Toxicological Sciences, Dunnick and NIEHS colleague Abraham Nyska found that bis(2-chloroethoxy)methane caused mitochondrial damage in hearts in a rodent model system. They hypothesized that the thiodiglycolic acid, a metabolite of bis(2-chloroethoxy)methane as well as many other chemicals, causes this chemical-related mitochondrial damage and heart toxicity. Dunnick and Nyska observed a biphasic response: initial damage to myocytes was repaired in an apparent temporary adaptive response that the animals were no longer able to launch as they aged.

Other areas of concern include genetic variations and expression, gene polymorphisms, oxidative stress, protein expression, and post-translational modifications. In addition, many researchers suspect indirect links with the immune, pulmonary, and neurological systems.

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