Biological plausibility for carbon monoxide as a copollutant in PM epidemiologic studies

Several recent epidemiologic studies investigating the short-term effects of particulate matter (PM) concentrations have shown carbon monoxide (CO) to have the strongest and most consistent statistical relationship with hospital admissions for cardiac diseases. This article suggests a potential hypothesis for these epidemiologic observations. Oxygen (O2) is transported, in reversible combination with hemoglobin, from the lungs to the tissues, where it diffuses into cardiac myocytes. Within the myocyte a portion of the O2 diffuses directly to the mitochondria, while the remaining O2 is transported by facilitated diffusion bound to myoglobin, a heme protein found in muscle. Within the mitochondria, O2 reacts to produce adenosine triphosphate (ATP), a high-energy phosphate compound that provides energy for all cell functions. Accordingly, the sustained production of ATP depends on the continuous delivery of O2 to the mitochondria, and failure at any point in the O2 transport system will compromise ATP production and myocardial function. Myoglobin, a fundamental constituent of cardiac muscle is essential for delivering O2 to the mitochondria. Myoglobin concentrations in cardiac tissue were 50% lower in patients with heart failure than in patients dying from noncardiac causes. Myoglobin concentrations are also severely depressed in animal models of congestive heart failure. Consequently, the role of myoglobin as a cellular transporter of O2 is seriously impaired by heart disease. Carbon monoxide reduces O2 transport to the tissues and, within the tissues, binds with myoglobin to form carboxymyoglobin (COMb). Thus, in cardiac patients CO further exacerbates the disease-related loss of myoglobin function. This further disrupts O2 transport and promotes adverse consequences for the compromised heart. Moreover, during hypoxia CO has the propensity of leaving the blood and binding with myoglobin in the intracellular compartment. Elderly persons with preexisting cardiopulmonary disorders appear to be at maximum risk of harmful health effects due to ambient air pollution exposure. Many of these disorders result in generalized or regional hypoxia. It is reasonable to hypothesize that CO also moves out of the blood of these patients and into the heart tissue whenever they are under hypoxic stress, such as exercise. Accordingly, CO binds with the marginal myoglobin concentrations present in the hearts of cardiac patients and further compromises cardiac function, resulting in poor tolerance of activity. Therefore, reduced cardiac myoglobin in people with heart disease, further exacerbated by CO moving into the cardiac tissue during episodes of hypoxia, may account for the positive association between ambient CO concentrations and hospitalization for heart disease.