A Model-Based Estimate of Carbon Monoxide Uptake by Heart Muscle During Exercise

描述(由申请人提供)：间歇性接触一氧化碳(CO)浓度超过允许水平被认为是导致暴露工人心血管疾病发病率增加的原因之一。事实证明，对与这些暴露相关的心脏风险进行有效评估是困难的，部分原因是关于这些暴露期间心脏组织中发生的缺氧程度的信息有限。虽然Coburn-Forster-Kane方程(CFKE)经常被用来预测血红蛋白(Hb)对CO的吸收和清除，但它不能估计血管外组织(如肌肉)对CO的吸收，因为肌肉是CO的一个潜在的大储存点，因为在年轻的成年男性中，肌肉约占体重的41%。因此，我们开发了一个CO吸收和排出的数学模型，并用人体数据进行了验证，该模型与CFKE不同，它包括一个肌肉间隔。我们的模型预测，肌肉中的CO浓度在暴露开始后不久就会增加，并随着碳氧血红蛋白(COHb)的增加而稳步上升。当被用来评估高氧下的CO洗脱时，我们的模型预测肌肉肌红蛋白(Mb)对CO的摄取进一步增加，即使COHb水平下降，这表明心肌缺氧损伤的风险增加。基于这些结果，我们假设，一个可以预测心肌中COB水平的数学模型将比单独使用COHb更准确地估计心脏缺氧的风险。因此，这项建议的目标是使用从两个人体一氧化碳暴露实验获得的数据集：1)增强我们的模型，使其能够预测运动和高氧下洗涤时的COHb和Comb，以及2)评估预测的心脏一氧化碳剂量与运动和高氧下洗涤时细微的心电变化之间的相关性。为了实现这些目标，我们将扩展模型以包括一个单独的心肌室，优化我们的方法来拟合模型和估计每个受试者在休息和运动期间的心肌梳，并将心肌梳水平的模型估计与心脏电不稳定的程度相关联。相关性：为了了解接触一氧化碳的工人患心脏病的风险增加，我们将使用我们的数学模型来分析接触一氧化碳的人的现有数据，以确定可能损害心脏的暴露条件。我们还将确定在某些情况下，100%氧气治疗是否有害。

DESCRIPTION (provided by applicant): Intermittent exposures to carbon monoxide (CO) concentrations that exceed permissible levels are thought to contribute to the increased incidence of cardiovascular disease in exposed workers. A valid assessment of the cardiac risk associated with these exposures has proved difficult, in part because of limited information regarding the degree of hypoxia that occurs in heart tissue during these exposures. Although the Coburn-Forster-Kane Equation (CFKE) is often used to predict CO uptake by, and removal from, hemoglobin (Hb), it can not estimate CO uptake by extravascular tissues such as muscle, a potentially large storage site for CO as muscle accounts for approximately 41% of body weight in young, adult males. Therefore, we developed, and validated with human data, a mathematical model of CO uptake and washout that, unlike the CFKE, includes a muscle compartment. Our model predicts that the CO concentration in muscle increases soon after the onset of the exposure and rises steadily as carboxyhemoblobin (COHb) increases. When used to assess CO washout under hyperoxia, the common treatment strategy for toxic CO exposures, our model predicts a further rise in CO uptake by muscle myoglobin (Mb), even as COHb levels fall, suggesting an increased risk for hypoxic injury to the myocardium. Based on these results, we hypothesize that a mathematical model that could predict COMb levels in cardiac muscle would provide a more accurate estimate of risk for cardiac hypoxia than COHb alone. Accordingly, the objectives of this proposal are to use data sets obtained from two human CO exposure experiments to: 1) enhance our model to enable it to predict COHb and COMb during exercise and washout under hyperoxia, and 2) evaluate the correlation between the predicted CO dose to the heart and subtle ECG changes during exercise and washout under hyperoxia. To accomplish these objectives we will expand the model to include a separate myocardial compartment, optimize our method for fitting the model and estimating myocardial COMb at rest and during exercise in each subject, and correlate model estimates of myocardial COMb levels with degree of cardiac electrical instability. Relevance: To understand the increased risk for heart disease in workers exposed to carbon monoxide, we will use our mathematical model to analyze existing data from exposed humans to determine the exposure conditions likely to damage the heart. We will also determine whether treatment with 100% oxygen may be harmful in some cases.