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Effect of carbon monoxide on cardiovascular disease
PREVENTIVE
MEDICINE
8, 271-278 (1979)
Effect of Carbon
Monoxide WILBERT
Cardiovascular
Section,
on Cardiovascular
Disease’
S. ARONOW~
Long Beach Veterans Adminisrration
Hospital,
Long Beach
California 90822, and the University of California, Irvine, California 92664 Carbon monoxide exposure from heavy smoking or heavy atmospheric carbon monoxide pollution depresses myocardial function in patients with coronary heart disease, aggravates angina pectoris, aggravates intermittent claudication of the calf or thigh, increases myocardial ischemia in patients with clinical and subclinical coronary heart disease, and contributes to an increased incidence of nonfatal and fatal myocardial infarction and sudden death from coronary heart disease. Carbon monoxide contributes to the increase in nonfatal and fatal myocardial infarction and in sudden death from coronary heart disease in cigarette smokers by (a) carboxyhemoglobin interfering with myocardial oxygen delivery at the time nicotine has caused an increase in myocardial oxygen demand, aggravating an episode of myocardial ischemia, (b) the negative inotropic effect of carboxyhemoglobin aggravating an attack of myocardial ischemia, (c) carboxyhemoglobin reducing the threshold for ventricular fibrillation during an episode of myocardial ischemia, and (d) carboxyhemoglobin increasing platelet stickiness, thereby, increasing a thrombotic tendency. Furthermore, experimental data indicate that exposure to carbon monoxide in concentrations found in heavy tobacco smokers or in persons with heavy occupational exposure to carbon monoxide plays a role in the pathogenesis of cardiovascular disease.
Smoking high-nicotine, low-nicotine, or nonnicotine cigarettes causes an increased carboxyhemoglobin level (5, 7, 8, 13, 28), which reduces the amount of oxygen available to the myocardium. As cigarette smoke exposes the pulmonary capillary blood to at least 400 ppm of carbon monoxide, smokers who inhale develop high carboxyhemoglobin levels. Increased carboxyhemoglobin levels may also result from exposure to passive smoking (3, 27, 33, 34, 40, 43, 47). Heavy atmospheric carbon monoxide pollution may also lead to increased carboxyhemoglobin levels. A major source of carbon monoxide in the urban atmosphere is automobile exhaust, in which carbon monoxide emission is greatest during idling and deceleration. Peak atmospheric carbon monoxide exposures have been reported to reach as high as 147 ppm in Los Angeles freeway traffic and 141 ppm in New York expressway traffic (41), 135 ppm at traffic intersections in Dayton, Ohio (42), and 217 ppm for 1 hr in a toll booth at the Queens midtown tunnel in New York (20). We observed that patients with angina pectoris who were driven for 90 min in peak early morning freeway trafTic in Los Angeles county during winter months increased their mean arterial carboxyhemoglobin level from 1.12 to 5.08% (10). ’ Presented at a Workshop on Carbon Monoxide and Cardiovascular Disease, sponsored by the American Health Foundation and the Federal Health Gflice, Federal Republic of Germany, Berlin, October 10-12, 1978. * Requests for reprints should be addressed to: Wilbert S. Aronow, M.D., Chief, Cardiovascular Section, Veterans Administration Hospital, Long Beach, Calif. 90822 271 0091-7435/79/030271-08$02.00/0 Copyri&l @ 1979 by Academic Press, Inc. All rights of mmduction in any form reserved.
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As the affinity of hemoglobin for carbon monoxide is approximately 245 times greater than its affinity for oxygen, carbon monoxide displaces oxygen from hemoglobin, reducing the amount of oxygen available to the myocardium. Ayres and associates demonstrated that acute elevation of the venous carboxyhemoglobin level from 0.98 to 8.96% in patients with coronary heart disease and noncoronary heart disease caused a 20% average reduction in mixed venous oxygen tension (2 1,22). The greater reduction in mixed venous oxygen tension relative to the rise in venous carboxyhemoglobin level resulted from a leftward shift of the oxyhemoglobin dissociation curve, with tighter binding of oxygen to hemoglobin in the presence of carboxyhemoglobin, further reducing the availability of oxygen to the myocardium. The increased carboxyhemoglobin level caused an increase in coronary blood flow in their patients with noncoronary heart disease but not in their patients with coronary heart disease. Myocardial oxygen extraction and extraction ratios decreased in their patients with coronary heart disease and noncoronary heart disease, but the myocardial lactate extraction ratio changed to lactate production only in their patients with coronary heart disease (2 1, 22). Carbon monoxide also combines with myoglobin and can impair the facilitated diffusion of oxygen to the mitochondria (53). Furthermore, carbon monoxide combines directly with cytochrome oxidase (a,), slowing oxidation of reduced nicotinamide-adenine-dinucleotide (52). In cigarette smokers with angina pectoris due to documented coronary artery disease, we investigated the effect of smoking three high-nicotine cigarettes within 50 min on cardiovascular hemodynamics (7). One week later, we investigated in these patients the effect on cardiovascular hemodynamics of breathing 150ppm of carbon monoxide until their rise in coronary sinus carbon monoxide level was similar to that produced after smoking their third cigarette (7). We found that an increase in mean coronary sinus carbon monoxide level from 2.04 to 3.86% caused no change in systolic or diastolic blood pressure or heart rate, a rise in left ventricular end-diastolic pressure, and a decrease in left ventricular dpldt, stroke index, and cardiac index. The negative inotropic effect caused by carboxyhemoglobin was responsible for the decrease in stroke index and for the rise in left ventricular end-diastolic pressure observed after smoking. The increase in heart rate, blood pressure, and positive inotropic effect induced by nicotine should have increased the left ventricular dpldt after smoking. However, these factors were offset by the negative inotropic effect caused by carboxyhemoglobin, resulting in no change in left ventricular dpldr after smoking. CO and Angina Pectoris Increased carboxyhemoglobin levels after smoking nonnicotine cigarettes (13) or placebo marihuana cigarettes (4), or after exposure to passive smoking (3) or to heavy freeway traffic (10) caused patients with angina pectoris due to documented coronary artery disease to have a reduction in exercise time until the onset of angina pectoris, associated with a decrease in the product of systolic blood pressure times heart rate at the onset of angina pectoris. Ischemic ST-segment depression 2 1.O mm after exercise-induced angina pectoris occurred earlier, after less exercise, and at a lower product of systolic blood pressure times heart rate at the onset of angina pectoris after exposure to carbon monoxide from nonnicotine
WORKSHOP:
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cigarettes (13), placebo marihuana cigarettes (4), passive smoking (3), or heavy freeway traffic (10) compared with the control periods (3, 4, 10, 13) or after breathing compressed, purified air (10). Since the patients with angina pectoris could not adequately increase their coronary blood flow while exercising, and since their elevated carboxyhemoglobin level made less oxygen available for delivery to the myocardium, their myocardial oxygen demand exceeded their myocardial oxygen supply, inducing angina pectoris earlier, and after less myocardial work. Two double-blind, randomized studies also have confirmed that exposure to carbon monoxide in concentrations found during heavy atmospheric carbon monoxide pollution aggravates exercise-induced angina pectoris. Anderson and associates (1) documented in a double-blind, randomized study that patients with angina pectoris who breathed carbon monoxide 50 ppm intermittently for 4 hr to raise their mean venous carboxyhemoglobin level from 1.3 to 2.9% had a decrease in exercise time until the onset of angina pectoris compared with that observed after breathing compressed, purified air. Exposure to carbon monoxide caused deeper ST-segment depression during and after exercise in 5 of their 10 patients, with earlier onset and longer duration of ST-segment depression. We demonstrated in a double-blind, randomized study that patients with angina pectoris due to documented coronary artery disease who breathed 50 ppm of carbon monoxide for 2 hr to raise their mean venous carboxyhemoglobin level from 1.03 to 2.68% had a reduction in exercise time until the onset of angina pectoris and a decrease in the product of systolic blood pressure times heart rate at the onset of angina pectoris (11). Ischemic ST-segment depression > 1.O mm after exercise-induced angina pectoris occurred earlier, after less exertion, and at a lower product of systolic blood pressure times heart rate at the onset of angina pectoris after exposure to carbon monoxide compared with the control periods or with the periods after breathing compressed, purified air (11). Kurt and associates have demonstrated that the ambient level of carbon monoxide in Denver has a low-level association with the frequency of acute cardiorespiratory complaints in an emergency room (38). Their data lead one to conclude that carbon monoxide from the macroenvironment must be considered a risk factor for cardiopulmonary disease. CO and Intermittent Claudication We also demonstrated in a double-blind, randomized study that patients with intermittent claudication of the calf or thigh due to angiographically documented iliofemoral occlusive arterial disease who breathed 50 ppm of carbon monoxide for 2 hr to raise their mean venous carboxyhemoglobin level from 1.08 to 2.77% had a reduction in exercise time until the onset of intermittent claudication compared with the control periods or after breathing compressed, purified air (14). Since the patients with documented iliofemoral occlusive arterial disease could not adequately increase the blood flow to their thigh and calf muscles while exercising, and since the elevated carboxyhemoglobin level made less oxygen available for delivery to their calf and thigh muscles, the oxygen demand exceeded the oxygen supply to these muscles, inducing intermittent claudication sooner, following less exercise.
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CO and Subclinical Heart Disease Fortuin and associates observed that 7 of 7 older “normal subjects” with probable subclinical coronary heart disease and electrocardiographic abnormalities (ST-segment abnormalities or arrhythmias) who breathed 100 ppm of carbon monoxide intermittently for 4 hr to raise their venous carboxyhemoglobin level to 5.7 to 7.1% developed exaggeration of their electrocardiographic abnormalities (32). We found in a double-blind, randomized study that healthy middle-aged persons who breathed 100 ppm of carbon monoxide for 1 hr to raise their mean venous carboxyhemoglobin level from 1.67 to 3.95% had a reduction in mean exercise time until exhaustion compared with the control periods or after breathing compressed, purified air (6). One of our 10 asymptomatic subjects (10%) manifested ischemic ST-segment depression Sl .O mm after exercise following carbon monoxide exposure but not in the control periods or after breathing compressed, purified air. The increased carboxyhemoglobin level may have precipitated myocardial ischemia in this person with suspected latent coronary heart disease. CO, Myocardial Infarction,
and Sudden Death
Cohen and associates showed an association between atmospheric carbon monoxide pollution in Los Angeles and case fatality rates for patients with acute myocardial infarction admitted to 35 Los Angeles hospitals (28). Carbon monoxide exposure may also precipitate myocardial infarction in patients with coronary heart disease (45). Decreases in mortality from cardiovascular disease were also observed in San Francisco county and in Alameda county during the fuel crisis of 1974 (26). DeBias and associates showed that in monkeys with experimental myocardial infarction, electrocardiographic evidence of a greater degree of myocardial ischemia occurred in the monkeys exposed to 100 ppm of carbon monoxide than in those breathing room air (3 1). DeBias and associates also demonstrated that inhalation of carbon monoxide 100 ppm for 6 hr to raise the mean arterial carboxyhemoglobin level to 10.2% was a significant factor in enhancing ventricular fibrillation in monkeys with acute myocardial infarction (30). In addition, we demonstrated in a blind, randomized study that breathing carbon monoxide 100 ppm for 2 hr to raise the mean arterial carboxyhemoglobin level to 6.34% caused a reduction in ventricular fibrillation threshold in dogs with acute myocardial injury (15). In my opinion, both nicotine and carbon monoxide contribute to the increase in nonfatal and fatal myocardial infarction and in sudden death from coronary heart disease in cigarette smokers. Carbon monoxide contributes by: (a) carboxyhemoglobin interfering with myocardial oxygen delivery at the time nicotine has caused an increase in myocardial oxygen demand (2, 5, 7-9, 12, 13, 16), aggravating an episode of myocardial ischemia (31), (b) the negative inotropic effect of carboxyhemoglobin (7) aggravating an attack of myocardial ischemia, (c) carboxyhemoglobin reducing the threshold for ventricular fibrillation during an episode of myocardial ischemia (15, 30), and (d) carboxyhemoglobin increasing platelet stickiness (24), thereby, increasing a thrombotic tendency.
WORKSHOP:
CARBON
MONOXIDE
AND
CVD
275
of Atherosclerosis Coronary heart disease is a multifactorial disorder. The presence of other risk factors in addition to smoking (including hypercholesterolemia, hypertension, hypertriglyceridemia, diabetes mellitus, marked obesity, and sedentary living) increases the risk of developing coronary heart disease. The greater the tobacco consumption, the greater the number of coronary risk factors, and the greater the degree of abnormality of these risk factors, the higher the risk of developing coronary heart disease. Wald and associates have demonstrated that carboxyhemoglobin levels in tobacco smokers correlate better than the smoking history with the development of myocardial infarction, angina pectoris, and intermittent claudication (50). These investigators found that the relative risk of developing coronary heart disease or intermittent claudication was 2 1.2 times greater in persons with carboxyhemoglobin levels of 5% or greater than in persons with carboxyhemoglobin levels below 3%. However, it should be pointed out that the higher levels of carboxyhemoglobin may also reflect the absorption of other constituents of tobacco smoke in addition to carbon monoxide. Nonsmoking foundry workers exposed to carbon monoxide have a high prevalence of coronary heart disease (35). The prevalence of angina pectoris in foundry workers showed a clear dose-response relationship with regard to carbon monoxide exposure from either occupation, smoking, or both (35). Exposure to carbon monoxide has also been associated with acute electrocardiographic changes in apparently healthy fire fighters at work (39). In addition, ischemic heart disease has been demonstrated in fire fighters with normal coronary arteries (23). In animal experiments, nicotine does not cause coronary atherosclerosis when administered in amounts much higher than the nicotine uptake by a smoker (46). However, experimental data have implicated carbon monoxide in the concentrations found in heavy tobacco smokers in the pathogenesis of coronary atherosclerosis. Astrup and associates demonstrated that carbon monoxide or decreased oxygen tension enhances coronary atherosclerosis in cholesterol-fed rabbits (17, 18), and that hyperoxia reverses rabbit atherosclerosis (36). Microscopic findings observed in the arterial wall suggested that increased arterial accumulation of lipids was caused by an increased endothelial permeability, leading to subendothelial edema (17, 18). Astrup and co-workers also hypothesized that high carboxyhemoglobin levels resulting from tobacco smoking were associated with development of occlusive arterial vascular disease (19). Bimstingl and co-workers confirmed that carbon monoxide enhances coronary atherosclerosis in cholesterol-fed rabbits (25). In addition, Webster and associates demonstrated that carbon monoxide enhanced coronary atherosclerosis in cholesterol-fed squirrel monkeys (5 1). Kjeldsen and associates demonstrated that rabbits on a normal diet exposed to carbon monoxide 180 ppm for 2 weeks to lead to a carboxyhemoglobin of 16 to 18% developed aortic lesions indistinguishable from early atherosclerosis (37). In addition, severe ultrastmctural changes were found in the myocardium of rabbits exposed to carbon monoxide (18,37). Thomsen found that monkeys on a normal CO and Pathogenesis
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diet exposed to carbon monoxide 250 ppm for 2 weeks developed widening of the subendothelial space of the coronary arteries and accumulation of lipid-laden cells there (48). Tillmanns and associates measured lipid synthesis and cholesterol uptake in vitro in perfused human coronary arteries obtained at autopsy. They found that nicotine failed to influence cholesterol uptake or lipid synthesis, and that carbon monoxide did not influence lipid synthesis in the arterial wall (49). However, these investigators demonstrated that carbon monoxide leads to a marked increase in cholesterol uptake in perfused human coronary arteries, regardless of the concentration of carbon monoxide in the perfused fluid. Increased uptake of cholesterol by arteries perfused with carbon monoxide is probably the result of tissue hypoxia (44). CONCLUSIONS
In conclusion, carbon monoxide exposure from heavy smoking or heavy atmospheric carbon monoxide pollution depresses myocardial function in patients with coronary heart disease, aggravates angina pectoris, aggravates intermittent claudication of the calf or thigh, increases myocardial ischemia in patients with clinical and subclinical coronary heart disease, and contributes to an increased incidence of nonfatal and fatal myocardial infarction and sudden death from coronary heart disease. Furthermore, experimental data indicate that exposure to carbon monoxide in concentrations found in heavy tobacco smokers or in persons with heavy occupational exposure to carbon monoxide plays a role in the pathogenesis of cardiovascular disease. REFERENCES 1. Anderson, E. W., Andelman, R. J., Strauch, J. M., Fortuin, N. J., and Knelson, J. H. Effect of low-level carbon monoxide exposure on onset and duration of angina pectoris. A study in ten patients with ischemic heart disease. Ann. Intern. Med. 79,46-50 (1973). 2. Aronow, W. S. The effect of smoking cigarettes on the apexcardiogram in coronary heart disease. Chest 59, 365-368 (1971). 3. Aronow, W. S. Effect of passive smoking on angina pectoris. New Engl. J. Med. 299, 21-24 (1978). 4. Aronow, W. S., and Cassidy, J. Effect of marihuana and placebo-marihuana smoking on angina pectoris. New Engl. J. Med. 291, 65-67 (1974). 5. Aronow, W. S., and Cassidy, J. Effect of smoking marihuana versus a high-nicotine cigarette on angina pectoris. Clin. Pharmacol. Ther. 17, 549-554 (1975). 6. Aronow, W. S., and Cassidy, J. Effect of carbon monoxide on maximal treadmill exercise. A study in normal persons. Ann. Intern. Med. 83,496-499 (1975). 7. Aronow, W. S., Cassidy, J., Vangrow, J. S., March, H., Kern, J. C., Goldsmith, J. R., Khemka, M., Pagano, J., and Vawter, M. Effect of cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics in anginal patients. Circulation 50, 340-347 (1974). 8. Aronow, W. S., Dendinger, J., and Rokaw, S. N. Heart rate and carbon monoxide level after smoking high-, low-, and nonnicotine cigarettes. A study in male patients with angina pectoris. Ann. Intern. Med. 74, 697-702 (1971). 9. Aronow, W. S., Goldsmith, J. R., Kern, J. C., Cassidy, J., Nelson, W. H., Johnson, L. L., and Adams, W. Effect of smoking cigarettes on cardiovascular hemodynamics. Arch. Environ. Health 28, 330-332 (1974). 10. Aronow, W. S., Harris, C. N., Isbell, M. W., Rokaw, S. N., and Imparato, B. Effect of freeway travel on angina pectoris. Ann. Intern. Med. 77, 669-676 (1972). 11. Aronow, W. S., and Isbell, M. W. Carbon monoxide effect on exercise-induced angina pectoris. Ann. Intern. Med. 79, 392-395 (1973).
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12. Aronow, W. S., Kaplan, M. A., and Jacob, D. Tobacco: A precipitating factor in angina pectoris. Ann. Intern. Med. 69, 529-536 (1%8). 13. Aronow, W. S., and Rokaw, S. N. Carboxyhemoglobin caused by smoking nonnicotine cigarettes. Effects in angina pectoris. Circulation 44, 782-788 (1971). 14. Aronow, W. S., Stemmer, E. A., and Isbell, M. W. Effect of carbon monoxide exposure on intermittent claudication. Circulation 49,415-417 (1974). 15. Aronow, W. S., Stemmer, E. A., Wood, B., Zweig, S., Tsao, K., and Raggio, L. Carbon monoxide and ventricular fibrillation threshold in dogs with acute myocardial injury. Amer. Heart J. 95, 754-756 (1978). 16. Aronow, W. S., and Swanson, A. J. The effect of low-nicotine cigarettes on angina pectoris. Ann. Intern. Med. 71, 599-601 (1969). 17. As&up, P. Effects of hypoxia and of carbon monoxide on experimental atherosclerosis. Ann. Intern. Med. 71,426-427 (1%9). 18. As&up, P. Carbon monoxide, smoking, and cardiovascular disease. Circulation 48, 1167- 1168 (1973). 19. Astrup, P., Hellung-Larsen, P., Kjeldsen, K., and Mellemgaard, K. The effect of tobacco smoking on the dissociation curve of oxyhemoglobin. Investigations in patients with occlusive arterial diseases and in normal subjects. &and. J. Clin. Lab. Invest. 18, 450-457 (1%6). 20. Ayres, S. M., Evans, R., Licht, D., Griesbach, J., Reimold, F., Ferrand, E. F., and Criscitiello, A. Health effects of exposure to high concentrations of automotive emissions: Studies in bridge and tunnel workers in New York City. Arch. Environ. Health 27, 168-178 (1973). 21. Ayres, S. M., Giannelli, S., Jr., and Mueller, H. S. Effect of low concentrations of carbon monoxide: Myocardial and systemic responses to carboxyhemoglobin. Ann. N. Y. Acad. Sci. 174, 268-293 (1970). 22. Ayres, S. M., Mueller, H. S., Gregory, J. J., Giannelli, S., Jr., and Penny, J. L. Systemic and myocardial hemodynamic responses to relatively small concentrations of carboxyhemoglobin (COHB). Arch. Environ. Health 18, 699-709 (1%9). 23. Barnard, R. J., Gardner, G. W., and Disco, N. V. “Ischemic” heart disease in fire fighters with normal coronary arteries. J. &cup. Med. 18,818-820 (1976). 24. Bimstingl, M. A., Brinson, K., and Chakrabarti, B. K. The effect of short-term exposure to carbon monoxide on platelet stickiness. Bit. J. Surg. 58, 837-839 (1971). 25. Bimstingl, M., Hawkins, L., and McEwen, T. Experimental atherosclerosis during chronic exposure to carbon monoxide. Eur. Surg. Res. 2, 92-93 (1970) (Abstract). 26. Brown, S. M., Marmot, M. G., Sacks, S. T., and Kwok, L. W. Effect on mortality of the 1974fuel crisis. Nature (London) 257, 306-307 (1975). 27. Cobum, R. F., Forster, R. E., and Kane, P. B. Considerations of the physiological variables that determine the blood carboxyhemoglobin concentration in man. J. Clin. Invest. 44, 1899-1910 (1965). 28. Cohen, S. I., Deane, M., and Goldsmith, J. R. Carbon monoxide and survival from myocardial infarction. Arch. Environ. Health 19, 510-517 (1969). 29. Cohen, S. I., Perkins, N. M., Ury, H. K., and Goldsmith, J. R. Carbon monoxide uptake in cigarette smoking. Arch. Environ. Heahh 22, 55-60 (1971). 30. DeBias, D. A., Banerjee, C. M., Birkhead, N. C., Greene, C. H., Scott, S. D., and Harrer, W. V. Effects of carbon monoxide inhalation on ventricular fibrillation. Arch. Environ. Health 31, 38-42 (1976). 31. DeBias, D. A., Banerjee, C. M., Birkhead, N. C., Harrer, W. V., and Kazal, L. A. Carbon monoxide inhalation effects following myocardial infarction in monkeys. Arch. Environ. He&h 27, 161-167 (1973). 32. Fortuin, N. J., Anderson, E. W., Strauch, J. M., and Knelson, J. N. Effects of low level carbon monoxide exposure on human cardiac function. I. Normal subjects. “Preliminary paper,” Environmental Protection Agency and the C. V. Richardson Laboratory, November 24, 1972. 33. Harke, H. P. Zum Problem des “Passiv-Rauchens.” Munch Wochenschr. 112,2328-2334 (1970). 34. Harmsen, H., and Effenberger, E. Tabakrauch in Verkehrsmitteln, Wohnund Arbeitsraumen. Archiv. Hyg. Bakteriol. 141, 383-400 (1957). 35. Hernberg, S., Kariiva, R., Koskela, R., and Luoma K. Angina Pectoris, ECG findings and blood pressure of foundry workers in relation to carbon monoxide exposure. &and. J. Work Environ. Hea/th 2, Suppl. 1, 54-63 (1976).
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36. Kjeldsen, K., A&up, P., and Wanstrup, J. Reversal of rabbit atheromatosis by hyperoxia. J. Afheroscler. Res. 10, 173-178 (1969). 37. Kjeldsen, K., Astrup, P., and Watts&up, J. Ultrastructural intimal changes in the rabbit aorta after a moderate carbon monoxide exposure. Atherosclerosis 16, 67-82 (1972). 38. Kurt, T. L., Mogielnicki, R. P., and Chandler, J. E. Association of the frequency of acute cardiorespiratory complaints with ambient levels of carbon monoxide. Chest 74, lo- 14 (1978). 39. Kurt, T. L., and Peters, J. M. Epidemiology of cardiac risks in tire fighters with Holter electrocardiograms and carbon monoxide sampling. Circulation 52, II-204 (1975) (Abstract). 40. Lawther, P. J., and Commins, B. T. Cigarette smoking and exposure to carbon monoxide. Ann. N. Y. Acad. Sci. 174, 135- 147 (1970). 41. Lynn, D. A., Tabor, E., Ott, W., and Smith, R. quoted by Jaffe, L. S. Sources, characteristics, and fate of atmospheric carbon monoxide. Ann. N. Y. Acad. Sci. 174, 76-88 (1970). 42. Ramsey, J. M. Concentrations of carbon monoxide at tratIic intersections in Dayton, Ohio. Arch. Environ. Health 13,44-46 (1966). 43. Russell, M. A. H., Cole, P. V., and Brown, E. Absorption by nonsmokers of carbon monoxide from room air polluted by tobacco smoke. Lancer 1, 576-579 (1973). 44. Sarma, J. S. M., Tillmanns, H., Ikeda, S., Grenier, A., Colby, E., and Bing, R. J. Lipid metabolism in perfused human and dog coronary arteries. Amer. J. Cardiol. 35,579-587 (1975). 45. Scharf, S. M., Thames, M. D., and Sargent, R. K. Transmural myocardial infarction after expo sure to carbon monoxide in coronary-artery disease. New Engl. J. Med. 291, 85-86 (1974). 46. Schievelbein, H., Londong, V., Londong, W., Grumbach, H., Remplik, V., Schauer, A., and Immich, H. Nicotine and arteriosclerosis: An experimental contribution to the influence of nicotine on fat metabolism. Z. Klin. Chem. 8, 190- 196 (1970). 47. Srch, M. Uber die Bedeutung des Kohlenoxyds beim Zigarettenrauchen im Personenkraftwageninneren. Deut. Z. Gesamte Gerichtl. Med. 60, SO-89 (1967). 48. Thomsen, H. K. Carbon monoxide-induced atherosclerosis in primates. An electron-microscopic study on the coronary arteries of macaca irus monkeys. Atherosclerosis 20,233-240 (1974). 49. Tillmanns, H., Sarma, J. S. M., Seeler, K., and Bing, R. I. Lipid metabolism in perfused human coronary arteries and saphenous veins, in “Atherosclerosis” (G. Schettler and A. Weizel, Eds.), Vol. 3, pp. 188-125. Springer-Verlag, New York/Berlin, 1974. 50. Wald, N., Howard, S., Smith, P. G., and Kjeldsen, K. Association between atherosclerotic diseases and carboxyhemoglobin levels in tobacco smokers. &it. Med. J. 1,761-765 (1973). 51. Webster, W. S., Clarkson, T. B., and Lofland, H. B. Carbon monoxide-aggravated atherosclerosis in the squirrel monkey. Exp. Mol. Parhol. 13, 36-50 (1968). 52. Whereat, A. F. Is atherosclerosis a disorder of intramitochrondrial respiration? Ann. Znrern. Med. 73, 125-127 (1970). 53. Wittenberg, J. B. The molecular mechanism of hemoglobin-facilitated oxygen diffusion. J. Biol. Chem. 241, 104-I 14 (1966).
MEDICINE
8, 271-278 (1979)
Effect of Carbon
Monoxide WILBERT
Cardiovascular
Section,
on Cardiovascular
Disease’
S. ARONOW~
Long Beach Veterans Adminisrration
Hospital,
Long Beach
California 90822, and the University of California, Irvine, California 92664 Carbon monoxide exposure from heavy smoking or heavy atmospheric carbon monoxide pollution depresses myocardial function in patients with coronary heart disease, aggravates angina pectoris, aggravates intermittent claudication of the calf or thigh, increases myocardial ischemia in patients with clinical and subclinical coronary heart disease, and contributes to an increased incidence of nonfatal and fatal myocardial infarction and sudden death from coronary heart disease. Carbon monoxide contributes to the increase in nonfatal and fatal myocardial infarction and in sudden death from coronary heart disease in cigarette smokers by (a) carboxyhemoglobin interfering with myocardial oxygen delivery at the time nicotine has caused an increase in myocardial oxygen demand, aggravating an episode of myocardial ischemia, (b) the negative inotropic effect of carboxyhemoglobin aggravating an attack of myocardial ischemia, (c) carboxyhemoglobin reducing the threshold for ventricular fibrillation during an episode of myocardial ischemia, and (d) carboxyhemoglobin increasing platelet stickiness, thereby, increasing a thrombotic tendency. Furthermore, experimental data indicate that exposure to carbon monoxide in concentrations found in heavy tobacco smokers or in persons with heavy occupational exposure to carbon monoxide plays a role in the pathogenesis of cardiovascular disease.
Smoking high-nicotine, low-nicotine, or nonnicotine cigarettes causes an increased carboxyhemoglobin level (5, 7, 8, 13, 28), which reduces the amount of oxygen available to the myocardium. As cigarette smoke exposes the pulmonary capillary blood to at least 400 ppm of carbon monoxide, smokers who inhale develop high carboxyhemoglobin levels. Increased carboxyhemoglobin levels may also result from exposure to passive smoking (3, 27, 33, 34, 40, 43, 47). Heavy atmospheric carbon monoxide pollution may also lead to increased carboxyhemoglobin levels. A major source of carbon monoxide in the urban atmosphere is automobile exhaust, in which carbon monoxide emission is greatest during idling and deceleration. Peak atmospheric carbon monoxide exposures have been reported to reach as high as 147 ppm in Los Angeles freeway traffic and 141 ppm in New York expressway traffic (41), 135 ppm at traffic intersections in Dayton, Ohio (42), and 217 ppm for 1 hr in a toll booth at the Queens midtown tunnel in New York (20). We observed that patients with angina pectoris who were driven for 90 min in peak early morning freeway trafTic in Los Angeles county during winter months increased their mean arterial carboxyhemoglobin level from 1.12 to 5.08% (10). ’ Presented at a Workshop on Carbon Monoxide and Cardiovascular Disease, sponsored by the American Health Foundation and the Federal Health Gflice, Federal Republic of Germany, Berlin, October 10-12, 1978. * Requests for reprints should be addressed to: Wilbert S. Aronow, M.D., Chief, Cardiovascular Section, Veterans Administration Hospital, Long Beach, Calif. 90822 271 0091-7435/79/030271-08$02.00/0 Copyri&l @ 1979 by Academic Press, Inc. All rights of mmduction in any form reserved.
272
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As the affinity of hemoglobin for carbon monoxide is approximately 245 times greater than its affinity for oxygen, carbon monoxide displaces oxygen from hemoglobin, reducing the amount of oxygen available to the myocardium. Ayres and associates demonstrated that acute elevation of the venous carboxyhemoglobin level from 0.98 to 8.96% in patients with coronary heart disease and noncoronary heart disease caused a 20% average reduction in mixed venous oxygen tension (2 1,22). The greater reduction in mixed venous oxygen tension relative to the rise in venous carboxyhemoglobin level resulted from a leftward shift of the oxyhemoglobin dissociation curve, with tighter binding of oxygen to hemoglobin in the presence of carboxyhemoglobin, further reducing the availability of oxygen to the myocardium. The increased carboxyhemoglobin level caused an increase in coronary blood flow in their patients with noncoronary heart disease but not in their patients with coronary heart disease. Myocardial oxygen extraction and extraction ratios decreased in their patients with coronary heart disease and noncoronary heart disease, but the myocardial lactate extraction ratio changed to lactate production only in their patients with coronary heart disease (2 1, 22). Carbon monoxide also combines with myoglobin and can impair the facilitated diffusion of oxygen to the mitochondria (53). Furthermore, carbon monoxide combines directly with cytochrome oxidase (a,), slowing oxidation of reduced nicotinamide-adenine-dinucleotide (52). In cigarette smokers with angina pectoris due to documented coronary artery disease, we investigated the effect of smoking three high-nicotine cigarettes within 50 min on cardiovascular hemodynamics (7). One week later, we investigated in these patients the effect on cardiovascular hemodynamics of breathing 150ppm of carbon monoxide until their rise in coronary sinus carbon monoxide level was similar to that produced after smoking their third cigarette (7). We found that an increase in mean coronary sinus carbon monoxide level from 2.04 to 3.86% caused no change in systolic or diastolic blood pressure or heart rate, a rise in left ventricular end-diastolic pressure, and a decrease in left ventricular dpldt, stroke index, and cardiac index. The negative inotropic effect caused by carboxyhemoglobin was responsible for the decrease in stroke index and for the rise in left ventricular end-diastolic pressure observed after smoking. The increase in heart rate, blood pressure, and positive inotropic effect induced by nicotine should have increased the left ventricular dpldt after smoking. However, these factors were offset by the negative inotropic effect caused by carboxyhemoglobin, resulting in no change in left ventricular dpldr after smoking. CO and Angina Pectoris Increased carboxyhemoglobin levels after smoking nonnicotine cigarettes (13) or placebo marihuana cigarettes (4), or after exposure to passive smoking (3) or to heavy freeway traffic (10) caused patients with angina pectoris due to documented coronary artery disease to have a reduction in exercise time until the onset of angina pectoris, associated with a decrease in the product of systolic blood pressure times heart rate at the onset of angina pectoris. Ischemic ST-segment depression 2 1.O mm after exercise-induced angina pectoris occurred earlier, after less exercise, and at a lower product of systolic blood pressure times heart rate at the onset of angina pectoris after exposure to carbon monoxide from nonnicotine
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cigarettes (13), placebo marihuana cigarettes (4), passive smoking (3), or heavy freeway traffic (10) compared with the control periods (3, 4, 10, 13) or after breathing compressed, purified air (10). Since the patients with angina pectoris could not adequately increase their coronary blood flow while exercising, and since their elevated carboxyhemoglobin level made less oxygen available for delivery to the myocardium, their myocardial oxygen demand exceeded their myocardial oxygen supply, inducing angina pectoris earlier, and after less myocardial work. Two double-blind, randomized studies also have confirmed that exposure to carbon monoxide in concentrations found during heavy atmospheric carbon monoxide pollution aggravates exercise-induced angina pectoris. Anderson and associates (1) documented in a double-blind, randomized study that patients with angina pectoris who breathed carbon monoxide 50 ppm intermittently for 4 hr to raise their mean venous carboxyhemoglobin level from 1.3 to 2.9% had a decrease in exercise time until the onset of angina pectoris compared with that observed after breathing compressed, purified air. Exposure to carbon monoxide caused deeper ST-segment depression during and after exercise in 5 of their 10 patients, with earlier onset and longer duration of ST-segment depression. We demonstrated in a double-blind, randomized study that patients with angina pectoris due to documented coronary artery disease who breathed 50 ppm of carbon monoxide for 2 hr to raise their mean venous carboxyhemoglobin level from 1.03 to 2.68% had a reduction in exercise time until the onset of angina pectoris and a decrease in the product of systolic blood pressure times heart rate at the onset of angina pectoris (11). Ischemic ST-segment depression > 1.O mm after exercise-induced angina pectoris occurred earlier, after less exertion, and at a lower product of systolic blood pressure times heart rate at the onset of angina pectoris after exposure to carbon monoxide compared with the control periods or with the periods after breathing compressed, purified air (11). Kurt and associates have demonstrated that the ambient level of carbon monoxide in Denver has a low-level association with the frequency of acute cardiorespiratory complaints in an emergency room (38). Their data lead one to conclude that carbon monoxide from the macroenvironment must be considered a risk factor for cardiopulmonary disease. CO and Intermittent Claudication We also demonstrated in a double-blind, randomized study that patients with intermittent claudication of the calf or thigh due to angiographically documented iliofemoral occlusive arterial disease who breathed 50 ppm of carbon monoxide for 2 hr to raise their mean venous carboxyhemoglobin level from 1.08 to 2.77% had a reduction in exercise time until the onset of intermittent claudication compared with the control periods or after breathing compressed, purified air (14). Since the patients with documented iliofemoral occlusive arterial disease could not adequately increase the blood flow to their thigh and calf muscles while exercising, and since the elevated carboxyhemoglobin level made less oxygen available for delivery to their calf and thigh muscles, the oxygen demand exceeded the oxygen supply to these muscles, inducing intermittent claudication sooner, following less exercise.
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CO and Subclinical Heart Disease Fortuin and associates observed that 7 of 7 older “normal subjects” with probable subclinical coronary heart disease and electrocardiographic abnormalities (ST-segment abnormalities or arrhythmias) who breathed 100 ppm of carbon monoxide intermittently for 4 hr to raise their venous carboxyhemoglobin level to 5.7 to 7.1% developed exaggeration of their electrocardiographic abnormalities (32). We found in a double-blind, randomized study that healthy middle-aged persons who breathed 100 ppm of carbon monoxide for 1 hr to raise their mean venous carboxyhemoglobin level from 1.67 to 3.95% had a reduction in mean exercise time until exhaustion compared with the control periods or after breathing compressed, purified air (6). One of our 10 asymptomatic subjects (10%) manifested ischemic ST-segment depression Sl .O mm after exercise following carbon monoxide exposure but not in the control periods or after breathing compressed, purified air. The increased carboxyhemoglobin level may have precipitated myocardial ischemia in this person with suspected latent coronary heart disease. CO, Myocardial Infarction,
and Sudden Death
Cohen and associates showed an association between atmospheric carbon monoxide pollution in Los Angeles and case fatality rates for patients with acute myocardial infarction admitted to 35 Los Angeles hospitals (28). Carbon monoxide exposure may also precipitate myocardial infarction in patients with coronary heart disease (45). Decreases in mortality from cardiovascular disease were also observed in San Francisco county and in Alameda county during the fuel crisis of 1974 (26). DeBias and associates showed that in monkeys with experimental myocardial infarction, electrocardiographic evidence of a greater degree of myocardial ischemia occurred in the monkeys exposed to 100 ppm of carbon monoxide than in those breathing room air (3 1). DeBias and associates also demonstrated that inhalation of carbon monoxide 100 ppm for 6 hr to raise the mean arterial carboxyhemoglobin level to 10.2% was a significant factor in enhancing ventricular fibrillation in monkeys with acute myocardial infarction (30). In addition, we demonstrated in a blind, randomized study that breathing carbon monoxide 100 ppm for 2 hr to raise the mean arterial carboxyhemoglobin level to 6.34% caused a reduction in ventricular fibrillation threshold in dogs with acute myocardial injury (15). In my opinion, both nicotine and carbon monoxide contribute to the increase in nonfatal and fatal myocardial infarction and in sudden death from coronary heart disease in cigarette smokers. Carbon monoxide contributes by: (a) carboxyhemoglobin interfering with myocardial oxygen delivery at the time nicotine has caused an increase in myocardial oxygen demand (2, 5, 7-9, 12, 13, 16), aggravating an episode of myocardial ischemia (31), (b) the negative inotropic effect of carboxyhemoglobin (7) aggravating an attack of myocardial ischemia, (c) carboxyhemoglobin reducing the threshold for ventricular fibrillation during an episode of myocardial ischemia (15, 30), and (d) carboxyhemoglobin increasing platelet stickiness (24), thereby, increasing a thrombotic tendency.
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of Atherosclerosis Coronary heart disease is a multifactorial disorder. The presence of other risk factors in addition to smoking (including hypercholesterolemia, hypertension, hypertriglyceridemia, diabetes mellitus, marked obesity, and sedentary living) increases the risk of developing coronary heart disease. The greater the tobacco consumption, the greater the number of coronary risk factors, and the greater the degree of abnormality of these risk factors, the higher the risk of developing coronary heart disease. Wald and associates have demonstrated that carboxyhemoglobin levels in tobacco smokers correlate better than the smoking history with the development of myocardial infarction, angina pectoris, and intermittent claudication (50). These investigators found that the relative risk of developing coronary heart disease or intermittent claudication was 2 1.2 times greater in persons with carboxyhemoglobin levels of 5% or greater than in persons with carboxyhemoglobin levels below 3%. However, it should be pointed out that the higher levels of carboxyhemoglobin may also reflect the absorption of other constituents of tobacco smoke in addition to carbon monoxide. Nonsmoking foundry workers exposed to carbon monoxide have a high prevalence of coronary heart disease (35). The prevalence of angina pectoris in foundry workers showed a clear dose-response relationship with regard to carbon monoxide exposure from either occupation, smoking, or both (35). Exposure to carbon monoxide has also been associated with acute electrocardiographic changes in apparently healthy fire fighters at work (39). In addition, ischemic heart disease has been demonstrated in fire fighters with normal coronary arteries (23). In animal experiments, nicotine does not cause coronary atherosclerosis when administered in amounts much higher than the nicotine uptake by a smoker (46). However, experimental data have implicated carbon monoxide in the concentrations found in heavy tobacco smokers in the pathogenesis of coronary atherosclerosis. Astrup and associates demonstrated that carbon monoxide or decreased oxygen tension enhances coronary atherosclerosis in cholesterol-fed rabbits (17, 18), and that hyperoxia reverses rabbit atherosclerosis (36). Microscopic findings observed in the arterial wall suggested that increased arterial accumulation of lipids was caused by an increased endothelial permeability, leading to subendothelial edema (17, 18). Astrup and co-workers also hypothesized that high carboxyhemoglobin levels resulting from tobacco smoking were associated with development of occlusive arterial vascular disease (19). Bimstingl and co-workers confirmed that carbon monoxide enhances coronary atherosclerosis in cholesterol-fed rabbits (25). In addition, Webster and associates demonstrated that carbon monoxide enhanced coronary atherosclerosis in cholesterol-fed squirrel monkeys (5 1). Kjeldsen and associates demonstrated that rabbits on a normal diet exposed to carbon monoxide 180 ppm for 2 weeks to lead to a carboxyhemoglobin of 16 to 18% developed aortic lesions indistinguishable from early atherosclerosis (37). In addition, severe ultrastmctural changes were found in the myocardium of rabbits exposed to carbon monoxide (18,37). Thomsen found that monkeys on a normal CO and Pathogenesis
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diet exposed to carbon monoxide 250 ppm for 2 weeks developed widening of the subendothelial space of the coronary arteries and accumulation of lipid-laden cells there (48). Tillmanns and associates measured lipid synthesis and cholesterol uptake in vitro in perfused human coronary arteries obtained at autopsy. They found that nicotine failed to influence cholesterol uptake or lipid synthesis, and that carbon monoxide did not influence lipid synthesis in the arterial wall (49). However, these investigators demonstrated that carbon monoxide leads to a marked increase in cholesterol uptake in perfused human coronary arteries, regardless of the concentration of carbon monoxide in the perfused fluid. Increased uptake of cholesterol by arteries perfused with carbon monoxide is probably the result of tissue hypoxia (44). CONCLUSIONS
In conclusion, carbon monoxide exposure from heavy smoking or heavy atmospheric carbon monoxide pollution depresses myocardial function in patients with coronary heart disease, aggravates angina pectoris, aggravates intermittent claudication of the calf or thigh, increases myocardial ischemia in patients with clinical and subclinical coronary heart disease, and contributes to an increased incidence of nonfatal and fatal myocardial infarction and sudden death from coronary heart disease. Furthermore, experimental data indicate that exposure to carbon monoxide in concentrations found in heavy tobacco smokers or in persons with heavy occupational exposure to carbon monoxide plays a role in the pathogenesis of cardiovascular disease. REFERENCES 1. Anderson, E. W., Andelman, R. J., Strauch, J. M., Fortuin, N. J., and Knelson, J. H. Effect of low-level carbon monoxide exposure on onset and duration of angina pectoris. A study in ten patients with ischemic heart disease. Ann. Intern. Med. 79,46-50 (1973). 2. Aronow, W. S. The effect of smoking cigarettes on the apexcardiogram in coronary heart disease. Chest 59, 365-368 (1971). 3. Aronow, W. S. Effect of passive smoking on angina pectoris. New Engl. J. Med. 299, 21-24 (1978). 4. Aronow, W. S., and Cassidy, J. Effect of marihuana and placebo-marihuana smoking on angina pectoris. New Engl. J. Med. 291, 65-67 (1974). 5. Aronow, W. S., and Cassidy, J. Effect of smoking marihuana versus a high-nicotine cigarette on angina pectoris. Clin. Pharmacol. Ther. 17, 549-554 (1975). 6. Aronow, W. S., and Cassidy, J. Effect of carbon monoxide on maximal treadmill exercise. A study in normal persons. Ann. Intern. Med. 83,496-499 (1975). 7. Aronow, W. S., Cassidy, J., Vangrow, J. S., March, H., Kern, J. C., Goldsmith, J. R., Khemka, M., Pagano, J., and Vawter, M. Effect of cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics in anginal patients. Circulation 50, 340-347 (1974). 8. Aronow, W. S., Dendinger, J., and Rokaw, S. N. Heart rate and carbon monoxide level after smoking high-, low-, and nonnicotine cigarettes. A study in male patients with angina pectoris. Ann. Intern. Med. 74, 697-702 (1971). 9. Aronow, W. S., Goldsmith, J. R., Kern, J. C., Cassidy, J., Nelson, W. H., Johnson, L. L., and Adams, W. Effect of smoking cigarettes on cardiovascular hemodynamics. Arch. Environ. Health 28, 330-332 (1974). 10. Aronow, W. S., Harris, C. N., Isbell, M. W., Rokaw, S. N., and Imparato, B. Effect of freeway travel on angina pectoris. Ann. Intern. Med. 77, 669-676 (1972). 11. Aronow, W. S., and Isbell, M. W. Carbon monoxide effect on exercise-induced angina pectoris. Ann. Intern. Med. 79, 392-395 (1973).
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