- Email: [email protected]
Serum free fatty acid and pressor responses to norepinephrine in healthy subjects and in those with ischemic heart disease
Serum free fatty acid and pressor responses to norepinephrine in healthy subjects and in those with ischemic heart disease A. C. Corcoran, M.D.* Cleveland, Ohio
A
dreuergic release, together with its effects on circulation, induces lipolysis of fat depots and release into plasma of free fatty acids (FFA). Most of this “fuel of muscular esercise”’ not consumed as energy is converted to triglyceride.* Several FFA shorten clotting time in vitro,3 and their saturated third is strongly thrombotic in vivo.4 Thus, release of FFA may be related to myocardial infarction, ntherogenesis, and thrombotic disease. Indeed, comparisons of the contents of FFA in the sera of patients dying of various causes indicate much higher concentrations in those dying of ischemic heart disease (IHD) than of other causes,5 although this may more plausibly reflect agonal adrenergic discharge than be a cause of the event. The present study was undertaken to define the relative responsiveness of the release of FFA and of arterial pressure to norepinephrine in healthy men and in a comparable group of men with IHD, the latter established by myocardial infarction months or years before test. During this period, other@*7 observed the excessive release of FFA into the serum of IHD subjects after smoking, and showed that this was due to nicotine-induced adrenergic discharge of catecholamines.
Such a response is attributable either to facilitated adrenergic release or to greater responsiveness of fat depots to the lipolytic action of catecholamines. The present data suggest that the former may be the case, since the latter is not. Procedures
Studies were done in men in apparent good health and in another group of men of similar socioeconomic level and build who had recovered from myocardial infarction. The former consisted of 22 who were 37 to 56 years old (median 48) and whose ponderal indices (P.l.)* ranged from 11.6 (heavy) to 13.1 (light) (median P.I. 12.4). The IHD group consisted of 14 who were 37 to 62 years old (median 49) and whose P.I. ranged from 11.9 to 13.0 (median 12.5). All came to the hospital from their homes after 12 to 14 hours of fasting from food and tobacco. Tests were begun after 30 to 40 minutes of rest under conditions of quiet and reassurance by a procedure similar to that of Klein and associates.g Blood (B,) was sampled during the placement of a Cournand needle in an arm vein; a needle was placed in another vein for infusion, and a second sample of blood was drawn 15 to 20 minutes later (BJ). Norepinephrine (NE)
From the Department of Clinical Investigation. St. Vincent Charity Hospital, Cleveland. Ohio. This study was supported by Grant H-04980 from the National Heart Institute, National Institutes partment of Health, Education and Welfare. Received for publication Aug. 2. 1963. *Special Research Fellow, National Heart Institute (HSP 13,190).
489
of Health,
De.
400
Salnple BO Bol Minutes 0 IO 20 30 45 60 *Since
CorroPnn
373 44.1 post-infusion 236 310 314 219 36 -50
520 890 620 780 610 920 240 120
200 240 -to -40 -30 -70 -400 -460
increments are made by reference to BJ, the listing (noted in text) on 3 IHD subjects who developed angina
21* 21
583 625
21 21 21 20 21 21
190 284 226 83 -10 6
1,020 I .ooo 120 660 540 420 240 280
280 300
11 11
10 130 50 -70 -270 -420
II I1 I1 11 11 11
excludes data on 1 healthy subject in whom this sample and did not receive the full 75 pg of norepinepbrine.
was then infused in saline (5 pg per minute for 15 minutes), and samples of blood were taken at 0, 10, 20, 30, 45, and 60 minutes after this infusion ended. Analyses of chilled sera for FFA were made promptly by the method of Schotz, Masson and Page.lo B, and the final sample were also analyzed for cholesterol and triglyceride; since these showed no significant differences between groups nor changes after infusion of NE, the data are not listed. Arterial pressure (auscultatory) and pulse rate were recorded frequently before, during, and after infusion. Two of the “healthy” and 3 of the IHD subjects were found to have mild hypertension* at rest. Onset of angina caused infusions to be terminated at 3, 5, and 8 minutes in 3 subjects with IHD. Data from these tests are not included in Table I. Those of hypertensive and angina1 subjects are not included in means of pressure and pulse data. Results
Data from analyses of serum FFA are summarized in Table I. Means of FFA in B, were higher? in subjects with IHD than in healthy men. Means of B,l were slightly higher than those of B, in both; these increments were not uniform, since increases of 50 NEq per liter occurred in 7 of 21 healthy and in 7 of 14 IHD subjects, with Hypertension is defined as systolic 160 mm. Hg or more and/or diastolic 95 mm. Hg or more. tDifference/standard error of differences of means 3.28.
was lost.
and also
equivalent decreasesin 1 of each group and small or negligible changes in other subjects. Distribution of fasting contents showed no association with body weight or with P.I. Post-NE increases in FFA were measured from B,l. With wide individual variations, means of increments were similar in healthy and IHD subjects. Maximum increases were usually found in the samples taken at 10 or 20 minutes, although at 0 and 30 minutes in 1 each of 2 healthy men, and at 0 minute in 2 IHD men. Respective increments at terminations of infusions of 15, 25, and 40 pg of NE during angina were 70, 270, and 30 mEq. per liter at 0 or 10 minutes post-NE, while in the last case a secondary rise of 1,180 PEq per liter occurred at 30 minutes, angina having recurred at about 20 minutes. -4s with fasting contents, responses to NE could not be associated with individual P.I. Preinfusion means of arterial pressure and pulse in the 20 normotensive health! and 10 normotensive IHD subjects were, respectively, 113/75 mm. Hg and 71 per minute, and 106/73 mm. Hg and 66 per minute. Means of maximum rises in pressure during infusion were, respectivelv, 12.5/10 and 19.4/10.4 mm. Hg; the systolic increment was greater* in the IHD subjects. Pulse decrements were nearly equal, rates during infusion being 62 per minute *Difference/standard
error
of differences
of means 3.3.
Volume Number
67 4
Serum free fatty a&d and pressor responses to norefiinephrine
in healthy subjects and 60 per minute in subjects with IHD; respective means of minima of immediate postinfusion pressures were 106/72 and 99/65 mm. Hg. The 2 healthy hypertensive subjects and 3 IHD subjects who developed angina showed greater than average rises in pressure: in the former, 32/20 and 41/18 mm. Hg; and in the latter 28/14, 36/12, and 70,/16 mm. Hg. The first 2 of the angina1 IHD group were hypertensive at rest, whereas the patient with the most severe angina1 pressor and FFA responses was not. A response close to the mean was noted in one hypertensive IHD subject (resting pressure of 165,198 mm. Hg) who did not experience angina. Comment Responsiveness to NE-induced release of FFA is similar and variable in healthy and IHD subjects of like ages and apparent general condition. The somewhat higher fasting content of serum FFA in IHD subjects may reflect greater apprehension of, or adrenergic release to, the test situation. The latter explanation would accord with greater responsiveness of such subjects to smoking,6 and also that those whose behavior pattern and serum lipid content are indicative of high 1HD risk show larger excretions of norepinephrine” and 3-methosy-4-hydroxymandelic acid12 during working hours than do those of different temperament and constitution. Although serum FFA is higher in obese than in normal subjects,13 no association of fasting FFA or response to NE with relative body weight was defined in these tests; however, the series is not large and none of the subjects was grossly obese. The greater systolic response of IHD than of healthy subjects to NE can plausibly be attributed to arteriosclerosis and diminished central arterial elasticity. However, the latter should also diminish bradycardic responseI to NE and presumably the post-NE decrement of pressure. These differences were not found. The angina associated with excessive pressor responses which was precipitated in 3 IHD subjects by doses of only 0.2 to 0.5 rg per kilogram of NE distributed over 3 to 8 minutes suggests a myocardial susceptibility to NE to which angina may have contributed.
491
Conclusions 1. Mobilization of lipids as circulating FFA in response to norepinephrine (NE) was similar, and individually variable, in healthy and postmyocardial infarct (IHD) subjects. 2. Systolic pressor responsiveness to small doses of norepinephrine was usually enhanced in IHD subjects, as also in 4 of 5 subjects with mild hypertension; of 3 post-IHD, 2 hypertensive and 1 normotensive rapidly developed angina and larger than average increments of pressure during intravenous infusion of norepinephrine at a rate of 5 pg per minute. I am deeply appreciative those of the Cleveland others, healthy and with who volunteered for these
of the cooperation of and of ischemic heart disease, tests.
Firemen’s Union
REFERENCES 1. Editorial: The fuel of muscular exercise, Lancet 2 :276, 1959. 2. Freidberg, S. J., Klein, R. F., Trout, D. L., Bogdonoff, M. D., and Estes, E. H., Jr.: The incorporation of plasma free fatty acids into plasma triglycerides in man, J. Clin. Invest. 40:1846, 1961. 3. Poole, J. C. F.: Effect of diet and lipemia on coagulation and thrombosis, Fed. Proc. 21: Suppl. 11, 20, 1962. 4. Connor, W. E., Hoak, J. C., and Warner, E. D.: Massive thrombosis produced by fatty acid infusion. T. Clin. Invest. 32:860. 1963. 5. Enticknap, J.’ B.: Serum fatty acids aftkr fatal heart attacks, Lancet 1:32, 1960. 6. Kerschbaum, A., Bellet, S., Caplan, R. P., and Feinberg, R. J.: Effect of cigarette smoking on free fatty acids in patients-with healed myocardial infarction. Am. 1. Cardiol. 10:204. 1962. 7. Kerschbaum, A.; Khorsandian, R., &plan, R. F., Bellet, S., and Feinberg, L. F.: The role of catecholamines in the free fatty acid response to cigarette smoking, Circulation 2852, -1963. 8. Sheldon. W. E.. Duoertuis. C. W.. and McDermott, E.: Atlas of man: a guide for somatotyping the adult male of all ages, New York, 1954, Harper and Brothers. 9. Klein, R. F., Estes, E. H., Jr., and Bogdonoff, M. D.: Effect of norepinephrine on plasma free fatty acids in man, J. Appl. Physiol. 16:343, 1961. 10. Schotz, M. C., Masson, G. M. C., and Page, I. H.: Effect of ACTH in vivo on release of nonesterified fatty acids from adipose tissues of adrenalectomized rats, Proc. Sot. Exper. Biol. & Med. 101:159, 1959. 11. Friedman, M., St. George, S., Byers, S. O., and Rosenman, R. H. : Excretion of catecholamines, If-ketosteroids, 17-hydroxy-corticoids and Shydroxy-indole in men exhibiting particular behavior pattern. (A) Associated with high I
492
12.
Corcoran
incidence of clinical coronary artery disease, J. Clin. Invest. 39:758, 1960. Byers, S. O., Friedman, M., Rosenman, I<. H., and Freed, S. C.: Excretion of 3.methoxy-& hydroxymandelic acid in men with behavior pattern associated with high incidence of coronary artery disease, Fed. Proc. 21:Suppl. 11, 99. 1962.
1.1. Opie, L. Ft., a11d Lk’allish, I’. G.: Plasma free fatty acid concentrations ill obesity, New England J. Med. 268:757, 1963. 14. Finnerty, F. :I., Jr., Tuckman, J., and Hajyan, A.: Changes in heart rate during levarterenol infusion: an index of arterial elasticitv. Circulation Res. 7:565, 19.59.
A
dreuergic release, together with its effects on circulation, induces lipolysis of fat depots and release into plasma of free fatty acids (FFA). Most of this “fuel of muscular esercise”’ not consumed as energy is converted to triglyceride.* Several FFA shorten clotting time in vitro,3 and their saturated third is strongly thrombotic in vivo.4 Thus, release of FFA may be related to myocardial infarction, ntherogenesis, and thrombotic disease. Indeed, comparisons of the contents of FFA in the sera of patients dying of various causes indicate much higher concentrations in those dying of ischemic heart disease (IHD) than of other causes,5 although this may more plausibly reflect agonal adrenergic discharge than be a cause of the event. The present study was undertaken to define the relative responsiveness of the release of FFA and of arterial pressure to norepinephrine in healthy men and in a comparable group of men with IHD, the latter established by myocardial infarction months or years before test. During this period, other@*7 observed the excessive release of FFA into the serum of IHD subjects after smoking, and showed that this was due to nicotine-induced adrenergic discharge of catecholamines.
Such a response is attributable either to facilitated adrenergic release or to greater responsiveness of fat depots to the lipolytic action of catecholamines. The present data suggest that the former may be the case, since the latter is not. Procedures
Studies were done in men in apparent good health and in another group of men of similar socioeconomic level and build who had recovered from myocardial infarction. The former consisted of 22 who were 37 to 56 years old (median 48) and whose ponderal indices (P.l.)* ranged from 11.6 (heavy) to 13.1 (light) (median P.I. 12.4). The IHD group consisted of 14 who were 37 to 62 years old (median 49) and whose P.I. ranged from 11.9 to 13.0 (median 12.5). All came to the hospital from their homes after 12 to 14 hours of fasting from food and tobacco. Tests were begun after 30 to 40 minutes of rest under conditions of quiet and reassurance by a procedure similar to that of Klein and associates.g Blood (B,) was sampled during the placement of a Cournand needle in an arm vein; a needle was placed in another vein for infusion, and a second sample of blood was drawn 15 to 20 minutes later (BJ). Norepinephrine (NE)
From the Department of Clinical Investigation. St. Vincent Charity Hospital, Cleveland. Ohio. This study was supported by Grant H-04980 from the National Heart Institute, National Institutes partment of Health, Education and Welfare. Received for publication Aug. 2. 1963. *Special Research Fellow, National Heart Institute (HSP 13,190).
489
of Health,
De.
400
Salnple BO Bol Minutes 0 IO 20 30 45 60 *Since
CorroPnn
373 44.1 post-infusion 236 310 314 219 36 -50
520 890 620 780 610 920 240 120
200 240 -to -40 -30 -70 -400 -460
increments are made by reference to BJ, the listing (noted in text) on 3 IHD subjects who developed angina
21* 21
583 625
21 21 21 20 21 21
190 284 226 83 -10 6
1,020 I .ooo 120 660 540 420 240 280
280 300
11 11
10 130 50 -70 -270 -420
II I1 I1 11 11 11
excludes data on 1 healthy subject in whom this sample and did not receive the full 75 pg of norepinepbrine.
was then infused in saline (5 pg per minute for 15 minutes), and samples of blood were taken at 0, 10, 20, 30, 45, and 60 minutes after this infusion ended. Analyses of chilled sera for FFA were made promptly by the method of Schotz, Masson and Page.lo B, and the final sample were also analyzed for cholesterol and triglyceride; since these showed no significant differences between groups nor changes after infusion of NE, the data are not listed. Arterial pressure (auscultatory) and pulse rate were recorded frequently before, during, and after infusion. Two of the “healthy” and 3 of the IHD subjects were found to have mild hypertension* at rest. Onset of angina caused infusions to be terminated at 3, 5, and 8 minutes in 3 subjects with IHD. Data from these tests are not included in Table I. Those of hypertensive and angina1 subjects are not included in means of pressure and pulse data. Results
Data from analyses of serum FFA are summarized in Table I. Means of FFA in B, were higher? in subjects with IHD than in healthy men. Means of B,l were slightly higher than those of B, in both; these increments were not uniform, since increases of 50 NEq per liter occurred in 7 of 21 healthy and in 7 of 14 IHD subjects, with Hypertension is defined as systolic 160 mm. Hg or more and/or diastolic 95 mm. Hg or more. tDifference/standard error of differences of means 3.28.
was lost.
and also
equivalent decreasesin 1 of each group and small or negligible changes in other subjects. Distribution of fasting contents showed no association with body weight or with P.I. Post-NE increases in FFA were measured from B,l. With wide individual variations, means of increments were similar in healthy and IHD subjects. Maximum increases were usually found in the samples taken at 10 or 20 minutes, although at 0 and 30 minutes in 1 each of 2 healthy men, and at 0 minute in 2 IHD men. Respective increments at terminations of infusions of 15, 25, and 40 pg of NE during angina were 70, 270, and 30 mEq. per liter at 0 or 10 minutes post-NE, while in the last case a secondary rise of 1,180 PEq per liter occurred at 30 minutes, angina having recurred at about 20 minutes. -4s with fasting contents, responses to NE could not be associated with individual P.I. Preinfusion means of arterial pressure and pulse in the 20 normotensive health! and 10 normotensive IHD subjects were, respectively, 113/75 mm. Hg and 71 per minute, and 106/73 mm. Hg and 66 per minute. Means of maximum rises in pressure during infusion were, respectivelv, 12.5/10 and 19.4/10.4 mm. Hg; the systolic increment was greater* in the IHD subjects. Pulse decrements were nearly equal, rates during infusion being 62 per minute *Difference/standard
error
of differences
of means 3.3.
Volume Number
67 4
Serum free fatty a&d and pressor responses to norefiinephrine
in healthy subjects and 60 per minute in subjects with IHD; respective means of minima of immediate postinfusion pressures were 106/72 and 99/65 mm. Hg. The 2 healthy hypertensive subjects and 3 IHD subjects who developed angina showed greater than average rises in pressure: in the former, 32/20 and 41/18 mm. Hg; and in the latter 28/14, 36/12, and 70,/16 mm. Hg. The first 2 of the angina1 IHD group were hypertensive at rest, whereas the patient with the most severe angina1 pressor and FFA responses was not. A response close to the mean was noted in one hypertensive IHD subject (resting pressure of 165,198 mm. Hg) who did not experience angina. Comment Responsiveness to NE-induced release of FFA is similar and variable in healthy and IHD subjects of like ages and apparent general condition. The somewhat higher fasting content of serum FFA in IHD subjects may reflect greater apprehension of, or adrenergic release to, the test situation. The latter explanation would accord with greater responsiveness of such subjects to smoking,6 and also that those whose behavior pattern and serum lipid content are indicative of high 1HD risk show larger excretions of norepinephrine” and 3-methosy-4-hydroxymandelic acid12 during working hours than do those of different temperament and constitution. Although serum FFA is higher in obese than in normal subjects,13 no association of fasting FFA or response to NE with relative body weight was defined in these tests; however, the series is not large and none of the subjects was grossly obese. The greater systolic response of IHD than of healthy subjects to NE can plausibly be attributed to arteriosclerosis and diminished central arterial elasticity. However, the latter should also diminish bradycardic responseI to NE and presumably the post-NE decrement of pressure. These differences were not found. The angina associated with excessive pressor responses which was precipitated in 3 IHD subjects by doses of only 0.2 to 0.5 rg per kilogram of NE distributed over 3 to 8 minutes suggests a myocardial susceptibility to NE to which angina may have contributed.
491
Conclusions 1. Mobilization of lipids as circulating FFA in response to norepinephrine (NE) was similar, and individually variable, in healthy and postmyocardial infarct (IHD) subjects. 2. Systolic pressor responsiveness to small doses of norepinephrine was usually enhanced in IHD subjects, as also in 4 of 5 subjects with mild hypertension; of 3 post-IHD, 2 hypertensive and 1 normotensive rapidly developed angina and larger than average increments of pressure during intravenous infusion of norepinephrine at a rate of 5 pg per minute. I am deeply appreciative those of the Cleveland others, healthy and with who volunteered for these
of the cooperation of and of ischemic heart disease, tests.
Firemen’s Union
REFERENCES 1. Editorial: The fuel of muscular exercise, Lancet 2 :276, 1959. 2. Freidberg, S. J., Klein, R. F., Trout, D. L., Bogdonoff, M. D., and Estes, E. H., Jr.: The incorporation of plasma free fatty acids into plasma triglycerides in man, J. Clin. Invest. 40:1846, 1961. 3. Poole, J. C. F.: Effect of diet and lipemia on coagulation and thrombosis, Fed. Proc. 21: Suppl. 11, 20, 1962. 4. Connor, W. E., Hoak, J. C., and Warner, E. D.: Massive thrombosis produced by fatty acid infusion. T. Clin. Invest. 32:860. 1963. 5. Enticknap, J.’ B.: Serum fatty acids aftkr fatal heart attacks, Lancet 1:32, 1960. 6. Kerschbaum, A., Bellet, S., Caplan, R. P., and Feinberg, R. J.: Effect of cigarette smoking on free fatty acids in patients-with healed myocardial infarction. Am. 1. Cardiol. 10:204. 1962. 7. Kerschbaum, A.; Khorsandian, R., &plan, R. F., Bellet, S., and Feinberg, L. F.: The role of catecholamines in the free fatty acid response to cigarette smoking, Circulation 2852, -1963. 8. Sheldon. W. E.. Duoertuis. C. W.. and McDermott, E.: Atlas of man: a guide for somatotyping the adult male of all ages, New York, 1954, Harper and Brothers. 9. Klein, R. F., Estes, E. H., Jr., and Bogdonoff, M. D.: Effect of norepinephrine on plasma free fatty acids in man, J. Appl. Physiol. 16:343, 1961. 10. Schotz, M. C., Masson, G. M. C., and Page, I. H.: Effect of ACTH in vivo on release of nonesterified fatty acids from adipose tissues of adrenalectomized rats, Proc. Sot. Exper. Biol. & Med. 101:159, 1959. 11. Friedman, M., St. George, S., Byers, S. O., and Rosenman, R. H. : Excretion of catecholamines, If-ketosteroids, 17-hydroxy-corticoids and Shydroxy-indole in men exhibiting particular behavior pattern. (A) Associated with high I
492
12.
Corcoran
incidence of clinical coronary artery disease, J. Clin. Invest. 39:758, 1960. Byers, S. O., Friedman, M., Rosenman, I<. H., and Freed, S. C.: Excretion of 3.methoxy-& hydroxymandelic acid in men with behavior pattern associated with high incidence of coronary artery disease, Fed. Proc. 21:Suppl. 11, 99. 1962.
1.1. Opie, L. Ft., a11d Lk’allish, I’. G.: Plasma free fatty acid concentrations ill obesity, New England J. Med. 268:757, 1963. 14. Finnerty, F. :I., Jr., Tuckman, J., and Hajyan, A.: Changes in heart rate during levarterenol infusion: an index of arterial elasticitv. Circulation Res. 7:565, 19.59.