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Effect of cigarette smoking on free fatty acids in patients with healed myocardial infarction
Effect of Cigarette
Smoking
Acids in Patients Myocardial
on Free Fatty
with Healed Infarction*
ALFRED KERSHBAUM, M.D., SAMUEL BELLET, M.D., F.A.c.c., R.~YMOND F. CAPLAN, M.D. and LEONARD J. FEINBERG, PH.D. Philadelphia,
Pennsylvania
I
in the three smoking groups except for the elimination of smoking. All studies were performed at 9:00 A.M. with no food intake since the previous evening meal. The same room was used and the technical procedure of the smoking test and blood sampling was kept constant for all subjects. External stimulation was avoided during the observations. Serum FFA concentrations were determined by a modification of the methods of Gordon2 and Davis3 In some instances repeated FFA determinations by the method of Trout and associates4 revealed no significant difference in results.
N A PREVIOUS study in this laboratory it was found that cigarette smoking caused a rapid and significant rise in the serum levels of free fatty acids (FFA) in normal subjects and in patients with various clinical disorders. It was also found that a rise occurred in dogs after the intravenous infusion of nicotine.’ In the study of human subjects, it was noted that those patients of the series who had recovered from a myocardial infarction developed a more marked elevation of FFA after smoking than normal subjects or patients with no coronary heart It was decided to pursue this study disease. further by noting the effect of smoking in a larger group of patients with healed myocardial infarction.
RESULTS Myocardial Infarction Patients: All 17 myocardial infarction patients developed a rise in FF.4 after smoking which persisted in most instances throughout the 40-minute postsmoking period (Table I). The maximal rise usually occurred 10 to 20 minutes after smoking and ranged from 345 to 2,304 pEq./L. with a mean of 858 pEq..,‘L. (65.6 per cent). This compared to a maximal change in nonsmoking controls ranging from -22 MEq.,‘L. to +82 PEq., L. with a mean rise of 20 pEq.,/L. 01 1.7 per cent (P < 0.001). The mean curve of FFA changes in all myocardial infarction patients is shown in Figure 1. Figure 2 and 3 are curves of FFA concentrations of 2 patients showing relatively constant levels for a 40 minute presmoking control period followed after smoking by a sudden rise that persisted for at least 40 minutes. Figure 4 is the curve of a patient who smoked 6 cigarettes in a 40 minute period. The FFA rise was prompt and marked. Glucose levels in
MATERIAL AND METHODS Seventeen patients with a history of one or more myocardial infarctions were selected from the wards and outpatient departments of the Philadelphia General Hospital (Table I). The infarctions had occurred 3 months to 12 years prior to this study. Two standard brand, large size: filter-type cigarettes were smoked in a IO-minute period; antecubital venous blood samples were taken before and immediately after smoking and at intervals of 10, 20 and 40 minutes for determinations of serum I’FA levels. The same smoking and blood sampling procedure was then followed in two additional groups of subjects. One group consisted of 16 patients with various noncoronary disorders [duodenal ulcer (2). lung carcinoma (2), subsiding pneumonitis (3), cirrhosis of the liver (3), rheumatoid arthritis (2), diabetes insipidus (l), syphilitic cndocarditis (1). pyelonephritis (1 j, hypopituitarism (l)]. A second group consisted of 10 normal individuals. In a third group of 13 control subjects. the same studies were performed as
Philadelphia, Pennsylvania. * From thr Division of Cardiology, Philadelphia General Hospital, and the Tobacco Industry Research aided by grants from the U. S. Public Health Service (H-5989) by Public Hralth Fellowship HF-11, 378Cl. National Heart Institute.
204
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AMERICAN
JOURNAL
This wurk Committw
OF
was and
CARDIOLOGY
Cigarette
Smoking
and Free Fatty
Acids
205
TABLE I Strum Free Fatty Acid Levels Before and After Smoking in Patients with Healed Myocardial Infarction
Patient ~-1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
48 36 38 52 49 57 55 43 64 55 58 51 40 46 54 36 48
Free Fatty Acids (pEq./L.) at Timed Intervals (min.)
Sex
Interval Since Infarction
Cigarettes Smoked Daily
0
lo*
M M M F M M M M M M M M M M M M M
2 years 3 years 4 years 4 years 3 months 6 months 2 years 18 months 10 years 5 years 11 months 12 years 6 years 3 years 16 months 5 years 7 years
40 20 40 10 30 30 20 20 20 20-30 20 10-15 20 10 20 30 20
1014 1986 1102 1336 2290 2378 1318 1070 920 1128 1224 666 972 1284 744 1126 1674
1208 2354 1810 1444 2394 2874 1772 1728 1464 1166 1506 778 1134 1384 952 1234 2102
20 1922 2462 1832 1798 2372 3696 1836 1652 1764 1638 1712 1186 1476 1624 900 1480 2316
30
50
3310 2246 1942 1924 4594 3048 1490 1428 2008 1844 1882 1119 1368 1754 970 1558 2156
2072 2050 1832 1444 2222 3134 1664 1296 1990 1806 2032 946 1116 1642 1090 1698 1978
* Two filter-tip cigarettes smoked between the 0 and 10 minute interval. this sullject, after an initial drop, rose with the for 50 minutes (epinephrine effect) and then became lower. The continued rise of FFA could he in part a reciprocal response to the drop in plasma glucose leve1.5,6 The presmoking levels of FFA (Table I) covered an expected broad range (666 to 2,378 pEq./‘L.) but showed no relation to the subsequent rise of FFA after smoking. Pre-
FFA
-
+mo + +200
smoking serum cholesterol levels also were unrelated to the FFA response to smoking. Noncoronary Patients and Normal Subjects: The subjects in the two smoking groups studied for comparison showed much less elevation of FFA after smoking than the myocardial infarction group (P < 0.001, P = O.OOl), hut developed elevations that were significantly greater than the nonsmoking controls (Fig. 5). The noncoronary patients had a maximal rise ranging from 98 to 590 pEq./L. with a mean of 320 pEq./L. or 27.2 per cent (P < 0.001). In the
-
+
5oo -
+
yoo
_
TWO CICK?ETTES SHOWED
0
In
20
30
40
M
60
10
60
90
Minu~as~ l-+------l-
O
10 Miz2utQs
20
30
YO
I-
50
FIG. 1. Mean FFA changes in 17 subjects with healed myocardial infarction after smoking two cigarettes. AUCIJST
1962
FIG. 2. Serum FFA levels during presmoking control period and after smoking two cigarettes. Patient was a 55 year old male who had a myocardial infarction two years previously. He smoked 20 ciaarettrs daily for 40 years.
206
Kershbaum
et al.
-
-
T
II-I-I-l-i-i-l-l-I-IO
lo
20
30
40
50
60
70
80
90
MYOCnRDlRL
Mincdtes -
INFRRCTIOU
FIG. 3. Serum FFA lev& during presmoking control period and after smoking two cigarettes. Patient was a 52 year old female who had a myocardial infarction four years previously. She smoked IO cigarettes daily for 30 vears.
group of normal subjects the maximal rise ranged from 202 to 444 pEq./L. with a mean of 292 wEq.;L. or 24.6 per cent (P < 0.001). Figure 6 shows the curves of FFA changes of all three smoking groups and the nonsmoking controls. The results of all experiments arc summarized in Table II. DISCIJSSION
Variability of FFA Response to Smoking: It will be noted that FFA presmoking levels and the changes after smoking varied considerably among subjects. It has heen oljserved by us and others’ that the fasting FF.4 level in a given subject, and the extent of its fluctuation, are highly variable and are influenced I)v the degree and duration of fasting, Ijody \veight,
O
-
NW-CORONni?v
NORl4RL
NON-SWOKIW
SUeJJECTS
CONTROLS
Patienk-
FIG. 5. Maximal FFA elevation after smoking in patients with healed myocardial infarction compared to effect in noncoronary patients. normal subjects and nonsmoking controls.
external stimulation and emotional state. In determining the FFA response to smoking, an attempt was made to control these factors. The small changes in FFA in the nonsmoking control group (Table II and Fig. 5) and the presmoking curves of the myocardial infarction patients (Fig. 2 and 3) indicate that these factors had no significant effect on the results of our experiments. The variability of FFA response to smoking among subjects when other influences are controlled is probably primarily an individual difference in the catecholaminereleasing effect of nicotine. Inhaling did not appear to affect the results. Tests were performed with and without inhaling /cLEC+/L+I300
$
+100
-
+600
-
-Ilo
Minutes
20
30
YO
50
60
-
Fro. 4. FFA and glucose lev& after smoking six cigarettes within a 40-minute period. Subject was a 55 year old malr \vith a history of myocardial infarction three years prc*viously. He smoked 20 to 40 cigarettes daily.
~‘IG. 6. Mean FFA changes after smoking in patients with myocardial infarction, noncoronary patients, normal sub.jects and nonsmoking controls. Two cigarettes were smoked between the 0 and lo-minute interval except in the nonsmoking controls. THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Cigarette
Smoking
and Free Fatty
Acids
207
TABLE 11 Free Fatty
Acid Elevation
After Cigarette Smoking in Patients with Myocardial Normal Subjects and Nonsmoking Controls
Subject Group A. B. C. D.
Myocardial infarction patients Noncoronary patients Normal subjects Nonsmoking controls
No. of Patients 17 16 10 13
Initial Mean FFA (/W/L.) 1308 1175 1188 1195
* S.E. = Standard error. t Difference of means of groups A, B and C and nonsmoking controls. P < 0.001; Groups A and c, P = 0.001.
with no significant difference in results; also, nonsmoking control subjects made to inhale deeply showed no effect on FFA. Mechanism of FFA Response: The results of the present study and of a previous report’ indicate that smoking causes a rapid, consistent and significant rise in serum free fatty acids. One cigarette smoked in a 5 minute interval resulted in FFA effects comparable to those observed after smoking two cigarettes in 10 minutes. Subjects who “chain-smoked” six cigarettes over a 40 minute period all developed FFA elevation that persisted during a 60 minute period of observation.’ The mechanism of this response is probably an increased release of epinephrine and norepinephrine from the adrenal medulla and postganglionic sympathetic nerve endings effected I)y the absorbed nicotine. Watts* and othersY-I2 have shown that cigarette smoking and nicotine administration cause a liberation of highly effective levels of catecholamines. The epinephrine and norepinephrine thus released could rapidly act on adipose tissue deposits to mobilize FFA.5J3,‘4 The most notable observation in the present study was the much greater effect of smoking on FFA in patients with myocardial infarction than in noncoronary patients and normal subjects; the mean FFA rise in the myocardial infarction group was more than double that in the other two groups. The explanation for this has not been definitely determined but is suggested by the results of recent studies’2.15-‘8 which have shown that an increase in circulating catecholamines occurs after acute myocardial infarction and after exercise in patients with angina pectoris. This could result from stimulation of tissue by accumulated cardiac chromafhn AUGUST
1962
Infarction,
Maximal
Noncoronary
FFA Rise
Mean and SE. * (pEq./L.)
% of rise
858 320 292 20
65.6 27.2 24.6 1.7
i & f +
Patients,
143 40 20 8
pi
Difference of means of groups A and B,
lactic acid in the ischemic cardiac tissue of these disease states.lg Similarly, in the smoking experiments, the patients with myocardial infarction may liberate greater quantities of cardiac catecholamines than the noncoronary and normal subjects and consequently produce greater mobilization of FFA. Another possible explanation for the presumed greater catecholamine release in myocardial infarction patients after smoking may be that these individuals are sympatho-adrenal hyperreactors. Friedman and associateszO found that a group of men exhibiting an overt behavior pattern, associated with a high incidence of coronary artery disease, had a far greater daytime excretion of norepinephrine than a control group. They believed that this difference in hormone secretion resulted from differences in psychological response to their environment. Sign$cance of FFA Elevation After Smoking: It has been shown that prolonged epinephrine administration causes an elevation of serum cholesterol and other lipoproteins in animals,13~14~2*~25probably as the result of an increase in circulating FFA which stimulates the liver to produce these lipids.‘3~‘4 The repeated FFA elevation that occurs in chronic smokers could also possibly result in a rise in serum lipoproteins, suggesting an explanation for the reported association between cigarette smoking, high blood cholesterol levels and coronary artery disease.23-26 Further, since a disturbance of lipid metabolism may influence the development and progress of atherosclerosis, anything contributing to lipid imbalance should be controlled in patients with myocardial infarction. SUMMARY
The
effect
of smoking
on serum
free
fatty
Kershbaum
208
acids was studied in 17 patients with healed There was an elevation myocardial infarction. of FFA in all sul)jects after smoking two cigarettes in a 10 minute period. A mean maximal rise of 858 pEq. I,. (65.6 per cent) occurred 10 to 20 minutes after smoking, and usually some elevation persisted for 40 minutes. Noncoronary patients and normal xul).jects also developed FFA cle\,ations of 320 PEq. I,. (27.2 per cent) and 292 pEq. I,. (24.6 per cent), respecti\rel!.. It is suggested that the greater FFA response in myocardial infarction patients is the result of a greater catecholamine release after nicotine stimulation.
et al. 12.
13.
14.
IS.
16.
17. I
2. 3.
4.
5.
6.
KERSIIB\U\!, ‘\., BEI.I.~.~, S., I)ICKSI.EIN, I<. R. dnd FEINBYRC, I.. .I. Effect of cigarrttc smoking and Bawd on a nicotine on strum free fatty acids.
study in the human subjxt and tht. exprrimcntal animal. C’wulu/ion R,,A., 0: 631, 1961. GORDON, K. S., .JR. Lncstrrificd fatt\. acid in human blood plasma. ‘rransport function of onII. rstel ilird fatty acid, ./. C!irz. Inir u., 36: SlO, 1957. DAVIS, B. H. Estimation of small amounts of fart! acid in the prrsrncc of polyxycthylenc sorbitan partial fatty acid ester (“‘Twrcn”~ and of wrum .4tch. ICodmn.. 15: 351, 1047. protcinq. TROU?., D. I,., f%XES. I<. H., .JR. anti I:RlWWRG, of frrc fatty acids of plasma: a s. .I. ‘Titration stud) of clwrrnt mrthods and a new modilication. .I. l_lfi~d Rrs.. 1 : 199, 1960. Kolc 01 thr sympaHAVFL, K. I..and Gor I)I I~.PI’.;\. thrtic nwvous systrrn in the metabolism of frw fatty acid?. .J. I$zd Rcs.. 1 : 102. 1959. D0r.l. V. I’. Kclation bctwccn non-&cl ilivd tatty acids ill plasma and thr mrtaholism of C~UCIISC~. .I. C/iv. In? $1.. 35: 150, I’JSh.
7. KLEIN; R. I:., HwIx~~~~I-I~, S:IIA\~., 1). M. Analysis
hf. II.,
l:s-ws.
18.
19.
20.
21.
22.
It. H. mtl
of thr factors affe-rting the “rcstiny” free fatty acid lcwl in normal man. Circul~i/ion, 22 : 772, 1060. S. WZTTS. D. ‘1’. Effwt of nicorinc and smokin: on :lr,n. .\IZC l.or! the sccrction of cpinrphrinc. ACLZ~.,Yc., 90: 74. 1960. 9. HAZARD, R., BEAUVAI.LE~, M. and I.K.\IJ, S. Teneur drl sang su&nal cn adrtnalinr ct en noradl&alinr chrA le chien soumis a I’action dr la nicotine. Cowz!~/.?~wl. cot. bid., 151 : 210. 1357. IO. MALMEJAC, .I., NEVERRE, G. and B~ANC~II, M. Analysr dcs actions crntrales ct periph&iqwr dc mCdullosurr&alr. la nicotine sur I’activitie Conl{~;. :m:!. sot. bid., 151: 707, 1957. 11. DESCHAEPI~RYVER, A. 1:. Phvsiopharmacolo$cnl cffrets on suprarcnal sccret~on of adrenaline and noradrenalinc in d~as. .4rch. inks/. phnvmrodv~~., 121: 222. 1959.
23.
24.
25.
26.
GALES, P. CL, RICHRDSON,
.I. A. arld \V~Jous,
It. I
Plasma catxholaminr roncrntrai.ions in myocardial inlarction and angina prctoris. Czriuinlinri, IO: 657, 1959. SIIAYRIR, I<., SUSSMAN. K. E. and STEINBERG, I). Rolr of the pituitary and the adrenal in the mobilization of free fatty acids and lipoproteins. .I. lipid Rrs., 1 : 459, 1960. SIIAFRIR, 1;. and STI;IKISERG,D. Essential role of the adwnal cortex in thf rpsponsr of plasma free lntty acids, cholesterol and phospholipids to cpintzphrinv. J. 0’1n. /w( r/., 39: 310, 1960. RIC:II.~RDSON, .I. r\., WOODS, 1’. F. and B.~GWELL, R. S. Circulatinq rpincphrinc and norcpinephrima in coronarv occlusion. Am. J. Cm-did., 5: 613, 1960. suprarenal discharges in anKaq W. Abnormal qina pcctoris and their control by x-ray therapy. J. Clin. Endoctinnl., 1 : 977, 1941. NUXUM, F. R. and BISCI~OFI~, F. ‘The urinary output of catechol derivatives including adrenaline in normal individuals in cssrntial hypertension and in myocardial infarction. Ci~cdorion, 7: 96, 1953. della S I‘.~RCICII, R. and tb.m.4NELL1, u. Importanza drtrrminazione de!lr catccholaminc plasmatiche in patolo+a coronarica. Ciot. c/in. mrd., 40: hc. 2. 1959. Woons, E. R., RICIIRIXON, .1. A., RICIIARDSON, .A. K. and BOZEM&P*', R. F., .JR. Plasma concentrations of rpinrphrinr and artermol following the actions of various agents on the adrenals. .J. Phn,_rrmd. @ lCxf~r,_. ‘f’hcr
THE AMERICANJOURNAL
OF CARDlOLOGY
Smoking
Acids in Patients Myocardial
on Free Fatty
with Healed Infarction*
ALFRED KERSHBAUM, M.D., SAMUEL BELLET, M.D., F.A.c.c., R.~YMOND F. CAPLAN, M.D. and LEONARD J. FEINBERG, PH.D. Philadelphia,
Pennsylvania
I
in the three smoking groups except for the elimination of smoking. All studies were performed at 9:00 A.M. with no food intake since the previous evening meal. The same room was used and the technical procedure of the smoking test and blood sampling was kept constant for all subjects. External stimulation was avoided during the observations. Serum FFA concentrations were determined by a modification of the methods of Gordon2 and Davis3 In some instances repeated FFA determinations by the method of Trout and associates4 revealed no significant difference in results.
N A PREVIOUS study in this laboratory it was found that cigarette smoking caused a rapid and significant rise in the serum levels of free fatty acids (FFA) in normal subjects and in patients with various clinical disorders. It was also found that a rise occurred in dogs after the intravenous infusion of nicotine.’ In the study of human subjects, it was noted that those patients of the series who had recovered from a myocardial infarction developed a more marked elevation of FFA after smoking than normal subjects or patients with no coronary heart It was decided to pursue this study disease. further by noting the effect of smoking in a larger group of patients with healed myocardial infarction.
RESULTS Myocardial Infarction Patients: All 17 myocardial infarction patients developed a rise in FF.4 after smoking which persisted in most instances throughout the 40-minute postsmoking period (Table I). The maximal rise usually occurred 10 to 20 minutes after smoking and ranged from 345 to 2,304 pEq./L. with a mean of 858 pEq..,‘L. (65.6 per cent). This compared to a maximal change in nonsmoking controls ranging from -22 MEq.,‘L. to +82 PEq., L. with a mean rise of 20 pEq.,/L. 01 1.7 per cent (P < 0.001). The mean curve of FFA changes in all myocardial infarction patients is shown in Figure 1. Figure 2 and 3 are curves of FFA concentrations of 2 patients showing relatively constant levels for a 40 minute presmoking control period followed after smoking by a sudden rise that persisted for at least 40 minutes. Figure 4 is the curve of a patient who smoked 6 cigarettes in a 40 minute period. The FFA rise was prompt and marked. Glucose levels in
MATERIAL AND METHODS Seventeen patients with a history of one or more myocardial infarctions were selected from the wards and outpatient departments of the Philadelphia General Hospital (Table I). The infarctions had occurred 3 months to 12 years prior to this study. Two standard brand, large size: filter-type cigarettes were smoked in a IO-minute period; antecubital venous blood samples were taken before and immediately after smoking and at intervals of 10, 20 and 40 minutes for determinations of serum I’FA levels. The same smoking and blood sampling procedure was then followed in two additional groups of subjects. One group consisted of 16 patients with various noncoronary disorders [duodenal ulcer (2). lung carcinoma (2), subsiding pneumonitis (3), cirrhosis of the liver (3), rheumatoid arthritis (2), diabetes insipidus (l), syphilitic cndocarditis (1). pyelonephritis (1 j, hypopituitarism (l)]. A second group consisted of 10 normal individuals. In a third group of 13 control subjects. the same studies were performed as
Philadelphia, Pennsylvania. * From thr Division of Cardiology, Philadelphia General Hospital, and the Tobacco Industry Research aided by grants from the U. S. Public Health Service (H-5989) by Public Hralth Fellowship HF-11, 378Cl. National Heart Institute.
204
rnk
AMERICAN
JOURNAL
This wurk Committw
OF
was and
CARDIOLOGY
Cigarette
Smoking
and Free Fatty
Acids
205
TABLE I Strum Free Fatty Acid Levels Before and After Smoking in Patients with Healed Myocardial Infarction
Patient ~-1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
48 36 38 52 49 57 55 43 64 55 58 51 40 46 54 36 48
Free Fatty Acids (pEq./L.) at Timed Intervals (min.)
Sex
Interval Since Infarction
Cigarettes Smoked Daily
0
lo*
M M M F M M M M M M M M M M M M M
2 years 3 years 4 years 4 years 3 months 6 months 2 years 18 months 10 years 5 years 11 months 12 years 6 years 3 years 16 months 5 years 7 years
40 20 40 10 30 30 20 20 20 20-30 20 10-15 20 10 20 30 20
1014 1986 1102 1336 2290 2378 1318 1070 920 1128 1224 666 972 1284 744 1126 1674
1208 2354 1810 1444 2394 2874 1772 1728 1464 1166 1506 778 1134 1384 952 1234 2102
20 1922 2462 1832 1798 2372 3696 1836 1652 1764 1638 1712 1186 1476 1624 900 1480 2316
30
50
3310 2246 1942 1924 4594 3048 1490 1428 2008 1844 1882 1119 1368 1754 970 1558 2156
2072 2050 1832 1444 2222 3134 1664 1296 1990 1806 2032 946 1116 1642 1090 1698 1978
* Two filter-tip cigarettes smoked between the 0 and 10 minute interval. this sullject, after an initial drop, rose with the for 50 minutes (epinephrine effect) and then became lower. The continued rise of FFA could he in part a reciprocal response to the drop in plasma glucose leve1.5,6 The presmoking levels of FFA (Table I) covered an expected broad range (666 to 2,378 pEq./‘L.) but showed no relation to the subsequent rise of FFA after smoking. Pre-
FFA
-
+mo + +200
smoking serum cholesterol levels also were unrelated to the FFA response to smoking. Noncoronary Patients and Normal Subjects: The subjects in the two smoking groups studied for comparison showed much less elevation of FFA after smoking than the myocardial infarction group (P < 0.001, P = O.OOl), hut developed elevations that were significantly greater than the nonsmoking controls (Fig. 5). The noncoronary patients had a maximal rise ranging from 98 to 590 pEq./L. with a mean of 320 pEq./L. or 27.2 per cent (P < 0.001). In the
-
+
5oo -
+
yoo
_
TWO CICK?ETTES SHOWED
0
In
20
30
40
M
60
10
60
90
Minu~as~ l-+------l-
O
10 Miz2utQs
20
30
YO
I-
50
FIG. 1. Mean FFA changes in 17 subjects with healed myocardial infarction after smoking two cigarettes. AUCIJST
1962
FIG. 2. Serum FFA levels during presmoking control period and after smoking two cigarettes. Patient was a 55 year old male who had a myocardial infarction two years previously. He smoked 20 ciaarettrs daily for 40 years.
206
Kershbaum
et al.
-
-
T
II-I-I-l-i-i-l-l-I-IO
lo
20
30
40
50
60
70
80
90
MYOCnRDlRL
Mincdtes -
INFRRCTIOU
FIG. 3. Serum FFA lev& during presmoking control period and after smoking two cigarettes. Patient was a 52 year old female who had a myocardial infarction four years previously. She smoked IO cigarettes daily for 30 vears.
group of normal subjects the maximal rise ranged from 202 to 444 pEq./L. with a mean of 292 wEq.;L. or 24.6 per cent (P < 0.001). Figure 6 shows the curves of FFA changes of all three smoking groups and the nonsmoking controls. The results of all experiments arc summarized in Table II. DISCIJSSION
Variability of FFA Response to Smoking: It will be noted that FFA presmoking levels and the changes after smoking varied considerably among subjects. It has heen oljserved by us and others’ that the fasting FF.4 level in a given subject, and the extent of its fluctuation, are highly variable and are influenced I)v the degree and duration of fasting, Ijody \veight,
O
-
NW-CORONni?v
NORl4RL
NON-SWOKIW
SUeJJECTS
CONTROLS
Patienk-
FIG. 5. Maximal FFA elevation after smoking in patients with healed myocardial infarction compared to effect in noncoronary patients. normal subjects and nonsmoking controls.
external stimulation and emotional state. In determining the FFA response to smoking, an attempt was made to control these factors. The small changes in FFA in the nonsmoking control group (Table II and Fig. 5) and the presmoking curves of the myocardial infarction patients (Fig. 2 and 3) indicate that these factors had no significant effect on the results of our experiments. The variability of FFA response to smoking among subjects when other influences are controlled is probably primarily an individual difference in the catecholaminereleasing effect of nicotine. Inhaling did not appear to affect the results. Tests were performed with and without inhaling /cLEC+/L+I300
$
+100
-
+600
-
-Ilo
Minutes
20
30
YO
50
60
-
Fro. 4. FFA and glucose lev& after smoking six cigarettes within a 40-minute period. Subject was a 55 year old malr \vith a history of myocardial infarction three years prc*viously. He smoked 20 to 40 cigarettes daily.
~‘IG. 6. Mean FFA changes after smoking in patients with myocardial infarction, noncoronary patients, normal sub.jects and nonsmoking controls. Two cigarettes were smoked between the 0 and lo-minute interval except in the nonsmoking controls. THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Cigarette
Smoking
and Free Fatty
Acids
207
TABLE 11 Free Fatty
Acid Elevation
After Cigarette Smoking in Patients with Myocardial Normal Subjects and Nonsmoking Controls
Subject Group A. B. C. D.
Myocardial infarction patients Noncoronary patients Normal subjects Nonsmoking controls
No. of Patients 17 16 10 13
Initial Mean FFA (/W/L.) 1308 1175 1188 1195
* S.E. = Standard error. t Difference of means of groups A, B and C and nonsmoking controls. P < 0.001; Groups A and c, P = 0.001.
with no significant difference in results; also, nonsmoking control subjects made to inhale deeply showed no effect on FFA. Mechanism of FFA Response: The results of the present study and of a previous report’ indicate that smoking causes a rapid, consistent and significant rise in serum free fatty acids. One cigarette smoked in a 5 minute interval resulted in FFA effects comparable to those observed after smoking two cigarettes in 10 minutes. Subjects who “chain-smoked” six cigarettes over a 40 minute period all developed FFA elevation that persisted during a 60 minute period of observation.’ The mechanism of this response is probably an increased release of epinephrine and norepinephrine from the adrenal medulla and postganglionic sympathetic nerve endings effected I)y the absorbed nicotine. Watts* and othersY-I2 have shown that cigarette smoking and nicotine administration cause a liberation of highly effective levels of catecholamines. The epinephrine and norepinephrine thus released could rapidly act on adipose tissue deposits to mobilize FFA.5J3,‘4 The most notable observation in the present study was the much greater effect of smoking on FFA in patients with myocardial infarction than in noncoronary patients and normal subjects; the mean FFA rise in the myocardial infarction group was more than double that in the other two groups. The explanation for this has not been definitely determined but is suggested by the results of recent studies’2.15-‘8 which have shown that an increase in circulating catecholamines occurs after acute myocardial infarction and after exercise in patients with angina pectoris. This could result from stimulation of tissue by accumulated cardiac chromafhn AUGUST
1962
Infarction,
Maximal
Noncoronary
FFA Rise
Mean and SE. * (pEq./L.)
% of rise
858 320 292 20
65.6 27.2 24.6 1.7
i & f +
Patients,
143 40 20 8
pi
Difference of means of groups A and B,
lactic acid in the ischemic cardiac tissue of these disease states.lg Similarly, in the smoking experiments, the patients with myocardial infarction may liberate greater quantities of cardiac catecholamines than the noncoronary and normal subjects and consequently produce greater mobilization of FFA. Another possible explanation for the presumed greater catecholamine release in myocardial infarction patients after smoking may be that these individuals are sympatho-adrenal hyperreactors. Friedman and associateszO found that a group of men exhibiting an overt behavior pattern, associated with a high incidence of coronary artery disease, had a far greater daytime excretion of norepinephrine than a control group. They believed that this difference in hormone secretion resulted from differences in psychological response to their environment. Sign$cance of FFA Elevation After Smoking: It has been shown that prolonged epinephrine administration causes an elevation of serum cholesterol and other lipoproteins in animals,13~14~2*~25probably as the result of an increase in circulating FFA which stimulates the liver to produce these lipids.‘3~‘4 The repeated FFA elevation that occurs in chronic smokers could also possibly result in a rise in serum lipoproteins, suggesting an explanation for the reported association between cigarette smoking, high blood cholesterol levels and coronary artery disease.23-26 Further, since a disturbance of lipid metabolism may influence the development and progress of atherosclerosis, anything contributing to lipid imbalance should be controlled in patients with myocardial infarction. SUMMARY
The
effect
of smoking
on serum
free
fatty
Kershbaum
208
acids was studied in 17 patients with healed There was an elevation myocardial infarction. of FFA in all sul)jects after smoking two cigarettes in a 10 minute period. A mean maximal rise of 858 pEq. I,. (65.6 per cent) occurred 10 to 20 minutes after smoking, and usually some elevation persisted for 40 minutes. Noncoronary patients and normal xul).jects also developed FFA cle\,ations of 320 PEq. I,. (27.2 per cent) and 292 pEq. I,. (24.6 per cent), respecti\rel!.. It is suggested that the greater FFA response in myocardial infarction patients is the result of a greater catecholamine release after nicotine stimulation.
et al. 12.
13.
14.
IS.
16.
17. I
2. 3.
4.
5.
6.
KERSIIB\U\!, ‘\., BEI.I.~.~, S., I)ICKSI.EIN, I<. R. dnd FEINBYRC, I.. .I. Effect of cigarrttc smoking and Bawd on a nicotine on strum free fatty acids.
study in the human subjxt and tht. exprrimcntal animal. C’wulu/ion R,,A., 0: 631, 1961. GORDON, K. S., .JR. Lncstrrificd fatt\. acid in human blood plasma. ‘rransport function of onII. rstel ilird fatty acid, ./. C!irz. Inir u., 36: SlO, 1957. DAVIS, B. H. Estimation of small amounts of fart! acid in the prrsrncc of polyxycthylenc sorbitan partial fatty acid ester (“‘Twrcn”~ and of wrum .4tch. ICodmn.. 15: 351, 1047. protcinq. TROU?., D. I,., f%XES. I<. H., .JR. anti I:RlWWRG, of frrc fatty acids of plasma: a s. .I. ‘Titration stud) of clwrrnt mrthods and a new modilication. .I. l_lfi~d Rrs.. 1 : 199, 1960. Kolc 01 thr sympaHAVFL, K. I..and Gor I)I I~.PI’.;\. thrtic nwvous systrrn in the metabolism of frw fatty acid?. .J. I$zd Rcs.. 1 : 102. 1959. D0r.l. V. I’. Kclation bctwccn non-&cl ilivd tatty acids ill plasma and thr mrtaholism of C~UCIISC~. .I. C/iv. In? $1.. 35: 150, I’JSh.
7. KLEIN; R. I:., HwIx~~~~I-I~, S:IIA\~., 1). M. Analysis
hf. II.,
l:s-ws.
18.
19.
20.
21.
22.
It. H. mtl
of thr factors affe-rting the “rcstiny” free fatty acid lcwl in normal man. Circul~i/ion, 22 : 772, 1060. S. WZTTS. D. ‘1’. Effwt of nicorinc and smokin: on :lr,n. .\IZC l.or! the sccrction of cpinrphrinc. ACLZ~.,Yc., 90: 74. 1960. 9. HAZARD, R., BEAUVAI.LE~, M. and I.K.\IJ, S. Teneur drl sang su&nal cn adrtnalinr ct en noradl&alinr chrA le chien soumis a I’action dr la nicotine. Cowz!~/.?~wl. cot. bid., 151 : 210. 1357. IO. MALMEJAC, .I., NEVERRE, G. and B~ANC~II, M. Analysr dcs actions crntrales ct periph&iqwr dc mCdullosurr&alr. la nicotine sur I’activitie Conl{~;. :m:!. sot. bid., 151: 707, 1957. 11. DESCHAEPI~RYVER, A. 1:. Phvsiopharmacolo$cnl cffrets on suprarcnal sccret~on of adrenaline and noradrenalinc in d~as. .4rch. inks/. phnvmrodv~~., 121: 222. 1959.
23.
24.
25.
26.
GALES, P. CL, RICHRDSON,
.I. A. arld \V~Jous,
It. I
Plasma catxholaminr roncrntrai.ions in myocardial inlarction and angina prctoris. Czriuinlinri, IO: 657, 1959. SIIAYRIR, I<., SUSSMAN. K. E. and STEINBERG, I). Rolr of the pituitary and the adrenal in the mobilization of free fatty acids and lipoproteins. .I. lipid Rrs., 1 : 459, 1960. SIIAFRIR, 1;. and STI;IKISERG,D. Essential role of the adwnal cortex in thf rpsponsr of plasma free lntty acids, cholesterol and phospholipids to cpintzphrinv. J. 0’1n. /w( r/., 39: 310, 1960. RIC:II.~RDSON, .I. r\., WOODS, 1’. F. and B.~GWELL, R. S. Circulatinq rpincphrinc and norcpinephrima in coronarv occlusion. Am. J. Cm-did., 5: 613, 1960. suprarenal discharges in anKaq W. Abnormal qina pcctoris and their control by x-ray therapy. J. Clin. Endoctinnl., 1 : 977, 1941. NUXUM, F. R. and BISCI~OFI~, F. ‘The urinary output of catechol derivatives including adrenaline in normal individuals in cssrntial hypertension and in myocardial infarction. Ci~cdorion, 7: 96, 1953. della S I‘.~RCICII, R. and tb.m.4NELL1, u. Importanza drtrrminazione de!lr catccholaminc plasmatiche in patolo+a coronarica. Ciot. c/in. mrd., 40: hc. 2. 1959. Woons, E. R., RICIIRIXON, .1. A., RICIIARDSON, .A. K. and BOZEM&P*', R. F., .JR. Plasma concentrations of rpinrphrinr and artermol following the actions of various agents on the adrenals. .J. Phn,_rrmd. @ lCxf~r,_. ‘f’hcr
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