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Coronary artery occlusion and blood lipids
Jwph J. Barboriak, Sc.D. Alfred A. &nun, Ph.D. Alfred J. Anderson, M.S. F&.X E. Trkani, M.D. John A. Walker, M.D. ibbert d. Fhma, M.D. MBamrrkee, wise.
Results of a number of epidemiologic studies have indicated that patients with elevated blood lipid levela show a higher incidence of cardiovaecular disease than individuals with low or normal lipid levels. l-I Investigations of patients with angiographically determined coronary heart dieease have also demonstrated that most o$ h patienta have high blood lipid levels. @a&&i and co-worker@ have studied a group of 27 patients with angiographically proved coronary disease and found 17 patienta with abnormal lipoprotein pattern. Heinle and co-worker@ h$ve observed a similar proportion of abnormal &a&&m&n (54 per cent) in 126 pat&&a with coronary luminal irregularity or btenoaia. Allard, Rtito, and Goulet’ have reported on 129 patients who needed aortocoronary bpprrare surgery and found only 14 patients with normal blood lipid levels. In our initial study of 162 patients with aortocoronary bypaas,8 all were found to have elevated plasma lipid levels. While an association between the incidence of coronary disease and abnormal blood lipid levels or lipoprotein patterns appear6 to be well documented, little is known about the. possible correhtion between the extent or the sites of the *nary obstruction, age of the patients, and From the Research, Medical, and Surgical Services, Wood Veterans Adrdabtratlon Center; Departments of Pher-logy, Biwtatietics, I#b&&e, and Surgery, The Medical Celiege of Wieconein; and tbe Lbectlaa of Cardi&gy and Thoracic Surgery, St. Luke’s Ho&al, Milwaukee, Wise. This etudy wee supported in part by Grant No. l&14378, National Inetitutee of Health, United Statea Public Health Service. E&eked for publication Sept. 4,1973. Beprint requests to: Dr. Joseph J. Barboriak, Reeearch Service (lSlB), V&mans Administration Center, Wood, Wii. 53193.
718
plasma lipid levels. The availability of information on the angiographically ascertained coronary obstruction and plasma lipid levels in 481 patients undergoing diagnostic arteriography offered an opportunity to investigate this possible relationship. The result of this study indicates that both advancing age and elevated plasma cholesterol levels may be of similar importance in the development of coronary obstruction. Methods A group of 481 male patients referred to St. Luke’s and Wood Veterans Administration Hospitals, Milwaukee, Wise., for a diagnostic angiographic examination were studied. An inquiry of a larger group of such patients (620) by questionnaire indicated that about 67 per cent of them did not have any treatment for control of blood lipids, while about 28 per cent followed some dietary restrictions, and 2 per cent of the patients received hypolipemic drugs. The plasma lipid levels of the patients with dietary treatment-237 f 45 mg. per 100 ml. for cholesterol and 151 f 71 mg. per 100 ml. for triglyceride (mean f standard deviation&were similar to values of the patients without the treatment230 f 45 mg. per 100 ml. and 174 f 168 mg. per 100 ml., respectively. The group receiving the drug treatment had higher levels for both plasma cholesterol (262 f 43 mg. per 100 ml.) and triglyceride (218 f 110 mg. per 100 ml.). The coronary arteriography was carried out as described by Sones and Shireye or Judkh@ and the film reviewed by cardiologists experienced in the interpretation of the angiograms. The degree of obstruction was rated as suggested by Rowe
June, 1974, Vol. 87, No. 6, pp. 716-721
Coronary artery occlusion and blood lipids
and co-workeran; however, the scale was inverted, i.e., the score of the patient without any coronary obstruction was set as 0 and a patient with all three main coronary arteries totally obstructed was assigned a score of 300. Fasting blood samples were collected before angiography prior to heparin administration and analyzed for serum total cholesterol by an automated procedure,12 triglycerides,13 and lipoprotein distribution.14Reproducibility of the triglyceride and cholesterol methods were determined by repeated assays of aliquots from a frozen pool of a standard serum at weekly intervals. Results for this pooled serum were: triglyceride, 137 zb 3.6 mg. per iO0 ml.; cholesterol, 202 f 4.9 mg. per 100 ml. Coefficients of variation were 2.6 and 2.4 per cent, respectively. Lipoprotein typing was carried out using the Friedewalt, Levy, and Fredrickson15 and Fredrickson, Levy, and Lees16 estimates of average age-adjusted cholesterol content of the individual lipoprotein fractions in conjunction with the lipoprotein electropherogram. Type III was confirmed by absence of the P-lipoprotein band on disc electrophoresis.” Results The pertinent data on the patients are compiled in Table I. In comparison with values obtained with a general population,lsJe the abnormal lipid elevation in our patients was mainly confined to the plasma triglyceride fraction. This was also reflected in plasma lipoprotein distribution since only 34, or 7.2 per cent, of the patients belonged to Type II while 193, or 41.2 per cent, belonged to Type IV. No lipoprotein typing was done in 12 patients. Because of some changes in the interpretation of lipoprotein types which occurred during the collection of data (i.e., introduction of Types IIa and IIb), it was decided to use only the original plasma lipid values for the study of the various correlations. The possible association between the blood lipid levels and the degree of coronary blood flow obstruction as represented by the occlusion score was evaluated in several ways: 1. Number blood lipids.
of affected
coronary
arteries
and
The association between the number of markedly affected coronary branches (75 per cent or more of the lumen blocked) and blood lipids is shown in Table II. A consistent and statistically significant increase in mean plasma American Heart Journal
I. Information on average age, plasma lipids, and other variables in the group of 481 patients Table
Age (years) Plasma choleeterol Cmg./lOO ml.) Plasma triglyceride (mg./lOO ml.) Lipoprotein distribution (%) Typa 11 Type IV Type III Normal Smokera (%) Hypertension (%) *Mean f standard deviation. tInformation obtained from medical
bietoriee
52 f 1.6' 256 f 55.7 212 zt133.2 7.2 41.2
0.9 50.7
82.Ot 35.0t
of 248 patients.
cholesterol level occurred with an increase in the number of coronary arteries occluded. Patients with no markedly occluded arteries had lower triglycerides than those with occluded arteries; however, differences according to the number of arteries affected were small and not statistically significant. ’ The breakdown of the plasma lipid values according to the specific coronary arteries blocked for at least 75 per cent of their lumen is also shown in Table II. The data indicate that no marked differences in plasma lipid levels were associated with occlusion of specific coronary arteries. 2. Coronary occlusion. age, and plasma cholesterol levels. The data on the association of the
extent of coronary impairment, age, and plasma cholesterol levels are shown in Table III. The age ranges were selected to include the decade group around the average age. The lowest average coronary occlusion score, 144, was observed in the group of patients less than 48 years of age with plasma cholesterol levels below the 225 mg. per 100 ml. value. However, even at this relatively low plasma cholesterol level, there was a statistically significant correlation between the progressing age and the increase in the coronary impairment (Groups A through G, P ( 0.01). In patients less than 48 years of age, the rise in plasma cholesterol levels was also connected with a statistically significant increase in the coronary occlusion score (Groups A through C, P (0.01). Similar, but less marked, changes in the score were observed with
717
Barboriak
et al.
Table II. Plasma cholesterol and triglyceride levels of patients occluded to at least 75 per cent of the lumen
None 2 One: LAD Right Two: CIR + Right Right Three: Right
76% occluded
48 107 62 36 154 28 58 35 174 126
LAD + LAD + CIR + LAD
+ CIR
222f6.2t 255 256 f 256 f 258 f 252 f 262 + 253 f 269 f 277 f
f
LAD = Left anterior descending artery. CIR = Circumfiex artery. ‘Because of the small number of patients having occlusion of the circumflex branches, these data were not included in the table. t&an zt standard error. tP < 0.01 in comparison with the group without any major occlusion.
Table
Ill. The effect of age and plasma
cholesterol
having one, two, or three coronary arteries
177 218 214 216 208 195 212 222 221 233
5.01 6.7$ 7.9t 4.1$ 8.0$ 6.3+ 9.8$ 4.7$ 5.4$
branch
only or occltion
of lesser branches
f f f f f f f f + +
17.3 15.4 20.9 20.7 8.5 24.4 12.2 19.6 10.6 13.7$
in combination
with main
levels on the coronary occlusion score Plasma chokstwol hng.llOO ml.)
Age (years.,
(225 144 zt (26) 172 zt (74) 205 f (36)
<48 48-57 >58
225-274 16.7' (a) 9.3 (d) 11.2 (B)
178 f 8.7 (54) cb) 188 f 7.6 (89) (e) 199 f 10.8 (46)f.h)
)275 202 f 8.4 (52) (c) 213 f 6.6 (75) WJ 198 f 13.2 (30) (i)
Number of patients in parentheses. P < 0.05: a-b, a-c, a-g, b-c, d-f, d-g. *Mean f standard error.
progressing elevation of plasma cholesterol levels in patients 48 to 57 years of age (Groups D through F, P ( 0.05), or with increasing age, in the group with a plasma cholesterol range of 225 to 274 mg. per 100 ml.,(Groups B through F). In the groups of patients with plasma cholesterol over 275 mg. per 100 ml. or older than 58 years of age, the further effect of age or rise in plasma cholesterol levels on the occlusion score was minimal. 3. Coronary occlusion, age, and triglyceride levels. A similar tabulation
average coronary
718
plasma
of the score was done for the three
age groups and three ranges of plasma triglycerides (Table IV). The lowest score, 165, was observed in patients less than 48 years of age having plasma triglyceride levels below the 150 mg. per 100 ml. mark; while the highest score, 214, was seen in the group with plasma triglyceride levels over 220 mg. per 100 ml. and age over 58 years. In contrast to the observation in the groups with the high cholesterol levels where the age effect was not apparent, the occlusion score in patients with high plasma triglyceride levels (over 220 mg. per 100 ml.) increased with age (Groups C through I, P ( 0.05). June, 1974, Vol. 87, No. 6
Coronary
Table IV. The effect of age and plasma
triglyceride
artery
levels on the coronary
occlusion
and blood lipids
score
Plasma triglycerides (mg.1100 ml.) Age < 150
(years)
<48
166 f (34) 173 f EXO 186 f (43)
48-67 > 58
150-219
14.9* (a) 8.7 Cd) 12.4 (g)
188 f (46) 192 + (71) 206 + (35)
> 220 185 * (52) 209 f (79) 214 f (33)
8.1 (b) 7.8 (e) 10.3 (h)
9.7 Cc) 6.8 0 10.8 (9
Number of patienta in parentheses. P ( 0.05: c-f, c-i, d-f. *Mean f standard error.
Table V. The effect of age and plasma cholesterol
Less
Age than 62
and triglyceride
Age
=s 180 1&w+
S 250 160 rt (78) 184 * (51)
9.2* (a) 9.4 Cc)
52 years
years
Plasma cholesterol hg.llOO Plasma tFi&CeFidtS hgJlO0 ml.)
levels on the coronary occlusion score
ml.) 251+
I
and over
Plasma cholesterol (mg.llOO ml.)
I
18? f 11.7 (38) (b) 196 f 6.6 (79) 63
S 250 181 zt 9.4 (75) (e) 208 zt 10.7 (40) (9,
I
251+ 212 * (53) 206 f (67)
8.1 (0 7.8 (h)
Number of patientsin parentheses. P < 0.05: e-h, a-d, e-f, e-g, e-h. ‘Mean f standard error.
Similarly, in patients over 68 years of age, the increasing levels of plasma triglycerides appeared to be correlated with the coronary occlusion (Groups G through I). 4. Coronary occlusion, age, and plasma lipids combined. Since the previous data indicated that
the age-lipid-coronary score interaction for plasma cholesterol and triglycerides may differ, a combined tabulation including all three factors was undertaken. In order to maintain a sufficient number of patients in the individual groups, only two subgroups for each variable were employed: for the age, below or above the mean of 52 years; for plasma cholesterol, below or above 250 mg. per 100 ml.; and for plasma triglycerides, below or above 180 mg. per 100 ml. The data as shown in Table V indicate that, at lower plasma cholesterol levels (< 250 mg. per 100 ml.), an increase in plasma triglyceride levels was associated with a
American
Heart Journal
rise in the occlusion score. This occurred in both age groups. For instance, in the “younger” patients (less than 52 years of age), the occlusion score in the low cholesterol and Zow triglyceride group was 160 f 9.2; while in the low cholesterol- high triglyceride group, it increased by 24 “points” to 184 f 9.0. In the “older” patients (over 52 years of age), the corresponding difference between the high and low triglyceride groups was 27 “points” (18i f 9.4 and 208 f 10.7). This occlusion-enhancing effect of higher triglyceride levels was not apparent in patients with high cholesterol levels (over 260 mg. per 100 ml.) of either age group. Discussion
All patients in the present study had some somatic complaints, suggesting involvement of the cardiovascular system; and the group thus
719
Barboriak
et al.
does not represent a “normal” or “average” male population as encountered in some of the epidemiologic investigations.29 3, 2o Furthermore, the group of patients consisted of individuals mostly in the 40- to 65year bracket, many of whom would be expected to show atherosclerotic changes. However, the range of the occlusion score, or of the number of markedly affected coronary arteries, was large enough to allow some conclusions on the possible association between the “risk factors” and the extent of the coronary occlusion. The variables most clearly associated with occlusion of the coronary artery lumen were increase in plasma cholesterol levels and progression in age or changes in factors connected with progressing age. The occlusion score of 200, or slightly over 200, which probably represents the highest score value compatible with survival, was reached by both older patients with relatively low plasma cholesterol levels and younger patients with high plasma cholesterol values (Table III). It would seem, therefore, that even moderately elevated plasma cholesterol levels in older subjects may be associated with a similar risk of coronary artery damage as elevated plasma cholesterol levels in younger patients. An increase in plasma triglyceride levels seemed to be less “occlusive” than a rise in plasma cholesterol levels; however, the presence of elevated plasma triglyceride levels tended to enhance the degree of coronary obstruction in patients with relatively low plasma cholesterol levels. The finding of marked coronary artery impairment at plasma cholesterol levels of 250 to 270 mg. per 100 ml. (Table II) again raises the question of “normal” or average plasma cholesterol values and their meaning. A recent compilation of opinions from a number of investigators in the field of atheroscleroais21 as well as the data from this study indicate the need for re-evaluation of the accepted normal lipid ranges. The data in Table II indicate that the transition from the relatively patent coronary arteries to having one main branch occluded is associated with a larger change in plasma lipid levels than is the transition from one vessel involvement to the involvement of two or three vessels. A similar difference in the progression of coronary lesions has been reported by Gensini and Kelly.22They observed that the severity of the arterial lesion increases faster in patients who have developed
720
some initial lesions already than in individuals without any visible coronary blood flow impairment. Bruschke, Proudlit, and Sones,23 in a large series of patients, have also failed to see development of angiographically determined coronary occlusion when the initial observation was normal. These findings suggest that either the patients consisted of several populations markedly differing in their plasma cholesterol levels and predilection for development of a significant arterial occlusion or that the development of atherosclerosis passes through a “threshold range” of plasma cholesterol levels after which the progress of occlusion accelerates at an increased pace. The data from Table II confirm the known predilection for the left anterior descending branch to be occluded. However, this was not associated with any marked changes in the blood lipid levels when compared with the rarer single occlusion of the right coronary or with the combination of two coronary arteries affected. It would seem, therefore, that some additional factors, possibly anatomic in nature, are operational in the determination of the occlusion sites. While not discussed in detail, preliminary studies were also carried out to find out whether the calculated correlations between the age, coronary occlusion score, and plasma lipid levels were affected by an unequal distribution of other coronary risk factors, especially of hypertension and smoking. Information obtained for about onehalf of the patients in each of the eight cells in Table V has shown an equal distribution of smokers (about 82 per cent of the patients) and only a slightly higher incidence of hypertension in patients over 52 years of age (33 per cent vs. 37 per cent of the patients). The results of the present study give further evidence to support the relationship between plasma lipid levels and coronary heart disease. Furthermore, they indicate that prevention or a vigorous treatment of elevated plasma cholesterol and triglycerides may be of value, especially in the younger patients. Summary
A possible correlation between the levels of plasma cholesterol and triglycerides and the extent of coronary artery occlusion as determined by angiography was studied in 481 male patients. In older patients (over 58 years of age), a ProJune, 1974, Vol. 87, No. 6
Coronary
nounced coronary occlusion was frequently found at plasma cholesterol levels which could be considered normal for that age; while in the younger group (less than 48 years of age), extensive occlusive disease was mainly seen in the presence of elevated plasma cholesterol levels. The correlation between plasma triglyceride levels and coronary occlusion seemed to be less pronounced than was the case with plasma cholesterol levels. However, in patients with low cholesterol levels, an increase of plasma triglycerides was associated with more severe occlusive disease. The authors wish to thank the members of the Milwaukee Cardiovascular Data Registry, Drs. James E. Auer, George E. Batayias, Larry W. Clark, H. David Friedberg, Hen6 H. Gale. John H. Huston. Michael H. Kealan. Jr.. Derward Lepley, Jr., John C. Manley, Alfred J. Tector,‘and ‘Howard J. Zeft for permission to use the data of their patients and their interest and cooperation in the study; and Mrs. Darlene Frye, Miss Jacqueline Owenby, Mrs. Virginia Seiling, and Mr. Erwin Gehrke for their valuable technical assistance. REFERENCES
1.
2. 3.
4. 5. 6.
7.
Epstein, F. H., Ostrander, L. D., Jr., Johnson, B. C., Pavne. M. W.. Havner. N. S.. Keller. J. B.. and Francis. T.,” Jr.: Epidemio&ical studies of cardiovascular dis: ease in a total community-Tecumseh, Michigan, Ann. Intern. Med. 62:11’70, 1965. Keys, A.: Epidemiologic aspects of coronary artery diseaee, J. Chronic Dis. 6552, 1957. Kannel, W. B., Castelli, W. P., Gordon, T., and McNamara, P. M.: Serum cholesterol, lipoproteins, and the risk of coronary heart disease: The Framingham study, Ann. Intern Med. 74:1,1971. Carlson, L. A., and B6ttiger, L. E.: Ischaemic heart disease in relation to fasting values of plasma triglycerides and cholesterol, Lancet 1:865, 1972. Falsetti, H. L., Schnats, J. D., Greene, D. G., and Bunnell, I. L.: Lipid and carbohydrate studies in coronary artery disease, Circulation 37:184, 1968. Heinle, R. A., Levy, R. I., Fredrickson, D. S., and Gorlin, R.: Lipid and carbohydrate abnormalities in patients with angiographically documented coronary artery disease, Am. J. Cardiol. 24~1781969. Allard, C., Ruscito, O., and Goulet, C.: Preoperative serum lipid profile in surgically treated patients with coronary atherosclerosis, Surg. Gynecol. Obstet. 133: 807,197l.
American
Heart Journal
artery
occlusion
and blood lipids
8. Barboriak, J. J., Rimm, A., Tristani, F. E., Walker, J. B., and Lepley, D., Jr.: Risk factors in patients un&r@@g aorto-coronary bypass surgery, J. Tkac. CW+ surg. 6492,1972. 9. SLUM, F. M., Jr., and Shirey, E. K.: Ciae cowmary gteriography, Mod. Concapte Cardiovaac. Dia 31:X%6, 1962.
10. Judkins, M. P.: Selective coronary radiography. A percutaneous transfemoral technic, RadioMgy (19816, 1967. 11. -Rowe, G. G., Thomsen, J. H., Stenlund, R. Il., MeKennp, D. H.. Sialer. S.. and Corlii R. J.: A s&u&r d hemodynamics and coronary bled flaw in ~~kit& coronary artery disease, Cireulatian 39:WQ,lW@. 12. Block, W. D., Jarrett, J. K., and Levine, J. B.: Use of I) single color reagent to improve the autemated dbtcmination of serum total cholesterol. br: Auboin&wr kr analytical chemistry, Skeepe, Jr., L. T., editor, NW York 1965, Media& Inc., pp. 345-347. 13. Emustein. M.. and Kreutz F. H.: Eine neue Bestimmurw der Neutraifette in B&serum und Gewebe, Kli; Wochenschr. 44:262,1966. 14. Noble, R. P.: Electrophoretic separation of plasma lipoproteins in agarose gel, J. Lipid Res. 0:693,1)68. 15. Friedewalt,. W. T., Levy, R. I., and Fredrickson, D. 5: Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preperative ultracentrifuge, Clin. Chem. l&499,1972. 16. Fredrickson, D. S., Levy, R. I., and Lees, R. S.: Fat transport in lipoproteins-an integrated approach to mechanisms and disorders, N. Engl. J. Med. 2763994, 148,215, and 273,197l. 17. Frings, C. S., Foster, L. B., and Cohen, P. 6.: Electrophoretic separation of serum lipoproteins In polyacrylamide gel, Clin. Chem. 17:111, 1971. 18. Schilling, F. J., Christ&is, G., Orbach, A., and Becker, W. H.: Serum cholesterol and triglyceride, Am. J. Clin. Nutr. 22:133, 1969. 19. Brown, D. F., and Daudiss, K.: Hyperlipoproteinam~: prevalence in a free-living population in Albany, N. Y., Circulation 47:568, 1973. 20. Kleinbaum, D. G., Kupper, L. L., Cassel, J. Cl, and Tyroler, H. A.: Multivariate analysis of risk of coron6ry heart disease in Evans County, Ga., Arch. Intern. Me& 126943,197l.
21. Wynder, normal? 22. Gensini, sion of 129:814,
E. L., and Hill, P.: Blood lipids. How mxmal is Prev. Med. 1:161, 1972. G. G., and Kelly, A. E.: Incidence and progracoronary artery disease, Arch. Intern. Me& 1972.
23. Bruschke, A. V. G., Proudllt, W. L., and Sones, F. M., Jr.: Clinical course of patients with normal and sli@Iy or moderately abnormal coronary arteriograms, Circelrrtion 47936, 1973.
Results of a number of epidemiologic studies have indicated that patients with elevated blood lipid levela show a higher incidence of cardiovaecular disease than individuals with low or normal lipid levels. l-I Investigations of patients with angiographically determined coronary heart dieease have also demonstrated that most o$ h patienta have high blood lipid levels. @a&&i and co-worker@ have studied a group of 27 patients with angiographically proved coronary disease and found 17 patienta with abnormal lipoprotein pattern. Heinle and co-worker@ h$ve observed a similar proportion of abnormal &a&&m&n (54 per cent) in 126 pat&&a with coronary luminal irregularity or btenoaia. Allard, Rtito, and Goulet’ have reported on 129 patients who needed aortocoronary bpprrare surgery and found only 14 patients with normal blood lipid levels. In our initial study of 162 patients with aortocoronary bypaas,8 all were found to have elevated plasma lipid levels. While an association between the incidence of coronary disease and abnormal blood lipid levels or lipoprotein patterns appear6 to be well documented, little is known about the. possible correhtion between the extent or the sites of the *nary obstruction, age of the patients, and From the Research, Medical, and Surgical Services, Wood Veterans Adrdabtratlon Center; Departments of Pher-logy, Biwtatietics, I#b&&e, and Surgery, The Medical Celiege of Wieconein; and tbe Lbectlaa of Cardi&gy and Thoracic Surgery, St. Luke’s Ho&al, Milwaukee, Wise. This etudy wee supported in part by Grant No. l&14378, National Inetitutee of Health, United Statea Public Health Service. E&eked for publication Sept. 4,1973. Beprint requests to: Dr. Joseph J. Barboriak, Reeearch Service (lSlB), V&mans Administration Center, Wood, Wii. 53193.
718
plasma lipid levels. The availability of information on the angiographically ascertained coronary obstruction and plasma lipid levels in 481 patients undergoing diagnostic arteriography offered an opportunity to investigate this possible relationship. The result of this study indicates that both advancing age and elevated plasma cholesterol levels may be of similar importance in the development of coronary obstruction. Methods A group of 481 male patients referred to St. Luke’s and Wood Veterans Administration Hospitals, Milwaukee, Wise., for a diagnostic angiographic examination were studied. An inquiry of a larger group of such patients (620) by questionnaire indicated that about 67 per cent of them did not have any treatment for control of blood lipids, while about 28 per cent followed some dietary restrictions, and 2 per cent of the patients received hypolipemic drugs. The plasma lipid levels of the patients with dietary treatment-237 f 45 mg. per 100 ml. for cholesterol and 151 f 71 mg. per 100 ml. for triglyceride (mean f standard deviation&were similar to values of the patients without the treatment230 f 45 mg. per 100 ml. and 174 f 168 mg. per 100 ml., respectively. The group receiving the drug treatment had higher levels for both plasma cholesterol (262 f 43 mg. per 100 ml.) and triglyceride (218 f 110 mg. per 100 ml.). The coronary arteriography was carried out as described by Sones and Shireye or Judkh@ and the film reviewed by cardiologists experienced in the interpretation of the angiograms. The degree of obstruction was rated as suggested by Rowe
June, 1974, Vol. 87, No. 6, pp. 716-721
Coronary artery occlusion and blood lipids
and co-workeran; however, the scale was inverted, i.e., the score of the patient without any coronary obstruction was set as 0 and a patient with all three main coronary arteries totally obstructed was assigned a score of 300. Fasting blood samples were collected before angiography prior to heparin administration and analyzed for serum total cholesterol by an automated procedure,12 triglycerides,13 and lipoprotein distribution.14Reproducibility of the triglyceride and cholesterol methods were determined by repeated assays of aliquots from a frozen pool of a standard serum at weekly intervals. Results for this pooled serum were: triglyceride, 137 zb 3.6 mg. per iO0 ml.; cholesterol, 202 f 4.9 mg. per 100 ml. Coefficients of variation were 2.6 and 2.4 per cent, respectively. Lipoprotein typing was carried out using the Friedewalt, Levy, and Fredrickson15 and Fredrickson, Levy, and Lees16 estimates of average age-adjusted cholesterol content of the individual lipoprotein fractions in conjunction with the lipoprotein electropherogram. Type III was confirmed by absence of the P-lipoprotein band on disc electrophoresis.” Results The pertinent data on the patients are compiled in Table I. In comparison with values obtained with a general population,lsJe the abnormal lipid elevation in our patients was mainly confined to the plasma triglyceride fraction. This was also reflected in plasma lipoprotein distribution since only 34, or 7.2 per cent, of the patients belonged to Type II while 193, or 41.2 per cent, belonged to Type IV. No lipoprotein typing was done in 12 patients. Because of some changes in the interpretation of lipoprotein types which occurred during the collection of data (i.e., introduction of Types IIa and IIb), it was decided to use only the original plasma lipid values for the study of the various correlations. The possible association between the blood lipid levels and the degree of coronary blood flow obstruction as represented by the occlusion score was evaluated in several ways: 1. Number blood lipids.
of affected
coronary
arteries
and
The association between the number of markedly affected coronary branches (75 per cent or more of the lumen blocked) and blood lipids is shown in Table II. A consistent and statistically significant increase in mean plasma American Heart Journal
I. Information on average age, plasma lipids, and other variables in the group of 481 patients Table
Age (years) Plasma choleeterol Cmg./lOO ml.) Plasma triglyceride (mg./lOO ml.) Lipoprotein distribution (%) Typa 11 Type IV Type III Normal Smokera (%) Hypertension (%) *Mean f standard deviation. tInformation obtained from medical
bietoriee
52 f 1.6' 256 f 55.7 212 zt133.2 7.2 41.2
0.9 50.7
82.Ot 35.0t
of 248 patients.
cholesterol level occurred with an increase in the number of coronary arteries occluded. Patients with no markedly occluded arteries had lower triglycerides than those with occluded arteries; however, differences according to the number of arteries affected were small and not statistically significant. ’ The breakdown of the plasma lipid values according to the specific coronary arteries blocked for at least 75 per cent of their lumen is also shown in Table II. The data indicate that no marked differences in plasma lipid levels were associated with occlusion of specific coronary arteries. 2. Coronary occlusion. age, and plasma cholesterol levels. The data on the association of the
extent of coronary impairment, age, and plasma cholesterol levels are shown in Table III. The age ranges were selected to include the decade group around the average age. The lowest average coronary occlusion score, 144, was observed in the group of patients less than 48 years of age with plasma cholesterol levels below the 225 mg. per 100 ml. value. However, even at this relatively low plasma cholesterol level, there was a statistically significant correlation between the progressing age and the increase in the coronary impairment (Groups A through G, P ( 0.01). In patients less than 48 years of age, the rise in plasma cholesterol levels was also connected with a statistically significant increase in the coronary occlusion score (Groups A through C, P (0.01). Similar, but less marked, changes in the score were observed with
717
Barboriak
et al.
Table II. Plasma cholesterol and triglyceride levels of patients occluded to at least 75 per cent of the lumen
None 2 One: LAD Right Two: CIR + Right Right Three: Right
76% occluded
48 107 62 36 154 28 58 35 174 126
LAD + LAD + CIR + LAD
+ CIR
222f6.2t 255 256 f 256 f 258 f 252 f 262 + 253 f 269 f 277 f
f
LAD = Left anterior descending artery. CIR = Circumfiex artery. ‘Because of the small number of patients having occlusion of the circumflex branches, these data were not included in the table. t&an zt standard error. tP < 0.01 in comparison with the group without any major occlusion.
Table
Ill. The effect of age and plasma
cholesterol
having one, two, or three coronary arteries
177 218 214 216 208 195 212 222 221 233
5.01 6.7$ 7.9t 4.1$ 8.0$ 6.3+ 9.8$ 4.7$ 5.4$
branch
only or occltion
of lesser branches
f f f f f f f f + +
17.3 15.4 20.9 20.7 8.5 24.4 12.2 19.6 10.6 13.7$
in combination
with main
levels on the coronary occlusion score Plasma chokstwol hng.llOO ml.)
Age (years.,
(225 144 zt (26) 172 zt (74) 205 f (36)
<48 48-57 >58
225-274 16.7' (a) 9.3 (d) 11.2 (B)
178 f 8.7 (54) cb) 188 f 7.6 (89) (e) 199 f 10.8 (46)f.h)
)275 202 f 8.4 (52) (c) 213 f 6.6 (75) WJ 198 f 13.2 (30) (i)
Number of patients in parentheses. P < 0.05: a-b, a-c, a-g, b-c, d-f, d-g. *Mean f standard error.
progressing elevation of plasma cholesterol levels in patients 48 to 57 years of age (Groups D through F, P ( 0.05), or with increasing age, in the group with a plasma cholesterol range of 225 to 274 mg. per 100 ml.,(Groups B through F). In the groups of patients with plasma cholesterol over 275 mg. per 100 ml. or older than 58 years of age, the further effect of age or rise in plasma cholesterol levels on the occlusion score was minimal. 3. Coronary occlusion, age, and triglyceride levels. A similar tabulation
average coronary
718
plasma
of the score was done for the three
age groups and three ranges of plasma triglycerides (Table IV). The lowest score, 165, was observed in patients less than 48 years of age having plasma triglyceride levels below the 150 mg. per 100 ml. mark; while the highest score, 214, was seen in the group with plasma triglyceride levels over 220 mg. per 100 ml. and age over 58 years. In contrast to the observation in the groups with the high cholesterol levels where the age effect was not apparent, the occlusion score in patients with high plasma triglyceride levels (over 220 mg. per 100 ml.) increased with age (Groups C through I, P ( 0.05). June, 1974, Vol. 87, No. 6
Coronary
Table IV. The effect of age and plasma
triglyceride
artery
levels on the coronary
occlusion
and blood lipids
score
Plasma triglycerides (mg.1100 ml.) Age < 150
(years)
<48
166 f (34) 173 f EXO 186 f (43)
48-67 > 58
150-219
14.9* (a) 8.7 Cd) 12.4 (g)
188 f (46) 192 + (71) 206 + (35)
> 220 185 * (52) 209 f (79) 214 f (33)
8.1 (b) 7.8 (e) 10.3 (h)
9.7 Cc) 6.8 0 10.8 (9
Number of patienta in parentheses. P ( 0.05: c-f, c-i, d-f. *Mean f standard error.
Table V. The effect of age and plasma cholesterol
Less
Age than 62
and triglyceride
Age
=s 180 1&w+
S 250 160 rt (78) 184 * (51)
9.2* (a) 9.4 Cc)
52 years
years
Plasma cholesterol hg.llOO Plasma tFi&CeFidtS hgJlO0 ml.)
levels on the coronary occlusion score
ml.) 251+
I
and over
Plasma cholesterol (mg.llOO ml.)
I
18? f 11.7 (38) (b) 196 f 6.6 (79) 63
S 250 181 zt 9.4 (75) (e) 208 zt 10.7 (40) (9,
I
251+ 212 * (53) 206 f (67)
8.1 (0 7.8 (h)
Number of patientsin parentheses. P < 0.05: e-h, a-d, e-f, e-g, e-h. ‘Mean f standard error.
Similarly, in patients over 68 years of age, the increasing levels of plasma triglycerides appeared to be correlated with the coronary occlusion (Groups G through I). 4. Coronary occlusion, age, and plasma lipids combined. Since the previous data indicated that
the age-lipid-coronary score interaction for plasma cholesterol and triglycerides may differ, a combined tabulation including all three factors was undertaken. In order to maintain a sufficient number of patients in the individual groups, only two subgroups for each variable were employed: for the age, below or above the mean of 52 years; for plasma cholesterol, below or above 250 mg. per 100 ml.; and for plasma triglycerides, below or above 180 mg. per 100 ml. The data as shown in Table V indicate that, at lower plasma cholesterol levels (< 250 mg. per 100 ml.), an increase in plasma triglyceride levels was associated with a
American
Heart Journal
rise in the occlusion score. This occurred in both age groups. For instance, in the “younger” patients (less than 52 years of age), the occlusion score in the low cholesterol and Zow triglyceride group was 160 f 9.2; while in the low cholesterol- high triglyceride group, it increased by 24 “points” to 184 f 9.0. In the “older” patients (over 52 years of age), the corresponding difference between the high and low triglyceride groups was 27 “points” (18i f 9.4 and 208 f 10.7). This occlusion-enhancing effect of higher triglyceride levels was not apparent in patients with high cholesterol levels (over 260 mg. per 100 ml.) of either age group. Discussion
All patients in the present study had some somatic complaints, suggesting involvement of the cardiovascular system; and the group thus
719
Barboriak
et al.
does not represent a “normal” or “average” male population as encountered in some of the epidemiologic investigations.29 3, 2o Furthermore, the group of patients consisted of individuals mostly in the 40- to 65year bracket, many of whom would be expected to show atherosclerotic changes. However, the range of the occlusion score, or of the number of markedly affected coronary arteries, was large enough to allow some conclusions on the possible association between the “risk factors” and the extent of the coronary occlusion. The variables most clearly associated with occlusion of the coronary artery lumen were increase in plasma cholesterol levels and progression in age or changes in factors connected with progressing age. The occlusion score of 200, or slightly over 200, which probably represents the highest score value compatible with survival, was reached by both older patients with relatively low plasma cholesterol levels and younger patients with high plasma cholesterol values (Table III). It would seem, therefore, that even moderately elevated plasma cholesterol levels in older subjects may be associated with a similar risk of coronary artery damage as elevated plasma cholesterol levels in younger patients. An increase in plasma triglyceride levels seemed to be less “occlusive” than a rise in plasma cholesterol levels; however, the presence of elevated plasma triglyceride levels tended to enhance the degree of coronary obstruction in patients with relatively low plasma cholesterol levels. The finding of marked coronary artery impairment at plasma cholesterol levels of 250 to 270 mg. per 100 ml. (Table II) again raises the question of “normal” or average plasma cholesterol values and their meaning. A recent compilation of opinions from a number of investigators in the field of atheroscleroais21 as well as the data from this study indicate the need for re-evaluation of the accepted normal lipid ranges. The data in Table II indicate that the transition from the relatively patent coronary arteries to having one main branch occluded is associated with a larger change in plasma lipid levels than is the transition from one vessel involvement to the involvement of two or three vessels. A similar difference in the progression of coronary lesions has been reported by Gensini and Kelly.22They observed that the severity of the arterial lesion increases faster in patients who have developed
720
some initial lesions already than in individuals without any visible coronary blood flow impairment. Bruschke, Proudlit, and Sones,23 in a large series of patients, have also failed to see development of angiographically determined coronary occlusion when the initial observation was normal. These findings suggest that either the patients consisted of several populations markedly differing in their plasma cholesterol levels and predilection for development of a significant arterial occlusion or that the development of atherosclerosis passes through a “threshold range” of plasma cholesterol levels after which the progress of occlusion accelerates at an increased pace. The data from Table II confirm the known predilection for the left anterior descending branch to be occluded. However, this was not associated with any marked changes in the blood lipid levels when compared with the rarer single occlusion of the right coronary or with the combination of two coronary arteries affected. It would seem, therefore, that some additional factors, possibly anatomic in nature, are operational in the determination of the occlusion sites. While not discussed in detail, preliminary studies were also carried out to find out whether the calculated correlations between the age, coronary occlusion score, and plasma lipid levels were affected by an unequal distribution of other coronary risk factors, especially of hypertension and smoking. Information obtained for about onehalf of the patients in each of the eight cells in Table V has shown an equal distribution of smokers (about 82 per cent of the patients) and only a slightly higher incidence of hypertension in patients over 52 years of age (33 per cent vs. 37 per cent of the patients). The results of the present study give further evidence to support the relationship between plasma lipid levels and coronary heart disease. Furthermore, they indicate that prevention or a vigorous treatment of elevated plasma cholesterol and triglycerides may be of value, especially in the younger patients. Summary
A possible correlation between the levels of plasma cholesterol and triglycerides and the extent of coronary artery occlusion as determined by angiography was studied in 481 male patients. In older patients (over 58 years of age), a ProJune, 1974, Vol. 87, No. 6
Coronary
nounced coronary occlusion was frequently found at plasma cholesterol levels which could be considered normal for that age; while in the younger group (less than 48 years of age), extensive occlusive disease was mainly seen in the presence of elevated plasma cholesterol levels. The correlation between plasma triglyceride levels and coronary occlusion seemed to be less pronounced than was the case with plasma cholesterol levels. However, in patients with low cholesterol levels, an increase of plasma triglycerides was associated with more severe occlusive disease. The authors wish to thank the members of the Milwaukee Cardiovascular Data Registry, Drs. James E. Auer, George E. Batayias, Larry W. Clark, H. David Friedberg, Hen6 H. Gale. John H. Huston. Michael H. Kealan. Jr.. Derward Lepley, Jr., John C. Manley, Alfred J. Tector,‘and ‘Howard J. Zeft for permission to use the data of their patients and their interest and cooperation in the study; and Mrs. Darlene Frye, Miss Jacqueline Owenby, Mrs. Virginia Seiling, and Mr. Erwin Gehrke for their valuable technical assistance. REFERENCES
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