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high-density lipoprotein cholesterol ratio as a new indicator of coronary artery disease
Predictive value of remnant-like particles cholesterol/high-density lipoprotein cholesterol ratio as a new indicator of coronary artery disease Hiroshi Masuoka, MD,a Ken Ishikura, MD,a Shigeru Kamei, MD, Toshihide Obe, MD,a Tetsuya Seko, MD,a Kazuaki Okuda, MD,a Sukenari Koyabu, MD,a Katsunobu Tsuneoka, MD,a Takuya Tamai, MD,a Masahiro Sugawa, MD,a and Takeshi Nakano, MDb Owase and Tsu, Japan
Background There is as yet no definite consensus on the predictive value of the various lipid profiles and fibrinolytic parameters that became available in clinical use recently for coronary artery disease.
Methods Levels of lipoprotein(a), high-density lipoprotein cholesterol (HDL-C), remnant-like particles cholesterol (RLP-C), tissue plasminogen activator (TPA), TPA inhibitor, antithrombin III, and protein C were measured in 124 patients who underwent diagnostic coronary angiograms.
Results Of these patients, 37 had no significant stenoses (group N) and 87 had significant stenoses (group S). There were no significant differences in patient characteristics between the two groups. HDL-C was significantly lower (p = 0.0071) and RLP-C was significantly higher (p = 0.0022) in group S. When a product and a ratio of each of two factors were calculated, RLP-C/HDL-C was demonstrated to be a highly significant predictor for coronary artery stenoses (p < 0.0001). There were also significant increases in RLP-C/HDL-C levels with increasing number of vessels involved (r = 0.359, p < 0.0001).
Conclusion Our present study disclosed the predictive value of RLP-C/HDL-C ratio as a new indicator of coronary artery disease. (Am Heart J 1998;136:226-30.)
The epidemiologic study of coronary artery disease has suggested a pathogenic role for hypercholesterolemia.1 Specific assays for the main components of the fibrinolytic system have also made it possible to establish an association between low fibrinolytic activity and atherothrombosis.2 However, there is as yet no definite consensus on the predictive value of the various lipid profiles and fibrinolytic parameters that have recently become available in clinical use. For instance, several epidemiologic studies have been inconclusive in demonstrating a link between lipoprotein(a) (Lp[a]) and future risk of myocardial infarction, some studies showing no relationship3,4 and others a clear link.5,6 We designed the present study to evaluate the predictive value of lipid and fibrinolytic variables as a new indicator of coronary artery disease.
From the aDivision of Internal Medicine, Owase General Hospital, and the bFirst Department of Internal Medicine, Mie University School of Medicine. Submitted June 17, 1997; accepted Jan. 23, 1998. Reprint requests: Hiroshi Masuoka, MD, Division of Internal Medicine, Owase General Hospital, 5-25 Ueno-cho, Owase, Mie 519-36, Japan. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/89586
Methods The study population was composed of 181 consecutive patients who underwent diagnostic coronary angiograms at our hospital. Data from repeated coronary angiograms for the same patient were excluded. Patients who had liver disease, endocrinologic disorders, nephrotic syndromes, neoplasma, and acute inflammatory disease were excluded. Patients who had suffered from an acute myocardial infarction within the preceding 1 month were also excluded. Of the remaining patients, the study population was limited to 124 patients. Coronary angiography was carried out mainly via the percutaneous brachial approaches and occasionally via the femoral approaches by use of the standard Judkin’s technique. At least five views of the left coronary artery and three of the right were obtained. According to the previous study,7 narrowing of >70% of luminal diameter in any projection, agreed on by more than two independent observers, was considered significant. Left main disease >50% was also considered significant. A venous blood sample was taken with minimal venostasis from an antecubital vein for the determination of each factor as follows: Lp(a); latex immunoassay by monoclonal antihuman Lp(a) antibody; high-density lipoprotein cholesterol (HDL-C) by selective inhibition assay; remnant-like particles
American Heart Journal Volume 136, Number 2
cholesterol (RLP-C) by immunoadsorption assay using monoclonal anti-apo B-100 and anti-apo A-I immunoaffinity mixed gels, tissue plasminogen activator antigen (TPA) by enzymelinked immunosorbent assay, TPA inhibitor type 1 antigen (PAI-1) by enzyme-linked immunosorbent assay, antithrombin III activity (AT III) by chromogenic substrate assay, and protein C activity by latex photometric immunoassay. In brief, the standard assay contains 5 µL of serum and 50 µL of mixed gel, which adsorbs lipoproteins containing apo A-I as well as most of the lipoproteins containing apo B-100. After 60 minutes of gentle shaking, unbound cholesterol present in the supernatant is measured enzymatically. Venous blood samples were collected before the catheterization and after the subjects had fasted for 12 hours. The four conventional coronary risk factors were determined in each patient as follows: hypertension (systolic pressure >160 mm Hg or diastolic pressure >95 mm Hg or a satisfactory prior diagnosis); smoking habit (present smoker or former smoker of >10 cigarettes per day); diabetes mellitus (overt diabetes necessitating treatment or abnormal oral glucose tolerance test); obesity (body mass index >26). All data were examined when each patient underwent coronary angiography. For statistical analysis, comparisons for normally distributed and not normally distributed values were made with unpaired two-tailed t test and Mann-Whitney U test, respectively, as appropriate. Discrete data were analyzed by the chi-square test. Multivariate analysis of variables was also performed with Cox proportional-hazard regression models. A p value <0.05 was considered significant in each test.
Results The mean age of the 124 patients studied was 63.4 ± 8.5 years (mean + SD) and ranged from 42 to 80 years. There were 88 men and 36 women. Of the patients, 37 (29.8%) had no significant stenoses or occlusions and 87 (70.2%) had significant organic stenoses. We defined the former 37 cases as group N (the group of patients who had no stenoses) and the latter 87 cases as group S (the group of patients who had at least one stenosis or occlusion). The number of cases found to have one-, two-, three-vessel, and left main disease in group S was 44, 23, 14, and 6, respectively. The mean age, malefemale ratio, and the prevalence of conventional risk factors were compared in group S and group N. There were no significant differences in these patient characteristics between the two groups, as shown in Table I. Mean levels of lipid and fibrinolytic variables in group N and group S are presented in Table II. HDL-C was significantly lower and RLP-C was significantly higher in group S. Protein C tended to be lower in group S but no significant difference was observed.
Masuoka et al. 227
Table I. Comparison of the baseline characteristics between the patients with (group S) and without (group N) angiographically determined coronary artery stenoses Group S (n = 87)
Group N (n = 37)
Test for trend
Age (yr) 63.8 ± 8.6 Men sex (%) 71.3 Coronary risk factors (%) Hypertension 43.7 Diabetes mellitus 23.0 Smoking 49.4 Obesity 21.8
62.5 ± 9.1 70.3
NS NS
40.5 9.0 43.2 24.3
NS NS NS NS
Data presented are mean ± SD or percent of patients. NS, not statistically significant.
To rule out the possibility that RLP-C is just a covariate of low-density lipoprotein cholesterol (LDL-C), we also analyzed the correlation between RLP-C and LDLC in each patient. No significant correlation was found between RLP-C and LDL-C (r = 0.083, p = 0.3601). A product and a ratio of each of two factors were calculated separately for each case. Some representative data are listed in Table III, including all factors that were significant or marginally significant. The RLPC/HDL-C ratio was demonstrated to be a highly significant (p < 0.0001) predictor for a coronary artery disease. Although RLP-C/HDL-C level of each patient in group N was less than 0.3, that of 25 patients (28.8%) in group S was more than 0.3, as shown in Fig. 1. Multivariate analysis also demonstrated that RLP-C/HDL-C is the most potent and independent predictor for coronary artery disease. As for the number of vessels involved, there were significant increases in RLPC/HDL-C levels, with increasing number of vessels diseased (r = 0.359, p < 0.0001), as can be seen in Fig. 2.
Discussion In the early studies of Gofman et al.,8 lipoproteins now considered to be very low-density lipoprotein (VLDL) remnants were suggested to be more atherogenic than low-density lipoprotein (LDL). The importance of this triglyceride-rich lipoprotein particle, recently described as a remnant-like particle (RLP),9 has now been established at the basic science level and in animal studies.10 A simple and rapid assay method for the determination of RLP was developed recently in Japan.9 This method uses an immunoaffinity gel mixture of anti-apo B-100 and anti-apo A-I monoclonal antibodies coupled to sepharose 4B. A subpopulation of triglyceride-rich particles is separated
American Heart Journal August 1998
228 Masuoka et al.
Table II. Comparison of the lipid and fibrinolytic parameters between the patients with (group S) and without (group N) angiographically determined coronary artery stenoses
Lp(a) (mg/dl) HDL-C (mg/dl) RLP-C (mg/dl) TPA (ng/ml) PAI-1 (ng/ml) AT III (%) Protein C (%)
Group S
Group N
p Value
24.67 ± 22.23 38.42 ± 11.65 7.02 ± 5.75 10.16 ± 4.69 167.36 ± 142.56 95.72 ± 14.83 96.76 ± 21.69
21.07 ± 18.83 53.06 ± 14.46 3.89 ± 2.66 9.22 ± 4.89 155.38 ± 129.95 98.67 ± 14.20 108.86 ± 22.93
0.2274 0.0071 0.0022 0.1322 0.9698 0.3066 0.0613
Data presented are mean ± SD.
Table III. Comparison of a product and a ratio of each parameter between the patients with (group S) and without (group N) angiographically determined coronary artery stenoses
Lp(a) × AT III Lp(a) × TPA Lp(a) × PAI-1 Lp(a)/HDL-C RLP-C/HDL-C RLP-C × AT III RLP-C × Lp(a) PAI-1 × TPA PAI-1/TPA TPA/HDL-C Protein C × AT III
Group S
Group N
p Value
2019.0 ± 1862.3 212.8 ± 211.1 3853.3 ± 5549.9 0.578 ± 0.562 0.213 ± 0.198 681.4 ± 621.4 125.2 ± 137.5 1843.5 ± 2328.4 18.39 ± 16.53 0.279 ± 0.208 9390.3 ± 2918.1
2501.9 ± 2414.1 193.6 ± 164.6 3918.0 ± 5340.4 0.461 ± 0.263 0.082 ± 0.068 393.3 ± 290.3 78.0 ± 64.5 1589.7 ± 2238.0 22.27 ± 25.92 0.195 ± 0.150 10,966.9 ± 3759.3
0.1900 0.8572 0.8079 0.9739 <0.0001 0.0169 0.2355 0.3271 0.5894 0.0456 0.0133
Data presented are mean ± SD.
in the unbound fraction enriched in apo E. By adding the anti-apo A-I affinity gel to the anti-apo B-100 gel, almost all apo A-I containing lipoproteins are adsorbed into the mixed gel. It was demonstrated that this subpopulation consists of chylomicron and VLDL remnant-like lipoproteins. A more detailed characterization has been given elsewhere.9 RLP-C was shown to be the most sensitive, precise, and convenient for the estimation of serum RLP level.9 However, the contribution of raised RLP-C to the risk of coronary artery disease in human subjects has not yet been established.1 Although there are some reports on the levels of intermediate-density lipoproteins (IDL) or VLDL remnants instead of RLP-C in patients with coronary artery disease,11 reports on the levels of RLP-C in these patients are very few and the subjects are limited.9,12 Our present study demonstrated that RLP-C levels were significantly high in the patients who had established coronary artery diseases. The HDL-C level has been reported to be inversely
related to the risk of coronary artery disease.13,14 Our present study was also compatible with these earlier reports. Our present study indicated that a ratio of RLP-C/HDL-C was a more sensitive predictor for the risk of coronary artery disease than either alone. In our present study, no patients in group N showed RLP-C/HDL-C values >0.3. Levels of RLPC/HDL-C of more than 0.3 appeared to be associated with organic coronary stenoses. Thus RLP-C/HDL-C levels may provide useful prognostic information and permit the early identification of patients with organic coronary stenoses. Several clinical and epidemiologic studies have shown that increased PAI-1 level and increased TPA level are predictors of coronary events. TPA level and PAI-1 level are prognostic in some studies,15,16 but not in others.17,18 Neither TPA level nor PAI-1 level showed significant relation to the existence of the coronary artery disease in our present study. We speculate that PAI-1 level is perhaps a large contributor to
American Heart Journal Volume 136, Number 2
Figure 1
Masuoka et al. 229
Figure 2
Values of RLP-C/HDL-C ratio in patients with (Group S) and without (Group N) angiographically determined coronary artery stenoses.
Distribution of RLP-C/HDL-C ratio plotted against numbers of coronary vessels diseased. Left main disease was classified as one vessel.
the trigger mechanisms that cause a “stenotic disease” to proceed to an “occlusive disease” but has little predictive value in stable, fixed coronary artery stenoses. Lp(a) has been considered to be an independent risk factor for the development of cardiovascular disease.5 There is as yet no definite consensus on the prognostic value of Lp(a). Several epidemiologic studies have been inconclusive in demonstrating a link between Lp(a) level and future risk of myocardial infarction, some studies showing no relationship3,4 and others a clear link.5,6 In our present study, no significant correlation between Lp(a) level and the existence of coronary artery disease was observed. But only particularly strong risk factors will emerge in a study of this size, and the negative results obtained here with regard to Lp(a) and thrombolytic factors should not be taken to imply a lack of involvement in atherogenesis, but only an indeterminancy of the analysis. The main limitation of the present study might be the small number of patients. However, we believe
that this limitation did not significantly influence the outcome of the results on RLP-C because the difference between the groups was too marked to have resulted from chance. In conclusion, our present study disclosed the predictive value of RLP-C/HDL-C ratio as a new indicator of coronary artery disease.
References 1. Grundy SM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997;95:1-4. 2. Stein B, Fuster V, Halperin JL, Chesebro JH. Antithrombotic therapy in cardiac disease: an emerging approach based on pathogenesis and risk. Circulation 1989;80:1501-13. 3. Jauhiainen M, Koskinen P, Ehnholm C, Frick MH, Manttari M, Manninen V, et al. Lipoprotein(a) and coronary heart disease risk: a nested case control study of the Helsinki Heart Study participants. Atherosclerosis 1991;89:59-67. 4. Ridker PM, Hennekens CH, Stamfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993; 270:2195-9. 5. Armstrong VM, Cremer E, Eberie A, Manke F, Shulze F, Wieland H, et al. The association between Lp(a) concentrations and angiograph-
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ically assessed coronary atherosclerosis. Atherosclerosis 1986; 62:249-57. Schaefer EJ, Lamon-Fava S, Jenner JL, McNamara JR, Ordovas JM, Davis CE. Lipoprotein(a) levels and risk of coronary heart disease in men: the lipid research clinics coronary primary prevention trial. JAMA 1994;271:999-1003. Roubin GS, Harris PJ, Phil D, Bernstein L, Kelly DT. Coronary anatomy and prognosis after myocardial infarction in patients 60 years of age and younger. Circulation 1983;67:743-9. Gofman JW, Glazier F, Tamplin A, Strisower B, De Lalla O. Lipoproteins, coronary heart disease, and atherosclerosis. Physiol Rev 1954;34:589-607. Nakajima K, Saito T, Tamura A, Suzuki M, Nakano T, Adachi M, et al. Cholesterol in remannt-like lipoproteins in human serum using monoclonal anti apo B-100 and anti apo A-I immunoaffinity mixed gels. Clinica Chimica Acta 1993;223:53-71. Superko HR. Beyond LDL cholesterol reduction. Circulation 1996;94: 2351-4. Phillips NR, Waters D, Havel RJ. Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation 1993,88:2762-70. Sekihara T, Nakano T, Nakajima K. High postprandial plasma rem-
13.
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nant-like particles-cholesterol in patients with coronary artery diseases on chronic maintenance hemodialysis. Jpn J Nephrol 1996;38:220-8. Wilson PWF, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortalty: the Framingham heart study. Arteriosclerosis 1988;8:737-41. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, et al. High-density lipoprotein cholesterol and cardiovascular disease. Circulation 1989;79:8-15. Gram J, Jespersen J, Kluft C, Rijken DC. On the usefulness of fibrinolysis variables in the characterization of a risk group for myocardial infarction. Acta Med Scand 1987;221:149-53. Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MB, Cardillo M, et al. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients: a case-control study. Arterioscler Thromb 1993;13:1412-7. Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease: a 7-year follow-up. Circulation 1993;88:2030-4. Jansson JH, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J 1991;12:157-61.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of American Heart Journal are available only to subscribers from the Publisher at a cost of $102.50 for domestic, $130.54 for Canadian, and $122.00 for international subscribers for Vol. 135 (January-June) and Vol. 136 (July-December), shipping charges included. Each bound volume contains subject and author indexes, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram, with the Journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, USA; (800)453-4351, or (314)453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
Background There is as yet no definite consensus on the predictive value of the various lipid profiles and fibrinolytic parameters that became available in clinical use recently for coronary artery disease.
Methods Levels of lipoprotein(a), high-density lipoprotein cholesterol (HDL-C), remnant-like particles cholesterol (RLP-C), tissue plasminogen activator (TPA), TPA inhibitor, antithrombin III, and protein C were measured in 124 patients who underwent diagnostic coronary angiograms.
Results Of these patients, 37 had no significant stenoses (group N) and 87 had significant stenoses (group S). There were no significant differences in patient characteristics between the two groups. HDL-C was significantly lower (p = 0.0071) and RLP-C was significantly higher (p = 0.0022) in group S. When a product and a ratio of each of two factors were calculated, RLP-C/HDL-C was demonstrated to be a highly significant predictor for coronary artery stenoses (p < 0.0001). There were also significant increases in RLP-C/HDL-C levels with increasing number of vessels involved (r = 0.359, p < 0.0001).
Conclusion Our present study disclosed the predictive value of RLP-C/HDL-C ratio as a new indicator of coronary artery disease. (Am Heart J 1998;136:226-30.)
The epidemiologic study of coronary artery disease has suggested a pathogenic role for hypercholesterolemia.1 Specific assays for the main components of the fibrinolytic system have also made it possible to establish an association between low fibrinolytic activity and atherothrombosis.2 However, there is as yet no definite consensus on the predictive value of the various lipid profiles and fibrinolytic parameters that have recently become available in clinical use. For instance, several epidemiologic studies have been inconclusive in demonstrating a link between lipoprotein(a) (Lp[a]) and future risk of myocardial infarction, some studies showing no relationship3,4 and others a clear link.5,6 We designed the present study to evaluate the predictive value of lipid and fibrinolytic variables as a new indicator of coronary artery disease.
From the aDivision of Internal Medicine, Owase General Hospital, and the bFirst Department of Internal Medicine, Mie University School of Medicine. Submitted June 17, 1997; accepted Jan. 23, 1998. Reprint requests: Hiroshi Masuoka, MD, Division of Internal Medicine, Owase General Hospital, 5-25 Ueno-cho, Owase, Mie 519-36, Japan. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/89586
Methods The study population was composed of 181 consecutive patients who underwent diagnostic coronary angiograms at our hospital. Data from repeated coronary angiograms for the same patient were excluded. Patients who had liver disease, endocrinologic disorders, nephrotic syndromes, neoplasma, and acute inflammatory disease were excluded. Patients who had suffered from an acute myocardial infarction within the preceding 1 month were also excluded. Of the remaining patients, the study population was limited to 124 patients. Coronary angiography was carried out mainly via the percutaneous brachial approaches and occasionally via the femoral approaches by use of the standard Judkin’s technique. At least five views of the left coronary artery and three of the right were obtained. According to the previous study,7 narrowing of >70% of luminal diameter in any projection, agreed on by more than two independent observers, was considered significant. Left main disease >50% was also considered significant. A venous blood sample was taken with minimal venostasis from an antecubital vein for the determination of each factor as follows: Lp(a); latex immunoassay by monoclonal antihuman Lp(a) antibody; high-density lipoprotein cholesterol (HDL-C) by selective inhibition assay; remnant-like particles
American Heart Journal Volume 136, Number 2
cholesterol (RLP-C) by immunoadsorption assay using monoclonal anti-apo B-100 and anti-apo A-I immunoaffinity mixed gels, tissue plasminogen activator antigen (TPA) by enzymelinked immunosorbent assay, TPA inhibitor type 1 antigen (PAI-1) by enzyme-linked immunosorbent assay, antithrombin III activity (AT III) by chromogenic substrate assay, and protein C activity by latex photometric immunoassay. In brief, the standard assay contains 5 µL of serum and 50 µL of mixed gel, which adsorbs lipoproteins containing apo A-I as well as most of the lipoproteins containing apo B-100. After 60 minutes of gentle shaking, unbound cholesterol present in the supernatant is measured enzymatically. Venous blood samples were collected before the catheterization and after the subjects had fasted for 12 hours. The four conventional coronary risk factors were determined in each patient as follows: hypertension (systolic pressure >160 mm Hg or diastolic pressure >95 mm Hg or a satisfactory prior diagnosis); smoking habit (present smoker or former smoker of >10 cigarettes per day); diabetes mellitus (overt diabetes necessitating treatment or abnormal oral glucose tolerance test); obesity (body mass index >26). All data were examined when each patient underwent coronary angiography. For statistical analysis, comparisons for normally distributed and not normally distributed values were made with unpaired two-tailed t test and Mann-Whitney U test, respectively, as appropriate. Discrete data were analyzed by the chi-square test. Multivariate analysis of variables was also performed with Cox proportional-hazard regression models. A p value <0.05 was considered significant in each test.
Results The mean age of the 124 patients studied was 63.4 ± 8.5 years (mean + SD) and ranged from 42 to 80 years. There were 88 men and 36 women. Of the patients, 37 (29.8%) had no significant stenoses or occlusions and 87 (70.2%) had significant organic stenoses. We defined the former 37 cases as group N (the group of patients who had no stenoses) and the latter 87 cases as group S (the group of patients who had at least one stenosis or occlusion). The number of cases found to have one-, two-, three-vessel, and left main disease in group S was 44, 23, 14, and 6, respectively. The mean age, malefemale ratio, and the prevalence of conventional risk factors were compared in group S and group N. There were no significant differences in these patient characteristics between the two groups, as shown in Table I. Mean levels of lipid and fibrinolytic variables in group N and group S are presented in Table II. HDL-C was significantly lower and RLP-C was significantly higher in group S. Protein C tended to be lower in group S but no significant difference was observed.
Masuoka et al. 227
Table I. Comparison of the baseline characteristics between the patients with (group S) and without (group N) angiographically determined coronary artery stenoses Group S (n = 87)
Group N (n = 37)
Test for trend
Age (yr) 63.8 ± 8.6 Men sex (%) 71.3 Coronary risk factors (%) Hypertension 43.7 Diabetes mellitus 23.0 Smoking 49.4 Obesity 21.8
62.5 ± 9.1 70.3
NS NS
40.5 9.0 43.2 24.3
NS NS NS NS
Data presented are mean ± SD or percent of patients. NS, not statistically significant.
To rule out the possibility that RLP-C is just a covariate of low-density lipoprotein cholesterol (LDL-C), we also analyzed the correlation between RLP-C and LDLC in each patient. No significant correlation was found between RLP-C and LDL-C (r = 0.083, p = 0.3601). A product and a ratio of each of two factors were calculated separately for each case. Some representative data are listed in Table III, including all factors that were significant or marginally significant. The RLPC/HDL-C ratio was demonstrated to be a highly significant (p < 0.0001) predictor for a coronary artery disease. Although RLP-C/HDL-C level of each patient in group N was less than 0.3, that of 25 patients (28.8%) in group S was more than 0.3, as shown in Fig. 1. Multivariate analysis also demonstrated that RLP-C/HDL-C is the most potent and independent predictor for coronary artery disease. As for the number of vessels involved, there were significant increases in RLPC/HDL-C levels, with increasing number of vessels diseased (r = 0.359, p < 0.0001), as can be seen in Fig. 2.
Discussion In the early studies of Gofman et al.,8 lipoproteins now considered to be very low-density lipoprotein (VLDL) remnants were suggested to be more atherogenic than low-density lipoprotein (LDL). The importance of this triglyceride-rich lipoprotein particle, recently described as a remnant-like particle (RLP),9 has now been established at the basic science level and in animal studies.10 A simple and rapid assay method for the determination of RLP was developed recently in Japan.9 This method uses an immunoaffinity gel mixture of anti-apo B-100 and anti-apo A-I monoclonal antibodies coupled to sepharose 4B. A subpopulation of triglyceride-rich particles is separated
American Heart Journal August 1998
228 Masuoka et al.
Table II. Comparison of the lipid and fibrinolytic parameters between the patients with (group S) and without (group N) angiographically determined coronary artery stenoses
Lp(a) (mg/dl) HDL-C (mg/dl) RLP-C (mg/dl) TPA (ng/ml) PAI-1 (ng/ml) AT III (%) Protein C (%)
Group S
Group N
p Value
24.67 ± 22.23 38.42 ± 11.65 7.02 ± 5.75 10.16 ± 4.69 167.36 ± 142.56 95.72 ± 14.83 96.76 ± 21.69
21.07 ± 18.83 53.06 ± 14.46 3.89 ± 2.66 9.22 ± 4.89 155.38 ± 129.95 98.67 ± 14.20 108.86 ± 22.93
0.2274 0.0071 0.0022 0.1322 0.9698 0.3066 0.0613
Data presented are mean ± SD.
Table III. Comparison of a product and a ratio of each parameter between the patients with (group S) and without (group N) angiographically determined coronary artery stenoses
Lp(a) × AT III Lp(a) × TPA Lp(a) × PAI-1 Lp(a)/HDL-C RLP-C/HDL-C RLP-C × AT III RLP-C × Lp(a) PAI-1 × TPA PAI-1/TPA TPA/HDL-C Protein C × AT III
Group S
Group N
p Value
2019.0 ± 1862.3 212.8 ± 211.1 3853.3 ± 5549.9 0.578 ± 0.562 0.213 ± 0.198 681.4 ± 621.4 125.2 ± 137.5 1843.5 ± 2328.4 18.39 ± 16.53 0.279 ± 0.208 9390.3 ± 2918.1
2501.9 ± 2414.1 193.6 ± 164.6 3918.0 ± 5340.4 0.461 ± 0.263 0.082 ± 0.068 393.3 ± 290.3 78.0 ± 64.5 1589.7 ± 2238.0 22.27 ± 25.92 0.195 ± 0.150 10,966.9 ± 3759.3
0.1900 0.8572 0.8079 0.9739 <0.0001 0.0169 0.2355 0.3271 0.5894 0.0456 0.0133
Data presented are mean ± SD.
in the unbound fraction enriched in apo E. By adding the anti-apo A-I affinity gel to the anti-apo B-100 gel, almost all apo A-I containing lipoproteins are adsorbed into the mixed gel. It was demonstrated that this subpopulation consists of chylomicron and VLDL remnant-like lipoproteins. A more detailed characterization has been given elsewhere.9 RLP-C was shown to be the most sensitive, precise, and convenient for the estimation of serum RLP level.9 However, the contribution of raised RLP-C to the risk of coronary artery disease in human subjects has not yet been established.1 Although there are some reports on the levels of intermediate-density lipoproteins (IDL) or VLDL remnants instead of RLP-C in patients with coronary artery disease,11 reports on the levels of RLP-C in these patients are very few and the subjects are limited.9,12 Our present study demonstrated that RLP-C levels were significantly high in the patients who had established coronary artery diseases. The HDL-C level has been reported to be inversely
related to the risk of coronary artery disease.13,14 Our present study was also compatible with these earlier reports. Our present study indicated that a ratio of RLP-C/HDL-C was a more sensitive predictor for the risk of coronary artery disease than either alone. In our present study, no patients in group N showed RLP-C/HDL-C values >0.3. Levels of RLPC/HDL-C of more than 0.3 appeared to be associated with organic coronary stenoses. Thus RLP-C/HDL-C levels may provide useful prognostic information and permit the early identification of patients with organic coronary stenoses. Several clinical and epidemiologic studies have shown that increased PAI-1 level and increased TPA level are predictors of coronary events. TPA level and PAI-1 level are prognostic in some studies,15,16 but not in others.17,18 Neither TPA level nor PAI-1 level showed significant relation to the existence of the coronary artery disease in our present study. We speculate that PAI-1 level is perhaps a large contributor to
American Heart Journal Volume 136, Number 2
Figure 1
Masuoka et al. 229
Figure 2
Values of RLP-C/HDL-C ratio in patients with (Group S) and without (Group N) angiographically determined coronary artery stenoses.
Distribution of RLP-C/HDL-C ratio plotted against numbers of coronary vessels diseased. Left main disease was classified as one vessel.
the trigger mechanisms that cause a “stenotic disease” to proceed to an “occlusive disease” but has little predictive value in stable, fixed coronary artery stenoses. Lp(a) has been considered to be an independent risk factor for the development of cardiovascular disease.5 There is as yet no definite consensus on the prognostic value of Lp(a). Several epidemiologic studies have been inconclusive in demonstrating a link between Lp(a) level and future risk of myocardial infarction, some studies showing no relationship3,4 and others a clear link.5,6 In our present study, no significant correlation between Lp(a) level and the existence of coronary artery disease was observed. But only particularly strong risk factors will emerge in a study of this size, and the negative results obtained here with regard to Lp(a) and thrombolytic factors should not be taken to imply a lack of involvement in atherogenesis, but only an indeterminancy of the analysis. The main limitation of the present study might be the small number of patients. However, we believe
that this limitation did not significantly influence the outcome of the results on RLP-C because the difference between the groups was too marked to have resulted from chance. In conclusion, our present study disclosed the predictive value of RLP-C/HDL-C ratio as a new indicator of coronary artery disease.
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