Abstract
Aim. To evaluate dyslipidemia as predictor of myocardial infarction (MI) in subjects with or without chronic kidney disease (CKD). Methods. In 142,394 middle-aged Swedes referred for laboratory evaluation, glomerular filtration rates (GFR) were estimated using the Modification of Diet in Renal Disease study equation. CKD was defined as GFR 15–60 mL/min/1.73 m2. Subjects were stratified into presence or absence of CKD, and lipid measures were related to MI using Cox's proportional hazards regression. Results. During 12 years of follow-up there were 5,466 MIs. The adjusted hazard ratio for MI for the highest versus the lowest quartile of the apolipoprotein (apo) B/apoA-1 ratio among individuals without CKD was 2.88 (95% confidence interval 2.54–3.26) and for those with CKD 3.35 (2.25–4.91). The corresponding estimates for the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio were 3.13 (2.78–3.52) and 3.54 (2.43–5.17), respectively. Receiver operator characteristics analyses showed an advantage in the prediction of MI for the apoB/apoA-1 ratio as compared to conventional lipids (P < 0.0001). Conclusions. The ratio of apoB/apoA-1, the ratio of total cholesterol/HDL cholesterol, and non-HDL cholesterol were all strong predictors of myocardial infarction, both among subjects with and without renal dysfunction, with a possible advantage for the apoB/apoA-1 ratio.
| Abbreviations | ||
| AMORIS | = | Apolipoprotein-related MOrtality RISk |
| Apo | = | apolipoprotein |
| AUC | = | area under the curve |
| CI | = | confidence interval |
| CKD | = | chronic kidney disease |
| eGFR | = | estimated glomerular filtration rate |
| GFR | = | glomerular filtration rate |
| HDL | = | high-density lipoprotein |
| HR | = | hazard ratio |
| LDL | = | low-density lipoprotein |
| MI | = | myocardial infarction |
| MDRD | = | Modification of Diet in Renal Disease |
| NHANES | = | National Health and Nutrition Examination Surveys |
| ROC | = | receiver operator characteristics |
| TC | = | total cholesterol |
Key messages
Dyslipidemia predicts a first myocardial infarction among previously healthy middle-aged men and women, also in the presence of renal dysfunction.
The ratio of apolipoprotein B/apolipoprotein A-1 may have advantage in predicting a first myocardial infarction compared to traditional lipid measures, both among individuals with and without renal dysfunction.
Introduction
Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular mortality and myocardial infarction (MI) independent of traditional risk factors such as smoking, diabetes, hypertension, and hypercholesterolemia (Citation1–4). Non-traditional risk factors may be more prevalent in individuals with CKD (Citation5,Citation6) but have largely failed to provide additional information about future risk of cardiovascular disease, taking traditional risk factors into account, among individuals with CKD (Citation6,Citation7).
Chronic kidney disease is associated with dyslipidemia characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol (Citation5,Citation6,Citation8,Citation9). Low-density lipoprotein (LDL) cholesterol has not consistently been found to be increased among individuals with CKD (Citation6,Citation8,Citation10). Already a mild impairment of renal function is associated with greater concentrations of small atherogenic low-density lipoprotein particles (Citation11). Thus, in CKD conventional lipids may not fully capture dyslipidemia and may not provide the same prognostic information as in individuals with normal renal function.
Apolipoprotein (apo) B provides a direct measure of the number of atherogenic lipoprotein particles present in serum (Citation12). ApoA-1 indicates the function and to some extent also the number of antiatherogenic particles in plasma, represented by HDL cholesterol-containing particles. Thus, it has been suggested that the apoB/apoA-1 ratio may summarize the burden of dyslipidemia better as compared to conventional lipids and lipoproteins (Citation13). In addition apoB may be elevated in individuals with CKD when LDL cholesterol is not (Citation6,Citation9). Also some (Citation14–17) but not all studies (Citation18–21) have found apoB and the apoB/apoA-1 ratio to be superior to LDL and HDL cholesterol in predicting cardiovascular events. However, none of these studies have taken level of renal function into account when assessing how well different lipid measures predict risk of cardiovascular disease.
In a large cohort of adults we aimed to describe different lipid measures and their association with incidence of first MI in relation to level of renal function. Of particular interest was to include the apoB/apoA-1 ratio in these analyses since it has not been done previously in a cohort of this size.
Material and methods
Study population
The Apolipoprotein-related MOrtality RISk (AMORIS) cohort includes 689,714 men and women, mainly living in Stockholm County (79%), who during 1985–1996 were referred for clinical laboratory testing as part of health check-ups or from out-patient clinics (Citation16). A total of 15% of the cohort was born in other countries than Sweden; the majority of these were from other Nordic countries. Less than 1% of the cohort was of African origin. No individuals were hospitalized at the time of investigation. All blood samples were analyzed at the same laboratory, CALAB Medical Laboratories, Stockholm, Sweden. Information on smoking was available for 8,278 women. Blood pressure levels or current medication were not known. Information on any hospitalization before inclusion was obtained from registers of hospital discharges.
All (n = 142,394) individuals between 20 and 85 years of age, with at least one registered creatinine value, an estimated glomerular filtration rate (eGFR) more than 15 mL/min per 1.73 m2, no previous MI, and complete information on apoB, apoA-1, glucose, triglycerides, and total cholesterol, were included in the present study. The socio-economic profile of the AMORIS cohort was similar to that of the Stockholm population in 1990.
The study complies with the Declaration of Helsinki, and it was approved by the ethics committee at Karolinska Institutet.
Laboratory methods
Blood samples were drawn after fasting overnight in most (64%) subjects, 16% were non-fasting, and the others had no information on food intake prior to examination. Total cholesterol and triglycerides were determined by enzymatic techniques, and apoB and apoA-1 by immunoturbidimetry (Citation22,Citation23). Methods used for apolipoprotein measurement were standardized according to the World Health Organization–International Federation of Clinical Chemistry, as described previously (Citation16,Citation22). Concentration of LDL cholesterol was calculated by a formula using concentrations of total cholesterol, triglycerides, and apoA-1: LDL cholesterol = 0.48 + 0.99 × total cholesterol – 0.23 × triglycerides – 1.58 × apoA-1. High-density lipoprotein cholesterol was then derived using the LDL cholesterol estimate from this formula: HDL cholesterol = total cholesterol – 0.45 × triglycerides – LDL cholesterol. Development and validation of these formulas has been described in detail previously (Citation16,Citation24). In four different populations, the correlation between concentrations of LDL cholesterol obtained by this formula and LDL cholesterol calculated by Friedewald's formula (Citation25) was between r = 0.97 and r = 0.99 (Citation16).
Altogether 6,442 subjects had information on directly measured HDL cholesterol in addition to apoB and apoA-1. Mean values of both measured and calculated HDL cholesterol were 1.48 mmol/L, respectively, and the linear correlation was r = 0.90 (P < 0.0001).
Diabetes mellitus was defined as fasting serum glucose more than 7.0 mmol/L (126 mg/dL) or hospitalization before the index examination with diabetes as discharge diagnosis.
Renal function
Serum creatinine was analyzed by a non-kinetic alkaline picrate method (Jaffé), using an AutoChemist-PRISMA (New Clinicon, Stockholm, Sweden) 1985–1992 and DAX-96 analyzer (Technicon/Bayer Corporations) 1993–1996. Coefficients of variation for creatinine determinations were less than 3.1% at 75.5 μmol/L (0.85 mg/dL), 1.7% at 212 μmol/L (2.4 mg/dL), and 1.6% at 547 μmol/L (6.2 mg/dL). Our creatinine values were compared with values from the National Health and Nutrition Examination Surveys (NHANES) 2001–2002 and 2003–2004, which previously have been found to correspond to standardized creatinine values (Citation26). Mean creatinine levels among white non-Hispanics in these NHANES surveys were 2.6 μmol/L (0.03 mg/dL) lower as compared to those in the AMORIS cohort. No direct or indirect adjustment of our creatinine values to standardized creatinine was made.
Renal function was classified according to eGFR using the simplified Modification of Diet in Renal Disease (MDRD) study equation and expressed in mL/min per 1.73 m2 body surface area (Citation27). Chronic kidney disease was defined as eGFR less than 60 but more than 15 mL/min per 1.73 m2.
Follow-up
The index date was chosen according to concurrent measurement of serum creatinine, apoB, apoA-1, total cholesterol, triglycerides, and glucose. The outcome studied was first fatal or non-fatal MI. Follow-up ended at the time of death, emigration, MI, or on 31 December 2002. The mean follow-up time was 12.1 years.
New cases of MI were identified from the Swedish Patient Register and the Swedish Causes of Death Register. The Swedish Patient Register was covering all emergency hospitals in the country from 1987, with nearly a complete coverage of the country in 1985 and for certain parts of the country in 1964. In the identification of first MI cases we used information from the Patient Register going back to 1964 to exclude recurrent cases. Causes of death were obtained from the Swedish Causes of Death Register, where all deceased individuals residing in Sweden at the time of death are registered since 1961. Information about emigration was collected from the Swedish Population and Migration Register.
Statistical analysis
Patient characteristics for subjects with different levels of renal function were presented using means with one standard deviation and proportions. The hazard ratio of first MI in relation to quartiles of different lipid measures, using the first quartile as reference and stratified for renal function, was estimated crude and in multivariable analysis using Cox's proportional hazards regression. We used multivariable analyses to reduce the influence of confounding in the evaluation of associations between different lipid measures and outcome following a ‘change in point estimate’ approach. Variables listed in , including age and gender, and in addition calcium, albumin, and phosphate, all measured in serum, that influenced the point estimate of the hazard ratio by at least 0.1 were retained in the final model. A multivariable model kept throughout all analysis included age, gender, glucose, total cholesterol, and triglycerides. Estimates of hazard ratios were accompanied by asymptotic 95% confidence intervals (CI). Examinations of log cumulative hazard plots and the Nelson–Aalen cumulative hazard function did not indicate violations of the proportional hazards assumption. The sensitivity and specificity of the apoB/apoA-1 ratio versus different lipid measures for the identification of MIs were analyzed by receiver operating characteristic (ROC) analysis after adjustment for age, glucose, and triglycerides. The areas under the ROC curves were calculated and compared using non-parametric methods by Mann–Whitney statistics together with a chi-square test for the differences in areas under the curve. The population-attributable fraction for dyslipidemia defined as an apoB/apoA-1 ratio more than 0.6 was calculated (Citation28). For evaluation of biological interaction between dyslipidemia and CKD in relation to incidence of MI, the synergy index together with a 95% confidence interval was calculated by methods suggested by Rothman (Citation28). All analyses were performed using SAS 9.1 (SAS Institute Inc., Cary, North Carolina, USA).
Table I. Characteristics of study population in relation to glomerular filtration rates estimated by the Modification of Diet In Renal Disease study equation.
Role of the funding source
The funding source had no role in the analysis or interpretation of data or in the decision to submit the manuscript for publication.
Results
Study participants
In 34.7% of study participants eGFR was more than 90 mL/min/1.73 m2, and 4.1% had CKD defined as eGFR less than 60 mL/min/1.73 m2 (). Average eGFR among women, with or without CKD, was 54 and 82 mL/min/1.73 m2, and among men 52 and 89 mL/min/1.73 m2, respectively. Hospitalization prior to inclusion for angina pectoris, heart failure, or stroke was unusual, 1.7%, 1.3%, and 0.9%, respectively. In both men and women HDL cholesterol decreased with worsening renal function. Apolipoprotein A-1 was unchanged in men, but increased in women with decreasing eGFR. All other lipid measures were increased in both genders among those with CKD ().
In a subgroup of 8,278 women similar smoking patterns were found for those with GFR < 60 mL/min/1.73 m2 compared to > 60 mL/min/1.73 m2 (16% versus 17%).
Incidence of myocardial infarction
During 12.1 years of follow-up there were 5,466 first MIs. The overall age-adjusted MI rate was 11 and 29 cases per 10,000 person-years for women and men, respectively. The cumulative incidence of MI was higher among those with (9.2%; n = 535) as compared to those without CKD (3.6%; n = 4,931). The increase in MI incidence associated with CKD among women was small, from 10 to 13 cases per 10,000 person-years. The corresponding rate among men increased from 21 among those without to 55 per 10,000 person-years among those with CKD. After adjustment for age, glucose, triglycerides, and total cholesterol the hazard ratio for MI among men associated with CKD was 1.32 (95% CI 1.14–1.53) and for women with CKD 1.04 (95% CI 0.90–1.18).
Among individuals with CKD strong associations with incident MI were found, in particular for apoB, non-HDL cholesterol, and ratios of apoB/apoA-1 and total cholesterol/HDL cholesterol (). Gender-specific analyses yielded similar results as those seen in (not shown). When corresponding analyses were performed in 6,442 individuals with measured HDL cholesterol and another 89,528 subjects known to be fasting, respectively, similar results were obtained ( and ). As opposed to standard lipid measures in general and triglycerides in particular, the levels of apolipoproteins are not affected by food intake and do not need to be taken in a fasting state.
Table II. Hazard ratiosa of myocardial infarction with 95% confidence intervals in relation to quartiles of lipoproteins and lipid ratios by level of estimated glomerular filtration rate. All individuals (n = 142,394).
The population-attributable fraction for hyperlipidemia defined as a ratio of apoB/apoA-1 more than 0.6 associated with MI was 38% and 61% among women with or without CKD, respectively. The corresponding figures for men were 55% and 56%, respectively. The population-attributable fraction describes the reduction in incidence of the studied outcome that would be observed if the whole study population were to be unexposed, in this case having a ratio of apoB/apoA-1 less than 0.6.
The hazard ratio for MI, for subjects with or without CKD and different quartiles of the apoB/apoA-1 ratio, is shown in . The hazard ratios for the combination of CKD and an apoB/apoA-1 ratio in the upper quartile were 3.7 for men and 3.1 for women compared to subjects without CKD and an apoB/apoA-1 ratio in the lowest quartile. Synergy index for an apoB/apoA-1 ratio in the highest quartile and eGFR between 15 to 60 mL/min/1.73 m2 was calculated and yielded an estimate of 1.36 (95% CI 0.88–2.24) for women and 1.35 (95% CI 0.90–2.00) among men. A synergy index more than 1 indicates that the absolute excess risk for those exposed both to CKD and a high apoB/apoA-1 ratio is greater than the sum of the absolute excess risks for those exposed to each separate risk factor (additive effects).
Figure 1. A: Hazard ratios for myocardial infarction for each quartile of the apoB/apoA-1 ratio, among men, with or without chronic kidney disease. Hazard ratios were calculated in relation to individuals in the quartile with the lowest apoB/apoA-1 ratio and no chronic kidney disease. B: Hazard ratios for myocardial infarction for each quartile of the apoB/apoA-1 ratio, among women, with or without chronic kidney disease. Hazard ratios were calculated in relation to individuals in the quartile with the lowest apoB/apoA-1 ratio and no chronic kidney disease.
Comparisons of different lipid measures
In ROC analysis the area under the curve (AUC) for the ratio of apoB/apoA-1 was 0.77 for men and 0.83 for women without CKD, and 0.65 and 0.74 among men and women with CKD, respectively. The corresponding areas for the ratio of total cholesterol/HDL cholesterol were 0.75 and 0.81 for men and women without CKD, respectively, and 0.61 and 0.72 for men and women with CKD, respectively. The AUCs for the apoB/apoA-1 ratio, for men and women, with or without CKD were significantly (P < 0.0001) larger than corresponding curves for the ratio of total cholesterol/HDL cholesterol. This was also true when the AUC for the apoB/apoA-1 ratio was compared with the AUCs for non-HDL cholesterol and LDL cholesterol.
Discussion
In 142,394 men and women, we found apoB, the ratio of apoB/apoA-1, the ratio of cholesterol/HDL cholesterol, and non-HDL cholesterol to be strong predictors of first MI, in both genders, with or without CKD. The combined exposure of CKD and dyslipidemia was associated with a highly elevated hazard ratio suggesting at least additive effects of these exposures. Receiver operator characteristics (ROC) analyses suggested a certain advantage in the prediction of MI for the apoB/apoA-1 ratio as compared to conventional lipids.
Only few studies have described concentrations of apoB and apoA-1 in non-dialysis-dependant renal insufficiency (Citation5,Citation7,Citation10,Citation11). These studies have found that concentrations of apoB are increased, and apoA-1 decreased, in individuals with moderate renal dysfunction even when levels of total cholesterol, LDL cholesterol, and HDL cholesterol are unchanged. In our study we found that triglycerides were increased and HDL cholesterol decreased, levels of apoB increased, but apoA-1 was unchanged in men and increased in women with CKD.
In our study, the population-attributable fraction for an elevated apoB/apoA-1 ratio suggested that around 55% of all first myocardial infarctions in men, irrespective of renal function, and 38% in women without CKD, and 61% in women with CKD, could be attributed to a high apoB/apoA-1 level, given a causal association and no confounding. Other studies have assessed whether apolipoproteins add any information about risk of future cardiovascular disease and found that the advantages, if any, are small and concluded that the use of apolipoproteins in routine clinical practice is not warranted (Citation18–21). Our data suggest that apoB and apoA-1 may add information about risk of future MI also among individuals with CKD.
The association between renal dysfunction and MI, among women, was weak. This may be explained by the small difference in eGFR, 28 mL/min/1.73 m2, between women with, compared to those without, CKD. In men the difference in eGFR between those with as compared to without CKD was larger, 37 mL/min/1.73 m2, and the association between renal dysfunction and MI was stronger. Biologically, women have lower GFR, yet the definitions for a decreased GFR are the same in both men and women. Therefore, an increased risk for MI associated with renal dysfunction among women may have a different association with GFR than among men. Another possible explanation for our findings is that misclassification of renal function using the MDRD study equation is greater for women than for men.
The main strength of the present study is the large study population and long follow-up, which enabled us to make detailed analyses of the association between different lipid measures and outcome. Methods used for analyses of apolipoproteins were standardized according to an international standard (Citation16,Citation22), and all blood samples were analyzed at one laboratory. In addition the proportion of subjects with GFR more than 90 mL/min per 1.73 m2 was similar to that reported from the most recent NHANES surveys (Citation26). The proportion of the study cohort which had eGFR less than 60 mL/min per 1.73 m2 was 4.1%, which is slightly lower than in the NHANES survey 1988–1994 (Citation26). This difference may partly be explained by a larger proportion of women being included in the NHANES survey compared to the AMORIS cohort.
Study limitations
One important limitation of the present study is that we could not adjust for blood pressure and smoking in multivariable analyses. However, in a subgroup of women with information on smoking, no association with renal dysfunction was found, a finding consistent with other studies (Citation2,Citation5). In addition, adjustment for hypertension and smoking has altered hazard ratios only slightly in previous studies (Citation3,Citation4). Also, there may have been an underestimation of the number of patients with diabetes, since the definition used was mainly based on fasting glucose levels. This may have led to well treated diabetics with normal fasting glucose levels being misclassified as not having diabetes mellitus. In the multivariable analyses we adjusted for glucose as a continuous variable in order to minimize this misclassification, but most likely there was some residual confounding from diabetes. We had no information on medication and thus could not adjust for lipid-lowering therapy or other medications that may have affected lipid levels or been related to outcome.
We could not calibrate our creatinine assays to an international standard. When we compared our creatinine values to those from the most recent NHANES surveys, we found that the overall difference was small. Creatinine values from these surveys have previously been shown to correspond to standardized creatinine values (Citation26). It is likely that if we had been able to calibrate our assays this would not have substantially affected our findings.
Another limitation is that LDL cholesterol and HDL cholesterol was calculated by formulas using triglycerides and apoA-1. These formulas have been validated previously and were found to give estimates of LDL cholesterol close to those calculated by the Friedewald formula, and estimates of HDL cholesterol close to measured HDL cholesterol values. Furthermore, analyses in a subset of individuals with information on both measured and calculated HDL cholesterol gave similar results irrespective of which method was used. Thus, it is unlikely that the use of calculated HDL cholesterol seriously biased our results. Also individuals who were fasting had similar hazard ratios compared with those who were non-fasting or had missing information on food intake. This is most likely explained by the fact that most of the individuals who had no information on food intake probably were fasting, since they were referred for analyses of lipids.
The proportion of non-Caucasian subjects in our study was low which is a limitation on the generalizability to populations of non-Caucasians in general or Africans in particular. The prevalence of CKD and also GFR in these populations may differ from Caucasian populations. However, a difference in prevalence of CKD would not necessarily impact on the main conclusions of our study regarding the association between dyslipidemia and MI in subjects with or without CKD.
Conclusions
In conclusion, we found that in a large cohort of mainly healthy individuals, the apoB/apoA-1 ratio, the total cholesterol/HDL cholesterol ratio, and non-HDL cholesterol all are strong predictors of first MI, among both men and women, with or without CKD. Our study indicates that the ratio of apoB/apoA-1 may add information about risk of future MI compared to conventional lipid measures. The usefulness of apolipoproteins in prediction of MI among individuals with CKD needs further investigation.
Appendix
Appendix Table I. Hazard ratiosa of myocardial infarction with 95% confidence intervals in relation to quartiles of lipoproteins and lipid ratios in 6,442 individuals with measured HDL cholesterol without stratification for renal function.
Appendix Table II. Hazard ratios a of myocardial infarction with 95% confidence intervals in relation to quartiles of lipoproteins and lipid ratios by level of estimated glomerular filtration rate in 89,528 individuals known to be fasting at the time of laboratory evaluation.
Declaration of interest: The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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