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(Stroke. 1997;28:83-87.)
© 1997 American Heart Association, Inc.

Articles

High-Density Lipoprotein Cholesterol and Risk of Ischemic Stroke Mortality

A 21-Year Follow-up of 8586 Men From the Israeli Ischemic Heart Disease Study

David Tanne, MD; Shlomit Yaari, BSc Uri Goldbourt, PhD

the Department of Epidemiology and Preventive Medicine, Sackler School of Medicine, Tel-Aviv University (U.G.); the Department of Neurology (D.T.) and Neufeld Cardiac Research Institute (U.G.), Sheba Medical Center, Tel-Hashomer; and the Computing Center, Bar-Ilan University, Ramat Gan (S.Y.), Israel.

Correspondence to U. Goldbourt, PhD, Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail goldbul@ccsg.tau.ac.il.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose While there is overwhelming evidence relating low levels of HDL cholesterol (HDL-C) with coronary heart disease, the association with cerebrovascular disease is not clear. The aim of the present report was to assess the association between HDL-C levels and ischemic stroke mortality obtained from a long-term follow-up in the Israeli Ischemic Heart Disease Study.

Methods The subjects of this report are 8586 men, tenured civil servants and municipal employees, aged 42 years or older at the time of HDL-C measurements in 1965. They were followed up for mortality for 21 years. Death due to cerebrovascular disease included the International Classification of Disease, 9th Revision, codes 430 to 438, of which presumed ischemic stroke included codes 433 to 438.

Results During the 21-year follow-up, 295 men died from cerebrovascular events, of which 241 deaths were due to presumed ischemic stroke. Individuals subsequently experiencing a fatal ischemic stroke had a marginally lower age-adjusted mean HDL-C (1.05 mmol/L) and a significantly lower (P<.001) age-adjusted mean percentage of serum cholesterol contained in the HDL fraction (%HDL) (19.3%) than counterparts surviving the follow-up period (1.06 mmol/L and 20.6%, respectively). Decreasing age-adjusted rates of ischemic stroke mortality were observed with increasing %HDL: 14.6, 14.0, and 11.8 per 10 000 person-years in the low, middle, and upper tertiles of %HDL, respectively. In multivariate analysis, a low concentration of HDL-C appeared to be significantly predictive of ischemic stroke mortality. The relative risk associated with a 5% decrease of %HDL was 1.18 (95% confidence interval, 1.03 to 1.34). Men at the lower tertile of HDL-C levels experienced a 1.32-fold increase of covariate-adjusted ischemic stroke mortality risk compared with counterparts at the upper tertile.

Conclusions In this prospective study of middle-aged and elderly men from a healthy, working population, we have demonstrated an independent negative association between HDL-C and ischemic stroke mortality during a long-term (21-year) follow-up.

Key Words: atherosclerosis • cerebral infarction • Israel • lipoproteins, HDL • mortality • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
There is overwhelming evidence for a strong independent, inverse relation between levels of HDL-C and coronary heart disease.¹ However, their association with cerebrovascular disease is not clear. Indeed, HDL-C is not usually mentioned as a risk factor for ischemic stroke.^{2 3} Recent reviews and expert panels placed increased emphasis on coronary heart disease risk status as a guide to cholesterol therapy.^{4 5}

The association between coronary artery disease and cerebrovascular disease can be ascribed to a common pathophysiological antecedent, atherosclerosis. Many patients with clinically apparent or silent myocardial ischemia have coexistent cerebrovascular disease. Atherosclerotic lesions tend to develop first in the aorta, then in the coronary arteries, and later in the cerebrovascular and peripheral circulation.⁶ The time lag for the development of atherosclerosis in the cerebral arteries compared with the coronary arteries is commensurate with the fact that ischemic strokes generally occur later in life than coronary artery disease. Although stroke is the leading cause of long-term disability and the third leading cause of mortality among adults in industrialized countries, surprisingly little direct evidence is available to elucidate the role of lipids in the pathogenesis of ischemic stroke.

Serum lipid levels have been related to carotid artery atherosclerosis in a variety of ultrasonographic and angiographic studies,⁷ but their relation to stroke is unclear. A negative association between HDL-C levels and risk of stroke or transient ischemic attacks has been found in several, although not all, case-control studies.⁸ Prospective studies addressing this issue include the Framingham Study and the Copenhagen City Heart Study.^{9 10} Both studies demonstrated a trend toward higher ischemic stroke risk associated with lower HDL-C levels among men. The respective RRs associated with a decrease of 0.26 mmol/L (10 mg/dL) in HDL-C in the two studies were 1.08 and 1.18. We report here the association between HDL-C levels and ischemic stroke mortality obtained from a 21-year follow-up in the IIHD.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This report uses the information collected in the IIHD, an investigation of 10 059 male, tenured civil servants and municipal employees in Israel. These men underwent extensive clinical, anthropometric, biochemical, and psychosocial evaluations in 1963, 1965, and 1968. Details of the study population, sampling procedures, mortality follow-up, and analysis have been described elsewhere.¹¹ Of the 10 059 men under study, 8586 participants (85%) aged 42 years or older at the second round of examinations who had a measurement of HDL-C were included in the present analysis. The order of examination in the study was not correlated with any health criteria and was dictated merely by administrative convenience.

Cholesterol was measured from venous blood drawn in a nonfasting state. Blood samples were kept refrigerated and were shipped daily in ice-cooled containers to a central laboratory, where tubes were centrifuged, serum was separated, and cells were discarded. Cholesterol levels were determined by the Anderson and Keys¹² modification of the Abell method. HDL-C was measured by the method of Burstein and Samaille,¹³ after precipitation of the LDL and VLDL fractions. We performed the univariate and life-table analyses for both HDL-C and the percentage of TC contained in HDL (%HDL). The rationale for analyzing the associations of both variables with ischemic stroke mortality rests on the putative competitive nature of the two lipoproteins involved in the two-way cholesterol transport (LDL is the lipoprotein carrying cholesterol to the cells, and HDL is responsible for reverse cholesterol transport).Thus, how much of the TC is carried in HDL may be as meaningful as or more meaningful than the serum concentration of HDL-C. The division into tertiles was as follows: for HDL-C, <0.92, 0.92 to 1.10, and >1.10 mmol/L; for %HDL, <17.6, 17.6 to 21.9, and >21.9%.

Information on death was derived from the Israeli Mortality Registry. The underlying cause of death was documented on the basis of individual reviews by a review panel for each of the deaths occurring until April 1970. Causes for later deaths were taken as the underlying cause based on the ICD-9.¹⁴ The final coding was determined after a process of checking and correction in the central Bureau of Statistics in Jerusalem. Stroke mortality was based on ICD-9 codes 430 to 438. Deaths from ischemic stroke included ICD-9 codes 433 to 438, which we presume are mostly, although not exclusively, ischemic in origin. Deaths from coronary heart disease were based on ICD-9 codes 410 to 414.

Results are not available for women because the study was confined to middle-aged tenured government and municipal employees, among whom there were too few women in the 1960s for a prospective study.

Statistical Methods
Age-adjusted means of baseline characteristics of participants dying from ischemic stroke and those surviving the follow-up period were computed. Age-adjusted ischemic stroke mortality rates per 10 000 person-years were calculated in tertiles of %HDL with the use of an SAS macro.¹⁵ Multivariate analysis of ischemic stroke and coronary heart disease mortality was performed using the Cox life-table proportional hazards model¹⁶ with estimates derived from Breslow's¹⁷ modifications for tied observations. The model incorporated age, body mass index, diabetes mellitus, TC, systolic blood pressure, history of coronary heart disease, and smoking status. HDL-C was introduced into one model as a continuous variable and into another model by tertiles of HDL-C represented by two indicator variables, with the upper tertile as the reference group. Product-limit survival estimates for participants grouped by tertiles of HDL-C and %HDL were plotted with the 21-year ischemic stroke mortality taken as the time-dependent event. These curves were adjusted by the variables that were incorporated into the multivariate analysis.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
During a period of 21 years, a total of 2865 deaths were recorded among the 8586 men included in this report. The distribution of the main causes of deaths is presented in Table 1. Death attributed to stroke accounted for slightly more than 10% of the total (295 of 2865). Of these, 241 were attributable to ischemic strokes. Deaths attributed to coronary heart disease were approximately three times more common, constituting approximately one third of all deaths.

View this table: [in this window] [in a new window]   Table 1. Distribution of Causes of Mortality During 21-Year Follow-up Among 8586 Men

The mean age at inclusion of men subsequently dying of an ischemic stroke was 5.5 years higher than that of 5725 individuals surviving the follow-up period. Therefore, age-adjusted means of characteristics at baseline of individuals in both groups are given in Table 2. Men subsequently experiencing a fatal ischemic stroke had higher mean systolic and diastolic blood pressure measurements and higher mean body mass index. A history of diabetes mellitus was almost three times as frequent among them. Participants subsequently dying of ischemic stroke had higher baseline TC levels than counterparts surviving the follow-up period. Almost no difference was found in mean HDL-C between the groups. However, the mean age-adjusted %HDL among men subsequently dying of ischemic stroke (19.3%) was significantly lower (P<.001) than that of counterparts surviving 21 years (20.6%).

View this table: [in this window] [in a new window]   Table 2. Age-Adjusted Means of Clinical Characteristics, Lipid Levels, and Smoking Prevalence Among Men Who Died From Ischemic Stroke and Those Surviving the 21-Year Follow-up Period*

Age-adjusted ischemic stroke mortality rates were calculated for each tertile of HDL-C and %HDL. Decreasing rates of ischemic stroke mortality were observed with increasing tertile of HDL-C, with rates of 14.2, 13.6, and 13.0 per 10 000 person-years. Age-adjusted rates declined from 14.6 to 14.0 and 11.8 per 10 000 person-years in the lower, middle, and upper tertiles of %HDL, respectively (Fig 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. Age-adjusted ischemic stroke mortality rates by tertiles of %HDL during 21-year follow-up. Rates are per 10 000 person-years.

Table 3 presents the covariate-adjusted RRs of the 21-year ischemic stroke and coronary heart disease mortality, associated with approximately 1 SD increment (for TC) or decrement (for HDL-C ) in the examined lipid levels. The RR of ischemic stroke mortality, associated with low HDL-C, was higher than the respective one associated with high TC levels. It was lower, however, than the risk of coronary heart disease mortality associated with low HDL-C. The RR associated with a 5% decrement of %HDL (eg, for a man with only 15% of his TC contained in HDL compared with someone with 20%, everything else being equal) was examined in a separate analysis. For fatal ischemic stroke, this RR was 1.18 (95% CI, 1.03 to 1.34). The comparable RR for fatal coronary heart disease was 1.40 (95% CI, 1.30 to 1.51). In an alternative model, we introduced HDL-C tertiles as two indicator variables, with the upper tertile as the reference group. Individuals in the middle tertile of HDL-C levels exhibited a 1.17-fold covariate-adjusted ischemic stroke mortality (95% CI, 0.85 to 1.61), while those in the lower tertile revealed a 1.32-fold increased risk (95% CI, 0.95 to 1.83). In comparison, adjusted RRs of 21-year ischemic stroke mortality associated with the established risk factors for stroke mortality were as follows (data not tabulated): 1.72 for a 5-year age increment, 1.68 for a systolic blood pressure increment of 20 mm Hg, 1.78 for diabetes mellitus, and 1.67 for smoking 11 to 20 cigarettes daily compared with never having smoked. No other factor measured for the sample of this study was associated with a relative ischemic stroke mortality risk above 1.10, and none of them was statistically significant at the P<.05 level.

View this table: [in this window] [in a new window]   Table 3. TC and HDL-C Levels in Prediction of 21-Year Ischemic Stroke and Coronary Heart Disease Mortality: Multivariate Analysis

Product-limit curves (Fig 2) showed an early increase of ischemic stroke mortality among men in the lowest tertile of %HDL. Toward the later part of the follow-up period, the results were also consistent with an increased mortality in the middle tertile, leaving men with relatively high %HDL at the lowest risk of ischemic stroke mortality. The differences are small, in concurrence with the modest increases in fatal stroke risk associated with reduced HDL-C and reduced %HDL.

View larger version (18K): [in this window] [in a new window]   Figure 2. Life-table curves by tertiles of %HDL: 21-year ischemic stroke mortality adjusted by age, body mass index, diabetes mellitus, TC, smoking, and history of coronary heart disease.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study of middle-aged and elderly men from a healthy, working population, we have demonstrated a negative independent association between serum HDL-C levels and ischemic stroke mortality in a long-term (21-year) follow-up. Decreasing rates of ischemic stroke mortality were observed with increasing tertiles of %HDL. This relation persisted after we controlled for established ischemic stroke risk factors as well as for factors affecting the plasma lipid profile.

Serum lipid levels have been related to carotid artery atherosclerosis in a variety of ultrasonographic and angiographic studies. A relation was identified between blood lipids and/or lipoproteins and the extent or severity of cerebrovascular atherosclerosis in all but three of 26 reviewed studies, in some of which HDL-C levels were negatively associated with carotid atherosclerosis in multivariate analysis.⁷

Whether high levels of TC are associated with ischemic stroke is controversial because of conflicting results. A recent meta-analysis of prospective studies found no overall association between TC levels and stroke¹⁸ as well as no significant reduction in stroke mortality and morbidity by lowering cholesterol levels.^{19 20} The lack of any overall association between TC levels and stroke might, however, conceal a positive association with ischemic stroke masked by a negative association with hemorrhagic stroke.²¹ Recent reports from trials in which HMG–coenzyme A reductase inhibitors were used demonstrated encouraging results regarding the prevention of ischemic stroke among high-risk patients through changes in blood lipids. In the Scandinavian Simvastatin Survival Study, a 30% reduction (P=.024) in fatal and nonfatal strokes was demonstrated (based on data-driven post hoc analysis) among coronary heart disease patients.²² In a pooled analysis of clinical events during pravastatin therapy based on four regression trials, a 62% reduction (P=.054) in the risk of fatal or nonfatal stroke, not a prespecified outcome, was noted.²³

In the Framingham Study, the first to assess the association between HDL-C and stroke prospectively,⁹ an inverse relation was identified between HDL-C and atherothrombotic brain infarction among men, but this was weak and nonsignificant. The authors have reported a standardized logistic regression coefficient of -0.101, adjusted for lipids and known cardiovascular risk factors. This represents an RR of 1.08 associated with a decrease of 0.26 mmol/L (10 mg/dL) in levels of HDL-C. In the Copenhagen City Heart Study,¹⁰ an inverse association was reported between HDL-C and risk of ischemic strokes, with an RR of 1.18 associated with the same decrease in HDL-C. Both studies based the analysis on a 6-year follow-up. In the Framingham Study there were 51 atherothrombotic brain infarcts among a cohort of 2723 subjects, and the Copenhagen City Heart Study included 279 nonhemorrhagic stroke cases among 11 342 subjects. In our cohort, 241 deaths attributed to ischemic stroke were identified during a 21-year follow-up of 8586 men. The RR for ischemic stroke mortality associated with a 0.26 mmol/L decrease of HDL-C was 1.17. Our results therefore agree with previous studies and provide additional evidence that low serum HDL-C should be considered a risk factor for ischemic stroke. It should, however, be noted that the impact of low HDL-C is clearly lower than that of age, high blood pressure, cigarette smoking, and diabetes mellitus.

Limitations inherent in such a long-term observational study that relates single baseline determinations of HDL-C to fatal stroke outcome include the problem of regression dilution,²⁴ possible random misclassification in the type of stroke leading to death as coded in death certificates, and the problem of competing risk with coronary heart disease. These limitations, if anything, represent analytical shortcomings that may lead to an underestimation of the true risk associated with low HDL-C.

A validation study indicated that deaths from stroke could be reliably grouped into hemorrhagic and ischemic strokes by death certificate diagnosis, especially if CT is used.²⁵ In our cohort, followed since the mid-1960s, the differentiation between hemorrhagic and ischemic fatal strokes was made mainly on clinical grounds until the advent of widespread use of CT and thus may have resulted in some misclassification in the diagnosis of stroke type.

The role of lipids in the pathogenesis of different ischemic stroke subtypes, namely embolic stroke, large-vessel atherothrombotic disease, and small-vessel disease (lacunar strokes) may differ. Patients with cortical subtype of cerebral infarction were shown to have lower HDL-C levels than counterparts with lacunar strokes, suggesting that HDL-C may be a risk factor for cortical but not lacunar infarction.²⁶ In a registry of fatal strokes, however, lacunar infarcts, associated with low case-fatality rates,²⁷ are probably relatively underrepresented.

Coronary heart disease tends to occur at a substantially higher rate and earlier age than ischemic stroke, and coronary atherosclerosis tends to precede that of cerebral arteries. Individuals may thus die from coronary heart disease before an episode of ischemic stroke has occurred, or they may potentially undergo lipid management because of their symptomatic coronary heart disease. Hence, high TC levels and low HDL-C levels, which are well-established important risk factors for coronary heart disease, may be underestimated as predictors of ischemic stroke.

This long-term observational study indicates that low levels of HDL-C, in addition to marking an increased risk of coronary heart disease mortality, also predict ischemic stroke mortality, albeit to a lesser extent. Levels of HDL-C are determined by environmental and genetic factors.²⁸ A direct antiatherogenic role of HDL-C has been assumed because of its various potentially antiatherogenic properties, including the ability to trigger the flux of cholesterol from peripheral cells to the liver ("reverse cholesterol transport").²⁹ Physical activity,³⁰ alcohol intake,³¹ smoking cessation,³² and possibly losing weight³³ can elevate HDL-C, and it has been known for a quarter of a century that drugs such as fibric acid derivatives or niacin have the same effect. Whether increasing HDL-C would reduce the incidence of cardiovascular disease is not yet clear. Large-scale controlled clinical trials are currently testing the efficacy of pharmacologically raising HDL-C levels among coronary heart disease patients.^{34 35} Well-designed prospective studies, delineating stroke subtypes, should evaluate the role of modifying lipids in the prevention of ischemic stroke among high-risk individuals.

	Selected Abbreviations and Acronyms

 

CI = confidence interval %HDL = percentage of serum cholesterol contained in the HDL fraction HDL-C = HDL cholesterol ICD-9 = International Classification of Diseases, 9th Revision IIHD = Israeli Ischemic Heart Disease Study RR = relative risk TC = total cholesterol

	Acknowledgments

 
Data collection, analysis, and the baseline and the two incidence examinations (1963, 1965, and 1968) were part of a collaborative study by the National Institutes of Health; the Ministry of Health, Israel; and the Hadassah medical organization, supported by PL 480 counterpart funds, research agreement No. 375106. The mortality follow-up from 1970 to 1978 was supported by the Israeli Academy of Sciences, Fund for Basic Research.

Received August 19, 1996; revision received September 17, 1996; accepted September 17, 1996.

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