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High long-chain n-3 fatty acid intake attenuates the effect of high resting heart rate on cardiovascular mortality risk: A 24-year follow-up of Japanese general population
Corresponding author at: Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan. Tel.: +81 77 548 2191; fax: +81 77 543 9732.
Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, JapanDepartment of Health Science, Shiga University of Medical Science, Otsu, JapanDepartment of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan
Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, JapanDepartment of Health Science, Shiga University of Medical Science, Otsu, Japan
Department of Health Science, Shiga University of Medical Science, Otsu, JapanDepartment of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan
Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, JapanDepartment of Medical Statistics, Shiga University of Medical Science, Otsu, Japan
Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, JapanDepartment of Health Science, Shiga University of Medical Science, Otsu, Japan
Increased resting heart rate (RHR) independently predicts cardiovascular mortality. Meanwhile, long-chain n-3 fatty acids (LCn3FAs) have a cardioprotective effect. Our aim was to evaluate whether higher LCn3FAs intake attenuates the elevated risk of cardiovascular mortality associated with increased RHR.
Methods
We conducted a population-based 24-year prospective cohort study of Japanese, whose LCn3FAs intake is relatively high. Study participants included 8807 individuals aged 30–95 years from randomly selected areas across Japan without cardiovascular diseases and anti-hypertensive drugs at baseline. The primary endpoint was cardiovascular mortality, and the secondary endpoints were cardiac and stroke mortality during 24 years of follow-up. Individual dietary LCn3FAs intake was estimated from household-based 3-day weighed food records. RHR was obtained from 3 consecutive R-wave intervals on 12-lead electrocardiography. Cox models were used to estimate the multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) adjusting for possible confounders.
Results
During the follow-up period, 617 cardiovascular deaths were observed. The median daily intake of LCn3FAs was 0.37% kcal (0.86 g/day). The interaction between dietary LCn3FAs intake and RHR in the risk of cardiovascular mortality was statistically significant (p = 0.033). The risk of cardiovascular mortality was significantly higher in the low-intake group (<0.37% kcal) with an RHR >85 beats/min (bpm) [hazard ratio (HR), 1.67; 95% confidence interval (CI), 1.15–2.43], but not in the high-intake group (≥0.37% kcal) with an RHR >85 bpm (HR, 0.92; 95% CI, 0.61–1.38), compared with those in the high-intake group with an RHR <70 bpm. Similar results were observed with stroke mortality, but not with cardiac mortality.
Conclusions
The risk of cardiovascular mortality associated with increased RHR is elevated in participants with low dietary LCn3FAs intake, but not in participants with high dietary LCn3FAs intake in a representative Japanese general population. These results suggest that high dietary LCn3FAs intake may prevent cardiovascular mortality associated with increased RHR.
Multiple lines of evidence from epidemiological and clinical studies have shown that resting heart rate (RHR) independently predicts cardiovascular mortality [
Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial.
]. Based on experimental study results, several pathophysiological plausible mechanisms between increased RHR and cardiovascular systems have been proposed, including autonomic imbalance, acceleration of atherosclerosis [
]. Each of these may contribute to a counteractive effect on the adverse cardiovascular influence by increased RHR. Therefore, we hypothesized that a high LCn3FAs intake attenuates the elevated risk of cardiovascular mortality associated with increased RHR in the general population free of cardiovascular diseases.
We tested this hypothesis in a 24-year prospective cohort study of a representative Japanese general population who participated in the National Survey of Circulatory Disorders and the National Nutrition Survey of Japan. This community-based Japanese population tends to have a higher LCn3FAs intake compared with other populations worldwide [
], and was therefore useful for this investigation.
Methods
Study participants
Cohort studies of the National Survey on Circulatory Disorders and the National Nutrition Survey of Japan are known as the National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged (NIPPON DATA). We analyzed data from NIPPON DATA80 using a baseline survey conducted in 1980. The detailed methods are described elsewhere [
Prognostic values of clockwise and counterclockwise rotation for cardiovascular mortality in Japanese subjects: a 24-year follow-up of the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980–2004 (NIPPON DATA80).
]. The present study was approved by the Institutional Review Board of Shiga University of Medical Science (No. 12-18, 2000; No. 17-21-1, 2010).
Members of an overall population (n = 13,771) aged ≥30 years from 300 randomly selected health districts throughout Japan were invited to participate in the study. Among them, 10,546 community-based individuals (76.6%) agreed to join the study. The survey consisted of a physical examination, blood test, self-administered questionnaire on lifestyle, dietary assessment, and standard 12-lead electrocardiography recording. For the present study, participants were followed up to 2004 (NIPPON DATA80, 1980–2004).
A total of 1739 participants were excluded from this analysis for the following reasons: history of cardiovascular diseases (n = 280), missing baseline information (e.g. electrocardiography, RHR, or dietary data) (n = 373), non-sinus rhythm (n = 62), and anti-hypertensive medication (n = 1024). Therefore, 8807 participants were finally included in the present analyses [4909 women; mean (SD) age, 48.3 (12.8) years; range, 30–95 years].
End-point determination
To determine the cause of death during the 24-year follow-up, the National Vital Statistics database of Japan was used with permission from the Management and Coordination Agency, Government of Japan. The underlying causes of death in the National Vital Statistics were coded according to the Ninth International Classification of Disease (ICD9) until the end of 1994, and according to the Tenth International Classification of Disease (ICD10) from 1995 onwards, as described elsewhere [
The primary endpoint was cardiovascular mortality, and the secondary endpoints were cardiac and stroke mortality occurring during the follow-up period. The corresponding ICD9 and ICD10 codes were as follows: cardiovascular mortality, 393 to 459 (ICD9) and I00 to I99 (ICD10); cardiac mortality, 393 to 429 (ICD9) and I01 to I09, I11, I13, and I20 to I52 (ICD10); and stroke mortality, 430 to 438 (ICD9) and I60 to I69 (ICD10).
Baseline dietary assessment
A dietary survey in each household was based on weighed food records for 3 consecutive representative days, avoiding weekends and holidays, by trained dietary interviewers. Dietary data were processed centrally to calculate nutrients. The nutrient intake reported for each household in the National Nutrition Survey of Japan in 1980 was proportionally allocated to each household member according to the mean consumption rate by age and sex. Dietary researchers were blinded to the participants’ electrocardiographic and outcome status. For energy-supplying nutrients, the intake was calculated as the percentage of total energy intake (% kcal). Other nutrients were calculated relative to total dietary intake (g/1000 kcal).
The detailed calculation procedure and the validity of the estimation have been described elsewhere [
Interaction between dietary marine-derived n-3 fatty acids intake and J-point elevation on the risk of cardiac death: a 24-year follow-up of Japanese men.
]. Furthermore, energy and macronutrient intake among Japanese individuals estimated using the same dietary assessment as in the present study were highly correlated to corresponding values with individual-based weighed food records (correlation coefficients, 0.90–0.92) [
RHR was determined by a standardized assessment, which is the measurement from 3 consecutive intervals between R waves on 12-lead electrocardiography by trained technicians after the participant rested quietly in the supine position for 5 min. Electrocardiographic measurements are described in more detail elsewhere [
Prognostic values of clockwise and counterclockwise rotation for cardiovascular mortality in Japanese subjects: a 24-year follow-up of the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980–2004 (NIPPON DATA80).
]. RHR and other electrocardiographic findings in accordance with the Minnesota Code (MC) were independently evaluated at a baseline survey by 2 trained researchers (blinded to participant dietary and outcome status). Findings that showed agreement between the 2 researchers’ assessments were accepted, and findings that showed disagreement were adjudicated by a panel of epidemiologists and cardiologists.
Electrocardiographic findings included Q wave abnormality (MCs 1.1–1.3), left ventricular hypertrophy (MCs 3.1–3.3), major ST depression (MCs 4.1–4.3), major T abnormality (MC 5.1 or 5.2), complete left bundle branch block (MC 7.1), and intraventricular block with a QRS duration ≥120 ms, except for complete left or right bundle branch block (MC 7.4) [
First, participants were divided into 2 groups according to median dietary LCn3FAs intake (0.37% kcal: 0.86 g/day) as high (≥0.37% kcal) or low (<0.37% kcal) intake. Baseline characteristics and nutritional intake are presented as means and standard deviations for continuous variables, and frequencies and percentages for categorical variables. Differences in baseline characteristics and nutritional parameters were evaluated using the unpaired Student's t-test, Mann–Whitney U-test, or χ2 test, as appropriate.
Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each cardiovascular outcome according to 6 groups cross-classified by 2 categories of LCn3FAs (high- or low-intake) and 3 categories of RHR [<70 beats/min (bpm), 70–85 bpm, and >85 bpm] as follows: high-intake group with an RHR <70 bpm (the reference); high-intake group with an RHR of 70–85 bpm; high-intake group with an RHR >85 bpm; low-intake group with an RHR <70 bpm; low-intake group with an RHR of 70–85 bpm; and low-intake group with an RHR >85 bpm. The choice of cutoff points of RHR was based on identical cutoff points in previous studies of RHR and cardiovascular mortality [
Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial.
To control potential confounders, multivariable models were adjusted for age, sex, body mass index, smoking status (never, ex-, and current), drinking habits (never, occasional, and daily), systolic blood pressure, total cholesterol, blood glucose, labor intensity (high, medium, and low), electrocardiographic findings [
] (left ventricular hypertrophy classified according to MC 3.1 or 3.3, and suspected coronary heart disease classified according to MCs 1.1–1.3, 5.1–5.2, 4.1–4.3, 7.1, or 7.4), and nutritional parameters (intake of saturated fatty acids, n-6 polyunsaturated fatty acids, sodium, and fiber). Tests for interaction between RHR and dietary LCn3FAs intake were performed by introducing a multiplicative interaction term into the main models.
We performed the following sensitivity analysis. To take into account the possibility of an effect by an unknown preclinical disease, we conducted a separate analysis where deaths within the first 5 years of follow-up were excluded. This exclusion was performed by dealing with deaths within the first 5 years as “censored” [
]. To assess interactions between RHR and other nutritional variables, we also analyzed the risk of cardiovascular mortality according to 6 groups cross-classified by 3 categories of RHR (<70 bpm, 70–85 bpm, and >85 bpm), and 2 categories of low- or high-intake, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and fish intake.
All analyses were performed with SAS version 9.1.3 (SAS Institute, Cary, NC, USA). All p-values were two-sided and p-values <0.05 were considered statistically significant.
Results
The baseline characteristics of the 2 groups of participants according to dietary LCn3FAs intake are shown in Table 1. Participants in the high-intake group tended to be older, have a higher proportion of women, were more often never smokers and never alcohol drinkers, had higher blood glucose levels, had higher systolic blood pressure, and were more likely to be labor intensive compared with those in the low-intake group. The baseline characteristics by 3 categories of RHR (<70 bpm, 70–85 bpm, and >85 bpm) are shown in Supplementary Table 1 (Supplemental Digital Content 1).
Table 1Baseline characteristics of 3898 men and 4909 women according to dietary long-chain n-3 fatty acids intake: NIPPON DATA80, Japan, 1980–2004.
The baseline nutritional parameters in both groups of participants are shown in Table 2. The mean dietary LCn3FAs intakes in the high- and low-intake groups were 0.59% kcal (1.38 g/day) and 0.24% kcal (0.58 g/day), respectively. Participants in the high-intake group had higher intake of sodium, fiber, vegetables, fruit, fish, and total n-3 fatty acids than those in the low-intake group. In contrast, participants in the high-intake group had less total energy intake and had a lower intake of meat, α-linolenic acid, n-6 polyunsaturated fatty acids, total fat, and trans fatty acids compared with those in the low-intake group. The baseline nutritional parameters by 3 categories of RHR (<70 bpm, 70–85 bpm, and >85 bpm) are shown in Supplementary Table 2 (Supplemental Digital Content 2).
Table 2Baseline nutritional variables of 3898 men and 4909 women according to dietary long-chain n-3 fatty acids intake: NIPPON DATA80, Japan, 1980–2004.
During the 24-year follow-up period [mean, 21.4 (5.5) years], 617 participants (7.0%) died from cardiovascular causes. Of these, 314 (3.6%) were from cardiac causes (121 from coronary heart disease, 1.4%) and 285 (3.2%) were from stroke (162 from ischemic stroke, 1.8%).
Fig. 1 shows the multivariable adjusted HRs and 95% CIs of cardiovascular outcomes among the groups according to the 6 categories cross-classified by LCn3FAs (high- or low-intake) and RHR (<70 bpm, 70–85 bpm, and >85 bpm). The risk of cardiovascular and stroke mortality were significantly elevated (adjusted HR, 1.67; 95% CI: 1.15–2.43, and adjusted HR, 2.05; 95% CI: 1.24–3.37, respectively), but the risk of cardiac mortality was not statistically significant (adjusted HR, 1.32; 95% CI: 0.74–2.38) in the low-intake group with an RHR >85 bpm compared with those in the high-intake group with an RHR <70 bpm. In contrast, in the high-intake group with an RHR >85 bpm, the risk of cardiovascular outcomes was not significantly elevated (adjusted HR, 0.92 for cardiovascular, 0.89 for stroke, and 0.98 for cardiac mortality). A multiplicative interaction between RHR and dietary LCn3FAs intake in the risk of cardiovascular and stroke mortality was statistically significant (p for interaction = 0.033 and 0.026, respectively), but not in the risk of cardiac mortality (p for interaction = 0.410). Because further adjustment for other nutritional parameters (e.g. total energy intake, and intake of vegetables, fruit, meat, α-linolenic acid, monounsaturated fatty acids, total fat, and trans fatty acids) did not appreciably change the results, we did not include these factors in the final model. Additionally, there was no evidence of a sex interaction with 6 categories cross-classified by LCn3FAs and RHR for any of the outcomes (p for interaction >0.2).
Fig. 1Hazard ratios and 95% confidence intervals of cardiovascular outcomes among groups according to 6 categories cross-classified by long-chain n-3 fatty acids and resting heart rate in 3898 men and 4909 women: NIPPON DATA80, Japan, 1980–2004. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular mortality (A), cardiac mortality (B), and stroke mortality (C) across 6 categories are shown. The high-intake group with a resting heart rate (RHR) <70 beats/min (bpm) served as the reference category. Filled circles and horizontal bars represent HRs and 95% CIs, respectively. HRs were adjusted for age, sex, body mass index, smoking status (never, ex-, and current), drinking habits (never, occasional, and daily), systolic blood pressure, total cholesterol, blood glucose, labor intensity (high, medium, and low), electrocardiographic findings (left ventricular hypertrophy and suspected coronary heart disease), and nutritional parameters (intake of saturated fatty acids, n-6 polyunsaturated fatty acids, sodium, and fiber).
Results were not substantially altered in the sensitivity analysis that excluded deaths within the first 5 years of follow-up for the risk of cardiovascular mortality (see Supplementary figure legends and Supplementary Figure 1, Supplemental Digital Content 3 and 4, respectively). In another sensitivity analysis according to EPA or DHA intake, participants in the low-intake group with an RHR >85 bpm had a significantly elevated risk of cardiovascular mortality (adjusted HR, 1.57 for EPA; 1.64 for DHA) compared with those in the high-intake group with an RHR <70 bpm. In contrast, participants in the high-intake group with an RHR >85 bpm did not have a significantly elevated risk (adjusted HR, 1.00 for EPA; 0.96 for DHA) (p for interaction between RHR and LCn3FAs intake: 0.034 for both) (see Supplementary figure legends and Supplementary Figure 2, Supplemental Digital Content 3 and 5, respectively). Furthermore, we observed a statistically marginal interaction between RHR and fish intake in the risk of cardiovascular mortality (p = 0.046), but not between RHR and the intake of α-linolenic acid or other nutritional parameters (data not shown).
Discussion
In this 24-year prospective study of a representative Japanese general population without known cardiovascular diseases and anti-hypertensive medications, the elevated risk of cardiovascular mortality associated with increased RHR was attenuated by a higher dietary intake of LCn3FAs, which remained after adjustment for possible confounding factors. This association persisted in sensitivity analyses. To the best of our knowledge, this is the first study to show a significant interaction between dietary LCn3FAs intake and RHR in the risk of cardiovascular mortality.
In the high-intake group of LCn3FAs, increased RHR was not associated with an elevated risk of cardiovascular mortality. Notably, the consumption of fish (63.8 g/1000 kcal: 135.3 g/day) and LCn3FAs (0.59% kcal: 1.38 g/day) in the high-intake group was markedly higher than that of most Western populations [
]. Accordingly, our findings that cardiovascular mortality associated with an increased RHR was attenuated by a higher dietary intake of LCn3FAs may not be observed in Western countries. This community-based Japanese population with a remarkably higher LCn3FAs consumption than that worldwide is the ideal cohort in which investigation for cardioprotective evidence of LCn3FAs can extend to much higher ranges of LCn3FAs intake.
], in the current study, increased RHR was associated with an elevated risk of metabolic abnormalities, including hyperglycemia and hypercholesterolemia, most likely via high sympathetic tone. The Japan EPA lipid intervention study (JELIS) reported that EPA treatment reduces the risk of major coronary events for patients with abnormal metabolic profiles more than for those without abnormal metabolic profiles [
Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: sub-analysis of the Japan EPA Lipid Intervention Study (JELIS).
Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS).
]. LCn3FAs may affect the cardiovascular system in a favorable manner, particularly when there is a disturbance in glucose or lipid metabolism as RHR increases.
In the low-intake LCn3FAs group in our study, increased RHR was associated with a higher risk of stroke mortality, but not cardiac mortality. This observation is not surprising. In the Asia-Pacific region, the association between increased RHR and stroke is stronger than that between increased RHR and coronary heart diseases [
]. In fact, in our study, there were more deaths from stroke than from coronary heart diseases. Such characteristics of our study population may explain why an increased risk by higher RHR was observed for stroke, but not for cardiac diseases.
In our study, there were no significant differences in RHR between categories of dietary LCn3FAs intake. Intake of n-3 fatty acids, particularly from fish oil, can contribute to a reduction in heart rate in a dose-dependent fashion, although additional effects appear small at higher levels of intake [
]. Even in the low-intake groups of our study, the mean value of LCn3FAs intake (0.24% kcal: 0.58 g/day) was equivalent to required and acceptable levels for LCn3FAs [
]. However, the exact mechanisms of no significant difference in the RHR between high- and low-intake groups remain unclear and deserve further investigation.
The strengths of our study include its prospective design and 24-year follow-up of participants of the national circulatory and nutritional surveys from randomly selected health districts in Japan. Our dietary assessment using weighed food records during 3 days also appears to be well suited for a large-scale prospective study, in which a broad evaluation of diet is usually desirable [
]. Although recent meta-analysis, including 20 randomized clinical trials, the majority of which were short-term studies ranging from 1 to 6.2 years, reported that n-3 fatty acids supplementation was not associated with a lower risk of cardiovascular diseases [
], we observed a long-term effect of dietary LCn3FAs intake against the cardiovascular risk by increased RHR. Furthermore, although RHR is a highly variable cardiovascular parameter because of the effects of physical, psychological, and environmental factors, our standardized measurement for RHR, assessed by electrocardiography, is more accurate than pulse palpitation for a reliable estimate [
There are some limitations to our findings. First, our analyses were based on a single baseline measurement and may not have accurately reflected long-term LCn3FAs intake and RHR in the follow-up period. Our analyses were also limited to the general population without known cardiovascular disease, and our results should not be generalized to patients with various cardiovascular diseases. Finally, although we carefully controlled for the major known confounders and intake of other fatty acids, we cannot deny the possibility of residual confounding by other unmeasured dietary and/or lifestyle factors, such as mental stress, physical activity, pulmonary disease, and hormonal function.
We used mortality data as endpoints, which might have led to misclassification of the causes of death. However, it has been reported that the death-certificate diagnosis of stroke in Japan is quite accurate [
Accuracy of diagnosis on death certificates for underlying causes of death in a long-term autopsy-based population study in Hisayama, Japan; with special reference to cardiovascular diseases.
]. Furthermore, mortality statistics for coronary heart disease by the end of 1994 may have been underestimated using the ICD9, because deaths coded as “heart failure” may hide certain coronary events [
]. However, in our study, we addressed those problems by death from all heart diseases by classifying them as “cardiac mortality”.
In conclusion, in this long-term prospective observation of a representative sample of the Japanese general population, the risk of cardiovascular mortality associated with increased RHR is elevated in participants with low dietary LCn3FAs intake, but not in participants with high dietary LCn3FAs intake. These results suggest that high dietary LCn3FAs intake may prevent cardiovascular mortality associated with increased RHR as a primary prevention. Whether the predictive role of increased RHR on cardiovascular diseases represents a causal relationship remains unclear, although it should not detract from the concept of RHR as a simple predictor of cardiovascular risk [
]. If our observed association is indeed causal, a higher intake of LCn3FAs by eating more fish may be a useful, low-cost intervention in primary prevention for the apparently healthy general population with a higher RHR.
Funding
This work was supported by a grant-in-aid from the Ministry of Health and Welfare under the auspices of the Japanese Association for Cerebro-cardiovascular Disease Control, by a Research Grant for Cardiovascular Diseases (7A-2) from the Ministry of Health, Labour and Welfare; and by Health and Labour Science Research Grants (Comprehensive Research on Aging and Health Grants H11-Chouju-046, H14-Chouju-003, H17-Chouju-012, and H19-Chouju-Ippan-014, and Comprehensive Research on Life-Style Related Diseases, including Cardiovascular Diseases and Diabetes Mellitus Grant H22-Jyunkankitou-Seisyu-Sitei-017), Tokyo, Japan.
Conflict of interest statement
All authors disclose no financial conflicts of interest. The sponsors did not participate in the design or conduct of the study; the collection; management, analysis, and interpretation of the study; or the preparation, review, or approval of the manuscript.
Acknowledgements
The authors are indebted to the public health centers that cooperated in this study. The members of the NIPPON DATA80/90 Research Group are listed in the Appendix.
Appendix A. Supplementary data
The following are the supplementary data to this article:
Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial.
Prognostic values of clockwise and counterclockwise rotation for cardiovascular mortality in Japanese subjects: a 24-year follow-up of the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980–2004 (NIPPON DATA80).
Interaction between dietary marine-derived n-3 fatty acids intake and J-point elevation on the risk of cardiac death: a 24-year follow-up of Japanese men.
Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: sub-analysis of the Japan EPA Lipid Intervention Study (JELIS).
Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS).
Accuracy of diagnosis on death certificates for underlying causes of death in a long-term autopsy-based population study in Hisayama, Japan; with special reference to cardiovascular diseases.
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