Prognostic Value of the Morning Blood Pressure Surge in 5645 Subjects From 8 Populations
Previous studies on the prognostic significance of the morning blood pressure surge (MS) produced inconsistent results. Using the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome, we analyzed 5645 subjects (mean age: 53.0 years; 54.0% women) randomly recruited in 8 countries. The sleep-through and the preawakening MS were the differences in the morning blood pressure with the lowest nighttime blood pressure and the preawakening blood pressure, respectively. We computed multivariable-adjusted hazard ratios comparing the risk in ethnic- and sex-specific deciles of the MS relative to the average risk in the whole study population. During follow-up (median: 11.4 years), 785 deaths and 611 fatal and nonfatal cardiovascular events occurred. While accounting for covariables and the night:day ratio of systolic pressure, the hazard ratio of all-cause mortality was 1.32 (95% CI: 1.09 to 1.59; P=0.004) in the top decile of the systolic sleep-through MS (≥37.0 mm Hg). For cardiovascular and noncardiovascular death, these hazard ratios were 1.18 (95% CI: 0.87 to 1.61; P=0.30) and 1.42 (95% CI: 1.11 to 1.80; P=0.005). For all cardiovascular, cardiac, coronary, and cerebrovascular events, the hazard ratios in the top decile of the systolic sleep-through MS were 1.30 (95% CI: 1.06 to 1.60; P=0.01), 1.52 (95% CI: 1.15 to 2.00; P=0.004), 1.45 (95% CI: 1.04 to 2.03; P=0.03), and 0.95 (95% CI: 0.68 to 1.32; P=0.74), respectively. Analysis of the preawakening systolic MS and the diastolic MS generated consistent results. In conclusion, a MS above the 90th percentile significantly and independently predicted cardiovascular outcome and might contribute to risk stratification by ambulatory blood pressure monitoring.
Several studies showed that the incidence of cardiovascular complications peaks in the morning.1,2 For instance, in the Multicenter Investigation of Limitation of Infarct Size Study1 and in the Thrombolysis in Myocardial Infarction Phase II Trial,2 the incidence of myocardial infarction was highest between 6:00 am and 12:00 am. Blood pressure also follows a circadian pattern, generally characterized by a fall during sleep and a sharp rise on awakening.3 This observation gave rise to the hypothesis that an exaggerated morning surge of blood pressure might predict cardiovascular outcome. However, previous studies of populations4 and hypertensive patients5–7 produced contradictory results, possibly because of the small number of events and the lack of statistical power. A further issue complicating the interpretation of previous studies is the varying definitions of the morning surge in blood pressure.8
With the goal to advance knowledge on the prognostic accuracy of the ambulatory blood pressure, a research consortium constructed the International Database of Ambulatory Blood Pressure in Relation to Cardiovascular Outcome.9–12 We used this resource to study whether the morning surge in blood pressure contributes to the stratification of cardiovascular risk.
Previous publications (for details, see the Expanded Methods in the online Data Supplement, available at http://hyper.ahajournals.org) described the construction of the International Database of Ambulatory Blood Pressure in Relation to Cardiovascular Outcome.9–12 At the time of writing this report, the International Database of Ambulatory Blood Pressure in Relation to Cardiovascular Outcome included prospective studies from 11 centers (11 786 subjects). All studies received ethical approval and have been reported in peer-reviewed publications. For the present analysis, we selected studies in which the participants completed a diary during ambulatory blood pressure monitoring, leaving 8 cohorts13–19 and 9488 subjects for possible analysis. In line with previous reports,9–12 we excluded 250 participants because they were <18 years of age and 2430 participants because they had <10 daytime or <5 nighttime blood pressure readings. For the analysis of the morning surge, we additionally disregarded 1163 subjects because they had <2 blood pressure readings during the 2 hours before (n=122) or after awakening (n=1041). Thus, the current analysis included 5645 participants: 1685 residents from Copenhagen, Denmark13; 532 subjects from Noorderkempen, Belgium14; 220 subjects from Novosibirsk, Russia15,16; 290 subjects from Padova, Italy16; 296 subjects from Kraków, Poland16; 1396 inhabitants from Ohasama, Japan17; 327 villagers from the JingNing county, China18; and 899 subjects from Montevideo, Uruguay.19 All participants gave informed written consent.
Blood Pressure Measurement
Conventional blood pressure was measured by trained observers with a mercury sphygmomanometer,13–16,18 with validated auscultatory17 (USM-700F, UEDA Electronic Works), or oscillometric19 (OMRON HEM-705CP, Omron Corporation) devices, using the appropriate cuff size, with the participants in the sitting position.13–19 Conventional blood pressure was the average of 2 consecutive readings obtained either at the person’s home14–16,18,19 or at an examination center.13,17 Hypertension was a conventional blood pressure of ≥140 mm Hg systolic, ≥90 mm Hg diastolic, or the use of antihypertensive drugs.
We programmed portable monitors to obtain ambulatory blood pressure readings at 30-minute intervals throughout the whole day17 or at intervals ranging from 1513 to 2014–16,18 minutes during daytime and from 3017 to 6013 minutes at night (for details, see the Expanded Methods available in the online Data Supplement). When accounting for the daily pattern of activities of the participants, we defined daytime as the interval ranging from 10:00 am to 8:00 pm in Europeans13–16 and South Americans,19 and from 8:00 am to 6:00 pm in Asians.17,18 The corresponding nighttime intervals ranged from 12:00 am to 6:00 am13–16,19 and from 10:00 pm to 4:00 am.17,18 Within individual subjects, we weighted the means of the ambulatory blood pressure level by the interval between readings. To quantify the nocturnal fall in blood pressure, we computed the night:day blood pressure ratio from the nighttime and daytime blood pressures.
For analysis of the morning surge in blood pressure, we determined the awake and asleep periods from the subjects’ diary cards. Subjects were asked to record the time when they got up in the morning and went to bed at night. The sleep-through morning surge was the difference between the morning pressure (the average blood pressure during the 2 hours after awakening) and the lowest nighttime blood pressure (the average of the lowest pressure and the 2 readings immediately preceding and after the lowest value).5 The preawakening morning surge was the difference between the morning blood pressure (the average blood pressure during the 2 hours after awakening) and the preawakening blood pressure (the average blood pressure during the 2 hours before awakening).4,5
We used the questionnaires originally administered in each cohort to obtain information on each subject’s medical history and smoking and drinking habits. Body mass index was body weight in kilograms divided by height in meters squared. We measured serum cholesterol and blood glucose by automated enzymatic methods. Diabetes mellitus was the use of antidiabetic drugs, a fasting blood glucose concentration of ≥7.0 mmol/L,13–19 a random blood glucose concentration of ≥11.1 mmol/L,14,17,18 a self-reported diagnosis,14,18,19 or diabetes mellitus documented in practice or hospital records.19
Ascertainment of Events
We ascertained vital status and the incidence of fatal and nonfatal diseases from the appropriate sources in each country, as described in previous publications (for details, see the Expanded Methods available in the online Data Supplement).9,17,20–23 Fatal and nonfatal stroke did not include transient ischemic attacks. Coronary events encompassed death from ischemic heart disease, sudden death, nonfatal myocardial infarction, and coronary revascularization. Cardiac events consisted of coronary events and fatal and nonfatal heart failure. Cardiovascular events included all aforementioned events plus cardiovascular mortality. In all outcome analyses, we considered only the first event within each category.
For database management and statistical analysis, we used SAS software, version 9.1.3 (SAS Institute). We compared means and proportions by the large-sample z test and the χ2 statistic, respectively. Statistical significance was a 2-sided P value of 0.05.
We used Kaplan-Meier survival function estimates and the log-rank test to compare the incidence rates of events in the top decile of the distributions of the sleep-through and preawakening morning surge with the rates in the rest of the study population. We used Cox regression to compute hazard ratios. We checked the proportional hazards assumption by the Kolmogorov-type supremum test, as implemented in the PROC PHREG procedure of the SAS package. Because the relation between cardiovascular complications and the morning surge in blood pressure was not linear, we used the deviation from the population mean coding24 to estimate the risk in the ethnic- and sex-specific deciles of the sleep-through and preawakening morning surge. This approach expresses the risk in each decile relative to the overall risk in the whole study population and allows computation of CIs for the hazard ratio in each decile without definition of an arbitrary reference group. In an attempt to refine the level of the morning surge that was associated with a significantly increased risk, we calculated for all cutoff points ranging from the fifth to the 95th percentile the hazard ratio expressing the risk in subjects whose morning surge exceeded the cutoff point versus the risk in the total study population. We plotted these hazard rates and their confidence limits versus the cutoff points and identified the cutoff point where the lower confidence limit crossed unity. We adjusted the hazard ratios for baseline characteristics, including cohort, sex, age, body mass index, the 24-hour blood pressure level, current smoking, use of alcohol, serum cholesterol, the presence of diabetes mellitus, a history of cardiovascular disease, and antihypertensive treatment. In fully adjusted models, the night:day blood pressure ratio was additionally included. In sensitivity analyses, we compared the hazard ratios according to baseline characteristics, using a normal approximation of the log-transformed point estimates and SEs.
Characteristics of Participants
The 5465 participants included 3023 Europeans (53.6%), 1723 Asians (30.5%), and 899 South Americans (15.9%). Of the 5645 participants, 3048 were women (54.0%), 1188 (21.1%) were taking blood pressure–lowering drugs, and 2305 (40.8%) had hypertension. Mean±SD age was 53.0±14.7 years. In the whole study population, the 24-hour blood pressure averaged 123.3±13.5 mm Hg systolic and 73.7±8.6 mm Hg diastolic. At enrollment, 1690 participants (29.9%) were current smokers, and 2667 (47.3%) reported intake of alcohol.
The median number of blood pressure readings (fifth to 95th percentile interval) used for the calculation of the within-subject preawakening blood pressure was 5 (2 to 9) and 4 (2 to 6) for the within-subject morning blood pressure. In all participants, the sleep-through and preawakening morning surge in systolic blood pressure averaged 20.7±12.9 and 13.1±11.9 mm Hg, respectively. However, there were significant ethnic and sex differences in the morning blood pressure surge. The mean values of the sleep-through systolic morning surge in the top decile were smaller in women than in men among Europeans (40.9 versus 43.2 mm Hg; P=0.003) and South Americans (38.8 versus 41.5 mm Hg; P=0.041), whereas the opposite was the case among Asians (52.4 versus 50.1 mm Hg; P=0.064). For the preawakening systolic morning surge, the differences between women and men showed similar trends: 26.8 versus 29.2 mm Hg (P=0.062), 22.5 versus 26.9 mm Hg (P=0.059), and 30.6 versus 27.4 mm Hg (P=0.13) in Europeans, South Americans, and Asians, respectively. These differences explain why we applied ethnicity- and sex-specific deciles to study the predictive value of the morning blood pressure surge. This also ensured an equal distribution of ethnicities and women and men across the deciles.
Table 1 shows the baseline characteristics of the participants categorized according to the 90th percentile of the sleep-through morning surge in systolic blood pressure. These 2 groups had significantly different characteristics (P<0.05), with the exception of the nighttime systolic pressure (P=0.35); the proportions of Europeans, Asians, and South Americans (P>0.89); and the percentages of women (P=0.93), smokers (P=0.12), and drinkers (P=0.51).
Incidence of Events
In the overall study population, median follow-up was 11.4 years (fifth to 95th percentile interval: 2.5 to 15.5 years). Across cohorts, median follow-up ranged from 2.5 years (fifth to 95th percentile interval: 2.3 to 2.6 years) in JingNing to 13.3 years (fifth to 95th percentile interval: 4.7 to 16.3 years) in Noorderkempen. During 57 412 person-years of follow-up, 785 participants died (13.7 per 1000 person-years), and 611 experienced a fatal or nonfatal cardiovascular complication (11.0 per 1000 person-years).
Mortality included 287 cardiovascular and 473 noncardiovascular deaths and 25 deaths from unknown cause. Considering cause-specific cardiovascular events, 281 patients experienced a fatal or nonfatal stroke. The first cerebrovascular event was fatal in 69 subjects. Of the 281 fatal and nonfatal cerebrovascular events, 140 were brain infarcts and 70 were hemorrhagic strokes, whereas the stroke subtype was unknown in 71 cases. Stroke occurred in 76 Europeans, 181 Asians, and 24 South Americans. Fatal or nonfatal cardiac events occurred in 317 subjects. The first cardiac event was fatal in 102 subjects. The 317 cardiac events included 47 fatal and 88 nonfatal cases of acute myocardial infarction, 20 sudden deaths, 10 deaths from ischemic heart diseases, 25 fatal and 84 nonfatal cases of heart failure, and 43 cases of surgical or percutaneous coronary revascularization. Of 317 fatal and nonfatal cardiac events, 222 occurred in Europeans, 43 in Asians, and 52 in South Americans.
Risk Associated With Sleep Trough and Preawakening Morning Surge
Figure 1 shows the Kaplan-Meier survival function estimates for total mortality and for all fatal combined with nonfatal cardiovascular events in subjects categorized according to the 90th percentile of the sleep-through and the preawakening morning surge in systolic blood pressure. The results for the morning surge in diastolic blood pressure were similar to that of systolic pressure. In this article, we, therefore, limit the presentation of the results to systolic blood pressure, whereas those for diastolic blood pressure appear in the online Data Supplement (Tables S1 through S3).
The morning surge in blood pressure varies with the difference between the daytime and nighttime blood pressures.1–4 We, therefore, analyzed the prognostic significance of the morning surge in blood pressure with and without additional adjustment for the night:day blood pressure ratio (Table 2) while accounting for other risk factors. With adjustments applied for cohort, sex, age, body mass index, the 24-hour systolic blood pressure, current smoking, use of alcohol, serum cholesterol, the presence of diabetes mellitus, a history of cardiovascular disease, and antihypertensive drug treatment, the risk of noncardiovascular mortality (P=0.04) and of all fatal combined with nonfatal cardiac events (P=0.03) was significantly higher in the top decile of the sleep-through morning surge compared with the average risk in the whole study population (Table 2). When further adjusted for the night:day ratio of systolic blood pressure, the risk of all-cause mortality was 32% (P=0.004) higher in the top decile of the sleep-through morning surge. For cardiovascular and noncardiovascular death, these estimates were 18% (P=0.30) and 42% (P=0.005) and for all cardiovascular, cardiac, coronary, and cerebrovascular events, 30% (P=0.01), 52% (P=0.004), 45% (P=0.03), and −5% (P=0.74), respectively (Table 2). Figure 2 shows the fully adjusted hazard ratios for all-cause mortality and for all fatal combined with nonfatal cardiovascular events by deciles of the morning blood pressure surge. Only in the top decile group was the risk significantly higher than the average risk in the whole population, whereas in the 50th percentile group, the risk was significantly lower by 35% (P<0.01) for all-cause mortality and for all cardiovascular events (Figure 2).
Compared with our findings for the systolic sleep-through morning surge, analysis of the systolic preawakening morning surge produced confirmatory results. While accounting for covariables and the night:day ratio of systolic pressure, subjects in the top decile group of the systolic preawakening morning surge had an increased risk of all-cause mortality (23%; P=0.049) and of all cardiovascular (45%; P=0.0008), cardiac (69%; P=0.0004), and coronary (64%; P=0.01) events compared with the average risk in the whole study population.
In an attempt to define in a more precise manner cutoff points for risk stratification in clinical practice, we explored the risk associated with all values of the sleep-through and preawakening morning surge in systolic blood pressure within the fifth to 95th percentile interval. The overall risk in the whole study population was used as a reference (Figure 3). For the sleep-through morning surge in systolic blood pressure, the lower boundary of the 95% CI of the risk function crossed unity of the hazard ratio at 24.6 and 20.9 mm Hg for total mortality and all cardiovascular events, respectively. For the preawakening morning surge in systolic blood pressure, these crossings occurred at 22.7 mm Hg and 21.5 mm Hg, respectively. The results of these analyses suggest that, for both measures of the morning surge in systolic blood pressure, a value <20 mm Hg is probably not associated with increased risk (Figure 3).
We checked the consistency of our results for total mortality and all cardiovascular events according to various baseline characteristics (Table 3). The hazard ratios expressing the risk in the top decile of the systolic morning surge were not statistically different across strata (0.12<P<0.98) with 2 exceptions. Irrespective of the definition of the morning surge in systolic blood pressure, in the top decile, smokers had a significantly higher risk for all-cause mortality than nonsmokers (P≤0.013). The hazard ratios of all cardiovascular events for the sleep-through morning surge between drinkers and nondrinkers in the top decile were also different (P=0.04). However, the power to detect heterogeneity between strata was low. For example, considering a 2-sided α-level of 0.05, we had only 28% power to detect a 0.23 difference between women and men in the log-transformed hazard ratio of all-cause mortality for the sleep-through morning surge.
Our current meta-analysis of individual data included >5000 people randomly recruited from 8 populations and covered on average 10 years of follow-up, during which 785 people died and 611 experienced a major cardiovascular complication. The key finding was that, while accounting for the night:day blood pressure ratio, the 24-hour blood pressure level, and other covariables, a morning surge in blood pressure exceeding the 90th percentile was a significant and independent predictor of mortality and cardiovascular events.
Ambulatory blood pressure monitoring enables testing of the hypothesis that the diurnal variation in the incidence of cardiovascular complications, such as stroke and myocardial infarction, tracks with changes in the blood pressure level.25 The seminal article by Kario et al,5 published in 2003, introduced the definitions of the sleep-through and preawakening morning surge in blood pressure as a way to study the risk associated with the rise in blood pressure on awakening. In 519 older hypertensive patients (mean age: 72 years) followed up for 41 months, Kario et al5 compared the risk of silent and clinical cerebrovascular diseases in the top decile (≥55 mm Hg) of the systolic sleep-through morning surge with the risk in the other patients. After matching for age and the 24-hour blood pressure, the risk of multiple brain infarcts was ≈2-fold higher in patients belonging to the top decile of the systolic sleep-through morning surge. Moreover, with adjustment for the 24-hour blood pressure, nocturnal dipping status, and the prevalence of silent infarcts at enrollment, the morning surge remained a significant predictor of stroke.5
In 1430 subjects (mean age: 61 years; 64% women) randomly recruited from the Ohasama population, 128 cerebrovascular events occurred during a mean follow-up of 10.4 years.4 The cerebrovascular complications included 86 ischemic strokes and 27 cases with intracerebral hemorrhage. With adjustments applied for the 24-hour systolic blood pressure and other cardiovascular risk factors, the preawakening morning surge in systolic pressure tended to be associated with an increased risk of cerebral hemorrhage (hazard ratio per 1 SD increase: 1.34; 95% CI: 0.95 to 1.89) but not with the risk of ischemic stroke (hazard ratio per 1 SD increase: 0.97; 95% CI: 0.79 to 1.19). The predictive value of the sleep-through morning surge was broadly similar to that of the preawakening morning surge.4
Gosse et al6 studied 507 untreated hypertensive patients without complications at enrollment. The average follow-up of these patients was 92 months, during which 31 cardiovascular events including 6 deaths occurred. The morning surge was the difference between the first systolic measurement after standing up in the morning and the last systolic value within the 30 minutes before assuming a standing position in the morning. A 1-mm Hg increase in the morning surge, adjusted for the 24-hour systolic blood pressure and age, was associated with a 3.3% increase (95% CI: 0.8% to 5.8%) in the risk of cardiovascular events.6
An exaggerated morning surge in blood pressure potentially originates from a low nighttime-through blood pressure and/or a high blood pressure after awakening. We therefore presented the hazard ratios with and without additional adjustment for the night:day blood pressure ratio (Table 2). Including this ratio in the multivariable Cox models yielded higher hazard ratios for total mortality and for all cardiovascular, cardiac, and coronary events compared with those in Cox models not including the night:day blood pressure ratio.
Similarly as in previous reports,4–6 subjects belonging to the top decile of the distribution of the morning surge in blood pressure, in which all of “the results of interest” occurred, were older, more likely to be on antihypertensive drugs, had higher 24-hour and daytime blood pressures, and had a lower night:day blood pressure ratio. While adjusting for these risk factors in multivariable Cox models, the morning surge in blood pressure in the top decile remained a significant and independent predictor of total mortality and of all cardiovascular and cardiac events, over and beyond classic risk factors. Moreover, sensitivity analyses stratified for major risk factors were also confirmatory. By and large our current findings suggest that the morning surge in blood pressure independently contributes to the risk stratification on the basis of ambulatory blood pressure monitoring.
In contrast to previous studies,4,5 the morning surge in blood pressure did not predict stroke. It is likely that the association between stroke and the morning surge depends on the stroke subtype.4,5 In our current study, Asians belonging to the top decile were at a significantly higher risk of hemorrhagic stroke (51 cases; hazard ratio [95% CI]: 2.28 [1.09 to 4.26]; P=0.03) but not ischemic stroke (127 cases; hazard ratio: 1.41 [0.67 to 2.98]; P=0.37) compared with Asians with a lesser morning surge. These results were consistent with a previous report from the Ohasama Study4 but was different from the study of Kario et al5 in which the sleep-through morning surge significantly predicted cerebral infarcts. Different characteristics of the populations under study might explain this diversity. Indeed, the study by Kario et al5 included older hypertensive patients (mean age: 72 years). The sleep-through morning surge in systolic blood pressure in the top decile (≥55 mm Hg) was greater in the study by Kario et al5 than in our current report (≥35 mm Hg in Europeans and South Americans and ≥43 mm Hg in Asians).
Although the morning surge in both systolic pressure and diastolic pressure (see Data Supplement) predicted risk, we would suggest using only the rise in systolic blood pressure in the morning as a risk indicator, because in middle-aged and older subjects systolic rather than diastolic blood pressure is the predominant risk factor.26 Using the morning surge in blood pressure as a risk indicator requires multiple blood pressure readings during sleep and during the preawakening and awakening periods. Subjects also have to complete a diary during ambulatory blood pressure monitoring to report the sleeping and awake periods. In our database, these 2 issues eliminated 4850 of 11 786 available subjects. Moreover, according to our recently published study in older patients with isolated systolic hypertension,27 the morning surge in blood pressure, irrespective of its definition, was poorly reproducible. Nearly 30% of the subjects changed their surge status either in the short term (median: 33 days) or in the long term (median: 10 months).27 These 3 factors might limit the clinical application of the morning surge in blood pressure as a cardiovascular risk factor.
The present study should be interpreted within the context of its possible limitations. Above all, none of the included studies was prospectively designed to evaluate the risk associated with the morning surge in blood pressure. On the other hand, our study was population based, prospective, large, and sufficiently powered with 785 deaths and 611 major cardiovascular events. Second, our study population consisted of more Europeans than Asians and South Americans. Although we did not detect any heterogeneity in the hazard ratios for all-cause mortality and all cardiovascular events, our findings may need replication in other populations. Third, our study did not address the mechanisms explaining why the morning surge behaves as an independent predictor of mortality and cardiovascular events. Several hypotheses have been put forward. A steep morning surge in blood pressure might cause structural damage to the large arteries if the pressure load during the morning period repeatedly exceeds the buffering capacity of the arteries. Indeed, an exaggerated pressure load leads to fracture of the elastin fibers, to disorganization and hypertrophy of the muscular layers of the arterial wall,28 and to plaque rupture.29 These mechanisms might be particularly active in atherosclerotic arteries,28 in the presence of oxidative stress,29,30 or in older subjects with impaired baroreflexes.31
Our study established the prognostic value of the morning surge in blood pressure in general populations. An exaggerated morning surge, exceeding the 90th percentile of the population, is an independent risk factor for mortality and cardiovascular and cardiac events, especially in smokers. Conversely, a sleep-through or preawakening morning surge in systolic blood pressure <20 mm Hg is probably not associated with an increased risk of death or cardiovascular events. Additional studies are necessary to refine the exact threshold to be used for risk stratification in clinical practice and to replicate our findings in other ethnicities, in particular blacks. Moreover, randomized clinical trials should investigate whether drug treatment specifically intervening with the morning surge in blood pressure might reverse the risk and improve prognosis.
We gratefully acknowledge the expert assistance of Sandra Covens and Ya Zhu (Studies Coordinating Centre, Leuven, Belgium). The International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes investigators are listed in the online Data Supplement.
Sources of Funding
The European Union (grants IC15-CT98-0329-EPOGH, LSHM-CT-2006-037093, and HEALTH-F4-2007-201550), the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (Ministry of the Flemish Community, Brussels, Belgium) (grants G.0575.06 and G.0734.09), and the Katholieke Universiteit Leuven (grants OT/00/25 and OT/05/49) gave support to the Studies Coordinating Centre in Leuven. The European Union (grants LSHM-CT-2006-037093 and HEALTH-F4-2007-201550) also supported the research groups in Shanghai, Kraków, Padova, and Novosibirsk. The Bilateral Scientific and Technological Collaboration between China and Flanders, Ministry of the Flemish Community, Brussels (grant BIL02/10), supported the fellowship of Y.L. in Leuven. The Danish Heart Foundation (grant 01-2-9-9A-22914) and the Lundbeck Fonden (grant R32-A2740) supported the studies in Copenhagen. The Ministries of Education, Culture, Sports, Science, and Technology (grants 15790293, 17790381, 18390192, and 18590587) and of Health, Labor, and Welfare (Health Science Research grants and Medical Technology Evaluation Research grants), Grant-in-Aid from the Japanese Society for the Promotion of Science (16.54041 and 18.54042), the Japan Atherosclerosis Prevention Fund, the Uehara Memorial Foundation, and the Takeda Medical Research Foundation supported research in Japan. The National Natural Science Foundation of China (grants 30871360 and 30871081), Beijing, China, the Shanghai Commission of Science and Technology (grant 07JC14047 and the “Rising Star” program, grant 06QA14043), and the Shanghai Commission of Education (grant 07ZZ32 and the “Dawn” project, grant 08SG20) supported the JingNing study in China.
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- Received June 29, 2009.
- Revision received July 16, 2009.
- Accepted January 14, 2010.
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