Serum Potassium Is Positively Associated With Stroke and Mortality in the Large, Population-Based Malmö Preventive Project Cohort

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1 Serum Potassium Is Positively Associated With Stroke and Mortality in the Large, Population-Based Malmö Preventive Project Cohort Linda S. Johnson, MD, PhD; Nick Mattsson, MD; Ahmad Sajadieh, MD, DMSc; Per Wollmer, MD, PhD; Martin Söderholm, MD, PhD Background and Purpose Low serum potassium is associated with stroke in populations with cardiovascular disease, hypertension, and diabetes mellitus but has not been studied in a mainly healthy population. We aimed to study the relation between serum potassium and incident stroke and mortality in the Malmö Preventive Project, a large cohort with screening in early mid-life and follow-up >25 years. Methods Serum potassium measurements and covariates were available in individuals (79% men, mean age 44 years). Mean follow-up time was 26.9 years for stroke analyses and 29.3 years for mortality analyses. There were 2061 incident stroke events and 8709 deaths. Cox regression analyses adjusted for multiple stroke risk factors (age, sex, height, weight, systolic blood pressure, fasting blood glucose, serum sodium, current smoking, prevalent diabetes mellitus, prevalent coronary artery disease, and treatment for hypertension) were fitted. Results There was an independent, linear association between serum potassium, per mmol/l increase, and both stroke (hazard ratio, 1.33; 95% confidence interval, ; P<0.0001) and mortality (hazard ratio, 1.20; 95% confidence interval, ; P<0.0001). This was significant in subjects both older and younger than the median age (46.5 years), and there was evidence of an interaction with serum sodium. The association was positive and significant for both ischemic stroke and intracerebral hemorrhage and in both hypertensive and normotensive subjects. Conclusions Serum potassium, measured in early mid-life, was linearly associated with both incidence of ischemic stroke and intracerebral hemorrhage and all-cause mortality. An interaction with serum sodium implies that factors related to electrolyte balance and incident hypertension may be mediating factors. (Stroke. 2017;48: DOI: / STROKEAHA ) Key Words: epidemiology mortality population potassium risk factor sodium stroke Low, as well as high, serum potassium (s-potassium) is associated with increased mortality in hypertensive subjects. 1 Green et al 2 have reported that low s-potassium is associated with increased risk of stroke among elderly users of diuretics in the Cardiovascular Health Study, and Smith et al 3 have found low s-potassium to be associated with ischemic and hemorrhagic stroke in patients with treated hypertension. Furthermore, diets rich in fruit and vegetables, and thereby potassium, are inversely associated with stroke risk 4,5 and stroke mortality. 6 The authors of a recent meta-analysis of potassium intake and stroke risk found a partly blood pressure dependent inverse association between potassium intake and stroke risk, 7 and high urinary sodium and low urinary potassium excretion have both been reported to be associated with increased risk of stroke in patients with established cardiovascular disease or diabetes mellitus. 8 High potassium intake has also been associated with a reduced risk of stroke in hypertensive, but not normotensive, women. 9 In light of this, it seems plausible to assume that there could be a link between low potassium intake, low s-potassium, and later stroke. S-Potassium is regulated via aldosterone secretion, which is closely related to dietary sodium intake, and may also be affected by renin angiotensin aldosterone system activation. High dietary sodium leads to reduced aldosterone release, which results in reduced excretion of potassium. It is possible, therefore, that the association between dietary potassium intake, s-potassium, and stroke may differ between hypertensive and normotensive subjects and, perhaps, also between younger and older subjects. Furthermore, s-potassium within the normal range has been shown to have a positive association with all-cause mortality in the National Health and Nutrition Examination Study, Multi-Ethnic Study of Atherosclerosis, Cardiovascular Health Study, and Atherosclerosis Risk in Communities Study cohorts, and the effect of the competing risk of death on the relationship between s-potassium and stroke has not been fully addressed. To our best knowledge, the association between s-potassium and incident stroke has not been studied in a largely nonhypertensive, healthy Received May 23, 2017; final revision received August 19, 2017; accepted August 23, From the Department of Clinical Sciences Malmö, Lund University, and Skåne University Hospital, Sweden (L.S.J., M.S.); Department of Cardiology, Copenhagen University Hospital of Bispebjerg, Denmark (N.M., A.S.); and Department of Translational Medicine, Lund University, and Skåne University Hospital, Malmö, Sweden (P.W.). Correspondence to Linda S. Johnson, MD, PhD, Inga-Marie Nilssons gata 49, Malmö, Sweden. linda.johnson@med.lu.se 2017 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 2974 Stroke November 2017 population, and the effect of serum sodium (s-sodium) on the association has not been assessed. The Malmö Preventive Project (MPP) is a large prospective cohort with a long follow-up time. The mean age at screening is comparatively young (44.8 years), a large proportion of the population is normotensive, and only 4% were using antihypertensive medication at baseline. We aimed to model the association between s-potassium and incident stroke, as well as all-cause mortality in the MPP cohort, including assessment of interaction by other stroke risk factors, as well as s-sodium. Another aim was to assess the association between s-potassium and stroke subtypes. We also wished to determine whether the competing risk of death influenced the association between s-potassium and stroke. Materials and Methods Study Population The MPP cohort consists of men and women who participated in a health examination intended to detect high-risk individuals and provide preventive intervention. The screening activities included physical examination, blood samples, and an extensive self-administered questionnaire. Subjects were recruited through invitation of prespecified full birth-year groups from the city of Malmö in southern Sweden, age range 21 to 61 years. The attendance rate was over 70%. 14 Men were screened mostly during the years 1974 to 1982 and women during 1982 to 1992, resulting in different lengths of follow-up, and the screening activities performed varied somewhat over different calendar years. S-Potassium was measured mainly in the years 1974 to 1980 and 1989 to 1992, resulting in a higher proportion of males in the present study (80.1%) compared with the full MPP cohort (67.3%). Interventions, in terms of lifestyle advice and drug therapy available at the time, were offered to around 25% of the screened population, but these measures had no effect on incident cardiovascular mortality or morbidity in general. 15 S-Potassium was available for men and 4912 women. From these subjects, we excluded cases of prevalent stroke at baseline (n=15), missing data for systolic blood pressure (n=17), body mass index (n=4), s-creatinine (n=60), fasting blood glucose (n=99), current smoking status (n=618), s-sodium (n=4), or s-cholesterol (n=27). The final study population (n=21 326) consisted of men and 4250 women. Data Collection Height (m) and weight (kg) were measured in light indoor clothing, without shoes, using a fixed stadiometer and balance beam scale, respectively. Body mass index was calculated as weight (kg)/ height (m) 2. Blood pressure (mm Hg) was measured twice after 10 minutes of supine rest using a sphygmomanometer with a modifiable cuff. Blood samples were drawn after overnight fast and analyzed using standard laboratory procedures at the Department of Clinical Chemistry at the Malmö University Hospital. Fasting blood glucose was analyzed using the glucose-oxidase method ( ) or the hexokinase-oxidase method ( ). These methods give similar results and were used without a conversion factor. Individuals who reported that they were current smokers were classified as such. Alcohol risk use was classified as 2 positive answers to a modification of the Michigan Alcohol Screening Test (Mm-Mast) 16 ; data were available for individuals. Sedentary lifestyle was defined as a positive answer to the question, Are you mostly sedentary in your spare time?, and these data were available for participants. Use of antihypertensive medication was defined as a positive answer to the question, Do you use medication for high blood pressure?. Prevalent coronary event was defined using International Classification of Diseases code 410* in the ninth revision or I21 in the tenth revision. Prevalent diabetes mellitus was defined as a baseline fasting blood glucose 6.1 mmol/l or a prior diagnosis of diabetes mellitus retrieved from multiple local and national registers. Diabetes mellitus ascertainment has been described in detail elsewhere. 17 The study complies with the declaration of Helsinki and has been approved by the regional ethics review board. Subjects gave oral consent, and the need for written consent was waived by the ethics review board. 15 Endpoint Retrieval Cases were retrieved through linkage with the stroke register of Malmö 18 and the Swedish National Hospital Discharge Register (SNHDR; International Classification of Diseases codes 430, 431, 434, and 436 for the ninth version and I60, I61, I63, and I64 for the tenth version), of which the latter is administered by The Swedish National Board of Health and Welfare. The stroke register of Malmö was started in 1989 and has been used to study the incidence of stroke in Malmö. A specialized research nurse has systematically searched for cases of stroke in both inpatient and outpatient departments at the Malmö University Hospital, which is the only hospital in the city. All diagnoses have been validated by review of medical records and sometimes also patient interviews. Stroke is defined in accordance with the World Health Organization. 18 Ischemic stroke was diagnosed when brain imaging or autopsy showed an infarction corresponding to the clinical neurological deficit or excluded hemorrhage and nonvascular disease. Intracerebral hemorrhage (ICH) was considered when imaging or autopsy showed intraparenchymal blood in the brain, and subarachnoid hemorrhage (SAH) diagnosis was based on imaging, autopsy, or lumbar puncture. If neither imaging nor autopsy was performed, the stroke was classified as unspecified (International Classification of Diseases- Ninth Revision, 436; International Classification of Diseases-Tenth Revision, I64). Further details of case finding and definitions of stroke types have been described previously Seventy-five percent of all stroke cases in the present study were retrieved from the stroke register of Malmö. Stroke events that occurred before 1989, or in hospitals outside of Malmö, were identified in the SNHDR, wherein diagnoses are made by physicians in routine care and approved by board-certified specialists, and which has been shown to have high coverage and overall validity. 21 The end of follow-up for stroke analyses was December 31, 2010, resulting in a mean follow-up time (SD) of 26.9 (7.9) years. The Swedish Cause of Death register was used to assess mortality rate. End of follow-up for mortality analyses was December 31, Mean follow-up (SD) in mortality analyses was 29.4 (8.5) years. Statistics Hazard ratios for incident stroke and mortality were estimated with Cox proportional hazards regression. Two prespecified statistical models were used based on plausible confounders of any association between s-potassium and stroke. The prespecified approach was chosen to avoid overfitting the model, while at the same time including all relevant possible confounders. Model 1 adjusts for age and sex, and model 2 additionally adjusts for height, weight, systolic blood pressure, fasting blood glucose (transformed by the natural logarithm), s-sodium, s-creatinine, s-cholesterol, current smoking, prevalent diabetes mellitus, prevalent coronary artery disease, and treatment for hypertension. A third model adjusting for alcohol risk use, self-reported history of angina, and sedentary lifestyle was tested, but these variables did not substantially affect results and were excluded from the final model. The proportional hazards assumption was assessed with log-log plots and was found to be valid. All covariates were tested for interaction with serum potassium. Stratified data were reported for s-sodium (P for interaction =0.045 in stroke analyses and in mortality analyses). The P value for all other interaction parameters was >0.10. Results Mean age (SD) at first stroke event was 68.2 (8.3) years, and mean age at death was 70.4 (9.8) years. Selected baseline characteristics are reported in Table 1. Briefly, 80.1% of the study population were male, and the mean age (SD) was 44.6

3 Johnson et al Serum Potassium, Stroke, and Mortality 2975 Table 1. Baseline Characteristics All Men Women N (%) (80.1) 4250 (19.9) Age, y 44.6 (6.5) 44.1 (5.4) 46.6 (9.4) Height, cm 174 (8) 177(7) 164 (6) Weight, kg 74.8 (12.7) 77.4 (11.5) 64.2 (11.5) Body mass index, kg/m (3.5) 24.7 (3.3) 23.9 (4.2) Systolic blood pressure, mm Hg 126 (15) 127 (15) 122 (16) Serum potassium, mmol/l 4.1 (0.3) 4.1 (0.3) 4.1 (0.3) Serum sodium, mmol/l 141 (2.6) 141(2.6) 140 (2.4) Fasting blood glucose, mmol/l* 4.9 (0.8) 4.9 (0.7) 4.8 (0.6) Serum cholesterol, mmol/l 5.7 (1.1) 5.6 (1.4) 5.6 (1.5) Serum creatinine, μmol/l 90 (18) 93 (18) 77 (12) Current smokers, % Alcohol risk use, % Sedentary lifestyle, % Prevalent coronary event, % Prevalent diabetes mellitus, % Prevalent heart failure, % Use of antihypertensive drugs, % Use of diuretics, % All values are mean (SD) unless stated otherwise. *Presented as median (interquartile range). (6.5) years. Mean (SD) systolic blood pressure was 126 (15) mm Hg, and <5% of the population were using antihypertensive drugs. The range of s-potassium was 2.3 to 8.4 mmol/ L (quartile 1, mmol/ L; quartile 2, mmol/l; quartile 3, mmol/l; and quartile 4, mmol/l). S-Potassium, Stroke Incidence, and Mortality A total of 2061 stroke events occurred, of which 1620 were ischemic strokes, 240 were ICH, 89 were SAH, and 112 were unspecified. There were significant positive associations between s-potassium and incident stroke and mortality (Table 2); both P for trend across quartiles of s-potassium were < There was no evidence of a quadratic trend in the full population (P=0.46 for stroke and 0.44 for mortality). The association between s-potassium and stroke and mortality was also tested in subgroups split at the median age of 46.5 years, using adjustment for model 2 covariates. Mean age (SD) was 39.7 (5.1) years in the younger group and 49.5 (3.2) in the older group. The associations, per mmol/l increase, were positive and statistically significant for both stroke (hazard ratio [HR], 1.50; 95% confidence interval [CI], ; P=0.001 in the younger subgroup and HR, 1.28; 95% CI, ; P=0.002 in the older subgroup) and death (HR, 1.32; 95% CI, ; P< in the younger subgroup and HR, 1.16; 95% CI, ; P< in the older subgroup) in both age groups. We also analyzed the association between s-potassium and incident stroke across tertiles of estimated glomerular filtration rate, as estimated by the Cockcroft Gault formula. The association was statistically significant and similar in each tertile (data not shown). S-Potassium and Stroke Subtypes We also analyzed serum potassium in relation to stroke subtypes. S-Potassium, per mmol/l, was independently associated with both ischemic stroke (HR, 1.30; 95% CI, ; P=0.001) and hemorrhagic (ICH and SAH) stroke (HR, 1.42; 95% CI, ; P=0.035) after model 2 adjustment. The proportion of stroke types was similar in validated and nonvalidated stroke events, but the proportion of unspecified stroke was higher (12% versus 2%) in nonvalidated stroke events. Results were largely unchanged when only validated ischemic and hemorrhagic stroke events were included. We also analyzed ICH and SAH separately. The association was similar for ICH (HR, 1.49; 95% CI, ; P=0.04) but weakened for SAH (HR, 1.19; 95% CI, ; P=0.61), compared with the whole group of hemorrhagic stroke, both in model 2. Normotensive and Hypertensive Subjects Furthermore, we also tested the association between s-potassium and stroke and mortality in subgroups of hypertensive and normotensive subjects. Hypertension was defined as either a systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or a positive response to the question, Are you using medication for hypertension?. The definition resulted in identification of 8699 hypertensive subjects (40.8%). After model 2 adjustment, there was a significant association between s-potassium, per mmol/l increase, and incident stroke among normotensive subjects (HR, 1.28; 95% CI, ; P=0.01), as well as among hypertensive subjects (HR, 1.36; 95% CI, ; P=0.001). S-Potassium, per mmol/l increase, was likewise associated with mortality among normotensive (HR, 1.22; 95% CI, ; P<0.0001) and hypertensive subjects alike (HR, 1.17; 95% CI, ; P=0.001) after model 2 adjustment. To rule out confounding by the use of antihypertensive drugs or diuretics on the association between s-potassium and incident stroke, we also performed a subanalysis wherein all subjects who reported use of either diuretics or antihypertensive medications were excluded. Results were largely unchanged (data not shown). Competing Risks Analyses Because stroke and mortality were both associated with s-potassium, we considered it relevant to test the association between s-potassium and stroke independently of the competing risk of death, using competing risks regression as described by Fine and Gray. 22 S-potassium was associated with stroke, independently of the competing risk of death; subhazard ratio 1.27 (95% CI, ; P<0.0001) after model 2 adjustment. Interaction With S-Sodium Table 3 presents the association between s-potassium and stroke and mortality by quartiles of s-sodium. The association was not significant for either endpoint in the top quartile of s-sodium and not significant for stroke in the bottom quartile of s-sodium.

4 2976 Stroke November 2017 Table 2. Cox Regression Analyses for Serum Potassium and Incident Stroke and Mortality, Stratified on Screening Year Discussion This is to our best knowledge the first study of S-potassium and stroke that has been conducted in a relatively young population mostly free of cardiovascular disease and hypertension. We found s-potassium, including in the normal range, to be linearly associated with increased incidence of stroke, after extensive adjustment for potential confounders. 1 3,23 Authors of previous studies have reported that hyperkalemia is associated with increased risk of death The present study confirms this and also shows that the positive association between s-potassium and stroke is independent of the competing risk of death. Compared with previous studies of s-potassium and stroke, the MPP is screened at a younger age and followed for a longer time. The result is a population with a comparatively low baseline prevalence of Model 1* Model 2 HR 95% CI P Value HR 95% CI P Value All stroke events Per mmol/l increase < < S-Potassium Q S-Potassium Q S-Potassium Q < < Ischemic stroke Per mmol/l increase < < S-Potassium Q S-Potassium Q S-Potassium Q < < Hemorrhagic stroke Per mmol/l increase S-Potassium Q S-Potassium Q S-Potassium Q Mortality Per mmol/l increase < < S-Potassium Q S-Potassium Q < S-Potassium Q < < Includes individuals, 2061 stroke events, and 8697 deaths. One-thousand six-hundred and twenty stroke events were classified as ischemic and 329 were classified as hemorrhagic strokes (intracerebral hemorrhage or subarachnoid hemorrhage). Quartiles of s-potassium: quartile 1, mmol/ L; quartile 2, mmol/l; quartile 3, mmol/l; and quartile 4, mmol/l. CI indicates confidence interval; HR, hazard ratio; and Q, quartile. *Adjusted for age and sex. Adjusted for model 1 + height, body mass index, systolic blood pressure, fasting blood glucose, serum sodium, current smoking, serum creatinine, serum cholesterol, prevalent diabetes mellitus, prevalent coronary artery disease, and treatment for hypertension. cardiovascular disease, hypertension, and diabetes mellitus and a low prevalence of hypertensive treatment. One can speculate that this constitutes the reason why the results of the present study differ from previous studies of the subject. We were also able to assess the association between s-potassium and stroke subtypes. S-Potassium was independently associated with both ischemic and hemorrhagic stroke. When the analysis of hemorrhagic strokes was split into ICH and SAH, the association was significant for ICH. The higher proportion of unspecified stroke events in the nonvalidated sample than the validated sample would likely bias the results toward null rather than exaggerate any associations between s-potassium and stroke subtypes. The results of the present study are not obviously consistent with other studies in which high intake of dietary potassium

5 Johnson et al Serum Potassium, Stroke, and Mortality 2977 Table 3. Cox Regression Analyses for Incident Stroke and Mortality Stratified on Screening Year, per mmol/l Increase in Serum Potassium and Presented by Quartile of Serum Sodium Model 1* Model 2 HR 95% CI P Value HR 95% CI P Value Stroke Q Q < < Q Q Mortality Q < < Q < Q < Q CI indicates confidence interval; and HR, hazard ratio. *Adjusted for age and sex. Adjusted for model 1 + height, body mass index, systolic blood pressure, fasting blood glucose, current smoking, serum creatinine, serum cholesterol, prevalent diabetes mellitus, prevalent coronary artery disease, and treatment for hypertension. Includes 3785 individuals, 364 stroke events, and 1463 deaths. Includes 5774 individuals, 530 stroke events, and 2130 deaths. Includes 6017 individuals, 559 stroke events, and 2403 deaths. Includes 5750 individuals, 608 stroke events, and 2701 deaths. has been associated with reduced risk of stroke. 5 9 However, the association between potassium intake and s-potassium is weak 24 and influenced by sodium intake. High dietary sodium leads to plasma volume expansion and reduced aldosterone release, which results in reduced potassium excretion. It has been argued that the kidney has evolved in the context of a high potassium, low sodium diet and is more effective at excreting excess potassium and conserving sodium than the opposite. 25 The western diet is a high-sodium, low-potassium diet. 26 Because of reduced aldosterone release, a high dietary sodium consumption would result in higher s-potassium. The association of s-potassium and incident stroke could, therefore, be because of s-potassium serving as a marker of sodium consumption rather than any direct effect of s-potassium on stroke risk. Dietary intake of sodium is associated with increased blood pressure, 27,28 and intermediate hypertension is, thus, a possible explanation for the association with s-potassium and stroke. The finding that s-potassium is independently associated with ICH strengthens this argument. Hypertension is the most important risk factor for ICH, 18 and increased blood pressure caused by dietary sodium is a plausible explanation for the link between s-potassium and ICH in this study, although there may also be other mechanisms, which should be addressed in future studies. We found an interaction with s-sodium and s-potassium and the risk of stroke and mortality, a subject that, to our best knowledge, has not been studied previously. The association between s-potassium and stroke was not present in either the top or bottom quartile of s-sodium. The reasons behind this interaction cannot be deduced from this observational study, but one might speculate that the top quartile of s-sodium may include a significant proportion of dehydrated subjects in whom high potassium simply constitutes a marker of dehydration. The bottom quartile of s-sodium could be composed of individuals with a low sodium consumption, in whom high sodium excretion has not induced potassium conservation. In these subjects, the s-potassium levels could be more closely related to dietary potassium, which has beneficial effects on stroke risk. We confirm previous reports of a positive association between s-potassium and mortality The present study has also permitted stratification on hypertension status, and results were largely independent of this. The low mean age of the cohort implies that the duration of any hypertension is probable to be rather low, and differences in the association between s-potassium and stroke or mortality among hypertensives with a longer duration of elevated blood pressure cannot be ruled out. The findings of the present study have clinical relevance because they imply that s-potassium should not be used as a predictive marker for stroke or mortality without consideration of the source population. Furthermore, the present study highlights the need for further studies on the subject of mechanisms linking s-potassium to stroke incidence in diverse populations. Strengths and Limitations The MPP cohort is large and population based, with a high attendance rate of invited subjects. Data regarding ethnicity were not available. At the time of screening, Malmö was an ethnically homogenous white population, and results from the present study may not be generalizable to other ethnicities. S-Potassium was not measured all screening years, but because no individual selections of which subjects were screened were made, this should not have introduced any bias. The study sample is roughly two thirds male, but there was no evidence of interaction between s-potassium and sex, and considering that >4000 women were included, we consider the results to be valid in both sexes. The study population is larger than previous studies of the subject, and the follow-up time, via national registries, is long. Because of the fact that all residents of Sweden have a unique personal identification number, there is no loss to follow-up at the time of linkage with registers. These are all strengths. Most stroke cases were retrieved from the local stroke register of Malmö, which has been used for studies of stroke incidence and has a high detection rate of both hospitalized and nonhospitalized nonfatal and fatal stroke. 18,20 All diagnoses have been validated by review of hospital records. Using this local stroke register as the main source of case finding is also a major strength. To identify cases of stroke occurring before 1989, or in hospitals outside of Malmö, the national hospital discharge register, SNHDR, was used (25% of all stroke in the present study). Review of medical records also of these cases would have been preferable. However, studies have shown that the detection rate is high and validity is reasonable for stroke in the SNHDR. 21 The proportion of stroke types was similar in cases from the local stroke register and from the SNHDR, although the proportion of unspecified stroke was somewhat higher in the SNHDR, as expected. A sensitivity analysis that included only validated stroke events showed largely unchanged results for the association between s-potassium and stroke. Stroke cases could potentially have been missed in the case of fatal cases

6 2978 Stroke November 2017 occurring out of hospital. However, review of autopsy records from patients dying suddenly outside of hospital has shown that fatal stroke cases occurring outside of hospital accounted for <1% of all cases of stroke in the stroke register of Malmö. 20 We have adjusted for many potential confounders and found results to be largely independent of these. However, residual confounding is always a potential limitation and cannot be entirely ruled out. Some factors associated with s-potassium, s-sodium, and intermediate causes, such as hypertension, were not available for adjustment, most notably s-aldosterone measurements. Further studies that include measures of renin angiotensin aldosterone system activation would be interesting. Dietary sodium and potassium intake, renin angiotensin aldosterone system activation, and s-sodium and s-potassium are inter-related, and there is a risk of bias in studying such factors. Individuals with poor health may choose to consume less sodium, introducing reverse causality. However, the duration of follow-up was long, and the population was mainly free of cardiovascular disease, which is a strength, in that such bias should be minimized. Only one measurement of s-potassium was available, and intraindividual variation is not accounted for. This is a limitation, but any bias introduced by this would have been toward null. Conclusions S-Potassium, including in the normal range, is positively and linearly associated with incident stroke and death among subjects screened in early mid-life and followed for >25 years. The risk of stroke is independent of the competing risk of death. Sources of Funding Drs Johnson and Söderholm are supported by governmental funding within the Swedish National Health Services. Dr Söderholm is supported by funds from the Swedish Stroke foundation. Dr Wollmer is supported by the Swedish Heart and Lung Foundation. 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