Blood Pressure and Brain Lesions in Patients With Atrial Fibrillation

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Article

Reference

Blood Pressure and Brain Lesions in Patients With Atrial Fibrillation

AESCHBACHER, Stefanie, et al. & Swiss-AF Investigators AUBERSON, Chloé (Collab.), et al.

Abstract

The association of blood pressure (BP) and hypertension with the presence of different types of brain lesions in patients with atrial fibrillation is unclear. BP values were obtained in a multicenter cohort of patients with atrial fibrillation. Systolic and diastolic BP was categorized in predefined groups. All patients underwent brain magnetic resonance imaging and neurocognitive testing. Brain lesions were classified as large noncortical or cortical infarcts, small noncortical infarcts, microbleeds, or white matter lesions. White matter lesions were graded according to the Fazekas scale. Overall, 1738 patients with atrial fibrillation were enrolled in this cross-sectional analysis (mean age, 73 years, 73% males). Mean BP was 135/79 mm Hg, and 67% of participants were taking BP-lowering treatment. White matter lesions Fazekas ≥2 were found in 54%, large noncortical or cortical infarcts in 22%, small noncortical infarcts in 21%, and microbleeds in 22% of patients, respectively. Compared with patients with systolic BP

AESCHBACHER, Stefanie, et al . & Swiss-AF Investigators, AUBERSON, Chloé (Collab.), et al . Blood Pressure and Brain Lesions in Patients With Atrial Fibrillation. Hypertension , 2020, vol.

77, no. 2, p. 662-671

PMID : 33356398

DOI : 10.1161/HYPERTENSIONAHA.120.16025

Available at:

http://archive-ouverte.unige.ch/unige:149190

Disclaimer: layout of this document may differ from the published version.

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1

Supplement

Blood Pressure and Brain Lesions in Patients with Atrial Fibrillation

Stefanie Aeschbacher, Steffen Blum, Pascal Meyre, Michael Coslovsky, Annina S. Vischer, Tim Sinnecker, Nicolas Rodondi, Jürg H. Beer, Giorgio Moschovitis, Elisavet Moutzouri, Christof Hunkeler, Thilo Burkard, Ceylan Eken, Laurent Roten, Christine S. Zuern, Christian Sticherling, Jens Wuerfel, Leo H. Bonati, David Conen, Stefan Osswald, Michael Kühne, for the Swiss-AF Investigators

Tables:

Table S1: Definition of hypertension

Table S2: Description of the neurocognitive tests

Table S3: Baseline characteristics stratified by hypertension categories Table S4: Prevalence of falls stratified by categories of systolic blood pressure Table S5: Prevalence and volume of brain lesions stratified by hypertension

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3 Table S1: Definition of hypertension

Description

Conventional hypertension (according to the ESC guidelines) Systolic or diastolic BP ≥ 140 and/or 90mmHg or antihypertensive treatment Conventional hypertension (according to the AHA guidelines) Systolic or diastolic BP ≥ 130 and/or 80mmHg or antihypertensive treatment Isolated systolic hypertension Systolic BP ≥ 140mmHg and diastolic BP < 90mmHg

Classification of hypertension including information on antihypertensive treatment (using Guidelines of the ESC)

Normotension Systolic and diastolic BP <140 and 90mmHg without antihypertensive

treatment

Controlled hypertension Systolic and diastolic BP <140 and 90mmHg with antihypertensive treatment Uncontrolled hypertension Systolic or diastolic BP ≥ 140 and/or 90mmHg independent of antihypertensive

treatment

Classification of hypertension including information on antihypertensive treatment (using Guidelines of the AHA)

Normotension Systolic and diastolic BP <130 and 80mmHg without antihypertensive

treatment

Controlled hypertension Systolic and diastolic BP <130 and 80mmHg with antihypertensive treatment Uncontrolled hypertension Systolic or diastolic BP ≥ 130 and/or 80mmHg independent of antihypertensive

treatment

Classification of hypertension according hypertension grade

Optimal blood pressure Systolic and diastolic BP <120 and 80mmHg

Normal blood pressure Systolic BP ≥ 120 and <130mmHg or diastolic BP ≥ 80 and <85mmHg

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4 High normal blood pressure Systolic BP ≥ 130 and <140mmHg or diastolic BP ≥ 85 and <90mmHg

Hypertension grade 1 Systolic BP ≥ 140 and <160mmHg or diastolic BP ≥ 90 and <100mmHg

Hypertension grade 2 Systolic BP ≥ 160 and <180mmHg or diastolic BP ≥ 100 and <110mmHg

Hypertension grade 3 Systolic BP ≥ 180mmHg or diastolic BP ≥ 110mmHg

AHA = American Heart Association; BP= blood pressure; ESC = European Society of Cardiology.

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5 Table S2: Description of the neurocognitive tests

Test Description Scale

The Trail Making Test (TMT) The Trail Making Test (TMT) is a validated neuropsychological test of executive functioning usually applied as two parts. In Part A (TMT A), the patient draws lines to connect circled numbers in ascending order (i.e., 1-2-3, etc.) as quickly and accurately as possible, allowing to measure visual attention and psychomotor speed. Similarly, part B (TMT B) requires connecting circled numbers and letters in an alternating numeric and alphabetic order (i.e., 1-A-2-B, etc.), assessing task switching abilities.^1,

2 We measured the time to correctly complete each part in seconds, correspondingly.

If the patient was not able to finish the test in 180 seconds (TMT A) or 300 seconds (TMT B), respectively, the test was stopped and the number of correct connections was noted. In order to use data of all patients, we used the number of correct connections per second.

0-XX correct connections per second

Semantic Fluency Test (SFT) The Semantic Animal Fluency test allows to examining executive abilities and brain functions.³ Patients have to enumerate as many animal names as possible within 60 seconds. During this task, they need to search for information from semantic memory and to produce the response. Test performance (i.e., total number of word productions) usually depends on the size and location of brain lesions.⁴ While semantic memory and word storage recruit the temporal lobe, modulation of attention and word search depend on processing by the frontal lobe⁵ or the prefrontal-lateral cerebellar system.⁴

0-XX correct animals in one minute

Digit Symbol Substitution Test (DSST)

The DSST is a test of psychomotor speed performance where patients receive a key grid of numbers and matching symbols and a test section with numbers and empty boxes. They have to fill as many empty boxes as possible with the symbol that matches the given number. The score is the number of correct number-symbol matches achieved within 120 seconds, taken to reflect the overall efficiency of cognitive operations.⁶

0-XX correct symbols in two minutes

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6 Table S3: Baseline characteristics stratified by hypertension categories

Normotension Controlled hypertension Uncontrolled hypertension p-value

n = 387 (22.3%) n = 642 (36.9%) 709 (40.8%)

Age, years 69.8 ± 9.3 73.2 ± 7.8 73.5 ± 8.1 <0.001

Sex, male 286 (73.9) 492 (76.6) 484 (68.3) 0.002

Body mass index, kg/m² 26.1 ± 3.8 28.6 ± 5.1 27.6 ± 4.6 <0.001

Smoking status* 0.04

Current 30 (8.0) 55 (8.6) 46 (6.5)

Past 171 (44.2) 333 (51.9) 336 (47.4)

Never 185 (47.8) 254 (39.6) 326 (45.9)

Systolic BP, mmHg 121.4 ± 11.2 124.4 ± 10.3 152.3 ± 13.3 <0.001

Diastolic BP, mmHg 73.1 ±8.8 73.4 ± 8.7 86.1 ± 11.7 <0.001

Antihypertensive treatment 0 (0) 642 (100) 516 (72.8) -

Number of antihypertensive drugs -

1 0 (0) 113 (17.6) 89 (12.6)

2 0 (0) 190 (29.6) 183 (25.8)

≥3 0 (0) 336 (52.3) 244 (34.4)

History of stroke 35 (9.0) 105 (16.4) 90 (12.6) 0.003

History of diabetes 19 (4.9) 137 (21.4) 115 (16.2) <0.001

History of heart failure* 57 (14.7) 191 (29.8) 130 (18.3) <0.001

History of coronary disease 66 (17.1) 232 (36.1) 165 (23.3) <0.001

CHA2DS2-VASc Score* 2.1 ±1.5 3.9 ± 1.5 3.5 ± 1.7 <0.001

AF type <0.001

Paroxysmal 195 (50.4) 265 (41.3) 335 (47.2)

Persistent 130 (33.6) 199 (31.0) 214 (30.2)

Permanent 62 (16.0) 178 (27.7) 160 (22.6)

Oral anticoagulation 329 (85.0) 592 (92.2) 645 (91.0) <0.001

Antiplatelet drugs** 15 (3.9) 50 (7.8) 31 (4.4) 0.006

Recurrent falls 16 (4.1) 45 (7.0) 56 (7.9) 0.05

Data are numbers (percentages), mean ± standard deviation or median (interquartile range). Groups were compared using Chi-square tests or Kruskal- Wallis Tests, as appropriate. BP = blood pressure. Normotension: systolic and diastolic blood pressure <140/90mmHg without antihypertensive treatment;

controlled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg without antihypertensive treatment. *n=2 missing values; **n=3 missing values

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7 Table S4: Prevalence of falls stratified by categories of systolic blood pressure

Systolic blood pressure categories Number Recurrent Falls

Overall 1738 117 (6.7)

<110mmHg 115 (6.6%) 11 (9.6)

110-120mmHg 240 (13.8%) 14 (5.8)

120-140mmHg 740 (42.6%) 40 (5.4)

140-160mmHg 469 (27.0%) 34 (7.2)

≥160mmHg 174 (10.0) 18 (10.3)

p-value 0.10

Data are presented as numbers (percentage).

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8 Table S5: Prevalence and volume of brain lesions stratified by hypertension categories

n (%) Prevalence

Fazekas ≥2 Volume WML mm³

Prevalence LNCCI

Volume LNCCI, mm³

Prevalence SNCI

Volume SNCI, mm³

Prevalence MB

Number MB Overall 933 (53.7) 3918 (1455; 9795) 390 (22.4) 1640 (258; 6865) 372 (21.4) 63 (30; 166) 373 (22.2) 1 (1; 2)

Conventional hypertension definitions Conventional

hypertension, ESC definition

1348 (77.6) 768 (57.0) 4563 (1674; 10846) 325 (24.1) 1884 (261; 7509) 309 (22.9) 66 (30; 165) 317 (24.3) 1 (1; 2) Conventional

hypertension, AHA definition

1502 (86.4) 834 (55.5) 4208 (1577; 10618) 345 (23.0) 1752 (258; 7452) 336 (22.4) 66 (30; 168) 339 (23.3) 1 (1; 2) Isolated systolic

hypertension

420 (24.2) 261 (62.1) 5316 (1886; 13776) 90 (21.4) 1118 (194; 7372) 121 (28.8) 63 (30; 141) 109 (26.7) 1 (1; 2) Hypertension categories using definition of the AHA

Normotension 236 (13.6) 99 (42.1) 2517 (969; 5979) 45 (19.1) 903 (273; 4317) 36 (15.3) 56 (36; 125) 34 (14.9) 1 (1; 2) Controlled HTN 329 (18.9) 173 (52.6) 3564 (1620; 8486) 88 (26.7) 3513 (395; 9146) 73 (22.2) 66 (33; 231) 81 (25.9) 1 (1; 2) Uncontrolled

HTN

1173 (67.5) 661 (56.4) 4437 (1554; 11238) 257 (21.9) 1548 (225; 6834) 263 (22.4) 66 (30; 164) 258 (22.6) 1 (1; 2) Hypertension categories using definition of the ESC

Normotension 387 (22.3) 165 (42.6) 2517 (921; 6783) 65 (16.5) 1113 (234; 3969) 63 (16.3) 57 (36; 165) 56 (14.2) 1 (1; 2) Controlled HTN 642 (36.9) 353 (54.9) 3996 (1707; 9503) 164 (25.7) 2204 (347; 8413) 133 (20.7) 84 (30; 216) 147 (23.1) 1 (1; 2) Uncontrolled

HTN

709 (40.8) 415 (58.5) 4830 (1641; 12321) 161 (22.7) 1230 (225; 7071) 176 (24.8) 60 (27; 153) 170 (24.0) 1 (1; 2) Hypertension grades

Optimal BP 314 (18.1) 147 (46.8) 3000 (1166; 7091) 74 (23.6) 1668 (324; 6181) 60 (19.1) 59 (31; 173) 66 (21.0) 1 (1; 2) Normal BP 340 (19.6) 161 (47.4) 3219 (1357; 7342) 77 (22.6) 1824 (270; 8487) 63 (15.5) 69 (38; 209) 60 (17.6) 1 (1; 2) High normal BP 375 (21.6) 210 (56.0) 4134 (1591; 10047) 78 (20.8) 1673 (269; 7185) 73 (19.5) 84 (30; 198) 77 (20.5) 1 (1; 2) HTN grade 1 496 (28.5) 270 (54.4) 4576 (1401;11332) 106 (21.4) 966 (194; 7305) 116 (23.4) 66 (30; 175) 110 (22.2) 1 (1; 2) HTN grade 2 182 (10.5) 122 (67.0) 5373 (2668;14230) 46 (25.3) 2822 (568; 6457) 50 (27.5) 39 (21; 114) 54 (29.7) 1 (1; 2) HTN grade 3 31 (1.8) 23 (74.2) 5328 (2036;15310) 9 (29.0) 2361 (585; 8637) 10 (32.3) 47 (26; 75) 6 (19.4) 1.5 (1; 3) Data are numbers (percentage) or median (interquartile range). Hypertension categories according to the Guidelines of the ESC: Normotension: systolic and diastolic blood pressure

<140/90mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg without antihypertensive treatment. Hypertension categories according to the Guidelines of the AHA:

Normotension: systolic and diastolic blood pressure <130/80mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg

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9 with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg without antihypertensive treatment. BP = blood pressure; HTN = hypertension, LNCCI = large non-cortical or cortical infarcts; MB = microbleeds; SNCI = small non-cortical infarcts; WML = white matter lesions

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1 Table S6: Association between hypertension and white matter lesions

Fazekas ≥ 2 Volume WML

OR (95% CI) Model 1

OR (95% CI) Model 2

β-coefficient (95% CI) Model 1

β-coefficient (95% CI) Model 2 Conventional hypertension definitions

Conventional Hypertension, ESC definition

1.38 (1.07; 1.78), p=0.01

1.33 (1.02; 1.73), p=0.03

0.31 (0.17; 0.45), p<0.001

0.29 (0.15; 0.43), p<0.001 Conventional hypertension,

AHA definition

1.34 (0.99; 1.83), p=0.06

1.35 (0.99; 1.85), p=0.06

0.29 (0.13; 0.46), p<0.001

0.29 (0.12; 0.46), p<0.001 Isolated systolic hypertension 1.16 (0.91; 1.48),

p=0.24

1.21 (0.94; 1.55), p=0.15

0.14 (0.01; 0.28), p=0.04

0.16 (0.03; 0.30), p=0.02 Hypertension categories according to the guidelines of the AHA

Normotension Reference Reference Reference Reference

Controlled hypertension 1.15 (0.79; 1.67) 1.04 (0.71; 1.53) 0.22 (0.02; 0.42) 0.17 (-0.04; 0.38) Uncontrolled hypertension 1.40 (1.03; 1.92) 1.44 (1.05; 1.99) 0.32 (0.15; 0.49) 0.32 (0.14; 0.49)

p for linear trend: 0.03 0.02 <0.001 <0.001

Hypertension categories according to the guidelines of the ESC

Controlled hypertension 1.29 (0.98; 1.71) 1.18 (0.87; 1.58) 0.22 (0.02; 0.42) 0.17 (-0.04; 0.38) Uncontrolled hypertension 1.47 (1.11; 1.93) 1.47 (1.11; 1.95) 0.32 (0.15; 0.49) 0.32 (0.14; 0.49)

p for linear trend: 0.006 0.01 <0.001 <0.001

Hypertension grades

Optimal BP Reference Reference Reference Reference

Normal BP 1.03 (0.73; 1.45) 1.08 (0.77; 1.53) 0.11 (-0.08; 0.29) 0.12 (-0.06; 0.31)

High-Normal BP 1.35 (0.97; 1.88) 1.48 (1.05; 2.07) 0.21 (0.03; 0.39) 0.24 (0.06; 0.42)

Hypertension grade 1 1.18 (0.86; 1.61) 1.30 (0.95; 1.79) 0.21 (0.04; 0.38) 0.24 (0.07; 0.42)

p for trend 0.003 <0.001 0.004 0.002

Data are odds ratios (95% confidence interval) or β-coefficients (95% confidence interval). Hypertension categories according to the Guidelines of the ESC:

Normotension: systolic and diastolic blood pressure <140/90mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood

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2 pressure ≥140 or ≥90mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg without

antihypertensive treatment. Hypertension categories according to the Guidelines of the AHA: Normotension: systolic and diastolic blood pressure

<130/80mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg without antihypertensive treatment. Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for educational status, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, and antithrombotic treatment. BP = blood pressure; HTN = hypertension; OR = odds ratio; WML = white matter lesions.

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Table S7: Association between blood pressure and large non-cortical or cortical infarcts (LNCCI)

Presence of LNCCI Volume LNCCI

OR (95% CI) Model 1

OR (95% CI) Model 2*

β-coefficient (95% CI) Model 2 Systolic Blood Pressure

<120 mmHg Reference Reference Reference Reference

120-140 mmHg 0.96 (0.71; 1.32) 0.95 (0.67; 1.34) -0.13 (-0.67; 0.42) -0.20 (-0.70; 0.31)

140-160 mmHg 0.90 (0.64; 1.27) 0.96 (0.66; 1.40) -0.27 (-0.86; 0.33) -0.20 (-0.75, 0.35)

≥160 mmHg 1.12 (0.73; 1.72) 1.21 (0.74; 1.96) 0.17 (-0.58; 0.91) 0.17 (-0.53; 0.87)

P for linear trend 0.40 0.55 0.76 0.28

Continuous, per 5 mmHg 1.00 (0.97; 1.03), p=0.89

1.01 (0.98; 1.05), p=0.44

0.005 (-0.05; 0.06), p=0.84

0.02 (-0.03; 0.06), p=0.54 Diastolic Blood Pressure

70-80 mmHg 0.92 (0.67; 1.25) 0.92 (0.65; 1.30) 0.29(-0.24; 0.83) 0.33 (-0.17; 0.83)

80-90 mmHg 0.82 (0.60; 1.14) 0.91 (0.64; 1.31) -0.38 (-0.94; 0.19) -0.32 (-0.85; 0.22)

≥90 mmHg 1.15 (0.80; 1.64) 1.20 (0.80; 1.80) -0.009 (-0.63; 0.61) 0.23 (-0.35; 0.81)

P for linear trend 0.60 0.39 0.48 0.95

1.03 (0.97; 1.08), p=0.36

-0.02 (-0.10; 0.06), p=0.60

0.005 (-0.07; 0.08), p=0.91 Data are odds ratio (95% confidence interval) or β-coefficients (95% confidence interval). Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for educational status, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, antithrombotic treatment and antihypertensive treatment. CI = confidence interval; LNCCI = large non-cortical or cortical infarcts; OR= odds ratio.

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4 Table S8: Association between hypertension and large non-cortical or cortical infarcts

Presence of LNCCI Volume LNCCI

OR (95% CI) Model 1

OR (95% CI) Model 2

Conventional hypertension, ESC definition

1.40 (1.04; 1.90), p=0.03

1.21 (0.87; 1.69), p=0.26

0.44 (-0.09; 0.98), p=0.10

0.24 (-0.25; 0.73), p=0.34 Conventional hypertension,

AHA definition

1.11 (0.78; 1.59), p=0.57

1.01 (0.69; 1.50), p=0.97

0.33 (-0.30; 0.96), p=0.31

0.13 (-0.44; 0.70), p=0.66 Isolated systolic hypertension 0.81 (0.61; 1.06),

p=0.13

0.87 (0.64; 1.17), p=0.31

-0.17 (-0.64; 0.31), p=0.50

-0.18 (-0.61; 0.25), p=0.42 Hypertension categories according to the guidelines of the AHA

Controlled hypertension 1.34 (0.89; 2.04) 1.07 (0.68; 1.70) 0.64 (-0.09; 1.37) 0.29 (-0.38; 0.97) Uncontrolled hypertension 1.04 (0.73; 1.51) 0.99 (0.67; 1.48) 0.22 (-0.42; 0.86) 0.08 (-0.50; 0.66)

p for linear trend 0.81 0.96 0.50 0.78

Hypertension grades

Normal BP 0.95 (0.66; 1.38) 0.95 (0.63; 1.44) 0.14 (-0.50; 0.79) 0.11 (-0.47; 0.70)

High-Normal BP 0.80 (0.56; 1.16) 0.82 (0.55; 1.23) 0.04 (-0.60; 0.69) -0.02 (-0.61; 0.57)

HTN grade 1 0.82 (0.59; 1.16) 0.87 (0.60; 1.28) -0.24 (-0.84; 0.36) -0.14 (-0.68; 0.41)

HTN grade 2 1.03 (0.66; 1.58) 1.12 (0.69; 1.81) 0.25 (-0.50; 0.99) 0.31 (-0.38; 1.00)

HTN grade 3 1.23 (0.51; 2.73) 1.59 (0.62; 3.76) 0.53 (-0.88; 1.93) 0.72 (-0.55; 1.99)

p for trend 0.57 0.23 0.48 0.23

Data are odds ratio (95% confidence interval) or β-coefficients (95% confidence interval). Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for educational status, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, and antithrombotic treatment. Hypertension categories according to the Guidelines of the ESC: Normotension: systolic and diastolic blood pressure

<140/90mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg without antihypertensive treatment. Hypertension categories

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5 according to the Guidelines of the AHA: Normotension: systolic and diastolic blood pressure <130/80mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg without antihypertensive treatment. BP = blood pressure; HTN = hypertension; LNCCI = large non-cortical or cortical infarcts.

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6

Table S9: Association between blood pressure and small non-cortical infarcts (SNCI)

Presence of SNCI Volume SNCI

OR (95% CI) Model 1

OR (95% CI) Model 2

β-coefficient (95% CI) Model 2 Systolic Blood Pressure

120-140 mmHg 1.03 (0.74; 1.45) 1.07 (0.76; 1.51) 0.11 (-0.24; 0.45) 0.08 (-0.27; 0.44)

140-160 mmHg 1.24 (0.87; 1.77) 1.31 (0.91; 1.90) 0.04 (-0.32; 0.40) 0.03 (-0.34; 0.40)

≥160 mmHg 1.71 (1.10; 2.64) 1.89 (1.20; 2.97) -0.33 (-0.75; 0.10) -0.26 (-0.70; 0.18)

1.05 (1.01; 1.08), p=0.006

-0.03 (-0.06; 0.00), p=0.03

-0.03 (-0.06; 0.00), p=0.07 Diastolic Blood Pressure

70-80 mmHg 0.96 (0.70; 1.32) 1.00 (0.72; 1.38) 0.006 (-0.32; 0.33) 0.03 (-0.29; 0.35)

80-90 mmHg 1.04 (0.75; 1.44) 1.17 (0.84; 1.65) -0.08 (-0.41; 0.25) -0.009 (-0.35; 0.33)

≥90 mmHg 0.96 (0.65; 1.41) 1.10 (0.73; 1.63) -0.32 (-0.72; 0.07) -0.23 (-0.64; 0.18)

1.02 (0.97; 1.07), p=0.46

-0.06 (-0.11; -0.01), p=0.01

-0.05 (-0.10; 0.00), p=0.06

Data are odds ratio (95% confidence interval) or β-coefficients (95% confidence interval).Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for educational status, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, antithrombotic treatment, and antihypertensive treatment. CI = confidence interval; SNCI = small non-cortical infarcts; OR= odds ratio.

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7 Table S10: Association between hypertension and small non-cortical infarcts

Presence of SNCI Volume SNCI

OR (95% CI) Model 1

OR (95% CI) Model 2

Conventional hypertension, ESC definition

1.25 (0.93; 1.72), p=0.15

1.19 (0.87; 1.64), p=0.30

0.02 (-0.30; 0.34), p=0.90

-0.02 (-0.35; 0.31), p=0.89 Conventional hypertension,

AHA definition

1.31 (0.90; 1.95), p=0.18

1.27 (0.86; 1.91), p=0.24

0.09 (-0.32; 0.50), p=0.66

0.10 (0.31; 0.51), p= 0.64 Isolated systolic hypertension 1.43 (1.10; 1.86),

p=0.007

1.45 (1.10; 1.89), p=0.007

-0.06 (-0.31; 0.20), p=0.67

-0.06 (-0.32; 0.20), p= 0.67 Hypertension categories according to the guidelines of the AHA

p for linear trend: 0.17 0.20 0.81 0.76

Controlled hypertension 1.10 (0.79; 1.56) 0.99 (0.69; 1.42) 0.16 (-0.19; 0.52) 0.10 (-0.26; 0.47) Uncontrolled hypertension 1.40 (1.01; 1.96) 1.36 (0.97; 1.92) -0.09 (-0.43; 0.26) -0.10 (-0.44; 0.24)

p for linear trend: 0.05 0.07 0.62 0.57

Hypertension grades

Normal BP 0.98 (0.65; 1.47) 1.01 (0.67; 1.54) 0.15 (-0.26; 0.57) 0.15 (-0.28; 0.57)

High-Normal BP 0.95 (0.64; 1.40) 0.99 (0.66; 1.48) 0.05 (-0.35; 0.45) 0.03 (-0.38; 0.44)

HTN grade 1 1.18 (0.82; 1.70) 1.25 (0.87; 1.83) 0.01 (-0.36; 0.38) -0.005 (-0.38; 0.37)

HTN grade 2 1.46 (0.93; 2.29) 1.62 (1.02; 2.56) -0.41 (-0.85; 0.03) -0.32 (-0.77; 0.13)

HTN grade 3 1.82 (0.77; 4.09) 2.15 (0.90; 4.87) -0.34 (-1.13; 0.45) -0.32 (-1.12; 0.49)

p for trend 0.05 0.02 0.11 0.17

Data are odds ratio (95% confidence interval) or β-coefficients (95% confidence interval). Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for educational status, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, and antithrombotic treatment. Hypertension categories according to the Guidelines of the ESC: Normotension: systolic and diastolic blood pressure <140/90mmHg

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8 without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg with antihypertensive treatment;

uncontrolled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg without antihypertensive treatment. Hypertension categories according to the Guidelines of the AHA: Normotension: systolic and diastolic blood pressure <130/80mmHg without antihypertensive treatment; controlled hypertension:

systolic and diastolic blood pressure ≥130 or ≥80mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg without antihypertensive treatment. BP = blood pressure; HTN = hypertension; OR = odds ratio; SNCI = small non-cortical infarcts.

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9 Table S11: Association between hypertension and microbleeds

Presence of Microbleeds OR (95% CI)

Model 1

OR (95% CI) Model 2 Conventional hypertension definitions

Conventional hypertension, ESC definition 1.60 (1.18; 2.22), p=0.004 1.50 (1.09; 2.10), p=0.01 Conventional hypertension, AHA definition 1.49 (1.02; 2.24), p=0.05 1.44 (0.98; 2.17), p=0.07

Isolated systolic hypertension 1.22 (0.94; 1.59), p=0.14 1.24 (0.95; 1.63), p=0.12

Hypertension categories according to the guidelines of the AHA

Normotension Reference Reference

Controlled hypertension 1.69 (1.09; 2.68) 1.53 (0.97; 2.46)

Uncontrolled hypertension 1.44 (0.98; 2.17) 1.41 (0.96; 2.15)

p for trend: 0.07 0.09

Normotension Reference Reference

Controlled hypertension 1.57 (1.11; 2.22) 1.42 (0.99; 2.04)

Uncontrolled hypertension 1.64 (1.17; 2.31) 1.58 (1.12; 2.24)

p for linear trend: 0.004 0.01

Hypertension grades

Optimal BP Reference Reference

Normal BP 0.78 (0.52; 1.16) 0.79 (0.53; 1.19)

High-Normal BP 0.89 (0.61; 1.30) 0.93 (0.64; 1.37)

HTN grade 1 0.97 (0.68; 1.38) 1.01 (0.70; 1.45)

HTN grade 2 1.45 (0.94; 2.23) 1.58 (1.01; 2.46)

HTN grade 3 0.76 (0.27; 1.84) 0.88 (0.31; 2.16)

p for trend 0.82 0.55

Data are odds ratio (95% confidence interval). Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for educational status, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, and antithrombotic treatment. Hypertension categories according to the Guidelines of the ESC: Normotension: systolic and diastolic blood pressure <140/90mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg without antihypertensive treatment. Hypertension categories according to the Guidelines of the AHA: Normotension: systolic and diastolic blood pressure <130/80mmHg without

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10 antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥130 or ≥80mmHg without antihypertensive treatment. BP = blood pressure, HTN = hypertension, OR

= odds ratio.

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11 Table S12: Association between blood pressure and microbleeds

Presence of Microbleeds OR (95% CI)

Model 1

OR (95% CI) Model 2 Systolic Blood Pressure

<120 mmHg Reference Reference

120-140 mmHg 0.98 (0.71; 1.37) 0.96 (0.69; 1.35)

140-160 mmHg 0.98 (0.69; 1.40) 0.95 (0.66; 1.36)

≥160 mmHg 1.57 (1.03; 2.41) 1.53 (0.98; 2.39)

P for linear trend 0.04 0.02

Continuous, per 5 mmHg 1.03 (0.99; 1.06),

p=0.10

1.03 (0.99; 1.06), p=0.12 Diastolic Blood Pressure

<70 mmHg Reference Reference

70-80 mmHg 1.17 (0.85; 1.62) 1.21 (0.87; 1.69)

80-90 mmHg 1.02 (0.73; 1.42) 1.11 (0.79; 1.57)

≥90 mmHg 1.13 (0.77; 1.66) 1.20 (0.81; 1.78)

P for linear trend 0.70 0.47

Continuous, per 5 mmHg 1.00(0.95; 1.05),

p=0.94

1.01 (0.96; 1.06), p=0.72

Data are odds ratio (95% confidence interval). Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for educational status, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, antithrombotic treatment and antihypertensive treatment. CI = confidence interval; MB = microbleeds; OR= odds ratio.

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12 Table S13: Neurocognitive function stratified by systolic and diastolic blood pressure

n (%) MoCA-score DSST Animal Fluency TMT - A TMT - B

Overall 1727 25.5 ± 3.0 45 ± 14 19.1 ± 5.4 0.54 ± 0.21 0.20 (0.14; 0.28)

Systolic BP

<120 mmHg 351 25.8 ± 2.9 46 ± 14 19.6 ± 5.5 0.56 ± 0.22 0.22 (0.15; 0.29)

120-140 mmHg 738 25.6 ± 3.1 45 ± 14 19.2 ± 5.3 0.55 ± 0.21 0.21 (0.15; 0.28)

140-160 mmHg 466 25.3 ± 3.0 44 ± 15 18.7 ± 5.3 0.54 ± 0.22 0.20 (0.14; 0.27)

≥160 mmHg 172 25.2 ± 3.3 41 ± 14 18.3 ± 5.4 0.49 ± 0.20 0.16 (0.11; 0.23)

p-value 0.10 0.008 0.04 0.005 <0.001

Diastolic BP

<70 mmHg 387 25.0 ± 3.2 42 ± 14 18.7 ± 5.5 0.50 ± 0.20 0.18 (0.12; 0.25)

70-80 mmHg 550 25.6 ± 3.2 44 ± 14 18.9 ± 5.3 0.54 ± 0.22 0.21 (0.14; 0.29)

80-90 mmHg 502 25.6 ± 2.9 46 ± 14 19.3 ± 5.3 0.58 ± 0.22 0.21 (0.15; 0.28)

≥90 mmHg 288 25.8 ± 2.7 46 ± 14 19.4 ± 5.6 0.55 ± 0.21 0.21 (0.15; 0.28)

p-value 0.006 <0.001 0.29 <0.001 <0.001

Data are presented as means ± standard deviations or median (interquartile range).

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13 Table S14: Association between blood pressure and neurocognitive function

MoCA-score DSST Semantic fluency TMT A TMT B

β (95% CI) multivariable adjusted

β (95% CI) multivariable adjusted Systolic blood pressure

<120 mmHg Reference Reference Reference Reference Reference

120-140 mmHg -0.10 (-0.46; 0.26) -0.84 (-2.36; 0.67) -0.33 (-0.98; 0.31) -0.003 (-0.03; 0.02) -0.003 (-0.009; 0.02) 140-160 mmHg -0.17 (-0.57; 0.23) 0.27 (-1.39; 1.94) -0.46 (-1.18; 0.25) 0.006 (-0.02; 0.03) -0.0008 (-0.01; 0.01)

≥160 mmHg -0.14 (-0.67; 0.39) -1.77 (-3.99; 0.46) -0.48 (-1.43; 0.47) -0.03 (-0.07; 0.00) -0.02 (-0.04; 0.01)

P for linear trend 0.54 0.23 0.29 0.13 0.004

Continuous, per 5 mmHg -0.01 (-0.05; 0.02), p=0.47

-0.02 (-0.18; 0.13), p=0.76

-0.04 (-0.10; 0.03), p=0.31

-0.0008 (-0.003; 0.002), p=0.53

-0.001 (-0.003; 0.000), p=0.02

Diastolic blood pressure

<70 mmHg Reference Reference Reference Reference Reference

70-80 mmHg 0.31 (-0.07; 0.68) -0.14 (-1.71; 1.42) -0.31 (-0.98; 0.35) 0.004 (-0.02; 0.03) 0.007 (-0.005; 0.02) 80-90 mmHg 0.17 (-0.21; 0.55) 0.35 (-1.27; 1.97) -0.26 (-0.95; 0.42) 0.03 (0.01; 0.06) 0.005 (-0.007; 0.02)

≥90 mmHg 0.31 (-0.14; 0.75) 0.65 (-1.22; 2.52) -0.13 (-0.93; 0.66) 0.005 (-0.02;0.03) -0.004 (-0.02; 0.01)

P for linear trend 0.26 0.41 0.78 0.36 0.54

Continuous, per 5 mmHg 0.01 (-0.05; 0.07), p=0.66

0.03 (-0.22; 0.28), p=0.81

-0.05 (-0.15; 0.05), p=0.35

0.0005 (-0.003; 0.004), p=0.80

-0.001 (-0.003; 0.0006), p=0.19

Data are presented as β (95% confidence interval). The multivariable adjusted model was additionally adjusted for age, sex and education, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, antithrombotic treatment and antihypertensive treatment.

DSST = Digit Symbol Substitution Test; MoCA = Montreal Cognitive Assessment; TMT = Trail Making Test.

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14 Table S15: Subgroup analyses for the association of blood pressure and neurocognitive function stratified for the presence of the respective brain lesion

Blood Pressure Hypertension

Normotension Controlled hypertension Uncontrolled hypertension β-coefficient (95% CI) β-coefficient (95% CI) β-coefficient (95% CI) β-coefficient (95% CI)

Faz ≥2 0.00 (-0.05; 0.05) Reference -0.93 (-1.50; -0.35) -0.55 (-1.10; 0.00)

Faz <2 -0.03 (-0.09; 0.03) Reference 0.22 (-0.27; 0.72) -0.10 (-0.57; 0.37)

P for interaction 0.73 0.007

LNCCI yes -0.01 (-0.09; 0.07) Reference -0.64 (-1.54; 0.26) -0.63 (-1.51; 0.25)

LNCCI no -0.02 (-0.06; 0.03) Reference -0.31 (-0.73; 0.11) -0.26 (-0.66; 0.13)

SNCI yes 0.04 (-0.04; 0.13) Reference -0.54 (-1.54; 0.46) -0.04 (-0.97; 0.89)

SNCI no -0.03 (-0.07; 0.01) Reference -0.34 (-0.74; 0.07) -0.38 (-0.77; 0.01)

MB yes 0.02 (-0.06; 0.09) Reference -0.10 (-1.01; 0.81) 0.07 (-0.81; 0.95)

MB no -0.02 (-0.06; 0.02) Reference -0.45 (-0.88; -0.03) -0.38 (-0.79; 0.02)

Data are presented as β (95% confidence interval). The multivariable adjusted model was adjusted for age, sex, education, body mass index, smoking status, previous stroke, diabetes, heart failure, coronary heart disease, oral anticoagulation, and antithrombotic treatment. Hypertension categories according to the Guidelines of the ESC: Normotension: systolic and diastolic blood pressure <140/90mmHg without antihypertensive treatment; controlled hypertension: systolic and diastolic blood pressure ≥140 or ≥90mmHg with antihypertensive treatment; uncontrolled hypertension: systolic and diastolic blood pressure ≥140 or

≥90mmHg without antihypertensive treatment. Faz = Fazekas; LNCCI = Large non-cortical or cortical infarcts; MB = Microbleeds; SNCI = Small non-cortical infarcts.