(1)Supplemental Digital Content 1

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Supplemental Digital Content 1. Medications used by the study subjects: number of subjects with each type of medication.

Normotensive n = 232

Hypertensive n = 155

Acetylsalicylic acid 0 5

Acyclovir 2 0

Alendronate 1 0

Allopurinol 1 1

Antidepressant (SSRI or SNRI) 6 13

Antihistamine 2 8

Benzodiazepine 2 1

Carbimazole 1 0

Contraceptive pills or other female hormone supplement

Oestrogen + progestin 26 11

Oestrogen 3 8

Progestin 2 1

Dehydroepiandrosterone 1 0

Doxycycline (low dose) 0 1

Flupentixol 0 1

Timolol (topical in eye drops) 0 1

Glucosamine 4 0

Hydroxyzine 0 1

Inhaled corticosteroids 9 6

Iron supplement 1 1

Levetiracetam 0 1

Lymecycline 1 0

Levonorgestrel via intrauterine device 18 9

Methenamine hippurate 1 0

Non-steroidal anti-inflammatory drugs 0 4

Oxcarbazepine 0 1

Potassium-phosphate 1 0

Pregabalin 0 1

Proton pump inhibitor 3 7

Salmeterol or formoterol 2 3

Sibutramine 0 1

Sodium-phosphate 1 0

Statin 3 10

Tacrolimus ointment 1 0

Tamoxifen 1 0

Tamsulosin 2 0

Thyroxin 10 3

Tibolone 1 0

Varenicline 1 0

Vitamin B12 supplementation 0 1

Vitamin D supplementation 4 8

Warfarin 2 0

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Supplemental Digital Content 2. Additional statistical information: data ranges in the study population.

Laboratory blood pressure (mmHg)

Normotensive (<135/85 mmHg) Hypertensive (≥135/85 mmHg)

Mean Min. Max. Mean Min. Max.

Number of subjects 232 155

Age 41 19 67 49 20 72

Body mass index (kg/m²) 25 18 35 28 19 40

Cornell voltage product (ms*mm)

1510 430 3840 1793 306 3024

Plasma

Potassium (mmol/l)* 3.8 3.1 4.6 3.7 3.0 4.4

Sodium (mmol/l) 139.9 134.0 145.0 140.6 132.0 147.0

HDL cholesterol (mmol/l) 1.65 0.72 3.09 1.52 0.81 2.81

LDL cholesterol (mmol/l) 2.6 0.8 7.8 3.1 1.1 5.5

Triglycerides (mmol/l) 1.02 0.32 4.34 1.35 0.43 15.89

Fasting glucose (mmol/l) 5.2 4.1 6.9 5.5 4.3 6.9

Creatinine (µmol/l) 73 46 116 74 42 113

eGFR (ml/min/1.73 m²)¹ 112 75 154 110 81 152

Values are means and maximums and minimums; HDL, high density lipoprotein; LDL, low density lipoprotein; eGFR¹, RULE formula for estimated glomerular filtration rate.

*Altogether 7 subjects had mild hypokalemia in initial measurements (plasma potassium was

3.2 mmol/l in 5 subjects, 3.1 mmol/l one, and 3.0 mmol/l in one subject; n=2 in normotensives and n=5 in hypertensives). In control measurements all potassium values were within the normal range, and secondary hypertension was excluded in all subjects. The initial values were used in the analyses.

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Supplemental Digital Content 3. Backward regression analyses for hemodynamics at rest.

Confidence interval Variable

B

Lower Upper

Beta P-value Heart rate (1/min) R² = 0.055, P<0.001

Presence of hypertension (yes/no) 3.652 1.805 5.499 0.196 <0.001

Sex (male) -3.078 -4.899 -1.258 -0.167 0.001

Cardiac index (l/min/m²) R² = 0.055, P<0.001

Presence of hypertension (yes/no) 0.141 0.021 0.241 0.134 0.011 Body mass index (kg/m²) -0.031 -0.044 -0.018 -0.242 <0.001 Stroke index (ml/m²) R² = 0.144, P<0.001

Sex (male) 3.444 2.126 4.762 0.245 <0.001

Body mass index (kg/m²) -0.565 -0.727 -0.403 -0.328 <0.001 Systemic vascular resistance index (dyn*s/cm⁵*m²) R² = 0.333, P<0.001

Age (years) 9.776 5.327 14.224 0.193 <0.001

Body mass index (kg/m²) 32.476 19.352 45.599 0.219 <0.001 Left cardiac work index (kg*min/m²) R² = 0.318, P<0.001

Sex (male) 0.214 0.052 0.375 0.112 0.010

Age (years) 0.006 0.000 0.013 0.077 0.089

Body mass index (kg/m²) -0.025 -0.046 -0.003 -0.105 0.023

Aortic augmentation pressure (mmHg) R² = 0.536, P<0.001

Sex (male) -4.622 -5.589 -3.655 -0.335 <0.001

Age (years) 0.339 0.297 0.381 0.584 <0.001

Augmentation index (%) R² = 0.529, P<0.001

Presence of hypertension (yes/no) 1.703 -0.174 3.580 0.067 0.075

Sex (male) -9.566 -11.33 -7.806 -0.381 <0.001

Age (years) 0.651 0.574 0.728 0.615 <0.001

Augmentation index, heart rate 75 (AIx@75) (%) R² = 0.568, P<0.001

Sex (male) -10.82 -12.49 -9.155 -0.434 <0.001

Age (years) 0.623 0.550 0.696 0.594 <0.001

Radial pulse pressure (mmHg) R² = 0.284, P<0.001

Sex (male) 2.182 0.435 3.929 0.108 0.015

Aortic pulse pressure (mmHg) R2 = 0.413, P<0.001

Sex (male) -1.866 -3.377 -0.354 -0.096 0.016

Age (years) 0.315 0.249 0.381 0.386 <0.001

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2 Pulse wave velocity (m/s) R² = 0.522, P<0.001

Sex (male) 0.316 0.106 0.525 0.107 0.003

Age (years) 0.068 0.059 0.077 0.552 <0.001

Body mass index (kg/m²) 0.039 0.012 0.067 0.109 0.005

CI, confidence interval; sex, age, body mass index and hypertension status were used to model the variable value in supine position.

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6

4

2

0

-2

-4

-6

-8 0 -1 -2 -3 -4 -5 -6

A B

D

Laboratory BP (mmHg) 135/85 135/85

RadialsystolicBP(mmHg) RadialdiastolicBP(mmHg)

AorticsystolicBP(mmHg)

6

4

2

0

-2 -4

-6 -8

-10

0 -2 -4 -6 -8 -10 -12

E

C

F

Radialpulsepressure(mmHg)Aorticpulsepressure(mmHg)

AorticdiastolicBP(mmHg)

Supplemental Figure S1. Change in radial systolic (A), diastolic blood pressure (B), and pulse pressure (C); aortic systolic (D), diastolic blood pressure (E), and pulse pressure (F) during head-up tilt; means and confidence intervals of the means. Change was calculated from average value during minutes 3, 4 and 5 in the supine position to average value during minutes 3, 4 and 5 during the head-up tilt. For statistical analyses, please see Table 2.

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15

10

5

0

0,0 -0,1 -0,2

-0,3 -0,4

-0,5

600 500 400 300 200 100 0

A B C

Heartrate(1/min) Cardiacindex(l/min/m)2 Systemicvascularresistance index(dyn*s/cm*m)52

0 -2 -4 -6 -8 -10 -12 -14

0,0 -0,1 -0,2 -0,3 -0,4 -0,5 -0,6

D E

StrokeIndex(ml/m)2 Leftcardiacworkindex(kg*min/m)2

0 -2 -4 -6 -8 -10 -12

0

-2

-4

-6

0

-2

-4

-6

F

G H

Augmentationindex(%)

Augmentationindex,heartrate75(%) Augmentationpressure(mmHg)

Supplemental Figure S2. Change in heart rate (A), cardiac index (B), systemic vascular resistance index (C), stroke index (D), left cardiac work index (E), augmentation index (F), augmentation index adjusted to heart rate 75 beats/min (G), and augmentation pressure (H) during head-up tilt; means and confidence intervals of the means. Change was calculated from average value during minutes 3, 4 and 5 in the supine position to average value during minutes 3, 4 and 5 during the head-up tilt.

For statistical analyses, please see Table 2.

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Supplemental Digital Content 4. Backward regression analyses for changes in hemodynamic variables during head-up tilt. In these analyses hypertension was defined as systolic blood pressure

≥135 mmHg or diastolic blood pressure ≥85 mmHg. The number of hypertensive subjects when using this cut-off was 155 out of 387.

Variable changing during tilt Coefficient Confidence interval Beta P-value

Lower Upper

Heart rate (1/min), adjusted R²: 0.151

Constant 11.91 10.96 12.86 <0.001

Presence of hypertension (yes/no) -2.660 -4.028 -1.292 -0.195 <0.001

Age (centered on 45) -0.129 -0.183 -0.074 -0.228 <0.001

Heart rate at rest (centered on 62) -0.066 -0.136 0.003 -0.091 0.061

Sex (male) 2.704 1.431 3.976 0.202 <0.001

Cardiac index (l/min/m²), adjusted R²: 0.512

Constant -0.542 -0.579 -0.505 <0.001

Age (centered on 45) -0.003 -0.006 -0.001 -0.095 0.010

Cardiac index at rest (centered on 29) -0.431 -0.485 -0.377 -0.571 <0.001

Sex (male) 0.298 0.243 0.354 0.381 <0.001

Body mass index (centered on 25) 0.016 0.008 0.023 0.163 <0.001 Stroke index (ml/m²), adjusted R²: 0.755

Constant -15.15 -15.60 -14.71 <0.001

Presence of hypertension (yes/no) 0.961 0.313 1.608 0.081 0.004

Age (centered on 45) 0.019 -0.007 0.045 0.039 0.146

Stroke index at rest (centered on 47) -0.671 -0.716 -0.627 -0.808 <0.001

Sex (male) 3.491 2.882 4.101 0.299 <0.001

Body mass index (centered on 25) 0.142 0.062 0.223 0.099 0.001

Systemic vascular resistance index (dyn*s/cm⁵*m²), adjusted R²: 0.187

Constant 589.8 526.9 652.8 <0.001

Age (centered on 45) 4.449 0.695 8.202 0.116 0.020

SVRI at rest (centered on 2300) -0.269 -0.349 -0.188 -0.356 <0.001

Sex (male) -292.4 -375.6 -209.2 -0.322 <0.001

Left cardiac work index (LCWI, kg*min/m²), adjusted R²: 0.420

Constant -0.543 -0.613 -0.472 <0.001

Age (centered on 45) -0.003 -0.007 0.001 -0.059 0.154

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2 LCWI at rest (centered on 3.27) -0.383 -0.442 -0.325 -0.607 <0.001

Sex (male) 0.430 0.336 0.524 0.359 <0.001

Body mass index (centered on 25) 0.031 0.019 0.043 0.211 <0.001 Aortic augmentation pressure (mmHg), adjusted R²: 0.356

Constant -4.024 -4.449 -3.600 <0.001

Aortic AP at rest (centered on 8.2) -0.328 -0.373 -0.283 -0.628 <0.001

Sex (male) -0.709 -1.338 -0.080 -0.098 0.027

Body mass index (centered on 25) 0.063 -0.012 0.138 0.071 0.099

Augmentation index, heart rate 75/min (%), adjusted R²: 0.137

Constant -3.415 -4.140 -2.691 <0.001

Presence of hypertension (yes/no) -0.996 -2.180 0.189 -0.082 0.099

AIx@75 (centered on 15) -0.167 -0.214 -0.120 -0.347 <0.001

Radial pulse pressure (mmHg), adjusted R²: 0.115

Constant -6.956 -7.900 -6.012 <0.001

Presence of hypertension (yes/no) 3.378 1.628 5.127 0.213 <0.001 Radial pulse pressure at rest (cent. on 50) -0.312 -0.397 -0.227 -0.405 <0.001 Aortic pulse pressure (mmHg), adjusted R²: 0.151

Constant -7.810 -8.750 -6.871 <0.001

Aortic pulse pressure at rest(cent. on 37) -0.320 -0.396 -0.244 -0.457 <0.001

Sex (male) -1.097 -2.374 0.180 -0.081 0.092

SVRI, systemic vascular resistance index; LCWI, left cardiac work index; AP, augmentation pressure;

AP, augmentation pressure; AIx@75, augmentation index adjusted to heart rate 75/min. The value of each variable at rest, age, body mass index, sex, and hypertension status were used to model the change in each variable in response to head-up tilt. Non-categorical variables were centred on chosen values for easier interpretation.

Example of interpretation: Centring of age was done by subtracting the value 45 from age, so that subjects aged 45 years had the numeric value “0” for the new variable. Then the mean change in heart rate during head-up tilt for a 50-year-old male with hypertension and resting heart rate of 70/min would be: 11.909 + (- 2.660)*1 + (-0.129)*(50-45) + (-0.066)*(70-62)+2.704*1 = 11.909 + (- 2.660) *1 + (- 0.129)*5 + (-0.066)*8+2.704*1 = 10.78 beats/min.

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≥140 mmHg or diastolic blood pressure ≥90 mmHg. The number hypertensive subjects when using this cut-off was 109 out of 387.

Variable changing during tilt Coefficient Confidence interval Beta P-value

Lower Upper

Constant 11.7 10.7 12.6 <0.001

Presence of hypertension (yes/no) -2.59 -4.06 -1.11 -0.192 0.001

Age (centered on 45) -0.132 -0.187 -0.077 -0.234 <0.001

Heart rate at rest (centered on 62) -0.072 -0.142 -0.003 -0.099 0.040

Sex (male) 2.53 1.27 3.80 0.189 <0.001

Constant -0.542 -0.579 -0.505 <0.001

Age (centered on 45) -0.003 -0.006 -0.001 -0.095 0.010

Sex (male) 0.298 0.243 0.354 0.381 <0.001

Constant -15.1 -15.5 -14.6 <0.001

Age (centered on 45) 0.020 -0.006 0.046 0.040 0.140

Sex (male) 3.53 2.93 4.14 0.303 <0.001

Body mass index (centered on 25) 0.152 0.072 0.232 0.106 <0.001 Systemic vascular resistance index (dyn*s/cm⁵*m²), adjusted R²: 0.188

Constant 602.4 542.1 662.6 <0.001

Age (centered on 45) 4.430 0.678 8.181 0.116 0.021

Sex (male) -284.2 -366.8 -201.5 -0.313 <0.001

Left cardiac work index (LCWI, kg*min/m²), adjusted R²: 0.425

Constant -0.538 -0.605 -0.472 <0.001

Age (centered on 45) -0.003 -0.007 0.001 -0.065 0.118

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2 LCWI at rest (centered on 3.27) -0.387 -0.444 -0.331 -0.614 <0.001

Sex (male) 0.435 0.342 0.529 0.364 <0.001

Constant -4.024 -4.449 -3.600 <0.001

Sex (male) -0.709 -1.338 -0.080 -0.098 0.027

Constant -3.522 -4.186 -2.858 <0.001

Presence of hypertension (yes/no) -1.025 -2.314 0.264 -0.085 0.119

AIx@75 (centered on 15) -0.168 -0.214 -0.121 -0.348 <0.001

Constant -6.67 -7.53 -5.80 <0.001

Presence of hypertension (yes/no) 4.03 2.05 6.01 0.257 <0.001 Radial pulse pressure at rest (cent. on 50) -0.329 -0.417 -0.240 -0.427 <0.001 Aortic pulse pressure (mmHg), adjusted R²: 0.157

Constant -7.66 -8.56 -6.76 <0.001

Presence of hypertension (yes/no) 3.04 1.36 4.73 0.224 <0.001 Aortic pulse pressure at rest(cent. on 37) -0.336 -0.414 -0.258 -0.480 <0.001

Sex (male) -1.03 -2.29 0.23 -0.076 0.108

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≥136 mmHg or diastolic blood pressure ≥80 mmHg. The number hypertensive subjects when using this cut-off was 169 out of 387.

Variable changing during tilt Coefficient Confidence interval Beta P-value

Lower Upper

Constant 11.97 11.00 12.94 <0.001

Presence of hypertension (yes/no) -2.664 -4.058 -1.271 -0.198 <0.001

Age (centered on 45) -0.125 -0.180 -0.069 -0.221 <0.001

Heart rate at rest (centered on 62) -0.058 -0.128 0.013 -0.079 0.108

Sex (male) 2.771 1.489 4.052 0.207 <0.001

Constant -0.542 -0.579 -0.505 <0.001

Age (centered on 45) -0.003 -0.006 -0.001 -0.095 0.010

Sex (male) 0.298 0.243 0.354 0.381 <0.001

Constant -15.04 -15.50 -14.59 <0.001

Presence of hypertension (yes/no) 0.575 -0.080 1.231 0.049 0.085

Age (centered on 45) 0.022 -0.004 0.049 0.045 0.098

Sex (male) 3.525 2.908 4.141 0.302 <0.001

Body mass index (centered on 25) 0.154 0.073 0.236 0.108 <0.001 Systemic vascular resistance index (dyn*s/cm⁵*m²), adjusted R²: 0.197

Constant 574.2 510.2 638.2 <0.001

Age (centered on 45) 4.326 0.544 8.109 0.113 0.025

Sex (male) -292.3 -375.6 -208.9 -0.322 <0.001

Body mass index (centered on 25) -8.642 -19.875 2.591 -0.077 0.131 Left cardiac work index (LCWI, kg*min/m²), adjusted R²: 0.420

Constant -0.547 -0.619 -0.475 <0.001

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2

Age (centered on 45) -0.003 -0.007 0.001 -0.063 0.134

LCWI at rest (centered on 3.27) -0.385 -0.445 -0.326 -0.610 <0.001

Sex (male) 0.429 0.334 0.523 0.358 <0.001

Constant -4.024 -4.449 -3.600 <0.001

Sex (male) -0.709 -1.338 -0.080 -0.098 0.027

Constant -3.341 -4.167 -2.514 <0.001

AIx@75 (centered on 15) -0.191 -0.240 -0.142 -0.397 <0.001

Sex (male) -0.919 -2.143 0.306 -0.077 0.141

Constant -6.942 -7.920 -5.965 <0.001

Radial pulse pressure at rest (cent. on 50) -0.287 -0.368 -0.206 -0.374 <0.001 Aortic pulse pressure (mmHg), adjusted R²: 0.147

Constant -7.825 -8.782 -6.867 <0.001

Aortic pulse pressure at rest(cent. on 37) -0.305 -0.378 -0.232 -0.435 <0.001

Sex (male) -1.075 -2.358 0.208 -0.079 0.100