Association of C-Terminal Pro-Endothelin-1 with Mortality in the Population-Based KORA F4 Study

Figures & data

Table 1 Characteristics of the Study Participants at KOFA F4 Overall and Stratified by Survival Status (Mean ± Standard Deviation, Median (First Quartile; Third Quartile), or Number of Participants (Proportion in %))

	Total Study Group	Survivors	Non-Survivors	P value^a
n	1554	1415	139
Male sex n (%)	763 (49)	675 (48)	88 (63)	< 0.001^b
Age (years)	56.9 ± 12.9	55.5 ± 12.4	70.7 ± 8.9	< 0.001^c
BMI (kg/m^2)	27.4 ± 4.6	27.3 ± 4.6	28.9 ± 4.8	< 0.001^c
HDL cholesterol (mmol/l)	1.40 (1.16; 1.68)	1.40 (1.19; 1.68)	1.34 (1.11; 1.60)	0.089^d
LDL cholesterol (mmol/l)	3.47 (2.87; 4.03)	3.47 (2.88; 4.06)	3.47 (2.84; 3.94)	0.601^d
Type 2 diabetes n (%)	181 (12)	138 (10)	43 (31)	< 0.001^b
Hypertension n (%)	618 (40)	521 (37)	97 (70)	< 0.001^b
eGFR (mL/min/1.73 m^2)	88.4 (77.0; 99.0)	89.6 (77.0; 99.0)	73.7 (61.7; 87.4)	< 0.001^d
Physically inactive n (%)	657 (42)	570 (40)	87 (63)	< 0.001^b
Smoker current/ex n (%)	273/639 (18/41)	253/574 (18/41)	20/65 (14/47)	0.361/0.138^b
CT-proET-1 (pmol/l)	45.5 (39.4; 53.3)	44.9 (39.0; 51.9)	57.6 (48.8; 71.2)	< 0.001^d
n	1269	1165	104
IMT (mm)	0.83 (0.74; 0.93)	0.82 (0.74; 0.92)	0.92 (0.86; 1.04)	< 0.001^d
n	1552	1414	138
White blood cell count per nl	5.7 (4.9; 6.8)	5.7 (4.8; 6.7)	6.2 (5.2; 7.7)	< 0.001^d
hsCRP (mg/l)	1.11 (0.55; 2.43)	1.05 (0.52; 2.24)	2.03 (0.92; 4.73)	< 0.001^d
n	1547	1409	138
Leptin (ng/mL)	11.8 (5.4; 24.0)	11.9 (5.4; 23.6)	11.05 (6.1; 29.2)	0.392^d
Retinol-binding protein-4 (g/l)	0.042 (0.035; 0.049)	0.042 (0.035; 0.049)	0.043 (0.033; 0.054)	0.181^d
n	1055	970	85
Chemerin (ng/mL)	171.8 (140.7; 205.4)	171.2 (140.7; 205.0)	193.6 (147.2; 216.5)	0.039^d
Progranulin (ng/mL)	126.4 (99.4; 170.8)	125.6 (99.1; 168.6)	143.4 (102.7; 183.3)	0.080^d
Vaspin (ng/mL)	0.61 (0.34; 1.14)	0.61 (0.35; 1.15)	0.68 (0.33; 1.11)	0.993^d
n	596	492	104
Interleukin-6 (pg/mL)	1.52 (1.04; 2.28)	1.47 (0.98; 2.09)	2.06 (1.50; 3.43)	< 0.001^d
Tumor necrosis factor-α (pg/mL)	2.02 (1.46; 2.99)	1.99 (1.45; 2.90)	2.25 (1.62; 3.56)	0.043^d
Interleukin-18 (pg/mL)	319.0 (254.0; 416.5)	316.0 (253.0; 408.0)	363.0 (257.5; 445.0)	0.015^d
Soluble intercellular adhesion molecule-1 (ng/mL)	232.2 (199.8; 260.9)	226.6 (196.3; 258.0)	247.8 (218.2; 296.0)	< 0.001^d
Myeloperoxidase (ng/mL)	154.9 (96.55; 223.9)	149.1 (94.0; 212.1)	204.9 (123.4; 266.7)	< 0.001^d
Superoxide dismutase-3 (ng/mL)	127.1 (112.2; 143.0)	126.4 (112.0; 141.3)	132.6 (113.7; 156.3)	0.006^d
Interleukin-22 (pg/mL)	6.24 (1.95; 13.27)	6.13 (1.95; 11.75)	8.54 (1.95; 20.81)	0.006^d
Interleukin-1 receptor antagonist (pg/mL)	303.9 (235.2; 409.0)	299.6 (230.3; 391.7)	338.0 (260.8; 453.6)	0.002^d

Notes: ^athe p value is related to the null hypothesis of no difference between survivors and non-survivors; ^bChi-square test; ^ct-test; ^dmann–Whitney U-test.

Table 2 Association of CT-proET-1 (as Dependent Variable) with Metabolic and Cardiovascular Risk Factors (as Independent Variables)

	β-Coefficient^a ± SE	p-value
Without adjustment
Male sex	0.161 ± 0.050	0.002
Age	0.481 ± 0.022	<0.001
BMI	0.320 ± 0.020	<0.001
Adjustment for sex, age and BMI
Type 2 diabetes	0.410 ± 0.072	<0.001
Hypertension	0.307 ± 0.051	<0.001
LDL cholesterol	−0.074± 0.022	<0.001
HDL cholesterol	−0.180 ± 0.025	<0.001
eGFR	−0.393 ± 0.027	<0.001
Current smoking^b	0.293 ± 0.063	<0.001
Former smoking	0.115 ± 0.049	0.018
Physically inactive	−0.116 ± 0.044	0.009

Notes: ^aper standard deviation increase of continuous variables (BMI, LDL and HDL cholesterol, eGFR) ^bas compared to never smokers.

Table 3 Hazard Ratios (95% Confidence Interval) of the Association Between CT-proET-1 (per Standard Deviation) with Cardiovascular Outcomes and All-Cause Mortality

Number of Participants/Events	Model 1^a	P value	Model 2^b	P value
Non-fatal or fatal incident stroke
1384/64	1.78 (1.39–2.28)	< 0.001	0.99 (0.69–1.41)	0.951
Non-fatal or fatal incident myocardial infarction
n = 1384/47	2.05 (1.50–2.75)	< 0.001	1.29 (0.84–1.97)	0.247
Non-fatal or fatal stroke or myocardial infarction
1384/101	1.79 (1.47–2.18)	< 0.001	1.00 (0.75–1.33)	0.993
Cardiovascular Mortality
1554/63	3.06 (2.37–3.95)	< 0.001	1.66 (1.10–2.51)	0.017
All-cause mortality
1554/139	2.93 (2.47–3.48)	< 0.001	2.03 (1.55–2.67)	<0.001

Notes: ^aModel 1: without adjustment; ^bModel 2: adjusted for sex, age, BMI, type 2 diabetes, hypertension, eGFR, LDL and HDL cholesterol, current and former smoking, physical activity; bold print indicates significance in the fully adjusted model after correction for multiple testing using the Bonferroni method (p < 0.01 (0.05 ÷ 5)).

Table 4 Association of CT-proET-1 (per Standard Deviation) with Biomarkers of Subclinical Inflammation (per Standard Deviation): β Coefficients ± Standard Error from Linear Regression Models Adjusted for Sex, Age, BMI, eGFR, Hypertension, Type 2 Diabetes, LDL and HDL Cholesterol, Current and Former Smoking, Physical Activity (Model 2)

	Number of Participants	β Coefficient ± Standard Error	p
Biomarkers of subclinical inflammation
White blood cell count	1546	0.015 ± 0.031	0.620
hsCRP	1552	0.085 ± 0.029	0.004
Interleukin-6	596	0.151 ± 0.047	0.001
Tumor necrosis factor alpha	596	0.201 ± 0.050	<0.001
Interleukin-18	596	0.171 ± 0.049	<0.001
SICAM-1	596	0.190 ± 0.050	<0.001
MPO	596	0.121 ± 0.051	0.019
SOD-3	596	0.095 ± 0.051	0.061
Interleukin-22	596	0.136 ± 0.043	0.002
IL1Ra	596	0.078 ± 0.047	0.099
Adipokines
Leptin	1547	0.072 ± 0.019	<0.001
RBP-4	1547	0.073 ± 0.029	0.012
Chemerin	1055	0.109 ± 0.035	0.002
Progranulin	1055	0.107 ± 0.039	0.006
Vaspin	1055	−0.025 ± 0.039	0.518

Note: Bold print indicates significance after correction for multiple testing using the Bonferroni method (p < 0.0033 (0.05 ÷ 15)).

Table 5 Hazard Ratios (95% Confidence Interval) of the Association Between CT-proET-1 (per Standard Deviation) and All-Cause Mortality Adjusted for IL-6 and sICAM-1, Respectively. N = 596, Events = 104

Adjustments	HR (95% CI)	P value
Model 1^a	2.08 (1.70–2.55)	< 0.001
Model 2^b	1.91 (1.42–2.56)	< 0.001
Model 1^a plus IL-6	1.73 (1.40–2.14)	< 0.001
Model 2^b plus IL-6	1.73 (1.29–2.33)	< 0.001
Model 1^a plus sICAM-1	1.94 (1.58–2.39)	< 0.001
Model 2^b plus sICAM-1	1.76 (1.32–2.36)	< 0.001
Model 2^b plus IL-6 and sICAM-1	1.61 (1.20–2.16)	0.002

Notes: ^aModel 1: without adjustment; ^bModel 2: adjusted for sex, age, BMI, type 2 diabetes, hypertension, eGFR, LDL and HDL cholesterol, current and former smoking, physical activity.

Data Availability

The data are subject to national data protection laws and restrictions were imposed by the Ethics Committee of the Bavarian Chamber of Physicians to ensure data privacy of the study participants. Therefore, data cannot be made freely available in a public repository. However, data can be requested through an individual project agreement with KORA via the online portal KORA.passt (https://epi.helmholtz-muenchen.de/).