Heart

CK (Creatine Kinase) Is Associated With Cardiovascular

Hemodynamics
The HELIUS Study
Lizzy M. Brewster , Yentl C. Haan, Aeilko H. Zwinderman, Bert Jan van den Born, Gert A. van Montfrans

Abstract —The ATP-regenerating enzyme CK (creatine kinase) is strongly associated with blood pressure, which lowers
upon experimental CK inhibition. The enzyme is thought to affect cardiovascular hemodynamics through enhanced
systemic vascular resistance, stroke volume, and cardiac contractility, but data on these parameters are lacking. We hereby
report hemodynamics by CK levels in the multiethnic, cross-sectional HELIUS study (Healthy Life in an Urban Setting).
Physical examination included sitting brachial blood pressure and noninvasively assessed supine systemic vascular
resistance, stroke volume, cardiac output, and cardiac contractility, which we associated with resting plasma CK. Data
from 14 937 men and women (mean age, 43.3; SD, 12.9) indicated that per log CK increase, blood pressure increased with
20.2 (18.9–21.4) mm Hg systolic/13.0 (12.2–13.7) diastolic, an odds ratio for hypertension of 6.1 (5.1–7.2). Outcomes
were similar by sex, body mass index, and ancestry, although higher blood pressures in men, with overweight/obesity,
and West-African ancestry were partially explained by higher CK, with an adjusted increase in systolic/diastolic pressure
of 10.5 (10.0–10.9)/6.4 (6.0–6.7) mm Hg per log CK increase. Systemic vascular resistance, stroke volume, cardiac
output, and cardiac contractility (n=7876), increased by respectively 20%, 39%, 14%, and 23% SD per log CK increase.
This study indicates that the association of CK with blood pressure likely results from an increase in systemic vascular
resistance and stroke volume. These data expand the knowledge on the nature of hypertension associated with CK and
may inform further experiments on CK inhibition as a means to lower blood pressure.  (Hypertension. 2020;76:373-380.
DOI: 10.1161/HYPERTENSIONAHA.120.14675.) Data Supplement •
Key Words: creatine kinase ◼ blood pressure ◼ body mass index ◼ cardiac output ◼ vascular resistance
Downloaded from http://ahajournals.org by on November 13, 2021

C K (creatine kinase), the enzyme that promotes ATP-

dependent vascular contractility and sodium retention,
has recently emerged as a new risk factor for hypertension.1–18
The enzyme is associated with blood pressure in several stud-
ies conducted across different populations1–11,13 with a crude
increase in systolic blood pressure (SBP) per log CK increase
of 14 (95% CI, 10–18) mm Hg and 9 (7–12) mm Hg in diastolic
blood pressure (DBP).2 CK is particularly high in men, obese
people, and people of West-African ethnicity.1,2,10,11,14,17,19,20
After adjustment for these factors, the increase in SBP was
3 to 8 mm Hg/log CK increase, with an odds ratio of hyper-
tension associated with high CK (ie, above the upper refer-
ence limit, or within the high tertile) between 1.2 and 3.9.11
CK is also associated with failure of antihypertensive treat-
ment, with an adjusted odds ratio of 3.7 (1.2–10.9)/log CK
increase.6,11 Therefore, CK is thought to be intimately involved
in pressor responses, but the hemodynamics of this process
are poorly understood.11 CK is proposed to facilitate an in-
crease systemic vascular resistance (SVR) and stroke volume
(SV), as the enzyme is bound near cytosolic ATPases involved
in cardiovascular contractility and sodium retention, including
Ca2+-ATPase, myosin ATPase, and Na+/K+-ATPase, where it
rapidly regenerates ATP in the reaction:1,2,12-17,21,22
Phosphocreatine+MgADP↔Creatine+MgATP
Human resistance artery contractility is highly
CK-dependent, and microvascular CK mRNA expression
strongly correlates with clinical blood pressure.12,13 In addi-
tion, CK metabolically supports Na+/K+-ATPase, the enzyme
that drives sodium retention throughout the kidney, and rest-
ing plasma CK is associated with excess sodium retention in
humans.16,17,22 Importantly, high CK precedes hypertension and
further increases with the rise in blood pressure, whereas CK
inhibition reduces human resistance artery contractility and
blood pressure in animal models.10,15,17Thus, the aggregated
evidence supports the notion that CK is associated with blood
pressure, probably through higher SVR and SV (Figure 1).
However, some studies did not find an association between
CK and blood pressure,11 and the majority of studies included
a small sample of one ancestry group (median number of par-
ticipants 133).11 In addition, the hemodynamics of the higher
blood pressure levels have not been investigated. Therefore, in
this study, we further characterize blood pressure and explore

Received January 6, 2020; first decision January 21, 2020; revision accepted May 17, 2020.
From the CK Foundation, Amsterdam, the Netherlands (L.M.B.); and Departments of Vascular Medicine (Y.C.H., B.J.v.d.B.), Clinical Epidemiology and
Biostatistics (A.H.Z.), and Internal Medicine (G.A.v.M.), Amsterdam UMC, the Netherlands.
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.120.14675.
Correspondence to Lizzy M. Brewster, CK Foundation, POB 23639, 1100 EC Amsterdam. Email mail@lizzybrewster.net
© 2020 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp DOI: 10.1161/HYPERTENSIONAHA.120.14675

373
 374  Hypertension   August 2020
Figure 1.  Proposed mechanism of CK (creatine [Cr] kinase)-induced hypertension.1 Cytoplasmic CK metabolically supports ATPases, as it rapidly
regenerates ATP from phosphocreatine (PCr) near these enzymes.1,2 Enhanced cardiovascular contractility and sodium retention are thought to lead to
greater vascular resistance and stroke volume, resulting in higher blood pressure. HR indicates heart rate.
cardiovascular hemodynamics associated with CK in a large,
multiethnic population sample.
Methods
Requests to access the dataset from qualified researchers trained in
human subject confidentiality protocols may be sent to the HELIUS
Study (Healthy Life in an Urban Setting ), Department of Public
Health, Amsterdam University Medical Center, P.O. Box 22700,
Amsterdam, the Netherlands.
Study Design
The HELIUS study is a large, cross-sectional population study on
health and health care in Amsterdam, the Netherlands, carried out
by Amsterdam UMC and partners.23 Noninstitutionalized, nonpreg-
nant, adult participants (<70 y) who did not need acute medical care
gave written informed consent before their inclusion in the study,
which was approved by the local Review Board. The population of
Amsterdam consists mainly of white-European (62%), West-African
(12%), Moroccan (9%), Asian (8%; of which around 40% South
Asian), and Turkish (5%) ancestry citizens.24 Disproportionate strat-
ified sampling with oversampling by non-European ancestry and
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simple random sampling per stratum was used to compare ancestry
groups with sufficient power (Table S1 in the Data Supplement). Data
collected between 2011 and 2015 included medical history, demo-
graphic data, self-reported exercise in the past 3 days,2,11 physical ex-
amination (with measurements conducted in duplo), and laboratory
studies under fasting conditions. Participants were requested to refrain
from smoking on the day of the physical examination. Sitting blood
pressure was assessed by trained staff after 5 minutes rest, with an
appropriately adjusted cuff on the left arm at heart level, using a vali-
dated automated digital device (Microlife WatchBP home, Microlife,
Widnau, Switzerland). Mean arterial pressure, heart rate, SVR, SV,
cardiac output (CO), and cardiac contractility (dP/dt) were estimated
during 5 minutes in as many participants as logistically possible with
beat-to-beat finger volume-clamp photoplethysmography after 5 min-
utes rest in a stable supine position, using the Nexfin device (Edwards
Lifesciences BMEYE BV, Amsterdam, the Netherlands). Please see
Extended Methods in the Data Supplement.25–28
Blood Pressure Categories
Hypertension was defined as blood pressure ≥140 mm Hg SBP or
≥90 mm Hg, or the use of antihypertensive drugs. Participants with
SBP <140 and DBP <90 mm Hg were classified as treated controlled
hypertension when they started to take antihypertensive drugs and
otherwise as normotension. Participants with SBP ≥140 or DBP ≥90
mm Hg were classified as uncontrolled hypertension, or as treated un-
controlled when they started to take antihypertensive drugs.
CK Estimations
Plasma CK activity was measured as described previously by our
group with an automated analyzer (Modular P, Roche/Hitachi
Systems, Roche Diagnostics, Indianapolis, IN) according to the pro-
cedure recommended by the International Federation of Clinical
Chemistry.2,11
Selection of the Participants
We selected participants with complete data on resting plasma CK
and blood pressure. For the substudy on hemodynamic parameters,
we selected participants with complete data on plasma CK and SVR.
Hypothesis and Outcomes
We expected CK to be positively associated with blood pressure,
SVR, and SV.29 The univariable association between resting plasma
CK activity and blood pressure was the primary outcome. We fur-
ther assessed this association across subgroups of age, sex, body mass
index (BMI), and ancestry and addressed the potential contribution
of CK to established predictors of blood pressure, before analyzing
the adjusted association of CK with blood pressure. Other outcomes
included the association of CK with hypertension, failure of antihy-
pertensive treatment, and hemodynamic parameters.
Sample Size Calculation
Based on previous reports,2,11 we estimated that the association be-
tween blood pressure and resting plasma CK has a Spearman's rank
correlation coefficient of 0.2. With 5 independent variables in multi-
variable regression, we calculated that around 500 people would be
sufficient to fit the regression model with α=0.05 and 1−β=0.95.
Statistical Analysis
Plasma CK values were log-transformed to the base of ten.2 Because
high CK values in men, people with overweight or obesity, and people
of West-African ancestry1,2,10,11,14,17,19,20,30 partially explain the associ-
ation of these risk factors with blood pressure,31 the variances of the
estimates of these parameters might be inflated in multivariable ordi-
nary least squares regression analysis. Therefore, we first assessed the
univariable real-world association between CK and blood pressure and
explored the association between CK and blood pressure in subgroups
by treatment status, ancestry, sex, age (arbitrarily cut off around the pop-
ulation mean, at ≤40 and >40 y), and BMI strata (<18.5, 18.5–24.9, and
≥25 kg/m2). We calculated Spearman's ρ for SBP, DBP, versus resting
CK activity, age, BMI, sex, and West-African versus other ancestry2,30
and conducted partial correlation analysis of these risk factors and blood
pressure adjusted for CK,31 before modeling the multivariable associ-
ation between blood pressure and these predictors with partial least
squares regression analysis, using full and restricted models. In addition,
we assessed CK in hypertension treatment categories and calculated
the odds ratio for hypertension and treated uncontrolled hypertension
(versus normotension) per log CK increase in univariable and multi-
variable logistic regression analyses. In the hemodynamics substudy,
we computed standardized associations between CK and mean arterial
pressure, heart rate, SVR, SV, CO, dP/dt, and body surface area (calcu-
lated as the square root of the height [cm] multiplied by the weight [kg]
divided by 3600)32 and assessed the association between mean arterial
pressure, and SVR versus SV by CK tertiles. Exercise increases plasma
CK, and to increase the precision of the estimates2,33 people with vig-
orous exercise in the past 3 days (defined as exercise that induced sweat-
ing and an increase in heart rate), statin users, and the remaining 2.5%
extreme plasma CK values were not included in the primary analysis but
reincluded in sensitivity analyses. We verified whether the assumptions
of the regression models were met. Missing data are not imputed. We
limit formal statistical testing and communicate statistical uncertainty
where relevant through 95% CI given between parentheses.34 Data in
parentheses are SD unless indicated otherwise. Statistical analyses were
 Brewster et al   CK and Cardiovascular Hemodynamics   375

performed with SPSS version 25.0 (SPSS, Inc, Chicago, IL) and with
XLSTAT 2019 (Addinsoft, New York, NY).
Results
Participants
At the time of this analysis, the study had included N=22 165
participants (3% of the population of Amsterdam). With non-Eu-
ropean ancestry groups oversampled, the participants were, re-
spectively, of West-African (29%), European (21%), Moroccan
(18%), Turkish (16%), and Asian (15%, of which 90% South
Asian) ancestry. To achieve this, we had used different sampling
fractions, respectively, 21% of the African-Ghanaian and 7% of
the African-Surinamese population for the West-African ancestry
participants; versus 1% of the European, 6% of the Moroccan,
9% of the Turkish, and 28% of the South Asian-Surinamese
ancestry citizens; and a small number of people classified as
self-defined other ancestry (Table S1). Differences in participa-
tion rates by ancestry were modest.23 Participants were between
18 and 73 years old (mean, 44.3; SD, 13.2), and 57.8% were
women (n=12 810), a men-to-women ratio of 0.73 versus 1.01
(18–70 y) in the general population.24 Mean BMI was 27.0 (5.3),
hypertension prevalence was 27.8% (44.3% among participants
of West-African ancestry), and the majority of hypertensives
across ancestry groups were uncontrolled (82%).
CK and Blood Pressure
CK was missing at random according to inspection and formal
testing in 125 participants. Plasma CK (n=22 040) ranged from
1 to 21 461 IU/L, with a highly skewed distribution (median 115
IU/L; skewness, 25.14, SE, 0.02). We excluded participants who
stated to have vigorous exercise in the past 3 days (n=4518; me-
dian CK, 151 IU/L, Table S2), statin users (n=1768; median CK
116 IU/L), and the 2.5% extreme values, resulting in skewness
of 0.46 (SE, 0.02) after log transformation to the base of 10,
with data on resting CK and blood pressure data available in
14 937 participants (participants’ flow, Figure S1). Results of the
sensitivity analyses with different selection criteria are below.
Table 1 shows clinical characteristics of these participants by
ancestry, and Table S3 by CK (Please see Table S4 for CK by
sex/ancestry and Table S5 for CK by blood pressure status). The
data indicated that CK was relatively high in men, in people
of West-African ancestry, and with uncontrolled hypertension.

Table 1.  Participants’ Characteristics

Total* White-Eur Asian W-African Turkish Moroccan

Main study
 N 14 937 3028 1977 4223 2656 2840
 Men, % 38.7 43.9 40.9 33.5 42.7 35.6
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  Age, y 43.3 (12.9) 46.0 (13.8) 43.2 (12.9) 46.1 (12.0) 39.5 (11.7) 39.7 (12.5)
  BMI, kg/m
2
27.0 (5.3) 24.6 (4.1) 25.9 (4.8) 27.9 (5.4) 28.4 (5.5) 27.4 (5.2)
  SBP, mm Hg 125.7 (17.4) 124.0 (16.4) 125.7 (17.6) 132.0 (18.4) 122.3 (15.5) 120.8 (15.6)
  DBP, mm Hg 78.6 (10.8) 77.3 (10.2) 79.2 (10.5) 82.5 (11.1) 77.4 (10.0) 74.6 (9.6)
 Heart rate, bpm 69.2 (10.0) 66.7 (10.0) 70.1 (10.1) 69.2 (10.3) 71.1 (9.7) 69.3 (9.4)
 Hypertension, % 27.8 22.1 27.9 44.3 21.1 15.0
   Treated, %† 40.7 33.2 39.7 47.5 36.4 28.6
   Controlled, %‡ 44.1 (18.0) 53.2 (17.7) 39.7 (15.8) 39.4 (18.7) 55.9 (20.4) 49.2 (14.1)
 Glucose, mmol/L 5.3 (1.0) 5.3 (0.7) 5.5 (1.0) 5.3 (1.2) 5.3 (0.8) 5.4 (1.0)
 Cholesterol, mmol/L 5.0 (1.0) 5.2 (1.1) 5.1 (1.0) 5.0 (1.0) 4.9 (1.0) 4.7 (0.9)
 CK, IU/L 129.0 (74.4) 104.5 (53.9) 124.9 (68.1) 175.5 (85.9) 105.6 (55.5) 110.4 (61.5)
Hemodynamics substudy
 N 7876 1527 992 2398 1371 1454
 SVR, dyn-s/cm5 1362.5 (427.9) 1415.4 (430.2) 1386.4 (452.3) 1464.2 (473.5) 1232.7 (325.8) 1231.3 (325.1)
 SV, mL 92.4 (17.5) 93.8 (18.5) 89.7 (18.7) 89.1 (17.0) 96.9 (15.9) 94.8 (16.0)
 CO, L/min 5.9 (1.2) 5.7 (1.2) 5.9 (1.3) 5.7 (1.2) 6.3 (1.1) 6.2 (1.1)
 dP/dt, mm  Hg/s 835.5 (311.7) 890.4 (306.6) 806.8 (308.8) 813.1 (322.0) 845.1 (282.3) 830.1 (324.7)
 BSA, m2 1.89 (0.21) 1.94 (0.21) 1.81 (0.22) 1.91 (0.21) 1.89 (0.21) 1.86 (0.21)
 Cardiac index, L/min/m 2
3.16 (0.62) 2.97 (0.59) 3.28 (0.68) 3.02 (0.60) 3.36 (0.57) 3.32 (0.59)
Data are  mean with SD (unless indicated otherwise), and are rounded to one decimal place (except for BSA and cardiac index). Cardiac index is adjusted for BSA.
BMI indicates body mass index; BSA, body surface area; CK, creatine kinase; CO, cardiac output; DBP, diastolic blood pressure; dP/dt, cardiac contractility; SBP, systolic
blood pressure; SV, stroke volume; SVR, systemic vascular resistance; W-African, people of West-African ancestry; and White-Eur, people of white-European ancestry.
*Including people of self-defined other ancestry.
†Percentage of participants with hypertension.
‡Percentage of treated participants (percentage of hypertensive participants).
 376  Hypertension   August 2020
Crude mean blood pressure levels in the low through the high
CK tertile (n=5075, n=4893, and n=4969, respectively) were
120.6 (16.2), 125.7 (16.8), and 130.9 (17.5) mm Hg for SBP and
75.3 (10.0), 78.6 (10.5), and 81.9 (10.7) for DBP (Figure 2A and
2B). In univariable analysis, blood pressure increase per log CK
increase was 20.2 (18.9–21.4) mm Hg for SBP and 13.0 (12.2–
13.7) for DBP. The association between CK and blood pressure
was present in subgroups by age, sex, BMI strata, and ancestry,
and when using different inclusion criteria (Table 2).
Correlation coefficients between blood pressure and predic-
tors including CK, ranging between 0.22 and 0.43, are shown in
Table S6. CK explained, respectively, 11%, 59%, and 61% of the
variance in SBP accounted for by BMI, sex, and West-African
ancestry in partial correlation analysis, with similar results for
DBP. Multivariable linear regression with a full model (age, sex,
BMI, and West-African ancestry) versus a restricted model (age
and BMI), confirmed the independent association of CK with
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blood pressure, an increase in, respectively, 10.5 (10.0–10.9)
versus 15.3 (14.6–16.0) mm Hg for SBP and 6.4 (6.0–6.7) versus
9.8 (9.1–10.5) for DBP/log CK increase (Table S6). The odds
ratio of hypertension 6.1 (5.1–7.2) in univariable analysis, was
respectively 1.7 (1.4–2.1) versus 4.9 (4.1–5.9)/log CK increase
in the full and restricted model, whereas the odds ratio of treated
uncontrolled hypertension (vs normotension) was 8.0 (5.9–10.7)
in univariable analysis, and, respectively, 1.9 (1.3–2.7) versus
6.9 (5.0–9.5)/log CK in the full and restricted model. The order
of variable entry had no impact on the outcomes.
CK and Cardiovascular Hemodynamics
In participants with hemodynamics data (n=7876, Table 1
and S7), SVR, SV, CO, and dP/dt increased by CK tertiles
(Figure 2C through 2F), with an increase per log CK increase
of, respectively, 87.10 (44.13–130.06) dyn-s/cm5 for SVR,
6.84 (5.08–8.59) mL for SV, 0.17 (0.05–0.30) mL/min for
Figure 2.  A–F, Hemodynamic parameters by
CK (creatine kinase) tertiles. Log plasma CK
(tertile I to III), respectively, n=5075, 4893,
and 4969 for sitting brachial blood pressure
(A and B), and n=2635, 2640, and 2601,
in the hemodynamics substudy (C–F). A,
Systolic blood pressure (SBP); (B) diastolic
blood pressure (DBP); (C) systemic vascular
resistance (SVR); (D) stroke volume; (E) cardiac
output; (F) cardiac contractility (dP/dt). Values
are mean (SE).
 Brewster et al   CK and Cardiovascular Hemodynamics   377

Table 2.  Sensitivity and Subgroup Analyses of CK and SBP

Blood Pressure
Category n CK SBP/log CK
Including all* 21 992 170.0 (345.3) 12.6 [11.8–13.4]
Excluding exercise/ 14 937 129.0 (74.4) 20.2 [18.9–21.4]
statins†
Excluding all treated 13 246 126.9 (73.3) 19.1 [17.8–20.3]
HT‡
Ancestry strata§
 White-European 3028 104.5 (53.9) 13.4 [10.3–16.5]
 Asian 1977 124.9 (68.1) 14.9 [11.2–18.6]
 West-African 4223 175.5 (85.9) 11.6 [9.0–14.3]
 Turkish 2656 105.6 (55.5) 17.4 [14.4–20.4]
 Moroccan 2840 110.4 (61.5) 19.0 [16.2–21.9]
Sex groups
 Men 5774 155.1 (82.4) 9.8 [7.9–11.7]
 Women 9163 112.5 (63.5) 22.2 [20.5–24.0]
Age groups
≤40 y
  5992 121.8 (71.5) 19.7 [18.3–21.2]
 >40 y 8945 133.8 (75.8) 16.4 [14.7–18.1]
Body mass index‖
 <18.5 261 103.6 (61.7) 23.9 [16.0–31.9]
 18.5–24.9 5703 117.6 (68.3) 17.5 [15.7–19.4]
≥25
  8960 137.0 (77.2) 16.1 [14.5–17.7]
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Exploration of the association between CK and SBP in sensitivity and

subgroup analyses. SBP/log CK, univariable increase in SBP per log CK increase
(mm Hg, [95% CI]), corresponding to a 10-fold increase in CK (IU/L). Ancestry,
sex, age, and BMI groups include all treated hypertensives. Data are rounded
to 1 decimal place. BMI indicates body mass index; BP, blood pressure; CK,
creatine kinase; HT, hypertension; and SBP, systolic blood pressure.
*All participants with CK and BP data, including nonresting CK; all other
categories are resting CK.
†Excluding interventions affecting CK.33
‡Excluding interventions affecting blood pressure.33
§Excluding those of self-defined “other” ancestry (n=213).
‖13 participants had missing body mass index data.
CO, and 71.58 (40.29–102.87) mm Hg/s for dP/dt. Figure 3A
and 3B, show higher values of SVR and SV with increasing
CK tertiles, superimposed upon the increase in SVR versus
the decline in SV as mean arterial pressure increases.29,35
Standardized outcomes for cardiovascular hemodynamics in-
dicated that per log CK increase, the increase in SVR, SV, and
systolic blood pressure was respectively 20%, 39%, and 116%
of their respective SD (Table S8).
Discussion
In this study, we report that cardiovascular hemodynamics are
associated with resting plasma CK in men and women of white-
European, Asian, West-African, and Mediterranean ancestry,
across predefined subgroups of age and BMI categories. CK was
independently associated with blood pressure and hypertension,
in particular (treated) uncontrolled hypertension. The data further
suggest that both higher SVR and SV contribute to the higher
blood pressure levels, with higher values by CK superimposed on
Figure 3.  Hemodynamic parameters by CK (creatine kinase) and mean
arterial pressure (MAP). Increasing systemic vascular resistance (SVR),
(A), and stroke volume (B) by CK tertiles, superimposed upon the increase
in SVR versus the decrease in stroke volume as mean arterial pressure
increases.29,35 CK tertile 1, dotted line (low CK, n=2635); tertile 2, dashed
line (intermediate CK, n=2640); tertile 3, solid line (high CK, n=2601).
Vertical lines are category range bars.
the SVR increase and SV decrease as blood pressure increases.29,35
This large, multiethnic study reduces the uncertainty reflected
in previous estimates of the association between CK and blood
pressure11 and provides data on hemodynamics. The exclusion
of interventions and the sample size that includes the full spec-
trum of population CK distribution1,2,10,11,14,17,19,20,30 improve the
precision and the rigor of the results.34 The well-validated, non-
invasive measurements provide biologically plausible findings
coherent with earlier observations. Thus, the evidence supports
and strengthens the notion of an important role of CK in the path-
ophysiology of hypertension (Table 3).1–22,30,31,36
Long-term blood pressure control is thought to be de-
termined by inversely related changes in CO and peripheral
resistance and ultimately by the kidney’s ability to excrete
water and salt.16,29,35 The CK enzyme system may promote
these functions through rapid ATP regeneration near myosin
ATPase, which is central to cardiac and resistance artery con-
tractility, and near tubular Na+/K+-ATPase, which drives so-
dium retention throughout the kidney.1,2,16,21,22,37 Consequently,
 378  Hypertension   August 2020
Table 3.  Summary of the Association Between CK, Blood Pressure, and
Hemodynamics
Causal Consideration CK, Blood Pressure, and Hemodynamics
Biological plausibility CK rapidly regenerates ATP near ATPases
involved in pressor responses, including
cardiovascular contractility and sodium
retention.1,12,13,21,22
Strength of the Per log CK increase, an increase of 14–20 mm Hg
association* in SBP; 7% of the mean (39% of the SD) in SV; and
6% of the mean (20% of the SD) in SVR.
Consistency* The association between CK and BP has been
observed by different groups and in different
populations, locations, and settings.2–5,7–11,13
The association with hemodynamics needs
independent replication.
Specificity CK is proposed to affect processes that highly
depend on the ATP/ADP ratio.17
Temporality High CK precedes high BP.10,13,17
Biological gradient* Increasing CK is associated with increasing
BP, resistance artery contractility, sodium
retention,1–14,16,17 SV, and SVR.
Coherence* The causal interpretation of CK and BP is in
accord with the known risk factors for the
condition (male sex, West-African ancestry,
obesity).1–11,19
There is coherence between findings in animal
studies, human tissue studies, and case-control,
clinical, and population studies.1–20
Experiment CK inhibition reduces blood pressure,15 resistance
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artery contractility,12,15 and evidence indicates it
promotes sodium excretion.15
Analogy* The association of CK with blood pressure was
reported by our group,2,6,10,13,31 replicated by
others,3–5,7–9,11 thus slighter (but similar) evidence
in new reports evidence is needed to establish
the association.
Causal considerations36 in the association between CK, BP, and
hemodynamics. BP, blood pressure; CK, creatine kinase; SBP, systolic blood
pressure; SV, stroke volume; and SVR, systemic vascular resistance.
*This study.
the enzyme may modulate extracellular and intracellular sig-
naling pathways leading to cardiovascular contractility and
ion transport, with high cellular CK, whether constitutive or
induced, potentially increasing the magnitude of pressor res
ponses.2,11–13,15–18,22 Predominance of high CK, type II skel-
etal muscle fibers, with relatively low oxidative capacity and
rarefaction of small arteries, may contribute to higher SVR
and blood pressure levels.17–20 Importantly, CK is associated
with sodium retention. After 3 days of high sodium intake
(>200 mmol/d) in healthy volunteers, urinary sodium excre-
tion (mmol/24 h) was 260.4 (SE, 28.3) in participants within
the high CK tertile versus 415.2 (26.3) mmol/24 h in the low
CK tertile, a reduction in urinary sodium excretion of 98.4
mmol/24 h/log CK.16. In addition, evidence indicates that CK
inhibition reduces sodium retention.15 Hence, the aggregated
evidence indicates that CK might affect multiple mechanisms
involved in long-term control of blood pressure, with a few
percentage points increase in SVR, SV, CO, and cardiac
contractility, and enhanced sodium retention sufficient to gen-
erate and maintain higher blood pressure levels.1,2,11,16,17,29
A main limitation of the study is the cross-sectional design.
Although an essential part of causal modeling, associations do
not prove causality. In addition, women and non-European an-
cestry groups were overrepresented, but the association with
cardiovascular hemodynamics was present across sex-ancestry
subgroups. Furthermore, mitochondrial octameric, cytoplasmic
dimeric, as well as plasma CK are reported to be associated
with blood pressure, with the latter two most studied.2,11–13,15–17
Mitochondrial CK rarely circulates, unless in critically ill
patients.2,10,11,17 Without organ damage, cytoplasmic CK is pro-
portionally released to the circulation, with a normal plasma dis-
tribution in normotensives and hypertensives of the dimeric CK
MM, MB, and BB isoenzymes (with M for mucle-type, and B
for brain-type monomers). Greater release with exercise or tis-
sue damage may attenuate the association of plasma CK with
blood pressure.2,13 Although we excluded participants on statins,
those with a history of recent strenuous exercise, as well as the
remaining extreme 2.5% CK values to account for undiagnosed
tissue damage,2,30 we cannot exclude that unacknowledged ex-
ercise or minor tissue damage affected the results nor that we
were more likely to have excluded those with high intracellular
CK (and perhaps greater hypertension risk), such as men or
people of West-African ancestry, potentially underestimating
the true association between CK and cardiovascular hemody-
namics.2,13,17 Finally, we did not collect data on sodium intake,
sodium excretion, or the renin-angiotensin-aldosterone-system
that is presumed to be suppressed with high CK levels, poten-
tially enhancing salt sensitivity.1,15,16,29,37
In this large, multiethnic study, we characterized the associa-
tion between CK and cardiovascular hemodynamics in men and
women of European, Asian, West-African, and Mediterranean
ancestry. We report per log CK increase a crude increase in blood
pressure of 20 mm Hg systolic and 13 mm Hg diastolic, resulting
in a 6× greater odds of hypertension versus normotension. The
data further indicate that higher SVR and stroke volume charac-
terize the higher blood pressure levels. Taking into account the
large variation in CK within the healthy population, the blood
pressure–lowering upon experimental cytoplasmic CK inhibi-
tion,15 and the successful first-in-human tolerance study with this
substance,38 the presented data could inform further experiments
on CK inhibition to lower blood pressure.
Perspective
A solid theoretical framework substantiated by an increasing
body of observational and experimental evidence supports the
fundamental role of CK in blood pressure generation and hyper-
tension risk. Rapid ATP regeneration by CK serves to supports
cellular functions with high energy demands, such as cardio-
vascular contractility and renal sodium retention. This study
establishes the association of cardiovascular hemodynamics
with CK across different age and sex/ancestry subgroups in the
general population. In light of recent work on CK inhibition to
reduce blood pressure, and the successful first-in-human toler-
ance study with a CK-inhibitor, future research could focus on
the potential clinical usefulness of CK to profile hypertension
risk or therapy failure, and study experimental CK inhibition as
a potential new therapeutic modality to reduce blood pressure.‍
 Brewster et al   CK and Cardiovascular Hemodynamics   379
Acknowledgments
We acknowledge the Amsterdam University Medical Center Biobank
for their support in biobank management and sample storage. We thank
the HELIUS study (Healthy Life in an Urban Setting) participants,
management team, and other staff who have taken part in this study.
L.M. Brewster, G.A. van Montfrans, and B.J. van den Born contrib-
uted to the design of the HELIUS study. L.M. Brewster designed the
CK (creatine kinase) substudy. L.M. Brewster conducted the analyses;
L.M. Brewster and G.A. van Montfrans drafted the article with tables
and figures. All authors critically reviewed the article and approved the
final text for publication.
Sources of Funding
L.M. Brewster is supported by the CK (creatine kinase) Foundation,
project number (19CKF905PH222201). The HELIUS study (Healthy
Life in an Urban Setting) is conducted by Amsterdam University
Medical Center and Public Health Amsterdam and cofunded by the
Dutch Heart Foundation, the Netherlands Organization for Health
Research and Development (ZonMw), the European Union (FP-7),
and the European Fund for the Integration of non-EU immigrants
(EIF). The funders had no role in the study design, data collection or
analysis, article preparation, or decision to publish.
Disclosures
L.M. Brewster is an inventor on the Netherlands NL patent
WO/2012/138226 (filed). The other authors report no conflicts.
Supplemental Material
Online Supplement: 1 Expanded Methods and Results
Online Figure
Table S1–S8
References: 2,23–28,30
Downloaded from http://ahajournals.org by on November 13, 2021
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Novelty and Significance
What Is New?
• In the general population, plasma activity of the ATP-regenerating en-
zyme CK (creatine kinase) is associated with blood pressure across
subgroups by sex, age, and body mass index, and by European, Asian,
West-African, and Mediterranean ancestry.
• In hemodynamic assessments, systemic vascular resistance, cardiac stroke
volume, cardiac output, and cardiac contractility increased by CK levels.
What Is Relevant?
• CK is thought to enhance cardiovascular contractility and sodium retention.
Downloaded from http://ahajournals.org by on November 13, 2021
36. Hill AB. The environment and disease: association or causation? Proc R
Soc Med. 1965;58:295–300.
37. Brewster LM, van Montfrans GA. Renin and antihypertensive drug
therapy in African ancestry patients. Am J Hypertens. 2019;32:617–619.
doi: 10.1093/ajh/hpz045
38. Karamat FA, Horjus DL, Haan YC, van der Woude L, Schaap MC,
Oudman I, van Montfrans GA, Nieuwland R, Salomons GS, Clark JF,
et al. The acute effect of beta-guanidinopropionic acid versus crea-
tine or placebo in healthy men (ABC-Trial): a randomized controlled
first-in-human trial. Br J Clin Pharmacol. 2017;83:2626–2635. doi:
10.1111/bcp.13390
• Experimental CK inhibition reduces blood pressure without apparent side
effects.
• CK might represent a new target for hypertension treatment.
Summary
We establish in a large, multiethnic population sample that CK is
associated with blood pressure, systemic vascular resistance, and
stroke volume, adding to the evidence that CK is relevant for pres-
sor responses and hypertension risk.