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Still reduced cardiovascular mortality 12 years after supplementation with selenium and coenzyme Q10 for four years: A validation of previous 10-year follow-up results of a prospective randomized double-blind placebo-controlled trial in elderly

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Background: Selenium and coenzyme Q10 are both necessary for optimal cell function in the body. The intake of selenium is low in Europe, and the endogenous production of coenzyme Q10 decreases as age increases. Therefore, an intervention trial using selenium and coenzyme Q10 for four years as a dietary supplement was performed. The main publication reported reduced cardiovascular mortality as a result of the intervention. In the present sub-study the objective was to determine whether reduced cardiovascular (CV) mortality persisted after 12 years, in the supplemented population or in subgroups with diabetes, hypertension, ischemic heart disease or reduced functional capacity due to impaired cardiac function. Methods: From a rural municipality in Sweden, four hundred forty-three healthy elderly individuals were included. All cardiovascular mortality was registered, and no participant was lost to the follow-up. Based on death certificates and autopsy results, mortality was registered. Findings: After 12 years a significantly reduced CV mortality could be seen in those supplemented with selenium and coenzyme Q10, with a CV mortality of 28.1% in the active treatment group, and 38.7% in the placebo group. A multivariate Cox regression analysis demonstrated a reduced CV mortality risk in the active treatment group (HR: 0.59; 95%CI 0.42-0.81; P = 0.001). In those with ischemic heart disease, diabetes, hypertension and impaired functional capacity we demonstrated a significantly reduced CV mortality risk. Conclusions: This is a 12-year follow-up of a group of healthy elderly participants that were supplemented with selenium and coenzyme Q10 for four years. Even after twelve years we observed a significantly reduced risk for CV mortality in this group, as well as in subgroups of patients with diabetes, hypertension, ischemic heart disease or impaired functional capacity. The results thus validate the results obtained in the 10-year evaluation. The protective action was not confined to the intervention period, but persisted during the follow-up period. The mechanisms behind this effect remain to be fully elucidated, although various effects on cardiac function, oxidative stress, fibrosis and inflammation have previously been identified. Since this was a small study, the observations should be regarded as hypothesis-generating. Trial registration: Clinicaltrials.gov NCT01443780.
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RESEARCH ARTICLE
Still reduced cardiovascular mortality 12 years
after supplementation with selenium and
coenzyme Q10 for four years: A validation of
previous 10-year follow-up results of a
prospective randomized double-blind
placebo-controlled trial in elderly
Urban Alehagen
1
*, Jan Aaseth
2
, Jan Alexander
3
, Peter Johansson
4,5
1Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linko
¨ping University,
Linko
¨ping, Sweden, 2Research Department, Innlandet Hospital Trust and Inland Norway University of
Applied Sciences, Elverum, Norway, 3Norwegian Institute of Public Health, Oslo, Norway, 4Department of
Social and Welfare studies, Linko
¨ping University, Norrko
¨ping, Sweden, 5Department of Medical and Health
Sciences, Linko
¨ping University, Norrko
¨ping, Sweden
These authors contributed equally to this work.
*Urban.Alehagen@liu.se
Abstract
Background
Selenium and coenzyme Q10 are both necessary for optimal cell function in the body. The
intake of selenium is low in Europe, and the endogenous production of coenzyme Q10
decreases as age increases. Therefore, an intervention trial using selenium and coenzyme
Q10 for four years as a dietary supplement was performed. The main publication reported
reduced cardiovascular mortality as a result of the intervention. In the present sub-study the
objective was to determine whether reduced cardiovascular (CV) mortality persisted after
12 years, in the supplemented population or in subgroups with diabetes, hypertension,
ischemic heart disease or reduced functional capacity due to impaired cardiac function.
Methods
From a rural municipality in Sweden, four hundred forty-three healthy elderly individuals
were included. All cardiovascular mortality was registered, and no participant was lost to the
follow-up. Based on death certificates and autopsy results, mortality was registered.
Findings
After 12 years a significantly reduced CV mortality could be seen in those supplemented
with selenium and coenzyme Q10, with a CV mortality of 28.1% in the active treatment
group, and 38.7% in the placebo group. A multivariate Cox regression analysis demon-
strated a reduced CV mortality risk in the active treatment group (HR: 0.59; 95%CI 0.42–
PLOS ONE | https://doi.org/10.1371/journal.pone.0193120 April 11, 2018 1 / 15
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OPEN ACCESS
Citation: Alehagen U, Aaseth J, Alexander J,
Johansson P (2018) Still reduced cardiovascular
mortality 12 years after supplementation with
selenium and coenzyme Q10 for four years: A
validation of previous 10-year follow-up results of a
prospective randomized double-blind placebo-
controlled trial in elderly. PLoS ONE 13(4):
e0193120. https://doi.org/10.1371/journal.
pone.0193120
Editor: Doan TM Ngo, University of Adelaide,
AUSTRALIA
Received: October 20, 2017
Accepted: January 29, 2018
Published: April 11, 2018
Copyright: ©2018 Alehagen et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: Under Swedish Law,
the authors cannot share the data underlying this
study and cannot do any further research than
what is specified in the ethical permissions
application. For inquires on the data, researchers
should first reach out to the owner of the database,
the University of Linko¨ping. Please reach out to the
corresponding author with requests and for
assistance with data requests. If the university
0.81; P = 0.001). In those with ischemic heart disease, diabetes, hypertension and impaired
functional capacity we demonstrated a significantly reduced CV mortality risk.
Conclusions
This is a 12-year follow-up of a group of healthy elderly participants that were supplemented
with selenium and coenzyme Q10 for four years. Even after twelve years we observed a sig-
nificantly reduced risk for CV mortality in this group, as well as in subgroups of patients with
diabetes, hypertension, ischemic heart disease or impaired functional capacity. The results
thus validate the results obtained in the 10-year evaluation.
The protective action was not confined to the intervention period, but persisted during the
follow-up period. The mechanisms behind this effect remain to be fully elucidated, although
various effects on cardiac function, oxidative stress, fibrosis and inflammation have previ-
ously been identified. Since this was a small study, the observations should be regarded as
hypothesis-generating.
Trial registration
Clinicaltrials.gov NCT01443780.
Introduction
Selenium is a trace element that can be found in all living cells[1,2]. Important selenoproteins
in the body are selenoprotein P, glutathione peroxidases, and thioredoxin reductase, all pro-
tecting against oxidative stress. Increased vascular oxidative stress and endothelial dysfunction
in patients with coronary heart disease have been reported, although the results are conflicting
[3,4]. In European populations with low dietary selenium intakes as a result of the low sele-
nium content in the soil, biofortification has been regarded as logical[5,6], as opposed to the
status in the United States where the selenium soil content is generally high. The estimated
serum selenium concentrations in US citizens are generally above 120 μg/L,[7,8] whereas con-
centrations below 90 μg/L are invariably reported from European countries.[913].
Xia et al. demonstrated an interrelationship between selenium and coenzyme Q10 (ubiqui-
none) in the metabolic pathway to the active form of coenzyme Q10 (ubiquinol) [14].
Moreover, an adequate presence of coenzyme Q10 is needed for optimal functioning of seleno-
proteins. Similarly, a deficiency of selenium could influence the ability to obtain adequate con-
centrations of active coenzyme Q10 in cellular compartments. Coenzyme Q10 is a powerful
anti-oxidant protecting against lipid peroxidation[15]. It has been shown that ubiquinone
reduces the inflammatory response [16]. The endogenous production of coenzyme Q10
decreases continually after the age of 20, and the endomyocardial production is reduced to half
at the age of 80 [17]. Thus, elderly people living in geographical areas with low selenium con-
tent in the soil and food may be at increased risk of heart disease and premature death due to a
possible deficiency of these antioxidants. Our research group have recently reported higher
CV mortality in a community population with low plasma selenium concentration [18].
We have previously reported on a dietary supplementation trial with both selenium and
coenzyme Q10 to 443 elderly Swedish community members performed during 2003 until 2010
[19]. The intervention time was four years, and the follow-up after 5.2 years showed signifi-
cantly reduced CV mortality, improved cardiac function as evaluated by echocardiography,
Still reduced cardiovascular mortality after 12 years
PLOS ONE | https://doi.org/10.1371/journal.pone.0193120 April 11, 2018 2 / 15
approves the request, researchers can submit an
application to the Regional Ethical Review Board
for the specific research question that the
researcher wants to examine.
Funding: Part of the analysis costs was supported
by grants from Pharma Nord Aps, Denmark, the
County Council of O
¨stergo¨tland, Linko¨ping
University. The funding organizations had no role in
the design, management, analysis, or interpretation
of the data, nor in the preparation, review or
approval of the manuscript. No economic
compensation was distributed.
Competing interests: We have read the journal’s
policy and the authors of this manuscript have the
following competing interests: This work was
partially supported by a grant (the trial tablets/
capsules) from Pharma Nord Aps, Denmark. The
authors do not have any knowledge of any patents,
products in development to declare. This does not
alter our adherence to all the PLOS ONE policies on
sharing data and materials.
and a reduced increase of the N-terminal fragment of proBNP (NT-proBNP), a cardiac peptide
biomarker. The long-term effects as seen after ten years have also been reported by our group,
where we still observed a significant reduction of CV mortality, even if the intervention lasted
for only four years[20]. Positive effects could also be seen in some subgroups of the study
population.
The primary aim of the present study was to evaluate possible CV effects of the intervention
in the same population 12 years after the introduction of a four-year period of supplementa-
tion as a way to validate the surprising results from the 10-year evaluation. A secondary aim
was to determine whether positive effects on CV risk could also be seen after 12 years in the
two genders, in those with diabetes, ischemic heart disease (IHD), hypertension and impaired
functional capacity as measured by the New York Heart Association functional Class (NYHA
class).
Materials and methods
The design of the main study has been published elsewhere [19]. In brief, 443 elderly healthy
participants were given dietary supplementation of 200 mg/day of coenzyme Q10 capsules
(Bio-Quinon 100 mg B.I.D, Pharma Nord, Vejle, Denmark) and 200 μg/day of organic sele-
nium yeast tablets (SelenoPrecise 200 μg, Pharma Nord, Vejle, Denmark), or a similar placebo
during 48 months, and then the interventions was finished. The study supplementation was
taken in addition to regular medication if used. All study medications (active drug and pla-
cebo) not consumed were returned and counted. All participants were examined by one of
three experienced cardiologists. A new clinical history was recorded, and a clinical examina-
tion was performed, including blood pressure, assessment of New York Heart Association
functional class (NYHA class) as well as ECG and echocardiography. Doppler echocardiogra-
phical examinations were performed with the participant in the left lateral position. The ejec-
tion fraction (EF) readings were categorized into four classes with interclass limits placed at
30%, 40% and 50% [21,22]. Normal systolic function was defined as EF50%, while severely
impaired systolic function was defined as EF<30%. The first participant was included in Janu-
ary 2003, and the last participant concluded the study in February 2010.
As the intervention time was unusually long for the main intervention study (48 months)
only 228 participants completed the study; 86 died during the intervention time, and 129
(29.1%) decided not to complete the study. The reasons for the latter have been presented in
detail in the main publication, but the main reason was there were too many tablets to take
[19]. A flowchart of the total follow-up period is presented as Fig 1.
Written, informed consent was obtained from all patients. The study was approved by the
Regional Ethical Committee in Linko¨ping, Sweden and conforms to the ethical guidelines of
the 1975 Declaration of Helsinki. This study was registered at Clinicaltrials.gov, and has the
identifier NCT01443780. As the trial started when registration in Clinicaltrials.gov, or else-
where was optional, the trial was not registered at the start. Registration took place at the time
of publication, when this became obligatory. There is presently no ongoing study from the
research group with the described preparations.
Biochemical analyses
All blood samples were obtained while the patients were at rest in a supine position. The blood
samples were collected in plastic vials containing EDTA (ethylenediamine tetracetic acid). The
vials were placed on ice before chilled centrifugation at 3000g, and then frozen at -70 ˚C. No
sample was thawed more than twice.
Still reduced cardiovascular mortality after 12 years
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Fig 1. CONSORT flow chart of the study.
https://doi.org/10.1371/journal.pone.0193120.g001
Still reduced cardiovascular mortality after 12 years
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Mortality
All instances of cardiovascular mortality (CV mortality) were registered. The mortality infor-
mation was obtained from the National Board of Health and Welfare in Sweden, which regis-
ters all deaths of Swedish citizens based on death certificates or autopsy reports. Written,
informed consent was obtained from all patients.
Statistical methods
Descriptive data are presented as percentages. Chi-square tests were used for discrete variables.
All evaluations are performed according to the intention-to-treat principle. Kaplan-Meier
analysis was used to demonstrate CV mortality during the follow-up period. Cox proportional
hazard regression analysis was used to evaluate risk of CV mortality. The independent vari-
ables included in the multivariate model were variables known to be associated with CV mor-
tality: age, male gender, smoking, hypertension, diabetes, IHD, NYHA class III, treatment
with beta blocker, ACE-inhibitor, Hb<120g/L, EF<40% and active treatment with selenium
and coenzyme Q10.
A P-value of <0.05 was considered statistically significant. All data were analyzed using
standard software (Statistica v. 13.2, Dell Inc, Tulsa, OK).
Results
The study population were followed regarding CV mortality during a median follow-up time
of 4233 days (range 348–5275), i.e. about 12 years. In the survival group the median follow-up
time was 4484 days (range 404–5275), and in the CV mortality group a median follow-up time
of 2818 days (range 348–4869) was recorded.
From the basal characteristics it could be seen that the two populations were balanced at the
start of the intervention in all but one variable, use of ACE-inhibitors (15.8% vs 24.3%;
P= 0.03). After 12 years there was no significant difference between the basal characteristics
variables (Table 1).
Upon analyses of the basal characteristics, it could be seen that at the start of the interven-
tion the active treatment group, and the placebo group had the same age (78 years), whereas in
survivors after 12 years the mean age had decreased to 75 years in the active treatment group,
and to 76 years in the placebo group. At the start of the intervention equal proportions of the
two groups had diagnosed diabetes (21%), whereas after 12 years a reduction of the diabetic
proportion could be seen in both groups, though it was more prominent in the placebo group
(Table 1). The numbers with diagnosed hypertension were equal both in the groups at the start
of the intervention, and after 12 years. Regarding IHD, the intervention and placebo groups
were balanced both at the start and after 12 years; however, both groups exhibited a decrease
in the number with IHD after 12 years.
Cardiovascular mortality within 12 years
When evaluating the CV mortality within the 12-year period, we found that those on active
treatment during the intervention had a significantly lower mortality also after 12 years (active
treatment group: 62/221; 28.1%, vs placebo: 86/222; 38.7%; χ
2
:13.8; P<0.0001). The differences
in CV mortality during the follow-up were also assessed and displayed in a Kaplan-Meier
graph, showing a clear separation of the two groups (Fig 2).
When applying the CV mortality results in univariate Cox regressions, we observed a highly
significant risk reduction resulting from supplementing the participants with selenium and
Still reduced cardiovascular mortality after 12 years
PLOS ONE | https://doi.org/10.1371/journal.pone.0193120 April 11, 2018 5 / 15
coenzyme Q10 for four years, also after 12 years (HR:0.58; 95%CI: 0.42–0.79; P<0.0007).
Applying the data into a multivariate Cox regression model where well-known variables influ-
encing the cardiovascular risk were included, a cardiovascular risk reduction appeared to
remain also after 12 years (HR:0.59; 95%CI: 0.42–0.81: P = 0.001) (Table 2).
Table 1. Population characteristics at inclusion, and after 12 years.
At study start After 12 years
Active p-value Placebo Active p-value Placebo
n221 222 100 81
Age, mean 78 78 75 76
Males/Females, n 115/106 110/112 42/58 33/48
Smokers, n (%) 21 (9.5) 0.86 20 (9.0) 2 (2.0) 0.27 4 (4.9)
Diabetes, n (%) 47 (21.3) 0.95 48 (21.6) 19 (19.0) 0.60 13 (16.1)
Hypertension, n (%) 158 (71.5) 0.28 168 (75.7) 69 (69.0) 0.84 57 (70.4)
IHD, n (%) 47 (21.3) 0.51 53 (23.9) 13 (13.0) 0.35 7 (8.6)
NYHA class III, n (%) 41 (18.6) 0.49 47 (21.2) 12 (12) 0.46 7 (8.6)
Medical Treatment
ACEI, n (%) 35 (15.8) 0.03 54 (24.3) 10 (10.0) 0.32 12 (14.8)
Beta blockers, n (%) 81 (36.7) 0.40 73 (32.9) 37 (37.0) 0.11 21 (25.9)
Statins, n (%) 45 (20.7) 0.50 51 (23.0) 20 (20.0) 0.97 16 (19.8)
Examinations
Hb<120g/L, n (%) 23 (10.4) 0.39 29 (13.1) 10 (10.0) 0.98 8 (9.9)
EF<40%, n (%) 16 (7.2) 0.87 17 (7.7) 5 (5.0) 0.98 4 (4.9)
Note: ACEI: ACE- inhibitors; EF: Ejection fraction according to echocardiography; IHD: Ischemic heart disease; NYHA: New York Heart Association functional class
https://doi.org/10.1371/journal.pone.0193120.t001
Fig 2. Kaplan-Meier graph illustrating cardiovascular mortality during a follow-up period of 12 years of those
supplemented with selenium and coenzyme Q10 versus placebo for four years on top of regular pharmaceutical
treatment.
https://doi.org/10.1371/journal.pone.0193120.g002
Still reduced cardiovascular mortality after 12 years
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Subgroup analyses
When analyzing the two genders separately, we found a highly significant difference in CV
mortality between the female intervention and the placebo groups, 20/106, and 46/112, respec-
tively (χ
2
:12.7; P= 0.0004) after up to 12 years of follow-up. Similarly, in the male group a
trend for difference between the groups was found (active group: 42/115, compared with the
placebo group; 54/110; χ
2
:3.63; P= 0.057).
In the group with IHD we found a reduced CV mortality risk after supplementation with
selenium and coenzyme Q10, also after 12 years of follow-up, in comparison with those on pla-
cebo (HR: 0.52; 95%CI: 0.30–0.90; P= 0.02) (Fig 3).
For the group with diabetes we also observed a reduced CV mortality risk after 12 years in
the active supplementation group (HR: 0.50; 95%CI: 0.27–0.93; P= 0.03) (Fig 4).
In the group with hypertension, a reduced CV mortality risk reduction could be seen as
well (HR: 0.60; 95%CI: 0.41–0.85; P= 0.005) (Fig 5).
For those with a severe functional impairment due to reduced cardiac function (NYHA
functional class III) a significant reduction of CV mortality risk could be observed (HR: 0.49;
95%CI: 0.27–0.88; P= 0.002) (Fig 6).
If combining those with IHD and those with impaired systolic cardiac function (EF<40%),
a reduced risk for CV death within the 12-year period could be found with an HR of 0.56 (95%
CI: 0.33–0.05; P= 0.03) (Table 3).
In order to further increase the group at CV risk, we combined the groups with hyperten-
sion, IHD and impaired systolic function. In this group, we found a significant risk reduction
with an HR of 0.60 (95%CI: 0.42–0.84; P= 0.004) as a result of the intervention (Table 3).
By adding those with diabetes to the above group, a significant risk reduction was still
observed, with an HR of 0.59 (95%CI: 0.42–0.83; P= 0.003)(Table 3).
Discussion
In an intervention study in 443 elderly healthy persons, selenium and coenzyme Q10 were
given as a combined dietary supplement for four years. After this period no intervention was
Table 2. Cox proportional hazard regression analysis evaluating risk of cardiovascular mortality by supplementa-
tion of selenium and coenzyme Q10 combined in a multivariate model after 12 years of follow-up after 4 years of
intervention to an elderly community population.
Variables Hazard ratio 95%CI P-value
Age 1.16 1.11–1.22 <0.0001
Male gender 1.80 1.30–2.51 <0.0001
Smoking 1.71 1.08–2.71 0.02
Hypertension 1.23 0.85–1.78 0.27
Diabetes 1.30 0.92–1.86 0.14
IHD 1.50 1.02–2.21 0.04
NYHA class 3 2.01 1.45–3.03 <0.0001
Beta blocker 0.85 0.59–1.21 0.37
ACE-inhibitor 1.11 0.76–1.61 0.59
Hb<120g/L 1.04 0.66–1.65 0.85
EF<40% 0.88 0.50–1.55 0.66
Active treatment 0.59 0.42–0.81 0.001
Notes: EF: Ejection fraction; IHD: Ischemic heart disease; NYHA: New York Heart Association functional class; Q4:
4
th
quartile
https://doi.org/10.1371/journal.pone.0193120.t002
Still reduced cardiovascular mortality after 12 years
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given, and thus some of the participants have been without the selenium and coenzyme Q10
intervention for ten years. Our results show a continual and significant reduction in CV mor-
tality during the whole follow-up period of 12 years, which also included the eight-year period
after termination of the intervention (Table 4).
Fig 3. Kaplan-Meier graph illustrating cardiovascular mortality in participants with ischemic heart disease
during a follow-up period of 12 years of those supplemented with selenium and coenzyme Q10 versus placebo for
four years on top of regular pharmaceutical treatment.
https://doi.org/10.1371/journal.pone.0193120.g003
Fig 4. Kaplan-Meier graph illustrating cardiovascular mortality in participants with diabetes during a follow-up
period of 12 years of those supplemented with selenium and coenzyme Q10 versus placebo for four years on top
of regular pharmaceutical treatment.
https://doi.org/10.1371/journal.pone.0193120.g004
Still reduced cardiovascular mortality after 12 years
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This appears clearly from the calculated mortality rates of the active treatment group, in com-
parison with those of the placebo group (Table 5), as we also did in the 10 years evaluation [20].
In Table 5, the figures from official Swedish mortality statistics are also added for compari-
son. The sample size of the present study is relatively small; therefore, the figures should be
Fig 5. Kaplan-Meier graph illustrating cardiovascular mortality in participants with hypertension during a
follow-up period of 12 years of those supplemented with selenium and coenzyme Q10 versus placebo for four
years on top of regular pharmaceutical treatment.
https://doi.org/10.1371/journal.pone.0193120.g005
Fig 6. Kaplan-Meier graph illustrating cardiovascular mortality in participants with NYHA functional class III
during a follow-up period of 12 years of those supplemented with selenium and coenzyme Q10 versus placebo for
four years on top of regular pharmaceutical treatment.
https://doi.org/10.1371/journal.pone.0193120.g006
Still reduced cardiovascular mortality after 12 years
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interpreted with caution. However, it is striking that the reduction in CV mortality also
remains after 12 years. Even though the reduction in CV risk measured as reduced CV mortal-
ity is still significant, the effect seems somewhat less after 12 years than after ten years [21],
especially in the male group.
This can probably be explained by the fact that ever-existing pathogenic factors catch up
with the positive effects obtained by our intervention. Also, as reported previously, females
have lower levels of coenzyme Q10 than males, presumably explaining why the females
benefited more than males from the supplementation [23].
The CV mortality risk reduction is significant and stable in all the well-known risk popula-
tions, including those with IHD, hypertension or diabetes. Even after combining groups in
order to increase stepwise the size to the subpopulations, the risk reduction is stable and com-
parable to the risk reduction obtained in the separate subgroups, indicating a robust effect
caused by the intervention. It is tempting to speculate that permanent or progressive structural
Table 3. Model testing the effect of intervention after 12 years on risk for cardiovascular mortality in different
groups.
Variable HR p-Value 95%CV
Total study population 0.58 0.0007 0.42–0.70
HT 0.59 0.005 0.41–0.85
IHD 0.52 0.02 0.30–0.90
DM 0.50 0.03 0.27–0.93
NYHA III 0.49 0.02 0.27–0.88
IHD+EF<40% 0.56 0.03 0.33–0.95
IHD+EF<40%+HT 0.60 0.004 0.42–0.84
IHD+EF<40%+HT+DM 0.59 0.003 0.42–0.83
Note: CV: Coefficient of variation; DM: Diabetes; HT: Hypertension; HR: Hazard ratio; IHD: Ischemic heart disease;
NYHA III: New York Heart Association functional class III
https://doi.org/10.1371/journal.pone.0193120.t003
Table 4. Difference in cardiovascular mortality within 5, 10 and 12 years after intervention of selenium and coenzyme Q10 combined or placebo for four years.
Follow-up time Mortality in active treatment group (%) Mortality in placebo group (%) χ
2
-value P-value
5 years 5.9 12.6 5.97 0.015
10 years 20.8 38.7 17.01 <0.0001
12 years 28.1 45.0 13.78 0.0002
https://doi.org/10.1371/journal.pone.0193120.t004
Table 5. Mortality rate after 5 years, 10 years and 12 years in the active treatment group compared to the placebo group, and to official mortality statistics.
5.2 years of follow-up 10 years of follow-up 12 years of follow-up
All-cause mort rate Cardiovasc mort rate All-cause mort rate Cardiovasc mort rate All-cause mort rate Cardiovasc mort rate
Active group 2433 1130 4427 2079 4542 2327
Placebo group 3115 2423 5400 3870 5993 3754
Reference pop 5794 2144 15,241699815,420 6326
Note: Mortality rate expressed as mortality /100,000/year
Note: Reference group: Official Swedish mortality statistics based on the age group 80–84 in the 5.2 year follow-up, and on the age group 85 years and above in the 10
years follow-up;
Figures based on statistics from 2014;
 Figures based on statistics from 2016
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Still reduced cardiovascular mortality after 12 years
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changes took place in the subjects of the placebo group during the interventional four-year
period, explaining the apparent slowing down of CV pathogenesis in the supplemented group.
Selenium-containing enzymes, as well as the coenzyme ubiquinone are strong antioxidants,
both being required in adequate amounts for normal cell function. Positive effects of supple-
mentation of coenzyme Q10 on endothelial function have also been reported [24]. It has been
shown that increased inflammatory activity[2527], and oxidative stress occur in the elderly
[28], and as one of the effects of the present intervention is to reduce signs of inflammatory
activity [29], and oxidative stress [30], it is tempting to speculate that this effect is partially
responsible for the long-lasting protection obtained in the present study. Moreover, endothe-
lial cells and platelets may be particularly vulnerable to oxidative stress as they are surrounded
by continuous oxygen transport in the circulation, and also exposed to increasing inflamma-
tory burden with age [31,32].
Furthermore, the persisting effects even eight years after termination of the supplementa-
tion could be related to the unusually long intervention time of four years, which as discussed
above, presumably was paralleled by structural changes in the placebos. The mean plasma con-
centration in this population was 67 μg/L[18]. For full expression of the extracellular seleno-
protein P, a concentration of >90–140 μg/L is needed [3335], implying that a selenium
deficiency in fact existed before the intervention and during the whole period in the placebo
group. Apparently, the size of the intervention, 200 μg Se/day was enough to give the needed
blood concentration, which has been reported previously [36]. On average, the supplemented
group had an estimated total daily selenium intake of about 235 μg, which is well above the
requirement to optimize selenoprotein P. It was also below a tolerable upper intake level of
300 μg as recommended by the European Food Safety Authority [37] and Nordic Nutrition
Recommendations [38]. In contrast, the population studied in the American SELECT trial had
a basal Se intake of at least 120 μg/d before supplementation; thus, their supplementation of
200 μg Se/d brought them into a marginal or hazardous zone of above 300 μg [39,40].
The long-lasting effect of the supplementation might also be related to the fact that a major
component of yeast selenium is selenomethionine, which is, at the expense of methionine,
incorporated into non-seleno proteins, which constitute the unspecific selenium pool having a
long elimination half-life [41]. Another partial explanation of the long-lasting effects might be
that the municipality under study developed an increased interest in supplementation with
selenium and coenzyme Q10 after the intervention period, and therefore some of the partici-
pants of the project may have continued to take supplementation. However, if this was the case,
even though it was not investigated in this study, we would expect that the amount randomized
to the placebo group that might have started post-project supplementation by random be
approximately as those that previously belonged to the active treatment group, and as a result
of the post-project supplementation, the difference between the groups should disappear.
The present 12-year evaluation of cardiovascular mortality after four years of intervention
is unique, and should be regarded as a validation of the surprising results from the 10-year
evaluation, and shows that the positive effects of the intervention persist.
Therefore, the hypothesis arising from our results remains that the intervention with sele-
nium and coenzyme Q10 inhibits the pathogenesis of irreversible, presumably structural,
changes preceding cardiovascular events.
Limitations
The presented study has a limited sample size, making the interpretation of the results difficult.
However, the statistical evaluations are extensive due to the many evaluations performed in
the study population, including those previously published.
Still reduced cardiovascular mortality after 12 years
PLOS ONE | https://doi.org/10.1371/journal.pone.0193120 April 11, 2018 11 / 15
The evaluations of the subgroups are even more uncertain as the sample sizes are smaller
compared to the main study group. However, also in this respect we would like to argue that
the different types of statistical methods used all point in the same direction; a reduction of
mortality was obtained by the intervention, confirming the previous suggestions that the opti-
mal selenium intake lies in the range 100–300 μg/d.
In this report the CV mortality within 12 years has been analyzed, a variable that could be
uncertain as it was based mainly on death certificates, and not on autopsy in a majority of the
participants. However, it is likely that the uncertainties in this study are of the same extent as
previous mortality studies that are not based on autopsies only. Hence, in spite of the limita-
tion we think our results provide interesting information.
The limited age span of the analyzed study population also represents a limitation, making
extrapolation of the results to larger populations difficult. However, the fact that the incidences
of CV as well as of other types of disease are higher in an elderly population compared to youn-
ger persons makes the obtained results of this 12-year follow-up even more intriguing.
Conclusion
We present a 12-year analysis of CV mortality in an elderly Swedish population that had been
given supplementation with selenium and coenzyme Q10 as a contribution to their diet for
four years. The present follow-up revealed a reduced CV mortality risk of more than 40%, and
a significant risk reduction in those with hypertension, IHD, impaired cardiac function, and
diabetes. We consider that the presented data, based on small sample sizes, should be regarded
as hypothesis-generating, as the data are both intriguing and surprising.
Supporting information
S1 Study Protocol.
(DOCX)
S1 Consort Checklist.
(DOC)
Author Contributions
Conceptualization: Urban Alehagen, Peter Johansson.
Formal analysis: Urban Alehagen.
Funding acquisition: Urban Alehagen.
Investigation: Urban Alehagen, Peter Johansson.
Methodology: Urban Alehagen, Peter Johansson.
Project administration: Urban Alehagen.
Resources: Urban Alehagen.
Software: Urban Alehagen.
Supervision: Jan Aaseth, Jan Alexander.
Validation: Urban Alehagen, Peter Johansson.
Writing – original draft: Urban Alehagen, Jan Aaseth, Jan Alexander, Peter Johansson.
Still reduced cardiovascular mortality after 12 years
PLOS ONE | https://doi.org/10.1371/journal.pone.0193120 April 11, 2018 12 / 15
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... In this regard, there is growing evidence that the very same interventions that target epigenetic regulators across different aged tissues, have a concomitant anti-ageing effect on the brain [170,267,[269][270][271][272]. Currently, the most accessible anti-ageing interventions that work through epigenetic regulation are physical exercise [90,[272][273][274][275][276], diet strategies (as for example, caloric restriction, intermittent fasting; [90,271,[275][276][277][278]) and nutritional (vitamins, macro-and micro-elements) supplementation [90,268,[279][280][281][282][283][284]. ...
... Omega-3 has been shown to display a decreased concentration in patients with dementia or pre-dementia syndrome [384], while supplementation with omega-3 improved cognitive function in elderly with mild cognitive impairment [385] and Alzheimer's disease [386]. Taking these observations together, one may conclude that there are multiple ways in which an individually-tailored combination of nutraceutical compounds may contribute to BBA reversal as well as BR enhancement by modulating the epigenome [280], thus safeguarding physical and mental health during CA, and hypothetically even reducing mortality [281]. ...
Preprint
Full-text available
BACKGROUND: There is a growing consensus that chronological age (CA) is not an accurate indicator of the ageing progress and that biological age (BA) instead is a better measure of an individual's risk of age-related outcomes and a more accurate predictor of mortality than actual CA. In this context BA measures the "true" age that is an integrated result of an individual's level of damage accumulation across all levels of biological organization, along with preserved resources. The BA is plastic and depends upon epigenetics. Brain state is an important factor contributing to health-and lifespan. METHODS AND OBJECTIVE: Quantitative electroencephalography (qEEG) derived brain BA (BBA) is a suitable and promising measure of brain ageing. In the present study we aimed to show that BBA can be decelerated or even reversed in humans (N = 89) by using customized programs of nutraceutical compounds or lifestyle changes (Mean duration = 13 months). RESULTS: We observed that the BBA was younger than CA in both groups at the end of the intervention. Further, the BBA of participants in the nutraceuticals group was 2.83 years younger at the endpoint of the intervention compared with BBA score at the beginning of the intervention, while the participants' BBA of the lifestyle group scored only 0.02 years younger at the end of the intervention. These results were accompanied by improvement in mental-physical health comorbidities in both groups. Pre-intervention BBA score, as well as sex of participants were considered as confounding factors and analyzed separately. CONCLUSIONS: Overall, the obtained results support the feasibility of the goal of this study and also provide the first robust evidence that halting and reversal of brain ageing is possible in humans within a reasonable (practical) timeframe of around one year.
... Because Se intake is low in Europe, and endogenous coenzyme Q 10 production declines after adolescence, supplementation is thought to restore an imbalance due to low antioxidant status, which otherwise may result in increased cardiovascular (CV) risk, among other effects. We have previously reported beneficial effects of combined supplementation with Se and coenzyme Q 10 on CV mortality and biomarkers related to inflammation [12][13][14], oxidative stress [15], endothelial dysfunction [16], and microRNA profiling [17]. ...
... Our previous published findings on the beneficial effects of combined supplementation with Se and coenzyme Q 10 on CV mortality [14,20,37] inflammation, oxidative stress and endothelial dysfunction [12,13,15,16], along with the present preventive effect on telomere attrition and indirectly CV mortality risk, underline the anti-inflammatory, anti-oxidative, and anti-ageing effects of such intervention in the elderly low in Se. ...
... Because Se intake is low in Europe, and endogenous coenzyme Q 10 production declines after adolescence, supplementation is thought to restore an imbalance due to low antioxidant status, which otherwise may result in increased cardiovascular (CV) risk, among other effects. We have previously reported beneficial effects of combined supplementation with Se and coenzyme Q 10 on CV mortality and biomarkers related to inflammation [12][13][14], oxidative stress [15], endothelial dysfunction [16], and microRNA profiling [17]. ...
... Our previous published findings on the beneficial effects of combined supplementation with Se and coenzyme Q 10 on CV mortality [14,20,37] inflammation, oxidative stress and endothelial dysfunction [12,13,15,16], along with the present preventive effect on telomere attrition and indirectly CV mortality risk, underline the anti-inflammatory, anti-oxidative, and anti-ageing effects of such intervention in the elderly low in Se. ...
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Short telomeres have been associated with ageing and cardiovascular disease. The influence on leukocyte telomere length (LTL) of long-term intervention with combined selenium and coenzyme Q10 is unknown. Our aim was to determine whether 42 months of selenium and coenzyme Q10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium (n = 118), aged 70–80 years, were included. Intervention time was 4 years, with 10 years’ follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group (p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. −0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL (p < 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival (p = 0.03). To conclude, preservation of LTL after selenium and coenzyme Q10 supplementation associated with reduced cardiovascular mortality.
... Moreover, a five-year prospective RCT among 443 Swedish citizens aged 70-88 years showed that the combined supplementation of Se and coenzyme Q10 significantly reduced CVD mortality, accompanied by a decreased level of N-terminal pro-BNP and a better cardiac function score, compared with the placebo group [93]. Even after 12 years, CVD mortality was significantly reduced in the actively supplemented group, as well as in subgroups of patients with diabetes, HT, ischemic heart disease, or impaired functional capacity, compared with the placebo group [94]. These results suggest that the protective action of Se supplementation was not confined to the intervention period but persisted during the follow-up period [94]. ...
... Even after 12 years, CVD mortality was significantly reduced in the actively supplemented group, as well as in subgroups of patients with diabetes, HT, ischemic heart disease, or impaired functional capacity, compared with the placebo group [94]. These results suggest that the protective action of Se supplementation was not confined to the intervention period but persisted during the follow-up period [94]. Alehagen et al. further indicated that supplementation with Se and coenzyme Q10 resulted in lower concentrations of both copeptin and MR-proADM (as oxidative stress biomarkers) in a four-year prospective RCT among 437 elderly Swedish citizens [95]. ...
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Selenium (Se), in the form of selenoproteins, is an essential micronutrient that plays an important role in human health and disease. To date, there are at least 25 selenoproteins in humans involved in a wide variety of biological functions, including mammalian development, metabolic progress, inflammation response, chemoprotective properties, and most notably, oxidoreductase functions. In recent years, numerous studies have reported that low Se levels are associated with increased risk, poor outcome, and mortality of metabolic disorders, mainly related to the limited antioxidant defense resulting from Se deficiency. Moreover, the correlation between Se deficiency and Keshan disease has received considerable attention. Therefore, Se supplementation as a therapeutic strategy for preventing the occurrence, delaying the progression, and alleviating the outcomes of some diseases has been widely studied. However, supranutritional levels of serum Se may have adverse effects, including Se poisoning. This review evaluates the correlation between Se status and human health, with particular emphasis on the antioxidant benefits of Se in metabolic disorders, shedding light on clinical treatment.
... Due to the biochemical properties of coenzyme Q10, it may play an important role in the prevention and treatment of HF, and in the treatment of some very common cardiovascular risk factors, such as arterial hypertension, insulin resistance, dyslipidemia, and atherosclerosis ( Figure 7) [10,15]. [30]. In the context of this study, it is worth mentioning that selenium supplementation may support the action of endogenous coenzyme Q10 because this element is a component of selenoproteins thioredoxin reductase which is involved in the regeneration of ubiquinol [31]. ...
... [38]. The result of the meta- [30]. In the context of this study, it is worth mentioning that selenium supplementation may support the action of endogenous coenzyme Q10 because this element is a component of selenoproteins thioredoxin reductase which is involved in the regeneration of ubiquinol [31]. ...
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Heart failure (HF) is a global epidemic that contributes to the deterioration of quality of life and its shortening in 1–3% of adult people in the world. Pharmacotherapy of HF should rely on highly effective drugs that improve prognosis and prolong life. Currently, the ESC guidelines from 2021 indicate that ACEI, ARNI, BB, and SGLT2 inhibitors are the first-line drugs in HF. It is also worth remembering that the use of coenzyme Q10 brought many benefits in patients with HF. Coenzyme Q10 is a very important compound that performs many functions in the human body. The most important function of coenzyme Q10 is participation in the production of energy in the mitochondria, which determines the proper functioning of all cells, tissues, and organs. The highest concentration of coenzyme Q10 is found in the tissue of the heart muscle. As the body ages, the concentration of coenzyme Q10 in the tissue of the heart muscle decreases, which makes it more susceptible to damage by free radicals. It has been shown that in patients with HF, the aggravation of disease symptoms is inversely related to the concentration of coenzyme Q10. Importantly, the concentration of coenzyme Q10 in patients with HF was an important predictor of the risk of death. Long-term coenzyme Q10 supplementation at a dose of 300 mg/day (Q-SYMBIO study) has been shown to significantly improve heart function and prognosis in patients with HF. This article summarizes the latest and most important data on CoQ10 in pathogenesis.
... Selenium and coenzyme Q10 were supplemented in a fouryear intervention study, to an elderly population (n = 443) with a low selenium status and because of old age, a low level of coenzyme Q10. A significantly reduced cardiovascular mortality was observed after five, 10 and 12 years [1][2][3]. Here we present an overview of the intervention trial including clinical outcomes and secondary analyses conducted mainly on different biomarkers. ...
... In addition, the positive long-term results have been validated in a follow-up evaluation after 12 years with a HR of 0.59 (95%CI 0.42-0.81; p = 0.001) of CV mortality risk when using a multivariate model [3]. It should be emphasized that the active intervention was terminated already after four years. ...
Article
Full-text available
Purpose Selenium and coenzyme Q10 have synergistic antioxidant functions. In a four-year supplemental trial in elderly Swedes with a low selenium status, we found improved cardiac function, less cardiac wall tension and reduced cardiovascular mortality up to 12 years of follow-up. Here we briefly review the main results, including those from studies on biomarkers related to cardiovascular risk that were subsequently conducted. In an effort, to explain underlying mechanisms, we conducted a structured analysis of the inter-relationship between biomarkers. Methods Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/ day), or placebo was given to 443 elderly community-living persons, for 48 months. Structural Equation Modelling (SEM) was used to investigate the statistical inter-relationships between biomarkers related to inflammation, oxidative stress, insulin-like growth factor 1, expression of microRNA, fibrosis, and endothelial dysfunction and their impact on the clinical effects. The main study was registered at Clinicaltrials.gov at 30th of September 2011, and has the identifier NCT01443780. Results In addition to positive clinical effects, the intervention with selenium and coenzyme Q10 was also associated with favourable effects on biomarkers of cardiovascular risk. Using these results in the SEM model, we showed that the weights of the first-order factors inflammation and oxidative stress were high, together forming a second-order factor inflammation/oxidative stress influencing the factors, fibrosis (β = 0.74; p < 0.001) and myocardium (β = 0.65; p < 0.001). According to the model, the intervention impacted fibrosis and myocardium through these factors, resulting in improved cardiac function and reduced CV mortality. Conclusion Selenium reduced inflammation and oxidative stress. According to the SEM analysis, these effects reduced fibrosis and improved myocardial function pointing to the importance of supplementation in those low on selenium and coenzyme Q10.
... However, observational studies reported that lower concentrations of serum selenium were associated with decreased recovery rate in COVID-19 patients (Moghaddam et al., 2020;Zhang et al., 2020). Low serum selenium levels in the elderly are associated with decreased survival and a higher mortality rate (Alehagen et al., 2016(Alehagen et al., , 2018Robberecht et al., 2019). Therefore, assessment of serum selenium concentrations in all hospitalized patients and appropriate supplement administration in documented deficiencies at any stage of disease would be beneficial. ...
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Background Malnutrition in COVID-19 hospitalized patients is associated with a high-risk condition to increase disease severity and prolonging the recovery period. Therefore, nutritional therapy, including supplements plays a critical role to reduce disease-related complications and the length of hospital stay. Aim To review the latest evidence on nutritional management options in COVID-19 hospitalized patients, as well as possibly prescribed supplements. Methods This review was conducted by considering the latest recommendations, using the guidelines of the American Society of Enteral and Parenteral (ASPEN) and the European Society of Enteral and Parenteral (ESPEN), and searching Web of Science, PubMed/Medline, ISI, and Medline databases. The relevant articles were found using a mix of related mesh terms and keywords. We attempted to cover all elements of COVID-19 hospitalized patients’ dietary management. Results Energy demand in COVID-19 patients is a vital issue. Indirect Calorimetry (IC) is the recommended method to measure resting energy expenditure. However, in the absence of IC, predictive equations may be used. The ratio of administered diet for the macronutrients could be based on the phase and severity of Covid-19 disease. Moreover, there are recommendations for taking micronutrient supplements with known effects on improving the immune system or reducing inflammation. Conclusions Nutritional treatment of COVID-19 patients in hospitals seems to be an important element of their medical care. Enteral nutrition would be the recommended feeding method for early nutrition support. However, data in the COVID-19 nutritional domain relating to micronutrient supplementation are still fragmentary and disputed, and further study is required.
... Dietary CQ 10 supplementation was associated with a significant reduction in percentage mortality when administered alone, or co-administered with LD in the PD model. The ability of CQ 10 to improve well-being in the elderly [53,54], and/or reduce mortality in persons with congestive heart failure [55] has been reported. CQ 10 ' is a potent antioxidant, and a central component of the electron transport chain [55,56]. ...
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Ubiquinone and ubiquinol represent the oxidized and reduced forms of Coenzyme Q10 (CoQ10 ). CoQ10 is present in membranes of almost all human tissues and organs, with highest concentration in the heart. In patients with heart failure, serum levels of the N-terminal pro-brain natriuretic peptide (NT-proBNP) are an indicator of disease severity. Here, we investigated the relationship between serum levels of CoQ10 and NT-proBNP in healthy volunteers of an elderly study population (mean age 52 years, n = 871). We found a negative association between serum levels of ubiquinol and NT-proBNP (P < 0.001). Accordingly, the CoQ10 redox state (% oxidized form of CoQ10 ) is positively associated with serum NT-proBNP level (P < 0.001). Compared to patients who survived a myocardial infarction (n = 21), healthy subjects have lower NT-proBNP level (500.39 ± 631.28 pg/ml vs. 76.90 ± 120.27 pg/ml, P < 0.001), higher ubiquinol serum level (0.43 ± 0.19 µmol/L vs. 0.71 ± 0.32 µmol/L; P < 0.001), and a lower CoQ10 redox state (27.6 ± 13.8% vs. 17.6 ± 10.1%; P < 0.001). Interestingly, ubiquinol supplementation (150 mg/day; 14 day; n = 53) slightly reduces the expression of CLCN6, a gene related to NT-proBNP level. In summary, higher serum levels of ubiquinol are associated with lower serum NT-proBNP levels in healthy elderly subjects. However, to what extent a high serum level of ubiquinol is a protective factor for heart failure remains to be elucidated in prospective studies. © 2015 BioFactors, 41(1):35-43, 2015. © 2015 International Union of Biochemistry and Molecular Biology.