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Citation: Sinclair, J.; Bottoms, L.;
Dillon, S.; Allan, R.; Shadwell, G.;
Butters, B. Effects of Montmorency
Tart Cherry and Blueberry Juice on
Cardiometabolic and Other
Health-Related Outcomes: A
Three-Arm Placebo Randomized
Controlled Trial. Int. J. Environ. Res.
Public Health 2022,19, 5317.
https://doi.org/10.3390/
ijerph19095317
Academic Editors: Han C. G. Kemper
and Paul B. Tchounwou
Received: 1 April 2022
Accepted: 24 April 2022
Published: 27 April 2022
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4.0/).
International Journal of
Environmental Research
and Public Health
Article
Effects of Montmorency Tart Cherry and Blueberry Juice on
Cardiometabolic and Other Health-Related Outcomes:
A Three-Arm Placebo Randomized Controlled Trial
Jonathan Sinclair 1, * , Lindsay Bottoms 2, Stephanie Dillon 1, Robert Allan 1, Gareth Shadwell 1
and Bobbie Butters 1
1Research Centre for Applied Sport, Physical Activity and Performance, School of Sport & Health Sciences,
Faculty of Allied Health and Wellbeing, University of Central Lancashire, Preston PR1 2HE, UK;
sdillon@uclan.ac.uk (S.D.); rallan1@uclan.ac.uk (R.A.); gshadwell3@uclan.ac.uk (G.S.);
bbutters2@uclan.ac.uk (B.B.)
2Centre for Research in Psychology and Sport Sciences, School of Life and Medical Sciences, University of
Hertfordshire, Hatfield AL10 9AB, UK; l.bottoms@herts.ac.uk
*Correspondence: jksinclair@uclan.ac.uk
Abstract:
The current study aimed to investigate the influence of tart cherry and blueberry juices
on cardiometabolic and other health indices following a 20-day supplementation period. Forty-five
adults were randomly assigned to receive tart cherry, blueberry, or a placebo, of which they drank
60 mL per day for 20 days. The primary outcome, which was systolic blood pressure, and sec-
ondary measures, including anthropometric, energy expenditure, substrate oxidation, hematological,
diastolic blood pressure/resting heart rate, psychological wellbeing, and sleep efficacy, were mea-
sured before and after the intervention. There were no statistically significant differences (
p> 0.05
)
for systolic blood pressure; however, total and LDL cholesterol were significantly improved with
blueberry intake (pre: total cholesterol = 4.36 mmol/L and LDL cholesterol = 2.71 mmol/L; post:
total cholesterol = 3.79 mmol/L
and LDL cholesterol = 2.23 mmol/L) compared to placebo (pre: total
cholesterol = 4.01 mmol/L and LDL cholesterol = 2.45 mmol/L; post:
total cholesterol = 4.34 mmol/L
and LDL cholesterol = 2.67 mmol/L). Furthermore, psychological wellbeing indices measured us-
ing the Beck Depression Inventory, State Trait Anxiety Inventory, and COOP WONCA improved
statistically in the blueberry arm compared to placebo. Given the clear association between lipid
concentrations and the risk of cardiovascular disease as well as the importance of psychological
wellbeing to health-related quality of life, this investigation indicates that it could be an effective
approach to assist in managing cardiometabolic disease.
Keywords: tart cherry; blueberry; cardiovascular disease; blood pressure; metabolic health
1. Introduction
Cardiometabolic disease is now the principal cause of global mortality and healthcare
expenditure [
1
]. Cardiometabolic syndrome itself is characterized by a range of symptoms,
including hypertension, insulin resistance, atherogenic dyslipidemia, low high-density
lipoproteins, high triglycerides, high adiposity, high body mass index, large waist-to-hip
ratio, and poor glucose regulation [
2
,
3
]. Within the epidemiological literature, distinct
pathophysiological markers of oxidative stress, nitric oxide, and inflammation have been
cited as being the mechanistic indicators associated with the clinical presentation of car-
diometabolic disease [4,5].
Pharmaceutical interventions represent the predominant treatment modalities for
cardiometabolic conditions [
6
]. However, while these medications are efficacious in regards
to the management of cardiometabolic disease, their cost-effectiveness remains ambigu-
ous [
7
], and significant negative side-effects remain common [
8
]. Globally, it has been
Int. J. Environ. Res. Public Health 2022,19, 5317. https://doi.org/10.3390/ijerph19095317 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2022,19, 5317 2 of 18
documented that 84% of adults over the age of 57 are prescribed at least one medication
per day [
9
]. As such, it is clear that further natural and cost-effective remedies are required
for cardiometabolic disease management and prevention [3].
Dietary practices are recognized as the most effective natural approach for the treat-
ment of cardiometabolic disease such that most national/international medical organiza-
tions advocate improved nutrition for the prevention and management of this condition [
10
].
There is therefore a clear rationale for the implementation of dietary over pharmaceutical
interventions, and indeed, Chiva-Blanch et al. [
11
] proposed that such approaches are
likely to be more cost-effective and safer for the treatment and prevention of metabolic
diseases. Diets rich in fruits and vegetables have been shown to attenuate the risk from
cardiometabolic disease [
12
] although maintaining such approaches over a sustained du-
ration has been shown to be difficult to accomplish [
13
]. Therefore, dietary supplements
represent a potentially more appealing treatment and prevention modality.
Anthocyanins are abundant in dark-colored fruit and vegetable groups [
14
], and it
is proposed that they may be able to confer significant improvements in cardiometabolic
health [
15
]. Montmorency tart cherries, blueberries, strawberries, cranberries, and black-
currants [
16
] in particular have been shown to possess high levels of anthocyanins [
17
]
although the majority of peer-reviewed literature has focused on tart cherries. Supplemen-
tation of anthocyanin-rich tart cherries has been shown to improve oxidative stress [
18
,
19
]
and inflammation [
19
–
21
], and blackcurrant supplementation was also shown to enhance
fat-oxidation rates [
22
]. Improved fat oxidation during rest and physical activity is linked
to long-term changes in body mass and composition allied with improvements in in-
sulin sensitivity [
23
]. Therefore, an increased capacity to oxidize fat at rest and during
moderate physical activity, initiated via anthocyanin-rich supplementation, may be ad-
vantageous for yielding improvements in body composition and insulin control, which is
pertinent to cardiometabolic health. Importantly, the aforementioned anti-inflammatory,
anti-oxidative, and substrate trafficking effects mediated through supplementation of
anthocyanin-rich fruits appear to conveniently target the underlying chronic low-grade
inflammation, pro-oxidant, and lipid-attenuating status that is central to cardiometabolic
disease pathophysiology [24].
However, the findings from parallel randomized controlled trials exploring the ef-
fects of anthocyanin-rich fruit supplementation on cardiometabolic outcomes have yielded
equivocal findings. Some studies exploring the effects of Montmorency tart cherry juice
supplementation have shown no effect on cardiometabolic indices of blood pressure, triglyc-
erides, insulin tolerance, or cholesterol [
25
–
28
], and some have revealed improvements
in systolic blood pressure, total cholesterol, and low-density lipoprotein (LDL) choles-
terol [
4
,
6
,
29
–
32
]. Studies exploring the efficacy of other anthocyanin-rich supplements
present a similarly equivocal picture, with some demonstrating positive effects on car-
diometabolic outcomes [33–37] and some showing no such effects [38–41].
1.1. Rationale
At the current time, there have yet to be any randomized intervention studies com-
paratively examining the efficacy of different anthocyanin-rich fruit supplements on car-
diometabolic outcomes. With some food biochemical investigations showing that antho-
cyanin contents in dark fruits, such as blueberries, are as high or even greater than in tart
cherries [17], further such investigations may be of both practical and clinical relevance.
1.2. Aim
The aim of the current study was to investigate the influence of 20 days of twice daily
Montmorency tart cherry or blueberry juice supplementation on cardiometabolic and other
health-related indices in healthy adults compared to placebo. The primary objective of this
randomized trial is to examine the influence of the tart cherry and blueberry supplements
on systolic blood pressure relative to placebo. Its secondary objectives are to assess if tart
Int. J. Environ. Res. Public Health 2022,19, 5317 3 of 18
cherry juice and blueberry supplementation impacted other risk factors associated with
and as a function of cardiometabolic disease.
1.3. Hypotheses
In relation to the primary outcome, it is expected that both Montmorency tart cherry
and blueberry supplement groups will mediate significant reductions in systolic blood
pressure compared to placebo, but no statistically significant differences will be observed
between supplement groups. Furthermore, for the secondary outcomes, the Montmorency
tart cherry and blueberry groups will produce improvements in cardiometabolic other
health-related parameters compared to placebo, but there will be no statistically significant
differences between the two supplement groups.
2. Materials and Methods
2.1. Study Design
This investigation represents a 20-day parallel, single-blind (blinded to participant),
randomized placebo-controlled trial (Figure 1). The 20-day supplementation period was
adopted in accordance with [
28
], and the protocol for this 3-arm randomized investi-
gation has been previously published elsewhere [
3
] and was designed according to the
updated guidelines for reporting parallel group randomized trials [
42
]. The study was
registered prospectively (NCT04177238) and approved by an institutional ethical review
board (HEALTH 0016).
Int. J. Environ. Res. Public Health 2022, 19, x FOR PEER REVIEW 4 of 19
Figure 1. Consort diagram showing the study design.
2.2. Inclusion Criteria
- 18 years of age and above;
- Non-smoker;
- BMI < 30;
- Able to give informed consent.
Exclusion criteria:
- Pregnancy;
- 65 years of age and above;
- Diabetes or any other metabolic/uncontrolled hypertensive conditions;
- Food allergies to cherries or blueberries;
- Habitual consumption of blueberries/cherries and/or blueberry/cherry products;
- Not regularly taking medication or antioxidant supplements.
Figure 1. Consort diagram showing the study design.
Int. J. Environ. Res. Public Health 2022,19, 5317 4 of 18
After screening for eligibility and enrollment, participants were then randomized by a
computer program (Random Allocation Software Version 1.0) to either (1) Montmorency
tart cherry, (2) blueberry, or (3) placebo group. All experimental variables were assessed
at (a) baseline (pre) and (b) after 20 days (post). In agreement with previous trials of
cardiometabolic health, the primary outcome measure was the between-group difference
in systolic blood pressure from baseline to post intervention [
27
]. Secondary outcome
measures were between-group differences in anthropometric, energy expenditure and
substrate oxidation (during rest and moderate intensity exercise), hematological, diastolic
blood pressure/resting heart rate, psychological wellbeing, and sleep efficacy indices. All
experimental testing took place in the morning in a
≥
10 h fasted state, with participants
having avoided strenuous exercise, alcohol, and nutritional supplements for 24 h and
caffeine for 12 h prior to data collection [28].
2.2. Inclusion Criteria
- 18 years of age and above;
- Non-smoker;
- BMI < 30;
- Able to give informed consent.
Exclusion criteria:
- Pregnancy;
- 65 years of age and above;
- Diabetes or any other metabolic/uncontrolled hypertensive conditions;
- Food allergies to cherries or blueberries;
- Habitual consumption of blueberries/cherries and/or blueberry/cherry products;
- Not regularly taking medication or antioxidant supplements.
2.3. Participants
Power calculations were performed for the primary outcome variable, i.e., the between-
groups difference in systolic blood pressure. This showed that a total sample size of 45 was
necessary to provide 80% power to detect a minimally important clinical difference (MCID)
of 6 mmHg between groups [
43
], with a projected standard deviation of 5.5 mmHg in each
group [
44
], accounting for a loss to follow up rate of 10%. Participants attended an eligibility,
enrollment, and familiarization session prior to the commencement of formal data collection
at the University of Central Lancashire. All participants provided informed consent in
written form and completed a Par-Q screening form before taking part, in compliance with
principles outlined in the declaration of Helsinki and the Oviedo Convention.
2.4. Dietary Intervention
After the conclusion of their baseline data collection session, participants were pro-
vided with either Montmorency tart cherry, blueberry, or placebo concentrate. Participants
were required to consume 30 mL of supplementation diluted in 100 mL of water twice daily:
once in the morning and again in the evening [
27
]. All supplementation was kept refriger-
ated throughout the 20 days. According to the manufacturer (ActiveEdge, Wintney, UK),
a 30 mL dose of Montmorency tart cherry concentrate (Energy: 102 Kcal, carbohydrates:
25 g of which sugars: 18 g, protein: 1.10 g, and fiber: 2.6 g) is equivalent to approximately
320 mg
of anthocyanins. Similarly, taking into account the manufacturers (ActiveEdge,
Wintney, UK) guidelines, a 30 mL dose of blueberry concentrate (Energy: 103 Kcal, car-
bohydrates: 22 g of which sugars: 22 g, protein: 0.2 g, and fiber: 0.2 g) is equivalent to
approximately 387 mg of anthocyanins.
Preparation of the placebo was undertaken in accordance with that outlined previously
within the literature; this method of placebo preparation has been shown by previous
intervention trials to provide an effective blinding strategy [
45
]. Placebo preparation
involved mixing 100% un-flavored maltodextrin carbs (MyProtein, Cheshire, UK) into
drinking water using a magnetic stirrer (Stuart Scientific, Staffordshire, UK) and stir bar
Int. J. Environ. Res. Public Health 2022,19, 5317 5 of 18
(Fisher Scientific, Waltham, MA, USA). A total of 666 g of maltodextrin was added to water
to create a liter of placebo concentrate, working out as 20 g of maltodextrin per 30 mL
serving closely matching the Montmorency tart cherry or blueberry supplementation. Even
amounts of red and black food coloring were added to match the color of the Montmorency
tart cherry concentrate and even amounts of red, blue, and black coloring were utilized to
match the color of the blueberry supplement. Either cherry or blueberry flavdrops (1 mL)
(MyProtein, Cheshire, UK) were then added to match the required flavor. Irrespective of
flavor, a 30 mL dose of placebo concentrate (100 Kcal, carbohydrates 25 g of which sugars:
0 g, protein: 0 g, and fiber 0 g) contained 0 mg of anthocyanins.
Throughout the study, the participants were encouraged to maintain their habitual diet
and exercise routines and asked to refrain from consuming any multivitamin or antioxidant
supplements [
25
]. For their post-intervention data collection session, all participants were
asked to return any unused supplementation to determine the actual amount of supple-
ment/placebo that was consumed (mL) and their % compliance. Furthermore, in order
to explore the total quantity of supplementary ingested anthocyanins (mg), experimental
average daily energy intake (Kcal/day) and supplementary average daily sugars (g/day)
as well as the amount of supplementation that was consumed was multiplied by the an-
thocyanin, energy, and sugar contents established by the manufacturer. Finally, in order to
examine blinding efficacy, each participant was asked whether they felt that they had been
allocated to the supplement or placebo group at the conclusion of their post-intervention
data collection session. In all three trial arms, loss to follow up was monitored as were any
adverse events.
2.5. Data Collection
2.5.1. Laboratory Visit Data
All measurements were undertaken at the University of Central Lancashire’s physi-
ology laboratory (Preston, UK) and undertaken in an identical manner on two occasions,
i.e., baseline and post intervention. The laboratories housed by the University of Central
Lancashire are fully accredited by the British Association for Sport and Exercise Sciences,
illustrating that they have undergone meticulous inspection and evidenced that all in-
strumentation is well maintained in terms of reliability, validity, and routine servicing;
staff have the appropriate professional and vocational qualifications; and that the requisite
operational procedures for health and safety are met.
2.5.2. Anthropometric Measurements
Anthropometric measures of mass (kg) and stature (m) (without shoes) were used to
calculate the body mass index (BMI) (kg/m
2
). Stature was measured using a stadiometer
(Seca, Hamburg, Germany) and mass using weighing scales (Seca 875, Hamburg, Germany).
In addition, body composition was examined using a phase-sensitive multifrequency bio-
electrical impedance analysis device (Seca mBCA 515, Hamburg, Germany) [
46
], allowing
percentage body fat (%) and fat mass (kg) to be quantified. Finally, waist circumference
was measured at the midway point between the inferior margin of the last rib and the
iliac crest and hip circumference around the pelvis at the point of maximum protrusion of
the buttocks, without compressing the soft tissues [
47
], allowing the waist-to-hip ratio to
be quantified.
2.5.3. Energy Expenditure and Substrate Oxidation
Respiratory gases were collected using a gas analysis system (MetaLyser 3B system,
Cortex Biophysic, Leipzig, Germany). The experimental laboratory was maintained using
an air-conditioning system at a fixed ambient temperature of 20
◦
C. To quantify resting
energy expenditure and substrate oxidation, participants laid supine for a period of
20 min
,
and data were extracted and averaged over the final 17 min [
48
]. Resting fat and carbohy-
drate oxidation rates (g/min) were quantified using the stoichiometric formulae outlined
by Freyn, ref. [
49
] (Equations (1) and (2)), assuming negligible protein utilization. To
Int. J. Environ. Res. Public Health 2022,19, 5317 6 of 18
quantify resting metabolic rate (RMR) (kcal/day) the formula of Weir [
50
] was adopted
(Equation (3)).
Carbohydrate (g/min) = (4.55 ×VCO2)−(3.21 ×VO2) (1)
Fat (g/min) = (1.67 ×VO2)−(1.67 ×VCO2) (2)
RMR (kcal/day) = [(3.941 ×VO2) + (1.1106 ×VCO2)] ×1440 (3)
In addition, carbohydrate- and fat-oxidation rates (g/min) and energy expenditure
per minute (kcal/min) were also examined during moderate intensity physical activity.
Participants walked on a treadmill (hp Cosmos Pulsar, Nussdorf, Germany) at a velocity
of 4.5 km/h for a period of 6 min. This walking velocity has reliably been shown to
correspond to moderate exercise intensities [
51
]. Data were averaged over the last minute of
the
6 min
test. Fat- and carbohydrate-oxidation rates (g/min) as well as energy expenditure
(kcal/min) during the exercise test were quantified using stoichiometric formulae outlined
by Jeukendrup and Wallis [
52
], specifically developed for the exercise intensity examined
in this study (Equations (4)–(6)).
Carbohydrate (g/min) = (4.21 ×VCO2)−(2.962 ×VO2) (4)
Fat (g/min) = (1.695 ×VO2)−(1.701 ×VCO2) (5)
Energy expenditure (kcal/min) = (0.550 ×VCO2)−(4.471 ×VO2) (6)
2.5.4. Hematological Testing
Capillary blood samples were also collected via finger-prick using a disposable lancet
after cleaning with a 70% ethanol wipe. Capillary triglyceride, total cholesterol, and
glucose levels (mmol/L) were immediately obtained using three handheld analyzers
(MulticareIn, Multicare Medical, Arezzo, Italy) and capillary hemoglobin levels (g/L)
using a single handheld analyzer (HemoCue, Ängelholm, Sweden). From these outcomes,
LDL cholesterol (mmol/L) was firstly quantified using the Anandaraja et al. [
53
] formula
with total cholesterol and triglycerides as inputs. In addition, high-density lipoprotein
(HDL) cholesterol (mmol/L) was also calculated by re-arranging the Chen et al. [
54
]
equation to make HDL the product of the formulae. Both of these approaches have
been shown to have excellent similarity to their associated lipoprotein values examined
using immunoassay techniques r = 0.948
−
0.970 [
55
,
56
] The ratios between total and
HDL cholesterol and between LDL and HDL cholesterol levels were also determined in
accordance with Millán et al. [55].
2.5.5. Blood Pressure and Resting Heart Rate
Blood pressure (mmHg) and resting heart rate (beats
·
min
−1
) measurements were
undertaken in an up-right seated position at the end of the above-described resting energy
expenditure test. Both peripheral measures of systolic and diastolic blood pressure and
resting heart rate were be measured via a non-invasive, automated blood pressure monitor
(OMRON M2, Kyoto, Japan), adhering to the recommendations specified by the European
Society of Hypertension [
56
]. Three readings were undertaken, each separated by a period
of 1 min [57], and the mean of the last 2 readings used for analysis.
2.5.6. Questionnaires
Sleep quality is diminished in patients with cardiometabolic disease [
58
], and intake
of dietary polyphenols [
59
] and supplementation of Montmorency tart cherry has been
demonstrated to enhance sleep quality and symptoms of insomnolence [
60
,
61
]. Therefore,
general sleep quality was examined using the Pittsburgh sleep quality index (PSQI) [
62
],
daytime sleepiness using the Epworth Sleepiness Scale [
63
] and symptoms of insomnolence
Int. J. Environ. Res. Public Health 2022,19, 5317 7 of 18
via the Insomnia Severity Index [
64
]. These questionnaires were utilized co-operatively to
provide a collective representation of sleep efficacy.
Furthermore, psychological wellbeing is lower in those with cardiometabolic dis-
ease [
65
], and a high intake of dietary polyphenols has been shown to enhance indices
of psychological wellbeing [
66
]. Therefore, general psychological wellbeing was exam-
ined using the COOP WONCA questionnaire [
67
], depressive symptoms using the Beck
Depression Inventory [
68
], and state/trait anxiety with the State Trait Anxiety Inventory
(STAI) [
69
]. Once again, these scales were utilized conjunctively to provide a collective
depiction of psychological wellbeing.
2.6. Statistical Analysis
All continuous experimental variables are presented as mean and standard deviations
(SD). Comparisons between participant characteristics and all experimental variables were
undertaken at baseline, as were the % compliance levels, experimental anthocyanins, exper-
imental energy intake, and experimental sugars (g/day) between the groups using linear
mixed models, with group modeled as a fixed factor and random intercepts by participants.
All analyses of the intervention-based data were performed using on an intention to treat
basis. To determine the effects of the intervention on all of the outcome measures, differ-
ences between the three groups were examined using linear mixed models with group
modeled as a fixed factor and random intercepts by participants adopted, adjusted for
baseline values modeled as a continuous fixed covariate. For linear mixed models the
mean difference (b), t-value and 95% confidence intervals of the difference are presented.
Effects sizes for all statistically significant comparisons were quantified using partial eta
squared (
ηP2
). Blinding efficacy was examined using a one-way chi-square (X
2
) goodness
of fit test. Finally, changes from baseline to 20 days in the experimental parameters were
used to create binary variables, i.e., improve/did not improve for each participant. Pearson
chi-square tests of independence were also used to undertake bivariate cross-tabulation
comparisons between the three trial groups, specifically to test differences in the number
of participants who exhibited improvements in the experimental outcomes, the number
lost to follow-up, and the number of adverse outcomes in each group. Probability values
for all chi-square analyses in this trial were calculated using Monte-Carlo simulation. All
analyses were conducted using SPSS v27 (IBM Inc., SPSS, Chicago, IL, USA), and statistical
significance for all analyses was accepted as the p
≤
0.05 level. In the interests of conciseness
and clarity, only experimental variables that presented with statistical significance as a
function of the intervention are presented in the results section.
3. Results
3.1. Baseline Characteristics
All of the experimental measurements were contrasted at baseline for the partici-
pants who completed the trial, and no significant differences between groups were found
(p= 0.06–0.98—Table 1).
Table 1. Baseline characteristics of completed study participants.
All Placebo Cherry Blueberry
Mean SD Mean SD Mean SD Mean SD
Age (years) 34.02 12.97 35.13 16.84 32.80 7.89 34.13 13.03
Mass (kg) 68.41 10.74 67.62 10.47 69.44 11.38 68.17 9.43
Stature (m) 1.68 0.09 1.67 0.10 1.69 0.10 1.68 0.08
BMI (kg/m2)24.26 2.90 23.82 2.98 24.90 2.35 24.07 3.10
Sex (m/f) 24/20 8/7 7/7 9/6
Int. J. Environ. Res. Public Health 2022,19, 5317 8 of 18
3.2. Loss to Follow Up, Compliance, Ingested Anthocyanins, and Adverse Events
Total trial completion numbers in each group were cherry (n= 14), placebo (n= 15),
and blueberry (n= 15), and number of adverse effects were cherry (n= 1), placebo (
n= 0
),
and blueberry (n= 0). The chi-square tests were non-significant (X
2(2)
= 2.05,
p= 0.36
;
X2(2) = 2.05
,
p= 0.36
), indicating that there were no statistically significant differences
between trial arms in either loss to follow up or adverse events (Figure 2).
Int. J. Environ. Res. Public Health 2022, 19, x FOR PEER REVIEW 9 of 19
Figure 2. Consort diagram showing of participant flow throughout the study.
There was no statistically significant difference in % compliance between the placebo
and cherry (b = 1.47, (95% CI = −1.01–3.95), t = 1.21, p = 0.24), placebo and blueberry (b =
0.80, (95% CI = −1.70–3.30), t = 0.66, p = 0.52), or between cherry and blueberry groups (b =
0.67, (95% CI = −1.45–2.79), t = 0.64, p = 0.53). For supplementary anthocyanins, however,
there were significant differences between the placebo and cherry (b = 6059.52, (95% CI =
5966.31–6152.73), t = 132.77, p < 0.001, ηP2 = 0.98), placebo and blueberry (b = 14,759.66, (95%
CI = 14,538.12–14,981.21), t = 136.06, p < 0.001, ηP2 = 0.99), and between cherry and
blueberry groups (b = 2640.62, (95% CI = 2351.08–2930.17), t = 18.63, p < 0.001, ηP2 = 0.92).
For supplementary daily sugars, there were significant differences between the placebo
and cherry (b = 17.04, (95% CI = 16.78–17.30), t = 132.66, p < 0.001, ηP2 = 0.98), placebo and
Figure 2. Consort diagram showing of participant flow throughout the study.
There was no statistically significant difference in % compliance between the placebo
and cherry (b= 1.47, (95% CI =
−
1.01–3.95), t = 1.21, p= 0.24), placebo and blueberry
(
b= 0.80
, (95% CI =
−
1.70–3.30), t = 0.66, p= 0.52), or between cherry and blueberry groups
(b= 0.67, (95% CI =
−
1.45–2.79), t = 0.64, p= 0.53). For supplementary anthocyanins,
however, there were significant differences between the placebo and cherry (b= 6059.52,
(95% CI = 5966.31–6152.73), t = 132.77, p< 0.001,
ηP2
= 0.98), placebo and blueberry
Int. J. Environ. Res. Public Health 2022,19, 5317 9 of 18
(
b= 14,759.66
, (95% CI = 14,538.12–14,981.21), t = 136.06, p< 0.001,
ηP2
= 0.99), and between
cherry and blueberry groups (b= 2640.62, (95% CI = 2351.08–2930.17), t = 18.63, p< 0.001,
ηP2
= 0.92). For supplementary daily sugars, there were significant differences between
the placebo and cherry (b= 17.04, (95% CI = 16.78–17.30), t = 132.66, p< 0.001,
ηP2= 0.98
),
placebo and blueberry (b= 41.95, (95% CI = 41.32–42.58), t = 136.57, p< 0.001,
ηP2= 0.99
),
and between cherry and blueberry groups (b= 7.87, (95% CI = 7.05–8.69), t = 19.61,
p< 0.001
,
ηP2
= 0.93). Finally, for supplementary daily energy intake, there were significant differences
between the placebo and cherry (b= 2.69, (95% CI = 0.27–5.12), t = 2.27, p= 0.031,
ηP2= 0.26
)
and the placebo and blueberry (b= 8.65, (95% CI = 3.82– 13.49), t = 3.66, p= 0.001,
ηP2
= 0.31)
but no differences between cherry and blueberry groups (b= 3.27, (95% CI =
−
0.92–7.45),
t = 1.59, p= 0.121) (Table 2).
Table 2. Supplementary compliance and consumption throughout the intervention.
Placebo Cherry Blueberry
Mean SD Mean SD Mean SD
Amount consumed (mL) 1127 45 1136 34 1144 34
Compliance (%) 94 4 95 3 95 3
Experimental anthocyanins (mg) 0 8 12,119 366 14,760 435
Experimental energy intake (Kcal/day)
188 8 193 6 196 6
Experimental sugars (g/day) 0 0. 34 1 42 1
3.3. Blinding Efficacy
Of the 44 participants that completed the trial, 52% (n= 23) correctly identified their
designated trial arm, and the chi-squared test was non-significant (X
2(2)
= 0.02, p= 0.89),
indicating that an effective blinding strategy was adopted.
3.4. Anthropometric Measurements
No statistically significant differences (p> 0.05) in anthropometric parameters were
found (Table 3).
Table 3. Anthropometric measurements as a function of each trial arm.
Placebo Cherry Blueberry
Pre Post Pre Post Pre Post
Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD
Mass (kg) 67.62
10.47
69.27
12.55
69.44
11.38
69.62 9.94 68.17 9.43 66.46 7.87
Fat mass (kg) 15.55 5.07 16.61 6.07 17.97 6.18 17.85 5.36 17.02 5.18 15.83 4.11
BMI (kg/m2)23.82 2.98 24.46 3.25 24.90 2.35 24.69 2.23 24.07 3.10 23.80 2.89
Body fat (%) 23.21 5.61 22.62 5.58 25.33 7.03 26.30 6.36 24.70 5.64 23.72 4.73
Waist circumference (m) 0.79 0.08 0.80 0.10 0.80 0.07 0.79 0.06 0.79 0.08 0.78 0.09
Waist:hip ratio 0.81 0.07 0.79 0.09 0.79 0.05 0.79 0.05 0.82 0.06 0.82 0.09
3.5. Energy Expenditure and Substrate Oxidation
No statistically significant differences (p> 0.05) in energy expenditure and substrate
oxidation parameters were found (Table 4).
Int. J. Environ. Res. Public Health 2022,19, 5317 10 of 18
Table 4. Energy expenditure and substrate oxidation measurements as a function of each trial arm.
Placebo Cherry Blueberry
Pre Post Pre Post Pre Post
Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD
Rest
Carbohydrate oxidation (g/min) 0.23 0.06 0.29 0.11 0.23 0.05 0.24 0.05 0.21 0.06 0.21 0.08
Fat oxidation (g/min) 0.04 0.03 0.03 0.03 0.02 0.01 0.03 0.02 0.04 0.03 0.03 0.02
% Carbohydrate 69.24
16.23
70.26
17.82
71.01 8.67 69.66
12.63
68.65
18.15
68.55
21.53
% Fat 30.76
16.23
29.74
17.82
28.99 8.67 30.34
12.63
31.35
18.15
31.45
21.53
RMR (kcal/day)
1816.84 416.87 1797.67 580.28 1627.67 347.90 1683.43 306.60 1631.41 421.40 1638.71 388.42
Moderate intensity exercise
Carbohydrate oxidation (g/min) 0.40 0.20 0.52 0.26 0.69 0.26 0.68 0.24 0.45 0.26 0.45 0.25
Fat oxidation (g/min) 0.23 0.12 0.17 0.11 0.11 0.08 0.12 0.08 0.20 0.09 0.18 0.10
% Carbohydrate 75.18
22.27
76.73
23.01
72.00
20.10
71.59
19.23
73.12
25.46
72.23
26.71
% Fat 24.82
22.27
23.27
23.01
28.00
20.10
28.42
19.23
26.88
25.46
27.77
26.71
Energy expenditure (kcal/min) 3.72 0.88 3.71 0.84 3.91 0.78 3.87 0.66 3.71 0.87 3.49 0.75
3.6. Hematological Values
Adjusted for baseline, total cholesterol (b= 0.72, (95% CI = 0.19–1.24), t = 2.79,
p= 0.009
,
ηP2
= 0.21) and LDL cholesterol (b= 0.53, (95% CI = 0.09–0.97), t = 2.56,
p= 0.020
,
ηP2= 0.17
) were significantly reduced in the blueberry arm compared to placebo. Further-
more, adjusted for baseline glucose was significantly lower in the placebo (b= 0.61, (95%
CI = 0.22–1.01
), t = 3.18, p= 0.003,
ηP2
= 0.08) and cherry (b= 0.41, (95% CI = 0.10–0.72),
t = 2.68
,p= 0.012,
ηP2
= 0.11) arms compared to blueberry. Finally, adjusted for baseline,
hemoglobin was significantly reduced in the placebo (b= 10.96, (95% CI = 1.61–20.32),
t = 2.39, p= 0.023, ηP2= 0.16) arm compared to blueberry (Table 5).
Table 5. Hematological values as a function of each trial arm.
Placebo Cherry Blueberry
Pre Post Pre Post Pre Post
Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD
Cholesterol (mmol/L) 4.01 0.68 4.34 0.90 4.04 0.70 4.10 0.64 4.36 0.50 3.79 A0.58
LDL (mmol/L) 2.45 0.56 2.67 0.75 2.47 0.72 2.55 0.59 2.71 0.48 2.23 A0.45
HDL (mmol/L) 1.19 0.10 1.25 0.19 1.18 0.15 1.17 0.10 1.23 0.15 1.19 0.20
Total:HDL ratio 3.42 0.46 3.51 0.69 3.49 0.82 3.59 0.68 3.64 0.60 3.21 0.48
LDL:HDL ratio 2.11 0.40 2.17 0.62 2.14 0.75 2.23 0.64 2.29 0.55 1.91 0.45
Glucose (mmol/L) 4.71 0.80 4.36 0.64 4.60 0.60 4.54 0.42 4.55 0.56 4.93
A,B 0.48
Triglycerides (mmol/L) 1.06 0.25 1.17 0.55 1.07 0.37 0.96 0.28 1.21 0.44 1.20 0.56
Hemoglobin (g/L)
141.40
18.77
136.05
12.58
140.07
11.30
142.45
13.17
145.37 12.38
146.93
13.18
Note:
A
= significant difference from baseline compared to placebo;
B
= significant difference from baseline
compared to cherry.
For total cholesterol, the chi-square test was significant (X
2(2)
= 8.92, p= 0.012), and
80%, 86.7%, and 40% of participants exhibited improvements in the cherry, blueberry,
and placebo groups, respectively. Similarly, for LDL cholesterol, the chi-square test was
Int. J. Environ. Res. Public Health 2022,19, 5317 11 of 18
significant (X
2(2)
= 8.89, p= 0.011), and 60%, 86.7%, and 33.3% of participants exhibited
improvements in the cherry, blueberry, and placebo groups, respectively. Finally, for
triglycerides, the chi-square test was also significant (X
2(2)
= 6.01, p= 0.049), and 80%,
73.3%, and 40% of participants exhibited improvements in the cherry, blueberry, and
placebo groups, respectively.
3.7. Blood Pressure and Resting Heart Rate
No statistical differences (p> 0.05) in blood pressure or resting heart rate were found
(Table 6).
Table 6. Blood pressure and resting heart rate measurements as a function of each trial arm.
Placebo Cherry Blueberry
Pre Post Pre Post Pre Post
Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD
Systolic blood pressure (mmHg) 123 20 120 16 118 9 119 9 120 12 122 14
Diastolic blood pressure (mmHg) 82 9 80 11 74 7 78 7 80 8 80 8
Resting heart rate (beats·min−1)66 13 65 9 65 6 64 9 65 11 67 13
3.8. Questionnaires
Adjusted for baseline, Beck Depression Inventory (b= 1.90, (95% CI = 0.09–3.72),
t = 2.14
,p= 0.041,
ηP2
= 0.13), COOP WONCA (b= 0.31
,
(95% CI = 0.06–0.56), t = 2.49,
p= 0.019
,
ηP2
= 0.17), state (b= 5.76, (95% CI = 1.04–10.49), t = 2.49, p= 0.018,
ηP2
= 0.17),
and trait (b= 7.18, (95% CI = 1.05–13.32), t = 2.39, p= 0.023,
ηP2
= 0.16) anxiety scores were
significantly reduced in the blueberry arm compared to placebo. Furthermore, adjusted for
baseline, trait anxiety (b= 6.64, (95% CI = 0.40–12.89), t = 2.17, p= 0.038,
ηP2
= 0.15) scores
were significantly reduced in the blueberry arm compared to cherry (Table 7).
Table 7. Questionnaire measurements as a function of each trial arm.
Placebo Cherry Blueberry
Pre Post Pre Post Pre Post
Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD
Beck depression inventory 7.00 9.79 7.01 7.97 6.13 5.26 5.27 5.74 3.67 3.33 2.53 A2.92
COOP WONCA 1.95 0.58 2.06 0.45 1.92 0.55 1.93 0.54 1.88 0.36 1.71 A0.38
STAI state 32.60 10.76 35.87 11.10 33.47 7.68 32.73 8.39 30.67 9.55 28.87 6.83
STAI trait 40.20 10.66 40.73 11.43 36.87 8.72 39.20 8.67 39.33 9.98
33.07
A8.94
PSQI 4.47 2.20 4.40 2.06 5.67 2.23 5.27 1.87 5.40 3.07 5.07 3.61
Insomnia severity index 5.93 4.35 3.16 4.29 7.13 4.00 5.40 2.72 6.67 5.42 4.73 4.59
Epworth sleepiness scale 5.47 3.50 5.73 3.10 5.80 4.23 6.07 3.59 6.67 5.00 5.67 4.30
Note: A= significant difference from baseline compared to placebo.
4. Discussion
The current study aimed to investigate the influence of 20 days of twice daily Mont-
morency tart cherry or blueberry juice supplementation on cardiometabolic and other
health-related indices in healthy adults compared to placebo. To date, this represents
the first investigation to explore the effects of these supplementary interventions in a
three-arm parallel placebo-controlled trial. The primary aim was to determine whether
systolic blood pressure was improved as a function of these supplements, whereas the
secondary aim(s) were to explore the effects of supplementation on other risk factors for
cardiometabolic disease.
Int. J. Environ. Res. Public Health 2022,19, 5317 12 of 18
In relation to the primary outcome, the current investigation does not support our
hypothesis in that there were significant reductions in systolic blood pressure in either the
cherry of blueberry supplementation groups compared to placebo (Table 6). This result is in
line with those of Lynn et al. [
25
], Desai et al. [
28
], and Kimble et al. [
27
], who showed that
tart cherry supplementation had no effect on systolic blood pressure in healthy patients,
while the current investigation also confirms a similar lack of efficacy for supplemental
blueberry ingestion. It could therefore be speculated that in healthy individuals, arterial
stiffness, which governs systolic blood pressure, is less responsive to short-term increases
in anthocyanin intake via both tart cherry and blueberry supplementation. However, in
healthy patients, Chai et al. [
6
] and Kent et al. [
32
] observed significantly lower systolic
blood pressure in the first 3 h after ingestion, as did Desai et al. [
29
] and Keane et al. [
4
], in
those with metabolic syndrome and early onset hypertension. Notably, Keane et al. [
30
]
showed that plasma anthocyanin metabolites peak in the first two hours following ingestion
with rapid clearance and return to basal within 4 h. This coincides with the aforementioned
previously observed statistical reductions in postprandial blood pressure and suggests that
the current and previous analyses adopting longitudinal rather than acute study designs
may have missed the peak effects of tart cherry and blueberry supplementation. Impor-
tantly, as no statistically significant differences in blood pressure were observed, the current
investigation lends further support to the concept that anthocyanin-rich supplementation
mediates a transient rather than sustained attenuation of systolic blood pressure. Although
physiologically important, the associated long-term clinical benefits of an acute reduction in
blood pressure from both prophylactic and treatment standpoints has not yet been explored.
Therefore, future analyses should seek to establish the enduring clinical efficacy of transient
reductions in systolic blood pressure mediated through anthocyanin-rich supplementation.
Although no statistically significant differences in the primary outcome were evident,
linear mixed-model and chi-square analyses support our hypothesis in that both total and
LDL cholesterol were significantly improved in the blueberry arm compared to placebo
(Table 5), and a larger number of participants experienced reductions in triglycerides in the
cherry and blueberry groups. As no changes in HDL cholesterol were evident, it is clear that
reductions in total cholesterol were mediated as a function of the corresponding attenuation
in LDL values. Previous trials have shown that consuming tart cherry mediated statistical
reductions in both total and LDL cholesterol in older patients [
6
] and those with metabolic
syndrome [
31
] although this is the first investigation to show similar effects in healthy
participants ingesting blueberry supplementation. It is proposed that the reductions in
cholesterol mediated via the blueberry trial arm are a reflection of the statistically greater
anthocyanin concentrations in this supplement (Table 2), lending support to the concept of
a dose response to supplementary anthocyanins in cardiometabolic disease [
70
]. In relation
to triglycerides, our observations concur with those in pathological patients [
6
], and the
current investigation notably shows similar effects in healthy participants and efficacy also
in those ingesting blueberry supplementation. Owing to the greater anthocyanin content
in the blueberry supplement, it is proposed that the reductions in LDL cholesterol in this
condition were mediated via the inhibition of plasma cholesteryl ester transfer protein
(CETP). Several studies have indicated that CETP inhibition is a crucial mechanism for
the attenuation of LDL cholesterol [
71
,
72
], and both human and animal analyses have
shown that anthocyanins decrease plasma CETP activity [
71
,
73
]. Taking into account the
long-standing and well-established association between lipid concentrations and the risk
of cardiovascular disease [
74
], these observations may have considerable clinical relevance.
While lipid-lowering pharmaceutics have been shown to exhibit a high level of efficacy,
they are associated with significant side-effects [
7
], impose significant monetary restrictions
on healthcare budgets, and contribute to the worldwide overreliance on prescription
medications [
8
]. Therefore, the findings from the current trial lend support the concept
that in particular blueberry supplementation may be important in the management of
cardiometabolic disease.
Int. J. Environ. Res. Public Health 2022,19, 5317 13 of 18
Further regarding the improvements in total and LDL cholesterol shown in the blue-
berry trial arm, the current investigation also importantly showed that this supplemental
condition was able to mediate statistical improvements in all indices of psychological
wellbeing compared to placebo. This observation concurs with those of Khalid et al. [
75
],
who showed improvements in mood state in both children and young adults ingesting a
blueberry concentrate compared to placebo. Previous analyses have linked cardiometabolic
disease to reduced levels of psychological wellbeing [65], so taking into account the afore-
mentioned improvements noted in the blueberry trial arm, this observation makes intuitive
sense. The mechanism responsible for the improvements in psychological wellbeing is not
currently known and requires further consideration given the global incidence of depres-
sion and other psychological disorders [
76
]. There are several conceivable mechanisms
that may explain our findings, including increased cerebral blood flow where cognitive
and emotional control is located [
77
] and reduced monoamine oxidase activity causing
increasing levels circulating monoamines, some of which are neurotransmitters associ-
ated with mood regulation [
78
]. Regardless, the observations from the current trial lend
further support to the concept that blueberry supplementation may be important in the
management of psychological disorders.
However, it is important to also acknowledge that despite the potentially exciting
improvements in blood lipid and psychological wellbeing profiles in the blueberry trial
arm, this supplement was associated with increased resting glucose values in relation
to both the placebo and cherry trial arms (Table 5). It is apparent that this observation
was caused by the increased sugar content (Table 3) in the blueberry supplement and
the statistically greater daily sugar intakes in this arm compared to the others. This
finding allied with the previously outlined reductions in blood lipids concurs with those of
Chai et al. [
6
] with tart cherries. This observation is biologically interesting, as typically,
increased blood glucose is met with corresponding increases in LDL cholesterol [
79
]. It is
not within the scope of the biological measurements examined in this trial to accurately
determine the mechanisms responsible for this finding. However, it can be speculated that
the unique nature of the anthocyanin-rich blueberry supplementation may be responsible.
Firstly, through the aforementioned CETP inhibition pathway as although potentially
responsible for the attenuation of LDL cholesterol, animal models have shown strong
correlations between CETP expression and bile acid signaling that may result in increased
glucose disposal [
80
]. In addition, new information has shown that the influence of
anthocyanins themselves on glucose and lipid metabolism in humans may be affected
by their distinct chemical composition [
81
]. Blueberries are characterized by a greater
number of hydroxyl groups [
82
] and belong to the malvidin variety of anthocyanins [
83
].
The malvidin group is associated with greater antioxidant capacity, which may explain
their greater potential for improvements in dyslipidemia [
84
] although there is insufficient
evidence concerning the effects of different anthocyanin compositions on blood glucose
regulation. As such, it is important for further investigation to be conducted into the
biological influence of anthocyanin chemical composition. Nonetheless, it is important
to note that the mean fasting blood glucose values remained within normal ranges [
85
],
and the long-term effects of elevated blood glucose levels remain unknown in healthy
individuals. However, in patients with cardiometabolic conditions or diabetes mellitus
characterized by poor glucose control, the findings from the current investigation do not
currently support habitual utilization of this supplement despite the improvements in
blood lipids. Therefore, it is important for future analyses to examine the longer-term
effects of blueberry supplementation and to explore continuous blood glucose control as
well as insulin and hemoglobin A1c indices in both healthy and pathological populations.
Overall, the current investigation exhibited a very effective level of blinding efficacy,
a low number of adverse incidences, a high retention rate, very good compliance levels,
as well as improvements in blood lipids and psychological wellbeing, predominantly in
the blueberry trial arm. However, owing to the statistically greater mean daily sugar and
associated kilocalorie intake (Table 3) in comparison to the cherry and placebo groups,
Int. J. Environ. Res. Public Health 2022,19, 5317 14 of 18
in agreement with Kimble et al. [
27
], those seeking to utilize blueberry juice as a dietary
supplement should utilize caution and seek to modify their daily dietary intake to account
for the increase in daily Kcal. Furthermore, recent analyses have shown that some fruit
phenolics constrain the formation of advanced glycation end products (AGE) [
86
] and thus
mediate cellular and tissue impairment by damaging protein function and clearance [
87
].
Therefore, to better understand its potential biological effects, further exploration of the
effects of blueberry juice should seek to examine the effects of this supplement on AGE
formation. As with all research, this trial is not without limitations. Firstly, the experimental
anthocyanin, energy, and sugar contents were reported according to the manufacturer’s
guidelines, which, for anthocyanins in particular, have been shown to exhibit variability
from sample to sample owing to differences in growing conditions [
27
]. While the current
investigation observed positive effects of blueberry supplementation on cardiometabolic
and psychological wellbeing indices, the mechanistic bases for these improvements was
not elucidated. Therefore, future investigations should seek to explore and perhaps better
utilize and exploit the mechanistic pathways of blueberry supplementation in order to
improve health-related outcomes. Furthermore, as participants were randomized into
their designated trial arms without consideration for their previous anthocyanin intake, a
stratified random sampling approach should be adopted for future interventions exploring
the effects of anthocyanin-rich fruits on cardiometabolic health indices. Finally, as many of
the experimental variables are positively influenced by exercise, that physical activity was
not monitored may serve as a limitation to this trial. Therefore, subsequent randomized
interventions may seek to quantify physical activity throughout the intervention period via
continuous actigraphy.
5. Conclusions
The current study aimed to investigate the influence of Montmorency tart cherry
or blueberry juice supplementation on cardiometabolic, and other health-related indices
compared to placebo. The current study did not support the primary hypothesis in that
neither cherry or blueberry supplementation improved systolic blood pressure compared
to placebo. However, the secondary hypothesis was supported in that 20 days of blueberry
supplementation was able to mediate improvements in blood lipid concentrations and
psychological wellbeing indices in relation to placebo. Given the clear and long-standing
association between lipid concentrations and the risk of cardiovascular disease and the
paramount importance of psychological wellbeing to health-related quality of life, the
current investigation indicates that blueberry juice could represent a useful means to
enhance cardiometabolic and psychological health. Future intervention trials and studies
should consider exploring the longer-term effects of blueberry juice, the effects of increased
supplemental sugar intake, as well as its efficacy in populations with cardiometabolic
abnormalities at baseline.
Author Contributions:
Conceptualization, J.S. and L.B.; methodology, J.S., R.A., G.S., B.B. and S.D.;
writing—original draft preparation, J.S. and L.B. writing—review and editing, J.S., R.A., G.S., S.D.,
B.B. and L.B.; funding acquisition, J.S. and G.S. All authors have read and agreed to the published
version of the manuscript.
Funding:
The sponsor of this research is the University of Central Lancashire, UK. This research
received no external funding, but the experimental supplementation has been provided by ActiveEdge
(Nutrition) Ltd. UK, who did not have any input into the research design.
Institutional Review Board Statement:
The study was be conducted according to the guidelines
of the Declaration of Helsinki and has been granted ethical approval by the University of Central
Lancashire Health Research Ethics Committee (ref: HEALTH 0016).
Informed Consent Statement:
All participants provided written informed consent in accordance
with the Declaration of Helsinki and the Oviedo Convention.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Environ. Res. Public Health 2022,19, 5317 15 of 18
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