High intakes of flavonoids are associated with reduced cardiovascular risk, and flavonoids such as cocoa and soy protein isolate have shown beneficial effects on blood pressure (BP). Anthocyanins constitute a flavonoid subgroup consumed in regular diets, but few studies have assessed the antihypertensive potential of anthocyanins. We aimed to assess whether high concentrations of relatively pure anthocyanins reduce BP and alter cardiovascular and catecholamine reactivity to stress. A total of 31 healthy men between 35–51 years of age with screening BP >140/90 mm Hg, not on antihypertensive or lipid-lowering medication, were randomised in a double-blind crossover study to placebo versus 320-mg anthoycanins twice daily. Treatment duration was 4 weeks, with a 4-week washout. Sitting and supine BP measurements, ambulatory BP recording and stress reactivity were assessed and analyzed by a paired sample t-test. In all, 27 patients completed all visits. Sitting systolic BP (primary endpoint) was 133 mm Hg after placebo versus 135 mm Hg after anthocyanin treatment (P=0.25). Anthocyanins did neither affect semiautomatic oscillometric BP measurements in the sitting or supine position nor 24-h ambulatory BP. No significant differences in stress reactivity were found across treatment periods. Overall, we conclude that high concentrations of these relatively pure anthocyanins do not reduce BP in healthy men with a high normal BP.
Flavonoids are potent antioxidants present in fruits, vegetables, and plant-based foods; and a high intake of flavonoids is associated with reduced risk of cardiovascular disease (CVD).1 Anthocyanins constitute a subclass of the flavonoids, and a 15-year follow-up study of 34 489 women found that anthocyanin intake also was associated with lower risk of CVD.2 A recent systematic review of 133 human randomized controlled trials assessing CVD-related effects of flavonoids found that ingestion of cocoa products reduced systolic and diastolic blood pressure (BP) by 6/3 mm Hg (five studies), and that soy protein isolate reduced diastolic BP by 2 mm Hg (four studies).3 More studies on commonly consumed flavonoid subclasses such as the anthocyanins were encouraged.
One placebo-controlled study reported a BP reduction of 11/7 mm Hg and also a reduction of angiotensin-converting enzyme activity after an anthocyanin-containing intervention,4 whereas another placebo-controlled study detected a systolic BP reduction of 7 mm Hg.5 However, these interventions contained other possibly biologically active substances as well, thus making the relative antihypertensive contribution from anthocyanins difficult to assess.
Medox capsules (Biolink AS, Sandnes, Norway) are relatively pure anthocyanin products that have been assessed in two different placebo-controlled randomized controlled trials; in the first trial, Medox treatment was reported to attenuate inflammatory markers of 120 healthy subjects after 3 weeks,6 and in the second trial, blood lipids were improved after 12 weeks of treatment in 120 dyslipidemic patients.7 Unpublished results from the first study showed that heart rate (HR) was 6 b.p.m. lower in the intervention group among male participants (n=59, P=0.003). Moreover, an investigator-masked randomized rat pilot study performed in our institution showed nearly significant BP-reducing effects after 1 week of Medox versus placebo (13 mm Hg difference, n=20, P=0.097; Torstein Lyberg, unpublished data, 2007).
We set out to test the hypothesis that intake of anthocyanins (Medox) could lower BP. This is the first double-blind randomized crossover study assessing whether high intakes of relatively pure anthocyanins can reduce BP and alter BP regulatory mechanisms in subjects with a high normal BP. We have previously shown that cardiovascular and catecholamine reactivity to mental stress predict BP after 18 years,8 and it has been suggested that increased stress reactivity per se has a role in the development of hypertension and CVD.9 Moreover, various antioxidants have been shown to attenuate BP responses to both cold pressor test (CPT)10 and mental stress test (MST),11 alleviate perceived stress and post-task cortisol levels after MST12 and alter the sympathetic nervous system.13, 14 Therefore, we also aimed to assess whether anthocyanins could alter CV or catecholamine levels during stress tests.
Participants and methods
The clinical trial was carried out at the Section of Cardiovascular and Renal Research, Oslo University Hospital. Patients were recruited in 2007/2008, and the trial was conducted in 2008/2009. The study was approved by the regional ethics committee. All procedures were in accordance with institutional guidelines and the Helsinki Declaration. All participants provided written informed consent. The study was registered at http://www.clinicaltrials.gov, NCT00634387.
The participants were recruited from a follow-up study in 2005/2006 or from paper advertisements and referrals by general practitioners aware of our project (Figure 1). All subjects recruited from sources other than the follow-up study had to go through a thorough screening procedure, including past medical history, medications, clinical examination, routine blood and urine samples, and BP obtained by a trained physician or nurse according to procedures from the follow-up study.8
We included participants between 35 and 51 years of age, with resting office systolic BP of >140 and/or diastolic BP >90 mm Hg or daytime average BP of more than 135/85 mm Hg if they had recently undergone a 24-h ambulatory BP recording. Subjects with diabetes mellitus, CVD, renal disease, or screening BP >180/110 mm Hg, or subjects using antihypertensive, anticoagulative, antiplatelet or cholesterol-lowering medication were excluded.
A double-blind randomized placebo-controlled crossover intervention study was conducted. Each treatment period lasted for 4 weeks separated by a 4-week washout (Figure 2).
The anthocyanin and placebo capsules were identically packaged, and capsule appearances were identical. The Medox capsule contained minimum 80-mg anthocyanins (Supplementary Appendix 2). A total of 17 different purified anthocyanins (mostly cyanidin 3-O-β-glucosides and delphinidin 3-O-β-glucosides, details described by Qin et al.7) were extracted from bilberry (Vaccinium myrtillus) and black currant (Ribes nigrum) through high-technological patented processes. According to the manufacturer, these capsules also contained 40-mg citric acid and 35-mg maltodextrin to maintain stability, as well as 25-mg fruit sugars and 13-mg lipids and traces of other polyphenols. Placebo capsule consisted of maltodextrin and was blue in colour.
The dose of anthocyanins was based on two previous studies. A human study performed by Karlsen et al.6 found that inflammatory responses were altered by Medox capsules with a daily intake of 320-mg anthocyanins. This dose did not affect BP, although BP was not a primary end point. The dose per kilo body weight used in the present study was based on the dose per kilo body weight given to rats in the pilot study mentioned in the introduction.
In our study, four capsules twice daily were self-administered for 4 weeks, yielding a daily intake of 640-mg anthocyanins. Participants were told to swallow capsules with water and to avoid ingestion closely related to meals. All participants were thoroughly instructed not to change their level of exercise, eating patterns, alcohol-drinking habits and intake of herbal products throughout the study, thus minimizing potential influence of these variables on outcome measures. Participants were told not to ingest blueberries or supplements or juices based on blueberries in the study period.
The participants came to four visits in total at 4-week intervals. The examination started at 0800 hours and lasted for 3 h. The subjects were examined after an 8-h fast that included caffeine, nicotine and alcohol and excluded their morning dose of study capsules. Two trained examiners were present at every visit; however, to ensure continuity, three examiners (doctor, nurse and bioengineer) were trained and they conducted the examination procedures.
The first visit included height, weight, electrocardiogram and clinical examination. All visits included oscillometric BP measurements, laboratory assessments and stress tests. Ambulatory BP was recorded during the consecutive 24 h after visit 2 and 4, while participants were still on intervention/placebo. Counts of unused capsules and adverse events were recorded after each treatment period. Participant instructions were reinforced at all visits.
Two stress tests, a CPT and a MST, were performed on each visit. The stress test sessions started with 45 min of rest in the supine position. CPT was announced, and the right hand was completely immersed in ice water (0 °C) for 1 min. They rested for another 30 min and then they were told of the MST and asked to mentally subtract the number 13 or 17 repetitively for 5 min starting with 1079. A metronome making noise at a frequency of 2 Hz was used to distract the subjects. They were continuously informed of any miscalculation. Thereafter, the subjects rested for 30 min.
Assessment of cardiovascular variables
Resting BP was measured three times on the right semiflexed arm in the sitting position after minimum 3 min rest by trained examiners with a semiautomatic oscillometric BP device (Dinamap Procare, GE Medical Systems Information Technologies Inc., Milwaukee, WI, USA) with appropriate cuff sizes, and was calculated as the mean of the last two measurements. Supine BP was measured with the same device after the Finometer baseline BP recording (see below) and was calculated as the mean of two measurements. Ambulatory BP recording was performed on the non-dominant arm using an oscillometric device (Spacelab model 90207, Spacelab Medical, Redmond, WA, USA). If BP values from one period were missing, the corresponding BP values were excluded in the other period.
HR and systolic and diastolic beat-to-beat BP during stress tests were measured non-invasively by Finometer (Finapres Medical System, Amsterdam, the Netherlands) without return-to-flow calibration.15 Electrocardiogram was measured continuously by a mingograph (Mingograph 7, Siemens-Elma, Solna, Sweden), and all CV parameters were transferred to BeatScope (BeatScopeH, Finapres Medical System) software.
Systolic BP, diastolic BP and HR derived from stress tests were obtained from specific intervals related to the collection of plasma catecholamines. Resting parameters were calculated at 2-min intervals (baseline before CPT, 30-min recovery after CPT/baseline before MST and 30-min recovery after MST). The 5-s sequences after 25 and 55 s were used during CPT, and 15-s sequences, after 1, 3 and 5min were used during MST. All sequences were manually controlled for recording artifacts.
Venous blood for catecholamine assay was collected from standard venous catheters after 45 min of supine rest, before both tests, after 45–60 s of the CPT, after 1, 3 and 5 min during MST, and 5, 15 and 30 min after the end of both stress tests. Catecholamine samples were immediately mixed with glutathione and EGTA, placed on ice and centrifuged at 4 °C; the plasmas were frozen at −70 °C, and catecholamine concentrations were measured by radio enzymatic technique according to Peuler and Johnson.16 Catecholamine concentrations in platelets were analyzed similarly after platelet pellet extraction, as described previously.17 Renin and aldosterone were analyzed using standard clinical analytic equipment at Oslo University Hospital. Angiotensin-converting enzyme was analyzed according to instructions by the manufacturer (Kit nr KK-ACK, Bühlmann laboratories AG, Schönenbuch, Switzerland).
Randomization and masking
Two separate computer-generated 4-block randomization lists stratified for recruitment source (follow-up study versus other sources) were created by a non-investigator. A nurse or doctor enrolled subjects. Scheduled subjects were consecutively assigned by a bioengineer unaware of enrolment status to treatment codes corresponding to labels on otherwise identical concealed containers. Treatment codes were revealed after all data were collected and analyzed; thus, participants, researchers and outcome assessors were masked.
Sitting systolic BP was the primary end point. Secondary outcomes were sitting diastolic BP and HR, supine BP and HR, 24-h ambulatory BP and HR, Finometer BP and HR, cardiovascular and catecholamine stress reactivity, renin, aldosterone, angiotensin-converting enzyme and catecholamines in platelets.
Sample size and statistics
Two placebo-controlled anthocyanin-containing intervention studies reported systolic BP reductions of 7 (see ref. 5) and 11 mm Hg (see ref. 4), and in addition, a non-placebo-controlled study demonstrated a reduction of absolute BP by 17/12 mm Hg after anthocyanin treatment of hypertensive subjects within a 4-week period.18 Thus, there was a rationale that anthocyanins possibly possessed a substantial BP-reducing potential within a 4-week period. As a guideline, we calculated that 22 participants were needed to detect a systolic BP reduction of 6 mm Hg with 80% power, assuming standard deviation of BP differences to yield 10 mm Hg.
A paired sample t-test was used when the difference between the two treatment periods were sufficiently normally distributed, otherwise Wilcoxon signed-rank test was used. Carryover effects were analyzed by comparing whether anthocyanin effects differed between the first and the second treatment period, and equally in the placebo group.19 Response to stress was defined baseline levels before the tests subtracted from mean levels during stress. Data were presented as means±s.e.m., unless otherwise specified. A significance level of 5% was used throughout. The data were analyzed using the statistical package SPSS 16.0 for Windows (SPSS Inc., Chicago, IL, USA).
Description of participants
Baseline characteristics of the participants completing the study are shown in Table 1. The participants were in general healthy. A total of 11 participants used some kind of health-promoting product in addition to their normal food consumption; 7 used vitamins, 6 used fish oil/omega-3 supplementation and 3 used other herbal products. Only four men did not exercise at all. In all, 15 men had a family history of hypertension among first-degree relatives, and 1 man had a first-degree family history of CVD. None had preclinical organ damage (microalbuminuria or electrocardiogram hypertrophy).
In all, 27 out of 31 men completed all the four visits. Average compliance was 90% in the placebo period and 88% in the anthocyanin period. One patient withdrew because of diarrhoea for several days in the middle of the anthocyanin period, possibly constituting an adverse effect. In the anthocyanin period, three patients reported minor headache of short duration, two patients reported that their stools were darker than usual and one of the latter patients also reported nausea. No adverse reaction was recorded from the placebo period.
BP and HR
Anthocyanins did not have significant effects on systolic BP, diastolic BP or HR assessed by an oscillometric BP recorder after 3 min in the sitting position or after 46 min in the supine position or when assessed by ambulatory BP monitoring (Table 2). Specifically, no significant difference was detected in periods closely related to intake of capsules, assessed by comparing relevant BP values with the ambulatory BP recording (Supplementary Appendix 1). Moreover, in a post hoc analysis, where subjects using other health supplements were excluded, BP and HR were not reduced following anthocyanin treatment.
No significant differences in levels of renin, aldosterone or angiotensin-converting enzyme were detected between treatment periods. In addition, concentrations of catecholamines in platelets were not significantly different.
Stress responses between treatment periods are illustrated in Figure 3. Systolic and diastolic BP increased significantly during CPT and MST in both treatment periods (P<0.001). HR increased significantly during MST (P<0.001) in both periods. However, during CPT HR increased significantly only in the anthocyanin period (P=0.042), not in the placebo period (P=0.058). Plasma adrenaline increased significantly during MST (P<0.001) in both periods, but not during CPT in any of the periods. Plasma noradrenaline increased significantly during CPT (P=0.009) and MST (P=0.034) in the placebo period, but not in the anthocyanin period. There was no substantial habituation in CV or catecholamine responses when comparing the second with the fourth visit.
No significant difference in delta responses (baseline values subtracted from stress values) across treatment periods were detected for any cardiovascular or catecholamine variable.
However, absolute BP measured by Finometer tended to be lower in the anthocyanin period. Systolic BP measured by Finometer during 43–45 min of supine rest was 6 (95% confidence interval, 2–11) mm Hg lower on anthocyanin treatment. Moreover, absolute systolic Finometer BPs were significantly lower at 30 min after CPT and at 15 and 30 min after MST, and diastolic Finometer BPs were lower after 5 min MST and 15 and 30 min after MST (Figure 3). Areas under the curve during the stress sessions (stress tests and recovery periods) were significantly lower for systolic BP (P=0.02) and for diastolic BP (P=0.04). Absolute plasma adrenaline and noradrenaline concentrations were not significantly different across treatment periods.
In a post hoc analysis, no significant effects of anthocyanins on BP or stress reactivity was found after analyzing the subgroup of high reactors, defined as participants within the upper tertile of systolic BP responses to MST at the first visit.
Overall, no carryovereffects were found.19
In the present study, anthocyanins did not significantly change sitting BP or 24-h ambulatory BP in a group of middle-aged men with slightly elevated BP. Differences in components of the rennin–angiotensin–aldosterone system, platelet catecholamines or differences in CV or catecholamine responses between treatment periods were not found. However, resting supine BP measured by Finometer tended to be lower in the anthocyanin period.
Our study was carefully designed to avoid systematic bias. The crossover design eliminates inter-individual differences across treatment groups and increases statistical power. Post hoc analysis revealed an 80% power to detect a 4.3 mm Hg difference in sitting systolic BP (n=27, s.d. of BP differences 8 mm Hg). As many as 266 participants in total would be needed to statistically achieve the same test power in a parallel group study assuming our 12.5 mm Hg s.d. of systolic BP in each group. As many variables were analyzed, we have to be cautious when interpreting significant results. A number of methodological considerations should be considered.
Average BP at screening was classified as mild hypertension, but dropped to high normal range during the course of the study. This may be explained by regression to the mean and by more pronounced white-coat effect at screening. Some studies have indicated that the antihypertensive effect is greater in subjects with higher baseline BP.5, 20 Therefore, it may be more difficult to reduce a slightly elevated BP than to reduce a highly elevated BP. However, including subjects with a much higher BP without giving them established antihypertensive medication was considered unethical.
The dropout rate was low and compliance estimates were satisfactory. Nutritional intake was not assessed, assuming that there were no major differences in reported intake in a crossover trial given our instructions not to change eating patterns. As we primarily wanted to assess the effects of high doses of relatively pure anthocyanins, we considered the relatively low contribution of anthocyanins from a normal diet and/or even various supplements to be of less importance. Except for the restriction of blueberry intake, we did not restrict or control the habitual intake of other sources of dietary flavonoids. Subjects with a high dietary flavonoid intake may be less likely to gain any extra benefits from anthocyanin supplementation, as underlying anthocyanin mechanisms may be of general anti-inflammatory or antioxidative nature. Some of our participants focused on healthy life styles; however, we do not know whether their intake of dietary antioxidants were higher than in the general population.
The daily dose of anthocyanins administered in our study (640 mg) was twice the dose used in the previous two studies assessing Medox anthocyanins.6, 7 The bioavailability of anthocyanins are generally low,21 and therefore we wanted to ensure a sufficiently high intake. Our subjects did not undergo a strict fast, as they ingested their morning dose before the examination. This was done to ensure high anthocyanin concentrations in vivo during BP measurements, as the plasma concentration of anthocyanins peaks within the first hours.21
Before our protocol was made, only one Medox intervention study had been conducted, and they found significant alterations in inflammatory markers after only 3 weeks of treatment.6 Anthocyanin-containing intervention studies supporting antihypertensive effects lasted 6 weeks,4, 5 whereas a study not supporting antihypertensive effect lasted 12 weeks.22 In the flavonoid meta-analysis, median treatment duration was 2–6 weeks, and studies of longer duration indicated reduced effect sizes compared with studies of shorter duration.3
Interestingly, we found that absolute Finometer BPs were significantly lower at certain intervals during periods of supine rest, and that areas under the curve for Finometer BPs during the stress testing were significantly lower following anthocyanin treatment. Although mean systolic Finometer BP from the 43rd–45th min of rest was 6 mm Hg (P<0.007) lower after anthocyanin treatment, no difference was detected between treatment periods of supine oscillometric measurements 1 min later (after collection of catecholamine samples). In general, BP measured after a long resting period is thought to reflect a basal BP with less influence of stress. BP obtained by the Finometer is importantly not affected by the BP measurement itself, contrary to oscillometric measurements, which may induce more stress in the individual. This aspect, combined with the blood collection procedure before oscillometric BP measurement, could have made the latter BP more influenced by stress than the basal Finometer BP. Our results may suggest that anthocyanins reduce basal BP, but not conventionally taken BP. Another theory is that BP of small finger arteries may be regulated differently compared with BP of large arteries as indicated by Raynaud's phenomenon; thus, we speculate whether anthocyanins influence finger BP but not brachial BP during rest. It may be argued that subtle changes in position of the finger cuff and finger temperature may influence absolute Finometer BP substantially. However, it is unlikely that inadequate precision affected our results in one particular direction, given our study design. Still, as these Finometer BPs were secondary outcomes and inconsistent with all other conventional methods used to assess BP differences, this finding will not be emphasized before it has been reproduced, as a statistical type 1 error cannot be excluded.
To our knowledge, this is the first human study primarily assessing antihypertensive effects of relatively pure anthocyanins. The main finding of the present study was that anthocyanins do not have substantial BP-reducing effects in men with slightly elevated BP in the range from high normal BP up to mild hypertension. Whether BP was recorded in the sitting or supine position by conventional methods or whether measured by ambulatory BP or by oscillometric device, the results were consistently negative. Our study did not have enough power to detect small BP differences that possibly could have an impact on a population level. However, the small and non-significant BP differences between the treatment periods tended to point in the opposite direction.
As other studies on anthocyanin-rich interventions included considerable amounts of non-anthocyanins, they may not be easily comparable to our study. However, to our knowledge, only two such placebo-controlled studies have found an antihypertensive effect, and another study found no effect. Curtis et al.22 commented that studies demonstrating effects on the CV system tended to assess participants with clinically diagnosed diseases with relatively low doses of anthocyanins. However, the most recent study showed antihypertensive effects on relatively healthy subjects with mean BP within the high normal range after a low-dose treatment.5 Although unlikely, because of low bioavailability, we cannot rule out the possibility that lower doses of anthocyanins may be more beneficial. Again, antihypertensive effects found in these studies may also be due to other substances than the anthocyanins.
Unpublished results from the first Medox Study did not reveal BP differences between the treatment groups.6 Moreover, no effects on BP were found in the most recent 12-week Medox Trial,7 suggesting that the duration of the treatment period is of less importance. Although the latter studies included participants that tended to have normal BP, the evidence so far is consistently not showing convincing antihypertensive effects of these anthocyanins. However, we cannot rule out that other anthocyanin molecules may possess antihypertensive effects.
Both the stress tests, CPT and MST, were included, as they were considered to activate the sympathetic system differently. This was demonstrated by the high plasma adrenaline and HR response to the MST, compared with the modest HR increase and higher BP levels during CPT. However, we found no cardiovascular or catecholamine differences in delta values (baseline levels subtracted from stress levels) between the two treatment periods. Some studies have shown lower levels of plasma noradrenaline and decreased renal sympathetic activity after intake of antioxidants like N-acetylcysteine, melatonin and tempol in hypertensive rat models or humans.13, 14, 23 Anthocyanins did not affect catecholamine levels in our study. Insufficient antioxidant potential in vivo may be one possible explanation.
A recent meta-analysis assessing antihypertensive effects of cocoa products in 10 randomized controlled trials reported a significant mean BP reduction of 4.5/2.5 mm Hg.20 Bogaard et al.24 commented that most of these studies did not include adequate placebo groups, and among the three studies that did provide placebo groups, no antihypertensive effects was found. Further, Bogaard et al.24 revealed no BP-reducing effects after flavonol-rich cocoa drinks in a 3-week placebo-controlled randomized controlled trial including 42 subjects. The authors of a flavonoid meta-analysis commented that study protocols were of variable quality.3 Important information from individual studies was missing or insufficiently reported, and some studies provided less than seven participants in their treatment arms. Particularly in research fields where both investigators and participants believe that a particular intervention is beneficial, the research quality is crucial. Systematic biases, such as inadequate placebo-interventions together with publication biases, may give an impression that beneficial effects of presumably healthy products appear greater in the published literature than what they truly are.
In the present study, we have assessed whether a mixture of relatively pure anthocyanins could reduce BP. In contrast to some previous studies,4, 5, 18 we did not find any convincing antihypertensive effects using conventional BP measurements. Although our Finometer findings may indicate some effects on resting finger BP, we conclude that these anthocyanins cannot be recommended as antihypertensive treatment in borderline hypertensive men.
Although anthocyanins do not appear to reduce BP, their intake may still be important in relation to CVD as indicated by large cohort studies. Both improvement of other established risk factors and antioxidative and anti-inflammatory effects in vivo are potential mechanisms by which anthocyanins may interfere with development of CVD. However, the most appropriate populations, doses, food mixtures and even anthocyanin molecules to maximize health benefits are yet to be found.
Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D . Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993; 342: 1007–1011.
Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong CP, Nettleton JA et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 2007; 85: 895–909.
Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008; 88: 38–50.
Naruszewicz M, Laniewska I, Millo B, Dluzniewski M . Combination therapy of statin with flavonoids rich extract from chokeberry fruits enhanced reduction in cardiovascular risk markers in patients after myocardial infraction (MI). Atherosclerosis 2007; 194: e179–e184.
McKay DL, Chen CY, Saltzman E, Blumberg JB . Hibiscus sabdariffa L tea (tisane) lowers blood pressure in prehypertensive and mildly hypertensive adults. J Nutr 2010; 140: 298–303.
Karlsen A, Retterstol L, Laake P, Paur I, Kjolsrud-Bohn S, Sandvik L et al. Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults. J Nutr 2007; 137: 1951–1954.
Qin Y, Xia M, Ma J, Hao Y, Liu J, Mou H et al. Anthocyanin supplementation improves serum LDL- and HDL-cholesterol concentrations associated with the inhibition of cholesteryl ester transfer protein in dyslipidemic subjects. Am J Clin Nutr 2009; 90: 485–492.
Flaa A, Eide IK, Kjeldsen SE, Rostrup M . Sympathoadrenal stress reactivity is a predictor of future blood pressure: an 18-year follow-up study. Hypertension 2008; 52: 336–341.
Schwartz AR, Gerin W, Davidson KW, Pickering TG, Brosschot JF, Thayer JF et al. Toward a causal model of cardiovascular responses to stress and the development of cardiovascular disease. Psychosom Med 2003; 65: 22–35.
Olatunji LA, Soladoye AO . Effects of chronic administration of vitamin E on haemodynamic responses to postural stress or cold pressor test in apparently healthy young men. Niger Postgrad Med J 2008; 15: 225–228.
Brody S, Preut R, Schommer K, Schurmeyer TH . A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Psychopharmacology (Berl) 2002; 159: 319–324.
Steptoe A, Gibson EL, Vuononvirta R, Williams ED, Hamer M, Rycroft JA et al. The effects of tea on psychophysiological stress responsivity and post-stress recovery: a randomised double-blind trial. Psychopharmacology (Berl) 2007; 190: 81–89.
Girouard H, Chulak C, LeJossec M, Lamontagne D, de CJ . Chronic antioxidant treatment improves sympathetic functions and beta-adrenergic pathway in the spontaneously hypertensive rats. J Hypertens 2003; 21: 179–188.
Nishiyama K, Yasue H, Moriyama Y, Tsunoda R, Ogawa H, Yoshimura M et al. Acute effects of melatonin administration on cardiovascular autonomic regulation in healthy men. Am Heart J 2001; 141: E9.
Guelen I, Westerhof BE, van der Sar GL, van Montfrans GA, Kiemeneij F, Wesseling KH et al. Finometer, finger pressure measurements with the possibility to reconstruct brachial pressure. Blood Press Monit 2003; 8: 27–30.
Peuler JD, Johnson GA . Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 1977; 21: 625–636.
Rostrup M, Mundal HH, Westheim A, Eide I . Awareness of high blood pressure increases arterial plasma catecholamines, platelet noradrenaline and adrenergic responses to mental stress. J Hypertens 1991; 9: 159–166.
Herrera-Arellano A, Miranda-Sanchez J, Avila-Castro P, Herrera-Alvarez S, Jimenez-Ferrer JE, Zamilpa A et al. Clinical effects produced by a standardized herbal medicinal product of Hibiscus sabdariffa on patients with hypertension. A randomized, double-blind, lisinopril-controlled clinical trial. Planta Med 2007; 73: 6–12.
Senn S, Lambrou D . Robust and realistic approaches to carry-over. Stat Med 1998; 17: 2849–2864.
Desch S, Schmidt J, Kobler D, Sonnabend M, Eitel I, Sareban M et al. Effect of cocoa products on blood pressure: systematic review and meta-analysis. Am J Hypertens 2010; 23: 97–103.
McGhie TK, Walton MC . The bioavailability and absorption of anthocyanins: towards a better understanding. Mol Nutr Food Res 2007; 51: 702–713.
Curtis PJ, Kroon PA, Hollands WJ, Walls R, Jenkins G, Kay CD et al. Cardiovascular disease risk biomarkers and liver and kidney function are not altered in postmenopausal women after ingesting an elderberry extract rich in anthocyanins for 12 weeks. J Nutr 2009; 139: 2266–2271.
Shi Z, Chen AD, Xu Y, Chen Q, Gao XY, Wang W et al. Long-term administration of tempol attenuates postinfarct ventricular dysfunction and sympathetic activity in rats. Pflugers Arch 2009; 458: 247–257.
van den Bogaard B, Draijer R, Westerhof BE, van den Meiracker AH, van Montfrans GA, van den Born BJ . Effects on peripheral and central blood pressure of cocoa with natural or high-dose theobromine: a randomized, double-blind crossover trial. Hypertension 2010; 56: 839–846.
We thank Vibeke Kjær and Christina Roaldsnes for substantial assistance during the study, Biolink AS for supply of Medox capsules and Anette Karlsen for angiotensin-converting enzyme analysis at the Department of Nutrition, Medical Faculty, University of Oslo, Oslo, Norway.
Biolink AS (Sandnes, Norway) provided anthocyanin and placebo capsules for free. They provided the corresponding author half his income for 1 year. They were encouraged to comment on the manuscript; however, the conduction, analysis and article preparation were investigator initiated, and unfavourable results could not be restricted from publication.
Supplementary Information accompanies the paper on the Journal of Human Hypertension website
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Cite this article
Hassellund, S., Flaa, A., Sandvik, L. et al. Effects of anthocyanins on blood pressure and stress reactivity: a double-blind randomized placebo-controlled crossover study. J Hum Hypertens 26, 396–404 (2012) doi:10.1038/jhh.2011.41
- blood pressure
- randomized controlled trial
- physiological stress reactivity
- cardiovascular diseases
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