Blood Pressure, 2014; Early Online: 1–7
ORIGINAL ARTICLE
The effect of kiwifruit consumption on blood pressure in subjects with moderately elevated blood pressure: A randomized, controlled study
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METTE SVENDSEN1, SERENA TONSTAD1, ELI HEGGEN1, TERJE R. PEDERSEN1,2, INGEBJØRG SELJEFLOT2,3, SIV K. BØHN4, NASSER E. BASTANI4, RUNE BLOMHOFF4, INGAR M. HOLME5 & TOR O. KLEMSDAL1 1Division
of Endocrinology, Obesity and Preventive Medicine, Section for Preventive Cardiology, Oslo University Hospital, Oslo, Norway, 2Faculty of Medicine, University of Oslo, Oslo, Norway, 3Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway, 4Institute of Nutrition Research, University of Oslo, Oslo, Norway, 5Department of Biostatistics, Epidemiology and Health Economics, Oslo University Hospital, Oslo, Norway, Abstract Background and aims. Kiwifruit contains bioactive substances that may lower blood pressure (BP) and improve endothelial function. We examined the effects of adding kiwifruit to the usual diet on 24-h ambulatory BP, office BP and endothelial function. Methods. In a parallel-groups study, 118 subjects with high normal BP or stage 1 hypertension (systolic BP 130–159 mmHg and/or diastolic BP 85–99 mmHg) were randomized to intake of three kiwifruits (intervention) or one apple (control) a day for 8 weeks. Office and 24-h ambulatory BP was measured along with biomarkers of endothelial function including metabolites of nitric oxide (NO) formation and finger photo-plethysmography. Results. At randomization, mean 24-h ambulatory systolic/diastolic BP was 133 ⫾ 13/82 ⫾ 9 mmHg (n ⫽ 106). After 8 weeks, BP was lower in the group assigned to kiwifruit versus apple intake (between group difference, ⫺ 3.6 mmHg [95% CI ⫺ 6.5 to ⫺ 0.7], p ⫽ 0.017 and ⫺ 1.9 mmHg [95% CI ⫺ 3.6 to ⫺ 0.3]; p ⫽ 0.040, for systolic and diastolic BP, respectively). Changes in office BP and endothelial function did not differ between the groups. Conclusions. Among men and women with moderately elevated BP, intake of three kiwifruits was associated with lower systolic and diastolic 24-h BP compared with one apple a day. The effect may be regulated by mechanisms other than improvement of endothelial function. Key Words: Ambulatory blood pressure, endothelial function, NO formation
Introduction Blood pressure (BP) is a continuous, consistent and independent risk factor for cardiovascular disease that is modifiable through lifestyle. Weight loss, increased physical activity, moderation of alcohol consumption, reduction in the intake of sodium and increased potassium intake have been recommended for BP reduction (1,2). Diet plays a major role in BP control. The Dietary Approaches to Stop Hypertension (DASH) studies showed that eating vegetables, fruit and low-fat dairy products lowered BP (1). In particular, the evidence for recommending vegetables and fruit to reduce BP is convincing (3,4). However, the recommended amounts of vegetables and fruit are almost double that of usual Western
diets (5). Favourable effects of beetroot (6) and berry (7) consumption on BP have been reported. Whether specific vegetables or fruits lower BP would help to target dietary advice for BP reduction. Kiwifruit enjoys popularity as a source of good nutrition and is rich in fibre, potassium, vitamin C and other antioxidants including lutein, an oxycarotenoid with high antioxidant capacity (8–10). Kiwifruit has been shown to exert cardioprotective properties (11). In the Oslo Antioxidant Study, we found that intake of three kiwifruits daily decreased systolic and diastolic BP, increased antioxidant capacity and upregulated genes involved in stress defence and DNA repair (12,13). Kiwifruit also inhibits angiotensin-converting enzyme (ACE) activity
Correspondence: Mette Svendsen, Division of Endocrinology, Obesity and Preventive Medicine, Section for Preventive Cardiology, Oslo University Hospital, PO Box 4956 Nydalen, N-0424 Oslo, Norway. Tel: ⫹ 4723016653. Fax: ⫹ 4722119975. E-mail: [email protected] (Received 12 June 2014 ; accepted 18 September 2014 ) ISSN 0803-7051 print/ISSN 1651-1999 online © 2014 Scandinavian Foundation for Cardiovascular Research DOI: 10.3109/08037051.2014.976979
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(13–15). Other possible mechanisms may involve increased potassium intake and/or vasodilation via nitritic oxide (NO)-mediated vascular reactivity. Oxidative stress has been postulated to have a possible role in the pathogenesis of hypertension (16). Higher intake of antioxidants may increase the bioavailability of nitric oxide (NO) by decreasing endogenous oxidant formation (17). The primary aim of the present study was to investigate whether kiwifruit consumption lowered office and ambulatory 24-h BP in men and women with moderately increased BP compared with apple consumption. We also compared endothelial function as assessed by biomarkers of NO metabolism (asymmetric dimetylarginine [ADMA], symmetric dimetylarginine [SDMA], L-arginine, L-arginine/ ADMA ratio) and finger photo-plethysmography between the fruit groups.
Methods Study population Men and women with office systolic BP 130–159 mmHg and/or diastolic BP 85–99 mmHg, aged 35–69 years, were invited to participate by newspaper advertisement, invitation letter or referrals to the Section for Preventive Cardiology at Oslo University Hospital. All participants underwent baseline examinations for eligibility (including medical history and an electrocardiogram for an assessment of left ventricular hypertrophy) by the study physicians. Exclusion criteria were antihypertensive pharmacotherapy, BMI ⬎ 35 kg/m2, symptomatic cardiovascular disease, renal dysfunction, drug-treated diabetes mellitus, use of vitamin and antioxidant supplements (and not willing to quit these supplements) or other conditions judged by the clinical investigator to influence compliance to study procedures. The Regional Committees for Medical and Health Research Ethics in Norway approved the study and all subjects gave their written informed consent. Study design The study was a randomized, controlled trial with parallel groups (Registration number in Clin. Trial Gov.: NCT00948363). The randomization was performed in blocks of unequal and unknown size to the researchers. At randomization, the study nurse opened sealed, consecutively numbered, opaque envelopes containing the randomization number and group assignment (kiwifruit or apple). The study nurse then allocated the next available number to each eligible participant. The study was conducted between September 2009 and December 2010. Subjects were included in three waves of about 30–40 individuals in each wave. During the run-in-period (a mean of 12 days) from screening to randomization, subjects were
advised to follow their usual diet, but were asked not to eat more than one kiwifruit a day or 10 apples a week. After randomization the subjects consumed three green kiwifruits (Actinida deliciosa) or one apple Royal Gala (Malus domestica) a day according to their group assignment. The fruits were delivered free of charge at the planned visits. The subjects in the kiwifruit group received a daily amount of about 360 g and the amount of apple was about 170 g in the control group. Since the main purpose of the study was to understand the effects of kiwifruit, subjects in the apple group were asked to refrain from eating kiwifruits. The subjects in the kiwifruit group, however, were not asked to refrain from eating apples as long as they ate three kiwifruits daily. Subjects in both groups met with a nutritionist and a study nurse at the screening visit and every second week thereafter for 8 weeks. Compliance with the intervention was documented by changes in levels of plasma carotenoids (lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene and lycopene). We expected plasma lutein to be increased in the kiwifruit group, given the high content of lutein in the kiwifruit. No biomarkers for the intake of apples were measured. Apples were chosen as the control fruit because apples have lower contents potassium and antioxidants compared with kiwifruit (Table I). The antioxidant capacity of the fruits was measured by the ferric-reducing antioxidant power (FRAP) method by standardized procedures (8). The mean of two measurements is shown in Table I. Clinical measurements The study physician measured BP at the screening visit and performed a medical and physical examination. Office BP at the screening visit was used as an inclusion criterion for participation in the study. After randomization, study nurses that were blinded to the group allocation measured office BP at the scheduled visits and conducted the 24-h BP measurement. Office BP was measured three times on the same arm, using an automatic device (Omron M10-IT, Omron Healtcare Co. Ltd., Kyoto, Japan) with an appropriate cuff after the subjects rested for Table I. Content of energy and some nutrients in study fruits. Nutrients
Kiwi
Apple
Energy, kcal/100 g Fibre, g/100 g Potassium, mg/100 g Vitamin C, mg/100 g Lutein, μg/100 g FRAP, mmol/100 g
57 2.7 290 59 160 91
59 2.0 147 3 84 13
Composition data except lutein are from the Norwegian nutrition composition table. Composition data for lutein are from ref. (9). Ferric-reducing antioxidant power (FRAP) measurements in kiwi and apple were done according to ref. (8).
Kiwifruit and blood pressure 5 min in a sitting position. The average of the last two measurements was used in the analyses. An automatic device (Spacelabs Medical® 90217-10, Spacelabs Healtcare, Hertford, UK) was used for the 24-h ambulatory BP measurement. Measurements were done every 30 min from 06:00 to 24:00 h and every 60 min during the night. An average of all the measurements was used in the analyses. Body weight (kg) was measured at every visit using a digital scale with subjects wearing light indoor clothing and no shoes. Height was measured using a standard stadiometer.
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Measurement of stiffness index, reflection index and pulse propagation time An automatic device was used for assessment of endothelial function (Pulse Trace PCA 2, Micro Medical Ltd., UK). An infrared sensor (photoplethysmography) was set at the subject’s third finger. The measurement was done 5 min after the BP measurement, when the subjects had been resting. The subjects were sitting and had their hand in the mid-chest region. Three measurements were performed. To minimize the influence of random disturbances, the two technically best measurements were selected based on clinical judgement. The mean of the selected measurements were used in the analyses. The recordings were evaluated blindly in relation to randomization group. Three outcomes were assessed including stiffness index, reflection index and the time from first peak to second peak (pulse propagation time) (18). Stiffness, seen as a variant of pulse wave velocity, was defined as height divided by pulse propagation time. Reflection index was defined as the height of the second peak divided by the height of the first peak. Reflection index is a parameter that is comparable with the “relative height of the dicrotic notch”, as has shown to be reduced after pharmacological interventions to increase NO bioavailability (19).
Assessment of diet and physical activity Assessments of diet and physical activity were performed at the screening visit and at the last visit. Trained nutritionists interviewed subjects regarding their food consumption during the last 8 weeks based on a validated food frequency questionnaire. Coding and calculation of total energy intake and energy percentage from protein, fat, carbohydrate and alcohol as well as intakes of calcium, sodium, potassium, magnesium and vitamin C were performed as described elsewhere (20). Physical activity was assessed by the short form of the International Physical Activity Questionnaire (IPAQ). Calculations of energy expenditure from physical activity were performed according to guidelines for data processing and analysis of the IPAQ (21).
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Laboratory measurements Fasting blood samples were collected at the time of randomization and at the end of the intervention period. Plasma and serum were prepared from blood samples within one hour after sampling, and stored at ⫺ 70°C until analysis. L-Arginine, ADMA and SDMA were analysed in EDTA–plasma and the measurements were performed by high-performance liquid chromatography (HPLC) and precolumn derivatization with o-phthaldialdehyde (Sigma Chemicals Co, St. Louis, MO, US) with minor modifications, as described elsewhere (22). The interassay CVs were ⬍ 5% for both. The carotenoids lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene and lycopene were determined in EDTA–plasma by HPLC as described previously (23). Statistics Based on the results of the Oslo Antioxidant Study (13), we calculated the number of subjects needed in each group to be 52 (based on the following parameters: α ⫽ 0.05, β ⫽ 0.90, SD of the between group difference ⫽ 11 mmHg, and difference between the groups ⫽ 7 mmHg). Allowing for about 10% dropouts, we aimed for 60 patients in each group. Data are presented as mean⫾ SD or confidence interval (CI). We used a general linear model with change in BP between randomization and 8 weeks as the dependent variable, intervention group as a categorical variable, and with adjustment for the baseline value of the analysed variable (model 1). In addition, for 24-h ambulatory BP we adjusted for BMI, gender, age and the baseline value of the analysed variable (model 2) for the between-group difference. Between-group differences in changes during the intervention period in other variables (i.e. weight, diet, physical activity, endothelial function and antioxidant status) were tested with unpaired t-tests. Associations between changes in continuous variables were tested by Pearson correlations. Missing values for body weight were replaced by multiple imputation (series means). The data of the completers were used in the statistical analyses. p ⬍ 0.05 was chosen as level of statistical significance. Statistical analyses were performed using SPSS software version 18 (SPSS Inc., Chicago, IL, USA). Results Figure 1 shows the flow diagram of the participants in the study. Among the 50 men and 68 women randomized, office systolic and diastolic BP at screening was 139 ⫾ 10 and 89 ⫾ 6 mmHg, respectively. At randomization, systolic and diastolic BP was 128 ⫾ 14 and 85 ⫾ 8 mmHg, respectively. The subjects were aged 55 ⫾ 9 years with BMI 26.0 ⫾ 3.2 kg/m2 and total cholesterol, HDL-cholesterol, triglycerides
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M. Svendsen et al. Screened by telephone interview after annoncement (n = 226) Did not pass the inclusion criteria (n = 66)
Assessed for egilibility at Preventive Cardiology (n = 160) Excluded (n = 42) with reasons: Blood pressure 159/99 mmHg (n = 14) Diabetes discovered (n = 1) Did not want to participate (n = 9)
Randomized (n = 118)
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Started in the kiwi group (n = 58) Discontinued in the kiwi group (n = 2) with reasons: Withdrew due to allergic reactions to kiwi (n = 1) Excluded due to end organ disease discovered (n = 1 )
Started in the apple group (n = 60 )
Discontinued in the apple group due to sleep disturbances (n = 1)
Completed in the kiwi group (n = 56)
Completed in the apple group (n = 59)
Figure 1. Flowchart of subjects.
and glucose within normal levels (data not shown). A total of 115 subjects completed the study, of whom 106 had 24-h ambulatory BP measurements at randomization and after 8 weeks. At randomization the mean 24-h systolic/diastolic BP was 133 ⫾ 13/82 ⫾ 9 mmHg. Table II shows the changes in 24-h ambulatory and office BP. After adjustment for baseline values of BP (model 1), significant between-group changes were seen in ambulatory systolic and diastolic BP. After adjustment for BMI, gender, age and the baseline value of the analysed variable (model 2), 24-h ambulatory systolic BP was lower in the kiwifruit group (between-group difference, ⫺ 3.3 mmHg [95% CI ⫺ 6.2 to ⫺ 0.4]; p ⫽ 0.029). Ambulatory diastolic
BP also tended to be lower in the kiwifruit group after adjustment for all covariates (⫺ 1.6 mmHg [95% CI –0.2, 3.4], p ⫽ 0.079; model 2). No betweengroup changes were seen in systolic or diastolic BP for day and night measurements (data not shown). In Table III, markers of endothelial function and related biomarkers and plasma carotenoid levels are shown. No difference in changes between the groups in endothelial function measured by finger photoplethysmography was seen. There were also no differences in changes between the groups in biomarkers of endothelial function (L-arginine, ADMA, SDMA, L-arginine/ADMA ratio). Furthermore, no significant correlations between baseline data or changes in stiffness index, reflection index, pulse propagation time
Table II. Blood pressure measured ambulatory and standardized at office before and after intervention in the kiwifruit and apple group.
24-h SBPrand 24-h SBPweek 8 Change in 24-h SBPc 24-h DBPrand 24-h DBPweek 8 Change in 24-h DBPc SBPrand SBPweek 8 Change in SBP DBPrand DBPweek 8 Change in DBPd
n
Kiwi fruit group
n
51 51 51 51 51 51 56 56 56 56 56 56
132 ⫾ 13b 131 ⫾ 12 ⫺ 1.1 (⫺ 3.2 to 1.1)d 82 ⫾ 8 82 ⫾ 9 ⫺ 0.2 (⫺ 1.5 to 1.1) 127 ⫾ 14 126 ⫾ 14 ⫺ 1.1 (⫺ 4.1,1.8) 84 ⫾ 9 81 ⫾ 9 ⫺ 3.0 (⫺ 4.8 to ⫺ 1.2)
55 55 55 55 55 55 59 59 59 59 59 59
Apple group
Between group difference in changea
133 ⫾ 13 135 ⫾ 14 2.5 (0.5–4.6) ⫺ 3.6 (⫺ 6.6 to ⫺ 0.6) 82 ⫾ 7 83 ⫾ 7 1.7 (0.5–3.0) ⫺ 1.9 (⫺ 3.7 to ⫺ 0.1) 129 ⫾ 14 127 ⫾ 16 ⫺ 1.8 (⫺ 4.6 to 1.1) 0.6 (⫺ 3.5 to 4.7) 85 ⫾ 7 83 ⫾ 8 ⫺ 1.3 (⫺ 3.1 to 0.5 ) ⫺ 1.7 (⫺ 4.2 to 0.8)
p
0.017
0.040
0.762
0.177
SBT, systolic blood pressure in mmHg; DBT, diastolic blood pressure in mmHg; rand, randomization; 24-h, ambulatory blood pressure measured for 24 h. aLeast square means, between group difference adjusted for blood pressure at randomization. bMean⫾ SD and all such values. cLeast square means, within group difference adjusted for blood pressure at randomization. dWithin and between group difference with 95% CI and all such values.
Kiwifruit and blood pressure
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Table III. Functional and biochemical markers of endothelial function and plasma antioxidants before and after intervention in the kiwifruit and apple group. Kiwifruit group
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n Endothelial function SI RI PPT Endothelial biomarkers L-arg, mmol/l ADMA, mmol/l SDMA, mmol/l L -arg/ADMA Plasma carotenoids Lutein, μM Zeaxanthin, μM β-cryptoxan, μM α-carotene, μM β-carotene, μM Lycopene, μM
Randomization
n
Apple group Week 8
n
Randomization
n
Week 8
Between group difference in changea
pb
⫺ 0.48 (⫺ 1.4 to 0.5) ⫺ 1.1 (⫺ 3.9 to 1.7) 7.8 (⫺ 6.7 to 22.3)
0.333 0.443 0.289
48 10.9 ⫾ 2.8c 48 80.3 ⫾ 6.3 48 171.3 ⫾ 51.0
48 48 48
54 11.4 ⫾ 2.9 11.5 ⫾ 2.7 54 81.7 ⫾ 7.1 80.1 ⫾ 7.9 160.1 ⫾ 45.0 54 162.5 ⫾ 44.1
54 11.6 ⫾ 2.3 54 80.4 ⫾ 6.5 54 159.0 ⫾ 40.1
54 54 54 54
89.9 ⫾ 14.4 0.58 ⫾ 0.09 0.43 ⫾ 0.07 157.4 ⫾ 25.4
52 52 51 52
88.0 ⫾ 15.8 0.59 ⫾ 0.09 0.42 ⫾ 0.08 150.3 ⫾ 27.4
57 57 57 57
88.9 ⫾ 12.6 0.59 ⫾ 0.10 0.41 ⫾ 0.09 154.5 ⫾ 28.7
56 55 56 56
87.4 ⫾ 12.3 0.58 ⫾ 0.10 0.41 ⫾ 0.07 151.5 ⫾ 21.0
1.1 (⫺ 2.3 to 4.5) ⫺ 0. 01 (⫺ 0.03 to 0.02) 0.01 (⫺ 0.02 to 0.03) 2.5 (⫺ 5.1 to 10.0)
0.520 0.541 0.576 0.519
55 55 55 55 55 55
0.31 ⫾ 0.12 0.07 ⫾ 0.03 0.19 ⫾ 0.14 0.21 ⫾ 0.15 0.75 ⫾ 0.50 0.61 ⫾ 0.25
55 55 55 55 55 55
0.41 ⫾ 0.16 0.07 ⫾ 0.02 0.21 ⫾ 0.16 0.18 ⫾ 0.13 0.69 ⫾ 0.40 0.63 ⫾ 0.25
59 59 59 59 59 59
0.29 ⫾ 0.12 0.06 ⫾ 0.03 0.18 ⫾ 0.11 0.17 ⫾ 0.12 0.68 ⫾ 0.37 0.62 ⫾ 0.26
59 59 59 59 59 59
0.25 ⫾ 0.11 0.06 ⫾ 0.02 0.21 ⫾ 0.16 0.17 ⫾ 0.16 0.63 ⫾ 0.36 0.59 ⫾ 0.26
0.13 (0.11–0.16) 0.01 (⫺ 0.001 to 0.13) ⫺ 0.02 (⫺ 0.08 to 0.03) ⫺ 0.03 (⫺ 0.07 to 0.13) ⫺ 0.01 (⫺ 0.08 to 0.06) 0.04 (⫺ 0.04 to 0.11)
0.000 0.129 0.464 0.167 0.790 0.328
SI, stiffness index; RI, reflection index; PPT, pulse propagation time; L-arg, L-arginine; ADMA, asymmetric dimetyl L-arginine; SDMA, symmetric dimetyl L-arginine; L-Arg/ADMA, ratio of L-arginine and asymmetric dimetyl L-arginine. aMean group difference with 95% CI and all such values. bThe between group difference was tested by independent sample Student t-test. cMean⫾ SD and all such values.
and L-arginine, ADMA, SDMA, L-arginine/ADMA were seen (data not shown). Plasma concentrations of lutein were increased in the kiwifruit group compared with the apple group, whereas no other differences in the other carotenoids were observed. Table IV shows no between group differences for body weight, energy expenditure from physical activity, energy intake and intakes of calcium, sodium and magnesium during the study. Between group differences were seen for potassium and vitamin C, which is in line with the nutritional content of
kiwifruit. Moreover, within the kiwifruit group the change in intake of potassium was inversely correlated to ambulatory systolic BP (r ⫽ ⫺ 0.396, p ⫽ 0.04) and diastolic BP (r ⫽ ⫺ 0.355, p ⫽ 0.011). Despite a decreased intake of sodium in the kiwifruit group, this was not related to change in ambulatory systolic (r ⫽ 0.173, p ⫽ 0.223) or diastolic BP (r ⫽ 0.131, p ⫽ 0.360). There was no association between change in intake of vitamin C and systolic (r ⫽ ⫺ 0.170, p ⫽ 0.234) or diastolic BP (r ⫽ ⫺ 0.190, p ⫽ 0.181).
Table IV. Body weight, physical activity energy expenditure and daily dietary intake before and after intervention in the kiwifruit and apple group. Kiwifruit group (n ⫽ 56) Randomization Body weightc, kg PAEEf, kcal Energy intake, kcal E% protein E% fat E% carbohydrate E% alcohol Calcium, mg Sodium, mg Potassium, mg Magnesium, mg Vitamin C, mg aMean
74.8 ⫾ 11.5d 551 ⫾ 655 2421 ⫾ 1077 17.1 ⫾ 2.2 35.1 ⫾ 5.9 41.3 ⫾ 7.9 3.1 ⫾ 2.5 994 ⫾ 571 2936 ⫾ 1373 4960 ⫾ 2103 488 ⫾ 231 177 ⫾ 77
Week 8 75.1 ⫾ 12.0e 459 ⫾ 837 2265 ⫾ 904* 16.4 ⫾ 2.4*
33.6 ⫾ 5.2 43.4 ⫾ 4.6* 3.3 ⫾ 2.6 923 ⫾ 561 2663 ⫾ 1117* 5074 ⫾ 2213 460 ⫾ 184 307 ⫾ 132***
Apple group (n ⫽ 59) Randomization
Week 8
Between group difference in changea
pb
78.8 ⫾ 12.7 450 ⫾ 395 2270 ⫾ 543 16.9 ⫾ 2.5 34.7 ⫾ 5.3 41.7 ⫾ 6.3 3.8 ⫾ 3.6 862 ⫾ 282 2740 ⫾ 824 4538 ⫾ 977 449 ⫾ 100 169 ⫾ 68
78.8 ⫾ 13.5 430 ⫾ 430 2135 ⫾ 618* 16.9 ⫾ 3.0 34.7 ⫾ 6.2 41.5 ⫾ 6.4 4.0 ⫾ 3.9 787 ⫾ 306* 2693 ⫾ 978 4291 ⫾ 1066 429 ⫾ 129 151 ⫾ 67*
0.29 (⫺ 1.37 to 1.95) ⫺ 95 (⫺ 396 to 206) ⫺ 20 (⫺ 185 to 145) ⫺ 0.6 (⫺ 1.5 to 0.3) ⫺ 1.5 (⫺ 3.6 to 0.6) 2.3 (⫺ 0.1 to 4.6) 0 (⫺ 0.9 to 0.9) 8 ( ⫺ 97 to 114) ⫺ 226 (⫺ 562 to 108) 361 (24–697) ⫺ 9 (⫺ 50 to 32) 149 (118–180)
0.143 0.534 0.811 0.177 0.163 0.051 0.939 0.876 0.182 0.036 0.670 0.000
group difference with 95% CI and all such values. between-group difference was tested by independent samples Student t-test. cWeights were missing for 21 subjects at randomization and three subjects at week 8, missing values were replaced by multiple imputation (series means). dMean⫾ SD and all such values. eThe within-group difference was tested by paired samples t-test. fPhysical activity data were missing for 7 subjects in the kiwi group and 2 subjects in the apple group. PAEE, physical activity energy expenditure; E%, energy percentage. *p ⬍ 0.05; **p ⬍ 0.01; ***p ⬍ 0.001. bThe
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Discussion This study showed that in subjects with moderately elevated BP, 24-h systolic and diastolic BPs were lower after intake of three kiwifruits daily for 8 weeks compared with an apple a day. Plasma concentrations of the antioxidant lutein increased in the kiwifruit group, providing evidence for compliance with the intervention. No differences in endothelial function assessed by finger photo-plethysmography or in biomarkers related to NO metabolism were seen. Eating more fruit is an important element of the DASH diet widely recommended for hypertension. In the present study, the additional recommendation of eating kiwifruit was on top of the usual background diet. This diet was nutrient dense and close to the DASH diet in regard to potassium and magnesium content (24). Some evidence has shown protective effects of kiwifruit on cardiovascular risk reduction (11,13) but to our knowledge, this is the first study to examine effects on ambulatory BP. We previously found that three kiwifruit a day reduced office BP among smoking men (13). However, no BP reducing effect was seen among men eating two kiwifruits a day in a recent study (25). In that study, normotensive subjects were included, with mean BP of 122/71 mmHg (25). Previous studies have mostly focused on enrichment of the diet with a variety of fruits (26,27), rather than studying the effect of a specific fruit. In a study that supplemented the normal diet with berries, moderate amounts of berries (100 g berries ⫹ 1 small glass of berry drink/day) showed similar effects on BP as did kiwifruit in the current study (7). Improved antioxidant status may be one explanation for these findings in line with the increase in lutein concentrations. Effects of increased antioxidation (27) and vitamin C supplementation (28) on BP have been shown in previous studies. In meta-analysis, supplementation with a median dose of 500 mg vitamin C daily for a duration of 8 weeks was associated with a reduction of 3.8 and 1.5 mmHg, respectively in systolic and diastolic BP (28). Increased potassium intake may be another explanation for our findings. In the group eating kiwifruit, increased potassium intakes were correlated to reduction in systolic and diastolic BP. A recent meta-analysis reported that increased potassium intake was associated with a reduced BP with effect sizes similar to our findings (2). The exact mechanism for the BP reducing effect of potassium is not elucidated. Potassium promotes vasodilation and glomerular filtration rate, and decreases renin, renal sodium reabsorption, reactive oxygen species production and platelet aggregation (29). It may be postulated that kiwifruit influence the renin–angiotensin system by inhibiting ACE (10,12–14,30) but we did not measure ACE activity in the current study. It has been shown that the DASH diet promoting a
high intake of fruit and vegetables may lower BP through changes in this system (31). The findings suggest that any effects of kiwifruit on ambulatory 24-h BP may be regulated by other mechanisms than measured by endothelial function parameters. On the other hand, parameters of endothelial function measured in the study may not be sufficiently sensitive to detect BP changes in the range of 3–4 mmHg. In addition, functional measures have a relatively high variability. Thus, improved endothelial function cannot entirely be excluded as mechanism for the kiwifruit effect on BP, but our findings did not support such a mechanism. The present study has several strengths. BP was measured for 24-h in an ambulatory setting. Ambulatory BP measurement has been recommended in clinical trials for its superiority of other BP measurements (32). Moreover, we used biomarkers to confirm compliance with the intervention. We assessed dietary intake during the intervention and showed no other differences between groups than expected with the dietary intervention. Likewise, other changes in plasma carotenoids were not observed, indicating no compensation of other fruit or vegetables in the apple group (33). The study has some limitations. The increased intake of potassium was not confirmed by urinary analyses. Furthermore, we did not measure plasma vitamin C concentrations. While the apple a day group was asked to consume only 75 kcalories of additional fruit, the kiwifruit group consumed about twice that amount energy-wise in order to maximize any potential effects. However, the energy content of the assigned fruit was small compared with the total daily energy intake, there were no differences in reported energy intake between groups and body weight stayed stable. Thus, the impact of this imbalance seems minor. Conclusions This study in subjects with moderately elevated BP, showed lower systolic and diastolic 24-h BP among men and women that consumed three kiwifruits daily compared with the apple a day group. No differences were seen in endothelial function assessed by the stiffness index, refection index and pulse propagation time or metabolites of NO metabolism despite an increase in the antioxidant lutein. Thus, the improvement in BP may be regulated by mechanisms other than endothelial function moderated by NO metabolites, with increased potassium, increased vitamin C and other antioxidants, and also inhibition of ACE activity among the more likely contributing factors. Acknowledgements We thank the subjects for their participation. We thank Lise Bergengen for help with the office and
Kiwifruit and blood pressure endothelial function measurements, Ragnhild Kleve for the 24-h BP measurements, Benedicte Olsen Høvding and Kristin Elisabeth Ruud Lode for study management and dietary calculations and Nicole Warmbrot for establishing the database. KIWI®, a widespread food store chain in Norway, provided both apples and kiwifruits for the study. A grant given by the Throne Holst foundation provided support for laboratory analyses. Clin. Trial Gov.: NCT00948363.
16. 17.
18.
19.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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References 1. Zhao D, Qi Y, Zheng Z, Wang Y, Zhang XY, Li HJ, et al. Dietary factors associated with hypertension. Nat Rev Cardiol. 2011;8:456–465. 2. Aburto NJ, Hanson S, Gutierrez H, Hooper L, Elliott, Cappuccio FP. Effect of increased potassium intake on cardiovascular risk factors and disease: A systematic review and meta-analyses. BMJ. 2013;346:f1378 doi: 10.1136/bmj. f1378 (published 5 April 2013). 3. Boein H, Bechthold A, Bub A, Ellinger S, Haller D, Kroke A, et al. Critical review: Vegetables and fruit in the prevention of chronic diseases. Eur J Nutr. 2012;51:637–663. 4. Bupathiraju S, Tucker KL. Coronary heart disease prevention: Nutrients, food, and dietary patterns. Clin Chim Acta. 2011;412:1493–1514. 5. Nötlings U, Boeing H, Mascarinec G, Sluik D, Teucher B, Kaaks R, et al. Food intake of individuals with and without diabetes across different countries and ethnic groups. Eur J Clin Nutr. 2011;65:635–641. 6. Webb AJ, Patel Nakul, Loukogergakis S, Okorie M, Aboud Z, Misra S, et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension. 2008;51:784–790. 7. Erlund I, Koli R, Alfthan G, Marniemi J, Pukka P, Mustonen P, et al. Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol. Am J Clin Nutr. 2008;87:323–331. 8. Halvorsen B, Carlsen MH, Philips KM, Bøhn SK, Holte K, Jacobs DR Jr, et al. Content of redox-active compounds (ie, antioxidants) in foods consumed in the United States. Am J Clin Nutr. 2006;84:95–135. 9. Calvo MM. Lutein: A valuable ingredient of fruit and vegetables. Crit Rev Food Sci Nutr. 2005;45:671–696. 10. Wolber FM, Beck KL, Conlon CA, Kruger MC. Kiwifruit and mineral nutrition. Adv Food Nutr Res. 2013;68:233–256. 11. Duttaroy AK. Cardioprotective properties of kiwifruit. Adv Food Nutr Res. 2013;68:273–282. 12. Bøhn SK, Myhrstad MC, Thoresen M, Holden M, Karlsen A, Tunheim SH, et al. Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers. BMC Med. 2010;8:54. http://wwww.biomedcentral.com/ 1741-7015/8/54. 13. Karlsen A, Svendsen M, Seljeflot I, Laake P, Duttaroy AK, Drevon CA, et al. Kiwifruit decreases blood pressure and whole-blood platelet aggregation in male smokers. J Hum Hypertens. 2012; doi:10.1038/jhh.2011.116. 14. Jung KA, Song TC, Han D, Kim IH, Kim YE, Lee CH. Cardiovascular protective properties of kiwifruit extracts in vitro. Biol Pharm Bull. 2005;28:1782–1785. 15. Dizdarevic LL, Biswa D, Uddin MMD, Jørgensen A, Falch E, Bastani N, et al. Inhibitory effects of kiwifruit extract
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on platelet aggregation and plasma angiotensi-converting enzyme activity. Platelets. 2013. Early online: 1–9. Ceriello A. Possible role of oxidative stress in the pathogenesis of hypertension. Diabetes Care. 2008;31 Suppl:S181–S184. McCarty MF. Scavenging of peroxynitrite-derived radicals by flavonoids may support endothelial NO synthase activity, contributing to the vascular protection associated with high fruit and vegetable intakes. Med Hypotheses. 2008;70:170–181. Millasseau SC, Ritter JM, Takazawa K, Chowienczyk PJ. Contour analysis of the photoplethysmographic pulse measured at the finger. J Hypertens. 2006;24:1449–1456. Klemsdal TO, Andersson TL, Matz J, Ferns GA, Gjesdal K, Anggård EE. Vitamin E restores endothelium dependent vasodilatation in cholesterol fed rabbits: In vivo measurements by photoplethysmography. Cardiovasc Res. 1994;9:1397–402. Svendsen M, Tonstad S. Accuracy of food intake reporting in obese subjects with metabolic risk factors. Brit J Nutr. 2006;95:640–649. Guidelines for data processing and analysis of the International Physical Activity Questionnaire, 2005. http://www. ipaq.ki.se/ scoring de Jong S, Teerlink T. Analysis of asymmetric dimethylarginine in plasma by HPLC using a monolithic column. Anal Biochem. 2006;15:353:287–289. Svilaas A, Sakhi A, Andersen LF, Svilaas T, Strøm EC, Jacobs Jr DR, et al. Intakes of antioxidants in coffee, wine, and vegetables are correlated with plasma caretenoids in humans. J Nutr. 2004;134:562–567. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, et al.; for the DASH Collaborative Research Group. A clinical trial of the effects of dietery patterns on blood pressure. New Engl J Med. 1997;336:1117–1124. Gammon CS, Kruger R, Brown SJ, Conlon CA, von Hurst PR, Stonehouse W. Daily kiwifruit consumption did not improve blood pressure and markers of cardiovascular function in men with hypercholesterolemia. Nutr Res. 2014;34:235–240. Woodside JV, Young IS, McKinley. Conference on dietary strategies for the management of cardiovascular risk. Fruit and vegetable and risk of cardiovascular disease. Proc Nutr Soc. 2013;72:399–406. Lopes H, Martin KL, Nashar K, Morrow JD, Goodfriend TL, Egan BM. DASH diet lowers blood pressure and lipid-induced oxidative stress in obesity. Hypertens. 2003;41:422–430. Juraschek SP, Guallar E, Appel LJ, Miller III ED. Effects of vitamin C supplementation on blood pressure: A meta-analysis of randomised controlled trials. Am J Clin Nutr. 2012;95:1079–1088. McDonough AA, Nguyen MTX. How does potassium supplementation lower blood pressure? Am J Physiol Renal Physiol. 2012;302:F1224–F1225. Dizdarevic LL, Biswas D, Uddin MDM, Jørgensen A, Falch E, Bastani NE, et al. Inhibitory effects of kiwifruit extract on platelet aggregation and plasma angiotensin-converting enzyme activity. Platelets. 2013 [Epub ahead of print] doi:10 .3109/09537104.2013.852658. Conlin PR, Erlinger TP, Bohannon A, Miller III ER, Appel LJ, Svetkey LP, et al. The DASH diet enhances the blood pressure response to losartan in hypertensive patients. Am J Hypertens. 2003;16:337–342. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al.; on behalf of the European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;9:1731–1768. doi: 10.1097/HJH.0b013e328363e964. Al-Delaimy WK, Ferrari P, Slimani N, Pala V, Johansson I, Nilsson S, et al. Plasma carotenoids as biomarkers of fruit and vegetables: Individual level correlations in the European Prospective Investigation into Cancer and Nutrition (EPIC). Eur J Clin Nutr. 2005;59:1387–1396.
ORIGINAL ARTICLE
The effect of kiwifruit consumption on blood pressure in subjects with moderately elevated blood pressure: A randomized, controlled study
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METTE SVENDSEN1, SERENA TONSTAD1, ELI HEGGEN1, TERJE R. PEDERSEN1,2, INGEBJØRG SELJEFLOT2,3, SIV K. BØHN4, NASSER E. BASTANI4, RUNE BLOMHOFF4, INGAR M. HOLME5 & TOR O. KLEMSDAL1 1Division
of Endocrinology, Obesity and Preventive Medicine, Section for Preventive Cardiology, Oslo University Hospital, Oslo, Norway, 2Faculty of Medicine, University of Oslo, Oslo, Norway, 3Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway, 4Institute of Nutrition Research, University of Oslo, Oslo, Norway, 5Department of Biostatistics, Epidemiology and Health Economics, Oslo University Hospital, Oslo, Norway, Abstract Background and aims. Kiwifruit contains bioactive substances that may lower blood pressure (BP) and improve endothelial function. We examined the effects of adding kiwifruit to the usual diet on 24-h ambulatory BP, office BP and endothelial function. Methods. In a parallel-groups study, 118 subjects with high normal BP or stage 1 hypertension (systolic BP 130–159 mmHg and/or diastolic BP 85–99 mmHg) were randomized to intake of three kiwifruits (intervention) or one apple (control) a day for 8 weeks. Office and 24-h ambulatory BP was measured along with biomarkers of endothelial function including metabolites of nitric oxide (NO) formation and finger photo-plethysmography. Results. At randomization, mean 24-h ambulatory systolic/diastolic BP was 133 ⫾ 13/82 ⫾ 9 mmHg (n ⫽ 106). After 8 weeks, BP was lower in the group assigned to kiwifruit versus apple intake (between group difference, ⫺ 3.6 mmHg [95% CI ⫺ 6.5 to ⫺ 0.7], p ⫽ 0.017 and ⫺ 1.9 mmHg [95% CI ⫺ 3.6 to ⫺ 0.3]; p ⫽ 0.040, for systolic and diastolic BP, respectively). Changes in office BP and endothelial function did not differ between the groups. Conclusions. Among men and women with moderately elevated BP, intake of three kiwifruits was associated with lower systolic and diastolic 24-h BP compared with one apple a day. The effect may be regulated by mechanisms other than improvement of endothelial function. Key Words: Ambulatory blood pressure, endothelial function, NO formation
Introduction Blood pressure (BP) is a continuous, consistent and independent risk factor for cardiovascular disease that is modifiable through lifestyle. Weight loss, increased physical activity, moderation of alcohol consumption, reduction in the intake of sodium and increased potassium intake have been recommended for BP reduction (1,2). Diet plays a major role in BP control. The Dietary Approaches to Stop Hypertension (DASH) studies showed that eating vegetables, fruit and low-fat dairy products lowered BP (1). In particular, the evidence for recommending vegetables and fruit to reduce BP is convincing (3,4). However, the recommended amounts of vegetables and fruit are almost double that of usual Western
diets (5). Favourable effects of beetroot (6) and berry (7) consumption on BP have been reported. Whether specific vegetables or fruits lower BP would help to target dietary advice for BP reduction. Kiwifruit enjoys popularity as a source of good nutrition and is rich in fibre, potassium, vitamin C and other antioxidants including lutein, an oxycarotenoid with high antioxidant capacity (8–10). Kiwifruit has been shown to exert cardioprotective properties (11). In the Oslo Antioxidant Study, we found that intake of three kiwifruits daily decreased systolic and diastolic BP, increased antioxidant capacity and upregulated genes involved in stress defence and DNA repair (12,13). Kiwifruit also inhibits angiotensin-converting enzyme (ACE) activity
Correspondence: Mette Svendsen, Division of Endocrinology, Obesity and Preventive Medicine, Section for Preventive Cardiology, Oslo University Hospital, PO Box 4956 Nydalen, N-0424 Oslo, Norway. Tel: ⫹ 4723016653. Fax: ⫹ 4722119975. E-mail: [email protected] (Received 12 June 2014 ; accepted 18 September 2014 ) ISSN 0803-7051 print/ISSN 1651-1999 online © 2014 Scandinavian Foundation for Cardiovascular Research DOI: 10.3109/08037051.2014.976979
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(13–15). Other possible mechanisms may involve increased potassium intake and/or vasodilation via nitritic oxide (NO)-mediated vascular reactivity. Oxidative stress has been postulated to have a possible role in the pathogenesis of hypertension (16). Higher intake of antioxidants may increase the bioavailability of nitric oxide (NO) by decreasing endogenous oxidant formation (17). The primary aim of the present study was to investigate whether kiwifruit consumption lowered office and ambulatory 24-h BP in men and women with moderately increased BP compared with apple consumption. We also compared endothelial function as assessed by biomarkers of NO metabolism (asymmetric dimetylarginine [ADMA], symmetric dimetylarginine [SDMA], L-arginine, L-arginine/ ADMA ratio) and finger photo-plethysmography between the fruit groups.
Methods Study population Men and women with office systolic BP 130–159 mmHg and/or diastolic BP 85–99 mmHg, aged 35–69 years, were invited to participate by newspaper advertisement, invitation letter or referrals to the Section for Preventive Cardiology at Oslo University Hospital. All participants underwent baseline examinations for eligibility (including medical history and an electrocardiogram for an assessment of left ventricular hypertrophy) by the study physicians. Exclusion criteria were antihypertensive pharmacotherapy, BMI ⬎ 35 kg/m2, symptomatic cardiovascular disease, renal dysfunction, drug-treated diabetes mellitus, use of vitamin and antioxidant supplements (and not willing to quit these supplements) or other conditions judged by the clinical investigator to influence compliance to study procedures. The Regional Committees for Medical and Health Research Ethics in Norway approved the study and all subjects gave their written informed consent. Study design The study was a randomized, controlled trial with parallel groups (Registration number in Clin. Trial Gov.: NCT00948363). The randomization was performed in blocks of unequal and unknown size to the researchers. At randomization, the study nurse opened sealed, consecutively numbered, opaque envelopes containing the randomization number and group assignment (kiwifruit or apple). The study nurse then allocated the next available number to each eligible participant. The study was conducted between September 2009 and December 2010. Subjects were included in three waves of about 30–40 individuals in each wave. During the run-in-period (a mean of 12 days) from screening to randomization, subjects were
advised to follow their usual diet, but were asked not to eat more than one kiwifruit a day or 10 apples a week. After randomization the subjects consumed three green kiwifruits (Actinida deliciosa) or one apple Royal Gala (Malus domestica) a day according to their group assignment. The fruits were delivered free of charge at the planned visits. The subjects in the kiwifruit group received a daily amount of about 360 g and the amount of apple was about 170 g in the control group. Since the main purpose of the study was to understand the effects of kiwifruit, subjects in the apple group were asked to refrain from eating kiwifruits. The subjects in the kiwifruit group, however, were not asked to refrain from eating apples as long as they ate three kiwifruits daily. Subjects in both groups met with a nutritionist and a study nurse at the screening visit and every second week thereafter for 8 weeks. Compliance with the intervention was documented by changes in levels of plasma carotenoids (lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene and lycopene). We expected plasma lutein to be increased in the kiwifruit group, given the high content of lutein in the kiwifruit. No biomarkers for the intake of apples were measured. Apples were chosen as the control fruit because apples have lower contents potassium and antioxidants compared with kiwifruit (Table I). The antioxidant capacity of the fruits was measured by the ferric-reducing antioxidant power (FRAP) method by standardized procedures (8). The mean of two measurements is shown in Table I. Clinical measurements The study physician measured BP at the screening visit and performed a medical and physical examination. Office BP at the screening visit was used as an inclusion criterion for participation in the study. After randomization, study nurses that were blinded to the group allocation measured office BP at the scheduled visits and conducted the 24-h BP measurement. Office BP was measured three times on the same arm, using an automatic device (Omron M10-IT, Omron Healtcare Co. Ltd., Kyoto, Japan) with an appropriate cuff after the subjects rested for Table I. Content of energy and some nutrients in study fruits. Nutrients
Kiwi
Apple
Energy, kcal/100 g Fibre, g/100 g Potassium, mg/100 g Vitamin C, mg/100 g Lutein, μg/100 g FRAP, mmol/100 g
57 2.7 290 59 160 91
59 2.0 147 3 84 13
Composition data except lutein are from the Norwegian nutrition composition table. Composition data for lutein are from ref. (9). Ferric-reducing antioxidant power (FRAP) measurements in kiwi and apple were done according to ref. (8).
Kiwifruit and blood pressure 5 min in a sitting position. The average of the last two measurements was used in the analyses. An automatic device (Spacelabs Medical® 90217-10, Spacelabs Healtcare, Hertford, UK) was used for the 24-h ambulatory BP measurement. Measurements were done every 30 min from 06:00 to 24:00 h and every 60 min during the night. An average of all the measurements was used in the analyses. Body weight (kg) was measured at every visit using a digital scale with subjects wearing light indoor clothing and no shoes. Height was measured using a standard stadiometer.
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Measurement of stiffness index, reflection index and pulse propagation time An automatic device was used for assessment of endothelial function (Pulse Trace PCA 2, Micro Medical Ltd., UK). An infrared sensor (photoplethysmography) was set at the subject’s third finger. The measurement was done 5 min after the BP measurement, when the subjects had been resting. The subjects were sitting and had their hand in the mid-chest region. Three measurements were performed. To minimize the influence of random disturbances, the two technically best measurements were selected based on clinical judgement. The mean of the selected measurements were used in the analyses. The recordings were evaluated blindly in relation to randomization group. Three outcomes were assessed including stiffness index, reflection index and the time from first peak to second peak (pulse propagation time) (18). Stiffness, seen as a variant of pulse wave velocity, was defined as height divided by pulse propagation time. Reflection index was defined as the height of the second peak divided by the height of the first peak. Reflection index is a parameter that is comparable with the “relative height of the dicrotic notch”, as has shown to be reduced after pharmacological interventions to increase NO bioavailability (19).
Assessment of diet and physical activity Assessments of diet and physical activity were performed at the screening visit and at the last visit. Trained nutritionists interviewed subjects regarding their food consumption during the last 8 weeks based on a validated food frequency questionnaire. Coding and calculation of total energy intake and energy percentage from protein, fat, carbohydrate and alcohol as well as intakes of calcium, sodium, potassium, magnesium and vitamin C were performed as described elsewhere (20). Physical activity was assessed by the short form of the International Physical Activity Questionnaire (IPAQ). Calculations of energy expenditure from physical activity were performed according to guidelines for data processing and analysis of the IPAQ (21).
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Laboratory measurements Fasting blood samples were collected at the time of randomization and at the end of the intervention period. Plasma and serum were prepared from blood samples within one hour after sampling, and stored at ⫺ 70°C until analysis. L-Arginine, ADMA and SDMA were analysed in EDTA–plasma and the measurements were performed by high-performance liquid chromatography (HPLC) and precolumn derivatization with o-phthaldialdehyde (Sigma Chemicals Co, St. Louis, MO, US) with minor modifications, as described elsewhere (22). The interassay CVs were ⬍ 5% for both. The carotenoids lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene and lycopene were determined in EDTA–plasma by HPLC as described previously (23). Statistics Based on the results of the Oslo Antioxidant Study (13), we calculated the number of subjects needed in each group to be 52 (based on the following parameters: α ⫽ 0.05, β ⫽ 0.90, SD of the between group difference ⫽ 11 mmHg, and difference between the groups ⫽ 7 mmHg). Allowing for about 10% dropouts, we aimed for 60 patients in each group. Data are presented as mean⫾ SD or confidence interval (CI). We used a general linear model with change in BP between randomization and 8 weeks as the dependent variable, intervention group as a categorical variable, and with adjustment for the baseline value of the analysed variable (model 1). In addition, for 24-h ambulatory BP we adjusted for BMI, gender, age and the baseline value of the analysed variable (model 2) for the between-group difference. Between-group differences in changes during the intervention period in other variables (i.e. weight, diet, physical activity, endothelial function and antioxidant status) were tested with unpaired t-tests. Associations between changes in continuous variables were tested by Pearson correlations. Missing values for body weight were replaced by multiple imputation (series means). The data of the completers were used in the statistical analyses. p ⬍ 0.05 was chosen as level of statistical significance. Statistical analyses were performed using SPSS software version 18 (SPSS Inc., Chicago, IL, USA). Results Figure 1 shows the flow diagram of the participants in the study. Among the 50 men and 68 women randomized, office systolic and diastolic BP at screening was 139 ⫾ 10 and 89 ⫾ 6 mmHg, respectively. At randomization, systolic and diastolic BP was 128 ⫾ 14 and 85 ⫾ 8 mmHg, respectively. The subjects were aged 55 ⫾ 9 years with BMI 26.0 ⫾ 3.2 kg/m2 and total cholesterol, HDL-cholesterol, triglycerides
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M. Svendsen et al. Screened by telephone interview after annoncement (n = 226) Did not pass the inclusion criteria (n = 66)
Assessed for egilibility at Preventive Cardiology (n = 160) Excluded (n = 42) with reasons: Blood pressure 159/99 mmHg (n = 14) Diabetes discovered (n = 1) Did not want to participate (n = 9)
Randomized (n = 118)
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Started in the kiwi group (n = 58) Discontinued in the kiwi group (n = 2) with reasons: Withdrew due to allergic reactions to kiwi (n = 1) Excluded due to end organ disease discovered (n = 1 )
Started in the apple group (n = 60 )
Discontinued in the apple group due to sleep disturbances (n = 1)
Completed in the kiwi group (n = 56)
Completed in the apple group (n = 59)
Figure 1. Flowchart of subjects.
and glucose within normal levels (data not shown). A total of 115 subjects completed the study, of whom 106 had 24-h ambulatory BP measurements at randomization and after 8 weeks. At randomization the mean 24-h systolic/diastolic BP was 133 ⫾ 13/82 ⫾ 9 mmHg. Table II shows the changes in 24-h ambulatory and office BP. After adjustment for baseline values of BP (model 1), significant between-group changes were seen in ambulatory systolic and diastolic BP. After adjustment for BMI, gender, age and the baseline value of the analysed variable (model 2), 24-h ambulatory systolic BP was lower in the kiwifruit group (between-group difference, ⫺ 3.3 mmHg [95% CI ⫺ 6.2 to ⫺ 0.4]; p ⫽ 0.029). Ambulatory diastolic
BP also tended to be lower in the kiwifruit group after adjustment for all covariates (⫺ 1.6 mmHg [95% CI –0.2, 3.4], p ⫽ 0.079; model 2). No betweengroup changes were seen in systolic or diastolic BP for day and night measurements (data not shown). In Table III, markers of endothelial function and related biomarkers and plasma carotenoid levels are shown. No difference in changes between the groups in endothelial function measured by finger photoplethysmography was seen. There were also no differences in changes between the groups in biomarkers of endothelial function (L-arginine, ADMA, SDMA, L-arginine/ADMA ratio). Furthermore, no significant correlations between baseline data or changes in stiffness index, reflection index, pulse propagation time
Table II. Blood pressure measured ambulatory and standardized at office before and after intervention in the kiwifruit and apple group.
24-h SBPrand 24-h SBPweek 8 Change in 24-h SBPc 24-h DBPrand 24-h DBPweek 8 Change in 24-h DBPc SBPrand SBPweek 8 Change in SBP DBPrand DBPweek 8 Change in DBPd
n
Kiwi fruit group
n
51 51 51 51 51 51 56 56 56 56 56 56
132 ⫾ 13b 131 ⫾ 12 ⫺ 1.1 (⫺ 3.2 to 1.1)d 82 ⫾ 8 82 ⫾ 9 ⫺ 0.2 (⫺ 1.5 to 1.1) 127 ⫾ 14 126 ⫾ 14 ⫺ 1.1 (⫺ 4.1,1.8) 84 ⫾ 9 81 ⫾ 9 ⫺ 3.0 (⫺ 4.8 to ⫺ 1.2)
55 55 55 55 55 55 59 59 59 59 59 59
Apple group
Between group difference in changea
133 ⫾ 13 135 ⫾ 14 2.5 (0.5–4.6) ⫺ 3.6 (⫺ 6.6 to ⫺ 0.6) 82 ⫾ 7 83 ⫾ 7 1.7 (0.5–3.0) ⫺ 1.9 (⫺ 3.7 to ⫺ 0.1) 129 ⫾ 14 127 ⫾ 16 ⫺ 1.8 (⫺ 4.6 to 1.1) 0.6 (⫺ 3.5 to 4.7) 85 ⫾ 7 83 ⫾ 8 ⫺ 1.3 (⫺ 3.1 to 0.5 ) ⫺ 1.7 (⫺ 4.2 to 0.8)
p
0.017
0.040
0.762
0.177
SBT, systolic blood pressure in mmHg; DBT, diastolic blood pressure in mmHg; rand, randomization; 24-h, ambulatory blood pressure measured for 24 h. aLeast square means, between group difference adjusted for blood pressure at randomization. bMean⫾ SD and all such values. cLeast square means, within group difference adjusted for blood pressure at randomization. dWithin and between group difference with 95% CI and all such values.
Kiwifruit and blood pressure
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Table III. Functional and biochemical markers of endothelial function and plasma antioxidants before and after intervention in the kiwifruit and apple group. Kiwifruit group
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n Endothelial function SI RI PPT Endothelial biomarkers L-arg, mmol/l ADMA, mmol/l SDMA, mmol/l L -arg/ADMA Plasma carotenoids Lutein, μM Zeaxanthin, μM β-cryptoxan, μM α-carotene, μM β-carotene, μM Lycopene, μM
Randomization
n
Apple group Week 8
n
Randomization
n
Week 8
Between group difference in changea
pb
⫺ 0.48 (⫺ 1.4 to 0.5) ⫺ 1.1 (⫺ 3.9 to 1.7) 7.8 (⫺ 6.7 to 22.3)
0.333 0.443 0.289
48 10.9 ⫾ 2.8c 48 80.3 ⫾ 6.3 48 171.3 ⫾ 51.0
48 48 48
54 11.4 ⫾ 2.9 11.5 ⫾ 2.7 54 81.7 ⫾ 7.1 80.1 ⫾ 7.9 160.1 ⫾ 45.0 54 162.5 ⫾ 44.1
54 11.6 ⫾ 2.3 54 80.4 ⫾ 6.5 54 159.0 ⫾ 40.1
54 54 54 54
89.9 ⫾ 14.4 0.58 ⫾ 0.09 0.43 ⫾ 0.07 157.4 ⫾ 25.4
52 52 51 52
88.0 ⫾ 15.8 0.59 ⫾ 0.09 0.42 ⫾ 0.08 150.3 ⫾ 27.4
57 57 57 57
88.9 ⫾ 12.6 0.59 ⫾ 0.10 0.41 ⫾ 0.09 154.5 ⫾ 28.7
56 55 56 56
87.4 ⫾ 12.3 0.58 ⫾ 0.10 0.41 ⫾ 0.07 151.5 ⫾ 21.0
1.1 (⫺ 2.3 to 4.5) ⫺ 0. 01 (⫺ 0.03 to 0.02) 0.01 (⫺ 0.02 to 0.03) 2.5 (⫺ 5.1 to 10.0)
0.520 0.541 0.576 0.519
55 55 55 55 55 55
0.31 ⫾ 0.12 0.07 ⫾ 0.03 0.19 ⫾ 0.14 0.21 ⫾ 0.15 0.75 ⫾ 0.50 0.61 ⫾ 0.25
55 55 55 55 55 55
0.41 ⫾ 0.16 0.07 ⫾ 0.02 0.21 ⫾ 0.16 0.18 ⫾ 0.13 0.69 ⫾ 0.40 0.63 ⫾ 0.25
59 59 59 59 59 59
0.29 ⫾ 0.12 0.06 ⫾ 0.03 0.18 ⫾ 0.11 0.17 ⫾ 0.12 0.68 ⫾ 0.37 0.62 ⫾ 0.26
59 59 59 59 59 59
0.25 ⫾ 0.11 0.06 ⫾ 0.02 0.21 ⫾ 0.16 0.17 ⫾ 0.16 0.63 ⫾ 0.36 0.59 ⫾ 0.26
0.13 (0.11–0.16) 0.01 (⫺ 0.001 to 0.13) ⫺ 0.02 (⫺ 0.08 to 0.03) ⫺ 0.03 (⫺ 0.07 to 0.13) ⫺ 0.01 (⫺ 0.08 to 0.06) 0.04 (⫺ 0.04 to 0.11)
0.000 0.129 0.464 0.167 0.790 0.328
SI, stiffness index; RI, reflection index; PPT, pulse propagation time; L-arg, L-arginine; ADMA, asymmetric dimetyl L-arginine; SDMA, symmetric dimetyl L-arginine; L-Arg/ADMA, ratio of L-arginine and asymmetric dimetyl L-arginine. aMean group difference with 95% CI and all such values. bThe between group difference was tested by independent sample Student t-test. cMean⫾ SD and all such values.
and L-arginine, ADMA, SDMA, L-arginine/ADMA were seen (data not shown). Plasma concentrations of lutein were increased in the kiwifruit group compared with the apple group, whereas no other differences in the other carotenoids were observed. Table IV shows no between group differences for body weight, energy expenditure from physical activity, energy intake and intakes of calcium, sodium and magnesium during the study. Between group differences were seen for potassium and vitamin C, which is in line with the nutritional content of
kiwifruit. Moreover, within the kiwifruit group the change in intake of potassium was inversely correlated to ambulatory systolic BP (r ⫽ ⫺ 0.396, p ⫽ 0.04) and diastolic BP (r ⫽ ⫺ 0.355, p ⫽ 0.011). Despite a decreased intake of sodium in the kiwifruit group, this was not related to change in ambulatory systolic (r ⫽ 0.173, p ⫽ 0.223) or diastolic BP (r ⫽ 0.131, p ⫽ 0.360). There was no association between change in intake of vitamin C and systolic (r ⫽ ⫺ 0.170, p ⫽ 0.234) or diastolic BP (r ⫽ ⫺ 0.190, p ⫽ 0.181).
Table IV. Body weight, physical activity energy expenditure and daily dietary intake before and after intervention in the kiwifruit and apple group. Kiwifruit group (n ⫽ 56) Randomization Body weightc, kg PAEEf, kcal Energy intake, kcal E% protein E% fat E% carbohydrate E% alcohol Calcium, mg Sodium, mg Potassium, mg Magnesium, mg Vitamin C, mg aMean
74.8 ⫾ 11.5d 551 ⫾ 655 2421 ⫾ 1077 17.1 ⫾ 2.2 35.1 ⫾ 5.9 41.3 ⫾ 7.9 3.1 ⫾ 2.5 994 ⫾ 571 2936 ⫾ 1373 4960 ⫾ 2103 488 ⫾ 231 177 ⫾ 77
Week 8 75.1 ⫾ 12.0e 459 ⫾ 837 2265 ⫾ 904* 16.4 ⫾ 2.4*
33.6 ⫾ 5.2 43.4 ⫾ 4.6* 3.3 ⫾ 2.6 923 ⫾ 561 2663 ⫾ 1117* 5074 ⫾ 2213 460 ⫾ 184 307 ⫾ 132***
Apple group (n ⫽ 59) Randomization
Week 8
Between group difference in changea
pb
78.8 ⫾ 12.7 450 ⫾ 395 2270 ⫾ 543 16.9 ⫾ 2.5 34.7 ⫾ 5.3 41.7 ⫾ 6.3 3.8 ⫾ 3.6 862 ⫾ 282 2740 ⫾ 824 4538 ⫾ 977 449 ⫾ 100 169 ⫾ 68
78.8 ⫾ 13.5 430 ⫾ 430 2135 ⫾ 618* 16.9 ⫾ 3.0 34.7 ⫾ 6.2 41.5 ⫾ 6.4 4.0 ⫾ 3.9 787 ⫾ 306* 2693 ⫾ 978 4291 ⫾ 1066 429 ⫾ 129 151 ⫾ 67*
0.29 (⫺ 1.37 to 1.95) ⫺ 95 (⫺ 396 to 206) ⫺ 20 (⫺ 185 to 145) ⫺ 0.6 (⫺ 1.5 to 0.3) ⫺ 1.5 (⫺ 3.6 to 0.6) 2.3 (⫺ 0.1 to 4.6) 0 (⫺ 0.9 to 0.9) 8 ( ⫺ 97 to 114) ⫺ 226 (⫺ 562 to 108) 361 (24–697) ⫺ 9 (⫺ 50 to 32) 149 (118–180)
0.143 0.534 0.811 0.177 0.163 0.051 0.939 0.876 0.182 0.036 0.670 0.000
group difference with 95% CI and all such values. between-group difference was tested by independent samples Student t-test. cWeights were missing for 21 subjects at randomization and three subjects at week 8, missing values were replaced by multiple imputation (series means). dMean⫾ SD and all such values. eThe within-group difference was tested by paired samples t-test. fPhysical activity data were missing for 7 subjects in the kiwi group and 2 subjects in the apple group. PAEE, physical activity energy expenditure; E%, energy percentage. *p ⬍ 0.05; **p ⬍ 0.01; ***p ⬍ 0.001. bThe
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M. Svendsen et al.
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Discussion This study showed that in subjects with moderately elevated BP, 24-h systolic and diastolic BPs were lower after intake of three kiwifruits daily for 8 weeks compared with an apple a day. Plasma concentrations of the antioxidant lutein increased in the kiwifruit group, providing evidence for compliance with the intervention. No differences in endothelial function assessed by finger photo-plethysmography or in biomarkers related to NO metabolism were seen. Eating more fruit is an important element of the DASH diet widely recommended for hypertension. In the present study, the additional recommendation of eating kiwifruit was on top of the usual background diet. This diet was nutrient dense and close to the DASH diet in regard to potassium and magnesium content (24). Some evidence has shown protective effects of kiwifruit on cardiovascular risk reduction (11,13) but to our knowledge, this is the first study to examine effects on ambulatory BP. We previously found that three kiwifruit a day reduced office BP among smoking men (13). However, no BP reducing effect was seen among men eating two kiwifruits a day in a recent study (25). In that study, normotensive subjects were included, with mean BP of 122/71 mmHg (25). Previous studies have mostly focused on enrichment of the diet with a variety of fruits (26,27), rather than studying the effect of a specific fruit. In a study that supplemented the normal diet with berries, moderate amounts of berries (100 g berries ⫹ 1 small glass of berry drink/day) showed similar effects on BP as did kiwifruit in the current study (7). Improved antioxidant status may be one explanation for these findings in line with the increase in lutein concentrations. Effects of increased antioxidation (27) and vitamin C supplementation (28) on BP have been shown in previous studies. In meta-analysis, supplementation with a median dose of 500 mg vitamin C daily for a duration of 8 weeks was associated with a reduction of 3.8 and 1.5 mmHg, respectively in systolic and diastolic BP (28). Increased potassium intake may be another explanation for our findings. In the group eating kiwifruit, increased potassium intakes were correlated to reduction in systolic and diastolic BP. A recent meta-analysis reported that increased potassium intake was associated with a reduced BP with effect sizes similar to our findings (2). The exact mechanism for the BP reducing effect of potassium is not elucidated. Potassium promotes vasodilation and glomerular filtration rate, and decreases renin, renal sodium reabsorption, reactive oxygen species production and platelet aggregation (29). It may be postulated that kiwifruit influence the renin–angiotensin system by inhibiting ACE (10,12–14,30) but we did not measure ACE activity in the current study. It has been shown that the DASH diet promoting a
high intake of fruit and vegetables may lower BP through changes in this system (31). The findings suggest that any effects of kiwifruit on ambulatory 24-h BP may be regulated by other mechanisms than measured by endothelial function parameters. On the other hand, parameters of endothelial function measured in the study may not be sufficiently sensitive to detect BP changes in the range of 3–4 mmHg. In addition, functional measures have a relatively high variability. Thus, improved endothelial function cannot entirely be excluded as mechanism for the kiwifruit effect on BP, but our findings did not support such a mechanism. The present study has several strengths. BP was measured for 24-h in an ambulatory setting. Ambulatory BP measurement has been recommended in clinical trials for its superiority of other BP measurements (32). Moreover, we used biomarkers to confirm compliance with the intervention. We assessed dietary intake during the intervention and showed no other differences between groups than expected with the dietary intervention. Likewise, other changes in plasma carotenoids were not observed, indicating no compensation of other fruit or vegetables in the apple group (33). The study has some limitations. The increased intake of potassium was not confirmed by urinary analyses. Furthermore, we did not measure plasma vitamin C concentrations. While the apple a day group was asked to consume only 75 kcalories of additional fruit, the kiwifruit group consumed about twice that amount energy-wise in order to maximize any potential effects. However, the energy content of the assigned fruit was small compared with the total daily energy intake, there were no differences in reported energy intake between groups and body weight stayed stable. Thus, the impact of this imbalance seems minor. Conclusions This study in subjects with moderately elevated BP, showed lower systolic and diastolic 24-h BP among men and women that consumed three kiwifruits daily compared with the apple a day group. No differences were seen in endothelial function assessed by the stiffness index, refection index and pulse propagation time or metabolites of NO metabolism despite an increase in the antioxidant lutein. Thus, the improvement in BP may be regulated by mechanisms other than endothelial function moderated by NO metabolites, with increased potassium, increased vitamin C and other antioxidants, and also inhibition of ACE activity among the more likely contributing factors. Acknowledgements We thank the subjects for their participation. We thank Lise Bergengen for help with the office and
Kiwifruit and blood pressure endothelial function measurements, Ragnhild Kleve for the 24-h BP measurements, Benedicte Olsen Høvding and Kristin Elisabeth Ruud Lode for study management and dietary calculations and Nicole Warmbrot for establishing the database. KIWI®, a widespread food store chain in Norway, provided both apples and kiwifruits for the study. A grant given by the Throne Holst foundation provided support for laboratory analyses. Clin. Trial Gov.: NCT00948363.
16. 17.
18.
19.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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