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Advance Access Publication 7 February 2007 Juice Powder Concentrate and Systemic Blood Pressure,Progression of Coronary Artery Calcium and AntioxidantStatus in Hypertensive Subjects: A Pilot Study M. C. Houston1, B. Cooil2, B. J. Olafsson3 and P. Raggi4 1Hypertension Institute of Nashville, Vanderbilt University School of Medicine and Saint Thomas Hospital,2Owen Graduate School of Management, Vanderbilt University, 3The Heart Group, Saint Thomas HeartInstitute and Saint Thomas Hospital, Nashville, TN and 4Department of Medicine and Division of Cardiology,Emory University School of Medicine, Atlanta, Georgia, USA Because micronutrients from plants may have beneficial cardiovascular effects, the hypothesisthat an encapsulated juice powder concentrate might affect several measures of vascular healthwas tested in free living adults at low cardiovascular risk. Blood pressure, vascular compliance,lipid and antioxidant markers, and serial electron beam tomography (to calculate a coronaryartery calcium score as a measure of atherosclerosis burden), were monitored in 51 pre-hypertensive and hypertensive subjects over 2 years. By the end of follow-up, systolicand (1.9 Æ 0.6 ml mmHgÀ1 Â 100, P50.01). The progression of coronary artery calcium score wassmaller than expected compared with a historical database (P50.001). Laboratory testingshowed a significant decrease in homocysteine (P ¼ 0.05), HDL cholesterol (P ¼ 0.025) and ApoA (P ¼ 0.004), as well as a significant increase in b-carotene, folate, Co-Q10 and a-tocopherol(all P50.001). The phytonutrient concentrate we utilized induced several favorable modifica-tions of markers of vascular health in the subjects. This study supports the notion that plantnutrients are important components of a heart healthy diet.
Keywords: antioxidant – blood pressure – coronary artery calcium – fruit – hypertension –vegetable advantages, supportive laboratory and epidemiological The protective effects of fruits and vegetables against evidence, randomized clinical trials of selected antiox- coronary heart disease and myocardial infarction have idant vitamins (A, C, E) and selenium have produced been reported in numerous populations worldwide (1–5).
conflicting results related to coronary heart disease and In observational studies, antioxidant vitamins, associated cardiovascular disease (9–15). Of interest, some cultures with an increased dietary intake of fruits and vegetables, rely heavily on the effect of herbal medicines for control have been inversely associated with cardiovascular disease of hyperlipidemia, hypertension and other ailments (16).
Science Advisory Council and the American College ofCardiology antioxidant vitamin supplements for cardiovascular pre- For reprints and all correspondence: Paolo Raggi, MD, 1365 Clifton vention; nonetheless, these organizations do recommend Road NE, AT-504, Atlanta, Georgia 30322, USA. Tel: (404) 778-5567;Fax: (404) 778-3540; E-mail: [email protected] the consumption of a diet high in sources of antioxidants ß 2007 The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work isproperly cited.
Phytonutrient effects on vascular markers and other nutrients such as fruits, vegetables, whole Imaging, Vascular Compliance, Blood Pressure grains and nuts to reduce the risk of cardiovascular All patients underwent imaging with electron beam This prospective pilot study was undertaken to evaluate tomography 3 times: at baseline, 12 and 24 months the effect of a proprietary encapsulated juice powder (though these time points were not tightly monitored and concentrate, made primarily of multiple fruits, vegetables some patients underwent the repeat scans at slightly and berries on several surrogate markers of cardio- different times but no more than a week or two from the vascular health and risk in asymptomatic adults. Assessed planned time). All electron beam tomography scans were were: progression of coronary artery calcium score, a sensitive marker of atherosclerosis; systemic and San Francisco, CA, USA) according to a standardized diastolic blood pressure; arterial compliance; markers protocol. In brief: 40 to 50 tomographic sections with of antioxidant status and serum lipid levels in patients a single slice thickness of 3 mm were obtained during a taking the phytonutrient preparation for 2 years.
single breath holding period. Scanning was electrocardio-graphically triggered at 60–80% of the R–R interval onthe surface electrocardiogram and imaging began at the level of the bronchial carina and extended to the level ofthe diaphragm. All areas of calcification with a minimal computed tomography attenuation of 130 HounsfieldUnits seen within the borders of the coronary arteries This 24-month prospective pilot study was approved by were computed. A calcified plaque was considered the local Institutional Review Board. Informed consent present if at least three contiguous pixels with a density was obtained from 54 ambulatory patients (44 men) of 130 Hounsfield Units or greater were detected.
between the ages of 40 and 75 years asymptomatic for All images were reviewed on a NetraMD workstation coronary heart disease. Subjects were recruited from the Hypertension Institute and the Saint Thomas Medical Scans were considered of acceptable research quality Group practices in Nashville, TN, USA. All subjects were only if the images were free from motion or metal asymptomatic for coronary heart disease (no clinical artifacts. All scans were read blindly by one (BJO) experienced investigator for consistency. A coronary revascularization) and had a coronary artery calcium artery calcium score for each area of interest was score at enrollment between 30 and 400. The lower calculated as originally described by Agatston et al. (20).
coronary artery calcium score threshold was chosen This scoring method incorporates the density and volume based on published evidence demonstrating better repro- of a calcified plaque, therefore a score increase may be due ducibility beyond this limit (19). A coronary artery to either plaque enlargement or increased density or both.
calcium score 4400 has been shown to be associated The reverse would be true for a score decrease. Total with a high risk of obstructive coronary artery disease calcium scores were calculated as the sum of all individual and cardiac events and it was therefore decided a priori to coronary artery scores. The published median inter-scan exclude such high risk patients. Further inclusion criteria coronary artery calcium score variability for the Agatston included baseline fasting LDL cholesterol 54.92 mmol lÀ1 score is 8–10% (21). The total radiation dose absorbed by and triglycerides 54.52 mmol lÀ1, and two or fewer risk each patient from the three scans was of $1.5 mSievert factors for coronary heart disease. Exclusion criteria (the maximum recommended yearly dose is 5 mSv for included symptomatic angina or known coronary heart disease, single vessel coronary artery stenosis over 50% or left main artery stenosis over 30%. Additional utilized for assessment of arterial wave forms and small therapy, concomitant use of any antioxidant, vitamin, vessel as well as large vessel arterial compliance.
nutritional or nutraceutical supplements and women of Compliance is measured as the change in vessel diameter After enrollment, no changes were allowed in anti- (ml /mmHgÀ1 Â 100). Arterial compliance was measured hypertensive medications, other prescription drugs or aspirin during the study period. No dietary or activity Baseline history, physical exam, blood pressure, weight, asked to maintain their habitual diet, exercise program, 4 months for 24 months. Blood pressure was recorded tobacco utilization, alcohol intake and other lifestyle as the average of two manual measurements and three automated measurements, taken after the subject lay in a supine position for 15 min. Laboratory tests for b-carotene, a-tocopherol, folate, Co-Q10, vitamin C, the study due to prescription of an excluded medication.
glycated hemoglobin and a lipid profile were performed These six subjects are included in the data until the time by a commercial diagnostic laboratory (Kronos Science of their withdrawal. Hence, comparisons were made only Laboratories, Inc., Phoenix, AZ, USA). Blood samples between patients who had baseline assessments and were collected at baseline, 4 months and 24 months.
remained in the study at each analysis point.
Annualized change and relative annualized change were calculated for each patient at 1- and 2-year intervals forblood pressure values, weight, arterial compliance values, Subjects were instructed to take three capsules of the coronary artery calcium score values (absolute scores and percentiles) and blood chemistries. Coronary artery Compliance with study protocol was determined by calcium score percentiles were calculated as the proportion review of patient diaries and investigators’ pill count at of patients with coronary calcium in predefined and each visit, and averaged 85% or better during the follow- non-overriding age groups from a database of 10 122 up period. The phytonutrient preparation (Juice PlusþÕ, asymptomatic patients (22). The annualized rates of NSA, Inc., Memphis,TN, USA) is an encapsulated juice absolute change and relative change in coronary artery powder concentrate blend consisting primarily of fruits, calcium score were compared to changes recorded in vegetables and berries including: acerola cherry, apple, historical untreated controls of 29.7 and 34.7%, respec- beet, bilberry, blackberry, black currant, blueberry, tively, (23) using one-sample t-tests. In general, changes broccoli, cabbage, carrot, cranberry, Concord grape, were annualized for primarily two reasons: patients did not elderberry, kale, orange, papaya, parsley, peach, pine- return for follow-up visits at precise 12-month intervals, apple, raspberry, red currant, spinach and tomato.
and annualization facilitates the comparison between Six capsules daily provided $7.5 mg b-carotene, 276 mg changes at intervals of 12 and 24 months (Table 1).
and about 63 kJ. Other than minor gastrointestinal coronary artery calcium score values because comparative complaints early in the study, there were no reports of historical data were only available in annualized format.
adverse effects attributed to the phytonutrient prepara- In each case, the paired t-statistic was used to construct tion over the 24 months of follow-up.
confidence intervals and to test for significant annualizedchanges between baseline and follow-up among all patients first and pre-hypertensive and hypertensive Of the 54 subjects entering the investigation, three with- patients later. The one-sample Wilcoxon test on medians drew before the first follow-up visit. One woman withdrew was used to confirm significance in this case. Welch’s due to the prescription of a medication excluded from the t-test was used to compare all baseline values of pre- study and two men due to gastrointestinal distress possibly hypertensive and hypertensive patients, and significant due to the phytonutrient preparation. The remaining results were confirmed using the Mann–Whitney rank 51 subjects contributed data. One man withdrew consent sum test. Best-subsets regression was used to study how after the 4-month follow-up visit, one man withdrew age, sex, hypertension, and baseline body weight, arterial consent after the 8-month follow-up visit, three subjects compliance values and coronary calcium measures were (one woman, two men) withdrew consent after the related to the annualized changes over 2 years in systemic 12-month follow-up visit and one man withdrew from blood pressure, arterial compliance and coronary calcium Table 1. Annualized changes at 12- and 24-month follow-up for coronary artery calcium scores, arterial compliance, and blood pressure, with valuesexpressed as mean Æ SEM (median, range) Small artery compliance (ml mmHgÀ1 Â 100) Large artery compliance (ml mmHgÀ1 Â 100) *P50.05; **P50.01; ***P50.001 (relative to baseline) by paired t-test (and Wilcoxon one-sample test).
aCalcium score comparisons with historical 29.7-point annual change: these are significant relative to annualized 24-month change for full cohort(P50.001), 24-month change for pre-hypertensives (P50.01) and 24-month change for hypertensives (P50.05); it is not significantly different fromthe 12-month change in the full cohort.
Phytonutrient effects on vascular markers measurements. The best models were chosen as those that 61 Æ 6.5 years. Table 1 shows the mean annualized minimized the Bayesian Information Criterion (BIC) changes (measured change divided by number of months subject to the constraint that the ratio of observations of observation and multiplied by 12) at 12 and 24 months of to parameters exceeded 5, but this ratio actually exceeded follow-up for coronary artery calcium scores, arterial 10 for all selected models. The BIC has been shown compliance and blood pressure. The annualized change to be a consistent criterion in very general theoretical in absolute coronary artery calcium score was 26 Æ 6 points settings and to provide models that perform well in at 12 months (P50.001 from baseline) and 17 Æ 3.2 points at 24 months (P50.001 from baseline). These valuescorresponded to a relative change of 26 Æ 6 and 20 Æ 4%, respectively from baseline (P50.001 in each case).
In comparison, the annualized change in absolute and Baseline Characteristics and Change in Coronary Artery relative coronary artery calcium score in historical untreated controls were 29.7 and 34.7%, respectively (23)(P50.001 for each, one-sample t-tests).
enrolled in the study are shown in Table 2. Most of the Change in Arterial Blood Pressure and Compliance Figure 1 shows the change over time in systolic blood The majority were men (80%) and the mean age was pressure and Fig. 2 shows the change over time in Table 2. Baseline clinical characteristics Mean Æ SD (median, range) Mean Æ SD (median, range) Mean Æ SD (median, range) Small artery compliance (ml mmHgÀ1 Â 100) Large artery compliance (ml mmHgÀ1 Â 100) Glycosylated hemoglobin, proportion of total hemoglobin 0.055 Æ 0.008 (0.056, 0.050) Values expressed as percentages, mean Æ SD, and median and range where appropriate.
The P-values refer to comparisons between pre-hypertensive and hypertensive patients: *P50.05; **P50.01; ***P50.001 by Welch’s t-test(and Mann–Whitney rank sum test).
diastolic blood pressure from baseline, at each of the six decrease in homocysteine (P50.05), HDL cholesterol follow-up visits. Both measures decreased significantly (P ¼ 0.025) and Apo A (P ¼ 0.004). Additionally, a in the full cohort at the end of 2 years of follow-up significant increase was seen in b-carotene, folate, Co-Q10 and a-tocopherol (all P50.001). Finally, glyco- P50.05 and diastolic À2.2 Æ 0.6 mmHg, P50.001) in sylated hemoglobin showed a borderline significant the absence of any modification in anti-hypertensive decrease (P ¼ 0.059), and LDL cholesterol a borderline therapy. Large artery compliance improved significantly (1.9 Æ 0.6 ml mmHgÀ1 Â 100, P50.01), while small arterycompliance showed a slight but non-significant decrease.
Table 4 summarizes the best models for all significant2-year changes (Table 1) in systemic blood pressure, Table 3 shows that compared with baseline, at the end arterial compliance and coronary calcium measurements.
of 24 months of follow-up there was a significant The baseline values of these variables, along with age,sex, and baseline weight, were considered as candidate predictors. Hypertension is significant in models for both change and relative change in calcium score, and baselinesystolic blood pressure is the pre-eminent predictor in both models for change in systemic blood pressure.
Our main findings could be summarized as follows: the mean calcium score changes at the end of follow-up in this group were statistically smaller than the changesrecorded in an historical population (29.7 and 34.7%, 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 respectively, P50.001 in each case). In addition, these pilot study subjects also had reduced systemic bloodpressure in the presence of stable anti-hypertensive Figure 1. Systolic blood pressure change over time, shown by full therapy and improved vascular compliance of large cohort and the hypertensive and pre-hypertensive subgroups, with eachbox plot showing the distribution of subject values for recorded systolic arteries in the absence of change in body weight (data blood pressure measured at baseline and 4-month intervals for six not shown). The above changes were concurrent with an follow-up visits. The means of each distribution are connected across improvement in markers of antioxidant status, homo- cysteine and glycosylated hemoglobin.
These data may provide a rationale for the observed reduced incidence of coronary heart disease in vegetar- ians, who demonstrate a 3–5 year overall longer survival compared to omnivores. The European Prospective Investigation into Cancer and Nutrition-Oxford studyof 56 000 British men and women demonstrated areduced risk for coronary heart disease in vegetarians (24). In several observational studies components of aplant-based diet, such as phytochemicals (25), fiber (26), nuts (27) and whole grain cereals (28), have been shown to reduce the risk for coronary heart disease.
Furthermore, vegetarian diets, coupled with intense lifestyle changes, have resulted in angiographic improvement of obstructive coronary artery disease (29). Multiple 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 studies have suggested that an optimal intake of fruits, vegetables, whole grains and fiber may provide a Figure 2. Diastolic blood pressure change over time, shown by full variety of cardio-protective nutrients and non-nutrient cohort and the hypertensive and pre-hypertensive subgroups, with each factors with improvement in endothelial function, blood box plot showing the distribution of subject values for recorded pressure, serum lipid levels, glucose, homocysteine, diastolic blood pressure measured at baseline and 4-month intervals forsix follow-up visits. The means of each distribution are connected weight, body fat and reduction in oxidative stress and vascular inflammation (30–34). It has been suggested Phytonutrient effects on vascular markers Table 3. Baseline and annualized 24-month change in lipids and other blood values expressed as mean Æ SD Glycosylated hemoglobin, proportion of total hemoglobin Table 4. Best models for variables of Table 1 that changed significantly over 24 months in terms of baseline values (for all Table 1 variables, alongwith sex, weight, and hypertension) Dependent (R-square) 24-month annualized change in: aWhen a constant is added to this model its coefficient is larger than its standard error. In each case, the direction of univariate association is thesame as the sign of multivariate coefficient.
that a plausible explanation for such favorable effects could be particularly helpful in patients at intermediate may be a nutrient–gene interaction that contributes to risk of events (36) where the presence of calcium increases a reduction in coronary heart disease.
(and its absence decreases) the probability of an event.
Coronary artery calcification is an excellent marker In this light, a middle-aged man with hypertension of atherosclerosis and its presence is associated with (as most of the patients in our study) may benefit from a substantially increased risk of cardiac events (35–38).
calcium screening for more accurate risk stratification.
Some investigators have suggested modifying the calcu- Recently, sequential coronary artery calcium scoring has lated Framingham Risk Score with data derived from been used to monitor the progression of atherosclerosis in calcium screening, thereby increasing or decreasing the adults treated with lipid-lowering agents (38), phosphate estimated risk of an event (39,40). Calcium screening binding agents in renal failure (41) as well as nutritional supplements (42). Of note, progression of coronary used to assess arterial compliance (42), others have artery calcium score has been shown to be associated disputed this opinion and finding the CR-2000 highly with a significant increase in risk of cardiovascular events (23,38). Hence, slowing of coronary artery calcium In summary, this pilot study showed a favorable effect score progression appears to be a worthy goal of therapy.
of an encapsulated juice powder concentrate, made Importantly, the best predictor of coronary artery primarily of multiple fruits, vegetables and berries, on calcium score progression in this study was hypertension, several surrogate markers of cardiovascular disease.
suggesting the very significant role played by this risk Additional placebo-controlled prospective studies will be factor in progression of atherosclerosis.
Abnormal arterial compliance, an accurate marker of vascular stiffness, has been shown to be associated withaging, multiple cardiovascular risk factors and with an adverse cardiovascular outcome (43). Improvement in This work was supported in part by the Dean’s Fund arterial compliance in this pilot study is further evidence Management, Vanderbilt University, Nashville, TN and vegetables on the overall vascular health of an individual.
by a grant from NSA, Inc., Memphis, TN, USA.
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