Hee Jun Myung; Han Saem Jeong; Tae Yeon Hwang; Kyoung Ho Go; Juwon Kim; Woori Cho; Yoon Kyung Choi; Jiae Park; Soon Jun Hong

doi:10.12997/jla.2016.5.1.49

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Myung, Jeong, Hwang, Go, Kim, Cho, Choi, Park, and Hong: Black Raspberry Improved Lipid Profiles and Vascular Endothelial Function in Patients with Metabolic Syndrome: A Subgroup Analysis of Statin Naïve Participants

Original Article

Journal of Lipid and Atherosclerosis 2016; 5(1): 49-59.

Published online: 30 June 2016

DOI: https://doi.org/10.12997/jla.2016.5.1.49

Black Raspberry Improved Lipid Profiles and Vascular Endothelial Function in Patients with Metabolic Syndrome: A Subgroup Analysis of Statin Naïve Participants

Hee Jun Myung^*, Han Saem Jeong^*, Tae Yeon Hwang, Kyoung Ho Go, Juwon Kim, Woori Cho, Yoon Kyung Choi, Jiae Park, Soon Jun Hong

Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea.

Corresponding Author: Soon Jun Hong, Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, 126-1, 5ka, Anam-dong, Sungbuk-ku, Seoul 136-705, Korea. Tel: +82-2-920-5445, Fax: +82-2-927-1478, psyche94@gmail.com

Equal contributor:

*These authors equally contributed to the manuscript.

Received 16 April 2016 Revised 16 May 2016 Accepted 20 May 2016

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Black raspberry (Rubus occidentalis) has been known for its anti-inflammatory and anti-oxidant effects and for improving vascular endothelial function in patients at high-risk for cardiovascular disease. We investigated short-term effects of black raspberry on lipid profiles, vascular endothelial function and circulating endothelial progenitor cells in statin naïve participants with metabolic syndrome.

Methods

Patients with metabolic syndrome (n=51) without lipid lowering medications were prospectively randomized into the black raspberry group (n=26, 750 mg/day) and placebo group (n=25) during the 12-week follow-up. Lipid profiles, brachial artery flow-mediated dilatation (baFMD) and inflammatory cytokines such as IL-6, TNF-α, C-reactive protein, adiponectin, sICAM-1, sVCAM-1 were measured at baseline and at 12-week follow-up. Central blood pressure and augmentation index were also measured at baseline and at 12-week follow-up.

Results

Decreases from baseline in total cholesterol levels (-22.7±34.3 mg/dL vs. 0.0±34.7mg/dL, p<0.05, respectively) and total cholesterol/HDL ratio (-0.34±0.68 vs. 0.17±0.56, p<0.05, respectively) were significantly greater in the black raspberry group when compared to the placebo group. Decreases from baseline in IL-6 (-0.5±1.4 pg/mL vs. -0.1±1.1 pg/mL, p<0.05, respectively) and TNF-α levels (-5.4±4.5 pg/mL vs. -0.8±4.0 pg/mL, p<0.05, respectively) were significantly greater in the black raspberry group. Increases from the baseline in adiponectin levels (2.9±2.1 µg/mL vs. -0.2±2.5 µg/mL, p<.05) were significant in the black raspberry group. Increases in baFMD at 12-week follow-up were significantly greater in the black raspberry group when compared to the placebo group (2.9±3.6 mm vs. 1.0±3.9 mm, p<0.05, respectively). Radial augmentation indexes were significantly decreased in the black raspberry group when compared to the placebo group (-2±10% vs. 4±13%, p<0.05).

Conclusion

The use of black raspberry significantly decreased serum total cholesterol levels, inflammatory cytokines, and augmentation index, thereby improving vascular endothelial function in statin naïve participants with metabolic syndrome during the 12-week follow-up.

Keywords: Black raspberry, Metabolic syndrome, Lipid, Endothelial function, Augmentation index

Figures and Tables

Table 1

Baseline patient characteristics

Variable	Black Raspberry (n=26)	Placebo (n=25)	p value
Age (yrs)	56.4±9.2	60.7±10.4	0.124
Men	11 (42.3%)	12 (48.0%)	0.683
Height (m)	1.61±0.08	1.62±0.09	0.522
Weight (kg)	67.4±16.2	65.2±11.9	0.587
Body mass index (kg/m²)	25.9±4.6	24.7±3.9	0.316
Waist (cm)	82.5±8.7	81.7±7.1	0.722
Risk Factors
Hypertension	17 (65.4%)	13 (52.0%)	0.332
Type 2 Diabetes	5 (19.2%)	4 (16.0%)	1.000
Hyperlipidemia	13 (50.0%)	10 (40.0%)	0.473
Smoker	3 (11.5%)	3 (12.0%)	1.000
Alcohol	11 (45.8%)	9 (36.0%)	0.484
Medications at baseline
Aspirin	4 (15.4%)	3 (12.0%)	1.000
Clopidogrel	4 (15.4%)	3 (12.0%)	1.000
ACE inhibitor	1 (3.8%)	2 (8.0%)	0.610
ARB	8 (30.8%)	10 (40.0%)	0.490
Beta blocker	3 (11.5%)	2 (8.0%)	1.000
Calcium channel blocker	8 (30.8%)	7 (28.0%)	0.828
Diuretics	1 (3.8%)	1 (4.0%)	1.000

Values are presented as mean±standard deviation or number (%).

Table 2

Changes in lipid profiles

Variable	Black Raspberry (n=26)		Placebo (n=25)
Variable	Baseline	12 Week F/U	Baseline	12 Week F/U
Total Cholesterol (mg/dL)	206.8±35.3	182.8±27.2^*	196.0±33.0	192.5±31.9
Changes from Baseline (mg/dL)	-22.7±34.3^†		0.0±34.7
Triglyceride (mg/dL)	154.7±47.2	163.8±54.2	127.4±65.0	148.2±67.3
Changes from Baseline (mg/dL)	14.3±48.2		20.2±48.4
HDL-Cholesterol (mg/dL)	52.0±14.1	50.2±12.2	54.0±13.6	50.6±10.5^*
Changes from Baseline (mg/dL)	-2.0±6.1		-3.5±7.2
LDL-Cholesterol (mg/dL)	101.3±17.5	93.3±19.4	98.7±19.2	97.2±19.0
Changes from Baseline (mg/dL)	-7.3±21.5		1.1±20.8
Lipoprotein (a) (mg/dL)	14.6±12.5^†	13.9±12.6^†	27.0±24.7	26.3±27.2
Changes from Baseline (mg/dL)	-1.2±5.3		-2.0±6.3
Apolipoprotein A-I (mg/dL)	142.6±23.5	137.2±23.6	132.0±20.0	133.7±16.6
Changes from Baseline (mg/dL)	-5.3±17.3		1.1±7.5
Apolipoprotein B (mg/dL)	96.6±20.4	97.7±17.7	94.7±15.9	93.8±19.2
Changes from Baseline (mg/dL)	2.4±18.9		1.0±18.7
LDL/HDL Ratio	2.04±0.51	1.94±0.52	1.92±0.57	2.00±0.50
Changes from Baseline	-0.12±0.42		0.11±0.35
Triglyceride/HDL Ratio	3.11±1.16	3.54±1.62^*	2.71±2.10	3.25±2.01^*
Changes from Baseline	0.50±1.01		0.48±1.00
Total cholesterol/HDL Ratio	4.12±0.83	3.82±0.82^*	3.79±0.96	3.92±0.88
Changes from Baseline	-0.34±0.68^†		0.17±0.56
Apolipoprotein B/A-I Ratio	0.69±0.16	0.73±0.16	0.74±0.18	0.72±0.18
Changes from Baseline	0.04±0.17		0.00±0.13

Values are presented as mean±standard deviation or number (%).

^*p<0.05 compared with baseline, ^†p<0.05 compared with placebo group

Table 3

Changes in inflammatory parameters during the 12-week follow-up

Variables	Black Raspberry (n=26)		Placebo (n=25)
Variables	Baseline	12 Week Follow-Up	Baseline	12 Week Follow-Up
IL-6 (pg/mL)	1.4±0.9	0.9±0.6^*†	1.5±1.5	1.4±1.2
Changes from Baseline (pg/mL)	-0.5±1.4^†		-0.1±1.1
TNF-α (pg/mL)	18.3±4.7	12.7±4.0^*†	15.9±7.1	15.0±6.2
Changes from Baseline (pg/mL)	-5.4±4.5^†		-0.8±4.0
C-reactive protein (mg/L)	1.3±1.6	1.2±2.0	2.0±2.9	1.8±2.2
Changes from Baseline (mg/L)	-0.1±1.4		-0.3±3.8
Adiponectin (µg/mL)	3.9±4.3^†	6.9±4.1^*	6.4±6.5	6.1±6.6
Changes from Baseline (µg/mL)	2.9±2.1^†		-0.2±2.5
sICAM-1 (ng/mL)	643±365	621±587^†	501±399	489±278
Changes from Baseline (ng/mL)	-19±102		-11±114
sVCAM-1 (ng/mL)	1080±552	1055±490	1002±477	1088±498
Changes from Baseline (ng/mL)	-23±379		81±401

Values are presented as mean±standard deviation or number (%).

^*p<0.05 compared with baseline, ^†p<0.05 compared with placebo group

Table 4

Changes in flow-mediated dilation during the 12-week follow-up

Variables	Black Raspberry (n=26)		Placebo (n=25)
Variables	Resting	Reactive Hyperemia	Resting	Reactive Hyperemia
Baseline
Brachial Artery Diameter (mm)	39.3±5.6	42.1±6.3^*	39.3±8.2	42.1±8.6^*
Changes in Diameter (mm)	2.8±2.4		2.9±2.5
12 Week Follow-Up
Brachial Artery Diameter (mm)	35.9±7.0	38.8±7.1^*	39.3±7.5	40.1±8.0
Changes in Diameter (mm)	2.9±3.6^†		1.0±3.9

Values are presented as mean±standard deviation or number (%).

^*p<0.05 compared with baseline, ^†p<0.05 compared with placebo group

Table 5

Changes in baPWV, carotid IMT and ankle brachial index during the 12-week follow-up

Variables	Black Raspberry (n=26)		Placebo (n=25)
Variables	Baseline	12 Week Follow-Up	Baseline	12 Week Follow-Up
Right Average IMT (mm)	0.74±0.19	0.74±0.23	0.72±0.17	0.71±0.15
Changes from Baseline (mm)	-0.01±0.11		-0.02±0.13
Left Average IMT (mm)	0.75±0.19	0.73±0.17	0.71±0.12	0.72±0.14
Changes from Baseline (mm)	-0.03±0.13		0.00±0.17
Right PWV (cm/s)	1475±348	1446±253	1419±256	1434±296
Changes from Baseline (cm/s)	-38±267		8±160
Left PWV (cm/s)	1487±354	1458±269	1439±253	1436±264
Changes from Baseline (cm/s)	-37±238		-9±142
Right ABI	1.15±0.09	1.16±0.10	1.13±0.07	1.13±0.07
Changes from Baseline	0.00±0.11		0.00±0.08
Left ABI	1.12±0.06	1.11±0.10	1.11±0.06	1.09±0.07
Changes from Baseline	-0.01±0.09		-0.02±0.07

Values are presented as mean±standard deviation or number (%).

^*p<0.05 compared with baseline, ^†p<0.05 compared with placebo group

baPWV; brachial artery pulse wave velocity, PWV; pulse wave velocity, IMT; intima-media thickness, ABI; ankle-brachial index

Table 6

Changes in central blood pressure and radial augmentation index

Variables	Black Raspberry (n=26)		Placebo (n=25)
Variables	Baseline	12 Week Follow-Up	Baseline	12 Week Follow-Up
Systolic blood pressure (mmHg)	130±18	125±14	124±13	119±11
Changes from Baseline (mmHg)	-5±13		-5±12
Diastolic blood pressure (mmHg)	77±12	74±10	73±10	72±11
Changes from Baseline (mmHg)	-3±10		-1±10
Central Systolic blood pressure (mmHg)	133±21	129±16	129±16	123±12
Changes from Baseline (mmHg)	-4±24		-5±15
Heart Rate (bpm)	71±11	68±12	67±9	69±10
Changes from Baseline (bpm)	-3±10		1±9
Radial augmentation index (%)	80±10	78±11	79±12	82±17
Changes from Baseline (%)	-2±10^†		4±13

Values are presented as mean±standard deviation or number (%).

^*p<0.05 compared with baseline, ^†p<0.05 compared with placebo group

Table 7

Changes in circulating endothelial progenitor cells during the 12-week follow-up

Variables	Black Raspberry (n=26)		Placebo (n=25)
Variables	Baseline	12 Week Follow-Up	Baseline	12 Week Follow-Up
CD34/KDR+ cells (/uL)	280±284	106±82^*	175±134	75±53^*
Changes from Baseline (/uL)	-181±295		-105±142
CD34/CD117+ cells (/uL)	510±721	566±484	281±393	380±191
Changes from Baseline (/uL)	36±821		96±520
CD34/CD133+ cells (/uL)	55±30	51±46	81±58	58±51^*
Changes from Baseline (/uL)	-4±59		-32±51

Values are presented as mean±standard deviation or number (%).

^*p<0.05 compared with baseline, ^†p<0.05 compared with placebo group

References

1. Kim EJ, Lee YJ, Shin HK, Park JH. Induction of apoptosis by the aqueous extract of Rubus coreanum in HT-29 human colon cancer cells. Nutrition. 2005; 21:1141–1148.

2. Wang SY, Lin HS. Antioxidant activity in fruits and leaves of blackberry, raspberry, and strawberry varies with cultivar and developmental stage. J Agric Food Chem. 2000; 48:140–146.

3. Lim JW, Hwang HJ, Shin CS. Polyphenol compounds and anti-inflammatory activities of Korean black raspberry (Rubus coreanus Miquel) wines produced from juice supplemented with pulp and seed. J Agric Food Chem. 2012; 60:5121–5127.

4. Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002; 106:1652–1658.

5. Zhao C, Kim HK, Kim SZ, Chae HJ, Cui WS, Lee SW, et al. What is the role of unripe Rubus coreanus extract on penile erection? Phytother Res. 2011; 25:1046–1053.

6. Yang HM, Oh SM, Lim SS, Shin HK, Oh YS, Kim JK. Antiinflammatory activities of Rubus coreanus depend on the degree of fruit ripening. Phytother Res. 2008; 22:102–107.

7. Ou HC, Chou FP, Sheen HM, Lin TM, Yang CH, Huey-Herng Sheu W. Resveratrol, a polyphenolic compound in red wine, protects against oxidized LDL-induced cytotoxicity in endothelial cells. Clin Chim Acta. 2006; 364:196–204.

8. Chen CK, Pace-Asciak CR. Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen Pharmacol. 1996; 27:363–366.

9. Rakici O, Kiziltepe U, Coskun B, Aslamaci S, Akar F. Effects of resveratrol on vascular tone and endothelial function of human saphenous vein and internal mammary artery. Int J Cardiol. 2005; 105:209–215.

10. Opie LH. Metabolic syndrome. Circulation. 2007; 115:e32–e35.

11. McAnulty LS, Collier SR, Landram MJ, Whittaker DS, Isaacs SE, Klemka JM, et al. Six weeks daily ingestion of whole blueberry powder increases natural killer cell counts and reduces arterial stiffness in sedentary males and females. Nutr Res. 2014; 34:577–584.

12. Ash MM, Wolford KA, Carden TJ, Hwang KT, Carr TP. Unrefined and refined black raspberry seed oils significantly lower triglycerides and moderately affect cholesterol metabolism in male Syrian hamsters. J Med Food. 2011; 14:1032–1038.

13. Lee SM, Choi Y, Sung J, Kim Y, Jeong HS, Lee J. Protective effects of black rice extracts on oxidative stress induced by tert-butyl hydroperoxide in hepg2 cells. Prev Nutr Food Sci. 2014; 19:348–352.

14. Jeong HS, Kim S, Hong SJ, Choi SC, Choi JH, Kim JH, et al. Black raspberry extract increased circulating endothelial progenitor cells and improved arterial stiffness in patients with metabolic syndrome: a randomized controlled trial. J Med Food. 2016; 19:346–352.

15. Jeong HS, Hong SJ, Cho JY, Lee TB, Kwon JW, Joo HJ, et al. Effects of Rubus occidentalis extract on blood pressure in patients with prehypertension: randomized, double-blinded, placebo-controlled clinical trial. Nutrition. 2016; 32:461–467.

16. Jeong HS, Hong SJ, Lee TB, Kwon JW, Jeong JT, Joo HJ, et al. Effects of black raspberry on lipid profiles and vascular endothelial function in patients with metabolic syndrome. Phytother Res. 2014; 28:1492–1498.

17. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340:1111–1115.

18. Wang SY, Jiao H. Scavenging capacity of berry crops on superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. J Agric Food Chem. 2000; 48:5677–5684.

19. Seeram NP, Nair MG. Inhibition of lipid peroxidation and structure-activity-related studies of the dietary constituents anthocyanins, anthocyanidins, and catechins. J Agric Food Chem. 2002; 50:5308–5312.

20. Viljanen K, Kylli P, Kivikari R, Heinonen M. Inhibition of protein and lipid oxidation in liposomes by berry phenolics. J Agric Food Chem. 2004; 52:7419–7424.

21. Shafiee M, Carbonneau MA, Urban N, Descomps B, Leger CL. Grape and grape seed extract capacities at protecting LDL against oxidation generated by Cu2+, AAPH or SIN-1 and at decreasing superoxide THP-1 cell production. A comparison to other extracts or compounds. Free Radic Res. 2003; 37:573–584.

22. Demrow HS, Slane PR, Folts JD. Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation. 1995; 91:1182–1188.

23. Vivancos M, Moreno JJ. Effect of resveratrol, tyrosol and beta-sitosterol on oxidised low-density lipoprotein-stimulated oxidative stress, arachidonic acid release and prostaglandin E2 synthesis by RAW 264.7 macrophages. Br J Nutr. 2008; 99:1199–1207.

24. Bhandary B, Lee GH, So BO, Kim SY, Kim MG, Kwon JW, et al. Rubus coreanus inhibits oxidized-LDL uptake by macrophages through regulation of JNK activation. Am J Chin Med. 2012; 40:967–978.

25. Nakanishi T, Mukai K, Yumoto H, Hirao K, Hosokawa Y, Matsuo T. Anti-inflammatory effect of catechin on cultured human dental pulp cells affected by bacteriaderived factors. Eur J Oral Sci. 2010; 118:145–150.

26. Ndiaye M, Chataigneau T, Andriantsitohaina R, Stoclet JC, Schini-Kerth VB. Red wine polyphenols cause endothelium-dependent EDHF-mediated relaxations in porcine coronary arteries via a redox-sensitive mechanism. Biochem Biophys Res Commun. 2003; 310:371–377.

27. Stein JH, Keevil JG, Wiebe DA, Aeschlimann S, Folts JD. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation. 1999; 100:1050–1055.

28. Karim M, McCormick K, Kappagoda CT. Effects of cocoa extracts on endothelium-dependent relaxation. J Nutr. 2000; 130:2105S–2108S.

29. Basu A, Fu DX, Wilkinson M, Simmons B, Wu M, Betts NM, et al. Strawberries decrease atherosclerotic markers in subjects with metabolic syndrome. Nutr Res. 2010; 30:462–469.

30. Graf D, Seifert S, Jaudszus A, Bub A, Watzl B. Anthocyanin-rich juice lowers serum cholesterol, leptin, and resistin and improves plasma fatty acid composition in fischer rats. PLoS One. 2013; 8:e66690.

31. Garcia-Diaz DF, Johnson MH, de Mejia EG. Anthocyanins from fermented berry beverages inhibit inflammationrelated adiposity response in vitro. J Med Food. 2015; 18:489–496.

32. Suzuki A, Yamamoto N, Jokura H, Yamamoto M, Fujii A, Tokimitsu I, et al. Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats. J Hypertens. 2006; 24:1065–1073.

33. Jennings A, Welch AA, Fairweather-Tait SJ, Kay C, Minihane AM, Chowienczyk P, et al. Higher anthocyanin intake is associated with lower arterial stiffness and central blood pressure in women. Am J Clin Nutr. 2012; 96:781–788.

34. 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.

35. Nagasawa SY, Okamura T, Iso H, Tamakoshi A, Yamada M, Watanabe M, et al. Relation between serum total cholesterol level and cardiovascular disease stratified by sex and age group: a pooled analysis of 65 594 individuals from 10 cohort studies in Japan. J Am Heart Assoc. 2012; 1:e001974.

36. Lawrence T, Willoughby DA, Gilroy DW. Anti- inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol. 2002; 2:787–795.

37. Boscá L, Zeini M, Través PG, Hortelano S. Nitric oxide and cell viability in inflammatory cells: a role for NO in macrophage function and fate. Toxicology. 2005; 208:249–258.

38. Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004; 84:1381–1478.

39. Verma S, Devaraj S, Jialal I. Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation. 2006; 113:2135–2150.

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