Effects of a nutraceutical combination on lipids, inflammation and endothelial integrity in patients with subclinical inflammation: a randomized clinical trial

Matteo Pirro, Massimo R Mannarino, Stefano Ministrini, Francesca Fallarino, Graziana Lupattelli, Vanessa Bianconi, Francesco Bagaglia, Elmo Mannarino, Matteo Pirro, Massimo R Mannarino, Stefano Ministrini, Francesca Fallarino, Graziana Lupattelli, Vanessa Bianconi, Francesco Bagaglia, Elmo Mannarino

Abstract

Cholesterol elevations are associated with systemic inflammation and endothelial fragmentation into microparticles. The cholesterol-lowering efficacy of nutraceutical combinations (NC) has not been investigated in patients with low-grade systemic inflammation and normal-borderline cholesterol levels. This is a 3-month prospective randomized open-label interventional study in patients with elevated plasma high sensitivity C-reactive protein (hsCRP) levels (>2 mg/L) and low-density lipoprotein (LDL) cholesterol of 100-160 mg/dL. The effect of either an oral cholesterol-lowering nutraceutical combination (NC) or no active treatment (noNC) was tested on LDL cholesterol, hsCRP and endothelial microparticle (EMPs) levels. Patients taking the NC had a significant reduction of total (-12%) and LDL cholesterol (-23%) compared to those who received noNC (p < 0.001 for both). Also, hsCRP and EMPs were significantly reduced by the NC (-41% and -16%, respectively). LDL cholesterol change was positively associated with hsCRP (rho = 0.21, p = 0.04) and EMP changes (rho = 0.56, p < 0.001), hsCRP and EMP changes being associated with each other (rho = 0.28, p = 0.005). Patients experiencing both LDL cholesterol and hsCRP reduction were those having the greatest EMP decrease. In conclusion, among patients with low-grade systemic inflammation, an oral NC significantly improved cholesterol profile and attenuated the degree of systemic inflammation and endothelial injury.

Figures

Figure 1. Post-intervention median EMP reduction according…
Figure 1. Post-intervention median EMP reduction according to the degree of LDL cholesterol and hsCRP changes.
Group 1 includes patients with both LDL cholesterol and hsCRP reductions. Group 2 includes patients with either a LDL cholesterol or hsCRP reduction. Group 3 includes patients without evidence of LDL cholesterol and hsCRP reduction. *p 

Figure 2

Correlations between LDL cholesterol change…

Figure 2

Correlations between LDL cholesterol change and either hsCRP change ( a ) or…

Figure 2
Correlations between LDL cholesterol change and either hsCRP change (a) or EMP change (b), and between changes in EMP and hsCRP levels (c). Data in the entire study population are presented as absolute changes, graphically differentiated according to the treatment group: NC group (black circles), noNC group (grey circles). LDL, low-density lipoprotein; hsCRP, high sensitivity C-reactive protein. EMP, endothelial microparticle.
Figure 2
Figure 2
Correlations between LDL cholesterol change and either hsCRP change (a) or EMP change (b), and between changes in EMP and hsCRP levels (c). Data in the entire study population are presented as absolute changes, graphically differentiated according to the treatment group: NC group (black circles), noNC group (grey circles). LDL, low-density lipoprotein; hsCRP, high sensitivity C-reactive protein. EMP, endothelial microparticle.

References

    1. Ross R. Atherosclerosis: an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).
    1. Vaudo G. et al.. Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity. Ann. Rheum. Dis. 63, 31–35 (2004).
    1. Vaudo G. et al.. Precocious intima-media thickening in patients with primary Sjögren’s syndrome. Arthritis. Rheum. 52, 3890–3897 (2005).
    1. Pirro M. et al.. Imbalance between endothelial injury and repair in patients with polymyalgia rheumatica: improvement with corticosteroid treatment. J. Intern. Med. 272, 177–184 (2012).
    1. Pirro M. et al.. Systemic inflammation in patients with psoriasis is associated with preclinical atherosclerosis. Eur. J. Prev. Cardiol. 22, 1027–1035 (2015).
    1. Tousoulis D. et al.. Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins. J. Am. Coll. Cardiol. 63, 2491–2502 (2014).
    1. Pirro M. et al.. Age and duration of follow-up as modulators of the risk for ischemic heart disease associated with high plasma C-reactive protein levels in men. Arch. Intern. Med. 161, 2474–2480 (2001).
    1. St-Pierre A. C. et al.. Inflammatory markers and long-term risk of ischemic heart disease in men. A 13-year follow-up of the Quebec Cardiovascular Study. Atherosclerosis. 182, 315–321 (2005).
    1. Kaptoge S. et al.. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 375, 132–140 (2010).
    1. Dignat-George F. & Boulanger C. M. The many faces of endothelial microparticles. Arterioscler. Thromb. Vasc. Biol. 31, 27–33 (2011).
    1. Rautou P. E. et al.. Microparticles, vascular function, and atherothrombosis. Circ. Res. 109, 593–606 (2011).
    1. Mallat Z. et al.. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation. 101, 841–843 (2000).
    1. Amabile N. et al.. Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure. J. Am. Soc. Nephrol. 16, 3381–3388 (2005).
    1. Preston R. A. et al.. Effects of severe hypertension on endothelial and platelet microparticles. Hypertension. 41, 211–217 (2003).
    1. Pirro M. et al.. Increased ratio of CD31+/CD42− microparticles to endothelial progenitors as a novel marker of atherosclerosis in hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 26, 2530–2535 (2006).
    1. Sabatier F., Camoin-Jau L., Anfosso F., Sampol J. & Dignat-George F. Circulating endothelial cells, microparticles and progenitors: key players towards the definition of vascular competence. J. Cell. Mol. Med. 13, 454–471 (2009).
    1. Rodríguez-Carrio J. et al.. Altered profile of circulating microparticles in rheumatoid arthritis patients. Clin. Sci. 128, 437–448 (2015).
    1. Sinning J. M. et al.. Circulating CD31+/Annexin V+microparticles correlate with cardiovascular outcomes. Eur. Heart. J. 32, 2034–2041 (2011).
    1. Ridker P. M. et al.. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 126, 2739–2748 (2012).
    1. Ridker P. M. et al.. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N. Engl. J. Med. 334, 1959–1965 (2001).
    1. Ridker P. M. et al.. Rosuvastatin to prevent vascular events in men and women with elevated C-Reactive Protein. N. Engl. J. Med. 359, 2195–2207 (2008).
    1. Pirro M. et al.. Influence of short-term rosuvastatin therapy on endothelial progenitor cells and endothelial function. J. Cardiovasc. Pharmacol. Ther. 14, 14–21 (2009).
    1. Banach M. et al.. Lipids, blood pressure and kidney update 2015. Lipids Health Dis. 14, 167 (2015).
    1. Banach M. et al.. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 11, 1–23 (2015).
    1. Banach M. & Serban M. C. Discussion around statin discontinuation in older adults and patients with wasting diseases. J Cachexia Sarcopenia Muscle. 7, (2016) (In press).
    1. Mannarino M. R., Ministrini S. & Pirro M. Nutraceuticals for the management of hypercholesterolemia. Eur. J. Intern. Med. 25, 592–599 (2014).
    1. Endo A. & Monacolin, K. A new hypocholesterolemic agent produced by a Monascus species. J. Antibiot. 32, 852–854 (1979).
    1. Dong H., Zhao Y., Zhao L. & Lu F. The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials. Planta Med. 79, 437–446 (2013).
    1. Marinangeli C. P., Jones P. J., Kassis A. N. & Eskin M. N. Policosanols as nutraceuticals: fact or fiction. Crit. Rev. Food. Sci. Nutr. 50, 259–267 (2010).
    1. Lin C. P., Lin Y. L., Huang P. H., Tsai H. S. & Chen Y. H. Inhibition of endothelial adhesion molecule expression by Monascus purpureus-fermented rice metabolites, monacolin K, ankaflavin, and monascin. J. Sci. Food. Agric. 91, 1751–1758 (2011).
    1. Meng S. et al.. Berberine ameliorates inflammation in patients with acute coronary syndrome following percutaneous coronary intervention. Clin. Exp. Pharmacol. Physiol. 39, 406–411 (2013).
    1. Thippeswamy G., Sheela M. L. & Salimath B. P. Octacosanol isolated from Tinospora cordifolia downregulates VEGF gene expression by inhibiting nuclear translocation of NF- <kappa>B and its DNA binding activity. Eur. J. Pharmacol. 588, 141–150 (2008).
    1. Park J. S., Chyun J. H., Kim Y. K., Line L. L. & Chew B. P. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Nutr. Metab. 5, 7–18 (2010).
    1. Affuso F., Ruvolo A., Micillo F., Saccà L. & Fazio S. Effects of a nutraceutical combination (berberine, red yeast rice and policosanols) on lipid levels and endothelial function randomized, double-blind, placebo-controlled study. Nutr. Metab. Cardiovasc. Dis. 20, 656–661 (2010).
    1. Pirro M. et al.. Nutraceutical combination (red yeast rice, berberine and policosanols) improves aortic stiffness in low-moderate risk hypercholesterolemic patients. Pharma. Nutrition. 1, 73–77 (2013).
    1. Ruscica M. et al.. Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with Armolipid Plus. J. Clin. Lipidol. 8, 61–68 (2014).
    1. Solà R. et al.. Effects of poly-bioactive compounds on lipid profile and body weight in a moderately hypercholesterolemic population with low cardiovascular disease risk: a multicenter randomized trial. PLoS One, 9(8), e101978, doi: 10.1371 (2014).
    1. Gonnelli S. et al.. Efficacy and Tolerability of a Nutraceutical Combination (Red Yeast Rice, Policosanols, and Berberine) in Patients with Low-Moderate Risk Hypercholesterolemia: A Double-Blind, Placebo-Controlled Study. Curr. Therap. Res. 77, 1–6 (2015).
    1. Pisciotta L., Bellocchio A. & Bertolini S. Nutraceutical pill containing berberine versus ezetimibe on plasma lipid pattern in hypercholesterolemic subjects and its additive effect in patients with familial hypercholesterolemia on stable cholesterol-lowering treatment. Lipids. Health. Dis. 11, 123, doi: 10.1186/1476-511X-11-123 (2012).
    1. Chen Y. et al.. Inflammatory stress induces statin resistance by disrupting 3-hydroxy-3-methylglutaryl-CoA reductase feedback regulation. Arterioscler. Thromb. Vasc. Biol. 34, 365–376 (2014).
    1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 285, 2486–2497 (2001).
    1. Burke F. M. Red yeast rice for the treatment of dyslipidemia. Curr. Atheroscler. Rep. 17(4), 4958 (2015).
    1. Cameron J., Ranheim T., Kulseth M. A., Leren T. P. & Berge K. E. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis. 201, 266–273 (2008).
    1. Ma K. Y. et al.. Red yeast rice increases excretion of bile acids in hamsters. Biomed. Environ. Sci. 22, 269–277 (2009).
    1. Zhao S. P. et al.. Xuezhikang, an extract of cholestin, protects endothelial function through antiinflammatory and lipid-lowering mechanisms in patients with coronary heart disease. Circulation. 110, 915–920 (2004).
    1. Li X. X. et al.. Berberine attenuates vascular remodeling and inflammation in a rat model of metabolic syndrome. Biol. Pharm. Bull. 38, 862–868 (2015).
    1. Sanoobar M. et al.. Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial. Nutr. Neurosci. 18, 169–176 (2015).
    1. Kinlay S. Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein: a meta-analysis. J. Am. Coll. Cardiol. 49, 2003–2009 (2007).
    1. Nakagawa K. et al.. Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes. Br. J. Nutr. 105, 1563–1571 (2011).
    1. Calder P. C. et al.. A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies. Br. J. Nutr. 109, Suppl. 1, S1–S34 (2013).
    1. Schiro A. et al.. Endothelial microparticles as conveyors of information in atherosclerotic disease. Atherosclerosis. 234, 295–302 (2014).
    1. Devaraj S., Kumaresan P. R. & Jialal I. C-reactive protein induces release of both endothelial microparticles and circulating endothelial cells in vitro and in vivo: further evidence of endothelial dysfunction. Clin. Chem. 57, 1757–1761 (2011).
    1. Leroyer A. S. et al.. Endothelial-derived microparticles: Biological conveyors at the crossroad of inflammation, thrombosis and angiogenesis. Thromb. Haemost. 104, 456–463 (2010).
    1. Angelot F. et al.. Endothelial cell-derived microparticles induce plasmacytoid dendritic cell maturation: potential implications in inflammatory diseases. Haematologica. 94, 1502–1512 (2009).
    1. Tramontano A. F. et al.. Statin decreases endothelial microparticle release from human coronary artery endothelial cells: implication for the Rho-kinase pathway. Biochem. Biophys. Res. Commun. 320, 34–38 (2004).
    1. McCall D. O. et al.. The assessment of vascular function during dietary intervention trials in human subjects. Br. J. Nutr. 106, 981–994 (2011).

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir