Atherosclerosis, Hypertension, and LDL by Dr. Elizabeth Owings, MD"Atherosclerosis is a leading cause of mortality and morbidity in countries which have a 'Westernized' diet and lifestyle. It is a form of arteriosclerosis, or hardening of the arteries, and represents the process of arterial damage and disease. The earliest signs may be found in infants if the mother had elevated cholesterol levels or elevated insulin levels. Atherosclerosis is firmly established by late teens. Lifestyle, control over diseases such as diabetes and hypertension, as well as genetic factors, influence how quickly cholesterol plaques are laid down and how stable they are. Generally, the process of atherosclerosis starts with cholesterol collecting in the lining of the blood vessel, and muscle cells grow and multiply in the blood vessel wall, making the vessel tighter and less flexible. Connective tissue components collect in the vessel wall, contributing to stiffness. These processes occur at gradually over decades, and may not even cause symptoms recognized by the individual. Finally, the unstable covering on a cholesterol plaque may rupture suddenly, causing an immediate clot which blocks off blood flow, triggering a heart attack or stroke.i
Atherosclerosis is accelerated by certain disease states, the most widely recognized of which is hypertension. Hypertension, or high blood pressure, is generally defined as a blood pressure of over 140/90 on three separate measurements. The management of hypertension is important because hypertension is a risk factor in many other disease states, including heart disease, heart attack, stroke, eye disease, kidney disease and kidney failure.ii Hypertension occurs due to a myriad of factors, but is generally associated with endothelial dysfunction. Endothelial dysfunction may be a precursor of hypertension; or, subsequent to its development, endothelial dysfunction may occur in accelerated form. The endothelium is the name of the lining of blood vessels, and it is arguably the largest organ in the body, lining 100,000 miles of blood vessels and covering roughly a soccer field in surface area. This lining is responsible for producing nitric oxide, which then relaxes the blood vessel, allowing more blood to flow through it and lowering blood pressure. When the endothelium is dysfunctional, it does not respond to the need for blood flow, and the vessel remains in a constricted state. Additionally, this dysfunctional endothelium is more susceptible to cholesterol plaques, and these plaques are more likely to rupture, triggering a local clot, which occurs in most heart attacks and strokes. This clot can even travel to another area of the body. This is how an “ulcerated” plaque in a vessel of the neck can cause a stroke in the brain.
Endothelial dysfunction is worsened by diabetesiii, kidney failureiv, elevated LDL cholesterolv, elevated homocysteine levelsvi, smokingvii, lack of antioxidant consumptionviii, and high salt diet.ix It is endothelial dysfunction which signals the initiation and progression of atherosclerosisx, contributing to worsening high blood pressure, heart attack, stroke, peripheral vascular disease, and erectile dysfunction.
Endothelial dysfunction, hypertension, oxidative stress, and elevated LDL cholesterol are interrelated factors which may accelerate atherosclerosis. Oxidative stress is a condition in which the natural antioxidants in the body are inadequate to reverse the damage done by free radicals. Free radicals are produced in the body by infection-fighting cells as well as in the natural processes of cell function. Measurable antioxidants in the body include Vitamin C and Vitamin E. In a plant-based raw diet (uncooked vegetables and greens), additional antioxidants are consumed and can augment the body's natural antioxidant systems. A number of supplements can be taken to increase antioxidant systems in the body. A diet high in processed foods (such as refined grains and sugars) creates free radicals and therefor increases oxidative stress. While it is endothelial dysfunction which signals the initiation and progression of atherosclerosis, it is only oxidized LDL cholesterol (ox-LDL) which is added to cholesterol plaquesxixii. Ox-LDL is central to the progression of atherosclerosis, because it directly promotes endothelial injury, attracts and traps specialized blood cells (monocytes) which subsequently form “foam” cells, which are active in plaque growth, smooth muscle overgrowth, and plaque rupture.xiii
Panoxol™, a patented combination of L-arginine, L-citrulline, horse chestnut seed extract, Ginkgo biloba, cayenne pepper, and red yeast rice, provides a novel non-prescription supplement to support the body's natural repair mechanisms. Combined with appropriate blood pressure control, diet, and exercise, this product can be expected to shift the balance toward a state of health. Each ingredient works at multiple points in the progression of endothelial dysfunction and atherosclerotic disease, and the combination is synergistic in effect.
L-arginine is an amino acid, which means it is found in protein, in dilute form. It is the precursor to nitric oxide and the only substrate needed to synthesize nitric oxide. Supplementing the diet with purified L-arginine helps increase nitric oxide levels, thus ameliorating endothelial dysfunction, as well as managing hypertension.xiv
L-Citrulline has been shown to both inhibit arginase (which would turn arginine into uric acid instead of nitric oxide) and to improve arginine stores better than arginine itself. The combination of citrulline and arginine have been shown to reverse endothelial dysfunction.xv In addition, it has been shown that the combination of citrulline and arginine enhances nitric oxide bioavailabilityxvi.
Horse chestnut is best known for improving ankle swelling and shrinking swollen leg veins. It has been shown to protect the endotheliumxvii, and also has an important role in stroke prevention and recovery. Aescin, the active ingredient, has been shown to prevent damaging inflammation and actually downregulates inflammatory genes and upregulates healing genes in a mouse model of stroke.xviii Inflammation is a major factor in the process of atherosclerosis.xix
Cayenne, a potent antioxidantxx which limits oxidative stressxxi, has been shown to improve not only atherosclerosis, but several contributory risk factors, such as hypertension, diabetes, and obesity.xxii
Red Yeast Rice improves cholesterol profile, as well as diminishing oxidation and limiting the expression of cell adhesion molecules, effectively making the endothelium less 'sticky' and therefore less likely form cholesterol plaque.
Ginkgo biloba is extensively studied. It is recognized as a neuroprotective supplement, protecting the brain from injury in cases of absent or diminished blood flow.xxiii It improves blood flow to the brain in patients who have experienced a hemorrhagic strokexxiv, and has been extensively studied and found helpful in both ischemic and hemorrhagic strokes.xxv In recent randomized, double blind, placebo-controlled study of ischemia stroke, Ginkgo biloba administration tripled the likelihood of 4 month improvement to half the original NIHSS score.xxvi Ginkgo has been shown to limit inflammation as well as the insulin resistance so dangerous in the metabolic syndrome and Type II diabetes.xxvii It lessens the endothelial dysfunction caused by ox-LDL.xxviii It decreases atherogenic plaque formation.xxix It prevents the oxidative state.xxx It has been found to be a free-radical scavenger which actually increases microcirculation (in blood vessels too small for surgery or stents) in the elderly.xxxi In a laboratory (in vitro) rat model of atherosclerosis in Type II diabetes, EGb761 was found to be effective against atherosclerosis.xxxii It diminishes the formation of inflammatory “foam” cells.xxxiii xxxiv It decreases ox-LDL-induced oxidative functional damage in endothelial cells.xxxv It is apparent that Ginkgo addresses almost every aspect of atherosclerosis.
Combined with diet high in fresh vegetables, exercise, and appropriate blood pressure control, daily use of Panoxol™ can be expected to improve quality of life and decrease risks of cardiovascular disease."
i Pathogenesis of Atherosclerosis: A multifactorial process. Exp Clin Cardiol. 2002 Spring; 7(1): 40–53. Singh RB, Mengi SA, Xu YJ, Arneja AS, Dhalla NS
ii American Diabetes Association “Diabetes Pro” Professional Resources online. http://professional.diabetes.org/resourcesforprof...
iii Endothelial dysfunction in diabetes mellitus. Vasc Health Risk Manag. 2007 Dec; 3(6): 853–876. Hadi AR ,Hadi and Jassim Al Suwaidi
iv Mechanism of endothelial dysfunction in chronic kidney disease. Clin Chim Acta. 2010 Oct 9;411(19- 20):1412-20. doi:10.1016/j.cca.2010.06.019. Epub 2010 Jun 22. Malyszko J
v New mechanisms of LDL-cholesterol induced endothelial dysfunction; correction by statins. Bull Mem Acad R Med Belg. 2002;157(10-12):427-31; discussion 431-4. Balligand JL
vi Homocysteine and endothelial dysfunction: a link with cardiovascular disease. J Nutr. 2000 Feb;130(2S Suppl):369S- 372S. McDowell IF, Lang D.
vii Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):509-15. doi: 10.1161/ATVBAHA.113.300156. Messner B, Bernhard D
viii Acute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension. 2012 Apr;59(4):818- 24. Wray DW1, Nishiyama SK,Harris RA, Zhao J, McDaniel J, Fjeldstad AS, Witman MA, Ives SJ, Barrett-O'Keefe Z, Richardson RS.
ix Vascular Endothelial Function and Hypertension: Insights and Directions. Curr Hypertens Rep. 2010 Dec; 12(6): 448– 455. Kodlipet Dharmashankar and Michael E. Widlansky
x Arterial endothelial dysfunction in baboons fed a high-cholesterol, high-fat diet; Am J Clin Nutr. 2005 Oct; 82(4): 751–759. Qiang Shi, et al.
xi Beyond Cholesterol. N Engl J Med. 1989;320:915. Steinberg D, et al.
xii LDL Hypercholesterolemia is Associated with Accumulatio of Oxidized LDL, Atherosclerotic Plaque Growth, and Compensatory Vessel Enlargement in Coronary Arteries of Miniature Pigs. Arteriosclerosis, Thrombosis, and Vasc. Biology; 1998; 18, p415- 422. Holvoet, P; Theilmeier, G, Shavalkar, B; Flameng, W; Collen, D.
xiv Nutraceuticals for Blood Pressure Control. Ann Med. 2015 Sep;47(6); 447-56. Sirtori CR, Arnoli A, Cicero AF. xv Meta Gene. 2013 Oct 15;1:8-14. doi: 10.1016/j.mgene.2013.09.001. ECollection 2013. The effect of citrulline and arginine supplementation on lactic acidemia in MELAS syndrome. El-Hattab AW1, Emrick LT2, Williamson KC2, Craigen WJ2, Scaglia F2.
xvi Oral supplementation with a combination of l-citrulline and l-arginine rapidly increases plasma l-arginine concentration and enhances NO bioavailability. Biochemical and Biophysical Research Communications. Volume 454, Issue 1, 7, November 2014, Pages 53–57. Masahiko Morita, Toshio Hayashi, Masayuki Ochiai, Morihiko Maeda, Tomoe
xvii Endothelial function impairment in chronic venous insufficiency: effect of some cardiovascular protectant agents. Angiology. 2009 Dec-2010 Jan;60(6):763-71. Carrasco OF1, Ranero A, Hong E, Vidrio H.
xviii Escin attenuates cognitive deficits and hippocampal injury after transient global cerebral ischemia in mice via regulating certain inflammatory genes. Neurochemistry 57(2):119-127. Sept 2010. International. Leiming Zhang, Fenghua Fu , Xiumei Zhang, Mei Zhu, Tian Wang, Huaying Fan
xix The relationship between inflammation and neoangiogenesis of epicardial adipose tissue and coronary atherosclerosis based on computed angiography analysis. Atherosclerosis. 2015 Sep 10;243(1):293-299. Kitagawa T, Yamamoto H, Sentani K, Takahashi S, Tsushima H, Senoo A, Yasui W, Sueda T, Kihara Y.
xx Antioxidant activity of capsinoids. J Agric Food Chem. 2002 Dec 4;50(25):7396-401. Rosa A, Deiana M, Casu V, Paccagnini S, Appendino G, Ballero M, Dessí MA
xxi Protection of lipid peroxidation and carbonyl formation in proteins by capsaicin in human erythrocytes subjected to oxidative stress. Phytother Res. 2006 Apr;20(4):303-6. Lugman S, Rizvi SI.
xxii Capsaicin may have important potential for promoting vascular and metabolic health. Open Heart. 2015 Jun 17;2(1):e000262. McCarty MF1,DiNicolantonio JJ2, O'Keefe JH2.
xxiii Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation.J Neuroinflammation. 2014 Sep 26;11:167. doi: 10.1186/s12974-014-0167-6. Jiang M, Li J, Peng Q, Liu Y, Liu W, Luo C, Peng J, Li J, Yung KK, Mo Z.
xxiv Effect of ginkgolide B on brain metabolism and tissue oxygenation in severe haemorrhagic stroke.Int J Clin Exp Med. 2015 Mar 15;8(3):3522-9. Chi CL, Shen DF, Wang PJ, Li HL, Zhang L
xxv Neuroprotective Effects of Ginkgolide B Against Ischemic Stroke: A Review of Current Literature.Curr Top Med Chem. 2015;15(21):2222-32.Nabavi SM, Habtemariam S, Daglia M, Braidy N, Loizzo MR, Tundis R, Nabavi SF
xxvi The Effect of Ginkgo biloba on Functional Outcome of Patients with Acute Ischemic Stroke: A Double- blind, Placebo-controlled, Randomized Clinical Trial. November 2013; Volume 22, Issue 8, Pages e557–e563 Darioush Savadi Oskouei, MD, Reza Rikhtegar, MD, Mazyar Hashemilar, MD, Homayoun Sadeghi-Bazargani, MD, PhD, Mohsen Sharifi-Bonab, MD, Elyar Sadeghi-Hokmabadi, MD, Sina Zarrintan, MD, Ehsan Sharifipour, MD
xxvii Combined lowering of low grade systemic inflammation and insulin resistance in metabolic syndrome patients treated with Ginkgo biloba. Atherosclerosis. 2014 Dec;237(2):584-8. Siegel G, Ermilov E, Knes O, Rodriguez M.
xxviii Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism. J Appl Physiol (1985). 2013 Jan 15;114(2):271-85. Ou HC, Hsieh YL, Yang NC, Tsai KL, Chen KL, Tsai CS, Chen IJ, Wu BT, Lee SD.
xxix EGb 761 promotes osteobastogenesis, lowers none marrow adipogenesis and atherosclerotic plaque formation. Phytomedicine. 2012 Sep 15; 19(12);1132-42. Gautm J, Kushwaha P, Swarnkar G, Khedgikar V, Nagar GK, Singh D, Singh V, Jain M, Barthwal M, Trivedi R.
xxx Ginkgo biloba extract (GbE) enhances the anti-atherogenic effect of cilostazol by inhibiting ROS generation. Exp Mol Med. 2012 May 31;44(5)311-8. Jung IH, Lee YH, Yoo JY, Jeong SJ, Sonn SK, Park JG, Ryu KH, Lee BY, Han HY, Lee SY, Kim DY, Lee H, Oh GT.
xxxi A new ginkgo fresh plant extract increases microcirculation and radical scavenging activity in elderly patients. Adv Ther. 2011 Dec;28(12):1078-88. Suter A, Niemer W, Klopp R.
xxxii EGb761, a Ginkgo biloba extract, is effective aginast atherosclerosis in vitro, in a rat model of type II diabetes. PLoS One. 2011;6(6);e20301. Lim S, Yoon JW, Kang SM, Choi SH, Cho BJ, Kim M, Park HS, Cho HG, Shin H, Kim YB, Kim HW, Jank HC, Park KS.
xxxiii EGb761 ameliorates the formation of foam cells by regulating the expression of SR-A and ABCA1:role of haem oxygenase-1. Cardiovasc Res. 2010 Dec 1;88(3):415-23. Tsai JY, Su KH, Shyue SK, Kou YR, Yo YB, Hsiao SH, Chiang AN, Wu YL, Ching LC, Lee TS.
xxxiv Inhibitions of vascular endothelial growth factor expression and foam cell formation by EGb761, a special extract of Ginkgo biloba, in oxidatively modified low-density lipoprotein-induced human THP-1 monocytes cells. Phytomedicine. 2009 Mar;16(2-3);138-45. Liu HJ, Wang XL, Zhang L, Qiu Y, Li TJ, Li R, Wu MC, Wei LX, Rui YC.
xxxv Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells. J Appl Physiol (1985). 2009 May;106(5):1674-85. Ou HC, Lee WJ, Lee IT, Chiu TH, Tsai KL, Lin CY, Sheu WH.