Herbal Intervention in Cardiovascular Diseases

  • Johnna Francis Varghese
  • Rohit Patel
  • Mohit Singh
  • Umesh C. S. YadavEmail author


Cardiovascular diseases (CVDs) are the most prevalent cause of morbidity and mortality worldwide. Oxidative stress and chronic inflammation are the major causes of CVDs. In the vasculature, inflammation occurs due to injury, oxidation of lipids, infection, etc. that result in damage to cells of the blood vessels and progression towards plaque formation. Inflammation portrays an important role in all stages of plaque formation which leads to cardiac arrest or heart failure, peripheral vascular diseases and stroke and could be fatal. Unlike plaque formation, the birth defect in cardiovascular system also leads to short and poor quality of life. Among all preventive and therapeutic strategies for CVDs, herbal interventions are known to be effective with little or no side effects. Herbal interventions have been in use for medical treatments from the beginning of civilisation. WHO report states that approximately 80% of the global population depends on the herbal resources, of which many have moved to clinical use in the recent times. Phytochemicals have a wide array of properties especially anti-inflammatory, anti-oxidative and anti-lipidaemic which are effective in preventing and treating CVDs. They increase the expression of antioxidant and anti-inflammatory molecules mainly via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and reduce the levels of cholesterol, low-density lipoprotein (LDL) and inflammatory cytokines, hence effective in treatment of CVDs. In this chapter, herbal derivative-induced alteration in the mechanisms pertaining to pathophysiology of CVDs has been discussed.


Cardiovascular diseases (CVDs) Phytochemicals Oxidative stress Inflammation ROS Nuclear factor erythroid 2-related factor 2 (Nrf2) 



Dr. Umesh C S Yadav acknowledges the award of Ramanujan Fellowship by DST, Govt. of India. Junior Research Fellowship to RP from SERB and to JFV from GSBTM is also acknowledged.


  1. 1.
    Cannon B (2013) Cardiovascular disease: biochemistry to behaviour. Nature 493(7434):S2–S3CrossRefGoogle Scholar
  2. 2.
    Six Types of Cardiovascular Disease. 2010 23.07.2010Google Scholar
  3. 3.
    Marijon E et al (2012) Rheumatic heart disease. Lancet 379(9819):953–964CrossRefGoogle Scholar
  4. 4.
    Arsenault BJ, Boekholdt SM, Kastelein JJ (2011) Lipid parameters for measuring risk of cardiovascular disease. Nat Rev Cardiol 8(4):197–206CrossRefGoogle Scholar
  5. 5.
    Qiao Q et al (2007) Metabolic syndrome and cardiovascular disease. Ann Clin Biochem 44(Pt 3):232–263CrossRefGoogle Scholar
  6. 6.
    Sauer H, Shah AM, Laurindo FRM (2010) Studies on cardiovascular disorders, oxidative stress in applied basic research and clinical practice. Humana Press, New YorkGoogle Scholar
  7. 7.
    Wang S et al (2014) 6-Gingerol attenuates hydrogen peroxide-induced DNA damage in human umbilical vein endothelia cells. Food Sci Technol Res 20(5):947–954CrossRefGoogle Scholar
  8. 8.
    Taube A et al (2012) Inflammation and metabolic dysfunction: links to cardiovascular diseases. Am J Physiol Heart Circ Physiol 302(11):H2148–H2165CrossRefGoogle Scholar
  9. 9.
    Sipahi I et al (2007) Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 147(1):10–18CrossRefGoogle Scholar
  10. 10.
    Sheppard RJ, Schiffrin EL (2013) Inhibition of the renin-angiotensin system for lowering coronary artery disease risk. Curr Opin Pharmacol 13(2):274–279CrossRefGoogle Scholar
  11. 11.
    Steg PG, Ducrocq G (2016) Future of the prevention and treatment of coronary artery disease. Circ J 80(5):1067–1072CrossRefGoogle Scholar
  12. 12.
    Ferdowsian HR, Barnard ND (2009) Effects of plant-based diets on plasma lipids. Am J Cardiol 104(7):947–956CrossRefGoogle Scholar
  13. 13.
    Vasanthi HR, ShriShriMal N, Das DK (2012) Phytochemicals from plants to combat cardiovascular disease. Curr Med Chem 19(14):2242–2251CrossRefGoogle Scholar
  14. 14.
    Brotons C et al (2015) A systematic review of aspirin in primary prevention: is it time for a new approach? Am J Cardiovasc Drugs 15(2):113–133CrossRefGoogle Scholar
  15. 15.
    Xie M et al (2014) Aspirin for primary prevention of cardiovascular events: meta-analysis of randomized controlled trials and subgroup analysis by sex and diabetes status. PLoS One 9(10):e90286CrossRefGoogle Scholar
  16. 16.
    Eikelboom JW et al (2012) Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e89S–e119SCrossRefGoogle Scholar
  17. 17.
    Witt DM et al (2016) Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis 41(1):187–205CrossRefGoogle Scholar
  18. 18.
    Neidecker M et al (2012) Use of warfarin in long-term care: a systematic review. BMC Geriatr 12:14CrossRefGoogle Scholar
  19. 19.
    Smith SA, Travers RJ, Morrissey JH (2015) How it all starts: initiation of the clotting cascade. Crit Rev Biochem Mol Biol 50(4):326–336CrossRefGoogle Scholar
  20. 20.
    Ojeda D et al (2010) Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa. J Ethnopharmacol 127(1):7–10CrossRefGoogle Scholar
  21. 21.
    Atsumi Shimada MI (2014) Angiotensin I-Converting Enzyme (ACE) inhibitory activity of Ursolic acid isolated from Thymus vulgaris, L. Food Sci Technol Res 20(3):711–714CrossRefGoogle Scholar
  22. 22.
    Lau CW et al (2001) Cardiovascular actions of berberine. Cardiovasc Drug Rev 19(3):234–244CrossRefGoogle Scholar
  23. 23.
    Ohlsson A et al (2010) Mixture effects of dietary flavonoids on steroid hormone synthesis in the human adrenocortical H295R cell line. Food Chem Toxicol 48(11):3194–3200CrossRefGoogle Scholar
  24. 24.
    Hasegawa E et al (2013) Effect of polyphenols on production of steroid hormones from human adrenocortical NCI-H295R cells. Biol Pharm Bull 36(2):228–237CrossRefGoogle Scholar
  25. 25.
    Paterna S et al (2015) Hypertonic saline in conjunction with high-dose furosemide improves dose-response curves in worsening refractory congestive heart failure. Adv Ther 32(10):971–982CrossRefGoogle Scholar
  26. 26.
    Yang Y et al (2011) Effects of some common food constituents on cardiovascular disease. ISRN Cardiol 141:1–16CrossRefGoogle Scholar
  27. 27.
    Urizar NL, Moore DD (2003) GUGULIPID: a natural cholesterol-lowering agent. Annu Rev Nutr 23:303–313CrossRefGoogle Scholar
  28. 28.
    Doggrell SA (2005) Berberine–a novel approach to cholesterol lowering. Expert Opin Investig Drugs 14(5):683–685CrossRefGoogle Scholar
  29. 29.
    Alwi I et al (2008) The effect of curcumin on lipid level in patients with acute coronary syndrome. Acta Med Indones 40(4):201–210PubMedGoogle Scholar
  30. 30.
    Militaru C et al (2013) Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition 29(1):178–183CrossRefGoogle Scholar
  31. 31.
    Kunkel SD et al (2012) Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease. PLoS One 7(6):e39332CrossRefGoogle Scholar
  32. 32.
    Hemn HO et al (2015) Antihypercholesterolemic and antioxidant efficacies of zerumbone on the formation, development, and establishment of atherosclerosis in cholesterol-fed rabbits. Drug Des Devel Ther 9:4173–4208PubMedPubMedCentralGoogle Scholar
  33. 33.
    Landete J (2011) Ellagitannins, ellagic acid and their derived metabolites: a review about source, metabolism, functions and health. Food Res Int 44(5):1150–1160CrossRefGoogle Scholar
  34. 34.
    Ding Y et al (2014) Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation. Int J Cardiol 175(3):508–514CrossRefGoogle Scholar
  35. 35.
    Dai G et al (2007) Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2. Circ Res 101(7):723–733CrossRefGoogle Scholar
  36. 36.
    Taha H et al (2010) Role of heme oxygenase-1 in human endothelial cells: lesson from the promoter allelic variants. Arterioscler Thromb Vasc Biol 30(8):1634–1641CrossRefGoogle Scholar
  37. 37.
    Saragih H et al (2014) PECAM-1-dependent heme oxygenase-1 regulation via an Nrf2-mediated pathway in endothelial cells. Thromb Haemost 111(6):1077–1088CrossRefGoogle Scholar
  38. 38.
    Chung HT, Pae HO, Cha YN (2008) Role of heme oxygenase-1 in vascular disease. Curr Pharm Des 14(5):422–428CrossRefGoogle Scholar
  39. 39.
    Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1(6):a001651CrossRefGoogle Scholar
  40. 40.
    Claude S et al (2014) Flavanol metabolites reduce monocyte adhesion to endothelial cells through modulation of expression of genes via p38-MAPK and p65-Nf-kB pathways. Mol Nutr Food Res 58(5):1016–1027CrossRefGoogle Scholar
  41. 41.
    Zhang LP et al (2016) Glabridin attenuates lipopolysaccharide-induced acute lung injury by inhibiting p38MAPK/ERK signaling pathway. Oncotarget 8:18935–18942PubMedCentralGoogle Scholar
  42. 42.
    Lee WJ et al (2010) Ellagic acid inhibits oxidized LDL-mediated LOX-1 expression, ROS generation, and inflammation in human endothelial cells. J Vasc Surg 52(5):1290–1300CrossRefGoogle Scholar
  43. 43.
    Kuo MY et al (2011) Ellagic acid inhibits oxidized low-density lipoprotein (OxLDL)-induced metalloproteinase (MMP) expression by modulating the protein kinase C-alpha/extracellular signal-regulated kinase/peroxisome proliferator-activated receptor gamma/nuclear factor-kappaB (PKC-alpha/ERK/PPAR-gamma/NF-kappaB) signaling pathway in endothelial cells. J Agric Food Chem 59(9):5100–5108CrossRefGoogle Scholar
  44. 44.
    Huang CS et al (2013) Isothiocyanates protect against oxidized LDL-induced endothelial dysfunction by upregulating Nrf2-dependent antioxidation and suppressing NFkappaB activation. Mol Nutr Food Res 57(11):1918–1930CrossRefGoogle Scholar
  45. 45.
    Yet SF et al (2003) Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling. FASEB J 17(12):1759–1761CrossRefGoogle Scholar
  46. 46.
    Yang Y et al (2002) Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(−/−) knockout mouse. Novel model system for a severely compromised oxidative stress response. J Biol Chem 277(51):49446–49452CrossRefGoogle Scholar
  47. 47.
    Shan Y et al (2012) Sulphoraphane inhibited the expressions of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 through MyD88-dependent toll-like receptor-4 pathway in cultured endothelial cells. Nutr Metab Cardiovasc Dis 22(3):215–222CrossRefGoogle Scholar
  48. 48.
    Shan Y et al (2010) Protective effect of sulforaphane on human vascular endothelial cells against lipopolysaccharide-induced inflammatory damage. Cardiovasc Toxicol 10(2):139–145CrossRefGoogle Scholar
  49. 49.
    Zhu Y et al (2013) Anti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: a randomized controlled trial. Nutr Metab Cardiovasc Dis 23(9):843–849CrossRefGoogle Scholar
  50. 50.
    Lee SG et al (2014) Berry anthocyanins suppress the expression and secretion of proinflammatory mediators in macrophages by inhibiting nuclear translocation of NF-kappaB independent of NRF2-mediated mechanism. J Nutr Biochem 25(4):404–411CrossRefGoogle Scholar
  51. 51.
    Speciale A et al (2013) Cyanidin-3-O-glucoside counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway. Mol Nutr Food Res 57(11):1979–1987CrossRefGoogle Scholar
  52. 52.
    Zhu Y et al (2011) Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin Chem 57(11):1524–1533CrossRefGoogle Scholar
  53. 53.
    Tzeng TF et al (2014) Lipid-lowering effects of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, in high-fat diet-induced hyperlipidemic hamsters. Food Chem Toxicol 69:132–139CrossRefGoogle Scholar
  54. 54.
    Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145(3):341–355CrossRefGoogle Scholar
  55. 55.
    Rudijanto A (2007) The role of vascular smooth muscle cells on the pathogenesis of atherosclerosis. Acta Med Indones 39(2):86–93PubMedGoogle Scholar
  56. 56.
    Eguchi A et al (2007) Zerumbone suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic cells. Biosci Biotechnol Biochem 71(4):935–945CrossRefGoogle Scholar
  57. 57.
    Zhu S, Liu JH (2015) Zerumbone, a natural cyclic Sesquiterpene, promotes ABCA1-dependent cholesterol efflux from human THP-1 macrophages. Pharmacology 95(5–6):258–263CrossRefGoogle Scholar
  58. 58.
    Shin JW et al (2011) Zerumbone induces heme oxygenase-1 expression in mouse skin and cultured murine epidermal cells through activation of Nrf2. Cancer Prev Res (Phila) 4(6):860–870CrossRefGoogle Scholar
  59. 59.
    Um MY et al (2014) Curcumin attenuates adhesion molecules and matrix metalloproteinase expression in hypercholesterolemic rabbits. Nutr Res 34(10):886–893CrossRefGoogle Scholar
  60. 60.
    Zeng C et al (2015) Curcumin protects hearts from FFA-induced injury by activating Nrf2 and inactivating NF-kappaB both in vitro and in vivo. J Mol Cell Cardiol 79:1–12CrossRefGoogle Scholar
  61. 61.
    Min KJ et al (2013) Curcumin inhibits oxLDL-induced CD36 expression and foam cell formation through the inhibition of p38 MAPK phosphorylation. Food Chem Toxicol 58:77–85CrossRefGoogle Scholar
  62. 62.
    Ren B et al (2016) Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats. Eur J Pharmacol 773:13–23CrossRefGoogle Scholar
  63. 63.
    Duarte S et al (2013) Apigenin protects endothelial cells from lipopolysaccharide (LPS)-induced inflammation by decreasing caspase-3 activation and modulating mitochondrial function. Int J Mol Sci 14(9):17664–17679CrossRefGoogle Scholar
  64. 64.
    Zeng P et al (2015) Apigenin attenuates Atherogenesis through inducing macrophage apoptosis via inhibition of AKT Ser473 phosphorylation and downregulation of plasminogen activator Inhibitor-2. Oxidative Med Cell Longev 2015:1Google Scholar
  65. 65.
    Zhang X et al (2014) Flavonoid Apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages. PLoS One 9(9):e107072CrossRefGoogle Scholar
  66. 66.
    Rizza S et al (2011) Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab 96(5):E782–E792CrossRefGoogle Scholar
  67. 67.
    Cacicedo Jé M et al (2011) Acute exercise activates AMPK and eNOS in the mouse aorta. Am J Physiol Heart Circ Physiol 301(4):H1255–H1265CrossRefGoogle Scholar
  68. 68.
    Elavarasan J et al (2012) Hesperidin-mediated expression of Nrf2 and upregulation of antioxidant status in senescent rat heart. J Pharm Pharmacol 64(10):1472–1482CrossRefGoogle Scholar
  69. 69.
    Agrawal YO et al (2014) Hesperidin produces cardioprotective activity via PPAR-gamma pathway in ischemic heart disease model in diabetic rats. PLoS One 9(11):e111212CrossRefGoogle Scholar
  70. 70.
    Guilherme L, Kalil J (2010) Rheumatic fever and rheumatic heart disease: cellular mechanisms leading autoimmune reactivity and disease. J Clin Immunol 30(1):17–23CrossRefGoogle Scholar
  71. 71.
    Zuhlke L et al (2015) Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the global rheumatic heart disease registry (the REMEDY study). Eur Heart J 36(18):1115–122aCrossRefGoogle Scholar
  72. 72.
    Six Types of Cardiovascular Diseases. 2010 23.07.2010Google Scholar
  73. 73.
    Mitchell Henry Wright MSJA, Lee CJ, Courtney R, Greene AC, Cock IE (2016) Qualitative phytochemical analysis and antibacterial activity evaluation of Indian Terminalia spp. against the pharyngitis causing pathogen Streptococcus pyogenes. Pharmacogn Commun 6(2):85–92CrossRefGoogle Scholar
  74. 74.
    Lu Y, Khoo TJ, Wiart C (2014) The genus Melodinus (Apocynaceae): chemical and pharmacological perspectives. Sci Res 5(5):540–550Google Scholar
  75. 75.
    Jiang J-H, Zhang W-D, Chen Y-G (2015) Phytochemical and pharmacological properties of the Genus Melodinus – a review. Trop J Pharm Res 14(12):2325–2344CrossRefGoogle Scholar
  76. 76.
    Zhang S et al (2016) Apigenin attenuates experimental autoimmune myocarditis by modulating Th1/Th2 cytokine balance in mice. Inflammation 39(2):678–686CrossRefGoogle Scholar
  77. 77.
    Barnes AG et al (2007) Bacillus subtilis spores: a novel microparticle adjuvant which can instruct a balanced Th1 and Th2 immune response to specific antigen. Eur J Immunol 37(6):1538–1547CrossRefGoogle Scholar
  78. 78.
    Liu Y et al (2009) The effect of Gd@C82(OH)22 nanoparticles on the release of Th1/Th2 cytokines and induction of TNF-alpha mediated cellular immunity. Biomaterials 30(23–24):3934–3945CrossRefGoogle Scholar
  79. 79.
    Liu X et al (2016) Protective mechanisms of berberine against experimental autoimmune myocarditis in a rat model. Biomed Pharmacother 79:222–230CrossRefGoogle Scholar
  80. 80.
    Martin R et al (2014) Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. J Mol Cell Cardiol 72:250–262CrossRefGoogle Scholar
  81. 81.
    What Are Congenital Heart Defects? 2011 1.07.2011Google Scholar
  82. 82.
    The Impact of Congenital Heart Defects. 2015 21.10.2015Google Scholar
  83. 83.
    Manes A et al (2014) Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. Eur Heart J 35(11):716–724CrossRefGoogle Scholar
  84. 84.
    Murphy JG et al (1993) Long-term outcome in patients undergoing surgical repair of tetralogy of Fallot. N Engl J Med 329(9):593–599CrossRefGoogle Scholar
  85. 85.
    Congenital heart defects in children. Diseases and conditions 04.02.2016Google Scholar
  86. 86.
    Ramkumar S, Raghunath A, Raghunath S (2016) Statin therapy: review of safety and potential side effects. Acta Cardiol Sin 32(6):631–639PubMedPubMedCentralGoogle Scholar
  87. 87.
    Javkhedkar AA et al (2015) Resveratrol restored Nrf2 function, reduced renal inflammation, and mitigated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 308(10):R840–R846CrossRefGoogle Scholar
  88. 88.
    Sung MM et al (2015) Resveratrol treatment of mice with pressure-overload-induced heart failure improves diastolic function and cardiac energy metabolism. Circ Heart Fail 8(1):128–137CrossRefGoogle Scholar
  89. 89.
    Stowe CB (2011) The effects of pomegranate juice consumption on blood pressure and cardiovascular health. Complement Ther Clin Pract 17(2):113–115CrossRefGoogle Scholar
  90. 90.
    Aviram M, Dornfeld L (2001) Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 158(1):195–198CrossRefGoogle Scholar
  91. 91.
    Aviram M et al (2004) Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr 23(3):423–433CrossRefGoogle Scholar
  92. 92.
    Laufs U et al (2015) Treatment options for statin-associated muscle symptoms. Dtsch Arztebl Int 112(44):748–755PubMedPubMedCentralGoogle Scholar
  93. 93.
    Pantan R et al (2016) Synergistic effect of atorvastatin and Cyanidin-3-glucoside on angiotensin II-induced inflammation in vascular smooth muscle cells. Exp Cell Res 342(2):104–112CrossRefGoogle Scholar
  94. 94.
    Ikemura M et al (2012) Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother Res 26(9):1272–1277CrossRefGoogle Scholar
  95. 95.
    Hao H et al (2011) Drug-eluting stent: importance of clinico-pathological correlations. Circ J 75(7):1548–1558CrossRefGoogle Scholar
  96. 96.
    Lu Q et al (2015) Accelerated recovery of endothelium function after stent implantation with the use of a novel systemic nanoparticle curcumin. Biomed Res Int 2015:291871PubMedPubMedCentralGoogle Scholar
  97. 97.
    Khoobchandani M et al (2016) Laminin receptor-avid Nanotherapeutic EGCg-AuNPs as a potential alternative therapeutic approach to prevent restenosis. Int J Mol Sci 17(3):316CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Johnna Francis Varghese
    • 1
  • Rohit Patel
    • 1
  • Mohit Singh
    • 1
  • Umesh C. S. Yadav
    • 2
    Email author
  1. 1.Metabolic Disorders and Inflammatory Pathologies Laboratory, School of Life SciencesCentral University of GujaratGandhinagarIndia
  2. 2.School of Life SciencesCentral University of GujaratGandhinagarIndia

Personalised recommendations