Abstract
Panax ginseng is commonly used in Chinese medicine and Western herbal preparations. However, it has also been recently noted to be associated with some cardiac pathologies-including cardiogenic shock due to acute anterior myocardial infarction, trans-ischemic attack, and stent thrombosis. This study was aimed to elucidate acute and subacute effects of the low and high doses of standardized Panax ginseng extract (sPGe) on cardiac functions. Rats were randomly assigned to control group, acute low-dose group (ALD), subacute low-dose group (SALD), acute high-dose group (AHD), and subacute high-dose group (SAHD). The cardiac effects of sPGe were evaluated using hemodynamic, biochemical, echocardiographic, genetic, and immunohistopathologic parameters. Mean blood pressures were significantly lower in all sPGe-treated groups compared with the control group. Troponin I and myoglobin levels were increased in the SALD, AHD, and SAHD groups. Mitral E-wave velocity was reduced after sPGe administration in all the groups. Acidophilic cytoplasm and pyknotic nucleus in myocardial fibers were observed in AHD and SAHD groups. Cu/Zn-SOD1 gene expressions were significantly higher in the sPGe-treated groups whereas caveolin 1 and VEGF-A gene expressions were not changed. According to our results, sPGe may have a potential effect to cause cardiac damage including diastolic dysfunction, heart failure with preserved ejection fraction, and reduction of blood pressure depending on the dose and duration of usage. Healthcare professionals must be aware of adverse reactions stemming from the supplementation use, particularly with cardiac symptoms.
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Abbreviations
- sPGe:
-
Standardized Panax ginseng extract
- ALD:
-
Acute low dose
- SALD:
-
Subacute low dose
- AHD:
-
Acute high dose
- SAHD:
-
Subacute high dose
- AV:
-
Atrioventricular
- AA:
-
Diameter of ascending aorta
- LA:
-
Diameter of left atrium
- IVSt:
-
Interventricular septal thickness in diastole
- LVED:
-
Left ventricular end-diastolic diameter
- LVES:
-
Left ventricular end-systolic diameter
- EF:
-
Ejection fraction
- FS:
-
Fractional shortening
- E/A:
-
Peak velocity of E-wave/peak velocity of A-wave
- EDT:
-
E-wave deceleration time
- CAV1:
-
Caveolin 1
References
Gallin, J. I. (2017). A historical perspective on clinical research. In Principles and practice of clinical research (4th Ed.) (pp 1–15). Amsterdam: Elsevier.
Qi, Z., & Kelley, E. (2014). The WHO traditional medicine strategy 2014–2023: A perspective. Science, 346, S5–S6.
Choi, K. T. (2008). Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng CA Meyer. Acta Pharmacologica Sinica, 29, 1109–1118.
Karmazyn, M., Moey, M., & Gan, X. T. (2011). Therapeutic potential of ginseng in the management of cardiovascular disorders. Drugs, 71, 1989–2008.
Buettner, C., Yeh, G. Y., Phillips, R. S., Mittleman, M. A., & Kaptchuk, T. J. (2006). Systematic review of the effects of ginseng on cardiovascular risk factors. Annals of Pharmacotherapy, 40, 83–95.
Caron, M. F., Hotsko, A. L., Robertson, S., Mandybur, L., Kluger, J., & White, C. M. (2002). Electrocardiographic and hemodynamic effects of Panax ginseng. Annals of Pharmacotherapy, 36, 758–763.
Paik, D. J., & Lee, C. H. (2015). Review of cases of patient risk associated with ginseng abuse and misuse. Journal of Ginseng Research, 39, 89–93.
Park, B.-J., Lee, Y.-J., Lee, H.-R., Jung, D.-H., Na, H.-Y., Kim, H.-B., & Shim, J.-Y. (2012). Effects of Korean red ginseng on cardiovascular risks in subjects with metabolic syndrome: A double-blind randomized controlled study. Korean Journal of Family Medicine, 33, 190–196.
Vuksan, V., Stavro, M., Woo, M., Leiter, L., Sung, M., & Sievenpiper, J. (2006). Korean red ginseng (Panax ginseng) can lower blood pressure in individuals with hypertension: a randomized controlled trial, in Proceedings of the 9th international ginseng symposium (pp 25–28). Geumsan: Korean Society of Ginseng.
Kim, N. D., Kang, S. Y., & Schini, V. B. (1994). Ginsenosides evoke endothelium-dependent vascular relaxation in rat aorta. General pharmacology, 25, 1071–1077.
Kang, S. Y., Schini-Kerth, V. B., & Kim, N. D. (1995). Ginsenosides of the protopanaxatriol group cause endothelium-dependent relaxation in the rat aorta. Life Sciences, 56, 1577–1586.
Wagner, H., & Liu, X. (1987). The international textbook of cardiology. New York: Pergamon Press.
Turfan, M., Tasal, A., Ergun, F., & Ergelen, M. (2012). A sudden rise in INR due to combination of Tribulus terrestris, Avena sativa, and Panax ginseng (Clavis Panax). Turk Kardiyoloji Dernegi arsivi: Turk Kardiyoloji Derneginin yayin organidir, 40, 259–261.
Torbey, E., Rafeh, N. A., Khoueiry, G., Kowalski, M., & Bekheit, S. (2011). Ginseng: a potential cause of long QT. Journal of Electrocardiology, 44, 357–358.
Gunes, H., Kucukdurmaz, Z., Karapinar, H., & Gul, I. (2012). [Acute anterior myocardial infarction presented with cardiogenic shock in a patient on herbal medication]. Turk Kardiyol Dern Ars, 40, 262–264.
Martínez-Mir, I., Rubio, E., Morales-Olivas, F. J., & Palop-Larrea, V. (2004). Transient ischemic attack secondary to hypertensive crisis related to Panax ginseng. Annals of Pharmacotherapy, 38, 1970–1970.
Yüksel, I., Arslan, S., Çağırcı, G., & Yılmaz, A. (2013). Acute massive pulmonary embolism in a patient using clavis panax. Turk Kardiyoloji Dernegi arsivi: Turk Kardiyoloji Derneginin yayin organidir, 41, 351–353.
Parlakpinar, H., Ozhan, O., Ermis, N., & Acet, A. (2016). Cardiovascular effects of Panax ginseng. Journal of Turgut Ozal Medical Center, 23, 482–487
Zheng, M.-M., Xu, F.-X., Li, Y.-J., Xi, X.-Z., Cui, X.-W., Han, C.-C., & Zhang, X.-L. (2017). Study on transformation of ginsenosides in different methods. BioMed Research International, 2017, 8601027–8601027.
Wu, Y., Xia, Z., Dou, J., Zhang, L., Xu, J., Zhao, B., Lei, S., & Liu, H. (2011). Protective effect of ginsenoside Rb1 against myocardial ischemia/reperfusion injury in streptozotocin-induced diabetic rats. Molecular Biology Reports, 38, 4327–4335.
Jiang, Q.-S., Huang, X.-N., Dai, Z.-K., Yang, G.-Z., Zhou, Q.-X., Shi, J.-S., & Wu (2007). Inhibitory effect of ginsenoside Rb1 on cardiac hypertrophy induced by monocrotaline in rat. Journal of Ethnopharmacology, 111, 567–572.
Deng, J., Lv, X.-T., Wu, Q., & Huang, X.-N. (2009). Ginsenoside Rg1 inhibits rat left ventricular hypertrophy induced by abdominal aorta coarctation: involvement of calcineurin and mitogen-activated protein kinase signalings. European Journal of Pharmacology, 608, 42–47.
Liu, Z., Li, Z., & Liu, X.J. (2002). Effect of ginsenoside Re on cardiomyocyte apoptosis and expression of Bcl-2/Bax gene after ischemia and reperfusion in rats. Journal of Huazhong University of Science and Technology [Medical Sciences], 22, 305–309.
Li, J., Xie, Z.-Z., Tang, Y.-B., Zhou, J.-G., & Guan, Y.-Y. (2011). Ginsenoside-Rd, a purified component from panax notoginseng saponins, prevents atherosclerosis in apoE knockout mice. European Journal of Pharmacology, 652, 104–110.
McGrath, J., Drummond, G., McLachlan, E., Kilkenny, C., & Wainwright, C. (2010). Guidelines for reporting experiments involving animals: The ARRIVE guidelines. British Journal of Pharmacology, 160, 1573–1576.
Teichholz, L. E., Kreulen, T., Herman, M. V., & Gorlin, R. (1976). Problems in echocardiographic volume determinations: Echocardiographic-angiographic correlations in the presence or absence of asynergy. The American journal of cardiology, 37, 7–11.
Walker, M., Curtis, M., Hearse, D., Campbell, R., Janse, M., Yellon, D., Cobbe, S., Coker, S., Harness, J., & Harron, D. (1988). The Lambeth Conventions: Guidelines for the study of arrhythmias in ischaemia, infarction, and reperfusion. Cardiovascular Research, 22, 447–455.
Parlakpinar, H., Olmez, E., Acet, A., Ozturk, F., Tasdemir, S., Ates, B., Gul, M., & Otlu, A. (2009). Beneficial effects of apricot-feeding on myocardial ischemia-reperfusion injury in rats. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 47, 802–808.
Kalkan, F., Parlakpinar, H., Disli, O. M., Tanriverdi, L. H., Ozhan, O., Polat, A., Cetin, A., Vardi, N., Otlu, Y. O., & Acet, A. (2018). Protective and therapeutic effects of dexpanthenol on isoproterenol-induced cardiac damage in rats. Journal of Cellular Biochemistry, 119(9), 7479–7489
Ozbek, E., Simsek, A., Ozbek, M., & Somay, A. (2013). Caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: Comparison of aged and adult rats. Archivio Italiano di Urologia e Andrologia, 85, 113–117.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2-∆∆CT method. Methods, 25, 402–408.
Curtis, M. J., Alexander, S., Cirino, G., Docherty, J. R., George, C. H., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Sobey, C. G., Stanford, S. C., Teixeira, M. M., Wonnacott, S., & Ahluwalia, A. (2018). Experimental design and analysis and their reporting II: Updated and simplified guidance for authors and peer reviewers. British Journal of Pharmacology, 175, 987–993.
WSSPAS: Web-Based Sample Size & Power Analysis Software [Software]. (2018). Accessed Oct 01, 2018, from http://biostatapps.inonu.edu.tr/WSSPAS/.
Xiang, Y. Z., Shang, H. C., Gao, X. M., & Zhang, B. L. (2008). A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological experiments and clinical trials. Phytotherapy Research, 22, 851–858.
Attele, A. S., Wu, J. A., & Yuan, C.-S. (1999). Ginseng pharmacology: Multiple constituents and multiple actions. Biochemical Pharmacology, 58, 1685–1693.
Zhou, W., Chai, H., Lin, P. H., Lumsden, A. B., Yao, Q., & Chen, C. (2004). Molecular mechanisms and clinical applications of ginseng root for cardiovascular disease. Medical Science Monitor, 10, RA187–RA192.
Cheng, Y., Shen, L. H., & Zhang, J. T. (2005). Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacologica Sinica, 26, 143–149.
Rhee, M.-Y., Cho, B., Kim, K.-I., Kim, J., Kim, M. K., Lee, E.-K., Kim, H.-J., & Kim, C.-H. (2014). Blood pressure lowering effect of Korea ginseng derived ginseol K-g1. The American Journal of Chinese Medicine, 42, 605–618.
Li, H.-X., Han, S.-Y., Ma, X., Zhang, K., Wang, L., Ma, Z.-Z., & Tu, P.-F. (2012). The saponin of red ginseng protects the cardiac myocytes against ischemic injury in vitro and in vivo. Phytomedicine, 19, 477–483.
Jovanovski, E., Bateman, E. A., Bhardwaj, J., Fairgrieve, C., Mucalo, I., Jenkins, A. L., & Vuksan, V. (2014). Effect of Rg3-enriched Korean red ginseng (Panax ginseng) on arterial stiffness and blood pressure in healthy individuals: A randomized controlled trial. Journal of the American Society of Hypertension, 8, 537–541.
Lee, K. H., Bae, I. Y., Park, S. I., Park, J.-D., & Lee, H. G. (2016). Antihypertensive effect of Korean Red Ginseng by enrichment of ginsenoside Rg3 and arginine–fructose. Journal of Ginseng Research, 40, 237–244.
Lim, K. H., Ko, D., & Kim, J.-H. (2013). Cardioprotective potential of Korean Red Ginseng extract on isoproterenol-induced cardiac injury in rats. Journal of Ginseng Research, 37, 273.
Yan, X., Wu, H., Ren, J., Liu, Y., Wang, S., Yang, J., Qin, S., & Wu, D. (2018). Shenfu Formula reduces cardiomyocyte apoptosis in heart failure rats by regulating microRNAs. Journal of Ethnopharmacology, 227, 105–112.
Jin, Z., & Liu, C. (1994). Effect of ginsenoside Re on the electrophysiological activity of the heart. Planta Medica, 60, 192–193.
Jiang, M., Murias, J. M., Chrones, T., Sims, S. M., Lui, E., & Noble, E. G. (2014). American ginseng acutely regulates contractile function of rat heart. Frontiers in Pharmacology, 5, 43.
Nakaya, Y., Mawatari, K., Takahashi, A., Harada, N., Hata, A., & Yasui, S. (2007). The phytoestrogen ginsensoside Re activates potassium channels of vascular smooth muscle cells through PI3K/Akt and nitric oxide pathways. The Journal of Medical Investigation: JMI, 54, 381–384.
Komishon, A., Shishtar, E., Ha, V., Sievenpiper, J., de Souza, R., Jovanovski, E., Ho, H., Duvnjak, L. S., & Vuksan, V. (2016). The effect of ginseng (genus Panax) on blood pressure: A systematic review and meta-analysis of randomized controlled clinical trials. Journal of Human Hypertension, 30, 619.
Luo, D., & Fang, B. (2008). Structural identification of ginseng polysaccharides and testing of their antioxidant activities. Carbohydrate Polymers, 72, 376–381.
Ponikowski, P., Voors, A. A., Anker, S. D., Bueno, H., Cleland, J. G., Coats, A. J., Falk, V., González-Juanatey, J. R., Harjola, V. P., & Jankowska, E. A. (2016). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure, 18, 891–975.
Afsin Oktay, A., & Shah, J., S (2015). Diagnosis and management of heart failure with preserved ejection fraction: 10 key lessons. Current Cardiology Reviews, 11, 42–52.
Disli, O. M., Sarihan, E., Colak, M. C., Vardi, N., Polat, A., Yagmur, J., Tamtekin, B., & Parlakpinar, H. (2013). Effects of molsidomine against doxorubicin-induced cardiotoxicity in rats. European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes, 51, 79–90.
Parlakpinar, H., Ozer, M. K., & Acet, A. (2005). Effect of aminoguanidine on ischemia-reperfusion induced myocardial injury in rats. Molecular and Cellular Biochemistry, 277, 137–142.
Ozer, M. K., Parlakpinar, H., Vardi, N., Cigremis, Y., Ucar, M., & Acet, A. (2005). Myocardial ischemia/reperfusion-induced oxidative renal damage in rats: protection by caffeic acid phenethyl ester (CAPE). Shock, 24, 97–100.
Elmore, S. A., Dixon, D., Hailey, J. R., Harada, T., Herbert, R. A., Maronpot, R. R., Nolte, T., Rehg, J. E., Rittinghausen, S., & Rosol, T. J. (2016). Recommendations from the INHAND apoptosis/necrosis working group. Toxicologic Pathology, 44, 173–188.
Milner, D. J., Weitzer, G., Tran, D., Bradley, A., & Capetanaki, Y. (1996). Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. The Journal of Cell Biology, 134, 1255–1270.
Pawlak, A., Gil, R., Kulawik, T., Pronicki, M., Karkucińska-Więckowska, A., Szymańska-Dębińska, T., Gil, K., Lagwinski, N., & Czarnowska, E. (2012). Type of desmin expression in cardiomyocytes—A good marker of heart failure development in idiopathic dilated cardiomyopathy. Journal of Internal Medicine, 272, 287–297.
Wang, Y., Xuan, L., Cui, X., Wang, Y., Chen, S., Wei, C., & Zhao, M. (2017). Ibutilide treatment protects against ER stress induced apoptosis by regulating calumenin expression in tunicamycin treated cardiomyocytes. PLoS ONE, 12, e0173469.
Colak, M., Parlakpinar, H., Tasdemir, S., Samdanci, E., Kose, E., Polat, A., Sarihan, E., & Acet, A. (2012). Therapeutic effects of ivabradine on hemodynamic parameters and cardiotoxicity induced by doxorubicin treatment in rat. Human & Experimental Toxicology, 31, 945–954.
Yuan, Y., Zhou, H., Wu, Q. Q., Li, F. F., Bian, Z. Y., Deng, W., Zhou, M. Q., & Tang, Q. Z. (2016). Puerarin attenuates the inflammatory response and apoptosis in LPS-stimulated cardiomyocytes. Experimental and Therapeutic Medicine, 11, 415–420.
Fujii, M., Sherchan, P., Soejima, Y., Doycheva, D., & Zhang, J. H. (2016). Subarachnoid hemorrhage-triggered acute hypotension is associated with left ventricular cardiomyocyte apoptosis in a rat model. In Brain edema XVI (pp 145–150). New York: Springer.
Riezzo, I., Centini, F., Neri, M., Rossi, G., Spanoudaki, E., Turillazzi, E., & Fineschi, V. (2009). Brugada-like EKG pattern and myocardial effects in a chronic propofol abuser. Clinical Toxicology, 47, 358–363.
Tanriverdi, L. H., Parlakpinar, H., Ozhan, O., Ermis, N., Polat, A., Vardi, N., Tanbek, K., Yildiz, A., & Acet, A. (2017). Inhibition of NADPH oxidase by apocynin promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress in rats. Free Radical Research, 51, 772–786.
Couet, J., Belanger, M. M., Roussel, E., & Drolet, M. C. (2001). Cell biology of caveolae and caveolin. Advanced Drug Delivery Reviews, 49(3), 223–235.
Engelman, J. A., Zhang, X. L., Razani, B., Pestell, R. G., & Lisanti, M. P. (1999). p42/44 MAP Kinase-dependent and-independent Signaling Pathways Regulate Caveolin-1 Gene Expression. Activation of Ras-MAP kinase and protein kinase a signaling cascades transcriptionally down-regulates caveolin-1 promoter activity. Journal of Biological Chemistry, 274, 32333–32341.
Acknowledgements
This research is supported by a research grant from the Scientific and Technological Research Council of Turkey (Project details: 3001/115S818 belongs to Dr. Parlakpinar). Authors thank Azibe Yıldız, PhD for technical assistance and histological interpretation.
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HP and AA are the coordinators of this study and they planned the study protocol design. LHT, HP, NE, and OO made the mandatory requirements for the study. LHT and OO were responsible for drug administration and data collection. HP and OO performed the surgical procedures. Hemodynamic parameters and cardiac results including ECG records were evaluated by NE and HP, NE performed the ECHO, LHT and OO conducted the biochemical analyses. The histopathological evaluations carried out by NV whereas YC performed genetic experiments. CC was responsible for data and statistical analysis and interpretation of the results. LHT was responsible for the design of figures and tables. This manuscript was written by HP, LHT, OO, NE, and YC The final manuscript is revised collaboratively by HP, LHT, and AA.
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Parlakpinar, H., Ozhan, O., Ermis, N. et al. Acute and Subacute Effects of Low Versus High Doses of Standardized Panax ginseng Extract on the Heart: An Experimental Study. Cardiovasc Toxicol 19, 306–320 (2019). https://doi.org/10.1007/s12012-019-09512-1
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DOI: https://doi.org/10.1007/s12012-019-09512-1