A systematic review on the cardiovascular pharmacology of Emblica officinalis Gaertn.

Introduction: The Emblica officinalis (EO) fruit has traditionally been considered as a cardioactive medication and has demonstrated remarkable cardiovascular effects in the pharmacological literature. The present study systematically reviews EO’s potential for prevention and therapy of cardiovascular diseases (CVD). Methods: PubMed, ScienceDirect, Scopus, Proquest, Ebsco, Google, Google Scholar, Ovid, and Cochrane databases were searched from 1966 to 2017 for the English and non-English literature using the terms including the cognates of EO including amla, Emblic myrobalan, Emblica officinalis, Emblica pectinata , Indian gooseberry, and Phyllanthus emblica together with antioxidant, arrhythmia, cardioprotective, cardiotoxicity, heart disease, heart failure, hyperlipidemia, hypertension, myocardial dysfunction, and oxidative stress. The inclusion criteria were in vitro, animal, and clinical cardiovascular pharmacological studies conducted on EO and full-text accessibility. The exclusion criterion was studies in which a combination of EO and at least one other plant was investigated. The reference lists of the retrieved articles were also searched manually for additional eligible articles. The methodological quality of clinical trials was assessed by the Jadad scale, and animal studies were evaluated by the ARRIVE checklist. Results: Nineteen articles concerning the cardiovascular pharmacological effects of EO were included in this review. The plant has shown antiatherogenic, anticoagulant, hypolipidemic, antihypertensive, antioxidant, antiplatelet, and vasodilatory effects as well as lipid deposition inhibitory properties. Moreover, it prevents from doxorubicin and isoproterenol cardiotoxicity and myocardial ischemia/reperfusion injury, and improves vascular endothelial function in animal studies. Some high-quality clinical studies report the vasodilatory and myocardial antioxidant properties as well as anti-platelet aggregation effects of this plant. Conclusion: EO influences various cardiovascular risk-factors. However, there is not sufficient evidence to confirm the plant efficacy in preventing and treating CVD.

fruit contains tannins, alkaloids, phenols, amino acids, carbohydrates, vitamins, flavonoids, and organic acids (Table 1 and Figure 2). 8,9 The fruit is highly nutritious and consumed as a food. 10,11  The EO fruit has also been mentioned in the literature of the Persian medicine (PM). 12 EO is one of the 50 cardioactive plants mentioned in the Avicenna book "The Treatise on Cardiac Drugs". 13 Cardiotonic action is one of the features attributed to this plant in the PM. [12][13][14] From the PM perspective, the fruit can be cardiotonic because it has astringent properties and can strengthen the cardiac tissue. 15 Besides, it can affect the heart by exerting impact on stomach diseases (including gastro-esophageal reflux and mal-temperaments of the stomach, which are, as noted, related to cardiac diseases). 14 Pharmacological studies have demonstrated diverse cardiovascular and other impacts for the fruit such as cytotoxic, hypoglycemic, hypolipidemic, hepatoprotective, cardioprotective, antiatherogenic, antioxidant, antipyretic, analgesic, antimicrobial, diuretic, and laxative effects. 7,[16][17][18] Numerous studies have been published on the effects of EO on various CVD; however, there has been no systematic review regarding the cardiovascular effects of EO nor is there a definitive decision on the efficacy of this plant. Therefore, this review was conducted to evaluate the plant potential for prevention and treatment of CVD.

Materials and Methods
To collect the studies on the cardiovascular effects of EO, PubMed, Science Direct, Scopus, Proquest, Ebsco, Google, Google Scholar, Ovid, and Cochrane databases were searched for the English and non-English literature from 1966 to 2017 using the terms amla, Emblic myrobalan, Emblica officinalis, Emblica pectinata, Indian gooseberry, and Phyllanthus emblica together with antioxidant, arrhythmia, cardioprotective, cardiotoxicity, heart disease, heart failure, hyperlipidemia, hypertension, myocardial dysfunction, and oxidative stress. The database of Irandoc and the online libraries of Iranian universities were also searched for the purposes of this study. Three persons performed the literature search and assessment. The inclusion criteria were in vitro, animal, and clinical cardiovascular pharmacological studies conducted on EO and full-text accessibility. The exclusion criterion was studies in which a combination of EO and at least one other plant was investigated. The reference lists of the retrieved articles were searched manually for additional eligible articles. All published cardiovascular pharmacological studies fulfilling the search criteria were included in the results section. For clinical studies, PICO was considered as patients with a type of cardiovascular disease who took the EO with or without a control group with the aim to identify changes in CVD during intervention. The methodological quality of clinical trials was assessed by the Jadad scale in terms of the presence of randomization, masking, and accountability of all patients including withdrawals, as described in the literature. 19 The methodological quality of animal studies was assessed by ARRIVE checklist. 20 The PRISMA flow diagram of this review is presented in Figure 3. The PRISMA flow diagram of this review is presented in Figure 3.    Restoration of hemodynamic and left ventricular function along with preservation of antioxidants, reduction of myocyte-injuryspecific marker enzymes and inhibition of lipid peroxidation in EO groups.  Serum TC, TG, HDL-C, LDL-C and VLDL-C levels, systolic and diastolic blood pressure Amla was better in decreasing TG and increasing HDL-C, atrovastatin was better in decreasing TC, LDL-C and VLDL-C. BP did not significantly change.

Results
There were no non-English and gray literature, theses and dissertations conforming to the search criteria. Summaries of the cardiovascular pharmacological studies fulfilling the search criteria are presented in Tables 2 and 3. The effects given in the results sections of the tables are statistically significant, unless otherwise stated.

Discussion
This review collected and presented the evidences concerning the effects of EO on hyperlipidemia, hypertension, myocardial and endothelial function, cardiac specific antioxidants, and coagulation factors.  40 The animal studies demonstrated that the EO extract has antiplatelet activity and may increase the risk of bleeding when taken with drugs that increase the risk of bleeding. Some examples include aspirin, anticoagulants such as warfarin or heparin, anti-platelet drugs such as clopidogrel, and non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen or naproxen. Phyllanthus emblica extract interacts pharmacodynamically with clopidogrel and ecosprin in patients with type II diabetes mellitus. 38 The EO fruit extract reduces blood sugar levels. 41,42 Thus, caution should be taken when using hypoglycemic medications, and patients taking insulin or drugs for diabetes need to be monitored closely. In addition, EO decreases serum lipid levels; hence, cholesterol-or triglyceride-lowering medications should be taken with caution. EO fruit is also a rich source of tannin and may interfere with intestinal absorption of iron. 43 Since EO is a rich source of ascorbic acid, it may trigger gastric hyperacidity and constipation. Alongside this, in the PM literature, it is believed that EO has a cold and dry nature and may have an astringent property. To reduce the astringent effect of EO, it is advised to use as a jam or to consume it together with almond oil and honey. 12 These must be considered in patients taking medications for their cardiovascular or other organs' disorders.
Overall, it is concluded that EO affects various cardiovascular disorders and risk factors. However, there is not sufficient clinical evidence to suggest that EO has efficacy in CVD prevention and treatment. Further studies, especially clinical trials, with EO in all fields of cardiovascular pharmacology are needed. Identification of the bioactive compounds and mechanisms mediating the cardiovascular effects of EO is also suggestable.

Competing interests
This review was not funded and there is no conflict of interest.

Ethical approval
Not applicable.