Introduction
Cardiovascular Diseases (CVDs) are still the major causes of mortality worldwide [1]. These diseases include ischemic heart disease, hypertension, congenital heart disease, rheumatic heart disease, cardiomyopathy, endocarditis, heart failure, and arrhythmias [1, 2]. One-third to one-half of all CVD cases is related to myocardial infarction and heart failure [3]. In 2013, the World Health Organization estimated that 17.3 million deaths or 31% of all deaths worldwide were due to CVD, which is predicted to reach 23.3 million by 2030 [1, 2]. Many conditions such as bad food habits, stress, smoking, physical inactivity, and diseases such as diabetes, atherosclerosis and hypertension are risk factors of CVD [2, 4].
The use of common therapies in the treatment of many CVDs, which have wide side effects, is not cost-effective for many people. On the other hand, the use of herbal medicines has been considered more due to cultural beliefs and adaptations, fewer side effects, availability, and being cheap [2, 5, 6]. Food condiments and spices are important elements of human nutrition. For thousand years, some of them have been used as herbal medicine in the treatment of many diseases including bacterial infections, coughs, colds, and CVDs [7]. They have various medicinal properties including immune regulatory effects and antioxidant and anti-inflammatory properties against various diseases including CVD [7, 8, 9]. Cinnamon (Cinnamomum) belongs to the Lauraceae family with 250 different species of evergreen shrubs, and is found mainly in Asia and Australia [10, 11]. The most common types of cinnamon include Cinnamomum cassia (C. cassia) and Cinnamomum verum (Figure 1) [10, 12, 13]. C. cassia is the most well-known type of cinnamon, which is found in China, Vietnam, and Sunda Islands. It is also called Chinese cinnamon or Saigon cinnamon; in Arabic, it is called Salikheh or Darsini [10, 12, 13]. Cinnamomum verum is a small evergreen tree with 5-7 meters tall that grows in India and Ceylon. This type of cinnamon is one of the best types of cinnamon and is known as Ceylon cinnamon [10, 12, 13]. Cinnamon tree’s leaves and bark have been used in different countries as an herbal medicine or as a flavoring or a spice in cooking since ancient times [5, 10]. In traditional medicine, cinnamon has been used in the treatment of arthritis and infections, or as an antitussive, antioxidant, anti-inflammatory and analgesic agent in dental and wound treatment [11, 14]. Cinnamon delays the occurrence of diabetes, colorectal cancer, and bleeding time [11, 15]. Due to the popularity of cinnamon use as a spice in food industry and in traditional medicine, more practical studies are required for investigating its effects on the prevention and treatment of diseases. Therefore, in this study, we aims to review studies conducted on the protective effects of cinnamon in CVD. 
Materials and Methods
This is a review study. The search was conducted using the keywords in English including Cinnamon, Cinnamomum, Cinnamaldehyde and Heart, Cardiac, and Cardiomyopathy based on MeSH terms and the keywords in Persian for the related articles in Web of Sciences, PubMed, ScienceDirect, Scopus, Google Scholar, and Scientific Information Database (SID) databases. The research was conducted by two experts separately published until March 2021. At the end, the results were saved in EndNote format in the presence of a third expert. Included studies were original articles in Persian and English, those with available full texts, in-vitro/in-vivo/ex-vivo studies, and clinical trials. Review articles and gray studies including dissertations and conference articles were excluded. Out of 204 articles found at initial search, 51 were fully reviewed and their information was used for the review study. Figure 2 illustrates the process of article selection. Results 
Cinnamon compounds 
The main compounds of cinnamon are Cinnamaldehyde, Cinnomic acid, Cinnamate and Eugenol. Its flavor is due to the presence of Cinnamaldehyde (Figure 3) [11, 16]. Moreover, Cinnamon contains amidone, mucilage, tannin, calcium oxalate, sugar, cinnamomine, essential oil, and resin [17]. Phenolic compounds of these oily substances are made in the phospholipid layer of plant cell membrane; if the amount of phenolic substances in the essential oil be higher, the antimicrobial properties of the essential oil will be more [18]. Different parts of cinnamon have different compounds such as cinnamyl acetate, camphor, terpene hydrocarbons, and trans-cinnamyl acetate [11].
Therapeutic effects of cinnamon from the perspective of traditional medicine 
In the books of traditional medicine, cinnamon have different names such as Darsini, Darchini, Gharfe al-Darchini and Salikheh. Ceylon cinnamon and Saigon cinnamon are two oldest types of cinnamon in the world, dating back to 3-4 centuries ago [12]. The temperament (mezaj) of cinnamon is warm and dry according to traditional medicine in Iran and India; in terms of properties, it is softener, refresher, and having the ability to open duct obstruction. Cinnamon has been used to treat obsessive-compulsive disorder and panic and insanity, and to eliminate bad breath or cleanse the breast, to treat coughing and shortness of breath, and to relieve the hoarseness caused by thick phlegm [12, 13]. In traditional Far-Eastern medicine, cinnamon has been prescribed as a stomach booster, liver, tonic and sedative, and as a medicine for postpartum pain. Generally, Cinnamon is known as a general stimulant that accelerates blood flow, stimulates respiration and digestion, and increases most of the body’s secretions [12, 13]. In India and China, Ceylon cinnamon’s branch bark has been used as a digestive stimulant, respiratory stimulant or blood flow stimulant. In contrast, Saigon cinnamon has been used more as a spice due to its spicy flavor. Moreover, it has been used as a kidney stimulant for urinary retention, treatment of stomach ache and frostbite on the hands and feet, relieving fever, and reduction of joint and back pain [12, 13].
Protective effects of cinnamon on the cardiovascular system 
Human studies
In a double-blind placebo-controlled study, using cinnamon extract capsules (250 mg/kg body weight) in patients with type 2 diabetes for two months reduced Total Cholesterol (TC), High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL) [19]. In a randomized clinical trial on patients with type 2 diabetes, the effect of using cardamom (3 g), cinnamon (3 g), ginger (3 g) and saffron (1 g) for 8 weeks was evaluated separately and the results showed that cinnamon reduced HDL and LDL in diabetic patients [16]. A double-blind, placebo-controlled clinical trial conducted by Pander et al. on pre-diabetic patients indicated that the use of cinnamon extract (500 mg/kg body weight) for one year had no beneficial effect in improving Electrocardiogram (ECG) indicators in individuals with diabetes [20]. In two studies, cinnamon increased total antioxidant power in healthy individuals by reducing lipid peroxidation [21, 22]. Ranjbar et al. in a cross-sectional study examined the antioxidant effects of cinnamon (reduction of lipid peroxidation). They prescribed cinnamon (100 mg/kg body weight) for two weeks and the results indicated that cinnamon had significant antioxidant ability and might be beneficial in reducing the complications of many oxidative stress-related diseases in humans [22]. Another study explained that the consumption of cinnamon (500 mg/kg body weight) in patients with type 2 diabetes for 2 months reduced blood sugar and blood lipid [23]. On the other hand, in a study on the effects of turmeric, chili peppers and cinnamon on blood lipids of patients with CVDs and cancer during an 11-year follow-up, the findings showed that cinnamon, unlike other spices, did not affect CVDs [24]. According to a case study conducted by Crawford et al., although daily consumption of cinnamon powder (1 g/kg body weight) for 16 months in male patients with type 2 diabetes reduced the complications of diabetes, it caused fluid retention and edema in the knee which increased the likelihood of progressive congestive heart failure [25]. Another study examined the effect of using cinnamon (1 g per day) for 3 months on lowering blood pressure in diabetic patients [26] (Table 1).




Animal studies
In a study, the use of cinnamon extract (300 and 600 mg/kg body weight) by gavage alone and with metformin (250 mg/kg body weight) for 30 days in rats with type 2 diabetes increased HDL level but reduced TC and LDL levels [27]. Another study showed that cinnamon extract (300 mg/kg body weight) consumed for 18 days improved serum level of HDL and LDL in pregnant rats with type 2 diabetes [28]. In another study, daily use of cinnamon alcoholic extract (300 mg/kg) along with captopril (20 mg/kg) for four weeks reduced TC and LDL levels, increased HDL level, and improved atherogenic index in rats with acute hypertension [29]. One study used supplemental treatment with cinnamon extract (100 mg/kg body weight) in rats with metabolic syndrome along with high-intensity endurance training for 12 weeks, and found that it significantly reduced TC and LDL levels and increased HDL level [30]. Other study used daily consumption of cinnamon alcoholic extract (200 mg/kg) along with an 8-week endurance training program (with gradual increase in speed and time) in rats and reported an improved cardiac hemodynamics, decreased serum Malondialdehyde (MDA) level, improved characteristics of hyperlipidemia, and decreased serum levels of TC, LDL, HDL and LDL/HDL ratio [31]. Another study investigated the effects of cinnamon extract (100 mg/kg body weight) compared to garlic extract (500 mg/kg body weight) for 24 hours in healthy rats. Their results revealed that cinnamon increased urea, Lactate Dehydrogenase (LDH) and serum Creatine Kinase (CK) level [32]. In other two studies, cinnamon alcoholic extract in different doses (500 and 300 mg/kg body weight) improved HDL and reduced TC and LDL levels in rats with type 2 diabetes and hyperlipidemia [33, 34]. The results of many animal studies have indicated that cinnamon extract in different doses in rats with type 2 diabetes reduce the serum level of Alanine Aminotransferease (ALT), Aspartate Aminotransferease (AST) and LDH [27]. In some studies, there are differences in the effects of cinnamon extract on these serum parameters, which may be due to difference in the extraction method, the type of solvent, or the dose of cinnamon [35]. 
In one study, simultaneous consumption of cinnamon and cardamom in rats with a high-fat diet improved oxidative stress by reducing the production of free radicals in heart tissue [36]. Another study indicated that consuming cinnamon extract (200 mg/kg body weight) in rats exposed sequentially to gamma radiation, significantly reduced damage to heart and liver tissue by reducing necrosis and apoptosis. It is noteworthy that, as the period of cinnamon use increased from 15 to 40 days in their study, its protective effects increased significantly [37]. The combination of cinnamaldehyde and allopurinol in rats with fructose-induced metabolic syndrome in one study reduced oxidative stress in cardiac tissue. In this study, cinnamon also reduced inflammation and fibrosis in heart tissue by inhibiting Transforming Growth Factor Beta (TGF-β)/SMAD cell path [38]. In-vitro studies have proved some vascular protection effects of cinnamon. Incubation of Vascular Smooth Muscle (VSM) with cinnamon extract (100 mM) in vitro in rats improved carotid artery damage by activating Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inhibition of neointimal hyperplasia by inhibiting VSM cell proliferation [39]. According to another study, cinnamon extract use (0.02 %) for 12 weeks reduced apoptosis and fibrosis in cardiomyocytes by reducing nitrotyrosine (P22phox) and neutrophil cytosol factor 1 (P47phox). Moreover, cinnamon improved oxidative stress by increasing the expression of Heme Oxygenase-1 (HO-1), Glutathione Peroxidase-1 (GPX-1), Quinone Oxidoreductase-1 (NQO-1) and catalase (CAT) in heart tissue of rat with type 2 diabetes. Therefore, cinnamon extract improved oxidative damage caused by high glucose in cardiomyocytes through the Transient Receptor Potential Ankyrin subtype 1 (TRPA1)/Nrf2 path [40].
Consuming alcoholic extract of cinnamon (50, 100 and 200 mg/kg body weight) reduced the amount of damage caused by myocardial infarction in rats and induced protective effects against ischemia-reperfusion injury and the resulting arrhythmia. Moreover, cinnamon increased heart rate in ischemic conditions and stabilized changes in the ST segment, QTc interval, and R-wave amplitude in the ECG. Furthermore, cinnamon significantly increased superoxide dismutase and glutathione peroxidase activities and decreased troponin I, LDH and MDA levels five days after induction of ischemia-reperfusion injury. Therefore, cinnamon can protect the heart against this injury due to its antioxidant properties [41]. In a study conducted by Song et al, the effects of cinnamaldehyde (22.5, 45 and 90 mg/kg body weight) and cinnamic acid (37.5, 75 and 150 mg/kg body weight) along with propranolol (30 mg/kg body weight) in rats were reported due to its antioxidant properties, protected the heart against ischemic injury and increased the activity of Nitric Oxide (NO) and Superoxide Dismutase (SOD) and reduced MDA in heart tissue [42]. The results of another study indicated that cinnamon improved systolic and diastolic dysfunctions by improving echocardiographic parameters and hemodynamic parameters in 7 weeks. Cardiac fibrosis and aortic stenosis were also reduced in these rats by the use of cinnamaldehyde [43]. In another study conducted on the effect of cinnamon used along with Mexilentine in arrhythmic models of rats, rabbits, guinea pigs, and rats whose diseases were induced by chloroform, adrenaline, Strophanthin-k (Spt-K), and barium chloride, it was found that cinnamon could reduce the occurrence of chloroform-induced ventricular fibrillation in rats and adrenaline-induced ventricular tachycardia in rabbits, and delayed the onset of this arrhythmia [44]. Cinnamon consumption also reduced the occurrence of Spt-K-induced arrhythmia in guinea pigs, as well as barium chloride-induced arrhythmia and decreased heart rate. Therefore, cinnamon has obvious antiarrhythmic effects on experimental arrhythmias [45]. In another study, simultaneous consumption of cinnamon bark extract (10%) and cardamom seeds improved oxidative stress by increasing the antioxidant enzymes of glutathione, SOD, CAT, GPX, glutathione S-transferase in the heart and reduced hydrocarbons of conjugated dienes and hydroperoxide in high-fat rats [46]. Accordingly, the antioxidant activity of cinnamon by inhibiting free radicals and inhibiting the enzyme 5 lipoxygenase has been reported in various studies [47, 48, 49]. In another study, cinnamon was reported to increase antioxidant activity and reduce apoptosis in heart tissue [28]. Consumption of cinnamon (0.02%) for 12 weeks in rats with leptin receptor significantly inhibited the production of Reactive Oxygen Species (ROS) maintained the NO production, increased phosphorylated endothelial nitric oxide synthase, and decreased nitrotyrosine. Moreover, it improved fibrosis by reducing the levels of type IV collagen and TGF. Therefore, cinnamon extract dilated the aorta, improved endothelial-dependent mesenteric blood flow, and reduced mesenteric vascular regeneration in rats [50]. Findings of Alvarez et al. indicated that consumption of cinnamon (10, 100 and 1000 μM) dilated the aortic artery and reduced blood pressure by reducing the activity of calcium channels. Cinnamon also induced negative inotropic and chronotropic effects in heart tissue of rats. The protective effects of cinnamon on ventricular cardiomyocytes were more evident than on the VSM cells [51]. The beneficial effects of cinnamon at different doses in lowering blood pressure have also been reported in other animal study  (Table 1) [29].
Discussion 
The high level of antioxidants in cinnamon has caused this plant to act as a cell protector against chemical damage caused by environmental toxins and harmful rays and against various types of stress to cells and tissues, and prevent cellular and tissue damage by reducing free radicals and balancing oxidants and antioxidants [37, 47]. In addition to its antioxidant effects, cinnamon plays a role in regulating blood lipids, reducing LDL and TC levels, and improving blood lipids in obese people with high-fat diets and diabetes [46, 47]. Many studies reviewed in this article had mentioned the beneficial effects of cinnamon on the heart; however, in the studies conducted by Pender et al. and Santos et al., it was indicated that cinnamon had no beneficial effect in regulating blood lipid factors [20, 23]. Moreover, there were conflicting reports about the effect of cinnamon in increasing HDL level, despite many reports about its effect in improving HDL level which may be due to the type of extract, solvent or the dose of cinnamon. Therefore, further studies are required to assess the effect of cinnamon on HDL [50].
In the reviewed studies, cinnamon was reported to have protective effects on the cardiovascular system by reducing oxidative stress and increasing HDL level, reduce ischemic damage including apoptosis in heart tissue in diabetics, reduce blood pressure, and have anti-arrhythmic effects [28, 29, 49]. Our study revealed the effect of cinnamon in different doses on blood sugar, triglyceride, TC, AST, ALT and LDL in patients with type 2 diabetes. Furthermore, we found that cinnamon had an effect in reducing HDL level in many articles [19, 27]. The reviewed studies indicated that cinnamon had a preventive effect on the formation of atherosclerotic plaque which can be effective in preventing the increase of neutrophil, fibrosis and hypertrophy and reducing serum NO concentration [29, 40, 50]. Cinnamon consumption causes the relaxation of VSM wall, the reduction of negative inotropic and chronotropic effects in the heart, and the improvement of systolic and diastolic dysfunctions by reducing the activity of calcium channels [29, 50].
The most of reviewed studies had examined the effect of cinnamon on serum levels of sugar, lipids, blood pressure, and cardiovascular changes. There is scant research on the effects of cinnamon on the cardiovascular tissue changes such as apoptosis, inflammation and fibrosis; therefore, more studies should be conducted in this field (Figure 4). Conclusion 
The results of most human and animal studies have indicated the effectiveness of cinnamon in preventing CVDs. Cinnamon and its various compounds have an effective role in preventing and treating CVDs by lowering risk factors such as blood lipid level and blood pressure, and improving the balance of oxidants and antioxidants (Figure 5). 
Ethical Considerations
Compliance with ethical guidelines
There was no need for ethical approval, since no experiments on human or animal samples were conducted in this study. 

Funding
This study received no financial support from any organization.

Authors' contributions
Searching and writing: Maryam Farazandeh; Investigation and classifying data: Sadegh Shabab; Presenting initial idea, editing and review: Maryam Mahmoudabadi: searching and editing: Zahra Gholamnejad.

Conflicts of interest
The authors declare no conflict of interest.

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