The role of flavonoids in the prevention and management of cardiovascular complications: a narrative review

Introduction

Cardiovascular diseases (CVDs) are the world’s leading cause of death, affecting an estimated 17.9 million people around the world (1). For the last few decades, CVDs have been the primary risk factor for mortality in developed countries, and developing countries are quickly catching up (2). The underlying pathology of atherosclerotic vascular disease results in coronary artery disease, cerebrovascular disease, peripheral vascular disease, and the subsequent development of cardiac arrhythmias. The main health issues for these conditions have been identified, and include elevated levels of low-density lipoprotein (LDL) cholesterol, smoking, hypertension, diabetes, abdominal obesity, psychological stressors, insufficient vegetable and fruit intake, excessive drinking, and a lack of regular physical activity (3). CVDs include coronary heart disease, cerebrovascular disease, rheumatic heart disease, and other complications. Four out of 5 deaths are observed which are associated with cardiovascular problems and are due to strokes and heart attacks (4). The risk factors are configurable; however, to date, the prevention or control measures, especially in developing countries, have been lacking. In the coming years, a population policy paired with a high-risk CVD prevention strategy could significantly alleviate the burden of disease (5,6). We present the following article in accordance with the Narrative Review reporting checklist (available at https://dx.doi.org/10.21037/apm-21-1343).

Methods

Risk factors

The world’s growing urbanization and industrialization have reduced people’s physical activity levels. Physical activity protects against a variety of chronic conditions at any age. By controlling weight and improving the body’s use of insulin, physical activity decreases the risk of CVDs (7). Tobacco and smoking are other modifiable factors associated with the progression of cardiovascular disorders. Tobacco smoke affects the endothelium, stimulates arterial fat deposits, enhances clotting, tends to increase LDL cholesterol and decrease high-density lipoprotein (HDL) cholesterol, and promotes coronary artery spasticity (8). There is a clear association between abnormal blood lipid concentrations and the likelihood of coronary artery disease, cardiac arrest, and cardiovascular failure. Abnormal blood lipids are also linked to dietary habits. A diet rich in saturated fats and trans fats contributes to high cholesterol levels (9,10).

Alcohol use has been observed to affect the cardiac muscle and raise the risk of stroke and cardiac arrhythmia. Other complications associated with drinking too much alcohol include high blood pressure, acute myocardial infarction, cardiomyopathy, liver cirrhosis, aggression, and suicide (11,12). Obesity is one of several significant risk factors for CVD as well as other hormonal disorders, such as diabetes. As shown by the rising rate of obesity, the general human population is becoming overweight. There are approximately 400 million adults globally who are obese and 1 billion who are overweight and suffer from the risk of CVDs (13).

Flavonoids

Reactive oxygen species are reactive molecules that are continuously formed in organisms by enzymatic reactions (14). Under normal conditions, reactive oxygen species are generated at lower concentrations than those needed for normal cell activity, and the body’s intrinsic anti-oxidant protection mechanisms are capable of minimizing any harmful effects (15). However, many proven health issues related to heart disease are being attributed to an increase in reactive oxygen species production, a condition called oxidative stress (16). Numerous epidemiological trials have found that daily flavonoid consumption is linked to a lower risk of heart disease (17). Flavonoids area type of natural product with a polyphenolic structure and basic components that consist of 3 heterocyclic rings (2 phenyl rings and a heterocyclic ring). These 3 elements combine to form the flava kernel, which is the central component of flavonoids (18). Flavonoids have been the subject of significant interest by experts in recent times due to the wide spectrum of possible benefits they provide. Owing to the variability of the molecular structures, complicated long-term research, and several reports have indicated that polyphenolic compounds can be useful as an adjunctive therapy for the management and cure of inflammatory diseases (19).

Discussion

The role of flavonoids in the management of hypertension

Flavonoids, a class of natural products with complex phenolic structures, are present in berries, herbs, nuts, wood, roots, branches, bulbs, coffee, and tea. The beneficial health effects of these natural substances are well recognized. Flavonoids are also known to be an essential ingredient in a multitude of pharmaceutical, nutraceutical, medical, and cosmetic products. This is due to their anti-oxidant, anti-inflammatory, anti-mutagenic, and anti-carcinogenic effects, and their ability to modulate crucial cellular enzyme activity (20). Rutin and quercetin are reported to regulate and restore elevated blood pressure and promote the anti-oxidant defense system. In one study, rats fed an 8% sodium chloride-supplemented diet (i.e., a high-salt diet) for 12 fortnights showed an increase in systolic, diastolic, pulse, and mean arterial blood pressures. Lipid peroxidation was increased and the anti-oxidant enzymes were down regulated. Treatment with rutin and quercetin for nearly 2 weeks resulted in notable reversals of these indices compared to the animals fed only the high-salt diet (the without treatment group). The high-salt diet also resulted in noteworthy increments in the serum urea, creatinine, glucose, triglycerides, low-density-lipoprotein, and total cholesterol levels. The administration of rutin and quercetin retarded the effects of the high-salt diet for these biochemical indices. The reference drug, nifedipine, was found to be less effective than rutin and quercetin. The outcomes of the study indicate the roles of rutin and quercetin as anti-hypertensive agents and anti-oxidants (21). The administration of rutin resulted in the restoration of baroreflex sensitivity in 2-kidney-1-clip rats. The cardiac contractility was also decreased, and vasorelaxation tended to be restored. The rutin treatment also resulted in a decrement in lipid peroxidation (22). In another independent study that used the 2-kidney-1-clip model, the administration of rutin restored systolic and diastolic blood pressure. The restoration of glutathione and plasma renin was observed to be dose dependent (23). In a clinical study, the administration of quercetin was found to result in a decrement in hypertension in stage 1 hypertensive patients, including reductions in systolic, diastolic, and mean arterial pressures (24).

The anti-hypertensive effects of catechin and its derivatives are widely acknowledged. Tea, specifically green tea, is an important source of catechin. Tea is widely consumed worldwide (25), and contains anti-oxidants that have been proven to be beneficial to health. Catechin constitutes about 3% of green tea (25,26). Numerous studies have reported that the consumption of green tea has beneficial effects on hypertension. Indeed, the administration of catechin-rich green tea has been shown to result in a decrement in systolic and diastolic blood pressure. The lipid profile was restored to normal levels. The decrement in LDL cholesterol is prominent. Alterations in blood glucose levels due to normotension appear to be significant (27). Catechin-rich oil has been reported to have an anti-hypertensive effect, as it upregulates nitric oxide (NO) levels. Research has shown a notable decrease in the wall-to-lumen ratio to near normal values under NO deficiency (28). Benifuuki tea is a popular green tea consumed in Japan. It is a rich source of (-)-epigallocatechin-3-O-(3-O-methyl) gallate. This polyphenol has a significant effect on the inhibition of the angiotensin I-converting enzyme. Benifuuki tea has also been shown to have an anti-hypertensive effect, especially on systolic pressure (29).

Oranges are one of the richest sources of hesperidin. Hesperidin is one of the major anti-oxidant flavonoids (30). In a preclinical study, the anti-hypertensive effects of glucosyl hesperidin and hesperetin were evaluated in animal models (spontaneously hypertensive rats and normotensive Wistar-Kyoto rats). The administration of glucosyl hesperidin (doses of 10 to 50 mg/kg) to the experimental animals resulted in a dose-associated decrement in systolic blood pressure; however, no notable effect was observed in the normotensive animals. Similarly, the intraperitoneal administration of hesperitin to spontaneous hypertensive rats resulted in a notable decrement in systolic blood pressure. Such a response was associated with the inhibition of NO synthase. The effect was observed due to NO-mediated vasodilation (31). The possible anti-hypertensive effects of hesperidin have been studied in type-2 diabetes patients. In a clinical study, patients were administered a 500-mg hesperidin capsule every day for 6 days. The placebo group received a starch filler capsule. Systolic and diastolic blood pressure were taken into consideration when determining the blood pressure of the patients. Patients’ systolic and diastolic blood pressure was restored to normal at the end of the protocol. The levels of tumor necrosis factor-(TNF)-α and interleukin (IL)-6 were notably decreased in the hesperidin treated group. An increase in total anti-oxidant capacity was also observed. This effect may be due to one of the metabolites of hesperidin; that is, hesperetin-O-glucuronide. The metabolite is associated with endothelium-dependent vasodilation and the suppression of inflammation of endothelial cells (31). The pharmacological effects of the administration of hesperidin and glucosyl hesperidin along with naringin were evaluated in stroke-prone spontaneously hypertensive rats. The study showed that the administration of these flavonoids resulted in the restoration of blood pressure and a decrement in thrombolytic tendency. The biosynthesis of NO was also increased. Further, the endothelial function was restored due to the administration of these natural flavonoids (31).

Genistein is another documented isoflavone present in various soybeans and soy products. Genistein has been the subject of considerable interest by the biomedical community due to its apparent positive effects on major human illnesses, such as cancer. Mechanistically, genistein has a propensity for apoptotic activation, arresting the cell cycle, and also has anti-angiogenic, anti-cancer, and anti-apoptotic effects. Genistein has a tendency to regulate NO biosynthesis. Specifically, it increases the expression of NO. It also increases aortic wall thickness and decreases hypertension (32). In high-sodium chloride (NaCl) diet-fed rats, the administration of genistein blunted hypertension. Studies also suggest that it has anti-hypertensive effects associated with the autonomic nervous system. Genistein has also been observed to decrease insulin resistance and restore triglycerides’ (33). The key mechanism by which genistein mediates cardiovascular function is via its association with estrogen receptors. Genistein is capable of binding to the estrogen-receptor beta (Erβ) and activating ER-dependent gene transcription. Genistein also greatly affects the protein expression implicated in vascular tone control; that is, the atrial natriuretic peptide receptor, endothelin converting enzyme 1, angiotensin converting enzyme, atrial natriuretic peptide receptor, and endothelial NO synthase (34,35). Erythropoietin and its receptor play a defensive role in the prevention of pulmonary hypertension. In one study, the administration of genistein in hypobaric conditions prevented vascular remodeling and pulmonary hemodynamics. Vasodilation associated with phosphatidylinositol 3-kinase and NO was also observed (36).

Due to the rise in hypoxia-inducible factor (HIF)-1α, hypertension-induced myocardial injury is often followed by impaired myocardial glucolipid metabolism. The potential benefits of apigenin for hypertension have been studied. Research has shown that the administration of apigenin resulted in a decrement in blood pressure and restored heart weight and serum angiotensin II. Additionally, apigenin administration resulted in a decrement in the expression of carnitine palmitoyltransferase-1, peroxisome proliferator-activated receptor-α, glycerol-3-phosphate acyltransferase genes, and glucose transporter-4 proteins. It has been suggested that apigenin may have beneficial effects in hypertensive cardiac hypertrophy (37). Table 1 details the effects of other flavonoids on hypertension.

Table 1 Anti-hypertensive mechanism of flavonoids
Full table

The role of anti-oxidants in the management of cardiac arrhythmia

Arrhythmia refers to a diverse variety of disorders associated with abnormalities in heart rate and rhythm. Based on heart rate, arrhythmias are classified as bradyarrhythmias or tachyarrhythmias. They are also classified based on their origin, mode of propagation, and the syndromes with which they are associated. Patients with arrhythmias can present with a wide range of clinical symptoms, ranging from being completely asymptomatic to sudden cardiac arrest. As arrhythmias can be paroxysmal, assessing their exact prevalence is challenging. The event of cardiac arrhythmia addresses the diagnosis and management of multiple arrhythmias, and also the involvement of multidisciplinary teams in the care of such cases.

Quercetin has been observed to have anti-ischemic and anti-arrhythmic effects, and has a beneficial role in the homeostasis of patients with ischemic heart disease (44). The administration of quercetin (120 mg/day orally) for a period of 2 months resulted in the restoration of the ejection fraction and left ventricular systolic function (45). A total decrement in the depression of ST segment depression was also observed due to quercetin administration (45). The Ganshanbian herb is used in the treatment of cardiac arrhythmias. In one study, the flavonoid-rich fraction of Ganshanbian was isolated and evaluated to examine its anti-arrhythmic effects in an animal model. The administration of the flavonoid-rich fraction to the animals resulted in an increase in the appearance time and a decrease in the duration of ischemia and heartbeat. There was an increase in the expression of cell membrane associated messenger ribonucleic acid (mRNA) of L-calcium channels α type Ca_L-α1C. The expression of K⁺ channel pore-forming subunit Kir6.1 (K_ATP-Kir6.1) mRNA was enhanced in myocardial cells. Treatment resulted in the restriction of calcium (Ca²⁺) ion inflow and the regulation of the concentration of Ca²⁺ion myocardial cells by inhibiting the time in which the L-type Ca²⁺ channels opened (46).

The potential anti-arrhythmic effects of flavonoids from the Chinese medicine Viscum coloratum have also been evaluated. The administration of 0.1 mg/mL of a flavonoid-rich extract of Viscum coloratum facilitated steps 2 and 3 in the repolarization of the fast response action and reduced the length of the action potential (47). In another study, the administration of the flavonoid-rich fraction of Viscum coloratum shortened the action potential and led to a decrement in the arrhythmia index. This effect was mediated by virtue of the inhibition of L-type Ca²⁺currents (48).

According to epidemiological studies, the intake and consumption of green tea and cardiovascular health are positively associated. Green tea comprises flavonoids and polyphenols that tend to demonstrate anti-oxidant and anti-hypertensive effects, which contribute to lower cardiovascular mortality (49). Epigallocatechin-3-Gallate, a polyphenol, is one of the important components of green tea. The supplementation of Epigallocatechin-3-Gallate resulted in the increased survival of myocytes (50). In low concentrations, Epigallocatechin-3-Gallate facilitated the Na⁺/H⁺ exchanger and reversed the Na⁺/Ca²⁺ exchanger, while in high concentrations, Epigallocatechin-3-Gallate activated the β2-adrenergic receptors. Thus, low doses of Epigallocatechin-3-Gallate offered cardio protection, and high doses of Epigallocatechin-3-Gallate raised the incidences of arrhythmia and diastolic dysfunction. The β2-adrenergic receptor was shown to be active in the cardiac effects of Epigallocatechin-3-Gallate (50). Epigallocatechin-3-Gallate administration was shown to be helpful in reducing the ion channel mutations related to irregular cardiac excitability phenotypes in a computer simulation. Computer simulations of action potentials reveal that 30 µM of Epigallocatechin-3-Gallate minimized and inhibited phenotypic action potential abnormalities (51).

Citrus fruits contain hesperidin, a flavanone glycoside. Hesperetin is the aglycone form of hesperidin. Its name is derived from the word ‘hesperidium’, which refers to citrus fruit (52). Numerous studies have shown the anti-arrhythmic and cardioprotective effects of hesperidin. One study examined the beneficial effects of hesperidin on ischemic reperfusion injury in rats. Due to ischemia, tissue nitrite and anti-oxidant levels decrease, and the incidences of arrhythmia and apoptosis of myocytes increase. The administration of hesperidin in animals restored nitrite in the cardiac tissues, and decreased arrhythmias, apoptosis, and inflammation. Hesperidin also caused a decrement in lipid peroxidation, and restored levels of superoxide dismutase and catalase. Similarly, a decrease in TNF-α and myeloperoxidase levels was also observed. The treatment also resulted in a decrement in the time lapse and occurrence of arrhythmias (53). At concentrations of 30 molL-1 or greater, hesperetin raised the QRS interval and heart rate while decreasing the corrected QT interval and cardiac and aortic contractile forces. With an effective inhibitory concentration of 100 molL-1, hesperetin blocked rat and human NaV 1.5 channels. Further, hesperidin prevented the slow inactivation phase of I_Na (54). According to reports, hesperidin reduces cardiac necrosis (55). Protein kinase B (Akt) expression was improved in animals treated with hesperidin (100 mg/kg), while the apoptosis regulator (BAX/BCL2) market ratio declined substantially. Irrespective of hesperidin administration, electrocardiogram ECG improvements were reversed in groups 2 hours after carbon monoxide CO exposure. In general, hesperidin minimized the detrimental cardiac effects of CO toxicity in rats (55). Table 2 sets out the anti-arrhythmic effects of other flavonoids.

Table 2 Anti-arrhythmic effects of flavonoids
Full table

The role of anti-oxidants in the management of angina and myocardial infarction

Angina is the most prevalent symptom of ischemic heart failure, and seems to be the leading risk factor for mortality around the world. Angina pectoris is characterized as substernal chest pain, strain, or irritation that is intensified by aerobic endurance and/or emotional tension, and persists for more than 30 to 60 seconds, but is improved by resting and nitroglycerine (62). A few studies have shown the anti-anginal properties of flavonoids. The anti-anginal effects of Ethyl-7-hydroxyaceto-flavone (63) and rutin (along with theophylline) have also been evaluated (64).

Myocardial infarction develops as blood circulation to a section of the heart reduces or ceases, triggering damage to the heart muscle. The most frequent symptoms of myocardial infarction include chest pain or stiffness that can spread to the arm, neck, spine, throat, or jaw. Various studies have sought to evaluate effects of flavonoid intake on the onset of myocardial infraction, and the beneficial role of flavonoids has been established. In one study, nutritional data were gathered using a questionnaire that had been verified for validity and replicability (65). The high consumption of anthocyanidins decreased the risk of myocardial infarction, even in alcoholics (65). Another study found an inverse relationship between flavanol and flavone intake and associated coronary mortality rates (66). A study conducted on a geriatric population also showed that flavonoids have a beneficial role in the prevention of myocardial infarction (67). Dietary flavonoids, such as quercetin, kaempferol, and myricetin, were shown to be substantially inversely related to fatal myocardial infarction (68). Flavonoids, such as chrysin, apigenin, and naringenin, increased post-ischemic responsive regeneration in the heart, which was correlated with reduced tissue injury extension. 5-methoxy flavone has been shown to have the same type of biological effects (69).

In one study, the total flavonoids of Abelmoschus Manihot were evaluated to examine whether they played a beneficial role against myocardial infarction. The results showed that total flavonoid administration resulted in a decrement in the levels of lactate dehydrogenase, downregulatedIL-6, IL-1β and TNF-α production, and decreased the expression of NLRPR3 inflammasome (70). Epimedium flavonoids also had protective effects against myocardial infarction. The myocardial infarcted area in the rats was found to be decreased to a different degree, and the activity of serum creatine phosphokinase, lactate dehydrogenase, and lipid peroxidation were found to be decreased. Additionally, the activity of anti-oxidant enzyme superoxide dismutase was found to be increased. The lowering of the ST-T segment, which began within 5 minutes, persisted for more than 3 hours (71). The flavonoids extracted from propolis were found to improve cardiac function. The extract decreased the degree of cardiac fibrosis and downregulated fibrosis-related factors, including collagen I, collagen III, matrix metalloproteinase-2, and 9. The activation of silent information regulator 1 was found to be the leading cause behind these beneficial effects (72).

The role of anti-oxidants in coagulation disorders

Coagulation diseases are pathogenies that impair the clotting processes of the blood. Coagulation abnormalities include hemophilia, hypercoagulable states, Von Willebrand disease, and deep venous thrombosis. The loss of normal anti-coagulation mechanisms, whether due to genetic deficiency or serious external trauma, might lead to thrombosis, which in turn can predispose people to deep vein thrombosis, stroke, and heart attack (73). Flavonoid-rich flavonoids may reduce the risk of the hyper-activation of platelets, the progression of CVDs, pain, and thrombosis. Flavonoids also reduce the risk of atherosclerosis and atherothrombotic diseases (74). Table 3 sets out the role of various flavonoids in blood-associated disorders.

Table 3 Beneficial role of flavonoids in coagulation disorders
Full table

Conclusions

This literature review summarized epidemiologic and mechanism-based studies that examined the benefits of flavonoids and polyphenol for the cardiovascular system and their role in lowering the likelihood of heart disease. The vascular endothelium is a central governor of vascular homeostasis. Endothelial dysfunction plays a key role in the pathophysiology and physiological manifestations of coronary heart disease. Platelet accumulation plays an important role in the etiology of acute coronary syndromes, such as cardiac arrhythmia and dysfunctional angina. Flavonoids are fairly soluble in physiological media and thus are a potential candidate for the possible management of cardiovascular and associated disorders. Notably, they are also non-toxic in nature. Alleviating the oxidative stress induced by reactive oxygen species using anti-oxidant-rich flavonoids could lower the chances of platelet hyperactivation, heart disease, discomfort, and fibrosis. Additionally, flavonoids could help to prevent endothelial dysfunction, which is implicated in the progression of coronary artery and vascular diseases.

Acknowledgments

Funding: This work was supported by National Science and Technology Major Special Project [2017ZX09301003].

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-1343

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-1343). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)