Addressing the Global Burden of Cardiovascular Diseases Assignment

Assignment Task

Introduction

In the globe today, cardiovascular diseases (CVDs) are still one of the main causes of morbidity and mortality accounting for 30% of fatalities. According to the WHO report, 17.9 million people die from CVDs each year. Numerous illnesses, including hypertension, dyslipidemias, cardiomyopathies, strokes, coronary heart disease, heart failure, heart attacks, and peripheral vascular disease (PVD), are classified under the category of cardiovascular diseases (CVD) {1}. The term "cardiovascular diseases" (CVDs) refers to a broad range of conditions that affect the heart and coronary blood vessels. Despite the fact that the initial indication of many chronic diseases like CVDs can be abrupt mortality, these conditions are frequently asymptomatic for a long time. An estimated 18.6 million fatalities per year are attributed to CVDs{2}. It was observed women (51% vs. 42% men) experience worse prognoses and greater fatality rates following acute cardiovascular events such as coronary heart disease, stroke, heart failure, and aortic disorders as compared to men {3}. Additionally, the World Health Organization (WHO) states that appropriate prevention of concentrating risk factors such as smoking habit, increasing body mass, physical inactivity helps in prevention of multiple comorbidities such as type 2 diabetes mellitus, arterial hypertension, dyslipidemia associated with CVD. In 2030, the World Health Organization (WHO) projects that there will be 22.2 million deaths from CVD. {4}.

Conventional treatments for CVDs are often quite expensive and also have several side effects. This potentiates the use of medicinal plants which are still a viable alternative therapy for a number of diseases, including CVDs{5}. Medicines have long been derived from plants and herbs, either as pure active ingredients or as purified extracts. An extraordinary push is currently underway to include herbal remedies into contemporary medical systems for treatment of arrhythmia, congestive heart failure, cerebral and venous insufficiency, atherosclerosis, angina pectoris, and systolic hypertension. Numerous plant parts include bioactive substances that have found significant use in producing cardioprotective effects.The reported phytochemicals with significant cardioprotective effects are phenols, flavonoids, terpenoids, glycosidic derivatives, alkaloids, iridoids, and saponins. Several people use traditional medicine derived from plants (phytochemicals) in addition to or instead of commercial available medications to treat their ailments in an effort to reduce and avoid CVD {6}.

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 are some of the medicinal plants best known for treating CVD{6}.Additionally, studies have demonstrated the cardioprotective effects of certain phytochemicals, including silymarin, cyclovirobuxine D, withanolides, curcumin, berberine, naringenin, tilianin, QUE, baicalin, resveratrol, allicin, and myricitrin. These plants contain flavonoids, polyphenols, plant sterol, plant sulphur compounds, and terpenoids as active phytochemicals responsible for this action {7}. Notoginsenoside R1 from Panax notoginsenoides, which also include ginsenosides Rg1, Rg3, Rb1, and R1, can suppress thrombosis, guard against ischemia myocardial cells, widen peripheral arteries, and avoid ischemic brain damage. Aortic aneurysm, myocardial infarction, stroke, and atherosclerosis have all been found to be prevented by curcumin, a naturally occurring phytoconstituent extracted from Curcuma longa rhizomes. Additionally, it has been suggested that anti-angiogenic medications like allicin, which is a key phytochemical found in garlic, have a significant role in reducing clot formation which lead to blokage in arteries resulting in a heart attack or stroke. The flavonoid quercetin is found in a variety of fruits and vegetables, including apples, citrus fruits, onions, and tea. It significantly reduces atherosclerosis (6,7).

CARDIOVASCULAR DISEASES

Cardiovascular disease (CVD) continues to be a leading factor in premature mortality and rising health care expenses. Major contributors to CVD include cardiometabolic, behavioural, environmental, and social risk factors. The American Heart Association estimates that CVD affects more than half of the population in the United States. In this nation, a cardiovascular disease-related death occurs in every 36 seconds. About 659,000 Americans pass away due to heart disease each year.(8) The main risk factors for cardiovascular Diseases (CVDs), such as

Coronary Heart Disease (CHD), atherosclerosis and cerebrovascular disorders, peripheral arterial disease, rheumatic heart disease, congenital heart defects, deep vein thrombosis, and pulmonary embolism, are believed to be inflammation-induced endothelial abnormalities, dietary practices, and consumption of tobacco. Currently, CVDs are the leading cause of mortality and morbidity worldwide and have risen to the top of the list of health-related problems. A healthy vascular endothelium is advantageous for CVDs prevention. Vasodilatory, anti-atherogenic, and anti- inflammatory characteristics are present in a healthy endothelium. Endothelial cell dysfunction, which has been linked to atherosclerosis, coronary vasoconstriction, and possibly myocardial ischemia, is caused by a number of CVD risk factors. EC dysfunction is an intriguingly reversible condition, which makes CVD therapy based on its reversion possible. {9}.

Figure

1. Types of Cardiovascular Diseases

High blood pressure is one of the risk factors for CVD that is associated with the highest evidence for causation and has a high exposure rate. Hyperlipidemia, a prevalent cause of numerous chronic illnesses, including cardiovascular disease, results from abnormal lipid metabolism. Heart and coronary blood vessel conditions are collectively referred to as "cardiovascular diseases" (CVDs). The inability of the heart muscle to pump enough blood to meet the body's needs for blood and oxygen causes heart failure, a chronic, progressive ailment. In essence, the heart is overwhelmed by its workload. The condition of hypertension, commonly referred to as high or rising blood pressure, causes the blood vessels' pressure to remain elevated.

For instance, inflammation can impede EC function in the case of atherosclerosis. Low- density lipoprotein (LDL) particles can build up in the intima of the vessel wall because to dysfunctional ECs, where they undergo oxidation and become oxidised LDL. Once the defective ECs are activated by oxidised LDL, VCAM-1 and ICAM-1 are released into the subendothelial region, where they attach to and draw inflammatory leukocytes (T-cells and monocytes) into the area {5}.Despite improvements in CVD management and therapy, CVDs still claim more lives than all of the different types of cancer combined. Because of this, CVD prevention has recently been subject to significant regulation. Given the continuous burden caused by CVDs, which is still significant, novel therapeutic options are urgently required for all forms of CVDs. New research from a variety of sources suggests that natural products are an economically efficient way to avoid CVDs.

NATURAL PRODUCTS FOR PREVENTION AND TREATMENT OF CVD

Chemicals synthesized through primary or secondary metabolism are known as phytochemicals, or natural compounds derived from plants. Primary or secondary metabolites found in plants can be used in pharmacological research since they typically exhibit biological action. Many studies have focused on using natural products and herbal treatments to prevent or treat cardiovascular disease. This momentum is caused by a number of variables. Particularly, the potential for a financially viable course of therapy has been contrasted with the current accepted standard of care and the widespread acceptance of its safety and efficacy. These findings have led to the use of numerous medicinal plants for the treatment of cardiovascular disease {11}. Numerous plant sproducts include bioactive substances that have found significant use in producing cardioprotective effects. The most frequently reported potential phytochemicals with significant cardioprotective effects are phenols, flavonoids, terpenoids, glycosidic derivatives, alkaloids, iridoids, and saponins. These phytochemicals are the ones that are most frequently studied and found to be effective in lowering cardiovascular risks, especially for lowering blood lipids, lowering obesity-related risk factors, monitoring glucose and type 2 diabetes effects, regulating inflammation and oxidative stress factors, and inhibiting platelet aggregation. Phytochemicals' mechanisms of action for their cardioprotective benefits are complicated, and many of them are yet unknown {12}.

ALLIUM SATIVUM L. (GARLIC)

Allium sativum L.(garlic) a common spice in India, contains a variety of bioactive components, including organic sulphides, saponins, phenolic compounds, and polysaccharides that have a number of health benefits. Since ancient times, people have utilised garlic, a plant of the Allium family, for both culinary and medical purposes. Garlic exhibits the well-described anti- inflammatory and antioxidant characteristics. The organosulfur chemicals that make up garlic are shown to be the cause of its medicinal benefits. The main bioactive components of garlic, including allicin, thiosulfates, and organosulfur compounds, have been linked to a number of methods for lowering plasma cholesterol and triglyceride levels {13}.

One way garlic decreases blood lipid levels is by preventing the production of cholesterol at various stages, i.e., by blocking HMG-CoA reductase, which is involved in the creation of hepatic cholesterol. Allium extracts contain seven dipeptides that inhibit the angiotensin converting enzyme (ACE), making them potent antihypertensive agents. Increased fatty acid and triglyceride catabolism is another way that garlic works. Garlic's saponins may prevent the gastrointestinal tract from absorbing as much cholesterol. Studies state that garlic had antihypertensive, anti-atherosclerotic, and antilipidemic properties that are beneficial to cardiovascular health {14}.

2. (a) White garlic (b) Black garlic

Studies are now becoming more focused on black garlic, a processed form of garlic with higher polyphenol and flavonoid contents and stronger antioxidant qualities than fresh garlic. In addition to lowering oxidative stress and increasing NO and hydrogen sulphide (H2S) production, garlic also inhibits the angiotensin converting enzyme, which lowers blood pressure. In a trial, garlic consumption (300 mg/day, 8 weeks) was demonstrated to lower cholesterol and low-density lipoprotein levels while raising high-density lipoprotein levels in individuals with diabetic dyslipidemia. Garlic, however, had no effect on the level of triglycerides. It is well-known for its heart-protective properties, which include vasorelaxant, antithrombotic, and antiatherosclerotic effects by preventing the progression of plaque and platelet aggregation as well as by reducing cholestrol levels in arterial cells {15}.

GINKGO BILOBA

Ginkgo biloba is regarded as flat, sweet, bitter, and astringent in traditional Chinese medicine. It has the ability to promote blood flow and remove blood stasis, clear blockages from channels to halt discomfort, astringe respiratory system and relieve cough, dissolve turbidity, and reduce fatty decoction. Ginkgo biloba's component flavonoids (ginkgo-flavone glycosides) and terpenoids are primarily responsible for the herb's medicinal effects and pharmacological effects (ginkgolides and bilobalide). It is often known as maidenhair, is a tree that is native to China and

has been cultivated for several purposes over thousands of years. It's frequently referred to as a living fossil because it's the only survivor of a long-extinct plant order. The majority of current study focuses on ginkgo extract, which is produced from the leaves, despite the fact that its leaves and seeds are frequently utilised in traditional Chinese medicine {16}. These Ginkgo biloba components are well known for having anti-inflammatory and antioxidant properties. The antioxidant and anti-inflammatory properties of ginkgo biloba are helpful in a wide range of illnesses, including those that affect the cardiovascular, pulmonary, and central neurological systems.

3. Ginkgo biloba tree: general appearance (autumn foliage; left); leaves (summer foliage; center); seeds (right).

Numerous CVDs, including vascular damage and the development of atherosclerotic plaques, are influenced by free radical production. The balance between free radical formation and antioxidant defence is significantly changed toward the former during CVD pathogenesis {16, 17}. Due to its antioxidant action, GBE significantly restores the disturbed oxidative state equilibrium and helps to both scavenge excess free radicals and lower free radical formation. Among other reported benefits that are advantageous in CVD, ginkgo biloba extract has demonstrated ACE inhibitor activities, activation of cholinergic pathways, enhancement of endothelial health, inhibition of endothelium activation and adhesion, and serum lipid-lowering activities. It improves lipid profile by decreasing PPARs levels. It controls hypertension and improves endothelial function by decreasing ACE activity, activating cholinergic pathways and limiting LPS-induced proliferation of VSMCs. It controls inflammation by suppressing TLR-4 expression and IL-1b Ameliorates oxidative stress responsible for a number of cardiac disorders

Ginko biloba prevents hypertrophy by activating M2 muscarinic receptors/NO pathway or by decreasing calcium overload and inhibiting the Na+/Ca2+ exchanger. By raising anti-apoptotic Bcl-2 expression and lowering caspase 3 and pro-apoptotic Bax expression, it prevents apoptosis cerebrovascular illnesses was addressed by a patent filed by Sun et al. in 2012. The flavone and terpene lactone-containing ethanolic extract was studied in adult and old Sprague Dawley rats (2 mg/kg, i.v. for both). Additionally, a Langendorff apparatus ex vivo experiment and cardiomyocyte cell culture were conducted {20}

CINCHONA LEDGERIANA

The bark of Cinchona ledgeriana is being used to extract about 700 metric tonnes of cinchona alkaloids each year. The chemical molecules with the most interesting biographies are the cinchona alkaloids, which were isolated from the bark of various cinchona tree species. As a key antimalarial medicine, a chemical that relaxes muscles, and a heart depressant (antiarrhythmic), quinine and quinidine obtained from its bark are employed, respectively{21}. The plant has been studied for its antiarrhythmic properties, including converting atrial flutter and fibrillation to sinus rhythm, battling supraventricular and ventricular arrhythmias, raising the excitability threshold, and lengthening the effective refractory period. The phytoconstituent quinine obtained from plant has been used as an antimalarial agent. The initial dose to extend the refractory period was found to be 200 mg for five oral doses, and the maintenance dose was found to be 200 to 400 mg oral four times per day {22}. Since the development of new antiarrhythmic medications, quinidine's usage as an antiarrhythmic has been restricted.

GINSENG

Korean red ginseng (P. ginseng Meyer), Chinese ginseng (P. notoginseng), and American ginseng are the most popular varieties (P. quinquefolium L.) of ginseng. One of the most popular herbal remedies, ginseng is said to have a variety of medicinal and pharmacological uses. The term Panax, which means "all healing," refers to the conventional wisdom that ginseng has the ability to treat all bodily ills. Additionally, ginseng may be helpful in the treatment of cardiovascular ailments. Instead of employing complete ginseng extracts, research on cardiovascular disease is concentrating on purified individual ginsenoside elements of ginseng to identify specific pathways..

4. (a) Cinchona ledgeriana (b) Panax ginseng C.A. Meyer aerial parts (c) Panax ginseng

C.A. Meyer root

When an organism is stressed, ginseng has been utilised to treat heart failure and to prevent tissue damage. Ginseng has been used to treat high blood pressure. Due to its role in improving vascular functioning, ginseng exerts hypotensive effects. It's interesting to note that ginsenosides help different vessels relax their muscles. Additionally, ACE activity in human umbilical vein endothelial cells (HUVECs) and angiotensin I-induced contractions of bovine mesenteric arteries have been demonstrated to be inhibited by the Panax ginseng G115 extract {24}.Ginseng also has anti-oxidant, anti-inflammatory and anti-hyperlipidemic characteristics in addition to its capacity to control Ca2+ channels.

COMMIPHORA MUKUL

The sap (gum resin) of the Commiphora mukul tree, which is indigenous to India, is processed to make guggul. Ayurvedic scriptures from as far back as 600 BC support the use of this resin for the treatment of atherosclerosis, hypercholestrolemia and lipid disorders. It has been utilised for millennia in Ayurvedic medicine. Today, guggul gum resin is used for weight loss, atherosclerosis (hardening of the arteries), arthritis, high cholesterol, acne, and other skin problems. Numerous phytochemical components, such as flavonoids, terpenes, phytosterols, and others, are present in C. mukul and have a variety of biological functions, including antibacterial, anti-inflammatory, anti-carcinogenic, and other significant medicinal effects {25}.

Guggulsterone is the primary active ingredient of gugulipid, a C. mukul extract used to treat a range of human conditions, such as dyslipidemia, obesity, and inflammation. A doctoral thesis submitted to the Banaras Hindu University (BHU) in January 1966 was the first to discuss the lipid-lowering effects of guggulu with a focus on atherosclerosis and obesity (medoraga). Guggulu is widely used as an Ayurvedic medicine to treat various forms of arthritis. The well- known Ayurvedic treatise Sushruta Samhita contains a somewhat obscure Sanskrit shloka that served as the inspiration for this piece {26}. The shloka discusses the etiology, pathogenesis, therapy, and repercussions of obesity and related lipid disorders in an incredibly clear and scientific way. The hypolipidemic action was demonstrated in both obese and hypercholesterolemic individuals as well as in animals.

The lipid-lowering elements of guggulu, called guggulsterones, successfully prevented in vitro LDL oxidation. Guggulu is therefore particularly effective against atherogenesis due to its combination of antioxidant and lipid-lowering effects. There is evidence that guggulsterones are powerful cardioprotectants. The reversal of blood and heart biochemical markers in ischemia rats treated with guggulsterone showed that it greatly prevented cardiac damage {27}.

The nuclear farnesoid X receptor (FXR), which controls the liver's metabolism of cholesterol, is antagonisted by guggulsterone. However, the cembrenoids reduced the cholate-activated rate of human pancreatic IB phospholipase A2 (hPLA2), which regulates gastrointestinal absorption of fat and cholesterol. The cembrenoids had no discernible impact on FXR.{28}

DIGITALIS LANATA AND DIGITALIS PURPUREAL

Grecin foxglove or Wooly foxglove are two names for D. Lanata. Both the plants are a member of the Scrophulariaceae family. For disorders like dropsy and others, it was utilised in 1785.

Recently, several formulations from the leaves of this plant were employed in Denmark as powder in tinctures, infusions, and tablets to assess heart function {29}. These plants' extracts contain cardiac glycosides (digoxin), digitoxin, and cardenolides that are used to treat cardiac problems. Anthraquinones (1-methoxy-2-methyl anthraquinone, 3-methoxy-2-methyl anthraquinone, and 1,4,8-thihydroxy-2-methyl anthraquinone); glucolanadoxin; glucoverodoin; tigogenin; gitogenin; digitogenin; apigenin; and glucoevatromoside are other chemicals found in both plants. Increased atrial natriuretic peptide release, cardiac hypertrophy, oxidative stress, and apoptosis are caused by the KATP channel being opened It reduces the need for oxygen for cardiac work by having a cardiotonic effect by increasing heterosides on cardiac contractility and decreasing excitability, conductivity, and rhythm {30}.

Curry leaf is a member of family of flowering plants that may be found in all of the tropical and subtropical nations of East Asia, including India, Pakistan, China, and northeastern Australia. In India, especially in the south, it is frequently used as a flavoring agent. Curry leaf has a wide range of pharmacological actions, and a number of its bioactive components have potent antioxidant activities {31}. The major benefits of curry leaf are associated with an increase in good HDL-C and a decrease in bad LDL-C, as well as a lowering of total cholesterol and a drop

in blood glucose levels in diabetic mice. In several studies, the anti-oxidant properties of curry powder were shown to diminish the early occurrence of atheroma induced by the oxidation of LDL cholesterol, suggesting the prevention of CVD. A preclinical investigation using curry powder on mice led to significant reductions in lipid peroxidation and lactate dehydrogenase levels, hypocholesterolemia and hypoglycemia after administration of the aqueous extract of fresh curry powder leaf {9}.

Glycyrrhiza glabra, the scientific name for licorice, is a member of the Leguminosae family. The herb Glycyrrhiza glabra is regarded as a "essential herbal medication" in traditional Chinese medicine (TCM). Licorice is one of the most potent herbal medicines for decreasing toxicity and enhancing the efficacy of other herbal medicines when used in combination, and it is said that "nine out of ten formulations contain licorice"{32}. Glycyrrhizin, saponins, flavonoids, and triterpene are its primary components. Cyclooxygenase activity, prostaglandin E2 in particular, and platelet aggregation were all inhibited. Glycyrrhetinic acid inhibited 11-hydroxysteroid dehydrogenase and displayed anti-inflammatory properties. An isoflavane, or isoflavonoid, is glabridin. The natural phenols are a more well-known family of chemicals generated from plants that this substance belongs to. Glabridin suppressed melanogenesis by inhibiting tyrosine and ROS generation, respectively G. glabra lower intracellular cholesterol buildup in an ex vivo investigation, demonstrating licorice's promising anti-atherogenic potential {33}.

Turmeric (Curcuma longa) belonging to a family of zingiberaceae contains curcumin, which has long been used in traditional medicine to treat a variety of illnesses. Numerous studies have shown that curcumin has a positive impact on the signalling pathways that control oxidative stress, inflammation, apoptosis, and proliferation. Several research have suggested that curcumin has cardiovascular preventive benefits against CVDs. CVDs include atherosclerosis, cardiac hypertrophy, cardiac fibrosis, heart failure, myocardial infarction, and ischemia may be eased by curcumin {34}. It was discovered that Curcumin's cardioprotective effects were influenced by its antioxidant, anti-apoptotic, and anti-inflammatory activities.

The modulatory actions of curcumin on the signalling pathways AMPK, Nrf2, JAK/STAT, NF- B, PI3k/Akt, MAPK, Notch, mTOR, PPARs, and arachidonic were thought to be the potential molecular mechanism behind its cardioprotective benefits. The cardiovascular problems brought on by inflammatory blood vessel conditions and atherosclerotic processes include acute coronary syndrome and atrial arrhythmias. Therefore, curcumin's anti-inflammatory and antioxidant effects are advantageous for preventing CVD. By restoring Ca2+ homeostasis, curcumin may be able to prevent atrial arrhythmias and may even help to avoid some ventricular arrhythmias. It has been claimed that piperine increases curcumin's absorption and bioavailability, although the underlying mechanism for this effect has not yet been identified {35}.

The dried roots of Polygonum cuspidatum are used to extract resveratrol for commercial purposes and its extract has been used to treat cardiovascular disease (atherosclerosis, hypertension, ischemia or reperfusion, heart failure), skin irritation, and fungus infections. The stillbene moiety of resveratrol is widely distributed in the skin of grapes, berries, and the leaves of eucalyptus, spruce, etc. Resveratrol controls COX-2 activity at a transcriptional level, preventing the formation of PGE2, which reduces the inflammation linked to atherosclerosis. Additionally, resveratrol offers cardioprotection as shown by improved postischemic ventricular recovery, a smaller myocardial infarct, and fewer apoptotic cardiomyocytes. Resveratrol protects the heart through a variety of redox signalling systems and its antioxidative effects {36}.It has been discovered that polydatin is crucial for avoiding heart failure and cardiac hypertrophy caused by pressure overload. The Ca2–calcineurin pathway may be inhibited by polydatin without altering cardiac contractility as the mechanism. In addition, trans-polydatin may reduce angiotensin expression, block the actions of renin and angiotensin-converting enzyme, and guard against myocardial ischemia injury. This implied that PC could be a novel medication for cardiac protection {37}.

BETA VULGARIS (BEETROOT)

Beta vulgaris commonly known as beetroot belongs to a family of Chenopodioideae. Red beet or beetroot extract has strong anti-inflammatory and antioxidant properties. Additionally, it contains a lot of inorganic nitrate. There are roughly 250 mg of nitrate per kg of fresh beetroot. Nitrate- Nitrite-Nitric Oxide (NO) pathway is a critical component of dietary nitrate. The high inorganic nitrate concentration of beetroot is assumed to be responsible for its antihypertensive and anti- platelet aggregation properties {38}. Along with cytoprotective action, immunological defence, and signal transmission in the cardiovascular and nervous system, NO2 and NO play a critical role in preserving proper cardiovascular homeostasis. In addition to being a powerful vasodilator that regulates systemic blood pressure, NO also prevents the recruitment of inflammatory cells that are involved in atherosclerosis The only vegetable that has been found to be successful in inducing enhanced systemic NO generation at the magnitude required to produce the desired pharmacological effects in those with cardiovascular disease risk factors is beet formulations, which are more convenient, appealing, and available. Betanin helps to maintain oxidative equilibrium and reduce vascular inflammation {39}.

According to descriptions, betanin is a bioactive substance that can suppress the peroxidation of lipid membranes and low-density lipoprotein (LDL), alter gene expression and ROS production to lessen the release of inflammatory cytokines, and boost antioxidant enzyme activities. Betanin has the potential to be employed as a complementary therapy to lessen the pathophysiological consequences of oxidative stress and inflammatory processes that result in CVD disorders {40}.

Bottle gourd, or Lagenaria siceraria (Molina) Standley fruit, is a popular vegetable in India that is thought to offer cardioprotective and cardiotonic properties. It is a member of the cucurbitaceae family and is traditionally used to treat atherosclerosis, hyperlipidemia, and coronary artery disease. Bottle gourd fruit extracts mostly contain sterols, curcubitacin, flavonoids, and saponins {41}. The bottle gourd's sterols and dietary fibres slow down the gut's.

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