Cardiovascular diseases (CVDs) are a significant health burden with an ever-increasing prevalence. They remain the leading causes of morbidity and mortality worldwide. The use of medicinal herbs continues to be an alternative treatment approach for several diseases including CVDs. Currently, there is an unprecedented drive for the use of herbal preparations in modern medicinal systems. This drive is powered by several aspects, prime among which are their cost-effective therapeutic promise compared to standard modern therapies and the general belief that they are safe. Nonetheless, the claimed safety of herbal preparations yet remains to be properly tested. Consequently, public awareness should be raised regarding medicinal herbs safety, toxicity, potentially life-threatening adverse effects, and possible herb–drug interactions. Over the years, laboratory data have shown that medicinal herbs may have therapeutic value in CVDs as they can interfere with several CVD risk factors. Accordingly, there have been many attempts to move studies on medicinal herbs from the bench to the bedside, in order to effectively employ herbs in CVD treatments. In this review, we introduce CVDs and their risk factors. Then we overview the use of herbs for disease treatment in general and CVDs in particular. Further, data on the ethnopharmacological therapeutic potentials and medicinal properties against CVDs of four widely used plants, namely Ginseng, Ginkgo biloba, Ganoderma lucidum, and Gynostemma pentaphyllum, are gathered and reviewed. In particular, the employment of these four plants in the context of CVDs, such as myocardial infarction, hypertension, peripheral vascular diseases, coronary heart disease, cardiomyopathies, and dyslipidemias has been reviewed, analyzed, and critically discussed. We also endeavor to document the recent studies aimed to dissect the cellular and molecular cardio-protective mechanisms of the four plants, using recently reported in vitro and in vivo studies. Finally, we reviewed and reported the results of the recent clinical trials that have been conducted using these four medicinal herbs with special emphasis on their efficacy, safety, and toxicity.
Cardiovascular diseases (CVDs) are diseases of the heart or blood vessels. CVDs register a global annual toll of more than 17 million deaths. As a result, CVDs remain the world's most common cause of death and are a major economic and health burden, worldwide. The World Health Organization (WHO) reported that CVDs account for 31% of annual global deaths (World Health Organization, 2017). In Europe, CVDs account for 45% of all deaths according to the European Cardiovascular Disease Statistics 2017 (Martinet et al., 2019). The American Heart Association's current statistics estimate that around half of the population of the USA has a form of CVD (Benjamin et al., 2019).
CVDs are a variety of diseases including peripheral vascular diseases, coronary heart disease (CHD), heart failure, heart attack (myocardial infarction), stroke, cardiomyopathies, dyslipidemias, and hypertension, among others (Figure 1) (Toth, 2007; Reiner et al., 2019). CVDs majorly originate from a vascular dysfunction, which then leads to organ damage. For example, the heart can suffer a heart attack, or the brain can suffer a stroke due to vascular impairment. Major culprits in vascular impairment include atherosclerosis, thrombosis, and high blood pressure (BP). Common risk factors for CVDs include smoking, unhealthy diet, diabetes mellitus, hyperlipidemia, elevated levels of low-density lipoprotein cholesterol (LDL), suppressed levels of high-density lipoprotein cholesterol (HDL), and hypertension (Figure 1) (World Health Organization, 2017).
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Figure 1 Pathological processes involved in the development and progression of CVDs. Several risk factors can predispose to CVDs. These can include hypertension, smoking, dyslipidemia stemming from an unhealthy diet, or endocrinopathies like diabetes mellitus, hypothyroidism, and aging. The risk factors can lead to pathological alterations most of which can be due to endothelial dysfunction or VSMC alterations. Endothelial dysfunction or VSMC alterations increase the risk of developing atherosclerosis and hypertension. Atherosclerosis and hypertension are themselves CVDs risk factors and enhancers for the development of other CVDs like myocardial infarction, coronary artery diseases, or stroke. VSMC, vascular smooth muscle cell; ECM, extracellular matrix; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; Ox-LDL, oxidized low-density lipoprotein.
CVDs prevention is favored by a healthy vascular endothelium. A healthy endothelium exhibits vasodilatory, anti-atherogenic, and anti-inflammatory properties (Celermajer, 1997). Several risk factors for CVDs lead to endothelial cell (EC) dysfunction, which has been implicated as a key event in the pathogenesis of atherosclerosis, coronary vasoconstriction, and, probably, myocardial ischemia. Interestingly, EC dysfunction is a reversible phenomenon, which opens the door for CVD therapies based on its reversion (Figure 1) (Celermajer, 1997).
Recently, inflammation has been confirmed as a risk factor for CVDs, especially during atherosclerosis and coronary artery disease. High levels of high-sensitivity C-reactive protein (hs-CRP) and/or interleukin-6 (IL-6) are associated with higher absolute cardiovascular risk (Ridker et al., 1997; Ridker et al., 2000), where the CANTOS study, for the first time, established reduced rates of cardiovascular events following an anti-interleukin-1 beta (IL-1β) based therapy, independent of cholesterol levels (Ridker et al., 2017). Furthermore, common CVDs risk factors, such as diabetes or hypertension, can predispose to CVDs by the mediation of inflammation (Dokken, 2008; Aday and Ridker, 2018).
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In the case of atherosclerosis, for example, inflammation can cause EC functional impairment. Dysfunctional ECs allow the accumulation of low-density lipoprotein (LDL) particles in the vessel wall intima where they become modified into oxidized LDL. Oxidized LDL can then activate the dysfunctional ECs to expose cell adhesion molecules (VCAM-1 and ICAM-1) that bind to and recruit inflammatory leukocytes (T-cells and monocytes) into the subendothelial space (Davies et al., 1993; Moore and Tabas, 2011). These inflammatory blood cells secrete interleukins and cytokines, produce reactive oxygen species (ROS) and thus form an inflamed microenvironment within the arterial wall. The inflamed microenvironment promotes vascular smooth muscle cell (VSMC) proliferation, matrix build-up, and lipid deposition, leading to the formation of an atherosclerotic plaque. The monocytes can reach the intima of the vessel, differentiate into macrophages, and uptake oxidized LDL to become foam cells (Tabas et al., 2007; Moore and Tabas, 2011; Douglas and Channon, 2014; Saleh Al-Shehabi et al., 2016; Martinet et al., 2019). Gradual intimal thickening takes place over the years and continues to expand causing decreased or complete occlusion of blood flow to organs, ultimately resulting in CVDs, such as myocardial infarction or stroke (Maguire et al., 2019). In addition, VSMCs proliferation leads to narrowing of the arterial lumen and dysregulation of the vasotone (Douglas and Channon, 2014). Usually several atherosclerotic plaques form in the intima and one of these may end up undergoing a necrotic breakdown, leading to acute luminal thrombosis, blood vessel occlusion, and cardiovascular complications, including myocardial infarction, unstable angina (chest pain caused by heart muscle ischemia), sudden cardiac death, or a stroke (Virmani et al., 2002). As a result, atherosclerosis is not only a risk factor but also a major contributor to CVD incidence. Around 50% of all deaths in developed countries are due to atherosclerosis (Tedgui and Mallat, 2006).
Hypertension also referred to as high BP, is a CVD and a major risk factor and contributor to other CVDs and other diseases (2017). Hypertension is an independent predisposing factor for heart failure, coronary artery disease, stroke, retinopathy, nephropathy, and peripheral arterial diseases (Sawicka et al., 2011; NCD Risk Factor Collaboration, 2017). Most of these diseases are associated with high mortality and morbidity (Abegaz et al., 2017). Additionally, hypertension is the single most significant risk factor for atherosclerosis, and any clinical outcome of atherosclerosis thereof (Sawicka et al., 2011). Hypertension is a “silent killer” as it does not show symptoms until later stages of the disease (Sawicka et al., 2011). Because of this, it is not surprising that hypertension affects 1.4 billion people and accounts for about 9.4 million deaths per year (Cooper et al., 2017; Egan et al., 2019). Lastly, hypertension prevalence is estimated to have a 30% worldwide increase by 2025 (Kearney et al., 2005).
The American Heart Association Hypertension Guidelines define hypertension as a persistent elevation of BP in the arteries [systolic BP (SBP) higher than 130/diastolic BP (DBP) higher than 80 mm Hg] (Muntner et al., 2018). If an elevated BP is left unmanaged, it can induce arterial remodeling; the walls of small vessels thicken, and the vessels lose their elasticity and become narrower. This process is called arteriosclerosis and can lead to “target organ damage” (TOD) (Triantafyllidi et al., 2010; Fan et al., 2017). TOD affects several organs such as the brain, kidney, or retina and may lead to death (Mensah, 2016; Abegaz et al., 2017). Arteriosclerosis can be witnessed in coronary vessels where it may cause a myocardial infarction (Rakugi et al., 1996). In the brain, arteriosclerosis can cause vessel lumen narrowing, vessel wall hardening, and blood clot formation, potentially causing a stroke (Johansson, 1999). Strokes have effects on cognitive and physical behaviors, and may result in dementia, paralysis, or death (Abegaz et al., 2017). Nephrosclerosis of the kidney is also due to arteriosclerosis which stiffens the nephron, ultimately affecting renal filtration and causing electrolyte imbalances (Bidani and Griffin, 2004; Lim et al., 2016). Overall, TOD proceed through hypertension-induced microvascular injuries in the cases of retinopathy and nephropathy and through hypertension-induced macrovascular injuries in the cases of stroke and myocardial
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