The Role of Essential Oils and Their Main Compounds in the Management of Cardiovascular Disease Risk Factors

Cardiovascular diseases (CVDs) are a global health burden that greatly impact patient quality of life and account for a huge number of deaths worldwide. Despite current therapies, several side effects have been reported that compromise patient adherence; thus, affecting therapeutic benefits. In this context, plant metabolites, namely volatile extracts and compounds, have emerged as promising therapeutic agents. Indeed, these compounds, in addition to having beneficial bioactivities, are generally more amenable and present less side effects, allowing better patient tolerance. The present review is an updated compilation of the studies carried out in the last 20 years on the beneficial potential of essential oils, and their compounds, against major risk factors of CVDs. Overall, these metabolites show beneficial potential through a direct effect on these risk factors, namely hypertension, dyslipidemia and diabetes, or by acting on related targets, or exerting general cellular protection. In general, monoterpenic compounds are the most studied regarding hypotensive and anti-dyslipidemic/antidiabetic properties, whereas phenylpropanoids are very effective at avoiding platelet aggregation. Despite the number of studies performed, clinical trials are sparse and several aspects related to essential oil’s features, namely volatility and chemical variability, need to be considered in order to guarantee their efficacy in a clinical setting.


Introduction
Cardiovascular diseases (CVDs) continue to impact global health, as demonstrated by World Health Organization (WHO) reports, which show that CVDs account for 31% of total deaths worldwide [1]. The onset and progression of these disorders is highly dependent on several risk factors (Figure 1), aging being one of the most important. Moreover, by 2030, it is expected that 20% of the world s population will be older than 65 years and CVDs will account for 40% of deaths in the elderly [2]. Besides aging, other non-modifiable risk factors, such as gender or genetic predisposition, play important roles in the onset of CVDs [1,3]. Furthermore, a family history of heart-related problems can lead to individuals developing CVDs, and genetic predisposition to other pathological conditions, such as type 2 diabetes, hypertension, or obesity increase the risk of CVD events [3]. Moreover, socioeconomic status and ethnicity are implicated in CVDs [3]. For example, individuals from African and Asian ethnicities have a higher risk of developing CVDs [4]. In addition to these risk factors, modifiable ones, such as hypertension, dyslipidemia, diabetes, obesity, smoking, alcohol misuse, unhealthy diet, sedentary lifestyle, and psychosocial factors are relevant and play determinant roles [5]; they are also included on the WHO target list to be reduced by 2025 [6]. The INTERHEART case-control study noted that 90% of acute myocardial infarction cases are due to these risk factors. Strikingly, controlling or eliminating them could, per se, lead to a drastic decrease in CVD mortality [7,8], strengthening the importance of new strategies to decrease the prevalence of these risk factors.
It was reported that non-adherence to therapeutics occurs in 60% of CVD patients [9]. To decrease this trend, new therapeutic and/or preventive strategies with less side effects are imperative. In this scenario, natural products, particularly aromatic and medicinal plants, have emerged as promising agents to tackle cardiovascular disorders and associated risk factors. Despite the development of synthetic drugs, herbal medicines continue to be the source of basic healthcare for around 80% of the world's population [10], thus pointing out their huge bioactive potential. Currently, herbs are used in the treatment of several chronic and acute conditions, including CVDs [11]. Their beneficial potential is also evidenced by the Mediterranean-style diet, which is embraced worldwide due to its reported health benefits, directly on CVDs or indirectly by reducing associated risk factors, such as cholesterol [12]. Furthermore, the European Medicines Agency (EMA) has 11 monographs approved for the use of herbal medicines in circulatory disorders [13]; thus, reinforcing their potential. The beneficial effects of herbal medicines are mainly attributed to their secondary metabolites [14], which are used in drug development, directly as therapeutic agents, or as starting materials and models for the synthesis of other drugs [11]. Secondary metabolites include phenolic compounds, terpenes, and alkaloids, among other classes [15]. Low molecular terpenes namely, monoterpenes (C10H16) and sesquiterpenes (C15H24) are the main compounds of essential oils. According to the International Standard Organization on Essential Oils (ISO 9235: 2013) [16] and the European Pharmacopoeia [17], an essential oil is defined as the product obtained from plant raw material by hydrodistillation, steam distillation, or dry distillation, or by a In addition to these risk factors, modifiable ones, such as hypertension, dyslipidemia, diabetes, obesity, smoking, alcohol misuse, unhealthy diet, sedentary lifestyle, and psychosocial factors are relevant and play determinant roles [5]; they are also included on the WHO target list to be reduced by 2025 [6]. The INTERHEART case-control study noted that 90% of acute myocardial infarction cases are due to these risk factors. Strikingly, controlling or eliminating them could, per se, lead to a drastic decrease in CVD mortality [7,8], strengthening the importance of new strategies to decrease the prevalence of these risk factors.
It was reported that non-adherence to therapeutics occurs in 60% of CVD patients [9]. To decrease this trend, new therapeutic and/or preventive strategies with less side effects are imperative. In this scenario, natural products, particularly aromatic and medicinal plants, have emerged as promising agents to tackle cardiovascular disorders and associated risk factors. Despite the development of synthetic drugs, herbal medicines continue to be the source of basic healthcare for around 80% of the world's population [10], thus pointing out their huge bioactive potential. Currently, herbs are used in the treatment of several chronic and acute conditions, including CVDs [11]. Their beneficial potential is also evidenced by the Mediterranean-style diet, which is embraced worldwide due to its reported health benefits, directly on CVDs or indirectly by reducing associated risk factors, such as cholesterol [12]. Furthermore, the European Medicines Agency (EMA) has 11 monographs approved for the use of herbal medicines in circulatory disorders [13]; thus, reinforcing their potential. The beneficial effects of herbal medicines are mainly attributed to their secondary metabolites [14], which are used in drug development, directly as therapeutic agents, or as starting materials and models for the synthesis of other drugs [11]. Secondary metabolites include phenolic compounds, terpenes, and alkaloids, among other classes [15]. Low molecular terpenes namely, monoterpenes (C 10 H 16 ) and sesquiterpenes (C 15 H 24 ) are the main compounds of essential oils. According to the International Standard Organization on Essential Oils (ISO 9235: 2013) [16] and the European Pharmacopoeia [17], an essential oil is defined as the product obtained from plant raw material by hydrodistillation, steam distillation, or dry distillation, or by a suitable mechanical process (for Citrus fruits). This definition excludes other aromatic products obtained by different extractive techniques, such as extraction with apolar solvents (concretes and absolutes). In some essential oils, phenylpropanoids, fatty acids, and their esters, as well as nitrogen and sulfur derivatives, are also present [18]. Bearing in mind the bioactive potential of these volatiles, the present review gathers a systematized compilation of the effects of essential oils and their compounds on major CVD risk factors, namely hypertension and dyslipidemia/diabetes. Moreover, other related beneficial effects are presented. In each section, a general consideration is included, followed by a compilation of the main studies, pointing out these effects. Then, mechanisms underlying the observed effects are referred, as well as the composition-activity relations reported in the cited paper or attempted by the authors of the present review. For this purpose, a bibliographic search was conducted using PubMed, Scopus, and Google Scholar databases, combining the keywords "essential oil", "terpene" or "phenylpropanoid" with "cardiovascular", "diabetes", "obesity", "dyslipidemia", "hypertension" or "vasorelaxation". Studies published over the last 20 years were considered; a total of 144 publications reporting these effects are included in the present review.

General Considerations
Hypertension mainly affects people from developed countries; its high prevalence (45% of general population) is attributed to poor lifestyle and behavioral habits, particularly diet, abusive consumption of alcohol, physical inactivity, and stress [19]. Elevated blood pressure is a red flag as it closely relates to an increased risk of heart disease [20]. Moreover, the majority of hypertensive patients concomitantly present other risk factors, increasing their risk of developing CVDs [21]. In the Framingham Heart Study, 80% of the enrolled hypertensive patients had at least one coexisting risk factor, whereas 55% of them had two or more risk factors [22]. These numbers are quite alarming, as it was shown that, in patients who have hypertension associated with other risk factors, the risk for CV events increases exponentially rather than the sum of individual risks [21]. Indeed, in prehypertensive individuals, the 10-year absolute risk for CVDs increases by 10%; however, when diabetes is also present, this risk increases by 40% [23].
Therapy relies on the use of drugs that usually control hypertension and decrease blood pressure; being the most frequently used diuretics, β-blockers, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). However, approximately 35% of hypertensive patients discontinue their medication within 6 months, and in about 50% of the cases, adverse effects are present [24]. These facts reveal an urgent need for more effective and amenable antihypertensive agents that would increase patient compliance and reduce the socioeconomic burden associated with hypertension, mainly in developed countries.

Hypotensive Essential Oils
Several studies show the antihypertensive potential of essential oils by assessing their effects in both normotensive and hypertensive pre-clinical models. In these models, hypertension is generally induced by deoxycorticosterone acetate (DOCA)-salt administration or nephrectomy. Moreover, since vasoconstriction is one of the major players associated with hypertension [25,26], the vasorelaxant effects of these extracts are frequently assessed. For vasorelaxation studies, ex vivo models are preferred, namely aortic rings (pre)contracted with different vasoconstrictor agents, such as phenylephrine (Phe) or high potassium concentrations. Table 1 summarizes the reported effects, with the studies being grouped according to the model used (in vitro, in vivo, or clinical trials).  BaCl 2 -barium chloride; CaCl 2 -calcium chloride; Ca 2+ -calcium ion; DBP-diastolic blood pressure; DOCA-deoxycorticosterone acetate; EC 50 -half maximum effective concentration; E max -ventricular end-systolic maximum elastance; EO-essential oil; HR-heart rate; IC 50 -concentration needed to achieve 50% of relaxation; K + -potassium ion; KCl-potassium chloride; L-NAME-N(G)-nitro-L-arginine methyl ester; MAP-mean arterial pressure; PGF 2α -prostaglandin F 2α ; Phe-phenylephrine; SBP-systolic blood pressure.
For the majority of the reported studies, the mechanisms by which the extracts exerted their beneficial effects were not disclosed. Nevertheless, in some cases, a more detailed study was performed, providing insight on possible underlying mechanisms. For example, the essential oils from Croton zehntneri induced hypotension that was abolished in the presence of capsaicin, a vanilloid receptor subtype 1 (TRPV1) inhibitor [77], suggesting that the essential oil might modulate this receptor s activity [42]. The hypotensive and tachycardic effects reported for Croton argyrophylloides seem dependent on the parasympathetic nervous system, particularly on the muscarinic acetylcholine receptors, since both effects were reduced in the presence of methylatropine. In addition, the essential oil seems to act on the sympathetic system, especially on the nicotinic acetylcholine receptor, since the tachycardic effect was transformed into bradycardia upon hexamethonium pretreatment [67]. Similarly, the bradycardic effect of Ocimum gratissimum seems to depend on both parasympathetic and sympathetic systems since the effect was reduced by bilateral vagotomy or with methylatropine and hexamethonium, respectively [72]. Similar effects were observed for the essential oils of Mentha x villosa [48,49,68]. Furthermore, the effects observed on anesthetized rats treated with the essential oil from Aniba rosaeodora var. amazonica seems dependent on both the parasympathetic nervous system and vanilloid receptors since both effects were reduced by bilateral vagotomy or pretreatment with capsaicin, respectively. Opposingly, the administration of this oil to conscious rats was only dependent on the parasympathetic nervous system [64]. Similarly, the activity induced by the oil from Aniba canelilla is dependent on the parasympathetic nervous system, as well as on the nitric oxide (NO) axis [32]. Artemisia campestris' essential oil seems to induce vasorelaxation via modulation of L-type Ca 2+ -channels and the activation of SERCA pumps [33]. The essential oil from Pectis brevipedunculata induces a vasorelaxant effect dependent on the NO/cyclic guanine monophosphate (cGMP) pathway since the pretreatment with L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor [78], decreased the observed relaxation [54]. The activity reported for the oil from Trachyspermum ammi is dependent on the extracellular Ca 2+ flux, since pretreatment with nifedipine, a calcium channel blocker [79], reduced its activity [59]. The vasorelaxation induced by the essential oil from Allium macrostemon seems to be due to the phosphorylation of eNOS via intracellular Ca 2+ /protein kinase A (PKA)/eNOS pathway [27]. The activity of another oil characterized by sulfur-containing compounds, namely Ferula asafoetida, also appears to be dependent on NOS activity, since the presence of L-NAME partially abolished the reported effect. In addition, the activity seems to be mediated by prostaglandin activity since indomethacin, a COX inhibitor [80], reduced the vasorelaxation induced by the essential oil [44].

Composition-Activity Relation
Essential oils are generally complex mixtures of several compound and it is known that their biological properties are, many times, due to synergistic effects between compounds [81] and/or the presence of active major/minor compounds. In this section, we present studies performed on isolated volatile compounds retrieved during the bibliographic search, in an attempt to identify putative active compounds present in the essential oils, and highlight possible composition-activity relations for the extracts compiled in Table 1.
For some of the essential oils compiled in Table 1, a composition-activity relation was highlighted. For example, the hypotensive effect reported for Alpinia zerumbet can be associated with the presence of high amounts of terpinen-4-ol and 1,8-cineole [62]. However, the vasorelaxant activity of this essential oil cannot be fully attributed to the presence of 1,8cineole, since the compound elicits a full relaxation whereas the essential oil only elicited a partial one [29]; thus, suggesting an antagonistic effect of other compounds present in the mixture. Moreover, the hypotensive potential of Mentha x villosa essential oil is greater in samples with higher amounts of piperitenone oxide [68]; thus, suggesting that this compound is the main active compound in the essential oil. The monoterpene α-pinene was reported as a smooth muscle relaxant [112]; it may be responsible for the vasorelaxant effect observed for Hyptis fruticosa essential oil that presents high amounts of this compound [46]. Moreover, the vasorelaxant activity of Citrus aurantium var. amara can be explained by the presence of linalool, since this compound elicits a relaxant activity dependent on the NO/cGMP pathway [35]. The oil of bergamot (Citrus bergamia) also elicited a vasorelaxant effect that can be partially explained by the presence of linalool and linalyl acetate [36]. Croton nepetaefolius essential oil's vasorelaxant activity might be due to the presence of 1,8cineole and α-terpineol [40]. The reported activity of Croton zehntneri and Foeniculum vulgare is related to the presence of anethole and estragole, since both compounds were widely reported as having hypotensive and vasorelaxant activities [42,65,103]. Although eugenol was reported as having similar effects to those of Ocimum gratissimum oil, this volatile mixture also contains 1,8-cineole, which might contribute to the activity of the essential oil. The activity of Ocotea quixos oil can be attributed mainly to cinnamaldehyde, since it had a stronger activity than the whole essential oil. Contrarily, methyl cinnamate had a weaker activity than the extract [53]. Allium macrostemon's major compound dimethyl trisulfide showed a vasoconstrictor activity whereas dimethyl disulfide had a preeminent vasodilator effect. Therefore, the activity described for Allium macrostemon is attributed mainly to dimethyl disulfide rather than to its major compound [27]. Pectis brevipedunculata exerted a vasorelaxant effect that may be attributed to the presence of citral, a mixture of neral and geranial, since these compounds alone are able to induce vasorelaxant effects, although to a lesser extent than that of the volatile extract [54]. In this case, the activity of the extract may have the contribution of geraniol, the other major compound of P. brevipedunculata, with both vasorelaxant and hypotensive activities reported [88].

General Considerations
Lipoprotein functions and/or levels associated with CVDs are often caused by a disturbance of lipid metabolism [113]. Although dyslipidemia includes a wide spectrum of lipids, the most widely studied (and implicated in CVDs) are the increased levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Indeed, high saturated and trans-fat-diets lead to high levels of cholesterol and increase the risk of heart disease and stroke [114]. Furthermore, increased blood cholesterol, particularly low-density lipoprotein cholesterol (LDL-C) and nonhigh-density lipoprotein cholesterol (non-HDL-C) are associated with higher mortality and odds of atherosclerotic cardiovascular disease [115]. In the presence of other factors, such as high blood pressure and tobacco use, the cholesterol-associated risk increases [116][117][118][119][120][121][122]. Therefore, compounds that impact on the levels of these lipids, either by inhibiting their absorption in the gut, such as phytosterols that inhibit cholesterol's metabolism [123], or by modulating the activity of lipid metabolism enzymes, such as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA), acyl CoA acyltransferase (ACAT), and sterol regulatory element-binding protein (SREBP) [124,125], are good candidates for lipid-lowering agents.
Another very important risk factor for CVDs is diabetes mellitus (DM), which is characterized by elevated blood glucose [122]. A meta-analysis showed that individuals with diabetes have a higher prevalence of CVDs when compared to non-diabetic ones [126], this risk being positively correlated with fasting blood glucose levels [127]. Indeed, in a 7-year follow-up, individuals with type 2 diabetes, with a history of acute myocardial infarction, had 42% death rate, whereas in cases where no history was found, this rate decreased to 15.4%. For non-diabetic individuals, these values were 15.9% and 2.1%, respectively [128]. Furthermore, diabetes also leads to an increase in free fatty acids (FFA) levels; thus, contributing to dyslipidemia [129]. Diabetes can be controlled through nonpharmacological approaches, including exercise, diet, and other lifestyle adaptations. In more severe cases, a pharmacological approach is required with the use of drugs that modulate glucose metabolism, such as metformin, glucagon-like peptide 1 (GLP1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sodium glucose co-transporter 2 (SGLT2) inhibitors [122,130]. In the following section, the effect of essential oils on dyslipidemia and diabetes is presented together, as many studies address these risk factors in parallel.
To the best of our knowledge, only one study assessed the mechanism underlying the antidiabetic/anti-dyslipidemic effects of essential oils. Indeed, turmeric (Curcuma longa) essential oils seem to ameliorate the oxidative stress and liver dysfunction elicited by a high fat diet, through modulation of the peroxisome proliferator-activated receptor α, liver X receptor α, and associated genes involved in lipid metabolism and transport [139].

Composition-Activity Relation
Several studies assessed the antidiabetic and/or anti-dyslipidemic potential of isolated compounds present in essential oils. For example, thymol was able to improve the lipid profile and blood glucose levels in mice with type 2 diabetes mellitus induced by a high fat diet [145]. Its isomer, carvacrol, had a similar effect in diabetic mice submitted to high fat diet, and in addition, an improvement in the associated inflammatory profile was observed [146]. Geraniol ameliorated the lipid profile on NIH nu/nu mice as well as the expression of receptors and enzymes associated with lipid metabolism [147]. In atherogenic diet-fed Syrian hamsters, geraniol had a similar effect [148]. The administration of camphene on hyperlipidemic rats improved their lipid profile [149]. Linalool seems to affect LDL metabolism by decreasing its oxidation, as well as increasing the affinity to LDL receptor [150]. β-Caryophyllene improved blood glucose, lipid profile, as well as the antioxidant system on streptozotocin-induced diabetes [151][152][153]. In rats fed highfat/fructose diets, this terpene had a similar effect [154,155]. It also increased hemoglobin levels with an accompanying decrease in glycated hemoglobin and restored the activity of glycolytic and lipogenic enzymes [156]. These activities are associated with the binding to type 2-cannabinoid receptor (CB2R) and with the activation of Arf6, a small G protein, in a dose-dependent manner, promoting glucose-induced insulin secretion [157]. Similarly, thujone improved the lipid profile on alloxan-induced diabetes [158], as well as fasting blood glucose in streptozotocin-induced diabetes [159,160]. The antidiabetic potential of thujones can be attributed to the inhibition of GLUT4 translocation mediated by AMPK phosphorylation and to the restoration of the phosphorylation levels of Akt, GSK-3β, and glycogen synthase [159,160]. β-asarone also improved blood glucose levels and glucose tolerance in high fat diet-induced obesity in rats [161]. In the same model, this compound improved the lipid profile and the antioxidant defense system [162]. On methylisobutylxanthine, dexamethasone, insulin (MDI)-induced 3T3-L1 differentiation, β-asarone decreased lipid droplets in a dose-dependent manner, as well as the expression of differentiation markers, and improved the lipid profile [131]. Furthermore, this compound improved the lipid profile in cholesterol-fed rats and decreased the atherogenic index [163]. Eugenol greatly improved the lipid profile in atherogenic diet-fed rats. Furthermore, it ameliorated the activity of lipid metabolism-associated enzymes, namely HMG-CoA and lipase, and improved the antioxidant system [164]. Similar effects were observed on tritoninduced hyperlipidemic rats [165] and microemulsions of eugenol were able to improve the lipid profile in high fructose-induced dyslipidemia [142]. Cinnamaldehyde decreased nitrotyrosine and ROS production by increasing the expression of Nrf2 with concomitant increase of associated antioxidant genes [166].
Some studies correlated the anti-dyslipidemic effect of essential oils with their main compounds. It was shown that linalool seems to be responsible for Plantago asiatica essential oil's effect [135]. Moreover, the anti-dyslipidemic activity of Pinus koraiensis essential oil seems to be partially explained by the anti-dyslipidemic activity of camphene, its major compound, although the authors also suggest a synergistic effect with other compounds [134]. The reported activity for Acorus calamus might be attributed to the presence of β-asarone, since this compound had an activity similar to that of the essential oil in the same experimental model [131]. However, the observed effect might also be attributed to the presence of cinnamaldehyde, since this phenylpropanoid was reported as having anti-dyslipidemic effects [166]. This compound might also contribute to the activity of Cinnamomum tamala due to the high amount found in the essential oil. Similarly, the high amount of thujone found in the essential oil from Salvia officinalis might explain the antidiabetic effects reported, since this compound showed blood glucose lowering effects in STZ-induced diabetes [159,160]. Moreover, eugenol, widely reported as having antidyslipidemic effects [164,165], might be responsible for the activity observed for Syzygium aromaticum due to its high content in the essential oil.

Antiplatelet Effect General Considerations
Platelet aggregation is fundamental in physiological conditions to prevent hemorrhaging. However, in pathological conditions, platelets can hyperaggregate leading to the formation of thrombus [167]. This hyperaggregability is caused by an overproduction of proaggregatory factors and/or a sub-production of antiaggregatory agents. Several risk factors for CVDs, such as hypertension, tobacco, and diabetes, can induce platelets hyperactivation [168]. This can lead to myocardial infarction and stroke [168][169][170]. To avoid this, antiplatelet drugs are used, namely acetylsalicylic acid, clopidogrel and glycoprotein IIb/IIIa inhibitors. Despite their wide use, the response of patients to therapy shows great variability due to gene polymorphisms as well as clinical and/or environmental factors [171]. Therefore, new antiplatelet aggregation agents are required to improve the overall response to therapy.

Essential Oils with Antiplatelet Effects
In this context, the majority of the studies assess the capacity of the essential oils to inhibit platelet aggregation induced by several clotting agents in platelet-rich plasma. Nevertheless, pre-clinical models of thromboembolism that allow assessing the capacity of the extract to prevent death and paralysis events have also been used, although in less extend. Table 3 summarizes the anticoagulant capacity of several essential oils, organized according to the type of studies performed. Table 3. Essential oils with antiplatelet aggregation capacity.
Overall, the essential oils in Table 3 are able to modulate the arachidonic acid cascade, since most of them inhibited platelet aggregation induced by arachidonic acid and collagen. However, other mechanisms also seem to play an important role since some of these extracts inhibited the aggregation induced by adenosine diphosphate (ADP), 4β-phorbol-12-myristate-13-acetate (PMA), and thromboxane A 2 agonist, without showing a prohemorrhagic potential, unlike acetylsalicylic acid, a widely used anticoagulant drug [45,53].
The antiaggregatory effects of Foeniculum vulgare seem to be due to the presence of high amounts of anethole in the oil, since this compound showed an activity similar to that of the whole oil [45].

Ion Channel Modulator Effect General Considerations
Calcium is relevant in several physiological and pathological situations in different organ systems [124]. In the cardiovascular system, calcium is a messenger in muscle contractility as well as in platelet aggregation. In addition, in some pathologies, the intracellular calcium release during diastole is impaired, thus decreasing the relaxation needed for the correct functioning of the heart [125]. Furthermore, high extracellular concentrations of this ion are associated with an increased risk of CVDs. Therefore, compounds that are able to maintain an adequate intracellular amount of calcium are important for a correct heart function.

Essential Oils with Ion Channel Modulation Capacity
Studies assessing the effect of essential oils on ion channel modulation are scarce and only in vitro models were used. Table 4 compiles the few available studies on the capacity of essential oils to maintain calcium homeostasis. In what concerns the mechanism underlying the calcium channels modulation effects, only one study addresses this topic. Indeed, the essential oil from Citrus aurantium L. var. amara seems to modulate intracellular Ca 2+ concentration via inhibition of channel-mediated extracellular Ca 2+ influx and store-operated Ca 2+ release mediated by the ryanodine receptor (RyR) signaling pathway [35].

Composition-Activity Relation
The ion modulation activity of several isolated compounds was reported as well. Indeed, thymol and carvacrol inhibited the L-type Ca 2+ current [177]. In addition, thymol suppressed the activity of Ca 2+ and K + channels [178] and triggered the release of Ca 2+ from the sarcoplasmic reticulum while blocking the activity of Ca 2+ pumps [179]. Similarly, carvacrol inhibited the Ca 2+ influx by L-type Ca 2+ -channels [94] and increased the intracellular Ca 2+ concentration [180]. Moreover, 1,8-cineole was able to decrease the contractility of left ventricular papillary muscles by reducing the sarcolemmal Ca 2+ influx [91]. Linalool and linalyl acetate decreased Ca 2+ influx [83,175]. β-Caryophyllene oxide, a sesquiterpenic compound, inhibited both Ca 2+ and K + currents [181] and eugenol inhibited the L-type Ca 2+ current [177]. The same effect was also reported for cinnamaldehyde [182].
The effect of Alpinia speciosa is linked to the presence of 1,8-cineole. Nevertheless, terpinene-4-ol [183] and γ-terpinene [184] have caused relaxation in non-cardiac muscles in a Ca 2+ dependent manner; thus, suggesting that these compounds might also contribute to the activity of the whole essential oil [28]. The effect of Citrus aurantium var. amara essential oil appears to be dependent on the presence of linalool, since the essential oil, similarly to the isolated compound, blocks Ca 2+ influx [35]. Citrus bergamia ion channel modulation seems to be due to the presence of linalyl acetate; however, other compounds may play a role, since the isolated compound had a weaker activity compared to the essential oil [175].

Other Beneficial Cardiovascular Effects
In addition to the reported effects of the essential oils on major modifiable risk factors for CVDs and related targets, other beneficial effects, such as the induction of cell proliferation under nefarious conditions, can also contribute to decrease the burden of CVDs. Therefore, other beneficial effects were considered, as compiled in Table 5. Almost all of the presented studies were carried out in vitro, with the exception of one that assessed the heart function in a pre-clinical model.

Composition-Activity Relation
To the best knowledge of the authors, no studies comparing the activity of the essential oils with that of the isolated compounds were conducted for the effects reported in Table 5. Therefore, this section will only present the reported activities of isolated volatile compounds present in essential oils.
For example, farnesol, an acyclic sesquiterpene alcohol, was able to decrease infarct size after ischemia/reperfusion (I/R) events and prevented cell death in isolated cardiomyocytes, after simulated I/R [186]. Carvacrol decreased rat aortic smooth muscle cells migration, and proliferation associated with platelet-derived growth factor (PDGF). Furthermore, it decreased ROS production and the phosphorylation of ERK1/2 and p38 MAPK. In addition, this compound also inhibited the outgrowth of aortic sprouts as well as neointima formation [187]. Borneol increased cell viability on hypoxia/reoxygenation-stimulated cardiomyocytes [188]. On an in vitro model of ischemia/reperfusion, eugenol increased cell viability of cardiomyocytes subjected to hypoxia/reoxygenation [188]. Eugenol reduced the acute cardiotoxicity elicited by doxorubicin [189] and on an isoproterenol-induced myocardial infarction model. This compound improved both hemodynamic function as well as histological markers associated with infarction [190]. These effects were also observed in isoproterenol-induced myocardial infarction animals after treatment with cinnamaldehyde or cinnamic acid [191]. On aortic banding-induced cardiac pressure overload, cinnamaldehyde improved heart function and decreased fibrosis. Furthermore, it normalized the expression of genes associated with hypertrophy (atrial and brain natriuretic peptides and β-myosin heavy chain) and prevented the activation of ERK1/2 [192]. On lipopolysaccharide (LPS)-stimulated rats, cinnamaldehyde improved cardiac function and decreased the inflammatory response [193]. α-Asarone treatment of angiotensin-II (Ang-II)-stimulated endothelial cells improved intracellular NO levels and decreased both ROS production and endothelial nitric oxide synthase (eNOS) phosphorylation [194].

Conclusions
The present review highlights the potential of essential oils and their compounds to decrease the burden of CVDs by targeting major associated risk factors and/or related targets. Despite the plethora of risk factors that lead to the development of CVDs, most of the studies using essential oils focus on hypertension, diabetes, and/or dyslipidemia/obesity. Nevertheless, other beneficial effects were also reported for these metabolites, namely avoidance of antiplatelet aggregation, modulation of ion channels, particularly calcium channels, as well as cellular protection against oxidative stress ( Figure 2). Although, several studies described the beneficial effects for some volatile compounds, most of them did not attempt a composition-activity relation, and the activity of several compounds remain unknown, thus limiting their applicability. Overall, monoterpenic compounds were the most studied regarding their hypotensive as well as antidiabetic/anti-dyslipidemic effects, whereas phenylpropanoids exceled on counteracting platelet aggregation. The essential oils from Alpinia spp. stood out as the most effective due to their broad effects on both CVDs major risk factors and related ion channels activity. Moreover, the essential oils from the genus Citrus were very effective hypotensive agents, and those from Foeniculum vulgare showed both antidiabetic and antiplatelet aggregation effects.

Conclusions
The present review highlights the potential of essential oils and their compounds to decrease the burden of CVDs by targeting major associated risk factors and/or related targets. Despite the plethora of risk factors that lead to the development of CVDs, most of the studies using essential oils focus on hypertension, diabetes, and/or dyslipidemia/obesity. Nevertheless, other beneficial effects were also reported for these metabolites, namely avoidance of antiplatelet aggregation, modulation of ion channels, particularly calcium channels, as well as cellular protection against oxidative stress ( Figure 2). Although, several studies described the beneficial effects for some volatile compounds, most of them did not attempt a composition-activity relation, and the activity of several compounds remain unknown, thus limiting their applicability. Overall, monoterpenic compounds were the most studied regarding their hypotensive as well as antidiabetic/antidyslipidemic effects, whereas phenylpropanoids exceled on counteracting platelet aggregation. The essential oils from Alpinia spp. stood out as the most effective due to their broad effects on both CVDs major risk factors and related ion channels activity. Moreover, the essential oils from the genus Citrus were very effective hypotensive agents, and those from Foeniculum vulgare showed both antidiabetic and antiplatelet aggregation effects. Although several in vitro and in vivo studies were performed over the last 20 years, clinical trials remain scarce and the majority focus on the hypotensive effects of essential oils. In these cases, the scientific name of the plant used, as well as its chemical characterization, are lacking, thus compromising a further exploitation for widespread use. In addition, Although several in vitro and in vivo studies were performed over the last 20 years, clinical trials remain scarce and the majority focus on the hypotensive effects of essential oils. In these cases, the scientific name of the plant used, as well as its chemical characterization, are lacking, thus compromising a further exploitation for widespread use. In addition, small groups of individuals from the same region were recruited and, therefore, the genetic variability was not taken into account, thus jeopardizing a potential use in a clinical setting.
Overall, despite the huge potential of essential oils in decreasing the burden of CVDs, additional studies are needed. For example, important features of these extracts need to be considered, namely their high volatility and hydrophobicity, which can compromise bioavailability and consequent therapeutic outcomes. Moreover, the chemical variability among samples from the same taxon can compromise therapeutic efficacy. Indeed, in aromatic plants, the composition of essential oils may vary, depending on both intrinsic (seasonal, ontogenetic, and genetic variations and part of the plant used) and extrinsic (ecological and environmental aspects) factors. For this reason, standardized oils need to be guaranteed to avoid this kind of variability.