Therapeutic Feasibility of the Natural Products in the Heart Complaints: An Overview

Medicinal plants with potential for the prevention and treatment of myocardial ischemia

Myocardial ischemia results from an imbalance in the blood flow of the heart, which leads to a decline in oxygen supply, ¹⁴ resulting in hypoxia, which disrupts oxidative metabolic pathways; cellular anaerobic pathways are activated, and mediators such as lactate are produced, which results in the sensation of pain (angina pectoris). Indeed, angina is closely related to coronary artery insufficiency, and it is one of the most common complaints encountered by emergency. The painful symptom has been considered the cardinal symptom of ischemic heart disease.

The evolution of the clinical feature can lead to MI, which occurs when the coronary artery occlusion by thrombus leads to severe myocardium ischemia resulting in irreversible injury and necrosis of the myocardium. ¹⁵ Although several classes of drugs relieve angina's pain and reduce lipid and cholesterol levels, alternative medicine is becoming popular, and the natural products that have cardiovascular protective activity are being highlighted. The medicinal plants with scientific studies reporting efficacy to reduce myocardial ischemic injury are displayed in Table 1.

Melissa officinalis L. is commonly known as “lemon-balm” and belongs to the Lamiaceae family. It is an aromatic herb native to southern Europe, Asia Minor, and North Africa. This plant's medicinal properties were first described by Dioscorides (40–90 AD)—the father of Pharmacology—in the Materia Medica. ¹⁶ It is already well established that M. officinalis has several biological activities, including antioxidant, hypoglycemic, hypolipidemic, anti-inflammatory, and spasmolytic properties. ^{17 –19} Javid et al. ²⁰ demonstrated that oral supplementation with M. officinalis had beneficial effects on biomarkers of lipid profiles, oxidative stress, and inflammation.

Aerial parts of M. officinalis were dried in the shade at room temperature for 12 days. Patients with chronic stable angina (CSA) received 3 g/day (3 capsules with 1 g each) of M. officinalis (n = 40) or 3 g/day (3 capsules) with placebo (n = 40) for 8 weeks. Seventy-three patients completed the trial where M. officinalis-treated group displayed reduced serum levels of malondialdehyde (an end product of lipid peroxidation), and high-sensitivity C-reactive protein, pointing out reduced oxidative stress and risk of heart attacks. Besides, M. officinalis group had a significant increase in paraoxonase 1 (PON1).

PON1 facilitates the antiatherogenic nature of HDL particles and regulates reverse cholesterol transport and several endothelial cell functions. Indeed, these patients also experienced reduced triglycerides (TG), total-cholesterol (TC), LDLc, and increased HDLc compared to the placebo group. ²⁰ The data showed that M. officinalis might be beneficial in CSA patients due to its lipid-lowering effects. However, the exact functional mechanism of M. officinalis concerning oxidative stress, inflammation, and lipid profile is unclear. Phytochemical investigations have revealed volatile compounds, triterpenes, phenolic acids, and flavonoids as the main active constituents of M. officinalis. ²¹

Besides, Joukar et al. ²² investigated the effects of the pretreatment with M. officinalis aqueous extract (50–100 and 200 mg/kg/day) for 7 days on the resistance of the myocardial injury induced by isoproterenol (ISO; 85 mg/kg on the sixth and seventh day) in rats. The lower tested dose of the extract (50 mg/kg) increased the heart resistance to cardiac injury, as evidenced by decreased malondialdehyde levels and improved balance of the injured hearts' redox system. However, the higher tested dose of the extract (200 mg/kg) intensified the injury of the ischemic heart (as evidenced by more elevated serum cardiac troponin I levels), possibly by increasing the cardiac contractility and myocardial oxygen demand. ²² Taking together, further studies are needed to assess the dose dependence of these effects, as well as randomized clinical studies with a larger number of patients.

Paeonia emodi Wall ex. Royle (common English name “Himalayan peony”) belongs to the Paeoniaceae family. This plant has been used for cardiac diseases such as hypertension, palpitations, congestive heart failure, and atherosclerosis. ²³

Ibrar et al. ²⁴ evaluated the possible cardioprotective effect of methanolic extract (Pe.ME) and fractions obtained from the rhizome of P. emodi in a model of ISO-induced MI in mice. The animals were pretreated with methanolic extract and fractions (500 mg/kg/day) or standard drug propranolol (10 mg/kg) for 15 days. On the 16th and 17th day, they received ISO (100 mg/kg) at an interval of 24 h for 2 days (except the normal group). Pe.ME and all fractions exhibited cardioprotective activity reducing serum levels of cardiac marker enzymes, being the ethyl acetate fraction (Pe.EA) the most potent among all the tested fractions.

The GC-MS analysis of Pe.EA confirmed the presence of esculetin, methyl eugenol, and isovanillic acid, which have been reported to be effective against cardiovascular diseases (CVDs). ²⁵ In addition, hyperlipidemia was induced by i.p. injection of 600 mg/kg of 30% (w/w) poloxamer 407 (P-407) to the mice. Pe.EA lowered the lipid levels in plasma in comparison to P-407 group. The atherogenic index and the serum levels of TC, LDLc, and TG were reduced in a dose-dependent manner, to an extent similar to the standard drug used (simvastatin 20 mg/kg). The authors also demonstrated that the fraction has a cardioprotective effect because it has cell membrane stabilizing activity and thrombolytic potential. Both results suggest the possibility of use in the treatment of MI of thrombotic origin.

Besides, Pe.EA protected against ISO-induced DNA damage and restored the injury at the cellular levels, effects that were comparable with those induced by propranolol. Toxicity studies confirmed the safe use of P. emodi in experimental animals. ²⁴ Indeed, ISO induces cardiac pathophysiological and morphologic alterations similar to those observed in acute MI in humans, producing tachycardia associated with relative ischemia due to an imbalance between increased myocardial oxygen demand and reduced coronary blood supply. ²⁶ Thus, the results above show that the extracts obtained from P. emodi have cardioprotective activity through several mechanisms that could be explored in depth.

Rosmarinus officinalis L. belongs to the Lamiaceae family and is commonly known as “rosemary.” Besides the culinary uses due to the characteristic aroma, it is also a medicinal plant used by the population. The extract obtained from rosemary has antioxidant activity, and its use is approved in the United States for food preservation. ²⁷ In addition, the leaves, berries, and flowers of Crataegus oxyacantha (Rosaceae family) have been used traditionally in various functional heart disorders. ²⁸

In this way, Cuevas-Durán et al. ²⁸ evaluated the effect of both species on rats subjected to MI. The ethanolic extracts of the R. officinalis (100 mg/kg/day) and Crataegus oxyacantha leaves (100 mg/kg/day) were administered to rats by 7 days. MI was induced by left anterior descending coronary artery (LAD) ligation. After 120 min of acute MI, the heart was cut out, and the ischemic area was separated to perform the analysis. The results showed that pretreatment with R. officinalis and C. oxyacantha increases the levels of SOD and CAT enzymes significantly. Moreover, after the ischemic event, the concentrations of endothelin-1 and angiotensin II have been found elevated in the infarcted area, and treatment with both extracts decreased their levels.

In addition, both treatments increased BH4:BH2 (tetrahydrobiopterin) ratio and nitric oxide (NO) levels that were decreased during the ischemic process. HPLC analysis showed that R. officinalis extract contains rosmarinic acid and carnosol, while C. oxyacantha extract exhibits rutin and quercetin. ²⁸ The present study demonstrated that R. officinalis and C. oxyacantha possess potent antioxidant effects and improve the balance between vasoconstrictor and vasodilator agents, leading to a decrease in the risk of CVDs.

Viscum album L., commonly known as “European mistleto,” belongs to the Santalaceae family and has been used in traditional medicine for its cardiotonic, vasodilating, tumor-inhibiting, thymus stimulating, and antispasmodic effects. ^29,30

Suveren et al. ³¹ demonstrated the effects of methanolic (MVa) and aqueous (AVa) extracts of V. album in a rat isolated heart model of coronary artery occlusion and reperfusion with infarct size as the end point of ischemia-reperfusion injury. Both extracts were prepared from dried leaves. Wistar male rats were subjected to ischemia-reperfusion protocol and MI. Briefly, hearts were excised and retrogradely perfused through the aorta on a Langendorff apparatus. Regional myocardial ischemia was induced by placing a reversible suture and snare occlude around the left descending coronary artery close to its origin. The heart was subjected to 35 min regional ischemia and then reperfused by releasing the coronary suture for 120 min.

Following reperfusion, the coronary artery was ligated to delineate the ischemic risk zone, and the hearts were perfused with Evans' Blue to stain the nonischemic tissue. To evaluate the extracts' activity, the hearts were perfused 10 min before the onset of coronary occlusion with AVa 1 or 10 mg/L and MVa 5, 10, or 20 mg/L, until 10 min after reperfusion. This study has not found any differences in heart rate between all groups after treatment with V. album extracts. The data showed that both treatments significantly reduced infarct size compared to control, with MVa in the lowest concentrations.

The results suggested NO participation in AVa and MVa effects, since the concomitant perfusion with L-NAME (a nonselective NO synthase inhibitor) abolished the protection afforded. Besides, glibenclamide abolished the protection induced by MVa extract, but did not annul the protection evoked by AVa, suggesting that its effect was independent of ATP-sensitive K⁺ channel function. However, toxicological effects must be investigated, since high doses of V. album (50 mg/mL) extract suddenly stopped the cardiac functions. ³¹

In accordance with these data, Karagöz et al. ²⁶ used a model of ISO-induced heart failure in male Wistar rats and confirmed that the upregulation of the NO pathway might mediate the cardioprotective effect of V. album, ameliorating cardiac hypertrophy and histopathological changes of the left ventricle. ²⁶ The cardiovascular effect of V. album may be related to its relaxing activity on smooth muscle. Khan et al. ³² showed that the crude extract and the ethanolic fraction of the V. album fruits had activity in smooth muscle.

Crude extract displayed an excellent spasmolytic activity and inhibited rabbit jejunum's spontaneous contractions, and both crude and ethanolic extract induced vasorelaxation in phenylephrine-induced contraction on rat aorta. The smooth muscle relaxant effect was mediated through voltage dependent Ca²⁺ channel blockade. The phytochemical analysis of V. album extracts revealed tannins, alkaloids, saponins, phenols, cardiac glycosides, flavonoids, steroids anthraquinone glycosides, and terpenoids.

Of all the species reviewed in this topic, V. album seems to be the most promising species as a source of new drugs or complementary therapies to treat cardiovascular disorders, since it has been tested in different chemical and mechanic models of MI with the elucidation of mechanisms of action involved. However, further studies on fractionation and isolation of main active compounds and the development of methods of standardization of the extracts are required.

Medicinal plants with antiarrhythmic potential

Arrhythmia, also known as cardiac arrhythmia, is an electric instability in the heart, in which the heartbeat is irregular. The most prevalent cardiac arrhythmia in the population is atrial fibrillation, marked by a failure to conduct electrical stimuli that cause the heart muscle to beat. ¹⁰ Moreover, it is one of the main cardiovascular disorders that lead to death in hypertensive patients. ³³ Other common conditions resulting from irregular heartbeat are the events of bradycardia (slow rhythm) or tachycardia (fast rhythm). ¹⁰

Although several antiarrhythmic agents have been used in the clinic, their action is limited by side effects. ^34,35 Therefore, medicinal plants are of great interest to this disorder and others that affect the cardiovascular system. According to Newman and Cragg, ³⁶ of the 17 new antiarrhythmic molecules discovered until September 2019, 1 molecule is of totally natural origin and 2 are synthetic drugs imitating a natural product. Some medicinal plants have been explored in different pharmacological models in vitro and/or in vivo to check for possible antiarrhythmic effects in recent years. Some of the plants that will be described in this topic are used worldwide, and others are used in some areas of the world. The medicinal plants with scientific studies reporting antiarrhythmic efficacy are mentioned in Table 2.

Zhou et al. ³⁷ investigated the effects of Arnebia euchroma (Royle) Johnst. (A.e.), a plant used in traditional Chinese medicine primarily to treat the blood-heat syndrome. In this work, a combination of acetylcholine and CaCl₂ was used to induce atrial fibrillation in male rats by injection into the caudal vein for 7 days. The aqueous extract from the roots of A. euchroma obtained by decoction was administered orally at a dose of 0.18 g/mL for 1 week before performing the atrial fibrillation model. Amiodarone (50 mg/kg) was used as the positive control. The experimental data were monitored by the electrocardiogram (ECG); besides, atrium histology was analyzed, and electrophysiological measurements were used to examine atrial size and function.

The results indicated that A. euchroma extract decreased atrial fibrillation, reduced atrial fibrosis, and improved cardiac function. These findings demonstrate the possible cardioprotective effect of the extract and that it may prove to be a pharmacological strategy to treat atrial fibrillation. The authors also showed that the phytochemical analysis of A. euchroma roots revealed a content of 1.335% of the naphthoquinone shikonin that could be used as a standardization marker for the extract in future studies. However, mechanisms of action were not elucidated.

Bauhinia championii (Benth.) Benth., popularly known as “chu-hua-mu,” is widely used in Taiwan's folk medicine to treat acute and chronic pain, and some studies reported its antioxidant and anti-inflammatory effect. ^38,39 Chen et al. ⁴⁰ evaluated B. championii extract's effect in an isolated heart model in C57BL/6JNarl mice. Ventricular arrhythmias were induced by 30-minute ischemia and 60-minute reperfusion by ligation of the LAD. The occurrence of ventricular arrhythmias was evaluated by the lead II ECG. In this study, before reperfusion, heart preparations were perfused with the aqueous extract of the aerial parts of B. championii at a concentration of 10 mg/L for 15 minutes.

The extract was able to reduce the occurrence of ventricular arrhythmias. Besides, the extract was able to prevent myocyte death. This effect was linked with the blocking of Na⁺ channels and decreased necroptosis, which may account for the protective effects of B. championii on myocytes' loss. The phytochemical analysis of B. championii revealed that gallic acid is the major component of the formulation, which might also account for the extract's beneficial actions in the ischemia/reperfusion-induced injury.

Camellia sinensis (L.) Kuntze, popularly known as “green tea,” is famous worldwide for its health benefits, mainly for its antioxidant properties. ^41,42 Four main types of tea can be produced according to the processing of C. sinensis—white, green, oolong, and black. Joukar and Dehesh ⁴³ found that black tea at 200 mg/kg/day increases heart rate variability in rats and improves sympathovagal balance after 7 days of treatment.

Unlike this study, Liu et al. ⁴⁴ carried out a case–control study in which they evaluated the relationship between green tea consumption and the incidence of atrial fibrillation in a Chinese population. In this study, 801 individuals were selected, with an average of 62 years, of which 56% were male and of that total 401 had atrial fibrillation and 400 had no disorder. The results obtained in this study showed that low doses of green tea (1 cup/day, being leaves representing less than 25% of the volume of the cup) had a significant protective effect on the incidence of paroxysmal and persistent atrial fibrillation. Since the type of tea varies widely between studies, the chemical variability of these preparations needs to be further investigated, as well as the deep mechanisms responsible for these effects.

Qiu et al. ⁴⁵ described the effect of fruit from Choerospondias axillaris (Roxb.) B.L.Burtt and A.W.Hill in a model of aconitine-induced arrhythmia using rats of both genders. In this study, the authors compared the effect of the fruit extract of C. axillaris with the fraction of total flavones extracted from it. Briefly, the animals received the positive control (verapamil—0.02 g/kg) orally, or the extract in the dose of 0.2 g/kg, or the flavone fraction in the doses of 0.1, 0.2, or 0.4 mg/kg for 7 days. On the last day, intravenous administration of aconitine, at a dose of 25 μg/kg, was performed, and the times of onset of ectopic ventricular beats, ventricular tachycardia, ventricular fibrillation, and cardiac arrest were recorded.

According to the results, the extract and the fraction rich in flavones were able to prolong the onset of all these records and reduce the heart rate without altering blood pressure. These findings demonstrated that both fruit extract and flavone-rich extract were equally effective in this model of aconitine-induced arrhythmia, and it is believed that the changes found can be attributed to the inhibition of ventricular contraction without altering the animals' ventricular diastolic function. The authors also mentioned that C. axillaris extracts' mechanism of action might involve suppressing Na⁺ transportation, since aconitine can bind to Na⁺ channels and prolong their open state inducing cardiac arrhythmias. No analysis of the interaction of the extracts with these channels was carried out in this study.

Cinnamomum zeylanicum Ness, popularly known as “cinnamon” and originating from Sri Lanka and India, has been widely used in traditional medicine and cuisine worldwide. Several studies have investigated its most varied pharmacological potentials. Sedighi et al. ⁴⁶ explored the effect of the ethanolic extract of barks from C. zeylanicum in the male rats' arrhythmia model. The rats received an oral administration of the extract at doses of 50, 100, and 200 mg/kg for 14 days. Subsequently, the animals were subjected to 30 minutes of ischemia due to occlusion of the LAD, followed by 5 days of reperfusion. The results demonstrated that the extract, in the highest dose, decreased ventricular arrhythmias and improved ECG parameters compared to the vehicle group.

Moreover, it increased GPX and SOD plasma levels, demonstrating its ability to counteract the oxidative stress imbalance by strengthening endogenous antioxidant defenses. This effect was also correlated with the direct antioxidant potential of the extract, detected by the reduction of the stable free radical 2,2-diphenyl-1-picrylhydrazyl. Chemical constituents such as Cinamic acid, Methyl eugenol, and Cinnamaldehyde were detected by HPLC analysis, but further studies are still needed.

Another genus that has been reported for its antiarrhythmic potential is Crataegus, popularly known as “espinheiro.” Pahlavan et al. ⁴⁷ evaluated the cardiac effects of the hydroethanolic extract of Crataegus pentagyna leaves in the electrophysiology of cardiomyocytes differentiated from human embryonic stem cells and induced pluripotent stem cells of healthy individuals and patients diagnosed with catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) and long QT syndrome type 2 (LQTS2). The results obtained with the hydroalcoholic extract of this plant demonstrated that only in CPVT1 cells, at concentrations of 300 and 1000 μg/mL, it reduced the beat frequencies and the occurrence of immature field potentials triggered by the adrenergic β1 stimulation in cardiomyocyte cells.

In this same study, the authors evaluated the effects of the flavonoids isoquercetin and vitexin, which slowed down the beating frequencies induced by ISO (5 mM) at concentrations of 3 and 10 μg/mL. In conclusion, it was possible to verify that the extract and the flavonoids had the antiarrhythmic potential in cells of patients with CPVT1, opening up future in vivo studies on this pathology.

Crocus sativus L., known as saffron, is widely used worldwide as spices in food preparation. In the chemical composition of saffron, terpenes, flavonoids, anthraquinones, and anthocyanins are predominant. ⁴⁸ Regarding the biological potential of C. sativus, the antioxidant, antidepressant, antimicrobial, and hypolipidemic effects and its effectiveness in treating CVDs can be highlighted. ⁴⁹

In sequence, Joukar and Dehesh ⁴³ investigated the safety of the aqueous extract of the stigmas of the flowers of C. sativus compared to the antiarrhythmic medication amiodarone in rats. The animals received saffron at doses 50, 100, and 200 mg/kg and amiodarone at dose 30 mg/kg orally for 7 days. On the eighth day, the animals were anesthetized to perform the ECG. The results obtained by the aforementioned study demonstrated that the animals' heart rate decreased in the group treated with 200 mg/kg of the extract and the RR interval, which is the time between successive R waves on the ECG, increased, suggesting that saffron has no detrimental effect on the activity of the cardiac autonomic nervous system and can improve the stability of the sympathetic-vagal balance of the heart in animals.

Although the results are promising, there was no phytochemical detail in both studies that could suggest the compounds responsible for the observed effect, which remains to be elucidated in future publications.

Echinodorus grandiflorus (Cham. and Schltdl.) Micheli, commonly known as “chapéu-de-couro,” has been studied for a long time for cardiovascular and kidney disorders. Gasparotto et al. ⁵⁰ evaluated the cardioprotective effect of the ethanol-soluble fraction of E. grandiflorus leaves on ventricular remodeling using a cholesterol-rich diet in male rabbits. In this study, the animals received a diet with 1% cholesterol for 60 days. After 30 days, they started the treatment once a day with the ethanolic fraction of E. grandiflorus (ESEG) at 10, 30, and 100 mg/kg doses. The control group received 2.5 mg/kg simvastatin. At the end of 60 days, the ECG analysis showed morphological and functional changes in animals fed a diet rich in cholesterol, indicating hypertrophy of the left ventricle and oxidative stress in serum analysis.

These changes were reduced with treatment at a dose of 100 mg/kg of the ESEG, evidencing the cardioprotective effect of E. grandiflorus on heart changes induced by a cholesterol-rich diet. Chemical analysis of ESEG showed a large number of flavonoids, including isoorientin, swertiajaponin, isovitexin, swertisin, and isoorientin-dimethyl ether, as well as several di-C-glycoside derivatives in their composition, which, individually or together, may be related to the effects induced by the tested fraction.

Indeed, the authors' hypothesis about the molecular mechanisms of the cardioprotective effects of ESEG is based on its antioxidant potential. Moreover, in the model used in this study, fatty infiltration is supposed to interfere with cardiac depolarization, which prolongs the QRS complex and contributes to the appearance of arrhythmias; since ESEG treatment reduces serum lipoprotein ratios, it would be very interesting to evaluate the effects of this plant in other models of arrhythmia not induced by the diet.

Medicinal plants used to treat heart failure

Heart failure is the heart's reduced capacity to pump and/or fill with blood. ⁵¹ There are various treatments for heart failure, ⁵² but one of the main adverse effects is kidney dysfunction. ⁵³ For this, in this section, the medicinal plants that have scientific proof in preclinical models of heart failure are described and summarized in Table 3.

Rhizomes of three species of Cimicifuga [C. dahurica (Turcz.) Maxim., C. foetida L., and C. heracleifolia Kom.] were investigated for their cardioprotective effect using the in vitro model of toad heart failure. The heart failure model is induced using a low-calcium Ringer's solution in an isolated heart. ⁵⁴ The results revealed that the ethanolic extract of the rhizomes of Cimicifuga at concentrations of 20 and 100 mg/mL improved the pathological changes of heart failure in a dose-dependent manner. However, despite the positive results described herein, it is essential to highlight that these species' potential still needs to be investigated using in vivo models of heart failure to prove these effects.

Enayati et al. ⁵⁵ investigated the cardioprotective effects of the methanolic extract and ethyl acetate fraction obtained from the roots of Potentilla reptans, commonly known as “cinco-em-rama.” In this study, hearts isolated from male rats that underwent ischemia and reperfusion were used, and the extract was administered in concentrations of 0.5, 1, and 2 μg/mL and the fraction at concentrations of 1, 2, and 3 μg/mL. The results demonstrated that the total extract of the plant decreased the infarct size in a concentration-dependent (0.5–2 μg/mL) manner. Moreover, the ethyl acetate fraction also displayed a concentration-dependent protective effect, with the best response at 2 μg/mL, that significantly decreased infarct size and arrhythmia scores.

Furthermore, this study also described that the cardioprotective effect of the ethyl acetate fraction of P. reptans was prevented when L-NAME was administered. Thus, it is believed that the plant's effect in question may be related to the NO pathway.

Unlike other studies that used isolated rat hearts, Latypova et al. ⁵⁶ have evaluated the effect of the solid extract of Primula veris L, popularly known as “prímula” on the myocardial contractile function using a chronic heart failure model in male rats. The experimental model used in these studies was the intraperitoneal injection of L-ISO at a dose of 2.5 mg/kg twice daily and the extract at 30 mg/kg for 21 days.

The results showed that the group treated with the extract had a lower number of deaths and a lower level of chronic heart failure markers in plasma. Besides, there was also an increase in the rate of myocardial contraction and relaxation, among other findings that demonstrated the extract's cardioprotective effect at a dose of 30 mg/kg compared to the negative control group L-ISO+purified water. In addition, the authors have also investigated the composition of the extract of P. veris, demonstrating the presence of flavonoid glycosides, polyethoxylated flavonoids, and aglycons.

Rhodiola crenulata (Hook.f. and Thomson) H. Ohba, commonly known as “raiz de ouro” or “raiz seca,” had its cardioprotective effect evaluated in rabbits with heart failure. ⁵⁷ In this study, heart failure was induced by coronary ligation in rabbits, and the animals received for 2 weeks the oral treatment with aqueous extract of R. crenulata at a dose of 270 mg/kg/day, and some analyses were performed. ⁵⁷

The results demonstrated that the extract of R. crenulata reversed the electrical remodeling of the left atrium, attenuated atrial fibrosis, and suppressed atrial fibrillation in animals with heart failure. According to the authors, its effect may be related to capacity of R. crenulata extract to increase PI3K mRNA expressions and Akt in animals with heart failure, since this pathway is involved in the regulation of several cellular processes. Moreover, collagen deposition was reduced in the animals treated with R. crenulata extract, which can be attributed to the antiapoptotic and anti-inflammatory effects of PI3K/Akt activation.

Another plant with preclinical records on its effect on an ischemia and reperfusion model in male rat heart is Scrophularia frigida Boiss. According to Garjani et al., ⁵⁸ the methanolic extract of S. frigida was administered at concentrations of 1, 5, and 10 μg/cc, in which 5 μg/cc has showed the better cardioprotective effect and decreased the infarct size. Besides, the extract improved the flow, developed pressure, and reduced ventricular tachycardia duration and arrhythmia. According to the authors, those effects may be related to the antioxidant potential of the extract due to its phenolic compounds, including the flavonoid class.

Recently, Romão et al. ⁵⁹ showed the cardioprotective effects of the hydroethanolic extract of Plinia cauliflora (Mart.) Kausel fruit peels (EEPC) in female rabbits in a model of doxorubicin-induced heart failure. Thirty female New Zealand rabbits received doxorubicin (1.5 mg/kg) intravenously weekly for 5 weeks. EEPC was orally administered at doses of 75 and 150 mg/kg daily for 42 days. Enalapril (5 mg/kg) was used as a reference cardioprotective drug.

At the end of the experimental period, blood pressure and heart rate were recorded. Serum parameters, including a lipid profile, troponin, creatinine, nitrotyrosine, malondialdehyde, nitrite, and brain natriuretic peptide, were measured. The electrocardiographic profile and renal vascular reactivity were evaluated. Cardiac histopathology and ventricular morphometry were performed, and the tissue enzymatic antioxidant system was investigated. A total of 37 compounds were detected in EEPC, including organic acids, phenolic acid derivatives, flavonoids, anthocyanins, and hydrolyzable tannins (gallotannins and ellagitannins).

EEPC treatment induced a cardiorenal protective response to prevent hemodynamic and functional alterations and prevented ventricle remodeling. These effects were associated with the normalization of creatinine and brain natriuretic peptide levels and modulation of the tissue antioxidant defense system. EEPC, especially at the highest dose tested, may be considered a cardioprotective coadjuvant to prevent doxorubicin-induced cardiotoxicity.