Ischemic heart diseases, also known as coronary heart diseases (CAD), alongside stroke and other cardiovascular diseases, are the causes of approximately 17.9 million deaths annually, which represents 32% of the total deaths in the world [1]. Out of these, more than 75% are registered in low and middle-income countries. Furthermore, in accordance with World Health Organization (WHO), ischemic heart disease is the leading cause of global death, with 16% of worldwide deaths, followed by stroke, which is responsible for 11%, respectively. Ischemic heart disease is characterized by narrowing or blockage of one or more coronary arteries, most frequently due to atherosclerosis, which is the main factor that reduced cardiac blood flow. It is clinically manifested by pectoral angina and heart attack [2]. The main incriminated risk factors that promote CAD are tobacco, an unhealthy diet with low fruit and vegetable intake, lack of physical activity, metabolic syndrome, and excessive use of alcohol ^[1][3][1,3]. Besides these, other pathologies like obesity, diabetes mellitus, nephrotic syndrome, and hypothyroidism could associate with dyslipidemia, which is characterized by elevated levels of LDL and total cholesterol and a reduced HDL level. Moreover, it was observed that people with different lifestyles, like workers who have permanent night shifts, are more likely to develop dyslipidemia [4].

All of these risks lead to atherosclerosis. In this term, atherosclerosis is defined as a multifactorial inflammatory disease of the innermost layer of an artery called intima, a build-up of cholesterol plaque, and a loss of the arterial wall elasticity [5]. Therefore, a primary target in the treatment of CAD is represented by the prevention of atherosclerosis development. In this regard, the management of CAD includes lifestyle changes like dietary modification, smoking cessation, and weight reduction alongside classical medication (nitrates, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors). Additional comorbidities like diabetes, hypertension, and dyslipidemia are controlled via oral antidiabetics or insulin, antihypertensive drugs, and statins, respectively.

Even if there are many efficient ways of reducing the incidence of associated risk factors, among which the pharmacological and surgical ones with proven results, CAD still represents the main cause of death worldwide. That is why this pathology represents a great interest for many researchers and their efforts are needed in identifying new ways to prevent and treat CAD. In this regard, plants have been always an inexhaustible source of discovering new compounds with potent pharmacological activities. Shifting from traditional plant utilization, a great alternative is represented by plant waste valorization. This new direction came along with the introduction of the circular economy, an economic system that proposes a reduced use of raw materials and increased reuse and recycling of different components and products already existing [6] (Figure 1).

A perfect example of the circular economy’s application is represented by the usage of grape pomace (GP). Therefore, it is estimated that annually are used more than 79 million tons of grapes, from which approximately 30% is represented by grape pomace ^[7][8][7,8]. Besides its use as fertilizer or animal feed, another field in which it can be used is the pharmaceutical one, due to the rich amount of bioactive compounds, especially phenolic ones [8]. Thereby, GP is reported to contain high quantities of resveratrol and polyphenols like flavanols: myricetin, quercetin, kaempferol; flavan-3-ols: catechin, epicatechin; cinnamic acids: p-coumaric and benzoic acids: syringic, gallic, and protocatechuic, 4-hydroxybenzoic [9]. It is known that polyphenols, the major compounds in GP waste have well-known antioxidant and anti-inflammatory effects [10]. Previous studies have reported their action on reducing LDL oxidation, inflammation, and platelet activation, all with positive effects in reducing the progression of atherosclerosis [11].

2. Red and White Grape Pomace—Bioactive Compounds

The utilization of grapes has a long history, which dates back to antiquity and spreads to the modern world, especially through their use in the wine industry. That is why there is a variety of literature studies that analyze and characterize grapes, grape derivatives especially wine, and GP composition and content ^[9][12][9,12] (Figure 2). It was observed that red grape pomace (RGP) and white grape pomace (WGP) have different phenolic compound fingerprints and different total phenolic content according to the grape cultivar and terroir. This means that all of the pedological, topographical, and geological aspects of a specific physical environment will alter the physical features of the grapes such as tastes, aromas, textures, and appearances [8]. RGP was found to be rich in stilbenes (resveratrol), phenolic acids (gallic acid, protocatechuic acid), flavanols (epigallocatechin), flavanols (myricetin-3-O-rhamnoside) and anthocyanins (delphinidil-3-O-glucoside, cyanidin-3-O-glucoside, petunidin-3-O-glucoside, peonidin-3-O-glucoside, malvidin-3-O-glucoside) [13]. WGP was reported to have high content of phenolic acids (p-hydroxyphenylacetic acid, vanillic acid, homovanillic acid, homoprotocatechuic acid, gentisic acid, syringic acid, 4-O-methylgallic acid, 3-O-methylgallic acid, dihydro-3-coumaric acid, hydroferulic acid, hydrocaffeic acid, isoferulic acid) and flavanols (catechin, epicatechin, procyanidin B1) [13], flavonoid glycoside (hyperoside, isoquercitrin, rutin, quercitrine), flavonoid aglycons (quercetin, luteolin), and protocatechuic acid [14]. It was also reported that WGP has a high quantity of gallic acid, procyanidin B3-4, epicatechin, and procyanidin gallates [15]. In both RGP and WGP was identified a similar amount of caffeic acid, coumaric acid, catechin, and its isomer epicatechin [14], and similar amounts of total tannins [16]. Overall, numerous studies concluded that RGP contains a higher amount of polyphenols than WGP [17]. However, some studies revealed types of WGP that possessed a greater content of polyphenols than RGP [13].

3. Potentially Toxic Effects of Polyphenols from Red and White Grape Pomace

Generally, literature studies focused on GP or GP by-products are emphasizing its health benefits rather than toxic or adverse reactions. Administration of GP may not be an issue in healthy people, but it must be considered in people with certain diseases who are receiving medical treatment [18]. Neag et al., (2019) observed the paradoxical effect of GP polyphenol extract on an animal model of acute kidney injury induced by cisplatin. They reported that when GP, was given alongside cisplatin, for its antioxidant properties, it did not decrease the cisplatin-induced nephrotoxicity, on the contrary, it increased it [19]. The lack of studies reporting the potentially toxic effects of polyphenols from grape pomace could be based on the fact that even if GP presents pro-oxidant activity at a higher dose than the one that presents the antioxidant effect ^[20][21][20,21], that effect is too low to cause changes at the level of an organ or the entire organism, changes that could be highlighted through routine analyses. Thus, this issue should be addressed in terms of precautions rather than acute or chronic toxicity [22].

4. Red and White Grape Pomace—Variability of Total Polyphenols Content and Antioxidant Capacity

It is well-known that GP possesses great antioxidant activity, but it is necessary to find out what are the differences between RGP and WGP to give them an appropriate valorization. Literature studies showed that GP has a strong antioxidant activity, because of the contained phenolic compounds. The antioxidant activity is strongly related to phenolic chemical structures. Thus, the number of existing hydroxyl groups gives them the ability to act as free radical scavengers [23] or to donate an atom of hydrogen ^[24][25][24,25]. Accordingly, several methods for antioxidant activity evaluation have been created over time. The main methods used for GP characterization reported so far were total polyphenol content (TPC), 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2′–azinobis-(3-ethyl-benzothiazoline-6-sulphonic acid) (ABTS), and ferric reducing antioxidant power assay (FRAP) for antioxidant activity (Table 1). Total phenolic content represents the reference assay for measuring the polyphenols in plants or other biological samples, by using the Folin–Ciocalteu assay ^[24][26][24,26]. This method involves a reaction between the polyphenols and a redox reagent. Accordingly, the phenolic content is determined using the spectrophotometric measurement of this reaction [27]. Further, the methods used to determine polyphenols’ antioxidant activity content are ABTS, DPPH, and FRAP. These assay methods analyze the antioxidant activity via the donation of a hydrogen atom (ABTS and DPPH) or via electron transfer (FRAP) ^[28][29][28,29]. Due to the variety of antioxidant activity methods that are used, it is very difficult to compare data from the literature. This situation leads to the development of a relevant correlation method, which could allow their comparison. In this case, Xu et al., (2016), in their study regarding the phenolic compounds extracted from four GP varieties, identified antioxidants and compounds with antibacterial properties and also developed a correlation method between TPC, DPPH, and ABTS [30]. They observed that between TPC and ABTS there is a significant positive correlation, but none between these and DPPH. A probable cause for this could be the fact that there are differences between the phenolic compounds involved in each method. Thus, it was reported that flavonoids and tannins contributed to the determination of antioxidant activity via ABTS, while in the case of DPPH anthocyanins, they had a major contribution. In comparison to this study, Marchante et al., (2018) observed that in the measurement of antioxidant activity using the DPPH method, a higher contribution was brought by (−)-epigallocatechin, while in the case of the ABTS method by flavan-3-ol monomers. Furthermore, they did not observe any differences between the contribution to the determination of ABTS and DPPH methods for (+)-catechin, (+)-gallocatechin, (+)-epigallocatechin, (+)-catechin gallate, (−)-epicatechin gallate, procyanidin B1, galloylated dimers, flavan-3-ol dimers, flavan-3-ol total oligomers, total flavan-3-ols, and trans-resveratrol-glucoside. Moreover, they also observed that the compound with the highest antioxidant property was (+)-catechin gallate, followed by (−)-epicatechin gallate, (+)-gallocatechin, (+)-catechin, and (−)-epigallocatechin [31]. Xia et al., (2019), also addressed the necessity of comparing and correlating the values of the different methods used in polyphenols quantification. To eliminate the variations of these values, the authors also chose to determine the antioxidant activity by using all the above-described methods. Thus, Xia et al., (2019), evaluated the TPC and measured the antioxidant assay using ABTS, DPPH, and FRAP of skin and seeds from 31 different cultivars of grapes. Firstly, they observed that the grape seeds have more polyphenols and more antioxidant activity as assayed via DPPH, ABTS, and FRAP than grape skins. Secondly, they observed that the European species have higher antioxidant properties than the American, Asian, or hybrid ones [10]. Even though the majority of studies determined that RGP possesses a higher polyphenolic content and antioxidant activity (Costa et al., 2018, Sagdic et al., 2011, Xu et al., 2016), there is no sufficient evidence yet to affirm that RGP is superior to WGP. Winkler et al., (2015) observed that even though the RGP cultivated in Rhineland-Palatinate, Germany had a higher TPC than WGP, the differences were not significant [32]. Further, Cerda-Carrasco et al., (2015) who investigated GP obtained from Vitis vinifera sp. cultivated in Maipo Valley, Chile, observed that two types of white grapes, Sauvignon Blanc and Chardonnay, had higher phenolic content and antioxidant capacity than the two red types, Cabernet Sauvignon and Carménère [15]. It can be concluded that both GP varieties represent great sources for further valorization, their prior analysis being a key step in directing toward the appropriate use, because of their large variation in terms of phenolic content and antioxidant activity.

* GAE—gallic acid equivalent ** TE—Trolox equivalent.

5. Red and White Grape Pomace—In Vitro Antioxidant and Anti-Inflammatory Activities

The fact that many studies investigating GP have shown that it possesses intense antioxidant activity has been a key factor in drawing the attention of researchers to continue the findings and to focus on the beneficial antioxidant and anti-inflammatory activities within the in vitro studies as presented in Table 2. Most literature data reports the antioxidant activity of GP on cells exposed to different oxidative stress factors or/and the anti-inflammatory activity on cells subjected to different proinflammatory factors.