Lycopene and Vascular Health




Lycopene is a lipophilic, unsaturated carotenoid, found in red-colored fruits and vegetables, including tomatoes, watermelon, papaya, red grapefruits, and guava. The present work provides an up to date overview of mechanisms linking lycopene in the human diet and vascular changes, considering epidemiological data, clinical studies, and experimental data. Lycopene may improve vascular function and contributes to the primary and secondary prevention of cardiovascular disorders. The main activity profile of lycopene includes antiatherosclerotic, antioxidant, anti-inflammatory, antihypertensive, antiplatelet, anti-apoptotic, and protective endothelial effects, the ability to improve the metabolic profile, and reduce arterial stiffness. In this context, lycopene has been shown in numerous studies to exert a favorable effect in patients with subclinical atherosclerosis, metabolic syndrome, hypertension, peripheral vascular disease, stroke and several other cardiovascular disorders, although the obtained results are sometimes inconsistent, which warrants further studies focusing on its bioactivity.Lycopene

Introduction
Cardiovascular disorders (CVD) are the leading mortality cause worldwide and prophylactic measures to combat it deserve special attention. Atherosclerosis is, in most cases, the main manifestation of CVD, and its progression may be clinical silent for a long time, up to a certain moment, when it directly leads into a severe adverse event (e.g., heart attack or stroke). Beneficial lifestyle changes are important and most cost-effective components of prevention or treatment of cardiovascular disorders. Compounds occurring in plants often display diverse bioactivities with therapeutic potential and different plants and plant-derived compounds have a long history of being reported to exhibit effects counteracting CVD (Atanasov et al., 2015; Waltenberger et al., 2016). Among lifestyle factors, a healthy diet is considered a cornerstone of cardiovascular disease prevention, and the inclusion of sufficient fruits and vegetables in the diet is regarded as especially important (Böhm, 2012; Piepoli et al., 2016). The prevalence of cardiovascular disorders is remarkably unevenly distributed in developed countries, and some areas, e.g., Southern Europe, seem to be protected by having significantly less prevalence of the disease. This effect has often been attributed to dietary factors, as e.g., the Mediterranean diet, with a lot of vegetables, including tomatoes, tomato products, and olive oil (Müller-Nordhorn et al., 2008; Krasinska et al., 2017). Tomatoes, tomato sauce, and watermelon are important sources of lycopene and may be a surrogate for the Mediterranean diet to some degree (Sesso et al., 2003; Burton-Freeman and Sesso, 2014; Naz et al., 2014).

Dietary lycopene is considered to confer cardiovascular benefits, as e.g., consuming at least 7 servings/week of lycopene-based products significantly decreased cardiovascular risk within seven years in postmenopausal women, free from prior cardiovascular disorders and cancer (Sesso et al., 2003). A negative correlation between serum lycopene concentration and cardiovascular mortality was also found in a follow-up study with a large Japanese cohort (Ito et al., 2006). Many studies about the relationship between lycopene and cardiovascular risk have been conducted and, although, some of the results are inconsistent, overall dietary lycopene intake and high-serum concentration of lycopene, significantly reduced the risk of major cardiovascular events (Cheng et al., 2017; Song et al., 2017). Not all outcomes were positive, as exemplified in the Physicians Health Study, including 499 patients with cardiovascular disorders, not revealing any association of higher plasma lycopene and CVD (Müller et al., 2016). Within the Kuopio Ischaemic Heart Disease Risk Factor (KIHD), no relationship was reported between low serum lycopene and an increased CVD mortality and sudden cardiac death, respectively, in Finnish, middle-aged men (Karppi et al., 2012; Müller et al., 2016).

Vascular health depends on endothelial function, arterial stiffness, and the presence of atherosclerotic plaques. The following section will discuss the different methods to measure vascular health. Endothelial dysfunction enables development of the atherosclerotic plaque. The flow mediated dilatation of the brachial artery was traditionally used to assess endothelial function for a long period, but forearm plethysmography and reactive hyperemia—peripheral arterial tonometry have become the gold standards for assessing endothelial vascular function (Kim et al., 2011; Gajendragadkar et al., 2014). While hyperemia—peripheral arterial tonometry is less operator-dependent and non-invasive, while being as reliable as the traditional method, forearm plethysmography additionally provides mechanistic information related to nitric oxide synthesis, is a marker for cardiovascular risk, and can improve risk prediction (Kim et al., 2011; Gajendragadkar et al., 2014).

An increased arterial stiffness is one of the first structural and functional changes of the vessel wall and is mainly caused by arteriosclerosis, atherosclerosis and vessel wall calcification (Cavalcante et al., 2011). Arterial stiffness is associated with cardiovascular risk and predicts cardiovascular disorders and mortality (Vlachopoulos et al., 2010; Mozos et al., 2017c). Pulse wave velocity (PWV) and augmentation indices are simple, noninvasive, inexpensive and validated methods used to assess arterial stiffness and as screening methods for the detection of pre-clinical cardiovascular disorders (Vlachopoulos et al., 2010; Mozos et al., 2017a).

Carotid intima-media thickness (IMT) assessed non-invasively by B-mode ultrasonography, is a simple, validated and safe method used to measure the extent of subclinical atherosclerosis (Dwyer et al., 2004; Wood and Johnson, 2004; Hosseini et al., 2017; Kim and Youn, 2017). IMT is defined by the measurement of the dimension of the intima and media of the arterial wall, whereas a value >0.9 mm is considered abnormal (Cooney et al., 2015; Piepoli et al., 2016). Although IMT has been considered as a surrogate measure of cardiovascular risk, predicting cardiovascular events, especially myocardial infarction and stroke (O'Leary et al., 1999; Touboul, 2015; Piepoli et al., 2016; Hosseini et al., 2017; Pleskovic et al., 2017), both the American and the European guidelines on cardiovascular disease prevention do not recommend the systematic measurement of IMT to improve risk assessment (Goff et al., 2014; Piepoli et al., 2016). Major concerns of IMT include lack of standardization, its high variability and low intra-individual reproducibility (Piepoli et al., 2016). Additionally, a trained sonographer is required to limit variability of the results due to the patient or medical equipment (Touboul, 2015). There are also methods available that can better predict cardiovascular events than IMT, most prominently MRI (magnetic resonance imaging) that can be used to monitor atherosclerotic plaques. Several methods are stronger predictor of myocardial infarction than IMT, such as monitoring atherosclerotic plaques and exploring the carotid wall by MRI (because the adventitia is also included in the measurement of the wall thickness; Zhang et al., 2014). However, the resources needed to access wall thickness by MRI are manifold higher than using ultrasonography, but especially for patients with abnormal findings in IMT screenings, a subsequent MRI scan might be useful to provide a more accurate description of the atherosclerotic plaque and the risk of major cardiovascular events (Zhang et al., 2014).

Despite the inevitable influence of aging, vascular changes are at least partially reversible, and dietary changes may improve vascular function. Lycopene has several advantages, such as almost no adverse reactions, its wide availability and low cost (Gao et al., 2016). The present review aims to give a current overview of the mechanisms linking lycopene in the human diet and vascular changes, considering epidemiological data, clinical observational, retrospective, intervention and randomized studies, dietary and biomarker studies, in vitro and in vivo research and discussing preventive benefits of lycopene intake in context of cardiovascular disease prevention.