Food processing can profoundly affect diet quality; however, there is a broad spectrum of food processing, ranging from minimal processing (e.g., frozen, dried vegetables, fruit with no added sugar or additives, pasteurized milk) to ultra-processing (e.g., soda, fast food, industrially produced bread, hot dogs) [
4]. Ultra-processed foods (UPFs), the result of repeated industrial processes, are tasty and pleasant on the palate, keep for a long time, are packaged and finished foods to be reheated and ready to be consumed. Ultra-processed foods include not only so-called “junk” foods, but also wide array of foods marketed and perceived as healthy, such as flavored yogurts, low-fat, low-calorie products, breakfast cereals, and nutrient-enriched products, ‘energy’ drinks, and sugared drinks [
4].
The recent epidemiological studies suggest that a greater consumption of UPFs is associated with an increased risk of CVDs. In a population-based cohort of 91.891 participants, after an average follow-up of 13.5 years, a high consumption of UPFs was associated with increased risks of overall cardiovascular and heart disease mortality, including heart disease deaths and cerebrovascular deaths [
5]. A recent metanalysis of a total of 39 cohort studies, involving more than 60 million participants, showed that a higher consumption of UPFs, up to 1 serving per day, significantly increases the risk of developing cardio-cerebrovascular diseases [
6].
Artificial sweeteners
Processing can alter both macro and micronutrient nutritional characteristics, physical characteristics such as the structure of the food, and chemical characteristics due to the presence of natural or artificial sweeteners, altering the glycemic index of foods with elevation of insulin and insulin resistance.
An example of chemical interference is fructose, some sugar widely used in the preparation of foods, especially drinks, with much lower costs than glucose but with superior organoleptic characteristics such as the almost non-existent property of crystallizing. Our body can metabolize 30–40 g of fructose per day due to the inability of GLUT5 and fructokinase, but the daily intake in industrialized populations has increased considerably up to 120 g. This leads to an increase in insulin resistance and uric acid and all those pathologies related to it such as metabolic syndrome, diabetes mellitus, Nonalcoholic Fatty Liver Disease (NAFLD), factors directly related to an increase in cardiovascular risk.
Artificial sweeteners have been used as sugar alternatives since the 1800s, but their consumption has significantly increased in the recent years. Even if there are no reports by randomized controlled trials investigating if long-term intake of artificial sweeteners results in negative cardiovascular consequences, several other studies associated artificial sweeteners with an increased risk of metabolic syndrome, hypertension, insulin resistance and dyslipidemia [
7]. Artificial sweeteners may contribute to cardiovascular disease 1) by the alteration of gut microbiota, disrupting the balance of gut bacteria species [
8]; 2) favoring the acceleration of atherosclerosis via impairment of function and structure of high-density lipoprotein (HDL) and its major protein constituent, ApoA-I [
9]; 3) by the regulation of cardiac electrophysiology by altering heart’s electrical conduction system [
10].
Among artificial sweeteners widely used in ultra-processed foods and especially in artificially sweetened beverages, some snacks, and low-calorie ready-to-go meals or dairy products, aspartame, acesulfame potassium, and sucralose were found associated with detrimental effects on cardiovascular health [
11]. The analysis of the consumption of artificial sweeteners from all dietary sources in the prospective NutriNet-Santé cohort revealed that aspartame intake was associated with an increased risk of cerebrovascular events whereas acesulfame potassium and sucralose were associated with increased coronary heart disease risk [
11].
A recent study by Witkowski and colleagues showed that circulating levels of erythritol were associated with incident risk for major adverse cardiovascular events [
12]. Moreover, erythritol enhances platelet responsiveness, and in vivo thrombosis formation in human blood and the carotid arteries of mice [
12].
Food additives and contaminants
Food additives and contaminants newly formed during processing may also play a role in cardiovascular risk. Additives contained into UPFs with adverse cardiometabolic effects include for example glutamates [
13,
14], emulsifiers [
15,
16], and sulfites [
17]. In chronic alcoholic (30% ethanol/100 g body weight) and normal adult male mice, the oral ingestion of monosodium glutamate (4 mg/g body weight and above) increased lipid peroxidation and decreased the levels of endogenous antioxidants [
14]. In adults with Type 2 Diabetes, higher intake of glutamate was associated with a higher risk of CVD incidence, CVD mortality, and total mortality [
13]. Emulsifiers are detergent-like molecules that are incorporated into many processed foods in order to improve texture and extend shelf life [
18]. In mice, relatively low concentrations of two commonly used emulsifiers, carboxymethylcellulose and polysorbate-80, induces microbial dysbiosis and low-grade inflammation promoting metabolic syndrome [
15]. In a prospective cohort study including 95.442 adults without prevalent CVDs, a positive association between higher intake of food additive emulsifiers (celluloses, carboxymethylcellulose, monoglycerides and diglycerides of fatty acids) and the risk of CVDs and coronary heart disease was found [
16].
During food processing, heat treatments produce neo-formed toxic compound such as acrylamide, a by-products that can be formed during the Maillard reaction [
19]. Several studies suggest that acrylamides in UPFs is associated with cardiovascular disease [
20‐
23]. The baseline examination of 8.290 adults from National Health and Nutrition Examination Survey (NHANES) 2003–2006 with self-reported diagnosis of CVDs, showed that hemoglobin adducts of acrylamide, biomarkers of internal exposure to acrylamide, were significantly associated with CVDs in smokers [
23]. Moreover, acrylamide was associated with platelet activation and suppression of circulating angiogenic cell levels, as well as increased risks of CVDs [
24].
Other mechanisms underlying the correlation between ultra-processed food intake and CVDs disease include the presence of bisphenol A (BPA) in the materials that make up ultra-processed food containers. BPA, which is very similar in structure to 17 beta estradiol, promotes insulin resistance, oxidative stress, inflammation, adipogenesis, pancreatic beta cell dysfunction by binding to estrogen-related receptors [
25].
All these compounds and characteristics of UPFs synergize to influence cardiovascular health involving complex mechanisms which are not yet fully understood. However, key potential biological mechanisms underlying the association between UPFs and CVD include the dyslipidemia, changes in the intestinal microbiota, body composition with an increase in fat mass, promotion of inflammation and oxidative stress phenomena, insulin resistance and blood pressure [
26].
Nitrite and nitrate salts are commonly used to season meat and other perishable products, such as cheese. They are added to foods to preserve them and help to hinder the growth of harmful microorganisms. They are naturally present in vegetables, especially leafy ones, such as lettuce and spinach and in water as they are used as fertilizers. The Acceptable Daily Intakes (ADI) for nitrite, established by the European Commission's Scientific Committee for Food (SCF) in 1997 and the Joint FAO-WHO Committee on Food Additives (JECFA) in 2002, are respectively 0.06 and 0.07 mg per kilogram of body weight per day (mg/kg bw/day). In the case of nitrate, on the other hand, both institutions set the ADI at 3.7 mg/kg bw/day.
When taken with the diet they are rapidly absorbed by the body and excreted in the urine. Nitrates can also survive passage through the stomach and enter the circulatory system. A variety of highly bioactive reactive nitric oxide species are formed in the acidic environment of the stomach or in blood and tissue. These may be involved in the generation of nitrosamines of toxicological importance when nitrites combine with secondary amines present in the stomach resulting in an increased risk of gastro-intestinal cancer [
27]. The presence of antioxidants in the diet inhibits the generation of nitrosamines. However, there are also benefits of dietary intake of nitrates and nitrites, which have been demonstrated in many studies. The positive effect of nitrates and nitrites is linked to the fact that they are exogenous donors of NO, which has a potentially beneficial role in physiology and therapy [
28]. The widely considered and described benefit of taking nitrates and nitrites is its positive effect on the cardiovascular system. The impact of nitrate and nitrite intake on endothelial function and blood pressure is extensively studied [
29‐
31].
N-nitrosamines (N-NA) in food represent harmful elements for health and public health when the quantities are high. This category includes the 10 food carcinogens (TCNA), namely NDMA, NMEA, NDEA, NDPA, NDBA, NMA, NSAR, NMOR, NPIP and NPYR. N-NAs are genotoxic and induce liver tumors in experimental animals and the available in vivo data are limited to detect their potency. The tolerated limit is 10 μg/kg of body weight per day beyond which the incidence of rat liver tumors is relevant, especially from NDEA. The dietary exposure of TCNAs was evaluated for cooked meat and fish. Exposures ranged from 0 to 208.9 ng/kg body weight per day. However, meat and meat products are the main food category contributing to exposure to TCNA. Only one experimental study was conducted about the role of N-nitrosamines as risk factors for the incidence of cardiovascular disease. The treatment of rats with 0.2 mg/kg body weight of several TCNAs for two weeks altered the lipid profile by increasing cholesterol and LDL levels and decreasing HDL [
32]. Moreover, TCNAs treatment increased levels of free radicals and decreased the activity of antioxidant enzymes such as glutathione levels, and glutathione reductase [
32].