**1. Introduction**

Cardiovascular disease (CVD) (includes heart disease and stroke) is the leading cause of death in the United States [1] and worldwide [2]. In the United States, heart disease is the number one contributor to death, causing 647,457 deaths (23% of total deaths), while stroke is the fifth leading cause of death, contributing to 146,383 deaths (5.2% of total deaths) in 2017 [1]. Worldwide, heart disease is the leading cause of death, leading to 8.9 million deaths, or 16% of the total deaths globally in 2019. Stroke is the second leading contributor to deaths worldwide, causing more than 6 million deaths, or 11% of the deaths, worldwide [2].

A suggested dietary strategy to decrease the risk factors for CVD is to replace a portion of saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) [3–10]. For example, the Nurses' Health Study [11] demonstrated that replacing 5% of energy from SFAs with equivalent

energy from MUFAs, PUFAs, or carbohydrates from whole grains, decreased the risk for coronary heart disease (CHD). A meta-analysis of randomized controlled trials reported that replacing saturated fat with polyunsaturated fat reduced CHD events [12].

However, certain authors and publications are not in agreement with these recommendations to decrease the risk factors for CVD, cardiovascular events, and/or mortality [13–22]. The PURE prospective cohort study concluded that intakes of total, saturated, and unsaturated fats were not significantly associated with the risk of myocardial infarction or CVD mortality [23]. Meta-analyses of prospective cohort studies demonstrated that consumption of saturated fat was not associated with an increased risk of CVD [24]. Interestingly, there was an inverse association between saturated fat intake and the risk of stroke [25]. Additionally, a meta-analysis of randomized controlled trials reported that replacing saturated fat with primarily polyunsaturated fat is "unlikely" to reduce CVD events or mortality [26]. Hooper et al. [27], in a review of randomized controlled trials, stated that there is "little or no effect of reducing saturated fat on all-cause mortality or cardiovascular mortality."

As noted, there is controversy regarding the effects of the consumption of fatty acids on CVD risk. One such controversy is the recommendation of linoleic acid, which is the essential omega-6 (or n-6) PUFA [28–30]. For example, it has been found that replacing saturated fat with linoleic acid lowers serum cholesterol, but does not lower the risk of death from CHD [21, 22]. Furthermore, there is concern regarding whether linoleic acid increases the risk for inflammation [31].

An analysis of prospective observational studies demonstrated that higher tissue and serum concentrations of linoleic acid decreased the risk for cardiovascular events [32]. The Cardiovascular Health Study, a prospective cohort study, discovered that higher circulating linoleic acid concentrations reduced total and CHD mortality [33]. A meta-analysis of prospective cohort studies found that decreased consumption of omega-6 PUFAs and increased intakes of saturated and transfatty acids increased CHD mortality [34]. Linoleic acid consumption reduced the risk of CHD events and death, according to another meta-analysis of prospective cohort studies [35]. A systematic review of randomized controlled trials, in which there was a replacement of dietary saturated and monounsaturated fatty acids with omega-6 fatty acids, concluded that omega-6 fatty acids lowered the risk of myocardial infarction. Additionally, the intake of omega-6 fatty acids reduced total serum cholesterol, but not "other blood fat fractions". It was also highlighted that "the benefits of omega-6 fats remain to be proven" [36].

According to the diet-heart hypothesis, a high consumption of saturated fat and cholesterol – and a low intake of polyunsaturated fat – increase the build-up of cholesterol and plaques in artery walls; these developments, therefore, increase the risks for atherosclerosis, cardiovascular disease, and myocardial infarction [18, 21, 37]. However, the diet-heart hypothesis has been evolving, and thus, some individuals recommend focusing more on overall dietary patterns, rather than individual fatty acids [37]. Moreover, there are a variety of factors that contribute to increasing the risk for CVD, such as high blood pressure, arrhythmia, inflammation, thrombosis, insulin resistance, endothelial dysfunction, obesity, cigarette smoke, genetics, the microbiome, a lack of exercise, a high alcohol consumption, and overall dietary patterns [14, 18, 37–42].

Lipid levels have also been proposed to be "strong" risk factors for CVD and mortality. These lipid risk factors include the following: high serum concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), lipoprotein(a), and very-low-density lipoprotein cholesterol (VLDL-C), as well
