David_Nehring

=Trans Fatty Acids and Their Influence in Increased Risk of Cardiovascular and Coronary Heart Disease= David Nehring Submitted 15 December 2013

Abstract:
Partial hydrogenation of oils was industrialized over 60 years ago [1] and not until the past two decades has much attention been paid to their adverse health effects and increased risk of vascular and heart disease. Intended to be a replacement to saturated fatty acids along with the additional effect of lengthening the shelf-life of baked goods and frying oils [2,3], partially hydrogenated oils contain //trans// fats, produced during their hydrogenation, which have been shown to increase the risk of both cardiovascular [2] and coronary heart disease [4,5]. As the U.S. Food and Drug Administration reconsiders the listing of “generally recognized as safe” label of partially hydrogenated oils [3], the present work reviews the health risks associated with //trans// fatty acids (TFAs). The chief health risks of interest are cardiovascular and coronary heart disease as a result of atherogenic effects [6], adverse lipid and lipoprotein profiles [7,8,9], and unfavorable cholesterol content [7,8] as a result of TFA intake. Furthermore, the findings presented herein suggest different TFA profiles [8], namely those from ruminant vs. partially hydrogenated origin [6], can have significantly different adverse health effects. Alternative fat sources are also considered, and trends in food production [1,10] are extrapolated to anticipate future concerns of trans fats and partial hydrogenated oils.

Introduction:
Since their industrialization in 1949, partially hydrogenated oils were thought to be the solution to foods high in saturated fat [1]; yet within the past decade, partially hydrogenated oils, and more specifically, //trans// fatty acids have come under intense scrutiny in both the United States [11,3] and European Union [12]. Fats and oils (such as vegetable oil or fish oil) are composed of fatty acids, or long carbon chain acids. The difference between the two is the presence of a double bond which directly effects the hydrogen saturation of the carbon chain. Saturated fats contain no double bond and thus are fully saturated giving them a linear structure which allows for them to compact more tightly and gives them their solid state at room temperature. Unsaturated fats (such as vegetable and fish oils) contain at least one double bond which reduces their saturation. Natural oils typically contain only //cis// double bonds which function like kinks in the long carbon chain which contributes to their liquid state at room temperature. By hydrogenating oils, an addition of hydrogen across the double bond increases the saturation of oils. This forms a more linear structure in the chain which gives the TFA similar properties to saturated fats: hydrogenated oils are solid or semi-solid at room temperature [13,14]. In the industrial hydrogenation of oils, a portion of the oils will undergo isomerization from the //cis// to //trans// state in the presence of heat [13]. **Figure 1.**


 * Figure 1.** An example of the //trans//- and //cis//- isomers of an 18-carbon fatty acid, containing one double bond located at the 11th carbon.

While trace amounts of TFAs exist in nature, their prevalence has only truly become evident since the middle of the 20th century when partially hydrogenated oils were being made on an industrial scale. The intention behind partially hydrogenating oils was to make them more like saturated fats, giving them two particular properties: provide a substitute for saturated fats and increase the shelf-life of foods otherwise containing saturated fats [1]. While saturated fats have a well-known history of increasing the risk for heart disease [15], //trans// fatty acids were initially considered a safe alternative with no adverse health effects [1]. It wasn’t until 1993 that a study on the negative health effects of TFAs showed that TFAs increased the risk of coronary heart disease in women[4]. Since then, more evidence has confirmed TFAs adverse health effects with respect to coronary heart disease [5] including its negative effect on lipoprotein profiles [7] prompting the United States Food and Drug Administration (FDA) in 2003 to require that the //trans//-fat content be included in the nutrition facts of packaged products by 2006 [12]. By 2009, further evidence pressed scientific advisers to the European Union’s Parliament to recommend to restrict //trans//-fat content to less than two percent of the total fat in food products [11]. In recent months (2013), the FDA has opened discussion to the public in order to reconsider the labelling of “generally recognized as safe” with respect to partially hydrogenated oils [3].

Health Risks:
It is specifically the //trans// fatty acid content in partially hydrogenated oils that contributes to increased risk of cardiovascular (CVD) [2] and coronary heart disease (CHD) [4] among other lipid and cholesterol imbalances [7,9]. Despite these known adverse health effects, in recent years there has been much inquiry on the exact agent(s) of TFAs that induce cardiovascular pathology. TFAs are responsible for increasing the risk of CVD and CHD by influencing three particular aspects of health. Firstly, TFAs act directly on the vascular system as atherogenic agents by increasing systemic inflammation which thereby increases the risk of atherosclerosis [6]. More pathways are proposed that diagram other potential atherogenic effects of TFAs [2]. It should be noted that it is still unknown which particular component(s) of TFAs are directly responsible for the adverse health effects listed herein [6]. Furthermore, atherosclerosis adversely alters metabolic processes including those that regulate blood serum lipid levels, leading to further cardiovascular complications [2].

As TFA intake increases, their effect on lipoprotein levels becomes increasingly dangerous [7]. To preface these findings, lipoproteins interact with cholesterol to give lipoprotein-cholesterol micelles which to lay persons can be defined as “good” and “bad” cholesterol. These lipoprotein-cholesterol micelles come primarily in two forms: low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) [16]. Both of these micelles are essential in allowing cholesterol (a fat that is insoluble in water) to be //trans//ported through the bloodstream, in which the plasma serum is mostly water. The lipoproteins’ effectiveness in disallowing the cholesterol to form a plaque build-up within blood vessels is representative of its “healthiness”. Thus the HDL-C is recognized as “healthy” for the cardiovascular system and has even shown to decrease the risk of heart disease, while the opposite is true of LDL-C [16].

Similarly, lipoproteins are categorized as either high-density (HDL), low-density (LDL), very low-density(VLDL), or intermediate-density (IDL) in blood plasma, with only HDL serving as “healthy” lipoprotein [17,18]. Of utmost importance when considering lipoprotein profiles is the ratio of HDL to LDL. A higher ratio is associated with increased health benefits, while a lower ratio can be used to diagnose dyslipidemia [17] and also has its own implications in increased risk of heart disease [18]. With this in mind, TFAs’ influence on lipoprotein levels, namely an increase in LDL and decrease in HDL or increase in both LDL and HDL with a marginally greater increase in favor of LDL [7,9], is characteristic of their associated negative health effects [18].

Dietary Trials and Epidemiological Studies:
The Nurses’ Health Study brought TFAs’ negative health effects into question when nearly 85,000 nurses were surveyed by dietary questionnaires which were analyzed for trends in fat consumption [4]. In the study’s 8 years of follow-up, cases of coronary heart disease (CHD) were recorded and found to be greatest among those women who ate margarine on a regular basis [4]. Besides margarine, intakes of baked goods were also significantly associated with higher risks of CHD [4]. The conclusion reached was that of partially hydrogenated vegetable oils being responsible for the TFA intake, citing average margarine products of the day to contain 5 to 30% fat content as TFAs [4].

Moreover, it was found that compared to a baseline of test subjects, those who consumed a diet high in partially hydrogenate vegetable oil or partially hydrogenated fish oil (PHSO) also had significantly lower concentrations of HDL-cholesterol and significantly higher concentrations of LDL-cholesterol in their blood [7]. This low ratio of HDL-C to LDL-C is cited as a known factor to increase the risk of CVD [18]. However, the study can be criticized that despite using controlled diets, a small sample size may raise concerns for sampling error. However, further evidence suggests that the partial hydrogenation of oils was in fact responsible for cholesterol imbalance; Vega-López et al.[9], in a 2006 lipoprotein study on the adverse health effects of hydrogenated soybean oil when compared to natural soybean oil led to an alteration of participants’ lipoprotein profile was responsible for an increased risk of cardiovascular disease. Moreover, the study determined that the intake of different types of dietary fat have a greater influence on risk of cardiovascular disease than the mere total amount of fat in a given diet [9].

Also in 2006, Pfeuffer and Schrezenmeir [6] compared epidemiological studies to determine if TFAs of different origins gave similar results of an association with increased risk of CVD and CHD. Sources of TFAs used in the study include partially hydrogenated vegetable oils and from ruminant (naturally occurring) sources. Ruminants are large mammals that typically eat low energy yield vegetables such as grass, for example cows. Such animals have naturally occurring TFAs present in their fat as vegetables are metabolized. These natural sources of TFAs can be influenced by animal diet and if wanted, can be intentionally altered [19]. It was found that with respect to the health effects of ruminant origin TFAs, there is no proof of significant positive effects nor is there proof of significant negative effects [6]. Furthermore, the primary TFA in ruminant sources was identified as vaccenic acid (t11,18:1) (**I**) which is converted to //cis//9,//trans//11-conugated linoleic acid (c9,t11-CLA, 18:2) (**II**) in humans and presented a novel association: vaccenic acid (**I**) showed to improve the LDL/HDL cholesterol ratio when compared to other conjugated //trans// fatty CLAs [6]. **Figure 2.** Since the first study on lipoprotein levels [7], it was known that the primary TFA in partially hydrogenated vegetable oils were (18:1) //trans// fats and, when preparing diets in that study, was accounted for. When considering the negative health effects associated with elaidic acid (t9,18:1) (**III**), the most common partially hydrogenated vegetable oil TFA, these findings provide evidence to suggest that different //trans// fats have differing effects on lipid and lipoprotein profiles, particularly those TFAs of ruminant versus partially hydrogenated vegetable oil origin [6].


 * Figure 2.** a. Primary ruminant source TFA: vaccenic acid (**I**) with a //trans//-double bond at the 11th carbon. b. In vitro metabolism of vaccenic acid gives //cis//-9-//trans//-11-conjugated linoleic acid (**II**) [6]. c. Primary partially hydrogenated oil source TFA: eladaic acid (**III**) with a //trans//-double bond at the 9th carbon. d-e. Structures of //trans//-4-octadecanoic acid (**IV**) and //trans//-10-octadecanoic acid (**V**) with //trans//-isomers of octadecanoic acid between the 4th and 10th carbon having the most significant influence on lipoprotein imbalance [8].

A similar conclusion was reached in 2011 where Kraft et al. [8] specifically identified //trans//-4-(**IV**) to //trans//-10-octadecanoic acids (**V**) as the most significant of the TFAs to influence lipoprotein (LDL:HDL) imbalance. Not only did the study determine differences among various 18:1 TFAs, but also identified a biological deficiency in hepatic (liver) LDL receptor which control levels of LDL in blood plasma which similarly differed between different partially hydrogenated oil sourced TFA profiles [8]. This evidence suggests further that different partially hydrogenated vegetable oil sourced TFA profiles differentially affect both lipid and lipoprotein levels as well as their metabolism [8]. Upon comparison to the previously proposed atherosclerotic effect on metabolic control of blood serum levels [2], those TFAs identified as most significantly unhealthy present an association with reduced hepatic LDL receptors, though the exact mechanism is not entirely known, but has been proposed [8].

Discussion:
Reconsideration of the adverse health effects of TFAs is motivated by a recent U.S. Food and Drug Administration (FDA) announcement on the future of partially hydrogenated oils. In 2013, the FDA made a tentative decision to re-label partially hydrogenated oils from “generally recognized as safe (GRAS)” to not generlly recognzed as safe pending a 60-day discussion open to the U.S. public [3,20]. Such a change in GRAS standing would effectively ban all partially hydrogenated oils from food products in the U.S. [21]. The overwhelming majority of the discussion on the FDA’s Federal Register is that of dieticians and the scientific community in support of a ban on partially hydrogenated oils in foodstuffs [20]. Such an action would prompt the FDA to find a way to phase out the use of partially hydrogenated oils over time [3].

It must not be forgotten however that hydrogenated fats and oils prevent rancidity and are used in foods to improve stability and lengthen shelf life because TFAs have greater stability than //cis// fats [1,14]. Despite their preservative properties, the health risks are staggering. In a review on the exact increase in rate of coronary heart disease as a result of increased TFA intake, it was determined that a 2% increase in total fat from strictly TFAs was associated with a 23% increased incidence of CHD [2]. This striking figure proposes how at risk people who use food products such as margarine, lard, and processed foodstuffs on a daily basis are of getting cardiovascular diseases. Based on a two thousand calorie diet and a conservative 33% energy from fat dietary guideline, a 2% increase in total fat is a mere 1.4g of TFAs per day. Trends in TFA content have been on a general decline since 2001[1,10], but processed food like popcorn and pie pose the greatest risks [10]. **Figure 3** [10]. One serving of popcorn every other day would therefore increase one’s total TFA intake by over 2% of total energy.


 * Figure 3** [10]. Average TFA content from 2007 through 2011 of different foodstuffs containing at least 0.5 g/serving TFA in 2007, by food categories [10]. “All products listing 0 g TFA but still containing partially hydrogenated oils in the ingredients list were considered to still contain 0.25 g per serving of TFA” [10].

In accordance with both the GRAS consideration of partially hydrogenated oils from the FDA [20] and the recommendation of EU scientific advisors [11] it is not surprising why these governmental bodies enacted such scrutiny on the presence of TFAs in foods. However, as a result of the increased scrutiny of //trans// fats in the past two decades, there has also sprouted an increasing awareness of the adverse health effects of partially hydrogenated oils and an even greater push by the public to remove those partially hydrogenated oils wherever possible [1], independent of the FDA’s decision. This is seen in the trend of replacing TFAs with natural fat alternatives and a general reduction of TFA content since 2001 [1,10]. Even McDonald’s has seen a reduction in its TFA content, although it has not been entirely eradicated of them [21]. Although partially hydrogenated oils were created to act as a healthy substitute to saturated fats [1] which have a long history of increased risk of cardiovascular disease and similar adverse effects on lipoprotein concentrations themselves, TFAs affect lipid levels more negatively than saturated fatty acids (SFAs) [15]. There is concern that removal of TFAs will simply be replaced by SFAs [21], causing similar adverse health effects while losing all the benefits of TFAs.

Industry Alternatives and Moving Forward:
If such a transition, an entire TFA to SFA shift, were to occur, prices of processed foods would likely increase [2] as a result of the shorter shelf-life of SFAs as compared to TFAs. However, the concern over this price spike is likely overstated. For instance, restaurants in Philadelphia, New York, and California, among others, have already cut back on their use of TFAs in the kitchen [21]. And further removal of //trans// fats will likely influence the costs of processed and "fast" foods more severely than the costs of market or restaurant foods. Albeit a difficult task, similar rulings in Denmark have shown that complete removal of TFAs is achievable, even by large "fast" food companies [22]. By requiring that food, whether made locally or imported, must contain less than 2% industrially produced TFAs in 2004, Denmark nearly eliminated the use of partially hydrogenated vegetable oils altogether [22]. It was largely the case that replacements in TFA containing foodstuffs were in favor of unsaturated fatty acids, saturated fatty acids, ad fully hydrogenated oils in that order [22].

The ideal, most beneficial, transition would be that of TFAs to be replaced by unsaturated, //cis// fats. If TFAs were to be replaced with unhydrogenated, //cis// fatty acids, as many as 12 to 22% of cases of CHD in the U.S. could be prevented [2]. Such a statistic provides warrant to the assertion that partially hydrogenated oils should be labeled as "not generally recognized as safe" and offers significant health benefits to lay persons who otherwise are unaware of TFAs adverse health effects. Those at an even higher risk are the poor and uneducated with less education on the ingredients contained in processed and "fast" foods. There is also promising work being done on conjugated unsaturated //cis// fats, such as omega fatty acids including conjugated linoleic acids, not as a replacement for TFAs, but rather an addition to one’s diet with prospects for increasing high-density lipoprotein levels as well as HDL-cholesterol levels [23]. A supplement to HDL could provide a solution to unbalanced HDL:LDL levels created by TFAs if a 2% rule were to be instituted like in Denmark [22], rather than a complete removal of TFAs.

Conclusion:
It is evident herein that not only do partially hydrogenated oils contain TFAs, but also that those TFAs have a compounded adverse effect on cardiovascular and coronary health. Subsequently, there is little, if any, evidence for the FDA to abandon its tentative assessment of partially hydrogenated oils as “not generally recognized as safe." However, it is recommended that in weaning the U.S. off of //trans// fats from partially hydrogenated oil sources that fat energy is replaced with unsaturated, //cis// fats as opposed to starches or carbohydrates due to potential increased health benefits [2]. Such measures could prevent a significant number of CHD patients in the U.S. each year [2]. While TFA content in processed foodstuffs has been on a downward trend over the past decade [1,10], FDA regulation may eliminate those remaining goods, such as popcorn and pies, which still have a comparatively high TFA content [10].