Impact of Dietary Fats on Cardiovascular Disease: History
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Contributor:
Aldo Pietro Maggioni
,
Giuseppe Poli
,
Pier Mannuccio Mannucci

Dietary habits have major implications as causes of death globally, particularly in terms of cardiovascular disease, but to precisely define the role of the single components of diet in terms of cardiovascular risk is not an easy task. As an example, complex and multifactorial are the possible nutritional or detrimental effects of dietary fats, due to the huge variety of lipid metabolites originating from either the enzymatic or non-enzymatic oxidation of polyunsaturated fatty acids, cholesterol and phospholipids. The area of research that has allowed the benefit/risk profile of a dietary supplement to be tested with controlled studies is that of omega-3 fatty acids. Omega-3 fatty acids have showed a potential therapeutic role only in secondary cardiovascular prevention, while controlled studies in primary prevention have consistently produced neutral results.

  • dietary fats
  • fat oxidation
  • nutritional research

1. Which Foods, or Food Shortages, Can Impact Mortality in Different AREAS of the World? What Kind of Non-Communicable Disease Can Be Impacted by Different Dietary Habits?

A very comprehensive publication discussing this topic has been recently published [1]. A systematic analysis from the Global Burden of Disease study, an initiative sponsored by the Melinda and Bill Gates Foundation, evaluated in 2017 across 195 different countries the role of the consumption of foods and nutrients or their suboptimal intake on the mortality and morbidity for non-communicable diseases. In 2017, cardiovascular disease was the leading cause of food-related deaths globally (10 million deaths), followed by cancer (913,090 deaths) and type 2 diabetes (338,714 deaths) (Figure 1). Although the impact of individual dietary factors varied between countries, the suboptimal intake of three dietary elements (low intake of whole grains and fruits, high intake of sodium) accounted for more than 50% of diet-attributable deaths (Figure 1).
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Figure 1. Unbalanced dietary factors, incidence/type of non-communicable diseases and deaths in 195 countries, in 2017 [1].
Therefore, although sodium, sugar and fat have been the main focus of dietary policy recommendations for the past two decades, some studies demonstrates that the main dietary risk factors for mortality are diets high in sodium, low in whole grains, low in fruit, nuts and seeds, low in vegetables and low in omega-3 fatty acids. These data suggest that dietary policies that focus on promoting the intake of dietary components for which the actual intake is under the optimal level may have a greater effect than policies targeting only sugar and fat reduction. Given the complexity of eating behaviors, diet improvement requires the active collaboration of a variety of actors across the food system, along with policies targeting multiple sectors of the food system [1].

2. Is It True That the Consumption of Saturated Fat Has a Negative Impact on Cardiovascular Mortality?

Recently, a review on the state of the art on the role of saturated fat intake on health profiles was published [2]. Their review also allowed a reassessment of the current guideline recommendations regarding food intake and suggested some proposals for their modification. The authors emphasized that the US dietary guidelines [3] recommend limiting the intake of saturated fatty acid (SFA) to <10% of total calories in order to reduce cardiovascular disease, despite evidence that a number of foods containing saturated fat, including dairy products such as yogurt, dark chocolate and unprocessed meat, are not associated with an increased risk of cardiovascular disease or diabetes [4][5][6][7]. The authors concluded that there was no solid evidence that the limits on saturated fat consumption, currently recommended by the U.S. guidelines, are able to prevent cardiovascular diseases or reduce mortality [2].

3. We Are Confronted with More Doubts Than Certainties: How Reliable Is Nutritional Epidemiology Research?

Ioannidis et al. [8] stated that the identified epidemiological associations of nutritional factors are often considered as causal effects, with the consequence to generate recommendations in public health guidelines. However, it is well known that associations do not mean causality. In recent meta-analyses of prospective cohort studies, nearly all foods revealed statistically significant associations with mortality risk [9][10]. Eating patterns are associated with many social and behavioral factors that vary over time, can affect health but cannot be fully taken into account as confounding factors in the analyses of available studies [11][12]. In other words, no current epidemiological cohort includes sufficient information that takes into account all the confounding factors typical of nutritional associations. Much of the literature assumes that the risk of disease is determined by the excess intake of certain components of food such as, for instance, carbohydrates or fats. However, chemical elements contained in food processing, contaminants and components that appear only in conditions or methods of food preparation (for example, cooking red meat) can affect the results. Further, nutrient combinations that confer potential cardiovascular risks may vary depending on the individual genetic background, metabolic profile, age and environmental exposure. Thus, untangling the potential influence of a single dietary component on a specific disease or mortality is difficult, if not impossible. Ioannidis concluded that readers and guideline developers generally ignore statements of causal inference and advocacy to public policy made by available nutritional epidemiology articles [8]. Observational studies, typical of nutritional epidemiology, are indeed unable to provide causal relationships between different food intake and risk of morbidity/mortality, they only provide evidence of associations [13]. Statements in guideline recommendations based only on observational studies should be avoided. For example, the US dietary guidelines, which recommend limiting the intake of saturated fatty acids to less than 10% of total calories in order to prevent the onset of cardiovascular disease, are not based on truly reliable scientific documentation [1].

4. From Uncertainties to Facts: What Are the Mechanisms Underlying the Metabolic Effects of Dietary Fats?

Complex and multifactorial are the possible nutritional or detrimental effects of dietary fats, because of the huge variety of lipid metabolites originating from either the enzymatic or non-enzymatic oxidation of polyunsaturated fatty acids (PUFA), cholesterol and phospholipids (Figure 2). Of note, enzymatically driven lipid oxidation is a biochemical process commonly regulated by negative feedback mechanisms and substrate availability, while the lipid autoxidation occurs randomly and can often overwhelm the physiological antioxidant system (Figure 2).
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Figure 2. Enzymatic and non-enzymatic products of lipid oxidation.
Focusing on PUFA oxidation, the enzymatic metabolism of omega-3 PUFA is well known to lead to products provided with anti-inflammatory and immunomodulatory properties [14]. Omega-3 competes with omega 6 PUFA as a substrate for cyclooxygenase and lipoxygenase, and in this way counteracts an excessive production of this second type of PUFA metabolites, some of them being strong pro-inflammatory mediators, thus potentially interfering with vascular homeostasis [14]. Recent clinical trial results suggest that increasing the intake of foods rich in omega-3 PUFA is beneficial for hypertension, also because of their metabolic products, namely omega-3 oxylipins, that reduce oxidative stress, protect the function of various membrane-related proteins and compete with omega-6 oxylipins in regulating vasodilator release [15].
Moreover, PUFA autoxidation products are easily generated by food heating, light exposure and/or improper storage, but at least the major omega-3 PUFA autoxidation product, namely 4-hydroxyhexenal, was shown to be much less cytotoxic than the corresponding omega-6 PUFA autoxidation product 4-hydroxynonenal (Figure 2) [16].
As for the omega-6 PUFA-derived 4-hydroxynonenal, a potential contribution to the pathogenesis of cardiovascular diseases appears to be given by oxidative derivatives of cholesterol (Figure 2), some of them clearly demonstrated to exert pro-atherogenic effects when present in excessive amounts [17].

This entry is adapted from the peer-reviewed paper 10.3390/jcm11226652

References

  1. GBD 2017 Diet Collaborators. Health effects of dietary risks in 195 countries, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2019, 393, 1958–1972.
  2. Astrup, A.; Magkos, F.; Bier, D.M.; Brenna, J.T.; De Oliveira Otto, M.C.; Hill, J.O.; King, J.C.; Mente, A.; Ordovas, J.M.; Volek, J.S.; et al. Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 76, 844–857.
  3. Mozaffarian, D.; Rosenberg, I.; Uauy, R. History of modern nutrition science-implications for current research, dietary guidelines, and food policy. BMJ 2018, 361, k2392.
  4. De Souza, R.; Mente, A.; Maroleanu, A.; Cozma, I.A.; Ha, V.; Kishibe, T.; Uleryk, E.; Budylowski, P.; Schünemann, H.; Beyene, J.; et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: Systematic review and meta-analysis of observational studies. BMJ 2015, 351, h3978.
  5. Harcombe, Z.; Baker, J.S.; Davies, B. Evidence from prospective cohort studies does not support current dietary fat guidelines: A systematic review and meta-analysis. Br. J. Sports Med. 2017, 51, 1743–1749.
  6. Ramsden, C.E.; Zamora, D.; Majchrzak-Hong, S.; Faurot, K.; Broste, S.K.; Frantz, R.; Davis, J.M.; Ringel, A.; Suchindran, C.M.; Hibbeln, J.R. Re-evaluation of the traditional diet-heart hypothesis: Analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ 2016, 353, i1246.
  7. Siri-Tarino, P.W.; Sun, Q.; Hu, F.B.; Krauss, R.M. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am. J. Clin. Nutr. 2010, 91, 535–546.
  8. Ioannidis, J.P.A. The Challenge of Reforming Nutritional Epidemiologic Research. JAMA 2018, 320, 969–970.
  9. Schwingshackl, L.; Schwedhelm, C.; Hoffmann, G.; Lampousi, A.-M.; Knüppel, S.; Iqbal, K.; Bechthold, A.; Schlesinger, S.; Boeing, H. Food groups and risk of all-cause mortality: A systematic review and meta-analysis of prospective studies. Am. J. Clin. Nutr. 2017, 105, 1462–1473.
  10. Poole, R.; Kennedy, O.J.; Roderick, P.; Fallowfield, J.A.; Hayes, P.C.; Parkes, J. Coffee consumption and health: Umbrella review of meta-analyses of multiple health outcomes. BMJ 2017, 359, j5024.
  11. Trepanowski, J.F.; Ioannidis, J.P.A. Perspective: Limiting Dependence on Nonrandomized Studies and Improving Randomized Trials in Human Nutrition Research: Why and How. Adv. Nutr. 2018, 9, 367–377.
  12. Ioannidis, J.P. Implausible results in human nutrition research. BMJ 2013, 347, f6698.
  13. Prasad, V.; Jorgenson, J.; Ioannidis, J.P.; Cifu, A. Observational studies often make clinical practice recommendations: An empirical evaluation of authors’ attitudes. J. Clin. Epidemiol. 2013, 66, 361–366.
  14. Endo, J.; Arita, M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J. Cardiol. 2016, 67, 22–27.
  15. Wang, H.; Li, Q.; Zhu, Y.; Zhang, X. Omega-3 Polyunsaturated Fatty Acids: Versatile Roles in Blood Pressure Regulation. Antioxid Redox Signal. 2021, 34, 800–810.
  16. Sottero, B.; Leonarduzzi, G.; Testa, G.; Gargiulo, S.; Poli, G.; Biasi, F. Lipid Oxidation Derived Aldehydes and Oxysterols Between Health and Disease. Eur. J. Lipid Sci. Technol. 2019, 121, 1700047.
  17. Gargiulo, S.; Testa, G.; Gamba, P.; Staurenghi, E.; Poli, G.; Leonarduzzi, G. Oxysterols and 4-hydroxy-2-nonenal contribute to atherosclerotic plaque destabilization. Free Radic. Biol. Med. 2017, 111, 140–150.
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