Hipótesis dieta-corazón

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La hipótesis dieta-corazón (o hipótesis lipídica) postula que la reducción de las grasas saturadas en la dieta reduce el colesterol sérico, disminuyendo el depósito de colesterol en la pared arterial, lo que reduce el riesgo de enfermedad cardiovascular (ECV),[1]​[2]​[3]​ la que incluye entre sus manifestaciones a la enfermedad coronaria, la insuficiencia cardíaca, el accidente cerebrovascular y la hipertensión;[4]​ en concordancia con ello, las pautas dietéticas recomiendan restringir la ingesta de grasas saturadas.[5]​[6]​

La gran cantidad de evidencia científica indica que el colesterol total y el colesterol LDL (lipoproteína de baja densidad), a menudo denominado 'colesterol malo', contribuyen a las enfermedades cardíacas;[7]​[8]​ sin embargo, existe evidencia que no encuentra relación de causalidad entre la ingesta de grasas saturadas y las enfermedades cardiovasculares; asimismo, hay estudios que evidencian una relación inversa entre la ingesta de grasa saturada y la salud cardiovascular; además la sustitución de grasas saturadas por grasas poliinsaturadas omega 6 no se traduce en una disminución del riesgo de padecer enfermedades cardiovasculares;[9]​ en tal sentido, los datos sugieren que el colesterol LDL por sí solo no es un predictor consistentemente bueno o una causa del riesgo de ECV;[10]​ consecuentemente, existen opiniones de que las pautas dietéticas globales deben reconsiderarse.[11]​

Historia[editar]

Véase también: Ancel Keys

La hipótesis de que las grasas saturadas causan CVD surgió a fines de la década de 1950, cuando los científicos observaron que estas grasas tienden a elevar la concentración de colesterol sérico total, que a su vez se consideraba un potente factor de riesgo de enfermedad cardíaca.[12]​ A partir de 1961, la Asociación Estadounidense del Corazón (AHA) recomendó a todos los hombres (y posteriormente a las mujeres) disminuir el consumo de grasas saturadas, reemplazándolas siempre que sea posible con aceites vegetales poliinsaturados, como la medida más prometedora de protección contra las enfermedades del corazón.[13]​[14]​ La hipótesis dieta-corazón ganó amplia aceptación en las décadas de 1970 y 1980.[15]​ El Comité Selecto de Nutrición y Necesidades Humanas del Senado de los Estados Unidos publicó los Objetivos Dietéticos para los Estados Unidos en 1977, que recomendaban que el público "reduzca el consumo de grasas saturadas para que represente aproximadamente el 10% de la ingesta total de energía..."[16]​

A pesar de que el público estadounidense sigue las recomendaciones para disminuir la ingesta absoluta de grasas en la dieta y específicamente disminuir la ingesta de grasas saturadas, se ha visto un aumento dramático en los últimos 40 años en las tasas de enfermedades cardiovasculares.[6]​

Numerosos metanálisis y revisiones sistemáticas de la literatura histórica y actual revelan que la hipótesis dieta-corazón no estaba, y aún no está, respaldada por la evidencia.[17]​ La primera compilación completa de argumentos sobre por qué las grasas saturadas no son malas para la salud fue publicada por Gary Taubes en los 2000.[18]​

Recomendaciones[editar]

Reino Unido recomienda, sobre las grasas saturadas, que no incluya más del 11% de las calorías de alimentos y bebidas, mientras que Estados Unidos y la Organización Mundial de la Salud recomiendan menos del 10%.[19]​[8]​

La aplicación de las recomendaciones, que además de estar centradas en limitar las grasas, especialmente las grasas saturadas, también lo están en una mayor ingesta de carbohidratos, ha coincidido con epidemias de obesidad y diabetes tipo 2 que están contribuyendo a la progresión de enfermedades cardiovasculares y otras enfermedades crónicas relacionadas con la alimentación.[20]​ La ingesta excesiva de carbohidratos fue reconocida por los Comités Asesores de Guías Alimentarias; el comité de 2000 expresó su preocupación de que el consejo del gobierno sobre el bajo contenido de grasas “podría generar un consumo excesivo de calorías totales en forma de carbohidratos, lo que daría lugar a las consecuencias metabólicas adversas de las dietas altas en carbohidratos”, y agregó: “Además, la posibilidad de que el consumo excesivo de carbohidratos puede contribuir a la obesidad no puede ser ignorada”.[21]​

La AHA y científicos individuales recomiendan el consumo de al menos 5-10 % de la energía como ácidos grasos poliinsaturados (AGPI) ω6 para reducir el riesgo de cardiopatía coronaria.[22]​

Fisiología[editar]

Del incremento de colesterol sérico[editar]

Algunos estudios refieren que una mayor ingesta de grasas saturadas proporciona sustratos para la síntesis de colesterol en forma de acetil-CoA.[23]​

Zinöcker, Svendsen y Nitter han propuesto el modelo de adaptación homeoviscosa a los lípidos dietéticos (HADL), que explica los cambios en el colesterol de lipoproteínas como ajustes homeostáticos adaptativos que sirven para mantener la fluidez de la membrana celular y, por lo tanto, una función celular óptima.[24]​ La base del modelo es que cuando las grasas saturadas reemplazan a las grasas poliinsaturadas en la dieta, se necesita menos colesterol en las membranas celulares, debido a que las grasas poliinsaturadas de la dieta entran en las membranas celulares y las hacen más fluidas; las células ajustan la fluidez de sus membranas incorporando colesterol reclutado del torrente sanguíneo.[25]​ Asimismo, de acuerdo con el modelo, la desregulación de la captación de colesterol es causada por la endotoxemia, que provoca inflamación y, por lo tanto, impide la captación de colesterol a través de los receptores de colesterol LDL.[26]​

Del depósito de colesterol en la pared arterial[editar]

Artículo principal: Ateroesclerosis

Se considera que cuando existe un exceso de colesterol se deposita en nuestras arterias engrosando las paredes de éstas.[27]​ Al respecto se asume que la retención subendotelial de lipoproteínas inicia la arterioesclerosis coronaria; sin embargo, de acuerdo con Subbotin, los depósitos iniciales de lípidos ocurren en las capas más profundas de la túnica íntima y que la enfermedad comienza con la expansión patológica de la íntima, lo que resulta en hipoxia de la íntima y neovascularización de los vasa vasorum adventicios, lo que facilita la extracción de lipoproteínas por los tejidos de la íntima profunda previamente avasculares.[28]​[29]​[30]​

Traunmüller propone la hipótesis de que cuando las células madre vasculares multipotentes se exponen a un exceso de insulina en un patrón rítmico de concentraciones que aumentan y disminuyen bruscamente, su diferenciación se desvía hacia linajes celulares adipogénicos y osteogénicos. Esto da como resultado una acumulación similar a una placa de adipocitos con depósito de grasa y colesterol a partir de restos de adipocitos y células osteogénicas (progenitoras) con una matriz calcificada en lesiones avanzadas. El crecimiento interno de capilares y la infiltración con macrófagos, que tras la absorción de lípidos se convierten en células espumosas, son reacciones pro-resolución inespecíficas.[31]​

De acuerdo con la hipótesis del ácido linoleico oxidado, se cree que el LDL oxidado (OxLDL) juega un papel importante en la formación de aterosclerosis, ello considerando que mayores cantidades de productos de oxidación del ácido linoleico se encuentran en LDL y plasma de pacientes con aterosclerosis y que el ácido linoleico es la grasa más abundante que se encuentra en las placas ateroscleróticas; sin embargo, es el ácido linoleico oxidado contenido en las LDL el que conduce a metabolitos del ácido linoleico oxidado (OXLAM) nocivos, que inducen la aterosclerosis y la cardiopatía coronaria.[32]​[33]​

Un aumento en la ingesta de ácido linoleico aumenta el contenido de ácido linoleico de las lipoproteínas de muy baja densidad (VLDL) y las lipoproteínas de alta densidad (HDL), aumentando su susceptibilidad a la oxidación, lo que aumenta aún más el riesgo de enfermedad cardiovascular.[34]​

Controversias[editar]

En consideración de la evidencia en contra de la hipótesis, de acuerdo con Ranskov, esta se mantiene porque los hallazgos supuestamente de apoyo, pero insignificantes, se inflan, y porque la mayoría de los resultados contradictorios se malinterpretan, se citan incorrectamente o se ignoran.[35]​ De otro lado, como lo advierte, las personas con niveles bajos se vuelven tan ateroscleróticas como las personas con niveles altos y su riesgo de sufrir ECV es igual o mayor.[36]​

Durante algunos años, muchos investigadores han cuestionado los resultados de los ensayos con estatinas porque se les ha negado el acceso a los datos primarios. Entre 2004-2005, las autoridades sanitarias de Europa y los Estados Unidos introdujeron las Nuevas Normas de Ensayos Clínicos, que especificaban que todos los datos de los ensayos debían hacerse públicos. Desde 2005, las afirmaciones de beneficio de los ensayos con estatinas prácticamente han desaparecido.[37]​

Añadido a ello, existen predictores emergentes de mortalidad por todas las causas y cardiovascular en la población general, tales como la proporción entre monocitos y lipoproteínas de alta densidad-colesterol (MHR, por sus siglas en inglés).[38]​

El reconocimiento de la aterogénesis como un proceso activo en lugar de una enfermedad de almacenamiento de colesterol o un depósito de calcio ha puesto de relieve algunos mecanismos inflamatorios clave.[39]​ De acuerdo con los conocimientos actuales, la aterosclerosis es una enfermedad multifactorial que implica la alteración del metabolismo de los lípidos, el aumento del estrés oxidativo, el deterioro de la función mitocondrial y la inflamación crónica.[40]​ Como resultado de la complejidad de este fenómeno, existe un acuerdo generalizado entre los investigadores de que determinar los parámetros del metabolismo de los lípidos no es suficiente para predecir lo que sucede en la capa subendotelial arterial.[41]​

Datos experimentales y clínicos sugieren que reducir la inflamación sin afectar los niveles de lípidos puede reducir el riesgo de enfermedad cardiovascular;[42]​ por ejemplo, en el Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), presentado en el Congreso de la Sociedad Europea de Cardiología (ESC) en Barcelona y publicado simultáneamente en el New England Journal of Medicine, la terapia antiinflamatoria dirigida a la vía de la inmunidad innata de la interleucina-1β con canakinumab, un anticuerpo monoclonal terapéutico, a una dosis de 150 mg cada 3 meses produjo una tasa significativamente menor de eventos cardiovasculares recurrentes que el placebo, independientemente de la reducción del nivel de lípidos.[43]​[44]​[45]​ El estudio Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reveló que los hombres y las mujeres con LDL-C bajo pero marcadores elevados de inflamación local de bajo grado (proteína C reactiva de alta sensibilidad (hs-CRP)) mostraron un importante riesgo cardiovascular. Los participantes que lograron hs-CRP de menos de 1 mg/L tuvieron una reducción del 79 % en los eventos vasculares y alcanzaron concentraciones de hsCRP que predijeron las tasas de eventos independientemente del punto final de lípidos.[41]​[46]​

Evidencia a favor[editar]

Ference demostró que, en primer lugar, la concentración de colesterol LDL es un factor de riesgo de ECV; y, en segundo lugar, una reducción terapéutica de este se asocia con una reducción del riesgo de ECV.[47]​

El Minnesota Coronary Experiment (MCE), un ensayo controlado aleatorizado realizado entre 1968 y 1973, fue el ensayo dietético más grande y quizás el más rigurosamente ejecutado para reducir el colesterol mediante el reemplazo de grasas saturadas con aceite vegetal rico en ácido linoleico. Sin embargo, posteriores hallazgos de publicación incompleta sugieren una sobreestimación de los beneficios y subestimación de los riesgos potenciales de reemplazar grasas saturadas con aceites vegetales ricos en ácido linoleico.[48]​[49]​[50]​

En relación con la recomendación del consumo de AGPI ω6, los metanálisis de Gordon y Rifkin y de Mozaffarian, Micha y Wallace respaldan la propuesta de que los AGPI en general, y los AGPI ω6 en particular, son cardioprotectores;[51]​ sin embargo, las dietas experimentales de los ensayos clínicos controlados y aleatorizados (ECA) incluidos en el metanálisis de Mozaffarian reemplazaron las margarinas "duras" comunes, las mantecas industriales y otras fuentes de ácidos grasos trans (AGT),[52]​ lo que explicaría la reducción en eventos de cardiopatía coronaria.[53]​

Evidencia en contra[editar]

En las décadas de 1960 y 1970 se llevaron a cabo grandes ECA, en los que las grasas saturadas se reemplazaron por grasas poliinsaturadas de aceites vegetales; estos ensayos proporcionaron poco apoyo a la hipótesis.[54]​

De acuerdo con Ramsden, ningún ECA ha demostrado que el reemplazo de grasas saturadas con ácido linoleico reduzca significativamente los eventos de enfermedad coronaria o las muertes.[2]​ Al respecto, su metanálisis revisado de ECAs publicado en 2010 mostró que la sustitución de ácidos grasos (AG) saturados por AGPI ω6 sin aumentar simultáneamente AGPI ω3 no presenta indicios de beneficio e incluso es probable que aumente el riesgo de ECV;[55]​ en ese sentido, consideró que se debe hacer una distinción clara entre los AGPI ω6 y ω3 en futuros metanálisis, revisiones, editoriales y avisos de salud pública.[56]​

El estudio de Framingham, que comenzó en 1948 y aún continúa, ha estado siguiendo el consumo de grasas en la dieta y el desarrollo de enfermedades del corazón entre sus más de 5000 habitantes, elegidos de Framingham, Massachusetts. Al final del primer seguimiento, los investigadores no pudieron encontrar ninguna correlación entre la ingesta de grasas, el colesterol y las enfermedades cardíacas.[57]​

El ensayo del Club Anti-Coronario encontró que más personas murieron en general y debido a enfermedades del corazón cuando se reemplazó la grasa saturada con grasa poliinsaturada.[58]​

Los hallazgos del estudio Prospective Urban Rural Epidemiology (PURE), un gran estudio epidemiológico de cohortes de personas de 35 a 70 años en 18 países con una mediana de seguimiento de 7·4 años, determinaron que la ingesta alta de carbohidratos se asoció con un mayor riesgo de mortalidad total, mientras que la grasa total y los tipos individuales de grasa se relacionaron con una mortalidad total más baja. La grasa total y los tipos de grasa no se asociaron con enfermedad cardiovascular, infarto de miocardio o mortalidad por enfermedad cardiovascular, mientras que la grasa saturada tuvo una asociación inversa con el accidente cerebrovascular.[59]​[11]​[60]​[61]​[62]​

Varios estudios japoneses han encontrado que el LDL-C no es un factor de riesgo de mortalidad por CHD en mujeres de cualquier edad. Hamazaki et al. concluyó: "La teoría de que cuanto más bajos son los niveles de colesterol, mejor es completamente errónea en el caso de Japón; de hecho, es exactamente lo contrario" y "parece claro que los niveles altos de colesterol no deben considerarse nocivos para la salud, especialmente en los ancianos".[63]​

Un estudio realizado por Mozaffarian y sus colegas encontró que las mujeres posmenopáusicas con un mayor consumo de grasas saturadas tenían menos progresión de la aterosclerosis coronaria (cuando se mide como porcentaje de estenosis y diámetro mínimo de la arteria coronaria).[64]​

A pesar de la utilización generalizada de estatinas para reducir el colesterol en Europa, los estudios observacionales indican que no ha habido una disminución concomitante en las muertes por enfermedad coronaria;[65]​ en una revisión de 16 ensayos angiográficos para reducir el colesterol, donde los autores habían calculado la exposición-respuesta, la correlación entre el colesterol y la ateroesclerosis solo estaba presente en uno de ellos, y en ese ensayo, el único tratamiento era el ejercicio.[66]​

Hipótesis alternativas[editar]

La hipótesis inflamatoria de la aterosclerosis[editar]

La comprensión actual de los mecanismos inflamatorios de la aterosclerosis ha llevado a la exploración de la hipótesis de que atacar la inflamación en sí misma reducirá los eventos y riesgos cardiovasculares.[45]​

Exiten biomarcadores de respuesta inflamatoria, un proceso clave en la aterosclerosis, entre ellos:[67]​

  1. CRP, una de las proteínas de fase aguda producida principalmente por el hígado en respuesta a la inflamación de bajo grado subyacente a la aterosclerosis;
  2. interleucina 6 (IL-6); una citocina proinflamatoria secretada, entre otras, por las células del músculo liso de la túnica media, cuyo papel principal consiste en activar los procesos inflamatorios y autoinmunes;
  3. Lp-PLA2, una enzima asociada con las vías tradicionales (ligada al colesterol) y novedosas (inflamatorias) de la aterosclerosis, que es sintetizada por las células inflamatorias y se une principalmente al LDL-C, con una pequeña fracción unida al HDL-C.

La 'teoría del ácido linoleico oxidado de la cardiopatía coronaria'[editar]

El ácido linoleico de la dieta, especialmente cuando se consume a partir de aceites vegetales omega-6 refinados, se incorpora a todas las lipoproteínas de la sangre (como LDL, VLDL y HDL) aumentando la susceptibilidad de que todas las lipoproteínas se oxiden y, por lo tanto, aumenta el riesgo cardiovascular.[68]​

Al respecto, se ha descubierto que los lípidos de las placas ateroscleróticas humanas contienen linoleato de colesterol oxidado (ésteres de colesterol que contienen ácido linoleico),[69]​ y, mientras que el colesterol está protegido de la oxidación si se une a grasas saturadas, es susceptible a la oxidación cuando se une al ácido linoleico.[70]​

En la oxidación de LDL, el ácido linoleico se convierte en hidroperóxidos, que luego se pueden convertir en hidroxiácidos, como 9-HODE (ácido 9-hidroxi-10,12-octadecadienoico). 9-HODE es extremadamente frecuente en las LDL oxidadas y es un buen indicador de la peroxidación lipídica.[71]​

Patrones dietéticos alternativos[editar]

Las dietas bajas en carbohidratos, que se basan en el lapso de tiempo de la evolución humana, tienen principios bioquímicos bien establecidos y ahora están respaldadas por múltiples ensayos clínicos en humanos que demuestran mejoras consistentes en múltiples factores de riesgo establecidos asociados con la resistencia a la insulina y la enfermedad cardiovascular (ECV).[72]​ Puesto que la diabetes mellitus tipo 2, el síndrome metabólico y las comorbilidades relacionadas son los principales factores de riesgo de ECV, una dieta destinada a apoyar la salud cardiovascular debería mejorar o revertir estos factores de riesgo subyacentes.[73]​ Recientes informes de consenso de organizaciones nacionales han respaldado las dietas bajas en carbohidratos para mejorar la glucemia y el riesgo cardiovascular. La reticencia entre las organizaciones de salud pública y algunos médicos para promover más ampliamente este enfoque nutricional terapéutico se debe principalmente al aumento del colesterol LDL en suero observado en una proporción de personas que adoptan una dieta baja en carbohidratos.[74]​

Referencias[editar]

  1. ↑ DuBroff, Robert; de Lorgeril, Michel (29 de mayo de 2019). «Fat or fiction: the diet-heart hypothesis». BMJ Evidence-Based Medicine 26 (1): 3-7. ISSN 2515-446X. doi:10.1136/bmjebm-2019-111180. Consultado el 26 de diciembre de 2022. «The concept that diet, serum cholesterol and cardiovascular disease are causally related gave rise to the diet-heart hypothesis nearly 70 years ago. This hypothesis postulates that reducing dietary saturated fat reduces serum cholesterol, thereby reducing the risk of cardiovascular disease. Today, this concept has been transformed from a hypothesis into public health policy as current guidelines recommend reducing the intake of dietary saturated fat.» 
  2. ↑ a b Ramsden, Christopher E; Zamora, Daisy; Majchrzak-Hong, Sharon; Faurot, Keturah R; Broste, Steven K; Frantz, Robert P; Davis, John M; Ringel, Amit et al. (12 de abril de 2016). «Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)». BMJ: i1246. ISSN 1756-1833. doi:10.1136/bmj.i1246. Consultado el 26 de diciembre de 2022. «The traditional diet-heart hypothesis1 2 predicts that the serum cholesterol lowering effects of replacing saturated fat with vegetable oil rich in linoleic acid will diminish deposition of cholesterol in the arterial wall,3 4 slow progression of atherosclerosis,5 reduce coronary heart disease events, and improve survival.6 7 This diet-heart paradigm is supported by evidence from randomized controlled trials showing that replacement of saturated fat with linoleic acid lowers serum total cholesterol and low density lipoprotein8 9 10 11 12 and by observational evidence linking serum cholesterol to coronary heart disease events and deaths (fig 1⇓).13 Despite these compelling relations, no randomized controlled trial has shown that replacement of saturated fat with linoleic acid significantly reduces coronary heart disease events or deaths (fig 1⇓).» 
  3. ↑ Pescador, Darío (4 de julio de 2019). «El queso y la paradoja francesa». elDiario.es. Consultado el 26 de diciembre de 2022. «Según la hipótesis lipídica, al sustituir la grasa saturada con grasa poliinsaturada (ácido linoléico, presente en grandes cantidades en aceites refinados de semillas como girasol, maíz y soja) se reduce el colesterol LDL y con ello el riesgo de enfermedades cardiovasculares. Por eso hay margarina de soja en tu supermercado y se vende como más saludable que la mantequilla.» 
  4. ↑ Papotti, Bianca; Escolà-Gil, Joan Carles; Julve, Josep; Potì, Francesco; Zanotti, Ilaria (2021-08). «Impact of Dietary Lipids on the Reverse Cholesterol Transport: What We Learned from Animal Studies». Nutrients (en inglés) 13 (8): 2643. ISSN 2072-6643. doi:10.3390/nu13082643. Consultado el 7 de enero de 2023. «Atherosclerosis is a common mechanism of various manifestations of CVD, including coronary heart disease, heart failure, stroke, and hypertension.» 
  5. ↑ DiNicolantonio, James J.; Lucan, Sean C.; O’Keefe, James H. (2016-03). «The Evidence for Saturated Fat and for Sugar Related to Coronary Heart Disease». Progress in Cardiovascular Diseases 58 (5): 464-472. ISSN 0033-0620. doi:10.1016/j.pcad.2015.11.006. Consultado el 26 de diciembre de 2022. «Dietary guidelines continue to recommend restricting intake of saturated fats. This recommendation follows largely from the observation that saturated fats can raise levels of total serum cholesterol (TC), thereby putatively increasing the risk of atherosclerotic coronary heart disease (CHD).» 
  6. ↑ a b Gershuni, Victoria M. (1 de septiembre de 2018). «Saturated Fat: Part of a Healthy Diet». Current Nutrition Reports (en inglés) 7 (3): 85-96. ISSN 2161-3311. doi:10.1007/s13668-018-0238-x. Consultado el 26 de diciembre de 2022. «Despite the American public following recommendations to decrease absolute dietary fat intake and specifically decrease saturated fat intake, we have seen a dramatic rise over the past 40 years in the rates of non-communicable diseases associated with obesity and overweight, namely cardiovascular disease. The development of the diet-heart hypothesis in the mid twentieth century led to faulty but long-held beliefs that dietary intake of saturated fat led to heart disease. Saturated fat can lead to increased LDL cholesterol levels, and elevated plasma cholesterol levels have been shown to be a risk factor for cardiovascular disease; however, the correlative nature of their association does not assign causation.» 
  7. ↑ Zinöcker, Marit Kolby; Svendsen, Karianne; Dankel, Simon Nitter (20 de enero de 2021). «The homeoviscous adaptation to dietary lipids (HADL) model explains controversies over saturated fat, cholesterol, and cardiovascular disease risk». The American Journal of Clinical Nutrition 113 (2): 277-289. ISSN 0002-9165. doi:10.1093/ajcn/nqaa322. Consultado el 26 de diciembre de 2022. «At the core of the diet–heart hypothesis lies 3-step reasoning: A dietary intervention enriched in SFAs leads to increased total and LDL cholesterol concentrations. Elevated total and LDL cholesterol concentrations are associated with atherosclerotic cardiovascular disease (ASCVD). Ergo, a diet rich in SFAs promotes ASCVD. Viewed separately, Steps 1 and 2 are well documented in the literature, although there are inconsistent findings and large individual differences both with respect to the LDL cholesterol response and its association with disease (1, 2). However, causal evidence for Step 3 is lacking (1), despite the large and still-growing number of studies that have addressed this question (3–5).» 
  8. ↑ a b «¿Realmente comer grasas saturadas aumenta el colesterol y el riesgo de enfermedades del corazón?». BBC News Mundo. Consultado el 26 de diciembre de 2022. 
  9. ↑ Domínguez, H.; Núñez, M. J.; Lema, J. M. (30 de octubre de 1993). «Eliminación de ácido clorogénico durante el procesado acuoso de las almendras de girasol». Grasas y Aceites 44 (4-5): 235-242. ISSN 1988-4214. doi:10.3989/gya.1993.v44.i4-5.1072. Consultado el 26 de diciembre de 2022. «En vista de la evidencia presentada se concluye que no se encuentra relación de causalidad entre la ingesta de grasas saturadas y las enfermedades cardiovasculares. Hay estudios que evidencian una relación inversa entre la ingesta de grasa saturada y la salud cardiovascular. La sustitución de grasas saturadas por grasas poliinsaturadas omega 6 no se traduce en una disminución del riesgo de padecer enfermedades cardiovasculares. Considerando estos aspectos, y teniendo en cuenta la revisión de los trabajos analizados en este artículo, entre los que se incluyen estudios del más alto rigor científico (metaanálisis y revisiones sistemáticas), se recomienda que se reconsidere en las guías dietéticas cubanas las limitaciones de la ingesta de grasa saturada para la población en general.» 
  10. ↑ Givens, David Ian (2022-12). «Saturated fats, dairy foods and cardiovascular health: No longer a curious paradox?». Nutrition Bulletin (en inglés) 47 (4): 407-422. ISSN 1471-9827. doi:10.1111/nbu.12585. Consultado el 7 de enero de 2023. «Studies that included blood cholesterol data do broadly support the positive relationship between SFA and blood low-density lipoprotein cholesterol (LDL-C) but without increased CVD risk resulting, despite LDL being a causal factor in atherosclerotic CVD. These data suggest that LDL-C alone is not a consistently good predictor or cause of CVD risk, perhaps particularly in relation to dairy food consumption although some non-dairy food studies have also shown LDL-C reduction was not reflected in reduced CVD risk.» 
  11. ↑ a b Dehghan, Mahshid; Mente, Andrew; Zhang, Xiaohe; Swaminathan, Sumathi; Li, Wei; Mohan, Viswanathan; Iqbal, Romaina; Kumar, Rajesh et al. (4 de noviembre de 2017). «Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study». The Lancet (en inglés) 390 (10107): 2050-2062. ISSN 0140-6736. PMID 28864332. doi:10.1016/S0140-6736(17)32252-3. Consultado el 26 de diciembre de 2022. «High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings.» 
  12. ↑ Astrup, Arne; Teicholz, Nina; Magkos, Faidon; Bier, Dennis M.; Brenna, J. Thomas; King, Janet C.; Mente, Andrew; Ordovas, José M. et al. (2021-10). «Dietary Saturated Fats and Health: Are the U.S. Guidelines Evidence-Based?». Nutrients (en inglés) 13 (10): 3305. ISSN 2072-6643. doi:10.3390/nu13103305. Consultado el 26 de diciembre de 2022. «The hypothesis that saturated fats cause CVD emerged in the late 1950s, when scientists observed that these fats tend to raise the concentration of total serum cholesterol, which in turn was considered a potent risk factor for heart disease. Ancel Keys, a physiologist at the University of Minnesota, postulated that saturated fats along with dietary cholesterol were the principal causes of cardiovascular disease, and his “diet-heart hypothesis” was adopted by leading groups, including the American Heart Association.» 
  13. ↑ Teicholz, Nina (2023-02). «A short history of saturated fat: the making and unmaking of a scientific consensus». Current Opinion in Endocrinology, Diabetes and Obesity (en inglés estadounidense) 30 (1): 65. ISSN 1752-296X. doi:10.1097/MED.0000000000000791. Consultado el 26 de diciembre de 2022. «Throughout the 1950s, the AHA had resisted giving advice on heart disease prevention, citing a lack of evidence, yet in 1960, Keys was appointed to the group's nutrition committee, and one year later, although no greater evidence could be cited, he had convinced his colleagues to recommend his idea as official AHA policy. Thus, from 1961 on, the AHA recommended that all men (and subsequently women) decrease their consumption of saturated fat, replacing these fats whenever possible with polyunsaturated vegetable oils, as the most promising measure of protection against heart disease». 
  14. ↑ «The Fat Lie You've Been Told About What's Hurting Your Heart». The Wire. Consultado el 26 de diciembre de 2022. «To begin with, the AHA had declared in 1961 that saturated fats were bad because they increased blood cholesterol, which blocked coronary arteries and caused heart attacks. The AHA was surprisingly driven to this conclusion by the hypothesis of one physiologist – who hadn’t bothered to submit a shred of evidence.» 
  15. ↑ Astrup, Arne; Teicholz, Nina; Magkos, Faidon; Bier, Dennis M.; Brenna, J. Thomas; King, Janet C.; Mente, Andrew; Ordovas, José M. et al. (2021-10). «Dietary Saturated Fats and Health: Are the U.S. Guidelines Evidence-Based?». Nutrients (en inglés) 13 (10): 3305. ISSN 2072-6643. doi:10.3390/nu13103305. Consultado el 26 de diciembre de 2022. «the diet-heart hypothesis gained widespread acceptance in the 1970s and 1980s, yet the results from the totality of these trials did not provide support for the hypothesis, as many critics at the time pointed out». 
  16. ↑ Teicholz, Nina (2023-02). «A short history of saturated fat: the making and unmaking of a scientific consensus». Current Opinion in Endocrinology, Diabetes and Obesity (en inglés estadounidense) 30 (1): 65. ISSN 1752-296X. doi:10.1097/MED.0000000000000791. Consultado el 26 de diciembre de 2022. «The U.S. government was the first in the world to recommend saturated-fat restriction. The United States Senate Select Committee on Nutrition and Human Needs published the Dietary Goals for the United States in 1977, which recommended that the public ‘reduce saturated fat consumption to account for about 10% of total energy intake …’». 
  17. ↑ Gershuni, Victoria M. (1 de septiembre de 2018). «Saturated Fat: Part of a Healthy Diet». Current Nutrition Reports (en inglés) 7 (3): 85-96. ISSN 2161-3311. doi:10.1007/s13668-018-0238-x. Consultado el 26 de diciembre de 2022. «Advances in understanding the role of various lipoprotein particles and their atherogenic risk have been helpful for understanding how different dietary components may impact CVD risk. Numerous meta-analyses and systematic reviews of both the historical and current literature reveals that the diet-heart hypothesis was not, and still is not, supported by the evidence. There appears to be no consistent benefit to all-cause or CVD mortality from the reduction of dietary saturated fat. Further, saturated fat has been shown in some cases to have an inverse relationship with obesity-related type 2 diabetes.» 
  18. ↑ Teicholz, Nina (2023-02). «A short history of saturated fat: the making and unmaking of a scientific consensus». Current Opinion in Endocrinology, Diabetes and Obesity (en inglés estadounidense) 30 (1): 65. ISSN 1752-296X. doi:10.1097/MED.0000000000000791. Consultado el 26 de diciembre de 2022. «Reviews and books critical of the diet-heart hypothesis were not unknown in the 1960s and 1970s, including a publication by a former editor of the Journal of the American Heart Association[22] and articles by other prominent scientists [23–25]. They argued that the hypothesis was not supported by the available data and was contradicted by numerous observations. Over time, however, these critics were effectively marginalized and silenced [2]. Not until the 2000s did this science again come to light, mainly through the work of journalist Gary Taubes [26,27]. The first comprehensive compilation of arguments about why saturated fats are not bad for health was published by this author, also a journalist [2].» 
  19. ↑ Astrup, Arne; Magkos, Faidon; Bier, Dennis M.; Brenna, J. Thomas; de, Oliveira Otto Marcia C.; Hill, James O.; King, Janet C.; Mente, Andrew et al. (18 de agosto de 2020). «Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations». Journal of the American College of Cardiology 76 (7): 844-857. doi:10.1016/j.jacc.2020.05.077. Consultado el 26 de diciembre de 2022. «•The U.S. Dietary Guidelines recommend the restriction of SFA intake to <10% of calories to reduce CVD. •Different SFAs have different biologic effects, which are further modified by the food matrix and the carbohydrate content of the diet. •Several foods relatively rich in SFAs, such as whole-fat dairy, dark chocolate, and unprocessed meat, are not associated with increased CVD or diabetes risk. •There is no robust evidence that current population-wide arbitrary upper limits on saturated fat consumption in the United States will prevent CVD or reduce mortality.» 
  20. ↑ Volek, Jeff S.; Phinney, Stephen D.; Krauss, Ronald M.; Johnson, Richard J.; Saslow, Laura R.; Gower, Barbara; Yancy, William S.; King, Janet C. et al. (2021-10). «Alternative Dietary Patterns for Americans: Low-Carbohydrate Diets». Nutrients (en inglés) 13 (10): 3299. ISSN 2072-6643. doi:10.3390/nu13103299. Consultado el 7 de enero de 2023. «The decades-long dietary experiment embodied in the Dietary Guidelines for Americans (DGA) focused on limiting fat, especially saturated fat, and higher carbohydrate intake has coincided with rapidly escalating epidemics of obesity and type 2 diabetes (T2D) that are contributing to the progression of cardiovascular disease (CVD) and other diet-related chronic diseases.» 
  21. ↑ Volek, Jeff S.; Phinney, Stephen D.; Krauss, Ronald M.; Johnson, Richard J.; Saslow, Laura R.; Gower, Barbara; Yancy, William S.; King, Janet C. et al. (2021-10). «Alternative Dietary Patterns for Americans: Low-Carbohydrate Diets». Nutrients (en inglés) 13 (10): 3299. ISSN 2072-6643. doi:10.3390/nu13103299. Consultado el 7 de enero de 2023. «excessive intake of carbohydrate was acknowledged and foreseen by previous Dietary Guidelines Advisory Committees (DGAC). The 2000 committee expressed concern that the government’s low-fat advice “could engender an overconsumption of total calories in the form of carbohydrates, resulting in the adverse metabolic consequences of high-carbohydrate diets,” adding, “Further, the possibility that overconsumption of carbohydrates may contribute to obesity cannot be ignored.”». 
  22. ↑ Ramsden, Christopher E.; Hibbeln, Joseph R.; Majchrzak, Sharon F.; Davis, John M. (2010-12). «n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials». British Journal of Nutrition (en inglés) 104 (11): 1586-1600. ISSN 1475-2662. doi:10.1017/S0007114510004010. Consultado el 26 de marzo de 2023. «The American Heart Association (AHA) and individual scientists advise consumption of at least 5–10 % of energy as n-6 PUFA to reduce CHD risk». 
  23. ↑ Zinöcker, Marit Kolby; Svendsen, Karianne; Dankel, Simon Nitter (20 de enero de 2021). «The homeoviscous adaptation to dietary lipids (HADL) model explains controversies over saturated fat, cholesterol, and cardiovascular disease risk». The American Journal of Clinical Nutrition 113 (2): 277-289. ISSN 0002-9165. doi:10.1093/ajcn/nqaa322. Consultado el 26 de diciembre de 2022. «Studies have investigated whether increased SFA intake increases the endogenous synthesis of cholesterol: for example, by providing substrates for synthesis in the form of acetyl-CoA.» 
  24. ↑ Zinöcker, Marit Kolby; Svendsen, Karianne; Dankel, Simon Nitter (20 de enero de 2021). «The homeoviscous adaptation to dietary lipids (HADL) model explains controversies over saturated fat, cholesterol, and cardiovascular disease risk». The American Journal of Clinical Nutrition 113 (2): 277-289. ISSN 0002-9165. doi:10.1093/ajcn/nqaa322. Consultado el 26 de diciembre de 2022. «SFAs play the leading role in 1 of the greatest controversies in nutrition science. Relative to PUFAs, SFAs generally increase circulating concentrations of LDL cholesterol, a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, the purpose of regulatory mechanisms that control the diet-induced lipoprotein cholesterol dynamics is rarely discussed in the context of human adaptive biology. We argue that better mechanistic explanations can help resolve lingering controversies, with the potential to redefine aspects of research, clinical practice, dietary advice, public health management, and food policy. In this paper we propose a novel model, the homeoviscous adaptation to dietary lipids (HADL) model, which explains changes in lipoprotein cholesterol as adaptive homeostatic adjustments that serve to maintain cell membrane fluidity and hence optimal cell function. Due to the highly variable intake of fatty acids in humans and other omnivore species, we propose that circulating lipoproteins serve as a buffer to enable the rapid redistribution of cholesterol molecules between specific cells and tissues that is necessary with changes in dietary fatty acid supply. Hence, circulating levels of LDL cholesterol may change for nonpathological reasons. Accordingly, an SFA-induced raise in LDL cholesterol in healthy individuals could represent a normal rather than a pathologic response. These regulatory mechanisms may become disrupted secondarily to pathogenic processes in association with insulin resistance and the presence of other ASCVD risk factors, as supported by evidence showing diverging lipoprotein responses in healthy individuals as opposed to those with metabolic disorders such as insulin resistance and obesity.» 
  25. ↑ admin (22 de enero de 2021). New perspectives challenge the idea that saturated fats cause heart disease. Consultado el 8 de abril de 2023. «The basis of the model is that when saturated fats replace polyunsaturated fats in the diet, less cholesterol is needed in the cell membranes," she explains. The opposite is true when eating more polyunsaturated fatty acids, which include omega-3 and omega-6 fatty acids. "This is because polyunsaturated fats from the diet enter our cell membranes and make them more fluid. The cells adjust the fluidity of their membranes by incorporating cholesterol recruited from the bloodstream. According to the model presented by the researchers, this can explain why blood cholesterol levels decrease when we eat more polyunsaturated fats. The authors have named the model the "Homeoviscous Adaptation to Dietary Lipids" (HADL) model. "Cells need to adjust their membrane fluidity according to changes in their environment, such as the access to different types of fat", says co-author Simon N. Dankel, researcher at the Department of Clinical Science, University of Bergen, Norway. "This phenomenon is called homeoviscous adaptation, and has been described in both microorganisms, vertebrates and in human skin cells. We argue that this is a critical principle in human physiology. Our cells are normally capable of adjusting their cholesterol content according to changes in dietary fats.» 
  26. ↑ Laila, Amar (2021-08). «Limitations in the “homeoviscous adaptation to dietary lipids” model». The American Journal of Clinical Nutrition 114 (2): 822-823. ISSN 0002-9165. doi:10.1093/ajcn/nqab230. Consultado el 26 de diciembre de 2022. «I read with interest the article by Zinöcker et al. (1), in which the authors proposed a model to explain the observed pathologic increase in LDL-cholesterol concentrations in response to higher SFA intake. The model de-emphasized the role of SFAs and suggested that dysregulation of cholesterol uptake is caused by endotoxemia, which causes inflammation and, therefore, prevents cholesterol uptake via LDL-cholesterol receptors. The authors’ conclusion was that, if the model is verified, recommendations should focus on reducing intake of refined carbohydrates, which increases the growth of LPS-containing gut bacteria, but not reducing intake of SFAs.» 
  27. ↑ Cardiavant (18 de marzo de 2022). «Colesterol: ¿Por qué es un factor de riesgo cardiovascular?». Cardiavant. Consultado el 26 de diciembre de 2022. 
  28. ↑ Subbotin, Vladimir M. (1 de octubre de 2016). «Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target». Drug Discovery Today (en inglés) 21 (10): 1578-1595. ISSN 1359-6446. doi:10.1016/j.drudis.2016.05.017. Consultado el 11 de agosto de 2023. «The consensus hypothesis on coronary atherosclerosis suggests high LDL-C levels as the major cause and pursues it as the therapeutic target, explicitly assuming: (i) tunica intima of human coronaries consists of only one cell layer – endothelium, situated on a thin layer of scarcely cellular matrix; and (ii) subendothelial lipoprotein retention initiates the disease. Facts showed: (i) normal tunica intima invariably consists of multiple cellular layers; and (ii) initial lipid depositions occurred in the deepest layers of tunica intima. This review suggests that coronary atherosclerosis starts with pathological intimal expansion, resulting in intimal hypoxia and neovascularization from adventitial vasa vasorum, facilitating lipoprotein extraction by previously avascular deep intimal tissues. Until the hypothesis incorporates real knowledge, our efforts will probably be off-target.» 
  29. ↑ Subbotin, Vladimir M. (1 de octubre de 2016). «Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target». Drug Discovery Today (en inglés) 21 (10): 1578-1595. ISSN 1359-6446. doi:10.1016/j.drudis.2016.05.017. Consultado el 11 de agosto de 2023. «During early stages of coronary atherosclerosis, the initial lipid deposition occurs in deep layers of the tunica intima, which are separated from the subendothelial region by numerous cell layers and matrix. At the same time, the subendothelial region and the part of the tunica intima proximal to the outer endothelium do not show any lipid accumulation. The initial lipid deposition in deep layers of the tunica intima occurred immediately above the internal elastic lamina and is not accompanied by macrophage infiltration. Even with further accumulation of lipids in the deep tunica intima, lipid deposits never coincide with macrophage infiltration.» 
  30. ↑ Subbotin, Vladimir M. (1 de octubre de 2016). «Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target». Drug Discovery Today (en inglés) 21 (10): 1578-1595. ISSN 1359-6446. doi:10.1016/j.drudis.2016.05.017. Consultado el 11 de agosto de 2023. «Everything eventually comes to a simple question: if at the initiation of coronary atherosclerosis lipids do not invade the coronary wall from a coronary lumen proper where do they come from? If there is no valid model of lipid invasion from the coronary lumen, is there an alternative route via which lipids can come? Yes, there is. This alternative route of lipid deposition is the vascularization of the coronary tunica intima from the adventitial or medial vasa vasorum, which has been shown by many studies to contribute to coronary plaque progression and instability (bear in mind that coronary plaques are confined to the coronary tunica intima)». 
  31. ↑ Traunmüller, Friederike (1 de julio de 2018). «Atherosclerosis is a vascular stem cell disease caused by insulin». Medical Hypotheses (en inglés) 116: 22-27. ISSN 0306-9877. doi:10.1016/j.mehy.2018.03.011. Consultado el 26 de diciembre de 2022. «The present article proposes the hypothesis that when multipotent vascular stem cells are exposed to excessive insulin in a rhythmic pattern of sharply rising and falling concentrations, their differentiation is misdirected toward adipogenic and osteogenic cell lineages. This results in plaque-like accumulation of adipocytes with fat and cholesterol deposition from adipocyte debris, and osteogenic (progenitor) cells with a calcified matrix in advanced lesions. The ingrowth of capillaries and infiltration with macrophages, which upon uptake of lipids turn into foam cells, are unspecific pro-resolving reactions. Epidemiological, histopathological, pharmacological, and experimental evidence in favour of this hypothesis is summarised.» 
  32. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 26 de diciembre de 2022. «The consumption of the omega-6 polyunsaturated fat linoleic acid has dramatically increased in the western world primarily in the form of vegetable oils. OxLDL is thought to play an important role in atherosclerosis formation; however, it is the oxidised linoleic acid contained in LDL that leads to harmful OXLAMs, which induces atherosclerosis and CHD. Thus, reducing the amount of dietary linoleic acid, mainly from industrial vegetable/seed oils, will reduce the amount of linoleic acid in LDL and likely reduce oxLDL as well as the risk for CHDcoronary heart disease.» 
  33. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 26 de diciembre de 2022. «Evidence implicating omega-6-rich vegetable oils as a causative factor in atherosclerosis and coronary heart disease Greater amounts of linoleic acid oxidation products are found in LDL and plasma of patients with atherosclerosis.14 Greater amounts of linoleic acid oxidation products are found within atherosclerotic plaques and the degree of oxidation determines the severity of atherosclerosis.22 A diet higher in oleic acid or lower in linoleic acid decreases LDL susceptibility to oxidation.14 Endothelial cells oxidise LDL forming linoleic acid hydroperoxides.14 Linoleic acid is the most abundant fatty acid in LDL and is extremely vulnerable to oxidation being one of the very first fatty acids to oxidise.14 A meta-analysis of randomised controlled trials in humans found that when saturated fat plus trans-fat is replaced with omega-6 fat (high in linoleic acid), there is an increase in all-cause mortality, ischaemic heart disease mortality and cardiovascular mortality.41 The oxidation of linoleic acid in LDL leads to conjugated dienes (malondialdehyde and 4-hydroxynonenal), which covalently bind to apoB altering its structure creating oxidised LDL. oxLDL is no longer recognised by the LDL receptors on the liver but by scavenger receptors on macrophages causing monocyte infiltration into the subendothelium, foam cell formation and eventual atherosclerosis.14 Oxidation products of linoleic acid (including 9-HODE and 13-HODE) are found in infarcted tissue.44 Ultrasound of the carotid arteries in healthy patients who have high 9-HODE in LDL have signs of atherosclerosis.14 The increase in 9-HODE begins between 40 and 50 years old prior to the clinical manifestation of atherosclerosis.14 9-HODE is a good indicator of oxLDL, especially if other causes of inflammation are excluded. An increased oxidised LDL, and hence levels of 9-HODE and 13-HODE in LDL, found in patients with rheumatoid arthritis may explain why they have an increased risk of heart disease.45 9-HODE and 13-HODE stimulate the release of interleukin 1B from macrophages.45 The linoleic acid metabolite 9-HODE is a strong promoter of inflammation45 and hence may be both a marker and inducer of atherosclerosis. Susceptibility of LDL to oxidation correlates independently with the extent of atherosclerosis.46 15) Linoleic acid free fatty acids and hydroxy acids (such as 13-HODE) can induce direct toxic effects to the endothelium causing an increase inflammation, reactive oxygen species and adhesion molecules.33 34 Exposure of the endothelium to linoleic acid has been found to increase LDL transfer across the endothelium, an essential step in the atherosclerosis process.35 Oxidised linoleic acid metabolites (OXLAMs) are recognised by immune cells and can recruit monocytes/neutrophils to atherosclerotic lesions.47 OXLAMs are considered a danger signal activating innate immune cells, which are involved in atherosclerosis formation.48 49 Linoleic acid is the most abundant fat found in atherosclerotic plaques, and this has been known since at least the 1960s.50 Oxidised linoleic acid but not oxidised oleic acid is found in atherosclerotic plaques.51 Consuming more linoleic acid increases the amount of linoleic acid in complicated aortic plaques.52 Linoleic acid in adipose tissue and platelets positively associates with CAD, whereas EPA and DHA in platelets are inversely correlated with CAD.3 Linoleic acid serum concentrations (as opposed to per cent of fatty acids) are higher in patients with CAD.4 Using the fat-1 transgenic mouse model, which converts omega-6 to omega-3 creating an omega-6:omega-3 ratio of around 1:1 in tissues and organs, reduces atherosclerotic lesions by inhibiting systemic and vascular inflammation.53 Mice fed fish oil (high in omega-3) as compared with corn oil (high in omega-6) have a significant reduction in atherosclerotic plaque formation possibly due to an increase in antioxidant enzyme activity.54 There is more thin fibrous cap atheroma, less thick fibrous cap atheroma, less stable plaque and a greater percentage of plaque rupture in patients given sunflower oil (high in omega-6) versus control.55 An excess dietary intake of linoleic acid causes greater endothelial activation compared with an excess of saturated fat.56 Linoleic acid can activate vascular endothelial cells, a critical step for inducing atherosclerosis.57 58 Linoleic acid is inflammatory to the vascular endothelium.59 Linoleic acid metabolites promote cardiac arrhythmias, cell death, organ failure and cardiac arrest.60 Patients who have died from sudden cardiac death have more linoleic acid and less omega-3 polyunsaturated fats in their coronary arteries versus control patients who died mostly from traffic accidents.61 B ox 2 summarises the opposing views for (1) why linoleic acid may reduce CHD and (2) why linoleic acid may increase the risk of CHD.» 
  34. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 7 de agosto de 2023. «Hence, the amount of linoleic acid contained in LDL can be seen as the true ‘culprit’ that initiates the process of oxLDL formation as it is the linoleic acid that is highly susceptible to oxidation. Additionally, an increase in the intake of linoleic acid intake increases the linoleic acid content of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) increasing their susceptibility to oxidise, which further increases the risk of cardiovascular disease.» 
  35. ↑ Ravnskov, Uffe (1 de noviembre de 2002). «A hypothesis out-of-date: The diet–heart idea». Journal of Clinical Epidemiology (en inglés) 55 (11): 1057-1063. ISSN 0895-4356. PMID 12507667. doi:10.1016/S0895-4356(02)00504-8. Consultado el 26 de diciembre de 2022. «An almost endless number of observations and experiments have effectively falsified the hypothesis that dietary cholesterol and fats, and a high cholesterol level play a role in the causation of atherosclerosis and cardiovascular disease. The hypothesis is maintained because allegedly supportive, but insignificant findings, are inflated, and because most contradictory results are misinterpreted, misquoted or ignored.» 
  36. ↑ Ravnskov, Uffe; de Lorgeril, Michel; Diamond, David M; Hama, Rokuro; Hamazaki, Tomohito; Hammarskjöld, Björn; Hynes, Niamh; Kendrick, Malcolm et al. (3 de octubre de 2018). «LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature». Expert Review of Clinical Pharmacology 11 (10): 959-970. ISSN 1751-2433. PMID 30198808. doi:10.1080/17512433.2018.1519391. Consultado el 26 de marzo de 2023. «The idea that high cholesterol levels in the blood are the main cause of CVD is impossible because people with low levels become just as atherosclerotic as people with high levels and their risk of suffering from CVD is the same or higher. The cholesterol hypothesis has been kept alive for decades by reviewers who have used misleading statistics, excluded the results from unsuccessful trials and ignored numerous contradictory observations.» 
  37. ↑ Ravnskov, Uffe; de Lorgeril, Michel; Diamond, David M; Hama, Rokuro; Hamazaki, Tomohito; Hammarskjöld, Björn; Hynes, Niamh; Kendrick, Malcolm et al. (3 de octubre de 2018). «LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature». Expert Review of Clinical Pharmacology 11 (10): 959-970. ISSN 1751-2433. PMID 30198808. doi:10.1080/17512433.2018.1519391. Consultado el 26 de marzo de 2023. «For some years, many researchers have questioned the results from statin trials because they have been denied access to the primary data. In 2004–2005, health authorities in Europe and the United States introduced New Clinical Trial Regulations, which specified that all trial data had to be made public. Since 2005, claims of benefit from statin trials have virtually disappeared». 
  38. ↑ Jiang, Ming; Yang, Jiaming; Zou, Huayiyang; Li, Menghuan; Sun, Wei; Kong, Xiangqing (18 de marzo de 2022). «Monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) and the risk of all-cause and cardiovascular mortality: a nationwide cohort study in the United States». Lipids in Health and Disease 21 (1): 30. ISSN 1476-511X. PMC 8931976. PMID 35300686. doi:10.1186/s12944-022-01638-6. Consultado el 26 de marzo de 2023. «Elevated monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) is relevant to higher all-cause and cardiovascular mortality in patients with coronary artery disease and other comorbidities. However, the predictive values of MHR for mortality in the general population have been underutilized. This study investigated the association of MHR with all-cause and cardiovascular mortality in the adult population of the United States.» 
  39. ↑ «Atherosclerosis and inflammation: overview and updates». portlandpress.com. Consultado el 26 de marzo de 2023. «The recognition of atherogenesis as an active process rather than a cholesterol storage disease or a repository of calcium has highlighted some key inflammatory mechanisms. For example, mononuclear phagocytes contribute to all stages of this disease, illustrating the link between inflammation and atherosclerosis. From a clinical perspective, harnessing inflammation may now help target therapeutics, change guidelines, and enter daily practice.» 
  40. ↑ Poznyak, A. V.; Silaeva, Y. Y.; Orekhov, A. N.; Deykin, A. V. (18 de mayo de 2020). «Animal models of human atherosclerosis: current progress». Brazilian Journal of Medical and Biological Research (en inglés) 53: e9557. ISSN 0100-879X. doi:10.1590/1414-431X20209557. Consultado el 5 de agosto de 2023. «According to current understanding, atherosclerosis is a multifactorial disease that involves altered lipid metabolism, increased oxidative stress, impaired mitochondrial function, and chronic inflammation». 
  41. ↑ a b Bargieł, Weronika; Cierpiszewska, Katarzyna; Maruszczak, Klara; Pakuła, Anna; Szwankowska, Dominika; Wrzesińska, Aleksandra; Gutowski, Łukasz; Formanowicz, Dorota (2021-07). «Recognized and Potentially New Biomarkers—Their Role in Diagnosis and Prognosis of Cardiovascular Disease». Medicina (en inglés) 57 (7): 701. ISSN 1648-9144. doi:10.3390/medicina57070701. Consultado el 5 de agosto de 2023. «As a result of the complexity of this phenomenon, there is widespread agreement among researchers that determining the parameters of lipid metabolism is not enough to predict what is happening in the arterial subendothelial layer. Sometimes, we can even draw the wrong conclusions if we rely on them. For example, consider the JUPITER study, which revealed that men and women with low low-density lipoprotein cholesterol (LDL-C) but increased markers of local low-grade inflammation (high sensitive C-reactive protein (hs-CRP)) showed a significant cardiovascular risk. Participants who achieved hs-CRP less than 1 mg/L had a 79% reduction in vascular events and achieved hsCRP concentrations that were predictive of event rates irrespective of the lipid endpoint». 
  42. ↑ CANTOS Trial Group; Ridker, P. M.; Everett, B. M.; Thuren, T.; MacFadyen, J. G.; Chang, W. H.; Ballantyne, C.; Fonseca, F. et al. (21 de septiembre de 2017). «Antiinflammatory therapy with canakinumab for atherosclerotic disease». New England Journal of Medicine 377 (12): 1119-1131. ISSN 0028-4793. doi:10.1056/NEJMoa1707914. Consultado el 26 de marzo de 2023. «Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease.» 
  43. ↑ Hassan, Mohamed. «CANTOS: A breakthrough that proves the inflammatory hypothesis of atherosclerosis». Global Cardiology Science & Practice 2018 (1): 2. ISSN 2305-7823. PMC 5857062. PMID 29644229. doi:10.21542/gcsp.2018.2. Consultado el 26 de marzo de 2023. «The CANTOS study was a randomized, double-blind, prospective, controlled clinical trial presented at the European Society of Cardiology (ESC) Congress in Barcelona and published simultaneously in the New England Journal of Medicine». 
  44. ↑ CANTOS Trial Group; Ridker, P. M.; Everett, B. M.; Thuren, T.; MacFadyen, J. G.; Chang, W. H.; Ballantyne, C.; Fonseca, F. et al. (21 de septiembre de 2017). «Antiinflammatory therapy with canakinumab for atherosclerotic disease». New England Journal of Medicine 377 (12): 1119-1131. ISSN 0028-4793. doi:10.1056/NEJMoa1707914. Consultado el 26 de marzo de 2023. «Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering.» 
  45. ↑ a b Moriya, Junji (1 de enero de 2019). «Critical roles of inflammation in atherosclerosis». Journal of Cardiology. Anticoagulants and bleeding (en inglés) 73 (1): 22-27. ISSN 0914-5087. doi:10.1016/j.jjcc.2018.05.010. Consultado el 26 de marzo de 2023. «Current understanding of the inflammatory mechanisms of atherosclerosis has led to exploration of the hypothesis that targeting inflammation itself will reduce cardiovascular events and risks. Recently, the results of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial have been reported with a significant reduction in recurrent cardiovascular events in patients with stable coronary artery disease at high inflammatory risk by using canakinumab, a therapeutic monoclonal antibody targeting interleukin (IL)-1β». 
  46. ↑ Ridker, Paul M; Danielson, Eleanor; Fonseca, Francisco A.H.; Genest, Jacques; Gotto, Antonio M.; Kastelein, John J.P.; Koenig, Wolfgang; Libby, Peter et al. (20 de noviembre de 2008). «Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein». New England Journal of Medicine (en inglés) 359 (21): 2195-2207. ISSN 0028-4793. doi:10.1056/NEJMoa0807646. Consultado el 5 de agosto de 2023. «Measurement of high-sensitivity C-reactive protein, an inflammatory biomarker that independently predicts future vascular events, improves global classification of risk, regardless of the LDL cholesterol level.» 
  47. ↑ van der Laarse, Arnoud; Cobbaert, Christa M. (2 de diciembre de 2021). «Biochemical risk factors of atherosclerotic cardiovascular disease: from a narrow and controversial approach to an integral approach and precision medicine». Expert Review of Cardiovascular Therapy (en inglés) 19 (12): 1085-1096. ISSN 1477-9072. doi:10.1080/14779072.2021.2022475. Consultado el 11 de agosto de 2023. «In numerous reviews, the lipid risk factors of atherosclerotic cardiovascular disease (CVD) and therapies of this disease have been documented. A landmark paper by Ference et al. elegantly demonstrated that firstly the low-density lipoprotein-cholesterol (LDL-C) concentration is a risk factor of CVD; and secondly a therapeutic reduction of LDL-C is associated with reduction of the risk of CVD». 
  48. ↑ Ramsden, Christopher E; Zamora, Daisy; Majchrzak-Hong, Sharon; Faurot, Keturah R; Broste, Steven K; Frantz, Robert P; Davis, John M; Ringel, Amit et al. (12 de abril de 2016). «Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)». BMJ: i1246. ISSN 1756-1833. doi:10.1136/bmj.i1246. Consultado el 26 de diciembre de 2022. «The Minnesota Coronary Experiment (MCE), a randomized controlled trial conducted in 1968-73, was the largest (n=9570) and perhaps the most rigorously executed dietary trial of cholesterol lowering by replacement of saturated fat with vegetable oil rich in linoleic acid. The MCE is the only such randomized controlled trial to complete postmortem assessment of coronary, aortic, and cerebrovascular atherosclerosis grade and infarct status and the only one to test the clinical effects of increasing linoleic acid in large prespecified subgroups of women and older adults.» 
  49. ↑ Ramsden, Christopher E; Zamora, Daisy; Majchrzak-Hong, Sharon; Faurot, Keturah R; Broste, Steven K; Frantz, Robert P; Davis, John M; Ringel, Amit et al. (12 de abril de 2016). «Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)». BMJ: i1246. ISSN 1756-1833. doi:10.1136/bmj.i1246. Consultado el 26 de diciembre de 2022. «Available evidence from randomized controlled trials shows that replacement of saturated fat with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. MCE findings add to growing evidence that incomplete publication has contributed to overestimation of benefits, and underestimation of potential risks, of replacing saturated fat with vegetable oils rich in linoleic acid.» 
  50. ↑ «The Fat Lie You've Been Told About What's Hurting Your Heart». The Wire. Consultado el 26 de diciembre de 2022. «In 1967-1973, doctors intervened in the diets of a group of people randomly picked from a cohort of 9,000 for the famous Minnesota Coronary Experiment. The intervened group had saturated fats replaced by a polyunsaturated vegetable oil. The control group continued with their regular American diet. These people were from enrolled from mental institutions and from homes for the elderly. More than 2,500 participants continued on their respective diets for at least a year, and autopsy reports were available for about 140 deaths. This trial’s results were never published until a group of investigators got its hands on all the raw data.» 
  51. ↑ Ramsden, Christopher E.; Hibbeln, Joseph R.; Majchrzak, Sharon F.; Davis, John M. (2010-12). «n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials». British Journal of Nutrition (en inglés) 104 (11): 1586-1600. ISSN 1475-2662. doi:10.1017/S0007114510004010. Consultado el 26 de marzo de 2023. «Two previous meta-analyses(Reference Gordon and Rifkin6, Reference Mozaffarian, Micha and Wallace7) have recently been cited to support the proposition that PUFA in general, and n-6 PUFA in particular, are cardioprotective(Reference Harris, Mozaffarian and Rimm1–Reference Kris-Etherton, Fleming and Harris5, Reference Katan8, Reference Katan, Brouwer and Clarke12).» 
  52. ↑ Ramsden, Christopher E.; Hibbeln, Joseph R.; Majchrzak, Sharon F.; Davis, John M. (2010-12). «n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials». British Journal of Nutrition (en inglés) 104 (11): 1586-1600. ISSN 1475-2662. doi:10.1017/S0007114510004010. Consultado el 26 de marzo de 2023. «Both the AHA Advisory(Reference Harris, Mozaffarian and Rimm1) and the Mozaffarian et al. (Reference Mozaffarian, Micha and Wallace7) meta-analysis of RCT imprecisely contend that they evaluated the effects of replacing SFA with PUFA, despite the inclusion of the ODHS and other RCT where experimental diets displaced large quantities of TFA-rich partially hydrogenated oils. Indeed, experimental diets replaced common ‘hard’ margarines, industrial shortenings and other sources of TFA in all seven of the RCT included in the meta-analysis by Mozaffarian et al.» 
  53. ↑ Ramsden, Christopher E.; Hibbeln, Joseph R.; Majchrzak, Sharon F.; Davis, John M. (2010-12). «n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials». British Journal of Nutrition (en inglés) 104 (11): 1586-1600. ISSN 1475-2662. doi:10.1017/S0007114510004010. Consultado el 26 de marzo de 2023. «In a recent pooled analysis of prospective cohort observational studies(Reference Mozaffarian, Aro and Willett66), each 2 en % replacement of TFA with SFA, MUFA or PUFA was associated with a CHD risk reduction of 20, 27 and 32 %, respectively. If this association is causal, the replacement of only 2 en % as TFA would be expected to account for the full 19 % reduction in CHD events that Mozaffarian et al. (Reference Mozaffarian, Micha and Wallace7) attributed to increasing unspecified PUFA in their meta-analysis. Unfortunately this potential confounding role of TFA was not appreciated.» 
  54. ↑ Teicholz, Nina (2023-02). «A short history of saturated fat: the making and unmaking of a scientific consensus». Current Opinion in Endocrinology, Diabetes and Obesity (en inglés estadounidense) 30 (1): 65. ISSN 1752-296X. doi:10.1097/MED.0000000000000791. Consultado el 26 de diciembre de 2022. «Governments around the world, including the United States, Norway, Finland, and Australia, among other countries, recognized the need for more rigorous, clinical trial data that could establish a causal relationship between saturated fat and heart disease. Large, randomized, controlled clinical trials (RCTs) were undertaken in the 1960s and 1970s, in which saturated fats were replaced by polyunsaturated fats from vegetable oils. Altogether, these ‘core’ trials tested the diet-heart hypothesis on about 67 000 people [15] and were especially important, because they assessed long-term clinical outcomes, that is, ‘hard endpoints,’ such as heart attacks and death. These outcomes are considered more reliable for making public health policy compared to studies that use ‘intermediary endpoints,’ such as cholesterol or inflammatory measures, whose value for predicting cardiovascular events is disputed. These trials provided surprisingly little support for the diet-heart hypothesis. Dramatic reductions in the consumption of saturated fats had successfully lowered the participants’ cholesterol, by an average of 29 mg/dl, ‘indicating a high level of compliance’ among subjects, according to one analysis [16], yet the expected reductions in either cardiovascular or total mortality were not observed in most trials [15]. In other words, although diet could successfully lower blood cholesterol, this reduction did not appear to translate into long-term cardiovascular gains.» 
  55. ↑ Ruiz-Núñez, Begoña; Dijck-Brouwer, D. A. Janneke; Muskiet, Frits A. J. (1 de octubre de 2016). «The relation of saturated fatty acids with low-grade inflammation and cardiovascular disease». The Journal of Nutritional Biochemistry (en inglés) 36: 1-20. ISSN 0955-2863. doi:10.1016/j.jnutbio.2015.12.007. Consultado el 26 de diciembre de 2022. 
  56. ↑ Ramsden, Christopher E.; Hibbeln, Joseph R.; Majchrzak, Sharon F.; Davis, John M. (2010-12). «n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials». British Journal of Nutrition (en inglés) 104 (11): 1586-1600. ISSN 1475-2662. doi:10.1017/S0007114510004010. Consultado el 26 de marzo de 2023. «Inclusion of the ODHS, which delivered several g of EPA and DHA per d and other mixed n-3/n-6 PUFA trials, and the exclusion of RCT that showed possible harm of n-6 PUFA, introduced significant confounds in the prior meta-analyses. These prior analyses were thus not appropriate for formulating advice specific to n-6 PUFA. Based on this evaluation of the specific effects of n-6 PUFA in RCT, advice to maintain or increase n-6 PUFA should be reconsidered, because there is no indication of benefit, and there is a possibility of harm. A clear distinction should be made between n-6 and n-3 PUFA in future meta-analyses, reviews, editorials and public health advisories.» 
  57. ↑ «The Fat Lie You've Been Told About What's Hurting Your Heart». The Wire. Consultado el 26 de diciembre de 2022. «The Framingham study, which began in 1948 and still continues, has been following the consumption of dietary fats and the development of heart disease among its 5000+ inhabitants, chosen from Framingham, Massachusetts. At the end of the first follow-up, the investigators were unable to find any correlation between fat-intake, cholesterol and heart disease.» 
  58. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 26 de diciembre de 2022. «https://openheart.bmj.com/content/5/2/e000898?cpetoc=#xref-ref-40-1». 
  59. ↑ Dehghan, Mahshid; Mente, Andrew; Zhang, Xiaohe; Swaminathan, Sumathi; Li, Wei; Mohan, Viswanathan; Iqbal, Romaina; Kumar, Rajesh et al. (4 de noviembre de 2017). «Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study». The Lancet (en inglés) 390 (10107): 2050-2062. ISSN 0140-6736. PMID 28864332. doi:10.1016/S0140-6736(17)32252-3. Consultado el 26 de diciembre de 2022. «The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35–70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7·4 years (IQR 5·3–9·3). Dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. Participants were categorised into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality. We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random intercepts to account for centre clustering.» 
  60. ↑ Teicholz, Nina (2023-02). «A short history of saturated fat: the making and unmaking of a scientific consensus». Current Opinion in Endocrinology, Diabetes and Obesity (en inglés estadounidense) 30 (1): 65. ISSN 1752-296X. doi:10.1097/MED.0000000000000791. Consultado el 26 de diciembre de 2022. «Data from the largest-ever epidemiological cohort study ever conducted, called Prospective Urban Rural Epidemiology (PURE), provides this type of contradictory evidence regarding the diet-heart hypothesis. PURE followed individuals aged 35–70 years, from 2003 to 2013, in 18 countries with a median follow-up of 7 4 years. The PURE investigators found that saturated fat was not associated with risk of myocardial infarction or cardiovascular disease mortality and was significantly associated with lower total mortality as well as lower risk of stroke». 
  61. ↑ «The Fat Lie You've Been Told About What's Hurting Your Heart». The Wire. Consultado el 26 de diciembre de 2022. «Finally: the Prospective Urban and Rural Epidemiological (PURE) survey examined cardiovascular risk factors around the world in 2003-2009, with more than 150,000 participants. Though the results are yet to be published, a recently leaked (and now unavailable) video stated that there seemed to be no correlation between saturated fats (red meat, white meat, dairy products) and heart disease but a positive correlation between carbohydrates and heart disease. Moreover, a very sensitive cardiac-risk-factor marker was found to have increased with carbohydrates and reduced by saturated fats. Vegetables and fruits had no effect on the marker.» 
  62. ↑ Givens, David Ian (2022-12). «Saturated fats, dairy foods and cardiovascular health: No longer a curious paradox?». Nutrition Bulletin (en inglés) 47 (4): 407-422. ISSN 1471-9827. doi:10.1111/nbu.12585. Consultado el 7 de enero de 2023. «The PURE study (Dehghan et al., 2017) was a prospective cohort study carried out in 18 countries (three high, 11 middle and four low income) from five continents which examined the association of fat and carbohydrate intakes with all-cause mortality and a range of CVD-related events. It involved 135 335 subjects aged 35–70 years with a median follow-up period of 7.4 years. The key findings in relation to SFA intake are summarised in Table 2, which show that increasing intake of SFA was associated with a significantly reduced risk of total mortality, stroke and non-CVD mortality but with no association with major CVD events, myocardial infarction (MI) or CVD mortality. Increased intake of MUFA and PUFA was also associated with reduced risk of total mortality but carbohydrate intake was associated with increased risk of total mortality but not risk of CVDs or CVD mortality. The relationships of SFA intake and blood lipids in the PURE study (Mente et al., 2017) showed that whilst increased SFA intake increased serum total cholesterol (TC) and LDL-C it also increased high-density lipoprotein cholesterol (HDL-C) leading to a reduction in the TC:HDL-C ratio, both associated with reduced CVD risk in agreement with the observed reduction in all-cause mortality and stroke (Mente et al., 2017). In addition, serum triacylglycerols (TAG) declined with increasing SFA intake, which was also associated with reduced CVD risk.» 
  63. ↑ van der Laarse, Arnoud; Cobbaert, Christa M. (2 de diciembre de 2021). «Biochemical risk factors of atherosclerotic cardiovascular disease: from a narrow and controversial approach to an integral approach and precision medicine». Expert Review of Cardiovascular Therapy (en inglés) 19 (12): 1085-1096. ISSN 1477-9072. doi:10.1080/14779072.2021.2022475. Consultado el 11 de agosto de 2023. «Several Japanese studies have found that LDL-C is not a risk factor for CHD mortality in women of any age. Hamazaki et al. concluded: ‘The theory that the lower the cholesterol levels are, the better is completely wrong in the case of Japan – in fact, the exact opposite is true’ and ‘it seems clear that high cholesterol levels should not be considered unhealthy especially in elderly people.’». 
  64. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 26 de diciembre de 2022. «A study by Mozaffarian and colleagues found that postmenopausal women with a higher saturated fat intake had less coronary atherosclerosis progression (when measured as per cent stenosis as well as minimal coronary artery diameter),38 whereas polyunsaturated fatty acid (PUFA) intake was associated with worsening (a decline) in the diameter of the coronary artery.» 
  65. ↑ DuBroff, Robert; Demasi, Maryanne (1 de diciembre de 2021). «Heart disease: The forgotten pandemic». Preventive Medicine (en inglés) 153: 106791. ISSN 0091-7435. doi:10.1016/j.ypmed.2021.106791. Consultado el 26 de marzo de 2023. «Despite the widespread utilization of cholesterol-lowering statins in Europe, observational studies indicate that there has been no accompanying decline in coronary heart disease deaths.» 
  66. ↑ Ravnskov, Uffe; de Lorgeril, Michel; Diamond, David M; Hama, Rokuro; Hamazaki, Tomohito; Hammarskjöld, Björn; Hynes, Niamh; Kendrick, Malcolm et al. (3 de octubre de 2018). «LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature». Expert Review of Clinical Pharmacology 11 (10): 959-970. ISSN 1751-2433. PMID 30198808. doi:10.1080/17512433.2018.1519391. Consultado el 26 de marzo de 2023. «If high TC were the major cause of atherosclerosis, there should be exposure–response in cholesterol-lowering drug trials; for example, the arteries of those whose lipid values are lowered the most should benefit the most. However, in a review of 16 angiographic cholesterol-lowering trials, where the authors had calculated exposure–response, this correlation was only present in one of them, and in that trial, the only treatment was exercise». 
  67. ↑ Bargieł, Weronika; Cierpiszewska, Katarzyna; Maruszczak, Klara; Pakuła, Anna; Szwankowska, Dominika; Wrzesińska, Aleksandra; Gutowski, Łukasz; Formanowicz, Dorota (2021-07). «Recognized and Potentially New Biomarkers—Their Role in Diagnosis and Prognosis of Cardiovascular Disease». Medicina (en inglés) 57 (7): 701. ISSN 1648-9144. doi:10.3390/medicina57070701. Consultado el 5 de agosto de 2023. «Keeping in mind that the development of atherosclerotic plaque formation stages is at least partly reversible, we reviewed some of the atherosclerosis biomarkers to discuss their ability to predict the development of CAD, giving patients and their doctors time to react. The main limitation in identifying a universal biomarker of the inflammatory response, a key player process in atherosclerosis, is the variability of the metabolic stress response among patients and the multifaceted nature of the complex disorder itself. Therefore, we recommend using more than one biomarker because there is still no one that fits all the patients and gives reliable results in every case. Our study reviewed biomarkers from different related processes to emphasize the complexity of forming atherosclerotic plaque and show future work directions to translate their role into clinical use. We included well-recognized biomarkers: (1) CRP, one of the acute-phase proteins produced mainly by the liver in response to low-grade inflammation underlying atherosclerosis; (2) interleukin 6 (IL-6); a pro-inflammatory cytokine secreted, among others, by tunica medias’ smooth muscle cells, whose leading role consists in activating the inflammatory and autoimmune processes; (3) Lp-PLA2, an enzyme associated with both traditional (cholesterol-linked) and novel (inflammatory) pathways of atherosclerosis, which is synthesized by inflammatory cells and bonded mainly to LDL-C, with a small fraction linked to high-density lipoprotein cholesterol (HDL-C). We have also included potentially new biomarkers, such as (4) miRNA regulating gene expression by silencing complementary to itself mRNA pieces, with overexpression related to the development of vascular changes and CVD; (5) osteocalcin (OC), which is a multifunctional hormone produced by osteoblasts whose action regulates mineralization, glucose, and lipid metabolism with a role in the process of vascular calcification and atherosclerosis; and (6) angiogenin, which is a protein involved in forming new blood vessels that interact with endothelium and smooth muscles, which possibly plays a role in destabilizing coronary plaque.» 
  68. ↑ DiNicolantonio, James J; O’Keefe, James H (26 de septiembre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart 5 (2): e000898. ISSN 2053-3624. doi:10.1136/openhrt-2018-000898. Consultado el 7 de agosto de 2023. «the ‘oxidised linoleic acid theory of coronary heart disease’, is as follows: dietary linoleic acid, especially when consumed from refined omega-6 vegetable oils, gets incorporated into all blood lipoproteins (such as LDL, VLDL and HDL) increasing the susceptibility of all lipoproteins to oxidise and hence increases cardiovascular risk.» 
  69. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 7 de agosto de 2023. «lipids from human atherosclerotic plaques have been found to contain oxidised cholesteryl linoleate (cholesterol esters containing linoleic acid)». 
  70. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 7 de agosto de 2023. «cholesterol was protected from oxidation if bound to saturated fat but susceptible to oxidation when bound to linoleic acid». 
  71. ↑ DiNicolantonio, James J.; O’Keefe, James H. (1 de octubre de 2018). «Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis». Open Heart (en inglés) 5 (2): e000898. ISSN 2053-3624. PMID 30364556. doi:10.1136/openhrt-2018-000898. Consultado el 7 de agosto de 2023. «On LDL oxidation, linoleic acid is converted to hydroperoxides, which can then be converted to hydroxy acids, such as 9-HODE (9-hydroxy-10,12-octadecadienoic acid). 9-HODE is extremely prevalent in oxidised LDL and is a good indicator of lipid peroxidation. In fact, 9-HODE is 20 times higher in young patients with atherosclerosis compared with healthy volunteers and 30-fold to 100-fold greater in patients with atherosclerosis aged 69 to 94 compared with young healthy individuals.» 
  72. ↑ Volek, Jeff S.; Phinney, Stephen D.; Krauss, Ronald M.; Johnson, Richard J.; Saslow, Laura R.; Gower, Barbara; Yancy, William S.; King, Janet C. et al. (2021-10). «Alternative Dietary Patterns for Americans: Low-Carbohydrate Diets». Nutrients (en inglés) 13 (10): 3299. ISSN 2072-6643. doi:10.3390/nu13103299. Consultado el 7 de enero de 2023. «Low-carbohydrate diets are grounded across the time-span of human evolution, have well-established biochemical principles, and are now supported by multiple clinical trials in humans that demonstrate consistent improvements in multiple established risk factors associated with insulin resistance and cardiovascular disease.» 
  73. ↑ Berger, Amy; Thorn, Eric (1 de octubre de 2022). «Can low-carbohydrate diets be recommended for reducing cardiovascular risk?». Current Opinion in Endocrinology & Diabetes and Obesity 29 (5): 413-419. doi:10.1097/MED.0000000000000750. Consultado el 7 de enero de 2023. «Type 2 diabetes mellitus (T2DM), metabolic syndrome, and related co-morbidities are major risk factors for cardiovascular disease (CVD). Ideally, then, a diet intended to support cardiovascular health should be one that improves or reverses these underlying risk factors.» 
  74. ↑ Berger, Amy; Thorn, Eric (1 de octubre de 2022). «Can low-carbohydrate diets be recommended for reducing cardiovascular risk?». Current Opinion in Endocrinology & Diabetes and Obesity 29 (5): 413-419. doi:10.1097/MED.0000000000000750. Consultado el 7 de enero de 2023. «Recent consensus reports from select national organizations have endorsed low-carbohydrate diets for improving glycemia and cardiovascular risk. Reluctance among public health organizations and some clinicians to more widely promote this therapeutic nutritional approach is driven primarily by the increase in serum low-density lipoprotein cholesterol (LDL-C) observed in a proportion of individuals who adopt a low-carbohydrate diet.» 
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