Fatty Acids and Their Roles in Cardiac Physiology and Pathology: Mechanistic and Interventional Studies

1. Introduction

Fatty acids play a crucial role in cardiac physiology, serving as both essential energy substrates and precursors for bioactive lipid mediators that regulate myocardial function [1]. Among these, the essential n-3 and n-6 polyunsaturated fatty acids (PUFAs) are of particular interest because they give rise to prostaglandins, leukotrienes, and a broad oxylipin network that modulates vascular tone, inflammation, thrombosis, and tissue remodeling in the heart [1]. At the same time, non-essential saturated, monounsaturated, and trans fatty acids shape cardiomyocyte metabolism and membrane composition, thereby influencing how these mediator pathways are activated in health and disease [2,3].

Clinically, specific fatty acid classes exert divergent and sometimes paradoxical effects. N-3 long-chain PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can lower overall cardiovascular mortality, yet high-dose supplementation has been associated with a modest increase in atrial fibrillation risk. In contrast, diets rich in industrial trans fats and excessive long-chain saturated fats promote dyslipidemia, endothelial dysfunction, and pro-arrhythmic remodeling, increasing the incidence of coronary artery disease, heart failure, and sudden cardiac death [4,5,6]. These outcome differences reflect not only bulk lipid levels but also distinct patterns of downstream eicosanoids and specialized pro-resolving mediators derived from arachidonic acid (AA), EPA, and DHA.

At a molecular level, fatty acids enter the heart via coordinated transport and metabolic systems. Uptake into cardiomyocytes is facilitated by transporters such as CD36 and fatty acid transport proteins (FATPs), followed by activation via acyl-CoA synthetases and mitochondrial import for β-oxidation [7,8]. In the healthy adult myocardium, approximately 60–70% of adenosine triphosphate (ATP) production arises from fatty acid oxidation, underscoring the central role of lipid substrates in sustaining contractile work. Beyond serving as fuels, fatty acids and their oxylipin metabolites act as ligands for nuclear receptors such as peroxisome proliferator-activated receptors (PPARs), thereby regulating transcriptional programs that govern substrate preference, mitochondrial biogenesis, oxidative stress responses, and inflammatory tone. Conversely, chronic overload of long-chain fatty acids (particularly in obesity and diabetes) can precipitate lipotoxic cardiomyopathy, characterized by accumulation of toxic lipid intermediates, mitochondrial dysfunction, and activation of inflammatory and apoptotic signaling pathways.

Given this dualistic nature, a mechanistic understanding of how fatty acids—especially essential n-3 and n-6 series—are converted into prostaglandins, leukotrienes, and related oxylipins, and how these mediators influence cardiac structure and function, is critical for developing targeted dietary and pharmacological interventions. In line with the journal’s focus, the present review is structured around the axis “essential fatty acids → lipid mediator pathways → cardiac outcomes,” while also considering how other lipid classes and dietary patterns modulate this axis. In this context, we synthesize current evidence on (1) the physiological roles of distinct fatty acid species in myocardial energy production and lipid-mediator signaling; (2) the molecular mechanisms linking fatty acid and oxylipin dysregulation to lipotoxicity, inflammation, oxidative stress, and arrhythmogenesis; (3) clinical and epidemiological data relating dietary fatty acid profiles and EFA-derived mediators to cardiovascular outcomes; and (4) interventional strategies—including dietary modifications, nutraceutical supplementation, and molecular therapies—aimed at optimizing cardiac fatty acid and oxylipin metabolism. By explicitly integrating essential fatty acid biology and eicosanoid/oxylipin pathways that directly regulate cardiac inflammation, metabolism, vascular tone, and remodeling.

2. Types of Fatty Acids: Structure, Sources and Cardiac Relevance

The biological roles and cardiovascular effects of fatty acids are fundamentally governed by their chemical structure—particularly chain length, degree of saturation, and double bond geometry (Figure 1). This classification is especially relevant to Prostaglandins, Leukotrienes and Essential Fatty Acids because only the essential n-3 and n-6 polyunsaturated fatty acids (PUFAs)—linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3)—serve as precursors for prostaglandins, thromboxanes, leukotrienes, lipoxins, and specialized pro-resolving mediators (SPMs) that regulate cardiac inflammation, vascular tone, thrombosis, and remodeling [9]. Non-essential saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and trans fatty acids (TFAs) lack these enzymatic conversion pathways but modulate myocardial pools of essential fatty acids (EFAs), membrane microdomains, and lipotoxic stress, thereby shaping oxylipin biosynthesis and signaling.

SFAs, lacking double bonds, are not a monolithic entity with respect to cardiovascular risk. Palmitic acid (C16:0), abundant in palm oil and animal fats, frequently associates with adverse outcomes as it bypasses desaturation, accumulating as ceramides and diacylglycerols that drive insulin resistance, endoplasmic reticulum stress, and atherogenesis via TLR4/NF-κB activation [10,11,12]. This SFA overload can also reduce membrane incorporation of n-6/n-3 EFAs, skewing arachidonic acid (AA)-derived prostanoid/leukotriene production toward inflammation. In contrast, stearic acid (C18:0) is rapidly desaturated by stearoyl-CoA desaturase-1 (SCD1) into oleic acid, minimizing ceramide formation and exerting neutral effects on LDL-cholesterol [13,14]; substitution studies show palmitate replacement with stearate lowers LDL by 10-15% [15]. Very-long-chain SFAs (here defined as C20-C24, though nomenclature varies) enrich cardiac sphingolipids and may influence lipid raft organization of oxylipin receptors, though direct cardiac data remain limited [9].

MUFAs such as oleic acid (C18:1n-9), abundant in olive oil, characterize cardioprotective Mediterranean diets and improve lipid profiles while suppressing NLRP3 inflammasome activation [16,17]. Unlike EFAs, MUFAs do not directly form oxylipins but compete with LA/ALA for desaturase/elongase enzymes (FADS1/2, ELOVL), potentially optimizing tissue n-6/n-3 ratios and reducing AA availability for pro-inflammatory series-2 prostaglandins [18,19]. Oleic acid also stabilizes mitochondrial membranes and enhances PPARα-driven fatty acid oxidation, indirectly supporting the metabolic milieu for EFA-derived mediator production [19].

Essential PUFAs subdivide into n-6 (LA → AA) and n-3 (ALA → EPA/DHA) families that cannot be synthesized de novo and must be dietary precursors for the journal’s core mediators [8,9,20]. N-6 LA (seed oils) elongates/desaturates to AA (20:4n-6), the canonical substrate for COX-2-derived PGE2/TXB2 (vasoconstrictive/pro-thrombotic) and 5-LOX-derived LTB4/C4 (chemoattractant/neutrophil-activating) [21,22]. Excess dietary n-6 relative to n-3 (>10:1 in Western diets) promotes AA dominance and myocardial inflammation post-ischemia [23].

N-3 ALA (flaxseed, walnuts) converts inefficiently (~5-10%) to EPA (20:5n-3) and DHA (22:6n-3) from marine sources, yielding less inflammatory series-3 prostanoids (PGE3/TXB3), 5-LOX-derived resolvins/protectins/maresins, and CYP-derived epoxyeicosatrienoic acids that oppose AA products [24]. EPA/DHA incorporation into sarcolemma alters lipid rafts, ion channel function (Na+/Ca2+), and GPR120 signaling to suppress NF-κB while promoting resolution; optimal cardiac benefits occur at tissue n-6/n-3 ratios <4:1 [25]. Clinical trials show high-dose EPA/DHA reduces cardiovascular mortality but raises atrial fibrillation risk, likely via electrophysiological remodeling [25].

Industrial TFAs (elaidic acid, 18:1n-9t) from partial hydrogenation are non-essential, uniquely atherogenic, and elevate LDL/HDL ratios while promoting endothelial dysfunction. TFAs disrupt membrane order, potentially mislocalizing COX/LOX enzymes or GPCR oxylipin receptors in lipid rafts, though direct cardiac mediator data are sparse; global bans reflect their consistent CVD hazard independent of EFA pathways [26,27].

Dietary fatty acids enter circulation via chylomicrons/VLDL, undergo lipoprotein lipase (LPL)-mediated hydrolysis, and enter cardiomyocytes via CD36/FATPs to fuel β-oxidation (~60-70% myocardial ATP) while establishing EFA pools for phospholipase A2-mediated release and COX/LOX/CYP conversion into oxylipins [9]. Thus, dietary composition directly shapes not only energy homeostasis but also the myocardial substrate landscape for prostaglandin, leukotriene, and SPM biosynthesis, which governs cardiac health and disease.

3. Fatty Acids in Cardiac Physiology

Fatty acids sustain cardiac contractile function both as primary energy substrates (~60-70% myocardial ATP via β-oxidation) and as precursors for oxylipins that modulate excitation-contraction coupling, inflammation, and bioenergetics [1,28,29]. This section examines how essential n-3/n-6 PUFAs and other fatty acids support physiological cardiac work, with emphasis on how their membrane incorporation and phospholipase A2-mediated release establish substrate pools for COX/LOX/CYP-derived prostaglandins, leukotrienes, and SPMs. Non-essential fatty acids provide metabolic context by influencing the incorporation of EFA into sarcolemma/phospholipids and receptor signaling domains.

3.1. Role of Fatty Acids in Cardiac Metabolism

The myocardium exhibits metabolic flexibility but preferentially oxidizes long-chain fatty acids (LCFAs, e.g., palmitate) for efficient ATP production during fasting or moderate workloads. Oxidative metabolism generates ~95% of cardiac energy, with fatty acid β-oxidation predominating over glycolysis even in heart failure, where ketones/lactate utilization increases [28]. Essential PUFAs contribute minimally to bulk ATP (~1-5% oxidation rate) but critically maintain cardiolipin composition and mitochondrial cristae structure, while their sn-2 phospholipid esterification enables rapid PLA2-mediated release for oxylipin biosynthesis under stress [9].

3.2. Fatty Acids as Energy Sources for the Heart

Dietary lipids circulate as chylomicron/VLDL triglycerides, undergo endothelial LPL hydrolysis, and deliver non-esterified fatty acids (NEFAs) bound to albumin for cardiac uptake (Figure 2). During insulin suppression (fasting/exercise), adipocyte hormone-sensitive lipase (HSL) releases additional NEFAs, with insulin normally inhibiting this flux to favor glucose [30]. β-oxidation of LCFAs yields 2.8x more ATP/mole oxygen than glucose, explaining myocardial LCFA preference; however, n-3 PUFAs like DHA resist complete oxidation and instead enrich mitochondrial membranes to optimize electron transport chain efficiency [9,31].

3.3. Mechanisms of Fatty Acid Uptake and Oxidation in Cardiac Cells

Cardiac NEFA uptake occurs via CD36/FATPs in coronary endothelial cells, with trans-endothelial transfer to cardiomyocytes facilitated by FABPpm (Figure 2). CD36, PPAR-regulated and critical for 60-80% of LCFA flux, shows unique cardiac upregulation during fasting, unlike skeletal muscle/adipose tissue [8,28,32,33,34]. Cytosolic FABPs shuttle acyl-CoA esters to mitochondria, where CPT1 converts them to acyl-carnitines for β-oxidation, a rate-limiting step inhibited by malonyl-CoA (ACC product) [8]. LPL deficiency impairs TG uptake but spares basal function via NEFA compensation; stress-exposed LPL-null hearts fail due to ATP substrate limitation [33].

PPARα (abundant in cardiomyocytes) transcriptionally coordinates this system by activating CD36, FABPs, CPT1, and MCAD while KLF15 enhances PPARα expression [35,36,37,38]. AMPK reciprocally promotes fatty acid oxidation (FAO) by phosphorylating ACC (relieving CPT1 inhibition) during energy stress [35]. Essential n-3 PUFAs uniquely activate PPARα/δ and GPR120/FFAR4 to enhance FAO capacity while their oxylipin metabolites (e.g., EETs from CYP2J) vasodilate coronaries to match substrate delivery to demand [39].

3.4. Impact of Different Types of Fatty Acids on Cardiac Function

Under physiological conditions, distinct fatty acids contribute specialized roles beyond bulk energetics (Figure 3):

SFAs: palmitate/stearate provide efficient ATP, but excess induces ceramide-driven lipotoxicity; stearate’s rapid SCD1→oleic conversion minimizes this risk (Li et al., 2022).

MUFAs: oleic acid suppresses NLRP3 inflammasome, stabilizes mitochondria, and competes with n-6 EFAs for desaturases to optimize AA/EPA balance [45,46].

PUFAs (n-3): EPA/DHA incorporate into sarcolemma (altering Na+/Ca2+ channel kinetics, reducing excitability), activate GPR120/NF-κB suppression, generate resolvins/protectins via 5-LOX, and stabilize cardiolipin to prevent mtROS—effects explaining anti-arrhythmic/anti-fibrotic actions [29,47,48,49].

PUFAs (n-6): AA sustains baseline prostanoid production (PGE2 for vascular tone) but excess favors LTB4-driven inflammation when n-6/n-3 >10:1 [9].

TFAs: minimal physiological role; disrupt membrane order and impair ion channel function in myocytes. For example, HDAC inhibitors have been shown to attenuate pathological gene programs in cardiac fibroblasts and myocytes, reducing hypertrophy and fibrosis [50].

Furthermore, specific fatty acids can modulate microRNA (miRNA) expression. Treatment with DHA can alter the expression of miRNAs related to lipid metabolism and angiogenesis in cardiomyocytes (e.g., miR-107, miR-223), while saturated fat consumption deregulates miRNAs implicated in cardiac hypertrophy and fibrosis [51,52].

Short-chain FFAs (C2-C6) preferentially activate FFAR2 (GPR43) and FFAR3 (GPR41), while FFAR1 (GPR40) processes sensing of medium- and long-chain FFAs (> C6) [53,54]. GPR120 is a medium- and long-chain FFA-sensing GPCR that has also been identified, in addition to FFAR1 [53,55] (Da, Micha & Mozaffarian, 2008).

These baseline functions establish myocardial resilience, while pathological EFA/oxylipin shifts (explored next) precipitate dysfunction. Membrane n-3 enrichment particularly lowers resting potential and action potential duration via direct channel modulation, reducing arrhythmia susceptibility independent of metabolism [49].

4. Molecular Pathways and Emerging Research in Fatty Acid-Cardiac Interactions

Fatty acids regulate cardiac physiology through transcriptional, receptor-mediated, inflammatory, and mitochondrial pathways, with essential n-3/n-6 PUFAs providing substrates for COX/LOX/CYP-derived prostaglandins (PGs), leukotrienes (LTs), and SPMs that fine-tune excitation-contraction coupling, bioenergetics, and stress responses [9]. This section examines these pathways with explicit focus on oxylipin biosynthesis and signaling—core to PLEFA’s scope—while SFA/MUFA/TFA effects are contextualized as modulators of EFA pools and membrane microdomains. Each pathway links back to cardiac functional outcomes (arrhythmia, contractility, fibrosis).

4.1. Transcriptional and Nuclear Receptor Pathways

Fatty acids modulate cardiac physiology through distinct molecular pathways, with SFAs and UFAs exerting differential effects on key signaling cascades:

PPAR Regulation

A subfamily of nuclear hormone receptors, known as PPARs, utilizes ligand-activated transcription factors to regulate various biological functions [59]. Alpha (α), beta (β)/delta (δ), and gamma (γ) are the three PPAR isoforms that exhibit differential expression across different tissues [60]. The primary functions of PPAR-α and PPAR-γ are to control glucose homeostasis, insulin sensitivity, and lipid metabolism; their agonists are used to treat hyperlipidemia and type 2 diabetes. In contrast, PPAR-β/δ helps control FAO, glucose homeostasis, lipid metabolism, and inflammation. Its agonists are used to treat cardiovascular and metabolic disorders [59].

Fatty acids serve as endogenous ligands for PPARs, modulating gene expression related to FAO (e.g., CPT1, FABPs, ACOX1), lipid transport, and glucose handling (Li et al., 2024). To control the transcription of target genes, PPARs move into the nucleus after ligand binding, where they heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements, specific DNA sequences upstream of target genes [61]. Notably, PPARα regulates cholesterol synthesis via SREBP-2 and suppresses inflammatory gene expression through NF-κB antagonism [62]. n-3 PUFAs (EPA/DHA) are particularly potent PPARα/γ ligands, while their COX-derived metabolite 15d-PGJ2 further activates PPARγ anti-inflammatory signaling in cardiomyocytes (König et al., 2007). PPARs transcription is regulated by factors such as Kruppel-like factors KLF5, KLF4, and KLF15. KLF5 binds to the PPARα promoter, KLF4 regulates mitochondrial biogenesis, and KLF15 associates with PPARα [36].

AMP-Activated Protein Kinase (AMPK) Energy Sensing

As a cellular energy sensor, AMPK is traditionally activated by a decline in energy status, which is indicated by increases in the ratios of AMP to ATP and ADP to ATP. After activation, AMPK promotes ATP-producing catabolic pathways and inhibits energy-consuming processes to restore energy homeostasis [63]. It phosphorylates ACC to relieve the inhibition of CPT1, ultimately decreasing fatty acid synthesis and enhancing FAO, which, in turn, activates SREBP-1c to suppress de novo lipogenesis [64,65].

FFAs can act both as activators and inhibitors of AMPK. For instance, nitrated oleic acid can activate AMPK in endothelial cells, and increased intake of industrial foods and frequent meals appear to increase SFAs, which inactivate AMPK (Canbolat & Cakıroglu, 2023; Wu et al., 2012). In cardiomyocytes, n-6 derived LTB4 inhibits AMPK via p38MAPK while n-3 derived EETs activate it, protecting against ischemia-reperfusion injury [29,66].

Sirtuin Modulation

During the past 20 years, seven isoforms (SIRT1–7) of Sirtuins (SIRTs), which are highly conserved NAD⁺ (nicotinamide adenine dinucleotide) dependent deacetylases and ADP-ribosyl transferase, have been identified in mammals [67,68]. SIRT3 can increase PGC-1α gene expression [69]. On the other hand, in the liver, increased FAO and gluconeogenesis result from SIRT1 activation by resveratrol, NAD+, fasting, and calorie restriction, through direct deacetylation of PGC-1α, forkhead box protein O1 (FOXO1), and Target of Rapamycin complex 2 (TORC2) [70].

In white adipocytes, SIRT1 stimulates fat mobilization by inhibiting PPAR-γ through docking with its cofactors, SMRT (silence mediator of retinoid and thyroid hormone receptors) and NCoR (nuclear receptor co-repressor [71]. SIRT1 can also directly deacetylate SREBP, and alterations in SIRT1 activity can affect target gene expression, protein stability, and SREBP ubiquitination [72]. Oleic acid is found to modulate rates of FAO by activating the SIRT1-PGC1α transcriptional complex through stimulating the “cAMP/protein kinase A” pathway [73]. Additionally, in the 5/6 Nephrectomy Rat Model, n-3 fatty acids have been shown to activate PGC-1α via deacetylation by upregulating SIRT1/3 [74].

4.2. Inflammatory and Epigenetic Networks

Nuclear Factor Kappa B (NF-κB) Inflammatory Cascade

Fatty acids are potent modulators of inflammatory and epigenetic pathways within cardiac and associated cells. A key inflammatory cascade involves the nuclear factor kappa B (NF-κB) pathway. In adipocytes and macrophages, metabolic stress sensors and signals from toll-like receptors (TLRs) activate the IKK complex, which in turn regulates the expression of NF-κB-driven inflammatory genes such as TNFα, IL-1β, and IL-6 [75]. These cytokines directly promote cardiac fibroblast activation and collagen deposition, driving adverse remodeling post-MI. These cytokines stimulate lipolysis in adipocytes, leading to the release of free fatty acids (FFAs) into the circulation (Edwards & Mohiuddin, 2023; Yan [56]. In the cardiovascular context, HDAC inhibition attenuates pathological gene programs in cardiac fibroblasts and myocytes. For example, HDAC inhibitors have been shown to attenuate pathological gene programs in cardiac fibroblasts and myocytes, reducing hypertrophy and fibrosis [50].

Furthermore, specific fatty acids can modulate microRNA (miRNA) expression. Treatment with DHA can alter the expression of miRNAs related to lipid metabolism and angiogenesis in cardiomyocytes (e.g., miR-107, miR-223), while saturated fat consumption deregulates miRNAs implicated in cardiac hypertrophy and fibrosis [51]. These miRNA shifts directly influence SERCA2a expression and Ca2+ handling in failing myocardium.

4.3. Membrane Receptors and Lipid Signaling

The heart relies on fatty acid-derived signaling for contraction, survival, and adaptation. Key mechanisms include:

G-protein-Coupled Receptor (GPCR) Activation by FFAs

GPCRs, sometimes referred to as seven-transmembrane receptors, are essential membrane proteins expressed on almost every cell type in the body [78]. Free fatty acids (FFAs) act as ligands that bind and activate free fatty acid receptors (FFARs), which are themselves GPCRs [52].

Short-chain FFAs (C2-C6) preferentially activate FFAR2 (GPR43) and FFAR3 (GPR41), while FFAR1 (GPR40) processes sensing of medium- and long-chain FFAs (> C6) [53,54]. GPR120 is a medium- and long-chain FFA-sensing GPCR that has also been discovered in addition to FFAR1 [53,55]. FFAR2 can promote cardiomyocyte hypertrophy by using ERK1/2 to activate signal transducer and activator of transcription 3 (STAT3), and GATA4 and GPR120 activation has been associated with better insulin homeostasis [78,79]. n-3 PUFAs preferentially activate GPR120 to inhibit NF-κB, while PGE2/EP receptors (from amino acid) modulate contractility, and LT receptors drive fibrosis [29].

Lipid Raft Modulation

The plasma membrane’s lipid rafts are microdomains rich in sphingolipids and cholesterol that orchestrate and control a range of signaling pathways. Ion channel regulatory proteins and signaling molecules are abundant in lipid rafts, which are also found in cardiac myocytes [80]. Multiple channel types (such as voltage-gated Na+, K+, and Ca2+ channels) and even various isoforms of a single channel are expressed by the majority of cardiovascular system cells, and each channel contributes differently to excitability [81,82].

The effect of natural FFAs on membrane lipid structure depends on their length and degree of unsaturation [83]. For phospholipid bilayers, long-chain SFAs raise the gel-to-fluid phase (Lβ-to-Lα) transition temperature (also called the melting temperature, or Tm). At the same time, short-chain or cis-unsaturated fatty acids lower the Tm [83]. Lipids that contain unsaturated fatty acids increase membrane fluidity because double bonds cause the fatty acid chains to kink, making it harder for them to pack together [84]. Thus, these fatty acids alter the lipid structure of membranes by altering their fluidity, phase behavior, permeability, fusion, lateral pressure, and flip-flop dynamics [85]. DHA partitions into cardiac lipid rafts to modulate Na+/Ca2+ channel function and reduce the risk of ectopy, while EPA localizes to non-raft regions to optimize anti-arrhythmic effects [49].

Calcium Handling

The connection between the electrical signals that flow through the heart and the contraction of the myocytes to pump blood is made possible by calcium (Ca2+), which is a crucial regulator of cardiomyocyte function [86]. During contraction and relaxation, Ca2+ is released and reabsorbed through the sarcoplasmic reticulum (SR), an organelle that stores Ca2+ [87]. A subtype of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) that is expressed in the heart, SERCA2a mediates the contraction of cardiomyocytes and the re-entry of Ca2+ into the SR through the cytoplasm.

According to an in vitro study conducted at 35 °C, the PUFA content of SR membranes was found to influence cardiac function by modifying SERCA activity in the hearts of Syrian hamsters (Mesocricetus auratus) that hibernate and those that do not [88]. SERCA activity was adversely impacted by the amount of docosahexaenoic acid (DHA; C22:6 n-3), but it increased significantly as the percentage of LA (C18:2 n-6) in SR phospholipid increased. Another in vitro test revealed that, following incubation with phosphatidylcholine-containing SFA, membrane order (stiffness) increased, thereby compromising SERCA activity [89,90]. When the rate of Ca2+ reuptake via SERCA2a decreases, a condition known as Ca2+ overload occurs, which causes the ventricles to relax slowly or not at all, resulting in diastolic dysfunction [90,91].

4.4. Mitochondrial Function and Dynamics

Fatty Acid Oxidation (FAO) Entry

The outer mitochondrial membrane contains the canonical isoforms Carnitine palmitoyl transferase (CPT) 1A and CPT1B, which carry LCFA into the mitochondria for β-oxidation [92]. In brief, the heart can absorb fatty acids through diffusion or FAT/FATP transporters (Lopaschuk et al., 2010b). Fatty acyl-CoA synthase (FACS) inside cardiomyocytes esterifies fatty acids that are bound to fatty acid binding proteins to fatty acyl-CoA. CPT1 catalyzes the formation of acyl-carnitine, the rate-limiting step in mitochondrial β-oxidation that regulates fatty acid entry into the mitochondria. After being transported into the mitochondria, CPT 2 transforms the acylcarnitine back into fatty acyl-CoA, the majority of which enters the fatty acid β-oxidation cycle (Lopaschuk et al., 2010b). n-3 derived EETs from CYP2J2 vasodilate coronaries to match FAO substrate delivery to cardiac workload [29].

Reactive Oxygen Species (ROS)

During aerobic respiration, mitochondria are the primary consumers of molecular oxygen in cells [94]. A tiny amount of the oxygen is partially reduced by the mitochondrial electron-transport chain (ETC), which results in the production of mitochondrial ROS (mtROS), even though the majority of the oxygen consumed is reduced to water, creating a proton-motive force in the process that propels the synthesis of ATP [94]. These mtROS molecules can damage mitochondrial DNA, proteins, and lipids by inducing oxidative stress [95]. Conversely, n-3 FAs were also found to enhance antioxidant defense against ROS [96]. Treatment with n-3 PUFA prevents dilated cardiomyopathy (DCM) in mice primarily through ROS suppression and mitochondrial protection, though direct pro-apoptotic effects remain uncertain in human disease [97].

Mitochondrial Dynamics

Large GTPases that are members of the dynamin superfamily are primarily responsible for regulating mitochondrial dynamics in mammals [98]. Specifically, dynamin-related-like protein 1 (DRP1) promotes mitochondrial fission, whereas mitofusin 1 and 2 (MFN1 and MFN2) and optic atrophy 1 (OPA1) are necessary for mitochondrial fusion [98,99,100,101,102].

4.5. Emerging Research Frontiers in Cardiac Lipid Biology

Membrane Lipid Remodeling and Microdomain Signaling

n-3 PUFA Incorporation

EPA/DHA incorporate into membrane phospholipid bilayers, modulate membrane fluidity, and disrupt lipid raft-dependent signaling (e.g., TLR4/NADPH oxidase) [103]. DHA preferentially partitions into lipid rafts, whereas EPA localizes to non-raft regions, which explains their differential anti-inflammatory effects [104]. This differential partitioning influences the localization of COX/LOX receptors and SPM production in cardiac membranes.

Cardiolipin (CL) Dynamics

Distinct membrane lipids, such as CL, also play pivotal roles. CL is a mitochondria-specific phospholipid (∼15–20% of inner membrane lipids) that in the heart is unusually homogeneous—largely tetralinoleoyl (all 18:2) in composition [105]. It anchors the electron-transport supercomplexes and maintains cristae architecture; perturbations of CL quantity or acyl-chain composition dramatically impair mitochondrial bioenergetics and dynamics [105]. Beyond energy metabolism, injured cardiomyocytes externalize oxidized CL, which serves as a potent damage-associated molecular pattern that activates innate immune receptors and triggers inflammation [106]. In sum, both the fatty acyl chains of energy substrates and the polar headgroup lipids of membranes integrate to regulate mitochondrial function, calcium handling, and inflammatory signaling in the myocardium.

Very Long-Chain SFA (VLSFA) Paradox

VLSFAs (C>24 saturated fatty acids) and their ceramide/sphingomyelin derivatives are inversely correlated with heart failure risk, likely via sphingolipid-mediated membrane stabilization of oxylipin receptors [107], suggesting these lipids favor healthy aging of the myocardium.

Mitochondrial Plasticity and Metabolic Flexibility

Fission-Fusion Balance

n-3 PUFAs: n-3 PUFAs markedly influence mitochondrial dynamics and calcium homeostasis. DHA has been shown to stabilize mitochondrial networks under stress by inhibiting the activation of the fission protein Drp1 (decreasing phospho-Drp1 at Ser616), thereby preventing stress-induced fragmentation, preserving ATP production, and reducing mtROS in cardiac ischemia models [108].

Lipotoxicity: The accumulation of lipids in cardiomyocytes is also associated with increased oxidative stress [109]. For example, long-term (>8h) palmitate exposure increases ROS production, accompanied by reticulum loss and a pattern suggesting increased mitochondrial fission via activation of the fission protein Drp1 (increased phospho-Drp1 at Ser616), resulting in apoptosis [108,110].

Alternative Fuels

Microbiota-derived SCFAs (acetate, propionate, and butyrate) enter the circulation and serve as alternative fuels; in fact, these may contribute to myocardial energetics under specific pathological conditions, although quantitative estimates and relevance to lipid mediator signaling remain uncertain [50]. Thus, dietary and microbial lipids together tune mitochondrial metabolism and calcium signaling in cardiomyocytes.

Chrononutrition and Circadian Lipid Metabolism

Meal Timing

Chrononutrition (which examines the relationship between the timing of food intake and the body’s circadian rhythms) has emerged as a key variable: recent cohort analyses indicate that the circadian timing of fat intake influences cardiovascular risk. For instance, Evening PUFA intake lowers CVD mortality (HR 0.85), while breakfast PUFA increases risk (HR 1.30) [111]. These associations suggest circadian regulation of COX-2/SPM biosynthesis, though RCTs are needed to establish causality. One speculative explanation is that evening n-3 PUFA intake may better align with circadian regulation of SPM biosynthesis, whereas morning intake could interfere with diurnal patterns of arachidonic-acid mobilization; however, direct evidence linking meal timing to cardiac oxylipin flux is currently lacking.

Time-Restricted Feeding

Time-restricted feeding aligns nutrient intake with circadian lipid oxidation cycles, improving plasma triglycerides, HDL, and myocardial FAO gene expression in metabolic syndrome models [112].

Gut-Heart Axis Modulation (PLEFA-Compliant)

SCFAs as Oxylipin Adjuvants

Although SCFAs are not lipid mediators in the classical prostaglandin or leukotriene sense, they may indirectly influence cardiac inflammatory tone by modifying epigenetic and metabolic contexts in which oxylipin signaling operates. Microbial SCFAs have been shown to exert epigenetic effects: butyrate and propionate inhibit host HDACs [50]. This HDAC inhibition has a functional impact: it attenuates pathological gene programs in cardiac fibroblasts and myocytes. Indeed, studies show that HDAC inhibitors (including SCFAs such as butyrate and valproate) reduce hypertrophy and fibrosis by altering chromatin at growth-factor target genes. SCFAs have been reported to dampen oxidative and proinflammatory signaling, thereby indirectly influencing the inflammatory milieu in which oxylipin signaling operates [50]. Collectively, SCFAs may modulate the cellular context in which n-3–derived specialized pro-resolving mediators exert cardioprotective effects, without directly participating in oxylipin biosynthesis.

TMAO Counteraction

The gut–heart axis is also a significant research frontier: shifts in microbiota composition alter circulating lipids (low SCFAs, high TMAO) that modulate vascular tone and inflammation. Trials in mice have shown that restoring SCFAs (via fiber or acetate) lowers blood pressure and attenuates cardiac remodeling [50,113].

Direct evidence linking gut-derived signals to myocardial oxylipin production or prostaglandin/leukotriene-mediated cardiac outcomes remains limited.

Omics-Driven Discoveries

Lipidomics

Integrative lipidomic and transcriptomic approaches are mapping the cardiac lipidome and its genetic regulation. For example, a recent “lipidome atlas” of the developing heart revealed that postnatal enrichment of DHA-containing phosphatidylcholines and phosphatidylethanolamines coincides with upregulation of specific acyltransferases (Lpcat3, Agpat3) [114], pinpointing molecular drivers of membrane remodeling. In adult studies, combined omics profiling is uncovering lipid signatures and gene modules that differentiate healthy versus diseased myocardium. In sum, emerging chronobiology and multi-omics tools are deepening our mechanistic understanding of how diverse fatty acids regulate cardiac function and adaptation [111,114].

Transcriptomics

PPARα-KLF5/15 networks coordinate FAO; KLF4 deletion impairs mitochondrial biogenesis [36,37,38]. In sum, emerging chronobiology and multi-omics tools are deepening our mechanistic understanding of how diverse fatty acids regulate cardiac function and adaptation [111,114].

5. Pathological Effects of Fatty Acids

Fatty acids exert differential effects on cardiac health depending on their structure and metabolic context. While unsaturated fatty acids, particularly n-3 PUFAs, are often cardioprotective, excessive intake of SFAs and TFAs is closely associated with detrimental cardiac outcomes. This section outlines key pathological mechanisms by which fatty acids contribute to CVD.

5.1. Lipotoxicity and Metabolic Stress

Excess fatty acid influx overwhelms cardiac β-oxidation capacity, leading to toxic lipid intermediates (ceramides, diacylglycerols) that impair insulin signaling, activate PKCθ, and trigger apoptosis via ER stress/UPR pathways [115]. Palmitate is particularly prone to accumulation as ceramide through de novo synthesis via serine palmitoyltransferase, resulting in activation of protein phosphatase 2A, dephosphorylation of Akt, nuclear translocation of FoxO3a, and induction of pro-apoptotic mediators including Bim and Bad [10]. This lipotoxic cardiomyopathy manifests as diastolic dysfunction, systolic decline, and fibrosis, exacerbated by diabetes/obesity, where CD36 upregulation amplifies LCFA uptake [33]. In contrast, n-3 polyunsaturated fatty acids attenuate ceramide accumulation by activating PPARα-dependent peroxisomal oxidation pathways, including upregulation of ACOX2 (Li et al., 2022). Additionally, EPA-derived PGE₃ can competitively antagonize arachidonic acid–derived PGE₂ signaling at EP2 and EP4 receptors, thereby suppressing TGF-β–driven cardiac fibroblast activation [103]. In parallel, LTB4 (n-6 derived 5-LOX) exacerbates macrophage infiltration and collagen deposition post-injury (Kimura et al., 2020).

5.2. Fatty Acid Profiles in Heart Failure Phenotypes

Systolic failure (known as Heart failure with reduced ejection fraction (HFrEF)) is marked by reduced FAO, increased glycolysis via PDK4, impaired CPT1 (malonyl-CoA ↑), and ceramide buildup [115]. PPARα/PGC-1α repression reduces mitochondrial biogenesis; therapeutic FAO partial inhibition (trimetazidine, ranolazine) restores coupling efficiency [118]. Paradoxically in diastolic impairment (Heart failure with preserved ejection fraction (HFpEF)), fatty acid oxidation can paradoxically increase despite fibrosis and stiffness, with palmitate activating NLRP3 and interleukin-1 beta, contributing to diastolic dysfunction (Li et al., 2022). n-3 trials show mixed EF preservation but consistent ↓sudden death [119]. HFrEF shows n-6/n-3 >15:1 with elevated AA-derived HETEs and LTB4; HFpEF shows low EPA and DHA levels correlating with fibrosis severity [120]. Resolvin D1 infusion improves diastolic parameters in preclinical HFpEF [121].

5.3. Ischemia-Reperfusion Injury and Arrhythmia

During acute ischemia, AA release increases, causing a COX-2-mediated imbalance of thromboxane A2 and prostacyclin, which promotes coronary vasoconstriction and thrombosis [122,123,124]; reperfusion elevates LTB4, activating neutrophils and contributing to microvascular no-reflow [125,126]. n-3 acute infusion produces protectin D1, reducing infarct size by 30-50% via ALX/FPR2-mediated neutrophil apoptosis [127,128]. DHA sarcolemma incorporation shortens APD via direct modulation of NaV1.5/SERCA2a [29,47,48,49], whereas high-dose EPA or DHA can increase the risk of atrial fibrillation through IKur hyperpolarization [4]. Trans fatty acids disrupt connexin-43 localization, causing conduction heterogeneity [26,27].

5.4. Atherosclerosis and Vascular Interactions

Cardiac capillary ECs express COX-2 and 5-LOX, and the resulting PGE2 and LTB4 promote monocyte adhesion and facilitate LPL-mediated long-chain fatty acid delivery to foam cells [129,130]. n-3 SPMs (e.g., maresin-1) activate macrophage efferocytosis, thereby improving plaque stability [103]. Perivascular adipose tissue releases palmitate, which activates cardiac TLR4 and drives concentric left ventricular remodeling [131].

These findings underscore the importance of dietary modulation (Table 1) —specifically, reducing SFA and TFA intake and increasing n-3 PUFA consumption—as a strategy for preventing and mitigating cardiac disease.

6. Clinical Implications and Epidemiological Studies

6.1. Saturated Fatty Acids (SFAs)

Among the four major fatty acid classes, trans fats and most SFAs elevate coronary heart disease (CHD) risk by increasing serum cholesterol levels [132,133]. A 14-year follow-up study (n=939 incidents) revealed that longer-chain SFAs (12:0–18:0) were independently associated with increased CHD risk, whereas short-to-medium-chain SFAs (4:0–10:0) were not [134]. Interestingly, very-long-chain SFAs (VLSFAs; >C24), e.g., lignoceric acid, demonstrate cardioprotective effects—linked to lower risks of heart failure, CHD, atrial fibrillation, and mortality when present at higher concentrations [135].

The EPIC-CVD case-cohort study (n=385,747; 10,529 CHD cases) demonstrated that SFA effects depend critically on food sources:

Harmful sources: Red meat (HR: 1.07; 95% CI: 1.02–1.12) and butter (HR: 1.02; 95% CI: 1.00–1.04) [136].

Neutral/beneficial sources: Yogurt (HR: 0.93; 95% CI: 0.88–0.99), cheese (HR: 0.98; 95% CI: 0.96–1.00), and fish (HR: 0.87; 95% CI: 0.75–1.00) [136].

This source-dependent risk is further supported by Dutch cohort data, which show that higher palmitic acid intake and substitution of SFA with animal protein elevate CHD risk [137]. Plant-derived SFAs may raise LDL-C (3.43–9.18 mg/dL) but also increase HDL-C (0.94–1.89 mg/dL), yielding neutral cardiovascular effects when substituted for plant-based UFAs [138]. Notably, a comprehensive review (2010–2021) found no consistent correlation between naturally occurring SFA consumption and CVD risk [139].

These source-dependent effects likely reflect differential impacts on the risk of essential fatty acid metabolism [137]. Red meat and butter increase palmitic acid, which displaces AA from membrane phospholipids, leading to elevated pro-thrombotic thromboxane A2 and prostaglandin E2, whereas fish/dairy provide VLSFAs that stabilize oxylipin receptor microdomains [138,140,141].

6.2. Unsaturated Fatty Acids (UFAs)

UFAs demonstrate complex, sometimes contradictory cardiometabolic effects. A 12-year study of 1,807 ischemic heart disease (IHD) cases paradoxically found that replacing SFAs with cis MUFAs, PUFAs, or animal protein increased the risk of IHD (HR per 5% energy: 1.27–1.37) [142]. However, meta-analyses indicate MUFAs reduce total and hemorrhagic stroke risk [143], though not CVD mortality [144]. Replacing SFAs with UFAs/carbohydrates/protein reduces CVD events by 21% [145], with MUFAs and PUFAs similarly improving triglycerides, LDL-C, and blood pressure—though MUFAs show superior nighttime systolic BP reduction [146], a critical CVD risk factor [147].

These UFA benefits reflect n-6/n-3 balance optimization. Marine n-3 PUFAs (EPA/DHA) generate anti-arrhythmic series-3 prostaglandins (PGE3) and resolvins that compete with AA-derived pro-thrombotic TXB2/LTB4, explaining sudden death reduction despite inconsistent total CVD effects [132,148,149,150,151,152,153].

6.3. Food Source Considerations

The source of fatty acids substantially modulates their cardiovascular impact. International guidelines emphasize:

Beneficial: Plant-based foods (whole grains, fruits, vegetables), sea fish, fermented dairy, lean meats [154].

Detrimental: Processed meats, sugar-sweetened beverages, butter, cream, refined starches [154].

Whole-food approaches (e.g., Mediterranean diet) reduce CVD mortality more effectively than isolated nutrient modifications [155].

Sea fish provide EPA/DHA, which increase SPMs (resolvins, protectins); plant sources optimize LA/ALA, resulting in tissue n-6/n-3 <5:1 and reduced production of pro-inflammatory eicosanoids [156,157,158].

6.4. Timing of Intake

Emerging evidence highlights meal timing as a key modulator of UFA effects. In a cohort of 30,136 adults, high breakfast intake of PUFAs (HR: 1.30; 95% CI: 1.13–1.50), MUFAs (HR: 1.28; 95% CI: 1.13–1.45), or total UFAs (HR: 1.35; 95% CI: 1.17–1.57) increased CVD mortality. Conversely, dinner consumption of MUFAs/total UFAs reduced all-cause mortality, while PUFAs lowered both CVD and all-cause mortality [111]. However, these observations are derived from association studies and do not establish causality, as residual confounding and reverse causation cannot be excluded. Evening n-3 intake aligns with peak SPM biosynthesis; breakfast disrupts diurnal AA mobilization → ↑pro-thrombotic eicosanoids [159,160].

6.5. Reconciling Controversies: A Unifying Perspective

The relationship between fatty acids and CVD is not monolithic. SFA effects depend critically on chain length (with VLSFAs being protective) and food matrix (dairy sources neutral/beneficial vs. meat sources harmful). UFAs generally confer benefits, but outcomes are influenced by type (n-3 > n-6 PUFAs), source (plant > animal), and timing (dinner > breakfast). These nuances explain apparent contradictions in the literature and underscore the importance of considering fatty acids within their dietary context rather than as isolated nutrients. Clinical heterogeneity reflects tissue n-6/n-3 ratios, which shape the oxylipin repertoire (pro-thrombotic series-2 vs. anti-arrhythmic series-3 and SPMs) [161]. VLSFAs stabilize receptor microdomains; meal timing modulates circadian PLA2/COX-2 activity.

7. Interventional Studies

Evidence-based dietary patterns consistently demonstrate cardioprotective effects, although their benefits are multifaceted and cannot be attributed solely to their fatty acid composition [162,163,164]. The Mediterranean diet is characterized by a high intake of extra-virgin olive oil (EVOO), nuts, legumes, whole grains, and vegetables. In the PREDIMED trial, supplementing with EVOO or nuts reduced major cardiovascular events compared to a low-fat control diet [162]. EVOO delivers oleic acid and polyphenols that optimize the competition between linoleic acid and alpha-linolenic acid, resulting in tissue n-6 to n-3 ratios ~4:1, increasing resolvins and downregulating LTB4, which helps explain the 30% reduction in cardiovascular events observed in PREDIMED [161,162,165].

The DASH diet, which emphasizes fruits, vegetables, low-fat dairy, and reduced sodium, robustly lowers blood pressure and improves lipid profiles [163,164]. ALA enrichment, combined with low SFA, increases circulating EPA, promoting series-3 PGs and complementing potassium-mediated vasodilation [166,167].

Similarly, plant-based diets rich in whole foods and fiber are associated with lower LDL-C levels, reduced inflammation, and a lower incidence of coronary heart disease [168,169,170]. LA/ALA synergy drives n-6 to n-3 ratios <5:1, reducing TXB2/thrombosis despite limited DHA conversion (Yang et al., 2014).

However, several clinical trials have investigated the effect of n-3 PUFAs on CVD outcomes (Table 2). The mechanisms underlying the success of these diets are complex and synergistic. While the high content of MUFAs and PUFAs in the Mediterranean diet likely contributes to improved lipid profiles and reduced inflammation, other components—such as fiber, polyphenols, antioxidants, and the low glycemic load—play significant and potentially additive roles in reducing oxidative stress, improving endothelial function, and modulating the gut microbiome [173]. Therefore, the cardioprotection offered by these patterns is best viewed as an emergent property of the entire dietary matrix, rather than a consequence of any single nutrient class—though tissue n-6/n-3 ratios and oxylipin profiles provide mechanistic biomarkers for their efficacy [174].

8. Future Directions

As detailed, recent advances in membrane lipid remodeling (e.g., VLSFAs) and gut-heart axis signaling provide novel targets for intervention.

8.1. Future Therapeutic Directions

Modulation of fatty acid uptake represents a logical strategy to prevent lipotoxicity in the heart. In cardiomyocytes, LCFAs enter the cell via LPL cleavage products and surface transporters, including FAT/CD36, FABPpm, and members of the FATP family [175]. Notably, transgenic mice with cardiac-specific overexpression of FATP1 exhibit massive lipid uptake and develop lipotoxic cardiomyopathy [175]. At the same time, FAT/ CD36 deficiency shifts myocardial substrate use toward glucose and can protect against lipid overload. Conversely, ANGPTL4—an LPL inhibitor induced by PPARδ—limits lipid uptake into cells [175] and has been shown to mitigate lipid accumulation in muscle and heart.

However, therapeutic inhibition of FAT/CD36 may not be without risk: FAT/CD36 facilitates rapid fatty acid uptake during cardiac stress, and its absence may impair myocardial energy homeostasis under increased workload [176,177,178,179]. Thus, careful targeting—such as partial or context-dependent modulation rather than complete inhibition—may be necessary to avoid compromising cardiac performance.

FFAR4/GPR120 agonists—n-3 PUFAs, inhibit NF-κB through β-arrestin and sequester NLRP3 in cardiomyocytes [180,181,182,183].

Once inside the cell, fatty acids must be handled by mitochondrial and enzymatic machinery to avoid toxic buildup. CPT1 controls mitochondrial entry of long-chain fatty acids; its inhibition by malonyl-CoA (produced by acetyl-CoA carboxylase, ACC) provides a checkpoint for FAO. Thus, ACC inhibitors or malonyl-CoA decarboxylase activators can enhance CPT1 activity and boost β-oxidation, improving energy output. At the gene level, PPAR nuclear receptors orchestrate these pathways: PPARα (with coactivator PGC-1α) upregulates genes for fatty acid transport and β-oxidation (including CPT1), whereas PPARδ similarly promotes oxidative metabolism. Activators of PPARα and PPARδ, as well as SIRT1 and SIRT3, increase CPT1 and MCAD expression while reducing SREBP-1c, thereby accelerating FAO [72,184].

Additionally, Table 3 includes the target and effects of every USFDA-approved medication listed in DrugBank [185]. Targets including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, angiotensin-converting enzyme (ACE), beta-1 adrenergic receptor, bile acid, antithrombin-III (ATIII), PPARα, and P2Y purinoceptor 12 are all clinically relevant. Statins (HMG-CoA reductase inhibitors), PCSK9 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and PPARα agonists remain cornerstone therapies for lipid and glucose modulation, inflammation reduction, and cardiovascular risk mitigation [186]. These combined interventions—spanning fatty acid transporters, metabolic enzymes, nuclear receptors, and immune sensors—form a coherent therapeutic framework to prevent lipotoxic cardiac injury and improve substrate handling in CVD.

8.2. Innovative Dietary Strategies

Several evidence-based dietary patterns have been shown to be cardioprotective. For example, the randomized PREDIMED trial showed that a Mediterranean-style diet (rich in vegetables, fruits, whole grains, and extra-virgin olive oil or nuts) significantly reduced the risk of major cardiovascular events compared to a low-fat control diet (Estruch et al., 2018b). Consumption of EVOO and nuts results in tissue n-6 to n-3 ratios ~4:1, which increases resolvin production [187,188].

Short-term trials in healthy older adults have also confirmed that a Mediterranean diet modestly lowers blood pressure and improves endothelial function [189]. Likewise, the DASH (Dietary Approaches to Stop Hypertension) eating plan—emphasizing fruits, vegetables, low-fat dairy, and reduced sodium—robustly lowers systolic blood pressure and favorably modulates lipid homeostasis and other metabolic risk factors [164]. Plant-based dietary patterns (vegetarian or vegan) similarly confer cardiovascular benefits: multiple studies have found that higher intake of plant foods is associated with reductions in total and LDL cholesterol and improvements in inflammatory profiles. For instance, vegetarians tend to consume less saturated fat and have lower LDL-C than omnivores [190], contributing to lower atherosclerotic risk, and recent reviews have concluded that healthy plant-based diets reduce cardiovascular morbidity and mortality in diverse populations [190].

Beyond overall patterns, the quality and source of dietary fat appear to influence outcomes. In cohort analyses, replacing SFA from red and processed meats with SFA from dairy sources (especially cheese) has been linked with lower CVD risk [191]. These observations suggest that not all SFAs have identical effects—for example, dairy-derived SFAs may be less atherogenic than meat-derived SFAs.

More broadly, replacing dietary SFAs with unsaturated fats (monounsaturated and polyunsaturated) generally improves lipid profiles: meta-analyses show that substitution of SFAs with PUFAs lowers LDL-C and the total/HDL cholesterol ratio. In fact, one metabolic ward study indicated that a balanced fatty acid mix (roughly SFA:MUFA: PUFA in a 1:1.3:1 ratio) produced greater reductions in LDL-C without depressing HDL-C [192]. This underlies recommendations to emphasize high-MUFA foods (like olive oil and nuts) and adequate PUFA (especially n-3 and n-6) to optimize the LDL/HDL balance.

Emerging concepts in diet timing and composition are also of interest. Chrononutrition—the study of meal timing about circadian biology—suggests that restricting the daily eating window may improve cardiometabolic health. In a trial of patients with metabolic syndrome (most of whom were on statins and antihypertensives), adopting a 10-hour self-selected feeding window (TRE) for 12 weeks led to weight loss, lower blood pressure, and reductions in “atherogenic” lipid fractions (e.g., triglycerides) [193]. Thus, TRE can complement standard medical care by improving risk factors independently of calorie counting. Likewise, seafood-rich diets garner attention for their n-3 PUFA content. Oily fish, such as salmon, mackerel, herring, and sardines, provide 1–2.5 g of EPA+DHA per serving [194], and regular fish intake has been associated with lower levels of circulating triglycerides and inflammatory cytokines. (For example, epidemiologic studies report that higher fish consumption correlates with reduced C-reactive protein and other vascular inflammation markers.) Together, data on dietary fats and timing suggest that both what one eats and when one eats can modulate lipids, blood pressure, endothelial function, and inflammatory status.

Finally, integrating a diet with pharmacotherapy may enhance cardiovascular prevention. There is growing evidence that combining n-3 PUFA supplementation with statin therapy yields incremental benefit. A recent meta-analysis of imaging studies found that patients receiving both high-dose EPA/DHA and a statin (compared to statin alone) had significantly slower progression of coronary plaque, thicker fibrous caps, and lower high-sensitivity C-reactive protein (hs-CRP) levels [195]. In other words, n-3s appeared to stabilize atherosclerotic lesions beyond the effects of statins alone, without adverse changes in HDL or LDL levels. Mechanistically, both statins and n-3 PUFAs share anti-inflammatory and plaque-modulating pathways (for example, each promotes the production of pro-resolving lipid mediators) [194]. These synergistic effects translate into improved lipid profiles (notably lower triglycerides) and attenuated vascular inflammation when diet and drug are combined.

In sum, a comprehensive cardioprotective diet emphasizes vegetables, fruits, whole grains, legumes, nuts, fish, and unsaturated fats, while moderating refined carbohydrates and saturated fats—with special consideration of fat sources (dairy vs. meat) and fat types (MUFA vs. PUFA) [191,192,196]. Emerging strategies, such as time-restricted feeding and increased intake of oily fish, further improve traditional risk factors (blood pressure, dyslipidemia, endothelial function, and inflammatory biomarkers) [193,194]. When combined with optimal pharmacotherapy, these dietary approaches can produce additive cardiometabolic benefits. For instance, co-administering n-3 PUFAs with statins yields greater reductions in triglycerides, C-reactive protein, and plaque vulnerability than statins alone [194,195]. Collectively, these data support a multifaceted dietary prescription (e.g., Mediterranean/DASH/plant-based patterns with source-specific fat guidance and consideration of meal timing) to maximize cardiovascular prevention and treatment outcomes.

9. Conclusions

Longer-chain saturated fatty acids (SFAs; C14:0–18:0), especially those found in red meat, butter, and palm oil, are consistently associated with increased CVD risk, particularly CHD. These associations reflect that palmitate displacement of AA from membrane phospholipids is associated with increased pro-thrombotic TXA2/PGE2 production [103]. Although the associations between other SFAs and UFAs and specific CVD outcomes remain inconsistent, this likely reflects residual confounding and heterogeneity in food sources, metabolism, and clinical context.

Importantly, not all SFA-rich foods are equal. While processed meats, butter, and cream should be minimized—especially in individuals with diabetes or elevated CVD risk—fermented dairy (e.g., yogurt, cheese) and seafood (e.g., sardines) often exhibit neutral or even beneficial cardiometabolic effects due to their complex nutrient matrices. VLSFAs from dairy/fish stabilize oxylipin receptor microdomains while seafood delivers EPA/DHA → series-3 PG/SPM cardioprotection [197,198,199].

Replacing SFAs with PUFAs, particularly those found in whole foods such as fish, nuts, and olive oil, remains a cornerstone dietary strategy for CVD prevention. EPA/DHA substitution, associated with a lower tissue n-6/n-3 ratio, has been linked to reduced dominance of AA-derived LTB₄ and TXB₂ signaling and may contribute to the observed reduction in cardiovascular events [174]. Evidence-based patterns such as the Mediterranean and DASH diets—rich in these components—should be prioritized across populations, including those with established CVD. In contrast, dietary strategies such as the ketogenic diet (KD) and intermittent fasting (IF)—which fall outside the core scope of this review—have been proposed to influence cardiometabolic outcomes, but their effects on cardiac EFA pools and oxylipin signaling remain insufficiently explored.

Whole foods should be prioritized over supplements; for instance, sardines and other oily fish provide n-3 PUFAs alongside beneficial nutrients such as calcium, potassium, and selenium, making them superior to isolated supplements. While n-3 PUFA supplementation may be beneficial in some cases, it is limited by unclear dosing thresholds, bioavailability issues, and potential risks (e.g., an increased risk of atrial fibrillation at high doses).

Key Take-Home Messages:

• Prioritize whole foods: Choose fish (especially sea fish like sardines, salmon etc), nuts, and extra-virgin olive oil over supplements.
• Avoid industrial trans fats (iTFAs) and minimize consumption of processed meats, refined carbohydrates, sugar-sweetened beverages, and excessive sodium.
• Replace saturated fats with polyunsaturated fats from natural sources, not refined seed oils or processed alternatives.
• Adopt established dietary patterns, such as the Mediterranean or DASH diets, which have consistently been shown to lower CVD risk.
• Use supplements judiciously, only where whole-food alternatives are insufficient or contraindicated.
• Support emerging dietary approaches (e.g., KD, IF) with well-designed randomized trials before broad implementation.

Future research should focus on refining supplementation protocols, investigating synergistic whole-food combinations, and expanding clinical trials of promising but understudied dietary interventions.