The perinatal life is a critical period in the development and physiology of cardiac tissue. Higher cardiac energy metabolism is required in response to early postnatal oxygen levels, and increased cell proliferation is needed to attain normal neonatal growth and development [12,13,14]. Cardiomyocyte regeneration is a highly energy-consuming process, and changes in energy metabolism happen as the neonatal cardiac development evolves rapidly within a short postnatal period; afterward, the cardiomyocytes exit the cell cycle. Fetal cardiomyocytes use glycolysis as the main source of energy during proliferation [15,16]. During early postnatal development, there is a shift from glycolysis to using fatty acid oxidation (FAO) [17,18], possibly due to increased energy demand during the transitioning from a fetal to postnatal period [19], suggesting a correlation between cardiomyocyte proliferation and high oxidative energy metabolism. It is not clear whether this heart metabolic shift accounts for cardiomyocyte proliferation and hypertrophy or it is a consequence of increased oxygen availability in postnatal environment. Animal studies have shown that in younger animals, FAO facilitates cardiomyocyte proliferation and hypertrophic growth [16]. Altered FAO could be associated with cardiac diseases [20,21]. Increased levels of oxygen during transition, from fetal to postnatal period, results in significantly increased oxidative stress as a result of the production of reactive oxygen species (ROS) with subsequent damage to cardiac tissue. These data could suggest that reducing the oxygen level and increased antioxidant levels might be useful to maintain the proliferative capacity of neonatal cardiomyocytes for a longer time [12,22]. These data suggest that the antioxidant could be used as a relevant therapy to extend the critical time window for cardiomyocyte proliferation by upregulating mitochondrial biogenesis and decrease mitophagy [12,23].

Cardiolipin (CL) is a phospholipid that is exclusively present in the inner mitochondrial membrane, where it is essential for optimal functions of various key enzymes involved in mitochondrial respiration [24,25]. Linoleic acid is one of the major fatty acids of CL in human myocardium [26]. Evidence has shown that CL must contain four linoleic acid side chains for optimal mitochondrial function, and loss of linoleic acid content in CL resulted in human and rat models of heart failure [26]. Furthermore, diet supplementation containing high linoleic acid attenuated contractile failure by improving mitochondrial dysfunction in rat models of hypertensive heart failure [27].

The resolution of inflammation is tightly regulated by endogenously produced lipid mediators such as SPMs. These molecules can be lipoxins, resolvins, protectins, and maresins [105]. SPMs resolve the inflammation by alleviating the pro-inflammatory response, reducing neutrophil infiltration, and clearing the apoptotic cells through macrophages, and thus, enhancing the host defense. In addition, SPMs restrict the T cells actions, which is the main cellular responses involved in chronic inflammation [106,107]. SPMs are an important modulator of oxidative stress. There is evidence showing lipoxins inhibit leukocyte-dependent generation of reactive species [63]. LXA4 treated cardiomyocytes activate MAP-kinase and Nrf2 pathways [108], whose antioxidant properties are essential for cardiac protection [109]. In animal models, RvD1 reduces reactive oxygen species-mediated IL-1β secretion in macrophages [110] and protects against oxidative stress inflammation inhibiting neutrophil infiltration [111]. RvD1 and maresin 1 have been shown to regulate Nrf2-dependent expression of glutathione peroxidase and superoxide dismutase [112,113]. Kang et al. have reviewed a details summary about the role of EPA- and DHA-derived SPMs and Nrf2-antioxidative responses in cardiac fibrosis [109].

SPMs cause a shift in macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory) [114,115]. In addition to regulating the innate immune response, SPMs are also important in the adaptive immune response by reducing the NK cells cytotoxicity [116], decreasing memory B cell and antibody production [117]. D-series resolvins and maresin 1 dampen the cytokines production by activated CD8⁺ T cells, TH₁, and TH₁₇ cells and promotes the differentiation of CD4⁺ T cells into Treg cells, while inhibiting the generation of TH₁ and TH₁₇ from naïve CD4⁺ T cells [106,118]. Patients with chronic heart failure (CHF) have significantly reduced the plasma levels of RvD1 and pretreatment of mononuclear cells of patients with CHF with RvD1 or RvD2, which did not affect cytokine release from CD8⁺ and CD4⁺ T cells. This impaired T cells response was associated with reduced GPR32 expression [107]. The interaction between SPMs, their receptors, and their effect depend on the level of SPMs, cell type, and surrounding environment. Uncontrolled and unresolved inflammation can result in cardiovascular diseases, suggesting the critical role of SPMs. An extensive review regarding the lipid signaling pathways in cells and these effects on adult cardiovascular physiology and regeneration was covered by Wasserman et al. [119].

The etiology of cardiovascular disease involves a chronic inflammatory process driven by the formation of lipid-rich lesions in the vascular wall leading to myocardial infarction and stroke. Evidence about the role of SPMs in cardiovascular diseases came from human and animal studies. Serhan et al. have shown increased lipoxin levels in humans after angioplasty [120]. Overexpression of 15-LOX in macrophages resulted in a significant reduction of atherosclerosis in rabbits [121,122], while there was delayed atherogenesis in mice [123]. Administration of RvE1 attenuated atherogenesis in rabbits fed with a high fat and cholesterol diet, possibly by reducing the levels of C-reactive protein (CRP) [124].

The formation of a vulnerable plaque region (a subset of atherosclerotic plaques), with increased inflammation, oxidative stress, and necrotic areas as a result of increased cell death, might lead to acute atherothrombotic clinical events, such as myocardial infarction and stroke, probably due to a defective inflammation-resolution process [125,126,127]. Advance plaque regions in Ldlr−/− or ApoE−/− mice fed a high-fat and high-cholesterol diet displayed an imbalanced ratio of SPMs and pro-inflammatory lipid mediator ratio compared to early plaque regions [128,129]. Furthermore, SPM administration, including RvD2 and Maresin 1, or aspirin-triggered lipoxin A4, caused delayed atherosclerosis and resulted in a more stable-like plaque phenotype [129,130], probably due to decreased necrosis, oxidative stress, and increased fibrous cap thickness and helping in tissue repair processes.

Decreased blood flow can lead to tissue injury, as a result of the inflammatory response, due to leukocyte infiltration and ROS production [131]. This suggests that controlled leukocyte infiltration, as well as their removal from the site of injury, is important to protect the heart and myocardium during ischemia. Indeed, in mice, exogenous administration of RvD1 has been shown to improve cardiac function by reducing leukocyte infiltration and fibrosis [132]. Moreover, in a rat model of myocardial ischemia/reperfusion injury, RvE1 protects the rat heart by decreasing infarct size [133]. In addition to the heart, the protective effects of SPMs have been reported in other tissues, including the kidney and lung [134,135], possibly by reducing leukocyte recruitment.

Atherothrombosis is one of the clinical manifestations which leads to myocardial infarction and stroke [136]. Platelets and neutrophils aggregation are important for plaque inflammation [137]. Increased levels of circulating leukocyte-platelets aggregates in cardiovascular diseases suggest their contribution to pathogenesis. Moreover, elevated levels of platelet–monocyte aggregates have been used as an early marker of acute myocardial infarction [138]. It is possible that platelets and neutrophils/macrophage aggregates cause plaque formation and cardiovascular disease and are unable to produce enough SPMs. The levels of lipid mediators, specifically thromboxane and prostacyclin, are critical for platelet activation and thrombosis. In a randomized human-clinical trial, healthy subjects receiving aspirin at a recommended dose for patients with cardiovascular diseases (low dose = 81 mg) resulted in aspirin-induced 15-epi-LXA4, and the levels were negatively correlated with plasma thromboxane B2 levels, reducing the platelets activation [139]. Moreover, EPA-derived RvE1 has been shown to have an antiplatelet aggregation activity [140]. In response to acute inflammation, the self-limiting events such as platelets and neutrophils aggregation are critical and involve the biosynthesis of SPM to timely resolve the inflammation by reducing platelets and neutrophils aggregation, decrease cytokines production, and increase apoptosis [141,142].

SPMs, such as marsein 1, induce a pro-resolving platelet phenotype by increasing platelet aggregation and decreasing the levels of pro-inflammatory and pro-thrombotic mediators. All these data suggest the key role of SPM in promoting resolution inflammation as well as thrombosis during inflammation, and thus, could have potential therapeutic implications in cardiovascular diseases.