Guide Lipid Metabolism in the Healthy and Disease Heart

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These muscle cells also become full of lipids, which determine their apoptosis. The atheroma is formed by gradual deposition of fat on the arterial wall. Muscle cells produce collagen, elastin and elastase, which stabilize the atheromatous plaque 15 , 16 , and its rupture leads to thromboembolic events. Frequently, dyslipidemic individuals also show arterial hypertension and DM, aspects that make up the metabolic syndrome, which is associated with high cardiovascular risk. DM favors atherosclerosis by several mechanisms.

Hyperglycemia induces endothelial dysfunction, expression of adhesion molecules, greater vascular permeability, and oxidative stress; besides, it favors the modification of LDL particles These disorders, frequently found together with visceral obesity, show insulin resistance as a common feature. Hypertrophic fatty tissue produces MCP-1, which stimulates the infiltration of M1 macrophages. There is clear evidence that circulating lipids are essential for the atherosclerotic process to develop. If these classic and new lipid biomarkers are investigated, the predictive ability for cardiovascular events may be improved.

Knowledge on the mechanisms may provide support not only for risk prediction, but also for the development of new therapeutic strategies.

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Major, classic or traditional risk factors are those defined from the Framingham studies, which are proven to predict the occurrence of cardiovascular events, specially coronary and cerebral ones. More recently, new risk biomarkers have been proposed, part of them lipids that are also involved in the physiopathology of atherosclerotic disease.

The Framingham cohorts began in , and are relevant milestones in the identification of cardiovascular factors. These cohorts identified the role of age; sex; total cholesterol, LDL-C and HDL-C levels; systolic pressure; smoking; high blood glucose; body weight; certain dietary habits; and physical inactivity. Based on these findings, cardiovascular risk scales were developed in order to evaluate the risk of an event in a ten-year period. Each of them was determined in a specific population, and none of them include all the known risk factors.

The Framingham score, for example, does not include weight, physical activity, and diet. Based on the recommendation of the international scientific society, all proposals use a group of variables to better estimate cardiovascular risk. To a large extent, the need for the identification of additional risk markers is due to the observation that a considerable proportion of the individuals that suffer from cardiovascular events show either few or none of the traditional risk factors 20 , Considering these characteristics, the quantification of coronary calcium by computer tomography may be an imaging biomarker New soluble cardiovascular biomarkers in the bloodstream do not have, in general, an established role in CVD prediction Among inflammatory biomarkers, ultrasensitive C-reactive protein has shown to be able to improve the predictive ability of LDL 23 for cardiovascular events.

The use of a new cardiovascular risk biomarkers should be based in improved discrimination and calibration of existing risk models These findings emphasize the importance of searching for evidence that emerging biomarkers may better identify plaques that are more vulnerable to rupture. Biomarkers related to lipid metabolism are highlighted in this review due to their important role in the physiopathology of atherosclerosis Table 1. It is expected that longitudinal studies may, in the medium range, provide subsides to their usefulness in clinical practice.

Besides, cost-benefit studies will also be necessary to support their use. After the role of hypercholesterolemia was recognized as a risk factor and as the main prognostic measure of coronary events, knowledge on the consequences of modified LDL oxidized LDL, electronegative LDL and glycosylated LDL was deepened. These molecule are pro-inflammatory and highly atherogenic Their structural modifications are recognized by mononuclear cells that produce inflammatory cytokines, maintaining a low-grade, chronic inflammatory status characteristic of atherosclerosis.

Oxidative modifications are highlighted, whose final product is oxidized LDL, a result of the action of countless oxidizing substances, such as the superoxide anion, hydrogen peroxide, and enzymes such as lipoxygenases and myeloperoxidases. Another target of this investigation has been the electronegative LDL LDL - or minimally modified LDL , produced by oxidation and other processes, such as non-enzymatic glycosylation, hyperactivity of lipoprotein-associated phospholipase A 2 Lp-PLA 2 , enrichment by non-esterified fatty acids, cross-binding with hemoglobin and apo B, and increase in apo C-III and apo E content 17 , In the bloodstream, the presence of modified lipoproteins stimulates the immunological system favoring chronic diseases, such as atherosclerosis.

In the chronic inflammatory process related to atherosclerosis, the adherence of monocytes to the endothelium is a key event for plaque development, and the accumulation of modified LDL is an important trigger to the initial damage to the artery. The association of these particles with cardiovascular risk has been reported, frequently in relation to the severity of the disease 27 , Controversial findings make it uncertain if antibodies are directly expressed in a deleterious environment, or if they are a protective response of the organisms against the atherogenic particles.

Some studies indicate an association between high levels of antibodies anti-LDL - or anti-LDLox, and CVD 30 , 31 , whereas other found an opposite relationship 32 , Laboratory analysis of modified LDL or antibodies requires careful work, besides being expensive. Therefore, it is not recommended in clinical practice, for it still requires standardization and determination of reference values.

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  8. Among the pro-inflammatory substances stimulated by the presence of oxidized LDL in the bloodstream is lipoprotein-associated phospholipase A 2 Lp-PLA 2 , an enzyme that is responsible for the hydrolysis of the sn-2 bond of oxidized lipids found in LDL particles. This action in initially considered to be protective, because it minimizes oxidative components associated with the particle However, as a result of this reaction, lisophopholipids are formed such as lisophosphatidilcholine , which drastically stimulate inflammation and take part in several stages of the formation of the atherosclerotic plaque.

    Therefore, it may be observed that Lp-PLA 2 activity favors the inflammatory process and the evolution of atherosclerosis Rallidis and cols. The mass and activity of the enzyme associated with the HDL particle are linked to lower risk of death by CVD, even after adjustment for the traditional risk factors. Several cohorts showed that the blood level and activity of Lp-PLA2 are associated with cardiovascular events, independent of other risk factors Packard and cols.

    In a follow-up carried out for 6 months in patients with acute coronary syndrome, it was observed that those with high Lp-PLA2 presented greater risk for important adverse cardiac events Based on this evidence, the authors proposed the use of Lp-PLA2 as a cardiovascular risk marker However, the standardization of reference values, the reduction in the cost of the analyses, and the greater understanding of its effect when associated with the different particles are some questions that need to be answered before the practical use of this determination is suggested.

    The evaluation of the plasma apolipoprotein profile is not part of the local monitoring of cardiovascular risk factors.

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    In fact, several investigators confirmed its usefulness in the prediction of cardiovascular events Apo A and B are easy to be measured and showed to be useful in the prediction of cardiovascular events in some studies 45 - The meta-analysis carried out with 23 studies showed that the greatest concentrations of apo B determined a relative risk of 1. Similarly, the association of the same parameters with the media-intima thickness suggest they may be early predictors of atherosclerosis In spite of the evidence, apolipoprotein dosage is not recommended by scientific societies for the diagnosis of dyslipidemia or risk estimation 3 , However, recent studies suggest that the quantification of apo B should be added to clinical practice to refine the evaluation of plasma lipids in individuals at increased risk Lipoprotein a , Lp a , is a particle with similar structure to LDL, containing one apo-B combined with an additional apo a.

    Its, cholesterol content, density and depuration are also very similar to those of the LDL particles. The structure of the apo a particle is similar to plasminogen, including a common gene sequence. Therefore, the presence of apo a shows prothrombotic potential, and it is able to interfere with the physiological role of plasminogen. Apo a inhibits plasminogen activation in plasmin, which is responsible for fibrin degradation 52 , Lp a concentrations are associated, therefore, with the atherogenic characteristics of the particles that contain apo B and the thrombogenic properties determined by apo a.

    There are distinct classes of apo a ; they differ by a small number of aminoacids. These classes are defined by genetic characteristics that also determine the rate of apo a synthesis. As a function of the strong genetic components, the concentration of Lp a in the bloodstream are weakly influenced by age, sex, and environmental factors Lp a blood levels behave as independent risk factor for CVD In the Emerging Risk Factors Collaboration, in which 36 prospective studies involving , participants were analyzed, it was observed that the concentration of Lp a was associated with increased risk for CVD.

    After adjustment for cholesterol and other stablished risk factors, the association were only slightly attenuated, reinforcing the hypothesis that this is an independent risk factor for coronary disease Similarly, in the European Prospective Investigation of Cancer cohort, it was observed that the associations of the Lp a concentrations with arterial coronary and cerebral disease were not modified by adjustment for LDL-C Its high concentration aids the identification of those individuals with even higher cardiovascular risk.

    It is suggested that Lp a should be used as a second risk factor to support lower LDL cholesterol targets 3. The American College of Cardiology and the American Heart Association, in a recent publication on the treatment of dyslipidemias in adults, understand that the future recommendations for the control of blood cholesterol will include Lp a as a marker of therapeutic effects and as a form of monitoring CVD evolution CETP concentrations are increased in obesity, dyslipidemia and atherosclerosis, and are directly associated with inflammatory markers However, their use as a risk biomarker is still controversial.

    Some researchers 58 , 59 observed, in high risk individuals, associations of CETP with cholesterol efflux capacity, which is in agreement with the protective role of the enzyme in atherosclerosis. Schierer and cols. LDL subclasses may be identified by means of ultracentrifugation or electrophoresis, enabling the definition of dyslipidemic individuals according to different phenotypes.

    In relation to the proportion of LDL subclasses, individuals with greater concentrations of small and dense particles are carriers of phenotype B, which is associated with higher risk of atherosclerosis. Larger and less dense LDL particles phenotype A present opposite characteristics and, thus, lower cardiovascular risk Increased proportions of small and dense LDL have been consistently associated with cardiovascular risk 64 , and some special groups of individual, such as DM 65 or metabolic syndrome 66 carriers, show this phenotype more frequently.

    Several researchers consider that more specific dosage of LDL particles is a promising technique to refine the prediction of cardiovascular risk 64 , However, this measurement still needs to become easier to be more widely used in clinical practice. As for HDL, existing data gathered with different methodologies demonstrate that the subclasses present heterogeneous biological activities.

    Small and dense fractions seem to exhibit atheroprotective properties. This effect is probably due to the greater antioxidant, anti-inflammatory, anti-cholesterol and cholesterol efflux capacity compared with the larger and less dense fraction 68 , However, its protective ability is attenuated in atherogenic dyslipidemia, probably due to the lipid and protein changes caused by this condition There are few studies in the literature that definitely clarify the role of HDL subfractions, specially changes in composition and structure of the atherosclerotic process.

    Based on this analysis of the lipid metabolism, its importance in the prediction of cardiovascular risk is reiterated. Classic measurements, such as LDL-C, HDL-C and triglycerides are established in clinical practice as important tools in risk prediction and therapy follow-up 3. Besides them, it is important to find other markers, due to the considerable number of individuals that suffer cardiovascular events with few or none of the risk factors 20 , Lipid metabolism has several elements with a potential role in the risk prediction and monitoring that are targets for the development of new therapeutic strategies for CVD, as many of these makers take part in the physiopathology of atherosclerosis.

    Among thee markers, Lp a dosage is already contemplated in NCEP 5 as a second risk factor to justify more strict lipid targets. It may be concluded that the fast evolution of knowledge on the subject may justify periodic reassessment of lipid metabolism. Monitoring and surveillance of chronic non-communicable diseases: progress and capacity in high-burden countries. Indicadores de mortalidade. Accessed on: Oct 4, J Clin Lipidol. High total serum cholesterol, medication coverage and therapeutic control: an analysis of national health examination survey data from eight countries.

    Bull World Health Organ. Impact of seasonality on the prevalence of dyslipidemia: a large population study. Chronobiol Int. Arq Bras Endocrinol Metab. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, participants in 14 randomised trials of statins. Teramoto T. Atheroscler Suppl. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med. Indian J Endocrinol Metab.

    Immunity as a link between obesity and insulin resistance. Mol Aspects Med. Why do anti-inflammatory therapies fail to improve insulin sensitivity? Acta Pharmacol Sin. Endothelial function and dysfunction: testing and clinical relevance.

    The interleukin-6 pathway and atherosclerosis. Fibrinogen and cardiovascular disease: genetics and biomarkers. Blood Rev. Effect of glycemic optimization on electronegative low-density lipoprotein in diabetes: relation to nonenzymatic glycosylation and oxidative modification.

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    Thomsen T. HeartScore: a new web-based approach to European cardiovascular disease risk management. Eur J Cardiovasc Prev Rehab. Simple scoring scheme for calculating the risk of acute coronary events based on the year follow-up of the prospective cardiovascular Munster PROCAM study. Potentially modifiable classic risk factors and their impact on incident myocardial infarction: results from the EPIC-Potsdam study. Eur J Cardiovasc Prev Rehabil.

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    May A, Wang TJ. Biomarkers for cardiovascular disease: challenges and future directions. Trends Mol Med. Wang TJ. New cardiovascular risk factors exist, but are they clinically useful? Eur Heart J. Ridker PM. Metabolites were identified using the LipidMap www. A statistical analysis was performed with Statistical Package for the Social Sciences software, version False discovery rate FDR analysis was conducted using the q-value program in R version 2. Relationships between specific lipid metabolites and acute inflammatory responses were evaluated using pearson and partial correlation coefficients.

    Cross-validation with seven cross-validation groups was used throughout the analysis to determine the number of principal components. A partial least-squares discriminant analysis PLS-DA and orthogonal partial least-squares discriminant analysis OPLS-DA were used as classification methods to model the discrimination by visualizing the score plot. The anthropometric and biochemical characteristics of the controls and patients with CAD angina pectoris and MI are shown in Table 1.

    The patients with CAD had higher serum concentrations of fasting glucose and lower concentrations of HDL cholesterol and triglycerides than did the controls. The serum concentrations of total cholesterol and LDL cholesterol were significantly different between the patients with angina and the controls. Drug treatments were not significantly different between the patients with angina and those with MI, with the exception of ACE inhibitors and calcium antagonists S1 Table.

    An OPLS-DA model one predictive component and two orthogonal components was constructed to investigate the difference between patients with angina and MI in comparison with control subjects Fig 1A and 1D. The cumulative R 2 Y and Q 2 values were In additional, PLS-DA was conducted to observe the metabolic pattern between patients with stable and unstable angina in both positive and negative modes S1 Fig.

    We identified lipid metabolites in the positive mode and 54 lipid metabolites in the negative mode S3 and S4 Tables. Among the annotated lipid metabolites, free fatty acids FFA , lysophosphatidylcholine lysoPC , and lysophosphatidylethanolamine lysoPE were identified as candidate markers shared by patients with angina and MI compared with the controls. Particularly, the levels of FFAs and lysoPCs containing unsaturated fatty acids were significantly higher in angina patients than MI patients. For the three negative predictors, including lysoPC-containing saturated long-chain fatty acids, the markers were associated with a 0.

    Heat map showing the fold changes in and VIP scores of altered metabolites in patients with MI compared with control subjects and patients with angina A and the risk of MI B. For the nine negative predictors, including PE-plasmalogen and PI, the markers were associated with a 0.

    Significant associations between specific metabolites of sphingolipid metabolism and acute inflammation markers C. However, no significant correlation was found between the control and angina groups. Eight species of lipid metabolites differed between the angina and control groups and three species between the MI and control groups. Despite the trend toward a decreased risk of angina or MI after LLD treatment, most lipid metabolites identified in the current study were unchanged by LLD in patients with angina or MI.

    Altered lipid metabolism associated with inflammation and oxidative stress is one of the primary drivers of the pathological changes associated with atherosclerotic plaque formation [ 8 , 9 ]. We also investigated the specific lipidomic signatures in patients with angina or MI to understand the different underlying mechanisms causing CAD.

    Furthermore, our study confirmed the presence of specific lipid metabolites and disturbed metabolic pathways by comparing patients with CAD and healthy controls. These approaches are useful for the identification of important lipid metabolites that may play significant roles in the development of angina or MI. Circulating lysoPC has pro-atherogenic roles in monocyte recruitment, macrophage proliferation, smooth muscle cell proliferation, increased expression of endothelial adhesion molecules, and endothelial dysfunction [ 18 — 24 ].

    For these reasons, lysoPC has been recognized as an independent risk factor for atherosclerosis [ 18 — 24 ].

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    In our study, patients with CAD showed higher levels of lysoPCs containing unsaturated fatty acids than did the control group. Similar to these significant increases, the serum levels and compositions of unsaturated FFA were also increased in patients with CAD. This hypothesis is consistent with a previous report in which high levels of lysoPC during oxidative modification were found in patients with atherosclerosis and CAD [ 25 , 26 ].

    Interestingly, our study showed that lysoPCs containing unsaturated fatty acids were down-regulated in patients with CAD, whereas lysoPCs containing SFA were upregulated in these patients. The signaling properties and biological effects of lysoPC in association with atherosclerosis have been observed in previous studies. We found opposing alterations in PC and PE-plasmalogens, which are glycerophospholipid metabolism-related lipid metabolites, in patients with MI compared with healthy subjects and patients with angina. Increased free fatty acid levels and the secretion of very low density lipoprotein and LDL promote the biosynthesis of PC, which is regulated by activation of the CDP-choline pathway [ 29 , 30 ].

    Additionally, the activation of PC synthesis may lead to an increase in SM and the accumulation of pro-apoptotic Cer. PC and sphingolipids are involved in cell proliferation, differentiation, and death [ 31 ]. Therefore, PC has been recognized as an independent risk factor for atherosclerosis [ 29 — 31 ]. On the other hand, plasmalogens, especially PE-plasmalogen, act as antioxidants and protect endothelial cells from oxidative injury. Plasmalogens are able to protect unsaturated membrane lipids against oxidation by reactive oxygen species without producing excessive toxic oxidation products [ 32 ].

    Our study is consistent with previous reports; altered levels of PC and PE in patients with MI might be the result of the different mechanism between MI and angina e. We also observed that the upregulation of sphingolipids is associated with an increased risk of MI. The sphingolipid, SM, and Cer signaling pathway is altered by stress, including oxidative stress, and is critically involved in cell proliferation and death as well as the contraction of cardiomyocytes and vascular smooth muscle cells [ 31 , 33 ].

    Various stressful conditions stimulate the catabolism of SM by sphingomyelinase [ 34 ]. The results of the present study might be due to thrombus formation and the development of MI. In line with our results, previous observations have shown increased sphingolipid levels and activated sphingomyelinase activity during atherogenesis [ 15 ]. Sphingolipids are a family of lipid second messengers that regulate various vascular cell functions. In particular, SM and Cer mediate cellular responses to cytokines and oxidative stress. The sphingolipid level is reportedly regulated during the acute phase of the response to inflammation, and increases in Cer and sphingosine lead to the upregulation of different acute-phase proteins [ 35 ].

    Moreover, elevation in the serum hs-CRP level has been suggested to be associated with an increased risk of CAD [ 36 ]. These findings are supported by our observation that the sphingolipid level was significantly associated with the hs-CRP level in patients with MI. Overall, we found that lysoPC and lysoPE species containing unsaturated fatty acids and FFAs were associated with an increased risk of CAD, whereas species of lysoPC and lyso-alkyl PC containing saturated fatty acids were associated with a decreased risk.

    Additionally, PC species containing palmitic acid, DG, SM, and Cer were associated with an increased risk of MI, whereas PE-plasmalogen and phosphatidylinositol species were associated with a decreased risk. Finally, global lipidomic profiling of patients with angina or MI suggested common alterations in lipid metabolism in these populations. We also confirmed different metabolic signatures resulting from acute inflammatory responses and upregulated sphingolipid and glycerophospholipid in patients with MI.

    In conclusion, lipidomic profiling was used successfully to identify specific metabolites in patients with angina or MI.

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    In addition, specific metabolites could use to diagnose developing CAD at an early stage. Conceived and designed the experiments: GSH. Performed the experiments: JYP. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Lipid metabolites are indispensable regulators of physiological and pathological processes, including atherosclerosis and coronary artery disease CAD.

    This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: All relevant data are within the paper and its Supporting Information files. Introduction Lipids are essential regulators of biological processes associated with normal cell function, metabolism, and distribution.

    Measurement of serum lipid profiles and fasting glucose Fasting serum total cholesterol, triglyceride, and high-density lipoprotein HDL cholesterol levels were measured using commercially available kits on a Hitachi Autoanalyzer Hitachi Ltd. Statistical analysis A statistical analysis was performed with Statistical Package for the Social Sciences software, version Results Anthropometric and biochemical characteristics The anthropometric and biochemical characteristics of the controls and patients with CAD angina pectoris and MI are shown in Table 1.

    Download: PPT. Table 1.

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    General characteristics of the controls and patients with coronary artery disease. Altered lipid metabolites in patients with CAD We identified lipid metabolites in the positive mode and 54 lipid metabolites in the negative mode S3 and S4 Tables.

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    Fig 2. Commonly altered lipid metabolites in patients with CAD. Fig 3. Significantly altered lipid metabolite in patients with MI. Fig 4. Association of specific metabolites and the acute inflammatory response. Discussion Altered lipid metabolism associated with inflammation and oxidative stress is one of the primary drivers of the pathological changes associated with atherosclerotic plaque formation [ 8 , 9 ]. Supporting Information.

    S1 Fig. S1 Table. Drug treatment in patients with angina and MI.

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    S2 Table. Serum glucose and cholesterol levels in patients with angina and MI according to lipid-lowering treatment. S3 Table. Identified lipid metabolites by class and number of significant association with angina and MI. S4 Table. Information of identified lipid metabolites. S5 Table. Levels of individual lipid species in patients with CAD and control subjects. S6 Table.