Cardiovascular Module Biochemistry Course For Medicine Students PDF

* Cardiovascular Module Biochemistry Course For Medicine Students By Tizazu Tekle Specialty: Medical Biochemistry (MSc.); Clinical Nutrition (Ph.D.) Wolaita Sodo University, School of Medicine Cardiovascular System Module Biochemistry Part-II...

* Cardiovascular Module Biochemistry Course For Medicine Students By Tizazu Tekle Specialty: Medical Biochemistry (MSc.); Clinical Nutrition (Ph.D.) Wolaita Sodo University, School of Medicine Cardiovascular System Module Biochemistry Part-II Impact of Lipids & Lipoproteins on Cardiovascular Diseases Cardiovascular disease (CVD) * Introduction is a broad term for conditions that affect the heart & blood vessels. It constitute a class of diseases that includes: Coronary artery diseases (e.g. angina, heart attack), Heart failure, Hypertensive heart disease, Rheumatic heart disease, Cardiomyopathy, Arrhythmia, Congenital heart disease, Valvular heart disease, Carditis, Aortic aneurysms, Peripheral artery disease, Thromboembolic disease, and Venous thrombosis  * Introduction *The underlying mechanisms of CVDs are complex and vary depending on the disease. It is estimated that dietary risk factors are associated with 53% of CVD deaths.  * Introduction *Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This may be caused by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and poor sleep, among other things.  * Introduction *High blood pressure is estimated to account for approximately 13% of CVD deaths, while *tobacco accounts for 9%, *diabetes 6%, *lack of exercise 6%, and *obesity 5%. *Rheumatic heart disease may follow untreated strep throat.  * Introduction * It is estimated that up to 90% of CVD may be preventable. * Prevention of CVD involves Improving risk factors through: healthy eating, exercise, avoidance of tobacco smoke and limiting alcohol intake. Treating risk factors, such as high blood pressure, blood lipids and diabetes is also beneficial. Treating people who have strep throat with antibiotics can decrease the risk of rheumatic heart disease.  The use of aspirin in people who are otherwise healthy is of unclear benefit  * Introduction *CVDs are the leading cause of death worldwide except Africa. *Together CVD resulted in 17.9 million deaths (32.1%) in 2015, up from 12.3 million (25.8%) in 1990. *Deaths, at a given age, from CVD are more common and have been increasing in much of the developing world, while *Death-rates have declined in most of the developed  * Introduction * Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% of CVD deaths in females. * Most CVD affects older adults. For example: In the United States 11% of people between age 20 and 40 have CVD, while 37% between 40 and 60, 71% of people between 60 and 80, and 85% of people over 80 have CVD.  * CVD Risk factors * There are many risk factors for heart diseases, including: Age, sex, tobacco use, physical inactivity, non-alcoholic fatty liver disease, excessive alcohol consumption, unhealthy diet, obesity, genetic predisposition and family history of CVD, hypertension, diabetes mellitus, hyperlipidemia, undiagnosed celiac disease, psychosocial factors, poverty and low educational status, air pollution, and poor sleep. * Impact of Lipids and Lipoproteins on CVDS Diet is one of the major modifiable risk- factors of CVDs. Among diets, Lipids and lipoproteins, their metabolism, and their transport are essential contributing factors of CVDs.  * Impact of lipids and lipoproteins on CVDs *Dietary Lipids and their transporters,lipoproteins, regulate plasma cholesterol concentration, enhancing cholesterol uptake by macrophages, leading to foam cell formation and ultimately resulting in plaque formation and inflammation. *However, lipids and lipoproteins have cardio- protective functions as well, such as: *preventing oxidation of pro-atherogenic molecules and *Down-regulating inflammatory proteins.  * The impact of lipids and lipoproteins on CVDs * Lipids and lipoproteins have a major impact on the genesis and progression of CVD by means of their: cellular synthesis, transportation, assembly, degradation, oxidation, and plasma concentrations.  * The Impacts of Lipids and Lipoproteins on CVD *Traditionally, lipids are classified based on their function as: ‘Storage lipids’ [e.g., fatty acids (FAs),TGs, and sterols] or ‘Structural lipids’ [e.g., phospholipids (PLs), glycolipids, and ceramides] A third group comprises the lipoproteins, subclassified into five types based on their density and size: Chylomicrons, VLDL, IDL, LDL, and HDL *These, lipids are essential for various physiological processes supporting biological life.  * Blood Cholesterol *Blood cholesterol level was identified as the first direct link between circulating lipids and CVD. Increased plasma cholesterol levels are associated with an increased 10-year risk of cardiovascular death from 3.8% to almost 19.6% in men with a pre-existing CVD. This risk increases from 1.7% to 4.9% in patients without CVD but with elevated cholesterol levels.  * Blood Cholesterol *Follow-up studies on the FHS identified elevated plasma LDL –C levels as a risk factor for cardiovascular events. *Patients with atherosclerotic plaques correlate with 45% higher plasma oxidised LDL (oxLDL) concentrations as compared with control subjects. *In addition, patients with high total LDL particles of 1.935– 3.560 nmol/L have a 3.7 times higher risk of coronary artery calcification than those with lower LDL particles of 620–1530 nmol/L.  * Classification of lipids and lipoproteins based on their impact on genesis and progression of CVD * Based on the mechanistic impact of lipids and lipoproteins on CVD, lipids and lipoproteins are classified into three novel categories such as: Lipids and lipoproteins with– 1. Enhancing CVDs, 2. A conditional impact on CVDs, and 3. No known effect on CVDs due to a lack of evidence.  This classification reflects: the current mechanistic knowledge of lipids affecting CVD discussing the major lipid classes that are vital for survival but are pathological only under altered concentrations. (A) Classification of lipids based on the function of lipids. (B) Classification of lipids based on their role in CVD development as enhancers, with a conditional impact or with no known effect on CVDs. Abbreviations: HDL-C, high-density lipoprotein cholesterol; IDL-C, intermediate-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol  * Impact of Lipids and Lipoproteins on CVDs *Common therapeutic interventions for the prevention and treatment of CVDs are: HDL increase, LDL decrease, and TG decrease. Lipids and lipoproteins enhancing CVDs * Lipids and lipoproteins enhancing CVDs are: LDL, VLDL, lipoprotein (a) [Lp(a)], TGs, trans-fatty acids (TFAs), phosphatidylcholine, and Lysophosphatidic acid (LPA) They have a strong impact on thrombosis and atherosclerosis.  * LDL, VLDL, and Lp(a) lipoproteins *High plasma concentrations of LDL, VLDL, IDL, and Lp(a) enhance CVD by promoting thrombus and plaque formation. *Native LDL and its post-translationally oxidised form, oxLDL, are the driving factors of the development of atherosclerotic plaques.  * LDL, VLDL, and Lp(a) lipoproteins * Macrophages within atherosclerotic lesions possess scavenger receptors (SRs) such as SR-A1, CD36, and ‘lectin-like oxLDL receptor-1’ which recognize oxidation-specific epitopes, such as ApoB-100 modification, cholesteryl ester modification, and PL oxidation on oxLDL, Thereby facilitate its uptake, but not native LDL. * LDL, VLDL, and Lp(a) lipoproteins *The susceptibility of LDL particles to oxidation depends on specific density: small and dense LDL particles are more likely than large ones to be oxidized. *The underlying mechanism of in vivo LDL oxidation are, to date, not fully understood; however, it is suggested that LDL is oxidised in the presence of a proinflammatory stage. * LDL, VLDL, and Lp(a) lipoproteins *The macrophage phagocytosed LDL and modified LDL are converted to free cholesterol by the liposomal acid lipase and further to cholesterol esters by acetyl- coenzyme A acetyltransferase, which are converted to free cholesterol in the endoplasmic reticulum and are exported out of the cells by cholesterol transporters.  * LDL, VLDL, and Lip(a) lipoproteins *The atherogenicity of modified LDL results from: its inability to be degraded by macrophages, thereby leading to foam cell formation. oxLDL and aggregates of LDL intensify atherosclerosis by triggering the secretion of inflammatory cytokines and growth factors from the arterial wall.  * LDL, VLDL, and Lp(a)lipoprotein * Furthermore, oxLDL causes: the production of asymmetric dimethylarginine by activating S-adenosylmethionine-dependent methyltransferases, Which deteriorate the vascular tone by decreasing nitric oxide production through endothelial nitric oxide synthase inhibition. Thus, LDL and oxLDL promote CVDs by enhancing foam cell formation, inflammation, and plaque formation.  * LDL, VLDL and Lp(a) *VLDL particles promote intercellular leukocyte migration by interaction with VLDL receptors on endothelial cells and fibrin, aiding foam cell formation and thereby promoting inflammation. *The presence of Lp(a) in combination with low oxidised lipid levels causes deposition of calcium and phosphate salts, resulting in plaque formation.  * LDL, VLDL, and Lp(a) *Lp(a) accelerates the calcification process in vitro by increasing the alkaline phosphatase activity and activating the p38 mitogen-activated *protein kinase (MAPK), glycogen synthase kinase 3 beta (GSK3β), and Wingless-related integration (Wnt) signal pathways. *Hypertriglyceridaemia leads to reduced activity of hepatic TG lipase and/or glycosylphosphatidylinositol-anchored HDL-binding protein 1, thereby leading to modified lipoprotein uptake by the liver, which increases the concentration of TGs in plasma. * Triglycerides * TG-rich lipoproteins produce inflammatory proteins derived from endothelial cells and macrophages, containing: monocyte chemoattractant protein-1, intercellular adhesion molecule-1 (ICAM-1), Eselectins, metalloproteases, platelet endothelial cell adhesion molecule-1, and interleukin (IL)-6, which are released through the activity of transcription factors:  nuclear factor kappa-lightchain-enhancer of activated B cells (NF- κB) and cAMP response element-binding protein. * TG *TG-rich lipoproteins migrate into the arterial wall and lead to: an accumulation of remnant cholesterol-aiding plaque formation, whereas remnant cholesterol remains in atherosclerotic plagues, triggering foam cell formation. * TG * Elevated levels of TGs activate endothelial cells to produce: hydroxylated linoleates 9-hydroxyoctadecadienoic acid (HODE) and 13-HODE by lipoprotein lipase (LPL) lipolysis upregulation of: reactive oxygen species (ROS), ICAM, and tumour necrosis factor-α (TNFα), promoting inflammatory responses, plaque formation, and atherosclerosis. * TG *9-HODE and 13-HODE interact with cells through peroxisome proliferator-activated receptors and surface receptors for FAs, enhancing CD36 expression as an atherogenic SR. *TGs cause inflammation along the arterial wall by promoting the release of inflammatory molecules such as: 9-HODE, 13-HODE, ROS, ICAM, and TNFα * TG * TFAs cause systemic inflammation by increasing IL-6, TNF receptor densities, and monocyte chemoattractant protein-1, causing atherosclerosis. * Increased TFA intake causes endothelial dysfunction by increasing soluble ICAM-1, and promoting transmigration of leukocytes from blood vessels to tissues. TFAs induce the release of vascular cell adhesion molecule-1 (VCAM-1) by acting as a scaffold for leukocyte migration and promoting endothelial signal transduction, stimulating inflammation * Trans-fatty acids (TFAs)  * PLs (phosphatidylcholine) * Phosphatidylcholine leads to foam cell formation, attributed to the increase in phosphatidylcholine biosynthesis during free cholesterol uptake by macrophages. * The increase in phosphatidylcholine biosynthesis maintains the free cholesterol/phosphatidylcholine ratio in the cell, a prerequisite to cell survival, and is achieved by free cholesterol activating the cholinephosphate cytidylyltransferase enzyme.  * PLs (phosphatidylcholine) *Phosphatidylcholine is metabolised by intestinal microbes, and the resulting metabolites, choline and betaine, upregulate macrophage SRs. Choline and betaine are metabolised by gut microflora into trimethylamine before it is converted to trimethylamine N- oxide (TMAO) by hepatic flavin monooxygenase.  * PLs (phosphatidylcholine) *There is a dose-dependent relationship between TMAO levels and atherosclerotic plaque burden. *High phosphatidylcholine intake leads to higher TMAO production and contributes to CVD risk in patients with end-stage renal disease.  * Lysophosphatidic acid * LPA accumulates in atherosclerotic plaques, promoting both platelet activation and thrombogenesis, as a cofactor alongside ICAM-1 or VCAM-1 and collagen type I or III. * LPA triggers proinflammatory cytokines, growth factors, and coagulation factors by inducing the expression of early growth response factor-1, promoting mineralisation and osteogenic differentiation of valve interstitial cells by interacting with the LPA receptor-1 and Ras homolog family member A (RhoA)/ NF-κB pathways. *LPA promotes CVD progression by stimulating tissue factor expression on smooth muscle cells, resulting in macrovascular thrombosis. *LPA suppresses autophagy, leading to cardiac dysfunction and hypertrophy by activating the LPA receptor-3 and the protein kinase B/mammalian target of rapamycin signalling pathway.  *Lipids and lipoproteins with a conditional impact on the genesis and/or progression of CVD *The lipids of this subclass have a profound effect on CVDs; however, the positive impact of this lipid subclass is conditional based on factors such as oxidation, presence of cofactors, and plasma concentration of other lipids. *Remodelling of nascent HDL particles to mature HDL through the esterification of cholesterol by the enzyme lecithin-cholesterol acyltransferase, as well as by the transfer of additional cellular cholesterol to HDL by the cell surface transporter ATP-binding cassette subfamily G *member 1, and the action of SR-B1, is essential for the prevention of atherosclerosis * HDL * Lipid-poor pre-β-HDL particles remove abundant cholesterol and oxLDL from macrophages via reverse cholesterol transport, which otherwise transforms them into foam cells having a proatherosclerotic effect. * HDL increases the production of the atheroprotective signalling molecule nitric oxide, which is triggered by the Src- and phosphatidylinositol 3-kinase- mediated signalling, along with Akt and MAPK signalling. * HDL * In addition, HDL inhibits the formation of oxLDL because it contains enzymes with antioxidant-like activities such as paraoxonase and platelet-activating factor acetylhydrolase. oHDL prevents plaque formation by inhibiting the transdifferentiation of smooth muscle cells to osteoblast-like cells by reducing the osteogenic activity of inflammatory cytokines IL-1β, IL-6, and minimally oxLDL. * HDL * High plasma levels of HDL are caused by a mutation on the endothelial type lipase G (LIPG) by a loss-of-function SNP. o The function of HDL changes with its composition, such as differences in PL or unsaturated lipid content; percentage of esterified lipids; Inflammation or glycation of apolipoprotein A-I (ApoA-I), myeloperoxidase, and paraoxonase; and modification of the serum lipid levels.. * HDL * Oxidised cargo molecules, glycated ApoA-I, and high glucose reduce the anti-inflammatory activity of HDL particles and promote HDL dysfunction. * A comparison between the cardiovascular risk-predicting potential of HDL-related analytes such as ApoA-I, HDL subfractions HDL2 and HDL3, and the HDL particle number (HDL-P) results in HDL-P emerging as a better predictor of incident events. * HDL *Thus, HDL functions, such as its ability to promote cholesterol efflux from cells and mediate reverse cholesterol transport, are essential to reduce cardiovascular risk in patients. *HDL * Role of triglycerides in CVD development. Triglycerides enhance CVD by inducing inflammation and foam cell formation by the depicted mechanisms. * Role of high-density lipoprotein cholesterol (HDL-C) in CVD development. HDL-C transports cholesterol, preventing its accumulation in plaques; acts as an anti-inflammatory molecule; and prevents foam cell formation * Polyunsaturated FAs omega-3 and omega-6 are counteractive in terms of inflammation, with * omega-3 reducing inflammation and omega-6 nullifying the effect of omega-3. * Omega-3 FAs from fish oils, such as the ‘eicosapentaenoic acid’ (EPA) and ‘docosahexaenoic acid’ (DHA), reduce plasma TGs up to 50%, thereby lowering cardiovascular risk. * Fatty acids * Omega-3 FAs improve endothelial function and reduce blood pressure, increase nitric acid production, improve vasodilatory responses, and have antithrombotic effects. * However, clinical trials and meta-analyses show that EPA and DHA have little to no protective effect on cardiovascular events, and * omega-3 FAs cause lipid peroxidation in predialysis patients. * These contrasting findings are attributed to low dosage, absence of cofactors of EPA and DHA, and not targeting patients with high TG levels *FAs * In addition, a high linoleic acid level, an omega-6 FA, is associated with a 7% risk reduction in cardiovascular events. * However, omega-6 FAs are known to promote TNF-mediated endothelial cell injury, leading to endothelial dysfunction, which reverses the anti-inflammatory effect of omega-3 FAs by enhancing cyclooxygenase-2 expression, resulting in a proinflammatory microenvironment. *FAs * Compilation of different trials did not show a reduction in the risk of CVD events after supplementation with omega-6 [relative risk 0.86 (0.69–1.07)] or an association with cardiovascular mortality [odds ratio 0.89 (0.74–1.06). * Therefore, the impact of omega-6 FAs on inflammation, atherosclerosis, and CVD is currently under scrutiny. *FAs *In vitro studies show phosphatidylserine internalises microvesicles into endothelial cells and regulates coagulation and inflammation by downregulating the production of IL-6, IL-8, prostaglandin E2, and vascular endothelial growth factor. * Phospholipids * In vivo it has been shown that dietary PLs reduce liver lipid levels by interfering with neutral sterol absorption in the intestinal lumen and downregulating bile acids and cholesterol secretion. I on vivo post-translational oxidation, leading to the formation of oxidised PLs, enhances uptake by macrophages causing proinflammatory and proatherogenic effects. * Phospholipids *In vivo study shows that the reduction in sphingosine-1- phosphate (S1P)/ceramide levels in the case of myocardial infarction leads to apoptosis. *S1P is involved in cell survival and resistance to apoptosis, proliferation, angiogenesis, and cell growth by binding to SIP receptor 1-5 G protein-coupled receptors. * Sphingolipids *S1P promotes leukocyte rolling by interacting with the S1P3 receptor and the Gα-subunit, which mobilises P-selectin, enabling it to assist in monocyte–platelet aggregate formation. Even though S1P promotes cardioprotective cellular mechanisms, they have not yet been explored as translational CVD treatment options. * Sphingolipids  * Lipids with an unknown effect on genesis and progression of CVD *Due to lack of evidence in existing literature proving their impact on CVD risk or events, biologically active lipids such as: mono- and diglycerides, prenol lipids, stearic acids, galactolipids, sterols, glycolipids, and sulpholipids are placed in this category, implying that these lipids are essential for biological functions but do not have known impact on the onset or progression of CVD. oLDL, VLDL, IDL, Lp(a), and TGs determine the plasma cholesterol concentration, and their imbalance enhances plaque formation; oTFAs lead to systemic inflammation; oPLs, specifically phosphatidylcholine, enhance the expression of SRs on macrophages; and oLPA enhances thrombus formation. Consequently, they have a cumulative impact on the enhancement of CVD development. * (A) Cumulative impact of lipids and lipoproteins in enhancing cardiovascular diseases (CVDs). *The cardioprotective properties of HDL are conditional and change with the oxidation of cargo molecules and cholesterol efflux capacity. Omega-3 FAs were initially shown to reduce CVDs, but large-scale human trials failed to prove these cardioprotective effects. PLs show cardioprotective properties such as reduced cholesterol secretion but PLs cause CVD enhancing outcomes when oxidised. S1P causes cardioprotective effects that are not yet supported by clinical studies. While certain properties of these lipid subclasses suggest an impact on cardiovascular health, this has not yet been confirmed by clinical studies.