14.4 Cardiovascular Biochemistry: Cholesterol, Lipoproteins, Dyslipidemias, Atherogenesis, Myocardial Energetics, Biomarkers & Heart Failure

Why this area matters

The TOS lists "biochemical mechanisms and properties underlying cardiovascular function and diseases such as heart failure, coronary artery disease, systemic atherosclerosis, infections, compensatory mechanisms to prevent organ dysfunction; myocardial energetics". Dyslipidemia, hypertension and diabetes drive the Philippine burden of ischemic heart disease and stroke. Lipid biochemistry underlies statin, ezetimibe and fibrate therapy in Pharmacology and Medicine.

Cholesterol Biosynthesis, HMG-CoA Reductase, and Statin Pharmacology

Cholesterol is synthesized from cytosolic acetyl-CoA in all nucleated cells, predominantly hepatocytes and steroidogenic tissues. Two acetyl-CoA molecules form acetoacetyl-CoA, which condenses with a third to generate HMG-CoA in the cytoplasm. The rate-limiting and committed reaction is catalyzed by HMG-CoA Reductase on the endoplasmic reticulum membrane:

$\text{HMG-CoA} + 2\text{ NADPH} + 2\text{ H}^+ \xrightarrow{\text{HMG-CoA Reductase}} \text{Mevalonate} + 2\text{ NADP}^+ + \text{CoA-SH}$

• Transcriptional Control: Sterol Regulatory Element-Binding Protein-2 (SREBP-2) upregulates HMG-CoA reductase gene expression when intracellular cholesterol is low. High intracellular cholesterol retains SREBP in the ER via SCAP (SREBP Cleavage-Activating Protein).
• Hormonal Control: Insulin activates HMG-CoA reductase via dephosphorylation; glucagon and AMPK phosphorylate and inactivate it.
• Pharmacological Inhibition: Statins (atorvastatin, rosuvastatin, simvastatin) are structural analogs of HMG-CoA that act as competitive, reversible inhibitors of HMG-CoA reductase. Decreased intracellular cholesterol upregulates LDL receptor (LDLR) expression on hepatocyte membranes, dramatically clearing atherogenic LDL particles from the circulation.

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Lipoprotein Metabolism and Apolipoproteins

Lipoproteins are spherical macromolecular complexes composed of a hydrophobic core (triacylglycerols and cholesteryl esters) surrounded by an amphipathic shell of phospholipids, unesterified cholesterol, and apolipoproteins.

High-Yield Human Apolipoproteins

Lipoprotein Remodeling Enzymes

• Lipoprotein Lipase (LPL): Anchored to capillary endothelial surfaces of adipose and muscle tissues; hydrolyzes core triacylglycerols in chylomicrons and VLDL into free fatty acids and glycerol.
• Lecithin-Cholesterol Acyltransferase (LCAT / PCAT): Activated by ApoA-I on HDL; transfers a fatty acid from lecithin (phosphatidylcholine) to free cholesterol, forming hydrophobic cholesteryl esters that migrate to the HDL core, transforming nascent discoidal HDL into spherical mature HDL.
• Cholesteryl Ester Transfer Protein (CETP): Facilitates the equimolar exchange of cholesteryl esters from HDL to VLDL, IDL, and LDL in return for triacylglycerols.

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Familial Hyperlipidemias (Fredrickson Classification)

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Molecular Biochemistry of Atherogenesis: From Endothelial Injury to Plaque Rupture

Atherosclerosis is a chronic inflammatory and fibroproliferative disease of elastic and large muscular arteries triggered by subendothelial retention of ApoB-containing lipoproteins.

1. Endothelial Dysfunction and Subendothelial Retention: Chronic hemodynamic shear stress, cigarette smoke oxidants, hyperhomocysteinemia, or diabetes disrupts endothelial integrity. Circulating LDL enters the subendothelial space of the arterial intima, binding to matrix proteoglycans.
2. Oxidative Modification: Entrapped LDL is modified by reactive oxygen species (ROS) and myeloperoxidase into minimally oxidized LDL and extensively oxidized LDL (oxLDL).
3. Monocyte Recruitment and Scavenger Receptors: OxLDL stimulates endothelial cells to express adhesion molecules (VCAM-1, ICAM-1) and Monocyte Chemoattractant Protein-1 (MCP-1). Monocytes transmigrate into the intima and differentiate into macrophages. Unlike the physiologic LDL receptor, macrophage Scavenger Receptors (SR-A and CD36) are not down-regulated by intracellular cholesterol accumulation. Macrophages uncontrollably endocytose oxLDL.
4. Foam Cell Genesis and Fatty Streak Formation: Macrophages engorged with cytosolic cholesteryl ester droplets transform into foam cells. Clusters of foam cells beneath the intact endothelium form the macroscopic fatty streak, the earliest visible atherosclerotic lesion.
5. Fibrous Cap Formation: Activated foam cells and $T_H1$ lymphocytes secrete inflammatory cytokines ($TNF-\alpha$, $IL-1$, $IFN-\gamma$) and growth factors ($PDGF$, $TGF-\beta$). Platelet-Derived Growth Factor (PDGF) stimulates vascular smooth muscle cells (VSMCs) to migrate from the media to the intima, proliferate, and synthesize dense extracellular collagen, forming a protective fibrous cap over a necrotic lipid core.
6. Plaque Rupture and Acute Thrombosis: Inflammatory macrophages in vulnerable shoulder regions secrete Matrix Metalloproteinases (MMPs) (collagenases) that degrade the fibrous cap matrix. Thinning and rupture of the fibrous cap exposes subendothelial tissue factor and necrotic core thrombogenic lipids to circulating platelets and factor VII, triggering acute occlusive thrombosis and culminating in acute myocardial infarction or ischemic stroke.

Other atherogenic factors

• Lipoprotein(a): LDL-like particles carrying apo(a), which is structurally similar to plasminogen. It promotes both atherosclerosis and thrombosis. Levels are genetically determined.
• Hyperhomocysteinemia: caused by B12, folate or B6 deficiency, renal failure or CBS mutations. It injures endothelium and favors thrombosis.
• Small dense LDL and high triglycerides with low HDL, as in insulin resistance.
• Smoking: oxidants and endothelial dysfunction. Diabetes: glycation and advanced glycation end-products. Hypertension: shear and stretch injury. Inflammation: high-sensitivity CRP.

Myocardial energetics

• The heart beats continuously and consumes a great deal of ATP but stores very little. It must regenerate ATP from:
  • fatty acid beta-oxidation, which provides about 60% to 90% of ATP in the resting adult heart;
  • glucose, lactate and ketones.
• Creatine phosphate buffers ATP and shuttles high-energy phosphate from mitochondria to myofibrils through mitochondrial and cytosolic creatine kinase.
• In ischemia, oxygen falls and oxidative phosphorylation stops within seconds. The heart shifts to anaerobic glycolysis from glycogen. Lactate and H+ accumulate, creatine phosphate falls, and contractility is lost within about 60 seconds. Irreversible injury begins after about 20 to 30 minutes. Ion pumps fail, Na+ and Ca2+ accumulate, and arrhythmias follow.
• In heart failure, the failing heart shifts toward glucose use, its creatine phosphate falls, and its mitochondria work less efficiently, an "energy-starved" state.
• Thiamine deficiency (wet beriberi) impairs pyruvate dehydrogenase and causes high-output failure that responds dramatically to thiamine.

Biochemical markers of myocardial injury

Heart failure: compensation becomes harm

When cardiac output falls, the body activates mechanisms meant to protect perfusion:

• Sympathetic activation: catecholamines raise heart rate and contractility and constrict vessels. Chronically, they cause beta-receptor downregulation, myocyte toxicity and arrhythmias. Beta-blockers counter this.
• Renin-angiotensin-aldosterone system: angiotensin II constricts vessels and promotes remodeling and fibrosis. Aldosterone retains sodium and water and causes myocardial fibrosis. This explains the benefit of ACE inhibitors, ARBs and ARNI, and mineralocorticoid antagonists.
• Vasopressin: water retention leading to hyponatremia.
• Natriuretic peptides (ANP, BNP): released when atria and ventricles are stretched. They cause natriuresis and vasodilation, but their effect is overwhelmed. BNP and NT-proBNP are diagnostic and prognostic markers. Sacubitril blocks neprilysin, the enzyme that degrades BNP.
• The Frank-Starling mechanism and hypertrophy: initially compensatory, they later cause increased wall stress, fibrosis and remodeling.
• SGLT2 inhibitors cause glycosuria, natriuresis and a metabolic shift, and reduce heart-failure hospitalization.

Infections and the heart (biochemical view)

• Rheumatic fever: molecular mimicry between streptococcal M protein and cardiac myosin. ASO and anti-DNase B titers document a preceding streptococcal infection.
• Infective endocarditis: bacteria adhere to fibrin-platelet vegetations through surface adhesins (dextran in viridans streptococci). Acute-phase reactants (CRP, ESR) are high. The anemia of chronic disease is mediated by hepcidin.
• Sepsis: cytokines such as TNF and IL-1 and nitric oxide depress myocardial contractility. Lactate rises from poor perfusion and impaired mitochondrial use.
• Diphtheria toxin inhibits protein synthesis by ADP-ribosylating EF-2, causing myocarditis. Chagas disease and viral myocarditis cause cardiomyopathy.