Cardiovascular biochemistry explores the molecular mechanisms underlying atherosclerosis, hypertension, heart failure, and myocardial infarction. Understanding these mechanisms is essential for developing preventive and therapeutic strategies.
Atherosclerosis
Atherosclerosis is a chronic inflammatory disease of the arterial wall, initiated by endothelial dysfunction and driven by lipid accumulation and immune responses. The process begins when LDL particles penetrate the endothelium and become trapped in the subendothelial space by binding to proteoglycans. Retained LDL undergoes oxidation by reactive oxygen species produced by endothelial cells and macrophages.
Oxidized LDL activates the endothelium, inducing expression of adhesion molecules such as VCAM-1 and ICAM-1 that recruit circulating monocytes. Monocytes differentiate into macrophages, which take up oxidized LDL through scavenger receptors such as SR-A and CD36. Unlike LDL receptor-mediated uptake, scavenger receptors are not downregulated by cholesterol accumulation, leading to foam cell formation. Foam cells accumulate in the intima, forming fatty streaks, the earliest atherosclerotic lesions.
Plaque Progression
Foam cells produce inflammatory cytokines including IL-1-beta and TNF-alpha, recruiting more immune cells and promoting smooth muscle cell proliferation and migration from the media to the intima. Smooth muscle cells synthesize extracellular matrix, creating a fibrous cap over the lipid-rich core. Advanced plaques contain a necrotic core of dead foam cells and cellular debris, with thin fibrous caps that are prone to rupture.
Plaque rupture exposes thrombogenic material, triggering platelet activation and coagulation, leading to acute thrombosis. Myocardial infarction or stroke results when the thrombus occludes the vessel lumen. Vulnerable plaques are characterized by a large necrotic core, thin fibrous cap, and dense inflammatory cell infiltration.
Biochemical Risk Factors
LDL cholesterol is causally linked to atherosclerosis. Each 1 mmol/L reduction in LDL reduces cardiovascular events by about 20%. Small, dense LDL particles are particularly atherogenic because they penetrate the endothelium more easily and are more susceptible to oxidation. HDL cholesterol is considered protective because it mediates reverse cholesterol transport and has anti-inflammatory and antioxidant properties.
Lipoprotein A is an LDL-like particle with an additional apolipoprotein A that is genetically determined and independently predicts cardiovascular risk. Elevated triglycerides are associated with increased risk, partly through remnant lipoproteins. Homocysteine levels are modifiable by B-vitamin supplementation, but clinical trials have not shown cardiovascular benefit from homocysteine lowering.
Myocardial Infarction
Acute myocardial infarction results from prolonged myocardial ischemia, causing irreversible injury and cell death. The loss of oxygen and nutrients impairs oxidative phosphorylation, depleting ATP and causing metabolic crisis. Anaerobic glycolysis produces lactate, causing intracellular acidosis that inhibits contractile function.
Calcium homeostasis is disrupted. Reduced ATP impairs calcium reuptake by the sarcoplasmic reticulum, and acidosis reduces myofilament calcium sensitivity. Uncontrolled calcium influx activates proteases and phospholipases, damaging cellular structures. Mitochondrial permeability transition pore opening releases cytochrome c, triggering apoptosis. Reperfusion, while necessary for tissue salvage, causes additional injury through oxidative stress and calcium overload.
Cardiac Biomarkers
Cardiac troponins I and T are the preferred biomarkers for myocardial infarction diagnosis. They are released from damaged myocytes within 3 to 6 hours and remain elevated for 7 to 14 days. High-sensitivity troponin assays detect very low concentrations and improve early diagnosis. Creatine kinase-MB is an alternative marker, and natriuretic peptides such as BNP and NT-proBNP are markers of heart failure.
Heart Failure
Heart failure is a clinical syndrome where the heart cannot pump enough blood to meet metabolic demands. Biochemical changes include activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which initially compensate but become maladaptive. Norepinephrine increases heart rate and contractility but also causes myocyte hypertrophy and apoptosis. Angiotensin II causes vasoconstriction, sodium retention, and myocardial fibrosis. Aldosterone promotes fibrosis and electrolyte abnormalities.
Drug Targets
Statins inhibit HMG-CoA reductase, lowering LDL and reducing cardiovascular events. They also have pleiotropic effects including improvement of endothelial function and reduction of inflammation. Antiplatelet drugs such as aspirin irreversibly inhibit cyclooxygenase-1, reducing thromboxane A2 production and platelet aggregation. P2Y12 inhibitors such as clopidogrel block ADP-induced platelet activation. ACE inhibitors and angiotensin receptor blockers reduce morbidity and mortality in heart failure and hypertension.
