Etiopathogenesis Flowcharts for Coronary Artery Disease
The three primary etiopathogenic mechanisms of CAD are atherosclerotic plaque formation, coronary vasospasm, and thrombosis—each representing distinct pathways that frequently overlap in individual patients and require different therapeutic approaches. 1, 2
Flowchart 1: Atherosclerotic CAD Pathway
Initial Trigger
- Endothelial dysfunction initiated by traditional risk factors (hypertension, dyslipidemia, diabetes, smoking, age) 2, 3 ↓
Lipid Accumulation Phase
- LDL cholesterol penetrates damaged endothelium and accumulates in arterial intima 2, 4
- Oxidative modification of lipoproteins occurs in vessel wall 3 ↓
Inflammatory Response
- Monocyte recruitment via chemokines and adhesion molecules 3, 4
- Macrophage transformation into foam cells after lipid uptake 2, 3
- Inflammatory cell infiltration (T-lymphocytes, mast cells) perpetuates chronic inflammation 2, 4 ↓
Plaque Development
- Smooth muscle cell proliferation and migration from media to intima 2, 3
- Extracellular matrix deposition forms fibrous cap 4
- Lipid core expansion with necrotic debris accumulation 2 ↓
Plaque Progression
- Stable plaque: Thick fibrous cap, small lipid core, produces fixed stenosis causing effort-induced angina 1
- Vulnerable plaque: Large lipid core (>40% plaque volume), thin fibrous cap (<65 μm), high macrophage density, low smooth muscle cell content 2, 4 ↓
Clinical Manifestations
- Chronic stable angina: Fixed stenosis >70% causes demand-supply mismatch during exertion 1
- Acute coronary syndrome: Plaque rupture/erosion triggers thrombosis (see Flowchart 3) 2, 4
Critical caveat: Arterial remodeling (compensatory enlargement) allows plaques to grow without causing stenosis visible on angiography—these non-obstructive lesions cause most acute coronary syndromes 4, 5
Flowchart 2: Coronary Vasospasm Pathway
Predisposing Factors
- Endothelial dysfunction with impaired nitric oxide production 6, 2
- Smooth muscle hyperreactivity to vasoconstrictor stimuli 6
- Autonomic dysregulation affecting vascular tone 6
- Genetic susceptibility: Japanese/Taiwanese populations show 3-fold higher prevalence than Caucasians 6 ↓
Triggering Events
- Smoking (most common trigger) 1, 6
- Cold exposure, hyperventilation 1, 6
- Cocaine or methamphetamine use 1
- Electrolyte disturbances (hypokalemia, hypomagnesemia) 6
- Emotional stress 1 ↓
Vasospastic Response
- Focal spasm: Intense vasoconstriction at single site (>90% diameter reduction) 1, 6
- Diffuse spasm: Multiple segments or entire vessel involvement 1, 6
- Can occur in: Normal arteries, non-obstructive CAD, or at sites of atherosclerotic plaque 1, 6, 2 ↓
Ischemic Cascade
- Transmural ischemia develops within seconds 1
- ST-segment elevation on ECG corresponding to affected territory 1
- Angina at rest typically in early morning hours (circadian pattern) 1 ↓
Clinical Outcomes
- Self-limited episodes: Spontaneous resolution or response to nitroglycerin 1
- Arrhythmias: Ventricular tachycardia, fibrillation, heart block 1
- Myocardial infarction: If spasm sustained >20 minutes 1
- Sudden cardiac death: Rare but possible 1
Overlap with Microvascular Dysfunction
- Concomitant CMD present in majority of vasospasm patients 6, 2
- Mixed MVA/VSA phenotype associated with worse prognosis than isolated epicardial spasm 6
Critical caveat: Prognosis depends heavily on underlying atherosclerotic burden—patients with normal arteries have 0.5% annual coronary death rate versus significantly worse outcomes when spasm occurs on stenotic lesions 6
Flowchart 3: Thrombotic CAD Pathway
Three Distinct Mechanisms of Plaque Disruption
Pathway A: Plaque Rupture (Most Common in Men)
- Vulnerable plaque with thin fibrous cap (<65 μm) 2
- Mechanical stress or inflammatory enzyme degradation 4 ↓
- Fibrous cap tears exposing thrombogenic lipid core 2, 4 ↓
- Platelet adhesion to exposed collagen and tissue factor 4 ↓
- Thrombus formation (see final common pathway below)
Pathway B: Plaque Erosion (More Common in Women)
- Endothelial denudation without cap rupture 2
- Proteoglycan-rich matrix exposed to bloodstream 2 ↓
- Platelet adhesion to denuded surface 2 ↓
- Thrombus formation (see final common pathway below)
Pathway C: Calcified Nodule (Least Common)
- Calcified plaque with nodular protrusion 2
- Fibrous cap disruption through calcified nodule 2 ↓
- Thrombus formation (see final common pathway below)
Final Common Pathway: Thrombosis
Solid-State Factors (Local plaque characteristics):
- Tissue factor exposure initiates extrinsic coagulation cascade 4
- Collagen exposure activates platelets via glycoprotein receptors 4
- Degree of stenosis determines flow disturbance and shear stress 4
Fluid-Phase Factors (Circulating blood):
- Enhanced platelet aggregation from systemic prothrombotic state 4
- Impaired fibrinolysis from elevated PAI-1 4
- Inflammatory mediators (IL-6, CRP) promote coagulation 3, 4 ↓
Thrombus Evolution
- White thrombus: Platelet-rich, forms in high shear areas 4
- Red thrombus: Fibrin and erythrocyte-rich, propagates distally 4 ↓
Clinical Syndromes Based on Thrombus Burden
- Partial occlusion: NSTEMI or unstable angina 4
- Complete occlusion: STEMI with transmural infarction 4
- Microembolization: Distal microvascular obstruction 4
- Spontaneous lysis: Transient symptoms, possible MINOCA 1
Critical caveat: Most acute coronary syndromes arise from plaques causing <50% stenosis on prior angiography—the "vulnerable plaque" concept means non-obstructive disease requires aggressive risk factor modification, not just revascularization of stenotic lesions 4, 5
Integration of Mechanisms
These three pathways frequently coexist and interact in individual patients: 1, 2
- Atherosclerotic plaques create substrate for both thrombosis and localized vasospasm 6, 2
- Endothelial dysfunction from atherosclerosis promotes abnormal vasomotion throughout coronary tree 2
- Vasospasm can trigger plaque rupture through mechanical stress 6
- Microvascular dysfunction commonly accompanies all three epicardial mechanisms 6, 2
Treatment must address all relevant mechanisms simultaneously: lipid-lowering and antiplatelet therapy for atherothrombosis, calcium channel blockers and nitrates for vasospasm, and risk factor modification for all pathways 1, 2, 3