What is the pathophysiology of Coronary Artery Disease (CAD)?

Pathophysiology of Coronary Artery Disease (CAD)

Coronary artery disease (CAD) involves complex structural and functional alterations in both macro- and microvascular compartments of the coronary tree, leading to myocardial demand-supply mismatch and ischemia. 1

Evolving Understanding of CAD Pathophysiology

• Traditional view: CAD was considered primarily a cholesterol storage disease with fixed, focal flow-limiting atherosclerotic stenosis as the main cause of ischemia 1, 2
• Current understanding: CAD is recognized as an inflammatory disorder with multiple pathophysiological mechanisms affecting both epicardial arteries and microcirculation 1, 2

Macrovascular Pathophysiology

Atherosclerotic Plaque Formation and Progression

• Atherosclerotic plaque accumulation in epicardial arteries is the fundamental pathological process in CAD 1
• Plaque formation begins with endothelial dysfunction, followed by lipid accumulation, inflammatory cell infiltration, and smooth muscle cell proliferation 1, 2
• Plaques prone to rupture typically have a large lipid core, low smooth muscle cell density, high macrophage density, and thin fibrous cap 1

Plaque Disruption Mechanisms

• Active rupture: Related to secretion of proteolytic enzymes (metalloproteinases) by macrophages that weaken the fibrous cap 1
• Passive disruption: Occurs at the weakest point of the fibrous cap due to physical forces, typically at the junction of plaque and adjacent normal wall 1
• Plaque erosion: Surface erosion without deep rupture can also trigger thrombosis 2

Beyond Stenosis: Diffuse Disease and Remodeling

• Not only fixed, flow-limiting stenoses but also diffuse atherosclerotic lesions without identifiable luminal narrowing can cause ischemia under stress 1
• Arterial remodeling (compensatory enlargement) may mask significant plaque burden on angiography 2
• Left main coronary artery disease occurs more frequently in radiation-associated CAD than in typical CAD 1

Microvascular Pathophysiology

Coronary Microvascular Dysfunction (CMD)

• CMD is increasingly recognized as a prevalent factor across the entire spectrum of CAD 1
• Functional and structural microcirculatory abnormalities can cause angina and ischemia even with non-obstructive epicardial disease (ANOCA/INOCA) 1
• Risk factors for epicardial atherosclerosis also promote endothelial dysfunction and abnormal vasomotion in the entire coronary tree 1

Microvascular Alterations

• Progressive loss or abnormal proliferation of endothelial cells 1
• Fibrinoid necrosis and adventitial fibrosis 1
• Media hyalinization and intimal thickening 1
• Chronic oxidative stress response and thrombus formation 1

Dynamic Components of CAD

Vasomotor Abnormalities

• Epicardial vasospasm can cause transient ischemia even without significant fixed stenosis 1
• Endothelial dysfunction leads to impaired flow-mediated vasodilation in epicardial arteries 1
• Macro- and microcirculatory vasoconstriction can occur due to endothelial dysfunction 1

Structural Abnormalities

• Myocardial bridging and congenital arterial anomalies can contribute to ischemia 1
• Radiation-induced CAD shows distinctive features: more fibrous tissue in media and adventitia, thinning of smooth muscle in the media 1

Systemic and Extracoronary Factors

• Anemia, tachycardia, and blood pressure changes can contribute to myocardial ischemia 1
• Myocardial hypertrophy and fibrosis increase oxygen demand and contribute to ischemia 1
• Hypertension increases LV output impedance and intramyocardial wall tension, raising myocardial oxygen demand 1
• Systolic hypertension and wide pulse pressure increase aortic impedance and central systolic pressure augmentation 1

Inflammatory and Thrombotic Mechanisms

• Inflammation plays a crucial role at every step of atherosclerosis, from initiation to progression 3
• Plaque disruption creates a "solid-state" stimulus to thrombosis 2
• Alterations in circulating prothrombotic or antifibrinolytic mediators in the "fluid phase" of blood can predispose to acute coronary syndromes 2
• Multiple "high-risk" plaques and widespread inflammation characterize patients prone to develop acute coronary syndromes 2

Clinical Implications

• CAD should be viewed as a dynamic, progressive condition that may destabilize at any moment 1
• Different mechanisms of ischemia may act concomitantly in the same patient 1
• Patients may transition between different types of chronic coronary syndromes and acute coronary syndromes throughout their lifetime 1
• Treatment should address both obstructive lesions and the underlying inflammatory and thrombotic processes 2

Interdependence with Other Cardiac Chambers

• Septum interventricular plays a key role in the function of both ventricles 4
• Left ventricular dysfunction from CAD can affect right ventricular function through septal mechanics and increased pulmonary pressures 4

Understanding these complex pathophysiological mechanisms is essential for appropriate diagnosis, risk stratification, and management of patients with CAD.