What is Coronary Artery Disease (CAD), its etiologies, epiopathogenesis, pathogenesis, pathophysiology, clinical features, diagnosis, treatment, and complications?

Coronary Artery Disease (CAD): Comprehensive Overview

Definition

CAD is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries (whether obstructive or non-obstructive), combined with structural and/or functional alterations in the coronary arteries and microcirculation that lead to myocardial demand-supply mismatch and ischemia. 1

The 2024 ESC Guidelines define chronic coronary syndromes (CCS) as clinical presentations arising from chronic diseases of the coronary arteries and/or microcirculation, which can manifest as angina, dyspnea, or remain asymptomatic, and may destabilize at any moment into acute coronary syndrome. 1

---

Etiologies

Primary Risk Factors

• Hypertension - increases left ventricular output impedance and intramyocardial wall tension, raising myocardial oxygen demand 2, 3
• Dyslipidemia - particularly elevated LDL cholesterol and triglycerides 1, 3
• Diabetes mellitus - accelerates atherosclerotic processes 1, 3, 4
• Smoking - promotes endothelial dysfunction and thrombosis 3, 5, 4
• Obesity and sedentary lifestyle 1, 3, 4
• Family history and genetic factors - including chromosome 9p21.3 association with premature CAD 3, 5
• Advanced age - prevalence increases from 5-7% in ages 45-64 to 10-12% in ages 65-84 1, 4
• Male gender - higher prevalence in men 1, 3

Secondary Contributing Factors

• Chronic kidney disease 3
• Elevated resting heart rate 1
• Psychosocial stress and depression 1, 5
• Homocystinuria 5

---

Etiopathogenesis & Pathophysiology

Macrovascular Pathophysiology Mechanism

1. Endothelial Dysfunction (Initial Step)

• Risk factors damage endothelial cells → impaired nitric oxide production 2, 6
• Increased endothelial permeability allows lipid infiltration 2, 6
• Promotes inflammatory cell adhesion and migration 6

↓

2. Lipid Accumulation & Inflammation

• LDL cholesterol accumulates in arterial intima 2, 6
• Oxidative modification of LDL triggers inflammatory response 3, 6
• Macrophages engulf oxidized LDL → foam cell formation 6

↓

3. Plaque Formation & Progression

• Smooth muscle cell proliferation and migration 2, 3
• Extracellular matrix deposition forms fibrous cap 2
• Continued inflammation and lipid accumulation expand plaque 6

↓

4. Vulnerable Plaque Characteristics

• Large lipid core with thin fibrous cap 2
• High macrophage density, low smooth muscle cell density 2
• Prone to rupture causing acute coronary syndrome 6

↓

5. Arterial Remodeling

• Compensatory enlargement maintains lumen initially 6
• Eventually leads to luminal narrowing and flow limitation 1, 6

Microvascular Pathophysiology

Coronary microvascular dysfunction (CMD) is increasingly recognized as prevalent across the entire CAD spectrum, affecting patients with and without obstructive epicardial disease. 1, 2

• Structural abnormalities: capillary rarefaction, perivascular fibrosis 1, 2
• Functional abnormalities: impaired vasodilation, increased vasoconstriction 1, 2
• Can cause angina and ischemia even without obstructive epicardial stenosis 1, 2

Dynamic Components

• Epicardial vasospasm - focal or diffuse spasm causing transient ischemia 1, 2
• Endothelial dysfunction - impaired flow-mediated vasodilation 2
• Myocardial bridging and congenital anomalies 1

Systemic Factors Contributing to Ischemia

• Anemia - reduces oxygen-carrying capacity 2
• Tachycardia - increases myocardial oxygen demand, reduces diastolic filling time 2
• Myocardial hypertrophy and fibrosis - increases oxygen demand 2

---

Clinical Features

Typical Angina Pectoris Characteristics

Location:

• Chest (near sternum), epigastrium, lower jaw/teeth, between shoulder blades, either arm to wrist and fingers 1

Character:

• Pressure, tightness, heaviness, strangling, constricting, or burning 1
• Many patients describe "discomfort" rather than "pain" 1

Duration:

• Lasts minutes with gradual exacerbation 3
• Maximum intensity reached gradually, not in seconds 3

Precipitating/Relieving Factors:

• Provoked by: exertion, emotion, stress 1
• Relieved by: rest, sitting, stopping activity, nitroglycerin within minutes 1, 3

Associated Symptoms

• Dyspnea - may be sole symptom or accompany chest discomfort 1
• Fatigue, faintness 1
• Nausea, burning sensation 1
• Restlessness, sense of impending doom 1

Severity Grading Systems

• CCS (Canadian Cardiovascular Society) classification 3
• Califf score 3
• Goldman scale 3

Asymptomatic Presentation

• Many patients with CAD remain asymptomatic despite ischemia and/or left ventricular dysfunction 1

---

Physical Examination

Key Findings to Assess

Cardiovascular Examination:

• Elevated resting heart rate - indicates worse prognosis 1
• Blood pressure measurement - assess for hypertension 1
• Jugular venous pressure - evaluate for heart failure 7
• Cardiac auscultation - assess for murmurs, S3/S4 gallops indicating ventricular dysfunction 1

Signs of Heart Failure:

• Peripheral edema - ankle and leg swelling 7
• Hepatomegaly - congestive hepatopathy 7
• Ascites - in advanced cases 7

Vascular Assessment:

• Peripheral pulses - assess for peripheral arterial disease 1
• Carotid bruits - indicate systemic atherosclerosis 1

General Assessment:

• BMI and waist circumference - obesity assessment 1
• Signs of hyperlipidemia (xanthomas, xanthelasmas) 1

---

Diagnosis

Clinical Diagnosis

A careful history remains the cornerstone of diagnosis, with confident diagnosis possible based on history alone in the majority of cases. 1

Electrocardiogram (ECG)

• Assess for ischemic changes, prior infarction, arrhythmias 1, 3
• May be normal at rest in stable CAD 1

Biomarkers

• Troponin - sensitive marker for myocardial injury; ultrasensitive assays detect minute troponin release with prognostic implications 1, 3
• BNP (Brain Natriuretic Peptide) - assess heart failure severity 7

Non-Invasive Imaging

Coronary CT Angiography (CTA):

• CAD-RADS 0: 0% stenosis - no CAD 1
• CAD-RADS 1: 1-24% stenosis - minimal non-obstructive CAD 1
• CAD-RADS 2: 25-49% stenosis - mild non-obstructive CAD 1
• CAD-RADS 3: 50-69% stenosis - moderate stenosis 1
• CAD-RADS 4: 70-99% stenosis or left main >50% or 3-vessel disease - severe obstructive CAD 1
• CAD-RADS 5: 100% total occlusion 1

Cardiac MRI:

• Quantitative assessment of ventricular function 7
• Myocardial tissue characterization 7
• Viability assessment 1

Stress Testing:

• Functional assessment of ischemia 1
• Exercise ECG, stress echocardiography, nuclear perfusion imaging 1

Invasive Coronary Angiography (ICA)

• Gold standard for anatomic assessment 1
• Indicated for CAD-RADS 3-5 lesions requiring further evaluation 1

---

Treatment

Medical Management (Cornerstone of Treatment)

Antiplatelet Agents:

• Aspirin and/or P2Y12 inhibitors for thrombosis prevention 3, 5

Anti-Ischemic Medications:

• Beta-blockers - reduce heart rate and myocardial oxygen demand 5
• Calcium channel blockers - vasodilation and heart rate control 5
• Nitrates - vasodilation for symptom relief 5
• Ranolazine - for chronic angina when other agents insufficient; take 500-1000mg twice daily, swallow whole, avoid grapefruit 8, 5

Lipid-Lowering Therapy:

• Statins are fundamental for reducing cardiovascular events 4
• Aggressive lipid management reduces events and should accompany revascularization 6

Risk Factor Modification:

• Hypertension control 1, 4
• Diabetes management 1, 4
• Smoking cessation 1, 4
• Weight reduction and exercise 1, 4

Revascularization

Indications Based on CAD-RADS:

• CAD-RADS 0-2: Preventive therapy and risk factor modification 1
• CAD-RADS 3: Consider functional testing and/or ICA if symptomatic or high-risk features 1
• CAD-RADS 4-5: ICA with revascularization as appropriate 1

Percutaneous Coronary Intervention (PCI):

• Effectively relieves ischemia 6, 4
• Number of procedures declining over past decade despite increasing CAD prevalence 4

Coronary Artery Bypass Grafting (CABG):

• Indicated for left main disease, three-vessel disease, or complex anatomy 4
• Patients increasingly older with more comorbidities, though mortality remains steady 4

Critical Concept: Revascularization effectively relieves ischemia, but attention must extend beyond stenotic lesions to encompass biology of non-stenotic plaques through aggressive medical management. 6

---

Complications

Acute Myocardial Infarction Complications

Mechanical Complications:

• Left ventricular dysfunction and heart failure 1, 3
• Cardiogenic shock 3
• Structural complications (ventricular septal rupture, papillary muscle rupture, free wall rupture) 3
• Left ventricular aneurysm 3

Electrical Complications:

• Arrhythmias - ventricular and supraventricular 7, 3
• Sudden cardiac death 1

Thrombotic Complications:

• Left ventricular thrombus 3
• Arterial embolism 3
• Venous thrombosis and pulmonary embolism 3

Inflammatory Complications:

• Pericardial effusion 3
• Pericarditis 3
• Post-myocardial infarction syndrome (Dressler syndrome) 3

Chronic Complications

Ischemic Cardiomyopathy:

• Progressive left ventricular dysfunction from prior necrosis and/or hibernating myocardium 1
• Reduced ejection fraction indicates worse prognosis 1

Right Ventricular Failure:

• Ventricular interdependence causes left ventricular dysfunction (especially from LAD lesions) to negatively affect right ventricle 7
• Septal dysfunction and geometry changes impair right ventricular function 7
• Chronic increased afterload leads to right ventricular hypertrophy and eventual failure 7

Recurrent Ischemia:

• Disease progression in native vessels or bypass grafts 3
• In-stent restenosis or thrombosis 3

Prognostic Factors Indicating Worse Outcomes

• Reduced left ventricular ejection fraction 1
• Greater number of diseased vessels 1
• More proximal stenosis locations 1
• More extensive ischemia 1
• Impaired functional capacity 1
• Older age 1
• Significant depression 1
• More severe angina 1

Important Clinical Caveat: CAD should be viewed as a dynamic, progressive condition that may destabilize at any moment with development of acute coronary syndrome, requiring both treatment of culprit lesions and rapid stabilization of other vulnerable plaques. 1, 2, 6