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Ischemic Heart Disease (IHD)

Definition

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Epidemiology

• Leading cause of death in higher-income nations; accounts for ~7.5 million deaths worldwide per year
• ~800,000 Americans experience an MI annually; roughly half die
• IHD mortality in the USA has declined ~50% since peaking in 1963 — attributed to smoking cessation, BP/DM control, statins, aspirin, CCUs, thrombolysis, PCI, and CABG
• The trend is threatened by aging populations and the global obesity epidemic

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Pathogenesis

1. Atherosclerosis (Chronic Fixed Occlusion)

• Plaques occluding < 70% of coronary lumen → typically asymptomatic
• ≥ 70% stenosis ("critical stenosis") → symptomatic on exertion (stable angina)
• > 90% stenosis → may cause symptoms at rest

2. Acute Plaque Change + Thrombosis

1. Atheromatous plaque is eroded or disrupted by endothelial injury, intraplaque hemorrhage, or mechanical forces → subendothelial collagen and necrotic contents exposed
2. Platelets adhere, aggregate, and activate → release thromboxane A₂, ADP, serotonin → further aggregation and vasospasm
3. Coagulation activated by tissue factor exposure → thrombus grows
4. Within minutes, thrombus may completely occlude the lumen

Angiography within 4 hours of MI shows thrombotic occlusion in ~90% of cases; by 12–24 hours only 60% even without intervention (some clear spontaneously).

3. Non-atherosclerotic Causes (minority)

• Increased demand: tachycardia, hypertension
• Reduced supply: hypotension/shock, anemia, CO poisoning, severe hypoxemia

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Clinical Syndromes

Vasospastic (Prinzmetal) Angina

• Occurs at rest, often at night; due to coronary artery spasm (not fixed stenosis)
• ECG: transient ST elevation during pain
• Responds to nitrates and calcium channel blockers

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Myocardial Response to Ischemia

• If flow restored before irreversible injury: myocardium salvageable ("stunned myocardium" may be dysfunctional for days)
• Reperfusion injury: contraction bands, free radical damage (but reperfusion is still always net beneficial)

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Morphological Changes in MI (Gross & Histological Timeline)

Note: Reperfused MI appears haemorrhagic (bleeding from damaged vessels) with contraction bands microscopically — a hallmark of reperfusion injury.

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Diagnosis

ECG

• STEMI: ST elevation in leads corresponding to infarcted territory; eventual Q waves (transmural)
• NSTEMI: ST depression, T-wave inversions; no Q waves
• Stable angina: normal at rest, may show ST depression on exercise stress test

Cardiac Biomarkers

Imaging & Other Tests

• ECG stress test: first-line for stable CAD evaluation
• Coronary CTA: anatomical; excellent negative predictive value (SCOTT-Heart trial: associated with reduced MI at 5 years)
• Echocardiography: wall motion abnormalities; LV function (EF)
• Radionuclide perfusion (SPECT/PET): functional ischemia
• Coronary angiography: gold standard; allows simultaneous intervention

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Management

Stable Angina / Chronic CAD

• Antiplatelet: Aspirin 75–100 mg/day (cornerstone)
• Beta-blockers: reduce myocardial O₂ demand; first-line for angina
• Nitrates: sublingual GTN for acute relief; long-acting for prophylaxis
• Calcium channel blockers: amlodipine/diltiazem — especially for vasospastic angina
• Statins: LDL-lowering; plaque stabilization (target LDL < 1.8 mmol/L for high risk)
• ACE inhibitors/ARBs: reduce cardiovascular events, especially if LV dysfunction or DM

• PCI (Percutaneous Coronary Intervention): balloon angioplasty + drug-eluting stent; preferred for single/double vessel disease
• CABG (Coronary Artery Bypass Grafting): preferred for left main disease, triple-vessel disease, LV dysfunction (EF < 35%), or diabetes with multi-vessel disease

ACS (NSTEMI / Unstable Angina)

• Dual antiplatelet therapy (DAPT): Aspirin + P2Y₁₂ inhibitor (clopidogrel, ticagrelor, or prasugrel)
• Anticoagulation: LMWH (enoxaparin) or fondaparinux or UFH
• Beta-blocker, statin, ACE inhibitor
• Early invasive strategy (angiography within 24–72 h) for high-risk NSTEMI (GRACE score, troponin positive, dynamic ECG changes)

STEMI — Emergency Management

Time is myocardium — aim: Door-to-balloon time < 90 minutes

• Primary PCI — treatment of choice; superior to thrombolysis if available within 90–120 min
• Thrombolysis (alteplase, tenecteplase) if PCI unavailable within 120 min; contraindicated in recent surgery, stroke, active bleeding
• Aspirin + P2Y₁₂ inhibitor + anticoagulation

• IV beta-blocker (if haemodynamically stable)
• Nitrates (not in inferior MI with RV involvement — may drop BP)
• Morphine for pain
• High-intensity statin

• DAPT for 12 months, then aspirin lifelong
• ACE inhibitor (especially if EF < 40%)
• Beta-blocker
• Aldosterone antagonist (eplerenone) if EF < 35% + symptoms of HF
• Cardiac rehabilitation
• ICD implantation if EF < 35% after ≥ 40 days

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Complications of MI

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Risk Factors

• Hypertension (most important)
• Dyslipidaemia (elevated LDL, low HDL)
• Diabetes mellitus
• Smoking
• Obesity / metabolic syndrome
• Physical inactivity
• Diet (saturated fat, trans fats)
• Psychosocial stress

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Key Points Summary

1. IHD results from coronary perfusion-demand mismatch; atherosclerosis is responsible in > 90%
2. Plaque rupture + thrombosis is the trigger for most acute events (MI, SCD)
3. Irreversible myocyte necrosis occurs after 20–40 minutes of ischemia
4. Troponin I/T are the gold-standard biomarkers; rise 2–4h, peak ~24h
5. ACS = unstable angina + NSTEMI + STEMI; each requires risk stratification and early treatment
6. STEMI demands primary PCI within 90 minutes (door-to-balloon)
7. Post-MI therapy: DAPT, beta-blocker, ACE-I, statin, cardiac rehab; ICD if EF < 35%
8. Major complications: arrhythmia (immediate), mechanical rupture (days 3–7), aneurysm/CHF (late)

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Pathogenesis of Atherosclerosis

Definition

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The "Response to Injury" Hypothesis (Contemporary/Accepted Theory)

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Step-by-Step Pathogenesis

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STEP 1 — Endothelial Injury and Dysfunction

• Increased vascular permeability
• Enhanced leukocyte adhesion (upregulation of VCAM-1, ICAM-1, E-selectin)
• Altered (pro-inflammatory) gene expression
• Reduced nitric oxide (NO) production → loss of vasodilation and anti-inflammatory signalling

1. Hemodynamic disturbances (turbulent, non-laminar blood flow) — explains why plaques localise at branch points, ostia of vessels, and the posterior abdominal aorta. Laminar flow induces the transcription factor KLF-2, which turns on atheroprotective genes; turbulent flow suppresses this.
2. Hypercholesterolaemia — most important biochemical cause
3. Hypertension — mechanical shear stress
4. Cigarette smoke toxins
5. Inflammatory cytokines (e.g., TNF-α)
6. Homocysteinaemia, infections, immune reactions

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STEP 2 — Lipoprotein Accumulation and Oxidation

• LDL cholesterol accumulates in the intima (subendothelial space) due to increased EC permeability
• LDL is oxidised by oxygen free radicals generated locally by macrophages and ECs → oxidised LDL (oxLDL)
• Chronic hyperlipidaemia accelerates NO decay (via free radical production), further impairing vasodilation
• oxLDL is cytotoxic to ECs and SMCs, and is a powerful pro-inflammatory stimulus
• Cholesterol crystals also form, contributing to local inflammation

Evidence for lipid role: Plaques consist predominantly of cholesterol; familial hypercholesterolaemia (defective LDL receptors) causes MI by age 20; lowering LDL with statins slows plaque progression and reduces cardiovascular events.

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STEP 3 — Monocyte Recruitment and Foam Cell Formation

• Dysfunctional ECs express adhesion molecules (VCAM-1) → circulating monocytes adhere to the endothelium
• Monocytes transmigrate into the intima, driven by chemokines (especially MCP-1)
• In the intima, monocytes differentiate into macrophages
• Macrophages engulf oxLDL via scavenger receptors (bypassing normal LDL receptor regulation — unregulated uptake)
• Lipid-laden macrophages become foam cells
• Accumulation of foam cells produces the earliest grossly visible lesion: the fatty streak (yellow, flat, intimal streak)

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STEP 4 — Platelet Adhesion and Activation

• EC injury → platelets adhere to exposed subendothelial collagen
• Activated platelets release:
  • PDGF (Platelet-Derived Growth Factor) → stimulates SMC migration and proliferation
  • TGF-β → promotes collagen synthesis
  • Thromboxane A₂ → vasoconstriction and further platelet aggregation

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STEP 5 — Smooth Muscle Cell (SMC) Proliferation and ECM Production

• Growth factors from platelets, macrophages, and ECs (especially PDGF, FGF, TGF-β) recruit SMCs from the media into the intima
• SMCs undergo phenotypic change from contractile to synthetic type
• Intimal SMCs proliferate and synthesise extracellular matrix (ECM) — collagen, proteoglycans, elastin
• This forms the fibrous cap overlying the lipid core
• T lymphocytes are also recruited → release cytokines (IFN-γ) that further activate macrophages

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STEP 6 — Plaque Development (Fibrofatty Atheroma)

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STEP 7 — Plaque Complication and Rupture

• Thin fibrous cap
• Large lipid/necrotic core
• Dense inflammatory infiltrate (macrophages + T cells)
• Few SMCs (reduced collagen synthesis)

• Macrophages secrete matrix metalloproteinases (MMPs) → collagen degradation → cap thinning
• IFN-γ (from T cells) inhibits SMC collagen synthesis
• Net effect: collagen breakdown > synthesis → mechanically weak cap

1. Plaque rupture → thrombogenic plaque contents exposed → platelet aggregation + thrombus → complete occlusion → STEMI / MI
2. Plaque erosion/ulceration → subendothelial basement membrane exposed → partial thrombosis → NSTEMI / unstable angina
3. Intraplaque haemorrhage → sudden expansion of plaque volume → rapid luminal narrowing
4. Embolisation → distal microinfarcts

Important: Most plaques that rupture cause acute MI had only mild-to-moderate stenosis (not "critical" stenosis) before rupture — the degree of stenosis does not predict rupture risk; plaque composition does.

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Morphological Progression (Summary)

Normal intima
    ↓
Fatty streak (foam cells, earliest lesion, seen even in young children)
    ↓
Intermediate lesion (more lipid + SMCs)
    ↓
Fibrofatty plaque (fibrous cap + lipid core) → stable angina when >70% stenosis
    ↓
Complicated plaque (rupture / calcification / haemorrhage / thrombosis)
    ↓
Acute coronary syndrome / Stroke / Peripheral vascular disease

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Role of Inflammation — Key Exam Point

• C-reactive protein (CRP) — elevated even in patients without hyperlipidaemia; adds prognostic information above Framingham risk score
• Statin drugs reduce cardiovascular risk partly through anti-inflammatory effects (independent of LDL-lowering), including upregulation of KLF-2
• Inflammatory cells (macrophages, T cells) are present throughout plaque evolution
• Clonal haematopoiesis of indeterminate potential (CHIP) — mutated monocyte clones with pro-inflammatory phenotype markedly increase atherosclerosis risk with aging

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Key Points for Exam

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ATHEROSCLEROSIS — Pathogenesis

For General Medicine Final Year MBBS Exam

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INTRODUCTION

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THEORIES OF PATHOGENESIS

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THE "RESPONSE TO INJURY" HYPOTHESIS (Current Accepted Theory)

"Atherosclerosis is a chronic inflammatory and healing response of the arterial wall to endothelial injury." — Robbins, Cotran & Kumar

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STEP-BY-STEP PATHOGENESIS

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Stage 1 — Endothelial Injury and Dysfunction

• ↑ Vascular permeability
• ↑ Leukocyte adhesion (upregulation of VCAM-1, ICAM-1, selectins)
• ↓ Nitric oxide (NO) production → loss of vasodilatory and anti-inflammatory protection
• Pro-thrombotic tendency

• Hemodynamic turbulence — most important physical cause
• Hypercholesterolaemia — most important biochemical cause
• Hypertension, cigarette smoke toxins, diabetes, homocysteinaemia, inflammatory cytokines (TNF-α)

Atheroprone sites: Branch points, ostia of vessels, posterior abdominal aorta — all areas of turbulent, non-laminar flow. Laminar flow induces the transcription factor KLF-2 which turns on atheroprotective genes; turbulence suppresses KLF-2, making these sites prone to atherogenesis.

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Stage 2 — Lipoprotein Accumulation and Oxidation

• ↑ EC permeability → LDL accumulates in the intima
• LDL is oxidised by oxygen free radicals from macrophages and ECs → oxidised LDL (oxLDL)
• oxLDL is central to atherogenesis because it:
  • Is cytotoxic to ECs and SMCs
  • Stimulates release of chemokines (MCP-1) attracting more monocytes
  • Upregulates adhesion molecules on ECs
  • Accelerates NO decay → further endothelial dysfunction
  • Promotes foam cell formation via macrophage scavenger receptors

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Stage 3 — Monocyte Adhesion, Migration, and Foam Cell Formation

• Dysfunctional ECs express VCAM-1 and selectins → circulating monocytes adhere
• Monocytes transmigrate into the intima driven by chemokine MCP-1 (Monocyte Chemotactic Protein-1)
• In the intima → monocytes differentiate into macrophages
• Macrophages engulf oxLDL via scavenger receptors (CD36, SR-A) — this is unregulated (unlike normal LDL receptor-mediated uptake which is subject to negative feedback)
• Lipid-laden macrophages = Foam cells
• Accumulation of foam cells → Fatty streak — the earliest visible lesion of atherosclerosis (yellow, flat intimal streaks; seen even in aortas of children)

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Stage 4 — Platelet Adhesion and Activation

• EC injury exposes subendothelial collagen → platelet adhesion and activation
• Activated platelets release:
  • PDGF (Platelet-Derived Growth Factor) → stimulates SMC proliferation and migration
  • TGF-β → promotes collagen and ECM synthesis
  • Thromboxane A₂ → vasoconstriction, further platelet aggregation

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Stage 5 — Smooth Muscle Cell (SMC) Migration and Proliferation

• Growth factors (PDGF, FGF, TGF-β) from platelets, macrophages, and ECs recruit SMCs from the media into the intima
• SMCs undergo phenotypic change: contractile → synthetic phenotype
• Intimal SMCs proliferate and synthesise collagen, elastin, proteoglycans → forming the fibrous cap
• T lymphocytes are also recruited → release IFN-γ activating macrophages further

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Stage 6 — Formation of the Atherosclerotic Plaque

Glagov phenomenon: Early in plaque development, the vessel wall remodels outward (compensatory enlargement) to preserve lumen size. Eventually this compensation is exhausted → lumen compromise.

Critical stenosis: ≥ 70–75% reduction in luminal cross-sectional area → sufficient to cause tissue ischaemia at rest or exertion.

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Stage 7 — Plaque Complication and Rupture (Clinically Most Important)

• Thin fibrous cap
• Large lipid/necrotic core (> 40% of plaque volume)
• Dense inflammatory infiltrate (macrophages + T cells at the shoulder region)
• Few SMCs → reduced collagen synthesis → mechanically weak cap

• Macrophages secrete Matrix Metalloproteinases (MMPs) → degrade collagen
• T cells secrete IFN-γ → inhibit SMC collagen synthesis
• Net result: collagen degradation > synthesis → thin, rupture-prone cap

⚠️ Critical exam point: Most plaques that rupture and cause MI had only mild-to-moderate stenosis (< 70%) before rupture — the plaque composition matters more than its size. Standard angiography cannot predict which plaques will rupture.

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SUMMARY FLOWCHART

Risk Factors (HTN, hyperlipidaemia, smoking, DM, etc.)
         ↓
  Endothelial Injury / Dysfunction
         ↓
  ↑ Permeability, ↑ Adhesion molecules, ↓ NO
         ↓
  LDL accumulation in intima → oxidised to oxLDL
         ↓
  Monocyte adhesion & migration → Macrophages
         ↓
  Macrophages engulf oxLDL (via scavenger receptors)
         ↓
  Foam cells → FATTY STREAK (earliest lesion)
         ↓
  Platelet adhesion → PDGF → SMC migration & proliferation
         ↓
  Fibrous cap formation → FIBROFATTY PLAQUE
         ↓
  MMP activity (macrophages) → cap thinning
         ↓
  VULNERABLE PLAQUE → Rupture → Thrombosis
         ↓
  ACUTE CORONARY SYNDROME / STROKE / PVD

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CLINICAL CONSEQUENCES OF ATHEROSCLEROSIS

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PREVENTION AND TREATMENT (Exam-relevant)

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HIGH-YIELD POINTS FOR THE EXAM

1. Theory = "Response to Injury" — chronic inflammatory response
2. Cornerstone = Endothelial injury/dysfunction
3. Earliest lesion = Fatty streak (foam cells only; reversible)
4. Foam cells = oxLDL-laden macrophages via scavenger receptors
5. Fibrous cap = Made by smooth muscle cells (collagen synthesis)
6. Cap degradation = MMPs from macrophages + IFN-γ inhibiting SMC collagen synthesis
7. Atheroprone sites = Areas of turbulent flow (branch points, ostia)
8. Critical stenosis = ≥ 70–75% luminal narrowing
9. Plaque rupture → Thrombosis → ACS (most plaques that rupture were < 70% stenosis)
10. CRP = Marker of inflammation; adds prognostic information beyond Framingham risk score

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Atherosclerosis — Pathogenesis

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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DEFINITION

"Epicardial coronary arteries are the major site of atherosclerotic disease." — Harrison's Principles of Internal Medicine, 22e, Chapter 285

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HARRISON'S PERSPECTIVE ON PATHOGENESIS

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STEP-BY-STEP PATHOGENESIS

1. Endothelial Dysfunction — The Initial Event

• Local control of vascular tone
• Maintenance of an anti-thrombotic surface
• Control of inflammatory cell adhesion and diapedesis

• Inappropriate vasoconstriction
• Luminal thrombus formation
• Abnormal monocyte and platelet interaction with the activated endothelium

"The loss of these defenses leads to inappropriate constriction, luminal thrombus formation, and abnormal interactions between blood cells, especially monocytes and platelets, and the activated vascular endothelium." — Harrison's 22e, Ch. 285 — Coronary Atherosclerosis

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2. Lipoprotein Accumulation → Foam Cell Formation

• LDL enters the dysfunctional intima and becomes oxidised → oxLDL
• oxLDL triggers release of chemokines and adhesion molecules promoting inflammation
• Monocytes are recruited → differentiate into macrophages
• Macrophages accumulate cholesterol → become foam cells (lipid-laden macrophages)
• Other activated macrophages release pro-inflammatory mediators: TNF, IL-1, oxygen/nitrogen free radicals, eicosanoids, and prothrombotic factors

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3. Smooth Muscle Cell Proliferation → Plaque Formation

• Growth factors from macrophages, platelets, and ECs → SMC migration from media into intima
• SMCs proliferate and synthesise collagen, proteoglycans, elastin → forming the fibrous cap
• This results in subintimal collections of fat, smooth muscle cells, fibroblasts, and intercellular matrix = the atherosclerotic plaque

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4. Progressive Stenosis

• When a stenosis is severe, distal resistance vessels maximally dilate to maintain flow
• A pressure gradient develops across the stenosis → post-stenotic pressure falls
• Myocardial blood flow becomes dependent on distal coronary pressure
• Ischaemia is precipitated by increased O₂ demand (exercise, stress, tachycardia)

"When the resistance vessels are maximally dilated, myocardial blood flow becomes dependent on the pressure in the coronary artery distal to the obstruction." — Harrison's 22e, Ch. 285

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5. Plaque Rupture / Erosion → Acute Coronary Syndrome (Most Clinically Important)

"STEMI usually occurs when coronary blood flow decreases abruptly after a thrombotic occlusion of a coronary artery previously affected by atherosclerosis." — Harrison's 22e, Ch. 286 — STEMI

• STEMI occurs when the surface of an atherosclerotic plaque is disrupted (rupture or erosion), exposing contents to blood
• Plaques prone to disruption have:
  • Rich lipid core
  • Thin fibrous cap
  • Expansive remodelling
  • Neovascularisation (angiogenesis)
  • Plaque haemorrhage
  • Adventitial inflammation
  • "Spotty" pattern of calcification

1. Plaque disrupts → subendothelial content exposed
2. Initial platelet monolayer forms at disruption site
3. Agonists (collagen, ADP, epinephrine, serotonin) activate platelets → release thromboxane A₂ (vasoconstriction + further aggregation)
4. Platelet GP IIb/IIIa receptor activates → binds fibrinogen → platelet cross-linking and aggregation
5. Tissue factor exposed from damaged ECs → activates factors VII and X → prothrombin → thrombin → fibrinogen → fibrin
6. Thrombus of platelet aggregates + fibrin strands occludes the artery → STEMI

Note: Slowly developing high-grade stenoses typically do not precipitate STEMI because collateral circulation develops over time. STEMI results from rapid thrombosis at a site of plaque disruption.

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6. Collateral Circulation

• Chronic severe coronary narrowing → development of collateral vessels
• When well developed, collaterals can maintain myocardial viability at rest but not during increased demand
• If stenosis occurs slowly, smaller adjacent vessels enlarge to partially compensate

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HARRISON'S RISK FACTORS FOR ATHEROSCLEROSIS

• Older age
• Diabetes mellitus
• Hypertension (most significant — target BP < 130/80 mmHg; SPRINT trial: SBP < 120 mmHg reduces MI/stroke by 43%)
• Tobacco smoking
• Elevated LDL cholesterol
• Low HDL cholesterol
• Lipoprotein (a) excess

• Obesity
• Hypertriglyceridaemia
• Hyperfibrinogenaemia
• Homocystinuria
• Physical inactivity
• Prior TIA/stroke (for cerebrovascular disease)

• Small, dense LDL particles + hypertriglyceridaemia + low HDL
• Associated with: ↑ fibrinogen, ↑ PAI-1 (plasminogen activator inhibitor-1), ↑ factor VII, platelet hyperactivity
• Creates both atherogenic and thrombotic risk

• Does not cause atherosclerosis
• Reflects ongoing inflammation that may accelerate the process
• JUPITER trial (Harrison's reference): Patients with elevated CRP but LDL < 130 mg/dL treated with rosuvastatin showed 51% reduction in primary stroke (HR 0.49)

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ANTIATHEROSCLEROTIC THERAPY (Harrison's)

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SUMMARY — HARRISON'S KEY POINTS

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ACUTE MYOCARDIAL INFARCTION (AMI)

Etiopathogenesis, Clinical Features, Investigations & Management

Final Year MBBS — General Medicine | Harrison's 22e

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PART 1: LEFT-SIDED CHEST PAIN — CAUSES (Differential Diagnosis)

"The pain of STEMI can simulate pain from acute pericarditis, pulmonary embolism, acute aortic dissection, costochondritis, and gastrointestinal disorders." — Harrison's 22e

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ACUTE MYOCARDIAL INFARCTION (AMI)

DEFINITION

MI = acute myocardial injury + clinical evidence of ischaemia + rise and/or fall of cardiac troponin (cTn) with at least one value above 99th percentile URL + at least ONE of:

• Symptoms of ischaemia
• New ischaemic ECG changes
• New pathological Q waves
• Imaging evidence of new wall motion abnormality / loss of viable myocardium
• Coronary thrombus on angiography/autopsy

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PART 2: ETIOPATHOGENESIS

Types of MI (Harrison's Classification)

Pathogenesis of Type 1 MI (Plaque Rupture → Thrombosis)

• Atherosclerotic plaque with rich lipid core + thin fibrous cap ruptures or erodes
• Rupture-prone features: expansive remodelling, neovascularisation, plaque haemorrhage, adventitial inflammation, "spotty" calcification
• Injury facilitated by: cigarette smoking, hypertension, lipid accumulation, inflammation

• Plaque contents exposed to blood → initial platelet monolayer at rupture site
• Agonists (collagen, ADP, epinephrine, serotonin) → platelet activation
• Release of thromboxane A₂ → potent vasoconstriction + further platelet activation
• GP IIb/IIIa receptor conformation change → binds fibrinogen → platelet cross-linking and aggregation

• Tissue factor exposed from damaged ECs → activates Factors VII and X
• Prothrombin → Thrombin → Fibrinogen → Fibrin
• Thrombin autoamplifies the cascade
• Culprit artery occluded by platelet aggregates + fibrin strands = coronary thrombus

• Complete occlusion → cessation of blood flow → ischaemia → infarction
• Irreversible necrosis begins after 20–40 minutes of sustained ischaemia

1. Territory supplied by affected vessel
2. Whether occlusion is complete
3. Duration of coronary occlusion
4. Collateral blood supply
5. Myocardial oxygen demand at time of occlusion
6. Spontaneous thrombus lysis
7. Adequacy of reperfusion when restored

Important: Slowly developing high-grade stenoses usually do NOT precipitate STEMI (collaterals develop); STEMI results from rapid thrombosis at a site of acute plaque disruption.

Precipitating Factors (Harrison's)

• Vigorous physical exercise
• Emotional stress
• Medical/surgical illness
• Circadian pattern — clusters in morning hours within hours of awakening (adrenergic surge)

Rare Causes of AMI (Non-Atherosclerotic)

• Coronary emboli
• Congenital coronary abnormalities
• Coronary artery spasm (vasospasm)
• Spontaneous coronary artery dissection (SCAD)
• Cocaine abuse
• Hypercoagulable states / collagen vascular disease

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PART 3: CLINICAL FEATURES

Symptoms

• Deep and visceral in quality
• Described as: heavy, squeezing, crushing (occasionally stabbing or burning)
• Location: Central chest and/or epigastrium
• Radiation: Left arm, left shoulder, neck, jaw (less commonly: back, abdomen, occipital area — never below umbilicus)
• Duration: > 30 minutes (does NOT subside with rest or GTN — unlike angina)
• Onset: Often at rest; if during exertion, does NOT resolve with cessation of activity

• Diaphoresis (profuse sweating — highly suggestive)
• Nausea and vomiting
• Anxiety and sense of impending doom
• Dyspnoea (from LV dysfunction / pulmonary oedema)
• Palpitations (arrhythmias)
• Syncope / sudden cardiac death (from VF)

"The combination of substernal chest pain persisting for > 30 min and diaphoresis strongly suggests STEMI." — Harrison's 22e

• Diabetics (autonomic neuropathy)
• Elderly patients
• Women
• May present only as dyspnoea, weakness, confusion, or unexplained hypotension

• Dyspnoea
• Epigastric discomfort
• Nausea
• Profound weakness

Physical Signs (Harrison's)

Killip Classification (Severity of LV Failure in AMI)

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PART 4: INVESTIGATIONS

1. Electrocardiogram (ECG) — Most Important Initial Investigation

• ST depression and/or T-wave inversion (no ST elevation, no Q waves)

2. Cardiac Biomarkers

Troponin levels rise 20–50 times the upper reference limit (99th percentile) in classic MI. Recanalization causes early peak ("washout" phenomenon) — useful to confirm reperfusion.

• WBC: Rises within hours, peaks 12,000–15,000/μL, persists 3–7 days
• ESR: Rises more slowly, peaks first week, may remain elevated 1–2 weeks
• CRP: Rises with inflammation

3. Cardiac Imaging

• Regional wall motion abnormalities — almost universally present
• LV ejection fraction (EF) — critical for prognosis and therapy decisions
• Detect: RV infarction, LV aneurysm, pericardial effusion, LV thrombus, MR (papillary rupture), VSD
• Doppler: identifies mitral regurgitation, VSD

• Gold standard for identifying the culprit lesion
• Guides primary PCI — simultaneous diagnostic and therapeutic

• Pulmonary oedema (Kerley B lines, bat-wing pattern, pleural effusion)
• Cardiomegaly
• Exclude aortic dissection, pneumothorax

• Radionuclide scanning (SPECT/PET): perfusion defects in ischaemic zones
• MRI: Late gadolinium enhancement → infarct size and viability; not first-line in acute setting

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PART 5: MANAGEMENT

A. IMMEDIATE MANAGEMENT (First 30 Minutes — "MONA + Heparin")

Time is myocardium — Goal: Door-to-balloon < 90 minutes (primary PCI)

B. REPERFUSION THERAPY (Core of STEMI Management)

• Balloon angioplasty + drug-eluting stent (DES) to culprit artery
• Superior to thrombolysis: higher patency, lower reocclusion, less bleeding
• Goal: Door-to-balloon < 90 minutes

• Previous haemorrhagic stroke (absolute)
• Ischaemic stroke within 3 months
• Active internal bleeding
• Suspected aortic dissection
• Recent major surgery (< 3 weeks)
• Severe uncontrolled hypertension (SBP > 180)

C. PHARMACOTHERAPY (In-Hospital)

D. CCU (Coronary Care Unit) Monitoring

• Continuous cardiac monitoring (arrhythmia detection)
• Haemodynamic monitoring (BP, urine output)
• Bed rest first 6–12 hours; gradual mobilisation by 24 h
• Discharge in 3–5 days if uncomplicated

E. COMPLICATIONS AND THEIR MANAGEMENT

F. SECONDARY PREVENTION (Long-Term)

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SUMMARY — HIGH-YIELD EXAM POINTS

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PATHOGENESIS OF ACUTE MYOCARDIAL INFARCTION

Harrison's 22e + Robbins, Cotran & Kumar — Final Year MBBS

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DEFINITION

"MI is defined as the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischaemia." — Universal Definition of MI (4th edition, 2018), cited in Harrison's 22e

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OVERVIEW — TWO-HIT CONCEPT (Harrison's)

The overlap of these two promotes hypercoagulability + hypofibrinolysis, especially in diabetics.

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STEP-BY-STEP PATHOGENESIS

STEP 1 — Atherosclerotic Plaque (The Substrate)

• Over years, atherosclerosis silently narrows coronary arteries
• A vulnerable (unstable) plaque has:
  • Large lipid-rich necrotic core (> 40% of plaque volume)
  • Thin fibrous cap (< 65 µm)
  • Dense inflammatory infiltrate (macrophages, T-cells at shoulder region)
  • Expansive remodelling, neovascularisation, plaque haemorrhage, adventitial inflammation, "spotty" calcification
• Key point: Most plaques causing STEMI did NOT have critical (> 70%) stenosis before rupture — it is plaque composition, not size, that determines rupture risk

"Slowly developing, high-grade coronary artery stenoses do not typically precipitate STEMI because of the development of a rich collateral network over time." — Harrison's 22e

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STEP 2 — Plaque Disruption (The Trigger)

• Intrinsic: Macrophages secrete MMPs (Matrix Metalloproteinases) → collagen degradation → cap weakening; T-cell IFN-γ → inhibits SMC collagen synthesis → net thinning
• Extrinsic: Adrenergic surge (morning awakening, exercise, stress) → BP spike → shear forces → cap tears
• Risk factors: cigarette smoking, hypertension, lipid accumulation, systemic inflammation

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STEP 3 — Platelet Activation and Aggregation

1. Subendothelial collagen + necrotic plaque contents exposed to blood
2. Platelets adhere to exposed collagen (via GP Ib–vWF axis) → form initial monolayer
3. Platelet activation by agonists: collagen, ADP, epinephrine, serotonin
4. Activated platelets release Thromboxane A₂ (TxA₂):
   • Potent vasoconstriction → further narrows lumen
   • Amplifies further platelet activation
   • Creates resistance to fibrinolysis
5. GP IIb/IIIa receptor undergoes conformational change → high affinity for fibrinogen → fibrinogen bridges two platelets → platelet cross-linking and aggregation

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STEP 4 — Coagulation Cascade Activation → Thrombus Formation

1. Tissue factor (expressed in vascular smooth muscle cells and macrophages of the plaque) is exposed at the rupture site
2. Tissue factor activates Factor VII → Factor X (extrinsic pathway)
3. Prothrombin → Thrombin (via Factor Xa + Va)
4. Thrombin → converts Fibrinogen → Fibrin strands
5. Thrombin autoamplification — fluid-phase and clot-bound thrombin further accelerate cascade
6. Fibrin strands + platelet aggregates + trapped RBCs → occlusive coronary thrombus forms within minutes

"The culprit coronary artery eventually becomes occluded by a thrombus containing platelet aggregates and fibrin strands." — Harrison's 22e

• Complete occlusion → STEMI (transmural infarction)
• Partial/stuttering occlusion → NSTEMI / Unstable Angina (subendocardial infarction)

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STEP 5 — Myocardial Response to Ischaemia

• ↓ ATP → failure of Na⁺/K⁺ ATPase → cell swelling
• Lactic acid accumulation → intracellular acidosis → enzyme dysfunction
• ↑ Intracellular Ca²⁺ → mitochondrial dysfunction → cell death
• Sarcolemmal rupture → intracellular proteins (Troponin, CK-MB, myoglobin) leak into circulation → forms the basis of cardiac biomarkers

• Necrosis begins in the subendocardium first (most vulnerable — furthest from epicardial supply + highest wall stress)
• Progresses outward like a wavefront toward the epicardium with prolonged ischaemia
• Reperfusion within 20–40 min can abort this wavefront and salvage myocardium

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STEP 6 — Reperfusion and Its Consequences

• Restores flow → salvages myocardium still alive at margins of infarct
• Limits infarct size; improves LV function and survival

• Despite being net beneficial, reperfusion can cause:
  • Contraction band necrosis (hypercontraction of myofibrils — hallmark microscopically)
  • Free radical damage (reactive oxygen species burst on reperfusion)
  • Stunning — post-ischaemic myocardium that is alive but dysfunctional for days after reperfusion

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STEP 7 — Causes of MI Without Atherothrombosis (~10% of cases)

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EVIDENCE SUPPORTING THROMBOTIC PATHOGENESIS

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SUMMARY FLOWCHART — EXAM READY

RISK FACTORS (HTN, DM, Smoking, Hyperlipidaemia, Age, Family Hx)
        ↓
VULNERABLE ATHEROSCLEROTIC PLAQUE
(thin cap + large lipid core + inflammation)
        ↓
PLAQUE RUPTURE or EROSION
(MMPs degrade cap; adrenergic surge triggers mechanical disruption)
        ↓
Subendothelial collagen + plaque contents exposed to blood
        ↓
PLATELET ADHESION → ACTIVATION → TxA₂ released
        ↓
GP IIb/IIIa activation → fibrinogen binding → PLATELET AGGREGATION
        ↓
TISSUE FACTOR exposed → Extrinsic pathway activated
        ↓
Prothrombin → Thrombin → Fibrinogen → FIBRIN
        ↓
OCCLUSIVE CORONARY THROMBUS
        ↓
Complete → STEMI            Partial → NSTEMI / UA
        ↓
CESSATION OF BLOOD FLOW → Area at risk
        ↓
Seconds: ATP depletion, lactic acid ↑
< 2 min: Loss of contractility
20–40 min: IRREVERSIBLE NECROSIS begins
        ↓
SUBENDOCARDIAL NECROSIS → WAVEFRONT → TRANSMURAL INFARCTION (6–12 hr)
        ↓
Sarcolemmal rupture → TROPONIN/CK-MB leak into blood (diagnostic biomarkers)

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HIGH-YIELD EXAM POINTS

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ETIOPATHOGENESIS OF ACUTE MI

(3-mark answer — ~10–12 lines)

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ETIOLOGY

• Coronary vasospasm (cocaine, Prinzmetal angina)
• Coronary embolism (AF, infective endocarditis)
• Type 2 MI — supply-demand mismatch (severe anaemia, tachycardia, shock)

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PATHOGENESIS

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Key exam lines:

• Most MI caused by plaque rupture + thrombosis, not by critical stenosis
• Irreversible necrosis begins at 20–40 minutes
• GP IIb/IIIa + Tissue factor are the key molecular triggers