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Pathogenesis | Ischemic Heart Disease | Blood Vessels and Heart | Special Pathology (Special Patho) | 4th Year (Fourth Year) | MBBS | Detailed Free Notes

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1. Core Concept: What Is Ischemic Heart Disease?

Ischemic heart disease represents a spectrum of myocardial disorders caused by an imbalance between myocardial oxygen supply and demand.

Exam anchor line:
Ischemic heart disease results from reduced coronary blood flow leading to myocardial ischemia and hypoxia.

2. Fundamental Pathophysiological Principle (Very High-Yield)

2.1 Oxygen Supply–Demand Mismatch

IHD develops when:

  • Myocardial oxygen supply is reduced, or

  • Myocardial oxygen demand is increased, or

  • Both occur simultaneously

2.2 Determinants of Myocardial Oxygen Supply

  • Coronary blood flow

  • Oxygen content of blood

  • Duration of diastole (coronary perfusion occurs mainly in diastole)

2.3 Determinants of Myocardial Oxygen Demand

  • Heart rate

  • Myocardial contractility

  • Wall tension (Laplace’s law)

  • Blood pressure

3. Etiological Classification of Ischemic Heart Disease

3.1 Major Causes

  1. Atherosclerotic coronary artery disease (≈ 90–95%)

  2. Coronary artery spasm

  3. Coronary thrombosis

  4. Coronary embolism

  5. Reduced oxygen-carrying capacity of blood

  6. Increased myocardial demand

👉 Atherosclerosis is the single most important cause and forms the backbone of pathogenesis.

4. Atherosclerosis of Coronary Arteries — Central Mechanism

4.1 Why Coronary Arteries Are Vulnerable

  • Coronary arteries are:

    • Medium-sized muscular arteries

    • Subjected to high pulsatile pressure

  • End-artery-like behavior:

    • Limited collateral circulation

4.2 Sites Commonly Affected (Exam Favourite)

  • Left anterior descending (LAD) artery — most commonly affected

  • Right coronary artery (RCA)

  • Left circumflex artery (LCX)

4.3 Distribution Pattern (High-Yield Table)

Artery Approximate Frequency
LAD ~40–50%
RCA ~30–40%
LCX ~15–20%

5. Step-wise Development of Atherosclerotic Lesion in Coronary Arteries

5.1 Endothelial Dysfunction (Initiating Event)

  • Caused by:

    • Smoking

    • Hypertension

    • Hyperlipidemia

    • Diabetes mellitus

Effects:

  • Increased endothelial permeability

  • Reduced nitric oxide production

  • Enhanced leukocyte adhesion

5.2 Lipid Accumulation

  • LDL cholesterol enters arterial wall

  • Oxidized LDL accumulates in intima

  • Triggers inflammatory response

5.3 Foam Cell Formation

  • Monocytes migrate into intima

  • Transform into macrophages

  • Ingest oxidized LDL

  • Form foam cells

  • Produce fatty streaks

5.4 Formation of Fibro-Fatty Plaque

  • Smooth muscle cell migration from media

  • Proliferation in intima

  • Deposition of:

    • Collagen

    • Proteoglycans

  • Formation of fibrous cap over lipid core

6. Progressive Luminal Narrowing (Chronic Ischemia)

6.1 Critical Stenosis Concept

  • 70% narrowing:

    • Causes ischemia on exertion

  • 90% narrowing:

    • Causes ischemia at rest

6.2 Clinical Correlation

  • Stable angina:

    • Fixed atherosclerotic narrowing

  • Symptoms appear when:

    • Oxygen demand exceeds supply during exertion

7. Plaque Instability — Turning Point in Pathogenesis

Not all plaques behave the same.

7.1 Stable Plaques

  • Thick fibrous cap

  • Small lipid core

  • Cause:

    • Chronic ischemia

    • Stable angina

7.2 Vulnerable (Unstable) Plaques (Very High-Yield)

  • Thin fibrous cap

  • Large lipid core

  • Rich in inflammatory cells

  • Prone to:

    • Rupture

    • Erosion

8. Plaque Rupture and Thrombosis (Acute Ischemia)

8.1 Mechanism

  • Plaque rupture exposes:

    • Thrombogenic lipid core

  • Platelet adhesion and aggregation

  • Activation of coagulation cascade

  • Formation of occlusive thrombus

8.2 Consequences

  • Sudden cessation of blood flow

  • Acute myocardial ischemia

  • Myocardial infarction if prolonged

9. Coronary Thrombosis — Final Common Pathway

  • Superimposed thrombosis on atherosclerotic plaque

  • Converts:

    • Chronic stable disease → acute coronary syndrome

10. PART 1 CONSOLIDATED TAKEAWAY

  • Ischemic heart disease results from oxygen supply–demand mismatch

  • Atherosclerosis of coronary arteries is the primary cause

  • Endothelial dysfunction initiates disease

  • Progressive plaque formation causes chronic ischemia

  • Plaque rupture with thrombosis causes acute events

  • LAD artery is most commonly affected

Written And Compiled By Sir Hunain Zia (AYLOTI), World Record Holder With 154 Total A Grades, 7 Distinctions And 11 World Records For Educate A Change MBBS 4th Year (Fourth Year / Professional) Special Pathology Free Material

11. Non-Atherosclerotic Causes of Myocardial Ischemia (Important Add-On)

Although atherosclerosis accounts for most cases, IHD can occur without significant fixed coronary obstruction.

Exam anchor line:
Ischemic heart disease may result from functional or systemic factors even in the absence of critical coronary atherosclerosis.

12. Coronary Artery Spasm (Prinzmetal / Variant Angina)

12.1 Definition

  • Transient, reversible constriction of coronary artery

  • Causes:

    • Sudden reduction in coronary blood flow

    • Myocardial ischemia at rest

12.2 Pathogenesis

  • Hyper-reactivity of coronary smooth muscle

  • Endothelial dysfunction → reduced nitric oxide

  • Increased vasoconstrictors:

    • Endothelin

    • Thromboxane A₂

12.3 Triggers

  • Smoking

  • Cocaine use

  • Emotional stress

  • Cold exposure

12.4 Clinical Correlation

  • Occurs at rest, often early morning

  • Transient ST-segment elevation

  • No fixed plaque obstruction required

12.5 Exam Note

Coronary artery spasm can cause ischemia even with angiographically normal coronary arteries.

13. Coronary Thrombosis Without Severe Atherosclerosis

13.1 Mechanism

  • Mild atherosclerotic plaque

  • Sudden plaque erosion

  • Endothelial denudation

  • Platelet aggregation and thrombosis

13.2 Clinical Significance

  • Explains:

    • Acute coronary syndrome in younger patients

    • MI with minimal plaque burden

14. Coronary Embolism (Rare but Exam-Relevant)

14.1 Sources of Emboli

  • Left atrial thrombus (atrial fibrillation)

  • Ventricular mural thrombus

  • Infective endocarditis vegetations

  • Prosthetic heart valves

14.2 Pathogenesis

  • Embolus lodges in coronary artery

  • Sudden occlusion

  • Acute myocardial ischemia

14.3 Key Differentiator

  • No underlying coronary atherosclerosis

  • Sudden onset ischemia

15. Reduced Oxygen-Carrying Capacity of Blood (Supply-Side Failure)

15.1 Severe Anemia

  • Reduced hemoglobin concentration

  • Decreased oxygen delivery to myocardium

  • Ischemia despite normal coronary arteries

15.2 Carbon Monoxide Poisoning

  • CO binds hemoglobin with high affinity

  • Reduces oxygen availability

  • Causes myocardial hypoxia

15.3 Clinical Importance

Myocardial ischemia can occur with normal coronary arteries if blood oxygen content is reduced.

16. Hypotension and Shock States

16.1 Mechanism

  • Reduced coronary perfusion pressure

  • Global myocardial ischemia

16.2 Common Settings

  • Septic shock

  • Cardiogenic shock

  • Massive hemorrhage

17. Demand-Side Factors Increasing Myocardial Oxygen Requirement

Even normal coronary arteries may fail to meet excessive myocardial demand.

18. Increased Heart Rate (Tachycardia)

18.1 Dual Effect

  • Increases oxygen demand

  • Shortens diastole → reduces coronary perfusion

18.2 Clinical Settings

  • Fever

  • Thyrotoxicosis

  • Arrhythmias

  • Anxiety

19. Left Ventricular Hypertrophy (LVH)

19.1 Pathogenesis

  • Increased muscle mass

  • Increased wall tension

  • Higher oxygen requirement

19.2 Supply–Demand Mismatch

  • Capillary density does not increase proportionally

  • Leads to subendocardial ischemia

19.3 Common Causes

  • Hypertension

  • Aortic stenosis

20. Increased Afterload (Laplace’s Law)

20.1 Mechanism

  • Wall tension ∝ pressure × radius

  • Increased blood pressure → increased wall tension

  • Increased oxygen demand

20.2 Clinical Correlation

  • Hypertension predisposes to ischemia even without severe CAD

21. Role of Inflammation in IHD (Modern Concept — Very High-Yield)

21.1 Atherosclerosis as an Inflammatory Disease

  • Chronic inflammation drives:

    • Plaque progression

    • Plaque instability

21.2 Cellular Mediators

  • Macrophages

  • T lymphocytes

  • Cytokines (IL-1, TNF-α)

21.3 Effect on Plaque Stability

  • Degradation of fibrous cap

  • Increased risk of rupture

  • Promotion of thrombosis

22. Endothelial Dysfunction — Central Integrator

22.1 Normal Endothelial Functions

  • Vasodilatation (via nitric oxide)

  • Antithrombotic surface

  • Anti-inflammatory signaling

22.2 Dysfunctional Endothelium

  • Reduced NO

  • Increased adhesion molecules

  • Increased thrombogenicity

22.3 Consequences

  • Vasoconstriction

  • Platelet activation

  • Inflammation

  • Accelerated atherosclerosis

23. Microvascular Dysfunction (Small Vessel Disease)

23.1 Definition

  • Dysfunction of:

    • Intramyocardial arterioles

  • Seen in:

    • Diabetes mellitus

    • Hypertension

    • Elderly

23.2 Clinical Importance

  • Angina with normal epicardial coronaries

  • Often called:

    • Microvascular angina

24. Subendocardial Vulnerability (Pathophysiological Insight)

24.1 Why Subendocardium Is Affected First

  • Highest wall stress

  • Compressed during systole

  • Last area to receive blood during diastole

24.2 Clinical Correlation

  • Subendocardial ischemia is most common

  • Leads to:

    • Non-ST elevation MI

    • Demand-related ischemia

25. PART 2 CONSOLIDATED TAKEAWAY

  • IHD can occur without fixed coronary obstruction

  • Coronary spasm causes transient ischemia

  • Emboli and thrombosis can acutely occlude coronaries

  • Anemia and hypotension reduce oxygen supply

  • Tachycardia, LVH and hypertension increase oxygen demand

  • Inflammation and endothelial dysfunction drive plaque instability

  • Subendocardium is most vulnerable to ischemia

Written And Compiled By Sir Hunain Zia (AYLOTI), World Record Holder With 154 Total A Grades, 7 Distinctions And 11 World Records For Educate A Change MBBS 4th Year (Fourth Year / Professional) Special Pathology Free Material

26. Spectrum of Ischemic Syndromes — Mechanistic Continuum

IHD is not a single entity but a continuum produced by the severity, duration, and reversibility of ischemia.

Exam anchor line:
The clinical manifestations of ischemic heart disease depend on the duration and severity of myocardial ischemia.

27. Angina Pectoris — Transient, Reversible Ischemia

27.1 Core Mechanism

  • Temporary mismatch between oxygen supply and demand

  • No irreversible myocyte necrosis

27.2 Stable Angina (Fixed Obstruction)

  • Cause:

    • Stable atherosclerotic plaque

    • Fixed luminal narrowing (≥70%)

  • Trigger:

    • Exertion

    • Emotional stress

  • Relief:

    • Rest

    • Nitrates

  • Pathogenesis:

    • Demand exceeds supply → transient subendocardial ischemia

27.3 Unstable Angina (Plaque Instability)

  • Cause:

    • Plaque rupture/erosion

    • Non-occlusive thrombus

  • Occurs:

    • At rest or minimal exertion

  • Pathogenesis:

    • Intermittent thrombosis + vasoconstriction

  • Significance:

    • Pre-infarction state

27.4 Variant (Prinzmetal) Angina

  • Cause:

    • Coronary artery spasm

  • Occurs:

    • At rest

    • Early morning

  • Pathogenesis:

    • Transient severe vasoconstriction → transmural ischemia

  • ECG:

    • Transient ST elevation

28. Myocardial Infarction — Prolonged, Irreversible Ischemia

28.1 Core Pathogenetic Event

  • Sustained ischemia (>20–30 minutes) causes:

    • Irreversible myocyte injury

    • Coagulative necrosis

28.2 Mechanism of Coronary Occlusion

  • Plaque rupture or erosion

  • Superimposed thrombus

  • Complete or near-complete arterial occlusion

28.3 Subendocardial vs Transmural Infarction

Feature Subendocardial MI Transmural MI
Ischemia Partial/prolonged Complete/prolonged
Territory Inner 1/3–1/2 Full thickness
ECG ST depression ST elevation
Pathogenesis Supply–demand mismatch Acute occlusion

29. Time-Dependent Evolution of Ischemic Injury (Very High-Yield)

29.1 Reversibility Window

  • <20 minutes:

    • Reversible injury

  • 20–40 minutes:

    • Onset of irreversible injury

  • 40 minutes:

    • Progressive necrosis

29.2 Wavefront Phenomenon (Exam Favourite)

  • Necrosis begins in:

    • Subendocardium

  • Progresses toward:

    • Epicardium

  • Complete transmural infarction evolves over:

    • 6–12 hours (if occlusion persists)

Exam anchor line:
Myocardial necrosis progresses as a wavefront from subendocardium to epicardium.

30. Cellular Events in Ischemic Myocyte Injury

30.1 Early Reversible Changes

  • ATP depletion

  • Switch to anaerobic glycolysis

  • Lactic acidosis

  • Impaired relaxation (diastolic dysfunction)

30.2 Irreversible Injury

  • Mitochondrial damage

  • Sarcolemmal disruption

  • Calcium influx

  • Activation of proteases and phospholipases

  • Cell death (necrosis)

31. Reperfusion Injury — Double-Edged Sword

Reperfusion saves myocardium but may paradoxically worsen injury.

31.1 Mechanisms of Reperfusion Injury

  • Oxygen-derived free radicals

  • Calcium overload

  • Mitochondrial permeability transition

  • Inflammation and neutrophil infiltration

31.2 Morphological Consequences

  • Contraction band necrosis

  • Endothelial swelling

  • Capillary plugging (no-reflow phenomenon)

31.3 Clinical Correlation

  • Occurs after:

    • Thrombolysis

    • Angioplasty

  • Limits full myocardial salvage

32. Stunning and Hibernation — Functional Ischemic States

32.1 Myocardial Stunning

  • Transient post-ischemic contractile dysfunction

  • Occurs despite:

    • Restored blood flow

  • Due to:

    • Free radical injury

    • Calcium dysregulation

  • Reversible over hours–days

32.2 Myocardial Hibernation

  • Chronic adaptive down-regulation of contractility

  • Due to:

    • Persistently reduced blood flow

  • Viable myocardium

  • Function improves after revascularization

33. Electrical Instability and Sudden Cardiac Death (SCD)

33.1 Mechanistic Basis

  • Acute ischemia alters:

    • Membrane ion gradients

    • Action potential duration

  • Leads to:

    • Ventricular arrhythmias

33.2 Common Arrhythmias

  • Ventricular fibrillation (most common cause of SCD)

  • Ventricular tachycardia

33.3 Timing

  • Often occurs:

    • Within first hour of MI

    • Sometimes without prior symptoms

34. Microvascular Dysfunction & No-Reflow

34.1 Mechanism

  • Endothelial swelling

  • Microthrombi

  • Neutrophil plugging

34.2 Clinical Impact

  • Limits benefit of reperfusion

  • Worsens infarct size

  • Predicts poor prognosis

35. OSCE Framing — Pathogenesis Station

OSCE Tasks

  • Explain:

    • Why LAD infarcts are common

    • Why subendocardium is most vulnerable

  • Diagram:

    • Wavefront necrosis

    • Plaque rupture → thrombosis

36. Viva Voce — High-Yield Questions

Q1. Why does ischemia affect subendocardium first?
A. Highest wall stress and least perfusion during systole.

Q2. Mechanism of unstable angina?
A. Plaque rupture with non-occlusive thrombosis.

Q3. Define reperfusion injury.
A. Myocardial injury caused by restoration of blood flow after ischemia.

Q4. Cause of sudden cardiac death in IHD?
A. Ventricular fibrillation due to electrical instability.

Q5. What is myocardial stunning?
A. Transient post-ischemic contractile dysfunction with restored perfusion.

37. Examiner Traps (PART 3)

  • Saying ischemia always causes necrosis

  • Ignoring demand-side ischemia

  • Forgetting wavefront progression

  • Missing reperfusion injury

  • Confusing stunning with infarction

38. FINAL CONSOLIDATED TAKEAWAY — PATHOGENESIS OF IHD

  • IHD arises from oxygen supply–demand mismatch

  • Atherosclerosis with plaque rupture drives acute events

  • Duration of ischemia determines reversibility

  • Necrosis progresses from subendocardium outward

  • Reperfusion can both salvage and injure myocardium

  • Electrical instability explains sudden cardiac death

Written And Compiled By Sir Hunain Zia (AYLOTI), World Record Holder With 154 Total A Grades, 7 Distinctions And 11 World Records For Educate A Change MBBS 4th Year (Fourth Year / Professional) Special Pathology Free Material

Hunain Zia

Hunain Zia has previously achieved considerable success in the high-school educational stream, gaining a massive 154 Total A Grades and 7 Major Distinctions, a process in which he broke/ set 11 different world records, including the most A grades ever achieved, most subjects ever appeared in, most distinctions, gaining distinctions across two separate boards (Pearson Edexcel and CAIE) within the same year/ ever, and even 19 hours of constant examination. All records stand intact today. Hunain pursued his Honors Accounting Degree from the prestigious Bentley University, and then completed an LLB (in Honors) from University of London. Currently, he manages multiple social and commercial projects, has founded digital streams and works tirelessly in the education sector.

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