Myocardial infarction. Pathogenesis. Classification.

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Myocardial Infarction: Pathogenesis and Classification

Definition

Myocardial infarction (MI) is the death of cardiac muscle due to prolonged ischemia. Roughly 800,000 MIs occur annually in the United States. The overwhelming majority are caused by atherosclerosis of the coronary arteries. - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 511

Pathogenesis

1. Atherosclerotic Background

Nearly all MIs arise on a substrate of coronary atherosclerosis. Atheromatous plaques progressively narrow the lumen and create a vulnerable substrate for acute events. Importantly, the culprit plaque often does not produce a critical (>70%) stenosis beforehand - it is the acute change in the plaque, not the degree of chronic stenosis, that precipitates infarction.

2. Acute Plaque Disruption - the Central Event

The typical sequence of events:

An atheromatous plaque is eroded or suddenly disrupted by endothelial injury, intraplaque hemorrhage, or mechanical forces, exposing subendothelial collagen and necrotic plaque contents to blood.
Platelets adhere, aggregate, and activate, releasing thromboxane A2, ADP, and serotonin - causing further platelet aggregation and vasospasm.
Activation of the coagulation cascade by tissue factor and other mechanisms adds to the growing thrombus.
Within minutes, the thrombus can completely occlude the coronary artery lumen.

Angiography within 4 hours of MI onset demonstrates coronary thrombosis in ~90% of cases. By 12-24 hours (without intervention), only ~60% show thrombosis, because some occlusions clear spontaneously.

3. Non-Atherothrombotic Mechanisms (~10% of Cases)

Vasospasm - with or without atherosclerosis; may be triggered by cocaine, ephedrine, or intrinsic mechanisms
Embolism - from mural thrombus (AF), infective endocarditis vegetations, prosthetic material, or paradoxical emboli via patent foramen ovale
Vasculitis - small intramural vessel inflammation
Hematologic - sickle cell disease, hypercoagulable states
Amyloid deposition in vascular walls

4. Myocardial Response to Ischemia

The outcome depends on severity and duration of blood flow deprivation:

Event	Time
Onset of ATP depletion	Seconds
Loss of contractility	< 2 minutes
ATP reduced to 50% of normal	10 minutes
ATP reduced to 10% of normal	40 minutes
Irreversible cell injury (necrosis)	20-40 minutes
Microvascular injury	> 1 hour

Source: Robbins, Cotran & Kumar - Table 12.4

The first biochemical consequence is cessation of aerobic metabolism within seconds → inadequate high-energy phosphate production (ATP, creatine phosphate) + accumulation of lactic acid. Contractility ceases within ~1 minute. Ultrastructural changes (myofibrillar relaxation, glycogen depletion, mitochondrial swelling) are initially reversible. Only ischemia lasting 20-40 minutes with flow ≤10% of normal produces irreversible necrosis.

5. Wavefront Phenomenon

Irreversible injury begins in the subendocardial zone - this region is most vulnerable because:

It is the last to receive blood from epicardial vessels
It is exposed to higher intramural pressures that impede inflow

With prolonged ischemia, a wavefront of cell death moves centripetally (outward toward the epicardium). A full-thickness (transmural) infarct evolves over 6-12 hours.

6. Reperfusion Injury

Restoration of blood flow salvages ischemic but still-viable myocardium - but can also cause reperfusion injury accounting for up to 50% of final infarct size. Mechanisms include:

Mitochondrial dysfunction - altered permeability, outer membrane rupture, apoptosis
Myocyte hypercontracture - calcium overload causes uncontrolled actin-myosin interaction → cytoskeletal damage
Free radical generation - O2•⁻, H2O2, •OH, peroxynitrite damage membrane proteins and phospholipids within minutes of reperfusion
Leukocyte aggregation - microvascular plugging causing "no-reflow" phenomenon; leukocytes also release proteases/elastases
Platelet and complement activation - endothelial injury

Reperfused infarcts are typically hemorrhagic grossly. Microscopically, irreversibly injured myocytes show contraction band necrosis (intense eosinophilic bands of hypercontracted sarcomeres from calcium influx).

Special states:

Stunned myocardium - prolonged contractile dysfunction after short-term ischemia, recovers over days
Hibernating myocardium - chronically reduced metabolism/function from chronic sublethal ischemia; recovers with revascularization

Morphological Evolution (Classification by Time)

The gross and histologic appearance evolves predictably (Table 12.5 from Robbins):

Time	Gross Features	Light Microscopy	Electron Microscopy
0-0.5 hr (reversible)	None	None	Myofibrillar relaxation, glycogen loss, mitochondrial swelling
0.5-4 hr	None	Usually none; variable waviness of fibers at border	Sarcolemmal disruption; mitochondrial amorphous densities
4-12 hr	Dark mottling (occasional)	Early coagulative necrosis; edema; hemorrhage	-
12-24 hr	Dark mottling	Coagulative necrosis; nuclear pyknosis; myocyte hypereosinophilia; contraction band necrosis; early neutrophilic infiltrate	-
1-3 days	Mottling with yellow-tan center	Coagulative necrosis with loss of nuclei and striations; brisk neutrophilic infiltrate	-
3-7 days	Hyperemic border; central yellow-tan softening	Disintegrating dead myofibers; dying neutrophils; macrophage phagocytosis at border; early granulation tissue	-
7-10 days	Maximally yellow-tan and soft; depressed red-tan margins	Well-developed granulation tissue with prominent vascularization at margins	-
10-14 days	Red-tan margins; yellow-tan center	Active granulation tissue and early collagen deposition	-
2-8 weeks	Gray-white fibrous scar forming	Increased collagen deposition with decreased cellularity	-
>2 months	Complete fibrous scar (white)	Dense collagen scar	-

Classification

I. By Depth of Necrosis (Anatomic / Pathological)

Distribution of transmural vs non-transmural infarcts by coronary artery territory

1. Transmural MI

Necrosis involves the full thickness (or near-full thickness) of the ventricular wall
Results from permanent epicardial vessel occlusion (atherothrombosis)
Associated with STEMI on ECG
A narrow rim (~0.1 mm) immediately beneath the endocardium is preserved by diffusion from the ventricular lumen

2. Subendocardial (Non-transmural) MI

Necrosis limited to the inner one-third to half of the ventricular wall
Results from:
- Transient/partial coronary obstruction (with reperfusion)
- Severe global hypoperfusion (circumferential subendocardial infarct)
Associated with NSTEMI on ECG
Types:
- Regional subendocardial - in the territory of a partially obstructed artery
- Circumferential subendocardial - affects the entire inner ring of the LV (from global hypotension/shock)

3. Microinfarction

Multiple tiny foci from small intramural vessel pathology (microembolism, vasculitis, catecholamine-induced vasospasm)

II. By Coronary Artery Territory (Localization)

Coronary Artery	Frequency	Territory Infarcted
LAD	40-50%	Anterior LV wall near apex; anterior 2/3 of ventricular septum; apex circumferentially
RCA	30-40%	Inferior/posterior LV wall; posterior 1/3 of septum; inferior/posterior RV free wall
LCX	15-20%	Lateral LV wall (except apex)

III. By ECG Pattern (Clinical)

Type	ECG	Pathology
STEMI (ST-elevation MI)	ST elevation → Q waves	Full-thickness (transmural) occlusion; complete coronary occlusion
NSTEMI (Non-ST-elevation MI)	ST depression, T-wave changes; no Q waves	Subendocardial or partial-thickness; troponin elevated without ST elevation
Unstable Angina	Transient ECG changes; no troponin rise	No necrosis; mural thrombus without complete occlusion

IV. By Cause - The Fourth Universal Definition (Types 1-5)

The Universal Definition of Myocardial Infarction (4th edition, 2018) classifies MI into 5 types based on mechanism:

Type	Name	Mechanism
Type 1	Spontaneous MI	Atherosclerotic plaque disruption/erosion with coronary thrombosis
Type 2	MI due to ischemic imbalance	Supply-demand mismatch without plaque rupture (e.g., coronary spasm, anemia, hypotension, tachyarrhythmia, hypertensive crisis)
Type 3	MI causing sudden cardiac death	Death before biomarkers can be obtained; ECG evidence of ischemia
Type 4a	PCI-related MI	MI within 48 hours of percutaneous coronary intervention
Type 4b	Stent thrombosis	Angiographically confirmed stent/scaffold thrombosis
Type 5	CABG-related MI	MI associated with coronary artery bypass grafting

V. By Timing (Clinical)

Acute MI - within 28 days of onset (first 7 days = "recent" MI)
Old/healed MI - scar present, >28 days

Sequelae and Complications

The sequelae of MI are shown in the pathophysiology diagram:

IHD pathophysiology flowchart: coronary artery disease → plaque change → MI → infarct healing, ventricular remodeling, hypertrophy/dilation → chronic ischemic heart disease → CHF → sudden cardiac death

Major complications include:

Ventricular rupture (3-7 days; free wall, VSD, papillary muscle)
Papillary muscle dysfunction/rupture → acute mitral regurgitation
Ventricular aneurysm - fibrous wall, paradoxical pulsation, mural thrombus
Mural thrombus → systemic embolism
Arrhythmias - most common cause of early death (VF)
Pericarditis (Dressler syndrome - weeks later)
Heart failure / cardiogenic shock
Infarct extension or reinfarction

Sources: Robbins, Cotran & Kumar - Pathologic Basis of Disease (pp. 511-519); Robbins & Kumar Basic Pathology (p. 318); Sabiston Textbook of Surgery - Classification of AMI (Fourth Universal Definition)

Can you give me exam oriented concise answer

Myocardial Infarction — Exam-Oriented Concise Answer

Definition

Death of cardiac muscle due to prolonged ischemia (>20-40 min of severe ischemia).

Pathogenesis

The Core Sequence (90% of cases)

Atherosclerotic plaque
        ↓
  Acute plaque disruption (rupture/erosion)
        ↓
  Platelet adhesion → aggregation → activation
  (releases TXA2, ADP, serotonin → vasospasm)
        ↓
  Coagulation cascade activation (tissue factor)
        ↓
  Complete coronary thrombosis
        ↓
  Prolonged ischemia → NECROSIS

Key Points to Remember

Culprit plaque often had <70% stenosis before rupture
Thrombus visible in 90% if angiography done within 4 hrs
~10% of MIs occur without atherothrombosis (vasospasm, embolism, vasculitis, cocaine)

Myocardial Response to Ischemia

Event	Time
Loss of contractility	< 2 min
Reversible injury	Up to 20-30 min
Irreversible necrosis begins	20-40 min
Complete infarction	6-12 hrs

Necrosis starts subendocardially (most vulnerable - last to receive blood, highest intramural pressure)
Progresses outward = wavefront phenomenon

Reperfusion Injury (4 mechanisms - must know)

Mitochondrial dysfunction → apoptosis
Ca²⁺ overload → myocyte hypercontracture → contraction band necrosis
Free radicals (O₂•⁻, H₂O₂, •OH) → membrane damage
Neutrophil aggregation → "no-reflow" phenomenon

Classification

1. By Depth (Anatomical)

Type	Features
Transmural	Full-thickness; permanent occlusion; → STEMI
Subendocardial	Inner 1/3 - 1/2 only; partial/transient occlusion; → NSTEMI
Microinfarction	Tiny foci; small vessel disease, vasospasm

2. By ECG (Clinical)

Type	ECG Change	Mechanism
STEMI	ST elevation → Q waves	Complete transmural occlusion
NSTEMI	ST depression / T changes; no Q waves	Partial/subendocardial; troponin ↑
Unstable angina	Transient changes; no troponin rise	No necrosis

3. By Coronary Territory

Artery	Frequency	Area Infarcted
LAD	40-50%	Anterior LV, anterior septum, apex
RCA	30-40%	Inferior/posterior LV, posterior septum, RV
LCX	15-20%	Lateral LV

4. Universal Definition - Types 1-5 (High-yield)

Type	Cause
Type 1	Spontaneous - plaque rupture + thrombosis
Type 2	Supply-demand mismatch (spasm, anemia, tachycardia, hypotension)
Type 3	Sudden death before biomarkers obtained
Type 4a/b	PCI-related / Stent thrombosis
Type 5	CABG-related

Morphological Evolution (Exam favorite)

Time	Gross	Microscopy
0-4 hr	Nothing visible	Wavy fibers, coagulative necrosis beginning
4-12 hr	Dark mottling	Early coagulative necrosis, edema
12-24 hr	Dark mottling	Pyknotic nuclei, hypereosinophilia, neutrophils begin
1-3 days	Yellow-tan center	Peak neutrophil infiltrate, loss of nuclei/striations
3-7 days	Soft, yellow-tan; red border	Neutrophils dying; macrophages appear; granulation tissue begins
7-10 days	Maximally soft	Granulation tissue prominent
2-8 wks	Gray-white scar forming	Collagen deposition ↑
>2 months	Dense white scar	Complete fibrosis

Mnemomic for neutrophils → macrophages → granulation tissue → scar: "Never Mind Getting Sick" (Neutrophils → Macrophages → Granulation → Scar)

Complications (by timing)

Timing	Complication
0-24 hrs	Arrhythmias (VF) - most common cause of early death
1-3 days	Cardiogenic shock
3-7 days	Free wall rupture (→ tamponade), VSD, papillary muscle rupture (→ acute MR)
Weeks	Ventricular aneurysm, mural thrombus, Dressler syndrome (pericarditis)
Long-term	Chronic heart failure, sudden cardiac death

High-yield one-liners:

Earliest detectable necrosis marker in blood: Troponin (rises 3-4 hrs, peaks 24-48 hrs, persists 7-10 days)
Earliest histologic change: Wavy fibers (0.5-4 hrs)
Earliest gross change: Dark mottling (4-12 hrs; TTC stain can show pale unstained zone)
Reperfusion hallmark: Contraction band necrosis
"No-reflow" caused by: Neutrophil microvascular plugging

Chronic lymphocytic leukemia. Etiology. Pathogenesis. Laboratory diagnostics. Main clinical syndromes. Treatment principles. Prognosis. Concise exam oriented answer

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Chronic Lymphocytic Leukemia (CLL) — Exam-Oriented Concise Answer

Definition

Monoclonal proliferation of mature, functionally incompetent B lymphocytes (CD5+ B cells) in blood, bone marrow, lymph nodes, spleen, and liver. Defined by absolute lymphocyte count ≥5 × 10⁹/L of clonal B cells. CLL and Small Lymphocytic Lymphoma (SLL) are the same disease - different presentations.

Etiology & Risk Factors

Factor	Detail
Age	Median diagnosis age 70; rare <40 yrs
Sex	Male:Female = 2:1
Race	Most common in Caucasians; rare in Asians
Genetics	Most familial leukemia - 8.5x risk in first-degree relatives; >40 low-penetrance SNPs
Agent Orange	Officially recognized risk (Vietnam/Middle East veterans)
Radiation	NOT associated (unlike most other leukemias)
Infections	No established viral link
Precursor state	Monoclonal B-cell lymphocytosis (MBL) → ~1-2%/year progression to CLL

High-yield: CLL is the most common leukemia in the Western world. It is NOT linked to radiation.

Pathogenesis

Cell of Origin

Mature B cell, immunophenotypically resembling a memory B cell (CD5+/CD23+).

Core Mechanisms

1. B-Cell Receptor (BCR) Signaling - Central driver

CLL cells show tonic BCR activation → antiapoptotic signaling → tumor survival
BCR drives NF-kB and PI3K/AKT pathways → proliferation + resistance to apoptosis
BTK (Bruton's Tyrosine Kinase) is key downstream mediator → target of ibrutinib

2. IGHV Mutation Status - Key prognostic divider

IGHV Status	Frequency	Course
Mutated (≥2% from germline)	~60%	Indolent, good prognosis
Unmutated (<2% from germline)	~40%	Aggressive, rapid progression, shorter survival

3. Cytogenetic Abnormalities (detected by FISH)

Abnormality	Frequency	Prognosis
del(13q14)	50-55%	Favorable (disrupts miR-15a/16-1 → BCL2 overexpression)
Trisomy 12	20%	Intermediate
del(11q22) - ATM gene	20%	Unfavorable - bulky nodes
del(17p13) - TP53 gene	10%	Worst prognosis - therapy resistant

4. Antiapoptosis via BCL-2

miR-15a and miR-16-1 (deleted in del13q) normally suppress BCL-2
Loss → BCL-2 overexpression → CLL cells accumulate (fail to die, not rapid proliferation)
BCL-2 is the target of venetoclax

5. Key Somatic Mutations (adverse)

TP53 mutation (independent of del17p) → chemorefractoriness
NOTCH1 - associated with unmutated IGHV, Richter transformation
SF3B1 - adverse; splicing factor
ATM - DNA damage response defect

Laboratory Diagnostics

Peripheral Blood Smear (Pathognomonic finding)

CLL peripheral blood smear showing small mature lymphocytes and a smudge/smear cell

Absolute lymphocytosis ≥5 × 10⁹/L
Small, mature-appearing lymphocytes with clumped ("soccer ball") chromatin, scant cytoplasm
Smudge/smear cells (Gumprecht shadows) - fragile CLL cells crushed during slide preparation - pathognomonic
± anemia, thrombocytopenia in advanced disease

Flow Cytometry (Immunophenotype) - ESSENTIAL for diagnosis

Marker	CLL	Significance
CD5	+	Aberrant (normally T-cell marker)
CD19, CD23	+	B-cell lineage
CD20	+ (dim)	Dimly positive
Surface Ig	+ (dim)	Single light chain (κ or λ) - monoclonal
CD10, Cyclin D1	negative	Differentiates from follicular, mantle cell
LEF1	+	Differentiates from other small B-cell lymphomas

Mnemonic for CLL phenotype: "5, 19, 23, dim 20" = CD5+, CD19+, CD23+, CD20 dim

Bone Marrow Biopsy

Diffuse/nodular/interstitial infiltration of small lymphocytes
Pattern matters: diffuse = worse prognosis

Key Laboratory Tests

Test	Purpose
FISH panel	del(13q), del(11q), del(17p), trisomy 12 - prognosis
IGHV mutational status	Key prognostic marker
TP53 mutation (NGS)	Guides therapy (BTK inhibitor vs chemo)
β2-microglobulin	Elevated = worse prognosis (tumor burden)
Serum immunoglobulins	Hypogammaglobulinemia (→ infection risk)
Stimulated karyotype	Complex karyotype = poor prognosis
Direct Coombs test	Screen for AIHA (autoimmune hemolytic anemia)

Main Clinical Syndromes

1. Asymptomatic Lymphocytosis (most common presentation)

~70-80% diagnosed incidentally on routine CBC
No symptoms, no treatment required

2. Lymphoproliferative Syndrome

Lymphadenopathy - cervical, axillary, inguinal; non-tender, rubbery
Splenomegaly - left upper quadrant fullness, early satiety
Hepatomegaly (less common)

3. Bone Marrow Failure / Cytopenias

Anemia - normocytic (marrow infiltration) OR hemolytic (AIHA - 10-25% of patients)
Thrombocytopenia - marrow infiltration OR immune (ITP)
Neutropenia - infection risk

4. Immunodeficiency Syndrome

Hypogammaglobulinemia - recurrent bacterial infections (sinusitis, pneumonia, UTIs)
Impaired T-cell function → viral and fungal infections
Infections = leading cause of death (~30-50% of deaths)

5. Autoimmune Complications

AIHA (autoimmune hemolytic anemia) - most common
ITP (immune thrombocytopenic purpura)
Pure red cell aplasia (rare)

6. Richter Transformation (~5-10%)

Transformation to diffuse large B-cell lymphoma (most common) or Hodgkin lymphoma
Presents: rapidly enlarging nodes, fever, weight loss, rising LDH
Median survival after transformation: 3-6 months

Staging

Rai Staging System (USA)

Stage	Features	Risk
0	Lymphocytosis only	Low
1	+ Lymphadenopathy	Intermediate
2	+ Splenomegaly/hepatomegaly	Intermediate
3	+ Anemia (Hb <11 g/dL)	High
4	+ Thrombocytopenia (<100,000/μL)	High

Binet Staging System (Europe)

Stage	Features	Median Survival
A	<3 lymphoid areas involved; no anemia/thrombocytopenia	>10 years
B	≥3 lymphoid areas; no anemia/thrombocytopenia	5-7 years
C	Anemia (Hb <10) and/or thrombocytopenia (<100k)	2-3 years

Treatment Principles

When to Treat (Indications - NOT stage alone)

Hb <10 g/dL or platelets <100,000/μL (marrow failure)
Symptomatic/bulky lymphadenopathy (>10 cm) or splenomegaly
Constitutional symptoms (B symptoms: fever, night sweats, weight loss)
Lymphocyte doubling time <6 months
Difficult-to-control AIHA or ITP

Important: Lymphocytosis alone is NOT an indication to treat.

First-Line Treatment (Current Standard - targeted therapy era)

For most patients (del17p/TP53 wild-type or mutant):

Agent	Mechanism	Notes
Ibrutinib (BTK inhibitor)	Blocks BTK → BCR signaling → apoptosis	First-line; oral; continuous
Acalabrutinib	2nd-gen BTK inhibitor	Better tolerability than ibrutinib
Venetoclax + obinutuzumab	BCL-2 inhibitor + anti-CD20	Fixed duration (12 months); preferred for fit patients
Zanubrutinib	3rd-gen BTK inhibitor	Fewer off-target effects

For del(17p) / TP53 mutation (chemo-resistant):

BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) - preferred
Venetoclax combinations
Avoid chemoimmunotherapy (FCR) - ineffective

Older chemoimmunotherapy (now 2nd/3rd line for fit, mutated IGHV, low-risk):

FCR: Fludarabine + Cyclophosphamide + Rituximab
BR: Bendamustine + Rituximab

Supportive Treatment

IVIg - for recurrent infections with hypogammaglobulinemia
Vaccinations - influenza, COVID-19, pneumococcal, zoster (recombinant; avoid live)
Steroids - for AIHA/ITP
Allogeneic SCT - considered in young patients with high-risk disease

Prognosis

Factor	Favorable	Unfavorable
IGHV	Mutated (≥2%)	Unmutated (<2%)
FISH	del(13q) alone	del(17p), del(11q)
TP53	Wild-type	Mutated
Karyotype	Normal / simple	Complex (≥3 abnormalities)
ZAP-70	Negative	Positive
CD38	<30%	≥30%
β2-microglobulin	Normal	Elevated
Lymphocyte doubling time	>12 months	<6 months
Stage	Rai 0-1 / Binet A	Rai 3-4 / Binet C

Overall survival: 5-year OS ~92% (2015 data); markedly improved with targeted therapies. ~30% of patients never need treatment.

Leading causes of death: Infections (~30-50%), Richter transformation, second malignancies, progressive CLL.

High-Yield One-Liners

CLL = most common leukemia in the Western world
NOT linked to radiation (unique among leukemias)
Smudge cells on PBS = pathognomonic
Immunophenotype: CD5+, CD19+, CD23+, CD20 dim, surface Ig dim
del(13q) = best prognosis; del(17p)/TP53 = worst prognosis
BCL-2 overexpression → cells accumulate (don't proliferate rapidly)
Treatment target: BTK (ibrutinib) and BCL-2 (venetoclax)
Richter transformation = CLL → DLBCL; very poor prognosis
AIHA = most common autoimmune complication

Sources: Harrison's Principles of Internal Medicine 22E (2025); Goldman-Cecil Medicine; Henry's Clinical Diagnosis and Management by Laboratory Methods

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