Myocardial infarction in detail

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Myocardial Infarction - Comprehensive Review

1. Definition

Myocardial infarction (MI) is necrosis of cardiac muscle resulting from sustained ischemia. The 2018 joint task force of U.S. and European Cardiology groups defines it as "the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischemia."

Robbins & Kumar Basic Pathology calls it "necrosis of the heart muscle resulting from ischemia"
Roughly 800,000 individuals in the United States experience an MI each year - nearly one MI every 40 seconds - causing almost 400,000 deaths annually
~605,000 new AMIs per year in the U.S. (Harrison's, 22nd Ed.)

2. Epidemiology

Feature	Detail
Age	~10% occur before age 40; 45% before age 65
Sex	Men > women during reproductive years; gap narrows after menopause
Menopause	Declining estrogen accelerates CAD; IHD is the #1 cause of death in older women
In-hospital mortality	STEMI ~9%; NSTEMI ~6%; overall <7% with modern treatment
Out-of-hospital STEMI	~1/3 die before reaching hospital, usually from arrhythmia within 1 hour
1-year mortality post-AMI	~15%; ~4x higher in patients >75 years

3. Classification

By ECG Pattern

STEMI (ST-Elevation MI): Complete occlusion; full-thickness (transmural) risk; requires immediate reperfusion
NSTEMI (Non-ST-Elevation MI): Incomplete occlusion; subendocardial/non-transmural; elevated troponins without ST elevation
Unstable Angina (UA): Plaque disruption with ischemia but no troponin elevation

By Depth

Transmural infarction: Full thickness necrosis; corresponds to STEMI pattern
Subendocardial infarction: Limited to inner 1/3 of myocardium; most susceptible due to highest intramural compressive pressure and furthest from epicardial vessels

Universal Classification (ESC/ACC Types)

Type	Mechanism
Type 1	Spontaneous MI from plaque rupture/erosion with thrombosis
Type 2	Ischemia due to supply/demand mismatch (e.g., spasm, anemia, tachycardia)
Type 3	Sudden cardiac death before biomarkers can be obtained
Type 4	PCI-related MI
Type 5	CABG-related MI

4. Etiology and Risk Factors

Primary cause (>90%): Atherosclerotic coronary artery disease

The remaining ~10% include:

Coronary vasospasm (Prinzmetal angina; cocaine/ephedrine use)
Embolism - from mural thrombus in AF, infective endocarditis vegetations, prosthetic valves, or paradoxical emboli via PFO
Vasculitis of small intramyocardial arterioles
Amyloid deposition in vessel walls
Sickle cell disease (stasis)
Aortic stenosis with marked hypertrophy
Dissection of a coronary artery
Profound hypotension/shock

Modifiable risk factors (accelerate atherosclerosis):

Cigarette smoking
Hypertension
Hyperlipidemia (especially LDL elevation)
Diabetes mellitus
Obesity
Physical inactivity

Non-modifiable: Age, male sex, family history

5. Pathogenesis

Step-by-Step Sequence (Typical STEMI)

Plaque disruption: An atheromatous plaque is eroded or ruptured by endothelial injury, intraplaque hemorrhage, or mechanical forces - exposing subendothelial collagen and necrotic plaque contents to blood. Plaques most prone to rupture have a rich lipid core and thin fibrous cap.
Platelet activation: Platelets adhere, aggregate, and are activated - releasing thromboxane A2, ADP, and serotonin - causing further platelet aggregation and vasospasm.
Coagulation cascade: Tissue factor exposure activates coagulation, adding to the growing thrombus. The glycoprotein IIb/IIIa receptor converts to a high-affinity state for fibrinogen, enabling platelet cross-linking and aggregation.
Complete occlusion: Within minutes, the thrombus can evolve to completely occlude the coronary artery lumen.

Evidence: Angiography within 4 hours of MI onset demonstrates coronary thrombosis in ~90% of cases. At 12-24 hours, only 60% show thrombus (some clear spontaneously).

Cellular Response to Ischemia

Time After Occlusion	Event
Seconds	Aerobic metabolism ceases; creatine phosphate and ATP production fails; lactic acid accumulates
~1 minute	Myocardial contractility ceases (before cell death)
Minutes	Ultrastructural changes: myofibrillar relaxation, glycogen depletion, mitochondrial swelling
20-30 min	Irreversible necrosis begins (if flow <10% of normal)
6-12 hours	Necrosis becomes complete
Hours to days	Sarcolemmal disruption - intracellular proteins leak into circulation (basis of biomarkers)

Key: Cardiac muscle requires ~1.3 mL O2/100g/min just to stay alive. If ≥15-30% of normal resting coronary flow is preserved, the muscle will not die. The central core of a large infarct often has near-zero collateral flow and dies.

Why Subendocardium First?

The subendocardial region is most vulnerable because:

It is the last zone to receive blood from epicardial vessels
It experiences the highest intramural compressive pressure during systole
It has the highest oxygen consumption

With prolonged ischemia, a wavefront of cell death moves centripetally from the subendocardium outward toward the epicardium.

6. Morphological Changes (Gross and Microscopic)

Gross Pathology

Time	Gross Appearance
0-12 hours	Usually normal; may stain negative with TTC (triphenyl tetrazolium chloride)
12-24 hours	Subtle pale/yellow area; hyperemia
1-3 days	Yellow-tan, soft, increasingly well-demarcated; surrounding hyperemic rim
3-7 days	Yellow-tan, soft center; maximal softening (highest rupture risk)
1-2 weeks	Yellow-tan center, red-gray vascularized margins
2-8 weeks	Progressively gray-white
>2 months	Dense white fibrous scar

Microscopic Pathology

Time	Microscopic Changes
0-0.5 hr	Reversible: wavy fibers, glycogen depletion, mitochondrial swelling
0.5-4 hr	Coagulation necrosis begins; "contraction bands" in reperfused areas
4-12 hr	Early coagulative necrosis; pyknotic nuclei; edema; hemorrhage
12-24 hr	Coagulative necrosis with loss of nuclei; neutrophil infiltration begins
1-3 days	Dense neutrophil infiltration; myofiber "ghosts" (outlines without nuclei)
3-7 days	Macrophage infiltration; phagocytosis of dead cells; granulation tissue at margins
1-3 weeks	Vascular granulation tissue; collagen deposition begins
>3 weeks	Dense fibrous scar forms

7. Clinical Features

Symptoms

Feature	Details
Chest pain	Severe, crushing, pressure-like; classically substernal; radiation to left arm, jaw, shoulder, or back
Duration	>20 minutes (vs. stable angina which resolves in <20 min)
Associated symptoms	Diaphoresis, nausea/vomiting, dyspnea, lightheadedness, sense of impending doom
Silent MI	Common in diabetics, elderly, and women; no chest pain; presents with dyspnea or fatigue

Atypical presentations (more common in women, diabetics, elderly):

Epigastric pain / indigestion
Back or jaw pain without chest pain
Exertional dyspnea
Syncope or palpitations

Physical Examination

Pallor, diaphoresis, anxiety
Tachycardia or bradycardia (inferior MI with vagal activation)
Hypotension (cardiogenic shock) or hypertension (pain/catecholamine surge)
S4 gallop (reduced LV compliance)
S3 gallop (large infarct with LV dysfunction)
Mitral regurgitation murmur (papillary muscle dysfunction)
Pericardial friction rub (Dressler syndrome or early fibrinous pericarditis)
Jugular venous distension (right ventricular infarction)

8. Diagnosis

ECG Changes

The ECG is the pivotal diagnostic and triage tool - distinguishing STEMI from NSTEMI.

Three major ECG abnormalities in acute MI (Ganong's Physiology):

Defect in Infarcted Cells	Current Flow	ECG Change (in leads over infarct)
Rapid repolarization	Out of infarct	ST segment elevation
Decreased resting membrane potential	Into infarct	TQ segment depression (manifested as ST elevation)
Delayed depolarization	Out of infarct	ST segment elevation

Evolutionary ECG changes:

Hyperacute T waves (minutes): Tall, peaked T waves (earliest change)
ST elevation (minutes to hours): Hallmark of acute transmural injury; reciprocal ST depression in opposite leads
Q waves (hours to days): Pathologic Q waves (>40 ms wide, >25% of R amplitude) indicate transmural necrosis - electrically silent dead tissue
T-wave inversion (days to weeks): Persists for weeks
Normalization: ST segments normalize over days; Q waves often persist permanently

Leads and corresponding territory:

ECG Leads	Territory	Artery
V1-V4	Anterior wall	LAD
I, aVL, V5-V6	Lateral wall	LCx
II, III, aVF	Inferior wall	RCA (usually)
V1, tall R in V1-V2	Posterior wall	RCA or LCx
V1 ST elevation + right-sided leads	Right ventricle	RCA

Biomarkers

Marker	Rise	Peak	Normalizes	Notes
Cardiac Troponin I/T	2-4 hr	24-48 hr	7-14 days	Most sensitive and specific; gold standard
CK-MB	3-6 hr	12-24 hr	2-3 days	Useful for reinfarction detection
Myoglobin	1-2 hr	4-8 hr	24 hr	Earliest but non-specific

Troponin levels rise to 20-50x the upper reference limit in classic MI
Early reperfusion causes earlier peak of biomarkers (rapid washout from infarct zone)
WBC: Polymorphonuclear leukocytosis (12,000-15,000/µL) peaks within 3-7 days
ESR: Rises more slowly, peaks in first week, may stay elevated for 1-2 weeks

Imaging

Echocardiography: Wall motion abnormalities almost universally present; useful for LV function assessment, complications detection
Coronary angiography: Definitive - shows occlusion site; allows immediate PCI
Cardiac MRI: Gold standard for infarct size quantification; late gadolinium enhancement
Nuclear imaging (SPECT): Perfusion defects; used for risk stratification

9. Management

STEMI epidemiology, mechanisms, management, and complications - Fuster & Hurst's The Heart, 15th Ed.

Immediate (First 10-30 minutes) - "MONA" + antiplatelet

Drug	Dose/Route	Rationale
Oxygen	If SpO2 <90%	Correct hypoxia
Morphine	IV 2-4 mg	Analgesia; reduce sympathetic activation
Aspirin	325 mg chewed immediately	Irreversible COX-1 inhibition; antiplatelet
Nitroglycerin	SL or IV	Pain relief, preload reduction (avoid if hypotensive or RV infarct)

Reperfusion (the Core Treatment)

Primary PCI (preferred) - Goal: door-to-balloon time <90 minutes (within 120 min if transferred)

Mechanical recanalization of the occluded artery by balloon inflation and stent placement
Superior to thrombolysis when performed within 120 min of first medical contact

Fibrinolysis (thrombolysis) - when primary PCI is not available within time targets

Alteplase (tPA) - tissue plasminogen activator
Reteplase - bolus dosing; easier to administer
Tenecteplase (TNK) - single bolus; most fibrin-specific
Streptokinase - older agent; not fibrin-specific; approved for acute MI, PE, DVT
Time window: Up to 12 hours after symptom onset; most effective within 3 hours

Contraindications to fibrinolysis:

Any prior intracranial hemorrhage
Recent stroke (<3 months)
Active internal bleeding
Suspected aortic dissection
Severe uncontrolled hypertension (>180/110)

Antiplatelet Therapy

Drug	Mechanism	Notes
Aspirin	COX-1 inhibitor	Lifelong after MI
Clopidogrel	P2Y12 inhibitor	75 mg/day; 12 months post-MI (DAPT)
Ticagrelor	P2Y12 inhibitor (reversible)	90 mg BID; faster onset than clopidogrel
Prasugrel	P2Y12 inhibitor (irreversible)	Preferred with PCI; avoid if prior stroke/TIA
GP IIb/IIIa inhibitors	Block fibrinogen binding to platelets	Eptifibatide, tirofiban; used perioperatively in high-risk PCI

Anticoagulation

Drug	Use
Unfractionated heparin (UFH)	IV bolus + infusion during PCI
LMWH (enoxaparin)	Preferred for NSTEMI; predictable dosing
Bivalirudin	Direct thrombin inhibitor; used in PCI
Fondaparinux	Factor Xa inhibitor; used in NSTEMI if conservative management

Long-term Secondary Prevention (Post-MI)

Drug	Rationale
Beta-blockers (metoprolol, carvedilol)	Reduce HR, myocardial O2 demand, ventricular remodeling; reduce sudden death
ACE inhibitors/ARBs (ramipril, lisinopril)	Reduce afterload, prevent LV remodeling; mandatory if EF <40%
Statins (high-intensity: rosuvastatin 40 mg, atorvastatin 80 mg)	Plaque stabilization, LDL reduction; reduce mortality
Aspirin (81 mg/day)	Lifelong
Eplerenone/Spironolactone	Aldosterone antagonist; indicated if EF <40% + HF or diabetes

NSTEMI/UA Management

Antiplatelet + anticoagulation
Stratify risk using TIMI score or GRACE score
Invasive strategy (coronary angiography + PCI) preferred for high-risk patients
Conservative (ischemia-driven) strategy for low-risk patients

10. Complications

Complications of MI: (A) Anterior free wall rupture; (B) Ventricular septal rupture; (C) Papillary muscle rupture; (D) Fibrinous pericarditis; (E) Mural thrombus with wall expansion; (F) LV aneurysm - Robbins Pathologic Basis of Disease

Nearly three-quarters of patients experience one or more complications post-MI:

Mechanical Complications

Complication	Time	Features
Free wall rupture	3-7 days (peak)	1-3% of MIs; rapidly fatal hemopericardium + cardiac tamponade
Ventricular septal rupture (VSD)	3-5 days	Left-to-right shunt; harsh pansystolic murmur; high mortality without surgery
Papillary muscle rupture	2-7 days	Acute severe mitral regurgitation; pulmonary edema; high mortality
Papillary muscle dysfunction	Subacute	Common; ischemic mitral regurgitation without rupture
LV aneurysm	Weeks to months	Thinned, fibrotic, non-contracting bulge; risk of mural thrombus + embolism
LV pseudoaneurysm	Days-weeks	Contained free wall rupture - hemopericardium contained by pericardium
Mural thrombus	Days-weeks	Forms over akinetic wall; source of systemic embolism

Electrical Complications

Arrhythmia	Notes
Ventricular fibrillation	Most common cause of early out-of-hospital death
Ventricular tachycardia	Non-sustained or sustained; defibrillate if pulseless
Accelerated idioventricular rhythm	"Reperfusion arrhythmia"; benign; no treatment needed
Sinus bradycardia / AV block	Inferior MI (RCA); vagal; may need atropine or temporary pacing
Complete heart block (3rd degree)	Inferior MI: usually transient; anterior MI: often permanent, high mortality

Other Complications

Complication	Notes
Cardiogenic shock	Occurs in ~10% of transmural MIs; >40% LV damage; mortality >50% without support
Acute heart failure / pulmonary edema	Common; manage with diuretics, vasodilators, O2
Right ventricular infarction	1-3% isolated; common with inferior MI; treat with IV fluids (NOT diuretics)
Pericarditis	Early (2-4 days): fibrinous pericarditis overlying infarct; Dressler syndrome (2-10 weeks): immune-mediated
Infarct expansion	Thinning and stretching of infarcted wall segment, leading to aneurysm formation

11. Cardiogenic Shock - Special Mention

Defined as systolic BP <90 mmHg + signs of hypoperfusion + elevated filling pressures
Occurs when 40% or more of LV is damaged
Causes of death: (1) decreased cardiac output, (2) pulmonary venous congestion/pulmonary edema, (3) ventricular fibrillation, (4) cardiac rupture (Guyton & Hall)
Systolic stretch: Non-functional segments bulge outward during systole, further reducing effective cardiac output
Treatment: Immediate revascularization (PCI/CABG), vasopressors (norepinephrine), inotropes (dobutamine), mechanical circulatory support (IABP, Impella, VA-ECMO)

12. Reperfusion Injury

When ischemic myocardium is reperfused, a paradoxical injury can occur:

Calcium overload in previously ischemic cells
Reactive oxygen species burst
Mitochondrial permeability transition pore (mPTP) opening
Manifests as: contraction band necrosis, ventricular arrhythmias, microvascular obstruction ("no-reflow"), myocardial stunning

13. Prognosis and Risk Stratification

Favorable factors:

Small infarct size
Preserved EF (>50%)
Early reperfusion
No complications
Absence of heart failure

Prognostic tools:

TIMI Risk Score: Predicts 30-day mortality in STEMI
GRACE Score: Validated for NSTEMI/UA risk stratification
LVEF (measured by echo): Single strongest predictor of long-term prognosis
- EF <35-40%: Indication for ICD (if persists >40 days post-MI)
- EF <40%: ACE inhibitor mandatory; consider aldosterone antagonist

14. Summary Table

Feature	STEMI	NSTEMI	UA
ECG	ST elevation	ST depression / normal	ST depression / T-wave changes
Troponin	Elevated	Elevated	Normal
CK-MB	Elevated	Elevated	Normal
Vessel occlusion	Complete	Partial	Partial
Infarct depth	Transmural	Subendocardial	No necrosis
Reperfusion urgency	Immediate (<90 min PCI)	Early invasive (2-24 hr)	Risk-stratified

Sources: Robbins & Cotran Pathologic Basis of Disease (10th Ed.) | Robbins & Kumar Basic Pathology | Harrison's Principles of Internal Medicine (22nd Ed., 2025) | Ganong's Review of Medical Physiology (26th Ed.) | Guyton & Hall Textbook of Medical Physiology | Fuster & Hurst's The Heart (15th Ed.) | Goldman-Cecil Medicine

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