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Stroke and Cardioembolic Predisposition

Overview of Ischemic Stroke Subtypes

1. Large-artery atherothrombosis (~33%) - thrombosis at ulcerated atherosclerotic plaques, especially at the ICA bifurcation
2. Small-vessel (lacunar) disease (~20%) - lipohyalinosis of penetrating vessels, closely tied to hypertension and diabetes
3. Cardioembolic (~20-25%) - embolism from a cardiac source
4. Other determined cause - dissection, vasculitis, hypercoagulable states
5. Cryptogenic / undetermined - >33% have no clear cause identified after full workup

• Harrison's Principles of Internal Medicine 22E, p. 3488; Rosen's Emergency Medicine, p. 2746

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Cardioembolic Stroke: Core Mechanism

• Sudden onset with maximal neurologic deficit at onset (no stuttering progression)
• Large, cortical, wedge-shaped infarcts - often involving deep gray and white matter simultaneously
• Multiple, bilateral, or simultaneous infarcts in different vascular territories
• Hemorrhagic transformation - petechial hemorrhages from reperfusion into ischemic territory
• Any vascular territory can be affected; the MCA, ICA terminus, and PCA are most frequently involved
• Harrison's 22E, p. 3489; Bradley and Daroff's Neurology, p. 2194

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Cardiac Sources of Embolism

High-Risk Sources

Intermediate / Lower-Risk Sources

• Bradley and Daroff's Neurology, Box 65.2, p. 2194-2201; Goldman-Cecil Medicine, p. 3932; Fuster's The Heart, 15th Ed., p. 714-715

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Predisposing Conditions to Cardioembolic Stroke

1. Atrial Fibrillation - The Dominant Risk Factor

• Harrison's 22E, p. 3489; Goldman-Cecil, p. 3932; [Clark et al., 2024 - PMID 38308431]

2. Left Atrial Myopathy

• Larger left atrial volume index
• Reduced LA emptying fraction
• Reduced LA reservoir strain

• [Clark et al., 2024 - Eur J Clin Invest - PMID 38308431]

3. Heart Failure and Reduced Ejection Fraction

4. Valvular Disease

• Mitral stenosis: even in sinus rhythm, the slow-moving blood in the enlarged left atrium predisposes to thrombus; risk is multiplied when AF supervenes
• Mitral valve prolapse: minor risk in isolation; risk elevated when combined with thickened leaflets, MR, or AF
• Prosthetic valves: mechanical valves carry higher thrombotic risk than bioprosthetics; require anticoagulation

5. Hypercoagulable and Prothrombotic States

• Antiphospholipid antibody syndrome (lupus anticoagulant, anticardiolipin antibodies)
• Protein S and C deficiencies
• Factor V Leiden, prothrombin gene mutation
• Sickle cell anemia, polycythemia vera
• Cancer-associated hypercoagulability
• Oral contraceptive use, pregnancy, and the postpartum state
• Rosen's Emergency Medicine, p. 2754

6. Structural Cardiac Anomalies - PFO and Right-to-Left Shunts

7. Other Predisposing Conditions

• Infectious endocarditis: vegetations on native or prosthetic valves
• Non-bacterial thrombotic (marantic) endocarditis: malignancy, SLE
• Chagas cardiomyopathy: apical aneurysms with cerebral embolism
• Mitochondrial cardiomyopathies (MELAS, Kearns-Sayre): cerebral infarctions via embolism
• Atrial myxoma and other intracardiac tumors: rare but important - can present as stroke
• Sleep apnea: emerging evidence links OSA to cardioembolic risk via AF, nocturnal hemodynamic instability, and endothelial dysfunction ([Dharmakulaseelan & Boulos, Chest 2024 - PMID 38815623])

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ESUS - Embolic Stroke of Undetermined Source

• Fuster's The Heart, p. 728-730; [Cozza et al. 2026 - PMID 41834030]

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Diagnostic Workup for Suspected Cardioembolism

1. Brain MRI (DWI) - pattern of multiple simultaneous infarcts in different vascular territories strongly suggests cardiac source
2. 12-lead ECG and prolonged cardiac monitoring - detects AF (including paroxysmal); monitoring >24h detects occult AF in up to 25% of cryptogenic cases
3. Transthoracic echocardiography (TTE) - first-line for LV thrombus, EF, valvular disease
4. Transesophageal echocardiography (TEE) - superior for left atrial appendage thrombus, prosthetic valves, PFO with bubble study, aortic arch atheroma
5. CT Angiography / MR Angiography - large vessel assessment
6. Hypercoagulable panel - especially in young patients
7. Blood cultures - if endocarditis suspected

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Treatment and Secondary Prevention

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Key Takeaways

• Cardioembolism accounts for ~20-25% of ischemic strokes and carries the worst prognosis due to large infarct size and high recurrence risk
• Atrial fibrillation is the dominant predisposing condition; the CHA₂DS₂-VASc score guides anticoagulation
• Left atrial myopathy is an emerging concept explaining why many cryptogenic stroke patients develop AF later
• A thorough cardiac workup - including prolonged monitoring, TTE, and TEE when indicated - is essential after any embolic-pattern stroke
• Identifying the cardiac source guides anticoagulation vs. antiplatelet decisions, which are mechanistically opposite therapies

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Stroke: A Comprehensive Review

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1. Definition and Epidemiology

• Stroke is the 4th leading cause of death and the #1 cause of adult disability worldwide
• ~600,000 first-ever ischemic strokes occur annually in the United States
• Prevalence in the US is approximately 4% overall, rising to ~14% in adults over 80
• By 2050, prevalence is projected to increase ~66% from 2020 levels
• Blacks and Hispanics have significantly higher stroke rates than non-Hispanic whites
• ~3-4% of all strokes occur in patients aged 15-45; average age of first stroke is trending younger
• 30-day mortality from ICH approaches 50%; ischemic stroke carries ~10-15% 30-day mortality
• Rosen's Emergency Medicine, p. 2746; Bradley and Daroff's Neurology, p. 668

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2. Classification

2.1 Ischemic Stroke (~85%)

2.2 Hemorrhagic Stroke (~15%)

• Intracerebral hemorrhage (ICH): ~10% of all strokes
• Subarachnoid hemorrhage (SAH): ~5% of all strokes, usually from aneurysm rupture

2.3 Transient Ischemic Attack (TIA)

• Defined as focal neurological deficit lasting <24 hours (most resolve in <1 hour), with no infarction on MRI
• The ABCD² score (Age, Blood pressure, Clinical features, Duration, Diabetes) stratifies 2-day stroke risk after TIA
• TIA carries ~10-15% risk of stroke in the first 90 days; the first 48 hours carry the highest risk
• Fuster's The Heart 15E, p. 714; Goldman-Cecil Medicine, p. 3931

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3. Pathophysiology

3.1 Ischemic Penumbra and Infarct Core

• Ischemic core: CBF <10 mL/100g/min - irreversibly infarcted within minutes ("dead tissue")
• Ischemic penumbra: CBF 10-20 mL/100g/min - electrically silent but metabolically viable; salvageable if reperfusion occurs within hours

3.2 Mechanisms of Neuronal Death

1. Energy failure: ATP depletion from interrupted oxidative phosphorylation
2. Ionic pump failure: Na⁺/K⁺-ATPase fails → cellular swelling → cytotoxic edema
3. Excitotoxicity: Excessive glutamate release → NMDA receptor activation → calcium influx → protease and lipase activation → cell death
4. Oxidative stress: Free radical generation, lipid peroxidation
5. Inflammatory cascade: Leukocyte infiltration, cytokine release
6. Apoptosis: Programmed cell death in peri-infarct zones

3.3 Large-Artery Atherothrombosis

3.4 Lacunar / Small-Vessel Disease

3.5 ICH Pathophysiology

• Exerts direct mechanical pressure and shear injury
• Disrupts the blood-brain barrier
• Triggers a perilesional inflammatory response
• Causes raised intracranial pressure (ICP)

3.6 SAH Pathophysiology

• Sudden massive ICP elevation ("thunderclap" headache)
• Transient global ischemia
• Delayed cerebral ischemia (DCI) from vasospasm, peaking at days 4-14
• Bradley and Daroff's, p. 2194-2200; Rosen's EM, p. 2748-2750

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4. Risk Factors

Modifiable Risk Factors

Non-Modifiable Risk Factors

• Age (risk doubles each decade after 55)
• Male sex (higher incidence; females have higher lifetime risk due to longevity)
• Race/ethnicity (Black and Hispanic populations disproportionately affected)
• Family history / genetics (CADASIL, MELAS, PFO, factor disorders)

Special Populations

• Young adults: oral contraceptives, pregnancy/postpartum, antiphospholipid syndrome, protein S/C deficiency, sickle cell disease, fibromuscular dysplasia, drug use (cocaine, amphetamines), cervical artery dissection
• Older adults: atherosclerosis, AF, CAA, prosthetic valves

• Goldman-Cecil, p. 3944; Rosen's EM, p. 2754; 2024 AHA/ASA Primary Stroke Prevention Guideline

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5. Clinical Presentation

5.1 Ischemic Stroke - By Vascular Territory

• Contralateral hemiparesis and hemisensory loss (arm > leg)
• Gaze deviation toward the lesion side (frontal eye field)
• Homonymous hemianopia
• Dominant hemisphere (left): Broca's aphasia (expressive), Wernicke's aphasia (receptive), or global aphasia
• Non-dominant hemisphere (right): Hemineglect, anosognosia, constructional apraxia

• Contralateral weakness and sensory loss - leg > arm
• Frontal lobe behavioral changes, urinary incontinence
• Apraxia of the left hand (disconnection syndrome)

• Contralateral homonymous hemianopia (macula often spared)
• Cortical blindness if bilateral
• Memory impairment (hippocampal involvement)

• Vertebrobasilar TIA/stroke can present with the "5 D's": Dizziness, Diplopia, Dysarthria, Dysphagia, Drop attacks
• Wallenberg (lateral medullary) syndrome: Ipsilateral face sensory loss, contralateral body sensory loss (crossed), ipsilateral Horner syndrome, ataxia, dysphagia - from PICA occlusion
• Weber syndrome: Ipsilateral CN III palsy + contralateral hemiplegia - from midbrain infarction

• Pure motor hemiparesis (internal capsule or pons)
• Pure sensory stroke (thalamus)
• Sensorimotor stroke
• Ataxic hemiparesis
• Dysarthria-clumsy hand syndrome

5.2 ICH Presentation

• Sudden onset focal neurological deficit during activity (vs. ischemic stroke which often occurs at rest or on awakening)
• Severe headache more common than in ischemic stroke
• Vomiting, elevated BP, rapid progression to decreased consciousness
• Location-specific deficits (putaminal: hemiplegia; thalamic: hemisensory + upgaze palsy; cerebellar: ataxia + vomiting ± obstructive hydrocephalus; pontine: coma, pin-point pupils, quadriplegia)

5.3 SAH Presentation

• Thunderclap headache - "worst headache of my life," sudden maximum-intensity onset
• Neck stiffness (meningismus) develops within hours
• Photophobia, nausea, vomiting
• Loss of consciousness (brief or prolonged)
• Focal deficits if associated intraparenchymal hemorrhage
• A sentinel headache ("warning leak") may precede the major rupture by days to weeks

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6. Diagnosis

6.1 Initial Assessment

• LA Prehospital Stroke Screen (LAPSS)
• Cincinnati Prehospital Stroke Scale
• RACE scale (for detecting large vessel occlusion in the field)

• Standardized 15-item neurological assessment
• Score 0-42; scores ≥6 suggest LVO; used for triage decisions
• Score roughly estimates infarct volume and helps determine reperfusion eligibility

6.2 Imaging

• Available 24/7, fast, rules out hemorrhage before thrombolysis
• Detects >95% of ICH and SAH (sensitivity for SAH is ~100% in first 3 days, falling with time)
• Early ischemic signs in up to 67% within 3 hours: hyperdense artery sign, loss of insular ribbon, gray-white blurring, sulcal effacement
• For acute ischemia, gross changes take 6-12 hours to appear

• Detects LVO for thrombectomy triage; can be done simultaneously with NCCT
• Detects intracranial aneurysms; first choice in acute SAH after NCCT

• Most sensitive for ischemic stroke - detects infarction within minutes of onset (hyperintense on DWI, hypointense on ADC)
• Superior for posterior fossa and brainstem strokes where CT is limited by artifact
• DWI-FLAIR mismatch used to estimate time of stroke onset in wake-up strokes
• GRE/SWI sequences detect microhemorrhages and chronic blood (SAH)

• Identifies penumbra vs. infarct core in extended time windows (>6 hours)
• Used for DAWN/DEFUSE 3-type patient selection for thrombectomy up to 24 hours

• Glucose (fingerstick immediately - hypoglycemia mimics stroke)
• CBC, electrolytes, BUN/Cr, coagulation (PT/PTT/INR), lipid profile
• ECG and telemetry (detect AF, STEMI)
• Troponin (neurogenic cardiac injury)

6.3 The SAH Workup

• Lumbar puncture: xanthochromia detectable 2 hours post-bleed, lasts weeks; elevated RBC count with xanthochromia confirms SAH
• 4-vessel catheter angiography with 3D reconstruction: gold standard for aneurysm localization when CTA negative or insufficient characterization

• Grade 1: No blood detected
• Grade 2: Thin diffuse blood, vertical layers <1mm
• Grade 3: Localized clot or layers ≥1mm (highest vasospasm risk)
• Grade 4: Diffuse or absent blood but intraparenchymal/intraventricular clot
• Rosen's EM, p. 2979-2997; Bradley and Daroff's, p. 1820-1840

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7. Acute Management

7.1 General Stabilization (All Stroke Types)

• Airway: Protect if brainstem involved or consciousness impaired; avoid routine intubation in alert patients
• Oxygen: Only if SpO₂ <95% - avoid hyperoxia
• IV access: Avoid dextrose solutions (hyperglycemia worsens ischemia); normal saline preferred
• Glucose: Treat hypoglycemia immediately; control hyperglycemia (target 140-180 mg/dL)
• Temperature: Treat fever aggressively; antipyretics for T>38°C; hypothermia not proven beneficial
• Swallowing assessment before any oral intake (aspiration risk)
• Positioning: Head-of-bed flat (or ≤30°) to maximize cerebral perfusion in ischemic stroke

7.2 Blood Pressure Management

• Permissive hypertension - withhold treatment unless SBP >220 or DBP >120 mmHg
• Rationale: elevated BP maintains collateral flow to ischemic penumbra

• BP must be <185/110 mmHg
• IV labetalol 10-20 mg over 1-2 min, or nicardipine infusion 5 mg/h (titrate to 15 mg/h), or clevidipine infusion

• Maintain BP <180/105 mmHg for first 24 hours (hemorrhagic transformation risk)

• Target SBP <140 mmHg when presenting SBP 150-220 mmHg (safe and recommended)
• More aggressive lowering (to <140 mmHg rapidly) may reduce hematoma expansion

7.3 IV Thrombolysis (tPA / alteplase)

• Odds of excellent outcome (mRS 0-1): OR 1.43 (95% CI 1.17-1.75)
• Odds of good outcome (mRS 0-2): OR 1.36 (95% CI 1.12-1.66)
• sICH increased (OR 4.25) but mortality not significantly different

• Age ≥18
• Clinical diagnosis of ischemic stroke with measurable deficit
• Symptom onset <3 hours (or 3-4.5 hours in selected patients)
• NCCT head showing no hemorrhage

• Any intracranial hemorrhage on CT
• Symptoms rapidly resolving (NIHSS score 0-1) or severe (relative)
• Prior stroke + diabetes combination
• Seizure at stroke onset
• Prior ICH or structural brain lesion
• Major surgery/trauma within 3 months
• INR >1.7, platelets <100,000
• Glucose <50 or >400 mg/dL
• BP >185/110 mmHg (not responsive to treatment)
• Active internal bleeding

7.4 Mechanical Thrombectomy (Endovascular Treatment)

• EVT vs. BMT: improved 90-day mRS (gOR 1.6, 95% CI 1.4-1.8)
• Independent ambulation (mRS 0-3): RR 1.9 (95% CI 1.5-2.5)
• Mortality reduction: RR 0.9 (95% CI 0.8-1.0)
• Higher sICH (RR 1.7) but mortality reduced
• Conclusion: EVT now benefits even patients with large infarct cores (ASPECTS 3-5 and even 0-2 in some analyses)

• LVO confirmed on CTA (ICA, M1, M2, basilar artery)
• ASPECTS score (CT-based ischemia scoring) guides decisions
• Pre-morbid function (mRS ≤2)
• Time from last seen well (clinical + imaging assessment in late window)

7.5 Antiplatelet and Anticoagulation in Acute Ischemic Stroke

• Aspirin 325 mg: Start within 24-48 hours of symptom onset (not within 24 hours of tPA)
• Dual antiplatelet therapy (DAPT - aspirin + clopidogrel): Now recommended for minor ischemic stroke or high-risk TIA (POINT and CHANCE trials) for 21 days, then single antiplatelet
• Anticoagulation: Not routinely initiated in acute ischemic stroke (hemorrhagic transformation risk); reserved for cardioembolism (start 4-14 days after, depending on infarct size)

7.6 Stroke Unit Care

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8. Hemorrhagic Stroke Management

8.1 ICH Management

• Reverse coagulopathy immediately: warfarin → FFP + vitamin K; dabigatran → idarucizumab; anti-Xa agents → andexanet alfa; heparin → protamine
• BP target: SBP 140-160 mmHg (aggressive lowering to <140 safe in SBP 150-220 range)
• Seizure prophylaxis: treat clinical seizures with AEDs; routine prophylaxis not recommended (ESO 2025 guideline - PMID 40401775)
• ICP management: elevate HOB to 30°, osmotherapy (mannitol, hypertonic saline), intubation/sedation for GCS decline
• Neurosurgical consultation for all patients

• Cerebellar ICH >3 cm with neurological deterioration: emergent surgical evacuation (strong indication)
• Supratentorial ICH: Benefit of conventional craniotomy debated; minimally invasive approaches (endoscopic, stereotactic aspiration + tPA) show promise in recent trials (ENRICH, MISTIE III)
• Intraventricular extension with hydrocephalus: external ventricular drain (EVD) + intraventricular tPA

• Age, ICH volume, intraventricular extension, hemorrhage location (infratentorial worse), GCS on admission
• 30-day mortality ~50% overall; 80% for large pontine hemorrhages

8.2 SAH Management

• Aneurysm securing (coiling preferred over clipping in most anatomies - ISAT trial) within 24-72 hours to prevent rebleeding (highest rebleed risk in first 24 hours)
• Nimodipine (oral 60 mg every 4 hours for 21 days) - reduces vasospasm-related DCI
• Euvolemia; avoid hypovolemia (worsens DCI)
• External ventricular drain for hydrocephalus
• Vasospasm monitoring: TCD (transcranial Doppler) daily from day 3 to 14; CTA/DSA if vasospasm suspected

• Grade I: Asymptomatic or minimal headache
• Grade II: Moderate-severe headache, nuchal rigidity, no deficit
• Grade III: Drowsiness, confusion, mild focal deficit
• Grade IV: Stupor, moderate-severe hemiparesis
• Grade V: Deep coma, decerebrate posturing
• Rosen's EM, p. 3035-3060; Frameworks for Internal Medicine, p. 467-475; Bradley and Daroff's, p. 1820-1840; [ESO/EANS ICH Guideline 2025 - PMID 40401775]

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9. Complications of Stroke

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10. Secondary Prevention

Antiplatelet Therapy (non-cardioembolic ischemic stroke)

• Aspirin 50-325 mg daily OR
• Clopidogrel 75 mg daily (superior to aspirin in the CAPRIE trial) OR
• Aspirin + dipyridamole (extended-release)
• DAPT (aspirin + clopidogrel) for 21 days after minor stroke/high-risk TIA, then single antiplatelet

Anticoagulation (cardioembolic stroke)

• AF: NOACs (apixaban, rivaroxaban, dabigatran, edoxaban) preferred over warfarin for non-valvular AF
• Mechanical valves or rheumatic MS: warfarin (INR 2.5-3.5)
• LV thrombus: anticoagulation 3-6 months
• PFO + cryptogenic stroke: device closure (left atrial appendage anatomy-dependent)

Lipid Lowering

Blood Pressure Control

• Target BP <130/80 mmHg in most post-stroke patients
• Thiazide diuretics, ACE inhibitors, or ARBs are first-line choices with stroke-specific evidence
• Benefit begins 24-48 hours after acute stroke stabilization

Other Modifiable Risk Factors

• Smoking cessation (most impactful single behavior change)
• Glycemic control (HbA1c <7% in diabetes)
• Weight management, dietary modification
• Physical activity (≥30 min moderate intensity daily)
• Carotid endarterectomy (CEA) or stenting for symptomatic stenosis ≥50% (CEA preferred for stenosis ≥70%)
• Goldman-Cecil, p. 3944-3946; [ESO Lacunar Stroke Guideline 2024 - PMID 38380638]

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11. Primary Prevention

• Screen all adults ≥18 for risk factors: hypertension, smoking, diabetes, dyslipidemia, physical inactivity, sleep disorders, and social determinants of health (a new addition)
• Routine ≥2 antihypertensive medications for most patients requiring pharmacologic BP treatment (only ~30% achieve BP control on monotherapy)
• Do not routinely screen asymptomatic patients for carotid artery stenosis
• Aspirin is not recommended for primary prevention in low-to-average risk individuals (net harm from bleeding outweighs benefit)
• The "Life's Essential 8" framework (AHA) encompasses: healthy diet, physical activity, no tobacco, healthy weight, blood pressure control, blood glucose control, lipid control, healthy sleep

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12. Stroke Mimics

• Rosen's EM, p. 2935-2937

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13. Rehabilitation

• Begin within 24-48 hours (early mobilization improves outcomes)
• Multidisciplinary stroke team: neurology, physiotherapy, occupational therapy, speech-language therapy, nursing, neuropsychology, social work
• Speech therapy for aphasia and dysphagia
• Constraint-induced movement therapy (CIMT) for upper limb rehabilitation
• tDCS and TMS (transcranial magnetic stimulation) show promise in aphasia and motor recovery research
• Goal: maximize functional independence; prevent complications (DVT, aspiration, pressure ulcers)

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Summary Reference Table

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