ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENESIS
Cardioembolic stroke
David Goldemund M.D.
Updated on 24/07/2024, published on 06/12/2022
Updated on 24/07/2024, published on 06/12/2022
- cardioembolism occurs in 20-30% of stroke patients (some recent data suggest this may be as high as 50%)
- ~ 50% of cardioembolic strokes are due to atrial fibrillation (Afib or AF) [Jabaudon, 2004]
- the most common source is the left atrium or ventricle
- paradoxical embolization via PFO is typically seen in younger patients
- emboli structure:
- fresh thrombus formed by fibrin and platelets (responsive to tPA)
- older organized thrombus
- calcified plaque
- valvular vegetations in endocarditis
- myxoma fragments
- an overview of cardiac conditions associated with cerebral embolization is shown in the table below
- embolization most commonly occurs in:
- non-valvular atrial fibrillation (NVAF) – the risk of stroke is 5-fold, depending on the CHA2DS2VASc score
- non-rheumatic and rheumatic valvular defects
- in most cases, cardioembolic stroke or its recurrence can be prevented with anticoagulants ⇒ early detection of a possible source of cardioembolism is essential for early initiation of optimal stroke prevention
|
The most common cardiac conditions associated with cerebral embolism
|
||
|
Arrhythmias
Valvular disease
Intra-cardiac lesions
|
Myocardial disorders
Septal defects and shunts (uncertain association)
|
|
| Overview of cardioembolic conditions by frequency of occurrence |
|
| very frequent |
atrial fibrillation/flutter (12-18% of all strokes) thrombus in the left atrium or ventricle |
| less frequent |
valvular heart disease spontaneous echo contrast in the left atrium atherosclerotic plaques and thrombi in the ascending aorta |
|
rare
|
patent ductus arteriosus (PDA)
|
| uncertain |
PFO and/or septal aneurysm
|
Atrial fibrillation (AF or Afib)
→ see separate chapter
Valvular heart disease (VHD)
| Atrial fibrillation | |
| mechanical valve, moderate-severe mitral stenosis | warfarin |
| other forms of valvular heart disease | DOAC |
| Sinus rhythm | |
| mechanical aortal/mitral valve | warfarin |
| rheumatic mitral valve disease | warfarin |
| non-rheumatic mitral valve disease | antiplatelet therapy |
| aortic valve disease | antiplatelet therapy |
| tissue aortal/mitral valve | antiplatelet therapy |
Endocarditis
- endocarditis occurs spontaneously or as a complication of preexisting valvular disease
- it can be a source of septic (infective endocarditis) or aseptic emboli, such as non-bacterial thrombotic endocarditis (NBTE) or Libman-Sacks endocarditis (LSE)
- clinical presentation involving CNS:
- transient ischemic attack (TIA) or stroke
- multiple microembolizations causing encephalopathy
- bleeding (from mycotic microaneurysms or rupture of an inflamed artery)
- endocarditis is a relatively uncommon cause of stroke, but stroke in patients with endocarditis is fairly common (clinically apparent in over 30% of patients and asymptomatically present in another 50%)
- diagnosis is based on:
- positive blood cultures + elevated inflammatory markers (white blood cell count, ESR, CRP)
- evidence of valvular vegetations or endocardial involvement on echocardiography
- neuroimaging showing recent ischemic brain lesion(s) or other systemic vascular phenomena
- use Duke criteria
- treatment of endocarditis depends on the cause of the infection
- antibiotics
- surgery may be needed to repair or replace damaged heart valves
- recurrent infarction several days after the initiation of appropriate antimicrobial therapy is an indication for valvular surgery as it suggests medical failure
- anticoagulation is not routinely given because of the increased risk of hemorrhage
- if the patient was on anticoagulants (e.g., because of a prosthetic valve or atrial fibrillation with a large left atrium), anticoagulation should be continued
- antiplatelet agents are unlikely to confer additional benefit
- prevention
- preventing dental infections
- avoiding intravenous drug use
- taking antibiotics before certain medical procedures
Nonbacterial thrombotic endocarditis (NBTE)
- formerly known as marantic endocarditis
- characterized by the formation of small sterile thrombotic vegetations on the valve leaflets (most commonly the mitral valve), resembling infective endocarditis but without signs of inflammation associated with infection (edema, cellular infiltration, possibly fibrinoid necrosis)
- usually present:
- in patients with malignant tumors as a paraneoplastic syndrome (most commonly in gastric, pancreatic, biliary, and ovarian adenocarcinomas). In these cases, NBTE may be related to the release of tumor-associated substances that promote platelet aggregation and thrombus formation.
- in patients with chronic thromboembolic diseases, chronic nephropathy with uremia, etc.
- in patients with malignant tumors as a paraneoplastic syndrome (most commonly in gastric, pancreatic, biliary, and ovarian adenocarcinomas). In these cases, NBTE may be related to the release of tumor-associated substances that promote platelet aggregation and thrombus formation.
- may present with embolism of dislodged vegetation affecting the brain, lungs, and kidneys – can cause a variety of symptoms, including stroke, transient ischemic attack (TIA), pulmonary embolism, and kidney infarction
- diagnosis of NBTE can be challenging
- the lack of inflammation in NBTE can make it difficult to identify on echocardiography
- blood cultures are negative in NBTE
- treatment of cancer may help to reduce the risk of NBTE; anticoagulation therapy may also be beneficial in some cases
Libman-Sacks endocarditis (LSE)
- LSE is a form of nonbacterial endocarditis, also known as atypical verrucous endocarditis, commonly associated with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and malignancy
- one of the most common cardiac manifestations of lupus (after pericarditis)
- one of the most common cardiac manifestations of lupus (after pericarditis)
- a hypercoagulable state leads to endothelial injury and subsequent deposition of thrombi and inflammatory molecules in affected valves (sterile vegetations). The vegetations are formed by immune complexes, platelet thrombi, fibrin, and mononuclear cells
- in addition to an asymptomatic course, LSE may present with embolization of dislodged vegetation
- cerebral or retinal emboli (presenting as stroke or transient ischemic attack)
- mesenteric ischemia (presenting as severe abdominal pain)
- peripheral arterial embolism causing pain, numbness, and discoloration in the affected areas
- the diagnosis of LSE is often challenging due to its nonspecific symptoms and the absence of bacterial infection
- echocardiography is a crucial tool for visualizing the vegetation on the heart valves
- blood cultures are usually negative, but elevated inflammatory markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), may be present
Rheumatic endocarditis
- valvular defects are the most serious complication of rheumatic fever (inflammation affecting children after tonsillitis or pharyngitis due to infection with group A β-hemolytic streptococcus)
- caused by cross-reactive antibodies that attack specific tissues – heart (pancarditis), joints (arthritis), brain (chorea minor), skin, and subcutaneous tissue (Cunningham, 2014)
Chronic heart failure (CHF)
| Content available only for logged-in subscribers (registration will be available soon) |
Acute myocardial infarction (MI)
- in the acute and subacute phases, mural thrombus may develop in the ischemic and akinetic wall segments
- in ~ 10% of patients with acute stroke, troponin elevation is present without concomitant MI; on the other hand, only borderline elevation of high-sensitivity troponin T may be found in some acute MI cases
- diagnostic evaluation:
- TTE (higher sensitivity than TEE is reported for detection of thrombi in the LV), sensitivity is further increased by using an ultrasound contrast agent
- cardiac MRI (high sensitivity) [Weinsaft, 2011]
- management:
- thrombus is demonstrated in LV: WARFARIN (INR 2.0-3.0) for 3-12 months (usually 3 months) (AHA/ASA 2021 I/B-NR)
- patients with TIA/stroke and acute anterior wall MI with reduced EF (< 50%) without evidence of left ventricular thrombus: consider warfarin for 3 months (AHA/ASA 2021 2b/C-EO)
- the safety of DOACs in this setting is uncertain (AHA/ASA 2021 2b/C-LD)
- LMWH may be used instead of warfarin or as bridging therapy (AHA/ASA 2014 IIb/C)
- in concomitant severe CAD with unstable AP, anticoagulant therapy may be combined with antiplatelet therapy
Patent foramen ovale (PFO)
Atrial septal defect
| Content available only for logged-in subscribers (registration will be available soon) |
Intracardiac tumors
- a relatively rare cause of systemic embolism
- incidence in the general population ~ 1.38 per 100 000/year; benign in ~ 90% of cases [Cresti, 2016]
- most common primary cardiac tumors are myxomas and fibroelastomas
- high risk of cardioembolism (from thrombi or detached tumor masses)
- classification
- primary
- benign (myxoma, papillary fibroelastoma, fibroma, neurofibroma, lipoma, hemangioma, lymphangioma, rhabdomyoma, teratoma)
- malignant (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, malignant mesothelioma)
- secondary (metastatic)
- malignant tumors of the breast, lung, etc.
- much more common than primary cardiac tumors, accounting for ~ 90% of all malignant cardiac tumors
- primary
- clinical presentation
- palpitations due to arrhythmias (caused by the tumor interfering with the heart’s electrical activity)
- chest pain (caused by the tumor pressing on the heart or by the tumor-induced pericarditis)
- embolism – embolism can lead to a stroke, myocardial infarction, or other serious problems
- diagnosis
- combination of medical history, physical examination, and imaging tests (echocardiography, cardiac CT or MRI)
- therapy
- in some cases, the tumor may be removed surgically; otherwise, radiation therapy or chemotherapy may be used
- the 3rd most common heart tumor (7%)
- usually < 1 cm in diameter
- most commonly located on the surface of the valves, primarily the aortic valve (83%)
- there is usually no valve dysfunction; patients are at risk of systemic embolization (to cerebral, coronary arteries, etc.)
- tumor mobility is an independent predictor of death and non-fatal embolization
- tumor mobility is an independent predictor of death and non-fatal embolization
- diagnostic evaluation:
- TEE (a high sensitivity)
- 3D echocardiography
- CT/MRI
- indication for surgical treatment (usually valve salvage surgery)
- clinical symptoms (embolization)
- in patients undergoing cardiac surgery for another reason
- in patients with highly mobile and large asymptomatic tumors
- long-term anticoagulation therapy is indicated in symptomatic patients who are not undergoing surgery
- a benign tumor that arises from the endocardium
- in ~ 80% of cases, it is located in the left atrium
- clinical presentation:
- embolization
- mitral orifice obstruction (dyspnea, increased fatigue, cough, hemoptysis, pulmonary edema)
- tricuspid valve obstruction (⇒ right-sided heart failure)
- diagnostic evaluation:
- history and physical examination
- TTE / TEE
- management:
- surgical removal through a minimally invasive direct cardiac surgery (MIDCAB)
- in some cases, a conservative approach with echocardiographic monitoring may be preferred
- patients who are not good candidates for surgery or who have small, asymptomatic tumors
Cardiomyopathy (CMP)
- stroke/TIA + cardiomyopathy (ischemic, nonischemic, restrictive) or left ventricular dysfunction with evidence of thrombi in the left atrium or ostium ⇒ anticoagulation for at least 3 months (AHA/ASA 2021 1/C-EO)
- stroke/TIA + mechanical support ⇒ warfarin + ASA (AHA/ASA 2021 2a/C-LD)
- avoid dabigatran (AHA/ASA 2021 3/B-R)
- in patients with low ejection fraction (EF) and sinus rhythm without evidence of intracardiac thrombus, the efficacy of anticoagulation is unclear; an individualized approach should be applied (AHA/ASA 2021 2b/B-R)
- stroke/TIA + noncompaction cardiomyopathy ⇒ consider warfarin (AHA/ASA 2021 2a/C-EO)
- insufficient data to recommend DOACs for intracardiac thrombi ⇒ warfarin is preferred
| cardiomyopathy + stroke/TIA + sinus rhythm | |||
| thrombus in LV or LAA | LVAD | noncompaction cardiomyopathy | other |
| warfarin (class 1) |
warfarin + aspirin (class 2a) |
warfarin (class 2a) |
an individual approach (class 2b) |
according to AHA/ASA 2021
Cardiac amyloidosis
- amyloidosis is a relatively heterogeneous group of diseases whose common feature is the deposition of amyloid (an insoluble proteinaceous material of fibrillar nature) in various tissues and organs, including the heart
- in cardiac forms (cardiac amyloidosis), fibrils accumulate within the myocardial interstitium, leading to restrictive and (pseudo)hypertrophic cardiomyopathies, characterized by diastolic dysfunction, arrhythmias, and often culminating in heart failure and death
- amyloid precursor proteins involved in cardiac amyloidosis are mainly immunoglobulin light chain (AL, formerly called primary amyloidosis) and transthyretin (TTR)
- transthyretin (TTR) is a protein that carries vitamin A (retinol) and thyroxine to different parts of the body
- as a result of genetic mutations or with advancing age, transthyretin molecules may misfold (lose their normal spatial conformation) and deposit in the heart and other organs as amyloid
- the diagnosis of TTR amyloidosis is confirmed by:
- serology tests
- light chains (AL)
- retinol-binding protein 4 (RBP4) (ATTR)
- a positive cardiac scintigraphy scan (but does not differentiate ATTR from AL)
- genetic testing (for the TTR variant)
- echocardiography and cardiac MRI (T1 mapping)
- endomyocardial biopsy with histopathology and immunohistochemistry has been used to definitively diagnose amyloidosis
- extracardiac tissue biopsies (such as abdominal fat aspirate or peripheral nerve biopsy) have varying sensitivity
- with high accuracy, it can be replaced by non-invasive methods (Hafeez, 2020)
- polyneuropathy diagnosis (EMG, biopsy)
- serology tests
- stroke mechanisms:
- atrial fibrillation (AF) – cardiac amyloidosis increases the risk of AF due to atrial infiltration and dysfunction
- intracardiac thrombus formation – especially in the atria
- autonomic dysfunction – potentially leading to episodes of hypotension or hypertension, contributing to cerebrovascular stress
- management:
- tafamidis (ATTR) (ATTR-ACT trial)
- tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis
- anticoagulation in patients with cardiac amyloidosis and AF or intracardiac thrombus
- complex heart failure treatment
- tafamidis (ATTR) (ATTR-ACT trial)
| type | protein Involved | origin | common features |
| AL amyloidosis | light-chains | clonal plasma cells producing light chains |
|
| TTR amyloidosis (ATTR) | transthyretin (TTR) | liver hereditary (hATTR) or wild-type (wtATTR) |
|
| AA amyloidosis | serum amyloid A | chronic inflammatory conditions ((e.g., rheumatoid arthritis, inflammatory bowel disease) | less commonly affects the heart, compared to AL and ATTR |
| localized amyloidosis | various | deposition of amyloid in specific organs without systemic distribution | rarely involves the heart |
Cardiac catheterization complications
- diagnostic coronary angiography and interventional procedures may result in thromboembolism or atheroembolism from the aorta or its branches
- peripheral embolization
- stroke or ischemic retinopathy
- periprocedural stroke is a rare complication with the use of low-profile catheters (< 0.5%); the risk is increased in:
- patients with extensive aortic atherosclerotic plaque
- procedures requiring multiple catheter exchanges or excessive catheter manipulation
- the need for large-bore catheters and stiff wires
- standard acute stroke therapy (thrombolysis, thrombectomy) and secondary prevention are used to manage these complications
- rarely, contrast-induced encephalopathy (CIE) may occur – a reversible neurological syndrome that can occur after exposure to contrast media
Cardiac surgery complications
- occurs during coronary artery bypass grafting (CABG) and intracardiac procedures → Neurological complications during extracorporeal circulation
