Neurologic Manifestations of Acquired Cardiac Disease and Arrhythmias

Introduction

The neurologic manifestations of acquired cardiac disease include (1) the sudden onset of a focal neurologic deficit due to occlusion of a cerebral or retinal artery by an embolus that has developed within the heart (cardiogenic embolism) and (2) transient, self-limited episodes of generalized cerebral ischemia that occur as a consequence of brief failure of cardiac output, due to rhythm disturbances or outflow obstruction, resulting in presyncope or syncope. Exceptions to these categorizations include atrial fibrillation (AF), an arrhythmia that is associated with embolus formation rather than syncope, and chronic sinoatrial disorder, which predisposes to both syncopal and embolic disturbances. This chapter reviews these neurologic manifestations, including the acute management and prevention of cardioembolic stroke, and also briefly discusses cardiomyopathies and their associated neurologic manifestations beyond stroke and syncope.

Cardioembolic Stroke

Ischemic stroke or transient ischemic attack (TIA) results from the sudden interruption of perfusion to a region of neural tissue, causing an abrupt interruption of behavior that corresponds to that region's topographic function. Many ischemic strokes are embolic. While most emboli are composed of thrombus, some—depending on their etiology—may be composed of tumor cells, calcific fragments, or infective components. Arterial emboli may originate from the heart chambers or valves, from the aortic arch or the large extracranial and intracranial arteries (atherosclerotic plaque or dissection), paradoxically from the venous system through a right-to-left shunt, or systemically during prothrombotic states.

Cardiogenic embolism accounts for about 20 percent of ischemic strokes. Approximately 25 percent of ischemic strokes are due to large-artery atherosclerotic disease, 25 percent relate to intracranial disease of small arteries, and 25 percent are cryptogenic, having no identifiable cause. The term embolic strokes of undetermined source (ESUS) has been defined as follows: (1) nonlacunar ischemic stroke on computed tomography (CT) scan or magnetic resonance imaging (MRI), (2) absence of extracranial or intracranial atherosclerosis causing more than 50 percent stenosis in arteries supplying the region of ischemia, (3) no major-risk cardioembolic source of embolism identified, and (4) no other specific cause of stroke identified (arteritis, dissection, recreational drug use, migrainous infarction, or vasospasm).

Cardiogenic brain embolism often manifests with greater clinical severity than strokes of other etiologies. In a population-based study of first stroke, patients with cardioembolic stroke had the lowest 2-year survival rate (55%) and were three times more likely to die than those with small-artery occlusion. The major etiologic categories of cardiogenic embolism are arrhythmias, atrial structural abnormalities, valvular heart disease, cardiomyopathies, cardiac tumors, infective and noninfective endocarditis, paradoxical emboli, and iatrogenic.

The most common cardiac cause of ischemic stroke is AF, which accounts for at least one-sixth of all strokes, and this proportion increases with increasing patient age. In addition to persistent or paroxysmal AF, other major-risk cardiac sources of emboli include intracardiac thrombus, mechanical cardiac valve, atrial myxoma and other cardiac tumors, rheumatic valve disease, recent myocardial infarction (within 4 weeks), left ventricular ejection fraction less than 30 percent, and endocarditis. Other cardiac causes of stroke are listed in Table 5-1 .

Table 5-1

Established and Putative Cardiac Causes of Stroke

Major Etiologic Category	Subtypes
Arrhythmia	Atrial fibrillation * Atrial flutter * Atrial high-rate episodes ^† Atrial asystole and sick sinus syndrome ^†
Left atrial abnormalities	Left atrial or appendage thrombus * Spontaneous echo contrast (smoke) ^† Atrial myopathy ^† Atrial septal aneurysm ^† Chiari network ^†
Valvular heart disease	Mechanical valves * Rheumatic heart disease * Mitral valve prolapse Myxomatous valvulopathy with prolapse ^† Mitral annular calcification ^† Aortic valve calcification ^† Aortic valve stenosis ^† Lambl excresences ^†
Left ventricular abnormalities	Acute myocardial infarction (<4 wk) * Left ventricular systolic dysfunction (ejection fraction <30% or regional akinesis) * Left ventricular diastolic dysfunction ^† Left ventricular endomyocardial fibrosis ^†
Cardiac masses	Atrial myxoma * Papillary fibroelastoma * Cardiac thrombus * Metastasis
Endocarditis	Infective * Marantic (thrombotic, nonbacterial) *
Paradoxical embolus	Patent foramen ovale ^† Atrial septal defect ^† Pulmonary arteriovenous fistula ^†
Aortic arch	Complex aortic arch atheroma *
Iatrogenic	Cardiac surgery Cardiac catheterization Percutaneous coronary intervention Cardioversion for atrial fibrillation and flutter

* High-risk cardiac sources of embolism.

† Minor-risk sources.

Some patients with ESUS may have cardiogenic embolism as many are found to have some of the common minor-risk cardiac sources of embolism listed in Table 5-1 . Long-term follow-up of patients with ESUS reveals paroxysmal AF in up to 30 percent. Emerging evidence suggests that some cryptogenic strokes may arise from an enlarged, fibrotic, and poorly contractile left atrium (i.e., “atrial myopathy”) in the absence of AF. Other cardiac abnormalities found in ESUS patients include ventricular systolic or diastolic dysfunction, left ventricular wall motion abnormalities, myxomatous mitral valve, mitral annular calcification, atrial septal defects, and aortic stenosis. These abnormalities are common and, in large population studies, have been associated with increased risk of stroke, but whether their presence implies causality in an individual patient with ESUS remains uncertain.

Clinical Features

Clinical features alone cannot reliably reveal the underlying type or etiology of ischemic stroke. This determination requires brain imaging, vascular imaging, and cardiac assessment by echocardiography and electrocardiography (ECG). Nonetheless, some clinical clues may be suggestive of a cardioembolic source of embolism.

Cardioembolic strokes often present with sudden neurologic deficits which are maximal at onset. This is in contrast to some cases of small-vessel occlusion where the onset of stroke deficits may begin with a gradually progressive or fluctuating course, probably reflecting fluctuations in blood pressure.

Furthermore, “cortical signs” are more common in cardioembolic stroke as emboli are more likely to lodge in distal arteries supplying the cortex. This is in contrast to occlusion of small vessels that supply the subcortical gray and white matter, sparing cortical regions. Cortical signs include forced gaze deviation, homonymous visual field deficits respecting the vertical meridian, hemispatial neglect, and aphasia of all types. Importantly, neurologic deficits that localize to multiple different vascular territories are also highly suggestive of a cardiogenic mechanism of stroke ( Table 5-2 ).

Table 5-2

Clinical Features Suggestive of Cardioembolic Stroke

Clinical Entity	Descriptor
Onset/course	Sudden onset, reaching maximal deficit within 5 min of onset Nonfluctuating neurologic deficits Rapid dramatic neurologic recovery
Severity	Impaired consciousness at stroke onset * High score on NIH stroke scale
Cortical signs	Aphasia Neglect (tactile or visuospatial; localizing to parietal lobe) Homonymous visual field deficit (localizing to temporal or parietal optic radiations or occipital cortex) Forced eye deviation (localizing to frontal eye field)
Clinical localization	Neurologic deficits localize to more than one vascular territory
Systemic signs	Fever ^† Livedo reticularis (suggestive of Sneddon syndrome, APLA, or SLE) Evidence of systemic embolization (Janeway lesions ^† , Osler nodes ^† , septic arthritis ^† , Roth spots ^† , cellulitis ^† , discitis ^† , signs of spinal cord infarct or ischemic limb) Venous thrombosis in legs (suggestive of hypercoagulable state)
Cardiac auscultation	Murmur of mitral stenosis Murmur of mitral regurgitation ^†
Investigations	ECG—ST elevation myocardial infarct, atrial fibrillation, atrial flutter TTE—evidence of intracardiac thrombus, vegetations ^† , wall motion abnormality, aneurysm, intracardiac tumor, valvular heart disease or left atrial enlargement Neuroimaging—acute strokes in multiple vascular territories Imaging evidence of systemic embolization—renal infarct or splenic infarct ^†

APLA, Antiphospholipid antibody syndrome; NIH, National Institutes of Health; SLE, systemic lupus erythematosus; TTE, transthoracic echocardiography.

* Also occurs with hemorrhagic stroke.

† Suggests infective endocarditis.

Investigations

Brain and Vascular Imaging

The first diagnostic investigation for suspected acute stroke is usually a noncontrast CT scan of the brain to exclude intracranial hemorrhage. Cardioembolic strokes can cause isolated cortical infarcts, combined cortical and subcortical infarcts, infarcts in the territory of large vessels, or showers of multiple acute small emboli. Acute embolic ischemic lesions that are bilateral or affecting different vascular territories in the same hemisphere simultaneously (e.g., anterior and posterior circulation) are highly suggestive of a cardiac source of embolism. In contrast, isolated deep subcortical infarcts smaller than 1.5 cm (lacunes) are usually due to small-vessel cerebrovascular disease rather than cardioembolism. A hyperdense vessel sign on noncontrast head CT may indicate an acute thrombus. For evaluating early acute ischemic changes on head CT in patients presenting within the first hours of symptom onset, a popular rating scale is the Alberta Stroke Program Early CT score (ASPECTS). CT scans have some limitations—acute ischemic stroke may not become visible for several hours, artifact may partially obscure the posterior fossa, and ischemia in the brainstem and cerebellum can be difficult to identify.

CT angiography (CTA) and magnetic resonance angiography (MRA) are important vascular imaging tests for the diagnostic evaluation of patients with stroke or TIA. CTA can be acquired rapidly and has become the vascular imaging procedure of choice at many emergency departments for patients presenting with stroke symptoms. CTA aids patient selection for acute stroke treatments (thrombolysis, endovascular therapy) and helps guide secondary stroke prevention management. It can identify embolic occlusions, vascular stenosis, and other vasculopathies within the major intracranial and extracranial arteries. When acquiring CTA it is important to capture the arch of the aorta; the origins of the common carotid and vertebral arteries and their course to the circle of Willis; and the branches off the circle of Willis to their distal termination. CTA can visualize aortic arch atheroma that can be a source of cerebral emboli, especially if large, mobile, or ulcerated. In the assessment of acute stroke, multiphase CTA permits an assessment of the integrity of the collateral vessels, and CT perfusion studies measure cerebral blood volume, blood flow, and mean transit time. The ability to identify potentially salvageable brain tissue with advanced imaging such as CT perfusion has enabled extended time windows (beyond 4.5 hours) for stroke treatment to be evaluated in clinical trials. The acute occlusion of a blood vessel causes a local core of infarction surrounded by brain tissue that is ischemic but not yet infarcted (penumbra). This brain tissue may survive temporarily by recruiting blood from collateral arteries and more permanently if perfusion can be restored expeditiously. Acute treatments are discussed later in this chapter.

MRI with diffusion-weighted imaging (DWI) sequences is far superior to noncontrast CT for identifying acute ischemia and small infarcts. As there are many stroke and TIA mimics (e.g., seizure, hypoglycemia, metabolic derangements, and migraine), MRI is invaluable in distinguishing between the various possibilities. The pattern of DWI abnormalities can help also to determine the most likely etiology of stroke. Acute strokes in more than one vascular territory are highly suggestive of a shower of emboli from a proximal source. The anterior circulation is affected four times more frequently than the posterior in cardioembolic stroke. MRI is the best modality to evaluate for ischemia acutely in the posterior circulation given the limitations of CT. On MRI, the presence of multiple acute infarcts, simultaneous infarcts in different circulations, multiple infarcts of different ages, and isolated cortical infarcts predict a greater 90-day risk of stroke recurrence. CT or MRI is also important in evaluating for and predicting hemorrhagic transformation after an acute infarct. Predictors of hemorrhagic transformation include larger infarcts, greater stroke severity, treatment with tPA or anticoagulation, and older age.

Echocardiography

Echocardiography plays an important role in the diagnostic work-up of embolic stroke. Transthoracic echocardiography (TTE) is easily administered and is noninvasive, but transesophageal echocardiography (TEE) is more sensitive and specific for detecting cardiac sources of embolism. TTE can image the left ventricle well, assess left ventricular function, identify akinetic segments, and reveal thrombus (may require contrast), prosthetic valve thrombus, endocarditis, cardiac tumors, and patent foramen ovale (PFO). TEE is better for assessing the left atrium, appendage, interatrial septum for PFO and valve vegetations. Echocardiography should be ordered judiciously; appropriate use criteria have been published.

For PFO detection, the diagnostic sensitivity is about 50 to 60 percent with TTE (with saline bubble study) and 90 percent with TEE. Transcranial Doppler (TCD) ultrasound has a 96 percent sensitivity for detecting right-to-left cardiac shunts by identifying microbubbles reaching the middle cerebral artery. In cryptogenic stroke cases where PFO may be causal, lower limb venous Doppler ultrasound can evaluate for deep vein thrombosis (DVT).

Electrocardiographic Monitoring

ECG is necessary for the diagnosis of AF. Given that AF is frequently paroxysmal and asymptomatic, it can easily be missed by a single 12-lead ECG or short-duration ECG monitoring. In patients with ischemic stroke presenting in sinus rhythm, ECG monitoring for 24 to 72 hours permits a new diagnosis of paroxysmal AF to be made in about 5 percent of patients. Randomized controlled trials have demonstrated that after an ischemic stroke, prolonged ECG monitoring with external wearable monitors (or implantable loop recorders) significantly increases the detection of AF. The longer the duration of monitoring, the greater is the probability of finding AF. The goal of such monitoring is to find a sufficient burden of AF to benefit from anticoagulant treatment. When only very brief, subclinical AF is detected, the clinical significance and treatment implications are still a matter of uncertainty and debate. In patients with pacemakers, subclinical AF is common and is associated with an increased risk of stroke. However, the stroke risk associated with brief device-detected subclinical AF appears lower than the stroke risk with clinical AF and the role of anticoagulant therapy in such cases is currently being tested in randomized trials. Reports by the AF-SCREEN International Collaboration provide a review and recommendations regarding AF screening after stroke and in the general population.

Cardiac Causes of Ischemic Stroke

Left Atrium

Atrial Fibrillation and Flutter

AF is the most common serious arrhythmia and is associated with a three- to fivefold increase in the risk of stroke. It is also associated with an increased risk of cognitive impairment and dementia. AF accounts for nearly half of all cardiac causes of stroke and more than one-quarter of strokes in the elderly. Strokes associated with AF tend to be more severe, more disabling, and have a higher mortality than ischemic strokes due to other causes.

The prevalence of AF in the general population is age dependent, ranging from 0.1 percent among adults younger than 55 years of age to 10 percent in those 80 years or older. AF currently affects 33 million people worldwide. With an aging population, the prevalence of AF and of AF-associated strokes is projected to increase. Atrial flutter also confers a greater risk of thromboembolism and often co-exists with AF, as they share similar pathophysiologic substrates.

Risk factors for AF include advanced age, hypertension, obesity, diabetes mellitus, underlying cardiac pathologies, hyperthyroidism, heavy alcohol consumption, and a sedentary lifestyle. Cardiac conditions associated with AF include valvular heart disease, rheumatic heart disease, congestive heart failure, coronary artery disease, cardiomyopathy, mitral valve prolapse, mitral annular calcification, and left atrial enlargement. However, AF may also occur as “lone AF” in young patients who do not have structural cardiac disease.

AF is not a binary entity and there are varying degrees of AF burden—the amount of time spent in AF—that vary between patients and over time in individual patients. AF can be symptomatic or asymptomatic and is classified as paroxysmal (self-terminating episodes lasting less than 7 days), recurrent (two or more episodes), persistent (more than 7 days), or permanent (continuous for more than 12 months). Paroxysmal AF is the most common subtype and is associated with a lower risk of stroke and lesser stroke severity than persistent AF.

Reversible or temporary causes of AF include acute systemic illness such as sepsis or pneumonia, alcohol, surgery, hyperthyroidism, acute myocardial infarction, pulmonary embolism, and pericarditis. In these precipitated settings, AF has been termed “secondary AF” and previously was thought not to increase stroke risk. However, studies now show that those with secondary AF may have an equivalent stroke risk to those with spontaneous AF. This highlights the fact that the acute medical precipitant of secondary AF merely reveals an underlying vulnerable atrial substrate which can confer an independent risk of stroke.

In patients with atrial flutter, the risk of thromboembolism is less than that of AF, but higher than for patients in sinus rhythm. Patients with atrial flutter often develop AF and the two atrial tachyarrhythmias frequently co-exist. For practical purposes, the anticoagulant treatment recommendations for atrial flutter are the same as those for AF.

Pathophysiology

The pathogenesis of AF relates to atrial cardiopathy. Histologically, atrial cardiopathy is characterized by interstitial fibrosis, loss of sarcomeres, and accumulating glycogen granules within atrial cardiomyocytes. This process is likely driven by a multifactorial interaction of risk factors including increasing age, genetic predisposition, dysrhythmias, local and systemic inflammation, endothelial dysfunction, and left atrial dilatation/myocardial stress (caused by systemic hypertension, pulmonary hypertension, elevated left ventricular filling pressure, heart failure, and/or mitral valve dysfunction). With increasing age, in conjunction with the aforementioned risk factors and left atrial dilatation, structural remodeling of the left atrial connective tissue occurs with the formation of atrial fibrosis. Furthermore, a critical component of AF pathogenesis is that the electrical disturbance of AF begets the formation of additional aberrant left atrial fibrotic substrate that propagates further AF.

As mentioned, myocardial stress promotes left atrial dilatation and further atrial fibrotic remodeling. An established biomarker of myocardial dysfunction is N-terminal fragment B-type natriuretic peptide (NT-proBNP), which is secreted in the atrium secondary to atrial or ventricular dysfunction. Elevated NT-proBNP has been associated with an increased risk of AF and thromboembolic events.

Myocardial ischemia also independently affects atrial fibrosis. In patients with AF, an elevated troponin in the blood is associated with an independent risk of stroke or systemic embolism. In such cases, troponin is likely an additional marker of vulnerable myocardium indicating ischemia, volume and pressure overload, or myocardial structural abnormalities. With this vulnerable myocardium, therefore, AF can be precipitated acutely during states of increased cardiac output and demand, such as pneumonia, sepsis, hyperthyroidism, and alcohol intoxication, thereby not only increasing stroke risk acutely but also promoting further aberrant left atrial remodeling.

There is emerging evidence that elevated levels of inflammatory markers, namely interleukin-6 (IL-6) and C-reactive protein (CRP), can be associated with the presence and burden of AF, and in those with AF they may identify greater risk of cardiovascular morbidity and mortality. These markers could reflect a prothrombotic state in AF, may reflect an inflammatory contribution to the development of aberrant atrial substrate, or not be causal at all.

There has been a shift in thinking regarding the manner in which AF leads to cardioembolic stroke. The traditional model has been that the dysrhythmia of AF leads to uncoordinated atrial function, thereby promoting left atrial stasis of blood that can lead to thrombus formation with eventual embolization to the brain. However, this century-old hypothesis incompletely captures the pathogenesis of embolic stroke in AF. The findings from trials of rate and rhythm control in paroxysmal AF have not demonstrated a reduced stroke risk and suggests that there may be another mediator of thromboembolism that is related to AF but that is not necessarily AF itself. There is an emerging appreciation that an abnormal left atrial substrate (endothelial dysfunction, fibrosis, left atrial dilatation, and left atrial appendage dysfunction) may be associated with cardioembolic stroke pathogenesis independent of AF. It is more likely that an aberrant left atrial substrate—atrial cardiopathy—is both sufficient to cause cardioembolic stroke and necessary for AF to arise. When AF arises, superimposed on an aberrant atrial substrate, there is an even greater risk of cardiogenic embolism. A newly proposed model of left atrial cardiopathy and AF in the pathogenesis of cardioembolic stroke is summarized in Fig. 5-1 .

Figure 5-1, Model of left atrial myopathy and atrial fibrillation as mechanisms of cardioembolic stroke.

Risk Stratification

The average annual risk of stroke in individuals with AF is 5 percent and is heavily dependent on age and the presence of additional risk factors. The most important predictor of stroke risk in patients with AF is a history of thromboembolism (i.e., previous TIA, stroke, or systemic arterial embolism). Other independent risk factors for stroke in patients with AF are increasing age, hypertension, congestive heart failure, diabetes mellitus, female sex, systolic hypertension, and left ventricular dysfunction.

There are two commonly used clinical tools to predict the risk of stroke in patients with AF based on the presence of additional risk factors. These are the CHADS ₂ score ( C ongestive heart failure, H ypertension, A ge ≥75 years of age, D iabetes, S troke or TIA) and the CHA ₂ DS ₂ -VASc scale, which adds on points for V ascular disease (coronary artery disease or peripheral vascular disease), A ge ≥65 years of age or ≥75 years of age, and female S ex. The CHADS ₂ scale ranges from 0 (low stroke risk, 1.9% per year) to 6 points (high stroke risk, 18.2% per year). The CHA ₂ DS ₂ -VASc scale is particularly helpful in discerning risk in those who score 0 or 1 on CHADS ₂ , and helps guide treatment decisions in these cases.

Another clinical risk factor associated with AF and independently associated with ischemic stroke is obstructive sleep apnea. During sleep, apneic episodes induce hypoxemia and sympathetic stimulation, which can induce tachycardia and nocturnal surges of hypertension, all of which can exacerbate AF.

There is interest in exploring biomarkers to help improve stroke risk prediction beyond the clinical CHADS scores. The duration and burden of AF are also important contributors to stroke risk in AF. There is a greater risk of stroke in those with persistent and permanent AF compared to paroxysmal AF. Despite this, current guidelines regarding treatment decisions have not incorporated AF burden in the determination of stroke risk in AF. Furthermore, non-AF arrhythmias may be suggestive of an abnormal atrial substrate. Frequent atrial ectopy (premature atrial beats) is associated with AF. Both frequent atrial ectopy and paroxysmal supraventricular tachycardia are associated with stroke risk independent of AF.

Echocardiographic features have been used for risk stratification in patients with AF. Left atrial enlargement, especially a diameter exceeding 45 mm or a left atrial volume index of 32 mL/m ² or more can potentiate a greater risk of stroke and systemic embolism. These markers are probably indicators of stasis and endothelial dysfunction. Furthermore, the left atrial appendage (LAA) is a common and known source of emboli in patients with AF as it is a low-pressure and highly trabeculated sac vulnerable to thrombus formation ( Fig. 5-2 ). The presence of LAA thrombus, best visualized with TEE, predicts an increased risk of stroke. LAA function can also be assessed on TEE and is emerging as a biomarker of stroke risk in AF. LAA flow velocity is reduced in AF and a velocity of <0.2 m/sec or spontaneous echo contrast on TEE is associated with an increased risk of thrombus formation and embolic events in AF. Spontaneous echo contrast or a “smoke-like” appearance on TEE represents stasis of blood in the atrium, and its presence may be a marker of increased stroke risk. There are also associations between stroke risk and LAA morphology, with certain configurations portending a greater stroke risk. There are four known morphologies of the LAA: “chicken wing,” “cactus,” “windsock,” and “cauliflower.” The chicken-wing morphology, compared to the other three variant morphologies, has the lowest risk of embolism. The cactus, windsock, and cauliflower morphologies may confer a greater stroke risk as they have lower LAA blood-flow velocities than the chicken-wing morphology. Furthermore large orifice area, ≥3 LAA lobes, and increased LAA trabeculations independently increase stroke risk in AF. Cardiac MRI is emerging as a biomarker of stroke risk in AF as it can visualize and quantify atrial fibrosis, unlike echocardiography. Atrial late gadolinium enhancement on cardiac MRI is associated with ischemic stroke risk.

Figure 5-2, Gross anatomic view of A , left atrial appendage (LAA) and B , left atrium (LA). The high density of trabeculations in the LAA contrasts with the smooth surface of the remaining left atrium. During states of low flow, the greater surface area conferred by the density of trabeculations in the LAA can predispose to thrombus formation.

Cardioversion

Cardioversion (electrical or pharmacologic) undertaken to convert AF back to sinus rhythm is associated with an increased risk of thromboembolism. Patients who have been in AF for 48 hours or more or in whom the duration of AF is unknown are at particular risk. In these individuals, anticoagulation should be started 3 weeks prior to and continued for 4 weeks after cardioversion.

Alternatively, TEE prior to cardioversion can be performed and if no left atrial or LAA thrombus is detected, cardioversion can occur as soon as the patient is anticoagulated. Even in these cases, anticoagulation should continue for at least 4 weeks. If a left atrial thrombus is detected on TEE, anticoagulation is recommended for at least 3 weeks prior to cardioversion and may need to be continued for a longer duration afterward. The recommendations for cardioversion in atrial flutter are the same as for AF.

Cardioversion within the previously acceptable 48-hour window from the time of AF onset may still be associated with a greater risk of cardioembolic stroke, in the vicinity of 0.7 to 1.1 percent. Even a delay of 12 hours or more from time of AF onset to cardioversion is associated with a greater risk of stroke as well. Risk factors for stroke in these settings include female sex, heart failure, diabetes mellitus, and older age. Therefore, the 2019 American Heart Association guidelines suggest that heparin or direct non-vitamin K oral anticoagulants be started prior to cardioversion for those with AF or atrial flutter of less than 48 hours duration with a CHA ₂ DS ₂ -VASc score of ≥2 in men and ≥3 in women. Anticoagulation should also be continued after cardioversion in these settings as well. For those with nonvalvular AF or atrial flutter for less than 48 hours, but with CHA ₂ DS ₂ -VASc scores of 0 in men and 1 in women, anticoagulation with heparin or direct non-vitamin K oral anticoagulants may be considered prior to cardioversion, without the need for postcardioversion anticoagulation.

Chronic Sinoatrial Disorder (Sick Sinus Syndrome)

Sinoatrial disorder or sick sinus syndrome is due to dysfunction of the heart's sinoatrial (SA) node. This condition manifests as a mixture of bradyarrhythmia, tachyarrhythmia, and chronotropic incompetence. Patients may also have sinus arrest. As such, patients usually presents with syncope, lightheadedness, and exercise intolerance.

There is a higher rate of systemic emboli and AF in those with chronic sinoatrial disorder compared to those with atrioventricular block. Therefore, patients with chronic sinoatrial disorder should be screened closely for AF and, if detected, anticoagulation is usually initiated. In particular, patients with the “brady-tachy” form of the disorder are at higher risk of developing AF and stroke. Studies have not found any difference in stroke risk or mortality whether sinoatrial disorder is managed with single-lead atrial pacing (AAIR) or dual-chamber pacing (DDDR), but prior studies reported a decreased risk of AF with AAIR. Pacing helps with the symptoms of syncope and exercise intolerance and facilitates the detection of AF, but does not reduce stroke risk. Nearly 30 percent of those individuals will have AF at the time of their pacing insertion and by 7 years this increases to 60 percent. DDDR has been demonstrated to reduce the progression of atrial tachyarrhythmias to long-duration and permanent AF in those with sinoatrial disorder.

Atrial Myxoma

Primary cardiac tumors—of which atrial myxomas and papillary fibroelastomas (PFE) are the most common—have a prevalence of 0.05 percent. Histologically, although both atrial myxoma and PFE are benign tumors, they have increased thrombogenic potential, often manifesting with cardioembolic stroke or systemic emboli. Embolic strokes arise either from tumor components or a dislodged thrombus. PFEs technically do not exist in the left atrium and affect the papilla of heart valves, but they are discussed here as they are of equal importance as rare causes of cardiogenic stroke.

Myxomas are more common in women than men and occur in the left atrium in more than 75 percent of cases. Rarely they can obstruct the mitral valve, causing valvular stenosis, which can manifest as exertional dyspnea. Nearly one-third of patients with myxomas have evidence of emboli, including silent brain infarcts. Management is often surgical, but there is a risk of recurrence after incomplete surgical resection. PFEs, while they mostly occur on the aortic and mitral valves, rarely cause valvular incompetence or stenosis. These tumors have fern-like projections from a central stalk and therefore have a large surface area upon which thrombus can form. Surgery is usually indicated for large or symptomatic tumors, whereas close monitoring may be employed for small or asymptomatic tumors.

Interatrial Septum: Paradoxical Embolus

A paradoxical embolus arises when a thrombus formed in the venous system passes into the arterial circulation through a right-to-left shunt such as a PFO, atrial septal defect, or ventriculoseptal defect. Incomplete closure of the foramen ovale in the first few days of life results in persistent PFO in approximately 25 percent of the population. In patients with cryptogenic stroke, a PFO is identified in 40 to 50 percent of cases. The risk of stroke recurrence with a PFO is about 1 to 2 percent per year.

In patients with cryptogenic embolic stroke who are found to have a PFO, it is necessary to determine whether the PFO was responsible or just an innocent bystander given its high population prevalence. A comprehensive stroke work-up is recommended to exclude alternate causes. Factors that increase the likelihood that a PFO is pathogenic include Valsalva maneuver or increased abdominal pressure at the time of stroke onset, younger age and absence of traditional vascular risk factors, recent immobility (surgery; prolonged land or air travel), prior or concomitant venous thromboembolism such as DVT or pulmonary embolism, known hypercoagulable state, history of migraine with aura, pulmonary hypertension, sleep apnea, and stroke occurring during sleep. The probability of a PFO being the causal mechanism of a stroke event can be estimated using the Risk of Paradoxical Embolism (ROPE) score. Certain echocardiographic features of a PFO have been associated with a greater risk of stroke, such as large shunt/PFO size, a hypermobile atrial septum, and atrial septal aneurysm.

There are other fetal structures that can persist into adulthood and may have relevance in cryptogenic stroke. In utero, the right valve of the sinus venosus directs blood flow through the PFO. A Chiari network—a web-like network of fibers—and the Eustachian valve are fetal remnants of the right valve of the sinus venosus, located at the entry point of the inferior vena cava into the right atrium. Approximately 2 to 3 percent of adults have a persistent Chiari network. A Eustachian valve and a prominent Chiari network are common in patients with PFO. A prominent Chiari network is also seen fairly frequently in patients with cryptogenic stroke, and these individuals also tend to have a PFO or atrial septal aneurysm. Together PFOs, Chiari networks, and/or atrial septal aneurysms are associated with cardioembolic stroke. It is hypothesized that the presence of prominent fetal Chiari network and Eustachian valve can direct blood from the inferior vena cava preferentially toward a PFO and may facilitate paradoxical embolization.

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