Atrial fibrillation and stroke

Atrial fibrillation: an important stroke risk factor

Meet Professor Tatjana Potpara,  School of Medicine, Belgrade University, Serbia and co-author of the 2020 European Society of Cardiology atrial fibrillation guidelines. In this video, Professor Potpara discusses the relationship between atrial fibrillation and stroke.

Association between atrial fibrillation and stroke

Atrial fibrillation (AF) is an important risk factor for stroke. In AF, disrupted heart rhythm may cause blood to pool in the heart’s atria and form clots. If a blood clot forms, it could dislodge from the heart and travel to the brain, blocking the blood flow and causing a stroke (Figure 1). Identifying and managing AF early and effectively can help prevent AF-related stroke¹.

Figure 1. How atrial fibrillation can lead to stroke.

It is now well known that atrial fibrillation (AF) and stroke are associated². This association is based on three concepts:

1. AF causes stroke
2. Stroke causes AF
3. AF is associated with other factors that can cause stroke

AF as a cause of stroke

AF increases stroke risk and systemic embolism 

AF increases stroke risk five-fold compared with people without the arrhythmia^3,4. The risk associated with AF is even higher in people with other stroke risk factors⁵. Overall, AF may cause up to half of cardioembolic strokes and 10–35% of acute ischaemic strokes^6,7,8.

Patient groups vulnerable to developing AF

Stroke risk with paroxysmal AF is the same as that with permanent or persistent AF⁴. Even a brief episode of subclinical AF doubles the risk of stroke in older patients with vascular risk factors².

Nevertheless, some patient groups seem to be especially vulnerable to developing AF-related strokes. For instance, stroke risk is 17-fold higher in AF patients with rheumatic mitral valve stenosis compared with people in sinus rhythm^6,7. Older people are at increased risk: 25% of all stroke in people older than 80 years occur in AF patients³. Women are also at higher risk of experiencing a cardioembolic stroke from AF compared with men (Figure 2)^4,9.

Figure 2. Cumulative stroke incidence for 60-year-old subjects (Adapted¹⁰). AF, atrial fibrillation.

The Copenhagen City Heart Study followed 29,310 subjects for a mean of 4.7 years⁹. Of these, 110 women and 166 men had documented AF. AF was 4.6 times more strongly associated with stroke in women (hazard ratio [HR] 7.8) compared with men (HR 1.7) after adjusting for age and⁹.

A study in 34,722 women free of AF and cardiovascular events at baseline, HRs (95% CI) of new-onset AF for all-cause 2.14 (1.64–2.77), cardiovascular 4.18 (2.69–6.51) and non-cardiovascular mortality 1.66 (1.19–2.30) revealed that new-onset AF was independently associated with cardiovascular, non-cardiovascular mortality and all-cause mortality¹¹. 

In the Copenhagen City Heart Study, AF was 2.5 times more strongly associated with cardiovascular mortality in women (hazard ratio [HR] 4.4) compared with men (HR 2.2)⁹

Stroke as a cause of AF

Stroke can increase the likelihood of developing AF². In about a third of AF patients, arrhythmia did not emerge until after the cerebrovascular event, despite being monitored for many months before the stroke². Indeed, 10% of patients with lacunar strokes have AF². Large-artery atherosclerosis is twice as common in AF patients as in people without arrhythmia⁸. This underscores the importance of routine long-term electrocardiogram (ECG) monitoring in all survivors of an ischaemic stroke without documented AF¹².  

AF-associated factors as causes of stroke

In addition to being an important stroke risk factor, AF is also associated with other factors that cause stroke. Age, male sex, hypertension, diabetes mellitus, valvular heart disease, heart failure, coronary heart disease, chronic kidney disease, inflammatory disorders, sleep apnoea, and tobacco use are risk factors for both AF and stroke. Interestingly, AF remains independently associated with stroke even after adjusting for shared risk factor⁸.

Outcomes after an atrial fibrillation-related stroke

Roughly 50% of people die within a year of an atrial fibrillation (AF)-related stroke. This compares with a mortality rate of 27% among people with strokes unrelated to AF¹³

AF-related strokes tend to produce large, multiple infarcts that may involve several vascular beds¹⁴. This might partly explain why outcomes after an AF-related stroke can be particularly poor. AF-related stroke is, for instance, associated with a 50% higher risk of serious disability than stroke from other causes³. A study from Ireland reported that 25.9% of patients were admitted to a nursing home after an AF-related stroke¹⁴.

Recurrences in AF-related stroke are also common underscoring the importance of secondary prevention with oral anticoagulants in AF patients. In the study from Ireland the five-year survival rates after an AF-related stroke of 39.2% and a five-year recurrence rate was 21.5%¹⁴.

Between 10% and 15% of AF patients show cognitive dysfunction, including vascular dementia, double the rate in patients without arrhythmia. In part, these cognitive disturbances follow a stroke or transient ischemic attack (TIA). About a fifth of people aged 85 years show cerebral infarctions on computed tomography. However, half of these did not show clinical symptoms¹⁵. Between 15% and 50% of AF patients show silent cerebral infarctions¹⁵. In addition, many AF patients show multiple asymptomatic cerebral emboli on cerebral imaging, which may also contribute to cognitive dysfunction³. Nevertheless, silent cerebral infarctions are associated with impaired cognition, neurological deficits, psychiatric disorder and an increased stroke risk¹⁵.

Epidemiology of stroke and atrial fibrillation

Epidemiology of stroke

Stroke is ranked as the second leading cause of death worldwide with an annual mortality rate of about 5.5 million. The burden of stroke not only lies in the high mortality, but also in the high morbidity, since up to 50% of survivors become chronically disabled¹⁶.

Age-adjusted stroke incidence varies from 95–290 per 1,000,000 of the European population annually¹⁷. About 1.1 million people experience a stroke in Europe each year. Transient ischaemic attacks (TIAs) are also common: the age-adjusted incidence ranged from 28–59 per 100,000 of the European population each year¹⁷.

Despite improved prevention, rapid diagnosis and prompt treatment, stroke remains common. Many stroke survivors develop serious complications and demographic changes mean that strokes and TIAs are likely to become even more common over the next few decades¹⁷.

Stroke incidence, for example, increases 100-fold between 40 and 80 years of age, while the age-adjusted incidence is 1.2–2.0 times higher in men than women, but life-expectancy is lower in males than females. Epidemiologists predict that, if current trends continue, by 2025, 1.5 million people in Europe will experience a stroke each year¹⁷.

Epidemiologists predict that, if current trends continue, by 2025, 1.5 million people in Europe will experience a stroke each year¹⁷

Types of stroke and outcomes following stroke

Despite advances in management, strokes generally show a poor prognosis including a high case fatality rate.

Ischaemic strokes account for about 80% of cases in Europe, although this varies from 55–90% depending on the study. Intracerebral and subarachnoid haemorrhages account for 10–25% and 0.5–5% of strokes respectively¹⁷. Numerous well-established factors contribute to the risk of developing a stroke including hypertension, dyslipidaemia, carotid stenosis and atrial fibrillation (AF)¹⁰. Nevertheless, cryptogenic strokes and TIAs with an unknown aetiology account for between 25%-39% of strokes¹⁸.

Ischaemic strokes interrupt the cerebral blood supply, causing areas of cell death in the brain¹⁹. The reduction in cerebral blood can fall beneath the threshold for brain function, generally 25–50% of the perfusion before the stroke. These areas generally recover if blood flow returns. A further decrease to about 20% or less of the flow before the stroke can lead to irreversible tissue damage, which is generally closer to the area of reduced blood supply. The penumbra refers to the range between these thresholds. The infarction develops from the core of ischaemia propagating a wave of irreversible tissue damage that spreads through the penumbra reaching areas less severely affected by the reduced blood flow²⁰.

In ischaemic stroke, the necrotic core can arise in three ways¹⁹:

• small vessel disease, which may be non-atherosclerotic or atherosclerotic, arises from blockages in the small cerebral perforating arteries
• large vessel disease results from occlusions or emboli released by the rupture of atherosclerotic plaques in the carotid artery or another large blood vessel
• cardioembolic stroke arises typically from emboli that travel from the heart to the cerebral arteries

AF may cause up to half of cardioembolic strokes⁷.

Outcomes following stroke

Case fatality rates after a stroke increase from about 15% at 1 month, to 25% at 1 year and 50% at 5 years; following intracerebral haemorrhage, case fatality rates increase from 55% at 1 year to 70% after 5 years¹⁰

Despite advances in management – such as tissue plasminogen activator, which, when used promptly, reduces the propagation of the ischaemic penumbra – strokes generally show a poor prognosis (Table 1), including a high case fatality rate. About 40% of people who survive are disabled, defined as a modified Rankin Scale score of 3–5, 1 month and 5 years after the stroke¹⁰.

Table 1. Outcomes of stroke in Europe (Adapted¹⁷).

Recurrent strokes are also common, highlighting the importance of secondary prevention with oral anticoagulants. Following an ischaemic stroke or TIA, the risk of recurrence is about 10% at 1 week and 18% at 3 months. Rapid assessment and treatment reduce the risk of recurrence by 80%. Longer term, the recurrence risk is about 10%, 25% and 40% after 1, 5 and 10 years respectively. The likelihood of recurrence is especially high among people with symptomatic atherosclerotic disease, vascular risk factors, an active source of thrombosis (such as AF), or who discontinued antiplatelet and antihypertensive drugs¹⁰.

Epidemiology of atrial fibrillation 

AF is common in Europe, although the number of patients affected is probably underestimated²¹.

As many AF patients are asymptomatic, current epidemiological estimates might underestimate the number of people with arrhythmia⁶

AF incidence in Europe is between 21 and 41 per 100,000 of the population a year². AF prevalence in Europe varies from 1.9–2.9%^3,6,11. However, insertable cardiac monitors can detect previously undocumented AF, suggesting that these figures are probably underestimates²¹.

Incidence of AF seems to be increasing, partly because the condition becomes more common with advancing age (Figures 3 and 4), partly because of an increased prevalence of AF risk factors, and partly because of improved survival follow acute coronary syndromes, such as myocardial infarction^3,11.

Figure 3. The prevalence of atrial fibrillation in Europe stratified by age (Adapted³).

Figure 4. Projected increase in atrial fibrillation prevalence among the elderly in EU 2016–2060 (Adapted¹²). AF, atrial fibrillation.

The risk of developing AF doubles for each decade of life, and there are variations between males and females⁶. The Rotterdam study (Figures 5 and 6) followed 6,808 people aged 55 years and older for a mean of 6.9 years. Overall AF prevalence was 6.0% in men and 5.1% in women. The overall incidence was 11.5 and 8.9 per 100 patient years, respectively. The lifetime risk of developing AF after the age of 55 years was 23.8% in men and 22.2% in women²². In Europe, AF is more common in men than women: the male: female ratio is 1.2:1. However, most AF patients are female, reflecting their longer average life expectancy³.

Figure 5. The prevalence of atrial fibrillation in the Rotterdam study (n=6,808) stratified by age and sex (Adapted²²). AF, atrial fibrillation.

Figure 6. The incidence of atrial fibrillation in the Rotterdam study (n=6,432) stratified by age and sex (Adapted²²). AF, atrial fibrillation.

Approximately 5–8% of patients undergoing percutaneous coronary intervention (PCI, formerly known as angioplasty with stent) have AF and one in three patients with AF also has coronary artery disease^23-25. Patients with AF and acute coronary syndrome (ACS) and/or PCI are therefore considered a special population²⁶.

AF incidence is lower in patients from certain ethnic backgrounds – for example, African Americans (3.8%), Hispanics (3.6%) and people of Asian descent (3.9%) compared with Caucasians (8.0%) – despite a higher prevalence of risk factors in some of these groups^4,11. Patients of Caucasian descent may have a genetic predisposition to developing AF⁴.

Find out more on screening and diagnosis for AF

Classification of atrial fibrillation 

Atrial fibrillation (AF) can present in several ways and correct clinical classification can guide the choice of treatment. AF can present from a single isolated episode to a constant arrhythmia (Table 2). 

Table 2. Classification of atrial fibrillation (Adapted¹²). AF, atrial fibrillation.

In about 2–3% of patients, AF can remain paroxysmal for several decades¹². Paroxysmal AF is more common than the persistent arrhythmia in young people and women¹¹. However, AF usually progresses.

Paroxysmal and persistent AF each occur in about 20–30% of patients³. Overall about 40–50% of AF patients develop permanent atrial arrhythmias³.

Up to a third of patients do not experience symptoms during an episode, so-called silent or subclinical AF⁸. Indeed, people with asymptomatic AF can experience clinically silent episodes¹². Symptomatic and silent AF share the same electrophysiological and mechanical pathogenesis. However, as silent AF is generally untreated, the progression from paroxysmal to persistent or permanent AF might be more rapid than in patients with documented AF⁸.

Mortality is between 1.5 and 1.9-fold higher among AF patients than in people without arrhythmia after adjusting for other cardiovascular risk factors⁷, partly because of the increased stroke risk.

Pathophysiology of atrial fibrillation

A network of pathways influences the onset and persistence of atrial fibrillation

In any particular patient, the onset and persistence of atrial fibrillation (AF) may involve a complex network of mutually reinforcing pathogenic pathways that are influenced by age, genetic factors and acquired risk factors^2,27. For example, acute coronary syndrome (ACS), such as myocardial infarction, as well as surgery or infection seem to precipitate a third of AF cases⁸. Table 3 summaries the possible pathophysiology of different AF types, which may overlap in clinical practice¹². This section takes a deep dive into the pathophysiology of this common arrhythmia and its relationship with stroke.

Table 3. Possible pathophysiology of different clinical types of atrial fibrillation (Adapted¹²). AF, atrial fibrillation; RAAS, renin-angiotensin-aldosterone system.

The genetics of atrial fibrillation

Atrial fibrillation (AF) incidence is lower in African Americans, Hispanics and people of Asian descent compared with Caucasians, which may suggest a genetic component⁴. Further evidence supporting a genetic component emerged in studies from a variety of populations showing that having a parent with AF markedly increases the likelihood of developing arrhythmia. In one study, the odds ratio of developing AF was 1.85 in people with one parent who had the arrhythmia compared with controls. This odds ratio increased to 3.23 in those whose parent developed AF when older than 75 years of age²⁸.

Family studies and genotyping of sporadic cases identified numerous rare genetic variants that seem to contribute to AF²⁷. Moreover, genome-wide association studies link more than 30 common genetic variants with AF, many of which encode loss-of-function or gain-of-function channelopathies (defects in ion channels caused by genetic or acquired factors, such as toxins or drugs)^27,29. Other polymorphisms linked to AF are associated with transcription factors (proteins that regulate gene activity by increasing or reducing binding of RNA polymerases to DNA) associated with cardiac genes²⁷. Future investigations of transcription factors might elucidate how developmental abnormalities affecting the heart may predispose to AF in later life²⁷.

Other polymorphisms associated with AF encode²⁷:

• structural components in the myocardium, such as the light and heavy chains of the contractile protein myosin
• structural components in gap junctions, which allow a depolarising current to travel between myocytes and help synchronise cardiac contraction
• proteins involved in signalling or protein turnover

Genetic interactions between AF and stroke

Conventional risk factors account for about 60% of the variation in stroke risk, suggesting a genetic component to cerebrovascular events as well as AF²⁸. Further studies need to assess the genetic relationship between AF and stroke¹⁹. However, some genetic polymorphisms associated with AF seem to be particularly strongly associated with cardioembolic stroke¹⁹. 

For instance, a single nucleotide polymorphism on the long arm of chromosome 4 (4q25) is associated with excessive calcium release from the sarcoplasmic reticulum and spontaneous electrical activity in human atrial myocytes³⁰. Polymorphisms in 4q25 are also associated with ischaemic and, in particular, cardioembolic stroke²⁸. Further research is needed. However, genetic polymorphisms form the backdrop against which the other pathophysiological pathways summarised in this section influence AF risk.

Aberrant electrical activity in atrial fibrillation

Normal heart beats depend on coordinated electrical activity that spreads from the sinoatrial node through the walls of the atria causing contraction (Figure 7).

Figure 7. Physiological electrical control in the heart. AV, atrioventricular; SA, sinoatrial.

Many atrial fibrillation (AF) cases arise when cardiomyocytes develop ‘pacemaker-like activity’ that over-rides control from the sinoatrial node⁷. These focal AF triggers cause spontaneous premature atrial depolarisations, re-entry circuits or both⁷.

Re-entry circuits in atrial fibrillation

Re-entry, an electrical impulse that repeatedly travels around an abnormal circuit, can arise from anatomical factors or from functional differences in the electrophysiological properties of neighbouring tissues

Anatomical and functional re-entry circuits seem to give rise to atrial flutter and AF respectively³¹. AF may arise from numerous wavelets of functional re-entry that travel through the atria, where they collide, combine or divide. This creates daughter wavelets that perpetuate AF. Conditions that increase atrial size, decrease conduction velocity or shorten the refractory period permit multiple wavelets and promote AF³¹. For instance, focal AF triggers usually arise from atrial myocytes in muscles running from the left atrium to the pulmonary veins. Transient ectopic tachycardia in the pulmonary veins decrease electrical refractoriness in the atria, which triggers AF⁴. 

Foci can, however, arise in several other areas including the walls of the right and left atria, the interatrial septum, the coronary sinus and the superior vena cava⁷. A few high-energy and rapidly firing re-entrant circuits, usually in the left atrium, can generate the abnormal electrical activity that overcome regular atrial pluses, thereby producing the disorganised rhythm associated with AF⁷.

Triggered activity may underlie more than 80% of cases of paroxysmal AF. Following AF onset, the arrhythmia may persist, possibly due to the effect of multiple independent re-entrant wavelets, focal activity in the ganglionic plexi in the atrium or small spiral re-entrant drivers (rotors). Over time, the repeated firing and remodelling of the atria results in self-sustaining AF⁴.

Atrial remodelling in atrial fibrillation

Over time, untreated atrial fibrillation (AF) leads to structural remodelling of the atria that can break the electrical connection between muscle bundles. This produces local changes in conduction that favour re-entry circuits and maintain AF. Some structural remodelling is irreversible, underscoring the importance of early detection and treatment¹².

For instance, increased left atrial pressure and size can disorganise connective tissue and cause interstitial fibrosis. These changes can slow atrial conduction, increase local electrical abnormalities and result in conduction block. Furthermore, congestive heart failure (CHF) and AF can activate the renin-angiotensin-aldosterone system (RAAS), which contributes to inflammation and fibrosis. This also results in remodelling. Age-related fibrosis could also contribute to AF onset and maintenance⁴. Structural remodelling can develop rapidly. In experimental models, structural remodelling can occur after a week of sustained rapid pacing, for example².

Abnormal calcium flux in atrial fibrillation

During each normal heartbeat, the wave of electrical activity means that calcium enters myocytes through L-type voltage-operated ion channels. This results in the controlled release of calcium from the sarcoplasmic reticulum that, in turn, activates contraction of the cardiac muscle³². In atrial fibrillation (AF), calcium can leak from the sarcoplasmic reticulum, which influences conduction velocity and the atrial refractory period⁴. 

In addition, atrial myocytes compensate for the increased inward calcium current caused by frequent depolarisation by downregulating L-type calcium channels. This, however, reduces the duration of action potentials and the atrial refractory periods. So, this compensatory mechanism paradoxically promotes AF³³. Calcium channel blockers can be used to control heart rate in some AF patients¹².

Inflammation in atrial fibrillation

Increasing evidence implicates inflammation in atrial fibrillation (AF) pathogenesis. For instance, levels of C-reactive protein (CRP), a marker of systemic inflammation, are higher in people with persistent than paroxysmal AF. Elevated CRP levels are associated with higher risk of embolism and relapse after cardioversion⁴. In addition, strokes cause necrotic cell death, which triggers inflammation. This might account in part for the increased risk of AF after a stroke².

Autonomic input in atrial fibrillation

Sympathetic tone increases heart rate and, therefore, maintains atrial fibrillation (AF)¹¹. Parasympathetic activation, such as increased vagal tone, tends to slow heart rate and produce a more variable rhythm⁴. However, sympathetic and parasympathetic activation can initiate or exacerbate AF by reducing the duration of the atrial refractory period. This enhances atrial susceptibility to re-entry and promotes spontaneous depolarisation³². Before the onset of AF, many patients seem to show increased adrenergic (sympathetic) input, followed by abrupt predominance of parasympathetic activity⁴.

Numerous diseases can influence parasympathetic innervation, including CHF and mitral valve disease, which increases left atrial pressure thereby producing atrial stretch. This, in turn, can facilitate focal electrical activity in the pulmonary vein⁷. Strokes can influence the autonomic nervous system innervating the atria, suggesting a role in causing and perpetuating AF after a cerebrovascular event². Beta-blockers, which reduce sympathetic drive, are an important treatment for some AF patients¹².

Pathophysiology of stroke in people with atrial fibrillation

Almost all AF patients show pathophysiological changes that increase stroke risk

AF’s characteristic aberrant electrical activity means that the atria does not have time to contract and move the blood into the ventricles. So, blood remains in the atria and a clot may form. This, in turn, may embolise resulting in an ischaemic stroke³⁴. Even short AF episodes can damage the atrial endothelium, which expresses factors that activate the coagulation cascade as well as activating platelets and inflammatory cells. As a result, even short AF episodes can increase stroke risk¹².

The left atrial appendage (LAA; Figure 8) is the most common site of thrombus formation in the heart⁴.

Figure 8. The left atrial appendage: the most common site of thrombus formation in the heart (Adapted⁶).

At least 90% of emboli that cause stroke in AF patients arise in the LAA³⁵. The left and right atrial appendages (sacs in the muscle wall) are embryological remnants. Nevertheless, during volume overload, the LAA can act as a reservoir and mediates adaptive responses to the reduction in circulating blood volume⁶. 

The LAA is a long, tubular structure with a narrow opening into the atrium⁶. AF means that the emptying of the LAA is often incomplete and slow³⁶. This makes the LAA particularly prone to blood stasis and thrombi are more likely to form in the LAA in patients with mitral valve disease (irrespective of underlying rhythm) and non-valvular AF than in other parts of the heart⁶. AF also promotes remodelling of the LAA. Post-mortem studies suggest that the LAA is considerably larger in AF patients compared with people without AF⁶.

Thrombi formed in the LAA tend to be relatively large. As a result, when the thrombi embolise, the fragment commonly causes ischaemic strokes and peripheral embolism³⁶.

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