Stroke and systemic embolism in adult congenital heart disease

Abstract

Despite striking improvement in survival of patients with congenital heart disease (CHD), the risk of long-term complications remains high. Stroke and systemic embolism are common and potentially devastating complications that significantly affect morbidity and mortality in CHD. The risk of stroke in adult congenital heart disease (ACHD) is higher than in the general population, patients are affected at an earlier age, and the risk continues to increase with age. Specific types of defects are at high-risk for stroke and other systemic embolisms, particularly patients with complex congenital heart disease, cyanotic heart disease, Fontan circulation, and cardiac shunts. Associated factors such as atrial arrhythmias, heart failure, mechanical valves and intracardiac devices, and infective endocarditis increase the risk of thromboembolic events. Acquired conventional risk factors for cardiovascular disease further increase the burden of stroke in the aging ACHD population. Anticoagulation is a cornerstone for prevention of thromboembolic events. Risk stratification in ACHD remains challenging and should be individualized. General risk stratification models, such as the CHA₂DS₂-VASc score, are not reliable in the heterogeneous ACHD population and should only be used in mild to moderate CHD. Anticoagulation is recommended as primary prevention in high-risk patients (patients with intracardiac repair, cyanotic CHD, Fontan circulation, or systemic right ventricle) with atrial arrhythmias. In patients with other CHD, general stratification models should be used to decide when to initiate anticoagulation, taking into account specificities of underlying heart disease and potential residua. Screening and treatment of conventional risk factors for cardiovascular disease may further improve long-term outcomes.

Graphical abstract

Highlights

• •Stroke and other systemic embolisms are common in ACHD; they increase morbidity and mortality in this patient population.
• •Various risk factors contribute to thromboembolic complications.
• •Anticoagulation is indicated in patients with atrial arrhythmias and intracardiac repair, cyanotic CHD, Fontan or systemic RV.
• •Better understanding of CHD-specific risk factors may help identify patients at highest risk for stroke.

1. Introduction

Stroke is not only a common disease, but also one of the leading causes of death and disability in adults worldwide [1]. As such, it represents an important global health burden.

Approximately 85% of strokes are ischemic and 15% are hemorrhagic [2]. Etiologically, ischemic stroke is most frequently embolic, atherothrombotic, or due to small vessel disease [2,3]. Hypoperfusion caused by hypotension may cause watershed stroke in the terminal areas of arteries.

The number of patients with adult congenital heart disease (ACHD) is rapidly increasing and patients are ageing. Advances in the management have reduced mortality and improved life expectancy even in patients with complex congenital heart disease (CHD) [4]. However, morbidity remains high and ACHD patients face different long-term cardiovascular complications [5]. Stroke and other systemic thromboembolic events are frequent in ACHD and account for approximately 4% of overall deaths [6].

2. Stroke and systemic embolism in ACHD

The risk of stroke and systemic embolism is significantly higher in ACHD than in the general population, especially in younger patients [[7], [8], [9], [10], [11]]. The annual incidence of cerebrovascular accidents in large European and Canadian retrospective study was as high as 0.05%, which is 10–100 times higher than in the general population [8]. The cumulative risk of ischemic stroke in a retrospective study from Quebec was 6.1% in women and 7.7% in men [7]. Compared to the general population, the risk was 9–12 times higher in patients younger than 55 years and 2 to 4 times higher in patients between 55 and 64 years. However, the cumulative incidence of stroke increases with age [9]. The etiology of stroke in ACHD is predominantly ischemic, with an embolic origin proven or suspected in more than 90% of cases [7,8].

Regardless of patient age, morbidity and mortality from stroke are significantly increased. Thirty-day mortality is as high as 5% [7]. Persistent neurological damage occurs in up to 25% of ACHD patients [8], significantly increasing the global health burden.

3. Risk factors for stroke and systemic embolism

The ACHD population is extremely heterogenous and the risk for stroke and systemic embolism is multifactorial. Several mechanisms can potentially be involved (Table 1). Stroke and systemic embolism may be related to the underlying CHD, to different associated conditions or to iatrogenic causes. The most important risk factors are complexity of CHD, cardiac shunts, atrial arrhythmias, and heart failure. Iatrogenic factors such as mechanical valves and intracardiac devices contribute to the risk of stroke and systemic embolism. With aging population, the role of conventional risk factors for cardiovascular disease becomes more apparent.

Table 1.

Mechanisms of stroke in ACHD.

Cause of stroke	Mechanism of stroke
Related to CHD type
•Right-to-left shunt (native or residual)	Paradoxical embolism
•Arrhythmia	Embolic
•Infective endocarditis	Embolic
•Cyanosis	Hyperviscosity, spherocytosis
•Chamber dilatation	Embolic
Iatrogenic
•Mechanical valves	Embolic (thrombo or septic)
•Surgical shunts and baffles	Paradoxical embolism
•Intracardiac devices	Embolic (thrombo, septic, paradoxical)
•Cardiac interventions	Embolic (thrombo, air)
•Cardiac surgery •Anticoagulation/antithrombotic therapy	Embolic, hypoperfusion – watershed infarct Hemorrhagic

CHD – congenital heart disease.

3.1. CHD complexity

CHD type and complexity are important in determining the risk for stroke. Patients with complex CHD, especially those with cyanotic CHD, Eisenmenger syndrome, Fontan circulation, and transposition of the great arteries after atrial switch repair are at high risk for stroke and systemic embolism [[7], [8], [9],12].

3.2. Cardiac shunts

Shunts represent a potential mechanism for paradoxical embolism and subsequent tromboembolic events. Shunts are either native or residual after surgical or interventional procedures. Atrial septal defect (ASD) is one of the most common CHD. Patients with an ASD have an increased risk of stroke [8,9]. The prevalence of stroke in an open ASD is 4% [8]. Two mechanisms are predominantly involved. Thromboembolic events can either be caused by paradoxical embolism or be related to atrial arrhythmias, which are common in this defect. The risk of stroke remains increased even after closure of the ASD and is mostly related to atrial fibrillation, which is a major risk factor for stroke in older patients with ASD.

3.3. Atrial arrhythmias

Due to specific cardiac anatomy, hemodynamic disturbances, and scar formation after surgery, patients with ACHD are at increased risk of atrial arrhythmias, which occur in 15% of patients with ACHD [13]. Atrial arrhythmias are more common in complex CHD and increase with age. More than 50% of patients with severe CHD develop atrial arrhythmias by the age of 65 years [13]. Intra-atrial re-entry arrhythmia (IART) is the most common form of atrial arrhythmia, although in older patients the prevalence of atrial fibrillation increases [14,15]. In younger patients paroxysmal arrhythmias are predominant, while in older patients permanent arrhythmias become more common [15]. Atrial arrhythmia is an important risk factor for stroke and systemic embolism. ACHD patients with atrial arrhythmias have twice the risk of stroke as patients without arrhythmias [13].

3.4. Heart failure

Heart failure is a recognized risk factor for stroke in the general population. Patients with heart failure have a 2- to 5-fold increased risk of stroke [16]. Several mechanisms may play a role, including thrombus formation, increased activity of procoagulant factors, platelet aggregation, endothelial dysfunction, and neuroendocrine disorders. Heart failure is prevalent in ACHD, especially in complex anatomy [17]. It has been shown to be an important risk factor for stroke in ACHD patients, with greater impact on younger patients [7,10,11].

3.5. Mechanical valves and intracardiac devices

Patients with CHD have relatively high prevalence of mechanical valves. Mehanical valve thrombosis is a rare but serious complication. Left-sided mechanical valve thrombosis is less frequent than right-sided mechanical valve thrombosis, but may result in stroke or systemic embolism. Meticulous monitoring of anticoagulation is essential for thrombosis prevention.

The indications for implantation of intracardiac devices are expanding. Transvenous leads are most commonly used. In patients with native or residual cardiac shunt, the risk of paradoxical embolism from transvenous leads is increased more than twofold [18]. Prevention with antiaggregation or anticoagulation therapy has not been shown to be effective. Therefore, in patients with known intracardiac shunt, the risks and benefits of transvenous versus epicardial approach have to be weighed. If feasible, the shunt should be closed prior to transvenous lead implantation; otherwise epicardial approach is preferable.

3.6. Cardiac surgery and catheter interventions

Cardiac surgery and catheter interventions are frequent in ACHD patients. Several factors contribute to stroke and systemic embolism. Perioperatively, patients are at risk of embolic stroke and watershed infarct due to hypoperfusion [19]. At the time of surgery, patients are exposed to global ischemia due to hypoperfusion during cardiopulmonary bypass and to localized injury from air or thromboembolism.

The number of catheter interventions is increasing. The risk of serious complication during the procedure is low, but patients are exposed to possible risk of stroke due to air or thromboembolism.

3.7. Infective endocarditis

Prosthetic valves, residual lesions, intracardiac devices, and cyanotic CHD are frequent in ACHD patients and represent high-risk situations for infective endocarditis, an important complication with high mortality. Infective endocarditis is more common in ACHD than in the general population. The incidence in the general population is between 5 and 7 per 100 000 patient-years, whereas the incidence in ACHD is about 1 per 1000 patient-years and is highly dependent on the type and complexity of CHD [20]. Embolic events are the major complication of infective endocarditis and are reported in over 30% of ACHD patients. Cerebral embolism is the most common embolic location and an important risk factor for mortality, which remains substantial.

3.8. Conventional risk factors

As the ACHD population ages, patients are increasingly exposed to conventional cardiovascular risk factors that further add to the burden of stroke. ACHD patients generally strive for a healthier lifestyle; for example, smoking rates apper to be lower in ACHD than in the general population [21]. However, arterial hypertension, hyperlipidemia, diabetes, obesity, and physical inactivity are prevalent also in this patient population. A retrospective study from Belgium found that almost 80% of ACHD patients had at least one of these conventional cardiovascular risk factors [21]. These data underline the importance of prevention and promotion of cardiovascular health in ACHD.

4. Fontan circulation

The specific anatomical and physiological features predispose patients with Fontan circulation to thromboembolic complications, which occur in up to 25% of patients [22]. Systemic thromboembolism is less frequent than non-systemic; Fontan conduit/right atrial thrombus and pulmonary embolism are the most common. Thromboembolic events are considered a major cause of morbidity and late mortality in Fontan patients [22,23].

Several mechanisms play a role in the development of thromboembolic events [12]. Blood stasis due to sluggish blood flow in the Fontan circulation, liver dysfunction due to elevated venous pressure, and abnormalities in procoagulant and anticoagulant factors result in an increased risk of thromboembolic complications. Atrial dilatation is common and atrial arrhythmias are prevalent, increasing the risk of embolism. Finally, surgical fenestrations increase the risk of paradoxical embolism. In particular, atrial arrhythmias and an atrio-pulmonary connection are the major risk factors for thromboembolic events in Fontan patients [22].

5. Cyanotic CHD

Patients with cyanotic CHD have an increased risk of stroke and other thromboembolic events [8,24]. Stroke has been observed in more than 20% of cyanotic CHD and in 5% of Eisenmenger patients [8]. Cyanotic patients have a 10-fold higher risk of stroke compared to other CHD.

Several mechanisms are involved. Secondary erythrocytosis due to chronic cyanosis causes hyperviscosity and increased thrombotic risk. In the past, phlebotomy was performed to reduce hematocrit in patients with secondary erythrocytosis. The use of phlebotomy was shown to be harmful, as the iron deficiency caused by repeated phlebotomies led to sperocytosis, which contributed to thrombus formation and thrombotic events. In cyanotic CHD, both bleeding and thrombotic risk are increased due to abnormalities in platelet and coagulation function.

Cyanotic patients have a constant, unprovoked right-to-left shunt, which makes them particularly susceptable to paradoxical embolism. The prothrombotic potential in cyanosis is high, and there is an increased risk for clot formation in the venous system, further increasing the risk of paradoxical embolism. Air filters should be advocated to prevent iatrogenic paradoxical air embolism in situations where intravenous lines are used.

Atrial arrhythmias are more common in complex non-Eisenmenger cyanotic patients and may add to the risk of stroke.

6. Prevention of stroke and systemic embolism

In the general population and in acquired heart disease, CHA₂DS₂-VASc and HAS-BLED scores are used for stroke risk stratification in patients with atrial fibrillation. These scores have not been sufficiently validated in ACHD, and it is questionable whether they are applicable in heterogeneous ACHD population. Data on primary prevention with anticoagulation therapy are controversial. The decision to initiate anticoagulation therapy remains challenging and should be individualized, taking into account clinical assessment of thrombogenic and bleeding risk together with associated risk factors.

According to the ESC guidelines, oral anticoagulation is recommended in all patients with atrial arrhythmias (atrial fibrillation, atrial flutter, or intra-atrial re-entrant tachycardia) and intracardiac repair, cyanotic CHD, Fontan circulation, or systemic right ventricle [14,25,26]. In patients with other CHD, general risk stratification should be followed taking into account also specificities of the underlying heart disease and potential residua; anticoagulation should be considered when one or more non-sex risk factors for stroke are present. An individualized approach is advised.

The use of anticoagulation in Fontan patients is still debated and varies between centers; optimal medical management remains elusive. Patients are at high risk for thromboembolic complications. However, the risk of bleeding is also increased; bleeding events can occur in up to 30% of patients treated with warfarin [22]. Currently, European guidelines recommend anticoagulation in Fontan patients with atrial thrombus, atrial arrhythmias, or thromboembolic events [14,25]. The use of direct oral anticoagulants (DOACs) in Fontan patients remains controversial [14,25,26]. The available data, although limited, show that DOACs are effective and safe in Fontan patients at low risk of bleeding. Guidelines currently do not recommend the use of DOACs in Fontan patients in general. The decision to use DOACs should be made on a case-by-case basis, taking into account the patient's risk for thrombosis and bleeding.

Despite the higher risk of stroke and systemic embolism in cyanotic patients, current data do not support routine anticoagulation therapy. The use of venous air filters reduces the risk of air embolisms and should be used to prevent iatrogenic causes of stroke.

Secondary prevention is indicated in patients with stroke or other embolic event and in patients with cardiac or vascular thrombus.

Warfarin (vitamin K antagonist – VKA) is a standard anticoagulation therapy and has been used in ACHD. In cyanotic patients, INR has to be corrected according to the hematocrit levels due to the methodological problems related to high hematocrit value [26]. The risk of bleeding in cyanotic patients is increased due to liver and platelet dysfunction.

DOACs are an alternative to warfarin and are currently preferred over warfarin in the general cardiology population. Based on initial studies, DOACs were also considered safe and effective in ACHD, but their efficacy and safety are less reliable in complex CHD and in cyanotic patients due to hemostatic abnormalities and increased risk of bleeding [27,28]. They are also contraindicated in mechanical valves and severe mitral stenosis. However, according to recent data, the use of DOACs in ACHD may result in more complications compared with VKAs [29]. Prospective studies are needed to determine the best anticoagulation strategy in ACHD.

In addition to drug treatment, engagement of general preventive measures is important to reduce the risk of conventional cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia, smoking, obesity, or physical inactivity, which are modifiable and treatable. In this regard, a healthy lifestyle, along with dental hygiene, must be strongly promoted. Early identification of these risk factors is advisable, and ACHD patients should undergo screening at least equivalent to that of the general population [30]. Addressing these issues earlier in life may represent a potential target in the prevention of cardiovascular complications and may improve long-term outcomes.

7. Conclusions

CHD confers a significant risk for stroke and systemic embolism, serious complications that significantly affect morbidity and mortality in ACHD. Several factors increase the risk of stroke, most importantly the complexity of CHD, cardiac shunts, atrial arrhythmias, and heart failure. The risk is particularly high in patients with cyanotic CHD and Fontan circulation, the two ACHD groups that require special attention. Acquired risk factors for cardiovascular disease emerge with advanced age, further increasing the risk of stroke. Anticoagulation is a cornerstone for prevention of thromboembolic events, however the best management strategies are still under debate. Standard risk stratification tools, such as the CHA₂DS₂-VASc score, are of limited value in ACHD. To reduce complications of anticoagulation therapy, each patient should be assessed individually, taking into account the specifics of CHD and the individual risk for stroke and bleeding. Better awareness and understanding of risk factors, specific mechanisms, and optimal management is indispensable to minimize risk and improve outcomes. Screening and timely management of conventional risk factors can further improve long-term results.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.