Where there is smoke, there is fire: afib in SCD

In this issue of Blood Advances, d’Humières et al¹ demonstrated an underappreciated mechanism of stroke in patients with sickle cell disease (SCD). Although SCD affects every organ in the body, stroke is among the most feared and devastating complication because of its impact on mobility, cognition, and employment. The prevalence of clinically evident first-time stroke in SCD is as high as 24% by the age of 45, which is a staggering number.² Stroke has many etiologies in SCD, including large vessel vasculopathy, ischemic and hemorrhagic small vessel disease,² and cardioembolic stroke.³ 

Cardioemboic stroke resulting from atrial fibrillation(afib) is well known in the general population,⁴ particularly in aging individuals with diastolic dysfunction, atrial dilation, and low cardiac output, a process termed heart failure with preserved ejection fraction.⁵ Patients with SCD develop a unique restrictive cardiomyopathy that shares this phenotype.⁶ The underlying pathophysiology remains somewhat cryptic but likely represents accelerated microvascular disease driven by abnormal red cell mechanics and heme-mediated vascular inflammation leading to reactive interstitial fibrosis.

Given this known substrate for atrial dilation, why has not afib previously been linked to stroke in SCD? As previously discussed, there are multiple other explanations for stroke in SCD that have been better studied. Although ischemic or hemorrhagic stroke can occur at any age, it is more common for ischemic stroke to occur in the first decade of life, with an increase in hemorrhagic stroke occurring in the fourth decade of life onward.² Many strides have been made in reducing early ischemic stroke in high-risk patients (transcranial Doppler screening, chronic transfusion therapy, hydroxyurea, etc), but challenges remain in fully understanding all mechanisms of stroke in patients with SCD and stroke prevention. Patients with SCD have many risk factors for afib, including chronic kidney disease, hypertension, left ventricular hypertrophy, and left atrial dilation to name a few. Afib holds a 2.4-fold increased risk of stroke. Ominously, the first sign of silent or occult afib could be a stroke, especially in those with an embolic appearance.⁴ 

In this study, the authors identified a high prevalence of atrial arrhythmias (26%) in patients with SCD. Although the minority of patients had paroxysmal or persistent afib, many presented with excessive supraventricular ectopic activity (ESVEA), defined as ≥720 premature atrial contractions per day or any episode runs of ≥20 premature atrial contractions.⁷ Although ESVEA exhibits an incident risk of afib in patients without SCD,⁷ its predictive value for patients with SCD remains unproven. However, in the present study, there was a strong independent association between ESVEA and a history of stroke, of which 28% were compatible with afib origin. This sizable percentage suggests that atrial arrhythmias, including paroxysmal afib, may play a larger role than previously thought in stroke in patients with SCD, underscoring the importance of early detection and treatment.

With or without SCD, there are several important aspects of care for patients with afib, including stroke risk assessment and prophylaxis, cardiac risk mediation (obesity, tobacco and alcohol usage, hypertension, etc), and symptom management (rate vs rhythm control). Stroke risk is estimated using scoring systems (eg, CHA₂DS₂-VASc, https://www.mdcalc.com/calc/801/cha2ds2-vasc-score-atrial-fibrillation-stroke-risk), and anticoagulation is recommended if the annual risk of stroke or thromboembolic events is ≥2%.⁴ Treating or preventing afib is important, because afib can lead to adverse cardiac remodeling, thromboembolic events, and other symptoms. Rhythm control, achieved with antiarrhythmics and/or cardiac ablation, when compared with rate control has been associated with a lower risk of death from cardiovascular causes and stroke.^8,9 Close follow-up is imperative because afib recurrence is common and up to 90% of episodes are not recognized by the patient.¹⁰ 

How does the presence of SCD alter the diagnosis and management of afib? To begin with, the index of suspicion has to be a lot higher. In this study, the authors advocate for systematic ambulatory rhythm monitoring in patients who have experienced a stroke not related to cerebral vasculopathy. But why should we start there? Instead, should we not advocate for earlier screening to detect ESVEA or paroxysmal afib before a clinical stroke? Ambulatory electrocardiogram recordings should be performed for all patients who complain of frequent palpitations, routinely beginning in the fourth and fifth decades of life. Early detection begets a more nuanced discussion among the hematologist, cardiologist, and neurologist regarding treatment options, as anticoagulation carries an increased risk of hemorrhagic stroke in patients with SCD with cerebral vascular disease. The relative merits of ablation, antiarrhythmics, rate control, and anticoagulation must be carefully assessed for each patient. It has been previously reported that patients with SCD and afib are less likely to be on antiarrhythmic drugs or undergo ablation for rhythm control compared with non-SCD counterparts, despite evidence that rhythm control improves outcomes.^8,9 Whether this represents physician ignorance, systemic racism, or limitations of patient insurance is unclear, but afib is underrecognized and undertreated in SCD. Arming clinicians with tools and information to better evaluate patients and inform them of treatment options would hopefully help address some of this inequity.

In summary, the authors of this article are to be commended for bringing to light a relatively underrecognized phenomenon that is likely contributing to strokes in patients with SCD. These new preliminary data should highlight the importance of having a high index of suspicion for arrhythmias in patients with SCD and start discussions regarding the timing of early ambulatory rhythm monitoring screening. With emerging research into atrial arrhythmias and SCD, new guidelines can be created to encourage regular periodic ambulatory monitoring to identify patients at risk and start appropriate treatment or intervene as needed. Although this may come at the cost of additional monitors and doctor visits, the quality of life that can be afforded by stroke prevention will remain priceless.

Conflict-of-interest disclosure: The authors declare no competing financial interests.