Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes the selective degeneration of upper and lower motor neurons in the motor cortex, brainstem, and spinal cord (1, 2). This causes progressive muscle weakness, atrophy, paralysis, and death, usually from respiratory failure, within 2–6 years of the onset of symptoms (1, 2). The average onset age is between 55 and 65 years, and the lifetime risk of ALS is approximately 1 in 300 (3). Most cases of ALS occur sporadically but about 5%–10% are familial, caused by inherited genetic mutations (3). The cause of sporadic ALS is still largely unknown. Nonetheless, suggested mechanisms include glutamate excitotoxicity and protein misfolding, oxidative damage, mitochondrial disease, and neuroinflammation (1, 4). As such, ALS remains an incurable disease with significant unmet medical needs.

Several cardiac arrhythmias can be observed among ALS. Such as supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, atrial fibrillation, long QT syndrome, and heart blocks (5). Epidemiological studies indicate that patients with ALS have higher rates of cardiovascular comorbidities, including coronary artery disease, stroke, and heart failure, compared to the general population (6). Studies have found that ALS can present with mild cardiovascular autonomic dysfunction in the early course of the disease, which increases the risk of arrhythmia and sudden death (7). Mandrioli et al. also discovered that cardiovascular diseases negatively associated with ALS included AF, heart failure, and hypertension, thus determining that cardiovascular disease may have a negative impact in the prognosis of ALS (8). Besides, Hoda et al. also found that AF is independent prognostic factors for the survival of ALS, and AF are independently associated with a shorter survival period of ALS (6).

AF is distinguished by rapid and disordered electrical activity in the atria, causing an irregular response from the heart (9). This leads to symptoms such as palpitations, fatigue, exercise intolerance, increased risk of heart failure, stroke, and death rates (9). In the general public, the lifetime risk of AF is about 25% (10).

While the association between ALS and AF has been documented, the nature and causality of this relationship remain unclear. One major limitation of previous observational studies is the inability to determine causality due to potential confounding and reverse causation biases. For instance, shared risk factors could predispose patients to ALS and AF. It is also plausible that AF could represent a consequence of ALS pathophysiology or that ALS may develop secondary to AF-related cerebral hypoperfusion and hypoxia (11). Therefore, elucidating the causal dynamics between ALS and AF has important implications. It may uncover novel etiological mechanisms and identify potential prognostic factors or therapeutic targets for ALS or AF.

Mendelian randomization (MR) has appeared as an effective technique to assess causal relationships between modifiable exposures and outcomes based on genetic variations as instrumental variables (IVs) (12). Given that different genetic variants are distributed at random during conception, MR is less susceptible to confounding (13, 14). Moreover, germline genetic variants precede disease onset. They are generally unaffected by the disease process itself, minimizing reverse causation. Two-sample MR utilizes summarizing genetic information from various genome-wide association studies (GWAS) of the exposure and outcome. This approach enhances statistical power by leveraging large GWAS datasets. MR techniques have been increasingly applied to investigate the causal relationships between various modifiable exposures and ALS or AF (15). For example, Xia et al. found a positive causal relationship between linoleic acid (LA) and ALS risk through MR analysis. At the same time, vitamin D was negatively correlated with ALS risk (16). Xia et al. also found a causal connection between increased telomere length and reduced hazard of ALS through MR analysis (17). Mohammadi-Shemirani et al. also found through MR analysis that Elevated Lipoprotein (a) is a potential causal mediator associated with increased risk of atrial fibrillation (15). However, MR studies examining the potential causal relationship between ALS and AF are lacking.

In this research, we used a two-sample MR analysis to look into the relationship between ALS and AF. utilizing GWAS data from large populations of European ancestry. Genetic instruments strongly associated with each trait were applied in bidirectional MR frameworks. Several sensitivity studies were carried out to assess and account for probable pleiotropy. Elucidating the possible causal relationship between ALS and AF will provide novel insights into disease mechanisms and may have important implications for patient prognosis, monitoring, and management.

This two-sample MR study supports a causal association between ALS and an increased risk of AF. The primary IVW analysis demonstrated a statistically significant positive causal effect of ALS on AF risk, with an odds ratio (OR) of 1.062 (95% CI 1.004–1.122, P = 0.035). This finding was corroborated by consistent directionality of effect estimates across several complementary MR approaches, including the WME, Simple mode, MR Egger, and Weighted mode models. Multiple sensitivity analyses showed no evidence of significant horizontal pleiotropy or heterogeneity among the genetic instruments. These results indicate that ALS may causally contribute to increased susceptibility to AF.

The potential mechanisms uncovering this association remain fully elucidated but may involve both central and peripheral pathophysiological processes related to ALS that predispose to cardiac arrhythmia (6). ALS is defined by the progressive degeneration and death of upper and lower motor neurons in the motor cortex or brainstem, which results in muscular atrophy and weakness (1). Autonomic nervous system dysfunction manifested as abnormal heart rate variability has been documented in ALS patients, even at early stages, indicative of cardiac autonomic imbalance (6). This autonomic neuropathy likely contributes to the increased risk of cardiac arrhythmias and sudden death observed in ALS (20, 21). At the tissue level, neurodegenerative changes in brain regions involved in central autonomic control, such as the hypothalamus, medulla, and intermediolateral cell columns of the spinal cord, may disrupt standard cardiovagal modulation and promote sympathoexcitation (22). Loss of inhibitory cortical inputs to the brainstem and spinal cord autonomic nuclei could further exacerbate autonomic dysfunction in ALS (6). Peripheral denervation of postganglionic sympathetic neurons innervating the heart may also directly alter electrophysiological properties and automaticity of cardiomyocytes, providing substrate for AF (23).

Furthermore, oxidative stress and mitochondrial dysfunction, key pathophysiological processes in ALS pathogenesis, likely also contribute to cardiac dysregulation and arrhythmogenesis (4, 24). Reactive oxygen species generation and antioxidant depletion intrinsically alter calcium handling, membrane excitability, and conduction in cardiomyocytes, facilitating triggered activity and re-entry (25). Impaired mitochondrial energetics and dysfunctional quality control further promote oxidative damage and protein aggregation in conduction system tissue (26, 27). Besides, neuroinflammation is another salient feature of ALS mediated by reactive astrocytes, microglia, and cytokines such as TGF-β, TNF-α, and IL-6 (28). Chronic inflammation is linked with AF susceptibility and commonly observed in atrial biopsy specimens from AF patients (29). Pro-inflammatory cytokines may contribute to fibrotic remodeling of atrial tissue as well as direct effects on ion channels and calcium handling proteins that influence arrhythmogenesis (29). The relationship between systemic inflammation and AF was further supported by Liu et al., showing IL-6 and TNF-α levels had causal effects on increased AF risk (29). Hence, neuroinflammation in ALS could potentially mediate AF via circulating cytokines.

Additional pathways by which ALS may lead to AF include respiratory compromise and acid-base abnormalities from progressive respiratory muscle weakness (30). Hypoxemia, hypercapnia, and acidosis can directly provoke arrhythmias and may exacerbate underlying cardiovascular dysfunction in ALS patients (31).

Our study has several strengths supporting the validity of its findings. MR circumvents biases from confounding and reverse causation inherent to conventional epidemiological studies by utilizing genetic instruments rather than directly measured phenotypes. Two-sample MR leverages massive GWAS datasets, enhancing statistical power to detect causal effects. The SNPs applied as instruments for ALS were selected based on stringent criteria and passed all prerequisite assumptions. The MR results were robust across several complementary analysis methods, and sensitivity analyses showed no significant issues with pleiotropy or heterogeneity.

In brief, this two-sample MR study provides evidence that ALS may play a causal role in increasing susceptibility to AF, potentially mediated through autonomic dysfunction, oxidative stress, neuroinflammation, respiratory compromise, and medication effects. The findings add to prior observational data associating ALS with more significant cardiovascular morbidity and earlier mortality. This relationship appears biologically plausible given pathophysiological processes in ALS predisposing to cardiac dysregulation and arrhythmogenesis. AF may serve as a prognostic factor in ALS and portend more significant risks of complications that could hasten functional decline. Clinicians may need heightened vigilance for cardiac rhythm abnormalities when evaluating and managing ALS patients. Future research should continue exploring this association's underlying mechanisms and translational implications. Confirmation across other large cohorts and ancestries is warranted. Exploring potential druggable targets influencing both diseases could yield therapeutic advances. This study provides novel insights into the causal relationships between neurodegenerative and cardiovascular disorders.

However, some limitations should be acknowledged. Given the rarity of ALS, there is currently a lack of observational studies confirming a higher incidence of AF in ALS patients. Therefore, the relevance of assessing the impact of ALS on AF risk seems limited. Despite large sample sizes overall, the number of eligible genetic instruments for ALS was modest, restricting analytical power. The populations studied were of European ancestry, limiting generalizability to other ethnicities. Also, We cannot exclude the possibility of residual pleiotropy from unmeasured traits influencing the results. MR estimates represent the lifetime effects of genetically determined exposures, whereas acquired factors modifying disease risk may further mediate observed associations. As summary data were used, exploring gene-environment or gene-gene interactions was impossible. Finally, the specific biological mechanisms linking ALS and AF remain speculative based on our analysis. Further studies must elucidate the pathophysiological pathways involved and confirm reproducibility in other populations.

In conclusion, this two-sample MR study shows that ALS causally increases AF risk, though the biological mechanism requires further research. More studies are needed to confirm this association and uncover the underlying pathways.