Debating the link between atrial fibrillation and psychiatric diseases through Ca2+/cAMP signaling

Abstract

Atrial fibrillation (AF) is a very common tachyarrhythmia in clinical practice. Several risk factors, such as higher inflammatory marker levels, diabetes mellitus, hypertension, valvular disease, ischemic heart disease, heart failure, and obesity have been proposed to enhance the risk of AF, contributing to higher healthcare system utilization rates and socioeconomic costs. Some interesting studies also investigated the link between AF and psychiatric diseases. This article debates this link between AF and psychiatric diseases from the perspective of Ca²⁺/cAMP signaling.

Key Words: Ca²⁺/cAMP signaling; Psychiatric diseases; Atrial fibrillation; Inflammatory diseases; Neurotransmitters

Core Tip: Atrial fibrillation (AF) is recognized as one of the most frequently occurring tachyarrhythmias in clinical practice. This condition has been associated with an elevated risk of cardiovascular complications and increased mortality rates. Various contributing factors, including heightened levels of inflammatory markers, diabetes mellitus, hypertension, valvular disease, ischemic heart conditions, heart failure, and obesity, have been identified as potential influences on AF development. This article debates the link between AF and psychiatric diseases from the perspective of Ca²⁺/cAMP signaling.

INTRODUCTION

Multiple studies have explored the connection between atrial fibrillation (AF) and mental health disorders[1-3]. AF is recognized as one of the most frequently occurring tachyarrhythmias in clinical practice[1]. This condition has been associated with an elevated risk of cardiovascular complications and increased mortality rates[1,2]. Various contributing factors, including heightened levels of inflammatory markers, diabetes mellitus, hypertension, valvular disease, ischemic heart conditions, heart failure, and obesity, have been identified as potential influences on AF development[4]. These risk factors further contribute to greater healthcare utilization and increased socioeconomic burdens[5]. This article debates this link between AF and psychiatric diseases from the perspective of Ca²⁺/cAMP signaling.

Presenting the link between AF and psychiatric diseases

Interestingly, a study indicated a correlation between psychiatric conditions, such as depression and anxiety, and an increased likelihood of AF among individuals with diabetes[2]. Drawing from the Korea National Health Insurance Service database, researchers[2] included a cohort of 2512690 individuals diagnosed with diabetes who had no prior AF between 2009 and 2012. The study[2] examined the following five psychiatric conditions: expression, insomnia, anxiety, bipolar disorder, and schizophrenia. During the follow-up period, cases of newly diagnosed AF were identified, and a multivariate Cox regression analysis was conducted[2].

Another study[3] validated these findings indicating a higher occurrence of AF among individuals with psychiatric disorders, such as bipolar disorder and schizophrenia. Yang et al[3] analyzed data from the Taiwan National Health Insurance nationwide database to identify individuals diagnosed with bipolar disorder and schizophrenia, both with and without AF. The study examined a total of 927915 participants (463050 males and 464865 females) recorded between 2001 and 2008. Among them were 2963 (3.2%) individuals with schizophrenia (1650 males and 1313 females) and 5112 (5.5%) individuals diagnosed with bipolar disorder (1934 males and 3178 females)[3].

Several studies have examined the relationship between mental health disorders and the onset of AF. One multicenter cohort study[6] included 6644 patients in the United States, aged 45 to 84 years, who had no clinically recognized cardiovascular disease[6]. This study explored the association between depression and incident AF, revealing that depression increased the likelihood of developing AF by 34%[6]. Garg et al[6] concluded that depressive symptoms are associated with a heightened risk of AF. They also highlighted that their findings point to a significant segment of the American population that may face an elevated risk of AF and could benefit from targeted prevention strategies[6]. Additionally, another prospective cohort study[7] found that sleep disturbances predicted new-onset AF in both the Health eHeart Study and the Cardiovascular Health Study, with a median follow-up period of 11.6 years[7]. Christensen et al[7] concluded that sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention. These results are consistent with the findings already described in this article[2,3].

Several hypotheses suggest a potential link between AF and mental disorders. One such hypothesis involves neurotransmitters, such as dopamine, norepinephrine (NE), and serotonin, which have been recognized as contributing factors in the development of mental disorders[1]. Notably, elevated NE signaling outside the brain, indicative of sympathetic hyperactivity, has been observed in individuals with bipolar disorder and may play a role in the onset of AF[8]. Furthermore, research has identified abnormal autonomic nervous system activation in individuals with depression, specifically in the form of heightened sympathetic activity and diminished vagal regulation[9]. Interestingly, both depressive and hypertensive individuals exhibit sympathetic hyperactivity[9], suggesting a possible reciprocal influence between depression and hypertension. Additionally, autonomic nervous system imbalance, such as sympathetic hyperactivity, has been associated with the development of AF[10].

Debating the link between AF and psychiatric diseases

Our studies[9,11-15] provide valuable insights into this field. We have demonstrated that an imbalance in Ca²⁺ signaling is associated with sympathetic hyperactivity, which subsequently leads to hypertension, a factor that could also establish a connection between AF and mental disorders[9,12]. As previously mentioned, mental disorders such as depression and anxiety contribute to autonomic dysregulation, leading to increased catecholamine levels (sympathetic hyperactivity) and a diminished parasympathetic response[16]. Disruptions in autonomic tone, particularly sympathetic hyperactivity resulting from autonomic imbalance, have been linked to a greater occurrence of paroxysmal AF and the development of an arrhythmogenic environment in the atrium[16].

Additionally, inflammatory markers, such as C-reactive protein, which are often elevated in individuals with mental disorders[14], have also been associated with an increased risk of AF onset[17]. Our findings[11,14,15] reveal a strong relationship between Ca²⁺ signaling dysregulation and inflammation. Moreover, our studies[11-15] have established that higher cAMP concentrations can stimulate Ca²⁺ release from the endoplasmic reticulum, emphasizing the Ca²⁺/cAMP signaling interaction. Interestingly, increased Ca²⁺ levels can result in lower cAMP concentrations due to a negative feedback mechanism. Disruptions in this Ca²⁺/cAMP signaling dynamic may contribute to both mental disorders and AF[11,14,15]. Given that the interplay between these disorders may involve elevated Ca²⁺ concentrations[18-20], disturbances in Ca²⁺/cAMP signaling interactions become a plausible contributing factor. Supporting this hypothesis, research has detected cAMP signaling imbalances in the platelets of individuals with schizophrenia[18]. Further studies analyzing cerebrospinal fluid, blood platelets, and postmortem brain samples from schizophrenia patients have confirmed this dysregulation[18]. Similarly, disturbances in cAMP signaling have been observed in individuals with depression[9,19]. Figure 1 visually summarizes these findings.

Figure 1 Ca²⁺/cAMP signaling dysregulations and their consequences. Up arrow: Increasing; Down arrow: Decreasing.

Ca²⁺/cAMP signaling and psychiatric diseases

Since the first Nobel Prize which was awarded for the discovery of cAMP in 1971[21], other Nobel prizes related to cAMP have been awarded[22,23], e.g., in 1992 and 1994. Furthermore, Nobel prizes related to Ca²⁺ have also been awarded[24-26]. Considering the relevance of this field for medicine and physiology, it would be plausible to speculate that more Nobel prizes related to cAMP and Ca²⁺ may be awarded in the near future. Within this field, Expertscape has ranked Dr. Leandro Bueno Bergantin as one of the leading experts on cAMP in the United States from 2013 to 2023. Specifically, Expertscape.com has recognized Dr. Bergantin as a "World Expert" in cAMP, placing him as the second-ranked global authority on the subject during this period (2013-23). This prestigious designation highlights his significant expertise, as Expertscape relies on data from the National Institute of Health’s PubMed database to objectively assess and rank physicians and researchers based on their contributions to specific topics. Additionally, Dr. Bergantin has been acknowledged by Expertscape as an "Expert" in Ca²⁺ from 2013 to 2023.

It has now become evident that a dysregulation of Ca²⁺/cAMP signaling[11-15,18-20] is implicated in the link between inflammatory diseases, e.g., depression and obesity, and an interesting report published in 2025 validated this conclusion, reinforcing the concept of an interplay between inflammatory diseases[27]. The report concluded that poor nutritional status was linked to neuropsychiatric symptom deterioration[27]. A diet lacking essential nutrients has been found to induce depression- and anxiety-like behaviors in APP/PS1 mice[27]. Specifically, malnutrition worsened neuropsychiatric symptoms linked to the cAMP signaling pathway within the midbrain and striatum[27]. The authors referenced our previous study[19], reinforcing our findings that dysregulation of the Ca²⁺/cAMP signaling pathway might serve as an initial mechanism connecting obesity and depression, potentially influencing neurotransmitter and hormone release and suggesting a relationship between nutritional status and neuropsychiatric conditions[19,27]. The study underscored that the aggravation of affective symptoms in APP/PS1 mice due to malnutrition was associated with downregulation of the cAMP signaling pathway in both the midbrain and striatum[27]. A reduction in cAMP/PKA signaling activity may disrupt neuronal excitation and impair synaptic plasticity, contributing to depression[19,27], whereas stimulation of the cAMP/PKA signaling pathway has been linked to rapid antidepressant effects[19,27]. Finally, this study[27] contributes to validating our unified theory[28] that connects inflammation and Ca²⁺/cAMP signaling. Indeed, these results have been validated by a longitudinal study that analyzed the link between serum Ca²⁺ levels and the incidence of inflammatory disorders, e.g., metabolic syndrome (MetS), diabetes, and hypertension[29]. This report[29] was performed through cross-sectional and longitudinal analyses (period 2010-2016). At baseline, there were 27364 patients in this analysis. Chou et al[29] concluded that higher serum Ca²⁺ levels were linked with an enhanced risk of inflammatory disorders, e.g., MetS, diabetes, and hypertension; thus, corroborating our findings and conclusions[11-15,18-20]. Diabetes, MetS and hypertension are considered independent risk factors for AF[30-32]. Figure 2 summarizes previous discussion.

Figure 2 Increasing Ca²⁺ levels through an inflammatory stimulus inhibits adenylyl cyclase and consequently reduces cAMP levels, leading to hypertension, diabetes, metabolic syndrome, atrial fibrillation and mental disorders. cAMP: 3'-5'-cyclic adenosine monophosphate; AC: Adenylyl cyclase; PDE: Phosphodiesterase. Up arrow: Increasing; Down arrow: Decreasing.

CONCLUSION

In conclusion, it would be fascinating to analyze the Ca²⁺/cAMP ratio in clinical studies related to AF and mental disorders[33]. There is a well-established connection between Ca²⁺ signaling, such as intensified Ca²⁺ signals, and inflammatory responses. Additionally, cAMP plays a role in regulating anti-inflammatory mechanisms. It is concluded that both signaling pathways play a significant role in the link between AF and mental disorders, thus impacting the pharmacotherapy involving Ca²⁺ channel blockers and pharmaceuticals which increase the levels of cAMP. Finally, it is recommended that future research includes clinical trials or experimental studies. Such clinical validation would provide concrete evidence to support the hypotheses discussed in this article, and will enhance the credibility of this article for clinical application.