Atrial fibrillation (AF) stands as one of the most prevalent heart arrhythmias, and its implications extend beyond mere inconvenience. It is not only a widespread condition but also a significant contributor to mortality rates worldwide. In this comprehensive analysis, we delve into the intricacies of AF, exploring its prevalence, symptoms, risk factors, and its potential link to microclots that may change our understanding of this heart condition.
The Global Burden of Atrial Fibrillation AF, often abbreviated as AFib, affects millions of individuals across the globe. In fact, its global incidence is estimated to account for approximately 1% of the population, with regional variations that can be significant. South Asia, for instance, reportedly has an AF incidence that is 12 times lower than North America. The prevalence of AF is on the rise, with the condition representing a substantial portion of healthcare expenditure, even reaching up to 1% of the budget of the National Health Service (NHS) in the past.
Understanding Atrial Fibrillation Atrial fibrillation is characterized by a supraventricular tachyarrhythmia with uncoordinated atrial electrical activation, leading to ineffective atrial contraction. Electrocardiographic features of AF include irregular R-R intervals (in cases where atrioventricular conduction is unaffected), the absence of distinct repeating P waves, and irregular atrial activations.
AF is not a monolithic condition; it encompasses various subclasses, each with its own severity levels and potential complications. Importantly, individuals with AF often present with multimorbidity, polypharmacy, and frailty, which significantly impact their treatment and outcomes.
The Menace of Clot Formation One of the most critical concerns associated with AF is the increased likelihood of clot formation within the atrial chamber. Clots that form in the atrium can potentially escape and lead to severe health consequences. Research has consistently linked AF to heightened risks of strokes, coronary heart disease, including myocardial infarction, or a combination of both. However, it’s worth noting that due to the often asymptomatic nature of AF, many studies have examined the incidence of cardiovascular events in individuals with pre-existing AF.
Microclots and the Genesis of AF Recent research has shed light on a particular type of microclot, referred to as ‘fibrinaloid,’ that possesses unique characteristics. These microclots, which range in size from 2-100 mm, are resistant to fibrinolysis, meaning they persist in the bloodstream. They contain various proteins and exhibit an amyloid nature, making them especially challenging to dissolve.
Several factors, including bacterial cell wall substances and the spike protein of SARS-CoV-2, have been identified as catalysts for the formation of these fibrinaloid microclots. This discovery raises the intriguing possibility that these microclots may play a role in the development of AF, adding a new dimension to our understanding of the condition.
A Systems Biology Approach To comprehend the potential connection between fibrinaloid microclots and AF, a systems biology perspective is essential. This approach considers the vast body of evidence from various sources to construct a coherent understanding of the disease’s mechanisms. By examining comorbidities and the relationships between diseases, researchers can gain valuable insights into the complex web of factors contributing to AF.
Risk Factors vs. Covariates In the realm of medicine, identifying risk factors is a common pursuit. However, it is crucial to distinguish between true risk factors and covariates. Covariates are variables that may correlate with a condition but do not necessarily cause it. Establishing causality often requires longitudinal data or experimental manipulation of independent variables.
The Role of Coherence and Comorbidities The principle of coherence is a valuable guide in understanding diseases like AF. When multiple lines of evidence converge on the same mechanism, it becomes more likely to be true. Additionally, considering comorbidities and associations between related diseases can enhance our understanding of the disease in question.
Fibrinaloid Microclots: Unveiling a New Understanding
Before we delve deeper into the potential connection between fibrinaloid microclots and atrial fibrillation (AF), it’s essential to understand the nature of these microclots and how they differ from conventional blood clots.
Fibrinaloid Microclots Unveiled Clotting and clot removal are dynamic processes that occur regularly within the human body to respond to various needs, including wound healing. At the core of this process lies soluble fibrinogen, a protein complex typically consisting of three different polypeptides (a2β2γ2) with a molecular weight of approximately 340 kDa. Thrombin, a serine protease, plays a crucial role in this process by removing two fibrinopeptides from fibrinogen, exposing “knobs” and “holes.” This exposure initiates a self-assembly process in which fibrin monomers polymerize to form staggered oligomers, further extending into protofibrils. These protofibrils then aggregate laterally to create fibers, which ultimately branch out to form a complex three-dimensional network representing clots.
In conventional clot formation, the typical fiber diameter ranges from a few hundred nanometers (approximately 100-400 nm), exhibiting a fractal morphology. This means that a single “unit” of fibrin fiber contains hundreds of fibrinogen monomers contributing to its diameter at any given point. Clots are eventually degraded by plasmin, an enzyme involved in fibrinolysis, with multiple activators and inhibitors regulating this process.
However, in certain pathological conditions, clots may not form correctly, adopt anomalous conformations, and degrade at unusually slow rates. This gives rise to what we refer to as fibrinaloid microclots, which may persist in specific diseases.
The Anomaly of Fibrinaloid Microclots Early electron microscope studies conducted by researchers revealed that the fibrin fibers in various chronic and inflammatory conditions did not resemble the well-structured appearance of normal clots. Instead, they exhibited a chaotic and tangled appearance, resembling parboiled spaghetti stuck together, a phenomenon initially termed “dense matted deposits.”
Remarkably, these anomalous fibrin fibers could be induced by the presence of free iron, a critical finding that linked their formation to certain conditions. Healthy blood exposed to ferric chloride showed this transformation. These observations indicated that these microclots were not typical in structure or composition.
Amyloid Transformation The concept of amyloid formation is crucial to understanding the nature of fibrinaloid microclots. Amyloid formation involves the stable folding of proteins into a beta-sheet-rich structure without alterations in their primary amino acid sequence. This phenomenon is associated with a range of diseases known as “classical amyloidoses,” characterized by the presence of unfolded protein forms, such as Abeta and alpha-synuclein. However, proteins like insulin and lysozyme can also undergo amyloid transformation.
Prion proteins represent the epitome of amyloid behavior, adopting stable amyloid-type states without sequence changes and catalyzing their own conformation. Studies later confirmed that the “dense matted deposits” observed in fibrinaloid microclots indeed exhibited amyloid characteristics. They could be stained with established amyloid stains like thioflavin T and commercial “Amytracker” stains. Furthermore, electron and fluorescence microscopy images correlated to reinforce this conclusion.
Implications of Amyloid Character Fibrinaloid microclots, akin to prion proteins, display exceptional resistance to proteolysis, particularly fibrinolysis. Their sizes vary widely, typically falling within the 2-100 mm diameter range. Importantly, these microclots can impede blood flow by blocking capillaries of suitable diameter, leading to reduced oxygen transfer to tissues. This phenomenon has been implicated in various medical conditions, including Long Covid, with symptoms such as fatigue, post-exertional symptom exacerbation, and autoantibody induction.
The presence of amyloid-type fibrinaloid microclots in muscle tissues of Long Covid patients further underscores their significance in health and disease. This newfound understanding of fibrinaloid microclots opens doors to exploring their role in conditions like atrial fibrillation and could potentially revolutionize our approach to diagnosis and treatment.
Having delved into the nature of fibrinaloid microclots, we now turn our attention to the intriguing link between these microclots and the risk factors associated with atrial fibrillation.
Risk Factors for Atrial Fibrillation: Unraveling the Complex Web
The journey into understanding the intricate connections between fibrinaloid microclots and atrial fibrillation (AF) takes us through a myriad of risk factors, some conventional and others more obscure. Let’s explore these factors to uncover the potential role of fibrinaloid microclots in the development of AF.
Risk Factors for AF Not Directly Linked to Disease Comorbidities Numerous studies have explored how the prevalence of AF varies based on factors such as age, gender, and BMI, which are not typically considered comorbidities themselves. These factors are often associated with AF, and it is essential to examine if they also correlate with the incidence of microclots. Age, in particular, is a well-established risk factor for AF, with the prevalence increasing significantly with advancing age. However, when assessing the connection between these factors and the presence of microclots, no robust associations emerge. This observation is significant because it suggests that while age and gender may be linked to AF, they do not necessarily correlate with microclots. This finding challenges the notion of a strong causal relationship between microclots and AF.
Lifestyle-Related Risk Factors Among the lifestyle factors, BMI stands out. While it could be viewed as both a cause and an effect, its significance in AF risk varies greatly among individuals. Factors like alcohol consumption and urban vs. rural living choices are more directly influenced by individual decisions. Urban living often exposes individuals to higher levels of particulate matter, primarily from vehicular emissions, which can have substantial health effects. These findings highlight the importance of environmental factors and suggest a potential role for particulate irritants, which may include fibrinaloid microclots.
Risk Factors Associated with Disease Comorbidities Chronic inflammatory diseases share common characteristics, such as inflammation, oxidative stress, and iron dysregulation. These shared properties suggest a possible common cause, labeled as “Y” in Figure 2. Infectious origins are strongly implicated in these diseases, adding a layer of complexity to their etiology.
Table 3 provides an overview of various diseases, their associated comorbidities, and their potential links to AF. Strikingly, many seemingly non-communicable diseases listed in Table 3 can be traced back to infectious origins. Components of both bacteria (e.g., lipopolysaccharides, lipoteichoic acid) and viruses (e.g., SARS-CoV-2 spike protein) have been identified as inducers of fibrinaloid microclots.
Connecting the Dots: Comorbidities and AF Table 4 delves deeper into the known comorbidities of various diseases and their relationships with AF. While longitudinal trends are often challenging to establish due to limited long-term screening data, associations between these diseases and AF are evident. This suggests that these diseases are interconnected, potentially sharing a common cause or causal chain. This intricate web of relationships raises questions about whether these diseases contribute to AF or vice versa, or if there is an underlying cause that triggers both.
Infections and Their Association with Atrial Fibrillation: Unveiling the Link
Exploring the relationship between infections and atrial fibrillation (AF) provides crucial insights into the potential role of infectious agents in triggering AF. Here, we delve into examples where infections have been observed to lead to AF, shedding light on this intriguing connection.
- Community-Acquired Pneumonia: Studies indicate that 7.6% of cases of community-acquired pneumonia result in new-onset AF (Corica et al. 2023b). This highlights the potential impact of respiratory infections on cardiac rhythm.
- COVID-19 and AF: The COVID-19 pandemic has brought attention to the association between SARS-CoV-2 infection (COVID-19) and AF. Multiple studies have reported AF as a common occurrence following COVID-19 infection (Abbasi 2022; Al- Abbas et al. 2021; Bagnato et al. 2022; Bhatla et al. 2020; Duckheim and Schreieck 2021; García- Granja et al. 2021; Kanuri et al. 2023; Mouram et al. 2022; Niehues et al. 2022; Rav-Acha et al. 2021; Wu et al. 2023a). Notably, a large study found that the Odds Ratio (OR) for AF 365 days after COVID-19 was significantly elevated compared to a well-established control group (Berman et al. 2023). This suggests a strong link between COVID-19 and subsequent AF.
- Protective Effect of DOACs: Interestingly, prior use of Direct Oral Anticoagulants (DOACs) has been found to be protective against AF following SARS-CoV-2 infection (Azaña Gómez et al. 2022). However, it’s essential to note that AF in individuals on anticoagulants may increase the risk of bleeding (Rubini- Costa et al. 2022).
- Mortality and AF in COVID-19: Studies have reported increased mortality from acute COVID-19 in patients with AF, especially among older individuals (Musikantow et al. 2021; Pardo Sanz et al. 2021; Zuin et al. 2021). This underscores the significance of AF as a comorbidity in the context of COVID-19.
- Long COVID and AF: Long COVID, characterized by persistent symptoms after acute COVID-19, has also been associated with AF (Huseynov et al. 2023). This suggests that the effects of COVID-19 on cardiac health may extend beyond the acute phase of the infection.
- Vaccination and AF: Notably, cardiac arrhythmias, including AF, have been reported following COVID-19 vaccination (Pari et al. 2023). Some vaccines contain components like the spike protein or RNA coding for it, which is known to induce microclots (Grobbelaar et al. 2022; Grobbelaar et al. 2021).
- Sepsis and AF: In cases of sepsis, the risk of new-onset AF increases significantly, especially as sepsis progresses to severe sepsis and septic shock. This phenomenon is associated with poorer outcomes (Aibar and Schulman 2021; Bashar et al. 2020; Bosch et al. 2019; Corica et al. 2022; Downes et al. 2023; Honorato et al. 2023; Induruwa et al. 2022; Klein Klouwenberg et al. 2017; Kuipers et al. 2014; Proietti and Romiti 2021; Walkey et al. 2013; Xiao et al. 2021). Sepsis often involves coagulopathies, and anticoagulants have shown protective effects in sepsis, particularly in the presence of disseminated intravascular coagulation (DIC) (Meziani et al. 2017; Scarlatescu et al. 2017; Qi et al. 2023; Umemura et al. 2023; Umemura and Yamakawa 2018).
These findings collectively raise the intriguing possibility that coagulopathies, including microclots, may precede the onset of AF. The association between infections and AF, along with the presence of coagulation abnormalities, points to a complex interplay between infectious agents, microclots, and cardiac arrhythmias. Further exploration of potential biomarkers may provide insights into the mechanisms linking infections to AF and offer new avenues for diagnosis and treatment in the future.
The Intriguing Link Between Infection, Stroke, and Other Diseases
The connection between infection, stroke, and various diseases reveals a complex interplay that has significant implications for understanding the underlying mechanisms. Here, we explore the associations and potential causative factors in these interactions.
- Stroke and Infection: Stroke and infection are frequently associated with each other (Bustamante et al. 2017; Kazemi et al. 2021; Kishore et al. 2018; Shim and Wong 2016; Westendorp et al. 2018). When they co-occur, they often lead to unfavorable outcomes (Vermeij et al. 2009; Westendorp et al. 2011), suggesting the possibility of co-causality. While infections that occur after a stroke are commonly referred to as ‘post-stroke infections,’ it is plausible that earlier stages of infection may precede the stroke event itself (Westendorp et al. 2011). Evidence supporting this includes similarities in changes observed in the gut microbiome, which could be predictive of both stroke occurrence and post-stroke infection (Haak et al. 2021). However, prophylactic antibiotics have shown limited effectiveness in preventing post-stroke infection, possibly because the amount of bacterial cell wall product required to induce microclots is exceedingly small (Pretorius et al. 2016c; Pretorius et al. 2018c). Moreover, certain antibiotics can increase the release of amyloidogenic bacterial cell wall materials, potentially offsetting the benefits of antibacterial treatment (Jackson and Kropp 1992; Mickiewicz et al. 2019; Opal et al. 1996; van Langevelde et al. 1998).
- Parkinson’s Disease and Infection: A similar co-association and potential causation involving infections can be observed in Parkinson’s disease (Dardiotis et al. 2018; Meng et al. 2019; Smeyne et al. 2021; Wang et al. 2020). Antibiotics have not proven to be protective in this context (Huang et al. 2018).
These intriguing connections between infection, stroke, and other diseases suggest the need for a deeper understanding of the underlying mechanisms. It appears that the relationships are not straightforward, and factors such as the microbiome, bacterial cell wall products, and amyloidogenic materials may play significant roles. Further research is essential to unravel the complexities of these interactions and their potential implications for disease prevention and treatment.
Discussion, Conclusions, and a Glimpse into the Future
In this exploration of atrial fibrillation (AF) and its potential links to fibrinaloid microclots, we have uncovered a broader perspective on cardiovascular disorders and their shared characteristics. It is evident that various cardiac and cardiovascular conditions, including type 2 diabetes, heart failure, myocarditis, peripheral arterial disease, and disorders of pregnancy, can be accompanied by thromboses and vascular complications. Even neurodegenerative diseases like Alzheimer’s and Parkinson’s have shown associations with vascular issues. Cardiac amyloidosis is of particular interest in this context.
The multifaceted nature of AF patients’ clinical complexity has led to a holistic and integrated approach to AF care, as recommended in guidelines. However, there remains a need to investigate and consider new risk factors for AF, including the potential role of fibrinaloid microclots. While these microclots have been implicated in various diseases, their independent contribution to AF risk has not yet been thoroughly studied, and this represents an area ripe for future research.
Looking ahead, a deeper understanding of the common factors linking these syndromes, particularly the involvement of fibrinaloid microclots, could lead to breakthroughs in the prevention and management of AF and related cardiovascular conditions. By recognizing and addressing shared mechanisms, researchers and healthcare providers can develop more effective strategies for diagnosing, treating, and ultimately preventing these diseases.
Funding Acknowledgment: The research conducted by EP and DBK was supported by funding from the NRF of South Africa, SA MRC (self-initiated research grant), Balvi Foundation, and the Novo Nordisk Foundation. It’s important to note that the content and findings reported in this study are the sole responsibility of the researchers and do not necessarily reflect the official positions or sentiments of the funding organizations.
reference link : https://www.preprints.org/manuscript/202401.1945/v1
