Introduction

The heart’s rhythm is controlled by electrical signals produced by the atria, located in the heart’s upper chambers. Atrial Fibrillation (Afib) occurs when these signals become chaotic and irregular. The disruption of the heart’s signal can lead to several complications, such as stroke and heart failure. This is a common condition with different forms: 

• Paroxysmal - on and off episodes lasting less than 7 days
• Persistent - episodes continue for at least 7 days straight
• Permanent - constant episodes

Understanding persistent Afib is crucial as it does not spontaneously return to normal heart rhythms, whereas paroxysmal Afib does. This means that persistent Afib risks progressing into permanent Afib. In this article, we will focus on the electrophysiological mechanisms of persistent atrial fibrillation. This focuses on the electrical signals which control the heart in Afib and how they can be remodelled to restore the heart’s rhythms.¹

Electrophysiology of normal atrial function

To keep the body supplied with oxygen-rich blood, the heart needs to beat in a steady, regular rhythm. This steady heartbeat controls blood pressure and keeps blood moving.

The heart has four chambers, including two upper ones called atria, one on each side. These atria receive blood and send out electrical signals that control how the heart beats. When the atria fill with blood, they contract and push it into the lower chambers, called ventricles.

The ventricles have strong, muscular walls that contract forcefully to pump blood either to the lungs or the rest of the body. This process keeps blood flowing in one direction. Special valves between the chambers make sure blood doesn’t flow backwards.

The left side of the heart sends oxygen-rich (oxygenated) blood to the body, and the right side sends deoxygenated blood to the lungs to pick up more oxygen.²

Within this signal circuit, there are 4 electrical phases. The cardiomyocytes, heart muscle cells that contract, experience different movements of ions across the cell membrane through ion channels. This causes a temporary shift in electrical charge called an action potential.³

Phase 0: Depolarisation 

In this phase, there is a rapid increase in sodium ions (Na+) through the cell membrane via voltage-gated sodium channels. This causes a spike in the membrane action potential of the cardiomyocytes, which become very positively charged.³

Phase 1: Early repolarisation 

The sodium channels close, stimulating the opening of the potassium channels. As a result, the potassium ions (K+) briefly leave the cell. This loss of positive charge brings partial balance back to the cardiomyocytes, resulting in a partial repolarisation.³

Phase 2: Plateau

At this point, the membrane potential is relatively stable. This is brought about by the inward movement of calcium ions (Ca2+) through calcium channels and the outward movement of K+. This is maintained by the sodium-potassium pump.³

Phase 3: Final repolarisation 

The calcium channels close, and the potassium channels remain open. This results in a rapid efflux of K+, returning the membrane potential to the resting state.³

Phase 4: Resting membrane potential 

This is the baseline membrane potential of the cardiomyocytes, which is ready to be triggered by the next action potential.³

This is all regulated by the sinoatrial (SA) node, the heart’s primary pacemaker, which produces the electrical signals that cause the atria to contract, initiating the heartbeat. The signals travel to the atrioventricular (AV) node, which is crucial for regulating signals between the atria and ventricles by preventing the ventricles from contracting excessively during atrial contractions. At the AV node, the signal is delayed to allow for the atria to fully empty the blood into the ventricle.⁴ 

Pathophysiology of persistent atrial fibrillation

The cardiac remodelling that occurs due to persistent Afib causes structural and electrical changes in the atria, contributing to the disruption of the cardiac rhythm. Structural remodelling occurs through changes in the cellular matrix and fibrous tissue, which can impact the length of electrical signal transmission and electrical remodelling.⁵

Structural problems in the heart, like those caused by high blood pressure, damaged valves, or blocked arteries, are the most common reasons for ongoing Afib. But scientists still don’t fully understand how Afib develops.

Some research suggests that genetics may play a role. For example, a mutation on chromosome 10 can cause certain pores in heart cells to stay open longer than they should. This increases activity in ion channels, which can upset the electrical balance in the heart and make it more likely for irregular rhythms to occur.⁵

Cardiovascular diseases can over-excite atrial activity. These triggers are mostly found around the pulmonary vein and cause chaotic firing of electrical heart signals. These impulses can vary, causing an abnormal flow of blood through the heart.  

Triggering factors include:

• Atrial ischemia 
• Inflammation 
• Alcohol 
• Drug use 
• Neurological disorders 
• Hormonal disorders 
• Advanced age 
• Genetic factors⁵

Atrial remodelling

A key idea in atrial fibrillation (Afib) is “Afib begets Afib,” meaning that once someone has Afib, it can change the heart’s structure and function, making future Afib episodes more likely. That’s why early treatment is important to prevent it from getting worse.⁶

These changes in the atria of the heart are called atrial remodelling. There are two main types:

1. Electrical remodelling:
   The heart’s tiny electrical channels and pumps change. For example, some calcium (Ca2+) channels decrease while potassium (K+) movement increases. This causes the heart cells to become more excitable and fire rapidly, helping Afib continue. Higher calcium levels in the cells also contribute to scarring (fibrosis), high blood pressure (hypertension), and changes in nerve signals⁷
2. Structural remodelling:
   The atria can get bigger and develop fibrosis, which means scar tissue builds up. This scar tissue disrupts the way electrical signals travel between heart cells, making it harder for the heart to beat normally and affecting the whole heart’s function⁷
   

Together, these changes make the heart more vulnerable to persistent Afib.

Functional and contractile remodelling

This remodelling refers to the changes in shape, size and function of the heart as a result of disease or injury. This has a wider effect on the heart’s ability to pump blood to the body effectively, which has several consequences:

• Reduced cardiac output
• Increased risk of heart failure
• Thrombus formation from changes in arterial size. This is due to the increased risk of blood clot formation in the heart chambers

The atria experience fibrosis, increased muscle thickness and dilation. All of which affects its ability to contract and relax effectively, impairing blood transport. Hence, atrial function gradually diminishes. 

The contractile remodelling refers to the atria’s ability to contract. In persistent Afib, the atria lose their contractile ability.⁸

Maintenance mechanisms of persistent AF

The main obstacle in treatment for Afib patients is maintaining a regular heartbeat. Several factors must be considered, such as:

• Previous health conditions 
• Duration of persistent Afib 
• Extent of atrial remodelling 
• Risk factor management

Time is of the essence in combating atrial remodelling. The earlier the intervention, the easier it is to reverse the process. It was found that the longer the remodelling of the atria was allowed to continue, the longer the recovery time. Progressive remodelling of the heart over long periods makes it more difficult to undo. Therefore, managing the associated risk factors combined with timely intervention can increase the chances of structural remodelling reversal. 

• Anti-arrhythmic therapy works to inhibit ion channels, thus reducing the activity of chaotic electrical signals
• Electrical cardioversion and radiofrequency ablation are used to restore the sinus rhythm by reversing the atrial remodelling. These techniques have shown significant progress in decreasing atrial size and improving atrial function
• Newer therapies are focusing on the genetic origins of persistent Afib and altering remodelling pathways⁸

Summary

Persistent atrial fibrillation (AF) is a long-lasting form of AF that continues for more than seven days and often requires medical intervention. It is sustained by ongoing atrial remodelling, which includes electrical, structural, and functional changes in the heart. 

Electrical remodelling involves altered ion channel activity, such as reduced L-type calcium currents and increased inward potassium currents, which promote abnormal reentrant circuits and increase the heart's excitability. 

Structural remodelling is marked by atrial dilation, fibrosis, and cell death, with scar tissue disrupting normal electrical pathways and encouraging uneven conduction. 

Functional remodelling reduces the atria’s ability to contract effectively, leading to impaired calcium handling and a loss of the "atrial kick," which increases the risk of blood clots. 

Clinically, persistent AF is harder to treat with standard therapies. Antiarrhythmic drugs may be less effective due to changes in ion channels, and catheter ablation often requires a more targeted approach. Because remodelling can become irreversible, early treatment is crucial. Future therapies are being developed to target the root causes of remodelling, including anti-fibrotic drugs and gene-based treatments.

FAQs

How does electrical remodelling promote atrial fibrillation?

 Electrical remodelling involves changes in ion channel expression, such as reduced calcium currents and increased potassium currents. This leads to a shorter refractory period and a reduced wavelength for reentrant circuits, making it easier to sustain AF.

What role does atrial remodelling play in sustaining persistent AF?

Atrial remodelling alters the electrophysiological and structural properties of the atrial tissue. Electrical remodelling shortens the atrial refractory period, and structural remodelling promotes fibrosis. Functional remodelling impairs atrial contractility. These changes create a substrate that allows AF to persist.

What is atrial fibrosis, and why is it important in AF?

Atrial fibrosis is the replacement of normal heart tissue with fibrotic (scar-like) tissue, often driven by inflammation, oxidative stress, and ageing. Fibrosis disrupts normal electrical conduction and contributes to the formation of reentry circuits that perpetuate AF.

Are there new therapies targeting atrial remodelling?

Research is ongoing into therapies that target the underlying remodelling processes, such as anti-fibrotic drugs, gene therapy, and modulators of ion channels. These treatments aim to modify the atrial substrate and potentially prevent AF progression.