Introduction

Left atrial enlargement (LAE) is the unusual increase in the size of the left atrium. It generally occurs due to a sustained rise in left atrial pressure. It is a clinically relevant finding, often identified in echocardiography or chest imaging. LAE is usually associated with various cardiovascular disorders such as hypertension, mitral valve disorders and heart failure. The presence of LAE is a predictor of serious cardiovascular conditions like atrial fibrillation, stroke and heart failure. Therefore, identifying and assessing the root causes of LAE at an early stage is essential to prevent the risk of deadly complications.¹

Pathophysiology

The left atrium is the reservoir chamber of the heart that collects blood from the pulmonary veins and regulates the filling of the left ventricle. The left atrium is connected to the left ventricle by the mitral valve. Enlargement of the left atrium can result from a persistent rise in pressure, an increased volume of blood within the atrium, or a combination of both factors. 

This enlargement triggers the remodelling of the atrial structure as a compensatory mechanism to the pressure and volume overload. Atrial remodelling involves an alteration in the size or function of the atrium, the extent of which depends on the nature, severity, and duration of the root cause of the overload. These changes can alter atrial contraction and conduction, leading to cardiac arrhythmias such as atrial fibrillation. Atrial remodelling can occur acutely within a week, which is usually reversible, or chronically over a period of time, which is mostly irreversible.¹

Causes

Left atrial enlargement can occur due to congenital and acquired disorders:¹

• Left ventricular diastolic dysfunction
• Atrial fibrillation
• Hypertension
• Obesity
• Aortic stenosis
• Mitral valve disease
• Left ventricular failure
• Left atrial masses

Genetic factors in LAE

The knowledge of the genetic impact on the dimension of the atrium helps in:²

• Identifying the people who are at higher risk of developing an enlarged left atrium at an early stage, even in the absence of high pressure or blood volume overload
• Understanding the structure and function of the heart at the molecular level
• Discovering novel therapeutic targets for the treatment of left atrial enlargement

Common genetic variants (GWAS findings)

Genetic testing has successfully identified 18 genetic loci associated with LAE in subjects without a history of heart failure or myocardial infarction. These genetic regions have been proven to be associated with genes involved in cardiomyopathy and arrhythmia. For example:¹

• Cardiomyopathy: MYO18B, TTN, DSP, ANKRD1 
• Arrhythmia: TTN, CASQ2, MYO18B, C9orf3 

The genetic risk of atrial fibrillation affects the structure of the atria, even before the diagnosis of atrial fibrillation, indicating an inherent relationship between the two.³

Genetic study on Caribbean Hispanics

A study revealed on Caribbean Hispanics that:² 

• Genetic factors have a medium impact on the alteration of left atrial size
• Multiple genes on chromosome 17p10 may regulate the size of the left atrium
• Polymorphism in the Myocardin (MYOCD) gene influences the size of the left atrium

Phenome-wide association study 

In females, a genetic predisposition to obesity is linked to an increase in left atrial diameter. In contrast, in males, genetic risks for conditions such as coronary artery disease (CAD) and atrial fibrillation are independently associated with left atrial diameter. These findings underscore the importance of developing sex-specific prevention strategies.⁴

Emerging biomarkers in LAE

Biomarkers indicate the pathological process occurring in the atrium due to pressure and volume overload. The presence of LAE is often associated with elevated levels of these biomarkers.¹

Cardiac-specific biomarkers

Cardiac damage or remodelling contributes to elevated levels of cardiac-specific biomarkers such as:^1,5

• Atrial natriuretic peptide
• Brain natriuretic peptide
• Troponins

Fibrosis-related biomarkers

Atrial remodelling is characterised by an increase in interstitial fibrosis and distinct changes in the heart's structure, leading to an enlarged atrium. The prothrombotic factors that together boost atrial fibrosis are:^1,5

• Angiotensin II
• Aldosterone
• Transforming growth factor-beta TGF-β
• Platelet-derived growth factor 
• Matrix Metallopeptidase-2 (MMP-2)
• Procollagen type I C-terminal propeptide (PICP)

Inflammatory markers

Atrial remodelling is influenced by systemic inflammation promoted by:¹

• C-Reactive protein (CRP)
• Interleukins (IL-6, IL-1β)
• Cytokines

MicroRNA biomarkers 

MicroRNAs (miRNA) influence the key processes of atrial remodelling, fibrosis, and inflammation of LAE. MicroRNA biomarkers can be measured by simple blood tests, which help monitor the changes frequently. The key MicroRNAs are:⁶ 

•  miR-21
•  miR-29b-3p

Metabolic biomarkers

Obesity is proven to be an important predictor of left atrial enlargement as people grow older, posing a greater risk than hypertension.¹ The hormones secreted by adipose tissue that have a positive association with cardiac remodelling and left atrial size are:⁷

• Adiponectin
• Resistin

Summary

Left atrial enlargement usually indicates an underlying cardiac pathology and is a predictor of life-threatening complications. Hence, the treatment of the underlying cause of the enlargement is important. Biomarkers help to understand the pathologic process of the condition and determine the prognosis and treatment of the condition. Similarly, identifying genetic factors helps to discover new therapeutic targets for the disease.