The Complex Relation between Atrial Cardiomyopathy and Thrombogenesis

Abstract

Heart disease, as well as systemic metabolic alterations, can leave a 'fingerprint' of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability.

Keywords: atrial cardiomyopathy; atrial fibrillation; cardiac remodeling; thrombogenesis.

Figure 1

Schematic representation of the relation between AF and atrial cardiomyopathy. Risk factors for AF lead to pathological structural and functional changes in the atria. These result in atrial cardiomyopathy of which AF is its most relevant clinical manifestation. Once AF develops, it supports and accelerates the ongoing pathological changes in the atria.

Figure 2

Atrial cardiomyopathy contributes to thrombogenesis. Unlike in the healthy atrium (left side), in the cardiomyopathic atrium (right side), pathological structural and functional changes (e.g., contractile dysfunction, atrial dilation, fibrosis, and fat infiltration) lead to aberrant blood flow and stasis in the atria cavity, endothelial dysfunction (and structural changes), and hypercoagulability, predisposing patients to thrombogenic events within the atrial cavity. Furthermore, hypoxic conditions, together with vascular leakage, may contribute to the activation of the coagulation cascade within the myocardial tissue. Abbreviations: NO = nitic oxide; vWF = von Willebrand factor; TF = tissue factor.

Figure 3

Activation of coagulation promotes atrial cardiomyopathy. Activated coagulation factors, such as Thrombin and FXa, modulate cellular processes via the activation of PAR expressed on cardiac cells. These processes, such as inflammation, fibrosis and cellular hypertrophy, may contribute to the worsening of atrial cardiomyopathy. Abbreviations: PAR = protease-activated receptor; FXa = Factor × activated; IL6 = Interleukin 6; CCL2 = C-C motif ligand 2; NNPA = atrial natriuretic peptide.

Figure 4

The complex association between AF and stroke. Monodirectional causation (left): various comorbidities lead to the onset of AF, followed by the activation of the coagulation system, and ultimately stroke. Multidirectional causation (right): atrial cardiomyopathy and hypercoagulability cause each other and share common pathophysiological pathways. These pathways, which may occur within and/or outside the atrial endothelium, can contribute to both proarrhythmic and prothrombotic mechanisms, resulting in the concomitant increased risk of AF and stroke.