Atrial Cardiomyopathy: An Unexplored Limb of Virchow's Triad for AF Stroke Prophylaxis

Abstract

The most dreaded complication of atrial fibrillation is stroke, and 70-80% of patients with AF-related stroke die or become disabled. The mechanisms of thromboembolism in AF are multifactorial, with evidence demonstrating that all three criteria of Virchow's triad are satisfied in AF: abnormal stasis of blood, endothelial damage, and hypercoagulability. Mechanistic insights into the latter two limbs have resulted in effective stroke prophylactic therapies (left atrial appendage occlusion and oral anticoagulants); however, despite these advances, there remains an excess of stroke in the AF population that may be due, in part, to a lack of mechanistic understanding of atrial hypocontractility resulting in abnormal stasis of blood within the atrium. These observations support the emerging concept of atrial cardiomyopathy as a cause of stroke. In this Review, we evaluate molecular, translational, and clinical evidence for atrial cardiomyopathy as a cause for stroke from AF, and present a rationale for further investigation of this largely unaddressed limb of Virchow's triad in AF.

Latest Insights into Mechanisms behind Atrial Cardiomyopathy: It Is Not always about Ventricular Function

“…There is an intimate relationship between atrial activity and ventricular systolic and diastolic performance; the main role of the left atrium (LA) is to manage the left ventricular filling pressures and cardiovascular performance by acting as a reservoir for the venous return during ventricular systole and as an additional pump for ventricular filling via an active atrial contraction [ 2 , 4 , 5 ].…”

“…The pathways leading to thrombogenesis in AF are various, and there is evidence to suggest that all three elements of Virchow’s triad are present in AF: abnormal stasis of blood flow, endothelial dysfunction, and hypercoagulability [ 4 ].…”

“…Specific echocardiographic assessment of atrial wall velocities in AF patients revealed that there is a significant impairment of atrial contractility. Several hypotheses were raised concerning the link between atrial contractile dysfunction and the increased stroke risk: atrial hypocontractility persists for up to two months following AF conversion to sinus rhythm; atrial dilation and hypocontractility may aggravate despite catheter ablation of AF [ 4 ]; atrial hypocontractility alone (without concomitant AF) is an independent risk factor for stroke [ 33 ]. …”

“…IL-6 can also interfere with the pro-thrombotic state during AF, by endothelial activation and platelet aggregation [ 4 , 10 ]. Increased levels of fibrinogen and TNF-α are also related to the persistence of AF and, therefore, to a continuum of atrial remodeling [ 13 ].…”

“…Another potential therapeutic target in improving atrial contractility is the Ca 2+ - sensitizing agent levosimendan. This option is sustained by some evidence concerning dysregulation of the myofilament response to Ca 2+ release or Ca 2+ impaired sensitivity, which are significant contributors to contractile dysfunction in AF [ 4 ]. Intracellular Ca 2+ homeostasis and subsequent contractility efficiency rely upon phosphorylation processes, which, in AF, are pathologically altered.…”