Figure 29.11 Vicious circles that...

Figure 29.11

$Vicious circles that contribute to the genesis of atrial fibrillation. Initiation and perpetuation of atrial fibrillation is caused by multiple factors in the vast majority of patients. Many of these are self-sustaining, i.e. they are part of ‘vicious circles’ that accelerate the progression of atrial fibrillation with each episode. The figure illustrates four of these vicious circles. Rapid atrial rates, e.g. caused by atrial fibrillation, atrial flutter, or atrial tachycardias, cause intracellular calcium overload. To protect itself against calcium-induced cell death, cardiomyocytes activate a ‘survival programme’ to extrude as much calcium as possible. This is done by shortening atrial action potential duration and refractoriness (‘electrical remodelling’). Although preventing cell death, this mechanism reduces wave length and contributes to atrial fibrillation recurrence after premature atrial activations. Focal activity within the pulmonary veins, a frequent trigger of ‘lone’ paroxysmal atrial fibrillation, can be caused by stretch within the atrial–atrial fibrillation junction or by calcium load in cardiomyocytes leading to spontaneous calcium release and afterdepolarizations, especially in the presence of sympathetic stimulation. Via calcium load, sympathetic activation, and increased stretch at the LA (left atrial)–PV (pulmonary vein) junction this mechanism is prone to a second vicious circle. Atrial fibrillation-induced structural changes occur already after several hours of atrial fibrillation. Many of these changes are mediated via activation of the renin–angiotensin system due to atrial stretch, atrial pressure increase, and peripheral hypovolemia. Activation of renin–angiotensin–aldosterone system (RAAS) will increase extracellular matrix formation, lead to cardiomyocyte isolation, create localized conduction barriers which will facilitate reentry within the atria, and thereby reduce atrial wave length. Rapid and irregular rate during atrial fibrillation, in conjunction with loss of atrial contractile function, reduce cardiac output and can cause left ventricular (LV) dysfunction. The systemic response to LV dysfunction is, again, RAAS activation, sympathetic activation (with in turn even more rapid ventricular rates), and thereby perpetuation of atrial fibrillation. Last but not least, activation of any of the cellular changes involved in these vicious circles can activate expression of prothrombotic factors in atrial endothelium. As delineated later in the text, therapeutic approaches to disrupt each of these vicious circles exist: electrical remodelling: antiarrhythmic drugs; focal activity: pulmonary vein isolation, structural changes: upstream therapy; LV dysfunction: rate control therapy (and, to some extent, successful rhythm control therapy). Modified with permission from Koebe J, Kirchhof P. Novel non-pharmacological approaches for antiarrhythmic therapy of atrial fibrillation. Europace 2008; 10: 433–7.$

Vicious circles that contribute to the genesis of atrial fibrillation. Initiation and perpetuation of atrial fibrillation is caused by multiple factors in the vast majority of patients. Many of these are self-sustaining, i.e. they are part of ‘vicious circles’ that accelerate the progression of atrial fibrillation with each episode. The figure illustrates four of these vicious circles. Rapid atrial rates, e.g. caused by atrial fibrillation, atrial flutter, or atrial tachycardias, cause intracellular calcium overload. To protect itself against calcium-induced cell death, cardiomyocytes activate a ‘survival programme’ to extrude as much calcium as possible. This is done by shortening atrial action potential duration and refractoriness (‘electrical remodelling’). Although preventing cell death, this mechanism reduces wave length and contributes to atrial fibrillation recurrence after premature atrial activations. Focal activity within the pulmonary veins, a frequent trigger of ‘lone’ paroxysmal atrial fibrillation, can be caused by stretch within the atrial–atrial fibrillation junction or by calcium load in cardiomyocytes leading to spontaneous calcium release and afterdepolarizations, especially in the presence of sympathetic stimulation. Via calcium load, sympathetic activation, and increased stretch at the LA (left atrial)–PV (pulmonary vein) junction this mechanism is prone to a second vicious circle. Atrial fibrillation-induced structural changes occur already after several hours of atrial fibrillation. Many of these changes are mediated via activation of the renin–angiotensin system due to atrial stretch, atrial pressure increase, and peripheral hypovolemia. Activation of renin–angiotensin–aldosterone system (RAAS) will increase extracellular matrix formation, lead to cardiomyocyte isolation, create localized conduction barriers which will facilitate reentry within the atria, and thereby reduce atrial wave length. Rapid and irregular rate during atrial fibrillation, in conjunction with loss of atrial contractile function, reduce cardiac output and can cause left ventricular (LV) dysfunction. The systemic response to LV dysfunction is, again, RAAS activation, sympathetic activation (with in turn even more rapid ventricular rates), and thereby perpetuation of atrial fibrillation. Last but not least, activation of any of the cellular changes involved in these vicious circles can activate expression of prothrombotic factors in atrial endothelium. As delineated later in the text, therapeutic approaches to disrupt each of these vicious circles exist: electrical remodelling: antiarrhythmic drugs; focal activity: pulmonary vein isolation, structural changes: upstream therapy; LV dysfunction: rate control therapy (and, to some extent, successful rhythm control therapy). Modified with permission from Koebe J, Kirchhof P. Novel non-pharmacological approaches for antiarrhythmic therapy of atrial fibrillation. Europace 2008; 10: 433–7.

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