Abstract
Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two—AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.
Highlights
Two highly prevalent forms of cardiovascular disease are atrial fibrillation (AF) and heart failure, and in spite of recent advances in treatment these conditions remain important causes of morbidity and mortality
Calcium plays a fundamental role in the pathophysiology of AF, as well as in the bidirectional relationship between AF and heart failure
Remodeling of calcium cycling in response to rapid atrial stimulation can be seen within days in the form of calcium signaling silencing
Summary
Two highly prevalent forms of cardiovascular disease are atrial fibrillation (AF) and heart failure, and in spite of recent advances in treatment these conditions remain important causes of morbidity and mortality. AF is an abnormal heart rhythm affecting more than 30 million patients worldwide (Chugh et al, 2014), and is characterized by rapid and disorganized electrical activity within the cardiac atria (Kirchhof et al, 2016) This results in the loss of atrial contraction, irregular ventricular contractions, and has a detrimental effect on the lives of those who suffer from it ranging from a reduction in day-to-day quality of life secondary to symptoms such as palpitations and exercise intolerance (Thrall et al, 2006), and an increased risk of heart failure (Stewart et al, 2002), stroke (Wolf et al, 1991), and premature death (Benjamin et al, 1998). Heart failure is defined as the presence of symptoms such as breathlessness resulting from cardiac structural or functional abnormalities that in general cause impaired contraction and/or relaxation of the myocardium (Ponikowski et al, 2016) This life-threatening condition affects 1–2% of the general population in the developed world (Mosterd and Hoes, 2007), and carries higher mortality rates than many. Those with AF are more likely to develop heart failure and vice versa
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