Both the left atrium (LA) and the right atrium secrete natriuretic peptides in response to atrial stretch and elevated atrial pressure and thereby participate actively in the maintenance of systemic homeostasis. The most important natriuretic peptide secreted by the atria is A-type or atrial natriuretic peptide (ANP). The atria are also capable of secreting B-type natriuretic peptide, which is known as brain natriuretic peptide (BNP), but the ventricular endocardium, not the atrium, is the main cardiac source for BNP. ANP and BNP exhibit antagonistic effects against angiotensin II via diuretic and natriuretic actions, vasodilatory actions, and inhibition of aldosterone secretion. C-type, or cerebral natriuretic peptide (CNP), was first identified in the porcine brain and is produced by multiple different cell types throughout the body. CNP helps regulate systemic homeostasis by impacting vascular tone, blood pressure, and the immune system. ,
Although both the right atrial appendage (RAA) and left atrial appendage (LAA) secrete ANP, the LAA is responsible for up to 30% of all cardiac ANP production. Active secretion of ANP by both appendages is likely attributable to their origin from the common primitive atrium, while the main body of the LA originates from the pulmonary vein buttons and the endocardial cushions. Because the LAA is relatively more compliant than the rest of the LA, it serves as an excellent reservoir that is especially sensitive to changes in systemic volume, exercise, and atrial stretch. However, the LAA has fewer autonomic nervous system fibers than the rest of the LA, suggesting that ANP production is primarily the result of mechanical stretch and volume overload of the LA rather than a result of neurologic influences.
Atrial Natriuretic Peptide Secretion During Atrial Fibrillation
Atrial fibrillation (AF) significantly alters the neurophysiology of the atrial wall. Because the LA is continuously stimulated electrically during AF, it is also constantly stretched. A 20% to 100% increase in ANP and BNP secretion can occur during AF in response to an increase in left atrial pressure of only 5 mm Hg. However, in hemodynamically stable patients with preserved left ventricular ejection fraction, ANP production and BNP production are not significantly influenced by changes in left atrial pressure during AF. Whereas ANP and BNP levels double when atrial pressure increases from 5 to 25 mm Hg in sinus rhythm patients, their levels remain essentially the same during AF regardless of pressure overload ( Fig. 42.1 ). This explains how patients in AF can lose the capability of atrial-induced diuresis and natriuresis secondary to volume overload. The increase in both ANP and BNP independent of left atrial pressure has been described in patients even after 20 minutes of AF induced by rapid atrial pacing. This suggests that the increase in both of the natriuretic peptides during AF is caused by the activation of atrial mechano-receptors and mechano-sensitive ion channels that are activated by permanent atrial stretch rather than by hemodynamic changes or atrial remodeling. ,
Correlation of mean left atrial (LA) pressure and natriuretic peptide plasma concentrations in patients in atrial fibrillation (AF; red ) or sinus rhythm (SR; blue ) . (A) Brain natriuretic peptide (BNP), (B) Midregional proatrial natriuretic peptide (MR-proANP).
Although the rapid increase in natriuretic peptide secretion occurs shortly after the initiation of AF, serum levels are higher in persistent AF than in paroxysmal AF. Paradoxically, serum ANP levels are often lower in patients with long-standing persistent AF (LSpAF), though they are consistently higher than ANP levels during sinus rhythm. The most likely reason for this apparent paradox is that patients with LSpAF tend to have more atrial scarring and therefore fewer active atrial myocytes that produce ANP.
AF is present in 60% of patients diagnosed with heart failure and preserved ejection fraction. However, the use of serum ANP and BNP levels alone as surrogates for left-sided pressure overload can result in an overdiagnosis of heart failure in patients with AF and an underdiagnosis of heart failure in patients who are in normal sinus rhythm.
Use of Brain Natriuretic Peptide or N-Terminal Prohormone of Brain Natriuretic Peptide for Atrial Fibrillation Screening
The secretion of both ANP and BNP is increased during AF, but the variation in the degree of increased ANP secretion prevents the use of ANP serum level as a screening test for AF detection. In contrast, several studies have suggested that serum BNP and N-terminal prohormone of BNP (NT-proBNP) levels can be used to detect subclinical AF. If true, elevated serum levels of BNP and NT-proBNP could prove to be useful in identifying AF as the source of stroke in patients who are in sinus rhythm at the time they have the stroke. Although there is no current consensus on which peptide is better for predicting AF, BNP has a shorter half-life than ANP, so higher BNP levels may better reflect episodes of AF. Also, other noncardiac conditions, such as renal failure, have less effect on serum BNP levels than on serum ANP levels. Although further studies are essential for confirmation, some contemporary studies suggest that serum BNP levels are more sensitive, but serum NT-proBNP levels are more specific for the detection of AF. ,
Influence of Left Atrial Appendage Closure or Exclusion on Atrial Natriuretic Peptide Secretion
Endocardial LAA occlusion (LAAO) devices implanted by catheters and endocardial suture closure of the LAA do not devascularize the myocardium of the LAA and therefore would not be expected to have a significant effect on serum ANP and BNP levels. However, in patients with AF, epicardial closure of the LAA with a clip, ligature, or stapling device, as well as LAA amputation, eliminates the production of ANP and BNP by the myocardium of the LAA. Therefore, these epicardial LAA closure techniques would be expected to decrease the serum levels of ANP and BNP. However, neither endocardial closure nor epicardial exclusion or amputation of the LAA in patients with AF results in a permanent decrease in serum ANP and BNP levels. After endocardial device implantation, ANP and BNP levels increase slightly in the first few hours and then normalize within 24 hours. Epicardial LAA exclusion and LAA amputation are followed by an immediate decrease in serum ANP and BNP levels and then by an increase in their levels that can last up to 30 days after LAA exclusion. However, after approximately 3 months, serum ANP and BNP levels have returned to pre-LAA exclusion levels ( Fig. 42.2 ).
Plasma levels of different hormones and blood pressure after endocardial or epicardial left appendage closure in patients who remain in atrial fibrillation (no ablation). Arrows indicate increased or decreased plasma levels compared with before the procedure. indicates no significant change. The blank box represents no data available. ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide.
In patients with AF, serum sodium levels decrease within 24 hours and normalize within 7 days after epicardial LAA exclusion or amputation, but the changes in absolute levels of sodium are minimal and do not significantly impact fluid balance. No significant changes in serum potassium or chloride levels have been described for up to 2 years after LAAO, LAA exclusion, or LAA amputation in patients with AF. Finally, no information is currently available regarding the impact of LAAO, LAA exclusion, or LAA amputation on ANP secretion in patients without a history of AF who are in sinus rhythm.
Left Atrial Appendage Closure and the Renin–Angiotensin–Aldosterone System
The relationship between the LAA and the renin–angiotensin–aldosterone system (RAAS) is not well defined in patients with AF. Epicardial LAA closure in patients with AF has been shown to lower serum renin and aldosterone levels for 3 months, and this effect is sustained for at least 2 years. Also, LAA closure has also been shown to decrease adrenaline and noradrenaline levels, resulting in improved blood pressure control in patients with hypertension. , These effects suggest that in patients with AF, the relationship between the LAA and the RAAS may not be entirely dependent on natriuretic peptide levels because the effect on RAAS goes beyond the normalization of ANP and BNP levels. The RAAS is either downregulated directly by some unknown action of the LAA or by permanent damage to the afferent and efferent autonomic nervous system. In contrast, endocardial LAA closure has not been shown to decrease adrenaline levels, though it does result in a significant decrease in serum aldosterone levels at 1 year (see Fig. 42.2 ).
These observations clearly indicate that LAA exclusion or amputation in patients with AF causes a downregulation of the RAAS that may explain the improved systolic and diastolic blood pressure control that is maintained over time. Clinical trials have demonstrated that RAAS antagonism reduces the incidence of AF in patients after myocardial infarction and heart failure. This suggests that LAA exclusion or amputation in patients with AF can help avoid AF recurrence after initial ablation not only by isolating atrial AF triggers and/or interrupting macro-reentrant AF drivers but also by RAAS downregulation.
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