During heart failure, the synthesis and secretion of both A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are enhanced, as reflected by an increase in their blood levels [1–3]. However, distinct mechanisms are responsible for ANP and BNP secretion. ANP is stored in granules within atrial myocytes and is immediately secreted from these upon stimulation via atrial stretch. This secretion mode is called the regulatory pathway. In contrast, BNP is primarily synthesized by stimulating the mechanical stretch of the myocardium. Owing to the absence of granules in the ventricular muscle, the protein is synthesized and directly secreted without storage [4–6]. This secretion mode is called the constitutive pathway. BNP has a slower stimulation-to-secretion time than ANP. However, because of the characteristics of its gene sequence containing an AU-rich sequence including several repeat units of AUUUA motif in the 3’-untranslated region of BNP mRNA, the rate of BNP synthesis is considerably faster than that of ANP and other proteins [4].
ANP is secreted from the atria and is easily affected by heart rate [7–10]. In contrast, BNP is primarily secreted from the ventricles and may be less affected by heart rate [10]. However, only a few studies have comprehensively investigated these aspects, with clinical studies in human being insufficient, which limits our understanding of the matter.
Elevated heart rate is a poor prognostic factor for heart failure, increasing the risk of cardiovascular events and heart failure hospitalization [11–13]. Elevated heart rate may affect cardiac morphology and intracardiac pressure, in addition to leading to various other pathophysiological changes. For example, an elevated heart rate is accompanied by a sustained increase in catecholamine levels, decreasing cardiac function [14]. Furthermore, elevated heart rate increases p66shc levels, resulting in oxidative stress and promoting myocardial apoptosis [15].
In our previous structure equation modeling (SEM), we reported a positive correlation between left ventricular end-systolic volume index (LVESVI) and plasma BNP levels as well as a negative correlation between left ventricular end-diastolic volume index (LVEDVI) and plasma BNP levels [16]. Univariate analysis revealed a positive correlation between LVEDVI and plasma BNP levels. However, when simultaneously considering LVESVI, LVEDVI was negatively correlated with plasma BNP levels. In other words, LVEDVI and plasma BNP levels exhibit a direct negative relationship. Meanwhile, several studies, including ours, have revealed a positive correlation between left ventricular end-diastolic pressure (LVEDP) and plasma BNP levels, which is easy to understand [2, 3, 17–19].
Studies have not explored the direct relationship between heart rate and plasma BNP levels in humans. An elevated heart rate may indirectly alter the cardiac morphology and intracardiac pressure, which could in turn increase plasma BNP levels. In other words, the relationship among (1) heart rate, (2) cardiac morphology and intracardiac pressure, and (3) plasma BNP levels cannot be verified without conducting a comprehensive study, particularly when assessing the direct relationship between heart rate and plasma BNP levels.
Herein, we determined the effects of heart rate on cardiac morphology, intracardiac pressure, and plasma BNP levels in patients with sinus rhythm. In other words, we verified whether elevated heart rate directly or indirectly affects plasma BNP levels via changes in cardiac morphology and intracardiac pressure.