Therapeutic Effects of BNP in Heart Failure, Good or Bad?

The natriuretic peptide system plays a critical role in the maintenance of cardiovascular homeostasis. Since the natriuretic peptides were discovered more than 2 decades ago, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) has become the most interesting biomarkers in diagnosis, risk stratification, and management of patients with heart failure (HF). More importantly, with the deepening of understanding of physiological and pathophysiological effects of BNP, increasing biological effects of BNP has been considered to be an attractive approach for treating HF. However, treatment effects of BNP in patients with both acute and chronic HF in various clinical trials have demonstrated different results. The biology of BNP is complex, there are many important issues not yet elucidated. In this review, we will focus on the the diversity of therapeutic effects of BNP in HF and give directions for the future studies. Abbreviations: HF: Heart Failure; BNP: B-type Natriuretic Peptide; CGMP: Cyclic Guanosine Monophosphate; HFREF: Heart Failure with Reduced Ejection Fraction; NT-ProBNP: N-Terminal proBNP; ASCEND-HF: Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure; PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortalilty and morbidity in Heart Failure Biomedical Journal of Scientific & Technical Research Volume 8Issue 1: 2018 Cite this article: Yuting Z, Yanfeng M, Rongsheng K, Dongye L. Therapeutic Effects of BNP in Heart Failure, Good or Bad?. Biomed Sci&Tech Res 8(1)2018. BJSTR MS.ID.001606. DOI: 10.26717/ BJSTR.2018.08.001606. 6318 Diversity of Therapeutic Effects of BNP in HF Patients Based on favorable evidence of hemodynamic and clinical effects shown in various clinical studies [11-13], intravenous infusion of recombinant human BNP (nesiritide) was approved for treating acute decompensated heart failure by the U.S. Food and Drug Administration in 2001 and was subsequently widespread used both in patients with acute HF and in patients with chronic HF around the world. However, the initial enthusiasm for BNP therapy in HF was diminished because of the ensuing metaanalyses, which indicated that nesiritide was associated with increased risk of death and worsening of renal function [14,15]. The subsequent ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) study showed that although intravenous infusion of nesiritide was not associated with a worsening of renal function, it failed to show improvements in clinical outcomes of patients with acute HF [16]. The results of FUSION II (Follow-up Serial Infusions of Nesiritide) trial also suggested no benefit of high-risk patients with chronic HF from long-term therapy with intermittent nesiritide infusion [17]. In addition, both the 2 trials indicated a higher risk of hypotension of BNP therapy. Although these results suggest the need for caution when considering BNP therapy for HF and decrease the attractiveness of treating HF with BNP infusion, studies for therapeutic effects of BNP have never stopped. Chen et al. conducted a small randomized double-blind placebo-controlled proof of concept study to detect safety and efficacy of chronic subcutaneous administration of BNP in patients with systolic HF. They found that subcutaneous BNP administration resulted in evidence of improved LV remodeling, decreased LV filling pressure, and improved Minnesota Living with Heart Failure score in these patients [18]. Very recently, the same group conducted another 2 trials and reported that subcutaneous administration of BNP could improve the cardiorenal response to volume expansion in patients with asymptomatic systolic HF [19] and that BNP therapy could improve diastolic dysfunction in patients with preclinical diastolic dysfunction [20]. Although there are major differences in the characteristics of patients, route of BNP administration and duration of BNP application, which might account for the diversity of therapeutic effects of BNP in patients with HF, the uncertain results indicate that there are many issues not yet elucidated. It is unclear whether the difference in pharmacokinetic effects between daily subcutaneous administration and intermittent intravenous infusion of BNP may lead to different clinical results. Does the subcutaneously daily use of BNP allow for decreased vasoactive side effects such as hypotension? An additional issue is that routine administration of BNP might not good enough for treating patients with HF. The regulatory mechanism and biological effects of BNP in HF are complex, it is reasonable to strictly monitor the dose of BNP so that not disturbing the homeostasis of the body. As far as we know, BNP altered Ca2+ cycling by inhibiting SERCA2 a activity and increasing L-type Ca2+ current, resulting in sympathetic overdrive [21]. The proadrenergic effects of BNP may offset its beneficial effects of maintaining hemodynamic stability. Further fundamental studies are needed to confirm the complex pathophysiology of BNP in HF. Apart from direct application of BNP, a less direct method to increase natriuretic peptide signaling has shown benefits in treating patients with HF. The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortalilty and morbidity in Heart Failure) trial demonstrated that LCZ696, which was a dual inhibitior of the renin-angiotensinaldosterone system and the neprilysin pathways, improved clinical outcomes in heart failure with reduced ejection fraction (HFrEF) patients [22]. The causes for difference in results between direct application of BNP and the less direct method need further study.


The Role of BNP in Cardio Protection
BNP exerts its physiological effects through binding to receptors of the target cells. Three natriuretic peptide receptors (NPR-A, NPR-B, and NPR-C) have been isolated. NPR-A and NPR-B are both transmembrane proteins coupled to guanylyl cyclases. They are capable of increasing the intracellular concentration of the second messenger molecule cyclic guanosine monophosphate (cGMP) after their extracellular domains bind to BNP. BNP exerts most of its biological effects through activating the cGMP dependent signaling cascade. Unlike NPR-A and NPR-B, NPR-C is considered to be a "clearance receptor" for BNP as it mediates the degradation of BNP [5]. The physiological effects of BNP are widespread. It exerts the effects of diuresis, natriuresis, vasodilation, and antagonism of the renin-angiotensin-aldosterone and the sympathetic nervous systems, playing a critical role in the maintenance of cardiovascular homeostasis [1]. Moreover, BNP may also have the actions of antihypertrophy, anti-fibrosis and anti-inflammation in myocardium [6][7][8].
In HF, it is well established that BNP levels are increased and acts to compensate for HF. However, dysfunction of natriuretic peptides also exits in the setting of HF [9]. The diminished effectiveness of natriuretic peptides may be due to decreased production and increased clearance of natriuretic peptides or reduction of target organ responsiveness. In addition, the counteraction between natriuretic peptides system and other neurohormonal systems may also account for the dysfunction of natriuretic peptides [10]. Because of the above reasons, increasing the beneficial effects of natriuretic peptide signaling through application of exogenous BNP is considered as a promising therapeutic strategy for HF. Various clinical trials have been conducted to test the therapeutic effects of BNP in patients with acute and chronic HF. However, the results of these clinical trials are uncertain.

Diversity of Therapeutic Effects of BNP in HF Patients
Based on favorable evidence of hemodynamic and clinical effects shown in various clinical studies [11][12][13], intravenous infusion of recombinant human BNP (nesiritide) was approved for treating acute decompensated heart failure by the U.S. Food and Drug Administration in 2001 and was subsequently widespread used both in patients with acute HF and in patients with chronic HF around the world. However, the initial enthusiasm for BNP therapy in HF was diminished because of the ensuing metaanalyses, which indicated that nesiritide was associated with increased risk of death and worsening of renal function [14,15]. The subsequent ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) study showed that although intravenous infusion of nesiritide was not associated with a worsening of renal function, it failed to show improvements in clinical outcomes of patients with acute HF [16]. The results of FUSION II (Follow-up Serial Infusions of Nesiritide) trial also suggested no benefit of high-risk patients with chronic HF from long-term therapy with intermittent nesiritide infusion [17].
In addition, both the 2 trials indicated a higher risk of hypotension of BNP therapy. Although these results suggest the need for caution when considering BNP therapy for HF and decrease the attractiveness of treating HF with BNP infusion, studies for therapeutic effects of BNP have never stopped. Chen et al. conducted a small randomized double-blind placebo-controlled proof of concept study to detect safety and efficacy of chronic subcutaneous administration of BNP in patients with systolic HF. They found that subcutaneous BNP administration resulted in evidence of improved LV remodeling, decreased LV filling pressure, and improved Minnesota Living with Heart Failure score in these patients [18]. Very recently, the same group conducted another 2 trials and reported that subcutaneous administration of BNP could improve the cardiorenal response to volume expansion in patients with asymptomatic systolic HF [19] and that BNP therapy could improve diastolic dysfunction in patients with preclinical diastolic dysfunction [20]. Although there are major differences in the characteristics of patients, route of BNP administration and duration of BNP application, which might account for the diversity of therapeutic effects of BNP in patients with HF, the uncertain results indicate that there are many issues not yet elucidated.
It is unclear whether the difference in pharmacokinetic effects between daily subcutaneous administration and intermittent intravenous infusion of BNP may lead to different clinical results. Does the subcutaneously daily use of BNP allow for decreased vasoactive side effects such as hypotension? An additional issue is that routine administration of BNP might not good enough for treating patients with HF. The regulatory mechanism and biological effects of BNP in HF are complex, it is reasonable to strictly monitor the dose of BNP so that not disturbing the homeostasis of the body. As far as we know, BNP altered Ca2+ cycling by inhibiting SERCA2 a activity and increasing L-type Ca2+ current, resulting in sympathetic overdrive [21]. The proadrenergic effects of BNP may offset its beneficial effects of maintaining hemodynamic stability. Further fundamental studies are needed to confirm the complex pathophysiology of BNP in HF. Apart from direct application of BNP, a less direct method to increase natriuretic peptide signaling has shown benefits in treating patients with HF. The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortalilty and morbidity in Heart Failure) trial demonstrated that LCZ696, which was a dual inhibitior of the renin-angiotensinaldosterone system and the neprilysin pathways, improved clinical outcomes in heart failure with reduced ejection fraction (HFrEF) patients [22]. The causes for difference in results between direct application of BNP and the less direct method need further study.

Conclusion
The key role of the natriuretic peptide system in sustaining circulatory homeostasis has been well recognized. The current uncertainty about the therapeutic effects of BNP in HF can't preclude that the natriuretic peptide system is a good target for treatment of HF. The "bad" results also set the stage for future studies. Additional efforts should aim at deepening understanding of BNP. For example, studies are necessary to confirm the right patient population, answer the question about safety of this drug, develop methods to reduce the proadrenergic side effects and so on. These further explorations will eventually enable a safe and effective treatment of HF with BNP.