Natriuretic Peptides in Heart Failure: Pathophysiologic and Therapeutic Implications

Natriuretic Peptides: Historical Background

The discovery of natriuretic peptides (NPs) changed the classical paradigm of the heart as solely a pump and developed the novel concept of the heart as an endocrine organ. The current and potential applications of NPs in clinical practice and medical research are endless. Currently, NPs remain the “gold standard” for the diagnosis and prognosis of heart failure (HF) and the evaluation of HF treatment efficacy. The NP story began in the 1950s when Gauer and his coworkers reported that distension of the left atrium after the expansion of an intra-atrial balloon resulted in a prompt diuresis linking this physiologic effect to the changes in circulating blood volume. Concurrently, Kisch first described specific dense homogenous granules in atria using a new electron microscopy technique, and Jamieson and Palade revealed the secretory nature of these granules. Later, Poche found that the number of granules depends on water intake. Indeed, Marie and colleagues confirmed that salt and water intake increases the numbers of granules in the atrial cardiomyocytes. In cross-circulation experiments in canines, De Wardner described the humoral nature of a substance with natriuretic properties. Although the presence of the “specific atrial granules” and their secretory phenotype were confirmed, the function of these storage granules remained a mystery.

In 1981 de Bold et al. performed the groundbreaking experiment that showed that the injection of atrial homogenates causes rapid renal sodium and water excretion and the reduction of blood pressure. Interestingly, the manuscript describing for the first time natriuretic, diuretic, and vasodilatory properties of atrial natriuretic peptide (ANP) was initially rejected by the journal to which the study was submitted. Following this landmark study several individual groups purified, sequenced, and synthesized ANP. Therefore ANP became the first peptide hormone isolated from the heart ( Fig. 9.1 ) . B-type NP (BNP), originally named brain-type natriuretic peptide, was first isolated from porcine brain tissues in 1988. Further studies revealed that BNP is also synthesized by both atrial and ventricular cardiomyocytes and like ANP is responsive to mechanical stretch. The discovery of ANP and BNP is considered a fundamental advance in the field of cardiovascular biology and has tremendously impacted HF treatment and diagnostics. Urodilatin (URO) is a molecular form of ANP derived from the ANP prohormone proANP and processed in the kidney, resulting in a more renal-specific NP. C-type NP (CNP), a third peptide in NP family, was first extracted from porcine brain and then from endothelial cells. CNP, like ANP, URO, and BNP, has a similar but distinct 17–amino acid disulfide bridge ring and is synthesized in vascular endothelium. Finally, the concept of the heart as an endocrine organ was importantly solidified by the landmark work of Murad’s group, which identified 3′,5′-cyclic guanosine monophosphate (cGMP) as the second messenger of ANP, and seminal studies identified particulate guanylyl cyclase receptors (pGC-A and pGC-B) as the targets of ANP, URO, BNP, and CNP.

The therapeutic effects of NPs have been widely applied in patients with acute decompensated heart failure (ADHF) (see Chapter 36 ). Synthetic ANP (Carperitide) and synthetic BNP (Nesiritide) have been approved in several countries for the treatment of HF. Carperitide was approved for the clinical management of ADHF in Japan in 1995. Nesiritide was considered as a first line therapeutic agent for ADHF. Initial clinical trials revealed that Nesiritide significantly led to beneficial hemodynamic and natriuretic effects, reduced pulmonary capillary wedge pressure, and increased cardiac output. The Natrecor Study Group has also confirmed the beneficial hemodynamic effects of Nesiritide in patients with ADHF. Moreover, Nesiritide was associated with significantly lower mortality than dobutamine in the PRECEDENT (Prospective, Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy) study, caused a faster and greater improvement in pulmonary capillary wedge pressure compared with intravenous nitroglycerin. Due to these results of the clinical trials, Nesiritide was approved for the treatment of ADHF in 2001 by the US Food and Drug Administration (FDA) and marketed under the trade name Natrecor. However, meta-analysis of Natrecor clinical trials by Sackner-Bernstein raised concerns about Nesiritide-associated mortality and renal dysfunction in patients with ADHF. These reports significantly contributed to a decline in both prescriptions and Nesiritide sales. The controversy between defenders of nesiritide, including its manufacturer, Johnson & Johnson, and their opponents was finally resolved by the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. The trial included 7141 patients with ADHF who received continuous intravenous infusion of Nesiritide or placebo. Results showed that there were no significant differences in the incidence of death or renal injury. On the other side, the trial also showed no significant differences in the end point of dyspnea. In addition, standard doses of Nesiritide caused symptomatic and asymptomatic hypotension. Finally, Nesiritide was not recommended for routine treatment of ADHF. This information was important for further development of chimeric NP designs specifically for the treatment and prevention of HF.

General Overview of Natriuretic Peptide System

The pharmacologic actions of NPs are based on interaction between specific molecular amino acid sequences in naturally occurring NPs and respective receptors (see Fig. 9.1 and Table 9.1 ). NPs all possess a similar but distinct 17–amino acid ring formed by an intramolecular disulfide bridge. This ring structure is essential for exerting biologic activity. ANP is synthesized and stored within atrial cardiomyocytes as a 151–amino acid preproANP peptide which is cleaved to generate 126–amino acid proANP. ANP is stored in atrial cardiomyocytes in granules as proANP. Studies have established that the atrium is the major site of ANP synthesis in which the level of ANP mRNA expression is 100-fold higher than in the ventricles. ANP is synthesized and stored within atrial cardiomyocytes as a 151–amino acid preproANP peptide which is cleaved to generate 126–amino acid proANP. When atrial myocytes are stretched, proANP is cleaved by corin, a myocardium-specific type II transmembrane protease, into the nonbiologically active N-terminus of pro-ANP and the biologically active C-terminal 28–amino acid ANP. Corin is also involved in BNP processing, which is initially synthesized as 134-amino acid preproBNP. After processing by corin or intracellular Golgi-localized protease furin, a low level of proBNP can be stored along with ANP in the atrial-specific granules. In contrast to ANP, BNP is predominantly secreted by ventricular myocardium and is constitutively released. Both ANP and BNP are secreted in response to myocardial stretch induced by volume or hemodynamic overload. Upon release into the circulation, proBNP is converted to a 76–amino acid inactive N-terminal fragment of proBNP and biologically active C-terminal 32–amino acid BNP. The lack of ANP in genetically modified mice may lead to chronic hypertension, cardiac dilation, hypertrophy, fibrosis, and HF. Mice lacking BNP do not develop cardiac hypertrophy or hypertension but display cardiac fibrosis that leads to ventricular stiffness, altered chamber compliance, and contractile dysfunction. In the cardiovascular system, CNP can be produced in the myocardium but at low levels, and highly expressed in vascular endothelium. PreproCNP is a 126–amino acid peptide, which is cleaved by a signal peptidase to form 103–amino acid proCNP. The latter is cleaved by furin to produce the biologically active 22–amino acid CNP and a larger 53–amino acid inactive fragment. Defects in CNP production lead to endothelial dysfunction, hypertension, atherogenesis, and aneurysm formation, and reduced ability of CNP to activate pGC-B leads to hypertension, tachycardia, and impaired left ventricular systolic function. Plasma CNP is also elevated in patients with HF, although its level is lower compared with ANP and BNP. Due to increased expression levels of pGC-B in HF, CNP may exert cardioprotective action against myocardial injury. Less information is known about the processing of URO.

As introduced previously, NPs act via transmembrane GC-coupled receptors. The receptors pGC-A and pGC-B are composed of an extracellular domain, which binds endogenous ligands, a single transmembrane region, a kinase homology domain, and intracellular catalytic domain with GC activity ( Fig. 9.2 ) . The pGC-A receptor mediates the physiologic action of ANP and BNP by generating the intracellular secondary messenger cGMP, which acts on cGMP-dependent protein kinase, or protein kinase G (PKG), cGMP-gated ion channels, and cGMP-regulated phosphodiesterases (PDEs). Studies have established that pGC-A is mostly expressed in kidneys, vascular smooth muscle, endothelium, heart, and adrenals, as well as adipocytes. The pGC-B receptor is predominantly expressed in the brain, kidney, heart, lung, and bone.

NPR-C mediates the clearance of NPs through an internalization and degradation process. NPR-C is expressed in several tissues, including kidneys, endothelium, heart, lungs, and adrenals. Although NPR-C is mainly known as a receptor involving in NP clearance from the circulation by receptor-mediated endocytosis, key studies have reported NPR-C–mediated inhibition of endothelial and vascular smooth muscle cell (VSMC) proliferation. Moreover, NPR-C may be involved in modulating coronary endothelial cell permeability and may be a target of CNP in modulating vascular tone. In addition to proteolytic inactivation and NPR-C–mediated clearance, enzymatic pathways clear the NPs. Specifically, NPs can be cleaved by the zinc metalloprotease insulin-degrading enzyme and by the membrane-bound zinc-dependent enzyme neutral endopeptidase or neprilysin (NEP), which plays a critical role both in regulating NP levels and also serving as a therapeutic target.

From a physiologic perspective, a growing concept is that the NP/pGC/cGMP system plays an important role in the long-term regulation of sodium and water balance and blood pressure homeostasis. An additional new role for the NP system is in metabolic regulation. In key genetic epidemiology studies, genetic variants of the ANP and BNP genes in which circulating ANP or BNP may be elevated, the phenotype is one of lower blood pressure, reduced risk for hypertension, and protection from obesity and metabolic syndrome. From studies in genetically altered mice and physiologic and pharmacologic studies in animals and humans, the key biologic properties of NPs are summarized in Table 9.2 and include inhibition of myocardial hypertrophy, organ fibrosis, maintenance of the endothelial barrier, vasorelaxation, natriuresis including an increase in glomerular filtration rate (GFR) and a decrease in proximal tubule reabsorption, suppression of aldosterone, and lipolysis.