Natriuretic Peptides and Cardiometabolic Health

Deepak K. Gupta; Thomas J. Wang

doi:10.1253/circj.CJ-15-0589

Abstract

Natriuretic peptides are cardiac-derived hormones with a range of protective functions, including natriuresis, diuresis, vasodilation, lusitropy, lipolysis, weight loss, and improved insulin sensitivity. Their actions are mediated through membrane-bound guanylyl cyclases that lead to production of the intracellular second-messenger cyclic guanosine monophosphate. A growing body of evidence demonstrates that genetic and acquired deficiencies of the natriuretic peptide system can promote hypertension, cardiac hypertrophy, obesity, diabetes mellitus, the metabolic syndrome, and heart failure. Clinically, natriuretic peptides are robust diagnostic and prognostic markers, and augmenting natriuretic peptides is a target for therapeutic strategies in cardiometabolic disease. This review will summarize current understanding and highlight novel aspects of natriuretic peptide biology.

Natriuretic Peptides (NPs) and Their Receptors

The NPs are a family of cardiac-derived hormones that have pleiotropic cardiometabolic protective effects.¹ Three NPs, atrial (ANP), B-type (BNP), and C-type (CNP), have been described, with ANP being the first, identified by de Bold et al and sequenced by Kangawa, Matsuo, and colleagues.²^–⁷ In humans, these peptides are encoded by the NPPA (NP precursor A) and NPPB genes located in tandem on chromosome 1, and NPPC on chromosome 2.⁸^–¹⁰ Mechanical stretch of cardiomyocytes and/or stimulation by endothelin, angiotensin II, the sympathetic nervous system, vasopressin, hypoxia, cold, or exercise induces the transcription factor GATA to bind the NP promoters.³^,¹¹ The NP precursor genes are transcribed and translated into preprohormones that undergo post-translational processing and cleavage into biologically active carboxy-terminal and inactive amino-terminal fragments by the serine proteases corin and/or furin (Figure 1).¹² ANP is predominantly synthesized, stored in preformed granules, and released from atrial cardiomyocytes; BNP is produced in atrial and ventricular cardiomyocytes; and CNP is largely derived from vascular endothelial cells and neurons.¹³^–¹⁵ The bioactive carboxy-terminal NPs have relatively short half-lives in the circulation, while the inactive amino-terminal fragments are more stable with longer half-lives.¹⁶

Figure 1.

The post-translational processing of natriuretic peptides (NPs). NP protein sequences and post-translational processing cleavage and degradation sites. ANP, atrial NP; BNP, B-type NP; CNP, C-type NP; NEP, neprilysin; DPPIV, dipeptidyl peptidase IV; IDE, insulin degrading enzyme. Reproduced with permission from Volpe M, et al.¹²

The NPs exert their actions by binding guanylyl cyclase receptors A (GC-A for ANP and BNP) and B (GC-B for CNP), which are transmembrane proteins that catalyze the conversion of intracellular guanosine triphosphate into cyclic guanosine monophosphate (cGMP), which then increases intracellular protein kinase G (PKG) (Figure 2).¹⁷ The NP receptor C (NPR-C) functions predominantly as a clearance receptor for all 3 NPs, but also exerts effects on inhibitory G-proteins and adenylyl cyclase with activation of phospholipase C.¹⁸ Receptors for the NPs are not only present on cardiomyocytes and fibroblasts, but also the kidneys, vascular and gastrointestinal smooth muscle, adrenal glands, brain, pancreas, adipocytes, chondrocytes, platelets, and the liver, suggesting that NPs have biologic actions beyond natriuresis. In addition to clearance through NPR-C, NPs are inactivated by neutral endopeptidases located within renal tubular cells and the vasculature, as well as insulin-degrading enzyme and dipeptidyl peptidase-IV, and may also be passively excreted in the urine (Figure 1).¹²

Figure 2.

The natriuretic peptide (NP) system responds to hemodynamic and metabolic stimuli through activation of guanylyl cyclase receptors resulting in cardiometabolic protective effects. Cardiomyocytes and endothelial cells are stimulated to release NPs, which bind receptors with guanylyl cyclase activity. This activation leads to increased intracellular cGMP with beneficial downstream effects mediated through protein kinase G (PKG). Phosphodiesterase (PDE) inactivates cGMP. CNP also inhibits adenylate cyclase to reduce cAMP levels through the NP receptor-C. ANP, atrial NP; BNP, B-type NP; CNP, C-type NP; NO, nitric oxide; SNS, sympathetic nervous system. Reproduced with permission from Volpe M, et al.¹²

Biologic Effects of NPs: Experimental Evidence

Genetic Models

Experimental evidence supports the broad range of cardiovascular and metabolic actions of the NPs. Transgenic overexpression or knockout mouse models for each of the NPs and their receptors provide consistent evidence of these hormones’ protective cardiometabolic effects (Table 1).¹¹ Overexpression of NPPA, NPPB, and GC-A leads to blood pressure lowering and protection against salt-sensitive hypertension.¹⁹^–²² Knockout of NPR-C yields a similar phenotype of lower blood pressure.²³ Mice overexpressing the BNP gene (NPPB) are also resistant to obesity and demonstrate lower glucose and insulin concentrations compared with wild-type mice, a finding attributed to increased skeletal muscle mitochondrial content and fatty acid oxidation.²⁴^–²⁶ In contrast, NPPA, NPPB, and GC-A knockout mice exhibit hypertension, salt-sensitivity, cardiac hypertrophy, cardiac fibrosis, and susceptibility to heart failure, as well as obesity.²⁷^–³⁷ Alterations in the corin protein (corresponding to known human genetic variants) that lead to reduced cleavage of the NP prohormone into the active peptide also result in salt-sensitive hypertension and cardiac hypertrophy.³⁸^,³⁹

Table 1. Summary of the Phenotypes Associated With Genetic Manipulation of the Natriuretic Peptide System in Animals

Gene disruption	Phenotype/physiology
ANP overexpression	Hypotension, decrease in hypoxic HT, normal salt excretion, increased H₂O intake and excretion
ANP knockout (Nppa^−/−)	HT, BP-independent right and LVH, impaired Na and Cl excretion
BNP overexpression	Hypotension, skeletal overgrowth, resistance to immune-mediated renal injury
BNP knockout (Nppb^−/−)	Load-dependent ventricular fibrotic lesions, no hypertrophy, no HT
CNP knockout (Nppc^−/−)	Dwarfism, early death
CNP overexpression (chondrocyte targeted)	Rescue of dwarfism phenotype
NPR-A (GC-A) overexpression	Hypotension, protection against salt-sensitive HT
NPR-A (GC-A) knockout (Npr1^−/−)	Salt-resistant HT, BP-independent ventricular hypertrophy, increase in sudden death, enhanced NHE-1 activity, increased susceptibility to HF
NPR-A targeted knockout
Cardiomyocyte	Hypertrophy, increase in hypertrophy markers, hypotension
Smooth muscle	Loss of ANP response, volume dependent HT
Vascular endothelium	Arterial HT and cardiac hypertrophy, increased plasma volume
NPR-B (GC-B) knockout (Npr2^−/−)	Dwarfism, neuronal disorders, female infertility
NPR-B (GC-B) dominant-negative overexpression (rat)	BP-independent cardiac hypertrophy, increased congestive HF, elevated heart rate
NPR-C knockout (Npr3^−/−)	Hypotension, bone overgrowth, reduced blood volume

ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; BP, blood pressure; CNP, C-type natriuretic peptide; HF, heart failure; HT, hypertension; LVH, left ventricular hypertrophy. Reproduced with permission from Gardner DG, et al.¹¹

Non-Genetic Experiments

In vitro experiments and in vivo data highlight the role of the NPs in cardiovascular and metabolic physiology. Animals exposed to infusion of ANP or BNP have lower blood pressure, not only through increased natriuresis and diuresis, but also through arterial and venodilation, increased vascular permeability (shifting volume from the intracellular to extracellular space), and direct suppression of the renin-angiotensin-aldosterone and sympathetic nervous systems.³^,⁴⁰^,⁴¹ CNP administration induces marked venodilation.³ The natriuretic and diuretic effects are caused by (1) enhanced glomerular filtration through simultaneous dilation of afferent arterioles and constriction of efferent arterioles and (2) direct effects on renal tubular cells through antagonism of angiotensin II and vasopressin.⁴²^–⁴⁴ The vasodilatory effects of ANP and BNP are also mediated centrally in the brainstem through decreased sympathetic outflow.⁴¹^,⁴⁵^,⁴⁶

ANP inhibits the growth of cardiac fibroblasts and can induce cardiomyocyte apoptosis.⁴⁷^–⁴⁹ Similar to ANP, CNP is a potent inhibitor of cardiac fibroblasts and exerts antifibrotic effects,⁵⁰ which may be in part mediated by PKG-dependent phosphorylation of Smad3, resulting in less nuclear translocation when stimulated by transforming growth factor-β.⁵¹ Through p38 MAPK, NPs also exhibit anti-mitogenic properties, with some indication of anti-neoplastic potential through reduction of inflammation and cell adhesion processes as well.⁵²^,⁵³

The p38 MAPK pathway may also modulate the effect of NPs on the induction of brown adipose tissue.⁵⁴ Further supporting a role for the NPs in the control of energy homeostasis, exposure of cultured adipocytes to physiologic doses of ANP and/or BNP promote cGMP-dependent activation of hormone sensitive-lipase, leading to lipolysis.⁵⁵^,⁵⁶

Biologic Effects of NPs: Clinical Evidence

Genetic Variants

The biologic importance of the NP system is supported by the finding that NPPA is highly conserved across species.⁵⁷ Nevertheless, genetic variants in the NPs, their receptors, and activating proteases have been identified in humans and their associations with cardiometabolic phenotypes described.⁵⁷ The results of these genetic variation studies in humans parallel the evidence from animal models regarding the role of the NP system.

A number of variants in the promoter, coding, intronic, and 3’ untranslated region of NPPA have been characterized (Table 2).⁵⁷ Candidate gene studies in Japanese and Italian individuals have associated a C-664G variant with lower circulating ANP, hypertension, and left ventricular hypertrophy.⁵⁸^–⁶⁰ There are mixed data regarding another missense variant, rs5063, which results in a valine to methionine substitution and has been linked to lower blood pressure among Chinese individuals and participants in the Women’s Genome Health study, although this was not observed among Japanese individuals.⁵⁸^,⁶¹^–⁶³ In other populations, the rs5063 variant was associated with an increased risk of hypertension or stroke.⁶⁴^–⁶⁶ Interestingly, the rs5065 (2238 T>C) variant in exon 3 has been associated with a decreased risk of hypertension,⁶⁷ but higher risk of myocardial infarction and stroke, which may be mediated through altered NPR-C activation and resultant endothelial dysfunction.⁶⁸^–⁷² Nonetheless, many of the aforementioned candidate genes have not been reliably reproduced in large-scale population genetic studies nor in meta-analyses of genome-wide association studies (GWAS).

Table 2. Summary of NPPA Genetic Variants in Humans and Their Associated Clinical Phenotypes

NPPA variant	HT	LVH	CV acute events	AF	MetS	HF
−664C>G	G allele more frequent in young subjects with HT; C allele more frequent in Japanese subjects with HT	G allele associated with increased LVH in HT	No association of either allele with stroke and AMI	No association of either allele with AF in high risk Italian patients	–	–
rs5063 (664G>A)	A allele associated with lower DBP; A allele associated with BP progression; no association in Japanese patients	–	A allele associated with increased risk of stroke; common allele associated with higher risk of acute events	A allele associated with increased risk of lone AF in Chinese patients; no association with AF in North American subjects	–	–
HpaII	Variant allele associated with increased risk of HT; common allele associated with increased risk of HT	–	Variant allele associated with increased risk of stroke	–	–	–
rs5065 (2238T>C)	C allele associated with a decreased risk of HT		C allele associated with an increased risk of stroke, AMI and MACE; no association with stroke; no association with CV events; C allele associated with a greater response to diuretic in HT	No association of C allele with AF in both North American and Italian patients		Allele variant associated with ANP plasma levels in NYHA class III–IV
rs5068	Allele variant associated with a decreased risk of HT	Allele variant associated with decreased occurrence of LVH	–	–	Allele variant associated with a decreased risk of the MetS	No association of allele variant with HF

AF, atrial fibrillation; AMI, acute myocardial infarction; CV, cardiovascular; DBP, diastolic BP; MACE, major adverse cardiovascular events; MetS, metabolic syndrome. Other abbreviations as in Table 1. Reproduced with permission from Rubattu S, et al.⁵⁷ See original publication for detailed references.

The most statistically robust findings to date have derived from studies with larger sample sizes. For instance, from a meta-analysis of data from the Framingham Heart Study, the Malmo Diet and Cancer Study, and the Finrisk study, the rs5068 A/G variant in the 3’ untranslated region of NPPA is associated with higher circulating ANP levels at a genome-wide level of significance (among carriers of the minor allele, G, P=8×10⁻⁷⁰). The G allele has been associated with lower blood pressure, less hypertension, and less ventricular hypertrophy.⁷³^,⁷⁴ Additional studies demonstrate that the rs5068 A/G variant relates to a favorable metabolic profile as evidenced by lower body mass index, smaller waist circumference, higher high-density lipoprotein and lower C-reactive protein levels, as well as less susceptibility to heart failure.⁷⁵^,⁷⁶ Recently, Arora et al elucidated the molecular mechanism by which the rs5068 variant influenced ANP production. The variant is in the non-coding 3’ UTR of NPPA, a region that is targeted by micro-RNAs. ANP expression was modulated through negative regulation by a specific microRNA, miR-425, which binds to the site of rs5068. Thus, individuals with the AG allele combination are resistant to miR-425, and therefore have higher circulating ANP levels and less hypertension compared with AA homozygote individuals.⁷⁷

Genetic variants in other NP and related genes have also been described. The rs198388 (presence of A allele) and 198389 (presence of the C allele) variants in NPPB are associated with lower blood pressure, improved left ventricular diastolic function, reduced left ventricular remodeling, and lower risk of diabetes mellitus.⁷³^,⁷⁸^–⁸¹ A functional deletion mutation in the 5’ flanking region of the NP receptor GC-A gene reduces transcription and is associated with hypertension and ventricular hypertrophy among Japanese individuals.⁸² In GWAS, the NPR-C variants are associated with hypertension in Caucasian and Asian individuals.⁸⁰^,⁸¹ Less is known about variants in NPPC and GC-B.⁵⁷ Missense variants in CORIN (555T>I and 568Q>P), which encodes a serine protease that cleaves natriuretic prohormones into the active carboxy- and inactive amino-terminal peptides, has been found in approximately 9% of African-Americans and is associated with a greater risk for hypertension and cardiac hypertrophy.⁸³^,⁸⁴

Physiologic Studies

The beneficial cardiovascular effects of NPs have been demonstrated through infusions of ANP, BNP, and CNP. All 3 NPs induce vasodilation, with ANP and BNP also lowering blood pressure.⁸⁵^,⁸⁶ Infusion of ANP, BNP, or CNP may also limit post-acute myocardial infarction adverse cardiac modeling.⁸⁷^–⁸⁹ In the setting of heart failure, ANP and BNP infusions decrease pulmonary capillary wedge pressure and systemic vascular resistance, leading to increased stroke volume.⁹⁰^–⁹⁴

NPs not only influence myocardial structure and function, but also exert positive influences on the vasculature. Cultured endothelial cells exposed to ANP or CNP demonstrated reduced expression of adhesion molecules (MCP-1 and P-selectin), which are needed for leukocyte infiltration into atherosclerotic plaques.⁹⁵^,⁹⁶ CNP also inhibits coronary vascular smooth muscle proliferation in models of atherosclerosis,⁹⁷^–⁹⁹ reduces platelet leukocyte aggregation, and limits thrombus formation through reduction in PAI-1, perhaps through NPR-C.¹⁰⁰^–¹⁰²

The beneficial metabolic effects of NPs have also been demonstrated in humans. Infusion of ANP at physiologic levels induced lipid mobilization from subcutaneous adipose tissue, with a concomitant increase in lipid oxidation by skeletal muscle.²⁵^,²⁶^,¹⁰³ BNP has been demonstrated to lower glucose levels,¹⁰⁴ and both ANP and BNP converted white to brown fat through mitochondrial uncoupling protein-1 and p38 MAPK.⁵⁴ It has also been suggested that exercise-induced lipolysis may be mediated through ANP.¹⁰⁵

Epidemiologic Associations

The cross-sectional associations between circulating NP levels and cardiovascular and metabolic disease have been examined in epidemiologic studies. An inverse relationship has been demonstrated between plasma NP levels and body mass index.¹⁰⁶^,¹⁰⁷ Similarly, low levels of NT-proBNP and NT-proANP have been found in individuals with the metabolic syndrome and/or left ventricular hypertrophy.¹⁰⁸^–¹¹¹ The association of NPs with endothelial function has also been demonstrated in the Framingham Heart Study.¹¹² Congruent with the animal studies, low NP levels have been associated with the development of diabetes mellitus.¹¹³^,¹¹⁴

NPs as Biomarkers

Although experimental, population genetic, and NP infusion studies demonstrate inverse associations between NP levels and cardiometabolic disease, clinical studies of NPs as prognostic biomarkers typically yield positive associations between circulating NP levels and adverse cardiovascular outcomes.¹⁶ This apparent paradox is attributable to the fact that NPs are counter-regulatory hormones that are released in response to cardiac stress. In population studies, higher NP levels, even within what might be considered a “normal” range, are commonly seen in the setting of subclinical cardiovascular disease. Thus, the elevated NP levels observed in clinical biomarker studies reflect normal physiologic responses to elevated cardiac wall stress.

For example, among individuals without prevalent cardiovascular disease in the Framingham Offspring Study and in Copenhagen, higher NP levels were positively and significantly associated with cardiovascular mortality¹¹⁵ or major adverse cardiovascular events,¹¹⁶ respectively. Among persons with stable coronary artery disease or acute coronary syndromes, higher NPs were significantly and positively associated with greater risk for recurrent cardiovascular events and/or death.¹¹⁷^–¹²¹ Similarly, higher NP levels are associated with worse outcomes among individuals with heart failure.¹²²^–¹²⁵ However, further evidence for the beneficial effects of NPs, even in the setting of subclinical or overt cardiovascular disease, comes from therapeutic trials in which augmentation of NPs led to favorable cardiovascular effects.

NPs as a Therapeutic Target

Most strategies for the prevention and treatment of cardiovascular disease have been directed at blocking the deleterious effects of the renin-angiotensin-aldosterone axis and sympathetic nervous system.¹² Given that hypertension, obesity, and insulin resistance are major risk factors for the development of cardiovascular disease and that NPs guard against the development and progression of these disorders, NPs are attractive therapeutic targets (Figure 3).

Figure 3.

Natriuretic peptides (NPs) as novel therapeutic targets in cardiometabolic disease. NPs exert beneficial effects on cardiac and vascular function directly and through inhibition of the renin-angiotensin-aldosterone axis (RAAS) and sympathetic nervous systems (SNS), making them ideal and novel targets for cardiovascular protection. BP, blood pressure; CAD, coronary artery disease; CO, cardiac output; HF, heart failure; HT, hypertension; SVR, systemic vascular resistance. Reproduced with permission from Volpe M, et al.¹²

Therapeutic approaches have included intravenous infusions of recombinant ANP or BNP, oral inhibitors of neutral endopeptidases, and synthetic or “designer” NP analogs.³ Intravenous infusions of ANP and BNP have been tested in clinical trials for hypertension¹²⁶ and heart failure, with favorable hemodynamic effects, but no clear benefit on long-term clinical outcomes.⁹⁴^,¹²⁷ Furthermore, oral formulations of ANP and BNP are not stable, currently limiting their therapeutic application in chronic disease.

An alternative strategy to direct supplementation of NPs is to limit the breakdown of endogenous NPs. Inhibitors of neutral endopeptidases are stable when given orally. The first to be tested in hypertension was candoxatril; however, this agent was not of substantial benefit because of simultaneous vasoconstriction due to increases in endothelin-1 and angiotensin II.¹²⁸^,¹²⁹ Subsequently, combined inhibition of neutral endopeptidases and angiotensin-converting enzyme (ACE) with omapatrilat was evaluated in hypertensive and heart failure patients in the OCTAVE, OVERTURE, and IMPRESS trials. Blood pressure was lower in omapatrilat-treated patients compared with those treated with enalapril alone; however, omapatrilat was associated with a higher frequency of angioedema and symptomatic hypotension, without demonstration of superior efficacy, thereby preventing approval for clinical use.¹³⁰^–¹³² More recently, neutral endopeptidase inhibition has been combined with angiotensin-receptor blockade to avoid the angioedema seen with ACE inhibition. The angiotensin-receptor and neprilysin inhibitor LCZ696 is efficacious for lowering blood pressure among patients with essential hypertension, without increased angioedema compared with valsartan alone.¹³³ In a phase II study of heart failure with preserved ejection fraction patients (PARAMOUNT), LCZ696 was superior to valsartan alone in reducing NT-proBNP levels over 12 weeks of follow up.¹³⁴ Recently, LCZ696 was demonstrated to be superior to enalapril for reducing cardiovascular death and heart failure hospitalizations in patients with heart failure and reduced ejection fraction (PARADIGM-HF),¹³⁵ lending further support for the therapeutic benefit of NPs.

“Designer” or synthetic NPs that are more stable than native NPs have been developed. For example, the ANP analog carperitide promotes vasodilation, natriuresis, and inhibition of the renin-angiotensin-aldosterone axis and is approved in Japan for treatment of acute decompensated heart failure.¹³⁶ Another analog, M-ANP, which is more resistant to neutral endopeptidase degradation than native ANP, has been designed and has favorable antihypertensive effects.¹³⁷ A novel chimeric molecule, CD-NP, has been engineered by combining the 15 amino acid carboxy-terminus of dendrapsis NP with CNP, resulting in a protein that is able to activate both GC-A and GC-B. This chimeric peptide demonstrates potent natriuresis and diuresis, as well as antifibrotic and antiproliferative properties.¹³⁸

Summary

NPs are cardiac-derived hormones and the principal counter-regulatory system guarding against salt-retention, volume expansion, cardiac stress, and remodeling. They also modulate energy metabolism, lipolysis, weight loss, and insulin sensitivity. Low NP activity can be associated with increased risk for hypertension, obesity, and diabetes mellitus, conditions that are increasing in prevalence and are major risk factors for cardiovascular disease. Consequently, NPs are attractive targets for new therapeutic approaches to cardiometabolic disease.

Acknowledgments

Funding for this study was from National Heart, Lung, and Blood Institute grants K12 HL109019 and R01-HL-102780, and the National Center for Advancing Translational Sciences of the National Institutes of Health award number UL1TR000445.

References

1. Wang TJ. The natriuretic peptides and fat metabolism. N Engl J Med 2012; 367: 377–378.
2. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981; 28: 89–94.
3. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998; 339: 321–328.
4. Matsuo H, Kangawa K. Human and rat atrial natriuretic polypeptides (hANP & rANP) purification, structure and biological activity. Clin Exp Hypertens A 1984; 6: 1717–1722.
5. Oikawa S, Imai M, Ueno A, Tanaka S, Noguchi T, Nakazato H, et al. Cloning and sequence analysis of cDNA encoding a precursor for human atrial natriuretic polypeptide. Nature 1984; 309: 724–726.
6. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature 1988; 332: 78–81.
7. Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic peptide (CNP): A new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun 1990; 168: 863–870.
8. Nemer M, Chamberland M, Sirois D, Argentin S, Drouin J, Dixon RA, et al. Gene structure of human cardiac hormone precursor, pronatriodilatin. Nature 1984; 312: 654–656.
9. Arden KC, Viars CS, Weiss S, Argentin S, Nemer M. Localization of the human B-type natriuretic peptide precursor (NPPB) gene to chromosome 1p36. Genomics 1995; 26: 385–389.
10. Ogawa Y, Itoh H, Yoshitake Y, Inoue M, Yoshimasa T, Serikawa T, et al. Molecular cloning and chromosomal assignment of the mouse C-type natriuretic peptide (CNP) gene (Nppc): Comparison with the human CNP gene (NPPC). Genomics 1994; 24: 383–387.
11. Gardner DG, Chen S, Glenn DJ, Grigsby CL. Molecular biology of the natriuretic peptide system: Implications for physiology and hypertension. Hypertension 2007; 49: 419–426.
12. Volpe M, Rubattu S, Burnett J Jr. Natriuretic peptides in cardiovascular diseases: Current use and perspectives. Eur Heart J 2014; 35: 419–425.
13. Yoshimura M, Yasue H, Okumura K, Ogawa H, Jougasaki M, Mukoyama M, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993; 87: 464–469.
14. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90: 195–203.
15. Nakagawa O, Ogawa Y, Itoh H, Suga S, Komatsu Y, Kishimoto I, et al. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy: Evidence for brain natriuretic peptide as an “emergency” cardiac hormone against ventricular overload. J Clin Invest 1995; 96: 1280–1287.
16. Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007; 50: 2357–2368.
17. Kuhn M. Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol 2004; 99: 76–82.
18. Rubattu S, Sciarretta S, Morriello A, Calvieri C, Battistoni A, Volpe M. NPR-C: A component of the natriuretic peptide family with implications in human diseases. J Mol Med (Berl) 2010; 88: 889–897.
19. Steinhelper ME, Cochrane KL, Field LJ. Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension 1990; 16: 301–307.
20. Veress AT, Chong CK, Field LJ, Sonnenberg H. Blood pressure and fluid-electrolyte balance in ANF-transgenic mice on high- and low-salt diets. Am J Physiol 1995; 269: R186–R192.
21. Ogawa Y, Itoh H, Tamura N, Suga S, Yoshimasa T, Uehira M, et al. Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J Clin Invest 1994; 93: 1911–1921.
22. Oliver PM, John SW, Purdy KE, Kim R, Maeda N, Goy MF, et al. Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner. Proc Natl Acad Sci USA 1998; 95: 2547–2551.
23. Matsukawa N, Grzesik WJ, Takahashi N, Pandey KN, Pang S, Yamauchi M, et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci USA 1999; 96: 7403–7408.
24. Miyashita K, Itoh H, Tsujimoto H, Tamura N, Fukunaga Y, Sone M, et al. Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes 2009; 58: 2880–2892.
25. Engeli S, Birkenfeld AL, Badin PM, Bourlier V, Louche K, Viguerie N, et al. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle. J Clin Invest 2012; 122: 4675–4679.
26. Birkenfeld AL, Boschmann M, Moro C, Adams F, Heusser K, Franke G, et al. Lipid mobilization with physiological atrial natriuretic peptide concentrations in humans. J Clin Endocrinol Metab 2005; 90: 3622–3628.
27. John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC, et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 1995; 267: 679–681.
28. John SW, Veress AT, Honrath U, Chong CK, Peng L, Smithies O, et al. Blood pressure and fluid-electrolyte balance in mice with reduced or absent ANP. Am J Physiol 1996; 271: R109–R114.
29. Melo LG, Veress AT, Chong CK, Pang SC, Flynn TG, Sonnenberg H. Salt-sensitive hypertension in ANP knockout mice: Potential role of abnormal plasma renin activity. Am J Physiol 1998; 274: R255–R261.
30. Wang D, Oparil S, Feng JA, Li P, Perry G, Chen LB, et al. Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension 2003; 42: 88–95.
31. Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, et al. Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 1995; 378: 65–68.
32. Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, et al. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci USA 2000; 97: 4239–4244.
33. Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS, Reddick RL, et al. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci USA 1997; 94: 14730–14735.
34. Lopez MJ, Garbers DL, Kuhn M. The guanylyl cyclase-deficient mouse defines differential pathways of natriuretic peptide signaling. J Biol Chem 1997; 272: 23064–23068.
35. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, et al. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 2001; 107: 975–984.
36. Kishimoto I, Rossi K, Garbers DL. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc Natl Acad Sci USA 2001; 98: 2703–2706.
37. Holtwick R, van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, et al. Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest 2003; 111: 1399–1407.
38. Wang W, Liao X, Fukuda K, Knappe S, Wu F, Dries DL, et al. Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity. Circ Res 2008; 103: 502–508.
39. Wang W, Cui Y, Shen J, Jiang J, Chen S, Peng J, et al. Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks. Hypertension 2012; 60: 1352–1358.
40. Charles CJ, Espiner EA, Richards AM. Cardiovascular actions of ANF: Contributions of renal, neurohumoral, and hemodynamic factors in sheep. Am J Physiol 1993; 264: R533–R538.
41. Schultz HD, Gardner DG, Deschepper CF, Coleridge HM, Coleridge JC. Vagal C-fiber blockade abolishes sympathetic inhibition by atrial natriuretic factor. Am J Physiol 1988; 255: R6–R13.
42. Marin-Grez M, Fleming JT, Steinhausen M. Atrial natriuretic peptide causes pre-glomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature 1986; 324: 473–476.
43. Harris PJ, Thomas D, Morgan TO. Atrial natriuretic peptide inhibits angiotensin-stimulated proximal tubular sodium and water reabsorption. Nature 1987; 326: 697–698.
44. Dillingham MA, Anderson RJ. Inhibition of vasopressin action by atrial natriuretic factor. Science 1986; 231: 1572–1573.
45. Yang R, Jin H, Wyss JM, Chen YF, Oparil S. Salt supplementation does not alter the pressor effect of blocking atrial natriuretic peptide in nucleus tractus solitarii. Hypertension 1992; 20: 242–246.
46. Steele MK, Gardner DG, Xie PL, Schultz HD. Interactions between ANP and ANG II in regulating blood pressure and sympathetic outflow. Am J Physiol 1991; 260: R1145–R1151.
47. Itoh H, Pratt RE, Dzau VJ. Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. J Clin Invest 1990; 86: 1690–1697.
48. Cao L, Gardner DG. Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. Hypertension 1995; 25: 227–234.
49. Wu CF, Bishopric NH, Pratt RE. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem 1997; 272: 14860–14866.
50. Furuya M, Aisaka K, Miyazaki T, Honbou N, Kawashima K, Ohno T, et al. C-type natriuretic peptide inhibits intimal thickening after vascular injury. Biochem Biophys Res Commun 1993; 193: 248–253.
51. Li P, Wang D, Lucas J, Oparil S, Xing D, Cao X, et al. Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 2008; 102: 185–192.
52. Vesely DL. Family of peptides synthesized in the human body have anticancer effects. Anticancer Res 2014; 34: 1459–1466.
53. Nojiri T, Hosoda H, Tokudome T, Miura K, Ishikane S, Otani K, et al. Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells. Proc Natl Acad Sci USA 2015; 112: 4086–4091.
54. Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessi-Fulgheri P, Zhang C, et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 2012; 122: 1022–1036.
55. Moro C, Lafontan M. Natriuretic peptides and cGMP signaling control of energy homeostasis. Am J Physiol Heart Circ Physiol 2013; 304: H358–H368.
56. Sengenes C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: A new lipolytic pathway in human adipocytes. FASEB J 2000; 14: 1345–1351.
57. Rubattu S, Sciarretta S, Volpe M. Atrial natriuretic peptide gene variants and circulating levels: Implications in cardiovascular diseases. Clin Sci (Lond) 2014; 127: 1–13.
58. Kato N, Sugiyama T, Morita H, Nabika T, Kurihara H, Yamori Y, et al. Genetic analysis of the atrial natriuretic peptide gene in essential hypertension. Clin Sci (Lond) 2000; 98: 251–258.
59. Rubattu S, Evangelista A, Barbato D, Barba G, Stanzione R, Iacone R, et al. Atrial natriuretic peptide (ANP) gene promoter variant and increased susceptibility to early development of hypertension in humans. J Hum Hypertens 2007; 21: 822–824.
60. Rubattu S, Bigatti G, Evangelista A, Lanzani C, Stanzione R, Zagato L, et al. Association of atrial natriuretic peptide and type a natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension. J Am Coll Cardiol 2006; 48: 499–505.
61. Zhang S, Mao G, Zhang Y, Tang G, Wen Y, Hong X, et al. Association between human atrial natriuretic peptide Val7Met polymorphism and baseline blood pressure, plasma trough irbesartan concentrations, and the antihypertensive efficacy of irbesartan in rural Chinese patients with essential hypertension. Clin Ther 2005; 27: 1774–1784.
62. Conen D, Glynn RJ, Buring JE, Ridker PM, Zee RY. Natriuretic peptide precursor a gene polymorphisms and risk of blood pressure progression and incident hypertension. Hypertension 2007; 50: 1114–1119.
63. Conen D, Cheng S, Steiner LL, Buring JE, Ridker PM, Zee RY. Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: The Women’s Genome Health Study. J Hypertens 2009; 27: 476–483.
64. Rutledge DR, Sun Y, Ross EA. Polymorphisms within the atrial natriuretic peptide gene in essential hypertension. J Hypertens 1995; 13: 953–955.
65. Beige J, Ringel J, Hohenbleicher H, Rubattu S, Kreutz R, Sharma AM. HpaII-polymorphism of the atrial-natriuretic-peptide gene and essential hypertension in whites. Am J Hypertens 1997; 10: 1316–1318.
66. Rubattu S, Ridker P, Stampfer MJ, Volpe M, Hennekens CH, Lindpaintner K. The gene encoding atrial natriuretic peptide and the risk of human stroke. Circulation 1999; 100: 1722–1726.
67. Niu W. The relationship between natriuretic peptide precursor a gene T2238C polymorphism and hypertension: A meta-analysis. Int J Hypertens 2011; 2011: 653698.
68. Gruchala M, Ciecwierz D, Wasag B, Targonski R, Dubaniewicz W, Nowak A, et al. Association of the ScaI atrial natriuretic peptide gene polymorphism with nonfatal myocardial infarction and extent of coronary artery disease. Am Heart J 2003; 145: 125–131.
69. Sciarretta S, Marchitti S, Bianchi F, Moyes A, Barbato E, Di Castro S, et al. C2238 atrial natriuretic peptide molecular variant is associated with endothelial damage and dysfunction through natriuretic peptide receptor C signaling. Circ Res 2013; 112: 1355–1364.
70. Rubattu S, Stanzione R, Di Angelantonio E, Zanda B, Evangelista A, Tarasi D, et al. Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans. Stroke 2004; 35: 814–818.
71. Barbato E, Bartunek J, Mangiacapra F, Sciarretta S, Stanzione R, Delrue L, et al. Influence of rs5065 atrial natriuretic peptide gene variant on coronary artery disease. J Am Coll Cardiol 2012; 59: 1763–1770.
72. Cannone V, Huntley BK, Olson TM, Heublein DM, Scott CG, Bailey KR, et al. Atrial natriuretic peptide genetic variant rs5065 and risk for cardiovascular disease in the general community: A 9-year follow-up study. Hypertension 2013; 62: 860–865.
73. Newton-Cheh C, Larson MG, Vasan RS, Levy D, Bloch KD, Surti A, et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet 2009; 41: 348–353.
74. Jujic A, Leosdottir M, Ostling G, Gudmundsson P, Nilsson PM, Melander O, et al. A genetic variant of the atrial natriuretic peptide gene is associated with left ventricular hypertrophy in a non-diabetic population: The Malmo preventive project study. BMC Med Genet 2013; 14: 64.
75. Cannone V, Boerrigter G, Cataliotti A, Costello-Boerrigter LC, Olson TM, McKie PM, et al. A genetic variant of the atrial natriuretic peptide gene is associated with cardiometabolic protection in the general community. J Am Coll Cardiol 2011; 58: 629–636.
76. Cannone V, Cefalu AB, Noto D, Scott CG, Bailey KR, Cavera G, et al. The atrial natriuretic peptide genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a Mediterranean population. Diabetes Care 2013; 36: 2850–2856.
77. Arora P, Wu C, Khan AM, Bloch DB, Davis-Dusenbery BN, Ghorbani A, et al. Atrial natriuretic peptide is negatively regulated by microRNA-425. J Clin Invest 2013; 123: 3378–3382.
78. Ellis KL, Newton-Cheh C, Wang TJ, Frampton CM, Doughty RN, Whalley GA, et al. Association of genetic variation in the natriuretic peptide system with cardiovascular outcomes. J Mol Cell Cardiol 2011; 50: 695–701.
79. Meirhaeghe A, Sandhu MS, McCarthy MI, de Groote P, Cottel D, Arveiler D, et al. Association between the T-381C polymorphism of the brain natriuretic peptide gene and risk of type 2 diabetes in human populations. Hum Mol Genet 2007; 16: 1343–1350.
80. International Consortium for Blood Pressure Genome-Wide Association Studies; Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011; 478: 103–109.
81. Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet 2011; 43: 531–538.
82. Nakayama T, Soma M, Takahashi Y, Rehemudula D, Kanmatsuse K, Furuya K. Functional deletion mutation of the 5’-flanking region of type A human natriuretic peptide receptor gene and its association with essential hypertension and left ventricular hypertrophy in the Japanese. Circ Res 2000; 86: 841–845.
83. Dries DL, Victor RG, Rame JE, Cooper RS, Wu X, Zhu X, et al. Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension. Circulation 2005; 112: 2403–2410.
84. Rame JE, Drazner MH, Post W, Peshock R, Lima J, Cooper RS, et al. Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload. Hypertension 2007; 49: 857–864.
85. Vesely DL, Douglass MA, Dietz JR, Gower WR Jr, McCormick MT, Rodriguez-Paz G, et al. Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, and/or kaliuresis in humans. Circulation 1994; 90: 1129–1140.
86. Nakamura M, Arakawa N, Yoshida H, Makita S, Hiramori K. Vasodilatory effects of C-type natriuretic peptide on forearm resistance vessels are distinct from those of atrial natriuretic peptide in chronic heart failure. Circulation 1994; 90: 1210–1214.
87. Hayashi M, Tsutamoto T, Wada A, Maeda K, Mabuchi N, Tsutsui T, et al. Intravenous atrial natriuretic peptide prevents left ventricular remodeling in patients with first anterior acute myocardial infarction. J Am Coll Cardiol 2001; 37: 1820–1826.
88. Chen HH, Martin FL, Gibbons RJ, Schirger JA, Wright RS, Schears RM, et al. Low-dose nesiritide in human anterior myocardial infarction suppresses aldosterone and preserves ventricular function and structure: A proof of concept study. Heart 2009; 95: 1315–1319.
89. Soeki T, Kishimoto I, Okumura H, Tokudome T, Horio T, Mori K, et al. C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction. J Am Coll Cardiol 2005; 45: 608–616.
90. Yoshimura M, Yasue H, Morita E, Sakaino N, Jougasaki M, Kurose M, et al. Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 1991; 84: 1581–1588.
91. Semigran MJ, Aroney CN, Herrmann HC, Dec GW Jr, Boucher CA, Fifer MA. Effects of atrial natriuretic peptide on myocardial contractile and diastolic function in patients with heart failure. J Am Coll Cardiol 1992; 20: 98–106.
92. Marcus LS, Hart D, Packer M, Yushak M, Medina N, Danziger RS, et al. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure: A double-blind, placebo-controlled, randomized crossover trial. Circulation 1996; 94: 3184–3189.
93. Mills RM, LeJemtel TH, Horton DP, Liang C, Lang R, Silver MA, et al; Natrecor Study Group. Sustained hemodynamic effects of an infusion of nesiritide (human B-type natriuretic peptide) in heart failure: A randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 1999; 34: 155–162.
94. Colucci WS, Elkayam U, Horton DP, Abraham WT, Bourge RC, Johnson AD, et al; Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000; 343: 246–253.
95. Scotland RS, Cohen M, Foster P, Lovell M, Mathur A, Ahluwalia A, et al. C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression. Proc Natl Acad Sci USA 2005; 102: 14452–14457.
96. Weber NC, Blumenthal SB, Hartung T, Vollmar AM, Kiemer AK. ANP inhibits TNF-alpha-induced endothelial MCP-1 expression: Involvement of p38 MAPK and MKP-1. J Leukoc Biol 2003; 74: 932–941.
97. Ikeda M, Kohno M, Yasunari K, Yokokawa K, Horio T, Ueda M, et al. Natriuretic peptide family as a novel antimigration factor of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17: 731–736.
98. Kohno M, Yokokawa K, Yasunari K, Kano H, Minami M, Ueda M, et al. Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells. Circ Res 1997; 81: 585–590.
99. Ueno H, Haruno A, Morisaki N, Furuya M, Kangawa K, Takeshita A, et al. Local expression of C-type natriuretic peptide markedly suppresses neointimal formation in rat injured arteries through an autocrine/paracrine loop. Circulation 1997; 96: 2272–2279.
100. Bouchie JL, Hansen H, Feener EP. Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells: Role of cGMP in the regulation of the plasminogen system. Arterioscler Thromb Vasc Biol 1998; 18: 1771–1779.
101. Yoshizumi M, Tsuji H, Nishimura H, Masuda H, Kunieda Y, Kawano H, et al. Natriuretic peptides regulate the expression of tissue factor and PAI-1 in endothelial cells. Thromb Haemost 1999; 82: 1497–1503.
102. Kairuz EM, Barber MN, Anderson CR, Kanagasundaram M, Drummond GR, Woods RL. C-type natriuretic peptide (CNP) suppresses plasminogen activator inhibitor-1 (PAI-1) in vivo. Cardiovasc Res 2005; 66: 574–582.
103. Moro C, Crampes F, Sengenes C, De Glisezinski I, Galitzky J, Thalamas C, et al. Atrial natriuretic peptide contributes to physiological control of lipid mobilization in humans. FASEB J 2004; 18: 908–910.
104. Heinisch BB, Vila G, Resl M, Riedl M, Dieplinger B, Mueller T, et al. B-type natriuretic peptide (BNP) affects the initial response to intravenous glucose: A randomised placebo-controlled cross-over study in healthy men. Diabetologia 2012; 55: 1400–1405.
105. Moro C, Pillard F, de Glisezinski I, Klimcakova E, Crampes F, Thalamas C, et al. Exercise-induced lipid mobilization in subcutaneous adipose tissue is mainly related to natriuretic peptides in overweight men. Am J Physiol Endocrinol Metab 2008; 295: E505–E513.
106. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004; 109: 594–600.
107. Fox ER, Musani SK, Bidulescu A, Nagarajarao HS, Samdarshi TE, Gebreab SY, et al. Relation of obesity to circulating B-type natriuretic peptide concentrations in blacks: The Jackson Heart Study. Circulation 2011; 124: 1021–1027.
108. Khan AM, Cheng S, Magnusson M, Larson MG, Newton-Cheh C, McCabe EL, et al. Cardiac natriuretic peptides, obesity, and insulin resistance: Evidence from two community-based studies. J Clin Endocrinol Metab 2011; 96: 3242–3249.
109. Olsen MH, Hansen TW, Christensen MK, Gustafsson F, Rasmussen S, Wachtell K, et al. N-terminal pro brain natriuretic peptide is inversely related to metabolic cardiovascular risk factors and the metabolic syndrome. Hypertension 2005; 46: 660–666.
110. Wang TJ, Larson MG, Keyes MJ, Levy D, Benjamin EJ, Vasan RS. Association of plasma natriuretic peptide levels with metabolic risk factors in ambulatory individuals. Circulation 2007; 115: 1345–1353.
111. Rubattu S, Sciarretta S, Ciavarella GM, Venturelli V, De Paolis P, Tocci G, et al. Reduced levels of N-terminal-proatrial natriuretic peptide in hypertensive patients with metabolic syndrome and their relationship with left ventricular mass. J Hypertens 2007; 25: 833–839.
112. Kathiresan S, Gona P, Larson MG, Vita JA, Mitchell GF, Tofler GH, et al. Cross-sectional relations of multiple biomarkers from distinct biological pathways to brachial artery endothelial function. Circulation 2006; 113: 938–945.
113. Magnusson M, Jujic A, Hedblad B, Engstrom G, Persson M, Struck J, et al. Low plasma level of atrial natriuretic peptide predicts development of diabetes: The prospective Malmo Diet and Cancer study. J Clin Endocrinol Metab 2012; 97: 638–645.
114. Lazo M, Young JH, Brancati FL, Coresh J, Whelton S, Ndumele CE, et al. NH2-terminal pro-brain natriuretic peptide and risk of diabetes. Diabetes 2013; 62: 3189–3193.
115. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004; 350: 655–663.
116. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA 2005; 293: 1609–1616.
117. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med 2005; 352: 666–675.
118. Sabatine MS, Morrow DA, de Lemos JA, Omland T, Sloan S, Jarolim P, et al. Evaluation of multiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease. Circulation 2012; 125: 233–240.
119. Schnabel R, Lubos E, Rupprecht HJ, Espinola-Klein C, Bickel C, Lackner KJ, et al. B-type natriuretic peptide and the risk of cardiovascular events and death in patients with stable angina: Results from the AtheroGene study. J Am Coll Cardiol 2006; 47: 552–558.
120. Bibbins-Domingo K, Gupta R, Na B, Wu AH, Schiller NB, Whooley MA. N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events, and mortality in patients with stable coronary heart disease. JAMA 2007; 297: 169–176.
121. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001; 345: 1014–1021.
122. van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013; 61: 1498–1506.
123. Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003; 107: 1278–1283.
124. Maisel A, Hollander JE, Guss D, McCullough P, Nowak R, Green G, et al. Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT): A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath. J Am Coll Cardiol 2004; 44: 1328–1333.
125. Gottlieb SS, Kukin ML, Ahern D, Packer M. Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure. J Am Coll Cardiol 1989; 13: 1534–1539.
126. Volpe M, Mele AF, Indolfi C, De Luca N, Lembo G, Focaccio A, et al. Hemodynamic and hormonal effects of atrial natriuretic factor in patients with essential hypertension. J Am Coll Cardiol 1987; 10: 787–793.
127. O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011; 365: 32–43.
128. Ando S, Rahman MA, Butler GC, Senn BL, Floras JS. Comparison of candoxatril and atrial natriuretic factor in healthy men: Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. Hypertension 1995; 26: 1160–1166.
129. Bevan EG, Connell JM, Doyle J, Carmichael HA, Davies DL, Lorimer AR, et al. Candoxatril, a neutral endopeptidase inhibitor: Efficacy and tolerability in essential hypertension. J Hypertens 1992; 10: 607–613.
130. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004; 17: 103–111.
131. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002; 106: 920–926.
132. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 2000; 356: 615–620.
133. Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: A randomised, double-blind, placebo-controlled, active comparator study. Lancet 2010; 375: 1255–1266.
134. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double-blind randomised controlled trial. Lancet 2012; 380: 1387–1395.
135. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993–1004.
136. Suwa M, Seino Y, Nomachi Y, Matsuki S, Funahashi K. Multicenter prospective investigation on efficacy and safety of carperitide for acute heart failure in the ‘real world’ of therapy. Circ J 2005; 69: 283–290.
137. McKie PM, Cataliotti A, Boerrigter G, Chen HH, Sangaralingham SJ, Martin FL, et al. A novel atrial natriuretic peptide based therapeutic in experimental angiotensin II mediated acute hypertension. Hypertension 2010; 56: 1152–1159.
138. McKie PM, Sangaralingham SJ, Burnett JC Jr. CD-NP: An innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease. Curr Heart Fail Rep 2010; 7: 93–99.

Corresponding author

Register with J-STAGE for free!