Journal of Investigative Medicine:
Determinants of Natriuretic Peptide Production by the Heart: Basic and Clinical Implications
de Bold, Adolfo J.; Kuroski de Bold, Mercedes L.
From the Cardiovascular Endocrinology Laboratory (A.J.d.B., M.L.d.B.), University of Ottawa Heart Institute, Ottawa, ON.
Address correspondence to: Dr. Adolfo J. de Bold, Cardiovascular Endocrinology Laboratory, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7; e‐mail: email@example.com.
The cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones synthesized, stored, and secreted by cardiac muscle cells (cardiocytes). The NPs modulate extracellular fluid volume and blood pressure and have potent growth‐regulating properties, which make them of great interest for cardiac remodeling in acute myocardial infarction and congestive heart failure. We have observed that the production of NP can be coordinately or discoordinately regulated. In the former type, muscle stretch‐elicited secretion triggers signals mediated by Gi/o protein, whereas agonists such as endothelin 1 independently signal through Gq. Discoordinated regulation is observed following stimulations by some cytokines, which selectively up‐regulate BNP. This regulation takes place at the translational and transcriptional levels and is dependent on a p38 signaling pathway. Further details of processes regulating NP secretion need to be defined to develop a comprehensive view of the endocrine function of the heart. Nevertheless, translational research in the area of NPs has demonstrated the usefulness of these hormones as a marker of disease and as potential therapeutic agents. The latter application of NP is particularly attractive given that ANF and BNP possess pharmacologic actions that require polypharmacy in the treatment of acute myocardial infarction and congestive heart failure.
The cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF)1,2 and brain natriuretic peptide (BNP)3 are polypeptide hormones synthesized, stored, and secreted by cardiac muscle cells (cardiocytes). Both ANF and BNP are costored in storage granules referred to as specific atrial granules. ANF and BNP are synthesized by cardiocytes as preprohormones that are enzymatically processed to yield prohormones and, ultimately, hormones that are released into the circulation. In humans, the prohormone proANF is a polypeptide that contains 126 amino acids (ANF1‐126) that is processed to ANF1‐98 (N‐terminal ANF = NT‐ANF) and ANF99‐126 (C‐terminal ANF = CT‐ANF). The latter is the biologically active portion in terms of natriuretic and other activities associated with the NP. Human proBNP, on the other hand, is 108 amino acids long and is processed to BNP1‐76 (N‐terminal BNP = NT‐BNP) and BNP77‐108 (C‐terminal BNP = CT‐BNP). Similar to CT‐ANF, CT‐BNP is the natriuretic peptide.
PHYSIOLOGIC ROLE OF NP
The biologic properties of NP include modulation of intrinsic renal mechanisms, the sympathetic nervous system, the renin‐angiotensin‐aldosterone system (RAAS), and other determinants of vascular tone and renal function.2 Owing to these properties, the NP limit increases in extracellular fluid volume and blood pressure. In addition, NPs have potent growth‐regulating properties, which make them of great interest in the regulation of cardiovascular growth, including cardiac remodeling in acute myocardial infarction (AMI) and in congestive heart failure (CHF). The properties of NP are predominantly mediated through increases in cyclic guanosine monophosphate (cGMP) in target cells produced by activation of guanylyl cyclase‐coupled receptors. Both ANF and BNP are agonists of the natriuretic receptor A (NPR‐A). Intracellular cGMP receptors include cGMP‐dependent protein kinases, cGMP‐gated ion channels, and cGMP‐regulated cyclic nucleotide phosphodiesterases.4
RELEVANCE OF STUDIES ON NP
The importance of the function of the endocrine heart is reflected by the fact that blockade or genetic disruption of NP genes or their receptors results in impairment of cardiorenal homeostasis.5‐7 ANF or NPR‐A gene disruption leads to salt‐sensitive or salt‐insensitive hypertension, respectively, in homozygous null mice.8,9 In NPR‐A‐ deficient homozygous mice, volume expansion fails to induce diuresis and natriuresis and to increase cGMP excretion as observed in wild‐type mice treated identically.9 In another NPR‐A knockout model, absence of NPR‐A causes hypertension and leads to cardiac hypertrophy with extensive interstitial fibrosis and, particularly in males, to sudden death.10 BNP knockouts do not develop hypertension or cardiac hypertrophy but show cardiac fibrosis.11
FACTORS CONTROLLING NP SECRETION
The conceptual understanding of the modulation of NP secretion is based on the fact that an increase in blood volume in the low‐pressure side of the circulation and the ensuing atrial muscle stretch trigger an increase in the rate of secretion of both ANF and BNP (stretch‐secretion coupling).12 This is a very rapid secretory response that occurs independently of hormone neosynthesis.13 In addition to mechanically induced NP secretion, the rate of secretion and gene expression of these hormones can be modulated by neurohumoral stimuli.14‐17
Pathophysiologic Stimuli for NP Gene Expression
The expression of both ANF and BNP increases in atria and in ventricles in conditions of chronic pressure or volume overload. In experimentally induced CHF, for example, advancement of the pathology is accompanied by an increase in ANF and BNP production in the ventricles in addition to the increase observed in the atria.18,19
The up‐regulation of ANF and BNP gene expression in the hypertrophic and failing ventricle is a well‐established measure of reexpression of the cardiac fetal gene program known to accompany pathologies characterized by a chronic increase in hemodynamic load on the heart. This is both an ontogenetic and a phylogenetic retracing of NP gene expression because such expression is normally found in the fetal mammalian ventricle and in the ventricular myocardium of nonmammalian vertebrates. The cardiac reexpression of ANF and BNP results in increased circulating levels of both hormones, and this is seen as a compensatory mechanism to decrease cardiac load and to modify tissue remodeling. This coordinated expression of ANF and BNP is in sharp contrast to the unique discoordinated up‐regulation of BNP observed clinically and discussed below.20
Coordinated Regulation of NP Production
Based on our work on the mechanisms responsible for basal and stimulated NP gene expression and release in the physiologic and pathophysiologic states,7,13,17,21‐23 we proposed that the endocrine response of the heart to pressure or volume load varies in relation to whether the challenge is acute, subacute, or chronic.23
The acute response to atrial stretch, as observed after an acute volume load or after head‐out water immersion,24 is based on a phenomenon referred to as stretch‐secretion coupling.25 The activation of this mechanism results in enhanced secretion of the NP stored in the atria. We have demonstrated that hormone secretion following atrial stretch is transitory and is made at the expense of a depletable ANF pool with no apparent effect on synthesis, at least for the first few hours following stretch.13
The endocrine heart response observed after stimulation of cardiac NP production during mineralocorticoid escape following 3 days of administration of deoxycorticosterone acetate (DOCA) is referred to as subacute and is characterized by stimulation of atrial ANF and BNP gene transcription secondary to volume overload. However, plasma ANF, but not plasma BNP, is significantly elevated. Expression of NP in the ventricles is not affected.7
With chronic stimulation, as seen in DOCA salt treatment at the hypertensive stage or in CHF, activation of the cardiac fetal program in the ventricle is seen, together with a stimulation of ANF and BNP production in both the atria and the ventricles. An increase in the plasma levels of ANF and BNP is also observed.21
Differential regulatory mechanisms exist at the transcriptional level that are activated by different stimuli of NP gene expression in vitro. We have reported that atrial stretch results in changes in the expression of the immediate early genes c‐fos, Egr‐1, and c‐myc, whereas endothelin 1 (ET‐1) stimulates Egr‐1 expression and the α1‐adrenergic agonist phenylephrine enhances the expression of Egr‐1 and c‐myc.22 These transcription factors regulate the cardiac phenotype,26 including the regulation of the NP genes.27,28
We have recently reported on the molecular signaling mechanisms underlying ANF stretch‐secretion coupling.29 Inhibition of Gi/o protein by pertussis toxin (PTX)‐promoted ribosylation abolishes atrial muscle stretch‐secretion coupling through a mechanism that is independent of Gq signaling agonists such as ET‐1 or phenylephrine. This is the first unequivocal demonstration of a component of the signaling mechanism that transduces mechanical stretch into atrial hormone secretion. We proposed that there are at least two types of regulated secretory processes in atrial cardiocytes: one is acutely responsive to muscle stretch and is PTX sensitive and the other is Gq‐mediated, is PTX insensitive, and may be responsible for changes in secretion following chronic changes in the neuroendocrine environment.
Discoordinated Regulation of NP Production
During clinical studies concerning elevated NP plasma levels observed in heart transplant recipients, we identified that NP did not normalize after transplant from the elevated levels found in advanced heart failure prior to transplant. The elevated NP circulating levels persisted even after intracardiac pressures and RAAS normalized. Further, we did not find any correlation between NP levels and circulating epinephrine or norepinephrine levels. Altogether, these findings suggested that factors other than hemodynamic ones or activation of RAAS or sympathetic nerve activity were at play in the observed elevation of NP circulating levels in transplant recipients.30
More recently, we found that circulating levels of BNP, but not ANF, increased in most patients who were about to suffer or were suffering from an acute rejection episode.20,31 Moreover, successful treatment of the rejection episodes with various immunosuppressive agents, including muromonab‐CD3, a monoclonal antibody that inhibits T‐lymphocyte activation, results in a decrease in BNP plasma levels, suggesting that activated T‐lymphocyte secretion products during a rejection episode modulate cardiocyte BNP secretion.20 This effect was not merely due to an improvement in hemodynamic parameters because ANF plasma levels did not show the same changes.
We tested whether proinflammatory and immunoregulatory cytokines were capable of selectively up‐regulating BNP gene expression and secretion in neonatal cardiocyte cultures. We found that specific cytokines (tumor necrosis factor α and interleukin‐1β) up‐regulate BNP at the transcriptional and translational levels through a specific (p38) signaling pathway.32
NATRIURETIC PEPTIDES AND CARDIOVASCULAR DISEASE
Soon after the development of specific and sensitive radioimmunoassays for ANF in plasma, it was apparent that the circulating levels of this hormone were significantly elevated in a variety of clinical conditions, all of which were underlaid by an increase in pressure or volume load on the heart. It was further established that the plasma levels of CT‐ANF were, in general, proportional to the degree and duration of this overload. Thus, the highest circulating plasma ANF levels were associated with long‐standing essential hypertension and in chronic CHF classes III and IV. A similar historical development may be found for BNP, for which the development of a radioimmunoassay demonstrated that elevated levels of circulating BNP were an indication of long‐standing pressure or volume overload. Further, in the case of BNP, a strong induction of the gene expression for these peptides was observed in the hypertrophied ventricle, resulting in a relatively larger elevation of plasma BNP levels than those of ANF, although, in absolute terms, circulating levels of ANF remained larger than those of BNP.
Having been established that important clinical entities are accompanied by changes in ANF and BNP gene expression, several clinical investigators explored the possibility that ANF and BNP plasma levels may be used as diagnostic or prognostic indicators of cardiovascular disease. In early investigations, ANF plasma levels were used to establish long‐term prognosis after AMI,33 to stratify patients in terms of response to angiotensin‐converting enzyme (ACE) inhibition post‐AMI,34 and to demonstrate asymptomatic left ventricular dysfunction.35,36 Richards and colleagues found a good correlation between plasma CT‐ANF and cardiac output in elderly patients and further showed that plasma CT‐ANF was a prognostic indicator of those who would subsequently develop chronic heart failure.37 Similarly, Davis and colleagues showed that in the elderly, CT‐ANF plasma levels identify subjects at risk of CHF, allowing for appropriate focusing of medical resources for the prevention, early detection, and treatment of this syndrome.38 At the Mayo Clinic, Lerman and colleagues showed that NT‐ANF is a highly sensitive marker for symptomless left ventricular dysfunction.35 Motwany and colleagues showed that CT‐BNP plasma levels identify patients with left ventricular dysfunction who had been identified by the Survival and Ventricular Enlargement study as likely to benefit from long‐term ACE treatment after AMI.34 In this study, it was found that plasma CT‐ANF was not as predictive as CT‐BNP. The usefulness of NT‐ANF plasma levels to evaluate clinical status was reemphasized in a study by Dickstein and colleagues, who showed that NT‐ANF correlated better than other variables with New York Heart Association (NYHA) functional class and was more closely associated with noninvasive measurements than NYHA functional class.39 Odds ratio measurement demonstrated a substantially increased risk of left ventricular dysfunction and dilatation, pulmonary hypertension, and NYHA functional class III or IV with increasing NT‐ANF value. The authors concluded that the data clearly indicated that the concentration of proANF is related to the degree of clinical heart failure. Moe and colleagues used NT‐ANF to characterize hormonal activation in severe heart failure patients treated with flosequinan and showed a significant decline in plasma NT‐ANF levels in the survivors only.40 The importance of NP plasma level measurement was reemphasized by Hall and colleagues, who, reporting for the Thrombolysis in Myocardial Infarction II investigators, showed that NT‐ANF, when measured during the first 12 hours after the onset of chest pain, is related to 1‐year mortality after AMI.33
Of late, much of the attention directed toward the clinical measurement of NP in blood has been focused on CT‐ and NT‐BNP. Some studies evaluated the usefulness of rapid BNP tests measurements and concluded that these tests are excellent screening tools to screen for left ventricular systolic or diastolic dysfunction and may preclude the need for echocardiography in many patients.41‐46 The determination of BNP plasma levels also appears to be useful in the diagnosis and titration of therapies in CHF and in the prediction of outcomes in patients admitted for decompensated heart failure. The prognostic value of BNP in acute coronary syndromes was demonstrated by de Lemos and colleagues, who concluded that a single measurement of BNP within a few days of the onset of ischemic symptoms predicts and risk stratifies across the spectrum of acute coronary syndromes, including AMI with and without ST‐segment elevation and unstable angina.47 Talwar and colleagues examined the optimum time of blood sampling for NT‐BNP determination following AMI, and, given that they found a biphasic pattern, they concluded that NT‐BNP plasma level was a better predictor of poor outcome when measured later during hospitalization than immediately after AMI.48
It is to be noted that the studies that have compared measurements of NP with other neuroendocrine variables, such as norepinephrine circulating levels, ANF, and BNP, have shown the closest correlation to cardiovascular functional status.39,49 It is tempting to speculate that in the early stages of heart failure, plasma renin activity and sympathetic activity are normal because the increased circulating levels of NP suppress them. This might explain why NPs are elevated before other neuroendocrine variables and why the determination of NP plasma levels is an early and sensitive indicator of ventricular dysfunction.
A number of studies have assessed the efficacy of ANF infusion in CHF in humans and animals.50‐56
Most studies using ANF in humans have been carried out in a hospital setting using intravenous (IV) administration of synthetic human ANF. An IV injection of human ANF to patients with mild hypertension or CHF results in a decrease in systolic blood pressure, preload, afterload, renin activity, and improvement in left ventricular performance without adverse side effects.57‐61 Long‐term IV administration of ANF (Carperitide) for 7 days in patients with acute CHF “who resisted various therapies” showed a significant hemodynamic improvement 48 hours after the start of the infusion. These patients showed a significant decrease in mean pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance but no changes in systolic blood pressure or heart rate.62 Hayashi and colleagues showed that a 24‐hour infusion of synthetic ANF (0.025 μg/kg/min) in patients with first anterior AMI prevented left ventricular remodeling and improved left ventricular ejection fraction.63 In addition, plasma levels of aldosterone, ET‐1, and angiotensin II were significantly decreased during the ANF infusion. It was suggested that the beneficial effects of ANF administration in these patients may be partly due to the suppression of aldosterone, ET‐1, and angiotensin II generation.
The beneficial effects of IV ANF administration after AMI were recently reported by Kuga and colleagues in a small group of patients.64 The patients received an intracoronary bolus of ANF (25 μg) within 12 hours after AMI and an IV infusion of 0.0025 μg/kg/min initiated on admission and maintained for 1 week. A similar group of patients received saline. ANF‐treated patients showed a significant increase in left ventricular ejection fraction. Left ventricular end‐diastolic volume index decreased significantly after 6 months compared with saline‐treated patients. Left ventricular regional wall motion of the infarcted segments also increased significantly in the ANF group. These results suggest that administration of ANF prevented reperfusion injury to the myocardium and conserved left ventricular function by improvement of regional wall motion of the infarcted segments. Finally, chronic infusion (> 48 hours) of ANF (50 μg/kg/min) has been shown to improve renal blood flow and the glomerular filtration rate in patients with acute renal impairment associated with cardiac surgery.65
The above results show that ANF administration increases cGMP generation, decreases cardiac preload and afterload, and improves left ventricular systolic and diastolic functions in hypertension and CHF, but as a treatment, it is restricted to continuous IV use.
Recently, the safety, efficacy, and therapeutic benefits of Natrecor (synthetic BNP) have been demonstrated by the Vasodilation and the Management of Acute Congestive Heart Failure and Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor clinical studies.66‐68 BNP use, however, is limited to decompensated acute heart failure in a hospital setting owing to the need for IV infusion.
In anesthetized Sprague‐Dawley rats, Tosti‐Croce and colleagues showed that a subcutaneous injection of 5 μg of ANF99‐126 induced a rapid and significant increase in plasma ANF, diuresis, and natriuresis (20 minutes).53 Chronic IV infusion (7 days) of synthetic ANF101‐126 (100 ng/h/rat) into conscious spontaneously hypertensive rats and Wistar Kyoto rats resulted in a significant decrease in blood pressure and diuresis 24 hours after the initiation of the infusion in the SHR rats, whereas no significant changes were observed in the WKY rats.69 In addition, IV administration of synthetic ANF (≈ 2 hours) to conscious SHR and WKY animals induced significant increases in urinary cGMP and sodium excretion in both strains and a significant decrease in blood pressure.55 The cardiovascular actions of ANF in conscious sheep with experimental low‐output cardiac failure were investigated by Parkes and colleagues.56 An IV infusion of ANF (100 μg/h) for 60 minutes administered on day 14 of pacing improved cardiac output and reduced total peripheral resistance and right atrial pressure, although no changes were observed in blood pressure or plasma renin levels.
The above studies show the beneficial effects of exogenous ANF administration in hypertension and CHF, confirming and expanding observations made in humans.
Almost 25 years have elapsed since the discovery of ANF and hence the establishment of the endocrine function of the heart.1,2,70 Over this time period, extensive translational work has taken place whereby the basic work embodied in the discovery of ANF has led to therapeutic and diagnostic applications of NP. Yet the factors that control the production of NP are some time from being fully understood. Having such understanding would undoubtedly lead to yet more valuable insights in cardiovascular endocrinology and into the etiopathogenesis of cardiovascular disease.
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Key Words:: natriuretic peptides; acute myocardial infarction; congestive heart failure; therapeutic infusion
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