In addition to being a pump, the heart also has an endocrine function. The peptides synthesized and secreted from the heart may exert endocrine, autocrine, and paracrine effects. The natriuretic peptides are a family of vasoactive hormones that play a dominant role in the regulation of cardiovascular and renal homeostasis. The 2 major hormones synthesized by the heart are the atrial and the brain natriuretic peptides, and elevated circulating levels of these substances have important prognostic and therapeutic implications. Although plasma natriuretic peptide measurements are helpful in excluding chronic heart failure in the ambulatory setting, many factors independent of heart failure may influence their levels. During the acute phase response of severe burn injuries, the severity of the cardiac stress can determine the postburn outcomes, and the pleiotropic effects exerted by the natriuretic peptide system play a key role in this process by activating compensatory mechanisms that promote systemic arterial dilatation, diuresis, natriuresis, and renin inhibition. Natriuretic peptides may also play a role in the wound healing process, which could be of clinical utility to reduce apparent scar formation in burn patients.
KEY WORDS: Atrial natriuretic peptide, Brain natriuretic peptide, Cardiac biomarkers, Endocrine system, Severe burns
The heart was always considered as an organ with a mechanical function, but this vision has changed since 1956, when secretory granules were found in the guinea pig atrium.1 The exact role of these atrial granules remained elusive until 1981; it is now clear that the heart not only has a mechanical function but also an endocrine function, and this property has been extensively investigated since then.1-5 The peptides synthesized and secreted from the heart may exert remote (endocrine) and local effects, (autocrine and paracrine effects)5,6 and include colons adrenomedullins, angiotensins, apelin, endothelins, follistatin-like 1, natriuretic peptides, and others.7-9 The proteins secreted from the cardiomyocytes, cardiac fibroblasts, endothelial cells, and smooth muscle are called "cardiokines," and the specific cardiomyocyte-derived peptides are called "cardiomyokines."10
Despite the numerous cardiac hormones discovered, such as those already mentioned, in this review, we have focused mainly on the natriuretic peptides, more specifically, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and their effects in severe burn injuries, since these 2 peptides play a major role in cardiac endocrine function.
HOW DOES THE HEART RESPOND TO BURNS?
Burns covering 30% or more of the total body surface area induce the release of inflammatory mediators and lead to significant hypovolemia with a subsequent systemic effect on organs distant from the burn areas.11,12 Severe burns trigger a cycle of inflammation, fibrosis, oxidative stress, and mitochondrial damage in the heart. The cardiac inflammatory response plays an important role in the pathogenesis of cardiac tissue damage13; increased mitochondrial uncoupling contributes to the hypermetabolic stress response and increased oxidative stress. All these cardiodynamic derangements contribute to multiple organ system failure, sepsis, and death.14 Xiao and associates demonstrated how myocardial injury occurs before hepatic, renal, and intestinal injuries, most likely due to the decrease in myocardial mechanical function after significant reduction of blood volume secondary to increased capillary permeability following the thermal injury.15
Immediately after burns, an ischemic/hypoxic myocardial damage with a functional myocardial impairment occurs.15 During the acute phase response of severe burn injuries, the severity of the cardiac stress can determine the outcomes after the burn injury, and the pleiotropic effects exerted by the natriuretic peptide system play a key role in this process. Immediately after the injury, during the ebb phase, the cardiac function is severely depressed. A decrease in myocardial contractility starts immediately after the injury and continues for approximately 36 hours after burn. However, by 48 hours after the burn injury, when the flow phase starts, cardiac function rebounds and the myocardium becomes tachycardic and a hyperinflammatory process that can elevate the energy expenditure and cardiac work for over a year after injury evolves.14,16
Postburn cardiac dysfunction is the major cause of failed resuscitation, and it is characterized by slowed isovolumic relaxation, impaired contractility, and decreased diastolic compliance of the left ventricle. The mortality rate following the burn trauma is an important outcome parameter, and the percentage of total body surface area involved usually correlates with mortality, whereas the depth of the burn determines morbidity.17
ENDOCRINE FUNCTION OF THE HEART: THE NATRIURETIC PEPTIDE FAMILY
The natriuretic peptides are a family of vasoactive hormones that play an important role in regulation of cardiovascular and renal homeostasis.18,19 Four natriuretic peptides have been described: types A, B, C, and D.18-21 Among these, ANP and BNP are mainly synthesized and secreted by the heart (they can also be produced by many other tissues, but the amounts are too low to generate endocrine effects) in response to various stimuli and regulated by multiple signaling pathways18-22 (Table 1). The GATA proteins play a pivotal role in cardiac gene expression, and several neuroendocrine factors can modulate the secretion of the ANPs and BNPs: acetylcholine, adrenergic agonists, angiotensin II, endothelin 1, glucagon-like peptide 1, glucocorticoids, prostaglandins, and thyroid hormones.18,22,23
The mechanisms of action of the natriuretic peptides are mediated by high-affinity natriuretic peptide receptors (NPR-A and NPR-B).24 These peptides reflect cardiac stress and function. Although the cardiovascular effects of natriuretic peptides are well known, these proteins play a much broader role in physiology than previously recognized. They act on the kidney to promote diuresis and natriuresis and exert vasodilation on peripheral capacitance vessels to maintain water and sodium homeostasis and systemic blood pressure levels; they also have cardiac antifibrotic and antihypertrophic effects, antagonizing the renin-angiotensin-aldosterone system effects.18-22 To reduce the blood volume, they restrain water reabsorption in the renal main collector via type 2 aquaporins by inhibiting salt intake, thirst, and the secretion of arginine vasopressin induced by angiotensin II in the pituitary gland.18,25,26 Natriuretic peptides are rapidly cleared mainly by 2 mechanisms: extracellular proteases (neprilysin is the main enzyme) and receptor-mediated degradation via NPR-C.21
Because these peptides increase drastically in patients with heart failure, mainly in response to myocardial stretching, the use of both BNP and the N-terminal pro-brain natriuretic peptide (NT-pro-BNP) as diagnostic biomarkers of heart failure has brought significant improvements in treating these patients. However, several inflammatory states can act as confounding factors to stimulate BNP synthesis, including aging, anemia, obesity, sepsis, hypertension, myocardial infarction, cardiac hypertrophy, pulmonary hypertension, atrial fibrillation, diabetes mellitus, renal failure, liver cirrhosis, severe burns, and cancer chemotherapy. These factors underline a mode of BNP regulation that can be dissociated from any hemodynamic variation (Table 2).27
ATRIAL NATRIURETIC PEPTIDE
ANP was the first member of the natriuretic peptide family identified, occurring in 1983. It is a 28-amino acid polypeptide mainly produced and stored in atrial granules, resulting from the C-terminal end of the prohormone pro-ANP. Small amounts are produced in the ventricle. mRNA of ANP is translated to pre-pro-ANP, a molecule of 151 amino acids and then cleaved into pro-ANP (126 amino acids), the main form of storage in atrial granules. The pro-ANP is rapidly cleaved by corin to form the biologically active ANP (composed of 28 amino acids and the biologically inactive NT-pro-ANP).18 The half-life in healthy humans is 2 to 4 minutes and ranges from 0.5 to 4 minutes in dogs, monkeys, mice, rabbits, and rats.28
ANP has also been involved in thermal injuries. Its levels have been reported to be elevated within the first 48 hours after burn injury in patients with a mean total burn area of 22% total body surface area. The reason for this elevation has not yet been clarified, but it could be a stress-related response or due to the large amounts of intravenous fluid required by the burn patient. During the acute phase of burns, there is also a marked sodium retention with a highly positive water balance, which could lead to volume overload, causing atrial stretch and the subsequent ANP release. ANP in burn patients, unlike the vasoconstrictor neurohormones that are also activated in the setting of thermal injuries, such as the renin and angiotensin system, has been found to be beneficial through its activation of compensatory mechanisms that promote systemic arterial dilatation, diuresis, natriuresis, and renin inhibition29 (Figure 1).
BRAIN NATRIURETIC PEPTIDE
The type B natriuretic peptide or BNP was first isolated from pig brains in 1988 by Sudoh and colleagues,3 which was soon followed by the discovery of the largest concentrations in cardiac tissue.30 Brain natriuretic peptide is localized in the cardiomyocytes of the atrium and stored in atrial granules with ANP; however, in contrast to ANP, it is not found in ventricular granules. The structure of BNP differs among species. The BNP in humans is synthesized as a 134 amino acids pre-prohormone, cleaved into 108 amino acids (pro-BNP cardiomyocytes), which in turn will be cleaved by corin or furin into the biologically active BNP of 32 amino acids and the biologically inactive NT-pro-BNP (76 amino acids). The half-lives of BNP and NT-pro-BNP are approximately 20 minutes and 120 minutes, respectively.18 The regulation of BNP gene transcription and excretion is based on the myocardial wall stretching resulting from volume overload and/or increased transmural gradient. The main function of the BNP is to control water homeostasis, and it does so through its paracrine function; it promotes diuresis and natriuresis, dilates the arterial system, and antagonizes renin.19-22,31
Because BNP has been implicated in many pathologies, such as heart failure and volume overload states, in the year 2000, the US Food and Drug Administration approved a rapid assay for BNP as an adjunct for the diagnosis of heart failure, giving an opportunity to the scientific community to explore its potential usefulness; in recent years, it has become a target of study as a prognostic marker.32 Lindahl and colleagues conducted a study to determine the relationship between the physiological stress of the body in response to burns by measuring NT-pro-BNP (it has a longer half-life) in adults with burn injuries greater than 10% of total body surface area. The investigators observed a gradual increase in BNP, reaching its peak on the fifth day of hospitalization, concluding that there is a relationship between the NT-pro-BNP and volume overload in burn patients. This volume overload is due to the edema that occurs as a result of capillary leakage and its subsequent increase in preload. They also found that high levels of NT-pro-BNP are related to better outcomes.33 Elevated BNP levels have also been reported in many other non-heart-related conditions.27 High levels of BNP have been found in patients with severe burns, indicating the hydration status of the burned patient. It was suggested that elevated BNP was also related to a decrease in capillary leakage and, contrary to the observation in other critically ill patients, to a better outcome33 (Figure 1).
The role of transforming growth factor β in reducing scar formation has been described,34 and it has been reported that BNP reduces myocardial scar formation by blocking transforming growth factor β.35 An in vitro proof-of-principal study revealed the presence of BNP around collagen, epithelial cells, and endothelial cells in human burned skin; in contrast, no BNP was observed in unscarred skin samples, indicating that BNP may be involved in skin wound healing and scarring.36 Further studies reported the responsiveness of fibroblasts to BNP37 and the improvement in the gross appearance of scars but without any histologic difference compared with controls in a rat burn model.38
EFFECTS OF BETA BLOCKER THERAPY ON CIRCULATING LEVELS OF NATRIURETIC PEPTIDES
Severe burns significantly alter the pharmacodynamics and pharmacokinetics of drugs.39 Because severely burned patients are usually receiving multiple drug regimens (including analgesia, antiemetic, ulcer prophylaxis), the effects of drug therapy on circulating levels of natriuretic peptides need to be taken into consideration when interpreting such levels.
The hypermetabolic state triggered by burns might become a source of morbidity if left untreated11,12; for this reason, many pharmacologic measures have been proposed to attenuate it, with beta blockers becoming first-line agents to reduce these adverse effects.40,41 However, the studies that have measured natriuretic peptides during beta blocker therapy are contradictory.42-45 Most of these studies have reported high levels of natriuretic peptides in healthy humans and patients with essential hypertension and coronary artery disease on selective or nonselective beta blocker therapy, probably due to an increase of the synthesis or an inhibition of plasma clearance.27,42,43 Interestingly, patients with heart failure showed a biphasic response on natriuretic peptides levels. During the first few days and weeks, their levels increased or showed minimal changes; in the long term, however, they markedly decreased. This fluctuation was reported to be in response to hemodynamic changes induced by beta blocker therapy, with the magnitude of this effect shown to be related to the level of natriuretic peptides at baseline.44-46 Another study showed that, in patients on long-term maintenance hemodialysis with dilated cardiomyopathy, ANP and BNP levels decreased and the left ventricular size and function improved after patients were on metoprolol for 4 months.47
The family of natriuretic peptides has great potential both as therapeutic agents and as biomarkers. They play a key role in water and sodium regulation. With regulation of the blood volume, they also contribute to blood pressure control. Although the greatest source of BNP release comes from the stretching of the myocardial wall, there are other mechanisms that produce its release, such as the inflammatory response triggered by burns. It has been suggested BNP may play a role in the wound-healing process, and it could be of clinical utility to reduce apparent scar formation; however, increased understanding of the molecular and cellular events that lead to scar formation and the effects of natriuretic peptides are critical to the development of effective therapies to minimize scarring.
Volume : 2
Issue : 2
Pages : 39 - 44
From the 1Benaim Burn Foundation, Buenos Aires, Argentina; the 2Central Florida Heart Care, Maitland, Florida, USA; and the 3Department of Cardiology, Hospital Provincial de Ovalle “Dr. Antonio Tirado Lanas,” Ovalle, Chile
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Santiago J. Santelis, Benaim Burn Foundation, Buenos Aires, Argentina and the Central Florida Heart Care, Maitland, Florida, USA
Table 1. Main Characteristics of the Atrial Natriuretic Peptide and Brain Natriuretic Peptide
Table 2. Common Causes of Brain Natriuretic Peptide Elevation Independent of Heart Failure
Figure 1. Endocrine Heart Response to Burns: Natriuretic Peptide-Releasing Mechanism Following Burn Stress