Because cardiac tissue is not available for the histological diagnosis of heart failure (HF), clinicians must rely on clinical signs and circulating markers when evaluating patients. Natriuretic peptides, available to cardiologists since the mid-1980s, have provided an additional tool for assessing patients with HF. Natriuretic peptides were initially isolated and characterised as atrial natriuretic peptide (ANP) or A-type natriuretic peptide, followed by brain natriuretic peptide (BNP) or B-type natriuretic peptide. Twenty years earlier, an extensive electron microscopy study had been published, showing that mammalian heart atria contained a large number of small granules near the nuclei, resembling those previously found in pancreatic insulin-secreting cells and most likely secretory in nature.1
Measurement of natriuretic peptides has become standard for diagnosing and monitoring HF; in particular, plasma NT-proBNP (the biologically inactive amino-terminal fragment of proBNP) is commonly used in the clinical management of the disease, as is the midregional proANP.2 However, their measurements have not met the initial expectations for diagnosing and following HF, so additional clinical tests are required.
The largest trial so far, GUIDE-IT – although criticised for its execution – failed to demonstrate that natriuretic peptide-guided therapy in high-risk HF patients would be more effective than usual care; the trial was terminated early due to its futility.3 Additionally, several systematic reviews conducted in this area have proved inconclusive; therefore, clinical guidelines on the use of natriuretic peptides in the diagnosis and follow-up of HF vary between countries and regions. However, a systematic review and meta-analysis conducted 3 years later that included all available evidence showed that natriuretic peptide-guided treatment reduced HF admissions and all-cause mortality.4
Why have natriuretic peptide-guided HF treatments failed to reach consistent results across different studies? Does an unnoticed cell physiological condition exist in the myocardium that would contribute to explaining the plasma levels of natriuretic peptides beyond the current paradigm in real-world patients?
Heart Stretching
According to a prevailing paradigm, myocardial stretching is considered the most potent stimulator for natriuretic peptide production and has directed all clinical studies on these peptides. This unchallenged paradigm stems from an influential letter published in Nature in the mid-1980s, which demonstrated that rapid increases in intravascular volume and atrial stretching in the rat led to elevated plasma ANP levels.5 However, these experiments were unphysiological, as terrestrial mammals that are constantly at risk of dehydration rarely encounter volume overload of this magnitude; thirst and urine concentration are the mechanisms that mammals effectively use to regulate intravascular volume. Since then, all guidelines and position papers on natriuretic peptides and their use in HF have been based on the findings reported in that letter, concluding that mechanical stretch regulates the synthesis and release of natriuretic peptides. The paradigm aligns well with the traditional view of cardiology, which considers the heart solely as a mechanical pump. Meanwhile, one of the most important and valid paradigms in cardiology – that mechanical load increases oxygen consumption – has been neglected in clinical studies of natriuretic peptides and HF.6
By definition, a failing heart also entails significant metabolic changes underlying the myocardium’s mechanical parameters.
Oxygen in Heart Disease
During biological evolution, oxygen homeostasis has been a critical constraint on cellular functions, including those of heart myocytes. Under normal conditions, oxygen consumption and availability in myocytes are matched to maintain normal myocardial function. In the myocardium, oxygen cannot be ignored when evaluating the endocrine heart; intracellularly, oxygen is the primary determinant of cardiac gene expression and is crucial for cardiac function and competence.7 In a normally functioning myocardium, large and varying oxygen gradients exist between the coronary arteries and mitochondria in myocytes, which contribute to the function of the endocrine heart. If the balance is disturbed, it will manifest as a cardiac disease.8 Although it was shown as early as the 1950s and 1960s that mechanical load was the primary factor determining myocardial oxygen consumption, research investigating the relationship between oxygen metabolism and natriuretic peptides in HF is lacking, and the mechanical stress paradigm has prevailed in the synthesis and release of natriuretic peptides.6
The key question remains: how do mammalian cells, including cardiac myocytes, sense oxygen levels and respond to hypoxic conditions? Due to the importance of maintaining cellular oxygen concentrations within a narrow range for metabolism, biological evolution has developed a specific hypoxia-sensitive pathway in which a nuclear transcription factor, hypoxia-inducible factor (HIF), serves as the oxygen sensor, enabling all cells to respond to reduced oxygen tension. This master switch exists in all tissues studied so far, and its structural components are phylogenetically conserved across the animal kingdom. HIF comprises a labile subunit (α 1–3), which is regulated, and a stable β unit, which is constitutively expressed. At normal oxygen tension, HIF-1α is rapidly oxidised by hydroxylase enzymes. In contrast, under hypoxic conditions, HIF-1α begins to accumulate, triggering the downregulation of thousands of genes involved in the progression, prevention and treatment of cardiovascular disease.9 The significance of the discovery of the HIF pathway was awarded the Nobel Prize in Physiology or Medicine in 2019.
Interestingly, in myocardial cell cultures, hypoxia was found to be a direct and sufficient stimulus for the expression of A-type and B-type natriuretic peptides via the HIF pathway; when expression was specifically prevented, the myocytes ceased to secrete natriuretic peptides.10,11 Intriguingly, in a human retinal pigment epithelium cell culture, in which mechanical stress cannot occur, cells began to secrete B-type natriuretic peptide under hypoxic conditions.12 However, in a recent scientific statement from influential HF societies regarding the role of natriuretic peptides in HF diagnosis and management, disturbed myocardial oxygen metabolism was not mentioned as a possible condition contributing to high plasma levels of natriuretic peptides.13
Natriuretic Peptides in Heart Failure
Despite high plasma levels documented in many studies, endogenous natriuretic peptides do not initiate natriuresis or diuresis in HF; the biology of myocardial secretion appears to differ from that of atrial secretion, following a different physiological pathway.14 However, this difference has not been recognised and therefore not further explored. Structurally, the heart atria have small granules that contain both A-type and B-type natriuretic peptides, as shown by immunoelectron microscopy.15 In contrast, a healthy myocardium lacks specific microscopic components associated with natriuretic peptides. In human cardiomyopathy, histochemical evidence showed that failing ventricles began to express natriuretic peptides, whereas standard controls showed no immunoreactivity for A- or B-type natriuretic peptides.16 Under stressful conditions, the heart generally responds by reverting to a pattern of foetal metabolism (remodelling); in failing ventricles, this results in the downregulation of adult gene transcript expression and the activation of intracellular pathways not typically functioning in healthy hearts.17 Why this transition from physiological adaptation to a dysfunctional state occurs in demanding conditions such as hypoxia is not fully understood. However, it has been demonstrated that foetal hearts possess a significant ability – through the HIF pathway – to adapt to hypoxia, which is crucial for prenatal myocardial development.18
Conclusion
The synthesis and release of natriuretic peptides are hypoxia-sensitive, as is undisputedly shown in myocardial cell cultures. The hypoxic response is directly mediated by the function of a nuclear transcription factor (HIF), an evolutionarily conserved pathway in cardiac myocytes, independently of heart stretching. The HIF pathway operates in all cell types studied to date and can be viewed as a master switch and sensor in the evolution of oxygen metabolism. In cardiac diseases, such as HF, the myocardium reverts to a foetal state (remodelling) then begins to express natriuretic peptides via the HIF pathway. Position papers and guidelines on HF diagnosis and treatment have neglected the role of oxygen metabolism and – according to a long-standing tradition in cardiology – have therefore assessed the function of the endocrine heart solely through mechanical parameters. Consequently, nothing is known about the oxygen metabolism of the myocardium in different types of HF and their relation to plasma levels of natriuretic peptides. In the heart, mechanical stress and oxygen metabolism are inextricably linked; they cannot be disconnected. The oxygen metabolism of the heart, via the HIF pathway, appears to be the common denominator in MI and AF, including HF, in the synthesis and release of natriuretic peptides.19,20
Most likely, varying myocardial oxygen metabolism during HF is a so-far uncharacterised condition that contributes to the synthesis and release of natriuretic peptides, providing additional evidence for interpreting plasma natriuretic peptide levels in real-world patients.