Summary
Over the past years, natriuretic peptides have been recognised not only as important contributors to cardiovascular regulation but also as valuable markers in overt cardiac disease, including heart failure or coronary disease. More recently, these markers have shown their ability to detect preclinical cardiac alterations in different settings. In this respect, natriuretic peptides offer a new perspective for risk stratification in hypertension. They are correlated to various features of cardiac remodelling provoked by hypertension. They also depend on vascular properties, including blood pressure level and aortic stiffness. In addition to being integrative markers of cardiovascular alterations, several studies have shown their value in predicting all-cause mortality or cardiovascular mortality and morbidity in the general population. At least three consistent studies are now available in hypertension also showing this prognostic value. This performance, together with the ease of measurement, low cost and widespread availability, should prompt the wide use of natriuretic peptides for risk stratification in hypertension, at least in patients with normal electrocardiography, but also in most hypertensive patients.
Résumé
Ces dernières années, l’importance des peptides natriurétiques a été reconnue non seulement pour leur contribution à la régulation cardiovasculaire mais surtout comme des marqueurs dans l’insuffisance cardiaque et la maladie coronaire. Plus récemment, ces marqueurs ont été utilisés pour détecter des atteintes cardiaques infracliniques. Dans ce contexte, ils offrent de nouvelles perspectives pour la stratification du risque dans l’hypertension. Leurs taux plasmatiques sont corrélés à différents aspects du remodelage cardiaque induit par l’hypertension. Ils dépendent également des propriétés vasculaires, incluant la pression et la rigidité aortique, et de la fonction rénale. Au-delà de l’aspect de marqueurs intégratifs des dysfonctionnements cardiovasculaires, plusieurs études ont récemment montré leur valeur dans la prédiction de la mortalité globale ou la morbi-mortalité cardiovasculaire dans la population générale. Au moins trois études sont maintenant disponibles confortant cette valeur pronostique dans l’hypertension artérielle. Cette performance associée à la facilité de la mesure, au coût modéré et à sa large disponibilité devraient accélérer l’utilisation du dosage des peptides natriurétiques pour la stratification du risque dans l’hypertension artérielle, au moins chez les patients avec un ECG normal si ne n’est chez la plupart des hypertendus.
Abbreviations
ANP
atrial natriuretic peptide
BNP
brain natriuretic peptide
ECG
electrocardiography
LVH
left ventricular hypertrophy
NT
N-terminal
Introduction
In response to volume expansion and pressure load, ventricular myocytes release cardiac hormones with potent natriuretic effect associated with vasodilation and strong antifibrotic effects. Theses hormones oppose the sympathetic and renin-angiotensin-aldosterone system in blood pressure control and cardiovascular remodelling ( Fig. 1 ). The two main peptides, ANP and BNP, stem from different genes and have specific spatiotemporal expression; they are differentially expressed in the heart . Both hormones are small cyclic peptides with very similar amino acid compositions, acting on the same membrane receptor (natriuretic peptide receptor-A), which is a membrane guanylate cyclase. Both are generated by proteolytic cleavage from a prohormone, which gives rise to an equimolar amount of the remnant peptide, NT-ANP or NT-BNP, and of each active ANP or BNP hormone ( Fig. 2 ). They are each of great interest, both in terms of pathophysiology and as potential drug targets . The availability of reliable plasma assays for the different players has identified BNP, together with its amino-terminal fragment (NT-proBNP), as the most promising markers for cardiac diseases. Over the past years, as a result of a tremendous amount of work in this field, these hormones have profoundly changed the management of heart failure and are now recommended for diagnosis, prognostic stratification, and treatment adjustment.
More recently, the potential of these markers in hypertension has been questioned. Why so? Reasons are numerous, ranging from the physiopathology of hypertension where ‘salt sensitivity’ is a key mechanism in hypertension and has to be related to the natriuretic peptide system, to detection of hypertension consequences in terms of target organ damage. In hypertension, detection of cardiac damage is critical for risk stratification, as emphasized by most guidelines . This is usually done by searching for LVH and more generally by identifying pathological cardiac remodelling. The ideal marker for screening should be easy to measure, widely available, reproducible, correlated with cardiac status and, most of all, correlated with outcomes.
ECG, which is recommended by most guidelines, apparently fits all these requirements, except that it is rarely performed in clinical practice because of either the lack of ECG devices or insufficient skills in the interpretation of ECG recordings. Echocardiography, which remains the ‘gold standard’ in clinical practice, suffers from a lack of availability for all hypertensive patients and from its cost, making this investigation not indicated for risk stratification of hypertensive patients in general. Thus, there is still room for new cardiac markers to be used for risk stratification.
Why are natriuretic peptides of potential interest in hypertension?
As mentioned above, some prerequisites should be met before a marker is considered as potentially interesting for risk stratification in hypertension. In this respect, assays of natriuretic peptides in plasma are easily available, independent of the operator’s skills, and their cost (€22.95 in France) compares with the cost of ECG. We have recently looked at the distribution of plasma NT-proBNP concentrations in a large cohort of hypertensive patients; while the plasma concentrations were, on average, much lower than in overt cardiac disease – namely, heart failure – they covered a wide range, from undetectable values to fairly high ones . Despite this wide interindividual variability, the intrapatient reproducibility of NT-proBNP measured at arrival in the hospital (ambulatory) and in decubitus after one night’s rest in hospital was very satisfactory, with a coefficient of variation around 5%. The fact that expression and secretion of BNP by ventricular myocytes is a landmark of cardiac remodelling is, of course, of particular interest in hypertension. In this context, NT-proBNP may be more suitable than BNP because of its longer half-life, lower intraindividual variability, and better ability to detect subtle preclinical cardiac changes . The secretion of natriuretic peptides mainly correlates with left ventricular wall stress, either systolic or diastolic , which is a complex interplay between pressure, left ventricular diameter, and wall thickness. Consistently, most studies have found an increased concentration of plasma natriuretic peptides associated with LVH; NT-proBNP was also found to be related to systolic dysfunction , diastolic dysfunction, and increased filling pressure , while BNP is secreted in response to myocardial ischaemia . Additional non-cardiac factors influence natriuretic peptide release. This is the case with ventricular afterload, particularly blood pressure and aortic stiffness . Finally, plasma natriuretic peptide concentrations are raised with renal failure , as a result of both insufficient clearance and increased blood volume or an impaired cardiovascular system ( Fig. 3 ). In this respect, natriuretic peptides act as integrative markers of cardiac, vascular, and even renal status, i.e. three major targets of elevated blood pressure. Indeed, it has been suggested that natriuretic peptides represent markers of cardiorenal distress .
