Brain Natriuretic Peptide: Structure, Action, and Role in the Diagnosis and Prognosis of Heart Failure

Brain natriuretic peptide (BNP) is a peptide hormone secreted by cardiomyocytes in response to atrial or ventricular wall stretch and/or pressure overload. It promotes a number of systemic effects, including vasodilatation, increase in urinary output and sodium excretion, as well as inhibition of the sympathetic nervous system and the renin–angiotensin–aldosterone system. Plasma BNP levels have been reported to be elevated in patients with left ventricular hypertrophy, congestive heart failure, acute coronary syndromes, atrial fibrillation, and impaired renal function. Moreover, elevated BNP levels have been shown to be a strong predictor of morbidity and mortality in patients with heart failure. Interestingly, it has also been found that the N-terminal peptide of BNP is slightly superior to BNP for predicting death or re-hospitalization for heart failure. Presumably, it is the longer half-life of N-terminal fragment of braintype natriuretic peptide (NT-pro-BNP) that may promote it as a more accurate index of ventricular stress and therefore a better predictor of prognosis. I N t r O D U c t I O N Over the past few decades, exciting advances have been made in the field of cardiac biomarkers and their key role as important tools for diagnosis, risk stratification and therapeutic decision-making in patients with suspected acute coronary syndromes and other cardiovascular disease. According to the World Health Organization, a biomarker is defined as “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease”. It has been concluded that a biomarker is accepted as clinically useful when the following criteria are fulfilled: i) availability of accurate and repeated measurements at a reasonable cost with short turnaround times, ii) provision of information that is not available from a thorough clinical examination and iii) assistance in clinical decision making. Indeed, cardiac troponins T and I play an essential role for diagnostic work up in patients suffering from acute myocardial infarction (MI). Currently, researchers are investigating several promising new biomarkers, with the brain-type natriuretic peptide (BNP) being one with proved diagnostic usefulness in a great number of studies, which has thus progressed from benchside to clinical revIew Fourth Department of Internal Medicine, Evagelismos General Hospital, Athens, Greece HOSPITAL CHRONICLES 2015, 10(4): 202–209 Address for correspondence: Emmanuel A. Andreadis, MD, Head, Fourth Department of Internal Medicine, “Evagelismos” General Hospital, AHEPA Building, Room 528, Ipsilantou 45-47, Athens 10676, Greece; Tel: +30-213-2041528; Fax: +30-213-2041606; Email: [email protected] Manuscript received April 27, 2015; Revised manuscript received July 14, 2015; Accepted August 19, 2015 Key wOrDs: cardiac biomarkers; brain-type natriuretic peptide; NT-pro-BNP; diuresis; natriuresis; vasodilation; hypertension; target organ damage; heart failure; renin-angiotensin-aldosterone axis; nesiritide; neprilysin Αbbreviations ACE = angiotensin converting enzyme ANP = atrial natriuretic peptide ARB = angiotensin II receptor blocker ARNI = angiotensin receptor neprilysin inhibitor BNP = brain-type natriuretic peptide cGMP = cyclic guanosine monophosphate CNP = C-type natriuretic peptide ECG = electrocardiogram MI = myocardial infarction MMP = matrix metalloproteinase NEP = neprilysin NFAT = nuclear factor of activated T cells NPR-A = natriuretic peptide receptor-A NT-pro-BNP = N-terminal fragment of brain-type natriuretic peptide PKG = protein kinase G Conflict of Interest: none declared BRAIN NATRIuRETIC PEPTIDE 203 FIgUre 1. Human brain natriuretic peptide (BNP) is produced as a 108 amino acid prohormone (proBNP-108), an inactive proform, which is converted to the biologically active peptide BNP32, and an inactive N-terminal (NT)-pro-BNP through cleavage by a proteolytic enzyme, called corin. application at the bedside. Specifically, BNP secreted by the cardiac ventricles has emerged as a novel biomarker for monitoring and prognosis of left ventricular dysfunction in hypertensive subjects. Besides, in recent studies, BNP has also been proposed as an independent marker for atrial fibrillation and cardioembolic stroke associated with poor clinical outcomes. In this review we are going to summarize existing data concerning the structural characteristics, the mode of action and the clinical significance of BNP and its N-terminal fragment (NT-pro-BNP) in the diagnosis and prediction of heart failure. Furthermore, we will review data assessing the validity of this biomarker in screening asymptomatic subjects at risk for heart failure. s y N t h e s I s , A c t I O N , A N D b N P c l e A r A N c e b y t h e K I D N e y s In recent years, researchers have isolated originally from porcine brain extracts a neurohormone named BNP, which along with atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) form a triple natriuretic peptide system of the heart muscle. All peptides share a similar amino-acid sequence homology. Heart failure, as well as renal insufficiency, constitute clinical conditions where the natriuretic peptide system can become activated. It has been demonstrated that BNP is synthesized and secreted by the cardiomyocytes in response to increased myocardial wall stress. Data suggest that a significant amount of BNP is produced and released into the blood circulation by the human ventricles in contrast to ANP, which is mainly secreted by the atria, and is involved in fluid, electrolyte and vascular homeostasis. Specifically, it has been shown that BNP is produced by ventricular cardiomyocytes in response to pressure overload in the left ventricle as an inactive prohormone, which is later cleaved by an enzyme called corin into the active hormone BNP and the inactive NT-pro-BNP (Fig. 1). Human BNP is produced as a 108 amino acid prohormone (pro-BNP-108), an inactive proform, which is converted to the biologically active peptide BNP32, and an inactive Nterminal (NT-pro-BNP) through cleavage by proteolytic enzymes. Previous studies have shown that both corin, a cardiac serine protease, and furin, a ubiquitous serine protease, are critical in mediating pro-BNP processing in cardiomyocytes.