Brain natriuretic peptide and optimal management of heart failure

Brain natriuretic peptide and optimal management of heart failure first-author †E-mail:nli_zum@yahoo.com.cn; wang_jian_an@tom.com †E-mail:nli_zum@yahoo.com.cn; wang_jian_an@tom.com nli_zum@yahoo.com.cn corresp ‡Corresponding Author ‡Corresponding Author †E-mail:nli_zum@yahoo.com.cn; wang_jian_an@tom.com †E-mail:nli_zum@yahoo.com.cn; wang_jian_an@tom.com nli_zum@yahoo.com.cn Division of Clinical Pharmacology and Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China Division of Clinical Pharmacology and Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China Aside from the important role of brain natriuretic peptide (BNP) in diagnosis, and differential diagnosis of heart failure, this biological peptide has proved to be an independent surrogate marker of rehospitalization and death of the fatal disease. Several randomized clinical trials demonstrated that drugs such as beta blocker, angiotensin converting enzyme inhibitor, spironolactone and amiodarone have beneficial effects in decreasing circulating BNP level during the management of chronic heart failure. The optimization of clinical decision-making appeals for a representative surrogate marker for heart failure prognosis. The serial point-of-care assessments of BNP concentration provide a therapeutic goal of clinical multi-therapy and an objective guidance for optimal treatment of heart failure. Nevertheless new questions and problems in this area remain to be clarified. On the basis of current research advances, this article gives an overview of BNP peptide and its property and role in the management of heart failure. Brain natriuretic peptide (BNP) Heart failure Drug therapy BRAIN NATRIURETIC PEPTIDE 1 Several studies demonstrated that the heart is an endocrine organ (Henry and Pearce, 1956 1956 ; Kisch, 1956 1956 ; de Bold, 1985 1985 ; de Bold et al., 1981 1981 ; 1996 1996 ; 2001 2001 ). Atrial natriuretic peptide (ANP) was the first cardiac hormone identified in 1984 (Kangawa et al., 1984 1984 ; de Bold et al., 1981 1981 ). Later on, a new compound from pig brain was found, which had similar natriuretic and diuretic effects as ANP (Sudoh et al., 1988 1988 ). This peptide was named brain (B-type) natriuretic peptide (BNP) whose actual site of synthesis is the ventricular myocardium (Mukoyama et al., 1991 1991 ). After discovery of BNP in 1988, a third compound called C-type natriuretic peptide (CNP) was identified from pig brain in 1990 (Sudoh et al., 1990 1990 ). Among the natriuretic peptide family, CNP is different from ANP and BNP in structure and is in higher level in the central nervous system and vascular tissues than in heart (Minamino et al., 1991 1991 ). BNP is constitutively released from ventricular myocyte as a preprohormone of 134 amino acids, which are cleaved into a proBNP hormone. Upon being stimulated into secretion, it is further cleaved to a 76 amino acid N-terminal fragment (N-terminal BNP) and a 32 amino acid active hormone and released into the blood (Hama et al., 1995 1995 ; Fig. 1 1 ). The N-terminal portion is a biologically inactive protein. BNP is synthesized in bursts as the promoter region of BNP gene contains the rapid-turnover nucleic acid sequence TATTTAT (Sudoh et al., 1989 1989 ). BNP gene expression may increase very rapidly in response to myocyte stretch (Hama et al., 1995 1995 ). The level of BNP in circulation is closely related to left ventricular pressure (Yoshimura et al., 1993 1993 ). BIOLOGICAL ACTIVITY OF BNP 1 Numerous studies found that the biological actions of BNP cover kidney, vascular vessels, endocrine and heart. The earliest finding of BNP biological action was the increase of glomerular filtration rate, renal plasma flow, urine flow rate and inhibiting distal sodium reabsorption, causing natriuresis and diuresis (Richards et al., 1993 1993 ; Jensen et al., 1998 1998 ). BNP can inhibit cardiac sympathetic nervous system activity by reducing norepinephrine spillover at low dose, suppressing renin activity and the renin-angiotensin-aldosterone system by suppressing plasma aldosterone (Brunner-La Rocca et al., 2001 2001 ; Clarkson et al., 1996 1996 ). BNP has antiproliferative and antifibrotic actions in the heart and vascular tissues (Cao and Gardner, 1995 1995 ; Fujisaki et al., 1995 1995 ). BNP may relax myocardium and vascular smooth muscle, causing arterial and venous dilation (Clarkson et al., 1995 1995 ; van der Zander et al., 1999 1999 ; 2002 2002 ). This action leads to blood pressure reduction and ventricular preload release. The recombinant human BNP may attenuate both pulmonary capillary wedge pressure and mean pulmonary artery pressure during exercise (Maisel, 2003 2003 ). BNP can increase ANP and adrenomedullin level indicating a hormonal interaction (Hunt et al., 1995 1995 ; Lainchbury et al., 1999 1999 ). In general, the actions of BNP are similar to ANP, while CNP acts in the local vasculature in central nervous system as a vasodilator and inhibitor of vascular cell proliferation (Charles et al., 1996 1996 ). Among three natriuretic peptide receptors (NPR): NPR-A, NPR-B and NPR-C, NPR-A is a binding receptor, while NPR-C is a clearance receptor of BNP (Suga et al., 1992 1992 ). BNP’s biological effect is due to its binding to both NPR-A and NPR-B (Koller and Goeddel, 1992 1992 ). The affinity of NPR-C for BNP may influence the plasma half-life of BNP. BNP is inactivated by neutral endopeptidase (Rademaker et al., 1997 1997 ). ANP is similar to BNP, but CNP is binding to NPR-B. ROLE OF BNP IN HEART FAILURE 1 BNP is not only taken as a cardiac biomarker but also a surrogate marker of heart failure, acute coronary syndrome, and myocardial infarction, because BNP is associated with all cause mortality independent of age, NYHA (New York Heart Association) class, previous myocardial infarction, and left ventricular ejection fraction. More and more studies revealed that BNP plays an important role in stratifying the severity of heart failure, the differential diagnosis of cardiac or pulmonary dyspnea. However, with regard to management of heart failure, there are still some questions lefts to answer. For example, when ACE (angiotensin converting enzyme) inhibitor or β blocker has been titrated to maximal dose in a patient, how long should be the duration of maintaining maximal dose? What is the reasonable combination of multi-drug therapy? Has BNP similar value in ethnically different patients? Two randomized trials showed that maximal suppression of BNP concentration should be a reasonable goal of therapeutic strategy. In this review, we will focus on the role of BNP in the management of heart failure. BNP AND NEW CLASSIFICATION OF HEART FAILURE 1 It is known that BNP is significantly correlated with NYHA classification class (Maisel et al., 2002 2002 ). The American Heart Association developed a heart failure classification and defined heart failure into four stages (Hunt et al., 2001 2001 ). At stage A, patients are at high risk for development of heart failure but have no apparent structural abnormality of the heart. At stage B, patients have a structural abnormality of the heart but have never had symptoms of heart failure. At stage C, patients have a structural abnormality of the heart and have current or previous symptoms of heart failure. At stage D, patients have end-stage symptoms of heart failure not responsive to standard treatment. In contrast to the traditional NYHA classification used to describe functional limitations and therefore is a subjective parameter, the new classification is an objective one that emphasizes the evolution and progression of heart failure. Unlike the traditional view of heart failure that focuses on the hemodynamic involved in the syndrome, the structural, functional, and biologic alterations of heart failure can account for the clinical outcomes of the disease’s management. There are several models established to illustrate the cascade of heart failure mechanisms. The conventional hemodynamic model of heart failure emphasized the effect of an altered load on the failing ventricle and introduced vasodilators and inotropic agents. The neurohumoral model emphasized the importance of activation of the rennin-angiotensin-aldosterone axis and the sympathetic nervous system in the progression of cardiac dysfunction. The most important advance is the recognition that cardiac hormones synthesized within the myocardium and excreted in an autocrine and paracrine manner. Representatively, BNP is produced by the ventricular myocardium in response to myocyte stretch and ischemia. The vasodilatory and natriuretic effects of BNP counteract the opposing actions of angiotensin II and aldosterone. Left ventricular remodeling of heart failure is the process of mechanical, neurohormonal, or genetic alteration in ventricular size, shape, and function. The characteristics of left ventricular remodeling include hypertrophy, loss of myocytes, and gain of interstitial fibrosis. It is a common progressive process that occurs in myocardial infarction, cardiomyopathy, hypertension, and valvular heart disease. BNP has a putative role in the counteractive response to ischemia. In patients with chronic stable angina, the alteration level of BNP was correlated with the size of the ischemic area (Tateishi et al., 2000 2000 ; Kyriakides et al., 2000 2000 ). BNP level in patients with unstable angina is higher than that in patients with stable angina or in healthy patients (Kikuta et al., 1996 1996 ). Reversible ischemia may increase left ventricular wall stress to cause an elevation of BNP level in circulation. BNP level is closely correlated to the severity of diastolic dysfunction provided the systolic function is preserved (Lubien et al., 2002 2002 ). Our clinical data showed that in patients with or without ischemic and non-ischemic heart failure, BNP level was inversely related to the left ventricular ejection fraction and end diastolic dimension (Fig. 2 2 and Fig. 3 3 ). On the other hand, the reverse remodeling process is a mechanism through which a variety of treatments control the heart failure syndromes. The reverse remodeling is associated with the pharmacological effects of ACE inhibitors, beta-adrenergic antagonists and aldosterone antagonists, or nonpharmacological effects of cardiac resynchronization and cardiac transplantation. All these therapeutic interventions promote a return to a more normal ventricular size and shape. The correlation between BNP and the new heart failure classification remains to be clarified. BNP might not be a superior screening test to diagnose heart failure patient at stage B, who is asymptomatic but has structure disorder. But BNP can sensitively and accurately reflect the progression or reverse remodeling process of heart failure. In patients with chronic heart failure, BNP was more closely associated with mortality than was NYHA class or ejection fraction or peak oxygen uptake during exercise testing. In patients with decompensated heart failure, BNP was associated with readmission for heart failure and outcomes after presentation to the emergency department for heart failure. Moreover, log BNP was the independent predictor superior to 16 other indices for sudden death in patients with chronic heart failure (Berger et al., 2002 2002 ). MANAGEMENT OF HEART FAILURE 1 Life style modification 2 Basic habits of moderate sodium restriction, weight monitoring, and adherence to medication schedules may aid in avoiding fluid retention or alerting the patient to its presence. A regularly scheduled exercise program such as walk is recommended as it may have beneficial effects on symptoms. Smoking cessation is advised and moderation of wine intake is encouraged. Multi-drug therapy 2 New guidelines for the evaluation and management of chronic heart failure were published by the American College of Cardiology. ACE inhibitors and angiotensin-receptor blockers (ARB) decrease afterload by interfering with the rennin-angiotensin-aldosterone system, resulting in peripheral vasodilatation. Drugs of the both class can affect left ventricular hypertrophy, remodeling, and renal blood flow. ACE inhibitors decrease the conversion of angiotensin I to angiotensin II, thereby minimizing the multiple pathophysiological effects of angiotensin II, and decrease the degradation of bradykinin. Bradykinin promotes vasodilatation in the vascular endothelium and causes natriuresis in the kidney. ACE inhibitors in heart failure management and after a myocardial infarction improve symptoms, cardiac performance, survival rate, and decrease rehospitalization rate. Beta-blockers inhibit the sympathetic nervous system and adrenergic receptors. They slow the heart rate, decrease blood pressure, and have a direct beneficial effect on the myocardium, enhancing reverse remodeling. Non-beta 1 selective beta-blockers can also block the alpha-adrenergic receptors and induce vasodilatation. Aldosterone stimulates renal sodium retention, potassium excretion and promotes ventricular and vascular hypertrophy. Selective or non-selective aldosterone antagonists counteract the effects of aldosterone. Diuretics decrease preload by stimulating natriuresis in the kidneys. Digoxin affects the Na + /K + -ATPase pump in the myocardial cell to increase contractility. Inotropics such as dobutamine and milrinone increase myocardial contractility. The combination of hydralazine and isosorbide dinitrate counteracts peripheral vasoconstriction and cause vasodilatation. The new drug Nesiritide (recombinant human brain natriuretic peptide) decreases pulmonary capillary wedge pressure and improves cardiac index and urinary flow rate in a dose-dependent manner (Fonarow, 2003 2003 ; Zineh et al., 2003 2003 ). It decreases preload by improving urinary flow and stimulates diuresis. In addition, it decreases norepinephrine and aldosterone concentrations and decreases afterload by vasodilatation. Nonpharmacological therapy 2 Cardiac resynchronization therapy with biventricular pacing improves left ventricular function and favors reverse remodeling. Cardiac resynchronization therapy, stem cell transplantation and cardiac transplantation are promising nonpharmacological therapies when heart failure responds poorly to poly-pharmacological therapy. BNP IN MANAGEMENT OF CHRONIC HEART FAILURE 1 BNP concentration can fall quickly in patients with decompensated heart failure after aggressive treatment with diuretics, vasodilators, ACE inhibitor, ARB, beta-blockers and aldosterone antagonist (Table 1 1 ). The BNP concentration when euvolumia is achieved is closely related to the prognosis of heart failure. The further reduction of BNP concentration after comprehensive treatment including titration of ACE inhibitor or β blocker may reflect the real reverse remodeling process. It should be stressed that serial monitoring of BNP concentration is superior to assessment of BNP on admission for once, as the alteration of BNP concentration is a result of a dynamic process. Clinically, reverse remodeling may be judged by a reduction in left ventricular end-systolic volume by > 15%. With this criterion, patients can be divided into responders and non-responders. However, among the non-responders some patients may have reduced BNP concentrations while others have sustained BNP concentration. The reduction of BNP may precede the alteration of ventricular sizes and therefore sensitively indicate an effective therapeutic strategy. The concept of BNP guided therapy is based on the two randomized trials. Whether titration of vasodilator according to blood BNP concentration is of value in individual optimization of vasodilator therapy in heart failure was investigated (Murdoch et al., 1999 1999 ). Twenty patients with mild to moderate heart failure were randomly assigned to titration of ACE inhibitor dose according to serial measurement of blood BNP concentration or empirical ACE inhibitor therapy for 8 weeks. The results showed that the BNP guided therapy group was associated with significant reduction of BNP concentration that was significantly greater than the empirical therapy group (−42% vs −12%, P =0.03). Another study sought to determine whether BNP guided therapy would produce outcome superior to empirical therapy (Troughton et al., 2000 2000 ). Study of sixty-nine heart failure patients who received either symptom-guided therapy or N-terminal BNP-guided therapy showed that the group assigned to N-terminal BNP-guided treatment received higher doses of ACE inhibitors, diuretics and spironolactone. Heart failure events in the N-terminal BNP-guided group were fewer than those in the symptom-guided group after 10 months of follow-up. More randomized trials to select BNP-guided non-pharmacological therapy (such as biventricular pacemaker and stem cell transplantation) are recommended. Authors Drugs BNP Heart failure type Sanderson et al., 1995 1995 Beta blocker ↓ Heart failure van Veldhuisen et al., 1998 1998 ACE inhibitor ↓ Chronic heart failure Murdoch et al., 1999 1999 Vasodilator ↓ Chronic heart failure Tsutamoto et al., 2001 2001 Spironolactone ↓ Congestive heart failure Latini et al., 2002 2002 Valsartan ↓ Heart failure Shiga et al., 2003 2003 Amiodarone ↓ Heart failure Tsutamoto et al., 1997 1997 Digitalis ↑ Congestive heart failure BNP ALGORITHM IN HEART FAILURE MANAGEMENT 1 A BNP algorithm can be established to aid the clinical decision-making including selection of drug, titration of drug dose or nonpharmacological therapy (Fig. 4 4 ). The euvolumia can be set as the primary goal of treatment for decompensated heart failure with BNP concentration as an evidence of discharge other than improvement of symptoms, because high level of BNP not only predicts the rehospitalization within 30 d but also indicates a high incidence of death. The further goal of treatment is reverse remodeling. BNP concentration assessment is adjunct to echocardiogram indices and might be much more sensitively and accurately judging response and non-response to reverse remodeling. Serial assessment of BNP concentration and clinical decision-making shall be routinely recorded in a computed feedback system to reflect more precisely the dynamic procedure of heart failure management. As a surrogate marker of heart failure endpoints, the lowest or normal BNP concentration achieved after intervention indicates a promising prognosis while sustained BNP concentration alerts a poor prognosis. For the purpose of better efficacy and lower adverse reaction in the management of chronic heart failure, establishing a computed feedback system is suggested to manage all personnel, diagnostic and therapeutic information of each patient including dynamic change of BNP. References R Berger , M Huelsman , K Strecker , A Bojic , P Moser , B Stanek , R Pacher . 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