Christian Hall

Essential biochemistry and physiology of (NT-pro)BNP.

Brain natriuretic peptide (BNP) is a 32 amino acid cardiac natriuretic peptide hormone originally isolated from porcine brain tissue. The human BNP gene is located on chromosome 1 and encodes the prohormone proBNP. The biologically active BNP and the remaining part of the prohormone, NT‐proBNP (76 amino acids) can be measured by immunoassay in human blood. Cardiac myocytes constitute the major source of BNP related peptides. The main stimulus for peptide synthesis and secretion is myocyte stretch. Recently, cardiac fibroblasts have also been shown to produce BNP. Other neurohormones may stimulate cardiac BNP production in different cardiac cell types. In contrast to atrial natriuretic peptides (ANP/NT‐proANP), which originate mainly from atrial tissue, BNP related peptides are produced mainly from ventricular myocytes. Ventricular (NT‐pro)BNP production is strongly upregulated in cardiac failure and locally in the area surrounding a myocardial infarction. In peripheral organs BNP binds to the natriuretic peptide receptor type A causing increased intracellular cGMP production. The biological effects include diuresis, vasodilatation, inhibition of renin and aldosterone production and of cardiac and vascular myocyte growth. In mice BNP gene knockout leads to cardiac fibrosis, gene over‐expression to hypotension and bone malformations. BNP is cleared from plasma through binding to the natriuretic peptide clearance receptor type C, but it seems relatively resistant to proteolysis by neutral endopeptidase NEP 24.11. Clearance mechanisms for NT‐proBNP await further study. While the plasma concentration of NT‐proBNP and BNP is approximately equal in normal controls, NT‐proBNP plasma concentration is 2–10 times higher than BNP in patients with heart failure. This relative change in peptide levels may be explained by shifts in cardiac secretion and/or clearance mechanisms.

N-terminal proatrial natriuretic factor. An independent predictor of long-term prognosis after myocardial infarction.

BACKGROUND Atrial natriuretic factor (ANF) is a peptide hormone secreted from cardiac atria in response to increased atrial pressure. Because of a longer half-life and greater stability, the N-terminal of ANF prohormone (N-terminal proANF) may be a better integrator of atrial peptide secretion than ANF itself. After myocardial infarction, elevation of ANF and other neurohormones has been associated with a poor prognosis. However, when left ventricular ejection fraction (LVEF) and other important clinical variables are included in multivariate analysis, the independent predictive value of these neurohormones has been reduced markedly. METHODS AND RESULTS To test the prognostic value of N-terminal proANF after myocardial infarction, its plasma concentration was measured a mean of 12 days after infarction in 246 patients in the Survival and Ventricular Enlargement (SAVE) Study. N-terminal proANF was a much stronger predictor of survival than ANF itself. Furthermore, in multivariate analysis of cardiovascular mortality and development of heart failure, N-terminal proANF in contrast to ANF and other neurohormones was still a powerful and independent predictor when the model included age, gender, prior myocardial infarction, hypertension, diabetes, use of thrombolysis, Killip class, infarct location, and LVEF. CONCLUSIONS The measurement of N-terminal proANF supplements presently used clinical and objective assessments and provides an important independent predictor of prognosis with respect to cardiovascular mortality and development of heart failure.

Neurohormonal activation rapidly decreases after intravenous therapy withdiuretics and vasodilators for class IV heart failure

OBJECTIVES This study was designed to determine whether therapy with vasodilators and diuretics, designed to normalize loading conditions in decompensated heart failure (HF), reduces neurohormonal activation in the short term. BACKGROUND; Elevated vasoactive neurohormone levels in chronic HF have adverse prognostic impact and may be targeted by specific therapies. METHODS Endothelin-1, catecholamines, renin, aldosterone, angiotensin and atrial natriuretic peptides (ANP, N-ANP and BNP) were measured in 34 patients with advanced HF before and after hemodynamically guided therapy with vasodilators and diuretics. The therapy was designed to reduce filling pressures and systemic vascular resistance (SVR) without inotropic therapy. Blood was drawn before therapy (A), after initial diuretic and nitroprusside therapy to optimize hemodynamics (B, mean 1.4 days) and after transition to an oral regimen designed to maintain improved hemodynamics (C, mean 3.4 days). RESULTS Mean pulmonary wedge pressure fell from 31 to 18 mm Hg, right atrial pressure from 15 to 8 mm Hg, and SVR from 1,780 to 1,109 dynes/s/cm(-5). Cardiac index increased from 1.7 to 2.6 l/min/m(2) without intravenous inotropic agents (all p < or = 0.05). Average endothelin levels declined by 30%, from 7.7 to 5.5 pg/ml, and remained low at time point C, 5.2 pg/ml (p < 0.01). Norepinephrine was 858 at time A, 817 at time B, and fell by time C to 608 pg/ml (p < or = 0.05). The mean plasma BNP level fell by 26% after only 1.4 days and by 53% at time C (p < 0.001). CONCLUSIONS Neurohormonal activation rapidly decreases after short-term therapy tailored to decrease severely elevated filling pressures and SVR without inotropic agents. Therapy designed to address neurohormonal activation should include therapy to improve severe resting hemodynamic compromise.

Comparison of the Effects of Losartan and Enalapril on Clinical Status and Exercise Performance in Patients With Moderate or Severe Chronic Heart Failure

OBJECTIVES This study assessed the feasibility of an efficacy trial comparing angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism in heart failure. Patients with moderate or severe heart failure whose condition had previously been stabilized by treatment with a converting enzyme inhibitor were randomly assigned to receive enalapril or losartan. The study was designed to detect any signs of clinical deterioration during double-blind treatment. BACKGROUND Losartan is a specific, nonpeptide angiotensin II receptor-1 antagonist with a vasodilator hemodynamic profile similar to that of converting enzyme inhibitors. Although therapy with specific receptor blockade has certain theoretic advantages over nonspecific converting enzyme inhibition, demonstration of a comparable therapeutic effect in patients with congestive heart failure will require a major effort comparing two active agents. METHODS One hundred sixty-six patients with stable heart failure in New York Heart Association functional class III or IV and an ejection fraction < or = 35% were included in a multicenter, double-blind, parallel, enalapril-controlled trial. After a 3-week stabilization period with optimal therapy, including digitalis, diuretic drugs and a converting enzyme inhibitor, patients were randomly assigned to 8 weeks of therapy with losartan, 25 mg/day (n = 52); losartan, 50 mg/day (n = 56); or enalapril, 20 mg/day (n = 58). Patients were assessed with frequent clinical and laboratory evaluation and exercise testing. RESULTS No significant differences between groups in terms of changes in exercise capacity (6-min walk test), clinical status (dyspnea-fatigue index), neurohumoral activation (norepinephrine, N-terminal atrial natriuretic factor), laboratory evaluation or incidence of adverse experience were observed. CONCLUSIONS The results suggest that losartan and enalapril are of comparable efficacy and tolerability in the short-term treatment of moderate or severe congestive heart failure. A trial designed to compare the efficacy, tolerability and effect on mortality of long-term angiotensin II receptor blockade with converting enzyme inhibition is both feasible and ethically responsible.

Prognostic value of N-terminal pro-atrial and pro-brain natriuretic peptide in patients with acute coronary syndromes.

In summary, we have shown that circulating Nt-proANP and Nt-proBNP levels are associated with early death, but not with nonfatal recurrent AMI, in patients with non-ST-segment elevation acute coronary syndromes. This nested case-control study suggests that Nt-proBNP measurements provide complementary prognostic information to conventional risk indicators, including troponin I.

Increased Atrial and Brain Natriuretic Peptides in Adults With Cyanotic Congenital Heart Disease Enhanced Understanding of the Relationship Between Hypoxia and Natriuretic Peptide Secretion

Background—Brain natriuretic peptide (BNP) levels are used in the evaluation of patients with heart disease, yet there is little understanding of the effect of hypoxia on natriuretic peptide secretion. Furthermore, recent data suggest that oxytocin may mediate stretch-induced atrial natriuretic peptide (ANP) secretion. Methods and Results—Ten patients with cyanotic congenital heart defects and 10 control subjects were studied. N-terminal proatrial natriuretic peptide and N-terminal probrain natriuretic peptide levels were 4-fold (P =0.02) and 12-fold (P =0.03) greater in cyanotic patients than in control subjects. Cyanotic patients had reduced body water compared with control subjects, although the difference did not reach statistical significance (P =0.22). In a separate group of patients, cardiac myocytes were isolated from the right atrial appendage during CABG. The amount of oxygen in the buffered saline was varied to simulate hypoxia. Isolated hypoxic atrial myocytes had 43% fewer dense surface secretory granules compared with normoxic myocytes (P <0.0001). Immunohistochemical staining demonstrated decreased ANP and BNP in hypoxic compared with normoxic right atrial tissue. Isolated myocytes also degranulated when incubated with oxytocin (P <0.0001), but there was no difference in oxytocin levels in cyanotic patients compared with control subjects (P =0.49). Conclusions—ANP and BNP are markedly elevated in adults with cyanotic congenital heart disease despite reduced body water. Our results show that hypoxia is a direct stimulus for ANP and BNP secretion in human cardiac myocytes. These findings may have implications for the interpretation of BNP levels in the assessment of patients with heart and lung disease.

Plasma levels of natriuretic peptides and hemodynamic assessment of patent ductus arteriosus in preterm infants.

The main purpose of this study was to investigate whether circulating natriuretic peptides in premature infants reflect the hemodynamic significance of a patent ductus arteriosus (PDA). The study comprises 120 examinations in 55 premature infants with a mean gestational age of 27.2 wk and a mean birthweight of 933 g. Based on clinical and echocardiographic findings, the hemodynamic influence of ductal shunting was classified as small, moderate or large. Blood samples for N‐terminal proatrial natriuretic peptide (Nt‐proANP) and brain natriuretic peptide (BNP) were analysed after completion of the clinical part of the study. Linear regression indicated a very strong association between Nt‐proANP and BNP (adjusted R2= 0.89). The mean levels of Nt‐proANP and BNP increased with the size of the shunt through a PDA, and peptide values followed hemodynamic alterations. The size of PDA accounted for 50% and 47% of the total variation in the plasma values of Nt‐proANP and BNP, respectively. In detecting an echocardio‐graphically significant PDA, the area under a ROC curve was 0.94 for Nt‐proANP and 0.90 for BNP.

Plasma proatrial natriuretic factor is predictive of clinical status in patients with congestive heart failure

Atrial stretch results in myocyte release of the prohormone atrial natriuretic factor (1-126). The N-terminal (1-98) fragment, proatrial natriuretic factor (proANF) is released on an equimolar basis with the C-terminal (99-126) active hormone and may be assayed simply due to in vitro stability. This study was undertaken to evaluate the relation between proANF and routinely available measures of clinical status. ProANF was sampled from 202 patients (median age 68 years [range 15 to 85], 77% men) recruited from an active outpatient heart failure clinic. Patients were subgrouped according to New York Heart Association functional class, radionuclide ejection fraction (EF), echocardiographic left ventricular (LV) end-diastolic diameter, and Doppler-determined systolic pulmonary arterial pressure. The median proANF (pmol/L) values for patients in New York Heart Association classes I, II, III, IV were 725, 1,527, 1,750, and 5,172, respectively. The proANF value for the group with EF > 40% was 1,534 versus 1,993 for EF < or = 40% (p < 0.05). The value for the group with LV diameter < 60 mm ws 838 versus 1,751 for LV diameter > or = 60 mm (p < 0.01). The value for the group with systolic pulmonary artery pressure < 45 mm Hg was 1,241 versus 2,660 for systolic pulmonary artery pressure > or = 45 mm Hg (p < 0.01). ProANF correlated better than the other variables with New York Heart Association functional class and was more closely associated with noninvasive measurements than New York Heart Association functional class.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study of atrial peptides ANF (1-98) and ANF (99-126) as diagnostic markers of atrial distension in patients with cardiac disease

To evaluate the possible role of atrial natriuretic peptides ANF (1-98) and ANF (99-126) as diagnostic parameters of atrial distension, measurements of peptide levels were performed in 47 patients with chronic ischemic and/or left sided valvular heart disease. Plasma samples were drawn from the pulmonary artery (PA) and superior vena cava (SVC) during diagnostic right heart catheterization. Forty of the patients also underwent left heart haemodynamic measurements, and in 28 patients two dimensional echocardiography with determination of left atrial diameter was performed. Enhanced plasma concentrations of both peptides were observed with increasing severity of heart failure assessed by the NYHA classification. Mean plasma levels of both peptides were closely correlated to mean pulmonary artery pressure (ANF (1-98): n = 47, r = 0.69 (SVC)/r = 0.72 (PA), p < 0.0001; ANF (99-126): n = 46, r = 0.75 (SVC)/r = 0.68 (PA), p < 0.0001) and mean pulmonary capillary wedge pressure (ANF (1-98): n = 47, r = 0.69 (SVC)/r = 0.72 (PA), p < 0.0001; ANF (99-126): n = 46, r = 0.70 (SVC)/r = 0.64 (PA), p < 0.0001). Positive correlations were also obtained between peptide levels and mean right atrial pressure and left ventricular end-diastolic pressure. When patients with high right atrial pressures (n = 2) were excluded from analysis, a significant correlation was found between peptide levels and echocardiography assessed left atrial diameter. The present study demonstrates the close correlation between concentrations of both atrial peptides and cardiopulmonary haemodynamics in patients with chronic heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of exercise training in patients with heart failure: a pilot study on autonomic balance assessed by heart rate variability.

Background Heart rate variability (HRV) is decreased in patients with congestive heart failure (CHF) and is a prognostic marker in this disease. Exercise training is now regarded as an important part of the treatment of patients with CHF, but the effect on HRV and the association between this effect and the effect on neurohormones are not well assessed. Methods Heart rate recording was performed in 12 patients with CHF (mean age 67 ± 8 years) with CHF NYHA functional class III, before and after 12 weeks of exercise training. The association with exercise capacity and serum levels of atrial natriuretic peptide was assessed. We also evaluated the correlation between HRV and survival at follow-up 87 months later. Results At baseline there was a significant correlation between mean heart rate and work performed during max cycle test (r=0.650, P=0.022) and the HRV parameter standard deviation normal to normal (SDNN) (r=0.678, P=0.015). After exercise training there was a significant increase in work performed (30.3 ± 14.2 versus 38.1 ± 14.1 kJ), 6-min walk test (502 ± 88 versus 552 ± 59 m, P=0.006) and SDNN (117.3 ± 40.7 versus 128.6 ± 42.3 ms, P=0.028). At 87 months of follow-up, there was a borderline significant difference between survivors and non-survivors. Only the survivors had a significant increase in SDNN after exercise training. Conclusion This pilot study demonstrates an improvement with regard to parameters for HRV after exercise training in patients with CHF. The study suggests that the positive effect of exercise training in patients with CHF involves an attenuation of the reduced HRV response, and that this improvement might have prognostic significance. Eur J Cardiovasc Prevention Rehab 11:162–167