N-terminal Atrial Natriuretic Peptide Research Articles

Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population

OBJECTIVETo report the mortality of left ventricular systolic dysfunction (LVD), assessed objectively by echocardiography, and its association with natriuretic peptide hormones in a random sample of 1640 men and women aged 25–74 years from a geographical, urban population.METHODSLeft ventricular function was measured by echocardiography in 1640 attendees studied in 1992–3. LVD was defined as a left ventricular ejection fraction (LVEF) ⩽ 30%. Plasma concentrations of N-terminal atrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP) were measured by standard radioimmunoassays. Mortality was documented at four years.RESULTSThe four year all cause mortality rate in the whole cohort was 4.9% (80 deaths). It was 21% (nine deaths) in those with an LVEF ⩽ 30% and 4% in those whose LVEF was > 30% (p < 0.001). The median (interquartile range) BNP concentration in those who died was 16.9 pg/ml (8.8–27) and 7.8 pg/ml (3.4–13) in survivors (p < 0.0001). Similarly, N-ANP had a median concentration of 2.35 ng/ml (1.32–3.36) in those with a fatal outcome and 1.27 ng/ml (0.9–2.0) in those alive at four years (p < 0.0001). Subjects with an LVEF ⩽ 40% also had a significant mortality rate of 17% if they also had a BNP concentration ⩾ 17.9 pg/ml compared with 6.8% if their BNP was below this concentration (p = 0.013). Multivariate analysis revealed the independent predictors of four year all cause mortality to be increasing age (p < 0.001), a BNP concentration ⩾ 17.9 pg/ml (p = 0.006), the presence of ischaemic heart disease (p = 0.03), and male sex (p = 0.04).CONCLUSIONSLVD is associated with a considerable mortality rate in this population. BNP also independently predicts outcome. In addition to its role as a diagnostic aid in chronic heart failure and LVD, it provides prognostic information and clarifies the meaning of a given degree of LVD.

Circulating immunoreactive proANP (1–30) and proANP (31–67) responses to acute exercise

The circulating immunoreactive atrial natriuretic peptide (C-terminal; α-ANP) increases during exercise to become suppressed in the first hours of the recovery. The response of the N-terminal ANP fragments to acute exercise is not known while proANP (31–67) appears to be elevated with chronic exercise. We evaluated the plasma concentrations of the N-terminal ANP fragments (1–30) and (31–67) in oarsmen ( n=10) before and after two acute exercise bouts separated by 5 h. As control, measurements were made on a day with no exercise ( n=12). At rest, the concentrations of proANP (1–30) and proANP (31–67) were 344±42 and 810±172 pmol l −1, respectively. Half an hour after the first exercise bout, proANP (1–30) was elevated (to 404±48 pmol l −1; P<0.05) and decreased below the pre-exercise level (to 316±41 pmol l −1; P<0.05) 4 h into the recovery period. Also, 30 min after the second exercise session, the concentration of proANP (1–30) was elevated to 408±45 pmol l −1 ( P<0.05) and the pre-exercise level was re-established on the following morning. Thus, proANP (1–30), rather than proANP (31–67), responded to acute exercise. These results suggest that atrial distension and, therefore, the central blood volume changes markedly in athletes during a day with repeated exercise bouts.

Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients.

To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients. Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction. No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV. Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.

Hypertension, cardiac state, and the role of volume overload during peritoneal dialysis.

The cardiac state and the prevalence of high blood pressure (BP) were analyzed in 21 pediatric patients (mean age 5.3 +/- 5.3 years) on chronic peritoneal dialysis (CPD), the aim being to specify the impact of hypervolemia in the etiology of hypertension. C- and N-terminal atrial natriuretic peptide (ANP-C, ANP-N) were measured as possible additional markers of hypervolemia. Baseline investigations were carried out 0.2 years after initiation of PD, and repeated after 0.9 +/- 0.2 years. Fifty-two percent of the patients had high BP, and in 40% the nocturnal BP decline was decreased. Left ventricular hypertrophy was present in 45%, but the systolic and diastolic functions of the heart were not impaired. Left ventricular mass correlated significantly with the severity of hypertension and with ANP-N (r = 0.79, P < 0.01 and r = 0.66, P < 0.01, Spearman rank correlation). Significant correlations were also found between the severity of hypertension and ANP-N and ANP-C (r = 0.82, P < 0.01 and r = 0.66, P < 0.01, Spearman rank correlation). High BP and cardiac impairment were more frequent in the younger and nephrectomized patients in whom volume overload seemed to be the most-important etiological factor. Our results suggest further that an ANP-N over 3.0 nmol/l combined with hypertension is strongly indicative of volume overload in patients on PD.

Fluid balance in patients with chronic renal failure assessed with N‐terminal proatrial natriuretic peptide, atrial natriuretic peptide and ultrasonography

The N-terminal proatrial natriuretic peptide (proANP) has become an important parameter for assessing the prognosis of patients with cardiac disease. Its use for evaluating the hydration status in patients with chronic renal failure, however, is still under investigation. The present study comprised 12 haemodialysis (HD) and 17 pre-dialysis patients. In the HD patients, the inferior vena cava diameter during quiet expiration (IVCe) was estimated by ultrasonography and plasma concentrations of N-terminal proANP, atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) were measured before and 4 h after termination of HD. In the pre-dialysis patients venous blood samples were taken during rest to measure plasma N-terminal proANP and ANP and serum creatinine. Normal values for N-terminal proANP and ANP were obtained from 18 healthy volunteers. The plasma concentrations of N-terminal proANP and ANP in healthy volunteers were 328 +/- 92 and 11.4.0 +/- 3.1 pM L-1, respectively. In pre-dialysis patients, serum creatinine ranged from 110 to 447 microM L-1 and was significantly correlated to plasma N-terminal proANP (r = 0.60, P < 0.05) but not to ANP. This may indicate that N-terminal proANP is more dependent on renal function for its clearance than ANP, which is probably cleared by extrarenal mechanisms as well. In HD patients, IVCe was significantly correlated to the three hormones before HD, most strongly to N-terminal proANP. After dialysis, IVCe was significantly correlated to ANP and cGMP but was not correlated to N-terminal proANP. This may suggest that proANP takes a longer time than other hormones to reflect changes in intravascular volume. In conclusion, N-terminal proANP is a hormone closely related to degree of renal function. Furthermore, it is a sensitive marker reflecting the interdialytic hydration status in HD patients, as indicated by its high correlation to IVCe, a standard method which is used frequently nowadays to assess the body hydration. However N-terminal proANP could not reflect the acute changes in fluid volume induced by HD, probably because it is slowly metabolized.

Prospective evaluation of the Batista procedure with circulating atrial natriuretic peptides

A proposed treatment of end-stage heart disease is partial left ventricular resection (i.e., Batista procedure). To determine if congestive heart failure objectively improves after this procedure, we prospectively evaluated partial left ventriculectomy with objective plasma markers of the severity of congestive heart failure (i.e., three N-terminal atrial natriuretic peptide prohormone radioimmunoassays and atrial natriuretic peptide radioimmunoassay) prior to and during the 12 months after partial left ventriculectomy. The four measured atrial natriuretic peptides improved in 30% of the subjects at 1 month post-surgery. Eighty percent of the subjects, however, had higher circulating atrial natriuretic peptides ( P<0.01) at 3, 6, and 12 months than prior to surgery indicating that their congestive heart failure was objectively worse than prior to surgery. Likewise, at 3, 6, and 12 months post-surgery the ejection fractions were not significantly better than prior to surgery. By 6 months the subjects with the highest circulating atrial natriuretic peptides had died (60% of subjects). In conclusion, congestive heart failure improves within 1 month in some patients but then deteriorates at 3, 6, and 12 months after the Batista procedure. There was no survival benefit with 60% of the patients expiring within 6 months after the Batista procedure.

N‐terminal atrial natriuretic peptide and left ventricular geometry and function in a population sample of elderly males

To investigate the relationships between N-terminal atrial natriuretic peptide (N-ANP) and left ventricular geometry and function. A cross-sectional study of a population-based cohort. Follow-up of a health survey in Uppsala county, Sweden. Two hundred and five men aged 70. A Delfia sandwich immunoassay was used to measure the plasma levels of N-ANP. M-mode and Doppler echocardiographic examinations were used to measure left ventricular dimensions, mass, geometry and systolic function and to classify the subjects into four groups (normal geometry, concentric remodelling, concentric hypertrophy or eccentric hypertrophy). Left ventricular systolic dysfunction was defined as a left ventricular ejection fraction </= 0.40. Plasma levels of N-ANP were significantly increased in subjects with left ventricular dysfunction compared to healthy subjects (702 +/- 486, n = 14 vs. 277 +/- 201 pmol L-1, n = 118, P < 0.0001), but there was a great overlap between the groups. N-ANP differed significantly between the four different left ventricular geometric groups (P = 0.02) with the highest N-ANP levels in the subjects with left ventricular eccentric hypertrophy (n = 40). However, N-ANP levels were no longer significantly associated with left ventricular geometry when taking the ejection fraction into account. This study showed that N-ANP levels were significantly elevated in subjects with left ventricular dysfunction, as well as in subjects with left ventricular hypertrophy. However, the increase in N-ANP seen in the eccentric hypertrophy group was mainly due to a decreased ejection fraction.

Serum N-terminal atrial natriuretic peptide in adult patients late after surgical repair of atrial septal defect.

The purpose of surgical closure of atrial septal defect (ASD) is to relieve the cardiovascular system from a haemodynamic burden. Excessive amounts of atrial peptides are released in congestive heart failure, valvular diseases and congenital heart diseases. To examine whether patients after surgical repair of ASD have higher concentrations of N-terminal atrial natriuretic peptide (ANP-N) than age-, sex- and body mass index (BMI)-matched control subjects. Medical history, physical examination, standard 12-lead electrocardiogram, and ANP-N concentrations were obtained in 65 adult patients operated for ASD at the age of 21+/-13 years (mean+/-standard deviation), 21+/-6 years after surgical closure of ASD. Sixty-seven healthy subjects matched for age, sex and BMI served as controls. In the patients serum ANP-N was higher than in the control subjects 0.41+/-0.32 nmol/l, median 0.31 nmol/l, interquartile range (IQR) 0.21-0.49 nmol/l vs. 0.24+/-0.12 nmol/l, median 0.23 nmol/l, IQR 0.17-0.29 nmol/l, (P=0.0003). Patients with concomitant diseases had higher ANP-N concentrations (0.51+/-0.39 nmol/l, median 0.34, IQR 0.26-0.73 nmol/l) than ASD patients without any history or signs of disease (0.28+/-0.16 nmol/l, median 0.27, IQR 0.17-0.40 nmol/l, P=0.01). The 'healthy' ASD patients had higher hormone concentrations than age-, sex- and BMI-matched control subjects (0.28+/-0.16 median 0.27 nmol/l, IQR 0. 17-0.40 nmol/l and 0.21+/-0.07 nmol/l, median 0.20 nmol/l, IQR 0. 15-0.27 nmol/l, P=0.01). Multiple stepwise linear regression analysis showed that age at operation was strongly associated with the post-operative ANP-N concentration (r(2)=0.25, P=0.0002). ASD patients have higher ANP-N concentrations late after surgical repair. Hormone levels correlate with age at operation. Our finding supports the clinical praxis of operating on these patients in their childhood and adolescence.

Neurohormonal activation in severe heart failure: Relations to patient death and the effect of treatment with flosequinan

Background Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse outcome, we conducted a substudy to examine the plasma levels of 3 neurohormonal systems known to have prognostic implications in heart failure. Methods At 20 participating Canadian centers, paired plasma samples at baseline and 1 month after randomization for the measurement of N-terminal atrial natriuretic peptide (N-ANP), angiotensin II, and norepinephrine were obtained in 234 patients (114 receiving flosequinan and 120 receiving placebo). Results Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at baseline to 1625 pmol/L at 1 month [ P = .0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [ P = .2700]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/mL [ P = .002]). These changes were not observed in the placebo group. Multivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseline and 1-month variables indicated that plasma N-ANP level predicted patients' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate analysis of baseline and 1-month data, the increase in plasma norepinephrine level did not predict the increase in heart rate associated with the use of flosequinan, suggesting that the 2 effects might be mediated by separate mechanisms. Conclusions Results of our study demonstrate that in patients with severe heart failure, baseline norepinephrine level predicts death. Flosequinan increases plasma norepinephrine level and heart rate in these patients through mechanisms that override its beneficial hemodynamic effects. Our study reinforces the concept that the direct actions of a pharmacologic agent may have a more profound impact on the prognosis of these patients than the hemodynamic effects.

Risk assessment of left ventricular systolic dysfunction in primary care: cross sectional study evaluating a range of diagnostic tests

Objectives: To assess the probability of left ventricular systolic dysfunction without echocardiography in patients from general practice.Design: Cross sectional study using multivariate regression models to examine the relation between clinical...

Cardiac peptide stability, aprotinin and room temperature: importance for assessing cardiac function in clinical practice

Brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and N-terminal ANP are good research indices of the severity of heart failure. The stability of these peptides at room temperature has become an important factor in assessing their use as indicators of cardiac function in routine clinical practice. Inhibitors such as aprotinin are routinely added in the blood collection process, but may provide no benefit in sample collection and routine clinical practice. We assessed the stability of BNP, ANP and N-terminal ANP in blood samples collected in either the presence or the absence of the protease inhibitor aprotinin. Blood, either with or without aprotinin, was processed immediately (initial; 0 h) and after blood samples had been left for 3 h, 2 days or 3 days at room temperature. These times were chosen to reflect processing in a hospital outpatient clinic (2-3 h), or when posted from general practice (2-3 days). Initial plasma BNP, ANP and N-terminal ANP levels in the absence of aprotinin were 28.2+/-5.4, 44.2+/-7.9 and 1997+/-608 pg/ml respectively, and were not significantly different from initial values in the presence of aprotinin (29.0+/-5.9, 45.2+/-8.0 and 2009+/-579 pg/ml respectively). After 3 h at room temperature, there was a significant fall in ANP in the absence of aprotinin (36. 7+/-7.9 pg/ml; P<0.005), but not in the presence of aprotinin (41. 2+/-7.6 pg/ml). Both BNP and N-terminal ANP were unchanged in either the absence (BNP, 27.6+/-5.5 pg/ml; N-terminal ANP, 2099+/-613 pg/ml) or the presence (BNP, 29.4+/-5.6 pg/ml; N-terminal ANP, 1988+/-600 pg/ml) of aprotinin. After 2 days at room temperature, ANP had fallen significantly in both the absence (16.9+/-3.4 pg/ml) and the presence (24.0+/-5.0 pg/ml) of aprotinin compared with initial values, and there was a significant difference in ANP levels in the absence and presence of aprotinin (P<0.001). ANP levels had decreased further after 3 days at room temperature, to 11.9+/-3.4 pg/ml (no aprotinin) and 20.3+/-5.0 pg/ml (aprotinin added); these values were significantly different (P=0.002). In contrast, there was no change in the levels of BNP or N-terminal ANP after 2 or 3 days at room temperature, in either the absence or the presence of aprotinin. These studies indicate that aprotinin adds little benefit to the stability of cardiac peptides at room temperature. Blood samples for BNP and N-terminal ANP measurement used as a test of heart function in hospital clinics and by general practitioners in the community could be taken into blood tubes containing only EDTA as anticoagulant and without the additional step of adding the routinely used inhibitor aprotinin.

Serum N-terminal atrial natriuretic peptide (NT-ANP) in the cardiac follow-up in children with cancer.

We studied serum N-terminal atrial natriuretic peptide (NT-ANP) in children during and after chemotherapy for cancer to determine its applicability in detecting cardiac dysfunction. Forty-three patients were receiving chemotherapy for malignancy. Forty-eight patients were off chemotherapy and survived between 0.9 and 13 (median 5) years after the diagnosis, receiving cumulative anthracycline doses between 0 and 600 (median 225) mg/m2. Cardiac evaluation of the patients included measurement of serum NT-ANP, recording of ECG, and assessment of systolic and diastolic function of the heart by echocardiography. During chemotherapy, serum NT-ANP levels were higher than in controls but varied markedly in the same individuals. Serum NT-ANP levels showed no consistent increase in the weeks following anthracycline administration. In late follow-up, serum NT-ANP levels were higher than in age-matched controls (median (range), 0.22 (0.06-0.47) vs. 0.14 (0.06-0.27) nmol/l, respectively, P < .001). The subgroup of patients with bone marrow transplantation and/or cardiac irradiation had the highest NT-ANP concentrations (0.30 (0.20-0.45) nmol/l). Thus, serum NT-ANP measurements seemed to represent a useful contribution in the long-term cardiac follow-up of children after cancer. This blood test can readily be included to laboratory follow-up, is reasonably inexpensive and may decrease the need for more laborious tests of cardiac function. When there is ongoing chemotherapy, NT-ANP levels are influenced by a variety of factors that invalidate its routine use during this period.

Influence of age on neurohormonal activation and prognosis in patients with chronic heart failure.

Heart failure is a major medical problem in the elderly. Neurohormonal activation plays a role in the pathophysiology of heart failure, but is also affected by ageing. The present study was carried out to examine the influence of age on neurohormonal activation and prognosis in patients with chronic heart failure. We studied 372 patients with moderate to severe chronic heart failure (New York Heart Association [NYHA] functional class III-IV), who were treated with angiotensin converting enzyme (ACE) inhibitors (95%), diuretics (99%), and digoxin (59%). Their mean age was 68 +/- 8 years (range 38-80), left ventricular ejection fraction 0.23 +/- 0.08, and 77% were males. The relationship between age and plasma neurohormones (norepineprine, epinephrine, dopamine, renin, aldosterone, atrial natriuretic peptide, N-terminal atrial natriuretic peptide, and endothelin), and age and prognosis was examined. Only atrial natriuretic peptide and N-terminal atrial natriuretic peptide showed an independent, positive correlation with age (P < 0.0001). On univariate analysis, norepinephrine also increased, while renin and aldosterone decreased (all P < 0.05). As regards mortality (25%), there was no linear increase with ageing for the group as a whole during follow-up, but patients in the highest age quartile (> 74 years) had a significantly higher mortality (risk ratio 1.9) than younger patients (P < 0.05). Although several plasma neurohormones are affected by ageing on univariate analysis, only atrial natriuretic peptide and N-terminal atrial natriuretic peptide show a highly significant increase with ageing on multivariate analysis. There is no linear increase in mortality with ageing, but in the truly elderly heart failure patients (> 74 years), age alone was an independent predictor for mortality.

Plasma N-Terminal Atrial Natriuretic Peptide Predicts Hospitalization in Patients with Heart Failure

The plasma concentration of N-terminal atrial natriuretic peptide (N-ANP) has been shown to be predictive of both clinical status and survival in patients with heart failure. In this analysis the relationship between N-ANP, morbidity and hospitalization time was evaluated in 417 patients with stable, congestive heart failure recruited from an active, outpatient heart failure registry. Hospital admissions along with the duration of stay occurring after the initial N-ANP sampling during the period of data collection were recorded. A total of 755 admissions occurred, accounting for 7917 days' hospitalization. Relative hospitalization times (in-hospital days/observation period) per N-ANP quartiles I-IV were: 1.2 (+/- 2.7)%, 5.5 (+/- 12.2)%, 10.0 (+/- 21.5)% and 20.8 (+/- 34.3)%, respectively. Although N-ANP levels were correlated with age (r = 0.234, p < 0.0001), division by age quartiles did not significantly predict relative hospitalization times. These data indicate that the degree of cardiac endocrine activation and subsequent N-ANP release is related to morbidity in patients with heart failure and that moderate elevation in N-ANP levels is associated with a substantially increased hospitalization time. N-ANP sampling should be of value as a supplement to clinical evaluation in the assessment of the individual patient with this common syndrome.

Biochemical detection of left-ventricular systolic dysfunction

In previous studies on the use of natriuretic peptides to detect left-ventricular systolic dysfunction, a higher rate of cardiac disorders in the control groups than in the study groups could have led to bias. We investigated the effectiveness of plasma N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) concentrations to show left-ventricular systolic dysfunction in a random sample of the general population. We randomly selected 2000 participants aged 25-74 years from family physicians' lists in Glasgow, UK. We sent all participants questionnaires. 1653 respondents underwent echocardiography and electrocardiography. We took a left-ventricular ejection fraction of 30% or less to show left-ventricular systolic dysfunction. NT-ANP and BNP were measured in plasma by RIAs. 1252 participants had analysable electrocardiograms and echocardiograms, completed questionnaires, and available blood samples. Median concentrations of NT-ANP and BNP were significantly higher in participants with left-ventricular systolic dysfunction (2.8 ng/mL [IQR 1.8-4.6] and 24.0 pg/mL [18.0-33.0]) than in those without (1.3 ng/mL [0.9-1.8] and 7.7 pg/mL [3.4-13.0]; each p < 0.001). Among participants with left-ventricular systolic dysfunction, both symptomatic and asymptomatic subgroups had raised NT-ANP and BNP concentrations. A BNP concentration of 17.9 pg/mL or more gave a sensitivity of 77% and specificity of 87% in all participants, and 92% and 72% in participants aged 55 years or older. Measurement of BNP could be a cost-effective method of screening for left-ventricular systolic dysfunction in the general population, especially if its use were targeted to individuals at high risk.

Brain natriuretic peptide is stable in whole blood and can be measured using a simple rapid assay: implications for clinical practice

ObjectivesTo compare the stability of brain natriuretic peptide (BNP) to that of N-terminal atrial natriuretic peptide (NT-ANP) in whole blood and plasma stored under different conditions. To compare a rapid,...

Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care

The reliability of a clinical diagnosis of heart failure in primary care is poor. Concentrations of natriuretic peptides are high in heart failure. This population-based study examined the predictive value of natriuretic peptides in patients with a new primary-care diagnosis of heart failure. Concentrations of plasma atrial (ANP and N-terminal ANP) and B-type (BNP) natriuretic peptides were measured by radioimmunoassay in 122 consecutive patients referred to a rapid-access heart-failure clinic with a new primary-care diagnosis of heart failure. On the basis of clinical assessment, chest radiography, and transthoracic echocardiography, a panel of three cardiologists decided that 35 (29%) patients met the case definition for new heart failure. ANP and NT-ANP results were available for 117 patients (34 with heart failure) and BNP results for 106 (29 with heart failure). Geometric mean concentrations of natriuretic peptides were much higher in patients with heart failure than in those with other diagnoses (29.2 vs 12.4 pmol/L for ANP; 63.9 vs 13.9 pmol/L for BNP; 1187 vs 410.6 pmol/L for NT-ANP; all p < 0.001). At cut-off values chosen to give negative predictive values for heart failure of 98% (ANP > or = 18.1 pmol/L, NT-ANP > or = 537.6 pmol/L, BNP > or = 22.2 pmol/L), the sensitivity, specificity, and positive predictive value for ANP were 97%, 72%, and 55%; for NT-ANP 97%, 66%, and 54%; and for BNP 97%, 84%, and 70%. Addition of ANP or NT-ANP concentration or both did not improve the predictive power of a logistic regression model containing BNP concentration alone. In patients with symptoms suspected by a general practitioner to be due to heart failure, plasma BNP concentration seems to be a useful indicator of which patients are likely to have heart failure and require further clinical assessment.

Combined inhibition of endothelin and angiotensin II receptors blocks volume load-induced cardiac hormone release.

Volume expansion has been shown to increase plasma atrial natriuretic peptide (ANP) levels, but the precise role of paracrine and autocrine factors in stretch-induced cardiac hormone release is not clear. In the present study, we report the effects of endothelin (ET) and angiotensin receptor (AT receptor) antagonists on baseline and atrial stretch-induced immunoreactive ANP (IR-ANP) and immunoreactive N-terminal ANP (IR-NT-ANP) release in vivo by using BQ-123 (ETA receptor antagonist), bosentan (ETA and ETB receptor antagonist), and losartan (AT1 receptor antagonist). Intravenous administration of BQ-123 had no significant effect on baseline hemodynamics in conscious rats, whereas bosentan (10 mg/kg) and losartan (10 mg/kg) decreased slightly (4 to 7 mm Hg, P < .05 to .001) the mean arterial pressure. Both the ETA receptor antagonist BQ-123 and ETA/ETB receptor antagonist bosentan decreased plasma ANP and NT-ANP responses to volume load (P < .05 to .001), whereas the AT1 receptor antagonist losartan had no significant effect on this response. The relative increase in plasma IR-ANP corresponding to a 3 mm Hg increase in right atrial pressure was 2.7-fold in the vehicle-treated group. BQ-123 (0.3 and 1.0 mg/kg) decreased this response 2.5- and 2.1-fold (P < .05); bosentan (3 and 10 mg/kg), 1.7-fold (P < .001) and 1.9-fold (P < .05); and bosentan (10 mg/kg)+losartan (10 mg/kg), 1.6-fold (P < .001). The responses in plasma IR-NT-ANP decreased simultaneously. These results indicate that combined inhibition of ETA/B and AT1 receptors almost completely blocks ANP response to acute volume load. Therefore, our study shows that endogenous paracrine and/or autocrine factors liberated in response to atrial wall stretch rather than myocyte stretch itself are responsible for the activation of ANP peptide secretion in response to acute volume load. Our results also show that ETA receptors are more important in the regulation of mechanical stretch-induced changes in cardiac hormone secretion than AT1 receptors.

Comparison of N-terminal pro-atrial natriuretic peptide and atrial natriuretic peptide in human plasma as measured with commercially available radioimmunoassay kits

Atrial natriuretic peptide (ANP) has become an important parameter for assessing the condition of patients with cardiac disease. Recently, attention has also focused on N-terminal pro-atrial natriuretic peptide (NtproANP) in this context. NtproANP circulates in plasma in higher concentration, is more stable ex vivo, and may be a better parameter for cardiac function over time. We have evaluated a new commercially available radioimmunoassay kit for NtproANP and compared results and method with those of ANP measurements. The NtproANP kit was found to be reliable and easy to use (no plasma extraction step is necessary), with good reproducibility (coefficients of variation 7–15%). Normal values in 15 healthy laboratory workers, 25 healthy elderly subjects and 25 patients with heart failure were 207 ± 70, 368 ± 134 and 1206 ± 860 pmol/l, respectively, 8.3, 11.8 and 13.0 times higher, respectively, than corresponding ANP concentrations. NtproANP correlated well with ANP ( r 0. 64 – 0.78). We conclude that plasma NtproANP measurement may be a good alternative to plasma ANP measurement: technically, it is easier to perform, and NtproANP is more stable in plasma. Whether NtproANP is a better diagnostic and prognostic parameter than ANP remains to be further established.

Cocaine increases circulating levels of atrial natriuretic peptide and pro atrial natriuretic peptide N-terminal fragment in conscious rats

We examined the effects of intravenously administered cocaine (1 and 3 mg/kg) on haemodynamics (mean arterial pressure, heart rate and right atrial pressure), plasma immunoreactive atrial natriuretic peptide (immunoreactive ANP) and immunoreactive N-terminal peptide of proANP (immunoreactive N-terminal ANP) in conscious, chronically cannulated Sprague-Dawley rats. The direct effect of cocaine (10 −6–10 −4 M) was also studied in primary cultures of neonatal rat cardiac ventricular myocytes. Intravenous injection of 1 mg/kg or 3 mg/kg of cocaine caused an immediate peak rise in mean arterial pressure (1 mg/kg: 44 ± 3 mm Hg, n = 8; 3 mg/kg 49 ± 2 mm Hg, n = 12), which was followed by a dose-dependent sustained pressor response. The right atrial pressure rose simultaneously and 10–20 s later heart rate decreased. Plasma immunoreactive ANP levels increased significantly (1 mg/kg: 56 ± 10 pmol/1; n = 8; 3 mg/kg: 130 ± 54; n = 12) and also immunoreactive N-terminal ANP levels rose significantly 2 min after the injection of the higher cocaine dose (230 ± 27 pmol/1, n = 12). Significant correlations between plasma immunoreactive ANP levels and all haemodynamic variables were found, especially between mean arterial pressure and plasma immunoreactive ANP levels ( r = 0.86, P < 0.001). In neonatal rat ventricular myocyte cultures, the highest concentration of cocaine (10 −4 M) reduced ANP release into the incubation medium (−41 ± 14%, n = 5) but the reduction was not statistically significant. Our results show that cocaine dose dependently increases ANP and N-terminal ANP secretion into the circulation in conscious rats and that this increase is mediated by haemodynamic changes. Thus, plasma ANP and N-terminal ANP levels could be used as markers for acute cocaine-induced cardiac toxicity.