Plasma adrenomedullin and natriuretic peptides in patients with essential or malignant hypertension.

Adrenomedullin (AM), a potent vasodilator and natriuretic peptide, is found in human blood. To investigate the pathophysiological role of AM in essential and malignant hypertension (EHT and MHT), we measured the plasma concentrations of AM in patients with EHT of WHO stage I or II (n = 42) and in those with MHT (n = 9) by a specific radioimmunoassay, and compared these concentrations with those in normotensive controls (n = 46). The plasma concentrations of atrial and brain natriuretic peptides (ANP and BNP) in these subjects were also measured by immunoradiometric assays, and their relations to plasma AM were examined. The plasma AM level in the EHT patients (7.15+/-0.21 pmol/l, mean+/-SEM) was significantly (p < 0.01) higher than that in the normotensive controls (6.14+/-0.25 pmol/l), and a further elevation was observed in the MHT patients (14.1+/-3.8 pmol/l). Similar elevations of plasma ANP and BNP were seen in the two patient groups. The plasma AM level significantly (p < 0.01) correlated with not only the systolic (r = 0.44) and diastolic (r = 0.46) blood pressures, but also with the plasma levels of ANP (r = 0.43) and BNP (r = 0.43). The elevated plasma concentration of AM in the MHT patients decreased significantly (p < 0.05) after antihypertensive treatment, and the plasma ANP and BNP levels similarly declined. These results suggest that AM may participate, along with ANP and BNP, in mechanisms counteracting a further elevation of blood pressure in patients with EHT and MHT.     

Plasma levels of atrial natriuretic peptides during pregnancy and post partum in the rat

Plasma concentrations of atrial natriuretic peptides (ANP) in female Wistar rats were measured by radioimmunoassay at oestrus, during pregnancy, during parturition and between 3 h and 4 days post partum. Concentrations of ANP in rats on days 10, 15 and 17 of pregnancy were not significantly different from those in non-pregnant animals in oestrus (32.5 +/- 2.2 pmol/l; mean +/- S.E.M., n = 9), but levels near term (days 20 and 21 of pregnancy) were reduced by approximately 50%. However, plasma concentrations of ANP at 6, 12 and 24 h post partum were approximately twice those of non-pregnant animals in oestrus, but returned to normal levels within 4 days after parturition. Maternal plasma volume increased significantly during pregnancy, and fell 15-20% 6-24 h post partum. These results suggest that the relationship between plasma volume and the plasma concentration of ANP is reset during pregnancy and changes rapidly post partum. The results do not necessarily, however, imply any changes in the relationship between atrial pressure and the concentration of ANP.     

Plasma atrial natriuretic Peptide and brain natriuretic Peptide levels after radiofrequency catheter ablation of atrial fibrillation

It has been reported that plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels are elevated in patients with atrial fibrillation (AF). The aim of this study was to investigate the change in these patients after pulmonary vein isolation (PVI). In 66 patients with paroxysmal AF (PAF) and without any structural heart disease, plasma ANP and BNP levels were measured before and 3 months after successful PVI. At baseline, in 14 patients, ANP and BNP levels were elevated, and in 52 patients, only BNP levels were elevated. There were no significant relations between the attack frequency or the duration of PAF episodes and ANP or BNP levels. Neither ANP nor BNP level at baseline was a valid predictor of AF recurrence. Even in 31 patients (47%) with recurrent PAF, attacks of PAF were significantly reduced. In 66 patients with elevated ANP and/or BNP levels at baseline, levels were significantly reduced after PVI independent of PAF recurrence (ANP: 69.0+/-23.0 vs 25.0+/-7.7 pg/ml, p<0.0001; BNP: 58.4+/-50.7 vs 22.5+/-27.1 pg/ml, p<0.0001). In 42 patients without AF recurrences, ANP and BNP levels were reduced to within the normal range. In conclusion, in patients with PAF without any structural heart disease, ANP and/or BNP levels were elevated. In those patients, relief of the AF burden by successful PVI significantly reduced elevated plasma ANP and BNP levels.     

Plasma and cardiac tissue atrial and brain natriuretic peptides in experimental heart failure

Objectives. This study evaluated the role of changes in heart rate, cardiac filling pressures and cardiac tissue atrial and brain natriuretic peptides in the modulation of their plasma levels in a model of heart failure.Background. Atrial and brain natriuretic peptides constitute a dual natriuretic peptide system that regulates circulator homeostasis.Methods. The effects of 1) acute ventricular pacing, 2) acute volume expansion, and 3) volume expansion after 1 week of continuous pacing on plasma atrial and brain natriuretic peptide levels were compared in eight dogs. Atrial and ventricular tissue levels of the peptides were examined in 5 normal dogs (control group), 21 dogs paced for 1 week (group 1) and 10 dogs paced for 3 weeks (group 2).Results. Both acute pacing and volume expansion increased plasma atrial natriuretic peptide levels (from 53 ± 41 to 263 ± 143 pg/ml [mean ± SD], p < 0.01, and from 38 ± 23 to 405 ± 221 pg/ml, p < 0.001, respectively). After 1 week, there was a marked incerase in plasma levels of atrial natriuretic peptide, but the level did not increase further with volume expansion (from 535 ± 144 to 448 ± 140 pg/ml, p = 0.72). By contrast, plasma brain natriuretic peptide levels increased only modestly with acute pacing (from 12 ± 5 to 20 ± 4 to 20 ± 8 pg/ml, p < 0.05) and after pacing for 1 week (from 13 ± 4 to 48 ± 20 pg/ml, p < 0.05) but did not change with acute or repeat volume expansion. In groups 1 and 2, atrial tissue levels of atrial natriuretic peptide (1.9 ± 1.3 and 2.0 ± 0.9 ng/mg, respectively) were lower than those in the control group (11.e7 ± 6.8 ng/mg, both p < 0.001), whereas ventricular levels were similar to those in the control group. Atrial tissue brain natriuretic peptide levels in groups 1 and 2 were similar to those in the control group. However, ventricular levels in group 2 (0.018 ± 0.006 ng/mg) were increased compared with those in the control group (0.013 ± 0.006 ng/mg, p < 0.05) and in group 1 (0.011 ± 0.006 ng/mg, p < 0.05).Conclusions. Atrial and brain natriuretic peptides respond differently to changes in heart rate and atrial pressures. Reduced atrial tissue atrial natriuretic peptide levels in heart failure may indicate reduced storage after enhanced cardiac release, However, the relatively modest change in the cardiac tissue brain natriuretic peptide levels suggests that the elevated plasma levels may be mediated by mechanisms other than increased atrial pressured.     

Peripheral and right atrial plasma levels of atrial natriuretic peptide and their relation to mean atrial pressure

Atrial myocytes produce natriuretic and vasodilating peptides. Animal experiments have shown that atrial natriuretic peptide (ANP) is released after stretching the atria and drained via the coronary vein effluent. In this study ANP-plasma levels were measured in 14 patients. Blood samples were simultaneously collected from the right atrial cavum and from an antecubital vein. In the right atrial samples, ANP-plasma concentrations were significantly higher than in samples drawn from a peripheral vein (140.3 +/- 114.8 pg/ml vs 96.9 +/- 69.2 pg/ml; p less than 0.05), but a significant linear correlation was found between both values (r = 0.88; p less than 0.001). In patients with elevated atrial pressures significantly higher ANP-levels could be detected than in patients with normal atrial pressures (204 +/- 115 pg/ml vs 55.3 +/- 18.5 pg/ml; p less than 0.05). Mean right atrial pressure correlated to ANP-levels in right atrial blood (r = 0.79; p less than 0.001) as well as to ANP-levels in peripheral blood (r = 0.68; p less than 0.01). These results indicate that higher ANP plasma levels can be measured in samples drawn from a site close to ANP production. On the other hand, atrial pressure might influence the amount of circulating ANP.     

Plasma brain natriuretic peptide and atrial natriuretic peptide concentrations correlate with left ventricular end-diastolic pressure

The present study was designed to investigate whether brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations correlate with left ventricular end-diastolic pressure (LVEDP), pulmonary capillary wedge pressure (PCWP), diastolic pulmonary arterial pressure (DPAP), right atrial pressure (RAP), or ejection fraction (EF). Plasma BNP and ANP levels were determined by commercial radioimmunoassays (Peninsula) after Sep Pak C₁₈ extraction in blood samples withdrawn from the pulmonary artery and the left ventricle or from the left ventricle and the femoral vein in 85 patients undergoing diagnostic cardiac catheterization. Linear and nonlinear regression analysis and the paired sample f-test were applied to the data. Pulmonary arterial plasma BNP and ANP levels showed a close nonlinear correlation with LVEDP (BNP: r=0.94, p < 0.001; ANP: r=0.81, p < 0.001), a significant linear correlation with PCWP, DPAP, and RAP, and a significant negative correlation with EE ANP concentrations decreased significantly from the pulmonary artery to the left ventricle and from the left ventricle to the femoral vein (p < 0.001). BNP levels also decreased significantly between the left ventricle and the femoral vein (p < 0.001), but there was no significant difference between pulmonary arterial and left ventricular BNP concentrations. BNP and ANP concentrations correlated significantly between pulmonary arterial and left ventricular blood samples (BNP: r = 0.99, ANP: r = 0.93, p < 0.001) and between left ventricular and peripheral blood samples (BNP: r=0.99, ANP: r=0.94, p<0.001). The present data suggest that peripheral plasma BNP and ANP levels are useful noninvasive indices of cardiac performance.     

Plasma atrial natriuretic peptide levels for predicting the outcome of atrial fibrillation.

The predictive value of plasma atrial natriuretic peptide (ANP) on the cardioversion outcome was evaluated in 46 hospitalized patients with recent-onset atrial fibrillation (AF). Cardioversion was successful in 42 (91%) patients, 7 (15%) of them regained sinus rhythm spontaneously. After 12 months, 14 (33%) cardioverted patients were in chronic AF. There were no differences in plasma ANP levels between groups where cardioversion failed, those who cardioverted but later developed chronic AF or those who remained in sinus rhythm. However, among patients who were on antiarrhythmic therapy, ANP levels obtained after cardioversion were lower in those who later remained in sinus rhythm. We conclude that lower ANP after cardioversion may be associated with increased chances of long-term preservation of sinus rhythm.     

Discordant atrial natriuretic peptide and brain natriuretic peptide levels in lone atrial fibrillation

OBJECTIVES: We sought to characterize natriuretic peptide levels in a cohort of rigorously characterized subjects with lone atrial fibrillation (AF). BACKGROUND: Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are sensitive biomarkers of cardiac contractile dysfunction. Both peptides have been reported to be elevated in cohorts with AF, but previous studies have included subjects with underlying structural heart disease. We studied these hormones in 150 subjects with lone AF. METHODS: Study subjects had electrocardiographic evidence of at least one episode of AF and a structurally normal heart on echocardiography. Subjects were excluded if they had a history of a myocardial infarction, rheumatic heart disease, cardiomyopathy, significant valvular disease, hyperthyroidism, or hypertension that preceded the onset of AF. Control subjects were obtained from a healthy outpatient primary care population. Plasma pro-ANP and N-terminal pro-BNP (nt-pro-BNP) levels were determined using commercially available immunoassays. RESULTS: A total of 150 serial subjects with lone AF were enrolled and studied, the majority during normal sinus rhythm. Median levels of nt-pro-BNP were significantly elevated in subjects with lone AF as compared with control subjects (166 vs. 133 fmol/ml, p=0.0003). There was no significant difference in pro-ANP levels between subjects with lone AF and control subjects (1,730 vs. 1,625 fmol/ml, p=0.90). CONCLUSIONS: Discordant natriuretic peptide levels were observed in this homogeneous population of subjects with lone AF. This biomarker pattern, which is present even in sinus rhythm, may represent an underlying subclinical predisposition to this common arrhythmia.     

Plasma brain natriuretic peptide levels and blood pressure tracking in the Framingham Heart Study

Increased brain natriuretic peptide (BNP) expression in the ventricles antedates elevated blood pressure (BP) in experimental studies. We hypothesized that higher plasma BNP levels in nonhypertensive individuals may be associated with a greater likelihood of future BP increase and/or hypertension. We evaluated the relations of plasma BNP to longitudinal BP tracking and incidence of hypertension in 1801 nonhypertensive Framingham Heart Study participants (mean age, 56 years; 57% women) by using gender-specific multivariable logistic regression. Progression of BP stage was defined as an increment of one or more BP categories, as classified by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Hypertension was defined as a systolic BP > or =140 or diastolic BP > or =90 mm Hg or use of antihypertensive medications. On follow-up 4 years from baseline, progression of BP category was observed in 36.2% of men and 33.1% of women; hypertension developed in 16.4% of men and 15.5% of women. In multivariable models adjusting for known risk factors, elevated plasma BNP level was associated with increased risk of BP progression in men (odds ratio of 1.15 for trend across categories, P=0.046) but not in women (P=0.82). There were no significant trends of increasing incidence of hypertension across BNP categories in men or women. In our community-based sample, higher plasma BNP levels were associated with increased risk of BP progression in men but not women. Additional investigations are warranted to confirm these findings and elucidate the basis for these gender-related differences.     

Plasma atrial natriuretic peptide levels in elderly hypertensives: effects of blood pressure reduction with amlodipine

Atrial natriuretic peptide (ANP) is a hormone of relatively recent discovery concerned with sodium homeostasis. Increased levels of ANP are found in the elderly and in hypertensives, but the mechanisms for this are unclear. This study determined the effect of amlodipine, a calcium antagonist, which is the only class of antihypertensive agent that has little or no influence on the renin-angiotensin system (Bauer and Reams, 1988) on plasma ANP in a group of 18 elderly hypertensives and a placebo (vit B complex) on a further group of 6 elderly hypertensives. The mean pre-treatment plasma ANP was 62.7 pg/ml (range 18-148.7 pg/ml) and 52.0 pg/ml (range 15.0-148.4 pg/ml) after treatment with amlodipine (not statistically significant). However, systolic blood pressure fell from a mean of 181.6 mmHg to 151.1 mmHg and diastolic blood pressure fell from a mean of 101.6 mmHg to 83.6 mmHg after treatment with amlodipine (statistically significant, P < 0.001). In the group treated with vit B complex, the mean plasma ANP level was 68.4 pg/ml (range 31.4-119.5 pg/ml) before treatment and 63.6 pg/ml (range 29.2-127.3 pg/ml) after treatment. This was not statistically significant and there was no significant change in blood pressure. These findings reinforce the theory that raised plasma ANP levels found in elderly hypertensives are a function of the aging process itself or of age-related physiological changes rather than the result of hypertension.     

Plasma levels of brain natriuretic peptide increase in patients with idiopathic bilateral atrial dilatation

Idiopathic bilateral atrial dilatation (IBAD) is an extremely rare anomaly and is usually associated with atrial fibrillation. Plasma levels of atrial natriuretic peptide (ANP) have been shown to increase in patients with atrial fibrillation. However, secretion of ANP and brain natriuretic peptide (BNP) in patients with IBAD remains unclear. We investigated the clinical features of 9 patients with IBAD and 16 age- and sex-matched patients with lone atrial fibrillation (LAF). Plasma levels of ANP and BNP were measured, and echocardiographic parameters were followed. Left (LAV) and right atrial volumes (RAV) were significantly higher in patients with IBAD than in patients with LAF (both p < 0.01). There were no differences between patients with IBAD and LAF in other echocardiographic parameters. The percent increases in LAV and RAV in patients with IBAD exceeded those in patients with LAF (both p < 0.01). Plasma levels of BNP and the BNP/ANP ratios in patients with IBAD were significantly higher than those in patients with LAF (both p < 0.01), but there was no significant difference in plasma levels of ANP. Regarding the clinical course of the patients with IBAD compared with those with LAF, the atrial volume increased gradually, and plasma levels of BNP were significantly higher. These findings suggested that IBAD was not only influenced by long-term atrial fibrillation, but also by subclinical left ventricular dysfunction.     

Plasma brain natriuretic peptide levels indicating thromboembolism in very elderly patients with non-valvular atrial fibrillation.

BACKGROUND: Assessment of left atrial (LA) function by transesophageal echocardiography is useful for detecting patients with a high risk thromboembolism secondary to atrial fibrillation (AF). A recent study showed that the atrium is the main source of brain natriuretic peptide (BNP) in AF patients without overt heart failure. The purpose of this study was to assess the possible relationship between LA function and plasma BNP levels in very elderly patients with non-valvular AF. METHODS AND RESULTS: Seventy-four consecutive patients with chronic non-valvular AF (aged, 82+/-6 years) underwent transthoracic and transesophageal echocardiography and measurement of plasma BNP. Thirteen AF patients who had a history of cerebral embolism or echocardiographic evidence of thrombus (TE+ group) were compared with 61 AF patients who had no such complications (TE- group). The TE+ group demonstrated a lower LA appendage (LAA) velocity and higher plasma BNP level than the TE- group. Assessment of variables by multiple logistic regression analysis revealed that BNP was a significant predictor of thromboembolism. There was a significant negative correlation between the plasma BNP level and the LAA peak flow velocity. CONCLUSIONS: The present findings would suggest the usefulness of measuring plasma BNP to detect very elderly non-valvular AF patients at high risk for thromboembolism.     

Plasma levels of atrial natriuretic hormone in Cushing's syndrome

To examine a possible role for atrial natriuretic hormone (ANH) in the water and electrolyte disturbances associated with hypercortisolism, plasma ANH levels were measured in 18 patients with endogenous Cushing's syndrome. Nine patients had elevated plasma ANH levels compared to normal subjects. The mean plasma ANH concentration [72.5 +/- 13.0 (+/- SE) pg/mL (23.5 +/- 4.2 pmol/L)] in the Cushing's syndrome patients was significantly higher than that in 40 normal subjects [37.6 +/- 1.9 pg/mL (12.2 +/- 0.62 pmol/L)]. A significant positive correlation was found between plasma ANH and cortisol levels in individual patients. There were no significant correlations, on the other hand, between plasma ANH concentrations and PRA, plasma aldosterone levels, or mean blood pressure. After treatment, plasma ANH concentrations decreased in all 6 patients who had elevated plasma ANH levels preoperatively. In 1 patient with Cushing's disease, plasma ANH levels changed in parallel with plasma cortisol concentrations during o,p'DDD treatment. Fifteen patients who were receiving long term synthetic glucocorticoid therapy for the treatment of miscellaneous diseases had a significantly higher mean plasma ANH level [50.2 +/- 4.0 (+/- SE) pg/mL (16.3 +/- 1.3 pmol/L)] than that in normal subjects. These results suggest that plasma ANH levels are elevated in a substantial number of patients with Cushing's syndrome due to either a direct stimulatory effect of glucocorticoid on atrial ANH secretion or, alternatively, intravascular volume expansion resulting from excessive cortisol secretion.     

Raised plasma levels of atrial natriuretic peptides in Addison's disease

Plasma levels of atrial natriuretic peptides (ANP) were significantly higher in 7 patients with treated Addison's disease (15.8 +/- 8.8 pg/ml, mean +/- SD) than in 7 control subjects (6.1 +/- 3.8 pg/ml) matched for sex, age, body weight and blood pressure. All subjects were studied on their usual sodium intake and had similar urinary sodium excretions. These findings indicate inappropriately high levels of plasma ANP in patients with treated Addison's disease and are possibly due to the lack of adrenal control on ANP synthesis and/or secretion in these patients.     

Plasma levels of atrial natriuretic peptide are increased in normotensive postmenopausal women as a function of age.

The aim of this study was to assess the changes in atrial natriuretic peptide (ANP) levels before and after menopause and to test whether they depend on age or are an integral part of the hormonal changes in menopause. We measured plasma ANP, plasma renin activity (PRA), plasma aldosterone, serum estradiol-17 beta and progesterone concentrations in 103 normotensive women, either in premenopause (n = 35; mean age: 24 years), in physiological menopause (n = 34; mean age: 43 years) or surgically induced menopause (n = 34; mean age: 55 years). The last two groups were matched for duration of menopause and were comparable in their estrogen and progesterone status. PRA and plasma aldosterone concentrations decreased in postmenopausal women, whereas systolic blood pressure and ANP increased. These results were not confirmed after adjustment for age by covariance analysis. In all of the groups, plasma ANP concentrations were not significantly correlated with systolic or diastolic blood pressure, nor with plasma aldosterone, estrogen and progesterone concentrations. These correlations were not improved by correction for age. Plasma ANP concentrations were consistently correlated with age. These data suggest that the increase in plasma ANP levels found in postmenopausal women is related with age and that ANP does not play a direct role in the physiological hormonal changes of menopause.     

Alterations in brain atrial natriuretic polypeptide levels in hypophysectomized rats.

Twelve days after hypophysectomy depleted atrial natriuretic polypeptide (ANP) concentrations were measured in the plasma and in 8 of 18 microdissected brain nuclei of rats. Reduced ANP levels were found in brain structures (subfornical organ, organum vasculosum laminae terminalis, preoptic and hypothalamic periventricular nuclei, paraventricular nucleus, lateral hypothalamic area), which are directly involved in the central regulations of salt and fluid homeostasis, as well as in the medial amygdaloid nucleus and the locus ceruleus. ANP concentrations in the median eminence, medial preoptic and arcuate nuclei did not alter by hypophysectomy. Elevated ANP concentrations were measured only in the supraoptic nucleus of hypophysectomized rats.     

Relationship between plasma atrial natriuretic peptide levels and atrial pressure in man

In an attempt to clarify the mechanisms regulating the release of atrial natriuretic peptide (ANP) in man, ANP levels in pulmonary arterial plasma determined by RIA were correlated to hemodynamic variables in 17 patients with heart disease who underwent cardiac catheterization and angiocardiography. In addition, plasma ANP levels in various blood vessels were determined in 7 patients with heart disease and in 7 normal subjects to determine the source and the site of removal of circulating ANP. A significantly positive correlation was found between plasma ANP levels and mean pulmonary arterial wedge pressure, while the correlation between plasma ANP levels and mean right atrial pressure was not significant. After the injection of contrast medium, both mean right arterial pressure and plasma ANP levels increased, and a significant positive correlation was found between the two variables. When ANP levels in plasma collected from various blood vessels were compared, the highest levels were found in the coronary sinus. Plasma ANP levels in the renal vein were the lowest and were 50% of the levels in the aorta. Plasma ANP levels in the superior vena cava and internal jugular vein were higher than that in the antecubital vein. Analysis of immunoreactive ANP in pooled plasma by high performance liquid chromatography revealed that the retention time of the main ANP peak coincided with that of synthetic human alpha ANP. These results indicate that circulating ANP mainly originates from the heart, the kidney rapidly takes up a significant amount of ANP from the circulation, and an increase in both left and right atrial pressure triggers ANP release in man.     

Plasma brain natriuretic peptide concentration: impact of age and gender

OBJECTIVES: We wished to examine the effects of age and gender on plasma brain natriuretic peptide (BNP) concentration in a population-based study. BACKGROUND: Measurement of BNP concentration is approved for use in the diagnosis of heart failure and may aid in the detection of left ventricular dysfunction. Although BNP is approved for clinical use, there are few data regarding the range of BNP observed in persons without cardiovascular disease or cardiac dysfunction. These data are essential for the interpretation of BNP. METHODS: In 2,042 randomly selected residents of Olmsted County, Minnesota, >44 years old, BNP (Shionogi and Biosite assays), Doppler echocardiography, and medical record review were performed. A normal subset of subjects (n = 767) in sinus rhythm without cardiovascular, renal, or pulmonary disease or diabetes; on no cardiovascular medications; and with normal systolic, diastolic, and valvular function was identified. RESULTS: Within the normal subset, the distribution of BNP differed by age, gender, and assay system. With both assays, BNP increased significantly with age and was significantly higher in women than men, leading to age-, gender-, and assay-specific reference ranges. Receiver operating characteristic analysis for the ability of BNP to detect an ejection fraction < or = 40% was performed in each age/gender stratum in the entire cohort (n = 2,042) and confirmed that discriminatory values for BNP for detection of reduced ejection fraction were higher in women and older persons and were different between the two assays. CONCLUSIONS: Interpretation of BNP should include consideration of age-, gender-, and assay-specific partition values.