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European Journal of Heart Failure 2001 3(6):699-708; doi:10.1016/S1388-9842(01)00181-7
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© 2001 European Society of Cardiology

Evaluation of impaired left ventricular ejection fraction and increased dimensions by multiple neurohumoral plasma concentrations

Bjoern A. Groenninga,b,*, Jens C. Nilssona, Lars Sondergaarda,b, Andreas Kjaerc,d, Henrik B.W. Larssona and Per R. Hildebrandtb

a Danish Research Centre of Magnetic Resonance, Section 340, H:S Hvidovre Hospital, University of Copenhagen Kettegaard Allé 30, DK-2650 Hvidovre, Denmark
b Department of Cardiology and Endocrinology, H:S Frederiksberg Hospital, University of Copenhagen Copenhagen, Denmark
c Department of Medical Physiology, the Panum Institute, University of Copenhagen Copenhagen, Denmark
d Department of Clinical Physiology and Nuclear Medicine, H:S Rigshospitalet, University of Copenhagen Copenhagen, Denmark

* Corresponding author. Tel.: +45-36322978; fax: +45-36470302. E-mail address: bjoerng{at}dadlnet.dk (B.A. Groenning).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: A range of neurohumoral substances have been suggested as diagnostic markers in heart failure. It is, however, undetermined which marker has the greatest diagnostic potential, and whether additional information is gained by a comprehensive neurohumoral evaluation.

Aims: The purpose of the study was to compare the value of epinephrine, norepinephrine, renin activity, aldosterone (ALDO), atrial (ANP) and brain (BNP) natriuretic peptides, arginine-vasopressin and endothelin (ENDO) as markers for left ventricular (LV) dimensions and ejection fraction (LVEF) in patients with systolic heart failure.

Methods: Forty-eight patients with symptomatic heart failure were examined with blood samples and magnetic resonance imaging along with 20 age and gender-matched normal controls.

Results: In multiple regression analyses, BNP was the strongest independent marker for LV end-diastolic (r=0.71, P<0.0001), and end-systolic (r=0.75, P<0.0001) volumes, myocardial mass (r=0.69, P<0.0001), and LVEF (r=–0.78, P<0.0001). ANP was a supplementary independent marker for LV end-diastolic (r=0.76, P<0.0001) and end-systolic (r=0.78, P<0.0001) (ANP and BNP combined) volumes, ENDO for myocardial mass [r=0.71, P<0.0001 (ENDO/BNP)], and ALDO for LVEF [r=–0.81, P<0.0001 (ALDO/BNP)].

Conclusion: BNP is the strongest marker for LV dimensions and LVEF in patients with systolic heart failure. However, a comprehensive neurohumoral evaluation may add some information to the diagnosis.

Key Words: Heart failure • Left ventricle • Diagnosis • Neurohormones • Natriuretic peptides • Magnetic resonance imaging

Received April 26, 2001; Accepted May 28, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The failing heart is characterized by left ventricular (LV) enlargement, which is often a precursor of clinical heart failure [1,2], and by a reduced ejection fraction in later stages. Diagnosis of LV systolic heart failure currently relies mainly on an echocardiographic evaluation of ejection fraction (LVEF) [3]. In an attempt to put in an additional diagnostic filter before this time- and cost-consuming examination, biochemical markers have been suggested as alternative markers for the disease. In recent years, much has been learned about the pathophysiology of heart failure, especially in the area of neurohumoral activation, and many different neurohormones and other substances have been identified as diagnostic and prognostic markers for the disease. In patients with heart failure, different neurohumoral substances have been associated with different aspects of the heart failure syndrome; some with increased morbidity and mortality, and some with clinical and LV echocardiographic findings.

It is, however, currently undetermined which plasma marker has the greatest diagnostic potential in heart failure, and whether measurements of more than one marker may provide important supplementary diagnostic and therapeutic information. The overall contribution of each of the potential markers to a detailed LV profile of the patients is unknown, which at least partly may be explained by the fact that previous studies of the associations between possible markers and LV measures have been performed with methods that did not allow for accurate measurements of LV dimensions and ejection fraction.

The aim of the present study was to compare the potential of a range of neurohumoral substances as diagnostic markers for LV dimensions and ejection fraction; and, in addition, to examine whether any supplementary information is gained by comprehensive neurohumoral profiles. In order to obtain as accurate cardiac measurements as possible, magnetic resonance imaging (MRI) was used, a technique generally considered to be current gold-standard for measuring LV volumes, myocardial mass and ejection fraction [4].


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
Between October 1997 and April 1998, 48 patients with symptomatic LV systolic heart failure from mixed aetiologies were consecutively referred from seven Danish hospital-based outpatient heart failure clinics, and were examined once with cardiac MRI and blood samples at our facility. In addition, 20 age- and gender-matched normal controls with no history or symptoms of heart disease or other chronic disease were studied.

Both male and female patients with impaired LV systolic function (by routine-echocardiography within 3 months before the examination) and symptomatic heart failure (New York Heart Association functional classes II–IV), for 3 months or more before examination in the study, and a stable clinical condition for at least 2 weeks prior to the study, were eligible. Exclusion-criteria were acute myocardial infarction or unstable angina within 28 days before the examination, valvular heart disease, uncontrolled hypertension, heart failure secondary to systemic disease, alcohol abuse, treatment with a β-blocking agent and severe renal disease (plasma creatinine >0.2 mmol/l). The rationale behind these last two exclusion criteria have since been confirmed in one isolated study, in which elevated plasma levels of BNP were associated with β-blockade [5], and, in another study, with increased plasma concentrations of creatinine [6] in patients with chronic systolic heart failure. Other exclusion-criteria with respect to the MRI-examination were atrial fibrillation, implanted pacemaker, prosthetic heart valves, implanted insulin pump and claustrophobia.

The study conformed with the principles outlined in the Declaration of Helsinki, and was approved by the local ethics committee. Written informed consent was obtained from the patients and healthy controls.

2.2. Neurohumoral measurements
Blood samples were taken immediately before the MRI examination after 20 min of rest for the determination of plasma levels of epinephrine (EPI), norepinephrine (NEPI), renin activity (RA), aldosterone (ALDO), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), arginine–vasopressin (AVP) and endothelin-1 (ENDO). In order to exclude the effects of any potential hormonal circadian rhythm, all subjects were examined between 13.00 and 16.00 h.

EPI and NEPI were determined simultaneously by a radioenzymatic assay described by Ben-Jonathan and Porter [7]. The sensitivity of the assay was 10–20 pg/ml. The intraassay coefficients of variation for EPI and NEPI were 4.3 and 6.8%, respectively. The interassay coefficients of variation were 12.3 and 14.8%, respectively.

Determination of RA was performed by a radioimmunoassay (RIA) of generated and antibody trapped angiotensin I according to a previously described procedure [8]. Synthetic angiotensin I (Bio-Schwartz), which was tested against Research standard A (Institute for Medical Research, Holy Hill, London, UK) served as reference preparation. The intra- and interassay coefficients of variation were 3.2 and 3.6%, respectively.

ALDO was measured by a RIA of unextracted plasma using a commercial kit according to the instructions of the manufacturer (Coat-A-Count, DPC, Los Angeles, CA, USA). The sensitivity of the assay was 16 pg/ml and the intra- and interassay coefficients of variation were 6 and 7%, respectively.

ANP was measured by a RIA of plasma extracted by means of C18 Sep-Pak cartridges (Waters, Milford, MA, USA) according to a previously described procedure [9]. Synthetic ANP (Peninsula Laboratories, Belmont, CA, USA) served as reference preparation. The sensitivity of the assay was 3.1 pg/ml and the intra- and interassay coefficients of variation were 4 and 5%, respectively.

BNP was measured in extracted plasma by a RIA using a commercial kit according to the instructions of the manufacturer (Peninsula Laboratories, Belmont, CA, USA). Extraction procedure: Thawed plasma samples were centrifuged at 1100xg for 10 min at 4°C and 2 ml of plasma was acidified to pH 2–3 by addition of 6 ml of 4% acetic acid. The C18 Sep-Pak cartridges were attached to plastic syringes and connected to a peristaltic pump (1.2 ml/min). The cartridges were primed by passing 6 ml 96% ethanol:4% acetic acid, 6 ml 100% methanol, 6 ml distilled water and 6 ml 4% acetic acid through them. The acidified plasma samples were poured into the syringes. The cartridges were then washed by 6-ml distilled water and allowed to suck air. BNP was eluted from the cartridges into polyethylene tubes containing 10 µl of 0.1% Triton-X by 3 ml of 96% ethanol:4% acetic acid. The extracts were dried by air overnight. The sensitivity of the assay was 5 pg/ml.

AVP was measured by a RIA of plasma extracted by means of C18 Sep-Pak cartridges according to a previously described procedure [10]. Synthetic AVP (Peninsula Laboratories Inc., Belmont, CA, USA) served as reference preparation. The sensitivity of the assay was 0.11–0.32 pg/ml plasma, and the intra- and interassay coefficients of variation were 8 and 12%, respectively.

ENDO was measured by a RIA using rabbit antiserum (RAS 6901) from Peninsula Laboratories, Belmont, CA, USA, 125I-endothelin from Amersham Life Science Ltd., Uppsala, Sweden, and standards from Peptide Institute, Osaka, Japan. Blood was collected in EDTA aprotenin tubes, and the plasma was extracted prior to analysis using Oasis HLB extraction cartridges from Waters, Milford, MA, USA. The interassay variation was 9%.

2.3. MRI investigation
All MRI studies were carried out on a whole-body MR scanner (Siemens Impact Magnetom, Siemens, Erlangen, Germany), operating at 1.0 T with a phased array chest coil as the receiver coil. Each slice was obtained over 15 heartbeats with an electrocardiographically triggered breath-hold fast low angle shot (FLASH) cinematographic pulse sequence, with a temporal resolution of 55 ms. Slice thickness was 10 mm, field of view was 263x350 mm2 and matrix size was 126x256. The left ventricle was covered by a stack of 10–15 slices in the true short axis plane with no inter-slice gaps [11].

A blind analysis of the MRI examinations was undertaken in one batch. End-systole was chosen at the point where the total LV blood pool was smallest. On the end-diastolic and end-systolic frames, LV volumes were measured by manual planimetry and subsequent multiplication with slice thickness. Finally, total volumes of the left ventricle were calculated by simple addition of the individual slice volumes in the stack of contiguous slices covering the left ventricle. In this manner, LV end-diastolic volume, LV end-systolic volume, and LVEF were determined. LV myocardial mass was determined in a similar way by using the difference between the inner and outer circumferences of the LV myocardium in end-diastole, and multiplying the volume with a density factor of 1.05 [12].

Heart rate was measured continuously during the MR investigation and determined as the average heart rate during the examination. Blood pressure was measured before the examination after 20 min rest in a sitting position. In addition, body weight and body height were measured, and body surface area was calculated [13]. Subsequently, all MRI variables, apart from LVEF, were indexed by division with body surface area. A simple estimate of left ventricular systolic global wall stress (SWS) was calculated by the formula:

SWS=0.133xsystolic blood pressurex[1+(3x(LV end-systolic volume index/LV mass index)] [14].

2.4. Statistics
Verification of normal distribution of data was accomplished using histograms and normal plots. LV volume measures, LVEF, myocardial mass and SWS fitted into a normal distribution model, whereas the neurohumoral plasma concentrations showed a logarithmic normal distribution, and were consequently logarithmically transformed. Two sample t-tests between mean values of variables in the two groups were performed. Multiple regression analyses with backwards elimination of LV volumes, myocardial mass, LVEF and SWS on log concentrations of all neurohumoral substances were performed, and standardized parameter estimates for each of the independent markers were calculated, which allowed for direct comparison between the independent markers in each of the models. Subsequently, correlation analyses were performed between LV measures and SWS and the neurohumoral plasma concentrations that came out as independent markers from the multiple regression analyses. Finally, correlation analyses between LV measures and the combined independent markers from each multiple regression analysis were performed. In all tests, a significance level of 5% has been used. All tests were performed in the SAS-system (SAS® Institute Inc., Cary, NC, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Mean values and 95% CI for all variables are given in Table 1. The heart failure patients and the normal controls were matched for age and gender. For body surface area, systolic and diastolic blood pressure, no differences were found between the groups. The heart rate was significantly higher in the patients than in the normal controls.


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  		Table 1 Baseline variables for heart failure patients and normal controlsa

 
In the heart failure patients, mean LV end-diastolic volume index (LVEDVI), end-systolic volume index (LVESVI), myocardial mass index (LVmassI) and SWS exceeded control values, and mean LVEF was below control value. The plasma levels of RA, ALDO, ANP and BNP in the heart failure group exceeded control values, whereas the plasma levels of EPI, NEPI, AVP and ENDO did not differ significantly between the groups (Table 1).

An elevated plasma level of BNP was strongly associated with high values of LVEDVI (r=0.71, P<0.0001), LVESVI (r=0.75, P<0.0001), LVmassI (r=0.69, P<0.0001), SWS (r=0.64, P<0.0001), and was associated with low values of LVEF (r=–0.78, P<0.0001) (Fig. 1).


Figure 1
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  		Fig. 1 Associations between the plasma level of BNP and LV dimensions and systolic function. BNP, brain natriuretic peptide; HF, heart failure patients; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; LVmassI, left ventricular myocardial mass index; X, normal controls; {Delta}, heart failure patients.

 
In the multiple regression analyses, BNP consistently came out as the most powerful independent marker for all LV measures and the estimated SWS. For each LV measure, BNP was accompanied by one supplementary independent marker. ANP was an almost equally powerful independent marker for LV volumes, ENDO came out as an independent marker for LVmassI, and ALDO was a supplementary independent marker for LVEF (Table 2).


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  		Table 2 Associations between left ventricular measures and neurohumoral plasma concentrationsa

 
When combining the independent markers from each multiple regression analysis, correlations with the LV measures improved slightly compared with BNP alone. For LVEDVI, the Pearson correlation coefficient with the combined independent markers (BNP and ANP) increased to r=0.76, P<0.0001; for LVESVI to r=0.78, P<0.0001 (BNP and ANP); for LVmassI to 0.71, P<0.0001 (BNP and ENDO) and for LVEF to r=–0.81, P<0.0001 (BNP and ALDO) (Table 2), which were all significantly different from correlations with BNP alone.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Plasma levels of a range of neurohumoral substances have been proposed as markers in heart failure. Plasma concentrations of EPI [15], NEPI [16], RA [17], ALDO, ANP [15], BNP [18], AVP [19], and ENDO [20] have been identified as prognostic predictors of mortality in patients with chronic LV systolic heart failure. Furthermore, elevated plasma levels of NEPI, RA, ANP, AVP [21], N-terminal pro ANP [22], and in particular BNP have proven promising as markers in the clinical diagnosis of heart failure, and BNP as a marker for the diagnosis of impaired systolic function [6,23] in patients suspected of heart failure in primary care. In addition, we have recently identified BNP as a strong marker for LV volumes and myocardial mass [24]. Nevertheless, implementation of any marker into clinical practice has until now been limited by insufficient diagnostic power. Our study represents the first attempt to stratify different components of the LV systolic heart failure syndrome, i.e. increased LV dimensions and myocardial mass, and decreased ejection fraction, with respect to the neurohumoral profile of the patients.

4.1. BNP
The main finding from our study is that the plasma level of BNP seems to be a powerful marker for LV volumes, myocardial mass and SWS, and that the marker is much more intimately associated with LVEF than could be expected from previous studies using echocardiography as the reference method for the determination of cardiac dimensions and systolic function. The consistency of these results supports a principal role for BNP in the diagnosis and classification of heart failure, and indicates that the marker holds important information on LV dimensions, myocardial mass and SWS beyond systolic function. The marker may therefore be capable of very early detection of LV dilatation, even before the disease progresses towards overt systolic heart failure. BNP is produced mainly locally in the LV in direct response to an increased wall tension or stretch [25,26], providing an explanation for the power of BNP as a marker for LV dimensions, and subsequently for LVEF in patients with systolic heart failure. In addition, elevated plasma levels of BNP have previously been found in subjects with other cardiac dysfunction such as LV hypertrophy [27], isolated diastolic heart failure [28] and right ventricular failure [29]. Clearly, this issue warrants further investigation, but does not seem to be an impediment for the introduction of the marker into clinical practice, since further examination is well indicated in these patient categories.

4.2. Supplementary neurohumoral profile
Our study shows that almost all relevant information on LV dimensions and ejection fraction can be provided solely by the plasma level of BNP. However, ANP came out as an almost equally powerful marker for LVEDVI and LVESVI, providing some information independent of BNP. These findings are in accordance with one previous study, in which elevated plasma levels of N-terminal pro ANP were associated with increased LV end-diastolic dimensions in patients with heart failure [30]. ANP is released from the atria in response to an increased atrial wall stretch [31], which is very likely to be present in patients with heart failure due to an elevated LV end-diastolic pressure, and ventricular dilatation, which in some cases may be followed by subsequent incompetence of the mitral valve. Furthermore, a simultaneous component of diastolic dysfunction of the dilated left ventricle may provide an additional explanation for the potential of ANP as a marker for LV volumes.

ENDO was an independent marker for LVmassI, giving additional information independent of BNP, even though the mean plasma concentration of ENDO was not elevated in the heart failure patients compared with the normal controls in our study. In several experimental studies, elevated plasma levels of ENDO have repeatedly been associated with an increased LV myocardial mass [32–34]. The responsible mechanism seems to be that ENDO exerts a hypertrophic effect directly on the cardiomyocytes [35] mediated through the myocardial endothelin-A receptors [34], and appears to be produced mainly by the cardiomyocytes themselves in proportion to the relative wall thickness of the left ventricle [36]. The fact that ENDO came out as an independent marker for LV myocardial mass in our study, even in the absence of significant activation of the endothelin system, indicates that the marker may add supplementary information to a neurohumoral profile of subjects suspected of LV dysfunction and/or hypertrophy, even in the early stages of the disease.

ALDO emerged as an independent marker for LVEF. This is in accordance with previous findings that elevated plasma levels of ALDO are associated with a reduced LVEF [26] as well as with an increased mortality [15] in patients with chronic systolic heart failure. Apart from being produced by the adrenal cortex in response to angiotensin II, the failing human left ventricle seems to produce ALDO locally in response to cardiac angiotensin II, and appears to exert its effects on the left ventricle in a paracrine or autocrine manner [26]. The elevated plasma level of ALDO in the heart failure patients, compared with the normal controls in our study, may to some degree be seen as a failure of the angiotensin converting enzyme (ACE) inhibitor treatment, which almost all of the patients were receiving. However, such failure to completely suppress the renin–angiotensin–aldosterone system is very common [37], even in the presence of high plasma concentrations of the ACE inhibitor, suggesting an alternative pathway for the synthesis of angiotensin II, and explaining why ALDO may have a potential as a marker for LV systolic function, even during treatment with ACE inhibitors.

Neurohumoral treatment monitoring in heart failure has recently been proposed as a promising alternative to clinically guided treatment. In a recent study, drug treatment guided by the plasma concentration of the amino terminal portion of BNP reduced the total number of cardiovascular events compared with clinically guided treatment [38]. Our results provide some of the pathophysiological explanation for these clinical findings, as the intimate association between BNP and the estimated SWS demonstrated in our study, closely reflects LV load conditions, which is the primary target of most heart failure drug therapy [39].

4.3. Study limitations
Our study was not community based, but reflects the associations between the neurohumoral substances and LV measures in consecutively included patients from hospital-based heart failure clinics and in age- and gender matched normal volunteers. Quite clearly, this is a less than optimal study design. A better approach would have been to use the battery of neurohumoral measurements as screens for heart failure in a random sample of the general population, and then compare this with measures of LV structure and function. However, with an assumed prevalence of undetected systolic heart failure of approximately 2–8% in the general population [40], this (optimal) study design would have required inclusion of between 1000 and 2000 subjects, which is unrealistic for an MRI study. We therefore settled for the present study design, which may be regarded as a potential weakness, but, as can be seen from Fig. 1, LV dimensions and systolic function considerably overlapped between the two groups, providing a realistic and clinically relevant setting for the study.

The use of drug therapy in the heart failure group is a potential problem, but is not likely to have biased the results in favour of the study, since if anything, treatment with ACE inhibitors, possibly as a simple consequence of an antiremodelling treatment effect, seems to be associated with a reduction in neurohumoral plasma concentrations, suggesting that the association between the neurohumoral markers and LV measures may be even stronger in untreated patients with heart failure [38].


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Among the tested neurohumoral substances, BNP is by far the most powerful marker for LV volumes, myocardial mass and ejection function in patients with systolic heart failure. Even though we find that a complete neurohumoral evaluation may add supplementary information to the diagnosis, our results suggest that BNP alone holds sufficient diagnostic power for implementation into clinical practice.


   Acknowledgements
 
We express our gratitude to the laboratory technicians and radiographers at the Danish Research Centre of Magnetic Resonance, H:S Hvidovre Hospital and in particular to laboratory technician Sussi Larsen for her invaluable assistance during the course of this study, and to laboratory technicians Elsa Larsen and Jytte Oxboel for skilful technical assistance with the hormone analyses. We are also grateful to the cardiology departments at Herlev County Hospital, H:S Rigshospitalet, Hilleroed Hospital, Glostrup County Hospital, Frederikssund Hospital and Hoersholm Hospital for the referral of patients to the study.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Vasan R.S., Larson M.G., Benjamin E.J., Evans J.C., Levy D. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med (1997) 336:1350–1355.[Abstract/Free Full Text]
  2. White H.D., Norris R.M., Brown M.A., Brandt P.W., Whitlock R.M., Wild C.J. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation (1987) 76:44–51.[Abstract/Free Full Text]
  3. The Task Force on Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J (1995) 16:741–751.[Free Full Text]
  4. Nagel E., Underwood R., Pennell D., et al. New developments in non-invasive cardiac imaging: critical assessment of the clinical role of cardiac magnetic resonance imaging. Eur Heart J (1998) 19:1286–1293.[Web of Science][Medline]
  5. Luchner A., Burnett J.C.J., Jougasaki M., Hense H.W., Riegger G.A., Schunkert H. Augmentation of the cardiac natriuretic peptides by beta-receptor antagonism: evidence from a population-based study. J Am Coll Cardiol (1998) 32:1839–1844.[Abstract/Free Full Text]
  6. Luchner A., Burnett J.C.J., Jougasaki M., et al. Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens (2000) 18:1121–1128.[CrossRef][Web of Science][Medline]
  7. Ben-Jonathan N., Porter J.C. A sensitive radioenzymatic assay for dopamine, norepinephrine, and epinephrine in plasma and tissue. Endocrinology (1976) 98:1497–1507.[Abstract/Free Full Text]
  8. Poulsen K., Jorgensen J. An easy radioimmunological microassay of renin activity, concentration and substrate in human and animal plasma and tissues based on angiotensin I trapping by antibody. J Clin Endocrinol Metab (1974) 39:816–825.[Abstract/Free Full Text]
  9. Schutten H.J., Johannessen A.C., Torp-Pedersen C., Sander-Jensen K., Bie P., Warberg J. Central venous pressure — a physiological stimulus for secretion of atrial natriuretic peptide in humans? Acta Physiol Scand (1987) 131:265–272.[Web of Science][Medline]
  10. Kjaer A., Knigge U., Warberg J. Involvement of oxytocin in histamine- and stress-induced ACTH and prolactin secretion. Neuroendocrinology (1995) 61:704–713.[Web of Science][Medline]
  11. Atkinson D.J., Edelman R.R. Cineangiography of the heart in a single breath hold with a segmented turboFLASH sequence. Radiology (1991) 178:357–360.[Abstract/Free Full Text]
  12. Mogelvang J., Stokholm K.H., Saunamaki K., et al. Assessment of left ventricular volumes by magnetic resonance in comparison with radionuclide angiography, contrast angiography and echocardiography. Eur Heart J (1992) 13:1677–1683.[Abstract/Free Full Text]
  13. Guyton A.C. Textbook of Medical Physiology (1986) 7th ed. Philadelphia: Saunders. p. 848.
  14. Regen D.M. Calculation of left ventricular wall stress. Circ Res (1990) 67:245–252.[Abstract/Free Full Text]
  15. Swedberg K., Eneroth P., Kjekshus J., Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation (1990) 82:1730–1736.[Abstract/Free Full Text]
  16. Cohn J.N., Levine T.B., Olivari M.T., et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med (1984) 311:819–823.[Abstract]
  17. Johnson G., Carson P., Francis G.S., Cohn J.N. Influence of prerandomization (baseline) variables on mortality and on the reduction of mortality by enalapril. Veterans Affairs Cooperative Study on Vasodilator Therapy of Heart Failure (V-HeFT II). V-HeFT VA Cooperative Studies Group. Circulation (1993) 87:VI32–VI39.[Medline]
  18. Tsutamoto T., Wada A., Maeda K., et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation (1997) 96:509–516.[Abstract/Free Full Text]
  19. Rouleau J.L., Packer M., Moye L., et al. Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril. J Am Coll Cardiol (1994) 24:583–591.[Abstract]
  20. Pacher R., Stanek B., Hulsmann M., et al. Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure. J Am Coll Cardiol (1996) 27:633–641.[Abstract]
  21. Francis G.S., Benedict C., Johnstone D.E., et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation (1990) 82:1724–1729.[Abstract/Free Full Text]
  22. Lerman A., Gibbons R.J., Rodeheffer R.J., et al. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction. Lancet (1993) 341:1105–1109.[CrossRef][Web of Science][Medline]
  23. McDonagh T.A., Robb S.D., Murdoch D.R., et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet (1998) 351:9–13.[CrossRef][Web of Science][Medline]
  24. Groenning B.A., Nilsson J.C., Sondergaard L., Kjaer A., Larsson H.B.W., Hildebrandt P. Natriuretic peptides are potent markers for left ventricular dimensions and mass in chronic heart failure (Abstract). Circulation (2000) 102:II-782.
  25. Yasue H., Yoshimura M., Sumida H., et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation (1994) 90:195–203.[Abstract/Free Full Text]
  26. Mizuno Y., Yoshimura M., Yasue H., et al. Aldosterone production is activated in failing ventricle in humans. Circulation (2001) 103:72–77.[Abstract/Free Full Text]
  27. Yamamoto K., Burnett J.C.J., Jougasaki M., et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension (1996) 28:988–994.[Abstract/Free Full Text]
  28. Redfield M.M., Mahoney D.W., Jacobsen S.J., Rodeheffer R.J. Isolated diastolic dysfunction in the community (Abstract). Circulation (1999) 100:I-381.
  29. Nagaya N., Nishikimi T., Okano Y., et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol (1998) 31:202–208.[Abstract/Free Full Text]
  30. Dickstein K., Larsen A.I., Bonarjee V., Thoresen M., Aarsland T., Hall C. Plasma proatrial natriuretic factor is predictive of clinical status in patients with congestive heart failure. Am J Cardiol (1995) 76:679–683.[CrossRef][Web of Science][Medline]
  31. Edwards B.S., Zimmerman R.S., Schwab T.R., Heublein D.M., Burnett J.C.J. Atrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ Res (1988) 62:191–195.[Abstract/Free Full Text]
  32. Ehmke H., Faulhaber J., Munter K., Kirchengast M., Wiesner R.J. Chronic ETA receptor blockade attenuates cardiac hypertrophy independently of blood pressure effects in renovascular hypertensive rats. Hypertension (1999) 33:954–960.[Abstract/Free Full Text]
  33. Hua L., Li C., Xia D., et al. Relationship between hypertensive left ventricular hypertrophy and levels of endothelin and nitric oxide. Hypertens Res (2000) 23:377–380.[Web of Science][Medline]
  34. Ito H., Hiroe M., Hirata Y., et al. Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload. Circulation (1994) 89:2198–2203.[Abstract/Free Full Text]
  35. Ito H., Hirata Y., Hiroe M., et al. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res (1991) 69:209–215.[Abstract/Free Full Text]
  36. Serneri G.G., Modesti P.A., Boddi M., et al. Cardiac growth factors in human hypertrophy. Relations with myocardial contractility and wall stress. Circ Res (1999) 85:57–67.[Abstract/Free Full Text]
  37. MacFadyen R.J., Lee A.F., Morton J.J., Pringle S.D., Struthers A.D. How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart (1999) 82:57–61.[Abstract/Free Full Text]
  38. Troughton R.W., Frampton C.M., Yandle T.G., Espiner E.A., Nicholls M.G., Richards A.M. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet (2000) 355:1126–1130.[CrossRef][Web of Science][Medline]
  39. Massie B.M. 15 years of heart-failure trials: what have we learned? Lancet (1998) 352(Suppl_1):SI29–SI33.[CrossRef][Medline]
  40. McDonagh T.A., Morrison C.E., Lawrence A., et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet (1997) 350:829–833.[CrossRef][Web of Science][Medline]

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