(Circulation. 1999;99:786-792.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Neurohumoral Prediction of Benefit From Carvedilol in Ischemic Left Ventricular Dysfunction
From the Department of Medicine, Christchurch Cardioendocrine Group, Christchurch School of Medicine, Christchurch, New Zealand.
Correspondence to Prof A. Mark Richards, Christchurch Cardioendocrine Group, Department of Medicine, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. E-mail bgriffin{at}chmeds.ac.nz
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Background—Plasma neurohormones were analyzed for prediction of adverse outcomes and response to treatment in 415 patients with ischemic left ventricular dysfunction randomly assigned to receive carvedilol or placebo.
Methods and Results—Atrial natriuretic peptide, brain natriuretic peptide (BNP), or norepinephrine (NE) levels above the group median were associated with increased mortality rates and heart failure. On multivariate analysis, both BNP and NE interacted with treatment to predict death or heart failure independent of age, New York Heart Association class, and left ventricular ejection fraction. For placebo, supramedian levels of BNP were associated with 3-fold the mortality rate of inframedian levels (20/104; 19% vs 6/99; 6%; P<0.01). For carvedilol, mortality rate was comparable in these 2 subgroups (12/109; 11% vs 8/94; 9%; NS). Corresponding rates for heart failure were 29/104 (28%) versus 3/99 (3%; P<0.001) for placebo and 16/109 (15%) versus 7/94 (7%; NS) for carvedilol. High NE levels did not predict additional benefit from carvedilol, which significantly reduced heart failure admissions only in those with NE levels below the median (13.1% to 4.0%; P<0.01). In the 23% of the study population with supramedian BNP but inframedian levels of NE, carvedilol reduced hospital admission with heart failure by >90% (P<0.001).
Conclusions—Carvedilol reduced mortality rates and heart failure in those with higher pretreatment BNP levels but lesser activation of plasma NE. Neurohumoral profiling may guide introduction of ß-blockade in heart failure.
Key Words: heart failure • natriuretic peptides • norepinephrine
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Neurohumoral responses to cardiac injury participate in the pathogenesis of heart failure.1 2 3 4 Plasma levels of neurohumoral factors offer an indication of cardiovascular prognosis1 4 5 6 and may aid risk stratification and choice of therapy. We hypothesized that plasma levels of
1 of norepinephrine (NE), the cardiac
natriuretic peptides atrial natriuretic peptide
(ANP) and brain natriuretic peptide (BNP), and arginine
vasopressin (AVP) would identify patients likely to benefit from
treatment with carvedilol. We report the results from 415 patients with
ischemic left ventricular impairment randomly
assigned to treatment with carvedilol or placebo for congestive heart
failure. |
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The study organization and the effects of carvedilol on left ventricular function, exercise tolerance, symptoms, morbidity, and mortality rates have been reported.7 8 Twenty centers in Australia and New Zealand participated (see "Appendix"). The study was coordinated by the Clinical Trials Research Unit, University of Auckland. Neurohormonal assays and related analyses were conducted by the Christchurch Cardioendocrine Group, Christchurch School of Medicine.
Patients (n=415) were recruited with chronic stable heart failure caused by ischemic heart disease, left ventricular ejection fraction (LVEF) by radionuclide ventriculography <45%, and current New York Heart Association class II or III or previous NYHA class II-IV. Exclusion criteria included current NYHA class IV; heart rate <50 bpm; sick sinus syndrome; second- or third-degree heart block; blood pressure <90 mm Hg systolic or >160/100 mm Hg; treadmill exercise duration <2 or >18 minutes (modified Naughton protocol); coronary event or procedure within 4 weeks; primary myocardial or valve disease; insulin-dependent diabetes; chronic airways disease; hepatic disease (serum transaminase >3 times normal); renal impairment (creatinine >250 µmol/L); and life-threatening noncardiac disease or current treatment with ß-blocker, ß-agonist, or verapamil.
Patients tolerating 6.25 mg BID carvedilol were randomly assigned, double-blind, to receive continued carvedilol (titrated to a maximum dose of 25 mg BID) or matching placebo for a trial period of 18 months. Measurements included LVEF (radionuclide scan), exercise tolerance (modified Naughton treadmill test and 6-minute walk test), and NYHA class. End points included change in LVEF, exercise tolerance, symptoms, morbidity (hospitalization with heart failure, coronary ischemic syndromes, or noncardiovascular illnesses), and mortality rates.
Neurohumoral sampling was conducted before randomization. Venous blood (EDTA) was collected (9 AM to noon) after intravenous cannulation and the patient having been seated for 30 minutes. The sample was separated within 20 minutes, and the plasma was stored at -80°C before transport on dry ice to the assay laboratory for assay within 6 weeks of sampling. Assays for ANP, BNP, NE, and AVP were conducted according to established methods.9 10 11 12 Interassay and intra-assay coefficients of variation were 5% to 12%.
Statistics
Plasma hormones were compared (2-sample t tests) to
age-matched normal subjects (n=168). Event rates were compared with the
use of 
2 tests with risk ratios (and 95% CI)
and Kaplan-Meier curves calculated for groups with admission levels
above and below the median of individual neurohumoral factors, LVEF,
exercise time, and distance. Analyses were conducted separately
for groups receiving carvedilol and placebo as well as for the total
patient population. Cox proportional hazards analysis was used
to examine potential indicators (NYHA class, LVEF, history of heart
failure or previous myocardial infarction, and BNP/NE by treatment
interactions) for independent prediction of death and admission with
heart failure.
P<0.05 (2-tailed) was taken to indicate statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Seventy percent of patients were in NYHA class II-III at randomization (43% had previously been class IV at some time). Eighty-eight percent had had a previous myocardial infarction and 43% a previous hospital admission for heart failure. Eighty-five percent were receiving an ACE inhibitor, 75% diuretics, and 38% digoxin. The average LVEF at entry was 29%, treadmill duration 10.5 minutes, and mean 6-minute walk distance 392 meters.
The effects of treatment on morbidity and mortality rates and surrogate end points have been reported.7 8 Carvedilol improved LVEF without deterioration in symptoms or exercise capacity. The combined end point of death or hospital admission for any reason was reduced by 26% (104 carvedilol vs 131 placebo; 95% CI -43% to -5%; 2P=0.02). Falls in death (20 vs 26; 95% CI -58% to +36%; 2P>0.1) and all admissions (99 vs 120; 95% CI -41% to 0%; 2P=0.054) were not significant. Fewer admissions for heart failure occurred in the carvedilol group (23 vs 33; NS). Numbers of events in patients receiving carvedilol compared with placebo did not differ significantly for acute coronary syndromes (25 vs 34), other cardiovascular events (40 vs 38), or noncardiovascular admissions (69 vs 51).
Markers of Morbidity/Mortality
Plasma BNP, ANP, and NE but not AVP exceeded normal values (30±23
vs 5.5±2.5 pmol/L [mean±SD], P<0.001; 43±36 vs 12.5±7
pmol/L, P<0.001; 4400±2100 vs 1550±650 pmol/L,
P<0.001; 3.3±4.1 vs 2.3±2.5 pmol/L, NS, respectively).
Tables 1
and 2 give event rates (death and heart
failure) for potential prognostic markers divided according to the
median levels of candidate markers (Table 1) and then further
divided according to administration of placebo or carvedilol (Table 2).
|
|
Kaplan-Meier curves for ANP and BNP levels above and below the group
median (irrespective of whether carvedilol or placebo was given)
indicated that patients with higher levels of ANP and BNP were at
increased risk of death and heart failure (Figures 1 and 2).
Norepinephrine showed less clear-cut separation of survival
curves, significant (P<0.01) for heart failure but not
death (P=0.0508). Survival curves for LVEF did not separate
significantly for death or heart failure. Patients with treadmill times
below the group median were at significantly increased risk of heart
failure (P<0.001) but not death. Six-minute walk distance
results paralleled those for treadmill time. Event curves for AVP
levels above and below the group median were not significantly
separated for any clinical end point. No marker predicted acute
coronary ischemic syndromes by either risk ratio or
Kaplan-Meier analyses.
|
|
P<0.001.
Death and heart failure were more frequent in patients with cardiac
peptide levels above the group median who received placebo. In such
patients randomly assigned to carvedilol, event rates did not differ
significantly from patients with inframedian peptide levels (Table 2
and Figures 1 and 2). The ratio of mortality in those
with ANP and/or BNP levels above the median to those with inframedian
levels was 
2:1 overall, 3:1 for placebo, and 1:1 for carvedilol
(Table 2 and Figure 1). For admissions with heart
failure, the corresponding ratios were 3:1, 8:1, and 2:1,
respectively (Table 2 and Figure 2).
In contrast to the cardiac peptides, higher plasma levels of NE did not
predict benefit from carvedilol. Instead, carvedilol reduced heart
failure in those with inframedian levels of plasma NE (Table 2),
and Kaplan-Meier analysis indicated an advantage for such
patients receiving carvedilol compared with placebo
(P<0.05). Similar trends for the interaction of NE,
treatment, and mortality rates were not significant (Table 2).
Twenty-three percent (n=97) of the total group had supramedian plasma
BNP with concurrent inframedian plasma NE levels. Cumulative heart
failure rates were identical in this subgroup (13/97, 13%) as in the
remainder of the group (39/303, 13%; Figure 3). However, the response to carvedilol
clearly differed in this defined neurohumoral subgroup. For placebo,
heart failure rates were higher in this subgroup (12/48, 25%) compared
with others (19/153, 12%, P<0.05), whereas carvedilol
reversed this pattern (1/49, 2% vs 20/153, 13%, P<0.03).
Hence, within this neurohumoral subgroup, carvedilol reduced heart
failure admissions from 12/48 (25%) to 1/49 (2%; P<0.001;
Figure 3). Increased benefit from carvedilol was also seen for
mortality rate (placebo 7/48, 15% vs carvedilol 2/46, 4%,
P=0.098), though mortality rate was too low for these
differences to achieve statistical significance. Therefore, nearly all
the reduction in heart failure admissions (23 vs 33, ie, 10 fewer
events) and deaths (20 vs 26) potentially attributable to carvedilol
occurred within this neurohormonal subgroup.
|
Relations between indicator/treatment interactions and clinical events
were statistically weak or nonsignificant by both risk ratio (Table 2) or Kaplan-Meier (not shown) analyses for LVEF,
treadmill time, 6-minute walk distance, and pretreatment blood
pressures and heart rate.
Cox proportional hazards analyses indicated that interactions
of treatment (ie, carvedilol or placebo) with BNP and NE predicted
death and heart failure independent of age, NYHA class, and LVEF (Table 3). Both were predictive of death
independent of previous myocardial infarction and for heart failure
independent of previous heart failure. ANP/treatment in place of
BNP/treatment interaction yielded similar though slightly weaker
results. Rotation of hypertension, diabetes, sex, blood pressure, and
heart rate through the model produced similar results, with
BNP/treatment and NE/treatment terms remaining independent predictors
for heart failure (P<0.03-P<0.001) but showing
only marginal statistical significance in some models for predicting
death (P
0.06 to 0.03). In an all-inclusive
analysis with 13 variables, both BNP/treatment and
NE/treatment interactions remained independently predictive of death
(P=0.04 for both) and heart failure (P=0.003 for
both).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Beyond confirming the known relations between circulating neurohormones and cardiovascular death in heart failure,1 4 5 6 the current study is the first to demonstrate neurohormonal prediction of response to carvedilol.
Recent trials of carvedilol in heart failure indicate that it is a significant advance in therapy for a common and lethal condition.7 8 13 14 15 However, appropriate patient selection and prediction of benefit have remained areas of uncertainty. The current report throws new light on these issues. Prerandomization plasma concentrations of cardiac natriuretic peptides above compared with below the median level for the group predicted a far greater risk of death (>3-fold) or heart failure (>7-fold) in those randomly assigned to placebo, but such patients receiving carvedilol exhibited marked reductions in those ratios to <2-fold (NS).
Plasma NE exhibited a different pattern in terms of predicting benefit from carvedilol. As expected, increased levels of plasma NE were associated with an increased risk of death and heart failure in the patient group overall. However, higher plasma NE levels did not predict additional treatment benefit. Carvedilol significantly reduced heart failure admissions only in patients with lower NE levels. This surprising finding concurs with that reported by Vantrimpont et al16 in their recent discussion of the additive beneficial effects of ß-blockers above and beyond converting enzyme inhibition in the Survival and Ventricular Enlargement (SAVE) study. In this retrospective analysis in >500 patients, ß-blockers "were not found to have a greater effect in patients with neurohumoral activation at the time of hospital discharge." In fact, increased NE levels were associated with significantly reduced efficacy of ß-blockers in prevention of cardiovascular death, whereas (in common with the current report), elevated ANP levels predicted benefit. These data are subject to several limitations that do not apply to the current study. The SAVE trial assessed the impact of ACE inhibition in patients selected for early postinfarction asymptomatic left ventricular dysfunction rather than the efficacy of ß-blockers. Within the neurohormonal substudy group, those receiving ß-blockers had a higher incidence of hypertension and higher average LVEF. The neurohormonal subgroup was younger, had less previous myocardial infarction, and had greater use of thrombolysis and revascularization than the overall SAVE population. That is, potential confounders may have distorted the apparent impact of ß-blockade, and it is questionable whether findings within the subgroup could be extended to SAVE trial participants in general. The Australia–New Zealand Heart Failure Study was specifically designed to assess the effect of carvedilol in stable ischemic left ventricular dysfunction, the randomization achieved matching of groups for relevant characteristics, and all participants underwent neurohormonal sampling. The current data confirm the findings of the SAVE neurohormonal substudy and extend them from standard ß-blockers to carvedilol.
Mechanisms underlying restriction of benefit to those with less activation of NE are unknown. Markedly increased plasma NE may indicate dependence on increased sympathetic traffic to sustain cardiac output. Alternatively, Vantrimpont et al16 suggested that the ß-blockade was insufficient, only effectively blocking harmful cardiac sympathetic drive in those with milder sympathetic activation. However, plasma NE is a poor surrogate measurement for cardiac sympathetic activity or for sympathetic nerve traffic as measured by peripheral microneurography.17 Further, lower levels of NE may simply have been a marker of less advanced (or better compensated) clinical heart failure, indicating those patients more likely to respond to many possible additional treatments.
What underlies the predictive power of ANP and BNP for benefit from carvedilol is also unknown. Carvedilol, in common with other ß-blockers, enhances plasma concentrations of ANP.18 This may reflect drug-induced downregulation of natriuretic peptide clearance receptors.19 It is possible that some of the benefit of carvedilol is derived from enhancing plasma ANP (and/or BNP) with promotion of natriuresis, vasodilation, and relative suppression of sympathetic and renin-angiotensin-aldosterone systems.
The current data are the first to interrelate pretreatment neurohumoral status and response to carvedilol. Existing reports relate neurohormones and response to converting enzyme inhibition. Swedberg et al20 reported that mortality benefit from enalapril in NYHA class IV heart failure was greater in patients with catecholamines, angiotensin II, aldosterone, and ANP above the group median. In the SAVE trial, elevated plasma renin activity predicted a moderate increase in efficacy of captopril in reducing 1-year but not total cardiovascular mortality rates.21 Enalapril offered a greater survival benefit in those with more markedly increased NE and renin levels in the Veterans Administration Heart Failure Trial II (V-HeFT II).4 The relation of neurohormonal status to treatment effect on rates of worsening heart failure was not addressed in the latter report. CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study), SAVE, and V-HeFT II did not provide data on BNP.
Therefore, available evidence suggests elevated pretreatment renin, NE, and cardiac peptide levels are positively associated with benefit from ACE inhibitor therapy, whereas ANP and BNP are positive predictors and plasma NE (surprisingly) a negative predictor of benefit when a ß-blocker is added. The specific experimental setting of the current study does not indicate whether plasma cardiac peptide levels would be useful in predicting benefit from carvedilol without prior introduction of ACE inhibitor treatment or from other antifailure therapy (such as endopeptidase inhibitors, angiotensin I receptor blockers, central sympathoinhibitory agents, or endothelin antagonists), and these questions should be addressed in future randomized trials of therapy in heart failure.
In summary, the current findings are consistent with previous reports indicating important associations of plasma concentrations of the cardiac peptides and plasma NE with left ventricular function and cardiac prognosis.1 2 4 Our data support a growing literature indicating that BNP in particular is a powerful prognostic indicator.6 22 23 This may reflect the direct relation between ventricular wall stress and secretion of BNP. BNP is the only truly "ventricular hormone" examined in the current neurohumoral panel. It is possible that greater stability of BNP than ANP on storage24 partially accounts for its better performance, although the degree of instability of ANP on freezing is disputed.25 BNP is also less responsive than ANP to short-term stimuli. The current report does not include data on N-terminal ANP,5 a stable product that may be superior to ANP as a prognostic marker. However, our experience23 suggests that it is still probably weaker than BNP.
The current results cannot be extrapolated to other treatments or patient groups. Examination of subgroups entails loss of statistical power and generates hypotheses rather than conclusive findings. Therefore, the current report requires confirmation. However, measurement of plasma levels of BNP and NE may usefully complement symptomatic status and/or left ventricular imaging as triggers for initiation of ß-blocker therapy in heart failure.
|
Acknowledgments |
|---|
This study was funded by a grant from SmithKline Beecham. Dr MacMahon is the recipient of Senior Research Fellowship from the Health Research Council of New Zealand. Dr Richards holds the New Zealand National Heart Foundation Chair of Cardiovascular Studies. Supplementary support for the neurohormonal assays was provided by the Health Research Council. Assistance with graphics was provided by Leanne Liggett. Barbara Griffin provided secretarial assistance.
|
Appendix 1 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Australia–New Zealand Heart Failure Research Collaborative Group: Participating Investigators
Australia: J. Bradbury, R. Burton, D. Colquhoun, M. Croot, D. Cross, T. Davidson, J. Garrett, C. Hall, A. Hamer, B. Hicks, J. Horowitz, B. Jackson, I. Jeffrey, V. Kinber, H. Krum, G. Lane, S. Leslie, D. Owensby, G. Rudge, J. Ryan, J. Shepherd, B. Singh, J. Stephensen, P. Taverner, P. Thompson, A. Thomson, A. Tonkin, A. Trotter, J. Turner, W. Walsh, S. Woodhouse, and Y. Zhang.
New Zealand: C. Bond, G. Brown, J. Bruning, A. Clayton, J. Crawford, R.N. Doughty, C. Hall, H. Ikram, G. Lewis, C. Low, H. McAlister, J. Murphy, L. Nairn, M. Richards, D. Scott, and N. Sharpe.
Received June 24, 1998; revision received October 14, 1998; accepted October 26, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
1. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819–823.[Abstract]
2.
Francis GS, Benedict C, Johnstone DE, Kirlin PC,
Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S. 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.
3. Rouleau JL, de Champlain J, Klein M, Bichet D, Moyé L, Packer M, Dagenais GR, Sussex B, Arnold JM, Sestier F, Parker JO, McEwan P, Bernstein V, Cuddy E, Lamas G, Gottlieb SS, McCans J, Nadeau C, Delage F, Hamm P, Pfeffer MA. Activation of neurohumoral systems in postinfarction left ventricular dysfunction. J Am Coll Cardiol. 1993;22:390–398.[Abstract]
4. Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A, for the V-HeFT VA Cooperative Studies Group. Plasma norepinephrine, plasma renin activity, and congestive heart failure: relations to survival and the effects of therapy in V-HeFT II. Circulation 1993;87(suppl VI):VI-40–VI-48.
5.
Omland T, Aakvaag A, Bonarjee VVS, Caidahl K, Lie RT,
Nilsen DW, Sundsfjord JA, Dickstein K. Plasma brain
natriuretic peptide as an indicator of left
ventricular systolic function and long-term
survival after acute myocardial infarction. Circulation. 1996;93:1963–1969.
6. Arakawa N, Nakamura M, Aoki H, Hiramori K. Plasma brain natriuretic peptide concentrations predict survival after acute myocardial infarction. J Am Coll Cardiol. 1996;27:1656–1661.[Abstract]
7.
Australia–New Zealand Heart Failure Research
Collaborative Group. Effects of carvedilol, a
vasodilator–ß-blocker, in patients with congestive heart
failure due to ischemic heart disease. Circulation. 1995;92:212–218.
8. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997;349:375–380.[Medline] [Order article via Infotrieve]
9. Yandle T, Espiner E, Nicholls M, Duff H. Radioimmunoassay and characterisation of atrial natriuretic peptide in human plasma. J Clin Endocrinol Metab. 1986;61:71–78.
10. Yandle TG, Richards AM, Gilbert A, Fisher S, Holmes S, Espiner EA. Assay of brain natriuretic peptide (BNP) in human plasma: evidence for high molecular weight BNP as a major plasma component in heart failure. J Clin Endocrinol Metab. 1993;76:832–838.[Abstract]
11. Goldstein DS, Feurstein G, Izzo JL, Kopin JJ, Keiser HR. Validity and reliability of liquid chromatography with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci. 1981;28:467–475.[Medline] [Order article via Infotrieve]
12. Sadler WA, Lynskey C, Gilchrist N, Espiner EA, Nicholls MG. A sensitive radioimmunoassay for measuring plasma antidiuretic hormone in man. N Z Med J. 1983;96:959–963.[Medline] [Order article via Infotrieve]
13.
Packer M, Bristow MR, Cohn J, Colucci WS, Fowler MB,
Gilbert EM, Shusterman NH, for the US Carvedilol Heart Failure Study
Group. The effect of carvedilol on morbidity and mortality in patients
with chronic heart failure. N Engl J Med. 1996;334:1349–1355.
14.
Packer M, Colucci WS, Sackner-Bernstein JD, Liang C-S,
Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M,
Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH,
Young ST, Lukmas MA, Shusterman NH, for the PRECISE Study Group.
Double-blind, placebo-controlled study of the effects of carvedilol in
patients with moderate to severe heart failure: the PRECISE Trial.
Circulation. 1996;94:2793–2799.
15.
Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler
MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H,
Krueger S, Young S, Shusterman N, for the MOCHA Investigators.
Carvedilol produces dose-related improvements in left
ventricular function and survival in subjects with chronic
heart failure. Circulation. 1996;94:2807–2816.
16. Vantrimpont P, Rouleau JL, Wun C-C, Ciampi A, Klein M, Sussex B, Arnold MO, Moye L, Pfeffer M, for the SAVE Investigators. Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. J Am Coll Cardiol. 1997;29:229–236.[Abstract]
17.
Rundqvist B, Elam M, Bergmann-Sverrisdottir Y,
Eisenhofer G, Friberg P. Increased cardiac adrenergic drive precedes
generalized sympathetic activation in human heart failure.
Circulation. 1997;95:169–175.
18.
Nakaoka H, Kitahara Y, Amano M, Imataka K, Fujii J,
Ishibashi M, Yamaji T. Effect of ß-adrenergic receptor blockade
on atrial natriuretic peptide in essential hypertension.
Hypertension. 1987;10:221–225.
19.
Yoshimoto T, Naruse M, Tanabe A, Naruse K, Seki T,
Imaki T, Muraki T, Matsuda Y, Demura H. Potentiation of
natriuretic peptide action by the ß-adrenergic
blocker carvedilol in hypertensive rats: a new antihypertensive
mechanism. Endocrinology. 1998;139:81–88.
20. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation. 990;82:1730–1736.
21. Rouleau J-L, Packer M, Moyé L, de Champlain J, Bichet D, Klein M, Rouleau JR, Sussex B, Arnold JM, Sestier F, Parker JO, McEwan P, Bernstein V, Cuddy TE, Lamas G, Gottlieb SS, McCans J, Nadeau C, Delage F, Wun C-C, Pfeffer MA. Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril. J Am Coll Cardiol. 1994;24:583–591.[Abstract]
22.
Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y,
Fukai D, Ohnishi M, Sugimoto Y, Kinoshita M. 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.
23.
Richards AM, Nicholls MG, Yandle TG, Frampton C,
Espiner EA, Turner JG, Buttimore RC, Lainchbury JG, Elliott JM, Ikram
H, Crozier IG, Smyth DW. Plasma N-terminal pro–brain
natriuretic peptide and adrenomedullin: new neurohormonal
predictors of left ventricular function and prognosis after
myocardial infarction. Circulation. 1998;97:1921–1929.
24.
Nelesen RA, Dimsdale JE, Ziegler MG. Plasma atrial
natriuretic peptide is unstable under most storage
conditions. Circulation. 1992;86:463–466.
25. Buckley MG, Sagnella GA, MacGregor GA. Stability of atrial natriuretic peptide during storage at -20°C. J Hum Hypertens. 1996;10:431–432.In 415 patients with ischemic left ventricular dysfunction, carvedilol reduced mortality rates (19.2% to 11.0%; P<0.05) and heart failure (27.9% to 14.7%; P<0.01) in those with supramedian brain natriuretic peptide (BNP) levels. In patients with inframedian norepinephrine levels, carvedilol reduced heart failure from 13.1% to 4.0% (P<0.01). In the subgroup (23%) with supramedian BNP but inframedian norepinephrine, carvedilol reduced heart failure admissions by >90% (P<0.001). Pretreatment neurohumoral profiling with plasma BNP and norepinephrine may identify patients who will benefit from carvedilol.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  J P Kaski, M T Tome-Esteban, S Mead-Regan, A Pantazis, J Marek, J E Deanfield, W J McKenna, and P M Elliott B-type natriuretic peptide predicts disease severity in children with hypertrophic cardiomyopathy Heart, October 1, 2008; 94(10): 1307 - 1311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maisel, C. Mueller, K. Adams Jr., S. D. Anker, N. Aspromonte, J. G.F. Cleland, A. Cohen-Solal, U. Dahlstrom, A. DeMaria, S. Di Somma, et al. State of the art: Using natriuretic peptide levels in clinical practice Eur J Heart Fail, September 1, 2008; 10(9): 824 - 839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R J Hillock, C M Frampton, T G Yandle, R W Troughton, J G Lainchbury, and A M Richards B-type natriuretic peptide infusions in acute myocardial infarction Heart, May 1, 2008; 94(5): 617 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Whalley, S. P. Wright, A. Pearl, G. D. Gamble, H. J. Walsh, M. Richards, and R. N. Doughty Prognostic role of echocardiography and brain natriuretic peptide in symptomatic breathless patients in the community Eur. Heart J., February 2, 2008; 29(4): 509 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Rose and W. R. Giles Natriuretic peptide C receptor signalling in the heart and vasculature J. Physiol., January 15, 2008; 586(2): 353 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Olsson, K. Swedberg, J. G.F. Cleland, P. A. Spark, M. Komajda, M. Metra, C. Torp-Pedersen, W. J. Remme, A. Scherhag, P. Poole-Wilson, et al. Prognostic importance of plasma NT-pro BNP in chronic heart failure in patients treated with a {beta}-blocker: Results from the Carvedilol Or Metoprolol European Trial (COMET) trial Eur J Heart Fail, August 1, 2007; 9(8): 795 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Jourdain, G. Jondeau, F. Funck, P. Gueffet, A. Le Helloco, E. Donal, J. F. Aupetit, M. C. Aumont, M. Galinier, J. C. Eicher, et al. Plasma Brain Natriuretic Peptide-Guided Therapy to Improve Outcome in Heart Failure: The STARS-BNP Multicenter Study J. Am. Coll. Cardiol., April 24, 2007; 49(16): 1733 - 1739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Williams, C. E. Handler, R. Akram, C. J. Smith, C. Das, J. Smee, D. Nair, C. P. Denton, C. M. Black, and J. G. Coghlan Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension Eur. Heart J., June 2, 2006; 27(12): 1485 - 1494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Mueller, K. Laule-Kilian, C. Schindler, T. Klima, B. Frana, D. Rodriguez, A. Scholer, M. Christ, and A. P. Perruchoud Cost-effectiveness of B-Type Natriuretic Peptide Testing in Patients With Acute Dyspnea. Arch Intern Med, May 22, 2006; 166(10): 1081 - 1087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schnabel, E. Lubos, H. J. Rupprecht, C. Espinola-Klein, C. Bickel, K. J. Lackner, F. Cambien, L. Tiret, T. Munzel, and S. Blankenberg B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina: Results From the AtheroGene Study J. Am. Coll. Cardiol., February 7, 2006; 47(3): 552 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Richards, M. G. Nicholls, E. A. Espiner, J. G. Lainchbury, R. W. Troughton, J. Elliott, C. M. Frampton, I. G. Crozier, T. G. Yandle, R. Doughty, et al. Comparison of B-Type Natriuretic Peptides for Assessment of Cardiac Function and Prognosis in Stable Ischemic Heart Disease J. Am. Coll. Cardiol., January 3, 2006; 47(1): 52 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Morrow, J. A. de Lemos, M. A. Blazing, M. S. Sabatine, S. A. Murphy, P. Jarolim, H. D. White, K. A. A. Fox, R. M. Califf, E. Braunwald, et al. Prognostic Value of Serial B-Type Natriuretic Peptide Testing During Follow-up of Patients With Unstable Coronary Artery Disease JAMA, December 14, 2005; 294(22): 2866 - 2871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Avgeropoulou, I. Andreadou, S. Markantonis-Kyroudis, M. Demopoulou, P. Missovoulos, A. Androulakis, and I. Kallikazaros The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and pro-inflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine Eur J Heart Fail, August 1, 2005; 7(5): 882 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A.H. Stewart Broader indications for B-type natriuretic peptide testing in coronary artery disease Eur. Heart J., February 1, 2005; 26(3): 207 - 209. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Hartmann, M. Packer, A. J.S. Coats, M. B. Fowler, H. Krum, P. Mohacsi, J. L. Rouleau, M. Tendera, A. Castaigne, S. D. Anker, et al. Prognostic Impact of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Severe Chronic Congestive Heart Failure: A Substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Trial Circulation, September 28, 2004; 110(13): 1780 - 1786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kokubo, S. Miyagawa-Tomita, H. Tomimatsu, Y. Nakashima, M. Nakazawa, Y. Saga, and R. L. Johnson Targeted Disruption of hesr2 Results in Atrioventricular Valve Anomalies That Lead to Heart Dysfunction Circ. Res., September 3, 2004; 95(5): 540 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Menezes Falcao, F. Pinto, L. Ravara, and P. A. van Zwieten BNP and ANP as diagnostic and predictive markers in heart failure with left ventricular systolic dysfunction Journal of Renin-Angiotensin-Aldosterone System, September 1, 2004; 5(3): 121 - 129. [Abstract] [PDF]
|
|
|
|
|
|
R. J. Rodeheffer Measuring plasma B-type natriuretic peptide in heart failure: Good to go in 2004? J. Am. Coll. Cardiol., August 18, 2004; 44(4): 740 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Januzzi, A. S. Maisel, R. W. Troughton, A. M. Richards, T. G. Yandle, M. G. Nicholls, T. Nishikimi, H. Matsuoka, and M. Packer Routine Measurement of Natriuretic Peptide to Guide the Diagnosis and Management of Chronic Heart Failure * Response Circulation, June 29, 2004; 109(25): e325 - e326. [Full Text] [PDF]
|
|
|
|
|
|
M. Richards and R. W. Troughton NT-proBNP in heart failure: therapy decisions and monitoring Eur J Heart Fail, March 15, 2004; 6(3): 351 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Givertz and E. Braunwald Neurohormones in heart failure: predicting outcomes, optimizing care Eur. Heart J., February 2, 2004; 25(4): 281 - 282. [Full Text] [PDF]
|
|
|
|
|
|
R. Latini, S. Masson, I. Anand, M. Salio, A. Hester, D. Judd, S. Barlera, A. P Maggioni, G. Tognoni, J. N Cohn, et al. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT Eur. Heart J., February 2, 2004; 25(4): 292 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. de Denus, C. Pharand, and D. R. Williamson Brain Natriuretic Peptide in the Management of Heart Failure: The Versatile Neurohormone Chest, February 1, 2004; 125(2): 652 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kjaer, J. Appel, P. Hildebrandt, and C. L. Petersen Basal and exercise-induced neuroendocrine activation in patients with heart failure and in normal subjects Eur J Heart Fail, January 1, 2004; 6(1): 29 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ishii, W. Cui, F. Kitagawa, T. Kuno, Y. Nakamura, H. Naruse, Y. Mori, T. Ishikawa, Y. Nagamura, T. Kondo, et al. Prognostic Value of Combination of Cardiac Troponin T and B-Type Natriuretic Peptide after Initiation of Treatment in Patients with Chronic Heart Failure Clin. Chem., December 1, 2003; 49(12): 2020 - 2026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.R Cowie, P Jourdain, A Maisel, U Dahlstrom, F Follath, R Isnard, A Luchner, T McDonagh, J Mair, M Nieminen, et al. Clinical applications of B-type natriuretic peptide (BNP) testing Eur. Heart J., October 1, 2003; 24(19): 1710 - 1718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Fisher, C Berry, L Blue, J J Morton, and J McMurray N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure Heart, August 1, 2003; 89(8): 879 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Richards, M. G. Nicholls, E. A. Espiner, J. G. Lainchbury, R. W. Troughton, J. Elliott, C. Frampton, J. Turner, I. G. Crozier, and T. G. Yandle B-Type Natriuretic Peptides and Ejection Fraction for Prognosis After Myocardial Infarction Circulation, June 10, 2003; 107(22): 2786 - 2792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ruskoaho Cardiac Hormones as Diagnostic Tools in Heart Failure Endocr. Rev., June 1, 2003; 24(3): 341 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bozkurt and D. L. Mann Use of Biomarkers in the Management of Heart Failure: Are We There Yet? Circulation, March 11, 2003; 107(9): 1231 - 1233. [Full Text] [PDF]
|
|
|
|
|
|
B. A. Groenning, J. C. Nilsson, P. R. Hildebrandt, A. Kjaer, T. Fritz-Hansen, H. B.W. Larsson, and L. Sondergaard Neurohumoral prediction of left-ventricular morphologic response to {beta}-blockade with metoprolol in chronic left-ventricular systolic heart failure Eur J Heart Fail, October 1, 2002; 4(5): 635 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. McGeoch, J. Lainchbury, G.I. Town, L. Toop, E. Espiner, and A.M. Richards Plasma brain natriuretic peptide after long-term treatment for heart failure in general practice Eur J Heart Fail, August 1, 2002; 4(4): 479 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hulsmann, R. Berger, B. Sturm, A. Bojic, W. Woloszczuk, J. Bergler-Klein, and R. Pacher Prediction of outcome by neurohumoral activation, the six-minute walk test and the Minnesota Living with Heart Failure Questionnaire in an outpatient cohort with congestive heart failure Eur. Heart J., June 1, 2002; 23(11): 886 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Maisel B-Type Natriuretic Peptide Levels: Diagnostic and Prognostic in Congestive Heart Failure: What's Next? Circulation, May 21, 2002; 105(20): 2328 - 2331. [Full Text] [PDF]
|
|
|
|
|
|
R. Berger, M. Huelsman, K. Strecker, A. Bojic, P. Moser, B. Stanek, and R. Pacher B-Type Natriuretic Peptide Predicts Sudden Death in Patients With Chronic Heart Failure Circulation, May 21, 2002; 105(20): 2392 - 2397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Anand, V. G. Florea, and L. Fisher Surrogate end points in heart failure J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1414 - 1421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.A de Boer and D.J van Veldhuisen Polypharmacy in chronic heart failure: practical issues regarding the use of angiotensin-converting enzyme inhibitors, beta-blockers and other drugs Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D111 - D116. [Abstract] [PDF]
|
|
|
|
|
|
J.o. Koglin, S. Pehlivanli, M. Schwaiblmair, M. Vogeser, P. Cremer, and W. vonScheidt Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1934 - 1941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Stanek, B. Frey, M. Hulsmann, R. Berger, B. Sturm, J. Strametz-Juranek, J. Bergler-Klein, P. Moser, A. Bojic, E. Hartter, et al. Prognostic evaluation of neurohumoral plasma levels before and during beta-blocker therapy in advanced left ventricular dysfunction J. Am. Coll. Cardiol., August 1, 2001; 38(2): 436 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.R Kalra, S.D Anker, A.D Struthers, and A.J.S Coats The role of C-type natriuretic peptide in cardiovascular medicine Eur. Heart J., June 2, 2001; 22(12): 997 - 1007. [PDF]
|
|
|
|
|
|
A. M. Richards, R. Doughty, M. G. Nicholls, S. MacMahon, N. Sharpe, J. Murphy, E. A. Espiner, C. Frampton, T. G. Yandle, and for the Australia-New Zealand Heart Failure Group Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: Prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1781 - 1787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. de Boer, H.-M. J. Siebelink, R. A. Tio, F. Boomsma, and D. J. van Veldhuisen Carvedilol increases plasma vascular endothelial growth factor (VEGF) in patients with chronic heart failure Eur J Heart Fail, June 1, 2001; 3(3): 331 - 333. [Full Text] [PDF]
|
|
|
|
|
|
V. Cheng, R. Kazanagra, A. Garcia, L. Lenert, P. Krishnaswamy, N. Gardetto, P. Clopton, and A. Maisel A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study J. Am. Coll. Cardiol., February 1, 2001; 37(2): 386 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Oxenham and N. Sharpe Prognostic stratification in heart failure: what's the point? Eur. Heart J., November 2, 2000; 21(22): 1815 - 1816. [PDF]
|
|
|
|
|
|
A. K. Agarwal, P. Venugopalan, C. Woodhouse, and D. de Bono Catecholamine levels in heart failure due to dilated cardiomyopathy and their relationship to the severity of heart failure Eur J Heart Fail, September 1, 2000; 2(3): 261 - 263. [Full Text] [PDF]
|
|
|
|
|
|
M. R COWIE BNP: soon to become a routine measure in the care of patients with heart failure? Heart, June 1, 2000; 83(6): 617 - 618. [Full Text]
|
|
|
|
|
|
T. Stefanec Endothelial Apoptosis: Could It Have a Role in the Pathogenesis and Treatment of Disease? Chest, March 1, 2000; 117(3): 841 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Feldman and C. McTiernan New Insight Into the Role of Enhanced Adrenergic Receptor-Effector Coupling in the Heart Circulation, August 10, 1999; 100(6): 579 - 582. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||