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(Circulation. 2001;103:1428.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Heart Rate and Cardiac Rhythm Relationships With Bisoprolol Benefit in Chronic Heart Failure in CIBIS II Trial
From the Pharmacology Department (P.L., J.-S.H.) and INSERM, Biostatistics and Mathematical Modeling Unit (S.E., A.M.), Pitié Salpêtrière Hospital, Paris; Clinical Pharmacology Unit, Lyon Hospitals (A.L.); Merck-Lipha, Clinical Research Department, Suresnes (M.W.-G.); and Hôpital Léon Binet, Provins (G.P.), France; and Clinical Research, University of Glasgow, UK (H.D.).
Correspondence to Prof Philippe Lechat, Service de Pharmacologie, Hôpital Pitié-Salpêtrière, 47 Boulevard de l’hôpital, 75013 Paris, France. E-mail philippe.lechat{at}psl.ap-hop-paris.fr
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Abstract |
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Background—ß-Blockade–induced benefit in heart failure (HF) could be related to baseline heart rate and treatment-induced heart rate reduction, but no such relationships have been demonstrated.
Methods and Results—In CIBIS II, we studied the relationships between baseline heart rate (BHR), heart rate changes at 2 months (HRC), nature of cardiac rhythm (sinus rhythm or atrial fibrillation), and outcomes (mortality and hospitalization for HF). Multivariate analysis of CIBIS II showed that in addition to ß-blocker treatment, BHR and HRC were both significantly related to survival and hospitalization for worsening HF, the lowest BHR and the greatest HRC being associated with best survival and reduction of hospital admissions. No interaction between the 3 variables was observed, meaning that on one hand, HRC-related improvement in survival was similar at all levels of BHR, and on the other hand, bisoprolol-induced benefit over placebo for survival was observed to a similar extent at any level of both BHR and HRC. Bisoprolol reduced mortality in patients with sinus rhythm (relative risk 0.58, P<0.001) but not in patients with atrial fibrillation (relative risk 1.16, P=NS). A similar result was observed for cardiovascular mortality and hospitalization for HF worsening.
Conclusions—BHR and HRC are significantly related to prognosis in heart failure. ß-Blockade with bisoprolol further improves survival at any level of BHR and HRC and to a similar extent. The benefit of bisoprolol is questionable, however, in patients with atrial fibrillation.
Key Words: heart failure • bisoprolol • receptors, adrenergic, beta • fibrillation • heart rate
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Introduction |
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The benefit of treatment with ß-blockers in heart failure is now well established, in view of the concordant results of several clinical trials with different compounds.1 2 3 4 The amplitude of benefit may vary, however, according to the baseline characteristics of patients and the pharmacological properties of ß-blockers, as suggested by the results of the BEST trial with bucindolol.5 Possible relationships between heart rate change, left ventricular function improvement, and prognosis were suggested by the first CIBIS trial.6 7 Experimental data have shown that the ß-blocker–induced benefit for left ventricular function in heart failure could depend on only heart rate reduction.8
To further study the mechanism of ß-blockade benefit in heart failure and to identify the best responders to such therapy, we studied the relationships between baseline parameters (including the level and nature of cardiac rhythm: sinus rhythm or atrial fibrillation), bisoprolol-induced hemodynamic changes with time (especially heart rate changes), and outcomes (survival and hospitalization for heart failure) in CIBIS II.3
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Methods |
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Population and Studied Parameters
Demography and the main results of the CIBIS II trial have been published.3 Patients could be divided at inclusion into 3 groups according to the nature of their cardiac rhythm: sinus rhythm, atrial fibrillation, and a third, small group including patients not in sinus rhythm but with supraventricular arrhythmias other than atrial fibrillation or with pacemakers. The third, much smaller group of other cardiac rhythms, 108 patients in CIBIS II (4%), was excluded from this analysis. These patients behaved similarly to patients in sinus rhythm.
Heart rate was measured at baseline and during follow-up visits by pulse rate measurement (especially in atrial fibrillation) or on ECG recording at rest in the supine position. Each recorded value of heart rate and blood pressure was the mean of 3 measurements at each visit. Blood pressure was measured by use of a sphygmomanometer.
Heart rate and blood pressure changes were those recorded between baseline and 2 months after inclusion. A similar delay was used previously in the CIBIS I study.7 In CIBIS II, the bisoprolol dose was started at 1.25 mg and increased by 1-week steps to 2.5, 3.5, and 5 mg and by 1-month steps to 7.5 and 10 mg.
Multivariate Analyses
Relationships between baseline parameters, heart rate
change, blood pressure change, and outcomes (all-cause mortality,
cardiovascular mortality, and hospitalization for heart failure
worsening) were studied. Such multivariate analysis, using heart rate
and blood pressure changes recorded at 2 months among covariates,
therefore excluded patients who died within the first 2 months after
inclusion.
Study of Hemodynamic Changes Over Time
Heart rate and blood pressure were recorded during
each follow-up visit. In both study treatment groups, we compared heart
rate and blood pressure changes between baseline and 2 months after
inclusion in patients in sinus rhythm and in atrial
fibrillation.
Statistical Analysis
Comparisons of baseline variables between groups were
performed with Student’s t
tests for continuous variables and 
2
tests for categorical variables. The level of significance was set at a
value of P<0.05.
Kaplan-Meier survival curves were calculated for the placebo and bisoprolol groups in patients with sinus rhythm and atrial fibrillation.
Univariate and multivariate analyses were computed with Cox’s proportional-hazards regression model. The variables that were included in the multivariate analysis were those related to survival in the univariate analysis at value of P<0.10.
As a complementary analysis, survival curves in the different subgroups defined by the tertiles of baseline heart rate and heart rate change at 2 months were compared between placebo and bisoprolol by use of the log-rank test. One-year survivals were those provided by Kaplan-Meier estimates.
Heart rate and blood pressure changes between baseline and 2 months after inclusion were compared between placebo and bisoprolol groups by Student’s t test in patients surviving at 2 months.
All statistical analyses were performed with SAS software.
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Results |
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Demography
The demography of patients according to cardiac rhythm and study treatment group at baseline is presented in Table 1
. Few significant differences were found
between cardiac rhythm groups (see
Table 1). Patients with atrial fibrillation were more often
treated with digitalis, amiodarone, and anticoagulants. Among each
cardiac rhythm group, no differences were recorded between placebo and
bisoprolol groups except for baseline heart rate, which was
significantly lower in atrial fibrillation in patients randomized to
bisoprolol than in those randomized to placebo
(Table 1).
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Mean doses of bisoprolol were similar in patients with sinus rhythm and atrial fibrillation at the different times during the study (2, 6, 12, and 24 months).
Hemodynamic Changes
Two months after inclusion, heart rate decrease
(baseline to 2 months) was 0.2±13.7 bpm (placebo) and 9.8±14.7 bpm
(bisoprolol), P<0.0001;
systolic blood pressure reduction was 2.3±16.4 mm Hg (placebo) and
4.1±16.4 mm Hg (bisoprolol),
P=0.001; and diastolic blood
pressure decrease was 0.9±10.9 mm Hg (placebo) and 2.6±10.7 mm Hg
(bisoprolol),
P<0.0001.
Multivariate Analysis
Because patients who died during the first 2 months
after inclusion and patients without sinus rhythm or atrial
fibrillation were excluded from this multivariate analysis, only 2184
patients were included for this analysis, with 282 deaths during
follow-up.
Parameters significantly related to survival in the Cox
multivariate analysis are presented in
Table 2. The baseline heart rate and heart rate change
after the first 2 months of treatment were both significantly related
to further survival in both univariate and multivariate analyses. The
best prognosis was obtained with the lowest baseline heart rate and
with the greatest heart rate reduction. No interaction was found
between study treatment and either baseline heart rate or heart rate
change, meaning that the benefit of bisoprolol on survival was not
influenced by the level of baseline heart rate or by the extent of
heart rate reduction. In addition, no interaction was found between
heart rate change–related survival improvement and baseline heart
rate. The nature of cardiac rhythm at baseline was not related to
survival. Survival curves of placebo groups comparing patients in sinus
rhythm with those in atrial fibrillation were completely superimposed.
Interaction between treatment and rhythm, however, was significant
(P<0.01): a benefit of
bisoprolol was obtained only in patients with sinus rhythm and was
questionable in patients with atrial fibrillation
(Figures 1 and 2). Results are given in
Table 2. For a patient with sinus rhythm, the treatment was
beneficial (relative risk 0.58,
P=0.0003), but conversely, for
a patient with atrial fibrillation, bisoprolol did not significantly
influence survival compared with placebo (relative risk
1.16).
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Similar results were obtained for cardiovascular deaths and
hospitalizations for heart failure worsening
(Tables 2
and 3), with a similar significant interaction
between treatment effect and nature of cardiac rhythm.
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The multivariate analysis also showed that the probability
of death or hospitalization for heart failure worsening decreased with
increasing values of baseline systolic blood pressure but increased
when systolic blood pressure decreased at 2 months. A diastolic blood
pressure decrease at 2 months, however, was associated with fewer
hospitalizations. Digoxin treatment was neutral on mortality but was
associated with 39% more hospitalizations
(P<0.001); amiodarone
treatment appeared to be associated with a poorer prognosis
(P=0.06) and more frequent
hospitalizations (P<0.001).
Patients on digoxin at baseline presented with a more altered left
ventricular function, with a higher heart rate, and more often in
atrial fibrillation than patients without digoxin treatment. Patients
receiving amiodarone had a slightly more severe alteration of left
ventricular function than patients without amiodarone treatment. Both
digoxin and amiodarone treatments were equally distributed among
placebo and bisoprolol groups
(Table 1).
Finally, women were at significantly lower risk of death than men.
Distribution of Heart Rate Change, Baseline
Heart Rate, and 1-Year Mortality Estimates (Kaplan-Meier)
Patients were split into 3 tertiles of distribution of
baseline heart rate and heart rate change at 2 months, obtained in the
entire population of patients (both treatment groups). The limits of
the tertiles were 
72, between 72 and 84, and >84 bpm for baseline
heart rate and <0 (heart rate increase), 
0 and <11 (moderate heart
rate reduction), and 11 (great heart rate reduction) bpm for heart
rate change at 2 months. The distribution of patients according to
heart rate change at 2 months according to study treatment is given in
Figure 3. As expected, the highest amplitude of heart rate
decrease was more often recorded in the bisoprolol group, with no
difference in dose between the 3 tertiles. Such results, however, can
be obtained even in patients with a low baseline heart rate. The
highest heart rate reduction with lowest baseline heart rate occurred
in 8.5% of patients in the bisoprolol group and in 1.3% in the
placebo group.
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Bisoprolol-induced mortality reduction was similar at all
levels of heart rate reduction
(Figure 4). These results demonstrate that for a given heart
rate reduction, bisoprolol treatment further reduced mortality to a
similar extent whatever the amplitude of heart rate reduction.
Probability values of log-rank tests comparing survival in the 3
tertiles of heart rate change were
P<0.04 (heart rate reduction
11 bpm), P<0.02 (heart rate
reduction between 0 and 11 bpm), and
P<0.04 for heart rate increase
(heart rate change <0 bpm).
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Bisoprolol-induced survival improvement was significant and
similar whatever the levels of baseline heart rates, without
interaction between study treatment group and baseline heart rate
(tested in the multivariate analysis,
Figure 5). Probability values of log-rank tests comparing
survival between placebo and bisoprolol were
P=0.01,
P=0.03, and
P=0.001 for the 3 tertiles of
baseline heart rate (from highest to lowest baseline heart
rate).
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Heart Rate and Blood Pressure Changes With Time
According to Nature of Cardiac Rhythm at Baseline
Heart rate reduction at 2 months was slightly but
significantly lower in the bisoprolol group in patients with atrial
fibrillation (-8.8±21.5 bpm) than in patients in sinus rhythm at
baseline (-10.6±12.4 bpm,
P=0.02). The mean blood
pressure (systolic and diastolic) decrease at 2 months was similar in
patients with atrial fibrillation and in patients with sinus rhythm. In
the bisoprolol group, however, patients in atrial fibrillation who
later died had a more important systolic blood pressure decrease at 2
months than those who died but who were in sinus rhythm at baseline:
-9.9±14.5 versus -4.4±15.9 mm Hg,
P=0.06 (no such difference was
observed in patients of the placebo
group).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The major findings reported here in this complementary analysis of the CIBIS II trial are (1) the confirmation of the prognostic value in heart failure of baseline heart rate and of heart rate reduction with time (baseline to 2 months), the latter being more often obtained with ß-blockade; (2) the similar benefit of bisoprolol compared with placebo whatever the level of heart rate at baseline and whatever the amplitude of heart rate change with time; and (3) the heterogeneity of bisoprolol effect according to the nature of cardiac rhythm: the benefit of bisoprolol on mortality, cardiovascular mortality, and hospitalization for heart failure was not significant in patients with atrial fibrillation.
Our results therefore confirm that heart rate reduction per se in patients with heart failure is associated with survival improvement. Such an effect was, as expected, more often obtained with ß-blockade. For a given heart rate reduction and for any level of baseline heart rate, however, bisoprolol further improved survival compared with placebo. Such results have an important therapeutic impact, because one could have hypothesized that the benefit of ß-blockade could have been restricted to heart rate reduction and that such benefit could not be obtained in patients with low baseline heart rate.
One possible link between heart rate reduction and survival is the left ventricular function improvement secondary to the induced reduction of ischemia, which is present to different degrees in dilated ventricles even in the absence of coronary artery disease.9
Our data clearly indicate, however, that heart rate reduction is not the only mechanism responsible for ß-blocker–induced benefit in heart failure. Indeed, such benefit was present even without heart rate reduction, and many other different mechanisms have been proposed.10 11
No benefit of bisoprolol was observed in patients with atrial fibrillation. This could have been the result of chance only, but a very similar trend was also found in the CIBIS I study. It will be important to see whether this finding is also observed in other studies, such as MERIT4 and COPERNICUS. There is no obvious explanation of such heterogeneity of the effect of bisoprolol according to cardiac rhythm. The bisoprolol dose was similar in patients in sinus rhythm and in patients with atrial fibrillation. Survival curves of patients in the placebo groups were similar between patients in sinus rhythm and atrial fibrillation, and none of the few baseline differences in recorded parameters between patients in sinus rhythm and atrial fibrillation could explain such a difference of the effect of bisoprolol. Even in the bisoprolol group, patients in atrial fibrillation had a slightly lower baseline heart rate, which should have tended to reduce mortality. Analysis of heart rate reduction with time showed that it was slightly lower at 2 months in the bisoprolol group in patients with atrial fibrillation than in those in sinus rhythm. Such lower heart rate reduction could participate in the loss of efficacy of bisoprolol in patients with atrial fibrillation, but its amplitude (2 bpm difference) does not appear to be sufficient to reasonably explain such a difference. Such results in heart rate are limited, however, by the poor value of the measure of heart rate in the presence of atrial fibrillation when only pulse rate during patient visit is used, and they should be completed with a 24-hour Holter monitoring study.
The bisoprolol-induced systolic blood pressure decrease could play a more deleterious role in some patients with atrial fibrillation. Indeed, the finding in the bisoprolol group of a more important systolic blood pressure decrease at 2 months in patients with atrial fibrillation who subsequently died suggests that when bisoprolol decreased blood pressure to too great an extent (-10 mm Hg), such a decrease was more deleterious in patients with atrial fibrillation than in sinus rhythm.
In addition to data on heart rate and cardiac rhythm, our analysis provides complementary information:
Women with heart failure have a better prognosis than men, but bisoprolol provides similar benefit (no interaction). This result based on CIBIS II data was presented in detail previously.12
Systolic blood pressure, which depends partly on left ventricular function, was at baseline positively associated with a better prognosis and fewer hospital admissions. Both systolic and diastolic blood pressure decreased with time but more importantly in the bisoprolol group than the placebo group. The systolic blood pressure decrease with time was per se deleterious and associated with a poorer prognosis and more hospitalizations, but the decrease of diastolic blood pressure, on the contrary, was beneficial and associated with fewer hospital admissions without impact on mortality. Interpretation of these data is not obvious: ß-blockade improves survival but simultaneously decreases both systolic and diastolic blood pressures, which have opposite effects on prognosis or hospitalization. The diastolic blood pressure decrease could be a consequence of sympathetic tone withdrawal (less systemic resistance), which should be beneficial, but too great a systolic blood pressure decrease as an effect of ß-blocker could reduce tissue perfusion and/or be a consequence of an altered left ventricular function despite ß-blocker treatment. When such alteration of left ventricular function occurred despite bisoprolol treatment in the first CIBIS study, it was found to be associated with a deleterious effect on survival.7
Digoxin treatment was not associated with any change of mortality rate but was associated with a markedly increased frequency of hospital admissions for heart failure worsening (63%). This result provided by the multivariate analysis indicates that digoxin per se increased hospitalization rate after adjustment for the other prognostic factors. Similar findings were observed with amiodarone, which increased the probability of death and rehospitalization. These results mean that independently of the higher level of risk of patients receiving either digoxin or amiodarone at baseline, these 2 treatments in this population were associated with deleterious consequences. One cannot exclude other unknown and therefore unstudied risk factors, however, that may have been more frequent in patients treated by digoxin or amiodarone. Here again, comparison and pooling of data from the other trials with ß-blocker treatment in heart failure would be very useful to confirm such findings, which appear to be in opposition to those of previous randomized studies testing digoxin or amiodarone in patients with heart failure.
Clinical implications of our results are as follows: Patients with heart failure in sinus rhythm with the initial lowest heart rate and the greatest heart rate reduction with time (2 months) will have the best prognosis. Bisoprolol-induced benefit over placebo is obtained to a similar extent, however, whatever the level of baseline heart rate and whatever the amplitude of heart rate reduction with time even when heart rate does not decrease. The best results for survival will then be obtained with ß-blocker treatment when heart rate reduction reaches the highest level, whatever the baseline heart rate (>10 bpm reduction), without marked systolic blood pressure decrease. To obtain such results for a given patient, dose adjustment may be required. If heart rate reduction >10 bpm is obtained with a low dose level, however, such dosage should be sufficient to improve survival and could be kept low, especially if systolic blood pressure has decreased.
Additional experiments will be needed to understand the reduction of the long-term benefit of bisoprolol in patients with atrial fibrillation. It could be partly related to the deleterious consequences of a too marked systolic blood pressure decrease when it occurs under ß-blockade in such patients. A definite therapeutic strategy for ß-blocker treatment in these patients will depend on the results of the other large-scale clinical trials.
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Footnotes |
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Drs Lechat, Leizorovicz (responsible for statistical analysis regarding CIBIS II), and Werhlen-Grandjean are members of the CIBIS II Steering Committee; Dr Dargie serves as Chairman of the CIBIS II Steering Committee. Dr Werhlen-Grandjean serves as a representative of Merck-Lipha, sponsor of the CIBIS II study.
Received September 27, 2000; revision received November 14, 2000; accepted November 16, 2000.
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P. R. Kowey A Review of Carvedilol Arrhythmia Data in Clinical Trials Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4_suppl): S59 - S68. [Abstract] [PDF]
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K. Fox Future perspectives of If inhibition in various cardiac conditions Eur. Heart J. Suppl., September 1, 2005; 7(suppl_H): H33 - H36. [Abstract] [Full Text] [PDF]
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K. Swedberg, L. G. Olsson, A. Charlesworth, J. Cleland, P. Hanrath, M. Komajda, M. Metra, C. Torp-Pedersen, and P. Poole-Wilson Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET Eur. Heart J., July 1, 2005; 26(13): 1303 - 1308. [Abstract] [Full Text] [PDF]
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L. Gullestad, J. Wikstrand, P. Deedwania, A. Hjalmarson, K. Egstrup, U. Elkayam, S. Gottlieb, A. Rashkow, H. Wedel, G. Bermann, et al. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker?: Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) J. Am. Coll. Cardiol., January 18, 2005; 45(2): 252 - 259. [Abstract] [Full Text] [PDF]
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 S. Nemoto, P. Razeghi, M. Ishiyama, G. De Freitas, H. Taegtmeyer, and B. A. Carabello PPAR-{gamma} agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H77 - H82. [Abstract] [Full Text] [PDF]
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K. Okoshi, M. Nakayama, X. Yan, M. P. Okoshi, A. J.T. Schuldt, M. A. Marchionni, and B. H. Lorell Neuregulins Regulate Cardiac Parasympathetic Activity: Muscarinic Modulation of {beta}-Adrenergic Activity in Myocytes From Mice With Neuregulin-1 Gene Deletion Circulation, August 10, 2004; 110(6): 713 - 717. [Abstract] [Full Text] [PDF]
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M. A. Quader, P. M. McCarthy, A. M. Gillinov, J. M. Alster, D. M. Cosgrove III, B. W. Lytle, and E. H. Blackstone Does preoperative atrial fibrillation reduce survival after coronary artery bypass grafting? Ann. Thorac. Surg., May 1, 2004; 77(5): 1514 - 1524. [Abstract] [Full Text] [PDF]
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P. Mulder, S. Barbier, A. Chagraoui, V. Richard, J. P. Henry, F. Lallemand, S. Renet, G. Lerebours, F. Mahlberg-Gaudin, and C. Thuillez Long-Term Heart Rate Reduction Induced by the Selective If Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure Circulation, April 6, 2004; 109(13): 1674 - 1679. [Abstract] [Full Text] [PDF]
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 M. J Janse Electrophysiological changes in heart failure and their relationship to arrhythmogenesis Cardiovasc Res, February 1, 2004; 61(2): 208 - 217. [Abstract] [Full Text] [PDF]
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M. Li, C. Zheng, T. Sato, T. Kawada, M. Sugimachi, and K. Sunagawa Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats Circulation, January 6, 2004; 109(1): 120 - 124. [Abstract] [Full Text] [PDF]
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