Skip Navigation

European Journal of Heart Failure 2008 10(6):550-555; doi:10.1016/j.ejheart.2008.04.005
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by De Ferrari, G. M.
Right arrow Articles by Tavazzi, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Ferrari, G. M.
Right arrow Articles by Tavazzi, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2008 European Society of Cardiology

Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure

Gaetano M. De Ferraria,*, Antonio Mazzueroa, Laura Agnesinaa, Alessandra Bertolettia, Maddalena Lettinoa, Carlo Campanaa, Peter J. Schwartza,b,c and Luigi Tavazzia

a Department of Cardiology, Fondazione IRCCS Policlinico San Matteo Pavia, Italy
b Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia Pavia, Italy
c Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Milan, Italy

* Corresponding author. Tel.: +39 0382 503715; fax: +39 0382 503161. E-mail address: g.deferrari{at}smatteo.pv.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Heart rate (HR) reduction may be useful in treatment of patients with heart failure (HF). There are no data on the haemodynamic effects of ivabradine (a selective If current inhibitor) in advanced HF patients.

Aims: To assess the haemodynamic effects of ivabradine in patients with advanced HF and markedly depressed left ventricular (LV) function.

Methods and results: Ten NYHA class III patients (50±12 years, LV ejection fraction 21±7%) underwent 24-h haemodynamic monitoring. Ivabradine 0.1 mg/kg was infused over 90', followed by 0.05–0.075 mg/kg in the subsequent 90'. Baseline HR was 93±8 bpm, cardiac index (CI) 2.2±0.6 l/min*m2; LV stroke volume 44±11 ml and systolic work 39±13 g.

Ivabradine significantly reduced HR, by a maximum of 27% (to 68±9 bpm) at 4h, without decreasing CI. Ivabradine increased stroke volume and LV systolic work by a maximum of 51% (to 66±17 ml) and 53% (to 58±20 g) at 4h. No serious adverse events occurred.

Conclusion: In patients with advanced HF and markedly depressed LV function, the acute administration of ivabradine is well tolerated, effectively reduces HR, markedly increases stroke volume and preserves cardiac output. Ivabradine appears a promising approach for the treatment of patients with moderate and advanced heart failure.

Key Words: Haemodynamics • Heart failure • Heart rate • Sinoatrial node

Received October 2, 2007; Revised March 10, 2008; Accepted April 14, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In patients with heart failure (HF), heart rate (HR) has been shown to be directly related to the risk of cardiac decompensation [1] and overall mortality [2]. A multivariate analysis of the CIBIS II trial indicates that both low baseline heart rate and a marked HR reduction caused by beta-blocker administration are significantly associated with a better prognosis in patients with heart failure [3]. Experimental data have shown that the beta-blocker-induced improvement in the left ventricular (LV) function in heart failure could depend solely on HR reduction, since this benefit is prevented by concomitant atrial pacing [4]. In pace-maker dependant patients with HF treated with beta-blockers, reversal of beta-blocker-induced bradycardia has deleterious effects on LV function [5].

Thus, a reduction in HR may be a useful target in the treatment of HF patients, perhaps because this intervention can be expected to reduce myocardial oxygen consumption and improve coronary blood flow. Ivabradine is a selective and specific inhibitor of If, which is a hyperpolarisation-activated, mixed sodium/potassium inward current that modulates the intrinsic pace-maker current in the sinoatrial node [6]. Ivabradine reduces HR without affecting contractility [7]. In a rat model of post myocardial infarction cardiac failure, Ivabradine improved LV function and structure [8,9]. Its potential utility in patients with stable ischaemic heart disease and LV systolic dysfunction is currently being tested in a large scale (10,500 patients) international clinical trial [10]. However, limited data are available on the effects of ivabradine in patients with HF [11], and no data are available on its use in patients with advanced HF. Therefore, the goal of the study was to assess the safety and efficacy of the acute administration of ivabradine in patients with advanced heart failure and marked left ventricular dysfunction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The present study was a single-centre open-label phase II pilot assessment performed in ten hospitalised patients with severe congestive HF and advanced LV dysfunction.

2.1. Study population
All NYHA class III patients undergoing Swan-Ganz catheterisation for clinical reasons and with a heart rate ≥80 bpm were screened as potential candidates for the study; therefore no hospitalisation or monitoring was performed solely for the purpose of the study. Seven patients underwent haemodynamic monitoring to assess the presence (n=5) or the persistence (n=2) of criteria for active heart transplant listing (elective hospitalisation in 6/7). Three patients underwent haemodynamic monitoring (with elective hospitalisation in two) to guide medical treatment. The two patients with non-elective hospitalisation underwent haemodynamic monitoring 15 days after full recovery following an episode of HF worsening. Thus, no patient was studied within 14 days of an acute decompensation of their chronic condition.

The main inclusion criteria were age: 18-75 years (inclusive), LV ejection fraction <35%, a history of chronic HF, NYHA class III, a resting HR≥80 bpm, systolic blood pressure>90 mmHg and a pulmonary capillary wedge pressure≥15 mmHg, (assessed in two consecutive measures,10 min apart). Patients had to be in sinus rhythm, clinically stable with no change in clinical findings or treatment for at least 24 h (with the exception of minor adjustments in diuretic dose), and not receiving infusion of inotropic or vasoactive agents. Patients on chronic beta-blocker treatment were included if they were receiving a stable (≥1 month) and maximally tolerated dose of beta-blocker, provided the daily dose was ≤25 mg for carvedilol, ≤50 mg for metoprolol or the equivalent dosage of another beta-blocker.

Patients with abnormalities in sinus node function, atrial fibrillation or flutter, second or third degree AV block or with trifascicular block with PR >240 ms were excluded, as were patients with a myocardial infarction or stroke in the previous 3 months, patients with hepatic disorders (AST and/or ALT>3 times the upper limit of normal (ULN), {gamma}GT>5 times the ULN), renal dysfunction (serum creatinine>2.5 mg/dl) or relevant electrolyte disorders (e.g., plasma potassium <3.5 mEq/L). Patients with implanted pace-maker and atrial paced beats were excluded. Patients taking antiarrhythmic drugs or medications known to interact with the metabolism of ivabradine (strong cytochrome P 450 3A4 inhibitors) were also excluded from the study.

The study complied with the Declaration of Helsinki, the protocol was approved by the independent Ethics Committee of our Hospital and each patient signed a written informed consent.

2.2. Study protocol
Pharmacological treatment was kept unchanged for the duration of the study. A Swan-Ganz catheter was placed in the right pulmonary artery under local anaesthesia and with fluoroscopic control at least 3 h before the beginning of the study (in 7/10 patients this was done the day before the start of the study) . Patients were kept in bed for 24 h before and after study initiation and were fasted from the evening before study initiation. A light snack was given between hour 4 and hour 6, a meal after hour 8.

The dose of ivabradine was selected based on previous data in healthy volunteers (data on file) and patients [11,12] and using PK/PD modelling with an objective of 20-25 bpm decrease after 3 h. Accordingly, ivabradine was infused, in the first 90 min, at a dose of 0.1 mg/kg followed in the subsequent 90 min, by a dose of either 0.075 mg/kg or 0.05 mg/kg (the latter if HR had fallen by more than 15 bpm). Therefore, the total duration of ivabradine infusion was 3 h. Infusion was stopped if HR fell below 60 bpm. A twelve-lead ECG and comprehensive haemodynamic measurements were obtained at baseline, and at 30, 60, 90, 120 min, 3, 4, 6, 8 and 24 h after the start of the infusion. Blood pressure was measured with an arm cuff. Pulmonary artery pressure (systolic, diastolic, mean and wedge) and right atrial pressure were measured at the end-expiratory phase. Cardiac output was obtained by the thermodilution method, following the injection of 10 ml of iced saline into the right atrium; three measures were averaged. Cardiac index, ventricular stroke volume, pulmonary and systemic vascular resistance, and left and right ventricular systolic work were all derived from these primary variables.

Echocardiographic evaluation was performed by the same operator at baseline, and after 3 and 24 h. LV end-systolic, end-diastolic volumes and ejection fraction were calculated from an apical four-chamber view with the modified Simpson's technique.

Measurement of plasma epinephrine, norepinephrine and BNP were performed at baseline, and after 1, 3 and 24 h.

2.3. Statistical analysis
Data are expressed as mean±SD or median and interquartile range for normal and non-normal distributions, respectively. Data on haemodynamic variables were analysed with ANOVA for repeated measures followed by pre-specified contrasts between baseline and 3, 4, 6, 8 and 24 h. A p value of 0.05 was considered the limit for significance. Because of the small sample size (n=10) and the inherent uncertainty of the normal approximation, p values less that 0.01 have been rounded off to p<0.01.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Table 1 presents the clinical characteristics of the ten patients enrolled in the study. All patients were in NYHA functional class III. LV ejection fraction averaged 21±7%. All patients were on optimised background therapy; this included diuretics in all 10 patients, ACE inhibitors/ARBs in 8/10, beta-blockers in 6/10 and digoxin in 4/10 patients.


View this table:
[in this window]
[in a new window]

  		Table 1 Characteristics of the study population (n=10 patients)

 
3.1. Efficacy
Ivabradine infusion decreased HR in all patients. On the basis of the reduction in HR observed in the first 90 min, five patients received an infusion of 0.075 mg/kg in the following 90 min, and the other five patients received 0.05 mg/kg. In one patient ivabradine infusion was stopped after 150 min, because HR had decreased to <60 bpm.

Table 2 presents the complete haemodynamic data from the study. Fig. 1 shows the behaviour of average and individual heart rates in the ten patients: HR decreased progressively, reaching a minimum 4 h after the beginning of the infusion, when the average decrease was 27% (24% and 30% among patients treated and not treated with beta-blockers, respectively). Heart rate was significantly reduced at all pre-specified time intervals including at 24 h, when HR still was 10 bpm lower than baseline.


View this table:
[in this window]
[in a new window]

  		Table 2 Haemodynamic data

 


Figure 01
View larger version (20K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Heart rate values at baseline (H0) and throughout the study. Each patient is represented by a different line and the mean value is represented by the bold line. Please note that the time intervals on the x axis are not exactly proportional.

 
This significant HR decrease did not cause a reduction in cardiac output. Fig. 2 shows the behaviour of cardiac index (dotted line), illustrating its preservation despite the marked HR decrease. Actually, a trend toward an increase in cardiac index was observed, most prominently at the time of the maximal HR effect (4 h). The lack of a reduction in cardiac output was based on a significant and substantial increase in stroke volume, as shown by the dashed line in Fig. 2. This increase was significant at all pre-specified time intervals and reached a peak, 51% higher than baseline, at 4 h after infusion initiation (1 h after the infusion was terminated).


Figure 02
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Mean cardiac index (dotted line, y axis scale on left side) and stroke volume (dashed line, y axis scale on right side) throughout the study. Please note that the time intervals on the x axis are not exactly proportional.

 
While systolic arterial blood pressure did not change, there was a modest but significant decrease in diastolic blood pressure which reached a nadir, 13% lower than baseline, at 6 h. As a consequence, a non-significant trend towards a decrease in mean blood pressure was observed (maximum –7% at 6 h). A different pattern was observed in pulmonary artery pressures: a significant increase in systolic arterial pressure was accompanied by no significant change in diastolic and mean pressures. Importantly, no change in pulmonary artery wedge pressure was observed throughout the study. A modest (maximum +3 mmHg at 6 and 8 h) increase in the right atrial pressure was observed.

Concomitant with these changes, systemic vascular resistance tended to decrease (maximum –15% at 4 h); no change occurred in total pulmonary vascular resistance.

Ivabradine infusion produced a significant increase in both left and right ventricular systolic stroke work. Maximum increase was observed at 4 h after initiation of the infusion, when systolic work was increased by 49% and 42% for the left and right ventricles, respectively. At 24 h a significant increase was still present (+15% and +17%).

Echocardiographic evaluation at 3 and 24 h showed no significant change in LV end-diastolic volumes (246±86 ml at baseline, 243±95 and 244±105 ml at 3 and 24 h, respectively), end-systolic volumes (199±76 ml at baseline, 188±67 and 188±78 ml at 3 and 24 h, respectively) and ejection fraction (21±7% at baseline, 22±9 and 23±8% at 3 and 24 h, respectively).

Table 3 shows the median plasma levels of BNP, epinephrine and norepinephrine, which did not increase and, in fact, tended to fall as HR fell.


View this table:
[in this window]
[in a new window]

  		Table 3 Neurohormonal data-median values (interquartile range)

 
3.2. Safety
Six adverse events were observed in five patients. These included one case of sinus bradycardia (HR<60 bpm) leading to interruption of ivabradine infusion and two cases of minor visual disturbances considered likely to be drug-related. There was also one case of hypokalaemia, one short run (<10 beats) of ventricular tachycardia and one hyperthermia (maximal temperature 38.5 °C internal), that were considered not to be related to the investigational drug. No clinically important changes were found in the blood tests following ivabradine infusion. No significant effect of ivabradine on the PR, QRS or QT intervals was found, the latter was corrected for HR with either the Bazett or the Fridericia formula.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study investigated the HR lowering effect of ivabradine, with its attendant haemodynamic consequences, in patients with advanced HF. The investigation was based on the hypothesis that, in structural heart diseases such as myocardial infarction and HF, reduction in HR, either direct (by If inhibition) or autonomically mediated (by vagal stimulation) could be beneficial [13,14]. Acute i.v. administration of ivabradine in patients with advanced LV dysfunction and HF, markedly reduced HR without negatively affecting cardiac output; it also increased stroke volume and stroke work without increasing diastolic volumes and without any apparent unfavourable haemodynamic consequences.

4.1. Effect on heart rate
The 27% reduction in HR achieved with an i.v. infusion of 0.15-0.175 mg/kg of ivabradine is consistent with that observed by Manz et al. (17.6% reduction) in a previous study [11] in patients with moderate LV dysfunction receiving an average of 0.2 mg/kg i.v. of ivabradine. Paralleling our findings, Manz et al. also found that the relatively short-term i.v. administration of ivabradine produced a long-lasting reduction in HR, detectable for up to 18 h after the end of the infusion.

Notably, the HR decrease observed by Manz et al. [11] after acute administration of ivabradine in patients with moderate LV dysfunction, and also the decreases observed after chronic administration in patients with stable angina by Borer at al. [15] (15-20% with 10 mg ivabradine b.i.d.) and by Tardif et al. [16] (approximately 18% with 10 mg ivabradine b.i.d.), were all recorded in patients not treated with beta-blockers. In contrast, most patients enrolled in the present study were on chronic beta-blocker treatment at a dose that, despite being relatively low, was the maximal tolerated by each patient.

Activity of cardiac If channels is modulated by intracellular cAMP concentration (and appears to underlie physiological variations of HR [17-19]). Accordingly, If in human atrial myocytes is modulated by beta-adrenoceptor stimulation [20] and mediates, at least in part, the HR lowering effects of beta-blockade. Thus, the demonstration of a significant HR lowering effect of ivabradine, when administered in addition to beta-blockade, has important implications for co-administration when patients with HF receive beta-blocking therapy, as suggested by current guidelines.

4.2. Effect on haemodynamics and left ventricular function
A significant finding of the present study is that, in beta-blocked patients with advanced HF, the HR decrease induced by ivabradine was not accompanied by a decrease in cardiac output. Previously, Manz et al. evaluated the echocardiographic response to the acute administration of ivabradine in patients with modestly depressed LV function (ejection fraction <50%), and reported that fractional shortening and LV ejection fraction were preserved [11]. However, none of the patients in that study had HF or were being treated with beta-blockers. The present study enrolled much more severely ill patients; all had NYHA class III HF with an average LV ejection fraction of 21% on optimised medical therapy. Despite the severity of disease and the presence of concomitant beta-blockade, the ivabradine-induced significant reduction in HR was not accompanied by a reduction in cardiac output; indeed cardiac output actually tended to increase, due largely to a marked and significant increase in stroke volume, (average maximal increase+51%). In parallel, a very pronounced increase in both left and right ventricular systolic stroke work was also observed.

In vitro studies of myocardial fibres indicate that while tension of non-failing heart fibres increased with a stimulation rate increase from 12 to 200/min, tension developed by failing heart fibres decreased over the same frequency [21], indicating the loss of the force-frequency relationship. Consistent with this experimental finding, in a study of nine NYHA class II and III patients with dilated cardiomyopathy, an increase in right ventricular pacing rate from 84 to 140 bpm caused a decrease in the average left ventricular ejection fraction from 27% to 19% [22]. However, the latter study explored the effect of artificially increasing rate by right ventricular pacing and could not explore the effect of lowering HR below baseline. Using ivabradine, we were able to explore for the first time, the force-frequency relationship at HR lower than baseline, in patients with severely depressed LV function. Our findings support the concept of a negative force-frequency relationship in patients with advanced HF.

4.3. Safety
Ivabradine administration was well tolerated and no serious side effects occurred. Two patients experienced mild and transient visual disturbances, an effect previously reported in healthy volunteers [23] and cardiac patients [15,16] and likely due to the presence of ion channels in the retina similar to those which mediate the effects of If [24,25], in the absence of any toxicity of ivabradine on ocular structures. No effect on ECG was observed, which is in agreement with the results of a previous study in 14 patients undergoing electrophysiological evaluation [12]. Notably, no increase in QTc occurred, indicating no prolongation of action potential duration in these patients with advanced HF, which is a very important safety issue for a drug which lowers HR. In fact, ivabradine may potentially exert a favourable effect on arrhythmia risk in HF patients given the over-expression of If found in vitro in ventricular myocytes from patients with this condition [26].

4.4. Limitations
The present study did not have a control group. We considered that since this was the first experience in patients with advanced heart failure, a pilot observational study would be preferable and safer. However, the major outcome variables were objective and were measured automatically, thus minimizing the likelihood of observer bias affecting our results. Moreover, it would have been difficult to conduct a placebo-controlled blinded study, due to the expected differences in HR following the acute administration of ivabradine and placebo.

The population studied was rather small. However, it was sufficient to demonstrate a significant increase in stroke volume despite a tendency towards a reduction in left ventricular end-diastolic volume; and to explore the overall haemodynamic response to ivabradine. Due to the inherent limitation of performing statistical analyses with a small sample, we have rounded off to p<0.01 all p values resulting nominally <0.01 (such as HR or LV systolic work, nominally both <0.000001).

In light of the encouraging preliminary results provided by the present study, more extensive studies are now justified.

4.5. Implications for future development
The present results confirm the safety of ivabradine in patients with HF, including patients with severe systolic left ventricular dysfunction treated with beta-blockers. Following these results, an oral formulation (up to 7.5 mg bid) of ivabradine is currently being investigated in patients with moderate to severe HF (ongoing SHIFT trial). Moreover, the present data may support the rationale for investigating the effects of i.v. ivabradine, in patients with acute HF in whom beta-blockers are contraindicated.

4.6. Conclusions
In patients with advanced HF and markedly depressed left ventricular function, receiving optimised medical therapy, the acute administration of ivabradine is well tolerated and effectively reduces HR by more than 20%. Importantly, this substantial HR reduction is associated with preserved cardiac output and significantly enhanced stroke volume and both left and right ventricular systolic stroke work. These findings support the safety of heart rate lowering, and of ivabradine in achieving this effect, in patients with left ventricular dysfunction and suggest a potential role for ivabradine in treatment of patients with moderate and advanced heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Opasich C., Rapezzi C., Lucci D., et al. Italian Network on Congestive Heart Failure (IN-CHF) investigators. Precipitating factors and decision-making processes of short-term worsening heart failure despite "optimal" treatment (from the IN-CHF Registry). Am J Cardiol (2001) 88:382–387.[CrossRef][Web of Science][Medline]
  2. Metra M., Torp-Pedersen C., Swedberg K., et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial. Eur Heart J (2005) 26:2259–2268.[Abstract/Free Full Text]
  3. Lechat P., Hulot J.S., Escolano S., et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation (2001) 103:1428–1433.[Abstract/Free Full Text]
  4. Nagatsu M., Spinale F.G., Koide M., et al. Bradycardia and the role of beta-blockade in the amelioration of left ventricular dysfunction. Circulation (2000) 101:653–659.[Abstract/Free Full Text]
  5. Thackray S.D.R., Ghosh J.M., Wright G.A., et al. The effect of altering heart rate on ventricular function in patients with heart failure treated with β-blockers. Am Heart J (2006) 152:713.e9–713.e13.[CrossRef][Medline]
  6. DiFrancesco D. The contribution of the "pacemaker" current (If) to generation of spontaneous activity in rabbit sino-atrial node myocytes. J Physiol (1991) 434:23–40.[Abstract/Free Full Text]
  7. Simon L., Ghaleh B., Puybasset L., Giudicelli J.F., Berdeaux A. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther (1995) 275:659–666.[Abstract/Free Full Text]
  8. Mulder P., Barbier S., Chagraoui A., et al. 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 (2004) 109:1674–1679.[Abstract/Free Full Text]
  9. Dedkov E., Zheng W., Christensen L., Weiss R., Mahlberg-Gaudin F., Tomanek R.J. Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen. Am J Physiol Heart Circ Physiol (2007) 293:H590–H598.[Abstract/Free Full Text]
  10. Fox K., Ferrari R., Tendera M., Steg P.G., Ford I. Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) Study. Am Heart J (2006) 152:860–866.[CrossRef][Web of Science][Medline]
  11. Manz M., Reuter M., Lauck G., Omran H., Jung W. A single intravenous dose of ivabradine, a novel If inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology (2003) 100:149–155.[CrossRef][Web of Science][Medline]
  12. Camm A.J., Lau C.P. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs R&D (2003) 4:83–89.[CrossRef]
  13. De Ferrari G.M., Vanoli E., Schwartz P.J. Cardiac vagal activity, myocardial ischemia and sudden death. In: Cardiac electrophysiology. From cell to bedside—Zipes DP, Jalife J, eds. (1995) II Edition. Philadelphia: WB Saunders Co. 422–434.
  14. De Ferrari G.M., Ajmone-Marsan N., Revera M., et al. Long term vagal stimulation in patients with advanced heart failure. First human experience. Eur Heart J (2007) 28:143. (Abstract Supplement).[Free Full Text]
  15. Borer J.S., Fox K., Jaillon P., Lerebours G. for the Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina. A randomized, double-blind, multicentered, placebo-controlled trial. Circulation (2003) 107:817–823.[Abstract/Free Full Text]
  16. Tardif J.C., Ford I., Tendera M., Bourassa M.G., Fox K. for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J (2005) 26:2529–2536.[Abstract/Free Full Text]
  17. Brown H.F., DiFrancesco D., Noble S.J. How does adrenaline accelerate the heart? Nature (1979) 280:235–236.[CrossRef][Medline]
  18. DiFrancesco D., Mangoni M. Modulation of single hyperpolarization-activated channels (If) by cAMP in the rabbit sino-atrial node. J Physiol (1994) 474:473–482.[Abstract/Free Full Text]
  19. Moroni A., Barbuti A., Altomare C., et al. Kinetic and ionic properties of the human HCN2 pacemaker channel. Pflugers Arch (2000) 439:618–626.[CrossRef][Web of Science][Medline]
  20. Porciatti F., Pelzmann B., Cerbai E., et al. The pacemaker current If in single human atrial myocytes and the effect of beta-adrenoceptor and A1-adenosine receptor stimulation. Br J Pharmacol (1997) 122:963–969.[CrossRef][Web of Science][Medline]
  21. Mulieri L.A., Hasenfuss G., Leavitt B., Allen P.D., Alpert N.R. Altered myocardial force-frequency relation in human heart failure. Circulation (1992) 85:1743–1750.[Abstract/Free Full Text]
  22. Hasenfuss G., Holubarsch C., Hermann H.P., Astheimer K., Pieske B., Just H. Influence of the force-frequency relationship on hemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J (1994) 15:164–170.[Abstract/Free Full Text]
  23. Ragueneau I., Laveille C., Jochemsen R., Resplandy G., Funck-Brentano C., Jaillon P. Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin Pharmacol Ther (1998) 64:192–203.[CrossRef][Web of Science][Medline]
  24. Demontis G.C., Longoni B., Barcaro U., Cervetto L. Properties and functional roles of hyperpolarization-gated currents in guinea-pig retinal rods. J Phisiol (1999) 515:813–828.[CrossRef]
  25. Satoh T.O., Yamada M. A bradycardic agent ZD7288 blocks the hyperpolarization-activated current (Ih) in retinal rod photoreceptors. Neuropharmacology (2000) 39:1284–1291.[CrossRef][Web of Science][Medline]
  26. Cerbai E., Pino R., Porciatti F., et al. Characterization of the hyperpolarization-activated current, If, in ventricular myocytes from human failing heart. Circulation (1997) 95:568–571.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur J Heart FailHome page
K. Swedberg, M. Komajda, M. Bohm, J. S. Borer, I. Ford, and L. Tavazzi
Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT)
Eur J Heart Fail, January 1, 2010; 12(1): 75 - 81.
[Abstract] [Full Text] [PDF]

Home page
 Circ Heart FailHome page
M. S. Maurer, J. D. Sackner-Bernstein, L. El-Khoury Rumbarger, M. Yushak, D. L. King, and D. Burkhoff
Mechanisms Underlying Improvements in Ejection Fraction With Carvedilol in Heart Failure
Circ Heart Fail, May 1, 2009; 2(3): 189 - 196.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by De Ferrari, G. M.
Right arrow Articles by Tavazzi, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Ferrari, G. M.
Right arrow Articles by Tavazzi, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?