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Original Article
Effects of Ivabradine in Mitral Valve Prolapse
Acta Cardiol Sin 2010;26:253-8
Electrophysiology
Effects of a Novel I(f) Inhibitor; Ivabradine,
on the Biochemical, Hemodynamic, and
Electrophysiological Parameters in
Symptomatic Patients with Mitral Valve Prolapse
Davran Cicek,1 H. Olcay Eldem,1 Nihat Kalay,2 Bulent Ozin3 and Haldun Muderrisoglu3
Introduction: We aimed to investigate the effects of ivabradine in symptomatic (sinus tachycardia) patients with
mitral valve prolapse. Ivabradine specifically inhibits the If current in the sinoatrial node to lower heart rate without
affecting other aspects of cardiac function.
Methods: The study included 48 MVP patients. After 2 weeks of wash-out, echocardiographic, electrocardiographic,
24-hour Holter, and routine blood examinations were conducted. Ivabradine therapy was started at a dosage of 5 mg
twice daily. After 1 mo of treatment, the abovementioned examinations were repeated.
Results: The treatment was completed by 45 patients. No significant differences were observed between the preand post-treatment values of the echocardiographic, hemodynamic, and electrophysiological parameters. However,
the symptom periods (164 ± 12 vs. 114 ± 9; p = 0.003) and the maximum (149 ± 18 vs. 136 ± 16; p = 0.001), mean (85
± 8 vs. 77 ± 8; p = 0.002), and minimum heart rates (61 ± 3 vs. 52 ± 5; p = 0.001) recorded by Holter monitoring were
significantly reduced.
Conclusion: Ivabradine is effective and safe to relieve palpitation symptoms due to sinus tachycardia in patients
with mitral valve prolapse. However, its safety in the longer term will require additional assessment.
Key Words:
Antiarrhythmic · Cardiac pharmacology · Ion channels · Mitral valve prolapse · Tachycardia
b-adrenergic blockade helps alleviate them.4 The conventional medical treatment for MVP involving palpitation due to sinus tachycardia is essentially based on
b-blockers. However, patient compliance with treatment
is poor because of the side-effects of b-blockers, such as
bronchoconstriction and negative inotropic and hypotensive effects. Therefore, we considered the use of
another agent that selectively reduces the heart rate by
inhibiting the If pacemaker current, without the potentially harmful hemodynamic effects of b-blockers.
The If current is the major current underlying the
spontaneous diastolic depolarization of the sinus node,5-8
which is the fundamental mechanism at the origin of the
spontaneous electrical activity of pacemaker cells. It is
directly regulated by cyclic AMP (cAMP), a secondary
messenger of the autonomic nervous system. 7-9 b-ad-
Mitral valve prolapse (MVP), defined as echocardiographic (ECHO), angiographic, and pathologic protrusion of the mitral leaflets into the left atrium during
systole, affects approximately 5% of the population
worldwide. It was first recognized in the mid-1960s.1-3
The typical symptoms that are associated with MVP are
often a result of anxiety and autonomic dysfunction, and
Received: April 13, 2010
Accepted: June 28, 2010
1
Department of Cardiology, Baskent University School of Medicine,
Antalya; 2Department of Cardiology, Erciyes University School of
Medicine, Kayseri; 3Department of Cardiology, Baskent University
School of Medicine, Ankara.
Address correspondence and reprint requests to: Dr. Davran Cicek,
Department of Cardiology, Baskent University School of Medicine,
Alanya, Antalya, Turkey. Tel: 90 532 3336466; E-mail: davrancicek@
mynet.com
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Acta Cardiol Sin 2010;26:253-8
Davran Cicek et al.
poprotein, high-density lipoprotein, triglycerides, thyroid-stimulating hormone, free T4, and microalbuminuria were determined in the routine blood examination.
Next, ivabradine (Coralan; Les Laboratoires Servier
Industrie; Gidy, France) therapy was started for all the
MVP patients at a dosage of 5 mg twice daily. After 1
mo of ivabradine treatment, the patients again underwent
24-h Holter recording, ECG examination, ECHO, and
routine blood tests. The 24-hour Holter recordings were
obtained on a 7-channel recorder (DMS 300-7 Holter
Recorder; MTM Multitechmed GmbH; Germany). Data
that were recorded for ³ 16 h and were of suitable quality for evaluation were analyzed. If these criteria were
not met, the data were recorded again.
renergic stimulation by an increase in the intracellular
concentration of cAMP in pacemaker cells increases the
If current and the slope of diastolic depolarization,
which decreases the diastolic time and accelerates the
heart rate; vagal stimulation has the opposite effects.
Therefore, direct inhibition of the If current appears to
be ideal in order to induce selective reduction of not
only the resting heart rate but also tachycardia mediated
by an increase in the sympathetic tone.10-12 In the present
study, we evaluated the effects of ivabradine used as an
alternative to b-blockers in MVP patients complaining of
palpitations due to sinus tachycardia.
METHODS
Statistical analysis
Quantitative variables were expressed as mean ±
standard deviation, and discrete variables were expressed as percentages. The paired t test was used to investigate changes, with time as a dependent variable.
The SPSS 11.0 (SPSS Inc.; Chicago, IL) statistical software package was used for analysis. A p value < 0.05
was considered statistically significant.
This study protocol was approved by the ethics committee of Baskent University School of Medicine, Ankara. Informed consent was obtained from all the subjects enrolled in this clinical trial. The study included 48
symptomatic MVP patients who could not tolerate bblocker treatment because of side effects; the patients
were all aged over 16 years. The MVP criterion was
valve prolapse ³ 2 mm above the mitral annulus in the
long-axis parasternal view.13 No patient had a history of
syncope or sustained ventricular tachycardia or a family
history of sudden cardiac death, and none of the patients
exhibited an accompanying cardiac or noncardiac disease or were under concomitant medication with any
other drugs.
After a 2-wk wash-out period for b-blockers, all the
patients underwent basal electrocardiographic examination (ECG), 24-h Holter recording, ECHO, and routine
blood tests. The symptom period was defined as the
number of events with sinus tachycardia, atrial or ventricular premature beats or supra-ventricular tachycardias including atrial fibrillation that were indicated
during 24-h Holter recording in patients when they experienced palpitation. The heart rate and PR and corrected
QT (QTC) intervals were obtained from ECG. We corrected the QT time for heart rate using Bazett’s Formula
= QT Interval / ( RR interval ), RR Interval = 60/HR.
Ejection fraction, left ventricular diameter, mitral E
wave, mitral A wave, and left atrial and aortic measurements were obtained from ECHO. The counts of white
blood cells and platelets and the levels of low-density liActa Cardiol Sin 2010;26:253-8
RESULTS
Of the 48 symptomatic MVP patients, 45 (94%)
lasted through the 1-mo treatment period; 36 (80%) were
female, and 9 (20%) were male. Their mean age was
28.8 ± 8.7 yr. Three patients withdrew from ivabradine
therapy because they presented vision symptoms. The
symptom periods obtained by 24-h Holter recording
were found to have decreased significantly (164 ± 12 vs.
114 ± 9 events/24 h; p = 0.003).
Biochemical effects
The biochemical effects of ivabradine are shown in
Table 1. No significant difference was observed in the
hematologic parameters, cholesterol levels, and thyroid
hormone levels after ivabradine treatment.
Hemodynamic effects
The effects of ivabradine on the echocardiographic
parameters and blood pressure are shown in Table 2. No
significant difference was observed between the baseline
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Effects of Ivabradine in Mitral Valve Prolapse
and post-treatment systolic (105 ± 14 vs. 102 ± 13
mmHg; p = 0.1) and diastolic (69 ± 10 vs. 66 ± 9 mmHg;
p = 0.05) blood pressures. Further, no difference was
noted in the echocardiographic parameters after treatment.
periods (164 ± 12 vs. 114 ± 9; p = 0.003), office heart
rate measurements (82 ± 15 vs. 72 ± 11 bpm; p = 0.001)
(Figures 1A, B), and the maximum (149 ± 18 vs. 136 ±
16 bpm; p = 0.001), mean (85 ± 8 vs. 77 ± 8 bpm; p =
0.002), and minimum heart rates (61 ± 3 vs. 52 ± 5 bpm;
p = 0.001) recorded by Holter monitoring were significantly decreased after treatment. As observed in the case
of our study (see Figure 1), the QT interval was pro-
Electrocardiographic effects
The effects of ivabradine on the electrocardiographic parameters are shown in Table 3. The symptom
Table 1. Biochemical effects of ivabradine
Hgb (g/dl)
WBC (c/mm3)
PLT (c/mm3)
LDL (mg/dl)
HDL (mg/dl)
TG (mg/dl)
FT4 (ng/dl)
TSH (IU/ml)
Microalbuminuria (mg/l)
Creatinin (mg/dl)
Baseline
1 month
p value
12.6 ± 0.5
07014 ± 2115
291000 ± 57000
098 ± 27
48 ± 9
090 ± 32
01.6 ± 2.3
01.9 ± 1.0
009.4 ± 12.4
00.7 ± 0.1
13.3 ± 0.80
6492 ± 1596
285000 ± 520000
95 ± 25
51 ± 10
90 ± 33
1.4 ± 1.2
1.7 ± 0.8
7.3 ± 8.5
0.8 ± 0.2
0.60
0.05
0.20
0.06
0.07
0.80
0.20
0.20
0.05
0.06
FT4, freeT4; Hgb, hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglycerides; TSH, thyroidstimulating hormone; PLT, platelets; WBC, white blood cells.
Table 2. Effects of ivabradine on echocardiographic parameters and blood pressure
Systolic BP (mmHg)
Diastolic BP (mmHg)
Ejection fraction (%)
LVDD (mm)
LVSD (mm)
Mitral E wave (m/s)
Mitral A wave (m/s)
Left atrium (mm)
Aorta (mm)
Baseline
1 month
p value
105 ± 14
069 ± 10
69 ± 5
42 ± 4
26 ± 3
01.0 ± 0.3
00.7 ± 0.3
29 ± 5
26 ± 4
102 ± 13
66 ± 9
67 ± 4
41 ± 5
26 ± 4
01.0 ± 0.2
00.7 ± 0.2
28 ± 4
26 ± 5
0.1
00.05
0.3
00.05
0.8
0.9
0.5
0.5
0.3
BP, blood pressure; LVDD, left ventricular diastolic diameter; LVSD, left ventricular systolic diameter.
Table 3. Effects of ivabradine on ECG parameters
Office HR b.p.m.
PR interval (ms)
QTc interval (ms)
Maximum HR b.p.m.
Mean HR b.p.m.
Minimum HR b.p.m
Symptom periods
Baseline
1 month
p value
082 ± 15
149 ± 21
427 ± 24
149 ± 18
85 ± 8
61 ± 3
164 ± 12
072 ± 11
145 ± 17
428 ± 26
136 ± 16
77 ± 8
52 ± 5
114 ± 90
0.001
0.100
0.900
0.001
0.002
0.001
0.003
b.p.m., beats per minute; ECG, electrocardiography; HR, heart rate; QTc, corrected QT.
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Acta Cardiol Sin 2010;26:253-8
Davran Cicek et al.
A
B
Figure 1. Electrocardiograpy of a 28-year-old female patient before (A) and after (B) ivabradine treatment. Heart rate decreased to 72 bpm from
112 bpm and the QT interval was prolonged (379 ms to 392 ms) as expected, but after appropriate correction for heart rate, no significant effect of
ivabradine on QT interval (QTc) was observed.
MVP patients who have palpitations due to sinus tachycardia. Ivabradine is a new drug that lowers the sinus
rate, and its safety and efficacy have been studied in
multiple trials. During the clinical development of ivabradine, Savelieva et al. showed that ivabradine has a
good safety profile via clinical studies involving more
than 3500 patients and 800 healthy volunteers. 14 The
most common adverse events were vision symptoms
(blurred vision, diplopia, etc.) in 16.4% of patients and
sinus bradycardia of 55 bpm or less in 3.2% of patients
longed as expected, but no significant effect of ivabradine on ventricular repolarization duration was demonstrated once the appropriate correction for heart rate
(i.e., QTc interval) was made and compared (see Table 3).
DISCUSSION
To our knowledge, this is the first clinical trial of the
novel selective If inhibitor ivabradine in symptomatic
Acta Cardiol Sin 2010;26:253-8
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Effects of Ivabradine in Mitral Valve Prolapse
and ejection fraction. These findings indicate that ivabradine can be used as an alternative to b-blockers to
treat symptomatic MVP patients who exhibit the sideeffects of the latter.
This study has several limitations, of which the
small number of patients, lack of direct randomization,
and short follow-up period are the main ones. Also the
effects of ivabradine on heart rate variability, which was
not specifically evaluated in this study, deserve further
investigation.
treated with the recommended dosages of 5 and 7.5 mg
twice daily. Less than 1% of patients withdrew from
therapy because of sinus bradycardia. As observed in the
case of our study, the QT interval was prolonged as expected, but no significant effect of ivabradine on ventricular repolarization duration was demonstrated once
the appropriate correction for heart rate was made and
the QT intervals were directly compared. Vision symptoms are transient and do not affect the quality of life.
Further, it was found that they led to few withdrawals
(< 1%; 24 of 2545 patients) and resolved during treatment in 77.5% (383 of 491) patients. Ivabradine does not
affect other tissues.14 The common adverse events were
vision symptoms in our study group as well (6.25%).
Further, the vision symptoms were once again transient,
but the patients withdrew from treatment nonetheless.
The QTc and PR intervals were not significantly altered.
The clinical development of ivabradine has been
carried out on the basis of these and other preclinical
data which indicate that by inhibiting the If pacemaker
current of the sinus node, this drug can selectively reduce the heart rate, both at rest and during exercise, with
a twice-daily dosing regimen. 14,15 Further, it does not
modify myocardial contractility, atrioventricular conduction, or ventricular repolarization, and it could be, by its
sole hemodynamic effect at least, as potent as a bblocker in preventing myocardial ischemia while offering better protection for regional myocardial contractility. 15-17 The anti-ischemic and anti-anginal effects of
ivabradine induced by a reduction in the heart rate have
been confirmed in multiple trials.15-18 The BEAUTIFUL
study 19 was designed to examine whether ivabradine
could decrease the incidence of cardiovascular events in
patients with coronary artery disease and left ventricular
systolic dysfunction (LVSD). The results, which have
been published,20,21 showed no benefits of ivabradine.
However, in a subgroup of patients who had a heart rate
of 70 bpm or more, the incidence of fatal and nonfatal
myocardial infarction (MI) and coronary revascularization was reduced. The BEAUTIFUL study also showed
that ivabradine could be safely used in the other subgroup of patients.
In our trial, we observed that the mean heart rate reduced by 8 bpm after 1 mo of treatment. The maximum
and minimum heart rates were also significantly decreased. Ivabradine had no effect on the blood pressure
CONCLUSION
Ivabradine can be used as an alternative treatment
for symptomatic MVP patients who cannot tolerate
b-blockers. However, the longer-term safety of ivabradine requires additional assessment.
ACKNOWLEDGEMENTS
All support for this study came from institutional
and departmental resources.
REFERENCES
1. Barlow JB, Bosman CK, Pocock WA, et al. Late systolic murmurs and non-ejection (“mid late”) systolic clicks. Br Heart J
1968;30:203-18.
2. Jeresaty RM. Mitral Valve Prolapse. New York, Raven Press,
1979.
3. Cheitlin MD, Byrd RC. The click-murmur syndrome: a clinical
problem in diagnosis and treatment. JAMA 1981;245:1357-61.
4. Boudoulas H, Wooley CF. Floppy mitral valve/mitral valve
prolaps/mitral valvular regurgitation: effects on the circulation. J
Cardiol 2001;37:15-20.
5. DiFrancesco D, Ferroni A, Mazzanti M, et al. Properties of the
hyperpolarizing-activated current (If) in cells isolated from the
rabbit sino-atrial node. J Physiol (Lond) 1986;377:61-88.
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.
7. DiFrancesco D. The onset and autonomic regulation of cardiac
pacemaker activity: relevance of the current. Cardiovasc Res
1995;29:449-56.
8. DiFrancesco D. The pacemaker current (If) plays an important
role in regulating SA node pacemaker activity. Cardiovasc Res
257
Acta Cardiol Sin 2010;26:253-8
Davran Cicek et al.
1995;30:307-8.
9. DiFrancesco D, Mangoni M. Modulation of single hyperpolarizationactivated channels (If) by cAMP in the rabbit sino-atrial
node. J Physiol 1994;474:473-82.
10. Heyndrickx GR, Pannier JL, Muylaert P, et al. Alteration in myocardial oxygen balance during exercise after b-adrenergic blockade in dogs. J Appl Physiol 1980;49:28-33.
11. Feigl EO. The paradox of adrenergic coronary vasoconstriction.
Circulation 1987;76:737-45.
12. Berdeaux A, Drieu la Rochelle C, Richard V et al. Opposed responses of large and small coronary arteries to propranolol during
exercise in dogs. Am J Physiol 1991;261:H265-70.
13. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006
guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (writing
Committee to Revise the 1998 guidelines for the management of
patients with valvular heart disease) developed in collaboration
with the Society of Cardiovascular Anesthesiologists endorsed by
the Society for Cardiovascular Angiography and Interventions
and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;
48:1-148.
14. Savelieva I, Camm AJ. If inhibition with ivabradine: electrophysiological effects and safety. Drug Saf 2008;31:95-107.
15. Manz M, Reuter M, Lauck G, et al. A single intravenous dose of
ivabradine, a novel I(f) inhibitor lowers heart rate but does not depress left ventricular in patients with left ventricular dysfunction.
Cardiology 2003;100:149-55.
Acta Cardiol Sin 2010;26:253-8
16. Jondeau G, Korewicki J, Vasiliauskas D. Effect of ivabradine in
patients with left ventricular systolic dysfunction and coronary artery disease. Eur Heart J 2004;25 [abs 2637:451].
17. Borer JS, Fox K, Jaillon P, et al. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized,
double blind, multicentered, placebo-controlled trial. Circulation
2003;107:817-23.
18. Tardif JC, Ford I, Tendera M. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic
stable angina. Eur Heart J 2005;26:2529-36.
19. Fox K, Ferrari R, Tendera M, et al, BEAUTIFUL Steering Committee. 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 left ventricULar dysfunction
(BEAUTIFUL) study. Am Heart J 2006;152:860-6.
20. Fox K, Ford I, Steg PG, et al. on behalf of the BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery
disease and left ventricular systolic dysfunction (BEAUTIFUL):
a randomised, double blind, placebo controlled trial. Lancet
2008;372:807-16.
21. Fox K, Ford I, Steg PG, et al. on behalf of the BEAUTIFUL Investigators. Heart rate as a prognostic risk factor in patients with
coronary artery disease and left ventricular systolic dysfunction
(BEAUTIFUL): a subgroup analysis of a randomised controlled
trial. Lancet 2008;372:817-21.
258