Effect of Metoprolol on Heart Rate Variability in Symptomatic Patients With Mitral Valve Prolapse Gülten Taçoy, MD*, Akif Serhat Balcıog˘lu, MD, Ug˘ur Arslan, MD, Emre Durakog˘lugil, MD, Güliz Erdem, MD, Murat Özdemir, MD, and Atiye Çengel, MD Metoprolol is widely used to eliminate symptoms in patients with mitral valve prolapse (MVP), a condition associated with enhanced sympathetic tone. In this study, effects of metoprolol on heart rate variability (HRV) indices were investigated in symptomatic patients with MVP. Thirty-nine symptomatic patients with MVP (26 women, mean age 26 ⴞ 7 years) and 16 age- and gender-matched controls were studied. After a baseline 24-hour Holter evaluation in all subjects, patients with MVP were started on metoprolol succinate therapy at a dose of 25 to 100 mg/d, and Holter analysis was repeated at the end of 3 months of metoprolol therapy. At the basal evaluation, all time– domain HRV indices with the exception of proportion of adjacent RR intervals differing by >50 ms in the 24-hour recording were significantly lower in patients with MVP than controls (SD of all normal-to-normal [NN] intervals, p ⴝ 0.013; SD of average NN intervals calculated during 5-minute periods of the entire recording, p ⴝ 0.03; triangular index, p ⴝ 0.025; and square root of mean squared differences in successive NN intervals, p ⴝ 0.026). After metoprolol treatment, all HRV indices significantly improved compared with baseline (SD of all NN intervals, p ⴝ 0.028; SD of average NN intervals calculated during 5-minute periods of the entire recording, p ⴝ 0.043; triangular index, p ⴝ 0.004; square root of the mean squared differences in successive NN intervals, p ⴝ 0.021; and proportion of adjacent RR intervals differing by >50 ms in the 24-hour recording, p ⴝ 0.014), and HRV indices after metoprolol treatment were similar to those of the control group (p >0.05). In conclusion, metoprolol significantly improved impaired HRV parameters in symptomatic patients with MVP. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1568 –1570)
The aim of this study is to determine time– domain heart rate variability (HRV) indices in symptomatic patients with mitral valve prolapse (MVP) and investigate effects of short-term metoprolol treatment on these indices. Methods Thirty-nine symptomatic patients with MVP diagnosed using transthoracic echocardiography and 16 age- and gendermatched healthy subjects were studied. Criteria for MVP were valve prolapse ⱖ2 mm above the mitral annulus in the long-axis parasternal view.1 The healthy volunteers did not have cardiac disease. No patient or control had a history of syncope, sustained ventricular tachycardia, or family history of sudden cardiac death, and none had an accompanying cardiac or noncardiac disease and concomitant use of drugs. All underwent basal 24-hour Holter recording. Thereafter, metoprolol succinate therapy was started in all patients with MVP at a dose of 50 mg/d. Metoprolol dose was adjusted every 2 weeks according to heart rate, blood pressure, and any adverse effects. The minimum dose of metoprolol was 25 mg/d, whereas the target dose was set at 100 mg/d. After Department of Cardiology, Gazi University School of Medicine, Ankara, Turkey. Manuscript received November 17, 2006; revised manuscript received and accepted January 10, 2007. *Corresponding author: Tel: ⫹90-312-202-5647; fax: ⫹90-312-2129012. E-mail address:
[email protected] (G. Taçoy). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.01.032
3 months of metoprolol treatment, 24-hour Holter examination was repeated in the study group only. Informed consent was obtained from all subjects, and the study protocol was approved by the local ethical committee. The 24-hour Holter recording was performed on a 3-channel digitized recorder (Del Mar Reynolds Medical Ltd, Hertford, United Kingdom). Recordings lasting ⱖ16 hours and of sufficient quality for evaluation were included in analysis. If these criteria were not achieved, recordings were repeated. Before analyzing the data, they were manually preprocessed. Time– domain HRV indices were analyzed. Using statistical methods, the square root of the mean squared differences in successive normal-to-normal (NN) intervals, SD of all NN intervals, SD of average NN intervals calculated during 5-minute periods of the entire recording, and proportion of adjacent RR intervals differing by ⬎50 ms in the 24-hour recording (pNN50) were measured. Using geometric methods, we measured HRV triangular index (total number of all NN intervals divided by the height of the histogram of all NN intervals measured on a discrete scale with bins of 7.8125 ms [1/128 s]). In addition, mean RR interval was measured. All measurements were performed in accordance with the Task Force of the European Society of Cardiology and North American Society of Pacing and Electrophysiology.2 Statistical analysis was performed using Statistical Package for Social Sciences (SPSS Inc, Chicago, Illinois), version 11.5 software for Windows. Mann-Whitney test and www.AJConline.org
Valvular Heart Disease/MVP, Heart Rate Variability,  Blocker Table 1 Baseline characteristics of the study population Variable
MVP Patients Control Group p Value (n ⫽ 39) (n ⫽ 16)
Age (yrs) Sex (M/F) LV end-diastolic volume (ml) LV end-systolic volume (ml) LV ejection fraction (%) LA diameter (cm) Anterior mitral leaflet thickness (mm) Posterior mitral leaflet thickness (mm) Leaflet displacement into left atrium (mm)
26.4 ⫾ 7.4 13/26 88.51 ⫾ 18.70 27.17 ⫾ 7.68 69.12 ⫾ 3.35 30.48 ⫾ 3.97 4.83 ⫾ 1.21
26.2 ⫾ 7.2 NS 5/11 NS 94.31 ⫾ 16.22 NS 29.93 ⫾ 6.32 NS 67.93 ⫾ 2.35 NS 32.50 ⫾ 3.96 NS 2.91 ⫾ 0.83 ⬍0.001
2.99 ⫾ 1.03
2.02 ⫾ 0.81
0.002
4.10 ⫾ 1.62
0.80 ⫾ 0.21
⬍0.001
LA ⫽ left atrial; LV ⫽ left ventricular.
Table 2 Baseline time– domain heart rate variability indices
Mean RR (ms) SDNN (ms) SDANN (ms) RMSSD (ms) pNN50 (%) TI
MVP Patients (n ⫽ 39)
Control Group (n ⫽ 16)
p Value
763 ⫾ 87 149 ⫾ 29 132 ⫾ 25 35 ⫾ 17 12 ⫾ 11 39 ⫾ 9
798 ⫾ 95 167 ⫾ 28 150 ⫾ 28 45 ⫾ 21 17 ⫾ 12 44 ⫾ 7
0.191 0.013 0.030 0.026 0.201 0.025
pNN50 ⫽ proportion of adjacent RR intervals differing by ⬎ 50 ms in the 24 hour recording; RMSSD ⫽ square root of mean squared differences of successive NN intervals; SDANN ⫽ SD of average NN intervals calculated over 5-minute periods of the entire recording; SDNN ⫽ SD of all NN intervals; TI ⫽ total number of all NN intervals divided by the height of the histogram of all NN intervals measured on a discrete scale with bins of 7.8125 ms (1/128 s).
Table 3 Heart rate variability indices before and after metoprolol treatment in patients with mitral valve prolapse
Mean RR (ms) SDNN (ms) SDANN (ms) RMSSD (ms) pNN50 (%) TI
Before Metoprolol
After Metoprolol
p Value
763 ⫾ 87 149 ⫾ 29 132 ⫾ 26 35 ⫾ 18 12 ⫾ 11 39 ⫾ 10
803 ⫾ 89 153 ⫾ 32 137 ⫾ 30 37 ⫾ 20 13 ⫾ 11 42 ⫾ 9
0.027 0.028 0.043 0.021 0.014 0.004
Abbreviations as in Table 2.
McNemar’s chi-square test were used for comparison of data, when appropriate. p Value ⬍0.05 is considered statistically significant. Results Baseline properties of the MVP and control groups were similar (Table 1). At the basal evaluation, all time– domain HRV indices except pNN50 were significantly lower in the MVP group compared with controls (Table 2). Metoprolol
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Table 4 Heart rate variability indices of patients with mitral valve prolapse after metoprolol treatment compared with controls
Mean RR (ms) SDNN (ms) SDANN (ms) RMSSD (ms) pNN50 (%) TI
Patients With MVP After Metoprolol Therapy (n ⫽ 39)
Control Group (n ⫽ 16)
p Value
803 ⫾ 89 153 ⫾ 32 137 ⫾ 30 37 ⫾ 20 13 ⫾ 11 42 ⫾ 9
798 ⫾ 95 167 ⫾ 28 150 ⫾ 28 45 ⫾ 21 17 ⫾ 12 44 ⫾ 7
0.926 0.093 0.117 0.061 0.228 0.303
Abbreviations as in Table 2.
use was associated with no adverse effects. Mean drug dose at the end of 3 months was 80.1 ⫾ 23.1 mg/d. After 3 months of metoprolol treatment, all HRV parameters significantly improved compared with the basal evaluation in patients with MVP (Table 3). HRV indices of patients with MVP after metoprolol were similar to basal HRV indices of control subjects (Table 4). Discussion The major finding of this study is that time– domain indices of HRV are significantly depressed in symptomatic patients with MVP, and these depressed indices can be improved with short-term metoprolol therapy. Findings in patients with MVP with regard to HRV have been inconsistent. Han et al3 found that time– domain and frequency– domain indices of HRV were lower in children with MVP than controls. Digeos-Hasnier et al4 showed that HRV parameters were not different between patients with and without MVP. They suggested that the asymptomatic MVP population they studied most likely did not have high enough sympathetic activity to create depressed HRV indices. In our study, symptomatic patients with MVP had significantly lower time– domain indices than controls with the exception of pNN50. Similar findings were reported previously.5–10 Furthermore, Frisinghelli et al11 found that the presence of mitral regurgitation in patients with MVP is related to increased vagal tone. None of our patients had mitral regurgitation, but all were symptomatic. Therefore, we believe the depression in time– domain HRV indices in our study population was caused by heightened sympathetic tone. We found that metoprolol improved depressed HRV parameters in symptomatic patients with MVP. The improvement in HRV indices using a  blocker constitutes strong proof that increased sympathetic activity is the cause of depressed HRV indices in symptomatic patients with MVP. To the best of our knowledge, effects of metoprolol on HRV indices in patients with MVP were not reported previously. The major limitation in this study is the absence of an asymptomatic MVP population, without which we could only speculate that HRV depression is caused by symptoms and heightened sympathetic tone at the basal evaluation. Another limitation is the relatively short (3 months) duration of metoprolol therapy, which precludes the applicabil-
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ity of our finding of improvement in HRV indices to longterm -blocker therapy in patients with MVP. 1. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, et al, for 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), Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons. 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:e1– e148. 2. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–1065. 3. Han L, Ho TF, Yip WC, Chan KY. Heart rate variability of children with mitral valve prolapse. J Electrocardiol 2000;33:219 –224.
4. Diegos-Hasnier S, Copie X, Paziaud O, Abergel E, Guize L, Diebold B, Jeunemaitre X, Berrebi A, Piot O, Lavergne T, Le Heuzey JY. Abnormalities of ventricular repolarization in mitral valve prolapse. Ann Noninvasive Electrocardiol 2005;10:297–304. 5. Kochiadakis G, Tsagournakis M, Zouridakis M, Parthenakis F, Plaitakis A, Vardas P. Assessment of autonomic function in patients with mitral valve prolapse. J Neurol Sci 1997;150(suppl 1):S140. 6. Rosano GM, Rillo M, Leonardo F, Pappone C, Chierchia SL. Palpitations: what is mechanism, and when should we treat them? Int J Fertil Womens Med 1997;42:94 –100. 7. Kochiadakis GE, Parthenakis FI, Zuridakis EG, Rombola AT, Chrysostomakis SI, Vardas PE. Is there increased sympathetic activity in patients with mitral valve prolapse? Pacing Clin Electrophysiol 1996; 19:1872–1876. 8. Pasternac A, Tubau JF, Puddu PE, Krol RB, de Champlain J. Increased plasma catecholamine levels in patients with symptomatic mitral valve prolapse. Am J Med 1982;73:783–790. 9. Davies AO, Mares A, Pool JL, Taylor AA. Mitral valve prolapse with symptoms of beta-adrenergic hypersensitivity. Beta 2-adrenergic receptor supercoupling with desensitization on isoproterenol exposure. Am J Med 1987;82:193–201. 10. Boudoulas H, Reynolds JC, Mazzaferri E, Wooley CF. Metabolic studies in mitral valve prolapse syndrome. A neuroendocrine– cardiovascular process. Circulation 1980;61:1200 –1205. 11. Frisingelli A, Turiel M, Milletich A, Crema C, Malliani A. The role of mitral regurgitation in the neurovegetative regulation of mitral valve prolapse. Cardiologia 1992;37:781–783.
