This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hamada, M. Articles by Hiwada, K. Search for Related Content PubMed PubMed Citation Articles by Hamada, M. Articles by Hiwada, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy

(Circulation. 1997;96:1520-1524.)
© 1997 American Heart Association, Inc.

Articles

Class Ia Antiarrhythmic Drug Cibenzoline

A New Approach to the Medical Treatment of Hypertrophic Obstructive Cardiomyopathy

Mareomi Hamada, MD; Yuji Shigematsu, MD; Shuntaro Ikeda, MD; Yuji Hara, MD; Hideki Okayama, MD; Koji Kodama, MD; Takaaki Ochi, MD; ; Kunio Hiwada, MD

From the Second Department of Internal Medicine, Ehime University School of Medicine, and Internal Medicine, Takanoko Hospital (T.O.), Ehime, Japan.

Correspondence to Mareomi Hamada, MD, The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-02, Japan.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background The class Ia antiarrhythmic drug disopyramide relieves the outflow tract obstruction of hypertrophic obstructive cardiomyopathy (HOCM). Disopyramide, however, has several adverse effects, such as dysuria and thirst, resulting from its anticholinergic activity. A new class Ia antiarrhythmic drug, cibenzoline, has little anticholinergic activity. The aim of this study is to elucidate whether cibenzoline attenuates left ventricular pressure gradient (LVPG) in patients with HOCM.

Methods and Results Ten patients with HOCM (mean age, 59±12 years) participated in this study. LVPG and left ventricular functions were measured before and 2 hours after administration of a single oral dose of 150 or 200 mg cibenzoline. LVPG decreased from 123±60 to 39±33 mm Hg (P=.0026). The E/A ratio in transmitral Doppler flow increased from 1.20±0.84 to 2.00±1.72 (P=.029). Isovolumic relaxation time increased from 73±16 to 101±23 ms (P=.0026). Left ventricular diastolic dimension remained unchanged, but left ventricular systolic dimension enlarged significantly, from 21.6±2.4 to 26.2±3.3 mm (P=.0004). Fractional shortening decreased from 47.6±6.1% to 34.6±8.8% (P=.0007). Left ventricular ejection time index decreased significantly, and preejection period index increased in all the patients. Decreased LVPG remained maintained even in the long-term treatment with cibenzoline.

Conclusions These results indicate that cibenzoline can markedly attenuate LVPG in patients with HOCM. A decrease in myocardial contractility seems to be closely related to a marked decrease in LVPG.

Key Words: antiarrhythmia agents • cardiomyopathy • contractility • echocardiography • hypertrophy

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
ß-Blockers and calcium antagonists are effective in alleviating symptoms and LVPG in many patients with HOCM, but these drugs are some times insufficient. In patients with HOCM in whom symptoms are refractory to medical therapy, surgical therapies such as ventriculomyectomy^{1 2} and pacemaker implantation^{3 4 5} have been performed, and good results and prognosis are attained. However, these invasive methods seem to put the patients under some stress. Thus, to decrease the stress and symptoms of the patients, other drugs to attenuate LVPG should be pursued.

Pollick⁶ reported that the class Ia antiarrhythmic drug disopyramide relieved the outflow tract obstruction of HCM. We also reported that disopyramide improved the diastolic function not only of patients with but also of those without LVPG.⁷ In addition, the effect of disopyramide on diastolic function of patients with HCM is similar to that of the calcium antagonist diltiazem.⁸ Disopyramide, however, has several troublesome adverse effects, such as dysuria and thirst, resulting from its anticholinergic activity. Thus, we cannot continue disopyramide to treat patients who suffer from these adverse effects. Recently, the class Ia antiarrhythmic drug cibenzoline, which has little anticholinergic activity,⁹ has been used as an antiarrhythmic drug in many countries. In this study, we examined whether cibenzoline attenuated LVPG in patients with HCM.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Patients
Ten patients with HCM whose LVPG was >30 mm Hg without provocation participated in this study after giving informed consent. Table 1 shows clinical profiles of these 10 patients. The diagnosis of HCM was made by echocardiography based on the World Health Organization/International Society and Federation of Cardiology definition of cardiomyopathies.¹⁰ All patients had been treated with ß-blockers and calcium antagonists, 7 patients with 30 to 60 mg of propranolol and 90 to 180 mg of diltiazem, and 3 with 30 to 60 mg of propranolol and 120 mg of verapamil per day. In addition to the combination therapy of ß-blockers and calcium antagonists, 4 patients had received 150 to 300 mg of disopyramide per day (patients 1, 3, 7, and 9). LVPG at rest, which was determined by the Doppler approach with the Bernoulli equation,¹¹ ranged between 44 and 213 mm Hg. We did not include patients who had systemic hypertension, significant valvular heart disease, or any other systemic conditions that might cause cardiac hypertrophy. In addition, patients with HCM who showed dilated cardiomyopathy–like features were also excluded from this study.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical and Echocardiographic Characteristics of Patients and Effects of Cibenzoline

Study Protocol
Cibenzoline was given orally to patients in the laboratory for noninvasive study. A single oral dose of 150 mg was administered to 2 female patients, and 200 mg was administered to 8 male patients. The plasma concentration of cibenzoline was measured 2 hours after oral administration, the time at which maximal plasma concentration is expected.^{12 13} Measurements of heart rate and blood pressure and ECG, M-mode and continuous-wave Doppler echocardiographic, and mechanocardiographic recordings were made before and 2 hours after oral administration of cibenzoline.

To evaluate the long-term effects of cibenzoline on LVPG, patients who had been treated with 300 mg/d of cibenzoline for >3 months received a repeated echocardiographic study. Echocardiography to determine LVPG was carried out in the morning 2 hours after the oral administration of cibenzoline.

M-Mode and Doppler Echocardiography
Echocardiographic studies were carried out with an SSD-9000 echocardiograph with a 3.5-MHz transducer (ALOKA Inc). M-mode echocardiographic recording was carried out after the cardiac anatomy was visualized by two-dimensional echocardiography. Interventricular septal thickness and left ventricular posterior wall thickness, left ventricular internal dimensions at end diastole and end systole, and left atrial dimension were measured according to the criteria of the American Society of Echocardiography.¹⁴ In addition, the distance from ventricular septum to mitral valve¹⁵ and fractional shortening were also calculated. LVPG was measured from continuous-wave Doppler recordings of the left ventricular outflow tract,¹¹ and peak A-wave and peak E-wave velocities and E/A ratio¹⁶ were measured from transmitral Doppler recordings. In addition, isovolumic relaxation time was measured from simultaneous recordings of phonocardiogram and Doppler echocardiogram. The M-mode echocardiogram and continuous-wave Doppler recording were recorded at a paper speed of 100 mm/s.

Systolic Time Intervals
Systolic time intervals were determined as reported previously.¹⁷ To measure left ventricular ejection time and preejection time, simultaneous recordings of the ECG, phonocardiogram, and carotid pulse tracing at a paper speed of 100 mm/s were performed with an MIC-8800 polygraph (Fukuda Denshi Co Ltd). Left ventricular ejection time and preejection time were shown by heart rate–corrected values with the regression equations of Weissler et al.¹⁸

Statistical Analysis
All values are expressed as mean±SD. Data obtained before and after administration or late after treatment of cibenzoline were compared by Student's t test for paired samples. A value of P<.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Change of LVPG
The changes of heart rate, blood pressures, and LVPG associated with administration of cibenzoline are shown in Table 1. Blood pressures remained unchanged, but heart rate decreased slightly but significantly. Conversely, LVPG decreased markedly in all patients. Fig 1 shows the change of M-mode echocardiographic findings in patient 1. Big systolic anterior motion of the mitral valve (arrow mark in Fig 1A) completely disappeared (Fig 1B), and systolic murmur markedly decreased.

View larger version (118K): [in this window] [in a new window]   Figure 1. Changes of M-mode echocardiograms associated with administration of cibenzoline in patient with HOCM (patient 1). Echocardiogram before cibenzoline (A) showed big systolic anterior motion of mitral valve (SAM) (arrow), loud systolic murmur, and reversed splitting of second heart sound; after cibenzoline (B), SAM completely disappeared and systolic murmur was markedly decreased. PCG indicates phonocardiogram; ACG, apex cardiogram; IVS, interventricular septum; LVPW, left ventricular posterior wall; and IIp and IIa, pulmonary and aortic components of second heart sound.

Echocardiographic Dimensional Changes
Changes of echocardiographic dimensions are shown in Table 2. Left ventricular end-diastolic dimension and left atrial dimension (from 45.7±5.9 to 45.8±5.4 mm) remained unchanged after the administration of cibenzoline. However, left ventricular end-systolic dimension increased significantly in all patients. The distance between ventricular septum and mitral valve was also increased in all patients.

View this table: [in this window] [in a new window]   Table 2. Changes in Echocardiographic Parameters Before and After Administration of Cibenzoline

Changes of Left Ventricular Functions
Table 2 shows the changes of left ventricular functions shown by echocardiography. Fractional shortening decreased in all patients after the administration of cibenzoline. E-wave velocity remained unchanged, but A-wave velocity decreased and E/A ratio increased in all the patients. Isovolumic relaxation time increased in all patients. Fig 2 shows the change of transmitral Doppler flow pattern in patient 1 associated with cibenzoline treatment. Both E-wave and A-wave velocity decreased, and E/A ratio increased. Isovolumic relaxation time was markedly prolonged.

View larger version (100K): [in this window] [in a new window]   Figure 2. Change of transmitral Doppler flow pattern before (A) and after (B) administration of cibenzoline in patient 1. After administration of cibenzoline, E/A ratio increased, A-wave velocity decreased, and isovolumic relaxation time (IRT) markedly prolonged. PCG indicates phonocardiogram.

Left ventricular ejection time index decreased markedly in all patients, from 453±40 to 390±30 ms (P=.0001), and preejection period index increased in all patients, from 122±16 to 158±10 ms (P=.0001). Fig 3 shows the changes of LVPG and left ventricular ejection time index associated with administration of cibenzoline. The decrease in LVPG was well coordinated with the decrease in left ventricular ejection time index.

View larger version (18K): [in this window] [in a new window]   Figure 3. Changes of left ventricular ejection time index and LVPG before and 2 hours after administration of cibenzoline. Arrows indicate intraoperative change in each patient from pretreatment () to posttreatment () of cibenzoline. There was a good relationship between the two variables.

Long-term Effect of Cibenzoline on LVPG and Clinical Symptoms
Table 1 also shows the effect of late posttreatment of cibenzoline on LVPG. The mean follow-up period in 8 patients was 4.8±1.4 months, and the mean value of LVPG was 44±36 mm Hg (P=.0082 versus pretreatment).

No adverse effects associated with the long-term treatment of cibenzoline were observed in any patients. On the contrary, frequent urination in the night observed in 3 patients who had been treated with disopyramide completely disappeared (patients 1, 3, and 7). In addition, 3 patients who were in NYHA class III or IV improved to class II.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrated for the first time that oral cibenzoline administration markedly reduced LVPG in patients with HOCM. Its mechanism for the decrease in LVPG was due mainly to a decrease in left ventricular myocardial contractility. In addition, a significant decrease in LVPG continued even in long-term treatment with cibenzoline.

Effect of Cibenzoline on Left Ventricular Function
Short-term effects of cibenzoline on left ventricular function in patients with HCM were characterized by a decrease in fractional shortening, an increase of E/A ratio and isovolumic relaxation time, and prolongation of preejection period. Of these hemodynamic parameters, both fractional shortening and preejection period are sensitive markers of myocardial contractility. Thus, our results indicate that cibenzoline has a potent negative inotropic action. Significant enlargement of left ventricular end-systolic dimension after administration of cibenzoline supports this finding. Millar and Vaughan Williams^{19 20} reported in experimental studies in rabbits that cibenzoline had a negative inotropic action and produced a bradycardia. Disopyramide is also known to have a potent negative inotropic action.^{7 21 22} In view of these findings, negative inotropic action may be a common characteristic of some types of class Ia antiarrhythmic drugs.

Left ventricular ejection time is known to reflect the severity of LVPG in patients with HOCM.²³ In the present study, we could confirm that there was a good correlation between differences in LVPG and in left ventricular ejection time index before and after administration of cibenzoline. In view of the marked prolongation of preejection period observed in association with the administration of cibenzoline, the decrease in left ventricular ejection time associated with cibenzoline may be related to the decrease of LVPG and to the change of left ventricular myocardial contractility.

It is well known that E/A ratio and isovolumic relaxation time are sensitive markers of left ventricular diastolic function.^{16 24 25} In the present study, after administration of cibenzoline, peak E-wave velocity remained unchanged, but peak A-wave velocity decreased in all patients. This finding suggests that in early diastole the pressure gradient between the left atrium and left ventricle remains unchanged but in late diastole it decreases. Conversely, cibenzoline increased isovolumic relaxation time in all patients. Usually, isovolumic relaxation time in patients with HCM prolongs according to the delay of mitral valve opening due to prolonged relaxation of the left ventricle.²⁵ However, elevation of left atrial pressure results in early opening of the mitral valve and shortens isovolumic relaxation time.^{26 27} Thus, the relatively short isovolumic relaxation time before administration of cibenzoline appears to be due to high left atrial pressure, and the prolongation of isovolumic relaxation time after administration may be the result of a decrease of left atrial pressure. Taking the findings of transmitral Doppler flow pattern and isovolumic relaxation time into consideration, it is highly conceivable that both left atrial and ventricular pressures decrease in patients after administration of cibenzoline.

Mechanism for Decrease of LVPG Associated With Administration of Cibenzoline
The exact mechanism for the decrease in LVPG by oral administration of cibenzoline remains to be determined. It is well known that the negative inotropic action of ß-blockers is related to a decrease of LVPG, and higher doses of propranolol produce greater effects on the fall in pressure gradient.²⁸ Thus, it is highly conceivable that the decrease in myocardial contractility associated with cibenzoline treatment is strongly related to a decrease of LVPG. A marked decrease of left ventricular excursion and enlargement of left ventricular outflow tract area contribute much to the decrease of LVPG in patients with HOCM.

It is also acknowledged that calcium antagonists attenuate LVPG in patients with HOCM.^{29 30} A few experimental studies show that cibenzoline possesses a certain calcium channel–blocking property.^{31 32} Rosing et al²⁹ reported that the intravenous administration of verapamil to patients with HOCM diminished basal and provocable LVPG. In their study, although cardiac output remains unchanged, both mean pulmonary artery wedge and left ventricular end-diastolic pressures decrease in most patients who have high left ventricular filling pressure. Thus, the beneficial effect of calcium antagonists on left ventricular diastolic function appears to contribute to the decrease of LVPG, but the precise mechanisms for the decrease of LVPG by calcium antagonist still remain to be determined. The changing pattern of pressures associated with verapamil administration seems to be similar to the changes of transmitral Doppler flow pattern associated with the administration of cibenzoline. Thus, the change of diastolic parameters in our study may be mainly due to the calcium channel–blocking property of cibenzoline.

Long-term Effect of Cibenzoline on LVPG and Clinical Implications
To elucidate whether cibenzoline is useful as a drug for HOCM, the long-term effect of cibenzoline on LVPG was examined in 8 patients who had been treated with 300 mg/d cibenzoline for >3 months. As shown in Table 1, a significant decrease in LVPG continued even in long-term treatment with cibenzoline in all 8 patients. This long-lasting good effect may indicate that cibenzoline can be an available drug for relieving LVPG in patients with HOCM.

No patients participating in this study complained of dysuria and thirst caused by the anticholinergic activity even after long-term treatment with cibenzoline. On the contrary, frequent urination in the night observed in patients treated with disopyramide disappeared. Thus, the anticholinergic effect of cibenzoline is remarkably weak compared with that of disopyramide.⁹ In addition, NYHA class markedly decreased in some patients after the treatment with cibenzoline. Although the improvement in survival by treatment with cibenzoline remains to be determined, our study suggests the potential clinical utility of cibenzoline in patients with HOCM.

	Selected Abbreviations and Acronyms

 

E/A ratio = ratio of E-wave velocity to A-wave velocity HCM = hypertrophic cardiomyopathy HOCM = hypertrophic obstructive cardiomyopathy LVPG = left ventricular pressure gradient

Received January 2, 1997; revision received March 6, 1997; accepted April 2, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. ten Berg JM, Suttorp MJ, Knaepen PJ, Ernst SMPG, Vermeulen FEE, Jaarsma W. Hypertrophic obstructive cardiomyopathy: initial results and long-term follow-up after Morrow septal myectomy. Circulation. 1994;90:1781-1785.[Abstract/Free Full Text]
   
2. Schoendube FA, Klues HG, Reith S, Flachskampf FA, Hanrath P, Messmer BJ. Long-term clinical and echocardiographic follow-up after surgical correction of hypertrophic obstructive cardiomyopathy with extended myectomy and reconstruction of the subvalvular mitral apparatus. Circulation. 1995;92(suppl II):II-122-II-127.
   
3. Jeanrenaud X, Goy JJ, Kappenberger L. Effects of dual-chamber pacing in hypertrophic obstructive cardiomyopathy. Lancet. 1992;339:1318-1323.[Medline] [Order article via Infotrieve]
   
4. Fananapazir L, Cannon RO, Tripodi D, Panza JA. Impact of dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and ß-adrenergic blocker therapy. Circulation. 1992;85:2149-2161.[Abstract/Free Full Text]
   
5. Fananapazir L, Epstein ND, Curiel RV, Panza JA, Tripodi D, McAreavey D. Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy: evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation. 1994;90:2731-2742.[Abstract/Free Full Text]
   
6. Pollick C. Muscular subaortic stenosis: hemodynamic and clinical improvement after disopyramide. N Engl J Med. 1982;307:997-999.[Medline] [Order article via Infotrieve]
   
7. Sumimoto T, Hamada M, Ohtani T, Shigematsu Y, Fujiwara Y, Sekiya M, Hiwada K. Effect of disopyramide on systolic and early diastolic time intervals in patients with hypertrophic cardiomyopathy. J Clin Pharmacol. 1991;31:440-443.[Abstract]
   
8. Sumimoto T, Hamada M, Ohtani T, Suzuki M, Abe M, Matsuoka H, Fujiwara Y, Sekiya M, Hiwada K. Effect of disopyramide on left ventricular diastolic function in patients with hypertrophic cardiomyopathy: comparison with diltiazem. Cardiovasc Drugs Ther. 1992;6:425-428.[Medline] [Order article via Infotrieve]
   
9. Cazes M, Chassaing C, Martinet M, Cloarec A, Provost D, Boucher M, Duchene-Marullaz P. Comparison of anticholinergic effects of cibenzoline, disopyramide, and atropine. J Cardiovasc Pharmacol. 1990;15:308-316.[Medline] [Order article via Infotrieve]
   
10. Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. Br Heart J. 1980;44:672-673.[Free Full Text]
    
11. Sasson Z, Yock PG, Hatle LK, Alderman EL, Popp RL. Doppler echocardiographic determination of the pressure gradient in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1988;11:752-756.[Abstract]
    
12. Khoo KC, Szuna AJ, Colburn WA, Aogaichi K, Morganroth J, Brazzell RK. Single-dose pharmacokinetics and dose proportionality of oral cibenzoline. J Clin Pharmacol. 1984;24:283-288.[Abstract]
    
13. Brazzell RK, Rees MMC, Khoo KC, Szuna AJ, Sandor D, Hannigan J. Age and cibenzoline disposition. Clin Pharmacol Ther. 1984;36:613-619.[Medline] [Order article via Infotrieve]
    
14. Sahn DJ, DeMaria A, Kisslo J, Weyman A, The Committee on M-mode Standardization of The American Society of Echocardiography. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58:1072-1083.[Abstract/Free Full Text]
    
15. Spirito P, Maron BJ. Significance of left ventricular outflow tract cross-sectional area in hypertrophic cardiomyopathy: a two-dimensional echocardiographic assessment. Circulation. 1983;67:1100-1108.[Abstract/Free Full Text]
    
16. Bryg RJ, Pearson AC, Williams GA, Labovitz AJ. Left ventricular systolic and diastolic flow abnormalities determined by Doppler echocardiography in obstructive hypertrophic cardiomyopathy. Am J Cardiol. 1987;59:925-931.[Medline] [Order article via Infotrieve]
    
17. Hamada M, Ito T, Hiwada K, Kokubu T, Genda A, Takeda R. Characteristics of systolic time intervals in patients with pheochromocytoma. Jpn Circ J. 1991;55:417-426.[Medline] [Order article via Infotrieve]
    
18. Weissler AM, Harris WS, Schoenfeld CD. Bedside technics for the evaluation of ventricular function in man. Am J Cardiol. 1969;23:577-583.[Medline] [Order article via Infotrieve]
    
19. Millar JS, Vaughan Williams EM. Pharmacological mapping of regional effects in the rabbit heart of some new antiarrhythmic drugs. Br J Pharmacol. 1983;79:701-709.[Medline] [Order article via Infotrieve]
    
20. Millar JS, Vaughan Williams EM. Effects on rabbit nodal, atrial, ventricular and Purkinje cell potentials of a new antiarrhythmic drug, cibenzoline, which protects against action potential shortening in hypoxia. Br J Pharmacol. 1982;75:469-478.[Medline] [Order article via Infotrieve]
    
21. Pollick C. Disopyramide in hypertrophic cardiomyopathy, II: noninvasive assessment after oral administration. Am J Cardiol. 1988;62:1252-1255.[Medline] [Order article via Infotrieve]
    
22. Pollick C, Giacomini KM, Blaschke TF, Nelson WL, Turner-Tamiyasu K, Briskin V, Popp RL. The cardiac effects of d- and l-disopyramide in normal subjects: a noninvasive study. Circulation. 1982;66:447-453.[Abstract/Free Full Text]
    
23. Pollick C, Rakowski H, Wigle ED. Muscular subaortic stenosis: the quantitative relationship between systolic anterior motion and the pressure gradient. Circulation. 1984;69:43-49.[Abstract/Free Full Text]
    
24. Lewis BS, Lewis N, Sapoznikov D, Gotsman MS. Isovolumic relaxation period in man. Am Heart J. 1980;100:490-499.[Medline] [Order article via Infotrieve]
    
25. Hamada M, Matsuzaki K, Kazatani Y, Nishitani K, Daimon F, Ochi T, Ito T, Joh T, Kokubu T. Diagnostic significance of early diastolic time intervals in patients with hypertrophic cardiomyopathy and myocardial hypertrophy due to essential hypertension. Jpn Circ J. 1983;47:522-527.[Medline] [Order article via Infotrieve]
    
26. Myreng Y, Smiseth OA. Assessment of left ventricular relaxation by Doppler echocardiography: comparison of isovolumic relaxation time and transmitral flow velocities with time constant of isovolumic relaxation. Circulation. 1990;81:260-266.[Abstract/Free Full Text]
    
27. Hamada M, Suzuki M, Shigematsu Y, Abe M, Matsuoka H, Fujiwara Y, Sumimoto T, Sekiya M, Hiwada K. Does isovolumic relaxation time reflect the severity of left ventricular hypertrophy in patients with essential hypertension? Am J Noninvas Cardiol. 1992;6:99-103.
    
28. Frank MJ, Abdulla AM, Watkins LO, Prisant L, Stefadouros MA. Long-term medical management of hypertrophic cardiomyopathy: usefulness of propranolol. Eur Heart J. 1983;4(suppl F):155-164.
    
29. Rosing DR, Kent KM, Borer JS, Seides SF, Maron BJ, Epstein SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy, I: hemodynamic effects. Circulation. 1979;60:1201-1207.[Abstract/Free Full Text]
    
30. Kaltenbach M, Hopf R, Kober G, Bussman WD, Keller M, Petersen Y. Treatment of hypertrophic obstructive cardiomyopathy with verapamil. Br Heart J. 1979;42:35-42.[Abstract/Free Full Text]
    
31. Holck M, Osterrieder W. Inhibition of the myocardial Ca²⁺ inward current by the class I antiarrhythmic agent, cibenzoline. Br J Pharmacol. 1986;87:705-711.[Medline] [Order article via Infotrieve]
    
32. Matsuoka S, Nawada T, Hisatome I, Miyamoto J, Hasegawa J, Kotake H, Mashiba H. Comparison of Ca²⁺ channel inhibitory effects of cibenzoline with verapamil on guinea-pig heart. Gen Pharmacol. 1991;22:87-91.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				Y. Hosokawa, H. Takano, T. Ohno, M. Takayama, and T. Takano Impact of Percutaneous Transluminal Septal Myocardial Ablation on Refractory Paroxysmal Atrial Fibrillation in Patients With Hypertrophic Obstructive Cardiomyopathy Angiology, July 1, 2008; 59(3): 329 - 334. [Abstract] [PDF]

				S.-i. Morimoto, A. Sugiura, M. Iwase, N. Kubo, S. Hiramitsu, A. Uemura, M. Ohtsuki, S. Kato, Y. Kato, and H. Hishida Relief of Left Ventricular Outflow Obstruction by Cibenzoline in a Patient With Fabry's Disease: A Case Report Angiology, March 1, 2006; 57(2): 241 - 245. [Abstract] [PDF]

				A. Sarkozy, A. Caenepeel, P. Geelen, P. Peytchev, M. de Zutter, and P. Brugada Cibenzoline induced Brugada ECG pattern Europace, January 1, 2005; 7(6): 537 - 539. [Abstract] [Full Text] [PDF]

				G. Hiasa, M. Hamada, H. Saeki, A. Ogimoto, T. Ohtsuka, Y. Hara, and Y. Shigematsu Cardiac Sympathetic Nerve Activity Can Detect Congestive Heart Failure Sensitively in Patients With Hypertrophic Cardiomyopathy Chest, September 1, 2004; 126(3): 679 - 686. [Abstract] [Full Text] [PDF]

				M. Hamada, Y. Shigematsu, K. Ohshima, J. Suzuki, A. Ogimoto, T. Ohtsuka, and Y. Hara Diagnostic Usefulness of Carotid Pulse Tracing in Patients With Hypertrophic Obstructive Cardiomyopathy Due to Midventricular Obstruction: A Comparison With Idiopathic Hypertrophic Subaortic Stenosis Chest, October 1, 2003; 124(4): 1275 - 1283. [Abstract] [Full Text] [PDF]

				M. Ashidagawa, M. Ohara, and Y. Koide An Intraoperative Diagnosis of Dynamic Left Ventricular Outflow Tract Obstruction Using Transesophageal Echocardiography Leads to the Treatment with Intravenous Disopyramide Anesth. Analg., February 1, 2002; 94(2): 310 - 312. [Abstract] [Full Text] [PDF]

				P. P. Dimitrow, K. Kodama-Takahashi, Y. Shigematsu, M. Hamada, K. Hiwada, Y. Kazatani, K. Matsuzaki, and E. Murakami Coronary Vasospasm in Hypertrophic Cardiomyopathy Chest, April 1, 2001; 119(4): 1289 - 1291. [Full Text] [PDF]

				H.-W. Hopp, F. M. Baer, C. Ozbek, K. H. Kuck, B. Scheller, and for the AtheroLink Study Group A synergistic approach to optimal stenting: Directional coronary atherectomy prior to coronary artery stent implantation--the AtheroLink registry J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1853 - 1859. [Abstract] [Full Text] [PDF]

				H. Li, H. Simon, T. M.A. Bocan, and J.T. Peterson MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition Cardiovasc Res, May 1, 2000; 46(2): 298 - 306. [Abstract] [Full Text] [PDF]

				T. Tokudome, K. Mizushige, T. Ueda, S. Sakamoto, H. Matsuo, and K. Mizushige Effect of Disopyramide on Left Ventricular Pressure Gradient in Hypertrophic Obstructive Cardiomyopathy in Comparison with Propranolol: A Case Report Angiology, April 1, 1999; 50(4): 331 - 335. [Abstract] [PDF]

				G. Hahalis, D. Alexopoulos, A. S. Manolis, M. Hamada, Y. Shigematsu, K. Hiwada, Y. Hara, S. Ikeda, H. Okayama, K. Kodama, et al. Altered Mitral Flow Pattern in Patients With Hypertrophic Obstructive Cardiomyopathy • Response Circulation, November 10, 1998; 98 (19): 2098 - 2102. [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hamada, M. Articles by Hiwada, K. Search for Related Content PubMed PubMed Citation Articles by Hamada, M. Articles by Hiwada, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy