Comparison of Acute Reduction in Left Ventricular Outflow Tract Pressure Gradient in Obstructive Hypertrophic Cardiomyopathy by Disopyramide Versus Pilsicainide Versus Cibenzoline




Negative inotropic agents are often administered to decrease the left ventricular (LV) pressure gradient in patients with obstructive hypertrophic cardiomyopathy (HC). Little information is available regarding comparisons of the effects on LV pressure gradient among negative inotropic agents. The present study compared the decrease in the LV pressure gradient at rest in patients with obstructive HC after treatment with pilsicainide versus treatment with disopyramide or cibenzoline. The LV pressure gradient and LV function were assessed before and after the intravenous administration of each drug. In 12 patients (group A, mean pressure gradient 90 ± 24 mm Hg), the effects of disopyramide, propranolol, and verapamil were compared. In another 12 patients (group B, mean pressure gradient 98 ± 34 mm Hg), a comparison was performed among disopyramide, cibenzoline, and pilsicainide. In group A, the percentage of reduction in the LV pressure gradient was 7.7 ± 9.9% with verapamil, 19.0 ± 20.2% with propranolol, and 58.6 ± 15.0% with disopyramide, suggesting that disopyramide was more effective than either verapamil or propranolol. In group B, the percentage of reduction in the LV pressure gradient was 55.3 ± 26.6% with disopyramide, 55.3 ± 20.6% with cibenzoline, and 54.7 ± 15.4% with pilsicainide, suggesting an equivalent effect on the LV pressure gradient for these 3 agents. In conclusion, these results indicate that the acute efficacy for the reduction of the LV pressure gradient at rest by pilsicainide (a pure sodium channel blocker) was equivalent to that of disopyramide or cibenzoline (combined sodium and calcium channel blockers). Accordingly, sodium channel blockade might be more important for reducing the LV pressure gradient at rest in patients with obstructive HC than calcium channel blockade or β blockade.


The present study compared the acute reduction of the left ventricular (LV) pressure gradient at rest produced by disopyramide versus that produced by propranolol or verapamil and that produced by pilsicainide (a pure sodium channel blocker) versus that produced by cibenzoline or disopyramide in patients with obstructive hypertrophic cardiomyopathy (HC).


Methods


We prospectively studied 24 patients with symptomatic obstructive HC who had a LV pressure gradient of ≥30 mm Hg at rest without provocation. All 24 participants had severe symptoms (angina in 12 [50%], dyspnea in 20 [87%], and presyncope in 3 [13%]) and were undergoing either a diagnostic pharmacologic or preoperative evaluation. The diagnosis of HC was determined by the identification using 2-dimensional echocardiography of a hypertrophic, nondilated left ventricle in the absence of another cardiac or systemic disease capable of causing a similar extent of hypertrophy. All patients had a septal thickness >15 mm without any apparent cause of hypertrophy, and they had obstruction of the left ventricular outflow tract due to systolic anterior motion of the mitral valve with a peak instantaneous gradient of ≥30 mm Hg with at rest conditions on the continuous-wave Doppler echocardiogram. We excluded patients who had systemic hypertension, significant valvular heart disease, other systemic conditions that might cause cardiac hypertrophy, or midventricular obstruction (≥30 mm Hg) at rest. The present study was performed according to the principles of the Declaration of Helsinki, and all patients gave informed consent after receiving a written explanation.


All 24 participants underwent baseline assessment of the LV function and LV pressure gradient during hospitalization and were then divided into 2 groups of 12 patients each. The first group (group A, mean LV pressure gradient at rest 90 ± 24 mm Hg) was used to evaluate the effects of propranolol, verapamil, and disopyramide. The second group (group B, mean LV pressure gradient at rest 98 ± 34 mm Hg) was used to evaluate the effects of pilsicainide, disopyramide, and cibenzoline.


Each drug was administered intravenously for a 5-minute period at the following dosages in a random order: propranolol, 0.20 mg/kg ; verapamil 0.10 mg/kg ; disopyramide 1.0 mg/kg ; cibenzoline 1.4 mg/kg ; and pilsicainide 1.0 mg/kg. Echocardiography was performed at the beginning of the study and at 5 minutes after the end of the intravenous administration of each drug. The interval between the intravenous administration of each drug during hospitalization was >24 hours (mean 30). Acute efficacy was defined as a significant reduction in the LV pressure gradient at rest by >50% after intravenous administration. All cardiac medications were withheld for 48 hours before the study.


Echocardiography was conducted using a Hewlett-Packard Sonos 5500 and a 3.5-MHz transducer. Standard techniques were used to obtain M-mode, 2-dimensional, and Doppler measurements. The severity and distribution of LV hypertrophy was assessed in short-axis views by dividing the LV wall into 4 segments (anterior septum, posterior septum, anterolateral wall, and posterior wall) at the level of the mitral valve and at the papillary muscles. The E-wave velocity/A-wave velocity (E/A) ratio and the deceleration time (DcT) were calculated from the transmitral Doppler recordings. Simultaneous recording of the phonocardiogram and Doppler echocardiogram was done to assess the isovolumic relaxation time (IRT). LV outflow tract obstruction was quantified by continuous-wave Doppler echocardiography under at rest conditions. In the present study, all echocardiographic data were obtained by an experienced sonographer and interpreted by 2 experienced echocardiographers who were unaware of the study drugs and that the patients were participating in the present study.


Analyses were performed using Statistical Analysis Systems, version 9.1, software (SAS Institute, Cary, North Carolina). The data are presented as the mean ± SD. A paired t test was used to compare the 2 groups. The Tukey-Kramer multiple comparison procedure was used for the continuous variables showing a normal distribution. Pearson’s correlation coefficient and a linear regression model was applied to evaluate the relation between 2 continuous variables. p Values <0.05 (2-tailed) were considered to indicate statistical significance. All analyses were performed by an independent biostatistics and data center (STATZ Institute, Tokyo, Japan).




Results


The changes in the LV pressure gradient at the end of the administration of each drug are listed in Tables 1 and 2 , and Figure 1 . In group A, the percentage of the reduction in the LV pressure gradient was −19.0 ± 20.2% with propranolol (p = 0.005), −7.7 ± 9.9% with verapamil (p = 0.030), and −58.6 ± 15.0% with disopyramide (p <0.001), suggesting that disopyramide was more effective than verapamil or propranolol (p <0.001 and p <0.001, respectively). In group B, the percentage of the reduction in the LV pressure gradient was −55.3 ± 26.6% with disopyramide (p <0.001), −55.3 ± 20.6% with cibenzoline (p <0.001), and −54.7 ± 15.4% with pilsicainide (p <0.001), suggesting that the acute effect of pilsicainide (a pure sodium-channel blocker) on the LV pressure gradient at rest was almost equal to that of disopyramide and cibenzoline ( Figure 1 ). The percentage of the reduction in the LV pressure gradient in each patient is shown in Figure 2 . Disopyramide reduced the LV pressure gradient at rest more than did either propranolol or verapamil in all 12 patients ( Figure 2 ). Regarding the acute effect of class I antiarrhythmic drugs on the LV pressure gradient at rest, however, 4 patients (33%) had a decrease in the LV pressure gradient by >50% or an LV pressure gradient of <30 mm Hg with 2 drugs, and 5 patients (42%) did so with all 3 drugs, suggesting that the acute efficacy of each drug varied among patients with HC ( Figure 2 ). Regarding the acute effect of these agents on the systolic blood pressure and heart rate, all 3 of the class I antiarrhythmic drugs (disopyramide, cibenzoline, and pilsicainide) significantly increased the systolic blood pressure (from 126 ± 11 to 138 ± 10, 128 ± 10 to 140 ± 11, and 125 ± 10 to 139 ± 12 mm Hg, respectively; p <0.001), although the heart rate was not changed significantly (from 74 ± 8 to 71 ± 11, 73 ± 6 to 70 ± 10, and 72 ± 8 to 68 ± 9 beats/min, respectively). After the intravenous administration of propranolol, the systolic blood pressure and heart rate did not change significantly (from 129 ± 11 to 131 ± 12 mm Hg and from 75 ± 6 to 73 ± 9 beats/min, respectively). The acute intravenous administration of verapamil caused a significant decrease in the systolic blood pressure from 128 ± 12 to 119 ± 9 mm Hg (p<0.001), although the heart rate was not changed significantly (from 74 ± 7 to 72 ± 9 beats/min).



Table 1

Baseline echocardiographic characteristics of patients in group A and acute effect of each drug on left ventricular (LV) pressure gradient










































































































































































































































Pt. No. Age (yrs) VST (mm) PWT (mm) LVDd (mm) FS (%) LVPG (mm Hg)
Disopyramide Propranolol Verapamil
Before After Change Before After Change Before After Change
1 25 32 13 36 47 64 30 34 70 70 0 70 68 2
2 26 18 14 28 39 75 10 65 70 60 10 60 50 10
3 38 18 14 50 41 81 49 32 100 100 0 84 84 0
4 45 16 14 40 40 125 35 90 100 92 8 100 100 0
5 48 28 15 47 43 108 57 51 100 100 0 100 100 0
6 53 26 12 36 56 100 23 27 130 128 2 100 100 0
7 56 16 12 40 40 40 15 25 74 40 34 40 40 0
8 58 16 16 40 50 108 60 48 121 85 46 100 100 0
9 58 30 20 32 30 134 81 53 130 108 22 125 100 25
10 58 24 16 48 38 96 42 54 80 63 17 75 53 22
11 61 16 16 46 32 71 25 46 81 40 41 81 70 11
12 70 15 13 43 49 70 28 42 71 36 35 108 100 8
Median 55 (42–58) 18 (16–27) 14 (13–16) 40 (36–47) 41 (39–48) 89 (71–108) 33 (24–53) ⁎ 47 (33–53) 91 (73–111) 78 (50–100) † 14 (0–35) 92 (73–100) 92 (61–100) † 1 (0–10)

Data in parentheses are interquartile ranges.

FS = fractional shortening; LVDd = left ventricular diastolic dimension; LVPG = left ventricular pressure gradient; Pt. No. = patient number; PWT = posterior wall thickness; VST = ventricular septal thickness.

⁎ p <0.001 versus before;


† p <0.05 versus before.



Table 2

Baseline echocardiographic characteristics of patients in group B and acute effect of each drug on left ventricular (LV) pressure gradient










































































































































































































































Pt. No. Age (yrs) VST (mm) PWT (mm) LVDd (mm) FS (%) LVPG (mm Hg)
Disopyramide Cibenzoline Pilsicainide
Before After Change Before After Change Before After Change
13 21 26 14 44 48 71 31 40 100 16 84 100 16 84
14 25 32 12 36 47 64 16 48 70 16 54 81 23 58
15 38 33 12 42 48 176 108 68 169 74 85 181 67 114
16 45 20 18 40 68 40 6 34 40 20 20 40 20 20
17 48 16 14 40 48 125 25 100 100 81 19 71 16 55
18 54 22 14 36 39 40 35 5 40 30 10 44 22 22
19 58 22 16 50 43 96 46 50 67 25 42 96 85 11
20 65 22 14 42 48 101 101 0 144 72 72 135 81 54
21 68 23 13 41 36 125 46 79 112 16 96 94 35 59
22 70 26 17 44 32 90 17 73 100 50 50 100 50 50
23 70 17 14 44 34 116 52 64 125 64 61 121 81 40
24 73 16 12 32 44 100 36 64 144 64 80 117 60 57
Median 56 (42–69) 21 (18–26) 14 (13–15) 42 (38–44) 46 (38–48) 98 (68–120) 36 (21–49) ⁎ 57 (37–71) 100 (69–135) 40 (18–68) ⁎ 58 (31–82) 98 (76–119) 42 (21–74) ⁎ 55 (31–59)

Data in parentheses are interquartile ranges.

Abbreviations as in Table 1 .

⁎ p <0.001 versus before.




Figure 1


Percentage of reduction in LV pressure gradient at rest after administration of each agent. (A) Percentage of reduction in LV pressure gradient at rest after intravenous administration of disopyramide, propranolol, or verapamil. (B) Percentage of reduction in LV pressure gradient at rest after intravenous administration of disopyramide, cibenzoline, or pilsicainide.

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Dec 22, 2016 | Posted by in CARDIOLOGY | Comments Off on Comparison of Acute Reduction in Left Ventricular Outflow Tract Pressure Gradient in Obstructive Hypertrophic Cardiomyopathy by Disopyramide Versus Pilsicainide Versus Cibenzoline

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