- Email: [email protected]
Left Ventricular End-Diastolic Pressure-Volume Relationships in Hypertrophic Cardiomyopathy
Left Ventricular End-Diastolic PressureVolume Relationships in Hypertrophic Cardiomyopathy* Changes Induced by Verapamil Michael Tendera, M.D.;t Lech Polonski, M.D.; and Ewa Kozielska, M.D.
In 16 patients with hypertrophic cardiomyopathy, an acute response of the left ventricular end-diastolic pressure and volume index to intravenously administered verapamil was assessed. Verapamil decreased the left ventricular enddiastolic pressure from 20:i:6to17 :i: 5 mm Hg (p<0.001) and increased the end-diastolic volume index from 82 :i: 22 to
v
erapamil has been found to be a promising drug in the treatment of hypertrophic cardiomyopathy. 1-7 Both symptomatic improvement''-9 and beneficial hemodynamic effects 2·"·10•11 were reported. Results of some studies indicate that verapamil may actually reverse hypertrophy in patients with hypertrophic cardiomyopathy;4·5·12 however, this opinion has not gained wide acceptance. 7 The present study was undertaken to evaluate changes in left ventricular end-diastolic pressure and volume in the setting of acute administration of verapamil and to determine if these changes depend on the baseline hemodynamic measurements. MATERIALS AND METHODS
Sixteen patients (13 men and three women) aged 17 to 51 years (mean ± SD, 33±10 years) were studied. All had echocardiographic evidence of asymmetric septa! hypertrophy with a septa! to free wall thickness ratio greater than 1.5 13·" in the absence of other cardiac disease. All patients were in sinus rhythm. An intraventricular pressure gradient of 20 to 130 mm Hg (mean, 49. 9 ± 36. 7 mm Hg) was found in eight patients; in the remaining eight, no gradient was demonstrated. All medications were withheld for 48 hours prior to the investigation. The nature of the procedure was explained to each patient, and informed consent was obtained. After premedication with IO mg of diazepam orally, a Swan-Ganz thermodilution catheter was placed in the pulmonary artery. Left heart catheterization was performed using a pigtail catheter (Cordis F 8). Pressures were measured by means of transducers (Statham P 23 ID), with the zero reference point at midchest level. Left ventricular end-diastolic presure (LVEDP) was measured 50 msec after the onset of the QRS complex. Cardiac output was calculated by a cardiac output computer (Edwards Laboratories 9520 A). After obtaining baseline pressures and cardiac output, a singleplane left ventriculographic study in the 30° right anterior oblique *From the Second Department of Cardiology, Silesian Medical Academy, Zabrze, Poland. tCardiology Fellow, Vanderbilt University-St. Thomas Hospital, Nashville, Tenn. Manuscript received November 29; revision accepted February 24.
54
91:i:23 ml/sqm (p<0.01). In 13 (81 percent) of 16 patients, an improvement of end-diastolic pressure-volume relationships occurred. In hypertrophic cardiomyopathy, intravenous verapamil exerts a beneficial effect on left ventricular filling conditions, producing an augmentation of filling volume at a lower filling pressure.
projection was performed. Only technically adequate ventriculograms, without catheter-induced arrhythmias, were analyzed. Twenty minutes after the first ventriculogram, measurements of cardiac output and pressure were repeated. In all patients, these values were found to have returned to baseline. At that point an intravenous injection of verapamil (lsoptin) was given in a dosage of 0.1 mg/kg of body weight over two minutes, followed by infusion of 0.01 mg/kg/min. After ten minutes of the infusion, all measurements of pressure, as well as left ventriculograms, were done again. Left ventricular volumes were calculated according to the arealength method, 1> the left ventricular mass index was established by the method of Rackley et al, 16 and the mean thickness of left ventricular free wall was measured with a planimeter. Selective coronary arteriograms employing the Judkins technique completed the study in all patients. No obstructive coronary lesions were round. In order to assess the influence of systolic loading conditions on diastolic measurements, peak systolic pressures in the aorta and left ventricle, as well as basal left ventricular outflow gradients, were also measured. Data were analyzed statistically using Students t-test. RESULTS
The results are summarized in Table 1. Verapamil significantly decreased both left ventricular peak systolic pressure from 136 ± 41 to 115 ± 30 mm Hg (p<0.001) and systolic aortic pressure from 111±17 to 102 ± 15 mm Hg (p<0.001). The left ventricular outflow gradient, present at rest in eight patients, was reduced by verapamil in seven and remained unchanged in one (baseline gradient, 50 ± 37 mm Hg; gradient after verapamil, 25±28 mm Hg [p<0.001)). In no instance did the gradient increase, even though the fall in peak aortic pressure was a uniform concomitant finding. The LVEDP declined by 1 to 8 mm Hg in 14 patients, remained unchanged in one, and rose by 3 mm Hg in one patient. The mean value for LVEDP dropped from 20±6 to 17±5 mm Hg (p<0.001). This represents an average decrease in LVEDP by 3 mm Hg (15 percent of the control value).
Prassure-1/0lume Relalionshlps In Hypertrophlc Cerdiomyopalhy (Tendera, Po/ons/d, Kozlelske)
Table !·-Baseline Hemodynamic Data and Verapamil-lnduced Changes in Patients with Hypertrophic Cardiomyopathy*
LVED\'l, mV,q m
L\'EDP, mm Hg Cai.e
----1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Mean ±SD
----
B
Heart Rate, heal• per min
LVES\'I.
mV•q
m
BA
ABABA
20 20 22 32 15 14 13 20 18 16 16 14 13 13 16 32 22 24 20 22 20t ±6
-------·
13 19 16 2&
77 86 105 65
60
85 100 77 95 109 106 109 70 56
10 18
9
94
110 129 131 78
58 83
83 48 56 112
2.5 16 16 17 22 17t ±5
9 21 12 16 27 28 25 18 13 18
17
76 62 119 85 98 91:1: ":23
60
86 82:1:
'.'.:22
79 78 24 16 23 18 ±7
LVSP, mm Hg A
B
-·
16 18 20 13 30 21 30 32 21 19 13
26 15 20 19 ±7
72 67 66 88 65 76 73 84 61 66 86 68 87 88 90 62 79 60 75§ ± 11
72 93 82 82 72 71 92 69
83 86 87 72 b5 62 78§ ±9
90 140 240 181 105 105 120 137 190 100 110 110 120 115 170 140 136t ±41
- - -- ----- · - - - - --------
-
Basal LV Outflow Gradient mm Hg
AoSP, nun Hg B
A
B
A
40 130 77
10 80 48
37 30
10 30
LV Free LV Wall Mass ThickIndex, ness, glsq m mm
----- ------- ------ - - - - --
90 102 180 143 96 100 100 llO 165 95 90 104 llO
85 162 105 115t -t30
.... -
90 100 llO 104 105 105 120 100 160 100 110 110 120 90 130 120 Ult tl7
90 92 100 95 96 100 100 100 135 95 90 104 110
85
25 40 20 sot ±37
140 105 102t :!: 15
0 22 0 25t ±28
134 352 225 241 492 173 280 478 276 150 245
12.6 21.3 19.0 19.5 28.0 12.8 17.4 25.4 20.3 14.0
353
32.3 27.0 19.6 24.1 18.4
396 314 329 279
17.5
- - -----------
*B, Baseline; A, after ve1apamil; L\'; left ventricular; LVSP, left ventricular peak •ystolic pressure; and AoSP, aortic peak systolic pressure. tp<0.001 for B v• A. :l:p<0.01 for B vs A. §p<0.02 for B vs A.
The left ventricular tmd-diastolic volume index (LVEDVI) increased after verapamil from the mean value of82 ± 22 to 91±23 ml/sq m (p<0.01). The mean rise in LVEDVI was 9 ml/sq m (11 percent of the control value). The LVEDVI remained virtually unchanged (in a range of ± 3 ml/sq m) in five subjects, rose in ten, and declined by 12 ml/sq m in one subject. The left ventricular end-systolic volume index (LVESVI) was not uniformly changed. The LVESVI remained unchanged in nine patients, rose in five, and decreased in two. The difference between mean values of 18 ± 7 ml/sq min the control state aud 19 ± 7 ml/sq m after verapamil was not statistically significant. LVEDP (mmHQ)
12
'\
9 '
lO
'
'
28
'~
26 24
I
I
I
''
'
o before veropam1I •
.
I
I
I
20
I
10...,1
.
I
18 16
1
14 12
10
.......
I
..........
"''
y
•
I
70
80
90
100 110
1-
120 150 140
EDY I (mlfmZ BSA)
1. Verapamil-induced changes in left ventricular enddiastolic pressure-volume relations. BSA, Body surface area. FIGURE
x
ALVEDVlt
ALVEDPt
LVEDVI LVEDP LV mai.s index LV free wall thickness
r= -0.167 r=0.159 r-=0.204 r=0.347
r=0.226 r= -0.528:1: r=0.152 r= -0.132
-----
I I
•
60
.
y
)-,
' 0..... \
- r- -,------r- r·~0
Table 2-Correlation Coefficienta between Verapanaillnduced Changes and Baseline Hemodynamic Values*
'? o----i
22
ofter verapam1I
Figure 1 shows changes in end-diastolic pressurevolume relationships induced by vcrapamil. In 12 patients (six with and six without obstruction), the relationships shifted downwards and to the right; in one (with a low basal gradient), the LVEDVI rose while LVEDP remained unchanged. This group of 13 patients (81 percent) represents a fraction in whom verapamil favorably modified left ventricular filling conditions. Of the remaining three patients, two showed a decrease in both pressure and volume, and in one, end-diastolic pressure increased with no change in volume. This last patient had no basal outflow obstruction. Relationships between changes in LVEDVI and LVEDP vs baseline hemodynamic indices are shown in Table 2. Changes in LVEDVI did not depend on the
*LV, Left ventricular. tChanges induced by verapamil. :l:p<0.05. CHEST I 84 I 1 I JULY, 1983
55
•
3.0
y=2.09-0.269• 0.0
Q.
......
......
.....
•
-3.0
0
..
> _,
E E
•
""':r
......
••
•
• ...... • .....
..... ..... •
-6.0
•
r • -0.528
•
-
..... .....
• .....
.....
......
•
•
-9.0
10.0
15.0
20.0
25.0
30.0
35.0
LVEDP BASELINE mm Ho FIGURE 2. Correlation between changes in LVEDP produced by verapamil and baseline values.
baseline values. A significant negative correlation was found between the extent of verapamil-induced changes in LVEDP and baseline LVEDP (r= -0.528; p<0.05; Fig 2). There was no significant correlation between changes in peak left ventricular systolic pressure induced by verapamil and changes in LVEDP (r= -0.117) and LVEDVI (r=0.311). DISCUSSION
The present study demonstrates that intravenous infusion of verapamil in patients with hypertrophic cardiomyopathy in most instances lowers LVEDP and increases LVEDVI. This indicates a beneficial effect on end-diastolic pressure-volume relations, with larger filling volumes occurring at lower pressure. All patients included in this study had elevated LVEDP. Verapamil decreased this pressure significantly, both in patients with and without obstruction. In normal subjects and in patients with conditions other than hypertrophic cardiomyopathy, verapamil tends to elevate LVEDP 11·18 due to its negative inotropic effect. In our group of patients, we observed a substantial decrease in LVEDP, congruent with the former observations by Kaltenbach et al, 5 Bonow et al, 2 and Rosing et al. 6 Only one patient, with the nonobstructive form of the disease, had an elevation of the LVEDP (13 to 16 mm Hg). Elevation of LVEDP after verapamil in patients with normal or near normal baseline values appears to be a common form of response. 6 Left ventricular volumes were calculated from two consecutive ventriculograms. Values after verapamil may have been affected by the first injection of contrast material; however, hemodynamic changes induced by the contrast medium should be negligible 15 to 20 minutes after injection. 19·21 We virtually excluded this effect by starting administration of verapamil after 58
cardiac output and left ventricular pressures had returned to baseline. Bonow et al, 1. 2 using radionuclide techniques, recently reported increasing LVEDV with higher doses of verapamil in patients with hypertrophic cardiomyopathy, further supporting the view that this finding results from direct action of verapamil, and not of the contrast material. The most pronounced pathophysiologic feature of hypertrophic cardiomyopathy is an impairment of diastolic compliance. 22 ·23 The verapamil-induced shift of left ventricular end-diastolic pressure-volume relations represents improved filling. Whether this effect is due to a true change in compliance is not clear, since the diastolic pressure-volume curve can be affected not only by changes in passive mechanical properties of the myocardium, but also by changes in relaxation, systolic loading conditions, and interaction between the two ventricles. 2-1.2.5 As pointed out by Glantz and Parmley, 24 it may be difficult to sort out, even with high-fidelity measurements, what mechanisms are involved. Therefore, it was not an objective of this study to clarify the mechanism, but rather to see if verapamil can beneficially modify the altered end-diastolic pressure-volume relations. In 13 (81 percent) of 16 patients studied, verapamil acutely improved LVEDP and LVEDVI or improved the LVEDP without affecting the volume. Epstein and Rosing26 state that patients with the obstructive form of the disease may adversely respond to verapamil. We did not see any detrimental hemodynamic effect with intravenous verapamil in any of our patients. The left ventricular outflow gradient declined in all eight patients in whom it was present in baseline conditions. In none of them was a rise in LVEDP observed. The extent of improvement in LVEDVI and LVEDP was not related to the baseline ventricular diastolic volume, nor to left ventricular mass index, wall thickness, or change in systolic loading conditions. Thus, none of those measurements can serve as a predictor of the efficacy of verapamil in a particular patient. In our study the drop in LVEDP induced by verapamil tended to be greater in patients with higher left ventricular filling pressures. Although the correlation was significant, it was weak and with considerable individual variations, so that the response of a given patient to verapamil could not be established from baseline hemodynamic measurements. Whether an acute response to the drug carries any information regarding predictability of the results in long-term treatment remains questionable. 8 We conclude that in a considerable percentage of patients with hypertrophic cardiomyopathy, intravenous verapamil acutely improves left ventricular end-diastolic pressure-volume relationships, resulting
Pressure-wlume Relationships In Hypertrophlc Cerdlomyopelhy (Tendera, Polanski, Kozlelska)
in lowered filling pressure and an augmented filling volume. Response to verapamil cannot be predicted on the grounds of baseline hemodynamic findings and has to be assessed in every patient individually. ACKNOWLEDGMENT: We thank Dr. W. B. Campbell for review of the manuscript.
REFERENCES
2
3
4
5
6
7
8
9
IO
Bonow RO. Ostrow HG, Rosing DR, Kent KM, Lipson LC, Allen SI, et al. Verapamil-induced changes in ventricular volume and diastolic function in hypertrophic cardiomyopathy: mechanisms for reduced subvalvular gradient and improved symptoms (abstract). Circulation 1981; 64:1V-ll, 1981 Bonow RO, Ostrow HG, Rosing DR, Lipson LC, Kent KM, Allen SI, et al. Scintillation probe measurement of left ventricular diastolic function: effect of verapamil in hypertrophic cardiomyopathy (abstract). Circulation 1981; 64:IV-35 Bonow RO, Rosing DR. Bacharach SL, Green MV, Kent KM, Lipson LC, et al. Effect of verapamil on left ventricular systolic function and diastolic filling in patients with hypertrophic cardiomyopathy. Circulation 1981; 64:787-96 Kaltenbach M, Hopf R, Keler M. Calciumantagonistische Therapie bei hypertrophobstruktiver Kardiomyopathie. Dtsch Med Wochenschr 1976; 101:1284-87 Kaltenbach M, Hopf G. Bussman WD, Keller M. Peterson Y. Treatment of hypertrophic obstructive cardiomyopathy with verapamil. Br Heart J 1979; 42:35-42 Rosing DR, Kent KM, Borer JS, Seides SF, Maron BJ, Epstein ES. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: I. Hemodynamic effects. Circulation 1979; 60:1201-07 Rosing DR, Condit JR, Maron BJ, Kent KM, Leon MB, Bonow RO. et al: Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: III. Effects of long-term administration. Am J Cardiol 1981; 48:545-53 Rosing DR. Kent KM, Maron BJ, Epstein SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: II. Effects on exercise capacity and symptomatic status. Circulation 1979; 60:1208-13 Bonow RO, Rosing DR. Bacharach SL, Green MV, Lipson LC. Condit JR, et al. Long-term effects of verapamil on left ventricular diastolic filling in patients with hypertrophic cardiomyopathy (abstract). Am J Cardiol 1981; 47:409 VanTrigt P, Olsen CO. Pellom GL. Peyton RB, Jones RN, Rankin JS, et al. The effect of verapamil on the diastolic mechanics of the left ventricle (abstract). Am J Cardiol 1981; 47:411
11 Hanrath P, Mathey DG, Kremer P, Sonntag F, Bleifeld W. Effect of verapamil on the left ventricular filling in hypertrophic cardiomyopathy. Am J Cardiol 1980; 45:1258-64 12 Troesch M, Hirzel HO, Jenni R, Krayenbuehl HP. Reduction of septa! thickness following verapamil in patients with assymetric septa! hypertrophy (abstract). Circulation 1979; 60:11-155 13 Doi YL, McKenna WJ, Gehrke J, Oakley CM, Goodwin JF. MMode echocardiography in hypertrophic cardiomyopathy: diagnostic criteria and prediction of obstruction. Am J Cardiol 1980; 45:6-14 14 Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a wide angle two-dimensional echocardiographic study of 125 patients. Am J Cardiol 1981; 48:418-28 15 Sandler H, Dodge HT. The use of single plane angiocardiograms for the calculation ofleft ventricular volume in man. Am Heart J 1968; 75:325-34 16 Rackley CE, Dodge HT, Coble YD, Hay RE. A method for determining left ventricular mass in man. Circulation 1964; 29:666-71 17 Singh BN, Roche AHG. Effects of intravenous verapamil on hemodynamics in patients with heart disease. Am Heart J 1977; 94:593-99
18 Lewis BS, Mitha AS. Gotsman MS. Immediate haemodynamic effects ofverapamil in man. Cardiology 1975; 60:366-76 19 Ferlinz J. Easthope JL. Aronow WS. Effect of verapamil on myocardial performance in coronary disease. Circulation 1979; 59:313-19 20 Mullins CB, Leshin JS. Mierzwiak DS, Alsobrook HD, Mitchell JH. Changes in left ventricular function produced by the injection of contrast media. Am Heart J 1972; 83:373-81 21 Stern L. Firth BG, Dehmer GJ, Markham RV. Lewis SE, Hillis LD. Effect of selective coronary arteriography on left ventricular volumes and ejection fraction in man. Am J Cardiol 1980; 46:827-31 22 Goodwin JF. Hypertrophic cardiomyopathy: a disease in search of its own identity. Am J Cardiol 1980; 45:177-80 23 Goodwin JF. Future trends in cardiomyopathy: I. predictions for the cardiomyopathies. In: Yu PN, Goodwin JF, eds. Progress in cardiology (Vol 10). Philadelphia: Lea and Febiger, 1981; 175-85 24 Glantz SA, Parmley WW. Factors which affect the diastolic pressure volume curve. Circ Res 1978; 42:171-80 25 Karliner JS, Peterson KL. Ross J Jr. Ventricular myocardial mechanics: systolic and diastolic function. In: Grossman W, ed, Cardiac catheterization and angiography. Philadelphia: Lea and Febiger, 1980; 245-67 26 Epstein SE, Rosing DR. Verapamil: its potential for causing serious complications in patients with hypertrophic cardiomyopathy. Circulation 1981; 64:437-41
CHEST I 84 I 1 I JULY, 1983
57
In 16 patients with hypertrophic cardiomyopathy, an acute response of the left ventricular end-diastolic pressure and volume index to intravenously administered verapamil was assessed. Verapamil decreased the left ventricular enddiastolic pressure from 20:i:6to17 :i: 5 mm Hg (p<0.001) and increased the end-diastolic volume index from 82 :i: 22 to
v
erapamil has been found to be a promising drug in the treatment of hypertrophic cardiomyopathy. 1-7 Both symptomatic improvement''-9 and beneficial hemodynamic effects 2·"·10•11 were reported. Results of some studies indicate that verapamil may actually reverse hypertrophy in patients with hypertrophic cardiomyopathy;4·5·12 however, this opinion has not gained wide acceptance. 7 The present study was undertaken to evaluate changes in left ventricular end-diastolic pressure and volume in the setting of acute administration of verapamil and to determine if these changes depend on the baseline hemodynamic measurements. MATERIALS AND METHODS
Sixteen patients (13 men and three women) aged 17 to 51 years (mean ± SD, 33±10 years) were studied. All had echocardiographic evidence of asymmetric septa! hypertrophy with a septa! to free wall thickness ratio greater than 1.5 13·" in the absence of other cardiac disease. All patients were in sinus rhythm. An intraventricular pressure gradient of 20 to 130 mm Hg (mean, 49. 9 ± 36. 7 mm Hg) was found in eight patients; in the remaining eight, no gradient was demonstrated. All medications were withheld for 48 hours prior to the investigation. The nature of the procedure was explained to each patient, and informed consent was obtained. After premedication with IO mg of diazepam orally, a Swan-Ganz thermodilution catheter was placed in the pulmonary artery. Left heart catheterization was performed using a pigtail catheter (Cordis F 8). Pressures were measured by means of transducers (Statham P 23 ID), with the zero reference point at midchest level. Left ventricular end-diastolic presure (LVEDP) was measured 50 msec after the onset of the QRS complex. Cardiac output was calculated by a cardiac output computer (Edwards Laboratories 9520 A). After obtaining baseline pressures and cardiac output, a singleplane left ventriculographic study in the 30° right anterior oblique *From the Second Department of Cardiology, Silesian Medical Academy, Zabrze, Poland. tCardiology Fellow, Vanderbilt University-St. Thomas Hospital, Nashville, Tenn. Manuscript received November 29; revision accepted February 24.
54
91:i:23 ml/sqm (p<0.01). In 13 (81 percent) of 16 patients, an improvement of end-diastolic pressure-volume relationships occurred. In hypertrophic cardiomyopathy, intravenous verapamil exerts a beneficial effect on left ventricular filling conditions, producing an augmentation of filling volume at a lower filling pressure.
projection was performed. Only technically adequate ventriculograms, without catheter-induced arrhythmias, were analyzed. Twenty minutes after the first ventriculogram, measurements of cardiac output and pressure were repeated. In all patients, these values were found to have returned to baseline. At that point an intravenous injection of verapamil (lsoptin) was given in a dosage of 0.1 mg/kg of body weight over two minutes, followed by infusion of 0.01 mg/kg/min. After ten minutes of the infusion, all measurements of pressure, as well as left ventriculograms, were done again. Left ventricular volumes were calculated according to the arealength method, 1> the left ventricular mass index was established by the method of Rackley et al, 16 and the mean thickness of left ventricular free wall was measured with a planimeter. Selective coronary arteriograms employing the Judkins technique completed the study in all patients. No obstructive coronary lesions were round. In order to assess the influence of systolic loading conditions on diastolic measurements, peak systolic pressures in the aorta and left ventricle, as well as basal left ventricular outflow gradients, were also measured. Data were analyzed statistically using Students t-test. RESULTS
The results are summarized in Table 1. Verapamil significantly decreased both left ventricular peak systolic pressure from 136 ± 41 to 115 ± 30 mm Hg (p<0.001) and systolic aortic pressure from 111±17 to 102 ± 15 mm Hg (p<0.001). The left ventricular outflow gradient, present at rest in eight patients, was reduced by verapamil in seven and remained unchanged in one (baseline gradient, 50 ± 37 mm Hg; gradient after verapamil, 25±28 mm Hg [p<0.001)). In no instance did the gradient increase, even though the fall in peak aortic pressure was a uniform concomitant finding. The LVEDP declined by 1 to 8 mm Hg in 14 patients, remained unchanged in one, and rose by 3 mm Hg in one patient. The mean value for LVEDP dropped from 20±6 to 17±5 mm Hg (p<0.001). This represents an average decrease in LVEDP by 3 mm Hg (15 percent of the control value).
Prassure-1/0lume Relalionshlps In Hypertrophlc Cerdiomyopalhy (Tendera, Po/ons/d, Kozlelske)
Table !·-Baseline Hemodynamic Data and Verapamil-lnduced Changes in Patients with Hypertrophic Cardiomyopathy*
LVED\'l, mV,q m
L\'EDP, mm Hg Cai.e
----1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Mean ±SD
----
B
Heart Rate, heal• per min
LVES\'I.
mV•q
m
BA
ABABA
20 20 22 32 15 14 13 20 18 16 16 14 13 13 16 32 22 24 20 22 20t ±6
-------·
13 19 16 2&
77 86 105 65
60
85 100 77 95 109 106 109 70 56
10 18
9
94
110 129 131 78
58 83
83 48 56 112
2.5 16 16 17 22 17t ±5
9 21 12 16 27 28 25 18 13 18
17
76 62 119 85 98 91:1: ":23
60
86 82:1:
'.'.:22
79 78 24 16 23 18 ±7
LVSP, mm Hg A
B
-·
16 18 20 13 30 21 30 32 21 19 13
26 15 20 19 ±7
72 67 66 88 65 76 73 84 61 66 86 68 87 88 90 62 79 60 75§ ± 11
72 93 82 82 72 71 92 69
83 86 87 72 b5 62 78§ ±9
90 140 240 181 105 105 120 137 190 100 110 110 120 115 170 140 136t ±41
- - -- ----- · - - - - --------
-
Basal LV Outflow Gradient mm Hg
AoSP, nun Hg B
A
B
A
40 130 77
10 80 48
37 30
10 30
LV Free LV Wall Mass ThickIndex, ness, glsq m mm
----- ------- ------ - - - - --
90 102 180 143 96 100 100 llO 165 95 90 104 llO
85 162 105 115t -t30
.... -
90 100 llO 104 105 105 120 100 160 100 110 110 120 90 130 120 Ult tl7
90 92 100 95 96 100 100 100 135 95 90 104 110
85
25 40 20 sot ±37
140 105 102t :!: 15
0 22 0 25t ±28
134 352 225 241 492 173 280 478 276 150 245
12.6 21.3 19.0 19.5 28.0 12.8 17.4 25.4 20.3 14.0
353
32.3 27.0 19.6 24.1 18.4
396 314 329 279
17.5
- - -----------
*B, Baseline; A, after ve1apamil; L\'; left ventricular; LVSP, left ventricular peak •ystolic pressure; and AoSP, aortic peak systolic pressure. tp<0.001 for B v• A. :l:p<0.01 for B vs A. §p<0.02 for B vs A.
The left ventricular tmd-diastolic volume index (LVEDVI) increased after verapamil from the mean value of82 ± 22 to 91±23 ml/sq m (p<0.01). The mean rise in LVEDVI was 9 ml/sq m (11 percent of the control value). The LVEDVI remained virtually unchanged (in a range of ± 3 ml/sq m) in five subjects, rose in ten, and declined by 12 ml/sq m in one subject. The left ventricular end-systolic volume index (LVESVI) was not uniformly changed. The LVESVI remained unchanged in nine patients, rose in five, and decreased in two. The difference between mean values of 18 ± 7 ml/sq min the control state aud 19 ± 7 ml/sq m after verapamil was not statistically significant. LVEDP (mmHQ)
12
'\
9 '
lO
'
'
28
'~
26 24
I
I
I
''
'
o before veropam1I •
.
I
I
I
20
I
10...,1
.
I
18 16
1
14 12
10
.......
I
..........
"''
y
•
I
70
80
90
100 110
1-
120 150 140
EDY I (mlfmZ BSA)
1. Verapamil-induced changes in left ventricular enddiastolic pressure-volume relations. BSA, Body surface area. FIGURE
x
ALVEDVlt
ALVEDPt
LVEDVI LVEDP LV mai.s index LV free wall thickness
r= -0.167 r=0.159 r-=0.204 r=0.347
r=0.226 r= -0.528:1: r=0.152 r= -0.132
-----
I I
•
60
.
y
)-,
' 0..... \
- r- -,------r- r·~0
Table 2-Correlation Coefficienta between Verapanaillnduced Changes and Baseline Hemodynamic Values*
'? o----i
22
ofter verapam1I
Figure 1 shows changes in end-diastolic pressurevolume relationships induced by vcrapamil. In 12 patients (six with and six without obstruction), the relationships shifted downwards and to the right; in one (with a low basal gradient), the LVEDVI rose while LVEDP remained unchanged. This group of 13 patients (81 percent) represents a fraction in whom verapamil favorably modified left ventricular filling conditions. Of the remaining three patients, two showed a decrease in both pressure and volume, and in one, end-diastolic pressure increased with no change in volume. This last patient had no basal outflow obstruction. Relationships between changes in LVEDVI and LVEDP vs baseline hemodynamic indices are shown in Table 2. Changes in LVEDVI did not depend on the
*LV, Left ventricular. tChanges induced by verapamil. :l:p<0.05. CHEST I 84 I 1 I JULY, 1983
55
•
3.0
y=2.09-0.269• 0.0
Q.
......
......
.....
•
-3.0
0
..
> _,
E E
•
""':r
......
••
•
• ...... • .....
..... ..... •
-6.0
•
r • -0.528
•
-
..... .....
• .....
.....
......
•
•
-9.0
10.0
15.0
20.0
25.0
30.0
35.0
LVEDP BASELINE mm Ho FIGURE 2. Correlation between changes in LVEDP produced by verapamil and baseline values.
baseline values. A significant negative correlation was found between the extent of verapamil-induced changes in LVEDP and baseline LVEDP (r= -0.528; p<0.05; Fig 2). There was no significant correlation between changes in peak left ventricular systolic pressure induced by verapamil and changes in LVEDP (r= -0.117) and LVEDVI (r=0.311). DISCUSSION
The present study demonstrates that intravenous infusion of verapamil in patients with hypertrophic cardiomyopathy in most instances lowers LVEDP and increases LVEDVI. This indicates a beneficial effect on end-diastolic pressure-volume relations, with larger filling volumes occurring at lower pressure. All patients included in this study had elevated LVEDP. Verapamil decreased this pressure significantly, both in patients with and without obstruction. In normal subjects and in patients with conditions other than hypertrophic cardiomyopathy, verapamil tends to elevate LVEDP 11·18 due to its negative inotropic effect. In our group of patients, we observed a substantial decrease in LVEDP, congruent with the former observations by Kaltenbach et al, 5 Bonow et al, 2 and Rosing et al. 6 Only one patient, with the nonobstructive form of the disease, had an elevation of the LVEDP (13 to 16 mm Hg). Elevation of LVEDP after verapamil in patients with normal or near normal baseline values appears to be a common form of response. 6 Left ventricular volumes were calculated from two consecutive ventriculograms. Values after verapamil may have been affected by the first injection of contrast material; however, hemodynamic changes induced by the contrast medium should be negligible 15 to 20 minutes after injection. 19·21 We virtually excluded this effect by starting administration of verapamil after 58
cardiac output and left ventricular pressures had returned to baseline. Bonow et al, 1. 2 using radionuclide techniques, recently reported increasing LVEDV with higher doses of verapamil in patients with hypertrophic cardiomyopathy, further supporting the view that this finding results from direct action of verapamil, and not of the contrast material. The most pronounced pathophysiologic feature of hypertrophic cardiomyopathy is an impairment of diastolic compliance. 22 ·23 The verapamil-induced shift of left ventricular end-diastolic pressure-volume relations represents improved filling. Whether this effect is due to a true change in compliance is not clear, since the diastolic pressure-volume curve can be affected not only by changes in passive mechanical properties of the myocardium, but also by changes in relaxation, systolic loading conditions, and interaction between the two ventricles. 2-1.2.5 As pointed out by Glantz and Parmley, 24 it may be difficult to sort out, even with high-fidelity measurements, what mechanisms are involved. Therefore, it was not an objective of this study to clarify the mechanism, but rather to see if verapamil can beneficially modify the altered end-diastolic pressure-volume relations. In 13 (81 percent) of 16 patients studied, verapamil acutely improved LVEDP and LVEDVI or improved the LVEDP without affecting the volume. Epstein and Rosing26 state that patients with the obstructive form of the disease may adversely respond to verapamil. We did not see any detrimental hemodynamic effect with intravenous verapamil in any of our patients. The left ventricular outflow gradient declined in all eight patients in whom it was present in baseline conditions. In none of them was a rise in LVEDP observed. The extent of improvement in LVEDVI and LVEDP was not related to the baseline ventricular diastolic volume, nor to left ventricular mass index, wall thickness, or change in systolic loading conditions. Thus, none of those measurements can serve as a predictor of the efficacy of verapamil in a particular patient. In our study the drop in LVEDP induced by verapamil tended to be greater in patients with higher left ventricular filling pressures. Although the correlation was significant, it was weak and with considerable individual variations, so that the response of a given patient to verapamil could not be established from baseline hemodynamic measurements. Whether an acute response to the drug carries any information regarding predictability of the results in long-term treatment remains questionable. 8 We conclude that in a considerable percentage of patients with hypertrophic cardiomyopathy, intravenous verapamil acutely improves left ventricular end-diastolic pressure-volume relationships, resulting
Pressure-wlume Relationships In Hypertrophlc Cerdlomyopelhy (Tendera, Polanski, Kozlelska)
in lowered filling pressure and an augmented filling volume. Response to verapamil cannot be predicted on the grounds of baseline hemodynamic findings and has to be assessed in every patient individually. ACKNOWLEDGMENT: We thank Dr. W. B. Campbell for review of the manuscript.
REFERENCES
2
3
4
5
6
7
8
9
IO
Bonow RO. Ostrow HG, Rosing DR, Kent KM, Lipson LC, Allen SI, et al. Verapamil-induced changes in ventricular volume and diastolic function in hypertrophic cardiomyopathy: mechanisms for reduced subvalvular gradient and improved symptoms (abstract). Circulation 1981; 64:1V-ll, 1981 Bonow RO, Ostrow HG, Rosing DR, Lipson LC, Kent KM, Allen SI, et al. Scintillation probe measurement of left ventricular diastolic function: effect of verapamil in hypertrophic cardiomyopathy (abstract). Circulation 1981; 64:IV-35 Bonow RO, Rosing DR. Bacharach SL, Green MV, Kent KM, Lipson LC, et al. Effect of verapamil on left ventricular systolic function and diastolic filling in patients with hypertrophic cardiomyopathy. Circulation 1981; 64:787-96 Kaltenbach M, Hopf R, Keler M. Calciumantagonistische Therapie bei hypertrophobstruktiver Kardiomyopathie. Dtsch Med Wochenschr 1976; 101:1284-87 Kaltenbach M, Hopf G. Bussman WD, Keller M. Peterson Y. Treatment of hypertrophic obstructive cardiomyopathy with verapamil. Br Heart J 1979; 42:35-42 Rosing DR, Kent KM, Borer JS, Seides SF, Maron BJ, Epstein ES. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: I. Hemodynamic effects. Circulation 1979; 60:1201-07 Rosing DR, Condit JR, Maron BJ, Kent KM, Leon MB, Bonow RO. et al: Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: III. Effects of long-term administration. Am J Cardiol 1981; 48:545-53 Rosing DR. Kent KM, Maron BJ, Epstein SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: II. Effects on exercise capacity and symptomatic status. Circulation 1979; 60:1208-13 Bonow RO, Rosing DR. Bacharach SL, Green MV, Lipson LC. Condit JR, et al. Long-term effects of verapamil on left ventricular diastolic filling in patients with hypertrophic cardiomyopathy (abstract). Am J Cardiol 1981; 47:409 VanTrigt P, Olsen CO. Pellom GL. Peyton RB, Jones RN, Rankin JS, et al. The effect of verapamil on the diastolic mechanics of the left ventricle (abstract). Am J Cardiol 1981; 47:411
11 Hanrath P, Mathey DG, Kremer P, Sonntag F, Bleifeld W. Effect of verapamil on the left ventricular filling in hypertrophic cardiomyopathy. Am J Cardiol 1980; 45:1258-64 12 Troesch M, Hirzel HO, Jenni R, Krayenbuehl HP. Reduction of septa! thickness following verapamil in patients with assymetric septa! hypertrophy (abstract). Circulation 1979; 60:11-155 13 Doi YL, McKenna WJ, Gehrke J, Oakley CM, Goodwin JF. MMode echocardiography in hypertrophic cardiomyopathy: diagnostic criteria and prediction of obstruction. Am J Cardiol 1980; 45:6-14 14 Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a wide angle two-dimensional echocardiographic study of 125 patients. Am J Cardiol 1981; 48:418-28 15 Sandler H, Dodge HT. The use of single plane angiocardiograms for the calculation ofleft ventricular volume in man. Am Heart J 1968; 75:325-34 16 Rackley CE, Dodge HT, Coble YD, Hay RE. A method for determining left ventricular mass in man. Circulation 1964; 29:666-71 17 Singh BN, Roche AHG. Effects of intravenous verapamil on hemodynamics in patients with heart disease. Am Heart J 1977; 94:593-99
18 Lewis BS, Mitha AS. Gotsman MS. Immediate haemodynamic effects ofverapamil in man. Cardiology 1975; 60:366-76 19 Ferlinz J. Easthope JL. Aronow WS. Effect of verapamil on myocardial performance in coronary disease. Circulation 1979; 59:313-19 20 Mullins CB, Leshin JS. Mierzwiak DS, Alsobrook HD, Mitchell JH. Changes in left ventricular function produced by the injection of contrast media. Am Heart J 1972; 83:373-81 21 Stern L. Firth BG, Dehmer GJ, Markham RV. Lewis SE, Hillis LD. Effect of selective coronary arteriography on left ventricular volumes and ejection fraction in man. Am J Cardiol 1980; 46:827-31 22 Goodwin JF. Hypertrophic cardiomyopathy: a disease in search of its own identity. Am J Cardiol 1980; 45:177-80 23 Goodwin JF. Future trends in cardiomyopathy: I. predictions for the cardiomyopathies. In: Yu PN, Goodwin JF, eds. Progress in cardiology (Vol 10). Philadelphia: Lea and Febiger, 1981; 175-85 24 Glantz SA, Parmley WW. Factors which affect the diastolic pressure volume curve. Circ Res 1978; 42:171-80 25 Karliner JS, Peterson KL. Ross J Jr. Ventricular myocardial mechanics: systolic and diastolic function. In: Grossman W, ed, Cardiac catheterization and angiography. Philadelphia: Lea and Febiger, 1980; 245-67 26 Epstein SE, Rosing DR. Verapamil: its potential for causing serious complications in patients with hypertrophic cardiomyopathy. Circulation 1981; 64:437-41
CHEST I 84 I 1 I JULY, 1983
57