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A single dose of cilazapril improves diastolic function in hypertensive patients
A Single Dose of Cilazapril Improves Diastolic Function in Hypertensive Patients ALON MARMOR, M.D., TIBERIOGREEN, M.D., JESSIEKRAKUER, M.D. Sa/ed, Israel THOMASSZUCS, M.D. ~set Switzer/and ADAMSCHNEEWEISS,M.D. TeI-Aviv, Israel
We studied the effect of a single dose of cilazapril, 5.0 mg orally, on systolic and diastolic cardiac function in eight hypertensive patients using a double-blind crossover placebo-controlled design. All patients had concentric left ventricular hypertrophy (measured by echocardiography), unimpaired systolic function (measured by radionuclide ventriculography), and long-standing hypertension treated by a combination of betablockers and diuretics. Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart. A two-week washout period of all cardioactive drugs preceded the study. Within three hours after oral administration of cilazapril, the time to peak filling rate of the left ventricle, expressed as a percentage of diastole, was reduced from 44.5 + 13.2 percent to 31.2 -- 7.2 percent (p <0.05). Systolic blood pressure was also significantly reduced by cilazapril. Heart rate was slightly reduced. Left ventricular ejection fraction, peak filling rate, and the absolute time to peak filling rate were not significantly altered. Cilazapril improves a sensitive index of diastolic cardiac function in hypertensive patients.
From the CardiologyDepartment, Safed Medical Center,Safed, Israel;Holfmann.La Roche, Basel, Switzerland; and the Geriatric Cardiology Research Foundation, TelAviv,Israel. Requests for reprints should be addressed to Dr. Adam Schneeweiss, 9 Kehilat Sofia Street, 69018 TeI-Aviv, Israel.
mpairment of diastolic function usually precedes alterations in systolic function in hypertensive paItients. This is evident mainly in the presence of secondary hypertrophy [1]. Diastolic dysfunction can lead to heart failure in the presence of normal ejection fraction. It is, therefore, essential for antihypertensive agents not to impair, and preferably to improve, diastolic function. Diastolic dysfunction can be reversed by several antihypertensive drugs, working by different mechanisms. Lowering of elevated blood pressure and regression of hypertrophy are, of course, the best methods, but they require long-term therapy. The present study was performed to evaluate the effect of a single dose of cilazapril, a new angiotensinconverting enzyme inhibitor [2-4], on diastolic and systolic cardiac function in patients with hypertension and myocardial hypertrophy.
PATIENTS AND METHODS Eight male patients with mild-to-moderate hypertension (mean age, 58.5 -+ 7.7 years) were studied. All had essential hypertension diagnosed by clinical and laboratory exclusion of secondary causes. All had diastolic blood pressure of 95 mm Hg or more on two occasions in the week immediately prior to the study (recorded by a sphygmomanometer at Korotkoff V). No patient had considerable impairment of systolic cardiac function as evaluated by radionuclide measm'ements of left ventricular ejection fraction (Table I). None had a history of congestive heart failure. All patients underwent two-dimensional-guided M-mode echocardiographic evaluation of left ventricular posterior wall and septal thickness (according to the recommendation of the American Society for Echocardiography; measurements from leading edge to leading edge). The patients had mild-to-moderate concentric left ventricular hypertrophy (posterior wall and septal thickness 1.5 -+ 0.2 cm). No patient had regional left ventricular contraction abnormalities. All patients gave written informed consent prior to the study. The patients were hoslSitalized and their antihypertensive medications were gradually withdrawn and discontinued two weeks prior to the study. All patients underwent routine clinical and laboratory examination. In the first day of the trial, a control radionuclide study was performed, according to a technique described next. Thereafter a single dose of cilazapril, 2.5 mg orally, or placebo, was given (in a double-blind randomized order) and the radionuclide study was repeated three hours later. One week later, a control study was again performed. Thereafter the patients crossed over to the other drug and the radionuclide study was repeated three hours after oral administration. The changes from control values in left ventriculmejection fraction, peak ejection rate, peak filling rate,
December 26, 1989 The American Journal of Medicine Volume 87 (suppl 6B)
6B-61S
SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY / MARMOR ET AL
TABLE I
Radionuciide Measurements of Left Ventricular Ejection Fraction Pretreatment
SBP DBP HR EF TPFR %IPFR NPFR
Post.Treatment
p Value (of difference)
Cilazapril
Placebo
Cilazapril
Placebo
Cilazapril
Placebo
173.4-+ 2410 98.2 -+ 4,5 73.2 + 4.9 64.6 + 8.2 171.6 + 30.8 44.5 + 13.2 2.2 c 0.7
181.0 -+ 31.0 102.8 -+ 7.2 70.0 -+ 6.2 65,5 -+ 9.2 172.0 + 45.1 42.9 -+ 9.6 2.4 + 0.8
129.1 +- 10.6 81.9 + 9.5 65.4 -+ 9.7 68.4 ± 9.4 140.4 *- 36.2 31.2 -+ 7.2 2.7 -+ ].0
168.6 -+ 31.1 94.2 -+ 9.5 70.1 + 5.3 65,1 t 10.4 176.5 _+32.4 45.3 -+ 9.3 2.3 t 0.5
0.02 NS 0.05 NS NS 0.05 NS
NS NS NS NS NS NS NS
SBP = systolic blood pressure (ram Hg}; DBP = diastolic blood pressure (ram Hg); HR = heart rate (beats/minute); EF = ejection fraction (percent); TPFR = time to peak filling rate (msec); %q'PFR= percentage of diastole required to reach peak filling rate (percent); NPFR = normalized peak filling rate (volume/second),
and time to peak filling rate were determined for cilazapril and placebo.
Statistical Methods The results were expressed as mean and SD. The t test was used to determine the statistical significance of the differences between the changes induced by cilazapril and placebo.
Technique of Radionuclide Study All patients underwent resting gated blood pool scintigraphy using in vivo-labeled red blood cells with 20 mCi of technetium-99m, a standard field-of-view camera, a low-energy medium resolution parallel hole collimator, and a digital processor (Elscint Apex). The camera was interfaced with a dedicated minicomputer system, and data were collected in 45 ° left anterior oblique with 15° caudal angulation. The cardiac cycle was divided into 24 equal frames, and 5 million counts were collected. Temporal and spatial smoothing of the data along with background subtraction was then perfol~ned followed by a time-activity cm-ves generation using a commercially available software program. The program uses a semiautomatic, second-derivativebased edge detection algolithm with edge tracking of each frame of the cardiac cycle. Each edge is subject to operator modification before final time activitycurve generation. Peak filling rate was calculated as the maximal slope of the time activity curve in the early filling phase using a five-point derivative algorithm after three-point smoothing to reduce statistical noise. Peak filling rate (representing the maximal slope of the first derivative of the early filling portion) was normalized by dividing it by end-diastolic counts and it is expressed as volumes per second. The time of end-diastole (maximal counts) and of end-systole (minimal counts) served as a reference system for the determination of the duration of the diastole and the time to peak filling rate. Time to peak filling rate was calculated as the time from minimal counts on the time activity curve to the time of peak value (milliseconds) and as a percentage of diastolic time (time to peak filling rate multiplied by 100 divided by diastolic time). These indices are considered today as good indicators of left ventricular diastolic function. The data were evaluated by two independent observers, who were not familiar with the trial medication. In case of disagreement between the observers, the patient was excluded.
6B-62S
RESULTS All patients completed the study without complications. Placebo had no significant effect on heart rate, blood pressure, or systolic cardiac function. Left ventricular ejection fraction was 65.5 - 9.2 percent before and 65.1 - 10.4 percent after administration of placebo. No significant effect on any of the measured parameters of diastolic function was observed. Cilazapril, 2.5 mg orally, reduced blood pressure, within three hours of administration from 173.4 +24.0/98.2 + 4.5 mm Hg to 129.1 -+ 10.6/81.9 +- 9.5 mm Hg. The decrease in systolic blood pressure reached statistical significance (p <0.05). Heart rate was slightly but significantly slowed. Cilazapril did not significantly alter left ventricular ejection fraction (from 64.6 +- 8.2 percent to 65.1 -+ 10.4 percent, not significant). Normalized peak left ventricular filling rate was slightly but not significantly increased from 2.2 -+ 0.7 to 2.7 -+ 1.0 volumes/second. Time to peak filling rate was slightly shortened from 171.6 +- 30.8 to 140.4 -+ 36.2 msec. This change did not reach statistical significance either. However, when time to peak filling rate was corrected for the length of diastole and expressed as the percentage of diastole to peak filling rate, it was reduced fi'om 44.5 _ 13.2 percent to 31.2 -+ 7.2 percent (p <0.05) (Table I). No side effects were observed. COMMENTS Our results show that a single dose of cilazapril improves a sensitive parameter of diastolic left ventricular function and does not impair systolic function in hypertensive patients with left ventricular hypertrophy. It may be expected that long-term treatment will improve more parameters of diastolic function. The effect was achieved in the presence of a slight decrease in heart rate, despite a considerable decrease in blood pressure. In this respect, cilazapril is supelior to the dihydropyridine calcium antagonists, which can also improve diastolic cardiac function in the presence of hypertrophy. At least pal~ of their effect may result, however, from shortening of diastole due to reflex tachycardia. Nifedipine has been reported to improve left ventlicular diastolic cardiac function in various conditions associated with myocardial hypertrophy. The most pronounced effect was observed in hypertrophic cardiomyopathy. Since the report of Hanrath et al [5] showing that disturbances of diastolic relaxation and
December26, 1989 The AmericanJournalof Medicine Volume87 (suppl6B)
SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY/MARMOR ET AL
filling in hypertrophic cardiomyopathy are in part dynamic, the effect of calcium antagonists in this condition has been extensively studied. Lorell et al [6] found that short-term oral administration of nifedipine reversed the impairment in left ventricular diastolic properties observed in hypertrophic cardiomyopathy. The drug shortened the abnormally prolonged left ventricular isovolumic relaxation time, accelerated the left ventricular pressure decay, and accelerated the depressed left ventricular filling. Nifedipine also improved left ventricular diastolic wall thinning. Motz et al [1], studying spontaneously hypertensive rats, demonstrated that antihypertensive agents, including nifedipine, may specifically induce variations in the intrinsic myocardial stiffness, independent of its effects on left ventricular hypertrophy and left ventricular chamber compliance [1]. White [7] reported that in patients with congestive heart failure nifedipine improved diastolic function of the heart by shortening the time to maximal filling at rest and increasing the peak filling rate during exercise. In a previous study in hypertensive patients [8], we have shown that captopril shortened the time to peak filling rate more than did nifedipine. This occurred even though nifedipine accelerated heart rate and shortened diastole, whereas captopril slowed heart rate and prolonged diastole. Cilazapril has a longer duration of action than capto.pril, allowing once daily administration. This may improve patients' compliance. Although in our study only one parameter of diastolic function was improved, it is one of the most sensitive parameters: the time to peak filling rate expressed as percentage of diastole. Long-term studies with this drug are required to detect potential improvement in less sensitive parameters. Comparative studies of cilazapril and calcium antagonists are also required. The mechanism of the change, which we define as "improvement" in diastolic function after single doses of antihypertensive drugs, may be due to intrinsic effects on the myocardium. In the case of angiotensin-converting enzyme inhibitors this may include an effect on the cardiac (tissue) renin-angiotensin system. It is very likely, however, that the change in indices of diastolic function results from altered loading conditions [9]. The important conclusion fl'om our findings is that cilazapril does not impair, and even improves diastolic function in hypertensive patients, and therefore is unlikely to cause heart failure due to diastolic dysfunction.
Limitation of Trial Several limitations of the trial relate mainly to the radionuclide method in general. The determination of left ventricular filling rates requires high temporal resolution. A low framing rate, a Iow count acquisition, and cycle length variations may cause significant errors. We tried to overcome these limitations by the specific radionuclide technique used and by correction for the length of diastole. Since heart rate was reduced rather than accelerated by cilazapril, it is unlikely to affect the results. The usefulness of the method is limited to resting state only [10]. We did not measure the first one third filling fraction: a parameter that has been recently shown to be a sensitive index of diastolic function in hypertensive patients [11]. This parameter is now measured in new patients enrolled to the same protocol. It should be emphasized, however, that in the majority of reported trials looking at diastolic function in hypertensive and normotensive patients this parameter was not measured.
REFERENCES 1. Motz W, Burger S, Strauer BE: Myocardial stiffness and ventdcular compliance in vadous stages of cardiac hypertrophy labstr). In: Proceedingsof an International Symposium-Diastolic Function of the Heart, Hamburg, September 24-2S. 1982. 2. Belz GG, Lange H, Tschollar W, Neis W: Cilazapril bei essentieller hypertonie. Med Kiln 1986; 81: 524-529. 3, S;tnchez RA, Traballi CA, Barclay CA, et al: Anti.hypertensive, enzymatic, and hormonal activity of cilazapdl, a new angiotensin-convertingenzyme inhibitor in patients with mild to moderate essential hypertension. J Cardiovasc Pharmacol 1988; 11: 230-234. 4. White WB, McCabe EJ: Effects of once daily ACE inhibition with cilazapril on casual ambulatory and exercise blood pressure (abstr). In: Proceedings of the 89th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Diego, California, March ]988. 5. Hanrath P, Mathey DG, Kremer P, Sonntag F, Bleifeld W: Effect of verapamil on left ventricular isovolumic relaxation time and regional left ventricular filling in hypertrophic cardiomyopalhy. Am J Cardiol 1980; 45: 1258-1264. 6. Lorelt BH, Paulus WJ, GrossmanW, WynneJ: Improved left ventricular diastolic properties in hypertrophic cardiomyopathy treated with nifedipine. In: Kaltenbach M, Neufeld HN, eds. Proceedings of the 5th International Adalat Symposium. Amsterdam, Oxford, Princeton: Excerpta Medica, 1983; 91. 7. White HD: Improved diastolic function with nifedipine at rest and exercise in patients with coronary artery disease (abstr). J Am Coil Cardiol 1983; 2: 92. 8. Marmor A, Traub Y, Chud A, Troshar D, SchneeweissA: Comparative effecls of captopril and nifedipine on diastolic and systolic cardiac function in elderly hypertensive patients. J Hypertens 1989; 6 (suppl 1): SIO]-S]03. 9. Plotnic GD, Kahn B, Rogers WJ, Fisher ML, Becker LC: Effect of postural changes, nitroglycerin and verapamil on diastolic ventricular function as determined by radionuclide angiography in normal subjects. J Am Coil Cardiol 1988; 12: 121-129. |0. Arora RA, Machac J, Goldman ME, Butler RN, Godin R, Horowilz SF: Atrial kinetics and left ventricular diastolic filling in the healthy elderly. J Am Cotl Cardio11987; 9." 12551260. 11. Camna M, AI-Khawaja I. Lahid A, Lewis J, Raffery EB: Radionuclide measurements of diastolic function for assessing early left ventdcular abnormalilies in the hypertensive patient. Br Heart J 1988; 59: 218-226.
December 26, 1989 The American Journal of Medicine Volume 87 (suppl 6B)
6B-63S
We studied the effect of a single dose of cilazapril, 5.0 mg orally, on systolic and diastolic cardiac function in eight hypertensive patients using a double-blind crossover placebo-controlled design. All patients had concentric left ventricular hypertrophy (measured by echocardiography), unimpaired systolic function (measured by radionuclide ventriculography), and long-standing hypertension treated by a combination of betablockers and diuretics. Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart. A two-week washout period of all cardioactive drugs preceded the study. Within three hours after oral administration of cilazapril, the time to peak filling rate of the left ventricle, expressed as a percentage of diastole, was reduced from 44.5 + 13.2 percent to 31.2 -- 7.2 percent (p <0.05). Systolic blood pressure was also significantly reduced by cilazapril. Heart rate was slightly reduced. Left ventricular ejection fraction, peak filling rate, and the absolute time to peak filling rate were not significantly altered. Cilazapril improves a sensitive index of diastolic cardiac function in hypertensive patients.
From the CardiologyDepartment, Safed Medical Center,Safed, Israel;Holfmann.La Roche, Basel, Switzerland; and the Geriatric Cardiology Research Foundation, TelAviv,Israel. Requests for reprints should be addressed to Dr. Adam Schneeweiss, 9 Kehilat Sofia Street, 69018 TeI-Aviv, Israel.
mpairment of diastolic function usually precedes alterations in systolic function in hypertensive paItients. This is evident mainly in the presence of secondary hypertrophy [1]. Diastolic dysfunction can lead to heart failure in the presence of normal ejection fraction. It is, therefore, essential for antihypertensive agents not to impair, and preferably to improve, diastolic function. Diastolic dysfunction can be reversed by several antihypertensive drugs, working by different mechanisms. Lowering of elevated blood pressure and regression of hypertrophy are, of course, the best methods, but they require long-term therapy. The present study was performed to evaluate the effect of a single dose of cilazapril, a new angiotensinconverting enzyme inhibitor [2-4], on diastolic and systolic cardiac function in patients with hypertension and myocardial hypertrophy.
PATIENTS AND METHODS Eight male patients with mild-to-moderate hypertension (mean age, 58.5 -+ 7.7 years) were studied. All had essential hypertension diagnosed by clinical and laboratory exclusion of secondary causes. All had diastolic blood pressure of 95 mm Hg or more on two occasions in the week immediately prior to the study (recorded by a sphygmomanometer at Korotkoff V). No patient had considerable impairment of systolic cardiac function as evaluated by radionuclide measm'ements of left ventricular ejection fraction (Table I). None had a history of congestive heart failure. All patients underwent two-dimensional-guided M-mode echocardiographic evaluation of left ventricular posterior wall and septal thickness (according to the recommendation of the American Society for Echocardiography; measurements from leading edge to leading edge). The patients had mild-to-moderate concentric left ventricular hypertrophy (posterior wall and septal thickness 1.5 -+ 0.2 cm). No patient had regional left ventricular contraction abnormalities. All patients gave written informed consent prior to the study. The patients were hoslSitalized and their antihypertensive medications were gradually withdrawn and discontinued two weeks prior to the study. All patients underwent routine clinical and laboratory examination. In the first day of the trial, a control radionuclide study was performed, according to a technique described next. Thereafter a single dose of cilazapril, 2.5 mg orally, or placebo, was given (in a double-blind randomized order) and the radionuclide study was repeated three hours later. One week later, a control study was again performed. Thereafter the patients crossed over to the other drug and the radionuclide study was repeated three hours after oral administration. The changes from control values in left ventriculmejection fraction, peak ejection rate, peak filling rate,
December 26, 1989 The American Journal of Medicine Volume 87 (suppl 6B)
6B-61S
SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY / MARMOR ET AL
TABLE I
Radionuciide Measurements of Left Ventricular Ejection Fraction Pretreatment
SBP DBP HR EF TPFR %IPFR NPFR
Post.Treatment
p Value (of difference)
Cilazapril
Placebo
Cilazapril
Placebo
Cilazapril
Placebo
173.4-+ 2410 98.2 -+ 4,5 73.2 + 4.9 64.6 + 8.2 171.6 + 30.8 44.5 + 13.2 2.2 c 0.7
181.0 -+ 31.0 102.8 -+ 7.2 70.0 -+ 6.2 65,5 -+ 9.2 172.0 + 45.1 42.9 -+ 9.6 2.4 + 0.8
129.1 +- 10.6 81.9 + 9.5 65.4 -+ 9.7 68.4 ± 9.4 140.4 *- 36.2 31.2 -+ 7.2 2.7 -+ ].0
168.6 -+ 31.1 94.2 -+ 9.5 70.1 + 5.3 65,1 t 10.4 176.5 _+32.4 45.3 -+ 9.3 2.3 t 0.5
0.02 NS 0.05 NS NS 0.05 NS
NS NS NS NS NS NS NS
SBP = systolic blood pressure (ram Hg}; DBP = diastolic blood pressure (ram Hg); HR = heart rate (beats/minute); EF = ejection fraction (percent); TPFR = time to peak filling rate (msec); %q'PFR= percentage of diastole required to reach peak filling rate (percent); NPFR = normalized peak filling rate (volume/second),
and time to peak filling rate were determined for cilazapril and placebo.
Statistical Methods The results were expressed as mean and SD. The t test was used to determine the statistical significance of the differences between the changes induced by cilazapril and placebo.
Technique of Radionuclide Study All patients underwent resting gated blood pool scintigraphy using in vivo-labeled red blood cells with 20 mCi of technetium-99m, a standard field-of-view camera, a low-energy medium resolution parallel hole collimator, and a digital processor (Elscint Apex). The camera was interfaced with a dedicated minicomputer system, and data were collected in 45 ° left anterior oblique with 15° caudal angulation. The cardiac cycle was divided into 24 equal frames, and 5 million counts were collected. Temporal and spatial smoothing of the data along with background subtraction was then perfol~ned followed by a time-activity cm-ves generation using a commercially available software program. The program uses a semiautomatic, second-derivativebased edge detection algolithm with edge tracking of each frame of the cardiac cycle. Each edge is subject to operator modification before final time activitycurve generation. Peak filling rate was calculated as the maximal slope of the time activity curve in the early filling phase using a five-point derivative algorithm after three-point smoothing to reduce statistical noise. Peak filling rate (representing the maximal slope of the first derivative of the early filling portion) was normalized by dividing it by end-diastolic counts and it is expressed as volumes per second. The time of end-diastole (maximal counts) and of end-systole (minimal counts) served as a reference system for the determination of the duration of the diastole and the time to peak filling rate. Time to peak filling rate was calculated as the time from minimal counts on the time activity curve to the time of peak value (milliseconds) and as a percentage of diastolic time (time to peak filling rate multiplied by 100 divided by diastolic time). These indices are considered today as good indicators of left ventricular diastolic function. The data were evaluated by two independent observers, who were not familiar with the trial medication. In case of disagreement between the observers, the patient was excluded.
6B-62S
RESULTS All patients completed the study without complications. Placebo had no significant effect on heart rate, blood pressure, or systolic cardiac function. Left ventricular ejection fraction was 65.5 - 9.2 percent before and 65.1 - 10.4 percent after administration of placebo. No significant effect on any of the measured parameters of diastolic function was observed. Cilazapril, 2.5 mg orally, reduced blood pressure, within three hours of administration from 173.4 +24.0/98.2 + 4.5 mm Hg to 129.1 -+ 10.6/81.9 +- 9.5 mm Hg. The decrease in systolic blood pressure reached statistical significance (p <0.05). Heart rate was slightly but significantly slowed. Cilazapril did not significantly alter left ventricular ejection fraction (from 64.6 +- 8.2 percent to 65.1 -+ 10.4 percent, not significant). Normalized peak left ventricular filling rate was slightly but not significantly increased from 2.2 -+ 0.7 to 2.7 -+ 1.0 volumes/second. Time to peak filling rate was slightly shortened from 171.6 +- 30.8 to 140.4 -+ 36.2 msec. This change did not reach statistical significance either. However, when time to peak filling rate was corrected for the length of diastole and expressed as the percentage of diastole to peak filling rate, it was reduced fi'om 44.5 _ 13.2 percent to 31.2 -+ 7.2 percent (p <0.05) (Table I). No side effects were observed. COMMENTS Our results show that a single dose of cilazapril improves a sensitive parameter of diastolic left ventricular function and does not impair systolic function in hypertensive patients with left ventricular hypertrophy. It may be expected that long-term treatment will improve more parameters of diastolic function. The effect was achieved in the presence of a slight decrease in heart rate, despite a considerable decrease in blood pressure. In this respect, cilazapril is supelior to the dihydropyridine calcium antagonists, which can also improve diastolic cardiac function in the presence of hypertrophy. At least pal~ of their effect may result, however, from shortening of diastole due to reflex tachycardia. Nifedipine has been reported to improve left ventlicular diastolic cardiac function in various conditions associated with myocardial hypertrophy. The most pronounced effect was observed in hypertrophic cardiomyopathy. Since the report of Hanrath et al [5] showing that disturbances of diastolic relaxation and
December26, 1989 The AmericanJournalof Medicine Volume87 (suppl6B)
SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY/MARMOR ET AL
filling in hypertrophic cardiomyopathy are in part dynamic, the effect of calcium antagonists in this condition has been extensively studied. Lorell et al [6] found that short-term oral administration of nifedipine reversed the impairment in left ventricular diastolic properties observed in hypertrophic cardiomyopathy. The drug shortened the abnormally prolonged left ventricular isovolumic relaxation time, accelerated the left ventricular pressure decay, and accelerated the depressed left ventricular filling. Nifedipine also improved left ventricular diastolic wall thinning. Motz et al [1], studying spontaneously hypertensive rats, demonstrated that antihypertensive agents, including nifedipine, may specifically induce variations in the intrinsic myocardial stiffness, independent of its effects on left ventricular hypertrophy and left ventricular chamber compliance [1]. White [7] reported that in patients with congestive heart failure nifedipine improved diastolic function of the heart by shortening the time to maximal filling at rest and increasing the peak filling rate during exercise. In a previous study in hypertensive patients [8], we have shown that captopril shortened the time to peak filling rate more than did nifedipine. This occurred even though nifedipine accelerated heart rate and shortened diastole, whereas captopril slowed heart rate and prolonged diastole. Cilazapril has a longer duration of action than capto.pril, allowing once daily administration. This may improve patients' compliance. Although in our study only one parameter of diastolic function was improved, it is one of the most sensitive parameters: the time to peak filling rate expressed as percentage of diastole. Long-term studies with this drug are required to detect potential improvement in less sensitive parameters. Comparative studies of cilazapril and calcium antagonists are also required. The mechanism of the change, which we define as "improvement" in diastolic function after single doses of antihypertensive drugs, may be due to intrinsic effects on the myocardium. In the case of angiotensin-converting enzyme inhibitors this may include an effect on the cardiac (tissue) renin-angiotensin system. It is very likely, however, that the change in indices of diastolic function results from altered loading conditions [9]. The important conclusion fl'om our findings is that cilazapril does not impair, and even improves diastolic function in hypertensive patients, and therefore is unlikely to cause heart failure due to diastolic dysfunction.
Limitation of Trial Several limitations of the trial relate mainly to the radionuclide method in general. The determination of left ventricular filling rates requires high temporal resolution. A low framing rate, a Iow count acquisition, and cycle length variations may cause significant errors. We tried to overcome these limitations by the specific radionuclide technique used and by correction for the length of diastole. Since heart rate was reduced rather than accelerated by cilazapril, it is unlikely to affect the results. The usefulness of the method is limited to resting state only [10]. We did not measure the first one third filling fraction: a parameter that has been recently shown to be a sensitive index of diastolic function in hypertensive patients [11]. This parameter is now measured in new patients enrolled to the same protocol. It should be emphasized, however, that in the majority of reported trials looking at diastolic function in hypertensive and normotensive patients this parameter was not measured.
REFERENCES 1. Motz W, Burger S, Strauer BE: Myocardial stiffness and ventdcular compliance in vadous stages of cardiac hypertrophy labstr). In: Proceedingsof an International Symposium-Diastolic Function of the Heart, Hamburg, September 24-2S. 1982. 2. Belz GG, Lange H, Tschollar W, Neis W: Cilazapril bei essentieller hypertonie. Med Kiln 1986; 81: 524-529. 3, S;tnchez RA, Traballi CA, Barclay CA, et al: Anti.hypertensive, enzymatic, and hormonal activity of cilazapdl, a new angiotensin-convertingenzyme inhibitor in patients with mild to moderate essential hypertension. J Cardiovasc Pharmacol 1988; 11: 230-234. 4. White WB, McCabe EJ: Effects of once daily ACE inhibition with cilazapril on casual ambulatory and exercise blood pressure (abstr). In: Proceedings of the 89th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Diego, California, March ]988. 5. Hanrath P, Mathey DG, Kremer P, Sonntag F, Bleifeld W: Effect of verapamil on left ventricular isovolumic relaxation time and regional left ventricular filling in hypertrophic cardiomyopalhy. Am J Cardiol 1980; 45: 1258-1264. 6. Lorelt BH, Paulus WJ, GrossmanW, WynneJ: Improved left ventricular diastolic properties in hypertrophic cardiomyopathy treated with nifedipine. In: Kaltenbach M, Neufeld HN, eds. Proceedings of the 5th International Adalat Symposium. Amsterdam, Oxford, Princeton: Excerpta Medica, 1983; 91. 7. White HD: Improved diastolic function with nifedipine at rest and exercise in patients with coronary artery disease (abstr). J Am Coil Cardiol 1983; 2: 92. 8. Marmor A, Traub Y, Chud A, Troshar D, SchneeweissA: Comparative effecls of captopril and nifedipine on diastolic and systolic cardiac function in elderly hypertensive patients. J Hypertens 1989; 6 (suppl 1): SIO]-S]03. 9. Plotnic GD, Kahn B, Rogers WJ, Fisher ML, Becker LC: Effect of postural changes, nitroglycerin and verapamil on diastolic ventricular function as determined by radionuclide angiography in normal subjects. J Am Coil Cardiol 1988; 12: 121-129. |0. Arora RA, Machac J, Goldman ME, Butler RN, Godin R, Horowilz SF: Atrial kinetics and left ventricular diastolic filling in the healthy elderly. J Am Cotl Cardio11987; 9." 12551260. 11. Camna M, AI-Khawaja I. Lahid A, Lewis J, Raffery EB: Radionuclide measurements of diastolic function for assessing early left ventdcular abnormalilies in the hypertensive patient. Br Heart J 1988; 59: 218-226.
December 26, 1989 The American Journal of Medicine Volume 87 (suppl 6B)
6B-63S