Effects of Fosinopril on Cardiac Function in Patients With Hypertension
Radionuclide Assessment of Left Ventricular Systolic and Diastolic Performance M. Zusman, Donna M. Christensen,
Joy Higgins,
Numerous pharmacologic agents are capable of lowering the blood pressure of hypertensive pa tients; however, each drug has a characteristic side effect profile and effect on cardiac performance. In this study, the hemodynamic effects of the angio tensin converting enzyme inhibitor fosinopril were assessed at rest and at peak upright bicycle exercise by first-pass radionuclide cineangiography in 12 patients with essential hypertension. Fosinopril re duced blood pressure at rest in the seated position from 152/101 to 131/85 mm Hg (P < .01) and at peak exercise from 206/103 to 184/91 mm Hg (P < .01). Fosinopril therapy was associated with an in crease in stroke volume and cardiac output and a
I
n the selection of antihypertensive medications, rel atively little attention has been paid to the hemody namic effects associated with their use. Recent em phasis has been placed on assessing left ventricular function in patients with hypertension and in matching therapy with the hemodynamic profile exhibited by the patient. Abnormalities of diastolic filling indices com monly characterize the hypertensive patient popula1
and Charles A.
Boucher
decrease in systemic vascular resistance at rest and during peak exercise. Both peak ejection rate and peak filling rate increased significantly at rest dur ing fosinopril therapy. The unique cardiotropic re sponse to fosinopril may reflect its effects on the myocardial renin-angiotensin system, and suggests that this agent may offer a therapeutic advantage compared with other angiotensin converting en zyme inhibitors. Am J Hypertens 1992;5:219-223.
KEY WORDS: Angiotensin converting enzyme inhi bition, cineangiography, exercise, lusitropy, dias tole, renin-angiotensin system.
tion. In addition, the change in end-diastolic ventricu lar volume in response to exercise in patients with hypertension may guide the selection of antihyperten sive therapy. ' In general, the use of vasodilating agents, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and α-adrenergic receptor blockers is increas ing at the expense of the use of diuretics, ^-adrenergic receptor blockers, and centrally acting sympatholytic agents. This shift in patient treatment patterns reflects a more physiologic approach to the treatment of patients with hypertension and a recognition of the potential adverse effects of these latter agents on metabolic and central nervous system function. The purpose of this study was to assess the hemody namic effects at rest and during exercise of fosinopril, a unique ACE inhibitor used to treat patients with hyper tension. Fosinopril ([l,4S]-4-cyclohexyl-l-[2-methyl-l1-1 -(1 -oxopropoxy)propoxyl] (4-phenyl-butyl)phos2
3 4
5
Received March 18, 1991. Accepted November 14, 1991. From the Division of Hypertension and Vascular Medicine, Cardiac Unit, Medical Services, Massachusetts General Hospital, and the De partment of Medicine, Harvard Medical School, Boston, Massachu setts. Support for this study, as well as the fosinopril, was generously provided by Bristol-Myers Squibb. Address all correspondence and reprint requests to Randall M. Zus man, MD, Division of Hypertension and Vascular Medicine, Massa chusetts General Hospital, 15 Parkman Street, ACC 482, Boston, MA 02114.
© 1992 by the American Journal of Hypertension, Inc.
6
0895-7061/'92/'$5.00
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
Randall
phinyl)-L-proline, monosodium salt; SQ28555) is a phosphinic acid derivative of captopril. Fosinopril is a pro-drug that is completely deesterified in the liver and the gastrointestinal mucosa to the biologically active diacid fosinoprilat (SQ27519). Unlike other angiotensin converting enzyme (ACE) inhibitors that are eliminated primarily by the kidney, fosinoprilat is cleared almost equally by renal and hepatic routes. Fosinopril has long-acting antihypertensive activity and is effective as a daily treatment for patients with mild to moderate hypertension. 7
8
METHODS
13
First-Pass Radionuclide Ventriculography Subjects underwent first-pass radionuclide evaluation before the initiation of fosinopril therapy and after the reduction of diastolic blood pressure to less than 90 mm Hg with a dose of fosinopril which had remained stable for a mini
9
S T A T I S T I C A L ANALYSIS The effects of fosinopril were assessed by paired t test comparison to data acquired during the subjects' treat ment with placebo. A Ρ < .05 was considered to repre sent a significant effect. RESULTS Blood Pressure and Heart Rate The mean ( ± S E M ) dose of fosinopril required to reduce diastolic blood pressure below 90 mm Hg was 52 ( ± 6) mg, range 20 to 80 mg. Fosinopril reduced blood pressure (Table 1) with the subject in the seated position at rest from 1 5 2 / 1 0 1 to 1 3 1 / 8 5 mm Hg (P < .01). Mean blood pressure was re duced from 1 4 7 / 1 0 4 to 1 3 0 / 9 0 mm Hg (P < .01) in patients at rest in the upright position and from 2 0 6 / 1 0 3 to 1 8 4 / 9 1 mm Hg (P < .01) at peak upright bicycle ex ercise during acquisition of the radionuclide ventriculo gram. Heart rate during fosinopril therapy was un changed compared with heart rate when the subject received a placebo in the seated and upright positions at rest and during peak exercise. Left Ventricular Systolic Function At rest, stroke vol ume and cardiac output were significantly increased by fosinopril therapy (Figure 1), although left ventricular end-diastolic volume and end-systolic volume were not significantly changed (Table 1); systemic vascular resistTABLE 1. EFFECT OF FOSINOPRIL ON BLOOD PRESSURE, HEART RATE, AND VENTRICULAR VOLUMES Placebo Blood pressure (mm Hg) Seated 152 ± 5 / 1 0 1 ± 1 Upright 147 ± 3/104 ± 1 Peak exercise 206 ± 6/103 ± 4 Heart rate (beats/min) Seated 75 ± 4 Upright 83 ± 4 Peak exercise 153 ± 4 End-diastolic volume (mL) Rest 131 ± 10 Peak exercise 149 ± 9 End-systolic volume (mL) Rest 53 ± 6 Peak exercise 59 ± 7 Each value represents the mean ± SEM.
* P < . 0 2 ν placebo.
Fosinopril 131±3*/85±1* 130 ± 3*/90 ± 2* 184 ± 6*/91 ± 2* 78 ± 4 89 ± 4 146 ± 5 131 ± 6 156 ± 15 49 ± 3 56 ± 7
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
Subject Population Hypertensive subjects of either sex, 18 to 65 years of age, with diastolic blood pressures between 95 and 110 mm Hg were eligible to participate in this study. Newly diagnosed hypertensive subjects or subjects previously treated for hypertension, but who had not taken any antihypertensive medication for a minimum of 2 weeks, were enrolled if their diastolic blood pressure met the above criteria. Subjects were excluded from participation if they had a history of asthma, allergic skin rash, or rhinitis, a history of myo cardial infarction or cerebrovascular accident within the previous 6 months, secondary hypertension, congestive heart failure, serum creatinine greater than 3 0 % above the laboratory upper limit of normal, concomitant ther apy with cytotoxic or immunosuppressant drugs, con comitant collagen vascular disease, leukopenia, or sig nificant liver function test abnormalities. Twelve subjects (nine men and three women) with a mean age of 48 years (range 28 to 68 years) participated in the study. Each subject received placebo therapy dur ing a 4-week lead-in period. Blood pressure was deter mined in triplicate in the seated and upright positions (measured 3 min after standing). Each subject was then blindly randomized to receive either placebo or 10, 40, or 80 mg of fosinopril every day for an additional 8 weeks. Blood pressure was monitored weekly during monotherapy. At the end of the 8-week period, the fo sinopril dose was adjusted to reduce diastolic blood pressure to less than 90 mm Hg with the subject in the sitting position with the minimum necessary dose of medication. Subjects originally randomized to placebo treatment began fosinopril treatment at week 8, and were titrated to an effective dose of fosinopril. This protocol was approved by the Subcommittee on Human Studies of the Committee on Research of the Massachusetts General Hospital. Each subject signed an informed consent to participation form for the trial.
mum of a month. The detailed exercise protocol and techniques for calculation of ventricular function in dices from first-pass left ventriculography has been previously described. Observers blinded to the sub jects' status and therapy performed and analyzed the first-pass radionuclide angiogram for calculation of ven tricular volumes and the ejection and filling indices.
2000
r
FIGURE 1. Effects of fosinopril on systemic vascular resistance, stroke volume, and cardiac output at rest and at peak exercise (EX). * Ρ < .05; ** Ρ < .01.
PLACEBO
^
FOSINOPRIL
ance at rest fell from 1684 dyne · sec · c m to 1234 d y n e - s e c - c m (P < .01) during fosinopril ther apy (Figure 1). At peak exercise, stroke volume and car diac output increased and systemic vascular resistance decreased significantly during fosinopril therapy (Fig ure 1); neither end-diastolic volume nor end-systolic volume was affected by fosinopril therapy. At rest, the absolute value of peak ejection rate in creased from—353 mL/sec to —417 mL/sec during fo sinopril therapy (P < .05) (Figure 2). The significantly greater peak ejection rate was sustained when these values were normalized for end-diastolic volume and stroke volume. Time to peak ejection rate was slightly, but not significantly, shorter during fosinopril therapy. - 5
-5
10
At peak exercise, neither peak ejection rate nor time to peak ejection rate was significantly affected by treat ment with fosinopril (Table 2). Ejection fraction in creased from 60 ± 3 % to 65 ± 2 % (P < .05) during fo sinopril therapy. Neither exercise time, peak exercise workload, nor maximal oxygen consumption was af fected by fosinopril therapy. Left Ventricular Diastolic Function At rest, the abso lute value of peak filling rate was increased significantly from 294 to 340 mL/sec (P < .05) during fosinopril ther apy (Figure 2). The absolute values of peak filling rate normalized for stroke volume or end-diastolic volume were significantly increased by treatment with fosino-
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
REST •
TABLE 2. EFFECTS OF FOSINOPRIL ON INDICES OF LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC PERFORMANCE Fosinopril
-353 ±27 -577 ±62
- 4 1 7 ± 28* - 6 0 7 ± 70
-4.54 ±0.13 -6.30 ±0.28
- 5 . 0 4 ± 0.15* - 6 . 0 0 ± 0.16
-2.74 ±0.12 -3.81 ±0.31
- 3 . 1 8 ± 0.16* - 3 . 8 7 ± 0.15
177 ± 9 106 ± 11
163 ± 7 92 ± 6
294 ± 3 3 747 ± 5 9
340 ± 41* 765 ± 78
3.63 ± 0 . 2 3 8.42 ± 0 . 2 6
4.09 ± 0.26* 7.68 ± 0.30
2.21 ± 0 . 1 8 4.99 ± 0 . 2 4
2.58 ± 0.20* 4.96 ± 0.24
1
1
1
1
173 ± 12 96 ± 8
185 ± 10 116 ± 7
PER = peak ejection rate; EDV = end-diastolic volume; SV = stroke volume; TPER = time to peak ejection rate; PFR = peak filling rate; TPFR = time to peak filling rate. Each value represents the mean ± SEM. * Ρ < .05 ν placebo.
9 11
14
15
16
17
18
19
pril. Time to peak filling rate was not significantly af fected by fosinopril treatment. At peak exercise, neither peak filling rate nor time to peak filling rate were signifi cantly affected by fosinopril treatment (Table 2). DISCUSSION The hemodynamic changes observed in subjects with mild hypertension treated with fosinopril are consistent with improved cardiac systolic and diastolic perform ance and systemic vasodilation. The reduced systemic vascular resistance with preservation of cardiac output in subjects treated with ACE inhibitors reflects the bal anced hemodynamic effect of these compounds with improvement in cardiac systolic function caused by pe ripheral vasodilation. However, previous studies with lisinopril or captopril did not reveal an increase in peak ejection rate or in stroke volume as seen after fo sinopril therapy. Similarly, earlier studies with captopril or lisinopril did not demonstrate any significant change in indices of diastolic function. Indeed, our previous studies have shown that the treatment of subjects with moderately severe hypertension with nifedipine is associated with improved indices of diastolic filling, but our studies 11
12
11,12
13
20
21
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PER (mL/sec) Rest Peak exercise PER/SV (sec" ) Rest Peak exercise PER/EDV (sec" ) Rest Peak exercise TPER (msec) Rest Peak exercise PFR (mL/sec) Rest Peak exercise PFR/SV (sec" ) Rest Peak exercise PFR/EDV (sec" ) Rest Peak exercise TPFR (msec) Rest Peak exercise
Placebo
using either propranolol, atenolol, or lisinopril ' in the treatment of subjects with mild hypertension similar to those studied in this project did not result in significant changes in diastolic function. Nonetheless, despite the theory that the importance of calcium in the regulation of myocardial cellular contraction and relaxation indi cates that calcium channel blockers should have a unique effect on ventricular diastolic function, fosino pril treatment was associated with an improvement in diastolic performance in subjects. Demonstration of the presence of the complete reninangiotensin cascade in isolated myocardial cells, as well as recognition of the potential importance of angio tensin I and angiotensin II as factors regulating cardiac function, suggest that the use of ACE inhibitors may modify intrinsic myocardial performance and overall left ventricular function. Indeed, the results of Shunkert et a l and of Lorell et a l have confirmed the deleteri ous effects of angiotensins I and II on diastolic proper ties of the hypertrophied pressure-loaded ventricle in rats; this provides a rationale observing improved dia stolic function after ACE inhibition with fosinopril. Furthermore, ACE inhibitors may exert different local effects as a result of various chemical group substitu tions to the basic converting enzyme inhibitor structure. For example, the sulfhydryl-containing ACE inhibitor captopril and its analogues have been demonstrated to stimulate cellular prostaglandin biosynthesis, a phe nomenon dependent upon the presence of the sulfhydryl-group substitution. Similarily, the presence of the sulfhydryl group on captopril may confer upon it free radical scavenging properties which lead to cardiopro tective effects in ischemic myocardial tissue. The pres ence of the phosphinic acid substitution in the bioactivated fosinopril molecule may also confer unique pharmacologic properties. Certainly, the presence of a phosphinic acid group may result in unique tissue pene tration and intracellular effects because of the unique characteristics of the compound, such as its lipophilicity. The recent studies of Cushman et a l have also dem onstrated varied effects of ACE inhibitors on myocardial enzyme activity, suggesting that the myocardial effects of ACE inhibitors may differ. The sulfhydryl-containing ACE inhibitors, captopril and zofenopril, have the most marked myocardial effects after a single oral dose ad ministered to rats. Fosinopril, although less effective than captopril or zofenopril, had a significantly greater effect on myocardial ACE activity than enalapril, lisino pril, or ramipril. Grover et a l have demonstrated the uptake of fosinoprilat by the myocardium of rat hearts to be 14.5 and 15.4 times greater than that of lisinopril and enalaprilat, respectively; the uptake of fosinoprilat is 10.9 and 500 times greater than that of fosinopril and enalapril, the precursor pro-drugs of the biologically active deesterified products. Of note, the inherent rate of deesterification of fosinopril and enalapril by the myocardium is significantly slower than that of the sulf-
REFERENCES
9.
Zusman RM, Christensen DM, Federman EB, et al: Nife dipine, but not propranolol, improves left ventricular sys tolic and diastolic function in patients with hyperten sion. Am J Cardiol 1989;64:51F-61F.
10.
Bonow R, Bacharach SL, Green MV, et al: Impaired left ventricular diastolic filling in patients with coronary ar tery disease: assessment with radionuclide angiography. Circulation 1981;64:315-323.
11.
Zusman RM, Christensen DM, Higgins J, Boucher CA: Lisinopril treatment maintains cardiac function in pa tients with hypertension (abst). Clin Res 1989;37:403A.
12.
Zusman RM, Christensen DM, Higgins J, Boucher CA: Fosinopril, but not lisinopril or captopril, improves left ventricular systolic and diastolic performance (abst). Pro ceedings of the Second International Symposium on ACE inhibition. London, England, February 1991; ρ 76.
13.
Zusman RM, Christensen DM, Higgins J, Boucher CA: Nifedipine improves left ventricular function in patients with hypertension. J Cardiovasc Pharmacol 1992;18:843-848.
14.
Dzau VJ, Pratt RE: Renin-angiotensin system: biology, physiology and pharmacology, in Fozzard HA, Haber E, Jennings RB, et al (eds): The Heart and Cardiovascular System, Vol. 2. New York, Raven Press, 1986, pp 1631 1662.
15.
Foult J-M, Tavolaro O, Antony I, Nitenberg A: Direct myocardial and coronary effects of enalaprilat in pa tients with dilated cardiomyopathy: assessment by a bi lateral intracoronary infusion technique. Circulation 1988;77:337-344.
16.
Shunkert H, Dzau VJ, Tang SS, et al: Increased rat car diac angiotensin converting enzyme activity and mRNA expression in pressure overload hypertrophy: effects on coronary resistance, contractility and relaxation. J Clin Invest 1990;86:1913-1920.
17.
Lorell BH, Weinberg EO, Ngoy S, Apstein C: Angioten sin II directly impairs diastolic function in pressure over load hypertrophy (abst). Circulation 1990;82(suppl III):III-112.
18.
Zusman RM: Effects of converting-enzyme inhibitors on the renin-angiotensin-aldosterone, bradykinin, and ara chidonic acid-prostaglandin systems: correlation of chemical structure and biologic activity. Am J Kid Dis 1987;10(suppl l):13-23.
1.
Zusman RM: The prevalence of left ventricular dysfunc tion in hypertension: therapeutic implications. Am J Car diol (in press).
2.
Smith VE, Weisfeldt ML, Katz AM: Relaxation and dia stolic properties of the heart, in Fozzard HA, Haber E, Jennings RB, et al (eds): The Heart and Cardiovascular System, Vol. 2. New York, Raven Press 1986, pp 8 0 3 817.
3.
Rocco T, Dilsizian V, Aroney C, et al: Therapeutic impli cations of the end-diastolic volume response to upright exercise in hypertension (abst). Clin Res 1988;36:432A.
4.
Zusman RM, Rocco T, Christensen D, et al: Abnormal exercise dilation characterizes the exercise response of a subgroup of hypertensive patients (abst). Clin Res 1989;37:403A.
5.
Gross TP, Wise RP, Knapp DE: Antihypertensive drug use: trends in the United States from 1973 to 1985. Hy pertension 1989;13(suppl I):I-113-I-118.
19.
Zusman RM: Alternatives to traditional first-line antihy pertensive therapy: unresolved questions and therapeu tic dilemmas. A personal approach. Hypertension 1989;13(suppl I):I-154-I-157.
Westlin W, Mullane K: Does captopril alleviate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation 1988;77:30S-35S.
20.
Singhvi SM, Duchin KL, Morrison RA, et al: Disposition of fosinopril sodium in healthy subjects. Br J Clin Phar macol 1988;25:9-15.
Cushman DW, Wang FL, Fung WC, et al: Differentiation of angiotensin-converting enzyme inhibitors by their se lective inhibition of ACE in physiologically important target organs. Am J Hypertens 1989;2:294-306.
21.
Grover GJ, Sleph PG, Dzwonczyk S, et al: Effects of different angiotensin-converting enzyme (ACE) inhibi tors on ischemic isolated rat hearts: relationship between cardiac ACE inhibition and cardioprotection. J Pharma col Exp Therap 1991;257:919-929.
6.
7. 8.
Anderson RJ, Duchin KL, Gore RD, et al: Once daily fosinopril, a phosphinic acid ACE inhibitor, in the treat ment of hypertension. Hypertension 1991;17:636-642.
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
hydryl-containing ACE inhibitors zofenopril or S-benzoylcaptopril. Indeed, our studies of the myocardial and hemodynamic effects of fosinopril in hypertensive pa tients demonstrate changes in diastolic ventricular per formance which we have not observed in clinical inves tigations with lisinopril or captopril. This cardiophilic property of fosinopril may be secondary to the presence of the phosphinic acid moiety within fosinopril, which may lead to its accumulation within the myocardium, and thus to myocardial effects not seen with other ACE inhibitors. Alternatively, fosinopril may diffuse easily across the myocardial cell membrane from the blood stream, but is trapped because of the low pK of the phosphinic acid, within the cytoplasm which prevents its diffusion out of the cell. The results of this study suggest that fosinopril has beneficial effects on both left ventricular systolic and diastolic performance; these effects appear desirable for the treatment of patients with mild to moderate hyper tension. However, the longer-term importance of an antihypertensive agent which improves indices of ven tricular systolic and diastolic function is still unclear and awaits larger scale epidemiologic trials.
Radionuclide Assessment of Left Ventricular Systolic and Diastolic Performance M. Zusman, Donna M. Christensen,
Joy Higgins,
Numerous pharmacologic agents are capable of lowering the blood pressure of hypertensive pa tients; however, each drug has a characteristic side effect profile and effect on cardiac performance. In this study, the hemodynamic effects of the angio tensin converting enzyme inhibitor fosinopril were assessed at rest and at peak upright bicycle exercise by first-pass radionuclide cineangiography in 12 patients with essential hypertension. Fosinopril re duced blood pressure at rest in the seated position from 152/101 to 131/85 mm Hg (P < .01) and at peak exercise from 206/103 to 184/91 mm Hg (P < .01). Fosinopril therapy was associated with an in crease in stroke volume and cardiac output and a
I
n the selection of antihypertensive medications, rel atively little attention has been paid to the hemody namic effects associated with their use. Recent em phasis has been placed on assessing left ventricular function in patients with hypertension and in matching therapy with the hemodynamic profile exhibited by the patient. Abnormalities of diastolic filling indices com monly characterize the hypertensive patient popula1
and Charles A.
Boucher
decrease in systemic vascular resistance at rest and during peak exercise. Both peak ejection rate and peak filling rate increased significantly at rest dur ing fosinopril therapy. The unique cardiotropic re sponse to fosinopril may reflect its effects on the myocardial renin-angiotensin system, and suggests that this agent may offer a therapeutic advantage compared with other angiotensin converting en zyme inhibitors. Am J Hypertens 1992;5:219-223.
KEY WORDS: Angiotensin converting enzyme inhi bition, cineangiography, exercise, lusitropy, dias tole, renin-angiotensin system.
tion. In addition, the change in end-diastolic ventricu lar volume in response to exercise in patients with hypertension may guide the selection of antihyperten sive therapy. ' In general, the use of vasodilating agents, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and α-adrenergic receptor blockers is increas ing at the expense of the use of diuretics, ^-adrenergic receptor blockers, and centrally acting sympatholytic agents. This shift in patient treatment patterns reflects a more physiologic approach to the treatment of patients with hypertension and a recognition of the potential adverse effects of these latter agents on metabolic and central nervous system function. The purpose of this study was to assess the hemody namic effects at rest and during exercise of fosinopril, a unique ACE inhibitor used to treat patients with hyper tension. Fosinopril ([l,4S]-4-cyclohexyl-l-[2-methyl-l1-1 -(1 -oxopropoxy)propoxyl] (4-phenyl-butyl)phos2
3 4
5
Received March 18, 1991. Accepted November 14, 1991. From the Division of Hypertension and Vascular Medicine, Cardiac Unit, Medical Services, Massachusetts General Hospital, and the De partment of Medicine, Harvard Medical School, Boston, Massachu setts. Support for this study, as well as the fosinopril, was generously provided by Bristol-Myers Squibb. Address all correspondence and reprint requests to Randall M. Zus man, MD, Division of Hypertension and Vascular Medicine, Massa chusetts General Hospital, 15 Parkman Street, ACC 482, Boston, MA 02114.
© 1992 by the American Journal of Hypertension, Inc.
6
0895-7061/'92/'$5.00
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
Randall
phinyl)-L-proline, monosodium salt; SQ28555) is a phosphinic acid derivative of captopril. Fosinopril is a pro-drug that is completely deesterified in the liver and the gastrointestinal mucosa to the biologically active diacid fosinoprilat (SQ27519). Unlike other angiotensin converting enzyme (ACE) inhibitors that are eliminated primarily by the kidney, fosinoprilat is cleared almost equally by renal and hepatic routes. Fosinopril has long-acting antihypertensive activity and is effective as a daily treatment for patients with mild to moderate hypertension. 7
8
METHODS
13
First-Pass Radionuclide Ventriculography Subjects underwent first-pass radionuclide evaluation before the initiation of fosinopril therapy and after the reduction of diastolic blood pressure to less than 90 mm Hg with a dose of fosinopril which had remained stable for a mini
9
S T A T I S T I C A L ANALYSIS The effects of fosinopril were assessed by paired t test comparison to data acquired during the subjects' treat ment with placebo. A Ρ < .05 was considered to repre sent a significant effect. RESULTS Blood Pressure and Heart Rate The mean ( ± S E M ) dose of fosinopril required to reduce diastolic blood pressure below 90 mm Hg was 52 ( ± 6) mg, range 20 to 80 mg. Fosinopril reduced blood pressure (Table 1) with the subject in the seated position at rest from 1 5 2 / 1 0 1 to 1 3 1 / 8 5 mm Hg (P < .01). Mean blood pressure was re duced from 1 4 7 / 1 0 4 to 1 3 0 / 9 0 mm Hg (P < .01) in patients at rest in the upright position and from 2 0 6 / 1 0 3 to 1 8 4 / 9 1 mm Hg (P < .01) at peak upright bicycle ex ercise during acquisition of the radionuclide ventriculo gram. Heart rate during fosinopril therapy was un changed compared with heart rate when the subject received a placebo in the seated and upright positions at rest and during peak exercise. Left Ventricular Systolic Function At rest, stroke vol ume and cardiac output were significantly increased by fosinopril therapy (Figure 1), although left ventricular end-diastolic volume and end-systolic volume were not significantly changed (Table 1); systemic vascular resistTABLE 1. EFFECT OF FOSINOPRIL ON BLOOD PRESSURE, HEART RATE, AND VENTRICULAR VOLUMES Placebo Blood pressure (mm Hg) Seated 152 ± 5 / 1 0 1 ± 1 Upright 147 ± 3/104 ± 1 Peak exercise 206 ± 6/103 ± 4 Heart rate (beats/min) Seated 75 ± 4 Upright 83 ± 4 Peak exercise 153 ± 4 End-diastolic volume (mL) Rest 131 ± 10 Peak exercise 149 ± 9 End-systolic volume (mL) Rest 53 ± 6 Peak exercise 59 ± 7 Each value represents the mean ± SEM.
* P < . 0 2 ν placebo.
Fosinopril 131±3*/85±1* 130 ± 3*/90 ± 2* 184 ± 6*/91 ± 2* 78 ± 4 89 ± 4 146 ± 5 131 ± 6 156 ± 15 49 ± 3 56 ± 7
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
Subject Population Hypertensive subjects of either sex, 18 to 65 years of age, with diastolic blood pressures between 95 and 110 mm Hg were eligible to participate in this study. Newly diagnosed hypertensive subjects or subjects previously treated for hypertension, but who had not taken any antihypertensive medication for a minimum of 2 weeks, were enrolled if their diastolic blood pressure met the above criteria. Subjects were excluded from participation if they had a history of asthma, allergic skin rash, or rhinitis, a history of myo cardial infarction or cerebrovascular accident within the previous 6 months, secondary hypertension, congestive heart failure, serum creatinine greater than 3 0 % above the laboratory upper limit of normal, concomitant ther apy with cytotoxic or immunosuppressant drugs, con comitant collagen vascular disease, leukopenia, or sig nificant liver function test abnormalities. Twelve subjects (nine men and three women) with a mean age of 48 years (range 28 to 68 years) participated in the study. Each subject received placebo therapy dur ing a 4-week lead-in period. Blood pressure was deter mined in triplicate in the seated and upright positions (measured 3 min after standing). Each subject was then blindly randomized to receive either placebo or 10, 40, or 80 mg of fosinopril every day for an additional 8 weeks. Blood pressure was monitored weekly during monotherapy. At the end of the 8-week period, the fo sinopril dose was adjusted to reduce diastolic blood pressure to less than 90 mm Hg with the subject in the sitting position with the minimum necessary dose of medication. Subjects originally randomized to placebo treatment began fosinopril treatment at week 8, and were titrated to an effective dose of fosinopril. This protocol was approved by the Subcommittee on Human Studies of the Committee on Research of the Massachusetts General Hospital. Each subject signed an informed consent to participation form for the trial.
mum of a month. The detailed exercise protocol and techniques for calculation of ventricular function in dices from first-pass left ventriculography has been previously described. Observers blinded to the sub jects' status and therapy performed and analyzed the first-pass radionuclide angiogram for calculation of ven tricular volumes and the ejection and filling indices.
2000
r
FIGURE 1. Effects of fosinopril on systemic vascular resistance, stroke volume, and cardiac output at rest and at peak exercise (EX). * Ρ < .05; ** Ρ < .01.
PLACEBO
^
FOSINOPRIL
ance at rest fell from 1684 dyne · sec · c m to 1234 d y n e - s e c - c m (P < .01) during fosinopril ther apy (Figure 1). At peak exercise, stroke volume and car diac output increased and systemic vascular resistance decreased significantly during fosinopril therapy (Fig ure 1); neither end-diastolic volume nor end-systolic volume was affected by fosinopril therapy. At rest, the absolute value of peak ejection rate in creased from—353 mL/sec to —417 mL/sec during fo sinopril therapy (P < .05) (Figure 2). The significantly greater peak ejection rate was sustained when these values were normalized for end-diastolic volume and stroke volume. Time to peak ejection rate was slightly, but not significantly, shorter during fosinopril therapy. - 5
-5
10
At peak exercise, neither peak ejection rate nor time to peak ejection rate was significantly affected by treat ment with fosinopril (Table 2). Ejection fraction in creased from 60 ± 3 % to 65 ± 2 % (P < .05) during fo sinopril therapy. Neither exercise time, peak exercise workload, nor maximal oxygen consumption was af fected by fosinopril therapy. Left Ventricular Diastolic Function At rest, the abso lute value of peak filling rate was increased significantly from 294 to 340 mL/sec (P < .05) during fosinopril ther apy (Figure 2). The absolute values of peak filling rate normalized for stroke volume or end-diastolic volume were significantly increased by treatment with fosino-
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
REST •
TABLE 2. EFFECTS OF FOSINOPRIL ON INDICES OF LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC PERFORMANCE Fosinopril
-353 ±27 -577 ±62
- 4 1 7 ± 28* - 6 0 7 ± 70
-4.54 ±0.13 -6.30 ±0.28
- 5 . 0 4 ± 0.15* - 6 . 0 0 ± 0.16
-2.74 ±0.12 -3.81 ±0.31
- 3 . 1 8 ± 0.16* - 3 . 8 7 ± 0.15
177 ± 9 106 ± 11
163 ± 7 92 ± 6
294 ± 3 3 747 ± 5 9
340 ± 41* 765 ± 78
3.63 ± 0 . 2 3 8.42 ± 0 . 2 6
4.09 ± 0.26* 7.68 ± 0.30
2.21 ± 0 . 1 8 4.99 ± 0 . 2 4
2.58 ± 0.20* 4.96 ± 0.24
1
1
1
1
173 ± 12 96 ± 8
185 ± 10 116 ± 7
PER = peak ejection rate; EDV = end-diastolic volume; SV = stroke volume; TPER = time to peak ejection rate; PFR = peak filling rate; TPFR = time to peak filling rate. Each value represents the mean ± SEM. * Ρ < .05 ν placebo.
9 11
14
15
16
17
18
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pril. Time to peak filling rate was not significantly af fected by fosinopril treatment. At peak exercise, neither peak filling rate nor time to peak filling rate were signifi cantly affected by fosinopril treatment (Table 2). DISCUSSION The hemodynamic changes observed in subjects with mild hypertension treated with fosinopril are consistent with improved cardiac systolic and diastolic perform ance and systemic vasodilation. The reduced systemic vascular resistance with preservation of cardiac output in subjects treated with ACE inhibitors reflects the bal anced hemodynamic effect of these compounds with improvement in cardiac systolic function caused by pe ripheral vasodilation. However, previous studies with lisinopril or captopril did not reveal an increase in peak ejection rate or in stroke volume as seen after fo sinopril therapy. Similarly, earlier studies with captopril or lisinopril did not demonstrate any significant change in indices of diastolic function. Indeed, our previous studies have shown that the treatment of subjects with moderately severe hypertension with nifedipine is associated with improved indices of diastolic filling, but our studies 11
12
11,12
13
20
21
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PER (mL/sec) Rest Peak exercise PER/SV (sec" ) Rest Peak exercise PER/EDV (sec" ) Rest Peak exercise TPER (msec) Rest Peak exercise PFR (mL/sec) Rest Peak exercise PFR/SV (sec" ) Rest Peak exercise PFR/EDV (sec" ) Rest Peak exercise TPFR (msec) Rest Peak exercise
Placebo
using either propranolol, atenolol, or lisinopril ' in the treatment of subjects with mild hypertension similar to those studied in this project did not result in significant changes in diastolic function. Nonetheless, despite the theory that the importance of calcium in the regulation of myocardial cellular contraction and relaxation indi cates that calcium channel blockers should have a unique effect on ventricular diastolic function, fosino pril treatment was associated with an improvement in diastolic performance in subjects. Demonstration of the presence of the complete reninangiotensin cascade in isolated myocardial cells, as well as recognition of the potential importance of angio tensin I and angiotensin II as factors regulating cardiac function, suggest that the use of ACE inhibitors may modify intrinsic myocardial performance and overall left ventricular function. Indeed, the results of Shunkert et a l and of Lorell et a l have confirmed the deleteri ous effects of angiotensins I and II on diastolic proper ties of the hypertrophied pressure-loaded ventricle in rats; this provides a rationale observing improved dia stolic function after ACE inhibition with fosinopril. Furthermore, ACE inhibitors may exert different local effects as a result of various chemical group substitu tions to the basic converting enzyme inhibitor structure. For example, the sulfhydryl-containing ACE inhibitor captopril and its analogues have been demonstrated to stimulate cellular prostaglandin biosynthesis, a phe nomenon dependent upon the presence of the sulfhydryl-group substitution. Similarily, the presence of the sulfhydryl group on captopril may confer upon it free radical scavenging properties which lead to cardiopro tective effects in ischemic myocardial tissue. The pres ence of the phosphinic acid substitution in the bioactivated fosinopril molecule may also confer unique pharmacologic properties. Certainly, the presence of a phosphinic acid group may result in unique tissue pene tration and intracellular effects because of the unique characteristics of the compound, such as its lipophilicity. The recent studies of Cushman et a l have also dem onstrated varied effects of ACE inhibitors on myocardial enzyme activity, suggesting that the myocardial effects of ACE inhibitors may differ. The sulfhydryl-containing ACE inhibitors, captopril and zofenopril, have the most marked myocardial effects after a single oral dose ad ministered to rats. Fosinopril, although less effective than captopril or zofenopril, had a significantly greater effect on myocardial ACE activity than enalapril, lisino pril, or ramipril. Grover et a l have demonstrated the uptake of fosinoprilat by the myocardium of rat hearts to be 14.5 and 15.4 times greater than that of lisinopril and enalaprilat, respectively; the uptake of fosinoprilat is 10.9 and 500 times greater than that of fosinopril and enalapril, the precursor pro-drugs of the biologically active deesterified products. Of note, the inherent rate of deesterification of fosinopril and enalapril by the myocardium is significantly slower than that of the sulf-
REFERENCES
9.
Zusman RM, Christensen DM, Federman EB, et al: Nife dipine, but not propranolol, improves left ventricular sys tolic and diastolic function in patients with hyperten sion. Am J Cardiol 1989;64:51F-61F.
10.
Bonow R, Bacharach SL, Green MV, et al: Impaired left ventricular diastolic filling in patients with coronary ar tery disease: assessment with radionuclide angiography. Circulation 1981;64:315-323.
11.
Zusman RM, Christensen DM, Higgins J, Boucher CA: Lisinopril treatment maintains cardiac function in pa tients with hypertension (abst). Clin Res 1989;37:403A.
12.
Zusman RM, Christensen DM, Higgins J, Boucher CA: Fosinopril, but not lisinopril or captopril, improves left ventricular systolic and diastolic performance (abst). Pro ceedings of the Second International Symposium on ACE inhibition. London, England, February 1991; ρ 76.
13.
Zusman RM, Christensen DM, Higgins J, Boucher CA: Nifedipine improves left ventricular function in patients with hypertension. J Cardiovasc Pharmacol 1992;18:843-848.
14.
Dzau VJ, Pratt RE: Renin-angiotensin system: biology, physiology and pharmacology, in Fozzard HA, Haber E, Jennings RB, et al (eds): The Heart and Cardiovascular System, Vol. 2. New York, Raven Press, 1986, pp 1631 1662.
15.
Foult J-M, Tavolaro O, Antony I, Nitenberg A: Direct myocardial and coronary effects of enalaprilat in pa tients with dilated cardiomyopathy: assessment by a bi lateral intracoronary infusion technique. Circulation 1988;77:337-344.
16.
Shunkert H, Dzau VJ, Tang SS, et al: Increased rat car diac angiotensin converting enzyme activity and mRNA expression in pressure overload hypertrophy: effects on coronary resistance, contractility and relaxation. J Clin Invest 1990;86:1913-1920.
17.
Lorell BH, Weinberg EO, Ngoy S, Apstein C: Angioten sin II directly impairs diastolic function in pressure over load hypertrophy (abst). Circulation 1990;82(suppl III):III-112.
18.
Zusman RM: Effects of converting-enzyme inhibitors on the renin-angiotensin-aldosterone, bradykinin, and ara chidonic acid-prostaglandin systems: correlation of chemical structure and biologic activity. Am J Kid Dis 1987;10(suppl l):13-23.
1.
Zusman RM: The prevalence of left ventricular dysfunc tion in hypertension: therapeutic implications. Am J Car diol (in press).
2.
Smith VE, Weisfeldt ML, Katz AM: Relaxation and dia stolic properties of the heart, in Fozzard HA, Haber E, Jennings RB, et al (eds): The Heart and Cardiovascular System, Vol. 2. New York, Raven Press 1986, pp 8 0 3 817.
3.
Rocco T, Dilsizian V, Aroney C, et al: Therapeutic impli cations of the end-diastolic volume response to upright exercise in hypertension (abst). Clin Res 1988;36:432A.
4.
Zusman RM, Rocco T, Christensen D, et al: Abnormal exercise dilation characterizes the exercise response of a subgroup of hypertensive patients (abst). Clin Res 1989;37:403A.
5.
Gross TP, Wise RP, Knapp DE: Antihypertensive drug use: trends in the United States from 1973 to 1985. Hy pertension 1989;13(suppl I):I-113-I-118.
19.
Zusman RM: Alternatives to traditional first-line antihy pertensive therapy: unresolved questions and therapeu tic dilemmas. A personal approach. Hypertension 1989;13(suppl I):I-154-I-157.
Westlin W, Mullane K: Does captopril alleviate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation 1988;77:30S-35S.
20.
Singhvi SM, Duchin KL, Morrison RA, et al: Disposition of fosinopril sodium in healthy subjects. Br J Clin Phar macol 1988;25:9-15.
Cushman DW, Wang FL, Fung WC, et al: Differentiation of angiotensin-converting enzyme inhibitors by their se lective inhibition of ACE in physiologically important target organs. Am J Hypertens 1989;2:294-306.
21.
Grover GJ, Sleph PG, Dzwonczyk S, et al: Effects of different angiotensin-converting enzyme (ACE) inhibi tors on ischemic isolated rat hearts: relationship between cardiac ACE inhibition and cardioprotection. J Pharma col Exp Therap 1991;257:919-929.
6.
7. 8.
Anderson RJ, Duchin KL, Gore RD, et al: Once daily fosinopril, a phosphinic acid ACE inhibitor, in the treat ment of hypertension. Hypertension 1991;17:636-642.
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 5, 2015
hydryl-containing ACE inhibitors zofenopril or S-benzoylcaptopril. Indeed, our studies of the myocardial and hemodynamic effects of fosinopril in hypertensive pa tients demonstrate changes in diastolic ventricular per formance which we have not observed in clinical inves tigations with lisinopril or captopril. This cardiophilic property of fosinopril may be secondary to the presence of the phosphinic acid moiety within fosinopril, which may lead to its accumulation within the myocardium, and thus to myocardial effects not seen with other ACE inhibitors. Alternatively, fosinopril may diffuse easily across the myocardial cell membrane from the blood stream, but is trapped because of the low pK of the phosphinic acid, within the cytoplasm which prevents its diffusion out of the cell. The results of this study suggest that fosinopril has beneficial effects on both left ventricular systolic and diastolic performance; these effects appear desirable for the treatment of patients with mild to moderate hyper tension. However, the longer-term importance of an antihypertensive agent which improves indices of ven tricular systolic and diastolic function is still unclear and awaits larger scale epidemiologic trials.
