Hemodynamic effects of dilevalol in patients with systemic hypertension and left ventricular dysfunction

Hemodynamic Effects of Dilevalol in Patients with Systemic Hypertension and Left Ventricular Dysfunction Vithal Kinhal, MD, Arun Kulkarni, MD, Rodney Pozderac, MD, and Judith Cubbon, MD

Hemodynamic and left ventricular function parameters were measured in patients with mild to moderate hypertension and compromised left ventricular function who were given dilevalol, an antihypertensive agent with selective &-agonism and nonselective #?-antagonist activity. After a 2- to 3-week placebo washout period, 9 patients were given dilevalol titrated upward from 100 to 600 mg twice daily over a 7-week period to achieve a supine diastolic blood pressure of
64

1

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

ilevalol is a unique antihypertensive agent that induces vasodilation with selective & agonism and also provides &antagonist effects. As previously demonstrated, 1-4 dilevalol significantly reduced heart rate and supine systolic and diastolic blood pressures at rest, and blunted exercise-induced responses. Left ventricular ejection fraction (LVEF), which has excellent correlation with angiographic-derived ejection fraction5 increased significantly (by approximately 17%), with no change during exercise. Peripheral resistance and cardiac output, calculated from radionuclide studies, showed no significant change. Atkins4 found that dilevalol decreased peripheral resistance without changing cardiac index in patients with hypertension and norma1 left ventricular function. Dilevalol’s effects in patients with hypertension and compromised left ventricular function has not been established.6-12 The present study was designed to assessthe effects of dilevalol in such patients.

D

METHODS Patient group: Nine men with long histories of mild to moderate hypertension, ranging from 6 to about 22 years, were recruited from the hypertension clinic. After a 2- to 3-week placebo washout of antihypertensive medications (phase I), patients were entered into the study if they met 3 criteria: history of at least 1 month of congestive heart failure, supine diastolic blood pressure >90 mm Hg, and left ventricular ejection fraction on radionuclide angiography 50.45. Digitalis glucoside and diuretic medications were continued throughout the study for those patients already receiving them. Table I shows the demographic profile of study subjects. Study design (Fig. 1): After the washout period, patients who met the study criteria underwent multigated radionuclide ventriculography at rest and during symptom-limited exercise. Exercise testing was performed on a supine bicycle ergometer beginning with 25W and increasing in increments of 25W at 4-minute intervals. Data were obtained at rest and during the last 2 minutes From the Noninvasive Cardiac Laboratory, Veterans Administration Medical Center, Allen Park, and Wayne State University School of Medicine, Detroit, Michigan; and Schering-Plough Corporation, Kenilworth, New Jersey. This study was supported by the Veterans Administration and a grant from the Schering-Plough Corporation. Address for reprints: Vithal Kinhal, MD, 18263 Ten Mile Road, Suite E, Roseville, Missouri 48066.

of exercise. Systolic and diastolic time intervals were obtained at rest. During phase II (1 to 7 weeks) the dose of dilevalol was increased in a stepwise fashion (100 to 600 mg twice daily) to achieve a supine diastolic blood pressure of <90 mm Hg with a decrease of at least > 10 mm Hg from baseline. Multigated radionuclide ventriculographic studies and determination of systolic and diastolic time intervals were repeated at the end of the 2-week maintenance period (phase III) and 7- to lo-day posttreatment discontinuation and placebo washout (phase IV). Hemodynamic measurements: Patients were entered into the study after informed consent was obtained. A complete history and physical examination were performed for each patient at the time of inclusion in the study, and a brief history was taken and a physical examination performed at the end of the pretreatment placebo washout and maintenance phases of the study. A complete history and physical examination were repeated at the end of the post-treatment placebo washout phase. Blood pressure measurements were obtained in triplicate by sphygmomanometry with the patient in the supine position in a quiet room after 5 minutes of rest. Systolic time intervals were determined with an Electronics for Medicine Honeywell Electrophonocardiogram and recorded on a strip-chart recorder at a paper speed of 100 mm/s, as previously described.13+‘4Measurements were made of the electromechanical systole (QS2, time from the beginning of the Q wave on the surface electrocardiogram to the first high-frequency deflection of the aortic component of the second heart sound on the phonocardiogram) and of LVEF (time from the beginning of the carotid upstroke to the incisural notch measured from the carotid pulse tracing). The preejection period (PEP) was calculated as the difference between QSz and LVEF. Measurements from 10 cardiac cycles were averaged to obtain the values of QS, and LVEF. These parameters were then corrected for heart rate.i3*i4 Diastolic time was determined from the cardiac cycle (RR interval) minus Q-&.is The double product was calculated as the product of systolic blood pressure and heart rate. Systolic time

TABLE

I Demographic

Profile

of Study

No. of patients Sex Male Race Caucasian Black Age W Mean Range Etiology of congestive heart failure lschemic heart disease Baseline ejection fraction Mean Range Classification of extertional symptoms of dyspnea Symptomatic with exercise Symptomatic with ordinary exertion Supine diastolic blood pressure (mm Hg) Average of last 2 phase I visits Concomitant medications Antihypertensive” Digitalis glycosidet Diuretic? Nitroglycerin patch*

9 9 6 3 60 4946 9 0.32 0.20 to 0.45

5 4

150/95 6 6 5

5

* Discontmued at first study visit. t Continued throughout all phases of study. t Used if necessary throughout study.

interval determinations, blood pressure measurements and radionuclide studies were performed between 8:30 AM and 11:OOAM. Statistical analyses: Data are presented as mean f 1 standard deviation. For comparison analyses, Student 2tailed 1for paired observations was used. A p value <0.05 was considered a statistically significant difference. RESULTS The median daily 444 mg (200 to 600 new clinical signs of motion abnormalities

maintenance dose of dilevalol was mg) (phase III). In no patient did heart failure or new regional wall develop. Blood pressure and heart rate at rest: Heart rate decreased significantly (p
r

STUDY DESIGN

-1

Phase I Washout (2-3Weeks)

Phase IV Washout

(7.10Days)

Systolic T6iaollc

FIGURE 1. Study design. BID = twice daily; CHF = congestive heart faikwe; EF = ejectlon fraction; SDBP = supine diastolic Mood-.

Subjects

3-7Daysto Achieve

Time lnler~als (RCSI) Multlgated Ventrlculography 1 Al Rest 2 At MaxImalExercise 1

w EntryPhaseII 1 HistoryCHF 2 SOBP>90 mmHg 3 EF(REST)545%

SDBP < 90 mmtia & 1 210 mmHg I from Basekne 100mg BID 200 mg BID 300mg BID 400mg BID 600 rn~ BID

splolIc Tmsrollc Time lnler~ls

m b7t~lCUlOgraQhy 1 Al Rest

2 At MaxImal Exercise

DoseI then Placebo5-7 Days %L Time Intervals (Rest) Multlgated Mntwlography 1 At Resl 2 DUMIQ Exercise At Workload Attainedal MaxImalExercise on D~le~lol I

L

THE AMERICAN

JOURNAL

OF CARDIOLOGY

JUNE 5,1989

65 I

A SYMPOSIUM: ANTIHYPERTENSION THERAPY IN THE 90s

TABLE II Effect of Dilevalol on Heart Rate and Blood Pressure at Rest and During Exercise Placebo Before Treatment Heart rate (beats/min) Rest (n = 9) Exercise (n = 7) Blood pressure (mm Hg) Rest (n = 9) Exercise (n = 7)

Dllevalol*

81f6 115f 11

66k7 89fll

144*14/91*5 185f21/105%6

128f11/74f3 167+12/97f5

Placebo After Treatment 79+6 108f 12 142f9/9Of5 189f13/111f8

* p < 0.01 at rest (dilevalol compared wth placebo before and after treatment).

ment placebo. Systolic/diastolic blood pressures at rest decreased significantly (p
and heart rate at maximal

exercise:

Exercise-induced changes in blood pressure and heart rate were significantly blunted during treatment (p
c, 050-j

DISCUSSION Conventional treatment of congestive heart failure has consisted of digitalis and diuretics to improve myocardial performance and decrease pulmonary congestion and peripheral edema. During the past decade, however, the use of vasodilators and angiotensin-converting enzyme (ACE) inhibitors has gained increased acceptance. The Veterans Administration Vasodilator Heart Failure Trial II6 demonstrated that the addition of hydralazine and isosorbide dinitrate to digitalis and diuretics in the treatment of congestive heart failure had a favorable effect on left ventricular function and on mortality. Preliminary data from Kleber et ali7 indicated that the ACE inhibitor captopril may prolong survival in patients with New York Heart Association functional class I to III heart failure. The Cooperative North Scandinavian Enalapril Survival StudyI demonstrated reduced mortality in patients with class IV heart failure when the ACE inhibitor enalapril was added to digitalis, diuretics and vasodilators. Use of /3 blockers in the treatment of idiopathic dilated cardiomyopathy and congestive heart failure has been

Exercise (n=7)

Rest (n = 91 060

LVEF ratio are shown in Figure 3. The relation between heart rate and systolic and diastolic time per beat with dilevalol is shown in Figure 4. As the heart rate decreased, the RR interval increased in a nonlinear fashion, with proportionately greater increases in diastolic compared with systolic time per beat.

1 FIGURE 2. Effect of dilevalol on ejection fractlen at rest and during exercise. NS = nel sipifieant.

J

Pretreatment Placebo

Dllevalol

t p
66 1

t,

Posttreatment Placebo

Pretreatment Placebo

Dllevalol


THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

Posttreatment Placebo

FIGURE 3. Effect ot dilevabi on systolic the intervals in 7 patients. LVET = left entridar ejdion time; PEP = preejecion period; Q& = elec-nical systale. *p
0

Pretreatment

m

D~levalol

controversial:19~20However, in recent years these agents have been shown to be beneficial in patients with idiopathic dilated cardiomyopathy and left ventricular dysfunction.2’m24 Recent evidence suggests that ,8 blockers not only may improve symptoms of congestive heart failure and increase left ventricular function, but also may reduce mortality in some patients with this particular cardiomyopathy.24 Dilevalol, the RR optical isomer of labetalol, has a selective &-agonist pharmacologic activity that is almost 7 times that of labetalol, with little cY-blocking activity.‘,25 Additionally, dilevalol is 3 to 4 times more potent than labetalol in its blockade of pi and 62 receptors.*j In our study, diievalol significantly increased LVEF and decreased PEP/LVEF ratio, indicating improved left ventricular performance.26y27In a study by Hammond et aI6 pindolol, a nonselective p blocker with intrinsic sympathomimetic properties at pi- and &receptor sites, decreased mean arterial blood pressure >lO% in hypertensive patients who had an abnormally elevated PEP/ LVEF ratio. In addition, hypertensive patients with a normal PEP/LVEF ratio had an increase in this ratio after receiving pindolol therapy, whereas those with an abnormally elevated pretreatment PEP/LVEF ratio had a decrease. The divergent effects of pindolol on left ven-

and Posttreatment

Placebo

‘p
x005

(Pretreatment (P&treatment

to D~levaloi) to D~levalol)

tricular function were attributed to less p blockade and a greater intrinsic sympathomimetic activity effect in patients with an abnormal pretreatment PEP/LVEF ratio. Rasmussen7 found that metoprolol, a cardioselective /? blocker, improved left ventricular performance as assessed by systolic time intervals; labetalol, an CYblocker with vasodilator and @blocking properties, produced a minor decrease in PEP without a significant change in PEP/LVEF ratio. 7 In contrast to pindolol, metoprolol and labetalol, we found that dilevalol decreased an abnormally elevated PEP and PEP/LVEF ratio in all patients, with significant reduction in mean arterial blood pressure. Alterations in left ventricular preload and afterload, in addition to the factors influencing the inotropic state of the left ventricle, may influence changes in systolic time intervals. No significant change in the resting cardiac output or calculated peripheral vascular resistance was noted in our study. Boudoulas et al’* reported that in hypertensive patients with mild to moderate left ventricular hypertrophy, systolic time intervals offer a more sensitive indicator of left ventricular dysfunction than echocardiographic measures and are independent of the influence of diastolic blood pressure. Increase in diastolic time with dilevalol confirms our previous observationsz8 that /3

1200-

q

lOOO-

FIGURE 4. Relation between heart rate and systolic and dlstolii time per beat in 7 patients. DT = diastotic time; R-R = cardiac cycle; Qs, = ekctnnmehanical syswe.

8 $ r

800-

a i=

600-

X

%f/

, 50

I 70

I 60 Heart

I 80

I 90

I 100

I 110

Rate (bestslmin)

THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 5.1989

67 I

A SYMPOSIUM:

ANTIHYPERTENSION

THERAPY

IN THE 90s

antagonists increase diastolic time while decreasing systolic time. These changes are expected to decrease myocardial oxygen consumption and left ventricular work and increase subendocardial flow, factors that are important in hypertensive patients with left ventricular hypertrophy or coronary artery disease, or both. Several /3 blockers have demonstrated regression of left ventricular hypertrophy in hypertensive patients, although such a beneficial effect remains controversia1.8,9,29,30 Trimarco et al8 found that long-term treatment with acebutolol in hypertensive patients resulted in improved left ventricular performance as assessedby left ventricular circumferential fiber shortening and ejection fraction. In a short-term study with labetaloL9 regression ‘of left ventricular hypertrophy without alteration in left ventricular function was noted as early as 4 weeks. Our study was short-term and no echocardiographic data were obtained to assessleft ventricular mass. However, our patients with a long history of hypertension and congestive heart failure most likely had increased left ventricular mass. The precise mechanism(s) by which dilevalol improved left ventricular performance in this study is not clear. Improvement in left ventricular ejection fraction may be attributed to improved left ventricular pumping function.5 Beta blockers improve left ventricular function by various other mechanisms, which were reviewed recently by Shanes et a1.2o,31These mechanisms include restoration of norepinephrine myocardial stores, up-regulation of p receptors, and decrease in enhanced sympathetic tone, which increases renin, angiotensin and aldosterone production. It is tempting to speculate that dileva101,by its &agonist properties, may increase cardiac contractility. CONCLUSION The present study demonstrates that dilevalol effectively reduced blood pressure and improved left ventricular function in patients with hypertension and compromised left ventricular function. The precise mechanism by which left ventricular performance improved is not clear. Further clinical trials to establish the long-term efficacy of dilevalol and to delineate the mechanisms involved in improvement of left ventricular function appear indicated. Dilevalol should prove an effective medication for use in patients with hypertension and compromised left ventricular function. REFERENCES 1. Baum T, Watkins RW, Sybertz EJ, Vemulapalli S, Pula KK, Eynon E, Nelson S, Vander Vliet G, Glennon J, Moran RM. Antihypertensive and hemcdynamic actions of SCH 19921, the U-R isomer of labetolol. J Phormacol Exp Ther 1981:218:444-452. 2. Flanigan W, Cubbon J. The antihypertensive effects of rising multiple doses of dilevalol, the R-R isomer of labetolol (abstract 141). In: Program and Abstracts of the I I th Scientific Meeting of the International Society of Hypertension. Heidelberg, Germany: 1986. Aug 31-Sep 6. 3. Wallin JD. Cook ME, Clifton GG, Blasucci DJ, Poland M. Intravenous dilevalol: effects of the R-R optical isomer of labetolol in patients with severe hypertension. Arch Intern Med 1988;148:534-538.

68

I

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

4. Atkins JM. The hemodynamic effects of dilevalol: the R-R isomer of labetolol (abstract 14D). In Ref. 2. 5. Trimarco B, DeLuca N. Cuacolo A, Ricciardelli B, Rosiello G, Lembo G, Volpe. M. Beta blockers and left ventricular hypertrophy in hypertension. Am Heart J 1987:J 14:975-983. 6. Hammond JJ, Kirkendall WM, Jacks-Nagle VL, Plotnick GD, Fisher ML, Hamilton JH, Robinson M, Carliner NH, Janoski AH, Hamilton BP. Pindolol and systolic time intervals in patients with hypertension. Am Heart J 1982; 104:456-464. 7. Rasmussen JB. The use of systolic time intervals in the evaluation of antihypertensive treatment with metoprolol, labetalol, and prazosin. Car Vasa 1983;

25(S):358-366. 8. Trimarco B, Ricciardelli B, DeLuca N, Volpe M, Venitero A, Cuocolo A, Condorelli M. Effect of acebutolol on left ventricular hemodynamics and anatomy in systemic hypertension. Am J Cardiol 1984;53:791-796. 9. Kaul U, Mohan JC, Bhatia ML. Effects of labetalol on left ventricular mass and function in hypertension-an assessment by serial echocardiography. Int J Cardiol 1984;5:461-473. 10. Hahn B, Strauer BE. The influence of beta-adrenoceptor blockade on left ventricular function. Br J Clin Pharmacol 1982;13:suppl 2;305Sm307S. 11. Mace PJ, Littler WA, Clover DR, Rowlands DB, Stallard TJ. Regression of left ventricular hypertrophy in hypertension: comparative effects of three different drugs. J Cardiouasc Pharmocol 1985;7:suppl 2:SS2XS55. 12. Boudoulas H, Mantzouratos D, Sohn YH, Weissler AM. Left ventricular mass and systolic performance in chronic systemic hypertension. Am J Cardiol 1986;57:232-237. 13. Weissler AM, Harris WS, Schoenfeld CD. Systolic time intervals in heart failure in man. Circulation 1968;37:149-159. 14. Lewis RP, Rittgers SE, Forester WF, Boudoulas H. A critical review of the systolic time intervals. Circulation 1977;56:146-158. 15. Boudoulas H, Rittgers SE, Lewis RP, Leier CV, Weissler AM. Changes in diastolic time with various pharmacological agents: implication for myocardial perfusion. Circulation 1979,60:164~169. 16. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dankman WB, Jacobs W, Francis GS, Flohr KH, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314tJ547-1552. 17. Kleber FX, Laube A, Ostekorn K, Konig E. Captopril in mild to moderate heart failure over eighteen months: effects on morbidity and mortality (abstr). JACC 1987;9:42A. 18. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987:316:1429-1435. 19. Alderman J, Grossman W. Are beta-adrenergic-blocking drugs useful in the treatment of dilated cardiomyopathy? Circulation J985;71:854-857. 20. Shanes JG. Beta blockade-rational or irrational therapy for congestive heart failure? (editorial) Circulation 1987;76:971-973. 21. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975;37:1022~1036. 22. Swedberg K, Hjalmarson A, Waagstein F, Wallentin 1. Beneficial effects of long-term beta blockade in congestive cardiomyopathy. Br Heart J 1980;44:1 J7133. 23. Engelmeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM. Improvement in symptoms and exercise tolerance by metoprolol in patients with cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulntion 1985;72536-546. 24. Waagstein F, Hjalmarson A, Swedberg K, Wallentin I. Beta-blockers in dilated cardiomyopathies: they work. Eur Heart I 1983;4:suppl A:J73-178. 25. Sybertz EJ, &bin CS, Pula KK, Vander Vliet G, Glennon J, Gold EH, Baum T. Alpha and beta adrenoceptor blocking properties of labetalol and its R-R isomer, SCH 19927. J Pharmacol Exp Ther 1981:218:435-443. 26. Garrard Cl Jr, Weissler AM, Dodge HT. The relationship of alterations in systolic time intervals to ejection fraction in patients with cardiac disease. Circulation 1970;42:455-462. 27. Ahmed SS, Levinson GE, Schwartz CJ, Ettinger PO. Systolic time intervals as measures of the contractile state of the left ventricular myocardium in man. Circulation 1972:46:559-571. 28. Jawad IA, Kinhal V, Talmers R, Weissler AM, Boudoulas H. The therapcutic implications of diastolic time changes in systemic hypertension. Am Heart J 1985;109:1339-1345. 29. Hill LS. Monaghan M, Richardson PJ. Regrassion of left ventricular hypcrtrophy during treatment with antihypertensive agents. Br J Clin Pharmocol 1979:7:suppl 2:25X?-260s. 30. Rowlands DB, Glover DR, Stallard TJ, Littler WA. Control of blood PESSUPand reduction of echocardiographically assessed left ventricular mass with oncedaily timolol. Br J Clin Pharmacol J982:J4:89m95. 31. Shanes J, Kasabali B, Blend M. Beta-adrenergic blockade in heart failure: potential mechanisms of action. Heart Failure 1986;2:138-146.