Effect of intravenous metoprolol on left ventricular performance in Q-wave acute myocardial infarction

Effect of Intravenous Metoprolol on Left Ventricular Performance in Q-Wave Acute Myocardial Infarction Louis J. Dell’ltalia, MD, and Richard A. Walsh, MD

To determine the effects of intravenous metoprolol on left ventricular (LV) function in acute myocardial infarction (AMI), 16 patients were studied within 48 hours of Q-wave AMI (mean ejection fraction 47 f 6%, mean pulmonary artery wedge pressure 22 f 6 mm Hg) with high fidelity pressure and biplane cineventriculography before and after intravenous metoprolol (dose 12 f 4 mg). Heart rate decreased from 90 f 13 to 74 f 11 beats/min (p
B

eta-adrenoreceptorblocking drugsreducemortality when given at varying intervals after Q-wave acute myocardial infarction (AMI). Recently, Yusuf et al1 reported that among 50,000 patients randomized in multiple multicenter trials to P-adrenergic blockade or placebo, there was a resultant 25% reduction in mortality for the treated group. Further, the first International Society of Infarct Survival-l trial recently demonstrated additional decreasein short-term mortality when atenolol, a selective ,C3antagonist, was given within 7 days after AMI. The greatestdecreasein mortality was observed in the first 24 to 48 hours after the event.2 Despite many potential beneficial effects after AMI,1-3 p blockade may precipitate or aggravate congestive heart failure in patients with acutely impaired left ventricular (LV) function by inhibiting the chronotropic and inotropic effects of compensatoryreflex sympathetic stimulation. Paradoxically, several studie&* have demonstrated that administration of /3-adrenergicblocking drugs to patients with severe chronic congestiveheart failure is well tolerated acutely and may result in improved longterm functional capacity. To date, no study has critically evaluated the effects of P-adrenergicblocking drugs on systolic and diastolic function in patients with acutely impaired LV performance consequentto AMI. Accordingly, we analyzed the effects of intravenous metopro101on LV performance in such patients using highfidelity micromanometer pressure measurementsand biplane ventriculographic volumes. METHODS

Patients: Sixteen patients with Q-wave AM1 documented by conventional enzyme and electrocardiographic criteria were studied within 48 hours of the onset of chest pain. There were 9 women and 7 men ranging between 35 and 65 years of age (mean 56 f 8). No patient had a history of previous AMI. All nitrates and calcium antagonist drugs were discontinued at least 8 hours before the study protocol and no patient was takFrom the University of Texas Health Science Center at San Antonio, ing ,&adrenergic blocking drugs before admission. Two San Antonio, Texas. This study was presentedin part at the American patients were Killip class I and 14 patients were Killip Federation for Clinical Research National Meeting, San Diego, Caliclass II or III. Eleven patients had Q-wave anterior and fornia, May 1987,and was supportedin part by a grant from the CibaGeigy Pharmaceutical Co. Manuscript received June 24, 1988;revised 5 patients had Q-wave inferior AMI. Mean peak cremanuscript received September 15, 1988,and accepted September 16. atine kinase was 3,363 f 1,972 for the group. Each paAddressfor reprints: Richard A. Walsh, MD, Department of Meditient gave informed consent on forms approved by the cine/Cardiology, University of Texas Health Science Center at San Institutional Review Board. Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7872. Protocol: All patients were premeditated with oral Dr. Dell’Italia’s present address: the Watson Clinic, Lakeland, diazepam (10 mg) and diphenhydramine (50 mg) beFlorida. 166

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/

I

TABLE I Group Hemodynamic

Before metoprolol After metoprolol

Data in Patients with Acute Q-Wave Infarction

Before and After Intravenous

Metoprolol

(n = 16)

RAP (mm Hg)

PAP (mm W

PAWP (mm Hg)

MAP (mm Hg)

SVR (dynes s cmd5)

Cl

(Ilter/min/m2)

(ml/beat/m2)

12zt4 13f4”

29 f 6 27 f 6”

22 f 6 21 i 6

104f 17 98 + 19+

1,740 f 603 2,195 f 781’

2.77 f 0.56 2.01 f 0.50s

31 f5 27 f 5t

* p <0.05: + p
PAP = mean pulmonary resistance.

arterial

pressure:

PAWP = mean pulmonary

arterial

SW

wedge pressure:

RAP = mean right atrial pressure;

I

I

TABLE II Group Hemodynamics 4)

Volumes Before and After Intravenous

+dP/dt

Wall Stress

(mm Hg/s)

Wcm2)

10

1,776 c+ 342

291*

97flO 74f 14

1,537 * 282 1,359 f 394

266f

HR (bpm) Before metoprolol After metoprolol Paced Unpaced

and Ventricular

97*

Metoprolol

During Right Atrial Pacing (n = LVESV (ml)

LVEF (%)

11

73+a

46f2

13ozk 17

75kl3

43 f 4

LVEDP (mm 4)

Tau VW

LVEDV (ml)

121

19&t

62 f 8

134f

116

19f4 18f4

68zk4 72k 10

Values are mean * 1 standard deviation. bpm = beats/min. EDV = end-diastolic volume; EF = ejection fraction: ESV = end-systolic wall stress: EDP = end-diastolic pressure; Tau = time constant of isovolumic relaxation.

fore cardiac catheterization. Right- and left-sided heart catheterization was performed within 48 hours of the onsetof symptomsusing the Seldinger technique via the right femoral approach. A 7Fr thermodilution SwanGanz catheter (American Edwards Laboratories) was inserted into the right femoral vein and its tip was positioned in the pulmonary artery. Coronary cineangiography was performed using standard 8Fr right and left Judkins catheters. Fifteen minutes after coronary cineangiography an 8Fr single pressure sensor high-fidelity pigtail angiographic catheter (Millar Instruments, Inc.) was inserted into the left ventricular cavity. Biplane left ventricular cineventriculography was performed 20 minutes after coronary cineangiography. Control heart rate, right atrial, pulmonary artery, pulmonary arterial wedge and femoral artery pressureswere then recorded in addition to triplicate thermodilution cardiac outputs. Intravenous metoprolol was then infused in 5-mg bolus dosesat 2minute intervals for a total of 15 mg; however, in contrast to the Goteberg trial9 a systolic blood pressure of 100 (not 90) mm Hg was used as the endpoint of therapy. Heart rate, right atrial, pulmonary artery, pulmonary arterial wedge,femoral artery pressuresand cardiac outputs were recorded 10 minutes after the last drug administration, Biplane LV cineventriculography was then repeated. Heart rate, right atria1 pressure, pulmonary arterial wedge pressure, LV end-diastolic pressure, cardiac index, dP/dt,,, and the time constant for relaxation were obtained before and after intravenous metoprolol in all 16 study patients (Table I). In 4 patients LV dP/dt,,,, peak systolic wall stress,end-diastolic pressure and the time constant of isovolumic relaxation were obtained at the same paced heart rate (right atrium) during cineventriculography before and after intravenous metopro101,to evaluate the negative inotropic effects independent of the negative chronotropic effects of ,&adrenergic blockade (Table II).

volume;

HR = heart rate; LV = left ventricular;

wall stress = peak systolic clrcumferentlal

Hemodynamics: High-fidelity LV pressure was recorded at 0 to 200 mm Hg scale and matched to the fluid LV pressure waveform measured at the angiographic lumen of the same catheter to correct for hydrostatic pressure effects. The +dP/dt,,, was obtained by manual digitization of the analog pressuresignal recorded at a paper speedof 100 mm/s. Analog to digital pressure conversion was accomplished as previously described for this laboratory.lO-I2 The isovolumic relaxation time constant (T) was calculated using the approach of Weiss et a1.i3Our method for data acquisition and analysis has been previously reported.l i Peak circumferential wall stress was derived from the frame by frame synchronization of LV volumes (formula of Mirsky for a thick walled ellipse of resolution and the iterative approach of Hugenholtz for angiographic wall thickness) and high fidelity pressuresusing a cineframe marker and software developedin our laboratory. i i Cineventriculography: LV cineangiography was performed by injecting 45 ml of Renografin-76 over 3 seconds at 450 psi into the angiographic lumen of the 8Fr high-fidelity catheter. The ventricle was imaged in the 30” right anterior oblique and 60” left anterior oblique/ 20” cranial angulation at 60 frames/s using a CGR biplane angiographic system. Patients were instructed before catheterization to avoid the performance of a Valsalva maneuver during injection. Left ventricular volumes were obtained by a cast-validated cineangiographic method that we have previously detailed using a Simpson’s rule algorithm. I4 End-diastole and end-systole were identified as the maximum and minimum excursions of the left ventricle during the cardiac cycle. The ventricular silhouettes were traced using a hand held sonic digitizer (Science Accessories) by an experienced technician unaware of the results of hemodynamic study. In addition, simultaneous high-fidelity LV pressure and volume were acquired every 16.6 ms during

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HEMODYNAMIC

EFFECTS

OF INTRAVENOUS

METOPROLOL

the cardiac cycle and pressure-volume loops were constructed before and after intravenous metoprolol in each patient (Figure 1). Pressure-volume areas were planimetered to provide a measure of external ventricular work (mm Hg/ml/beat). The integrated pressure volume area also is an estimate of myocardial oxygen consumption since previous animal studies have shown that total mechanical energy correlates with measured oxygen consumption.t5J6However, calculation of total mechanical energy (potential energy + external work) includes the area bounded by diastole and the end-systolic pressure volume line determined from multiple beats during altered ventricular loading. This approach was not possible in the present study due to the effects of cumulative dye administration.

Statistical analysis: Group data in the tables and figures are expressedas the mean f 1 standard deviation. Hemodynamic data before and after drug administration were analyzed by a 2-tailed paired t test. A level of p SO.05 was consideredstatistically significant.

RESULTS Hemodynamics: Figure 2 demonstratesthe effectsof intravenous metoprolol on the major determinants of myocardial oxygen demand in the 16 study patients during sinus rhythm. Heart rate decreasedfrom 90 f 13 to 74 f 11 beats/min (p
FIGURE 1. Left ventricular pressurevolume loops acquired in a representative patient before and after intravenous metoprolol. Diastolic pressure volume relations are unchanged after p-adrenergic blockade while the pressure volume area is reduced, indicating decreased external left ventricular work.

Control Post-Metoprolol ______.__.___.______.

J

0 ( 0

I

I

I

I

I

I

I

20

40

60

80

100

120

140

Left Ventricular Volume (ml)

\ lkl***

2500

120 100

600

2000

z

3

Tz

*O

$

60

if E

2 1000 E

40 20

***

= p
I

Con

ii 2 u

500

E g

400

isz

300

5 7%

200

Y z a,

100

*I

1500

-5

.EE

5

500 ***

= p-=0.001

I Con

I

Met

1 Met

+ = pKO.05 I

I

Con Met

FIGURE 2. Left and center panels demonstrate the changes in heart rate (HR) and dP/dt,., in the 16 study patients before and after intravenous metoprolol (Met). Changes in peak systolic wall stress (right) are depicted for the 12 patients who did not undergo right atrial pacing before and after intravenous metoprolol. Con = control.

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the 12 patients who did not undergo atria1 pacing during cineventriculography. In the 16 patients (Figure 3) the time constant of left ventricular relaxation (Tau) was substantially prolonged from 59 f 13 to 72 f 12 ms (p
Biplane cineangiographic volumes: In the 12 patients who did not undergo atria1 pacing LV ejection fraction decreasedsignificantly after intravenous metopro101(48 f 7 to 43 f 7% p <0.05) (Figure 4). This resulted from an increase in LV end-systolicvolume (85 f 19 to 93 f 19 ml, p <0.05) as LV end-diastolic volume remained unchanged (161 f 30 to 163 f 30 ml, difference not significant). External LV work decreased significantly after intravenous metoprolol from 5,527 f 2,275 to 3,835 f 1,542 mm Hg/ml/beat (p
blockade

during

right

atrial

1,

100 -

FIGURE 3. Changes in of isovolumic relaxation ventricular end-diastolic in the 16 study patients intravenous metoprolol control.

pac-

The heart rate in the patients who were atrially paced before and after intravenous metoprolol was 97 f 10 beats/min while the spontaneous heart rate decreasedto 77 f 14 beats/min. Peak systolic circumferential wall stressdecreasedin each patient. In addition, LV +dP/dt,,, decreasedfrom 1,776 f 342 to 1,537 f 282 mm Hg/s during atria1 pacing and decreasedfurther in the unpaced state in each patient to 1,359 f 394 mm Ha/s. Similar results were observed for the time constant of LV relaxation (Tau). The effects of intraveing:

F 30-E20 El

the time constant (Tau) and left pressure (LVEDP) before and after (Met). Con =

5

Con

10

1

Con

Met

Met

60.

225 * = p-=0.05

50-

Con

Met

FIGURE 4. Left wentricwlar (LV) end- iastolic volume (EDV), end-systolic volume (ESV), and ejection fraction patients without right atriai pacing before and after intravenous metoprolol (Met). Con = control.

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HEMODYNAMIC

EFFECTS

OF INTRAVENOUS

METOPROLOL

nous metoprolol on LV end-diastolic and end-systolic volumes were similar to those observed in the 12 patients with spontaneous heart rate. Thus LV ejection fraction decreasedfrom 46 f 2 to 43 f 4%. In addition, external work decreased in each of the patients with constant heart rate from a mean of 4,568 f 1,504 to 3,064 f 940 mm Hg ml/beat. DISCUSSION

The present investigation demonstratesthat intravenous metoprolol diminishes the major determinants of myocardial oxygen demand in patients with Q-wave AMI. Heart rate, myocardial contractility estimated from the peak rate of change of isovolumic LV pressure (+)dP/dtmax and peak systolic wall stress were each substantially reduced with acute intravenous P-adrenergic blockade in these patients with mildly to moderately depressedLV performance. These changeswere associated with a significant decreasein external LV work as derived from the integrated LV pressure volume area after drug administration (Figure 1). Despite an increasedend-systolic volume, impaired ventricular relaxation and a lengthened ventricular diastolic filling period, neither the pulmonary artery wedge nor LV enddiastolic filling pressure was increased in these patients. In fact elevated LV end-diastolic pressurestended to be reduced while normal LV filling pressureswere mildly elevated by metoprolol in these patients. Although metoprolol is a relatively selective /3i antagonist, total systemic vascular resistance was increased by adrenergic blockade. This effect may have been mediated by reflex stimulation of cu-adrenergic receptors in vascular smooth muscle. When metoprolol was administered during atria1 pacing the decreasein dP/dt,,, and the time constant of ventricular relaxation was only partially attenuated (Table II). These results indicate that the negative effects of metoprolol on the rate of isovolumic pressure development and decay are a consequenceof both the negative chronotropic and inotropic properties of P-adrenergic blockade. Prior studies with metoprolol, propranolol and esmo101that have reported conventional right-sided heart catheterization hemodynamics in patients with acute or threatened AM1 have made similar observations regarding the effects of ,&adrenergic blockade on left heart filling pressures.*‘Mz2 Several potential mechanisms may account for the failure of D-adrenergic blockade to exascerbatepulmonary venous hypertension in patients with cardiac dysfunction produced by myocardial infarction despite the negative inotropic properties of these compounds. Betaadrenergic blockade produces a favorable balance between the principal determinants of myocardial oxygen supply and demand. The negative chronotropic effect of these agents prolongs the diastolic perfusion period for coronary blood flow and may offset the decreasein coronary perfusion pressure produced by drug-induced systemic arterial hypotension in individual patients. Recently Guth et al4 demonstrated that this property is completely responsible for the improved regional blood 170

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

flow and function produced by /3-adrenergicblockadein an animal model of exercise-inducedreversible ischemia. Mueller et all9 demonstrateda significant increase in myocardial lactate extraction in 20 patients who were treated with intravenous propranolol during AMI. It is conceivable that the favorable effects of ,&adrenergic blockade on myocardial supply and demand relations may attenuate residual areas of myocardial ischemia under these conditions. This possibility seemslesslikely to explain the results observedin most studies,including the present one, since there was no evidenceof active myocardial ischemia (chest pain or electrocardiographic changes) before drug administration. Furthermore our data demonstrate that metoprolol continues to impair ventricular relaxation when heart rate is maintained constant by atria1 pacing. If significant improvement in regional function and decreasedasynchrony has been produced by metoprolol, ventricular relaxation should have improved. An alternative explanation for the dichotomous effects of ,&adrenergic blockade on ventricular filling pressurein patients with AM1 who have normal in contrast to elevated ventricular filling pressuresinvolvespotentially favorable changesin systemic and pulmonary venous return. Acute downward shifts of diastolic pressure volume relations may be produced by pharmacologically induced systemic hypotension in both ventricles by agents devoid of direct myocardial properties by diminishing systemic venous return. The resultant decrease in cardiac filling reduces total cardiac volume and the effects of pericardial restraint in maintaining or augmenting diastolic pressure for any given chamber volume.23-25It is conceivablethat the more pronounced negative inotropic effect of /3-adrenergicblockadein patients with impaired ventricular function reduces systemic and pulmonary venous return to a greater extent than in individuals with normal filling pressures.This action may offset the deleterious effects of these agents on ventricular pressuredevelopment,shortening and relaxation, which would in concert produce or aggravate pulmonary venous hypertension. ’ Acknowledgment: We thank Debbie Jung for typing the manuscript and appreciate the technical assistance of Betty Heyl, our cardiac fellows and the staff of the UT Medical Center Hospital Cardiac Catheterization Laboratory.

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