Effects of Ouabain on Early Ventricular Relaxation in Patients with Acute Myocardial Infarction

Effects of Ouabain on Early Ventricular. Relaxation in Patients with Acute Myocardial Infarction* Henry S. Loeb, M.D.;o 0 M. Ziad Sinno, M.D.;t Shahbudin H. Rahimtoola, M.D., F.C.C.P.;t and Rolf M. Gunnar, M.D., F.C.C.P.§

The effects of the administration of ouabain on the peak negative left ventricular (LV) dP/ dt were studied in 14 patients with acute myocardial infarction. Prior to administration of ouabain, negative LV dP/ dt was lower than previously reported for patients without coronary arterial disease. One hour after administration of ouabain, significant (P < 0.05) increases in peak positive LV dP/ dt and maximal velocity of contractile-element shortening and decreases in LV diastoUc pressure were present.

These changes were associated with' small and insignificant increases in negative LV dP/dt. Early LV relaxation rate is impaired in patients with acute myocardial infarction; however, the reduction in LV diastolic pressures which occurs after administration of ouabain does . not appear to be due to an increase in the rate of early LV relaxation but rather is probably related to improved contractility•

Although it has been well established that left ventricular (LV) filling pressure is frequently increased in patients sustaining acute myocardial infarction, the precise mechanism or mechanisms responsible for the increased filling pressure are unclear. 1 Current possibilities include a decrease in ventricular muscular compliance or an increase in end-diastolic volume due to diminished systolic ejection, or both. Among those factors which might result in decreased myocardial compliance, impaired venmcnlar relaxation has been postulated. 2 Although a precise assessment of the rate and extent of ventricular relaxation might be possible by angiographic techniques, such studies are rarely performed in patients with uncomplicated acute myocardial infarction. Recently, the negative phase of the LV pressure derivative tracing has been used to assess ventricular relaxation in experimental myocardial infarction3

and in patients with coronary disease. 4 •fi Our group has previously described the effects of ouabain on ventricular diastolic pressures and contractile indices in a group of patients studied within a few days of acute myocardial infarction. 6 Since a reduction in the LV diastolic pressure, which was measured directly, consistently occurred following administration of ouabain, we believed it worthwhile to examine the effects of ouabain on the early phase of ventricular relaxation as reflected by the peak negative dP/ dt. The results to be reported suggest that reduction in LV diastolic pressure following administration of ouabain is independent of changes in early ventricular relaxation.

I

°From the Department of Adult Cardiology, Cook County Hospital, Chicago, and the Section of Cardiology, Department of Medicine, Loyola University Stritch School of Medicine, Maywood, Ill. Supported in part by National Institutes of Health grant 15040. ° °Professor of Medicine and Program Director in Cardiology, Veterans Administration Hospitat Hines, Ill. tClinical Assistant Professor of Me
258 LOEB ET AL

MATERIALS AND METHODS

The study group consisted of 14 patients (eight men and six women) hospitalized at the Cook County Hospital for symptoms of acute myocardial infarction. In each patient the diagnosis of acute myocardial infarction was subsequently confinned by serial electrocardiograms and serum levels of enzymes. The average age of the patients was 63 years, with a range of from 47 to 81 years. Eight patients had transmural infarction, and six had nontransmural infarction. Studies were performed in a specially equipped laboratory adjacent to the coronary care unit on the day of admission (eight patients) or on the following day (four patients). The remaining two patients were studied two and six days following admission. At the time of study, only one patient had significant clinical cardiac failure, and none was in shock or had serious arrhythmias. Left ventricular pressure was measured from a No. SF ~theter (Teflon) inserted percutaneously over a guidewire

CHEST, 70: 2, AUGUST, 1976

dP dt mmHg'Se< 3000

200

2000 1000

ISO

0 1000 2000

100

3000

SO

o Pressure

mmHg

ample tracing obtained from patient with cute myocardial infarction. Pap r p dJ are 100 mm/sec (at left) and 25 mm/se (at right). lectrocardiogram is at bottom. Left ventricular pres llre and its first deri ative (dP/dt) ar shown. Th two phase (positive and negative) of dP/ dt can he estimated from scale at upper right. At far right of tracing, zero reference level for hoth pressure and dP/ dt has been recorded. and directed under fluoroscopic control to the left ventricle. To avoid catheter-fling artifact, we found it necessary to interpose a 20-inch long, 2-ml connecting tubing between the proximal end of the catheter and the transducer (Statham 23db). An R-C differentiating circuit was used to estimate the first derivative of the LV pressure pulse. Although this system yields pressure and derivative wave forms similar in appearance to those obtained with a catheter-tip transducer (Fig 1), the characteristics of the system differed considerably from those of a rigid fluid-filled system or from a catheter-tip transducer. By utilizing the stepwise pressurechange technique outlined by Fry,7 we found this system to have a natural frequency of 6.3 cycles per second, a dampening ratio of 0.45, and a flat response (::!: 10 percent) to a frequency of approximately 4.5 cps. Although these characteristics are less than optimal for quantitative measurement of dP /dt,~ our major interest was to assess acute changes in positive and negative dP/ dt following administration of ouabain. For convenience the data will be presented in the usual units (mm Hg/sec); however, these values should be considered as rough approximations in view of the limitations discussed. All recordings
CHEST, 70: 2, AUGUST, 1976

negative LV dP / dt were averaged from several complexes recorded at paper speeds of 10 or 25 mm/sec over more than one respiratory cycle. The LVEDP was either the nadir between the presystolic A wave and the rapid rise in LV pressure or a consistent notch in the upstroke of the LV pressure occurring approximately 0.05 second after the onset of the QRS complex as demonstrated while recording at a rapid paper speed. Maximal velocity of contractile-element shortening (V max) was estimated in muscle lengths from the LV pressure and derivative tracings made at paper speeds of 100 or 200 mm/sec by plotting the ratio of positive dP/ dt to IP (where IP is instantaneous isovolumic LV pressure and K is a constant with a value of 32) and extrapolating to ~ 0. 9 Three to six beats were analyzed.

=

RESULTS

C antral Data Measurements obtained for C I and C 2 were averaged (Tables 1 and 2). Prior to infusion of ouabain, the heart rate was 86 ± 3 beats per minute (Table 1). The LVSP was 157 ± 12 mm Hg, LVDP was 13 ± 1 mm Hg, and LVEDP was 24 ± 2 mm Hg, exceeding 12 mm Hg in all but one patient. The positive LV dP/dt was 1,912 ± 150 mm Hg/sec, and V max averaged 1.20 ± 0.04 muscle lengths per second (Table 2). The negative LV dP/ dt averaged 1,718 ± 109 mm Hg/sec.

Ouabain Changes in heart rate were not significant following administration of ouabain (Table 1). The LVSP was increased by 18 ± 4 mm Hg at T-O and by 16 ±

OUABAIN EFFECTS ON EARLY VENTRICULAR RELAXATION 259

Table I-Effect.

0/ Ouabain on Indice. 0/ Ventricular Function in Potien" IDith Acute Myocardial In/arction * A

A

A

A

LVEDP, mm Hg

LVDP, mm Hg

LVSP, nun Hg

Heart Rate, Beats per Minute

T-O

T-30

T-60

C

T-O

T-30

T-60

C

T-O

T-30

T-60

12 39 10 20 26 15 24 11 30 23 20 20 40 34

14 30 4 12 13 13 15 8 30 22 16 12 40 24

14 33 5 8 4 2 12 6 28 24 8 6 36 30

Patient

C

T-O

T-30

T-60

C

1 2 3 4 5 6 7 8 .. 9 10 11** 12 13 14

84 72 75 94 68 102 96 78 104 100 84 72 96 72

80 100 61 85 64 104 88 77 100 103 80 75 92 59

80 68 73 85 68 108 86 84 100 107 66 82 84 61

84 68 77 85 64 100 84 93 100 109 66 80 84 55

135 154 113 99 210 156 255 143 154 146 173 142 105 206

142 208 135 108 230 174 270 150 164 180 170 160 125 230

148 184 137 111 230 166 272 158 168 177 138 146 126 256

145 175 136 102 182 167 246 164 160 180 180 134 124 220

12 18 5 11 16 13 14 7 13 12

7 18 4 8 13 11 15 4 14 16

8 11 2 5 4 8 11 2 10 17

6 10 2 4 4 9 10 2 10 20

10 22 18

10 24 16

4 26 24

4 23 12

22 36 10 22 29 21 27 15 30 20 16 20 33 34

Mean

86

83

82

82

157

175

173

165

13

12

10

9

24

23

19

16

3

4

4

4

12

12

13

10

2

2

2

2

2

3

3

NS

NS

NS

NS

NS

NS

SE Pvaluet

<0.01 <0.01

NS

<0.01

<0.05 <0.01

*C, Control. **Junctional rhythm. tCompared to control. NS, Not significant.

5 mm Hg at T-30 (P < 0.01), but at T-60 the LVSP averaged only 9 ± 4 mm Hg above control (not significant). Changes from control for LVDP were . not significant at T-0 or T -30, but the average fall of 4 mm Hg by T-60 was significant (P < 0.01). The fall in LVEDP was also not significant at T-O, but significant decreases had occurred by T-30 ( - 5 mm Hg; P < 0.05) and T-60 ( -8 mm Hg; P < 0.01).

Positive LV dP/ dt and V max were both significantly increased (P < 0.01) at T-O and remained so at T30 and T-60 (Table 2). The maximum increase for both positive LV dP/ dt and V max occurred at T-30 and averaged + 433 ± 89 mm Hg/ sec and + 0.27 ± 0.04 muscle lengths per second, respectively. In contrast to the effects of ouabain on LV filling pressures and contractile indices, which were max-

Table 2--Effect. of Ouabain on Po.iti"e and Negative LV dP/dt and V max in Patient• ..,ith Acute Myocardial Infarction *

Positive LV dP/dt, mm Hg/sec

V max, muscle lengths per second

A

Patient

C

T-O

T-30

T-60

C

1 2 3 4 5 6 7 8 9 10 11** 12 13 14

1,592 1,685 1,111 1,170 2,106 1,975 2,943 2,316 2,362 2,436 2,574 1,568 1,326 1,599

1,882 2,244 1,404 1,092 2,340 2,432 3,280 2,779 2,509 2,798 2,652 1,785 1,560 2,028

2,026 1,809 1,560 1,657 2,652 2,779 3,426 3,358 2,316 3,088 2,301 2,075 1,638 2,145

2,026 2,171 1,521 1,404 2,730 2,605 2,606 2,702 2,606 3,088 2,652 1,785 1,716 2,240

Mean

1,912

2,199

2,345

150

162 <0.01

SE .p valuet

Negative LV dP/dt, mm Hg/sec

A

A

T-O

T-30

T-60

C

T-O

T-30

T-60

1.14 1.03 1.20 1.05 1.06 1.34 1.31 1.45 1.30 1.32 1.42 1.28 0.98 0.96

1.37 0.90 1.32 1.11 1.20 1.63 1.48 1.57 1.33 1.48 . 1.66 1.35 0.98 1.10

1.37 1.24 1.60 1.37 1.32 1.77 1.56 1.83 1.33 1.83 1.83 1.46 1.06 1.11

1.33 1.46 1.47 1.33 1.59 1.60 1.70 1.25 1.57 1.63 1.46 1.02 1.11

1,423 1,990 1,199 1,111 2,028 1,708 2,412 1,737 2,171 2,203 1,599 1,744 1,150 1,579

1,496 2,195 1,326 1,404 2,106 1,814 2,508 2,258 2,668 2,509 1,560 1,882 1,170 1,833

1,640 1,737 1,287 1,287 2,418 1,814 2,992 2,046 2,123 2,412 1,170 1,930 1,560 1,872

1,544 2,051 1,287 1,248 2,418 1,621 2,220 1,776 2,123 2,702 1,560 1,592 1,482 1,872

2,275

1.20

1.32

1.48

1.42

1,718

1,880

1,877

1,820

168

38

0.04

0.06

0.07

0.06

109

118

134

114

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

<0.05

NS

*C, Control. **Junctional rhythm. tCompared to control. NS, Not significant.

260 LOEB ET AL

CHEST, 70: 2, AUGUST, 1976

imal at T-30 or T-60, the effect of ouabain on negative LV dP/dt was maximal at T-O. At T-O, negative LV dP/ dt had increased by 162 ± 38 mm Hg/ sec (P < 0.01), but this increase declined to + 159 ± 70 mm Hg/sec by T-30 (P < 0.05) and to +103 ± 56 mm Hg/ sec by T -60 (not significant). DISCUSSION

Impaired ventricular relaxation has been postulated to result from myocardial ischemia10 and might, in part, explain the altered diastolic pressurevolume relationships present during ischemia or following acute myocardial infarction. Echocardiographic studies by Fogelman et al 2 showed a reduction in maximal and mean diastolic endocardial velocity during angina caused by exercise. Since the peak rate of decline in LV pressure occurs between aortic valve closure and mitral valve opening (ie, during the "isovolumic" relaxation period) , it is probably closely related to the peak rate at which myocardial wall tension decreases, and its measurement has thus been used to assess early ventricular relaxation. Watanabe et al 3 observed a reduction in negative LV dP/dt prior to changes in positive LV dP/dt or in LV pressures in dogs subjected to coronary ligation and concluded that negative LV dP/ dt might be a sensitive and early sign of myocardial ischemia. A fall in negative LV dP/ dt after left ventriculographic studies has been reported by Crelinsten et al 5 and was believed to represent an alteration of ventricular relaxation secondary to the effects of contrast media on the ventricle. McLaurin and his group4 measured negative LV dP/ dt and the ratio of negative LV dP/ dt to positive LV dP/ dt before and during atrial pacing in patients with and without coronary arterial disease and concluded from their studies that tachycardia-induced ischemia might lead to impaired or incomplete LV relaxation. Although the mean negative LV dP/dt in our patients (1,718 ± 109 mm Hg/ sec) was significantly lower than McLaurin et al 4 reported for their patients without .coronary arterial disease (2,661 ± 217 mm Hg/ sec), their studies were performed using a catheter-tip transducer; and, therefore, a direct comparison of our values against theirs is difficult to interpret. Since errors in the measurement of dP/ dt imposed by using a fluid-filled system should apply equally to both the negative and positive phases of dP/ dt, such errors should have a minimal effect on the ratio of negative to positive dP/ dt. In our patients, this ratio averaged 0.92 ± 0.04, which was significantly less P( < 0.(01) than the average of 1.72 ± 0.12 found by McLaurin et al 4 in all of their patients prior to atrial pacing; however, during pacing-induced ischemia, McLaurin et al4 observed CHEST, 70: 2, AUGUST, 1976

the negative/ positive LV dP/ dt ratio to fall to an average of 0.91 ± 0.08, which was essentially the same ratio as we found in our patients with acute myocardial infarction. We believe, therefore, that the lower negative LV dP/dt and particularly the reduced negative/positive LV dP/dt ratio observed in our studies is evidence for impaired peak rate of early ventricular relaxation in patients with acute myocardial infarction. If as postulated, elevation of LV filling pressure following acute myocardial infarction might be related to impaired ventricular relaxation, one might expect to see evidence of improved relaxation following interventions which result in a reduction of the abnormal filling pressure. Incomplete relaxation of mammalian myocardium induced by various experimental procedures can be improved by administration of catecholamines,11 and improved ventricular relaxation might be expected to result following administration of other inotropic agents, such as ouabain. In the present study, serial measurements of negative LV dP/ dt following administration of ouabain failed to show any striking effects; and, in fact, after 60 minutes, negative LV dP/ dt was not significantly +30

+25

~ +15

z x (.)
~ +10

L&J (.)

a:

L&J Q.

+5

T-O

T-30

T-60

2. Percentage of change (+ 1 SE) from control for positive LV dP/ dt (diagonally lined bars) and negative LV dP/dt (open bars) is shown immediately (T-o), 30 minutes ( T -30), and 60 minutes (T -60) following administration of ouabain. Although changes for positive LV dP/dt and negative LV dP/ dt are similar at T -0, by T -30 and T -60 the positive LV dP/dt has increased further, while negative LV dP/dt has decreased toward control value. FIGURE

~UABAIN

EFFECTS ON EARLY VENTRICULAR REWATION 261

different from the control value. In contrast, ouabain had a much greater effect on positive LV dP/ dt (Fig 2) which was maximal at 30 minutes and still highly significant at 60 minutes, at which time the LV filling pressures had reached their lowest values.This temporal separation of the effects of ouabain (maximal on negative LV dP/ dt at T-0, but on contractile indices and LV filling pressures at T-30 and T-60) do not support the hypothesis that improved ventricular relaxation played an important role in the hemodynamic normalization that followed administration of ouabain. From our data, it appears that although the peak rate of LV relaxation is impaired in patients with acute myocardial infarction, improved contractility following administration of ouabain is probably the mechanism by which ouabain reduces an elevated LV filling pressure present in such patients. REFERENCES

1 Forrester JS, Diamond G, PannIey WW, et aI: Early increase in left ventricular compliance after myocardial infarction. J Clin Invest 51 :598-603, 1972 2 Fogelman AM, Abbasi AS, Pearce ML, et al: Echocardiographic study 9f the abnonnal motion of the posterior left ventricular waIl during angina pectoris. Circulation 46:005-913, 1972

3 Watanabe T, Shintani F, Fu L: Maximal rate of left ventricular pressure fall (peak negative dp/dt) in early stages of experimental myocardial infarct. Clin Res 22:310A, 1974 (abstract) 4 McLaurin LP, Rolett EL, Grossman W: Impaired left venbicular relaxation during pacing-induced ischemia. Am J Cardiol 32:751-757, 1973 5 Crelinsten 0, Fenton T, Marpole D, et al: The significance of early changes in positive and negative dp/dt following contrast venbiculography. Am J Cardiol 35: 130, 1975 6 Rahimtoola SH, Sinno MZ, Chuquimia R, et aI: Effects of ouabain on impaired left venbicular function in acute myocardial infarction. N Engl J 1vfed 287 :527-531, 1972 7 Fry DL: Physiologic recordings by modern instruments with particular reference to pressure recording. Physiol Rev 40:753-788, 1960 8 Knopp TJ, Rahimtoola SH, Swan HJC: First derivative of ventricular pressure recorded by means of conventional cardiac catheters. Cardiovasc Res 4:398-404, 1970 9 Mason DT, Spann JR Jr, Zelis R: Quantification of the contractile state of the intact human heart: Maximal velocity of contractile element shortening determined by the instantaneous relaxation between the rate of pressure rise and pressure in the left ventricle during isovolumic systole. Am J CardioI26:248-257, 1970 10 Cooley DA, Reul OJ Jr, Wukasch DC: Ischemic myocardial contracture ("stone heart"): A complication of cardiac surgery. Isr J Med Sci 11 :203-210, 1975 11 Morad M, RolettEL: Relaxing effects of catecholamines on mammalian heart. J PhysioI224:537-558, 1972

Mythologic Romance Daughter of Phoenix or of Agenor, King of Phoenicia, and of Telephassa, the young Europa was playing one day at the water's edge, gathering flowers with her companions. Her attention was caught by the sight of a bull with glistening hide who browsed peacefully among her father's herd. His air, gentle and at the same time majestic, struck her. She did not suspect that this bull was none other than the master of the gods, Zeus himself, who assumed this shape to deceive the girl, of whom he became enamored. Trustingly Europa approached and caressed the animal who very gallantly knelt before .her. She climbed playfully on to his mighty back and

282 LOEB ET At

began to wreathe flowers around his powerful horns. Suddenly the bull reared to his feet, sprang into the waves and carried the weeping virgin across the vast sea. They finally reached the southern coast of Crete. The plane tree under which Zeus made the young Phoenician his mistress was still pointed out in the days of Theophrastus. Europa gave birth to Minos, Rhadamanthis and Sarpedon. All three were adopted by the King of Crete, Asterius, who subsequently became Europa's husband. Cuirand, F: Creek Mythology (translated from French by Ames, D) London, Hamlyn, F, 1963

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