COMPARISON OF THE EFFECTS OF SUSTAINED-RELEASE AND SUBLINGUAL NITROGLYCERINE ON THE APEXCARDIOGRAM AND SYSTOLIC TIME INTERVALS HOWARD H. WAYNE, M.D. San Diego, California
ABSTRACT
The effects of a sustained-release form of nitroglycerine on left ventricular function were studied in 13 patients with ischemic heart disease in the absence of chest pain. The results were compared to those of sublingual nitroglycerine and placebo. Sustained release nitroglycerine produced a reduction in a wave amplitude on the apexcardiogram from a mean of 20% to 15% (P < 0.05) and an increase in the slope of the systolic wave from a mean of 18 mm/sec to 44 mm/sec (P < 0.01). The left ventricular ejection time corrected for heart rate (ALVET) did not change significantly, nor did the true isovolumic contraction (TIVC) time. Isovolumic relaxation (IVR) time increased from a mean of 121 msec to 137 msec (P < 0.025). The reduction in a wave amplitude and the lengthening of the IVR time reflected the fall in left ventricular end diastolic pressure. The increase in slope of the systolic wave indicated an improvement in wall motion-that is, less dyskinesis in comparison to the resting recordings. In most instances these changes occurred within 1 to 2 hours, with residual effects persisting for 4 to 6 hours. Following the administration of sublingual nitroglycerine, similar changes occurred in a wave amplitudes and IVR times, while the slope of the systolic wave increased from 24 mm/sec to 34 mm/sec. This value, however, was still significant (P < 0.01). In addition, unlike sustainedrelease nitroglycerine, ALVET showed a striking decrease from -26 msec to -47 msec. No change in any of the parameters studied were seen following placebo administration. These results suggest that both the sustained release and sublingual forms of nitroglycerine cause an improvement in left ventricular function and wall motion, but by different mechanisms. Sublingual nitroglycerine appears to work by causing a decrease in preload and wall tension, thereby reducing myocardial oxygen demands. Sustained-release nitroglycerine does not do this, a fact indicating perhaps a direct increase in myocardial perfusion to ischemic areas. Finally, the improvement in left ventricular function after the administration of both forms of nitroglycerine, suggests that the long-acting preparation in particular would be a useful adjunct in the treatment of patients with ischemic heart disease, even in the absence of chest pain. From the San Diego County Diego, California.
Heart Center, Donald N.
Sharp Memorial Community Hospital, San
Presented at the Western Clinical Conference of the American
College of Angiology, Tucson,
Arizona.
190
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191 INTRODUCTION
In
spite
of the
widespread
use
of so-called
..
long-acting
’
coronary
vaso-
dilators, there is little objective information on the efficacy of these preparations over prolonged periods of time-i.e., for more than 1-2 hours. use of these preparations has been directed toward the relief of angina pectoris in symptomatic patients, rather than toward improvement in left ventricular function in the diseased but asymptomatic patient. That such improvement in left ventricular function occurs following the administration of the short and long-acting nitrates is well established. Direct
Clinical
measurements have documented a fall in left ventricular end diastolic 1-4 and pulmonary artery wedge pressure,’,’ and an improvement pressure in left ventricular function’-’3 with an increase in coronary blood flow.14-19 Most of these studies have been carried out for only short intervals of time in any given patient. This is understandable because it is hardly to record serial measurements for the duration of time during which these drugs are claimed to be effective. Noninvasive techniques are not subject to the limitations of direct methods, yet may effectively document directional changes in left ventricular function and wall motion over prolonged periods. These procedures lend themselves admirably to the study of so-called long-acting nitrates. Therefore a study was undertaken on the effects of a sustainedrelease form of nitroglycerine using apexcardiography, as well as systolic and diastolic time intervals. The purpose was to determine (1) whether improvement in left ventricular function could be demonstrated by these techniques in patients with ischemic heart disease in the absence of chest pain, and (2) their effective duration of action.
justifiable
MATERIALS AND METHODS
Thirteen patients aged 47 to 71 were studied. There were 11 males and 2 females. All had evidence of left ventricular dysfunction due to ischemic heart disease. The diagnosis of ischemic heart disease was based upon a history of chest pain in conjunction with either electrocardiographic evidence of a myocardial infarction and/or ischemic ST segment depression during or after a graded maximal ergometer stress test. Left ventricular dysfunction was based upon the finding of impaired exercise tolerance in conjunction with a significantly abnormal apexcardiogram and/or prolonged systolic time intervals.
Recording of Noninvasive Parameters Our method of recording the apexcardiogram has been described in detail (20). The patient was placed in the left lateral position and the apex impulse was carefully marked. The end piece of a B-D Fleischer stethoscope with the diaphragm removed (lumen diameter 4.2 cm, depth 5 mm) was placed directly over the apex impulse and held in place with a wide rubber strap. The stethoscope pickup was connected by 25 cm of rubber
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192 an Elema-Schonander EMT 510 transducer with a time constant of 3.0 seconds. Great care was taken to avoid artifactual tracings as previously described (20) or alterations in the wave form due to patient rotation or respiration. The pickup over the apex impulse was left in position for the entire sublingual nitroglycerine portion of the study and for a substantial period after the administration of the sustained-release preparation. The calibration of the transducer and the gain setting of the amplifier was not disturbed. In addition to the pickup over the apex impulse for recording the apexcardiogram, an Elema-Schonander EMT 25B contact microphone was placed along the left sternal border at the second or third interspace for optimum recording of the second heart sound. A carotid pulse tracing was simultaneously recorded with a second Elema-Schonander EMT 510 transducer connected to a small funnel pickup. Finally, lead II of an electrocardiogram was recorded with all of the above. All parameters were transcribed simultaneously on an Elema-Schonander mingograf 81 polygraph.
tubing to
.
of Drugs and Frequency of Measurements All patients were studied at three different settings. After a 15-30 minute rest period, control recordings were made. Nitroglycerine (0.4 mg) was given sublingually to 6 patients, and repeat recordings were made at 3, 6, 9, and 15 minutes. Occasionally recordings were also made at 20 and 30 minutes if the effects of the drug had not worn off. A similar number of patients received a placebo, but recordings were made at 1, 2, 4, and 6 hours. Thirteen patients received sustained-release nitroglycerine and again recordings were made at 1, 2, 4, and 6 hours. Administration
Measurements
Figure 1 shows an ACG recorded in conjunction with lead II of the ECG, the carotid pulse, and a phonocardiogram. The a wave amplitude was taken as its vertical height divided by the entire amplitude of the ACG complex from the E point (onset of ejection) to the 0 point (opening of the mitral valve). The slope of the systolic wave was measured as follows: a horizontal line (E-E’ in Figure 1) was extended from the E point for 100 mm or 1 second 100 mm/sec). A perpendicular line was drawn until it (paper speed intersected the line extending from point E along the top of the systolic wave through S (line E-S-S’ in Figure 1 ), thus allowing measurement of the slope in mm/sec. The steeper the slope, the more rapidly the ventricular wall is moving away from the apex pickup. The gain of the amplifier was not disturbed during the recording sessions. =
Measurement
of the Sy.stolic and Diastolic
Time Intervals
Figure 1 also shows the breakdown of the cardiac cycle into its respecsystolic and diastolic intervals. The true isovolumic contraction (TIVC) time was measured from the onset of the initial upstroke of the tive
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193
FIG. l. An apexcardiogram (ACG) recorded in conjunction with the electrocardiogram (ECG ), the carotid pulse tracing (CPT), phonocardiogram (PCG), first differential) of the carotid pulse tracing (dp/dt CPT), and first differential of the apexcardiogram (dp/dt ACG). The various systolic and diastolic time intervals are also shown. The method of measurement is described in the text. Other onset of ejection, 0 onset of ventricular contraction, E abbreviations: a atrial filling wave, C left ventricular mechanical systole, LVET aortic second sound, C-A2 mitral valve opening, A2 ejection time, IVR isovolumic relaxation time, Si first heart sound, S2 second heart sound, S true slow filling wave, TIVC shoulder of systolic wave, RFW rapid filling wave, SFW standardization deflection. isovolumic contraction time, and Q =
=
=
=
=
=
=
=
=
=
=
=
=
=
=
(point C) to the first high frequency vibration of the aortic of component the second heart sound (C-A2 interval). The left ventricular ejection time (LVET) from the simultaneously recorded carotid pulse was subtracted from the C-A, interval. The TIVC time therefore represents that interval from the onset of ventricular contraction to the opening of the aortic valve corrected for pulse delay. The A LVET was derived by subtracting the measured LVET from the predicted LVET corrected for heart rate and sex, by using the regression equations of Weissler (21). Isovolumic relaxation time was measured from the first high frequency component of the aortic second sound to the opening of the mitral valve at the 0 point of the ACG. The a wave duration was measured from the beginning upstroke of the a wave to its nadir at point C of the ACG. Its duration is related to the length of atrial systole. Finally, in addition to the above measurements, heart rate and blood pressure were recorded each time recordings were made. systolic
wave
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194
All the cardiac parameters recorded were keypunched and stored on for computer processing. A CDC 6600 computer was used for data reduction as well as statistical computations. Effects of treatment over time as well as comparisons between treatment were assessed by the
magnetic tape
students’ t test. .
~
RESULTS
.
_
Figure 2 shows the effects upon the ACG before and after the administration of sublingual NTG. It can be seen that the u wave amplitude is reduced from 57% to 30% while the duration decreases from 130 to 100 msec. At the same time the slope of the systolic wave becomes transformed from a paradoxical bulge to a distinct downslope after administration of the drug. Figure 3 shows the effects upon the ACG before and after the administration of sustained-release nitroglycerine. The results are qualitatively similar to those seen after sublingual nitroglycerine. In the control panel a
FIG. 2. Effect of sublingual nitroglycerine on the apexcardiogram. Abbreviations are the same as in Figure l; NTG nitroglycerine. Note the large a wave (amplitude 57%, duration 130 msec) and the paradoxical bulge. After sublingual (SL) NTG the a wave decreases to 30% and 100 msec while the paradoxical bulge disappears. =
.
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195
FIG. 3. Effect of sustained-release (SR) nitroglycerine on the apexcardiogram. Note the changes are similar to that seen with sublingual nitroglycerine (Figure 2). The duration of effect, however, extends to at least 6 hours in this patient.
distinct paradoxical bulge is present. At 1 hour after the administration of sustained-release nitroglycerine, the systolic wave is sustained but the bulge has disappeared. At 3 hours there is a definite downslope. At 6 hours the downslope of the systolic wave is very steep. Figure 4 compares the mean effects in all patients of the sublingual and sustained-release form of nitroglycerine as well as the placebo on the a wave of the apexcardiogram. The control mean a wave amplitude for the sublingual NTG patients was 17%. It fell to a low of 12% (P < 0.05) an average of 6 minutes after the administration of the sublingual preparation. The control mean a wave amplitude for the sustained release nitroglycerine patients was 20%, with a fall to a mean of 15% at 2 hours (P < 0.05). In contrast, following administration of placebo, a wave amplitude rose from a mean of 17% to 19% at 1 hour and 18% at 2 hours. Figure 5 compares the mean effects in all patients of the three preparations on the systolic wave of the ACG. After the administration of sublingual nitroglycerine, the slope of the systolic wave increased from a control of 24 mm/sec to 34 mm/sec (P < 0.01 ) at 3 minutes. Following the administration of sustained-release nitroglycerine, the slope of the systolic wave increased from a mean of 18 mm/sec to 44 mm/sec at 2 hours (P < 0.01). In contrast, after the administration of the placebo, the slope of the systolic wave showed no significant change.
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196
FIG. 4. Mean effect of sustained-release nitroglycerine, placebo, and sublingual nitroglycerine on amplitude in all patients. Left-hand figure shows SR NTG and placebo. Right hand figure shows SL NTG. mean a wave
Duration
of Action
Peak effects following the administration of sublingual nitroglycerine were seen between 3 and 6 minutes, with some residual effects evident at 15 minutes. Full recovery was always seen between 20 and 30 minutes. After the administration of sustained-release nitroglycerine, peak effects were seen in about 2 hours. However significant effects were still seen at 4 and 6 hours in most patients.
Systolic and Diastolic Time Intervals True Isovolumic Contraction (TIVC) Time. The TIVC time remained essentially unchanged following the administration of all three preparations. ALVET.
Figure 6 shows the mean effects in all patients of the three preparations on the ALVET. A profound change was seen after sublingual nitroglycerine. The ALVET fell from a mean control of -26 msec to -47 msec. A much smaller change was seen after sustained-release nitroglycerine : the ALVET fell from a mean control of -18 msec to -26 msec at I hour, with gradual recovery over 6 hours. After the administration of placebo, the ALVET decreased from a mean control of -15 msec to -23 msec. Thus the mean change in the ALVET following sustained release
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197
FIG. 5. Mean effect of sustained-release nitroglycerine, wave of the apexcardiogram in all patients.
placebo, and sublingual nitroglycerine on the
systolic
nitroglycerine was not significant (P > 0.05) when compared to placebo, whereas the effect of sublingual nitroglycerine was highly so (P < 0.01 ). Isovolumic Relaxation (I VR Time. Figure 7 compares the mean effects in all patients of the three preparations on the IVR time. After sublingual nitroglycerine the IVR time increased from a mean control of 152 msec to 160 msec at 3 minutes. Following the administration of sustained-release nitroglycerine, the IVR time increased from a mean control of 121 msec to 137 msec at 2 hours, and residual effects persisted for 6 hours. After placebo an opposite effect was once again apparent with the IVR time decreasing from 141 to 132 msec. DISCUSSION
The results of this investigation show that qualitatively similar effects on left ventricular function and hemodynamics occur following the administration of both sublingual and sustained-release nitroglycerine. Thus the a wave amplitude was reduced, the slope of the systolic wave improved, the IVR time lengthened. The duration of these effects for sublingual nitroglycerine was only about 15 minutes. We have previously shown that sublingual nitroglycerine has little effect beyond 15 minutes on the parameters used in this study (22). In contrast, sustained release nitroglycerine showed a peak effect at 2 hours and significant residual effects lasting for 4 to 6 hours.
Interpretation of Hemodynamic Changes A close correlation between a wave amplitude and left ventricular end diastolic pressure (LVEDP) has been well documented.23-28 A fall in a wave amplitude usually reflects a comparable decrease in LVEDP. Whenever LV EDP decreases from a previously elevated level, left atrial pressure falls as well. Accordingly, left ventricular pressure will take longer to fall below the lower left atrial pressure. Since IVR time is that interval be-
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198
FIG. 6. Mean effect of sustained-release nitroglycerine, placebo, and z left ventricular ejection time (ALVET) in all patients.
sublingual nitroglycerine on the
valve closure and mitral valve opening, this time period will It is reasonable to assume, therefore, that the combination of a decrease in a wave amplitude and lengthening of the IVR times was a consequence of a decrease in LVEDP following the administration of tween aortic
lengthen.
and sustained-release nitroglycerine. Direct measurements have shown a similar fall in LVEDP following nitroglycerine administration.’-’ Systolic Wave. A number of studies have shown that the contour of the systolic wave of the ACG reflects wall motion as determined by direct left ventriculography.2’-31 We recently reported that a close correlation also exists between the slope of the systolic wave and left ventricular function, and that it was possible to measure ejection fraction from the systolic wave.32 Such measurements showed a very high correlation with the ejection fraction as measured angiographically. Thus the steeper downslope of the systolic wave after both sublingual and sustained-release nitroglycerine suggested a decrease in abnormal wall motion and more complete emptying of the left ventricle. These observations are supported by studies of wall motion during left ventriculography following the administration of nitroglycerine. Areas of hypokinesis clearly showed improvement in the contraction pattern. 9,10,33-35 The primary mechanism of action of nitroglycerine is a matter of controversy. It is generally agreed that coronary artery dilatation takes place with increased flOW14-18 in conjunction with peripheral pooling,2~36-39
sublingual
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199
FIG. 7. Mean effect of sustained-release nitroglycerine, placebo, and isovolumic relaxation (IVR) time in all patients.
with
sublingual nitroglycerine on the
reduction in both preload4° and afterload.41 Whether dilatation in vessels that are already sclerotic and narrowed is doubtful. Nevertheless blood flow may well increase in marginally ischemic areas. In fact it is now well documented that there is an improved flow in collaterals following nitroglycerine administration.42-44 The other postulated mechanism, peripheral pooling, by reducing venous filling or preload will cause a very significant reduction in wall tension.’ Associated with this is a reduction in left ventricular end diastolic volume4,45 and left ventricular end systolic volume.16,46,4’ As a result, myocardial oxygen demands decrease. Regardless of which mechanism predominates, wall motion improves, myocardial contractility increases,’,’ ventricular emptying and ejection fraction increase,7,10,13 and left ventricular end diastolic pressure falls.1-4 It is interesting that although the qualitative effects of sublingual and sustained-nitroglycerine were similar, there were important differences. Sublingual nitroglycerine caused a marked reduction in the ALVET. Presumably this reduction was due to peripheral pooling with a decrease in venous return and stroke volume, and a resulting decrease in the LVET and ALVET. Sustained-release nitroglycerine, on the other hand, did not cause any change in the ALVET when compared to placebo. Nevertheless the slope of the systolic wave of the ACG not only improved after sustained release nitroglycerine, but did so to a greater degree than after a
occurs
sublingual nitroglycerine. These differences raise the question of whether the primary mechanism of action of sublingual nitroglycerine is different from that of sustained-
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200
nitroglycerine. The improvement in function following sublingual nitroglycerine might be primarily due to peripheral pooling with reduction in preload and wall tension and a decrease in oxygen demands. In contrast, sustained-release nitroglycerine may work by increasing coronary and collateral flow to ischemic tissue and thereby cause an improvement in contractility. Indeed, recent studies have shown that akinetic areas of myocardium do not improve following nitroglycerine16,48 unless they happen to be assorelease
ciated with collateral vessels.&dquo; F_it_h_e_r mechanism of action results in ( 1 ) a fall in left ventricular end diastolic pressure and a wave amplitude, and (2) improvement in wall motion and the systolic wave of the apexcardiogram. It is interesting that no significant change was seen in the TIVC time. Since improved contractility was evident in all patients studied, one would have expected a decrease in this time interval. It is known that a decrease in venous return will cause a lengthening of this time period preceding ejection.19 Presumably, therefore, the lengthening of the TIVC time due to peripheral pooling with a reduction in venous return was sufficient to offset the decrease in this same time interval due to improved contractility. Using both the apexcardiogram and systolic time intervals, other investigators have found similar results. Sawayama et a1.49 found a reduction in a wave amplitude and an improved systolic wave following the sublingual administration of nitroglycerine. These same investigators as well as Harris et al.8 found a reduction in the LVET index after sublingual
nitroglycerine. No previous studies document the efficacy of sustained-release nitroglycerine with these noninvasive methods. The present study not only confirms the qualitative similarity of sustained-release nitroglycerine to sublingual nitroglycerine, but documents its effectiveness over several hours in patients with ischemic heart disease even in the absence of chest pain. Additionally, the results suggest that sublingual nitroglycerine works by causing peripheral pooling with a reduction in preload and wall tension and a reduction in myocardial oxygen demands. Sustained-release nitroglycerine, on the other hand, seems to work by causing a direct increase in flow to ischemic areas. The improvement in left ventricular performance in such patients encourages the more regular use of such preparations. Howard H. Wayne, M. D. San Diego County Heart Center Donald N. Sharp Memorial Community Hospital San Diego, California 92123 REFERENCES 1. Bussman, W. D., Kaltenbach, M.: IV infusion of nitroglycerine and oral isosorbide nititrate in left ventricular failure Circulation, 51, 52: 166, 1975 (abstr.) (suppl. II). 2. Campion, B. C., Frye, R. L., Zitnik, R. S.: Effects of nitroglycerine on capacitance vessels: Mechanism for reduction of left ventricular end diastolic pressure. Mayo Clin. Proc., 45: 573, 1970.
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201 3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13.
J. T., Reid, P. R., Kelly, D. T., et al.: Intravenous nitroglycerine in acute myocardial infarction. Circulation, 51: 132, 1975. Armstrong, P. W., Walker, K. C., Burton, J. R., et al.: Vasodilator therapy: Acute myocardial infarction. A comparison of sodium nitroprusside and nitroglycerine. Circulation, 52: 1118, 1975. Delgado, C. E., Pitt, B., Taylor, D. R., et al.: Role of sublingual nitroglycerine in patients with acute myocardial infarction. Br. Heart J., 37: 392, 1975. Gold, H. K., Leinbach, R. C., Sanders, C. A.: Use of sublingual nitroglycerine in congestive failure following acute myocardial infarction. Circulation, 46: 839, 1972. Greenberg, H., Dwyer, E. M., Jameson, A. G., et al.: Effects of nitroglycerine on the major determinants of myocardial oxygen consumption. Am. J. Cardiol., 36: 426, 1975. Harris, W. S., Aytan, N., Pouget, J. M.: Effects of nitroglycerine on responses of the systolic time intervals to exercise. Circulation, 47: 499, 1973. Henning, H., Crawford, M. H., Karlinger, J. S., et al.: Beneficial effects of nitroglycerine on abnormal ventricular wall motion at rest and during exercise in patients with previous myocardial infarction. Am. J. Cardiol., 37: 623, 1976. McAnulty, J. H., Hattenhouer, M. T., Rosch, J., et al.: Improvement in left ventricular wall motion following nitroglycerine. Circulation, 51: 140, 1975. Reichek, N., Goldstein, R. E., Redwood, D. R., et al.: Sustained effects of nitroglycerine ointment in patients with angina pectoris. Circulation, 50: 348, 1974. Banka, V. S., Bodenheimer, M. M., Helfant, R. H.: Nitroglycerine in experimental myocardial infarction: Effects on regional left ventricular length and tension. Am. J. Cardiol., 36: 453, 1975. Bodenheimer, M. M., Banka, V. S., Helfant, R. H.: Reversible asynergy and its determinants.
Flaherty,
Chest, 69: 87, 1976. 14. Fam, W. M., McGregor, M.: Effect of nitroglycerine and dipyridamole on regional coronary resistance. Circ. Res., 22: 649, 1968. 15. Horwitz, L. D., Gorlin, R., Taylor, W. J., et al.: Effects of nitroglycerine on regional myocardial blood flow in coronary artery disease. J. Clin. Invest., 50: 1578, 1971. 16. Lang, T., Meerbaum, S., Corday, E., et al.: Regional and global myocardial effects of intravenous and sublingual nitroglycerine treatment after experimental acute coronary occlusion. Am. J. Cardiol., 37: 533, 1976. 17. Marchetti, G. V., Merlo, L., Antonnetti, R. M.: The effects of nitroglycerine on the coronary blood flow and oxygen consumption of the myocardium in anesthetized dogs. Am. J. Cardiol., 13: 51, 1964. 18. Mathes, P., Rival, J.: Effect of nitroglycerine on total and regional blood flow in the normal and ischemic canine myocardium. Cardiovasc. Res., 5: 54, 1971. 19. Bernstein, L., Friesinger, G. C., Lichtien, P. R., et al.: The effect of nitroglycerine on the systemic and coronary circulation in man and dogs. Circulation, 33: 107, 1966. 20. Wayne, H. H.: Noninvasive Technics in Cardiology. Chicago, Year Book Medical Publishers, 1973. 21. Weissler, A. M., Harris, W. S., Schoenfeld, C. D.: Systolic time intervals in heart failure in man. Circulation, 37: 149, 1968. 22. Wayne, H. H.: Unpublished data. 23. Tavel, M. E., Campbell, R. W., Feigenbaum, H., et al.: The apexcardiogram and its relationship to hemodynamic events within the left heart. Br. Heart J., 27: 829, 1965. 24. Rios, J. C., Massumi, R. A.: Correlation between the apexcardiogram and left ventricular pressure. Am. J. Cardiol. 15: 647, 1965. 25. Fleming, J. S.: The assessment of failure in aortic stenosis from the diastolic movements of the left ventricle. Am. Heart J., 76: 235, 1968. 26. Voigt, G. C., Friesinger, G. C.: The use of apexcardiography in the assessment of left ventricular diastolic pressure. Circulation, 41: 1095, 1970. 27. McGinn, F. X., Gould, L., Lyon, A. F.: The phonocardiogram and apexcardiogram in patients with ventricular aneurysm. Am. J. Cardiol., 21: 467, 1968. 28. Lane, F. J., Carroll, J. M., Levine, H. D., et al.: the apexcardiogram in myocardial asynergy. Circulation, 37: 890, 1968. 29. Ahuja, S. P., Gutierrez, M. R.: Apexcardiography in the elucidation of a double or multiple impulse apex beat. Am. J. Cardiol., 19: 468, 1967. 30. McDonald, I. G.: The shape and movements of the human left ventricle during systole. Am. J. Cardiol., 26: 221, 1970. 31. El-Sherif, A., Saad, Y., El-Said, G.: Praecordial tracings of myocardial aneurysms. Br. Heart J. 31: 357, 1969. 32. Wayne, H. H., Kuzman, W. J., Miner, R. W.: Correlation of apexcardiographic abnormalities
Downloaded from ang.sagepub.com at University of Manitoba Libraries on June 7, 2015
202 with coronary
arteriography
and left
ventriculography. Circulation, 52: 51, 1975 (abstr) (suppl.
II). 33. Helfant, R. H., Pine, R., Meister, S. G., et al.: Nitroglycerine to unmask reversible asynergy: Correlation with post coronary bypass ventriculography. Circulation, 50: 108, 1974. 34. Pine, R., Meister, S. G., Banka, V. S.: Detection of reversible ventricular contraction abnormalities with nitroglycerine. Correlation with post-coronary bypass ventriculography. Circulation, 48: 104, 1973 (Suppl. 4). 35. Sniderman, A. D., Hersconitch, P., Marpole D., et al.: Restoration of regional wall motion by nitroglycerine therapy in patients with left ventricular asynergy. Chest, 66: 545, 1974. 36. Lee, S. G. K., Sung, Y. K., Zaragoza, A. J.: Effects of nitroglycerine on left ventricular volumes and wall tension in patients with ischemic heart disease. Br. Heart J., 32: 790, 1970. 37. Mason, D. T., Zelish, A., Amersterdam, E. A.: Actions of the nitrates on the peripheral circulation and myocardial oxygen consumption: Significance in the relief of angina pectoris. Chest, 59: 296, 1971. 38. Mason, D. T., Braunwald, E.: The effects of nitroglycerine and amyl nitrite on arteriolar and venous tone in the human forearm. Circulation, 32: 755, 1965. 39. Barnes, H. B., Kaiser, G. C., William, V. L.: Effect of nitroglycerine and papaverine on coronary flow in man. Am. Heart J., 88: 13, 1974. 40. Williams, D. O., Amsterdam, E. A., Mason, D. T.: Hemodynamic effects of nitroglycerine in acute myocardial infarction: Decrease in ventricular pre-load at the expense of cardiac output.
Circulation, 51: 421, 1975. 41. Robinson, B. F.: Mode of action of nitroglycerine in angina pectoris. Br. Heart J., 30: 295, 1968. 42. Fam, W. F., McGregor, M.: Effect of coronary vasodilator drugs on retrograde flow in areas of chronic myocardial ischemia. Circ. Res, 15: 355, 1964. 43. Cohen, M. V., Downey, J. M., Sonneblick, E. H., et al.: The effects of nitroglycerine on coronary collaterals and myocardial contractility. J. Clin. Invest., 52: 2836, 1973. 44. Goldstein, R. E., Stinson, E. B., Scherer, J. L., et al.: Intraoperative coronary collateral function in patients with coronary occlusive disease: Nitroglycerine responsiveness and angiographic correlations. Circulation, 49: 298, 1974. 45. Willis, W. H., Jr., Russell, R. O., Jr., Mentle, J. A., et al.: Hemodynamic effects of isosorbide dinitrate versus nitroglycerine in patients with unstable angina. Chest, 69: 15, 1976. 46. Burggraf, G. W., Parker, J. O.: Left ventricular volume changes after amyl nitrate and nitroglycerine in man as measured by ultrasound. Circulation, 49: 136, 1974. 47. Williams, J. F., Jr., Click, G., Braunwald, E.: Studies on cardiac dimensions in intact unanesthetized man versus effects of nitroglycerine. Circulation, 32: 767, 1965. 48. Dumesnil, J. G., Ritman, E. L., David, G. D., et al.: Regional left ventricular wall dynamics before and after sublingual administration of nitroglycerine. Am. J. Cardiol., 36: 419, 1975. 49. Sawayama, T., Masuru, T., Katsume, H., et al.: Polygraphic studies of the effect of nitroglycerine in patients with ischaemic heart disease. Br. Heart J., 1234 : 35, 1973.
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ABSTRACT
The effects of a sustained-release form of nitroglycerine on left ventricular function were studied in 13 patients with ischemic heart disease in the absence of chest pain. The results were compared to those of sublingual nitroglycerine and placebo. Sustained release nitroglycerine produced a reduction in a wave amplitude on the apexcardiogram from a mean of 20% to 15% (P < 0.05) and an increase in the slope of the systolic wave from a mean of 18 mm/sec to 44 mm/sec (P < 0.01). The left ventricular ejection time corrected for heart rate (ALVET) did not change significantly, nor did the true isovolumic contraction (TIVC) time. Isovolumic relaxation (IVR) time increased from a mean of 121 msec to 137 msec (P < 0.025). The reduction in a wave amplitude and the lengthening of the IVR time reflected the fall in left ventricular end diastolic pressure. The increase in slope of the systolic wave indicated an improvement in wall motion-that is, less dyskinesis in comparison to the resting recordings. In most instances these changes occurred within 1 to 2 hours, with residual effects persisting for 4 to 6 hours. Following the administration of sublingual nitroglycerine, similar changes occurred in a wave amplitudes and IVR times, while the slope of the systolic wave increased from 24 mm/sec to 34 mm/sec. This value, however, was still significant (P < 0.01). In addition, unlike sustainedrelease nitroglycerine, ALVET showed a striking decrease from -26 msec to -47 msec. No change in any of the parameters studied were seen following placebo administration. These results suggest that both the sustained release and sublingual forms of nitroglycerine cause an improvement in left ventricular function and wall motion, but by different mechanisms. Sublingual nitroglycerine appears to work by causing a decrease in preload and wall tension, thereby reducing myocardial oxygen demands. Sustained-release nitroglycerine does not do this, a fact indicating perhaps a direct increase in myocardial perfusion to ischemic areas. Finally, the improvement in left ventricular function after the administration of both forms of nitroglycerine, suggests that the long-acting preparation in particular would be a useful adjunct in the treatment of patients with ischemic heart disease, even in the absence of chest pain. From the San Diego County Diego, California.
Heart Center, Donald N.
Sharp Memorial Community Hospital, San
Presented at the Western Clinical Conference of the American
College of Angiology, Tucson,
Arizona.
190
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191 INTRODUCTION
In
spite
of the
widespread
use
of so-called
..
long-acting
’
coronary
vaso-
dilators, there is little objective information on the efficacy of these preparations over prolonged periods of time-i.e., for more than 1-2 hours. use of these preparations has been directed toward the relief of angina pectoris in symptomatic patients, rather than toward improvement in left ventricular function in the diseased but asymptomatic patient. That such improvement in left ventricular function occurs following the administration of the short and long-acting nitrates is well established. Direct
Clinical
measurements have documented a fall in left ventricular end diastolic 1-4 and pulmonary artery wedge pressure,’,’ and an improvement pressure in left ventricular function’-’3 with an increase in coronary blood flow.14-19 Most of these studies have been carried out for only short intervals of time in any given patient. This is understandable because it is hardly to record serial measurements for the duration of time during which these drugs are claimed to be effective. Noninvasive techniques are not subject to the limitations of direct methods, yet may effectively document directional changes in left ventricular function and wall motion over prolonged periods. These procedures lend themselves admirably to the study of so-called long-acting nitrates. Therefore a study was undertaken on the effects of a sustainedrelease form of nitroglycerine using apexcardiography, as well as systolic and diastolic time intervals. The purpose was to determine (1) whether improvement in left ventricular function could be demonstrated by these techniques in patients with ischemic heart disease in the absence of chest pain, and (2) their effective duration of action.
justifiable
MATERIALS AND METHODS
Thirteen patients aged 47 to 71 were studied. There were 11 males and 2 females. All had evidence of left ventricular dysfunction due to ischemic heart disease. The diagnosis of ischemic heart disease was based upon a history of chest pain in conjunction with either electrocardiographic evidence of a myocardial infarction and/or ischemic ST segment depression during or after a graded maximal ergometer stress test. Left ventricular dysfunction was based upon the finding of impaired exercise tolerance in conjunction with a significantly abnormal apexcardiogram and/or prolonged systolic time intervals.
Recording of Noninvasive Parameters Our method of recording the apexcardiogram has been described in detail (20). The patient was placed in the left lateral position and the apex impulse was carefully marked. The end piece of a B-D Fleischer stethoscope with the diaphragm removed (lumen diameter 4.2 cm, depth 5 mm) was placed directly over the apex impulse and held in place with a wide rubber strap. The stethoscope pickup was connected by 25 cm of rubber
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192 an Elema-Schonander EMT 510 transducer with a time constant of 3.0 seconds. Great care was taken to avoid artifactual tracings as previously described (20) or alterations in the wave form due to patient rotation or respiration. The pickup over the apex impulse was left in position for the entire sublingual nitroglycerine portion of the study and for a substantial period after the administration of the sustained-release preparation. The calibration of the transducer and the gain setting of the amplifier was not disturbed. In addition to the pickup over the apex impulse for recording the apexcardiogram, an Elema-Schonander EMT 25B contact microphone was placed along the left sternal border at the second or third interspace for optimum recording of the second heart sound. A carotid pulse tracing was simultaneously recorded with a second Elema-Schonander EMT 510 transducer connected to a small funnel pickup. Finally, lead II of an electrocardiogram was recorded with all of the above. All parameters were transcribed simultaneously on an Elema-Schonander mingograf 81 polygraph.
tubing to
.
of Drugs and Frequency of Measurements All patients were studied at three different settings. After a 15-30 minute rest period, control recordings were made. Nitroglycerine (0.4 mg) was given sublingually to 6 patients, and repeat recordings were made at 3, 6, 9, and 15 minutes. Occasionally recordings were also made at 20 and 30 minutes if the effects of the drug had not worn off. A similar number of patients received a placebo, but recordings were made at 1, 2, 4, and 6 hours. Thirteen patients received sustained-release nitroglycerine and again recordings were made at 1, 2, 4, and 6 hours. Administration
Measurements
Figure 1 shows an ACG recorded in conjunction with lead II of the ECG, the carotid pulse, and a phonocardiogram. The a wave amplitude was taken as its vertical height divided by the entire amplitude of the ACG complex from the E point (onset of ejection) to the 0 point (opening of the mitral valve). The slope of the systolic wave was measured as follows: a horizontal line (E-E’ in Figure 1) was extended from the E point for 100 mm or 1 second 100 mm/sec). A perpendicular line was drawn until it (paper speed intersected the line extending from point E along the top of the systolic wave through S (line E-S-S’ in Figure 1 ), thus allowing measurement of the slope in mm/sec. The steeper the slope, the more rapidly the ventricular wall is moving away from the apex pickup. The gain of the amplifier was not disturbed during the recording sessions. =
Measurement
of the Sy.stolic and Diastolic
Time Intervals
Figure 1 also shows the breakdown of the cardiac cycle into its respecsystolic and diastolic intervals. The true isovolumic contraction (TIVC) time was measured from the onset of the initial upstroke of the tive
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193
FIG. l. An apexcardiogram (ACG) recorded in conjunction with the electrocardiogram (ECG ), the carotid pulse tracing (CPT), phonocardiogram (PCG), first differential) of the carotid pulse tracing (dp/dt CPT), and first differential of the apexcardiogram (dp/dt ACG). The various systolic and diastolic time intervals are also shown. The method of measurement is described in the text. Other onset of ejection, 0 onset of ventricular contraction, E abbreviations: a atrial filling wave, C left ventricular mechanical systole, LVET aortic second sound, C-A2 mitral valve opening, A2 ejection time, IVR isovolumic relaxation time, Si first heart sound, S2 second heart sound, S true slow filling wave, TIVC shoulder of systolic wave, RFW rapid filling wave, SFW standardization deflection. isovolumic contraction time, and Q =
=
=
=
=
=
=
=
=
=
=
=
=
=
=
(point C) to the first high frequency vibration of the aortic of component the second heart sound (C-A2 interval). The left ventricular ejection time (LVET) from the simultaneously recorded carotid pulse was subtracted from the C-A, interval. The TIVC time therefore represents that interval from the onset of ventricular contraction to the opening of the aortic valve corrected for pulse delay. The A LVET was derived by subtracting the measured LVET from the predicted LVET corrected for heart rate and sex, by using the regression equations of Weissler (21). Isovolumic relaxation time was measured from the first high frequency component of the aortic second sound to the opening of the mitral valve at the 0 point of the ACG. The a wave duration was measured from the beginning upstroke of the a wave to its nadir at point C of the ACG. Its duration is related to the length of atrial systole. Finally, in addition to the above measurements, heart rate and blood pressure were recorded each time recordings were made. systolic
wave
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194
All the cardiac parameters recorded were keypunched and stored on for computer processing. A CDC 6600 computer was used for data reduction as well as statistical computations. Effects of treatment over time as well as comparisons between treatment were assessed by the
magnetic tape
students’ t test. .
~
RESULTS
.
_
Figure 2 shows the effects upon the ACG before and after the administration of sublingual NTG. It can be seen that the u wave amplitude is reduced from 57% to 30% while the duration decreases from 130 to 100 msec. At the same time the slope of the systolic wave becomes transformed from a paradoxical bulge to a distinct downslope after administration of the drug. Figure 3 shows the effects upon the ACG before and after the administration of sustained-release nitroglycerine. The results are qualitatively similar to those seen after sublingual nitroglycerine. In the control panel a
FIG. 2. Effect of sublingual nitroglycerine on the apexcardiogram. Abbreviations are the same as in Figure l; NTG nitroglycerine. Note the large a wave (amplitude 57%, duration 130 msec) and the paradoxical bulge. After sublingual (SL) NTG the a wave decreases to 30% and 100 msec while the paradoxical bulge disappears. =
.
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195
FIG. 3. Effect of sustained-release (SR) nitroglycerine on the apexcardiogram. Note the changes are similar to that seen with sublingual nitroglycerine (Figure 2). The duration of effect, however, extends to at least 6 hours in this patient.
distinct paradoxical bulge is present. At 1 hour after the administration of sustained-release nitroglycerine, the systolic wave is sustained but the bulge has disappeared. At 3 hours there is a definite downslope. At 6 hours the downslope of the systolic wave is very steep. Figure 4 compares the mean effects in all patients of the sublingual and sustained-release form of nitroglycerine as well as the placebo on the a wave of the apexcardiogram. The control mean a wave amplitude for the sublingual NTG patients was 17%. It fell to a low of 12% (P < 0.05) an average of 6 minutes after the administration of the sublingual preparation. The control mean a wave amplitude for the sustained release nitroglycerine patients was 20%, with a fall to a mean of 15% at 2 hours (P < 0.05). In contrast, following administration of placebo, a wave amplitude rose from a mean of 17% to 19% at 1 hour and 18% at 2 hours. Figure 5 compares the mean effects in all patients of the three preparations on the systolic wave of the ACG. After the administration of sublingual nitroglycerine, the slope of the systolic wave increased from a control of 24 mm/sec to 34 mm/sec (P < 0.01 ) at 3 minutes. Following the administration of sustained-release nitroglycerine, the slope of the systolic wave increased from a mean of 18 mm/sec to 44 mm/sec at 2 hours (P < 0.01). In contrast, after the administration of the placebo, the slope of the systolic wave showed no significant change.
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196
FIG. 4. Mean effect of sustained-release nitroglycerine, placebo, and sublingual nitroglycerine on amplitude in all patients. Left-hand figure shows SR NTG and placebo. Right hand figure shows SL NTG. mean a wave
Duration
of Action
Peak effects following the administration of sublingual nitroglycerine were seen between 3 and 6 minutes, with some residual effects evident at 15 minutes. Full recovery was always seen between 20 and 30 minutes. After the administration of sustained-release nitroglycerine, peak effects were seen in about 2 hours. However significant effects were still seen at 4 and 6 hours in most patients.
Systolic and Diastolic Time Intervals True Isovolumic Contraction (TIVC) Time. The TIVC time remained essentially unchanged following the administration of all three preparations. ALVET.
Figure 6 shows the mean effects in all patients of the three preparations on the ALVET. A profound change was seen after sublingual nitroglycerine. The ALVET fell from a mean control of -26 msec to -47 msec. A much smaller change was seen after sustained-release nitroglycerine : the ALVET fell from a mean control of -18 msec to -26 msec at I hour, with gradual recovery over 6 hours. After the administration of placebo, the ALVET decreased from a mean control of -15 msec to -23 msec. Thus the mean change in the ALVET following sustained release
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197
FIG. 5. Mean effect of sustained-release nitroglycerine, wave of the apexcardiogram in all patients.
placebo, and sublingual nitroglycerine on the
systolic
nitroglycerine was not significant (P > 0.05) when compared to placebo, whereas the effect of sublingual nitroglycerine was highly so (P < 0.01 ). Isovolumic Relaxation (I VR Time. Figure 7 compares the mean effects in all patients of the three preparations on the IVR time. After sublingual nitroglycerine the IVR time increased from a mean control of 152 msec to 160 msec at 3 minutes. Following the administration of sustained-release nitroglycerine, the IVR time increased from a mean control of 121 msec to 137 msec at 2 hours, and residual effects persisted for 6 hours. After placebo an opposite effect was once again apparent with the IVR time decreasing from 141 to 132 msec. DISCUSSION
The results of this investigation show that qualitatively similar effects on left ventricular function and hemodynamics occur following the administration of both sublingual and sustained-release nitroglycerine. Thus the a wave amplitude was reduced, the slope of the systolic wave improved, the IVR time lengthened. The duration of these effects for sublingual nitroglycerine was only about 15 minutes. We have previously shown that sublingual nitroglycerine has little effect beyond 15 minutes on the parameters used in this study (22). In contrast, sustained release nitroglycerine showed a peak effect at 2 hours and significant residual effects lasting for 4 to 6 hours.
Interpretation of Hemodynamic Changes A close correlation between a wave amplitude and left ventricular end diastolic pressure (LVEDP) has been well documented.23-28 A fall in a wave amplitude usually reflects a comparable decrease in LVEDP. Whenever LV EDP decreases from a previously elevated level, left atrial pressure falls as well. Accordingly, left ventricular pressure will take longer to fall below the lower left atrial pressure. Since IVR time is that interval be-
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198
FIG. 6. Mean effect of sustained-release nitroglycerine, placebo, and z left ventricular ejection time (ALVET) in all patients.
sublingual nitroglycerine on the
valve closure and mitral valve opening, this time period will It is reasonable to assume, therefore, that the combination of a decrease in a wave amplitude and lengthening of the IVR times was a consequence of a decrease in LVEDP following the administration of tween aortic
lengthen.
and sustained-release nitroglycerine. Direct measurements have shown a similar fall in LVEDP following nitroglycerine administration.’-’ Systolic Wave. A number of studies have shown that the contour of the systolic wave of the ACG reflects wall motion as determined by direct left ventriculography.2’-31 We recently reported that a close correlation also exists between the slope of the systolic wave and left ventricular function, and that it was possible to measure ejection fraction from the systolic wave.32 Such measurements showed a very high correlation with the ejection fraction as measured angiographically. Thus the steeper downslope of the systolic wave after both sublingual and sustained-release nitroglycerine suggested a decrease in abnormal wall motion and more complete emptying of the left ventricle. These observations are supported by studies of wall motion during left ventriculography following the administration of nitroglycerine. Areas of hypokinesis clearly showed improvement in the contraction pattern. 9,10,33-35 The primary mechanism of action of nitroglycerine is a matter of controversy. It is generally agreed that coronary artery dilatation takes place with increased flOW14-18 in conjunction with peripheral pooling,2~36-39
sublingual
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199
FIG. 7. Mean effect of sustained-release nitroglycerine, placebo, and isovolumic relaxation (IVR) time in all patients.
with
sublingual nitroglycerine on the
reduction in both preload4° and afterload.41 Whether dilatation in vessels that are already sclerotic and narrowed is doubtful. Nevertheless blood flow may well increase in marginally ischemic areas. In fact it is now well documented that there is an improved flow in collaterals following nitroglycerine administration.42-44 The other postulated mechanism, peripheral pooling, by reducing venous filling or preload will cause a very significant reduction in wall tension.’ Associated with this is a reduction in left ventricular end diastolic volume4,45 and left ventricular end systolic volume.16,46,4’ As a result, myocardial oxygen demands decrease. Regardless of which mechanism predominates, wall motion improves, myocardial contractility increases,’,’ ventricular emptying and ejection fraction increase,7,10,13 and left ventricular end diastolic pressure falls.1-4 It is interesting that although the qualitative effects of sublingual and sustained-nitroglycerine were similar, there were important differences. Sublingual nitroglycerine caused a marked reduction in the ALVET. Presumably this reduction was due to peripheral pooling with a decrease in venous return and stroke volume, and a resulting decrease in the LVET and ALVET. Sustained-release nitroglycerine, on the other hand, did not cause any change in the ALVET when compared to placebo. Nevertheless the slope of the systolic wave of the ACG not only improved after sustained release nitroglycerine, but did so to a greater degree than after a
occurs
sublingual nitroglycerine. These differences raise the question of whether the primary mechanism of action of sublingual nitroglycerine is different from that of sustained-
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200
nitroglycerine. The improvement in function following sublingual nitroglycerine might be primarily due to peripheral pooling with reduction in preload and wall tension and a decrease in oxygen demands. In contrast, sustained-release nitroglycerine may work by increasing coronary and collateral flow to ischemic tissue and thereby cause an improvement in contractility. Indeed, recent studies have shown that akinetic areas of myocardium do not improve following nitroglycerine16,48 unless they happen to be assorelease
ciated with collateral vessels.&dquo; F_it_h_e_r mechanism of action results in ( 1 ) a fall in left ventricular end diastolic pressure and a wave amplitude, and (2) improvement in wall motion and the systolic wave of the apexcardiogram. It is interesting that no significant change was seen in the TIVC time. Since improved contractility was evident in all patients studied, one would have expected a decrease in this time interval. It is known that a decrease in venous return will cause a lengthening of this time period preceding ejection.19 Presumably, therefore, the lengthening of the TIVC time due to peripheral pooling with a reduction in venous return was sufficient to offset the decrease in this same time interval due to improved contractility. Using both the apexcardiogram and systolic time intervals, other investigators have found similar results. Sawayama et a1.49 found a reduction in a wave amplitude and an improved systolic wave following the sublingual administration of nitroglycerine. These same investigators as well as Harris et al.8 found a reduction in the LVET index after sublingual
nitroglycerine. No previous studies document the efficacy of sustained-release nitroglycerine with these noninvasive methods. The present study not only confirms the qualitative similarity of sustained-release nitroglycerine to sublingual nitroglycerine, but documents its effectiveness over several hours in patients with ischemic heart disease even in the absence of chest pain. Additionally, the results suggest that sublingual nitroglycerine works by causing peripheral pooling with a reduction in preload and wall tension and a reduction in myocardial oxygen demands. Sustained-release nitroglycerine, on the other hand, seems to work by causing a direct increase in flow to ischemic areas. The improvement in left ventricular performance in such patients encourages the more regular use of such preparations. Howard H. Wayne, M. D. San Diego County Heart Center Donald N. Sharp Memorial Community Hospital San Diego, California 92123 REFERENCES 1. Bussman, W. D., Kaltenbach, M.: IV infusion of nitroglycerine and oral isosorbide nititrate in left ventricular failure Circulation, 51, 52: 166, 1975 (abstr.) (suppl. II). 2. Campion, B. C., Frye, R. L., Zitnik, R. S.: Effects of nitroglycerine on capacitance vessels: Mechanism for reduction of left ventricular end diastolic pressure. Mayo Clin. Proc., 45: 573, 1970.
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201 3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13.
J. T., Reid, P. R., Kelly, D. T., et al.: Intravenous nitroglycerine in acute myocardial infarction. Circulation, 51: 132, 1975. Armstrong, P. W., Walker, K. C., Burton, J. R., et al.: Vasodilator therapy: Acute myocardial infarction. A comparison of sodium nitroprusside and nitroglycerine. Circulation, 52: 1118, 1975. Delgado, C. E., Pitt, B., Taylor, D. R., et al.: Role of sublingual nitroglycerine in patients with acute myocardial infarction. Br. Heart J., 37: 392, 1975. Gold, H. K., Leinbach, R. C., Sanders, C. A.: Use of sublingual nitroglycerine in congestive failure following acute myocardial infarction. Circulation, 46: 839, 1972. Greenberg, H., Dwyer, E. M., Jameson, A. G., et al.: Effects of nitroglycerine on the major determinants of myocardial oxygen consumption. Am. J. Cardiol., 36: 426, 1975. Harris, W. S., Aytan, N., Pouget, J. M.: Effects of nitroglycerine on responses of the systolic time intervals to exercise. Circulation, 47: 499, 1973. Henning, H., Crawford, M. H., Karlinger, J. S., et al.: Beneficial effects of nitroglycerine on abnormal ventricular wall motion at rest and during exercise in patients with previous myocardial infarction. Am. J. Cardiol., 37: 623, 1976. McAnulty, J. H., Hattenhouer, M. T., Rosch, J., et al.: Improvement in left ventricular wall motion following nitroglycerine. Circulation, 51: 140, 1975. Reichek, N., Goldstein, R. E., Redwood, D. R., et al.: Sustained effects of nitroglycerine ointment in patients with angina pectoris. Circulation, 50: 348, 1974. Banka, V. S., Bodenheimer, M. M., Helfant, R. H.: Nitroglycerine in experimental myocardial infarction: Effects on regional left ventricular length and tension. Am. J. Cardiol., 36: 453, 1975. Bodenheimer, M. M., Banka, V. S., Helfant, R. H.: Reversible asynergy and its determinants.
Flaherty,
Chest, 69: 87, 1976. 14. Fam, W. M., McGregor, M.: Effect of nitroglycerine and dipyridamole on regional coronary resistance. Circ. Res., 22: 649, 1968. 15. Horwitz, L. D., Gorlin, R., Taylor, W. J., et al.: Effects of nitroglycerine on regional myocardial blood flow in coronary artery disease. J. Clin. Invest., 50: 1578, 1971. 16. Lang, T., Meerbaum, S., Corday, E., et al.: Regional and global myocardial effects of intravenous and sublingual nitroglycerine treatment after experimental acute coronary occlusion. Am. J. Cardiol., 37: 533, 1976. 17. Marchetti, G. V., Merlo, L., Antonnetti, R. M.: The effects of nitroglycerine on the coronary blood flow and oxygen consumption of the myocardium in anesthetized dogs. Am. J. Cardiol., 13: 51, 1964. 18. Mathes, P., Rival, J.: Effect of nitroglycerine on total and regional blood flow in the normal and ischemic canine myocardium. Cardiovasc. Res., 5: 54, 1971. 19. Bernstein, L., Friesinger, G. C., Lichtien, P. R., et al.: The effect of nitroglycerine on the systemic and coronary circulation in man and dogs. Circulation, 33: 107, 1966. 20. Wayne, H. H.: Noninvasive Technics in Cardiology. Chicago, Year Book Medical Publishers, 1973. 21. Weissler, A. M., Harris, W. S., Schoenfeld, C. D.: Systolic time intervals in heart failure in man. Circulation, 37: 149, 1968. 22. Wayne, H. H.: Unpublished data. 23. Tavel, M. E., Campbell, R. W., Feigenbaum, H., et al.: The apexcardiogram and its relationship to hemodynamic events within the left heart. Br. Heart J., 27: 829, 1965. 24. Rios, J. C., Massumi, R. A.: Correlation between the apexcardiogram and left ventricular pressure. Am. J. Cardiol. 15: 647, 1965. 25. Fleming, J. S.: The assessment of failure in aortic stenosis from the diastolic movements of the left ventricle. Am. Heart J., 76: 235, 1968. 26. Voigt, G. C., Friesinger, G. C.: The use of apexcardiography in the assessment of left ventricular diastolic pressure. Circulation, 41: 1095, 1970. 27. McGinn, F. X., Gould, L., Lyon, A. F.: The phonocardiogram and apexcardiogram in patients with ventricular aneurysm. Am. J. Cardiol., 21: 467, 1968. 28. Lane, F. J., Carroll, J. M., Levine, H. D., et al.: the apexcardiogram in myocardial asynergy. Circulation, 37: 890, 1968. 29. Ahuja, S. P., Gutierrez, M. R.: Apexcardiography in the elucidation of a double or multiple impulse apex beat. Am. J. Cardiol., 19: 468, 1967. 30. McDonald, I. G.: The shape and movements of the human left ventricle during systole. Am. J. Cardiol., 26: 221, 1970. 31. El-Sherif, A., Saad, Y., El-Said, G.: Praecordial tracings of myocardial aneurysms. Br. Heart J. 31: 357, 1969. 32. Wayne, H. H., Kuzman, W. J., Miner, R. W.: Correlation of apexcardiographic abnormalities
Downloaded from ang.sagepub.com at University of Manitoba Libraries on June 7, 2015
202 with coronary
arteriography
and left
ventriculography. Circulation, 52: 51, 1975 (abstr) (suppl.
II). 33. Helfant, R. H., Pine, R., Meister, S. G., et al.: Nitroglycerine to unmask reversible asynergy: Correlation with post coronary bypass ventriculography. Circulation, 50: 108, 1974. 34. Pine, R., Meister, S. G., Banka, V. S.: Detection of reversible ventricular contraction abnormalities with nitroglycerine. Correlation with post-coronary bypass ventriculography. Circulation, 48: 104, 1973 (Suppl. 4). 35. Sniderman, A. D., Hersconitch, P., Marpole D., et al.: Restoration of regional wall motion by nitroglycerine therapy in patients with left ventricular asynergy. Chest, 66: 545, 1974. 36. Lee, S. G. K., Sung, Y. K., Zaragoza, A. J.: Effects of nitroglycerine on left ventricular volumes and wall tension in patients with ischemic heart disease. Br. Heart J., 32: 790, 1970. 37. Mason, D. T., Zelish, A., Amersterdam, E. A.: Actions of the nitrates on the peripheral circulation and myocardial oxygen consumption: Significance in the relief of angina pectoris. Chest, 59: 296, 1971. 38. Mason, D. T., Braunwald, E.: The effects of nitroglycerine and amyl nitrite on arteriolar and venous tone in the human forearm. Circulation, 32: 755, 1965. 39. Barnes, H. B., Kaiser, G. C., William, V. L.: Effect of nitroglycerine and papaverine on coronary flow in man. Am. Heart J., 88: 13, 1974. 40. Williams, D. O., Amsterdam, E. A., Mason, D. T.: Hemodynamic effects of nitroglycerine in acute myocardial infarction: Decrease in ventricular pre-load at the expense of cardiac output.
Circulation, 51: 421, 1975. 41. Robinson, B. F.: Mode of action of nitroglycerine in angina pectoris. Br. Heart J., 30: 295, 1968. 42. Fam, W. F., McGregor, M.: Effect of coronary vasodilator drugs on retrograde flow in areas of chronic myocardial ischemia. Circ. Res, 15: 355, 1964. 43. Cohen, M. V., Downey, J. M., Sonneblick, E. H., et al.: The effects of nitroglycerine on coronary collaterals and myocardial contractility. J. Clin. Invest., 52: 2836, 1973. 44. Goldstein, R. E., Stinson, E. B., Scherer, J. L., et al.: Intraoperative coronary collateral function in patients with coronary occlusive disease: Nitroglycerine responsiveness and angiographic correlations. Circulation, 49: 298, 1974. 45. Willis, W. H., Jr., Russell, R. O., Jr., Mentle, J. A., et al.: Hemodynamic effects of isosorbide dinitrate versus nitroglycerine in patients with unstable angina. Chest, 69: 15, 1976. 46. Burggraf, G. W., Parker, J. O.: Left ventricular volume changes after amyl nitrate and nitroglycerine in man as measured by ultrasound. Circulation, 49: 136, 1974. 47. Williams, J. F., Jr., Click, G., Braunwald, E.: Studies on cardiac dimensions in intact unanesthetized man versus effects of nitroglycerine. Circulation, 32: 767, 1965. 48. Dumesnil, J. G., Ritman, E. L., David, G. D., et al.: Regional left ventricular wall dynamics before and after sublingual administration of nitroglycerine. Am. J. Cardiol., 36: 419, 1975. 49. Sawayama, T., Masuru, T., Katsume, H., et al.: Polygraphic studies of the effect of nitroglycerine in patients with ischaemic heart disease. Br. Heart J., 1234 : 35, 1973.
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