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Evaluation of contractile reserve by dobutamine echocardiography: Noninvasive estimation of the severity of heart failure

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Evaluation of contractile reserve by dobutamine echocardiography: Noninvasive estimation of the severity of heart failure
  Evaluation of contractile reserve by dobutamine echocardiography: Noninvasive estimation of the severity of heart failure Alon Marmor, MD, Theodor Raphael, MD, Meir Marmor, MD, and David Blondheim, MD Haifa, Israel Functional status in chronic heart failure is evaluated in general by subjective means, such as the New York Heart Association class, or by invasive techniques difficult to use routinely. The aim of this study was to evaluate noninva- sively the contractile reserve in cases of heart failure as a means to define the functional status of the patients. Cardiac peak power, a new noninvasively obtained afterload-inde- pendent index of contractility, was calculated from online Doppler and central arterial blood pressure estimated non- invasively in 35 patients with heart failure and 10 healthy subjects during dobutamine infusion. Cardiac output in- creased in all patients to the same extent, without differen- tiation among the functional classes. Contractile reserve, as assessed by peak power, was found to be a good marker of functional class: it was significantly higher in functional class 1 than in functional classes 2 through 4. A correlation of r= 0.99 and probability of p < 0.001 was found with the functional status. This new, noninvasive contractility index, peak power, allows an objective evaluation of the severity of heart failure. Am Heart J 1996;132:1195-201.) Dobutamine, by its well-known direct positive ino- tropic action, 1 is known to increase cardiac perfor- mance in patients with heart failure. 2 Increase in performance is achieved mainly by an increase in contractility, 1 a reduction in systemic vascular re- sistance 3, 4 (SVR), and to some degree an increment in heart rate. 1 It is reasonable to assume that as heart failure progresses, the contractile reserve of the heart decreases and therefore augmentation in cardiac performance would be achieved in the ad- vanced stages ofheart failure by lowering the SVR and increasing the heart rate, rather than by in- creasing the contractility. Recently Gorcsan at al. 5 demonstrated attenuated contractile reserve in chronic severe heart failure by From the Division of Cardiology, Safed Hospital, Safed and Technion Fac- ulty of Medicine. Received for publication Nov. 10, 1995; accepted March 15, 1996. Reprint requests: Alon Marmor, MD, Division of Cardiology, Rebecca Sieff Hospital, Safed 13100, Israel. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/ 5.00 + 0 4/1//5862 using an automated noninvasive pressure-volume relation during dobutamine echocardiography. How- ever, they did not differentiate between the func- tional classes and did not correlate the severity of the heart failure to the degree of contractile reserve. The purpose of the current study was to evaluate the contractile reserve in patients with three distinct functional classes of heart failure (New York Heart Association class 1, class 2 and 3, and class 4) by us- ing a new noninvasive approach during a given standard inotropic stimulus of dobutamine. The hy- pothesis was that contractile reserve gradually de- creases with increasing severity of heart failure, while left ventricular performance is maintained in the advanced stages of heart failure mainly by a de- crease in SVR rather than an increase in contractil- ity. METHODS Patient population. From 42 patients referred to our outpatient clinic with various symptoms, 35 were included in the study. Their mean age was 60 _+ 5 years; there were 26 men and 9 women; and their mean blood pressure (sys- tolic/diastolic) was 135 _+ 10/83 _+ 5 mm Hg. After careful anamnestic evaluation 15 patients were classified as New York Heart Association functional class 1, 13 as functional class 2 and 3, and 7 as functional class 4. Patients were as- signed to functional classes by two independent experi- enced cardiologists unaware of the study. For only 2 patients was there a discrepancy between the two special- ists, and a third competent cardiologist decided the func- tional class in these subjects. None of the patients had had an acute coronary event in the preceding 6 months. All pa- tients had a history ofischemic heart disease and had doc- umented myocardial infarction. Twenty of the 35 had had more than one myocardial infarction. All patients with symptoms of heart failure were treated with digoxin and diuretic agents, and all patients from the groups of func- tional classes 2 through 4 were treated with captopril 25 mg two times per day or three times per day in addition to digoxin and diuretic agents. In 10 additional subjects referred to our outpatient clinic for atypical chest pain, coronary artery disease was ex- 1195  December 1996 1196 Marmor et al. American Heart Journal Table I. Cardiac output (liters per minute) during dobutamine infusion Infusion rate FC2 ttg/kg/min) Healthy FC1 and FC3 FC4 Rest 5.55 ± 0.7 4.38 _+ 0.5 4.15 ± 0.2 4.27 +_ 0.5 5 5.48 _+ 0.7 4.90 -- 0.4 4.31 _+ 0:4 5.55 +_ 0.8 10 6.69 + 0.5 5.30 +_ 0.7 5.67 +_ 0.3 5.06 _+ 0.5 20 8.43 ± 1.1 5.57 ± 0.6 6.17 ± 0.4 6.14 _+ 0.8 30 10.54 _+ 1.5 6.91 _+ 1.0" 6.60 +_ 0.4* 6.31 _+ 0.8* 40 8.93 ± 2.0 8.01 ± 0.7 8.03 ± 0.9 7.31 _+ 0.9 A_NOVA <0.001 <0.001 <0.001 <0.001 ANOVA, Analysis of variance; FC, New York Heart Association functional class. *p < 0.016 for comparison with healthy group. cluded by exercise testing, exercise thallium perfusion scanning, and echocardiographic dobutamine stress test- ing. All other organic heart conditions were excluded by Doppler echocardiography. These subjects were included in the study as a control group, and their functional class was considered to be 1. Measurements of aortic flow. Aortic velocities were measured by continuous-wave Doppler in an apical five- chamber view. Aortic diameter was measured in a two-di- mensional parasternal long-axis view, just below the aor- tic orifice, from the inner to inner echo at rest only because aortic valve is thought to remain constant during exercise or dobutamine infusion. 6 Aortic valve area was also mea- sured. The following variables were obtained at rest and during dobutamine infusion: stroke volume 6 ([~/4 x (Aor- tic diameter] 2 x [Aortic velocity-time integral]) and aortic flow. Aortic flow was calculated as the Velocity-time integral x Valve area/ejection time. Doppler measure- ments of exercise stroke volume at the aortic orifice have been previously validated by comparison with thermodi- lution 7 and recently by Dahan at al. 6 and Borow et al. s End-diastolic volume was measured by using the estab- lished area-length method. Central arterial pressure measurement. Central arte- rial pressure was obtained noninvasively by a newly designed computer-controlled device. 9' i0 This device con- sists of three components: a sphygmomanometric arm cuff attached to an air pressure unit; a Doppler transducer attached to the arm at the antecubital space over the brachial artery; and an electrocardiographic monitoring system. Noninvasive pressure waveforms are generated by mea- suring the time delay between the R wave on the electro- cardiogram and the onset ofbrachial artery flow (Doppler) during computer-controlled upper-arm deflation. This de- lay shortens with decreasing cuff pressure, so that a plot of pressure versus time delay yields the ascending portion of the arterial waveform. These waveforms were compared with the simultaneous invasive ascending aortic pressure, and correlations of r = 0.98 for systolic pressure and r = 0.99 for diastolic pressure were found, ii Cardiac peak power measurement. Peak power, repre- senting the maxima] product of systolic pressure and flow, occurs early in ejection and is not significantly affected by afterload. Experimental data 12-i4 indicate that cardiac peak power is a relatively afterload-independent contrac- tility index. It is obtained with the following formula: Peak power = Maximal product of(P x dV/dt), where P is central aortic pressure and dV/dt is aortic flow. Aortic flow was computed as (Velocity-time integral × Aortic valve area)/ Ejection time, measured in the apical five-chamber view by Doppler echocardiography. By aligning the beginning of the flow with the simultaneously recorded central aortic pressure, instantaneous power measurements are made and maximal peak power is obtained. Statistics. The results are expressed as means +-- SD. For repeated comparison between the healthy and patient groups, repeated-measures analysis of variance was used. One-way analysis of variance was performed for compar- ison within the same group of patients at different rates of dobutamine infusion. When analysis of variance showed statistical significance (p < 0.05), the Student-Newman- Keuls test was used for comparison of the groups. Corre- lations between functional class and change in cardiac output, SVR, heart rate, and peak power were calculated by linear regression analysis, i5 Functional classes were scored on a scale of 1 to 3, where 1 is healthy and 3 is func- tional class 4. RESULTS Results were obtained in 42 patients and were of good enough quality for accurate analysis in 35 sub- jects, who were included in the study. Acute ischemic episodes were ruled out by looking at regional wall motion abnormalities and electrocardiographic changes during dobutamine infusion. Only patients without new regional motion abnormalities or other documented ischemic episodes were included in the study. Therefore the patient population was homogeneous with respect to lack of active ische- mic events. Seven patients were assigned to func- tional class 4, 13 patients to class 2 and 3, and 15 to functional class 1. All 10 healthy subjects had good quality studies and were included as the control group. The maximal increase in cardiac output was ob-  Volume 132, Number 6 American Heart Journal Marmor et a 1197 Cardiac Output Mean SEM Healthy 6 3 0.8 FC1 3.42 0.74 FC2-3 2 89 0 48 FC4 4.27 0 89 r = 0.57 p = NS Peak Power Mean SEM Healthy 10.89 1.28 FC1 7.76 1.22 FC2-3 5 53 0.95 FC4 3.47 0.64 r = 0.995 p<0.005 Heart Rate Mean SEM Healthy 52.3 5.56 FC1 28 91 7.16 FC2-3 24.45 4.95 FC4 36.58 4.94 r = 0.54 p=NS -SVR Mean SEM Healthy 512 172 FC1 966 161 FC2-3 666 190 FC4 1184 239 r= 0.73 p = NS Healthy FCI FC2-3 FC4 a.. + 15 10 5 0 Healthy FC1 FC2-3 FC4 60 g ~ 4o e~ • ~ 20 Healthy FC1 FC2-3 FC4 A =~15oo 1000 u 500 n, o i Healthy FC1 FC2-3 FC4 Fig. 1. Maximal changes in four hemodynamic parameters induced by dobutamine stress testing. Max- imal differences in cardiac output (CO), peak power, heart rate, and SVR are shown for each functional class. FC, Functional class; NS, not statistically significant; r, correlation between functional classes and hemodynamic parameters. tained with 40 pg dobutamine in the patients in functional classes I through 4 and with 30 pg in the healthy subjects. As expected, the increase in cardiac output was substantially higher in the healthy sub- jects than in all patient groups (Table I). However, cardiac output achieved at the peak dobutamine dose was remarkably similar in all patient groups, re- gardless of their functional class (Table I). In the healthy group, cardiac output increased from 5.5 _+ 0.7 L/minto 10.5 _+ 1.5 L/min (p < 0.01) at 30 ~g of dobutamine and reached a plateau of 8.9 L/rain at 40 pg (Table I and Fig. 1). Stroke volume increased by 31%, from 73 to 96 ml at 40 pg (p < 0.05). The main component responsible for the increase in stroke volume, and subsequently in cardiac output, was the massive increase in contractility. Peak pow- er/end-diastolic volume increased from 11.46 to 21.97 W/ml (p < 0.001) at 40 pg dobutamine (Table II), representing an increase of 92% in this contractility index. Heart rate increased from 74 _+ 3 beats/min to 102 _+ 10 beats/rain (p < 0.01) (Table III). SVR de- creased from 1483 to 917 dyne • cm -5 • sec (38%), a relatively modest decrease compared with the change in peak power (Table IV).  December 1996 1198 Marmor et al American Heart Journal Table II. Cardiac peak power/end-diast01ic volume (watts per milliliter) during dobutamine infusion Infusion rate FC2 Ttg/kg/min) Healthy FC1 and FC3 FC4 Rest 11.46 _+ 1.4 8.81 ± 1.1 7.98 -+ 0.9 6.56 -+ 1.0' 5 12.28 ± 1.3 9.66 ± 1.1 10.14 -+ 1.7 6.89 _+ 1.8 10 13.97 -+ 1.6 11.44 ± 1.3 10.80 ± 2.0 7.71 ± 1.1 20 17.36 _+ 1.9 12.45 ± 1.3 11.80 ± 1.5t 8.35 -+ 1.2t 30 20.11 ± 2.6 14.73 -+ .2 12.47 ± 1.8t 8.82 -+ 1.2t 40 21.97 ± 5.4 18.11 -+ 1.9 10.56 ± 2.5 9.53 _+ 2.15 ANOVA <0.001 <0.001 <0.001 <0.001 Abbreviations as in Table I. *p < 0.02 for comparison with healthy group. tp < 0.01 for comparison with healthy group. Sp < 0.04 for comparison with healthy group. Table III. Heart rate beats per minute) during dobutamine infusion Infusion rate Itg/kg/min) Healthy FC1 FC2 and FC3 FC4 Rest 74.10 -+ 3.2 79.36 _+ 5.0 81.73 ± 5.2 83.50 -+ 5.1 5 75.70 + 2.9 80.70 -+ 4.6 78.73 -+ 7.1 95.14 -+ 6.6 10 83.20 -+ 4.1 81.40 ± 6.6 91.00 _+ 5.9 88.75 _+ 4.4 20 95.70 -+ 8.0 90.90 -+ 6.3 98.00 -+ 5.3 94.83 -+ 6.3 30 110.25 ± 7.4 104.38 ± 10 97.17 -+ 5.6 110 _+ 5.6 40 102.25 _+ 10.2 95.40 -+ 10.2 116 -+ 24 126 ± 4.2 ANOVA <0.001 <0,001 <0.001 <0.001 Abbreviations in Table I. Table IV. Systemic vascular resistance dynes. centi- meter -5 • second) during dobutamine infusion Infusion rate ~tg/ FC2 kg/min Healthy FC1 and FC3 FC4 Rest 1483 _+ 144 2097 - 202 5 1548 ± 196 1831 ± 174 10 1328 _+ 164 1857 + 223 20 1096 + 147 1768 ± 228 30 877 -+ 120 1465 ± 199" 40 917 -+ 121 1158- 91 ANOVA <0.001 <0.001 1830 -+ 202 2217 -+ 288 1735 -+ 189 1475 +- 177 1418 -+ 177 1867 +- 323 1281 -+ 147 1530 +- 223 1090 +- 153 1112 -+ 136 996+196 1034+-110 <0.001 <0.001 Abbreviations as in Table I. *p < 0.05 for comparison with healthy group. A different pattern was found in patients with moderately reduced cardiac function (functional class 2 and 3). Cardiac output increased substantially, from 4.15 to 8.03 L/min (p < 0.001) at 40 pg dob- utamine (Table I). This increase of more than 93% was achieved by a substantial increase in contractil- ity (peak power/end-diastolic volume increased by 57%, from 7.98 to 12.5 W/ml) and by a substan- tial, 45% decrease in SVR from 1830 to 996 dyne. cm -5- sec (p < 0.001) (Tables II and IV). In the functional class 4 group, cardiac output in- creased by 71%, from 4.27 to 7.31 L/min at 40 llg of dobutamine (Table I). This substantial increase can be explained also by some increase in contractility; peak power increased significantly (by 46%, from 6.56 to 9.53 W/ml at 40 llg) (Table II). However, the increase in cardiac output can be explained mainly by a marked decrease in SVR (Table IV). At the same dose the absolute value of SVR decreased by half, from 2217 +_ 288 to 1034 +_ 110 dyne. cm -5 • sec (p < 0.001) (Table IV). Thus the increases in cardiac output and stroke volume (51 to 58 ml) can be explained by the direct vasodilatory effect of the drug. The cardiac output increase was achieved mainly by the 50% increase in heart rate, from 83.5 to 126 beats/min, rather than the modest increase of 13% in stroke volume and a decrease in SVR. The best discriminator among functional classes was the contractile reserve, as reflected by the increase in cardiac peak power. Contractile reserve also showed excellent correlation with functional status when functional classes were scored from 1  Volume 132, Number 6 American Heart Journal Marmor et al 1199 (healthy) to 3 (functional class 4). A correlation of r = 0.995 and probability ofp < 0.005 was found, in contrast with the relatively low correlation found with cardiac output (r = 0.57; p not significant). DISCUSSION Numerous attempts have been made to assess noninvasively, on line, ventricular performance, s Left ventricular ejection fraction, though a good per- formance index, is affected mainly by afterload 16 and does not reflect adequately the exercise capacity or severity of functional class. 16 Analysis of pressure-volume relations is essential to define the complex determinants of ventricular performance, including preload, afterload, and con- tractile state. 17-22 Until recently, invasive methods were used to measure pressure-volume indexes. Noninvasive methods of estimating end-systolic pres- sure-volume relations by echocardiography or nu- clear medicine techniques have been described. The difficulty in noninvasively measuring pressure-vol- ume indexes resides in the lack of accurate measure- ment of volume and of the central arterial pressure. The method used in the current study accurately es- timates central arterial pressure noninvasively. 11 By multiplying the time-velocity integral obtained by Doppler ultrasonography with the aortic valve area measured by echocardiography, a reasonable esti- mate of stroke volume and aortic flow can be ob- tained. This method was recently extensively vali- dated. 6.s At the beginning of ejection both the cali- brated central aortic pressure and aortic flow curve can be aligned and a power curve can be calculated. The peak value of this curve, peak power, is the in- dex used in the current study to measure contractile reserve. During dobutamine infusion very little change in end-diastolic volume was observed (Table V). Thus, in the same patient changes in peak power are not substantially affected by changes in end-di- astolic volume. Similar results were found by using a ~/ camera during exercise. 23,24 Thus, although great effort was made to measure end-diastolic vol- ume accurately, the accuracy of this measurement was not critical in our opinion for the interpretation of the results. Recently Gorcsan at al. 5, 25 reported assessment of left ventricular performance by on-line analysis of the pressure-area relation through echocardio- graphic automated border detection, but they used the peripheral arterial pressure obtained from a fin- ger cuff photoplethysmograph for their calculation, thus allowing substantial errors in the estimation of pressure-based ventricular performance. As shown in previous studies 11, 26 the contour ofperiphera] ar- Table V. End-diastolic volume (milliliters) during dobuta- mine infusion Infusion rate ~tg/ FC2 kg/min Healthy FC1 and FC3 FC4 Rest 124 -- 8 134 _+ 6 183 _+ 30 217 _+ 27 5 125 -+ 8 136 _+ 7 180 _+ 27 248 _+ 33 10 126 -+ 7 137 -+ 7 185 _+ 31 209 _+ 23 20 128 _+ 6 133 _+ 7 177 +_ 30 206 +_ 22 30 121 _+ 11 132 _+ 11 165 _+ 23 207 _+ 24 40 131 +- 21 121 _+ 15 220 ~- 30 173 '__ 40 ANOVA p = NS p = NS p = NS p = NS NS, Not statistically significant; other abbreviations as in Table I terial pressure is completely different from that of central arterial pressure because of numerous re- flections and summations of peripheral arterial waves. It is therefore erroneous to calculate work or power indexes of the heart from peripheral pressure data. This principle is especially important when dobutamine infusion is used for evaluating contrac- tile reserve. Dobutamine has certain vasodilatory effects that change peripheral vascular resistance and affect the peripheral pulse waveform. However, with pressure-volume area relations and indexes such as stroke work, the error involved in measure- ment is reduced, and serial changes during do- butamine infusion within the same subject may have an important physiologic meaning. As shown in previous studies, 1214 cardiac peak power is a reliable noninvasive afterload-indepen- dent index of left ventricular performance that re- flects changes in contractility. In a previous study, 14 preload-adjusted maximal power was shown to be an afterload-independent index very sensitive to inotro- pic changes. When compared with the end-systolic pressure-volume relation, there was excellent cor- relation, withlinearregressiongivenby%AEes = 0.91 * %APWRmJEDV 2 + 5.8 (r = 0.9, p < 0.001), where Ees is ventricular elastance, P~ is maximal car- diac power, and EDV is end-diastolic volume. Simi- lar correlations were obtained in comparisons of the power index to the slope of stroke work-end-diastol- ic volume relation (r = 0.67; p = 0.002). Dobutamine infusion, in addition to producing the expected in- crease in contractility, substantially reduces periph- eral resistance, thereby improving ventricular-arte- rial coupling and thus the energy transfer from the heart to the periphery. Similar results were obtained by Binldey at a1.,27 who showed a marked reduction in aortic input impedance during dobutamine infu- sion. They also showed that reduction in pulsatile load, especially in patients with heart failure, ira- proves the efficiency of energy transfer, an improve-
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