- Email: [email protected]
Cardiotonic agents in the management of chronic cardiac failure
Volume
103
Number
4, part 2
Ventricular
Dr. J. Mason: I agree. The proper single method, the proper combination of methods, and the proper order of methodsof evaluating patients with VT and VI? have not been determined. However, I don’t seethat this will be determined by any retrospective analysis of data from various laboratories. I do think that a possibleapproach is to randomize patients either to a monitoring technique or
tachycardia
induction
studies
to an invasive technique and compare how well the two techniques protect the patients. I think that that can be done, and I think it can be done in one center. Dr. Temple: The only thing wrong with that is that many physicians are invested in a particular treatment mode and would not be willing to randomize their own patients.
Cardiotonic agents in the management chronic cardiac failure
of
Heart failure is a syndrome with distinct ciinicat signs and symptoms. The severity of cardiac failure and a deterioration in functional capacity can be determined by a progressive exercise test and by the noninvasive determination of maximum oxygen uptake. in patients with severe cardiac failure refractory to medical therapy, particularly those with cardiomyopathy or ischemic heart disease, survival is seriously compromised, resembling the most serious malignancy. Cardiotonic agents may be useful in improving the quality of life, provided that they are effective and are given sufficiently early in the course of the disease. Dobutamine given intravenously augments cardiac perfqrmance and improves renal function in patients with very advanced disease refractory to multiple diuretics; long-term survival, however, remains dismal. Amrinone appears to be a promising agent for the long-term treatment of chronic cardiac failure; the utility of pirbuteroi, an oral catechoiamine analog, remains to be determined. (AM HEART J 103:62g, 1982.)
Karl T. Weber, M.D., Virginia Andrews, R.N., and Joseph S. Janicki, Philadelphia, Pa.
Clinically, heart failure refers to a syndrome consisting of distinctive symptoms and signs that originate in congested circulatory beds and hypoperfused organs because the heart has failed to sustain its pumping function.’ The aim of treatment of chronic cardiac failure is to correct and reverse the pathologic sequence that led to the development of the clinical syndrome, including the augmentation of cardiac output and the reduction of ventricular filling pressure. Cardiotonic agents having positive
From the University
Cardiovascular-Pulmonary of Pennsylvania.
Division,
Department
of Medicine,
Supported in part by Program Project Grant HL-03805 from the National Heart, Lung and Blood Institute, National Institutes of Health (NIH), and by NIH Grant 5 MO1 RRooo40 to the Clinical Research Center of the Hospital of the University of Pennsylvania. Drs. Weber and Janicki supported by Research Career Development Awards HL-00187 and HL00411, respectively, from the National Heart, Lung and Blood Institute. Reprint requests: Karl T. Weber, M.D., Pennsylvania, 3400 Spruce St., Philadelphia,
0002~8703/82/040639
+ 11$01.00/0
Hospital of the PA 19104.
@ 1982
The
University
C. V. Mosby
of
Co.
Ph.D.
inotropic properties are known to promote greater ventricular emptying. To be useful clinically, however, it is not sufficient that these agents be inherently effective and safe; the failing myocardium must be responsive to their inotropic effects. Moreover, their ultimate value in enhancing a patient’s quality of life will depend on their ability to improve cardiac performance not only at rest but also during physical activities. At the turn of the century, there was great enthusiasm for finding effective cardiotonic agents.*s3 Today the search continues. Digitalis is the only cardiotonic agent currently recognized as effective in the long-term management of chronic cardiac failure. Many patients, however, remain symptomatic despite therapeutic levels of digitalis and are, therefore, thought to have nonresponsive myocardia and “refractory” heart failure. Because of its narrow therapeutic-to-toxic ratio, the inotropic stimulus provided by therapeutic levels of digitalis may be 639
April,
640
Weber, Andrews,
and Janicki
Amerlcen
I
0
CLASS
B
A CLASS
C
D CLASS
D
900
700
“E \ c
500
j t
300
N .2
100
Heart
1982
Journal
cation the pumping reserve of the heart can best be assessed during muscular work.g-ll In our experience,” it has not been possible to predict this reserve from the resting cardiac output, left ventricular (LV) filling pressure, radiographic heart size, or historical information. The defect in oxygen delivery that occurs in patients with cardiac disease can be assessed by the noninvasive monitoring of respiratory gas exchange 11-14to determine maximum oxygen uptake (VO, max) and the onset of anaerobic metabolism.“, l5 Accordingly, the severity of cardiac failure is defined by the VO, max (cc/min/kg) achieved during upright treadmill exercise as follows: minimal to no failure, > 20 (class A); mild to moderate
3.0
5.0
7.0
AVO;!
9.0
11.0
Diff.CVols
13.0
15.0
%>
Fig. 1. Response( + SEM) in cardiac index and arterovenousoxygen (AVOJ difference during upright treadmill exercisefor exercise classB, C, and D patients. The work program consistsof 2-minute stagesof progressiveexercise as previously reported. I1 Data were obtained during the last 30 secondsof each stage. VO, = oxygen uptake.
modest. That catecholamines such as dobutamine and dopamine,4* 5 when given intravenously, are able to improve hemodynamic function of the failing heart supports this contention and suggests that equally potent orally active agents are needed. In this connection, the pharmaceutical industry has invested considerable effort in developing such compounds, including the catecholamine-like drugs pirbutero16 and prenalteroP and a noncatecholamine agent amrinone.8 During the past several years, we have been interested in advancing the management of chronic cardiac failure with cardiotonic agents. Our experience with dobutamine, pirbuterol, and amrinone is reviewed here. DEFINWG
SEVERITY
OF CARDIAC
FAILURE
The heart, lungs, and oxygen-carrying capacity of blood constitute the oxygen transport system. Muscular work involves the complex interplay of diverse physiologic mechanisms designed to maintain oxygen delivery at a rate commensurate with the oxygen requirements of the metabolizing tissues. A defect in cardiac pumping function will limit oxygen delivery and, with it, exercise capacity. Physiologically, heart failure is defined as the inability of the heart to maintain oxygen delivery relative to oxygen demand. This defect in delivery often requires the increased demand of exercise to become apparent. Hence the severity of cardiac failure, and by impli-
failure, 15 to 20 (class B); moderate to marked failure, 10 to 15 (class C); and severe failure, < 10 (class D). The syndrome of congestive heart failure exists in all class D patients. It may also exist in the more compromised class C patients having a VO, max between 10 and 12 cc/min/kg, suggesting that the transition from compensated to decompensated failure is identifiable in its earliest stages. The exercise response in cardiac output and arterovenous oxygen difference for class B, C, and D patients has been superimposed on isopleths of oxygen uptake in Fig. 1. Class D patients have virtually no cardiac reserve; the cardiac output response to exercise is essentially nonexistent. Oxygen extraction, on the other hand, progresses to maximal (> 70% ) levels in all three groups, as shown in Fig. 2, A. Hence, by segregating patients according to V02 max, we are primarily identifying the response in exercise cardiac output and thereby the cardiac reserve. Thus VO, max can be used to estimate noninvasively the severity of cardiac failure. LV filling (wedge) pressures, which we have found to be elevated in class C (19 k 2 mm Hg) and class D
(24 -t 2 mm Hg) patients,‘” are normal (8 * 3 mm Hg) in class B patients. Wedge pressure rises during exercise in each group, as indicated in Fig. 2, B. The rate and extent of this elevation, however, is more dramatic in classes C and D, where it quickly exceeds 30 mm Hg within 70% or less of maximum aerobic capacity. From these observations, it appears that maximum cardiac output and, by inference, fatigue are the dominant factors regulating a patient’s tolerance to progressive exercise. During prolonged submaximal work, on the other hand, elevated ventricular filling and pulmonary venous pressures, along with abnormal work of breathing and the sensation of breathlessness, may dominate. Ideally, then, we would expect a cardiotonic agent to provide the same or augmented systemic flow from a
Volume Number
103 4, pert
Cardiotonic
2
therapy
in heart failure
641
nUASS A
D c CLASSB
am
l
R=O.
0A b I
983 I
40
80
% $0.
MAX
20
80
100
0B
O’oioo % HOP
MAX
Fig. 2. Responses( + SEM) in oxygen extraction (A) and wedgepressure(B) are given for eachstageof exercisein exerciseclassB, C, and D patients and expressedasa function of the percent maximum oxygen uptake (% VO, max). See text for details.
OH-CH2 H-C-W
OH
CH3
I
i
N-H
i-H
I
I
ISOPROTERENOL
PIRBUTEROL
DOBUTMINE
N
Fig. 3. Chemical structure of four cardiotonic agents.
lesser filling pressure during progressive exercise and to maintain a reduced filling pressure during submaximal work. If such conditions were realized, we might reasonably expect performance and aerobic capacity to improve. A final determination in the overall efficacy of these agents relates to the clinical condition of the patients and the inherent nature of their cardiac disease. Patients with severe cardiac disease having very advanced secondary pulmonary hypertension
and impaired hepatic and renal function are less apt to improve clinically with a cardiotonic agent, even though LV pump function may be increased. During the past several years, many patients with severe heart failure have been referred to us for these cardiotonic agents. Regrettably, a significant number are no longer alive, having died of advanced disease. Among class D patients, for example, 16 of 23 (70.% 1 with idiopathic cardiomyopathy (mean age 50 + 2 years; range 24 to 66) died within 5 months,
642
Weber, Andrew,
and Janicki
Amerkm
ApriJ, 1982 Heart Journal
Fig. 4. Cachetic-appearingclassD patient (patient 7 in Table I) with ascites,oliguria, and very advanced
severecardiac failure refractory to medical therapy. Dobutamine was given to initiate a diuresis.
and 12 of 19 (63%) with ischemic heart disease (mean age 63 + 2 years; range 48 to 79) died within 3 months. This simple expression of survival is intended to emphasize an important point: aggressive medical therapy must be instituted eariier in the course of cardiac disease if there is to be any hope of controlling this malignant process. CARD~OTONIC AGENTS IN MANAGEMENT CHRONIC CARDIAC FAILURE
OF
Dobutamine. Dobutamine (Eli Lilly) is a new synthetic catecholamine chemically resembling isoproterenol (Fig. 3) and having selective beta-receptor activity.16 In patients with chronic severe heart failure: 5 dobutamine (2.5 to 10 pg/kg/min) has been shown to improve cardiac performance without raising heart rate or blood pressure. We have used dobutamine in selected patients with severe biventricular failure and chronic low cardiac output refractory to medical therapy. These patients typically had congestive cardiomyopathy or long-standing valvular heart disease with peripheral edema and ascites and had become progressively o&uric, azotemic, and cachetic despite chronic digitalis therapy and large doses of a potent loop diuretic, furosemide (Fig. 4 and Table I). Potassium-spming diuretics (e.g., spironolactune and trimatereae), which act on the distal tubule, generally provided only a modest additional diuresis. The intense prox-
imal tubular reabsorption of sodium and water had inhibited the ability of the kidneys to excrete adequate free water; consequently, hyponatremia accompanied the oliguria and anasarca. Met&zone, a diuretic with proximal tubular activity, may induce a greater diuresis under these conditione; more commonly, however, the oliguria persists despite the combination of multiple diuretics. To initiate a diuresis and to restore responsiveness to diuretics, we have found it useful to administer dobutamine intravenously (2.5 to 10 cbg/min/kg dry body weight). Given for 36 to 48 hours, along with careful hemodynamic and ECG monitoring in the intensive care unit, dobutamine produced a significant (> 30% ) increase in cardiac output, accompanied by a vigorous diuresis (Table I). In each case, cardiac output rose significantly, indieating that. the myocardium was not truly refractory but did indeed possess a systolic reserve.17 The hyponatremia improved, and it again became possible to control fluid balance with diuretics. We chose dobutamine over dopamine for this purpose, because on an equimolar basis it has greater inotropic potency and because, unlike dopamine, dobut++ mine is independent of the endogmous -release of norepinephrine for ita inotropic effe&.s. Sbut+&ie therefore promotes a greater rise then dopm%ne in cardiac output, urine output, and urinary sodium concentration18 without an associated elevation in
Volume
103
Number
4, part 2
Table
Cardiotonic
in heart failure
643
I. Responseto 36- to 48-hour dobutamine infusion in patients with severe cardiac failure and oliguria Dobut-
Patient
therapy
Daily medications
Age (yr)
Sex
Cause
37
M
ICM
49
M
ICM
61
57
56
66
57
66 58
M
M
M
F
M
F M
ICM ICM IHD MVR AVR AVR IHD ICM
(mgl24 hrl 0.125 240 150 0.25 160 150 0.25 240 0.25 400 300 0.25 160 100 0.25 260 400 0.125 360 150 0.125 80 0.125 240 300
Digoxin Lasix Aldactone Digoxin Lasix Aldactone Digoxin Lasix Digoxin Lasix Triamterene Digoxin Lasix Aldactone Digoxin Lasix Aldactone Digoxin Lasix Aldactone Digoxin Lasix Digoxin Lasix Triamterene
amine (t.glkgl min)
Mean Heart
Cardiac
output
L VFP
(Llmin)
(mm
Hg)
rate (bpm)
arterial pressure (mm
Hg)
Serum
Urine BUN
sodium (mEqlL)
(mgldl)
output (L/24
5
2.83 3.80
38 28
122 114
71 68
119 122
110 85
0.4 1.9
-
1.83 2.74
25 19
93 89
62 64
121 131
104 59
0.5 3.7
5
2.61 3.55 2.52 3.81
38 26 35 24
106 94 110 95
82 81 72 80
123 127 124 138
54 32 61 55
0.3 2.3 0.3 2.6
5
2.29 4.69
45 30
116 106
70 72
133 136
25 23
0.3 2.4
2.5
3.46 4.67
30 25
83 80
86 86
121 129
142 110
1.1 2.2
3.30 5.27
30 22
100 89
74 79
117 126
132 115
0.4 2.5
1.62 3.60 4.08 8.37
28 15 35 -
120 91 107 118
67 75 92 92
130 134 134 140
27 15 102 95
0.9 1.5
6 6 -
-
-
10 8 10
AVR, Aortic valve replacement; ICM, idiopathic cardiomyopathy; IHD, pulmonary artery disatolic pressure; MVR, mitral valve replacement.
arterial pressure or heart rate. Despite these shortterm gains, however, the majority of the patients were dead within 6 months, underscoring the need for earlier, more aggressive management. Pirbuterol. The acute hemodynamic improvement noted with dobutamine in patients with chronic cardiac failure has quite naturally prompted the suggestion that similar compounds would be highly desirable in long-term management.‘g Heretofore, an orally active catecholamine-like compound has not been available. Pirbuterol (Pfizer), whose chemical structure is analogous to isoproterenol (Fig. 3), represents a significant advancement in this direction. It has been ‘shown to have both positive inotropic (beta,) and vasodilator (be@) properties.6 The beneficial acute hemodynamic effects of pirbuterol (0.4 mg/kg) have recently been demonstrated in patients with chronic cardiac failure.ls Of note is that the increment in cardiac output and the reduction in filling pressure observed with pirbuterol compare favorably with that obtained with dobutamine.20 To determine whether pirbuterol is effective as a cardiotonic agent in the long-term treatment of chronic cardiac failure, and specifically to examine
hr)
ischemic
heart disease; LVFP,
left ventricular
filling
pressure
from wedge or
its effect on exercise tolerance, we undertook a 7-week controlled clinical trial in 15 patients (seven men, eight women; mean age 58 years, range 36 to 78).21 The study was approved by our institutional review board for human studies; each patient gave written consent to participate. All patients had stable, chronic (> 6 months) New York Heart Association (NYHA) class III or IV heart failure as evidenced by a reproducible aerobic exercise capacity documented before enrollment, and all were taking digitalis and diuretics. All patients received a single-blind placebo for 1 week, after which their exercise tolerance was reassessed. Thereafter, double-blind randomization (pirbuterol versus placebo) was begun, with 30 mg pirbuterol given daily for 2 weeks and then increased to 60 mg daily, if tolerated, for the remaining 4 weeks. One patient receiving the placebo died suddenly 4 weeks into the program; two patients receiving pirbuterol had to discontinue the study because of intercurrent illness. Twelve patients (six in each group) completed the study. Their clinical status was monitored weekly, and exercise performance was reassessed at 4 and 7 weeks. The baseline exercise tolerance and VO, max in
April,
644
Weber, Andrews,
and Janicki
American
WLSLE
TIME
Heart
1982
Journal
BLIND
m
PIRBUTEROL
0
PLACEBO
(WEEKS)
Fig. 5. Response in maximum oxygen uptake (VO, max) is shown for patients participating co&rolled clinical trial of pirbuterdlr
the groups given pirbuterol and placebo (+ SD) were 571 + 172 versus 544 f 204 seconds and 11.8 2 1.9 versus 11.3 + 1.7 cc/min/kg, respectively, consistent with functional class C and D cardiac failure. Neither group showed a statistically significant improvement in clinical status or exercise performance after 1 week of placebo or 4 and 7 weeks of double-blind therapy (Fig. 5). Four patients received 60 mg pirbuterol; one of them experienced nervousness, tremulousness, and diaphoresis, which he did not, however, find intolerable. These same symptoms were sufficiently troublesome in two other patients to require a reduction in daily dose to 45 mg. We have continued this study, crossing the patients on placebo over to open pirbuterol therapy while maintaining pirbuterol therapy beyond 7 weeks in the rest. Our results are quite preliminary at present, and although conclusions cannot be drawn regarding the relative merits of this agent in the long-term treatment of chronic cardiac failure, our early experience has not been encouraging. Amrinone. Amrinone (Sterling-Winthrop) is a bipyridine derivative whose chemical structure and mechanism of action are quite different from those of the catechoIamines or digit&s (Fig. 3).* Amrinone has been shown to increase cardiac output and reduce LV filling pressure when given intravenous1y22-24or orally25 to patients with severe cardiac failure. We have treated a large number of patients with chronic cardiac failure with amrinone; these patients’ symptoms were poorly controhed with digitalis, multiple diuretics, and a variety of vasodilators including hydralazine, nitrates, praxosin, and trimazosin. All patients gave written consent to
in the
participate; each study was approved by our institutional review board. We began evaluating this cardiotonic agent by administering amrinone intravenously to establish an optimal infusion rate and dose tog&her with minimal side effects.25 We enrolled 15 patients (10 men, five femalea; mean age 54 years, range 34 to 75) with severe cardiac faihtre (seven with NYHA class IV, eight with class III) of varying cause (six with idiopathic cardiomyopathy, three with valvular heart disease, and six with ischemic hea& d’rscaae). We found that a rapid infusion of 1.9 + 0.1 m&g (0.2 mg/min) would significantly 0, < 0.01) raise the cardiac index 47% (from 1.9 t- 0.1 to 2.8 + 0.1 L/min/m2) and the stroke volume index 51% #urn 22 + 1 to 33 + 1 cc/m2) while reducing wed@ pressure 38% (from 24 + 2 to 15 f 2 mm I&I). &art rate and mean systemic and pulmonary arterial pressures were unchanged from control. Seven patients receiving a&none therapy orally (1.94 k 3 m&g given every 8 hours) who were able to undergo a treadmill exercise test before amrinone were exercise tested again within 24 hours of receiving the drug. Their standing baseline cardiac index before a&none therapy was 1.36 + 0.1. L/min/m2, andthemeanLVMngpresaurewas28+2mm Hg. After am&one, the mean cardiac in&x and the mean filling pressure in the upright no&ion were 1.95 + 0.1 L/min/m2 and 14 + 2 mm Hg, respectively. Following amrinone, it was possible to generate the same cardiac output response dur% &r&se, but from a Ie+er SIling .-pressure. Wedge pressure was < 25 mm lag t&irou out exercise in two patients and < 25 mm Hg during submaximal levels of exercise in the rest. For the group, wedge pressure
Volume
103
Number
4, part 2
lo 1
Cardiotonic
CLASS
therapy
in heart failure
645
C
A
n
BASELINE
A
0
AMRINONE
9 H P-
,BASE
32
TIME 1 5
I
10
LV
I
15
FILLING
I
20
1
25
PRESSURE
30
r
1
35
0
40
CMM HG>
Fig. 6. Averaged hemodynamic responseto exercise in classC and D patients before and after administration of amrinone for 32 hours. LV filling pressurederived from wedge or pulmonary artery diastolic pressure for each stage of treadmill exercise. was significantly 0, < 0.01) less at rest and during each stage of exercise. Within 24 hours of amrinone therapy, only one patient achieved a peak cardiac
index (4.05 L/min/m2) during exercise that was significantly greater than during the control state. Hence the acute administration of amrinone improved the function of the failing heart at rest and during exercise; 00, max, however, remained unchanged, which is consistent with the observation that maximum cardiac output was unchanged. We would not, however, expect steady-state blood levels of amrinone within this short period. Of note is the fact that at 4 weeks 00, max had improved significantly in these patients.25 More recently, we have reexamined the response in exercise performance to amrinone in 14 patients (nine males, five females; mean age 56 years, range 45 to 67) with chronic cardiac failure (nine with NYHA class III, five with class II; or seven each in exercise classes C and D). The causes of cardiac disease included idiopathic cardiomyopthy in six patients, ischemic heart disease in four, and chronic mitral or aortic valvular incompetence, or both, in four. We found the optimal unit dose of amrinone orally to be 1.6 & 0.05 mg/kg given every 8 hours, based on a documented increase in cardiac index of 53 + 5 % . Amrinone therapy was maintained for 32
HRS
2 UKS
DURING
4 YKS
12 IJKS
THERAPY
7. Responsein maximum oxygen uptake ($‘O, max) before therapy and after 32hours and 2,4, and 12weeksof amrinone therapy. See text for details.
Fig.
hours, representing four half-lives, when steadystage blood levels are more likely to be reached, before exercise was repeated. The baseline hemodynamic response to exercise is shown in Fig. 6. Following amrinone, wedge pressure was reduced (p < 0.05) at standing rest and for each stage of exercise, and cardiac output was increased (p < 0.05) throughout exercise. Correspondingly, 00, max was also increased (Fig. 7). Hence, with steady-state levels of amrinone, the responses in both cardiac index and filling pressure during exercise were improved. The long-term response to exercise has been followed in these same patients, treated with 1.6 mg/kg amrinone orally every 8 hours. The marked (p < 0.01) improvement in ir0, max apparent at 32 hours was also seen at 1 and 4 weeks and was sustained to 12 weeks (Fig. 7). This augmented exercise tolerance has been translated into an obvious improvement in the quality of life. Patients became progressively less symptomatic, and many began to engage in physical activities that previously were limited by fatigue or breathlessness. They no longer experienced orthopnea or paroxysmal nocturnal dyspnea, and with the improvement in effort tolerance, they were able to return to a gainful existence. With amrinone therapy, we were also able to reduce the daily diuretic requirement of six patients. Throughout the outpatient follow-up period, body weight was stable, and
no evidence of peripheral edema was seen. In several patients, radiographic heart size was significantly reduced within 12 weeks of therapy (Fig. 8).
646
April.
Weber, Andrews, and Janicki
American
1992
Heart Journal
Fig. 6. Reduction in radiographic heart sizeand cardiothoracic ratio after 12 weeksof amrinone therapy is apparent in a classD patient. Tabte
It. Platelet counts during long-term amrinone therapy
Patient
Baseline
Day
2
Day
7
Week
1 2 3 4 5 6 7 8 9 10 11 12
256 175 223 193 250 200 179 295 257 221 214 290
184 143 166 165 188 156 198 258 241 208 197 155
321 207 267 172 245 188 229
13 14 15 16
257 275 316 281
246 211 296 295
194 250 322 275
163
Mean
231 10
202 11
233 14
226 21
k SEM Platelet
counts (XlOl mm’) are current
as of the writing
218 290 160 155
340 292 267 270 250 135 135 303 238 184 136
4
Week
6
Week
356 431 272 231 348 107 158 318 173 268 183 124
241 265 156 155 285 143 210 289 -
-
-
247 29
218 21
12
of this report.
A number of adverse effects were noted with amrinone. Two patients developed nausea following the bolus infusion of amrinone, although the nausea resolved within several hours. In two others, ventricular arrhythmias (isolated premature contractions, couplets, and three- to five-beat ventricular tachycardia) appeared in our early experience when the first few patients were given amrinone too rapidly (1 mg/min). This problem was subsequently eliminated by administering the drug more slowly (0.2 mg/min). The increased frequency of ventricular arrhythmias was therefore primarily confined to the 24-hour period following the very rapid infusion of amrinone. After 2 and 4 weeks of amrinone given orally, there was no evidence, as judged by serial Holter monitoring, of increased rhythm dtiurbance. Two patients developed abnormal liver function studies during maintenance therapy, which resolved
after discontinuing amrinone. On recha&mge, only one had a recurrence prohibiting continued therapy. Thrombocytopenia (< 150,ooO mm3) has been reported with amrinone tharapy.26 In our experience, this has been a problem only in hospital&& patients with severe heart failure who are oliguric and who, in all likelihood, have elevated plasma leveIs of the drug. In outpatients with less severe failure receiving smaller doses (5 2 mg/kg), we have not found thrombocytopenia to be a major problem.25 Our current experience in 16 additional patients (Table II) is consistent with these earlier findings. We wish to acknowledge the dedicated technical assistance of T. Nusbickel, D. Ward, and J. Daweil during the conduct of these studies. The secretarial asaiatance of S. Wahl andJ. Stofmanin preparing the manuscript is appreciated. We also wish to tliank Eli Lilly, Pfizer Laboratories, and Sterling-Winthrop for their support and encouragement during the studies.
Volume
103
Number
4, part 2
REFERENCES
1. Fishman AP: Heart failure. In Beeson PB, McDermott W, editors: Cecil textbook of medicine, ed 15. Philadelphia, 1979, WB Saunders, p 1080. 2. Coupland S: The year-book of treatment for 1897. Philadelphia, 1897, Lea Brothers and Co, p 4. 3. Yeo IB: A manual of medical treatment of clinical therapeutics, vol. I. Chicago, 1906, W T Keener and Co, p 325. 4. Leier CV. Webel J. Bush CA: The cardiovascular effects of the continuous infusion of dobutamine in patients with severe heart failure. Circulation 56:468, 1977. 5. Stoner JD, Bolen JL, Harrison DC: Comparison of dobutamine and dopamine in treatment of severe heart failure. Br Heart J 23:536, 1977. 6. Moore PF, Constantine JW, Barth WE: Pirbuterol, a selective beta 2 adrenergic bronchodilator. J Pharmacol Exp Ther 207:410, 1978. 7. Carlsson E, Dahlof C-G, Hedberg A, Persson H, Tangstrand B: Differentiation of cardiac chronotronic and inotronic effects of B-adrenoceptor agonists. Naunyn Schmiedebergs Arch Pharmaco1300:101, 1977. 8. Alousi AA, Farah AE, Lesher GY, Opalka CJ Jr: Cardiotonic activity of amrinone: Win 40680 (5amino-3, 4’-bipyridinG(IH)-one). Circ Res 45:666, 1979. 9. Donald KW, Bishop JM, Wade OL: A study of minute to minute changes of arteriovenous oxygen content differences, oxygen uptake and cardiac output and rate of achievement of a steady state during exercise in rheumatic heart disease. J Clin Invest 33:1146, 1954. 10. Ross J Jr, Gault JH, Mason DT, Linhart JW, Braunwald E: Left ventricular performance during muscular exercise in patients with and without cardiac dysfunction. Circulation 34:597, 1966. 11. Weber KT, Kinasewitz GT, Janicki JS, Fishman AP: 0, utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation. (In press.) 12. Weber KT, Janicki JS, Fishman AP: Respiratory gas exchange during exercise to evaluate noninvasively the severity of chronic cardiac failure. In Braunwald E, Mock M, Watson J, editors: Symposium on advanced cardiac failure. Prog Cardiovasc Dis. (In press.) 13. Donald KW: Exercise and heart disease: A studv in regional circulation. The Bradshaw Lecture. Br Med J 1:985, 1959. 14. Wasserman K, Whipp BJ: Exercise physiology in health and disease. Am Rev Respjr Dis 112:219, 1975. 15. Wasserman K, McIlroy MB: Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 14:844, 1964. 16. Tuttle RR, Mills J: Dobutamine: Development of a new catecholamine to selectively increase cardiac contractility. Circulation 36:185, 1975. 17. Weber KT, Janicki JS: The heart as a muscle-pump system and the concept of heart failure. AM HEART J 90~371, 1979. 18. Leier CV, Hebans PT, Huss P, Bush CA, Lewis RP: Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Circulation 58:466, 1978, 19. Awan NA, Evenson MK, Needham KE, Evans TO, Hermanovich J, Taylor CR, Amsterdam E, Mason DT: Hemodynamic effects of oral pirbuterol in chronic severe congestive heart failure. Circulation 63:196, 1981. 20. Awan NA, Needham K, Evenson MK, Mason DT: Comparison of hemodynamic actions of pirbuterol and dobutamine on cardiac function in severe congestive heart failure. Am J Cardiol 47:665, 1981. 21. Weber KT, Andrews V, Janicki JS, Reichek N: Pirbuterol in the long term treatment of chronic cardiac failure Circulation 64(suppl IV):307, 1981. (Abst.) 22. Benotti JR, Grossman W, Braunwald E, Davalos DD, Alousi AA: Hemodynamic assessment of amrinone. N Engl J Med 299:1373, 1978. 23. LeJemtel TH, Keung E, Sonnenblick EH, Ribner HS, Matsumoto M, Davis R, Schwartz W, Alousi AA, Davolos D:
Cardiotonic
therapy in heart failure
647
Amrinone: A new nonglycosidic, nonadrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man. Circulation 59:1098, 1979. 24. LeJemtel TH, Keung E, Ribner HS, Davis R, Wexler J, Blaufox MD, Sonnenblick EH: Sustained benefical effects of oral amrinone on cardiac and renal function in patients with severe connestive heart failure. Am J Cardiol 45:123, 1980. 25. Weber KTY Andrews V, Janicki JS, Wilson JR, Fishman AP: Amrinone and exercise performance in patients with chronic heart failure. Am J Cardiol48:164, 1981. 26. Wynn J, Malacoff RF, Benotti JR, Curfman GD, Grossman W, Holman BL, Smith TW, Braunwald E: Oral amrinonein refractory congestive heart failure. Am J Cardiol 45:1245, 1980. DISCUSSION Dr. Cohn:
Concerning your observations on oxygen consumption and the dependenceon cardiac output for limited exercise tolerance, I think you are familiar with someof the data that we have collected in exercisetesting of patients
during
both acute and chronic
administration
of vasodilator drugs. As exercisetolerance improves with time, the increasein oxygen consumption seensto be out of proportion to the rise of cardiac output, so that we actually seewhat appearsto be improved oxygen extraction. Yet you have suggested
that there
is nothing
the
matter with extraction in heart failure. How do you put those two observationstogether? Dr. Weber: You have raised a very important point, which I believe relates to the effects of training. The data that I presented indicate that oxygen extraction, measured from arterial and mixed-venous oxygen content, is not impaired and that maximum levels of oxygen extrac-
tion can be achieved during exercise.We are not, however, describing
the distribution
of flow
or regional
oxygen
extraction within skeletal muscle. For example, it is my impression that when we provide the proper pharmacologic control of symptom-limited exercise, these patients
can, in fact, train themselvesand improve their oxygen uptake.
In my opinion,
heart failure
is a deconditioning
process related to the physical rest prescribed by the physician and to the fact that the patient is often hospitalized or. bedridden. Consequently, there are changesin the peripheral circulation and skeletal muscle that will alter the patient’s ability to engage in work. These changes do not indicate a change in cardiac pump function, but
reflect differences within skeletal muscle blood flow and metabolism.As another example, I would expect that with training
there
would
be a delay
in the appearance
of
lactate during exercisewithout a changein cardiac output. We are currently investigating the role of training in patients with chronic cardiac failure. Dr. Cohn: Would you suggest,from your preliminary
observations, that pirbuterol doesnot affect the training response? Dr. Weber: That is correct, inasmuchassymptomatically the patients were not improved. They were not able to engagein more activity. On the other hand, with the alpha blocker trimazosin (Weber et al: N Engl J Med 303~242, 1980), we saw a very clear improvement in exercise performance in the great majority of patients. I do not know if this occurred because there was an alpha-blockade
646
Weber, Andrews,
and Janicki
effect on the skeletal musclecirculation during exerciseor whether other factors were operative, but certainly the patients were able, in a nonsupervisedfashion at least, to train themselvesand to improve their exercise capacity. Dr. Goldberg: Did pirbuterol increasethe heart rate? Dr. Weber: On average,the heart rate wasnot increased in any consistent manner with unit dosesof 10, 15, 20, or 30 mg pirbuterol. A mild chronotropic responsewasnoted in a few patients, but this was not more than a 15 bpm increaseabove baseline. Dr. Goldberg: Did the patients continue to receive digitalis? Dr. Weber: Yes, we maintained whatever doseof digitalis and diuretics the patient wasreceiving on entry into the study. Dr. Goldberg: The more I think about these cardiotonic drugs, the more I realize that we will probably have to use them in combination with’ an alpha-adrenergic blocking agent or vasodilator. Somesort of vasodilation is required, because, as Dr. Swan has noted, these patients have intense vasoconstriction. Combination therapy, with prazosin, for example, may be useful. Dr. Weber: Earlier in the conference,I askedyou where you would like to direct the augmented systemic flow. I, too, agree with Dr. Swan. However, the autoregulatory behavior of any given regional circulation will depend on the metabolic requirements of its end organ. During exercise, for example, flow should be increasedprimarily to skeletal muscle. This is less true at rest. As you well know, if we can effectively improve the systemic blood flow, secondary to increasedmyocardial contractility and not by nonspecific pharmacologic vasodilation, we may potentially invoke a reflex withdrawal of the adrenergic nervous system and of the renin-angiotensin system. If systemic flow were improved adequately, and it is my impressionthat this occurs with amrinone, we certainly would see an appropriate reapportionment of flow to skeletal muscle and the kidney, and there would be no need to manipulate the peripheral circulation pharmacologically. Dr. Goldberg: I am not sure that I understand the hemodynamicsof amrinone, but it seemsto have some vasodilating activity of its own. Certainly systemic vascular resistancedecreasesmarkedly, although I do not know that it happens in normal subjects or whether it is seen only in patients with heart failure where excessivesympathetic tone already exists. I wonder if anybody knows that. Dr. Weber: We have studied amrinone in the experimental laboratory and in human subjects. In our experimental preparation, we can either administer the drug as an intracoronary infusion or give it intravenously to a dog that is maintaining an isolated heart in crosscirculation. Thus, in our experimental model, we can assess either the direct myocardial effects or both the systemic and myocardial effects. In normal dogs, we do find some mild vasodilation at large doses.In the main, the major effect of amrinone is inotropic. In patients with heart failure who are given amrinone, we may also have a reflex withdrawal
American
April, 1982 Heart Journal
of vasoconstriction with increased systemic flow. It is difficult to separate these issuesin human subjects. Let me put it this way: When we improve cardiac performance clinically by raising output and lowering wedgepressure, it is difficult to say that this central hemodynamicresult is due entirely to an inotropic effect or alsoto someadditional vasodilation. Dr. William Grossmanand his co-workers at the Peter Bent Hospital in Boston have previously emphasizedthe difficulty in separating these issues.My own bias is that we must resort to the experimental laboratory to sort them out. Dr. Mason: In the study with pirbuterol, was a control measurementdone after the drug was withdrawn to be sure that the patients had not deteriorated? In other words, after withdrawing the drug, did you repeat the exercisetest? Dr. Weber: Yes, we did that in a number of patients, becausethey simply did not improve. Some had adverse reactions, which prompted our discontinuing the drug; they were then exercisetested again. Among the patients we have studied to date, exercise performance has not declined and doesnot differ from baselineresponse.With trimazosin, on the other hand, we studied 27 patients for 52 weeks and then discontinued the drug; they were exercisetested again within 2 to 6 weeks(Weber et al: AM HEART J 102:569, 1981). In class D, or the severely compromisedpatients, exercise performance declined to baseline,often within 2 weeksafter stopping the drug. In classC and classB patients, the lessseverelycompromised groups, there was less of a change in exercise when we discontinued the drug. Frequently, their improved exercise performance was sustained. My interpretation of thesefindings is that clinically apparent heart failure does not necessarilyhave to recur within 24or 48 hours, or even 2 to 6 weeks.The reappearanceof symptoms will depend on the underlying severity of cardiac failure. Dr. Temple: You did seedeterioration when trimazosin was discontinued? Dr. Weber: Yes, there was a decline in augmented exercisetolerance when trimazosin wasdiscontinued. This occurred primarily in class D patients. It was more variable in the class C and B groups. The decline in exercise performance, however, was not below baseline levels. SomeclassC patients had an early (weeks)decline in exercise performance, but in most, improvement was maintained for up to 6 weeks. We have not, however, systematically gone back to retreat these patients with trimazosin. Dr. Temple: The real question, of course, is whether people improve simply by being in a study and receiving more overall attention. We have beenasking investigators to do randomized withdrawal studies; that is, after 52 weeks, continue to give some subjects the drug and discontinue it in others to seewhat happens.I don’t know the outcome of that yet. Not too many people have done it. Dr. Weber: Those are very difficult studies to conduct, but certainly worth doing. Dr. Gorlin: Something occurred to me about anaerobic
Volume Number
103 4, part 2
Cardiotonic
threshold and lactic acid concentrations. As we begin using drugs that alter the distribution of cardiac output, do you think we will get different responses,depending on whether, for example, muscleflow is altered with an alpha blocker, so that there is better perfusion and perhaps better washout of lactate in sometissues,or whether the splanchnic circulation is altered, thus changing uptake and reconversion?Do you think we will be able to predict distribution responses,depending on whether the anaerobic threshold is affected between these two, lactate production and glycogen resynthesis? Dr. Weber: I think that is a terribly important question, but one for which I do not have a definite answer. Certainly, aswe reported (Weber KT et al: N Engl J Med
therapy
in heart failure
303:242, 1980) with the alpha blocker trimazosin, the onset of the anaerobic threshold was delayed in most patients. I would agreethat if flow to skeletal muscle, for example, could be reapportioned in a more efficient manner, the appearanceof lactate may be delayed. The liver and its role in metabolizing lactate may also be important. I would like to think that in the future we will be able to profile our patients with heart failure with respect to the renin-angiotensin system, adrenergic nervous system, and heart, lung, liver, and kidney function. Based on this profile, we could utilize a seriesof drugs, whether from existing or from new compounds,to manipulate and correct that profile in the most efficient manner.
High temporal resolution synchronous volumetric scanning tomography: Potential roles in clinical evaluation of ischemic heart disease A new quantitative imaging device, the Dynamic Spatial Reconstructor (DSR), is described. Because, unlike commercially avallable computed tomography scanners, It obtains stop-action (0.01 second) images of a volume rather than a slice at a repetition rate of 60 volumetric scans per second, the DSR is particularly well suited for the study of ischemic heart disease. Its capabilities for recording the transit and dilution of contrast media within the coronary vasculature and all regions of the myocardium simultaneously with regional and global myocardial mechanics are being evaluated as a research tool for physiologic and ultimately clinical investigations. (AM HEART J 103:649, 1982.)
Earl H. Wood, M.D., Ph.D., Barry K. Gilbert, Ph.D., Lowell D. Harris, Ph.D., James H. Kinsey, Ph.D., Erik L. Ritman, M.D., Ph.D., and Richard A. Robb, Ph.D. Rochester, Minn.
Since 1961, when the Mayo Clinic diagnostic Cardiac Catheterization Laboratory was transferred from the Department of Physiology to St. Mary’s Hospital,l our cardiovascular physiology group has become increasingly involved in the development and application of quantitative computer-based x-ray imaging techniques using high temporal resolution for studies of cardiac, circulatory, and pulmo-
From the Biodynamics Research Unit, Mayo Clinic. Research supported in part by research grants HL-04664 the National Institutes of Health. Reprint requests: Earl H. Wood, M.D., Ph.D., Biodynamics Mayo Clinic, Rochester, MN 55905. OOOZ-8703/82/040649
+ 11$01.10/O
@ 1982 The
and RR-7 from
C. V.
Research Unit,
MO&y
Co.
nary dynamics2-” Fig. 1 shows the current stage of this evolution’: the Dynamic Spatial Reconstructor, commonly called the DSR. Figs. 2 and 3 provide additional visual impressions of the system, whose modes of operation have been described elsewhere . ‘-12 DYNAMIC
SPATIAL
RECONSTRUCTIDN
SYSTEM
This new type of computed axial tomography (CAT) scanner can capture 120 synchronous crosssectional scans of, for example, the thorax in one hundredth of a second, in contrast to all current CAT scanners, which provide a single cross section and require a time scan of one to several seconds.13 By means of a computer-based display assembly, the 649
103
Number
4, part 2
Ventricular
Dr. J. Mason: I agree. The proper single method, the proper combination of methods, and the proper order of methodsof evaluating patients with VT and VI? have not been determined. However, I don’t seethat this will be determined by any retrospective analysis of data from various laboratories. I do think that a possibleapproach is to randomize patients either to a monitoring technique or
tachycardia
induction
studies
to an invasive technique and compare how well the two techniques protect the patients. I think that that can be done, and I think it can be done in one center. Dr. Temple: The only thing wrong with that is that many physicians are invested in a particular treatment mode and would not be willing to randomize their own patients.
Cardiotonic agents in the management chronic cardiac failure
of
Heart failure is a syndrome with distinct ciinicat signs and symptoms. The severity of cardiac failure and a deterioration in functional capacity can be determined by a progressive exercise test and by the noninvasive determination of maximum oxygen uptake. in patients with severe cardiac failure refractory to medical therapy, particularly those with cardiomyopathy or ischemic heart disease, survival is seriously compromised, resembling the most serious malignancy. Cardiotonic agents may be useful in improving the quality of life, provided that they are effective and are given sufficiently early in the course of the disease. Dobutamine given intravenously augments cardiac perfqrmance and improves renal function in patients with very advanced disease refractory to multiple diuretics; long-term survival, however, remains dismal. Amrinone appears to be a promising agent for the long-term treatment of chronic cardiac failure; the utility of pirbuteroi, an oral catechoiamine analog, remains to be determined. (AM HEART J 103:62g, 1982.)
Karl T. Weber, M.D., Virginia Andrews, R.N., and Joseph S. Janicki, Philadelphia, Pa.
Clinically, heart failure refers to a syndrome consisting of distinctive symptoms and signs that originate in congested circulatory beds and hypoperfused organs because the heart has failed to sustain its pumping function.’ The aim of treatment of chronic cardiac failure is to correct and reverse the pathologic sequence that led to the development of the clinical syndrome, including the augmentation of cardiac output and the reduction of ventricular filling pressure. Cardiotonic agents having positive
From the University
Cardiovascular-Pulmonary of Pennsylvania.
Division,
Department
of Medicine,
Supported in part by Program Project Grant HL-03805 from the National Heart, Lung and Blood Institute, National Institutes of Health (NIH), and by NIH Grant 5 MO1 RRooo40 to the Clinical Research Center of the Hospital of the University of Pennsylvania. Drs. Weber and Janicki supported by Research Career Development Awards HL-00187 and HL00411, respectively, from the National Heart, Lung and Blood Institute. Reprint requests: Karl T. Weber, M.D., Pennsylvania, 3400 Spruce St., Philadelphia,
0002~8703/82/040639
+ 11$01.00/0
Hospital of the PA 19104.
@ 1982
The
University
C. V. Mosby
of
Co.
Ph.D.
inotropic properties are known to promote greater ventricular emptying. To be useful clinically, however, it is not sufficient that these agents be inherently effective and safe; the failing myocardium must be responsive to their inotropic effects. Moreover, their ultimate value in enhancing a patient’s quality of life will depend on their ability to improve cardiac performance not only at rest but also during physical activities. At the turn of the century, there was great enthusiasm for finding effective cardiotonic agents.*s3 Today the search continues. Digitalis is the only cardiotonic agent currently recognized as effective in the long-term management of chronic cardiac failure. Many patients, however, remain symptomatic despite therapeutic levels of digitalis and are, therefore, thought to have nonresponsive myocardia and “refractory” heart failure. Because of its narrow therapeutic-to-toxic ratio, the inotropic stimulus provided by therapeutic levels of digitalis may be 639
April,
640
Weber, Andrews,
and Janicki
Amerlcen
I
0
CLASS
B
A CLASS
C
D CLASS
D
900
700
“E \ c
500
j t
300
N .2
100
Heart
1982
Journal
cation the pumping reserve of the heart can best be assessed during muscular work.g-ll In our experience,” it has not been possible to predict this reserve from the resting cardiac output, left ventricular (LV) filling pressure, radiographic heart size, or historical information. The defect in oxygen delivery that occurs in patients with cardiac disease can be assessed by the noninvasive monitoring of respiratory gas exchange 11-14to determine maximum oxygen uptake (VO, max) and the onset of anaerobic metabolism.“, l5 Accordingly, the severity of cardiac failure is defined by the VO, max (cc/min/kg) achieved during upright treadmill exercise as follows: minimal to no failure, > 20 (class A); mild to moderate
3.0
5.0
7.0
AVO;!
9.0
11.0
Diff.CVols
13.0
15.0
%>
Fig. 1. Response( + SEM) in cardiac index and arterovenousoxygen (AVOJ difference during upright treadmill exercisefor exercise classB, C, and D patients. The work program consistsof 2-minute stagesof progressiveexercise as previously reported. I1 Data were obtained during the last 30 secondsof each stage. VO, = oxygen uptake.
modest. That catecholamines such as dobutamine and dopamine,4* 5 when given intravenously, are able to improve hemodynamic function of the failing heart supports this contention and suggests that equally potent orally active agents are needed. In this connection, the pharmaceutical industry has invested considerable effort in developing such compounds, including the catecholamine-like drugs pirbutero16 and prenalteroP and a noncatecholamine agent amrinone.8 During the past several years, we have been interested in advancing the management of chronic cardiac failure with cardiotonic agents. Our experience with dobutamine, pirbuterol, and amrinone is reviewed here. DEFINWG
SEVERITY
OF CARDIAC
FAILURE
The heart, lungs, and oxygen-carrying capacity of blood constitute the oxygen transport system. Muscular work involves the complex interplay of diverse physiologic mechanisms designed to maintain oxygen delivery at a rate commensurate with the oxygen requirements of the metabolizing tissues. A defect in cardiac pumping function will limit oxygen delivery and, with it, exercise capacity. Physiologically, heart failure is defined as the inability of the heart to maintain oxygen delivery relative to oxygen demand. This defect in delivery often requires the increased demand of exercise to become apparent. Hence the severity of cardiac failure, and by impli-
failure, 15 to 20 (class B); moderate to marked failure, 10 to 15 (class C); and severe failure, < 10 (class D). The syndrome of congestive heart failure exists in all class D patients. It may also exist in the more compromised class C patients having a VO, max between 10 and 12 cc/min/kg, suggesting that the transition from compensated to decompensated failure is identifiable in its earliest stages. The exercise response in cardiac output and arterovenous oxygen difference for class B, C, and D patients has been superimposed on isopleths of oxygen uptake in Fig. 1. Class D patients have virtually no cardiac reserve; the cardiac output response to exercise is essentially nonexistent. Oxygen extraction, on the other hand, progresses to maximal (> 70% ) levels in all three groups, as shown in Fig. 2, A. Hence, by segregating patients according to V02 max, we are primarily identifying the response in exercise cardiac output and thereby the cardiac reserve. Thus VO, max can be used to estimate noninvasively the severity of cardiac failure. LV filling (wedge) pressures, which we have found to be elevated in class C (19 k 2 mm Hg) and class D
(24 -t 2 mm Hg) patients,‘” are normal (8 * 3 mm Hg) in class B patients. Wedge pressure rises during exercise in each group, as indicated in Fig. 2, B. The rate and extent of this elevation, however, is more dramatic in classes C and D, where it quickly exceeds 30 mm Hg within 70% or less of maximum aerobic capacity. From these observations, it appears that maximum cardiac output and, by inference, fatigue are the dominant factors regulating a patient’s tolerance to progressive exercise. During prolonged submaximal work, on the other hand, elevated ventricular filling and pulmonary venous pressures, along with abnormal work of breathing and the sensation of breathlessness, may dominate. Ideally, then, we would expect a cardiotonic agent to provide the same or augmented systemic flow from a
Volume Number
103 4, pert
Cardiotonic
2
therapy
in heart failure
641
nUASS A
D c CLASSB
am
l
R=O.
0A b I
983 I
40
80
% $0.
MAX
20
80
100
0B
O’oioo % HOP
MAX
Fig. 2. Responses( + SEM) in oxygen extraction (A) and wedgepressure(B) are given for eachstageof exercisein exerciseclassB, C, and D patients and expressedasa function of the percent maximum oxygen uptake (% VO, max). See text for details.
OH-CH2 H-C-W
OH
CH3
I
i
N-H
i-H
I
I
ISOPROTERENOL
PIRBUTEROL
DOBUTMINE
N
Fig. 3. Chemical structure of four cardiotonic agents.
lesser filling pressure during progressive exercise and to maintain a reduced filling pressure during submaximal work. If such conditions were realized, we might reasonably expect performance and aerobic capacity to improve. A final determination in the overall efficacy of these agents relates to the clinical condition of the patients and the inherent nature of their cardiac disease. Patients with severe cardiac disease having very advanced secondary pulmonary hypertension
and impaired hepatic and renal function are less apt to improve clinically with a cardiotonic agent, even though LV pump function may be increased. During the past several years, many patients with severe heart failure have been referred to us for these cardiotonic agents. Regrettably, a significant number are no longer alive, having died of advanced disease. Among class D patients, for example, 16 of 23 (70.% 1 with idiopathic cardiomyopathy (mean age 50 + 2 years; range 24 to 66) died within 5 months,
642
Weber, Andrew,
and Janicki
Amerkm
ApriJ, 1982 Heart Journal
Fig. 4. Cachetic-appearingclassD patient (patient 7 in Table I) with ascites,oliguria, and very advanced
severecardiac failure refractory to medical therapy. Dobutamine was given to initiate a diuresis.
and 12 of 19 (63%) with ischemic heart disease (mean age 63 + 2 years; range 48 to 79) died within 3 months. This simple expression of survival is intended to emphasize an important point: aggressive medical therapy must be instituted eariier in the course of cardiac disease if there is to be any hope of controlling this malignant process. CARD~OTONIC AGENTS IN MANAGEMENT CHRONIC CARDIAC FAILURE
OF
Dobutamine. Dobutamine (Eli Lilly) is a new synthetic catecholamine chemically resembling isoproterenol (Fig. 3) and having selective beta-receptor activity.16 In patients with chronic severe heart failure: 5 dobutamine (2.5 to 10 pg/kg/min) has been shown to improve cardiac performance without raising heart rate or blood pressure. We have used dobutamine in selected patients with severe biventricular failure and chronic low cardiac output refractory to medical therapy. These patients typically had congestive cardiomyopathy or long-standing valvular heart disease with peripheral edema and ascites and had become progressively o&uric, azotemic, and cachetic despite chronic digitalis therapy and large doses of a potent loop diuretic, furosemide (Fig. 4 and Table I). Potassium-spming diuretics (e.g., spironolactune and trimatereae), which act on the distal tubule, generally provided only a modest additional diuresis. The intense prox-
imal tubular reabsorption of sodium and water had inhibited the ability of the kidneys to excrete adequate free water; consequently, hyponatremia accompanied the oliguria and anasarca. Met&zone, a diuretic with proximal tubular activity, may induce a greater diuresis under these conditione; more commonly, however, the oliguria persists despite the combination of multiple diuretics. To initiate a diuresis and to restore responsiveness to diuretics, we have found it useful to administer dobutamine intravenously (2.5 to 10 cbg/min/kg dry body weight). Given for 36 to 48 hours, along with careful hemodynamic and ECG monitoring in the intensive care unit, dobutamine produced a significant (> 30% ) increase in cardiac output, accompanied by a vigorous diuresis (Table I). In each case, cardiac output rose significantly, indieating that. the myocardium was not truly refractory but did indeed possess a systolic reserve.17 The hyponatremia improved, and it again became possible to control fluid balance with diuretics. We chose dobutamine over dopamine for this purpose, because on an equimolar basis it has greater inotropic potency and because, unlike dopamine, dobut++ mine is independent of the endogmous -release of norepinephrine for ita inotropic effe&.s. Sbut+&ie therefore promotes a greater rise then dopm%ne in cardiac output, urine output, and urinary sodium concentration18 without an associated elevation in
Volume
103
Number
4, part 2
Table
Cardiotonic
in heart failure
643
I. Responseto 36- to 48-hour dobutamine infusion in patients with severe cardiac failure and oliguria Dobut-
Patient
therapy
Daily medications
Age (yr)
Sex
Cause
37
M
ICM
49
M
ICM
61
57
56
66
57
66 58
M
M
M
F
M
F M
ICM ICM IHD MVR AVR AVR IHD ICM
(mgl24 hrl 0.125 240 150 0.25 160 150 0.25 240 0.25 400 300 0.25 160 100 0.25 260 400 0.125 360 150 0.125 80 0.125 240 300
Digoxin Lasix Aldactone Digoxin Lasix Aldactone Digoxin Lasix Digoxin Lasix Triamterene Digoxin Lasix Aldactone Digoxin Lasix Aldactone Digoxin Lasix Aldactone Digoxin Lasix Digoxin Lasix Triamterene
amine (t.glkgl min)
Mean Heart
Cardiac
output
L VFP
(Llmin)
(mm
Hg)
rate (bpm)
arterial pressure (mm
Hg)
Serum
Urine BUN
sodium (mEqlL)
(mgldl)
output (L/24
5
2.83 3.80
38 28
122 114
71 68
119 122
110 85
0.4 1.9
-
1.83 2.74
25 19
93 89
62 64
121 131
104 59
0.5 3.7
5
2.61 3.55 2.52 3.81
38 26 35 24
106 94 110 95
82 81 72 80
123 127 124 138
54 32 61 55
0.3 2.3 0.3 2.6
5
2.29 4.69
45 30
116 106
70 72
133 136
25 23
0.3 2.4
2.5
3.46 4.67
30 25
83 80
86 86
121 129
142 110
1.1 2.2
3.30 5.27
30 22
100 89
74 79
117 126
132 115
0.4 2.5
1.62 3.60 4.08 8.37
28 15 35 -
120 91 107 118
67 75 92 92
130 134 134 140
27 15 102 95
0.9 1.5
6 6 -
-
-
10 8 10
AVR, Aortic valve replacement; ICM, idiopathic cardiomyopathy; IHD, pulmonary artery disatolic pressure; MVR, mitral valve replacement.
arterial pressure or heart rate. Despite these shortterm gains, however, the majority of the patients were dead within 6 months, underscoring the need for earlier, more aggressive management. Pirbuterol. The acute hemodynamic improvement noted with dobutamine in patients with chronic cardiac failure has quite naturally prompted the suggestion that similar compounds would be highly desirable in long-term management.‘g Heretofore, an orally active catecholamine-like compound has not been available. Pirbuterol (Pfizer), whose chemical structure is analogous to isoproterenol (Fig. 3), represents a significant advancement in this direction. It has been ‘shown to have both positive inotropic (beta,) and vasodilator (be@) properties.6 The beneficial acute hemodynamic effects of pirbuterol (0.4 mg/kg) have recently been demonstrated in patients with chronic cardiac failure.ls Of note is that the increment in cardiac output and the reduction in filling pressure observed with pirbuterol compare favorably with that obtained with dobutamine.20 To determine whether pirbuterol is effective as a cardiotonic agent in the long-term treatment of chronic cardiac failure, and specifically to examine
hr)
ischemic
heart disease; LVFP,
left ventricular
filling
pressure
from wedge or
its effect on exercise tolerance, we undertook a 7-week controlled clinical trial in 15 patients (seven men, eight women; mean age 58 years, range 36 to 78).21 The study was approved by our institutional review board for human studies; each patient gave written consent to participate. All patients had stable, chronic (> 6 months) New York Heart Association (NYHA) class III or IV heart failure as evidenced by a reproducible aerobic exercise capacity documented before enrollment, and all were taking digitalis and diuretics. All patients received a single-blind placebo for 1 week, after which their exercise tolerance was reassessed. Thereafter, double-blind randomization (pirbuterol versus placebo) was begun, with 30 mg pirbuterol given daily for 2 weeks and then increased to 60 mg daily, if tolerated, for the remaining 4 weeks. One patient receiving the placebo died suddenly 4 weeks into the program; two patients receiving pirbuterol had to discontinue the study because of intercurrent illness. Twelve patients (six in each group) completed the study. Their clinical status was monitored weekly, and exercise performance was reassessed at 4 and 7 weeks. The baseline exercise tolerance and VO, max in
April,
644
Weber, Andrews,
and Janicki
American
WLSLE
TIME
Heart
1982
Journal
BLIND
m
PIRBUTEROL
0
PLACEBO
(WEEKS)
Fig. 5. Response in maximum oxygen uptake (VO, max) is shown for patients participating co&rolled clinical trial of pirbuterdlr
the groups given pirbuterol and placebo (+ SD) were 571 + 172 versus 544 f 204 seconds and 11.8 2 1.9 versus 11.3 + 1.7 cc/min/kg, respectively, consistent with functional class C and D cardiac failure. Neither group showed a statistically significant improvement in clinical status or exercise performance after 1 week of placebo or 4 and 7 weeks of double-blind therapy (Fig. 5). Four patients received 60 mg pirbuterol; one of them experienced nervousness, tremulousness, and diaphoresis, which he did not, however, find intolerable. These same symptoms were sufficiently troublesome in two other patients to require a reduction in daily dose to 45 mg. We have continued this study, crossing the patients on placebo over to open pirbuterol therapy while maintaining pirbuterol therapy beyond 7 weeks in the rest. Our results are quite preliminary at present, and although conclusions cannot be drawn regarding the relative merits of this agent in the long-term treatment of chronic cardiac failure, our early experience has not been encouraging. Amrinone. Amrinone (Sterling-Winthrop) is a bipyridine derivative whose chemical structure and mechanism of action are quite different from those of the catechoIamines or digit&s (Fig. 3).* Amrinone has been shown to increase cardiac output and reduce LV filling pressure when given intravenous1y22-24or orally25 to patients with severe cardiac failure. We have treated a large number of patients with chronic cardiac failure with amrinone; these patients’ symptoms were poorly controhed with digitalis, multiple diuretics, and a variety of vasodilators including hydralazine, nitrates, praxosin, and trimazosin. All patients gave written consent to
in the
participate; each study was approved by our institutional review board. We began evaluating this cardiotonic agent by administering amrinone intravenously to establish an optimal infusion rate and dose tog&her with minimal side effects.25 We enrolled 15 patients (10 men, five femalea; mean age 54 years, range 34 to 75) with severe cardiac faihtre (seven with NYHA class IV, eight with class III) of varying cause (six with idiopathic cardiomyopathy, three with valvular heart disease, and six with ischemic hea& d’rscaae). We found that a rapid infusion of 1.9 + 0.1 m&g (0.2 mg/min) would significantly 0, < 0.01) raise the cardiac index 47% (from 1.9 t- 0.1 to 2.8 + 0.1 L/min/m2) and the stroke volume index 51% #urn 22 + 1 to 33 + 1 cc/m2) while reducing wed@ pressure 38% (from 24 + 2 to 15 f 2 mm I&I). &art rate and mean systemic and pulmonary arterial pressures were unchanged from control. Seven patients receiving a&none therapy orally (1.94 k 3 m&g given every 8 hours) who were able to undergo a treadmill exercise test before amrinone were exercise tested again within 24 hours of receiving the drug. Their standing baseline cardiac index before a&none therapy was 1.36 + 0.1. L/min/m2, andthemeanLVMngpresaurewas28+2mm Hg. After am&one, the mean cardiac in&x and the mean filling pressure in the upright no&ion were 1.95 + 0.1 L/min/m2 and 14 + 2 mm Hg, respectively. Following amrinone, it was possible to generate the same cardiac output response dur% &r&se, but from a Ie+er SIling .-pressure. Wedge pressure was < 25 mm lag t&irou out exercise in two patients and < 25 mm Hg during submaximal levels of exercise in the rest. For the group, wedge pressure
Volume
103
Number
4, part 2
lo 1
Cardiotonic
CLASS
therapy
in heart failure
645
C
A
n
BASELINE
A
0
AMRINONE
9 H P-
,BASE
32
TIME 1 5
I
10
LV
I
15
FILLING
I
20
1
25
PRESSURE
30
r
1
35
0
40
CMM HG>
Fig. 6. Averaged hemodynamic responseto exercise in classC and D patients before and after administration of amrinone for 32 hours. LV filling pressurederived from wedge or pulmonary artery diastolic pressure for each stage of treadmill exercise. was significantly 0, < 0.01) less at rest and during each stage of exercise. Within 24 hours of amrinone therapy, only one patient achieved a peak cardiac
index (4.05 L/min/m2) during exercise that was significantly greater than during the control state. Hence the acute administration of amrinone improved the function of the failing heart at rest and during exercise; 00, max, however, remained unchanged, which is consistent with the observation that maximum cardiac output was unchanged. We would not, however, expect steady-state blood levels of amrinone within this short period. Of note is the fact that at 4 weeks 00, max had improved significantly in these patients.25 More recently, we have reexamined the response in exercise performance to amrinone in 14 patients (nine males, five females; mean age 56 years, range 45 to 67) with chronic cardiac failure (nine with NYHA class III, five with class II; or seven each in exercise classes C and D). The causes of cardiac disease included idiopathic cardiomyopthy in six patients, ischemic heart disease in four, and chronic mitral or aortic valvular incompetence, or both, in four. We found the optimal unit dose of amrinone orally to be 1.6 & 0.05 mg/kg given every 8 hours, based on a documented increase in cardiac index of 53 + 5 % . Amrinone therapy was maintained for 32
HRS
2 UKS
DURING
4 YKS
12 IJKS
THERAPY
7. Responsein maximum oxygen uptake ($‘O, max) before therapy and after 32hours and 2,4, and 12weeksof amrinone therapy. See text for details.
Fig.
hours, representing four half-lives, when steadystage blood levels are more likely to be reached, before exercise was repeated. The baseline hemodynamic response to exercise is shown in Fig. 6. Following amrinone, wedge pressure was reduced (p < 0.05) at standing rest and for each stage of exercise, and cardiac output was increased (p < 0.05) throughout exercise. Correspondingly, 00, max was also increased (Fig. 7). Hence, with steady-state levels of amrinone, the responses in both cardiac index and filling pressure during exercise were improved. The long-term response to exercise has been followed in these same patients, treated with 1.6 mg/kg amrinone orally every 8 hours. The marked (p < 0.01) improvement in ir0, max apparent at 32 hours was also seen at 1 and 4 weeks and was sustained to 12 weeks (Fig. 7). This augmented exercise tolerance has been translated into an obvious improvement in the quality of life. Patients became progressively less symptomatic, and many began to engage in physical activities that previously were limited by fatigue or breathlessness. They no longer experienced orthopnea or paroxysmal nocturnal dyspnea, and with the improvement in effort tolerance, they were able to return to a gainful existence. With amrinone therapy, we were also able to reduce the daily diuretic requirement of six patients. Throughout the outpatient follow-up period, body weight was stable, and
no evidence of peripheral edema was seen. In several patients, radiographic heart size was significantly reduced within 12 weeks of therapy (Fig. 8).
646
April.
Weber, Andrews, and Janicki
American
1992
Heart Journal
Fig. 6. Reduction in radiographic heart sizeand cardiothoracic ratio after 12 weeksof amrinone therapy is apparent in a classD patient. Tabte
It. Platelet counts during long-term amrinone therapy
Patient
Baseline
Day
2
Day
7
Week
1 2 3 4 5 6 7 8 9 10 11 12
256 175 223 193 250 200 179 295 257 221 214 290
184 143 166 165 188 156 198 258 241 208 197 155
321 207 267 172 245 188 229
13 14 15 16
257 275 316 281
246 211 296 295
194 250 322 275
163
Mean
231 10
202 11
233 14
226 21
k SEM Platelet
counts (XlOl mm’) are current
as of the writing
218 290 160 155
340 292 267 270 250 135 135 303 238 184 136
4
Week
6
Week
356 431 272 231 348 107 158 318 173 268 183 124
241 265 156 155 285 143 210 289 -
-
-
247 29
218 21
12
of this report.
A number of adverse effects were noted with amrinone. Two patients developed nausea following the bolus infusion of amrinone, although the nausea resolved within several hours. In two others, ventricular arrhythmias (isolated premature contractions, couplets, and three- to five-beat ventricular tachycardia) appeared in our early experience when the first few patients were given amrinone too rapidly (1 mg/min). This problem was subsequently eliminated by administering the drug more slowly (0.2 mg/min). The increased frequency of ventricular arrhythmias was therefore primarily confined to the 24-hour period following the very rapid infusion of amrinone. After 2 and 4 weeks of amrinone given orally, there was no evidence, as judged by serial Holter monitoring, of increased rhythm dtiurbance. Two patients developed abnormal liver function studies during maintenance therapy, which resolved
after discontinuing amrinone. On recha&mge, only one had a recurrence prohibiting continued therapy. Thrombocytopenia (< 150,ooO mm3) has been reported with amrinone tharapy.26 In our experience, this has been a problem only in hospital&& patients with severe heart failure who are oliguric and who, in all likelihood, have elevated plasma leveIs of the drug. In outpatients with less severe failure receiving smaller doses (5 2 mg/kg), we have not found thrombocytopenia to be a major problem.25 Our current experience in 16 additional patients (Table II) is consistent with these earlier findings. We wish to acknowledge the dedicated technical assistance of T. Nusbickel, D. Ward, and J. Daweil during the conduct of these studies. The secretarial asaiatance of S. Wahl andJ. Stofmanin preparing the manuscript is appreciated. We also wish to tliank Eli Lilly, Pfizer Laboratories, and Sterling-Winthrop for their support and encouragement during the studies.
Volume
103
Number
4, part 2
REFERENCES
1. Fishman AP: Heart failure. In Beeson PB, McDermott W, editors: Cecil textbook of medicine, ed 15. Philadelphia, 1979, WB Saunders, p 1080. 2. Coupland S: The year-book of treatment for 1897. Philadelphia, 1897, Lea Brothers and Co, p 4. 3. Yeo IB: A manual of medical treatment of clinical therapeutics, vol. I. Chicago, 1906, W T Keener and Co, p 325. 4. Leier CV. Webel J. Bush CA: The cardiovascular effects of the continuous infusion of dobutamine in patients with severe heart failure. Circulation 56:468, 1977. 5. Stoner JD, Bolen JL, Harrison DC: Comparison of dobutamine and dopamine in treatment of severe heart failure. Br Heart J 23:536, 1977. 6. Moore PF, Constantine JW, Barth WE: Pirbuterol, a selective beta 2 adrenergic bronchodilator. J Pharmacol Exp Ther 207:410, 1978. 7. Carlsson E, Dahlof C-G, Hedberg A, Persson H, Tangstrand B: Differentiation of cardiac chronotronic and inotronic effects of B-adrenoceptor agonists. Naunyn Schmiedebergs Arch Pharmaco1300:101, 1977. 8. Alousi AA, Farah AE, Lesher GY, Opalka CJ Jr: Cardiotonic activity of amrinone: Win 40680 (5amino-3, 4’-bipyridinG(IH)-one). Circ Res 45:666, 1979. 9. Donald KW, Bishop JM, Wade OL: A study of minute to minute changes of arteriovenous oxygen content differences, oxygen uptake and cardiac output and rate of achievement of a steady state during exercise in rheumatic heart disease. J Clin Invest 33:1146, 1954. 10. Ross J Jr, Gault JH, Mason DT, Linhart JW, Braunwald E: Left ventricular performance during muscular exercise in patients with and without cardiac dysfunction. Circulation 34:597, 1966. 11. Weber KT, Kinasewitz GT, Janicki JS, Fishman AP: 0, utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation. (In press.) 12. Weber KT, Janicki JS, Fishman AP: Respiratory gas exchange during exercise to evaluate noninvasively the severity of chronic cardiac failure. In Braunwald E, Mock M, Watson J, editors: Symposium on advanced cardiac failure. Prog Cardiovasc Dis. (In press.) 13. Donald KW: Exercise and heart disease: A studv in regional circulation. The Bradshaw Lecture. Br Med J 1:985, 1959. 14. Wasserman K, Whipp BJ: Exercise physiology in health and disease. Am Rev Respjr Dis 112:219, 1975. 15. Wasserman K, McIlroy MB: Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 14:844, 1964. 16. Tuttle RR, Mills J: Dobutamine: Development of a new catecholamine to selectively increase cardiac contractility. Circulation 36:185, 1975. 17. Weber KT, Janicki JS: The heart as a muscle-pump system and the concept of heart failure. AM HEART J 90~371, 1979. 18. Leier CV, Hebans PT, Huss P, Bush CA, Lewis RP: Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Circulation 58:466, 1978, 19. Awan NA, Evenson MK, Needham KE, Evans TO, Hermanovich J, Taylor CR, Amsterdam E, Mason DT: Hemodynamic effects of oral pirbuterol in chronic severe congestive heart failure. Circulation 63:196, 1981. 20. Awan NA, Needham K, Evenson MK, Mason DT: Comparison of hemodynamic actions of pirbuterol and dobutamine on cardiac function in severe congestive heart failure. Am J Cardiol 47:665, 1981. 21. Weber KT, Andrews V, Janicki JS, Reichek N: Pirbuterol in the long term treatment of chronic cardiac failure Circulation 64(suppl IV):307, 1981. (Abst.) 22. Benotti JR, Grossman W, Braunwald E, Davalos DD, Alousi AA: Hemodynamic assessment of amrinone. N Engl J Med 299:1373, 1978. 23. LeJemtel TH, Keung E, Sonnenblick EH, Ribner HS, Matsumoto M, Davis R, Schwartz W, Alousi AA, Davolos D:
Cardiotonic
therapy in heart failure
647
Amrinone: A new nonglycosidic, nonadrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man. Circulation 59:1098, 1979. 24. LeJemtel TH, Keung E, Ribner HS, Davis R, Wexler J, Blaufox MD, Sonnenblick EH: Sustained benefical effects of oral amrinone on cardiac and renal function in patients with severe connestive heart failure. Am J Cardiol 45:123, 1980. 25. Weber KTY Andrews V, Janicki JS, Wilson JR, Fishman AP: Amrinone and exercise performance in patients with chronic heart failure. Am J Cardiol48:164, 1981. 26. Wynn J, Malacoff RF, Benotti JR, Curfman GD, Grossman W, Holman BL, Smith TW, Braunwald E: Oral amrinonein refractory congestive heart failure. Am J Cardiol 45:1245, 1980. DISCUSSION Dr. Cohn:
Concerning your observations on oxygen consumption and the dependenceon cardiac output for limited exercise tolerance, I think you are familiar with someof the data that we have collected in exercisetesting of patients
during
both acute and chronic
administration
of vasodilator drugs. As exercisetolerance improves with time, the increasein oxygen consumption seensto be out of proportion to the rise of cardiac output, so that we actually seewhat appearsto be improved oxygen extraction. Yet you have suggested
that there
is nothing
the
matter with extraction in heart failure. How do you put those two observationstogether? Dr. Weber: You have raised a very important point, which I believe relates to the effects of training. The data that I presented indicate that oxygen extraction, measured from arterial and mixed-venous oxygen content, is not impaired and that maximum levels of oxygen extrac-
tion can be achieved during exercise.We are not, however, describing
the distribution
of flow
or regional
oxygen
extraction within skeletal muscle. For example, it is my impression that when we provide the proper pharmacologic control of symptom-limited exercise, these patients
can, in fact, train themselvesand improve their oxygen uptake.
In my opinion,
heart failure
is a deconditioning
process related to the physical rest prescribed by the physician and to the fact that the patient is often hospitalized or. bedridden. Consequently, there are changesin the peripheral circulation and skeletal muscle that will alter the patient’s ability to engage in work. These changes do not indicate a change in cardiac pump function, but
reflect differences within skeletal muscle blood flow and metabolism.As another example, I would expect that with training
there
would
be a delay
in the appearance
of
lactate during exercisewithout a changein cardiac output. We are currently investigating the role of training in patients with chronic cardiac failure. Dr. Cohn: Would you suggest,from your preliminary
observations, that pirbuterol doesnot affect the training response? Dr. Weber: That is correct, inasmuchassymptomatically the patients were not improved. They were not able to engagein more activity. On the other hand, with the alpha blocker trimazosin (Weber et al: N Engl J Med 303~242, 1980), we saw a very clear improvement in exercise performance in the great majority of patients. I do not know if this occurred because there was an alpha-blockade
646
Weber, Andrews,
and Janicki
effect on the skeletal musclecirculation during exerciseor whether other factors were operative, but certainly the patients were able, in a nonsupervisedfashion at least, to train themselvesand to improve their exercise capacity. Dr. Goldberg: Did pirbuterol increasethe heart rate? Dr. Weber: On average,the heart rate wasnot increased in any consistent manner with unit dosesof 10, 15, 20, or 30 mg pirbuterol. A mild chronotropic responsewasnoted in a few patients, but this was not more than a 15 bpm increaseabove baseline. Dr. Goldberg: Did the patients continue to receive digitalis? Dr. Weber: Yes, we maintained whatever doseof digitalis and diuretics the patient wasreceiving on entry into the study. Dr. Goldberg: The more I think about these cardiotonic drugs, the more I realize that we will probably have to use them in combination with’ an alpha-adrenergic blocking agent or vasodilator. Somesort of vasodilation is required, because, as Dr. Swan has noted, these patients have intense vasoconstriction. Combination therapy, with prazosin, for example, may be useful. Dr. Weber: Earlier in the conference,I askedyou where you would like to direct the augmented systemic flow. I, too, agree with Dr. Swan. However, the autoregulatory behavior of any given regional circulation will depend on the metabolic requirements of its end organ. During exercise, for example, flow should be increasedprimarily to skeletal muscle. This is less true at rest. As you well know, if we can effectively improve the systemic blood flow, secondary to increasedmyocardial contractility and not by nonspecific pharmacologic vasodilation, we may potentially invoke a reflex withdrawal of the adrenergic nervous system and of the renin-angiotensin system. If systemic flow were improved adequately, and it is my impressionthat this occurs with amrinone, we certainly would see an appropriate reapportionment of flow to skeletal muscle and the kidney, and there would be no need to manipulate the peripheral circulation pharmacologically. Dr. Goldberg: I am not sure that I understand the hemodynamicsof amrinone, but it seemsto have some vasodilating activity of its own. Certainly systemic vascular resistancedecreasesmarkedly, although I do not know that it happens in normal subjects or whether it is seen only in patients with heart failure where excessivesympathetic tone already exists. I wonder if anybody knows that. Dr. Weber: We have studied amrinone in the experimental laboratory and in human subjects. In our experimental preparation, we can either administer the drug as an intracoronary infusion or give it intravenously to a dog that is maintaining an isolated heart in crosscirculation. Thus, in our experimental model, we can assess either the direct myocardial effects or both the systemic and myocardial effects. In normal dogs, we do find some mild vasodilation at large doses.In the main, the major effect of amrinone is inotropic. In patients with heart failure who are given amrinone, we may also have a reflex withdrawal
American
April, 1982 Heart Journal
of vasoconstriction with increased systemic flow. It is difficult to separate these issuesin human subjects. Let me put it this way: When we improve cardiac performance clinically by raising output and lowering wedgepressure, it is difficult to say that this central hemodynamicresult is due entirely to an inotropic effect or alsoto someadditional vasodilation. Dr. William Grossmanand his co-workers at the Peter Bent Hospital in Boston have previously emphasizedthe difficulty in separating these issues.My own bias is that we must resort to the experimental laboratory to sort them out. Dr. Mason: In the study with pirbuterol, was a control measurementdone after the drug was withdrawn to be sure that the patients had not deteriorated? In other words, after withdrawing the drug, did you repeat the exercisetest? Dr. Weber: Yes, we did that in a number of patients, becausethey simply did not improve. Some had adverse reactions, which prompted our discontinuing the drug; they were then exercisetested again. Among the patients we have studied to date, exercise performance has not declined and doesnot differ from baselineresponse.With trimazosin, on the other hand, we studied 27 patients for 52 weeks and then discontinued the drug; they were exercisetested again within 2 to 6 weeks(Weber et al: AM HEART J 102:569, 1981). In class D, or the severely compromisedpatients, exercise performance declined to baseline,often within 2 weeksafter stopping the drug. In classC and classB patients, the lessseverelycompromised groups, there was less of a change in exercise when we discontinued the drug. Frequently, their improved exercise performance was sustained. My interpretation of thesefindings is that clinically apparent heart failure does not necessarilyhave to recur within 24or 48 hours, or even 2 to 6 weeks.The reappearanceof symptoms will depend on the underlying severity of cardiac failure. Dr. Temple: You did seedeterioration when trimazosin was discontinued? Dr. Weber: Yes, there was a decline in augmented exercisetolerance when trimazosin wasdiscontinued. This occurred primarily in class D patients. It was more variable in the class C and B groups. The decline in exercise performance, however, was not below baseline levels. SomeclassC patients had an early (weeks)decline in exercise performance, but in most, improvement was maintained for up to 6 weeks. We have not, however, systematically gone back to retreat these patients with trimazosin. Dr. Temple: The real question, of course, is whether people improve simply by being in a study and receiving more overall attention. We have beenasking investigators to do randomized withdrawal studies; that is, after 52 weeks, continue to give some subjects the drug and discontinue it in others to seewhat happens.I don’t know the outcome of that yet. Not too many people have done it. Dr. Weber: Those are very difficult studies to conduct, but certainly worth doing. Dr. Gorlin: Something occurred to me about anaerobic
Volume Number
103 4, part 2
Cardiotonic
threshold and lactic acid concentrations. As we begin using drugs that alter the distribution of cardiac output, do you think we will get different responses,depending on whether, for example, muscleflow is altered with an alpha blocker, so that there is better perfusion and perhaps better washout of lactate in sometissues,or whether the splanchnic circulation is altered, thus changing uptake and reconversion?Do you think we will be able to predict distribution responses,depending on whether the anaerobic threshold is affected between these two, lactate production and glycogen resynthesis? Dr. Weber: I think that is a terribly important question, but one for which I do not have a definite answer. Certainly, aswe reported (Weber KT et al: N Engl J Med
therapy
in heart failure
303:242, 1980) with the alpha blocker trimazosin, the onset of the anaerobic threshold was delayed in most patients. I would agreethat if flow to skeletal muscle, for example, could be reapportioned in a more efficient manner, the appearanceof lactate may be delayed. The liver and its role in metabolizing lactate may also be important. I would like to think that in the future we will be able to profile our patients with heart failure with respect to the renin-angiotensin system, adrenergic nervous system, and heart, lung, liver, and kidney function. Based on this profile, we could utilize a seriesof drugs, whether from existing or from new compounds,to manipulate and correct that profile in the most efficient manner.
High temporal resolution synchronous volumetric scanning tomography: Potential roles in clinical evaluation of ischemic heart disease A new quantitative imaging device, the Dynamic Spatial Reconstructor (DSR), is described. Because, unlike commercially avallable computed tomography scanners, It obtains stop-action (0.01 second) images of a volume rather than a slice at a repetition rate of 60 volumetric scans per second, the DSR is particularly well suited for the study of ischemic heart disease. Its capabilities for recording the transit and dilution of contrast media within the coronary vasculature and all regions of the myocardium simultaneously with regional and global myocardial mechanics are being evaluated as a research tool for physiologic and ultimately clinical investigations. (AM HEART J 103:649, 1982.)
Earl H. Wood, M.D., Ph.D., Barry K. Gilbert, Ph.D., Lowell D. Harris, Ph.D., James H. Kinsey, Ph.D., Erik L. Ritman, M.D., Ph.D., and Richard A. Robb, Ph.D. Rochester, Minn.
Since 1961, when the Mayo Clinic diagnostic Cardiac Catheterization Laboratory was transferred from the Department of Physiology to St. Mary’s Hospital,l our cardiovascular physiology group has become increasingly involved in the development and application of quantitative computer-based x-ray imaging techniques using high temporal resolution for studies of cardiac, circulatory, and pulmo-
From the Biodynamics Research Unit, Mayo Clinic. Research supported in part by research grants HL-04664 the National Institutes of Health. Reprint requests: Earl H. Wood, M.D., Ph.D., Biodynamics Mayo Clinic, Rochester, MN 55905. OOOZ-8703/82/040649
+ 11$01.10/O
@ 1982 The
and RR-7 from
C. V.
Research Unit,
MO&y
Co.
nary dynamics2-” Fig. 1 shows the current stage of this evolution’: the Dynamic Spatial Reconstructor, commonly called the DSR. Figs. 2 and 3 provide additional visual impressions of the system, whose modes of operation have been described elsewhere . ‘-12 DYNAMIC
SPATIAL
RECONSTRUCTIDN
SYSTEM
This new type of computed axial tomography (CAT) scanner can capture 120 synchronous crosssectional scans of, for example, the thorax in one hundredth of a second, in contrast to all current CAT scanners, which provide a single cross section and require a time scan of one to several seconds.13 By means of a computer-based display assembly, the 649