24-Hour mean pulse

CLINICAL STUDlES

24-Hour Mean Pulse Simple Predictor of Doxorubicin-Induced Cardiac Damage

WILLIAM J. M. HRUSHESKY, M.D. MARJORIE VUKELICH, M.D. BART STEINER, B.S. IRVE DELL, III, B.A. KIYOSHI MUKAI, M.D. Minneapolis,

Minnesota

From the Departments of Medicine (Section of Medical Oncology) and Laboratory Medicine and Pathology, University of Minnesota Medical Schocl and Masonic Cancer Center, Minneapolis, Minnesota. This work was supported in part by Minnesota Medical Foundation Student Fellowship MMF-129-81, St. Louis Park Medical Center Research Foundation, American Cancer Society Junior Faculty Fellowship 509 (Dr. Hrushesky), General Clinical Research Center Grant 5MOlRR00400, and National Institutes of Health Grant ROl-CA-3 1635-O 1. Requests for reprints should be addressed to Dr. William J. M. Hrushesky, P.O. Box 414, University of Minnesota Hospitals, Minneapolis, Minnesota 55455. Manuscript accepted September 27, 1983.

Nineteen adult patients with cancer received six to 10 monthly treatments of doxorubicin and cisplatin. Recumbent pulse was measured for 24 to 30 hours before each treatment. Treatment was stopped for disease progression or when a total doxorubicin dose of 550 mg/m2 was reached. Rising serial 24-hour pulse averages predicted congestive heart failure reliably. No patient had congestive heart failure during therapy, but three patients had congestive heart failure two to four months afler receiving 540,525, and 530 mg/m2 of doxorubicin. In these, two to six months before completion of therapy, the 24-hour rhythm-qualified mean (mesor) of pulse showed a positive slope by linear regression analysis (p CO.05) that was apparent at cumulative doxorubicin doses of 300, 420, and 240 mg/m2. All 19 patients received similar total doses of doxorubicin and were followed to death or 12 months after the last doxorubicin dose. In addition, a progressive rise in the 24-hour mean pulse coincided with histologically documented doxorubicin-induced lethal congesttve heart failure in Wistar-Kyoto rats of both sexes. A noninvasive, simple, sensitive, and cost-effective test for predicting the patients who will have clinically relevant anthracycline-induced cardiac damage has been elusive [l-3]. Changes in serial history and physical examination, electrocardiography, phonocardiography, echocardiography, and cardiac impedance have each failed to be highly predictive [4]. The literature is contradictory with regard to the predictive capacity of the radionuclide ejection fraction and endomyocardial biopsy [5,6]. Each index of cardiac functional capacity is substantially and predictably variable within the circadian time frame [7-l 11. Although it is true that a myriad of things affect the heart rate, we hypothesized that a time-qualified consideration of this simple measure of cardiac function might reduce its apparent variability. Potentially, changes in the circadian rhythm parameters of pulse might be used to predict the development of cardiac damage. It can be readily appreciated that if a physiologic function exhibits a high-amplitude circadian rhythm and if that function is measured infrequently or randomly within the cycle, highly variable values result. If that same endpoint were measured frequently in an equispaced manner throughout one or more full circadian cycles, the variability of its “rhythm-adjusted” mean is much smaller. Moreover, the rhythmicity itself can be quanitified by estimates of rhythm parameters including the rhythm-adjusted mean (mesor), half of peak-trough difference (amplitude), and timing of peak (acrophase), These parameters of the circadian pulse rhythm and their 95 percent confidence intervals, which are each derived from the

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TABLE I

Patient Characteristics

Patient

Age/Sex

1 2 3 4 5 6 7

48/F 65/F 62/F 55/M 62/F 47/F 70/F 64/M

6

ia 19 Total

Prior Therapy’

52/F 66/M 73/F 45/F 54/F 69/F 67/F 29/F 73/F 49/F

Prior Heart Disease’

1

-

3 -

-

-

Ovarian cancer Endometrial cancer Ovarian cancer Urachal cancer Ovarian cancer Bladder cancer Ovarian cancer Bladder cancer Ovarian cancer Ovarian cancer Bladder cancer Ovarian cancer Ovarian cancer Ovarian cancer Ovarian cancer Ovarian cancer Ovarian cancer Ovarian cancer Leiomyosarcoma

58/F

9 10 11 12 13 14 15 16 17

Diagnosis

-

2

4 6 7 -

10 9 9 9 7 5

a

5 2 5 -

Numberof Coursest

9 7 9 4

a 9 9

a 9 9 9 9 156

1 = concomitant hydroxyprogesterone caproate; 2 = mild hypertension; 3 = cyclophosphamide (50 mg three times a day), thiotepa (20 mg a week) for one year; 4 = thiotepa instillation to bladder; 5 = prior myocardial infarction; 6 = pelvic radium implants (three times), melphalan (1 mg/kg every eight weeks for seven and a half months); 7 = L-PAM (10 mg a day for five doses three times). l

t Each course consisted of 60 mg/m* of doxorubicin intravenously over 30 minutes.

least-squares cosine function best approximating all data, were calculated and compared as a function of doxorubicin dosage in human beings and Wistar-Kyoto rats.

SUBJECTS AND METHODS Murine Studies. Thirty lo- to 16-month-old (mean 12.3) Wistar-Kyoto rats, weighing 200 to 300 g each, stratified by age and sex, and kept on a 12-hour Iight/lBhourdark regimen for 21 days prior to experimentation, were randomly assigned to receive intravenous (tail vein) injections of doxorubicin or an equal volume of normal saline on four occasions at four hours after lighting onset. Doxorubicin was mixed freshly and injected at a concentration of 4 mg/ml, so that the volume injected was 0.3 ml for a 250 g rat. Each total dose was to be 5 mg/kg at each injection, and total doses of 20 mg/kg were planned for each rat. Some of these injections, however, were incomplete or missed. The amount of doxorubicin received at each injection was estimated by the approximate volume left in the syringe and scored. A total miss was scored 0 and represented 0 to 1 mg; a partial miss was scored as 1 and represented approximately I mg to 4 mg/kg; and a total intravenous injection was scored as 2 and represented the full 5 mg/kg dose. Prior to the initial injection, the pulse of each rat was determined at four-hour intervals around the clock, using a Beckman physiograph machine (model Mark IV). This pulse profile and all further profiles were determined on Wednesdays. Subsequent injections were carried out on Thursdays. Pulse profiles were repeated weekly for 11 weeks, whereas the four injections were performed during the first and second

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and sixth and seventh weeks. Each rat was weighed prior to each injection. The 24-hour mean pulse and circadian pulse amplitude were determined for each rat weekly. Cages were inspected twice daily, and rats were followed until death; their survival time in days from the time of initial injection was calculated. Upon death each rat was dissected, and its heart was removed, rinsed in normal saline, preserved in 10 percent formalin, and embedded in glycol methacrylate; 1 /L sections were inspected for abnormalities via light microscopy. The surgical pathologist was unaware of whether the rats had received a placebo or doxorubicin. Hearts were scored as normal (-I), slightly damaged (-2), moderately damaged (-3), or severely damaged (-4) in five categories: vacuolization, myofibrillar and nuclear degeneration, necrosis, interstitia! edema, and interstitial inflammation. The numerical scores were averaged for each heart to give an overall tabulation of damage. Patient Characteristics. Sixteen women and three men, aged 29 to 73 years and each with advanced-stage solid tumors, were studied. All patients were diurnally active, nocturnally sleeping, and eating mostly at 7 A.M., 12 noon, and 5 P.M. Fifteen of the 19 patients had received no prior chemotherapy, and none of the previously treated patients had received doxorubicin or cisplatin. The most common diagnoses were ovarian and bladder carcinoma (Table I). No patient received prior or concurrent mediastinal irradiation. Four of the 19 patients had a prior history of some cardiovascular disease, which included a prior myocardial infarction in two patients and a history of mild hypertension in the other two patients. Initial physical examination, electrocardiography, chest radiography, phonocardiography, impedance

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rNrXEAsE PREDICTSCONGESTIVE HEARTFAILURE-HRIJSHESKY E-r AL

cardiography, and determination of radionuclide ejection fraction revealed no detectable compromise in cardiovascular function prior to therapy in any of these 19 patients. Therapeutic Regimen and Drug Timing. Doxorubicin and cisplatin were each given monthly at a fixed dose of 60 mg/m*. Doxorubicin was given first, followed 12 hours later by cisplatin. Each agent was infused over a span of 30 minutes. The clock hour of doxorubicin treatment was alternated between 6 A.M. and 6 P.M. from month to month. Intravenous hydration in the nine-hour time span bracketing cisplatin administration included 4,100 ml of 5 percent dextrose, 0.45 percent sodium chloride solution. All pulse monitoring was completed at least four hours before doxorubicin was administered and before an intravenous line was placed. Patient Monitoring. Patients were admitted to the General Clinical Research Center at the University of Minnesota Hospitals for each treatment. Nineteen patients received a total of 156 courses of chemotherapy. The patients were allowed six to 12 hours of acclimatization to the hospital setting, after which heart rates were measured for 24 to 30 hours. During this span, patients remained supine with the exception of brief trips to the toilet, located within four meters of the patient’s bed. The patients were awake between 7 A.M. and 11 P.M., and slept or rested between 11 P.M. and 7 A.M. Pulses were monitored manually in all patients and automatically in six patients. A single method of pulse-taking was used for analysis of heart damage throughout the entire study in each patient. Manual pulse measurements were made by a General Clinical Research Center staff nurse over a oneminute span every two hours while the patient was awake and once during mid-sleep at approximately 3 A.M. Automatic heart rate monitoring was accomplished with Nippon Colin (model BP-203x) or Dinamap automatic monitoring devices. The recordings were automatically obtained every 12 minutes. Each machine operates by inflation of a blood pressure cuff and subsequent deflation. The systolic and diastolic blood pressures and the pulse rate are then printed out on a paper tape. Most patients found that their sleep was not severely disrupted by this procedure. The patients whose pulse was determined manually at 3 A.M. would be awakened by the procedure. Hemoglobin concentration was determined prior to each series of heart rate measurements. No patient had fever, infection, bleeding, or other acute medical illness during monitoring.

sistent with new congestive heart failure and chest radiographic findings of increased heart size and fluid overload in patients who had recently received doxorubicin and had no other explanatory events by history or physical examination, electrocardiography, and appropriate laboratory investigation. Patient Follow-Up. Each patient was followed regularly for a minimum of 12 months after the last dose of doxorubicin, unless death intervened.

Individual circadian rhythm characStatistical Analysis. teristics of pulse rates were estimated by the single cosinor method [ 121.The population mean cosinor method was used to summarize rhythm characteristics from groups of individuals [ 131. The resulting population values were compared by means of Hotelling t* tests at different stages during treatment [ 14-161. Heart rate changes and hemoglobin changes were inspected for trends by linear regression analysis. Pearson correlation coefficients were determined for heart rate and hemoglobin associations. Heart rate nIeS0r.S were also tested for differences as a function of (I) subsequent development of congestive heart failure and (2) total doxorubicin dose by two-way analysis of Variance.

Criterfa for the Diagnosis of Doxorubicin-Induced CarDoxorubicin-induced cardiomyopathy was diomyopathy. defined as a history of symptoms and physical findings con-

RESULTS Murine Results. The total doxorubicin dose was found to correlate positively with the degree of cardiac damage (p X0.02) and body weight loss (p
mean

heart

rate

rose steadily

in doxorubicin-treated animals but not in those that received a placebo injection (linear regression p = 0.03) (Figure 1). A two-way analysis of variance of the mean of individual heart rate 24-hour means was used to inspect these data for differences as a function of whether the rats received doxorubicin or a placebo and as a function of the number of weeks after initial injection. Large differences were found for each variable (placebo versus doxorubicin, f = 2.6, p <0.02; number of weeks after first treatment, f = 15.4, p 0.50). All 19 patients studied were followed until death or

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f’ULSE INCREASE PREDICTS CONGESTIVE HEART FAILURE-HRUSHESKY

Time

Patient Groups with and without Development of Congestive Heart Failure

Number Age Range Median Sex Male Female Prior heart disease Yes No Prior anticancer therapy Yes NO

Development of pulse mesor increase during therapy Yes No Cumulative doxorubicin dose (mg/m2 f SE)

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Cardiomyopathy

Asymptomatic

3

16

48-65 62

29-73 62

0 3

3 13

1 2

3 13

1 2

4 12

3 0 514 f 19

Figure 1. Pulse mesor of rats given a series of four infrav&nous 5 mgt kg doxorubicin injections (Rx) rises (slope of linear regression p <0.03), but this d&s not occur in a comparable group of animals given equal-volume saline placebo injections.

in weeks

at least 12 months after final doxorubicin dose. No substantial differences in pertinent patient characteristics are apparent between those with and without development of congestive heart failure (Table II). Each of the three patients in whom doxorubicininduced congestive heart failure developed two to four months after their final course of therapy showed relative tachycardia (a positive slope by linear regression analysis) in their 24hour heart rate average before their eighth course of therapy. One of these patients had congestive heart failure two months after finishing the

TABLE II

ET AL

2 14 500 f 17

ninth course of therapy, and the other two patients had signs and symptoms of congestive heart failure three and four months after their final course of chemotherapy. In each of these cases (Patients 1, 2, and 3), statistically significant increases in individual 24-hour heart rate averages were present for eight, three, and nine months, respectively, prior to the development of the clinical syndrome and, more importantly, substantially before the maximal planned doxorubicin dosage of 540 mg/m* had been administered (Table Ill). When the 24-hour pulse averages of the two groups (patients with or without congestive heart failure) were compared as a function of cumulative doxorubicin dosage, a clear elevation of the recumbent pulse mesor predated the development of congestive heart failure (Figure 2). This was true of each individual patient’s data series as outlined in Table Ill as well as in these group data; 24-hour heart rate evaluation was of predictive utility for the individual patient and not just for the group. When group data were analyzed by analysis of variance, there was a statistically significant difference in heart rate (expressed as percent of pretreatment 24-hour average) as a function of course number between the groups with and without development of congestive heart failure (f = 15.5, p
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PULSE INCREASE PREDICTS CONGESTIVE

TABLE III

Palisnl 1 2 3 4 50 6 7 8 9 10 11 12 13 14 15 16 17 18 19

HEART FAILURE-HRUSHESKY

ET AL

Summary of Linear Regression Analyses of Results of Serial Evaluation of Pulse and Hemoglobin Changes as a Function of Total Doxorubicln Dose

Cumulative Dsxorubicin Dose (m@m2) 550 (300)+ 525 (420)+ 530 (240)+ 540 (540)+ 428 (360)+ 356 475 534 420 529 353 480 506 534 523 540 540 560 529

Congestive Heart Failure

Pulse Mesor Slope

Hemoglobin Slope

P’

P’

0.01

-

NS

4.6292

0.01

-

NS

+

1.0568

0.05

-0.5382

0.001

-2

1.0901

0.02

-0.3317

0.02

-t

3.4496

0.01

-

NS

-

NS NS NS NS NS 0.01 NS NS NS NS NS NS NS NS

-

-

NS NS NS NS 0.01 NS NS NS NS NS 0.01 NS NS 0.01

+

2.1673

+

-

-3.5415 -

-

-

Numberof PretreatmsnfPulse Profiles Evaluated before Detectable ProgressivePulse Rise’ Mean of Mean of Three Single Pulse 6-10 A.M. Random 6 A.M. Mssor Pulse Pukes PI&

-0.1815 -

-0.2683 -0.4373

9

-

-

8” 8” -

-

-

Point at which the slope of the line best fitting the values is different from zero by linear regression analysis. The last four columns compare the behavior of different subsets of pulse data over the nine months during which pulse was recorded. Pulse mesor combines all data from 24 hours prior to treatment; 6 to 10 A.M. pulse represents all pulses obtained during this span prior to each treatment; mean of three random pulses and a single 6 A.M. pulse were also compared for their predictive capacity. + Cumulative doxorubicin dose received prior to the development of increasing pulse mesor. + Histologic evidence of myocardiopathy at autopsy without clinical syndrome. 5 Doxorubicin therapy discontinued because of elevated pulse mesor. False-positive results. l

l

l

120 L

Figure 2, Pulse mesor and standard errors analyzed by linear regression analysis reveals a statistically significant rise several months prior to the onset of congestive heart failure (U-IF). In these patients at risk for the development of congestive heart failure, the slope invariably becomes positive long before the 550 mgfm2 dosage is reached.

P--O

CHFgroup /n=3,

-

No CHFgroup

9oc

in=,61

1

Treatment n

I

2

3

t 0

I I

I 2

4 L

5 I

6 I

3

4

5

7 I 1 6

8 I

9 I

10 I

7

8

9

14

IC

Months ofter lnttiol Treatment

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ejection fraction determined prior to the first treatment, at the fifth and ninth treatments, and when symptoms of congestive heart failure occurred, confirmed the presence of congestive heart failure in each of the three cases of doxorubicin-induced cardiomyopathy, but gave abnormal results before the development of overt congestive heart failure in only one case. The result of this test became abnormal (31 percent) in Patient 2 one month before the appearance of overt clinical symptoms, but four months after the patient’s 24-hour pulse average had shown a statistically significant rise. In the other two cases (Patients 1 and 3), the ejection fraction was reported as normal at completion of therapy (56 percent and 58 percent, respectively) whereas the 24-hour pulse average had been increasing for several months. Comparison of individual 24-hour pulse average with mean of all peri-awakening (6 to 10 A.M.) pulses, single 6 A.M. pulse, and mean of three random pretreatment pulses: In order to define whether rhythmometric analysis of full 24-hour profiles is necessary for the prediction of doxorubicin-induced cardiomyopathy, periawakening (6 to 10 A.M.) pulse means, a single pretreatment time-qualified 6 A.M. pulse, and the mean of three random pulse measurements, each performed prior to each course of therapy, were analyzed in every patient by linear regression. Two of the five patients who had a rising 24-hour pulse mean also demonstrated a rise in the periawakening pulse mean (p CO.05). These patients (Patients 1 and 2) were two of the three in whom overt congestive heart failure ultimately developed. The average number of peri-awakening pulse measurements made prior to each course of therapy was five for Patient 1 and nine for Patient 2. In both Patients 1 and 2, the linear regression of 24-hour pulse average became statistically significant after five and seven monthly courses, whereas the regression of peri-awakening pulse means became significant only after the completion of all courses. Therefore, peri-awakening pulse data were useless for modifying dosage prior to the administration of the planned dose maximum. Patient 3, who had an average of 16 peri-awakening pulse measurements prior to each course, ultimately had overt congestive heart failure but showed no trend in the 6 to 10 A.M. peri-awakening pulse averages. This patient’s 24-hour pulse mean had risen significantly prior to her fifth of nine courses of therapy (nine months before congestive heart failure). Patient 4, who had evidence of severe cardiomyopathy at autopsy, also had an increasing mesor but no increase in peri-awakening pulse mean. Patient 5, in whom doxorubicin therapy was stopped because of a rising pulse mesor and in whom autopsy also showed histologic findings consistent with

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ET AL

healed doxorubicin-induced cardiac damage, had no increase in the 6 to 10 A.M. peri-awakening Pulse mean. Similar analyses of the single 6 A.M. pretreatment pulse identified no patients at risk for cardiac damage, whereas averages of three randomly SeleCted Pretreatment pulses showed linear increases in two Patients in whom congestive heart failure developed, as well as two patients in whom therapy was completed more than 12 months and who have demonstrated no cardiac dysfunction. Heart rate-hemoglobin associations: There was a statistically significant fall in the hemoglobin level in two (Patients 3 and 4) of the five patients with a progressively rising pulse, and in three of the 14 patients without (chi-square 0.05, p >0.50). When the individual patients in whom congestive heart failure developed were compared as a group with those in whom it did not, no linear trend was seen in either group with regard to hemoglobin change. Statistically significant correlations were not apparent between heart rate and hemoglobin changes either for patients with 0T without cardiomyopathy (r = 0.04, p >0.50 and r = 0.013, p >0.50, respectively) or for the population as a whole. COMMENTS Doxorubicin’s usefulness is marred by the fact that an increasing proportion of patients have serious and often fatal congestive cardiomyopathy as a result of increased total dose. An arbitrary cumulative dose limit of 550 mg/m* has been found to allow safe treatment of about 90 percent of patients. When this drug is given intermittently in high doses, the incidence of cardiac complications is greater than when it is given as a continuous infusion or in lower weekly doses [ 17,181. It is not clear whether its full effectiveness is maintained by these schedules in all varieties of malignancy. Although congestive heart failure secondary to doxorubicin develops in some patients long before the 550 mg/m* total dose has been reached, others tolerate substantially more drug without the development of cardiac compromise, regardless of administration schedule. It is sometimes necessary to drop doxorubicin from a drug combination in a patient showing response to treatment, with subsequent relapse and death from progressive disease. This problem sometimes arises in the treatment of advanced breast cancer, small cell lung cancer, aggressive lymphomas, sarcomas, and occasionally ovarian carcinoma. Our data indicate that individual longitudinal evaluation of serial 24-hour rhythm-qualified pulse means (circadian pulse mesor) allows us to simply, reproducibly, and noninvasively predict the patients who can tolerate less or more than the recommended total dosage of doxorubicin.

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Manual pulse measurement proved satisfactory for assessing a reliable rhythm-qualified mean, Thus, determination of the pulse mesor, in order to predict doxorubicin-induced cardiomyopathy, has universal applicability. Patient self-measurement, as well as automatic home measurement, is also quite feasible and would totally eliminate the need for hospitalization [ 12,191. Our manually obtained data are not dense or equispaced enough to allow us to reliably determine whether or not a change in a patient’s circadian amplitude or timing of the daily pulse peak might predictably accompany or even precede a change in the 24hour mean. This kind of premonitory amplitude change has been documented for the case of spontaneous blood pressure elevation in rats [20] and by the amplitude results in our concurrent murine study. On the other hand, our data do show that a single time-qualified pretreatment pulse, the average of several time-qualified pen-awakening pulse measurements (6 to 10 A.M.), and the mean of three randomly selected pretreatment pulses are not adequate to make an accurate or early prediction of cardiac damage. It is noteworthy that 24-hour pulse data obtained from animals that have received doxorubicin demonstrated an immediate, as well as long-term and sustained, dose-related rise in the circadian pulse average. This sustained 24-hour average pulse increase was preceded by an even more dramatic fall in circadian pulse amplitude in our rats. This 24-hour average pulse rise and amplitude fall occurred when doxorubicin was given at a circadian stage associated with high histologically proved cardiac mortality [ 211. No such rise occurred in rats treated with a placebo [22]. A 24-hour span of frequent pulse measurement could easily precede each doxorubicin treatment. A simple linear rgression analysis of these longitudinal 24-hour mean pulse series could be calculated before each planned treatment. In patients found to have a pro-

ET AL

gressively increasing 24-hour mean pulse, as a function of the number of courses (amount of doxorubicin) received, dose reduction or schedule modification, further pretreatment testing, or discontinuation of doxorubicin therapy should be considered. In patients whose cumulative doxorubicin dosage approaches 550 mg/m* and whose serial pulse mesors show no progressive rise, serious consideration should be given to continuation of doxorubicin if this drug was responsible for maintaining a tumor response. The total cost of serial radionuclide ejection fraction measurements prior to each treatment throughout the course of therapy would approximate $2,000 per patient. In our experience, pulse measurement is better than this index of cardiac function for predicting the development of cardiac dysfunction. ACKNOWLEDGMENT We are indebted to Mr. M. Shinoda, President, Nippon Colin Ltd., 1200-4, Muranaka, Komaki 485, Japan, for three automatic pulse and blood pressure monitoring machines and for implementing suggested improvements on these. The printout of the Nippon Colin machine (but not that of the Dinamap) lists date and clock-hour. This machine can be moved to a distance from the patient, e.g., to the bathroom or outside the bedroom. The single Nippon Colin unit is provided with a handle; it can be carried readily from room to room and has been used extensively for real-life profiles at home and laboratory, being transported back and forth daily without any malfunction for years. We thank Mr. Todd Langevin for his excellent technical help and Ms. Rochelle Fabian for her secretarial expertise. We especially thank Professor Franz Halberg for his always open door and invaluable suggestions, some of which led very directly to the conception of these preclinical and clinical studies of the circadian rhythm characteristics of heart rate.

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2.

3.

4.

5.

AlexanderJ, Dainiak N, Berger HJ, et al: Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J f&d 1979; 300: 278-283. BlumRH, Carter SK: Adriamycin, a new anticancer drug with significant clinical activity. Ann Intern f&d 1974; 80: 249-259. Ritchie JL, Singer JW, Thorning D, et al: Anthracycline cardiotoxicity: clinical and pathologic outcomes assessed by radionuclide ejection fraction. Cancer 1980; 46: 11091116. Gottdiener JS. Mathisen DJ, Borer JS, et al: Doxorubicin cardiotoxicitv: assessment of late left ventricular dysfunction by radionuclide cineangiography. Ann Intern f&d 1981; 94: 430-435. Bristow MR. Mason JW, Billingham ME, et al: Doxorubicin

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cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 1978; 88: 168-175. Myers CE: Epilogue. Cancer Treat Rep 1978; 62: 979. Bethea NJN: Human performance, physiological rhythms, and circadian time relations (doctoral dissertation). Texas Tech University, Lubbock, Texas, 1975. 142 pp. Clench J. Barton SA, Schull WJ, et al: Circadian heart rate rhythmicity; comparison between an eskimo and other population groups. Chronobiologia 1981; 8: 119-122. Richardson DW, Honour AJ, Fenton GW, et al: Variation in arterial oressure throughout the day and night. Clin Sci 1964; 26: 445-460. Schroder R, Dennert J, Heumann H: 25studen-rhythm is inotropiezustand des herzmuskels bei gesunden jungen

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11.

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mannern. Verh Dtsch Des Kreislaufforsch 1969; 35: 370-375. Wertheimer L, Hassen A, Delman A, et al: Cardiovascular circadian rhythm in man. In: Scheving LE, Halberg F, Pauly JE, ads. Chronobiology. Tokyo: lgaku Shoin Ltd., 1974; 742-747. Halberg F, Johnson EA, Nelson W, et al: Autorhythmometry procedures for physiologic self-measurements and their analysis. Physiol Teach 1972; 1: l-l 1. Halberg F, Tong YL, Johnson EA: Circadian system phasean aspect of temporal morphology; procedures and illustrative examples. In: Mayersback HV, ed. The cellular aspects of biorhythms. New York: Springer-Verlag, 1967; 20-48. Hotelling H: Hotelling t* test. Ann Math Stat 1931; 2: 360. Morrison DF: Multivariate statistical methods. New York: McGraw-Hill, 1967. Tarquini 6, Gheri R, Roman0 S, et al: Circadian mesorhyperprolactinemia in fibrocystic mastopathy. Am J Med 1979; 66: 229-237. Benjamin R, Legha S, Mackay B, et al: Reduction of adriamycin

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ET AL

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cardiac toxicity using a prolonged continuous infusion (abstr). Proc Am Assoc Cancer Res 1981; 22: 179. Chlebowski RT, Paroly WS, Pugh RP, et al: Adriamycin given as a weekly schedule without a leading course: clinically effective with reduced incidence of cardiotoxicity. Cancer Treat Rep 1980; 64: 47-51. Halberg E, Halberg F, Shankaraiah K: Plexo-serial linearnonlinear rhythmometry of blood pressure, pulse and motor activity by a couple in their sixties. Chronobiologia 1981; 8: 351-366. Halberg J, Halberg E, Hayes DK, et al: Schedule shifts, life quality and quantity-modeled by murine blood pressure evaluation and arthropod lifespan. Int J Chronobiol 1980; 7: 17-64. Levi F, Halberg F, Haus E, et al: Synthetic adrenocorticotropin for optimizing murine circadian chronotolerance for adriamycin. Chronobiologia 1980; 7: 227-244. Steiner B, Mukai K, Hrushesky W, et al: Changes in circadian rhythm characteristics of pulse indicate doxorubicin-induced cardiac damage (DCHF) (abstr). Proc Am Assoc Cancer Res 1982; 23: 634.