Acute effects of doxorubicin on human left ventricular systolic and diastolic function

Volume Number

118 5, Part

Mitral

1

25. Yellin EL, Yoran C, Sonnenblick EH, Gabbay S, Frater RWM. Dynamic changes in the canine mitral regurgitant orifice area during ventricular ejection. Circ Res 1979;45:677. 26. Boltwood CM, Tei C, Wong M, Shah PM. Quantitative echocardiography of the mitral complex in dilated cardiomyopathy: the mechanism of functional mitral regurgitation. Circulation 1983;68:498. 27. Sarnoff SJ, Berglund E. Ventricular function. I. Starling’s law of the heart studied by means of simultaneous right and left ventricular function curves in the dog. Circulation 1954;9:706. 28. Katz AM. The descending limb of the Starling curve and the failing heart. Circulation 1965;32:871.

regurgitation

during

isometric exercise

29. Greenberg BH, DeMots H, Murphy E, Rahimtoola SH. Arterial dilators in mitral regurgitation: effects on rest and exercise hemodynamics and long-term clinical follow up. Circulation 1982;65:181. 30. Packer M, Kessler PD, Lee WH. Does the presence of prosthetic mitral valve prevent hydralazine from exerting its beneficial effects in patients with congestive heart failure? Circulation 1986;74:II-56. 31. Stevenson LW, Brunken RC, McKay GM, Belel D, Schelbert HR, Till&h JH. Afterload reduction decreases ventricular volume and mitral regurgitation during upright exercise in severe heart failure. Circulation 1988;78:11-214.

Acute effects of doxorubicin on human left ventricular systolic and diastolic function Although the long-term cardiotoxic effects of cumulative doses of doxorubicin are well established, the short-term effects on cardiac function are uncertain. Therefore we examined the short-term effects of doxorubicin on left ventricular systolic and diastolic function following a total of 56 doses of doxorubicin in 15 patients with normal resting left ventricular function. Resting radionuclide ventrlculography was performed 1 hour before and 4 hours after each dose of doxorubicin. Left ventricular ejection fraction increased significantly from 64 i 1% to 67 f 1% (p < 0.001) after doxorubicin. In addition, peak ejection rate (p < 0.005) and peak filling rate (p < 0.0005) increased significantly following short-term doxorubicin administration. There was no relationship between either the individual or cumulative dose of doxorubicin and the acute ejection fraction, peak ejection rate, or peak filling rate response. Our data suggest that doxorubicin acutely increases left ventricular systolic and diastolic function. (AM HEART J 1989; 1 l&979.)

Kenneth A. Brown, MD, Alton J. Blow, MD, Robert James A. Stewart, MD. Burlington, Vt.

Doxorubicin (Adriamycin) is a widely used antitumorigenic agent that has broad applications in cancer medicine. Although the long-term cardiotoxic effect of cumulative doses of doxorubicin is well established,lm3 the short-term effect of doxorubicin on left ventricular contractile and relaxation function has not been well studied in man. Experimental studies have found that low doses of doxorubicin cause a positive inotropic action, while higher doses cause a negative inotropic action in the rabbit papillary

From the University Received Reprint Medical 4/l/15201

Cardiology of Vermont for publication

and Oncology Units, College of Medicine. March

3, 1989;

requests: Kenneth A. Brown, Center Hospital of Vermont,

accepted

Department July

of Medicine, 12, 1989.

MD, Cardiology Unit-McClure Burlington, VT 05401.

1,

M. Weiss, MD, and

muscle4 or in the isolated chick heart.5 Such a biphasic response may be related to dose-dependent changes in calcium flux. 4, 5 In humans, systolic time intervals and echocardiographic percent diameter shortening have been shown to improve at 4 and 24 hours after doxorubicin administration,6 although the effect of dosage on left ventricular response was not noted. Furthermore, although long-term doxorubicin administration appears to have a deleterious effect on left ventricular filling rate,7 to date no study has examined the short-term effects of doxorubicin on diastolic function. To better examine the shortterm effects on left ventricular systolic and diastolic function, we performed resting radionuclide ventriculograms before and 4 hours after a total of 56 acute doses of doxorubicin in 15 patients. We tested the hypothesis that doxorubicin increases indices of left 979

980

Brown et al.

American

2.6 70

c6

8 X6 li

r

*p-Co.001

2.5

6

s z Y6 iiT 6

.ooo5 II 172

p=NS

170 C

p 2.5 8

‘2t

Fig. 1. Effect of short-term doxorubicin doseon left ventricular ejection fraction, peak ejection rate, peak filling rate, and time to peak filling rate. Stippled bar, Baseline; open bar, 4 hours post-doxorubicin.

ventricular systolic and diastolic function over the short term and that such a response is related to the dosage of doxorubicin. METHODS Patient population.

We studied 15patients who received a total of 56 dosesof doxorubicin for treatment of various tumors, including breast (n = 6), lymphoma (n = 6), bladder (n = 2), and lung (n = 1). Individual dosesof doxorubicin rangedfrom 25to 60mg/m2(mediandose,45 mg/m2). Total cumulative dosesrangedfrom 40to 500mg/m2(mean 244 + 117 mg/m2). There were seven men and eight women,with a mean ageof 53 t- 11years. No patient had known cardiac diseaseand all had normal resting left ventricular ejection fractions by radionuclide ventriculogram (see below) prior to treatment. Although all patients received other concomitant chemotherapy, including cyclophosphamide, fluorouracil, bleomycin, vincristine, methotrexate, cisplatin, or dexamethasone,none received adjuvant radiation therapy. Although several patients developed post-chemotherapygastrointestinal symptoms,no patient had any significant vomiting or diarrhea prior to the 4-hour radionuclide ventriculogram (seebelow). Radionuclide ventriculographic data acquisition and analysis. Equilibrium gated blood pool radionuclide ven-

triculograms were obtained approximately 1 hour before and 4 hours after eachdoseof doxorubicin. The number of studies per patient was 3.7 -+ 2.4, with a range of 1 to 8. Patients fasted between the two studies. Radionuclide

November 1989 Heart Journal

ventriculograms were performed with a standard Anger gammacamera(No. 420,GE Medical Systems,Milwaukee, Wise.) equipped with a parallel hole collimator and an 0.5 inch crystal, positioned over the heart in the left anterior oblique position that best separatedthe right and left ventricles. Autologous red blood cellswerelabeled with 25 mCi of technetium-99m with a modified in vitro technique.’ Gated imageswere collected in a 64 X 64 matrix in 32 frames per cardiac cycle for a count density of 250,000 counts in the left ventricular region of interest. End-diastolic and end-systolic left ventricular regions of interest were drawn manually. Ejection fraction wascalculated as background-corrected [(end-diastolic) - (end-systolic)]/ (end-diastolic) counts. Regionsof interest were drawn and ejection fraction calculations were performed twice for each study. The averageof these two calculations was recordedasthe measuredejection fraction. In our laboratory, the standard deviation for repetitive measurementsof left ventricular ejection fraction using this method is 1.6’C) (ejection fraction units). Peak ejection rate, peak filling rate, and time to peak filling rate were determined from a first-derivative analysisof a separateleft ventricular timeactivity curve generatedusing a semiautomatedprogram.Y Peak ejection and filling rates were expressedin end-diastolic volumes per second(EDV/sec). Statistical analysis. Mean values are presented as +standard error of the mean (SEM). Differences in left ventricular ejection fraction, peak ejection rate, peak filling rate, and time to peak filling rate betweenpre- and 4-hour post-doxorubicin radionuclide ventriculograms were analyzed by meansof a paired t test. Linear regressionwasused to relate dosageof doxorubicin and other patient variables to acute change in parameters of left ventricular systolic and diastolic function. RESULTS Systolic

function. There was no significant change in heart rate from baseline (81 st 2 beats/min) to postdoxorubicin (84 + 2 beats/min). The mean left ventricular ejection fraction increased from a baseline of 64 & 1% to 67 t 1% (p < 0.001) 4 hours after the administration of doxorubicin (Fig. 1). Peak ejection rate also increased significantly (p < 0.0005) at 4 hours post-doxorubicin (Fig. l), with a mean increase of 12 t- 3% above baseline. There was no significant correlation between either the individual or cumulative dose of doxorubicin and the change in left ventricular ejection fraction or peak ejection rate. Furthermore, when comparing patients receiving individual doses of doxorubicin of >45 mg/m2 (n = 28) versus those receiving individual doses 945 mg/m2 (n = 28), there was no significant difference in mean left ventricular ejection fraction change, in the proportion of patients showing an increase in ejection fraction, or in the percent change of the peak ejection rate. Finally, there was no rela-

Volume

118

Number

5, Part

1

tionship between resting ejection fraction and the change in ejection fraction following doxorubicin administration. Diastolic function. Peak filling rate increased significantly at 4 hours post-doxorubicin (p < 0.0005) (Fig. l), with a mean increase of 13 + 2% above baseline values. However, time to peak filling rate showed no significant change (Fig. 1). There was no significant correlation between either individual or cumulative dose of doxorubicin and change in peak filling rate or time to peak filling rate. In addition, there was no significant difference in percent change of peak filling rate or time to peak filling rate when comparing patients who received individual doxorubicin doses of >45 mg/m2 versus those who received 545 mg/m2. However, change in peak filling rate was significantly correlated with change in peak ejection rate (r = 0.65, p < 0.001). DISCUSSION

We found that administration of doxorubicin produces a modest, but significant short-term increase in left ventricular function. Our findings are consistent with those of Unverferth et a1.,6 who described an improvement in left ventricular function by echocardiographic dimensional changes and systolic time intervals at 4 and 24 hours following treatment. The cause of such a positive inotropic effect is uncertain, but experimental evidence suggests that increased intracellular calcium may play a key role.4, 5 It has been hypothesized that such overloading of intracellular calcium can eventually lead to reduced adenosine triphosphate (ATP) production, reduced energy availability for cellular function, and necrosis, ultimately resulting in the cardiomyopathy that is now well described in patients receiving long-term doxorubicin treatment.lm5 Van Boxtel et al4 found that doxorubicin produced a dose-dependent prolongation of time to peak developed force in an isolated rabbit papillary muscle preparation. Such prolongation has been related to decreased re-uptake of intracellular calcium.lOp I1 Further, mitochondria and sarcoplasmic reticulum, which are thought to be responsible for intracellular calcium regulation,12s l3 undergo acute swelling within 4 hours of doxorubicin administration.6 Inotropic responses manifest by the peak rate of rise of force (df/dt) showed a biphasic response with an increase in dfldt at lower doses of doxorubicin and a fall below control levels at higher doses4 Since maximal developed force is a function of both rate of muscle contraction and duration of time of contraction, the net effect on peak developed force was positive, even at higher doses of doxorubi-

Acute cardiac effects

of

doxorubicin

981

tin. More recently, Azuma et a1.5 found that low concentrations of doxorubicin enhanced calcium inward current, associated with an increase of peak developed force in isolated chick hearts. Higher concentrations of doxorubicin decreased both calcium current and peak force.5 However, in our study, there was no relationship between the short-term dosage of doxorubicin and the ejection fraction or peak ejection rate response. Alternatively, doxorubicin may act indirectly through release of catecholamines. Bristow et a1.14 have demonstrated that short-term administration of doxorubicin in canine and rabbit preparations leads to a release of norepinephrine within hours. It is possible that such a catecholamine response caused the short-term increase in left ventricular function that we observed. Finally, the positive inotropic action of doxorubicin could relate to its chemical resemblance to cardiac glycosides. In this regard, doxorubicin has been shown to inhibit sodiumpotassium-activated adenosine triphosphatase (ATPase) in cardiac cells,15 and could lead to a higher intracellular calcium concentration via the calciumsodium exchange reaction. Further, Van Boxtel et a1.4 have demonstrated that doxorubicin interferes with the dose-response of ouabain on rabbit papillary muscle contraction and may activate similar binding sites. Diastolic function. Doxorubicin increased left ventricular peak filling rate over the short term. This response may be directly related to the positive inotropit effect of doxorubicin. Prior studies have demonstrated that a positive inotropic stimulus is associated with enhanced left ventricular relaxation in normal subject@? l7 and in patients with coronary artery d&easel6 or congestive cardiomyopathy.18 It has been postulated that the observed increased relaxation in the setting of stimuli that increase myoplasmic calcium levels is related to enhanced calcium re-uptake due to either an increased concentration gradient of calcium between myofilaments and sarcoplasmic reticulum or to a coupling between calcium influx and clearance.16 Our observation that peak filling rate significantly correlated with peak ejection rat.e supports these findings. Limitations of current study. We studied patients who received acute doxorubicin doses ranging from 25 to 60 mg/m2, approximately a two and a halffold difference. This two and a halffold range corresponds fairly closely with the range of experimental doses used by Anzuma et a1.5 (0.02 to 0.05 mg/ml) that produced a biphasic inotropic response described above. Although we found no relationship between dosage of

November

982

Brown

et al.

American

doxorubicin and the short-term positive inotropic response, it is possible that doses of doxorubicin >60 mg/m2 may produce short-term negative changes in left ventricular function. Because we did not record blood pressure changes, we cannot completely exclude the possibility that changes in loading conditions following doxorubicin were responsible for the changes in left ventricular function. However, the absence of any change in heart rate after the short-term dose of doxorubicin argues against significant autonomic influences. In addition, prior studieslg have shown that comparable short-term doses of doxorubicin do not produce any effect on arterial pressure or systemic vascular resistance. Furthermore, although doxorubicin may decrease end-diastolic volume very early after administration (which would favor a fall in systolic performance), this effect does not persist beyond 1 hour.]” Finally, no patient had any significant vomiting or diarrhea prior to the 4-hour study. Therefore for all these reasons it is unlikely that alterations in loading conditions elicited by doxorubicin can explain the short-term increase in left ventricular systolic and diastolic function at 4 hours. In conclusion, doxorubicin increases left ventricular systolic and diastolic function over the short term in patients with normal resting function. Such an effect does not appear to be dose-dependent.

15.

The authors thank Nancy Perrine in the preparation of this report.

16.

for her expert

secretarial

5.

6.

7.

8.

9.

10.

11.

12. 13.

14.

help

REFERENCES

1. Lenaz L, Page JA. Cardiotoxicity of Adriamycin and related anthrocyclines. Cancer Treat Rev 1976;3:111-20. 2. Von Hoff DD, Lavard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:7 I O17. 3. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 19’78;88:168-75. 4. Van Boxtel CJ, Olson RD, Boerth RC, Oates JA. Doxorubicin: inotropic effects and inhibitory action on ouabain. J Pharmaco1 Exp Ther 1978;207:277-83.

17.

18.

19.

Heart

1989 Journal

Azuma J, Sperelakis N, Hasegawa H, Tanimoto T, Vogel S, Ogura K, Awata N, Sawamura A, Harada H, Ishiyama T, Morita Y, Yamamura Y. Adriamycin cardiotoxicity: possible pathogenic mechanisms. J Mel Cell Cardiol 1981;13:381-97. Unverferth DV, Majorien RD, Unverferth BP, Talley RI,, Balcerzak SP, Baba N. Human myocardial morphologic and functional changes in the first 24 hours after doxorubicin administration. Cancer Treat Rep 1981;65:1093-7. Lee BH, Goodenday LS, Muswick GJ, Yasnoff WA, Leighton RF, Skeel RT. Alterations in left ventricular diastolic function with doxorubicin therapy. J Am Co11 Cardiol 1987;9:184-8. Callahan RJ. Froelich JW. McKusick KA. Leoao 3. Strauss HW. A modified method for the in vivo labelidg’ of rkd blood cells with Tc-99m: concise communication. J Nucl Med 1982; 23:315-18. Mancini GBJ, Ylutsky RA, Norris SL, Bhargava V, Ashburn WL, Higgins CB. Radionuclide analysis of peak filling rate, filling fraction and time to peak filling rate. Response to supine bicycle exercise in normal subjects and patients with coronary disease. Am ,J Cardiol 1983;51:43-51. Reiter M. Electrolytes and myocardial contractility. In: Krayer 0, Kovarikova A, eds. Pharmacology of cardiac function. New York The MacMillan Company. 1964:25-42. Blinks cJR. Olson CB. Jewel1 BR. Braverv P. Influence of caffeine and &her methylxanthines on mechanical properties of isolated mammalian heart muscle. Circ Res 1972;30:357-92. Chance B. The energy-linked reaction of calcium with mitochondria. J Biol Chem 1965;240:2729-48. Lehninger AL. Ca ++ transport by mitochondria and its possible role in the cardiac contraction-relaxation cycle. Circ Res 1974;34,35(Suppl 111):83-a. Bristow MR, Minobe WA, Billingham ME, Marmor JB, Johnson GA. Ishimot,o BM. Sageman WS. Daniels JR. Anthracycline-associated cardiac aid renal damage in rabbits. Evidence for mediation by vasoactive substances. Lab Invest 1981;45:157-68. Gonsalvez M, van Rossmum GDV, Blanc0 MF. Inhibition of sodium-potassium-activatedadenosine 5’.triphosphataseand ion transport by Adriamycin. Cancer Res 1979;39:257-61. Rousseau MF, Pouleur H, Detry Jr, Brasseur LA. Relationship between change in left ventricular inotropic state and relaxation in normal subjects and in patients with coronary artery disease. Circulation 1981;64:736-43. Bahler RC, Vrobel TR, Martin P. The relaxation of heart rate and shortening to echocardiographic indexes of left ventricular relaxation in normal subjects. J Am Co11 Cardiol1983;2:92633. Carroll JD, Lang RM, Neumann AL, Borow KM, Rajfer SI. The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation 1986;74:815-25. Bristow MR, Sageman WS, Scott RH, Billingham ME, Bowden RE, Kernoff RS, Snidow GH, Daniels dR. Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release. J Cardiovasc Pharmacol 1980;2:487-515.