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European Journal of Heart Failure 2000 2(2):167-173; doi:10.1016/S1388-9842(00)00073-8
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© 2000 European Society of Cardiology

Negative inotropic effects of recombinant interleukin 2 in patients without left ventricular dysfunction

René A. Tioa,*, Judith Niekenb,c, Elisabeth G.E. de Vriesb, Carolein Pfeiffera, Mike J.L. de Jongstea, Els Piepera, Han Moshaged, Piet C. Limburgc and Nanno H. Mulderb

a Thoraxcenter, Department of Cardiology, University Hospital Groningen P.O. Box 30.001, 9700 Groningen, The Netherlands
b Department of Internal Medicine, Division of Medical Oncology, University Hospital Groningen P.O. Box 30.001, 9700 Groningen, The Netherlands
c Department of Internal Medicine, Division of Clinical Immunology, University Hospital Groningen P.O. Box 30.001, 9700 Groningen, The Netherlands
d Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Hospital Groningen P.O. Box 30.001, 9700 Groningen, The Netherlands

* Corresponding author. Tel.: +31-50-3612365; fax: +31-50-3614643. E-mail address: r.a.tio{at}thorax.azg.nl (R.A. Tio).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Cardiovascular changes
 5. Discussion
 References
 
Experimental data have shown that rIL2 has negative inotropic properties. This has not been investigated in humans with normal left ventricular function. Seventeen consecutive renal cell carcinoma patients who received rIL2 therapy because of dissemination were analyzed before and after treatment with a low dose of rIL2 subcutaneously. Left ventricular ejection fraction (echocardiography), heart rate variability parameters (24 h electrocardiography), and TNF{alpha}, IL1β and nitric oxide metabolites (NOx) were measured. LVEF decreased from 54 ± 7 to 50 ± 6% (mean ± S.D.; P = 0.012), with a concomitant increase in heart rate from 87 ± 13 to 94 ± 13 beats/min (P = 0.031). All frequency domain HRV parameters decreased: the total power from 18.0 ± 7.9 to 14.0 ± 5.0 ms (P = 0.001), the low frequency from 10.3 ± 5.4 to 8.3 ± 3.4 ms (P = 0.001), and the high frequency from 6.3 ± 2.6 to 4.5 ± 1.1 ms (P = 0.001). There was no measurable effect on TNF{alpha}, IL1β concentrations. Plasma levels of nitrate (NOx) increased from 22.8 ± 14.4 to 41.8±26.6 µmol/l (P = 0.007).

Conclusions: A low dose of rIL2 has a negative inotropic effect that may be mediated by increased NO concentrations. It also reduces sympathetic activity as reflected in HRV parameters.

Key Words: Heart failure • Interleukin-2 • Nitric oxide • Heart rate variability

Received September 23, 1999; Revised February 23, 2000; Accepted March 6, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Cardiovascular changes
 5. Discussion
 References
 
Several studies support a pathophysiologic role for inflammatory cytokines in heart failure. Cytokines, such as tumor necrosis factor-{alpha} (TNF{alpha}), interleukin-6 and interleukin-2 (IL2) have a negative inotropic effect on hamster and human isolated papillary muscle [1,2]. In patients with severe heart failure elevated circulating TNF{alpha} concentrations have been found to correlate with severity of heart failure [3]. Furthermore, indications for an activated cellular immune system in patients with congestive heart failure, have been described, namely: increased circulating IL2 receptors and soluble CD8 [4]. In addition to systemic activation, T-cell infiltration in the myocardium and an enhanced IL2 production may be present in dilated cardiomyopathy or heart failure patients [5,6].

It is as yet unclear whether IL2 has a direct negative inotropic effect in vivo in humans. Recombinant interleukin-2 (rIL2), which is administered either alone or in conjunction with in vitro generated autologous lymphokine-activated killer cells or tumor-infiltrating lymphocytes, is widely used in patients with disseminated or recurrent renal cell carcinoma [7–9]. The initial high-dose intravenous rIL2 dose regimens that were complicated by serious and potentially life-threatening cardiovascular toxicity [10–12] have now been substituted by low dose subcutaneous regimens.

In the present prospective study, the effect on the left ventricular function was investigated by utilizing echocardiography in patients without left ventricular dysfunction. For analysis of changes in autonomic activity during decreased left ventricular function, heart rate variability parameters were evaluated. Blood samples were collected to evaluate the potential activation of other cytokines.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Cardiovascular changes
 5. Discussion
 References
 
2.1. Patients
All patients had a histologically confirmed diagnosis of disseminated renal cell carcinoma and were scheduled for subcutaneous (SC) rIL2 monotherapy. Exclusion criteria for SC rIL2 treatment were the presence of cerebral metastases, unstable angina pectoris, or congestive heart failure. Additional exclusion criteria for this study included previous chemotherapy with cardiac depressant drugs, and radiation therapy involving the cardiac region. Patients were included only after informed consent was obtained. The investigation conforms to the principles outlined in the Declaration of Helsinki.

2.2. Treatment regimen
Patients received SC rIL2 (aldesleukin, Proleukin; Chiron Benelux b.v., Amsterdam, The Netherlands) in a 5-day cycle with a 9-day rest period in between. During the first cycle, 18 000 000 IU rIL2 were administered once daily. During subsequent cycles, patients were given 9 000 000 IU rIL2 at days 1 and 2, and 18 000 000 IU rIL2 at days 3–5. One rIL2 course consisted of two consecutive 5-day cycles; patients received a maximum of four courses. To alleviate pyretic reactions, a daily maximum dose of 3 g acetaminophen was prescribed concomitantly. No non-steroid, anti-inflammatory drugs were allowed.

2.3. Toxicity and cardiovascular screening
Toxicity was scored according to standard WHO criteria [13]. A careful history with emphasis on pre-existing cardiovascular symptoms was recorded before the start of rIL2 therapy. Blood pressure, pulse rate, temperature, and body weight were measured daily during the first IL2 cycle. Prior to rIL2 administration (day 0), and after completing the first 5-day cycle (day 6), patients underwent cardiovascular evaluation, consisting of 24-h ambulatory electrocardiographic (ECG) recordings on the one hand, and echocardiography on the other.

2.4. Electrocardiographic recordings
Electrocardiographic recordings (24 h) were performed before the start of rIL2 therapy (day 0), on the first treatment day (day 1), and at the end of the first treatment cycle (day 6). The ECG recordings were analyzed on a Marquette 8000 Holter system (Marquette Electronics, Inc., Milwaukee, WI, USA). Heart rate variability (HRV) analysis was performed utilizing commercially available Marquette HRV analysis software (version 002A). From the 24-h recordings, time domain, heart rate variability parameters such as the standard deviation of all normal to normal RR-intervals during 24 h (S.D.), the standard deviation of all mean values of normal to normal RR-intervals for 5-min segments during 24 h (S.D.A.N.N.), the root mean square of successive differences between normal RR-intervals (R.M.S.S.D.), and the percentage of differences between successive normal RR-intervals >50 ms (pNN50) were analyzed. The S.D.N.N. represents parasympathetic as well as sympathetic inputs into heart rate control. The pNN50 and especially the R.M.S.S.D. may be more specific for parasympathetic activity. Furthermore, frequency domain analysis using Fourier transformation was performed over 2-min segments to determine the low frequency (LF; ms 0.04–0.15 Hz), the high frequency (HF; ms 0.15–0.40 Hz) and the total power (TP; ms) [14].

2.5. Echocardiography
Echocardiography was performed 1 day before administration of rIL2 treatment and at the end of the first treatment cycle. Standard ejection fractions were calculated from the apical two-chamber and four-chamber views using commercially available software (Vingmed Sound, Horten, Norway). Two cineloops from each view were used for each measurement.

2.6. Serology
Hematological and biochemical tests were performed on days 0, 3 and 6 of the first rIL2 cycle, and on the first day of subsequent cycles. Parameters measured included full blood cell counts, hemoglobin, differential white blood cell counts, creatinine, urea, creatinine phosphokinase (CPK), CPK-MB, lactate dehydrogenase (LDH), liver enzymes, sodium, potassium, calcium, total protein, and albumin. Before and at the end of the 5 days rIL2 administration, serum samples were drawn for determination of nitric oxide metabolites (NOx), tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin 1β (IL-1β). Samples were stored at –80°C until use. TNF-{alpha} (detection limit, 15.6 pg/ml) and IL-1β (detection limit, 3.9 pg/ml) were measured using enzyme-linked immunosorbent assays [15]. NOx (detection limit, 3.1 µmol/l), was measured with the Griess reaction as previously described by Moshage et al. [16].

2.7. Statistics
For statistical analysis, the Student’s paired t-test was used. P-values less than 0.05 were considered to be significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Cardiovascular changes
 5. Discussion
 References
 
Seventeen consecutive renal cell carcinoma patients were enrolled in this study, of whom 12 were evaluable for echocardiographic measurements. In five patients, it was not possible to obtain a baseline and/or treatment ejection fraction, either due to poor quality of the echocardiogram (four) or to unexpected logistic problems (one). Patient’s characteristics are outlined in Table 1.


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  		Table 1 Patient characteristics

 
3.1. Toxicity
Side-effects arising from SC IL2 administration were similar to previously reported findings. All patients experienced mild to moderate constitutional symptoms, WHO grade I–III fevers and chills, as well as transient inflammation and induration at the injection sites. No substantial changes in diastolic and systolic blood pressure were observed throughout rIL2 administration. Body weight did not change during rIL2 treatment (from 76.3±4.5 to 75.3±4.7 kg after 1 week) The temperature increased after rIL2 administration from 36.7±0.3 to a maximal of 38.7±0.8°C during the evening hours. The following morning no fever was found. The temperature on the morning of testing the body temperature was 36.9±0.3°C. Serum levels of neither CPK, CPK-MB nor creatinine were altered significantly during IL2 therapy. During treatment, most patients developed peripheral blood eosinophilia, with mean cell counts from 0.19x109/l±0.04 at entry to 0.53x109/l±0.09 on the 5th day and further to a maximum of 4.39x109/l±1.13 after 4 weeks. Within 3 days after the start of rIL2 therapy, lymphocyte counts decreased from 1.40x109/l±0.17 to 0.39x109/l±0.05, after which a rebound lymphocytosis up to 4.42x109/l±0.45 (4 weeks) was found. No significant changes in the numbers of erythrocytes and thrombocytes were observed throughout rIL2 administration.


   4. Cardiovascular changes
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Cardiovascular changes
5. Discussion
 References
 
4.1. Effect on ejection fraction
In 10 patients, biplane ejection fractions could be determined, and in two, only single plane ejection fractions could be assessed. Neither end systolic (49±12 at baseline vs. 50±16 cm3 at day 6) nor end diastolic volumes (109±28 vs. 103±38 cm3) were significantly changed after rhIL2. The left ventricular ejection fraction decreased from 54±7 at baseline to 50±6 at day 6 (P=0.012). The heart rate during echocardiography increased from 87±4 at baseline to 95±4 at day 6 (P=0.031). No differences in either systolic (baseline 137±16 vs. 134±11 at day 6) or diastolic blood pressure (78±12 vs. 76±9) were present. The individual LVEF responses for each patient are shown in Fig. 1.


Figure 1
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  		Fig. 1 The effect of recombinant interleukin-2 (rIL2) on left ventricular ejection fraction (LVEF). The lines represent the effect of rIL2 on LVEF in each individual patient. The 95% confidence interval of the change in LVEF was 0.60–7.94.

 
4.2. Effect on rhythm and HRV
No adverse effects on heart rhythm were observed. The average heart rate during 24 h recording did not significantly change after 1 day of rIL2 treatment (89±32 to 72±26 beats/min; n=7, P=0.057). At the end of the first treatment cycle it was slightly decreased from 79±26 to 66±26 beats/min (n=12, P=0.047). The frequency domain parameters, TP and LF were decreased after 1 day of treatment (Fig. 2a). No effect on the time domain parameters was present after 1 day of treatment except for a decreased S.D. [from 30.6±4.7 to 24.7±3.9; (n=12) P=0.008]. All frequency domain parameters (TP, HF and LF) were decreased after 5 days of rIL2 therapy (Fig. 2b). The only time domain parameter that decreased after the first rIL2 cycle was the S.D.A.N.N. [from 79.0±0.5 to 66.4±7.6; (n=7) P=0.008]. The ratio between HF and LF did not change during rIL2 treatment.


Figure 2
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  		Fig. 2 Frequency domain heart rate variability parameters: TP=total power (ms); HF=high frequency (ms); LF=low frequency (ms). (a) Effect after 1 day of treatment. (b) Effect after the complete (5 day) treatment cycle. Mean values±S.D.; significant differences are indicated *(P<0.05).

 
4.3. Cytokines and NOx
Serum cytokine levels were assayed in all patients. Pretreatment serum levels of IL-1β were below detectable limits in 12 patients; in five patients low levels (range, 8–25) were identified. No significant changes in serum IL-1β levels were observed at the end of the first IL2 cycle. Serum TNF{alpha} levels were undetectable before as well as after the first IL2 cycle. Pretreatment serum NOx levels increased from 14±4 to 27±7 µmol/l (P=0.007) after the first treatment cycle. No relation between NOx increase and change in LVEF was present.


   5. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Cardiovascular changes
 5. Discussion
References
 
In this study rIL2 caused a small reduction in LVEF in patients with a prior normal LV function. The role of cytokines in the pathogenesis of cardiac dysfunction in humans is increasingly recognized. Apart from lymphocytes, and endothelial cells, even myocytes can produce and release various kinds of cytokines. Furthermore, IL2 production of peripheral blood lymphocytes is increased in patients with dilated cardiomyopathy [5]. In patients with congestive heart failure T-cell infiltrates in the myocardium can be found [6]. T-cells are an important source of IL2. IL2 itself has negative inotropic activity and it is able to stimulate production of TNF{alpha} and other cytokines [17–20]. Increased plasma levels of TNF{alpha} have been found in patients with advanced heart failure [3]. Based on experimental and clinical data, TNF{alpha} and interferon have been implicated to exert negative inotropic activity by upregulating the expression of inducible nitric oxide (NO) synthase (iNOS) in cardiac myocytes [21,22].

In our study, low-dose SC IL2 therapy caused a small but significant decrease in the left ventricular ejection fraction. The concomitant increase in heart rate has to be considered in relation to LVEF changes. Several authors [23,24] have described the influence of heart rate changes on left ventricular ejection fraction. They did not find an influence of heart rate changes on ejection fraction during atrial pacing within the range of 80–100 beats/min [24] or even higher heart rates [23]. These studies were performed with radionuclide ventriculography. Also with two-dimensional echocardiography no negative effect was found on ejection fraction with a heart rate increase from 80 to 100 beats/min [25]. The small increase in heart rate during rIL2 administration, observed in the present study was within this range. The negative inotropic effects of IL2 in vitro have been described by Finkel et al. [1]. They used an in vitro contraction model with hamster myocardium and showed that IL2 reduced the contractility. In addition, Sobotka et al. [26] found negative inotropic effects of IL2 in an isolated rat heart model. In addition to the effects on systolic function found in this study, others found a decreased diastolic function during high doses of rIL2 treatment [27]. Therefore, the observed reduction in ejection fraction may be considered as a true in vivo negative inotropic effect.

In patients with an impaired left ventricular function and heart failure, counter-regulatory mechanisms, such as the sympathetic nervous system, are activated. Small changes in left ventricular function may evoke subtle changes of the autonomic balance, to maintain cardiovascular homeostasis.

Although, a small negative inotropic effect was found, there were no HRV signs of a compensatory elevated sympathetic activity. On the contrary, all frequency domain HRV parameters related with sympathetic activity decreased during IL2 administration. It has been suggested that cytokines such as TNF{alpha} increase sympathetic activity [28,29]. The present finding, that despite a negative inotropic effect, a decrease in sympathetic activity was found, supports the possibility of an effect of IL2 on autonomic balance opposite to that of TNF{alpha}.

Absence of an increase in TNF{alpha} or IL1β concentrations could have been caused by the timing of the blood sampling. Samples were taken at the end of the first rIL2 cycle on the morning after the last dose was given. Elevated TNF{alpha} concentrations have been found 48 h after a 5-day continuous rIL2 infusion [30]. Such a long-lasting increase has not been found after a bolus infusion [31]. In the latter study, only a transient increase in TNF{alpha} concentration was found that lasted less than 6 h. On the other hand, the low dose of rIL2 given in the present treatment regimen may have been too low for induction of TNF{alpha} or IL1β production. Interestingly, despite the timing of the blood sampling and despite the lower rIL2 dose, elevated NOx concentrations were found. Such an increase has also been described during continuous infusion by others [32].

A limitation of the study is the small number of patients and the absence of a placebo group. This is obviously due to the nature of the underlying disease: disseminated renal cell carcinoma is rare and it is unethical to perform a placebo-controlled study and hence withhold half of the patients a small change of curation.

In conclusion, low-dose subcutaneous recombinant interleukin-2 reduces left ventricular ejection fraction in patients without prior left ventricular dysfunction. It may also modulate the autonomic balance. In patients with pre-existent impaired left ventricular function, this may be of clinical importance. These findings support a pathophysiological role of cytokines in the development of heart failure.


   Acknowledgements
 
R.A. Tio is supported by the Netherlands Heart Foundation (Grant D95-019), the Hague, the Netherlands.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Cardiovascular changes
 5. Discussion
 References
 

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