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European Journal of Heart Failure 2004 6(2):195-201; doi:10.1016/j.ejheart.2003.09.005
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© 2003 European Society of Cardiology

Pentoxifylline in ischemic, hypertensive and idiopathic-dilated cardiomyopathy: effects on left-ventricular function, inflammatory cytokines and symptoms

Philipp Bahrmann*, Uta M. Hengst, Babara M. Richartz and Hans R. Figulla

Clinic of Internal Medicine I Friedrich-Schiller-University, Erlanger Allee 101, 07740 Jena, Germany

* Corresponding author. Tel.: +49-3641-939138; fax: +49-3641-939363. E-mail address: philipp.bahrmann{at}med.uni-jena.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Introduction: Tumor necrosis factor (TNF)-{alpha} and interleukin-6 (IL-6) are significantly elevated in patients with congestive heart failure (CHF). Pentoxifylline, a xanthin-derived agent, is known to inhibit the production of TNF-{alpha} and IL-6. Recent studies have shown that pentoxifylline produces an increase in ejection fraction, a decrease in left-ventricular chamber size and an improvement in clinical status in patients with idiopathic-dilated cardiomyopathy. Therefore, we studied the effects of pentoxifylline in ischemic, hypertensive and idiopathic-dilated cardiomyopathy.

Methods: Primary endpoint was left-ventricular ejection fraction (LVEF) assessed by contrast 2D echocardiography. Secondary endpoints were concentrations of TNF-{alpha}, IL-6, brain natriuretic peptide, maximal oxygen uptake (VO2 max) assessed by cardiopulmonary exercise testing and Minnesota Living with Heart Failure Questionnaire score or New York Heart Association scale.

Results: Forty-seven patients (31.9% ischemic, 21.3% hypertensive, 10.6% ischemic and hypertensive, 36.2% idiopathic-dilated cardiomyopathy) were randomly assigned to pentoxifylline 600 mg BID (n=23) or placebo (n=24) if they had a compensated CHF with a LVEF less than or equal to 40% and had taken their standard treatment consisting of angiotensin-converting enzyme inhibitors, diuretics and β-blockers for at least 3 months. Baseline demographic and clinical characteristics of each group were similar. Forty-one patients completed the study protocol and were analysed for primary and secondary endpoints. After 6 months of treatment, LVEF was unchanged in the pentoxifylline group compared with placebo (29±7 to 33±10% vs. 27±9 to 34±9%, respectively, P=NS). Also the secondary endpoints did not significantly change during follow-up.

Conclusion: Additional treatment with pentoxifylline is neutral with regard to left-ventricular function, inflammatory cytokines and symptoms in patients with ischemic, hypertensive and idiopathic-dilated cardiomyopathy.

Key Words: Cardiomyopathy • Heart failure treatment • Ejection fraction • Cytokines • Pentoxifylline

Received November 1, 2002; Revised May 16, 2003; Accepted September 15, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Because neuroendocrine pathophysiological changes, especially of the renin–angiotensin–aldosterone system and sympathetic nervous system, play an important role in the progression of congestive heart failure (CHF), angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic blockers are routinely used for therapy. Despite optimal inhibition of the neuroendocrine systems by ACE inhibitors and β-adrenergic blockers, left-ventricular function may deteriorate over time [1].

Other mechanisms contributing to cardiac dysfunction may be involved such as activation of various cytokines. Numerous experimental and clinical studies have shown that higher levels of cytokines are found in the circulation and in the myocardium of patients with CHF than in controls. Pro-inflammatory cytokines like tumor necrosis factor (TNF)-{alpha} and interleukin-6 (IL-6) might be involved in the progression of CHF, inducing cardiac dysfunction, apoptosis, ventricular remodeling and dilatation [2–9]. In consequence, studies have been undertaken with TNF antagonists. In a short-term pilot study, the soluble TNF receptor etanercept produced dose-dependent increases in ejection fraction, decreases in left-ventricular chamber size and improvement in clinical status [10,11]. However, large-scale trials (RENAISSANCE, RECOVER and RENEWAL) with etanercept in CHF were stopped early because of the low likelihood that the drug would show favourable effects. One possible explanation may be that the membrane-bound myocardial rather than the circulating TNF-{alpha} has an unfavourable effect on cardiac function [12]. But the membrane-bound myocardial TNF-{alpha} is not in range of the soluble TNF receptor etanercept.

Pentoxifylline, a xanthin-derived agent, is known to decrease the level of inflammatory mediators through transcriptional blockade of inflammatory gene expression [9]. Consequently, the production of mediators like TNF-{alpha}, IL-6 and Fas/Apo-1 is reduced [13–15]. Recent studies have shown that pentoxifylline produces an increase in ejection fraction, a decrease in left-ventricular chamber size and an improvement in clinical status in patients with idiopathic-dilated and ischemic cardiomyopathy [16–20]. Therefore, we studied the effects of pentoxifylline on left-ventricular function, inflammatory cytokines and symptoms in ischemic, hypertensive and idiopathic-dilated cardiomyopathy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Patients
Forty-seven patients with compensated CHF were included in a single centre, prospective, double-blind, randomised, placebo-controlled trial between January 1999 and May 2002. The Institutional Ethics Committee approved the study protocol and all patients gave written, informed consent. The investigation conformed with the principles outlined in the Declaration of Helsinki. Inclusion criteria were (1) age between 18 and 70 years, (2) stable New York Heart Association (NYHA) class II or III CHF due to ischemic and hypertensive cardiomyopathy or idiopathic-dilated cardiomyopathy, (3) left-ventricular ejection fraction (LVEF) less or equal than 40% assessed by contrast 2D echocardiography and (4) sinus rhythm. Exclusion criteria were (1) chronic obstructive pulmonary disease, (2) significant valvular heart disease, (3) disorders other than cardiomyopathy that could increase TNF-{alpha} and IL-6 concentrations (i.e. rheumatoid arthritis, sepsis, vasculitis, autoimmune disorders), (4) pregnancy, (5) severe liver disease (defined as enzymes more than twice the normal upper limit), (6) acute myocardial infarction, (7) haemorrhage and (8) any clinical condition judged by the investigators to prevent inclusion in the study.

The diagnosis of cardiomyopathy was based on the patient's medical history, echocardiography, coronary angiography and ventriculography. All patients had taken their standard treatment consisting of ACE inhibitors, diuretics and β-blockers for at least 3 months prior to inclusion. All patients were randomly assigned to pentoxifylline 600 mg BID (n=23) or placebo (n=24). Clinical examination, contrast 2D echocardiography, cardiopulmonary exercise testing and TNF-{alpha}, IL-6 and brain natriuretic peptide (BNP) plasma level measurements were made at the beginning and after 6 months. After 3 months, a meeting was scheduled for clinical evaluation of compliance and adverse events. Primary endpoint was LVEF assessed by contrast 2D echocardiography. Secondary endpoints were concentrations of TNF-{alpha}, IL-6, BNP, VO2 max assessed by cardiopulmonary exercise testing and Minnesota Living with Heart Failure Questionnaire (LHFQ) scores or NYHA class. We estimated the patient compliance by counting the number of returned pills. In our study, an average of 92% of pills were taken by patients with ischemic and hypertensive cardiomyopathy.

2.2. Chemokine and hormone measurement
Blood samples for the measurement of TNF-{alpha}, IL-6 and BNP were collected at baseline and after 6 months. Following venepuncture of the antecubital vein, plasma was collected on ice into serum separator tubes and within 30 min of collection centrifuged at approximately 1000xg for 10 min. Samples were aliquoted and stored at –80 °C. For the quantitative determination of human TNF-{alpha} and IL-6 concentrations in plasma, we used Quantikine HS immunoassays (R&D Systems, Minneapolis, USA). For the quantitative determination of BNP concentrations in plasma we used the Triage point-of-care assay system (Biosite Diagnostics, San Diego, USA). A few drops of blood were added to a small disposable test device and the device was inserted into the Triage Meter, a hand-held battery powered fluorometer.

2.3. Functional class and exercise test
For the assessment of LHFQ scores in patients with ischemic and hypertensive cardiomyopathy, we used a standardised questionnaire [21]. NYHA class in patients with idiopathic-dilated cardiomyopathy was recorded by a physician who was unaware of the treatment assigned. All patients performed incremental exercise tests on a cycle ergometer. In this protocol, measurements of gas exchange were made at rest, while the work rate was increased by 25 W every 2 min until the patient was limited by symptoms or was unable to continue safely and during a post-exercise period of 4 min. Simultaneously, the attending physician checked blood pressure and ECG recordings. VO2 max was determined according to the principles of exercise testing and interpretation by Wasserman [22].

2.4. Echocardiographic studies
All echocardiographic studies were performed and analysed by one person blinded to treatment assigned. Patients were studied supine in partial left lateral position using one echocardiographic machine (Power-Vision 8000, Toshiba, Tokyo, Japan). For all contrast studies, 10 ml of saline with 0.2 ml of microbubbles (Levovist, Schering, Berlin, Germany) was injected rapidly through a 20G cannula in the antecubital vein. Two-dimensional imaging was performed with gains and dynamic range optimized for microbubbles detection. The images were acquired in a digital format and stored. The measurements were manually traced on the screen and the built-in contour detection algorithm assessed LVEF. It was repeated 3 times, and the average was used for further calculations.

2.5. Statistical analysis
Treatment effects between the groups were compared by the Mann–Whitney U-test. Changes in the quantitative parameters at baseline compared to the results at 6 months within each treatment group were assessed using the Wilcoxon-matched pairs test. All probability values were calculated two sided. Data were expressed as mean±standard deviation. All calculations were done with SPSS for Windows (Version 11.0.1, SPSS, Chicago, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Baseline characteristics
In total, 47 patients (mean age 57±12 years, 3 women, 44 men) were randomly allocated to pentoxifylline 600 mg BID (n=23) or placebo (n=24). The cause of CHF in our study was in 31.9% ischemic, in 21.3% hypertensive, in 10.6% ischemic and hypertensive cardiomyopathy and in 36.2% idiopathic-dilated cardiomyopathy. Baseline characteristics of the study population were similar (Table 1).


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  		Table 1 Baseline characteristics of the study population

 
Forty-one patients (20 placebo, 21 pentoxifylline) completed the study protocol and were analysed for primary and secondary outcome (Table 2). Of the six patients who did not complete the study protocol, one patient died of gastrointestinal cancer (placebo), three patients complained about adverse events like bleeding (placebo) or side-effects like nausea or insomnia (placebo, pentoxifylline) and two patients failed to complete the course of study (placebo, pentoxifylline).


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  		Table 2 Results at baseline and at 6 months for all patients who completed the study period

 
Of 41 patients, 26 had ischemic and hypertensive cardiomyopathy and 15 idiopathic-dilated cardiomyopathy. Results for patients with ischemic and hypertensive cardiomyopathy are listed in Table 3 and for patients with idiopathic-dilated cardiomyopathy in Table 4.


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  		Table 3 Results at baseline and at 6 months for the patients with ischemic and hypertensive cardiomyopathy who completed the study period

 


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  		Table 4 Results at baseline and at 6 months for the patients with idiopathic-dilated cardiomyopathy who completed the study period

 
3.2. LV dimension and function
In both groups, end-diastolic and end-systolic diameters did not change during follow-up (Table 2). In both groups, LVEF significantly improved after 6 months of treatment compared to baseline (P<0.05). But differences in LVEF between both groups were not significant (Fig. 1). Subgroup analysis for patients with ischemic and hypertensive cardiomyopathy or idiopathic-dilated cardiomyopathy showed similar results (Tables 3 and 4).


Figure 1
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  		Fig. 1 Ejection fraction (EF, %) in the placebo group and the pentoxifylline group at baseline and at the end of the study. NS, non-significant. *P-value is within the group between baseline and 6 months; **P-value is the difference between the groups during the study.

 
3.3. TNF-{alpha}, IL-6 and BNP levels
In both groups, plasma levels of TNF-{alpha} and IL-6 remained unchanged after 6 months of treatment compared to baseline. In the placebo group, the BNP plasma levels significantly decreased from baseline to 6 months (P<0.05) while in the pentoxifylline group, they showed a trend toward a no significant decrease, indicating an improvement (Table 2). But if subgroups with ischemic and hypertensive cardiomyopathy or idiopathic-dilated cardiomyopathy were independently assessed, BNP did not significantly change (Tables 3 and 4).

3.4. LHFQ scores, hemodynamics and exercise tolerance
LHFQ scores and NYHA scale did not significantly change in both groups (Table 2). No significant difference was observed in systolic, diastolic blood pressure, heart rate and exercise time, but VO2 max significantly increased in both groups after 6 months (Table 2). But only the pentoxifylline-treated subgroup with ischemic and hypertensive cardiomyopathy showed significant increases in exercise time (P=0.006) and VO2 max (P=0.022) compared with placebo (Table 3).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
4.1. Pentoxifylline and left-ventricular function
The degree of improvement in LVEF for the pentoxifylline-treated group with idiopathic-dilated cardiomyopathy in our study was comparable to Skudicky's results [18]. But in contrast to our results, he did not find a significant increment in LVEF for the placebo-treated patients. Sliwa also showed an improvement in LVEF for patients with idiopathic-dilated cardiomyopathy but not for patients with peripartum cardiomyopathy under treatment with pentoxifylline [16,19,23].

The mechanism of the underlying principle is yet not clearly understood. Barnett and Touchon showed that the clinical improvement of pentoxifylline is related to its haemorheological properties [20]. Sliwa hypothesized that the inhibition of phosphodiesterase activity by pentoxifylline led to the improvement in LVEF via increase in intracellular cyclic adenosine monophosphate and decrease in TNF-{alpha} [16]. Skudicky also suspected that an inhibition of apoptosis by pentoxifylline is responsible for its beneficial effects on LVEF [17,18].

4.2. Pentoxifylline and inflammatory cytokines
In our study, baseline TNF-{alpha} plasma concentrations were 4–5 times higher compared to a previous study done by Skudicky et al. Nevertheless, baseline LV end-diastolic diameter and standard treatment consisting of ACE inhibitors, diuretics and β-blockers for at least 3 months were similar in both studies [18].

ACE inhibition and β-adrenergic blockade are associated with a dose-dependent decrease in cytokine levels [24,25]. Therefore, altered doses of ACE inhibitors and β-blockers may be taken into account for the different TNF-{alpha} plasma levels since the prescribed amount of pentoxifylline was similar in both studies. However, elevation of cytokine levels in CHF is inconstant. Even in severe CHF, normal values can be present [26]. Also, plasma levels of TNF-{alpha} and IL-6 may underestimate cardiac tissue levels. Cardiac intracellular cytokine concentrations are not taken into account by our measurements [27].

In our study, TNF-{alpha} and IL-6 levels after 6 months of treatment were not significantly reduced in comparison to baseline. Also, Skudicky did not find a significant change in TNF-{alpha} plasma concentration under the same dose of pentoxifylline [18]. The latter concluded that an additive treatment with carvedilol might have suppressed TNF-{alpha} plasma concentrations in their study since β-adrenergic blockade decreases myocardial expression of TNF-{alpha} [25].

But Sliwa et al. revealed a significant lower TNF-{alpha} plasma concentration in the pentoxifylline-treated group with idiopathic-dilated cardiomyopathy than in the placebo group [16,19]. Recently, Sliwa confirmed that pentoxifylline reduces the levels of both apoptotic mediators, TNF-{alpha} and Fas/Apo-1, in patients with severe, decompensated heart failure due to idiopathic-dilated cardiomyopathy [19]. But in both studies, patients were not treated with β-blockers. Therefore, Skudickys results are in agreement with our study.

4.3. Pentoxifylline and symptoms
Cardiovascular disability assessed by LHFQ scores or NYHA scale did not change in both groups. These findings are in contrast to the results of various other studies [16–18,20,23]. Several studies have demonstrated that circulating BNP concentrations increase with the severity of CHF based on NYHA classification [28,29]. In our study, additional treatment with pentoxifylline is neutral with regard to BNP levels and VO2 max, another objective assessment for grading severity. However, in patients with ischemic and hypertensive cardiomyopathy, pentoxifylline had a beneficial influence on VO2 max while placebo showed a trend towards an increase.

In conclusion, the results of this randomised, placebo-controlled study show that addition of pentoxifylline to treatment with ACE inhibitors, diuretics and β-blockers is neutral with regard to left-ventricular function, inflammatory cytokines and symptoms in patients with ischemic, hypertensive and idiopathic-dilated cardiomyopathy.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
We thank Mrs Köhler and Mrs Schmidt for excellent technical assistance.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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