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European Journal of Heart Failure 2001 3(3):331-333; doi:10.1016/S1388-9842(01)00129-5
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© 2001 European Society of Cardiology

Carvedilol increases plasma vascular endothelial growth factor (VEGF) in patients with chronic heart failure

Rudolf A. de Boera, Hans-Marc J. Siebelinka, René A. Tioa, Frans Boomsmab and Dirk J. van Veldhuisena,*

a University Hospital Groningen, Thoraxcenter, Department of Cardiology P.O. Box 30001, Groningen 9700 RB, Netherlands
b COEUR/Department of Internal Medicin, University Hospital Dijkzigt Rotterdam, Netherlands

* Corresponding author. Tel.:+31-503612355; fax: +31-503614391 E-mail address: d.j.van.veldhuisen{at}thorax.azg.nl (D.J. van Veldhuisen).

Received October 24, 2000; Revised December 15, 2000; Accepted January 17, 2001


   1. Background and aim of the study
Top
 1. Background and aim...
2. Methods
 3. Results
 4. Conclusions
 References
 
Vascular endothelial growth factor (VEGF) production leads to increased angiogenesis, which may reduce myocardial ischemia. Myocardial ischemia could lead to ischemic heart disease (IHD), which may cause chronic heart failure (CHF). Tissue ischemia has been reported in CHF [1], possibly due to a combination of increased oxygen demand (wall stress) and a decreased supply (coronary vasoconstriction and endothelial dysfunction). The use of beta-blockers has emerged as a beneficial treatment in patients with CHF [2–4], but whether increased VEGF production may play a role in this effect is unknown. Reducing heart rate (HR) may lead to increased myocardial VEGF production [5]. Therefore, we speculated that the use of beta-blockade was associated with myocardial VEGF production, which is reflected by increases in plasma VEGF [6,7]. This may cause counteraction of tissue ischemia, which is assumed to be beneficial in CHF [8].


   2. Methods
Top
 1. Background and aim...
 2. Methods
3. Results
 4. Conclusions
 References
 
We studied patients with CHF, who were clinically stable on angiotensin converting enzyme inhibition and diuretics, with or without digoxin. All patients had coronary artery disease (CAD) and an old myocardial infarction and there were no signs of myocardial ischemia during exercise testing. Left ventricular ejection fraction was <0.40. Exclusion criteria were previous or current beta-blocker use, use of calcium channel blockers and amiodarone. The study was a double-blind, placebo-controlled trial, in which patients were randomized to carvedilol or placebo (in a 2:1 ratio). Patients were treated according to an uptitration schedule (final doses ranging from 6.5 to 50 mg bid) for 3 months with the maximum dose tolerated. All patients gave their written informed consent. A 10-cm3 blood sample was taken at baseline and at the end of the study to determine various neurohormonal parameters. The blood was anticoagulated with EDTA and taken on ice, centrifuged for 15 min at 3000 rpm at 4°C and stored at –80°C. Immunoreactive VEGF was measured with an ELISA kit (R&D systems, Abingdon, UK, detectable range, 5–115 pg/ml). Plasma atrial natriuretic peptide (ANP, pmol/l), N-terminal atrial natriuretic peptide (nt-ANP, nmol/l) and brain natriuretic peptide (BNP, pmol/l), were measured (after SepPak extraction) with kits from the Nichols Institute (Nijmegen, Netherlands) and Peninsula Laboratories (California, USA), as described previously [9,10]. Results are given in means±S.E.M. For comparisons between groups an unpaired t-test for normally distributed variables and a Wilcoxon test for skewed variables were used.


   3. Results
Top
 1. Background and aim...
 2. Methods
 3. Results
4. Conclusions
 References
 
All patients completed the study. Main reason for not tolerating further uptitration was dizziness, no other side-effects were observed. In Table 1, it is shown that the two treatment groups were generally well-matched (carvedilol, n=12, placebo, n=5) at baseline (LVEF, NYHA class, blood pressure, etc.), although there was a higher heart rate in the placebo-treated group (P<0.01). Baseline VEGF concentrations were comparable to those previously reported in patients with severe CAD [6]. After treatment with carvedilol, natriuretic peptides, blood pressure and heart rate changed equally in patients on carvedilol and placebo (Table 1, the differences between alterations of clinical and neurohormonal parameters within groups were statistically tested, results are under ‘P-value delta’). In Fig. 1 it is depicted that plasma VEGF increased to a larger extent in patients on carvedilol (23.2±4.2 pg/ml to 34.8±4.4 pg/ml, P=0.06) than in patients on placebo (29.8±11.2 pg/ml to 20.7±9.8 pg/ml, P=0.54). This difference between the increase in the carvedilol treated group and the decrease in the placebo-treated group was significant (P=0.02).


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  		Table 1 Patients characteristics at baseline and after 3 months

 


Figure 1
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  		Fig. 1 Changes in plasma VEGF levels in patients with carvedilol and placebo. Patients on carvedilol showed an increase in plasma VEGF, while patients on placebo did not show a change in plasma VEGF. The difference between groups was statistically significant (P=0.02).

 

   4. Conclusions
Top
 1. Background and aim...
 2. Methods
 3. Results
 4. Conclusions
References
 
The present findings confer an appealing concept to explain the beneficial effect of beta-blockers in CHF and IHD. Since VEGF is upregulated by hypoxia-sensing pathways [11], it is not fully comprehensible why VEGF is produced by a potentially anti-ischaemic drug. However, several effects might account for this observation. The decrease in heart rate as is generally observed with beta-blockade causes a prolonged diastole during which capillary diameters are maximal. Enhanced diastolic filling causes both capillaries and myocytes to stretch, which might account for increased tissue induction of VEGF [5]. Previous studies have also shown that angiogenesis may occur, when heart rate is lowered [12]. In our study, patients with carvedilol had a significant decrease in heart rate, however, no individual correlation between heart rate and plasma VEGF levels was found, possibly due to randomization bias that caused a higher heart rate at baseline in patients with placebo.

Carvedilol might increase VEGF in concordance with the increase of other peptides, such as observed for natriuretic peptides in a large clinical trial [13]. In our study, patients generally had a better neurohormonal profile after initiation with carvedilol, while their plasma levels of ANP, N-terminal ANP, and BNP tended to increase, whereas, in patients on placebo no such trend was observed. Alternatively, we cannot exclude that ancillary properties of carvedilol, like alpha-blockade or an anti-oxidative effect [14], might have played a role in the VEGF production.

Clearly, there are limitations that have to be acknowledged. We only investigated a small number of patients. Results should, therefore, be interpreted with caution and results of this exploratory study should be confirmed in larger studies. Carvedilol is a combined alpha- and beta-blocker and has also anti-oxidative properties, so our findings may also be attributed to other effects of carvedilol than beta-blockade alone. We treated patients for only 3 months, so long term effects of beta-blockade on plasma VEGF levels still have to be established. All patients suffered from CHF due to IHD, so results cannot be extrapolated to patients with CHF due to other causes.

In conclusion, we found an increase of VEGF in CHF patients who used the beta-blocker carvedilol and we speculate that at least part of the anti-ischemic effect of beta-blockers in patients with heart disease may be due to increased angiogenesis by production of this pro-angiogenic cytokine.


   Acknowledgements
 
Dr. Van Veldhuisen is a clinical established investigator of Netherlands Heart Foundation (Grant D97-017); Dr. Tio is supported by Netherlands Heart Foundation (Grant D95-019).


   References
Top
 1. Background and aim...
 2. Methods
 3. Results
 4. Conclusions
 References
 

  1. van den Heuvel AFM, van Veldhuisen DJ, van der Wall EE, Blanksma PK, Siebelink HM, Vaalburg WM, van Gilst WH, Crijns HJGM. Regional myocardial blood flow reserve impairment and metabolic changes suggesting myocardial ischemia in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol (2000) 35:19–28.[Abstract/Free Full Text]
  2. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. carvedilol heart failure study group. N Engl J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
  3. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
  4. The MERIT Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet (1999) 353:2001–2007.[CrossRef][Web of Science][Medline]
  5. Zheng W, Brown MD, Brock TA, Bjercke RJ, Tomanek RJ. Bradycardia-induced coronary angiogenesis is dependent on vascular endothelial growth factor. Circ Res (1999) 85:192–198.[Abstract/Free Full Text]
  6. Symes JF, Losordo DW, Vale PR, et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg (1999) 68:830–836.[Abstract/Free Full Text]
  7. Tio RA, Tkebuchava T, Scheuermann TH, et al. Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium. Hum Gene Ther (1999) 10:2953–2960.[CrossRef][Web of Science][Medline]
  8. Pagano D, Camici PG, Bonser RS. Revascularization for chronic heart failure: a valid option? Eur J Heart Fail (1999) 1:269–273.[Free Full Text]
  9. van Veldhuisen DJ, Genth-Zotz S, Brouwer J, et al. High- vs. low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril. J Am Coll Cardiol (1998) 32:1811–1818.[Abstract/Free Full Text]
  10. Hillege HL, Girbes AR, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation (2000) 102:203–210.[Abstract/Free Full Text]
  11. Guillemin K, Krasnow MA. The hypoxic response: huffing and HIFing. Cell (1997) 89:9–12.[CrossRef][Web of Science][Medline]
  12. Wright AJ, Hudlicka O. Capillary growth and changes in heart performance induced by chronic bradycardial pacing in the rabbit. Circ Res (1981) 49:469–478.[Free Full Text]
  13. Richards AM, Doughty R, Nicholls MG, et al. Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Australia-New Zealand heart failure group. Circulation (1999) 99:786–792.[Abstract/Free Full Text]
  14. Frishman WH. Carvedilol. N Engl J Med (1998) 339:1759–1765.[Free Full Text]

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