Physicians' Academy for Cardiovascular Education

Ivabradine stimulates coronary collateral function in patients with chronic stable CAD

Literature - Gloeker et al. Heart. Nov 2013 - Heart. 2013 Nov 1


The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease.

 
Gloekler S, Traupe T, Stoller M, et al.
Heart. 2013 Nov 1. doi: 10.1136/heartjnl-2013-304880. [Epub ahead of print]
 

Background

Because size of a myocardial infarction (MI) is the main prognostic determinant in patients with coronary artery disease (CAD), reduction of infarct size is the main strategy to reduce cardiovascular mortality [1]. In addition to limiting coronary occlusion time, promotion of collateral artery growth may reduce infarct size [2]. In rabbits it has been shown that tangential fluid shear stress is the major trigger of collateral growth (arteriogenesis) [3]. In patients, lower-leg external counterpulsation during diastole creates tangential endothelial shear stress in addition to the flow signal related to cardiac stroke volume [4]. This effectively augmented coronary collateral function in patients with CAD [4,5].
Bradycardia at rest may be developed by exercise training . The coronary arteriogenic action of exercise may therefore be the result of extension of diastole, allowing prolonged action of tangential shear force on the endothelium [6]. In this context, a bradycardia-inducing drug, without the vasoconstrictive action of beta-blockers, could theoretically positively influence collateral function [7].
This study therefore tested the effect of ivabradine treatment for 6 months on coronary collateral function in 46 patients which chronic stable CAD. The primary endpoint of collateral flow index (CFI) was considered intraindividually and in comparison to placebo.
 

Main results

  • In the placebo group, CFI decreased from 0.140 + 0.097 at baseline to 0.109 + 0.067 after 6 months (P=0.12), while it increased from 0.111+0.078 at baseline to 0.156 + 0.089 at follow-up in the ivabradine group (P=0.0461).
  • Heart rate changed over the same period by +0.2 +7.8 beats/min in the placebo group, and by -8.1 + 11.6 beats/min in the ivabradine group (P=0.0090).
  • Intracoronary ECG ST segment shift normalised for R/S amplitude changed non-significantly from -0.241+0.324 at baseline to 0.291+0.303 at follow-up in the placebo group, while patients on ivabradine showed a decrease from 0.353 +0.279 at baseline to 0.181+0.163 after 6 months (P=0.0196).
  • The occurrence of angina pectoris during coronary occlusion for CFI measurement  changed from 15 to 18 out of 23 cases in the placebo group, and from 17 to 18 in the ivabradine group.
  • A weak inverse correlation was seen between change in heart rate during follow-up and the change in CFI was seen (r=-0.28, P=0.0441).
 

Conclusion

This is the first clinical study that showed that ivabradine had a beneficial effect on coronary collateral function in patients with chronic stable CAD, which was accompanied by diminished signs of ischaemia on ECG. This work provides the proof of concept that a non-beta-blocker bradycardia-inducing drug  has arteriogenic potential with regard to the human coronary collateral circulation.
                                       

References

1 Reimer KA, Ideker RE, Jennings RB. Effect of coronary occlusion site on ischaemic bed size and collateral blood flow in dogs. Cardiovasc Res 1981;15:668–74.
2 Seiler C, Engler R, Berner L, et al. Prognostic relevance of coronary collateral function: confounded or causal relationship? Heart 2013;99:1408–14.
3 Eitenmüller I, Volger O, Kluge A, et al. The range of adaptation by collateral vessels after femoral artery occlusion. Circ Res 2006;99:656–62.
4 Gloekler S, Meier P, de Marchi SF, et al. Coronary collateral growth by external counterpulsation: a randomised controlled trial. Heart 2010;96:202–7.
5 Buschmann EE, Utz W, Pagonas N, et al. Improvement of fractional flow reserve and collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial). Eur J Clin Invest 2009;39:866–75.
6 Vogel R, Traupe T, Steiger VS, et al. Physical coronary arteriogenesis: a human "model" of collateral growth promotion. Trends Cardiovasc Med 2010;20:129–33.
7 Schirmer SH, Degen A, Baumhäkel M, et al. Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis. Eur Heart J 2012;33:1223–31.

 
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