Effect of Heart Rate Reduction by Ivabradine
Objective To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD).
Methods This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure.
Results During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by –8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to −0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113).
Conclusions Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD.
In patients with coronary artery disease (CAD), the size of myocardial infarction is the main prognostic determinant after such an event. Hence, it is the primary strategy to reduce cardiovascular mortality by reducing infarct size which, in itself, is influenced by the duration of coronary occlusion, ischaemic area at risk for infarction, lack of collateral blood supply to the ischaemic zone, absence of ischaemic preconditioning before the infarct and myocardial oxygen consumption during the infarct. Aside from curtailing coronary occlusion time, the option of reducing infarct size by collateral artery growth promotion is appealing.
It has been demonstrated in rabbits undergoing femoral artery occlusion with connection of the distal arterial stump to the adjacent vein, that tangential fluid shear stress is the major trigger of collateral growth (arteriogenesis). Lower-leg external counterpulsation (ECP) triggered to occur during diastole induces a flow velocity signal and, thus, tangential endothelial shear stress in addition to the flow signal related to cardiac stroke volume. ECP has been shown to effectively augment coronary collateral function in patients with CAD. Since one of the effects of exercise training is the development of bradycardia at rest, an element of the coronary arteriogenic action of exercise could be the extension of diastole with prolonged action of tangential shear force on the endothelium. In this context, a bradycardia-inducing drug without the coronary vasoconstricting action of β-blockers could, theoretically, have a positive effect on collateral function. Therefore, the present investigation in patients with chronic, stable CAD tested the hypothesis that ivabradine given for 6 months augments coronary collateral function intraindividually and in comparison with placebo.
Abstract and Introduction
Abstract
Objective To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD).
Methods This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure.
Results During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by –8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to −0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113).
Conclusions Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD.
Introduction
In patients with coronary artery disease (CAD), the size of myocardial infarction is the main prognostic determinant after such an event. Hence, it is the primary strategy to reduce cardiovascular mortality by reducing infarct size which, in itself, is influenced by the duration of coronary occlusion, ischaemic area at risk for infarction, lack of collateral blood supply to the ischaemic zone, absence of ischaemic preconditioning before the infarct and myocardial oxygen consumption during the infarct. Aside from curtailing coronary occlusion time, the option of reducing infarct size by collateral artery growth promotion is appealing.
It has been demonstrated in rabbits undergoing femoral artery occlusion with connection of the distal arterial stump to the adjacent vein, that tangential fluid shear stress is the major trigger of collateral growth (arteriogenesis). Lower-leg external counterpulsation (ECP) triggered to occur during diastole induces a flow velocity signal and, thus, tangential endothelial shear stress in addition to the flow signal related to cardiac stroke volume. ECP has been shown to effectively augment coronary collateral function in patients with CAD. Since one of the effects of exercise training is the development of bradycardia at rest, an element of the coronary arteriogenic action of exercise could be the extension of diastole with prolonged action of tangential shear force on the endothelium. In this context, a bradycardia-inducing drug without the coronary vasoconstricting action of β-blockers could, theoretically, have a positive effect on collateral function. Therefore, the present investigation in patients with chronic, stable CAD tested the hypothesis that ivabradine given for 6 months augments coronary collateral function intraindividually and in comparison with placebo.
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