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Ivabradine improves coronary flow reserve in patients with stable coronary artery disease
Atherosclerosis 215 (2011) 160–165
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Ivabradine improves coronary flow reserve in patients with stable coronary artery disease Emmanouil I. Skalidis a,∗ , Michalis I. Hamilos a , Gregory Chlouverakis b , Evangelos A. Zacharis a , Panos E. Vardas a a b
Cardiology Department, University Hospital of Heraklion, Crete, Greece Biostatistics Lab, University of Crete, Greece
a r t i c l e
i n f o
Article history: Received 28 August 2010 Received in revised form 23 October 2010 Accepted 27 November 2010 Available online 5 December 2010 Keywords: Coronary artery disease Coronary blood flow Ivabradine Microcirculation
a b s t r a c t Objectives: Although treatment with ivabradine reduces the incidence of hospital admissions for myocardial infarction and coronary revascularisation, there are no data concerning its effect on coronary circulation. The purpose of this study was to assess the effects of ivabradine on coronary flow velocity and flow reserve (CFR) in patients with stable coronary artery disease (CAD). Methods: During diagnostic coronary angiography (baseline), twenty-one patients with stable CAD underwent coronary flow velocity measurements (APV cm/s) in a non-culprit vessel, using a Doppler guidewire, at rest (r) and after adenosine administration to achieve maximal hyperaemia (h). During programmed coronary intervention in the culprit vessel, the same measurements were repeated one week after treatment with ivabradine (5 mg twice daily), both at the intrinsic heart rate and at a paced heart rate identical to that before treatment. CFR was defined as h-APV/r-APV. Results: Heart rate was significantly lower after treatment with ivabradine (78 ± 14 bpm vs 65 ± 9 bpm, p < 0.001). Also, a reduction of r-APV (17.0 ± 5.5 vs 19.7 ± 7.6, p = 0.003) and augmentation of h-APV (57.9 ± 17.8 vs 53.5 ± 21.4, p = 0.009) leading to CFR improvement (3.51 ± 0.81 vs 2.78 ± 0.61, p < 0.001) were observed. During pacing, although r-APV reverted to values similar to those before treatment (20.0 ± 6.5 vs 19.7 ± 7.6, p = NS), a sustained improvement in h-APV was observed (59.5 ± 19.7 vs 53.5 ± 21.4, p = 0.007) and CFR remained higher than before treatment (3.04 ± 0.66 vs 2.78 ± 0.61, p < 0.001). Conclusions: Ivabradine treatment significantly improves hyperaemic coronary flow velocity and CFR in patients with stable CAD. These effects remain even after heart rate correction indicating improved microvascular function. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Heart rate is a major determinant of myocardial oxygen consumption under physiological and pathological conditions and heart rate reduction is one of the main therapeutic targets in patients with myocardial ischaemia. In addition, resting heart rate has prognostic implications. A high resting heart rate is a predictor for total and cardiovascular mortality, independently of other risk factors, in patients with stable coronary artery disease [1,2]. Moreover, in patients with stable coronary artery disease and left ventricular systolic dysfunction, a heart rate >70 bpm is associated with a greater risk for hospitalisation due
∗ Corresponding author at: Cardiology Department, Heraklion University Hospital, Lofos Livadas, P.O. Box 1352, 71110 Heraklion, Greece. Tel.: +30 2810 392706; fax: +30 2810 542055. E-mail address: [email protected] (E.I. Skalidis). 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.11.035
to heart failure, myocardial infarction and need for coronary revascularisation [2]. Although this cutoff value of 70 bpm was stronger for heart failure than for myocardial ischaemia endpoints, heart rate reduction with ivabradine treatment, in the recently published BEAUTIFUL trial, did not affect heart failure endpoints but, surprisingly, significantly reduced hospitalisation for myocardial infarction and coronary revascularisation in these patients [3]. The pathophysiological basis for this discrepancy remains unknown. Although coronary flow reserve predicts adverse cardiovascular long-term outcome (ischaemia endpoints) [4,5] and decisions for coronary revascularisation are based on a physiological assessment of coronary artery lesions [6,7], there are no data in humans concerning the effect of ivabradine on coronary haemodynamics. Accordingly, the purpose of this study was to assess the effects of ivabradine on coronary blood flow velocity and flow reserve (CFR) in patients with stable coronary artery disease.
E.I. Skalidis et al. / Atherosclerosis 215 (2011) 160–165
161
2. Methods
2.3. Statistical analysis
2.1. Patients
Summary descriptive statistics are presented as mean values ± standard deviation for continuous and as frequency (%) for categorical variables. APV and CFR were measured for each patient under three different conditions (baseline, ivabradine, ivabr-pace). Repeated measures analysis of variance (ANOVA) with one within factors was used to evaluate parameter changes between the three conditions. In case of significant findings a post-hoc Bonferroni adjusted t-test was used to pinpoint differences. The criterion of significance was set at 5% for all analyses.
The study assessed 21 patients with stable coronary artery disease of one or two vessels, who were eligible for percutaneous coronary intervention and who consented to undergo functional assessment of the coronary circulation following the completion of programmed routine cardiac catheterisation. The following exclusion criteria were applied: rhythm other than sinus rhythm, resting heart rate <60 bpm, sick sinus syndrome, sinoatrial or atrioventricular block, patients with tortuous anatomy, previous myocardial infarction or coronary revascularisation, and patients with congenital or valvular heart disease. All medications were continued in the same dosage during the study period. No medications were added before the completion of the study. All patients gave their written informed consent to participation in the study. The study protocol was approved by the hospital’s Ethics Committee. 2.2. Coronary flow velocity measurements Immediately following coronary angiography the culprit vessel(s) for coronary intervention were defined according to guidelines and a non-culprit vessel was selected for coronary flow measurements. The non-culprit vessel was selectively engaged with a guide catheter. Intracoronary nitroglycerine (200 g) was given every 15 min during the procedure to prevent catheterinduced coronary artery spasm and to avoid changes in coronary artery diameter. A 0.014 , 15 MHz Doppler guide wire (FloWire, Volcano Therapeutics, Inc.) was advanced through the catheter to the non-culprit vessel. The origin of a side branch or a bend of the artery was used as a landmark. The tip of the wire was positioned before or after the landmark in a non-tapered segment of the vessel and the position of the wire was recorded for review when repeat measurements were performed. Frequency analysis of the Doppler signals was carried out in real time by fast Fourier transform using a velocimeter (FloMap, Volcano Therapeutics, Inc.). Once resting flow-velocity data had been obtained, a 30 g bolus injection of intracoronary adenosine was given so that data during hyperaemia could be obtained. To confirm that maximal hyperaemia had been achieved, increasing doses in 30 g increments were infused until a plateau in flow velocity was reached. All measurements were made in the non-culprit vessel: 1. during diagnostic coronary angiography (Baseline); 2. during programmed coronary intervention in the culprit vessel(s) (before the procedure), one week after treatment with ivabradine (5 mg twice daily), at the same location at the intrinsic heart rate (Ivabradine) and 3. at a pacing heart rate identical to baseline (Ivabr-pace), accomplished by pacing the right atrial appendage via a temporary pacing lead. Time-averaged peak coronary flow velocity (APV cm/s) was measured and CFR was determined as the ratio of APV at maximal hyperaemia to APV at rest. Since at the beginning of the diastolic period extravascular compressive forces are minimised and coronary perfusion pressure is highest, maximum coronary blood flow occurs in the early diastolic period [8]. Consequently, changes in maximum diastolic peak coronary flow velocity (MPV cm/s) at maximal hyperaemia were used as an index of early diastolic blood flow alterations. Pretreatment and measurements were carried out as previously described [9].
3. Results Of the 21 patients initially included in the study two had poor quality recordings: these patients were excluded from the final analysis. For the remaining 19 patients (14 men) the mean age was 63 ± 9 years. Ten (53%) of them had dyslipidaemia, eight (32%) had diabetes mellitus and six (32%) had hypertension. Eight patients (42%) were taking b-blockers and the mean ejection fraction was 54 ± 8. The left anterior descending artery was the measured vessel in 12 (63%) patients, the left circumflex coronary artery in 5 (26%) and the right coronary artery in 2 (11%) patients. 3.1. Heart rate and arterial blood pressure Heart rate, systolic and diastolic blood pressures recorded at baseline, ivabradine and ivabr-pace are given in Table 1. There was a significant reduction of heart rate during ivabradine treatment compared to baseline (95% confidence interval of mean difference: −18 to −8, p < 0.001). 3.2. Coronary flow velocity measurements The Doppler parameters recorded at rest and at maximum hyperaemia are given in Table 1. A representative case is shown in Supplementary files (figure and baseline, ivabradine and ivabr-pace records). 3.2.1. Resting time-averaged peak coronary flow velocity There was a significant effect of ivabradine treatment on r-APV (Fig. 1). Resting-APV at ivabradine was significantly lower than at baseline (95% confidence interval of mean difference: −1.0 to −4.3, p = 0.003). However, there was no significant difference in r-APV between ivabr-pace and baseline (95% confidence interval of mean difference: −1.1 to 1.7, p = 0.6). Table 1 Doppler and other parameters recorded at baseline (Baseline) and one week after Ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that before treatment (Ivabr-pace). Baseline HR (beats/min) SBP (mm Hg) DBP (mm Hg) r-APV (cm/s) h-APV (cm/s) h-MPV (cm/s) CFR
78 137 76 19.7 53.5 84.9 2.78
± ± ± ± ± ± ±
14 20 13 7.6 21.4 32.1 0.61
Ivabradine 65 138 74 17.0 57.9 95.4 3.51
± ± ± ± ± ± ±
9* 17 10 5.5* 17.8* 27.4* 0.81*
Ivabr-pace 78 141 73 20.0 59.5 97.7 3.04
± ± ± ± ± ± ±
14 21 12 6.5 19.7* 29.7* 0.66*
APV – time-averaged peak flow velocity, Baseline – before treatment, CFR – coronary flow reserve, DBP – diastolic blood pressure, h – hyperaemia, HR – heart rate, Ivabradine – one week after ivabradine treatment at the intrinsic heart rate, Ivabr-pace – one week after ivabradine treatment at a paced rate identical to that of baseline, MPV – time-averaged maximum peak flow velocity, r – resting, SBP – systolic blood pressure. * p < 0.01 compared to baseline.
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Fig. 1. Box-plots of resting (r) time-averaged peak coronary flow velocity (APV cm/s) at baseline (Baseline) and after one week’s ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that at baseline (Ivabr-pace).
3.2.2. Hyperaemia time-averaged and maximum peak coronary flow velocity There was a significant effect of ivabradine treatment on both MPV and APV (Fig. 2). MPV and h-APV at ivabradine were significantly higher than at baseline (95% confidence intervals of mean difference: 4.7 to 16.2, p = 0.001 and 1.2 to 7.6, p = 0.009 respectively). Similarly, MPV and h-APV at ivabr-pace was significantly higher than at baseline (95% confidence intervals of mean difference: 6.3 to 19.3, p = 0.001 and 1.9 to 10.2, p = 0.007 respectively). 3.2.3. Coronary flow reserve Ivabradine treatment also had a significant effect on CFR (Fig. 3). CFR after ivabradine was significantly higher than at baseline (95% confidence interval of mean difference: 0.51 to 0.93, p < 0.001). Similarly, CFR at ivabr-pace was significantly higher than at baseline (95% confidence interval of mean difference: 0.13 to 0.38, p < 0.001). 4. Discussion We found that ivabradine treatment significantly reduces resting coronary blood flow velocity and increases hypaeremic coronary flow velocity, leading to CFR improvement in patients with stable CAD. Also, although resting coronary blood flow velocity returns to the pre-treatment values after heart rate correction, the enhancement of hyperaemic coronary blood flow velocity remains. Therefore, even after heart rate correction, CFR remains significantly higher than the pre-treatment values, indicating improved microvascular function with ivabradine treatment. Heart rate is a major determinant of myocardial oxygen consumption and therefore the resting myocardial blood flow and coronary flow reserve. However, hyperaemic coronary blood flow in the absence of haemodynamically significant epicardial coronary artery stenosis is not heart-rate dependent and is associated with the integrity (either functional or structural) of the microcirculation [10]. Ivabradine is a selective inhibitor of the If -channel and reduces heart rate by inhibition of the If -channels in the sinus node. Consequently, changes in r-APV are easily explained by corresponding
alterations in heart rate during ivabradine treatment, both at the intrinsic heart rate and at a pacing rate identical to that before treatment. Hyperaemic coronary blood flow velocity increases after ivabradine treatment because the diastolic period is prolonged (per cardiac beat and per minute) as expected. Nevertheless, the mechanism underlying h-APV enhancement after heart rate correction is hypothetical. The most probable explanation is the improvement of ventricular relaxation caused by ivabradine treatment, which in turn enhances coronary blood flow velocity during hyperaemia. The If -channel gene was first discovered in the mouse brain. Four isoforms of the hyperpolarisation-activated, cyclic nucleotidegating channel protein (HCN 1,2,3,4) have been identified in animal hearts [11,12]. In the animal heart, HCN4 levels are higher than HCN1 in the sinus node while HCN2 are lower in ventricular myocardium. Nevertheless, HCN2 is considered to be the dominant isoform because of the larger mass of ventricular myocytes compared to sinus tissue [13]. Ivabradine, by blocking the ventricular If -channel, reduces entry of Na+ into the myocytes, leading to reduced cytosolic calcium. Moreover, ivabradine improves the reuptake of calcium by the sarcoplasmic reticulum. The cumulative effect of these ivabradine actions is an improvement of ventricular relaxation [14,15]. Furthermore, Heusch et al. [16] and Fox et al. [17] have previously reported a beneficial effect of ivabradine that was at least in part heart-rate independent and support the pleiotropic actions of ivabradine [18,19]. In addition, it is possible enhanced diastolic relaxation may increase early diastolic coronary blood flow by a “suction effect” [20]. In fact, the increase in h-APV after ivabradine treatment is not related only to the increase of the diastolic period, but also to the overall improvement of flow, since h-MPV—which represents early diastolic flow—is higher. Therefore, as can be seen in Fig. 4, despite the shortening of the diastolic period after heart rate correction by pacing, the improvement of flow velocity remains because the average flow velocity (C) which will replace the missing period (B) per minute is not less than the average flow during the missing period (missing period = diastolic time at ivabradine − diastolic time at ivabr-pace).
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Fig. 2. Box-plots of maximal hyperaemia (h) time-averaged peak coronary flow velocity (APV cm/s) at baseline (Baseline) and after one week’s ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that at baseline (Ivabr-pace).
4.1. Previous studies To the best of our knowledge, there are only two invasive studies that showed an improvement of CFR in response to pharmacological intervention in patients with stable coronary artery disease. One involved metoprolol [21] and the other nebivolol [22]. These studies (from the same research group) used different methodologies. Both were carried out in the post-stenting
artery of patients with coronary artery disease; significant changes in rate pressure were detected after treatment, since heart rate was not stable, and vasodilating actions were allowed because intracoronary nitroglycerine was not used—at least in the second study. Consequently, the observed increase in CFR could be explained by differences in heart rate, endothelial function and/or coronary artery diameter, and not as a result of an improvement in microvas-
Fig. 3. Box-plots of coronary flow velocity reserve (CFR) at baseline (Baseline) and after one week’s ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that at baseline (Ivabr-pace).
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cular function. In support of this are the control group of the latter study, but also the control group from a study recently published from our department [23]. In both of these, no changes in hyperaemic coronary flow velocity were observed with b-blocker treatment. 4.2. Limitations In the present study, coronary blood flow was assessed using intracoronary Doppler measurements of flow velocity. Although flow velocity does not actually represent volumetric flow, extensive animal studies have proved the accuracy of this technique in the assessment of changes of coronary flow [24,25]. Consequently, given that flow velocities were measured at the same location under the three different conditions (baseline, ivabradine, ivabrpace), while changes in coronary artery diameter were avoided by intracoronary nitroglycerine administration, it seems reasonable to assume that flow velocity at maximal hyperaemia provided a valid means of comparing coronary flow at the three different conditions. Nevertheless, minimal changes in cross-sectional area could not be excluded. Unfortunately, we have no data on ventricular relaxation. Such data would be very helpful in confirming our hypothetical underlying mechanism of improved ventricular relaxation with ivabradine . This could be the object of a future study. Given the short and long-term reproducibility (repeatability) of baseline and hyperaemic myocardial blood flow measurements [26,27], the absence of a control group in this study does not weaken our conclusions. 4.3. Possible implications Although the pathophysiological explanation of our findings remains to be elucidated by other studies, if the effect of ivabradine on microvascular function is confirmed in similar studies then we have an additional therapeutic approach for patients with coronary artery disease, targeting the microvascular function, with profound clinical implications [4,5]. 4.4. Conclusions This study shows for the first time that ivabradine treatment significantly improves hyperaemic coronary flow velocity and CFR in patients with stable CAD. These effects remain even after heart rate correction, indicating improved microvascular function. Conflict of interest No financial support was received for this study and none of the authors has a conflict of interest. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.atherosclerosis.2010.11.035. Fig. 4. Comparison of maximal hyperaemia time-averaged peak coronary flow velocity recordings. (A) After one week’s ivabradine treatment at the intrinsic heart rate, (B) the missing diastolic flow after heart rate correction and (C) at a paced rate identical to that of baseline.
References [1] Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967–74. [2] Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372:817–21. [3] Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:807–16.
E.I. Skalidis et al. / Atherosclerosis 215 (2011) 160–165 [4] Britten MB, Zeiher AM, Schächinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron Artery Dis 2004;15:259–64. [5] Herzog BA, Husmann L, Valenta I, et al. Long-term prognostic value of 13Nammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol 2009;54:150–6. [6] Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49:2105–11. [7] Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. [8] Gould KL. Pressure-flow characteristics of coronary stenoses in unsedated dogs at rest and during coronary vasodilation. Circ Res 1978;43:242–53. [9] Skalidis EI, Kochiadakis GE, Koukouraki SI, et al. Phasic coronary flow pattern and flow reserve in patients with left bundle branch block and normal coronary arteries. J Am Coll Cardiol 1999;33:1338–46. [10] Rossen JD, Winniford MD. Effect of increases in heart rate and arterial pressure on coronary flow reserve in humans. J Am Coll Cardiol 1993;21:343–8. [11] Accili EA, Proenza C, Baruscotti M, et al. From funny current to HCN channels: 20 years of excitation. News Physiol Sci 2002;17:32–7. [12] Ludwig A, Zong X, Jeglitsch M, et al. A family of hyperpolarization-activated mammalian cation channels. Nature 1998;393:587–91. [13] Shi W, Wymore R, Yu H, et al. Distribution and prevalence of hyperpolarizationactivated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 1999;85:e1–6. [14] Ceconi C, Cargnoni A, Francolini G, et al. Heart rate reduction with ivabradine improves energy metabolism and mechanical function of isolated ischaemic rabbit heart. Cardiovasc Res 2009;84:72–82. [15] Gewirtz H. ’Funny’ current: if heart rate slowing is not the best answer, what might be? Cardiovasc Res 2009;84:9–10. [16] Heusch G, Skyschally A, Gres P, et al. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabra-
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Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Ivabradine improves coronary flow reserve in patients with stable coronary artery disease Emmanouil I. Skalidis a,∗ , Michalis I. Hamilos a , Gregory Chlouverakis b , Evangelos A. Zacharis a , Panos E. Vardas a a b
Cardiology Department, University Hospital of Heraklion, Crete, Greece Biostatistics Lab, University of Crete, Greece
a r t i c l e
i n f o
Article history: Received 28 August 2010 Received in revised form 23 October 2010 Accepted 27 November 2010 Available online 5 December 2010 Keywords: Coronary artery disease Coronary blood flow Ivabradine Microcirculation
a b s t r a c t Objectives: Although treatment with ivabradine reduces the incidence of hospital admissions for myocardial infarction and coronary revascularisation, there are no data concerning its effect on coronary circulation. The purpose of this study was to assess the effects of ivabradine on coronary flow velocity and flow reserve (CFR) in patients with stable coronary artery disease (CAD). Methods: During diagnostic coronary angiography (baseline), twenty-one patients with stable CAD underwent coronary flow velocity measurements (APV cm/s) in a non-culprit vessel, using a Doppler guidewire, at rest (r) and after adenosine administration to achieve maximal hyperaemia (h). During programmed coronary intervention in the culprit vessel, the same measurements were repeated one week after treatment with ivabradine (5 mg twice daily), both at the intrinsic heart rate and at a paced heart rate identical to that before treatment. CFR was defined as h-APV/r-APV. Results: Heart rate was significantly lower after treatment with ivabradine (78 ± 14 bpm vs 65 ± 9 bpm, p < 0.001). Also, a reduction of r-APV (17.0 ± 5.5 vs 19.7 ± 7.6, p = 0.003) and augmentation of h-APV (57.9 ± 17.8 vs 53.5 ± 21.4, p = 0.009) leading to CFR improvement (3.51 ± 0.81 vs 2.78 ± 0.61, p < 0.001) were observed. During pacing, although r-APV reverted to values similar to those before treatment (20.0 ± 6.5 vs 19.7 ± 7.6, p = NS), a sustained improvement in h-APV was observed (59.5 ± 19.7 vs 53.5 ± 21.4, p = 0.007) and CFR remained higher than before treatment (3.04 ± 0.66 vs 2.78 ± 0.61, p < 0.001). Conclusions: Ivabradine treatment significantly improves hyperaemic coronary flow velocity and CFR in patients with stable CAD. These effects remain even after heart rate correction indicating improved microvascular function. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Heart rate is a major determinant of myocardial oxygen consumption under physiological and pathological conditions and heart rate reduction is one of the main therapeutic targets in patients with myocardial ischaemia. In addition, resting heart rate has prognostic implications. A high resting heart rate is a predictor for total and cardiovascular mortality, independently of other risk factors, in patients with stable coronary artery disease [1,2]. Moreover, in patients with stable coronary artery disease and left ventricular systolic dysfunction, a heart rate >70 bpm is associated with a greater risk for hospitalisation due
∗ Corresponding author at: Cardiology Department, Heraklion University Hospital, Lofos Livadas, P.O. Box 1352, 71110 Heraklion, Greece. Tel.: +30 2810 392706; fax: +30 2810 542055. E-mail address: [email protected] (E.I. Skalidis). 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.11.035
to heart failure, myocardial infarction and need for coronary revascularisation [2]. Although this cutoff value of 70 bpm was stronger for heart failure than for myocardial ischaemia endpoints, heart rate reduction with ivabradine treatment, in the recently published BEAUTIFUL trial, did not affect heart failure endpoints but, surprisingly, significantly reduced hospitalisation for myocardial infarction and coronary revascularisation in these patients [3]. The pathophysiological basis for this discrepancy remains unknown. Although coronary flow reserve predicts adverse cardiovascular long-term outcome (ischaemia endpoints) [4,5] and decisions for coronary revascularisation are based on a physiological assessment of coronary artery lesions [6,7], there are no data in humans concerning the effect of ivabradine on coronary haemodynamics. Accordingly, the purpose of this study was to assess the effects of ivabradine on coronary blood flow velocity and flow reserve (CFR) in patients with stable coronary artery disease.
E.I. Skalidis et al. / Atherosclerosis 215 (2011) 160–165
161
2. Methods
2.3. Statistical analysis
2.1. Patients
Summary descriptive statistics are presented as mean values ± standard deviation for continuous and as frequency (%) for categorical variables. APV and CFR were measured for each patient under three different conditions (baseline, ivabradine, ivabr-pace). Repeated measures analysis of variance (ANOVA) with one within factors was used to evaluate parameter changes between the three conditions. In case of significant findings a post-hoc Bonferroni adjusted t-test was used to pinpoint differences. The criterion of significance was set at 5% for all analyses.
The study assessed 21 patients with stable coronary artery disease of one or two vessels, who were eligible for percutaneous coronary intervention and who consented to undergo functional assessment of the coronary circulation following the completion of programmed routine cardiac catheterisation. The following exclusion criteria were applied: rhythm other than sinus rhythm, resting heart rate <60 bpm, sick sinus syndrome, sinoatrial or atrioventricular block, patients with tortuous anatomy, previous myocardial infarction or coronary revascularisation, and patients with congenital or valvular heart disease. All medications were continued in the same dosage during the study period. No medications were added before the completion of the study. All patients gave their written informed consent to participation in the study. The study protocol was approved by the hospital’s Ethics Committee. 2.2. Coronary flow velocity measurements Immediately following coronary angiography the culprit vessel(s) for coronary intervention were defined according to guidelines and a non-culprit vessel was selected for coronary flow measurements. The non-culprit vessel was selectively engaged with a guide catheter. Intracoronary nitroglycerine (200 g) was given every 15 min during the procedure to prevent catheterinduced coronary artery spasm and to avoid changes in coronary artery diameter. A 0.014 , 15 MHz Doppler guide wire (FloWire, Volcano Therapeutics, Inc.) was advanced through the catheter to the non-culprit vessel. The origin of a side branch or a bend of the artery was used as a landmark. The tip of the wire was positioned before or after the landmark in a non-tapered segment of the vessel and the position of the wire was recorded for review when repeat measurements were performed. Frequency analysis of the Doppler signals was carried out in real time by fast Fourier transform using a velocimeter (FloMap, Volcano Therapeutics, Inc.). Once resting flow-velocity data had been obtained, a 30 g bolus injection of intracoronary adenosine was given so that data during hyperaemia could be obtained. To confirm that maximal hyperaemia had been achieved, increasing doses in 30 g increments were infused until a plateau in flow velocity was reached. All measurements were made in the non-culprit vessel: 1. during diagnostic coronary angiography (Baseline); 2. during programmed coronary intervention in the culprit vessel(s) (before the procedure), one week after treatment with ivabradine (5 mg twice daily), at the same location at the intrinsic heart rate (Ivabradine) and 3. at a pacing heart rate identical to baseline (Ivabr-pace), accomplished by pacing the right atrial appendage via a temporary pacing lead. Time-averaged peak coronary flow velocity (APV cm/s) was measured and CFR was determined as the ratio of APV at maximal hyperaemia to APV at rest. Since at the beginning of the diastolic period extravascular compressive forces are minimised and coronary perfusion pressure is highest, maximum coronary blood flow occurs in the early diastolic period [8]. Consequently, changes in maximum diastolic peak coronary flow velocity (MPV cm/s) at maximal hyperaemia were used as an index of early diastolic blood flow alterations. Pretreatment and measurements were carried out as previously described [9].
3. Results Of the 21 patients initially included in the study two had poor quality recordings: these patients were excluded from the final analysis. For the remaining 19 patients (14 men) the mean age was 63 ± 9 years. Ten (53%) of them had dyslipidaemia, eight (32%) had diabetes mellitus and six (32%) had hypertension. Eight patients (42%) were taking b-blockers and the mean ejection fraction was 54 ± 8. The left anterior descending artery was the measured vessel in 12 (63%) patients, the left circumflex coronary artery in 5 (26%) and the right coronary artery in 2 (11%) patients. 3.1. Heart rate and arterial blood pressure Heart rate, systolic and diastolic blood pressures recorded at baseline, ivabradine and ivabr-pace are given in Table 1. There was a significant reduction of heart rate during ivabradine treatment compared to baseline (95% confidence interval of mean difference: −18 to −8, p < 0.001). 3.2. Coronary flow velocity measurements The Doppler parameters recorded at rest and at maximum hyperaemia are given in Table 1. A representative case is shown in Supplementary files (figure and baseline, ivabradine and ivabr-pace records). 3.2.1. Resting time-averaged peak coronary flow velocity There was a significant effect of ivabradine treatment on r-APV (Fig. 1). Resting-APV at ivabradine was significantly lower than at baseline (95% confidence interval of mean difference: −1.0 to −4.3, p = 0.003). However, there was no significant difference in r-APV between ivabr-pace and baseline (95% confidence interval of mean difference: −1.1 to 1.7, p = 0.6). Table 1 Doppler and other parameters recorded at baseline (Baseline) and one week after Ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that before treatment (Ivabr-pace). Baseline HR (beats/min) SBP (mm Hg) DBP (mm Hg) r-APV (cm/s) h-APV (cm/s) h-MPV (cm/s) CFR
78 137 76 19.7 53.5 84.9 2.78
± ± ± ± ± ± ±
14 20 13 7.6 21.4 32.1 0.61
Ivabradine 65 138 74 17.0 57.9 95.4 3.51
± ± ± ± ± ± ±
9* 17 10 5.5* 17.8* 27.4* 0.81*
Ivabr-pace 78 141 73 20.0 59.5 97.7 3.04
± ± ± ± ± ± ±
14 21 12 6.5 19.7* 29.7* 0.66*
APV – time-averaged peak flow velocity, Baseline – before treatment, CFR – coronary flow reserve, DBP – diastolic blood pressure, h – hyperaemia, HR – heart rate, Ivabradine – one week after ivabradine treatment at the intrinsic heart rate, Ivabr-pace – one week after ivabradine treatment at a paced rate identical to that of baseline, MPV – time-averaged maximum peak flow velocity, r – resting, SBP – systolic blood pressure. * p < 0.01 compared to baseline.
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Fig. 1. Box-plots of resting (r) time-averaged peak coronary flow velocity (APV cm/s) at baseline (Baseline) and after one week’s ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that at baseline (Ivabr-pace).
3.2.2. Hyperaemia time-averaged and maximum peak coronary flow velocity There was a significant effect of ivabradine treatment on both MPV and APV (Fig. 2). MPV and h-APV at ivabradine were significantly higher than at baseline (95% confidence intervals of mean difference: 4.7 to 16.2, p = 0.001 and 1.2 to 7.6, p = 0.009 respectively). Similarly, MPV and h-APV at ivabr-pace was significantly higher than at baseline (95% confidence intervals of mean difference: 6.3 to 19.3, p = 0.001 and 1.9 to 10.2, p = 0.007 respectively). 3.2.3. Coronary flow reserve Ivabradine treatment also had a significant effect on CFR (Fig. 3). CFR after ivabradine was significantly higher than at baseline (95% confidence interval of mean difference: 0.51 to 0.93, p < 0.001). Similarly, CFR at ivabr-pace was significantly higher than at baseline (95% confidence interval of mean difference: 0.13 to 0.38, p < 0.001). 4. Discussion We found that ivabradine treatment significantly reduces resting coronary blood flow velocity and increases hypaeremic coronary flow velocity, leading to CFR improvement in patients with stable CAD. Also, although resting coronary blood flow velocity returns to the pre-treatment values after heart rate correction, the enhancement of hyperaemic coronary blood flow velocity remains. Therefore, even after heart rate correction, CFR remains significantly higher than the pre-treatment values, indicating improved microvascular function with ivabradine treatment. Heart rate is a major determinant of myocardial oxygen consumption and therefore the resting myocardial blood flow and coronary flow reserve. However, hyperaemic coronary blood flow in the absence of haemodynamically significant epicardial coronary artery stenosis is not heart-rate dependent and is associated with the integrity (either functional or structural) of the microcirculation [10]. Ivabradine is a selective inhibitor of the If -channel and reduces heart rate by inhibition of the If -channels in the sinus node. Consequently, changes in r-APV are easily explained by corresponding
alterations in heart rate during ivabradine treatment, both at the intrinsic heart rate and at a pacing rate identical to that before treatment. Hyperaemic coronary blood flow velocity increases after ivabradine treatment because the diastolic period is prolonged (per cardiac beat and per minute) as expected. Nevertheless, the mechanism underlying h-APV enhancement after heart rate correction is hypothetical. The most probable explanation is the improvement of ventricular relaxation caused by ivabradine treatment, which in turn enhances coronary blood flow velocity during hyperaemia. The If -channel gene was first discovered in the mouse brain. Four isoforms of the hyperpolarisation-activated, cyclic nucleotidegating channel protein (HCN 1,2,3,4) have been identified in animal hearts [11,12]. In the animal heart, HCN4 levels are higher than HCN1 in the sinus node while HCN2 are lower in ventricular myocardium. Nevertheless, HCN2 is considered to be the dominant isoform because of the larger mass of ventricular myocytes compared to sinus tissue [13]. Ivabradine, by blocking the ventricular If -channel, reduces entry of Na+ into the myocytes, leading to reduced cytosolic calcium. Moreover, ivabradine improves the reuptake of calcium by the sarcoplasmic reticulum. The cumulative effect of these ivabradine actions is an improvement of ventricular relaxation [14,15]. Furthermore, Heusch et al. [16] and Fox et al. [17] have previously reported a beneficial effect of ivabradine that was at least in part heart-rate independent and support the pleiotropic actions of ivabradine [18,19]. In addition, it is possible enhanced diastolic relaxation may increase early diastolic coronary blood flow by a “suction effect” [20]. In fact, the increase in h-APV after ivabradine treatment is not related only to the increase of the diastolic period, but also to the overall improvement of flow, since h-MPV—which represents early diastolic flow—is higher. Therefore, as can be seen in Fig. 4, despite the shortening of the diastolic period after heart rate correction by pacing, the improvement of flow velocity remains because the average flow velocity (C) which will replace the missing period (B) per minute is not less than the average flow during the missing period (missing period = diastolic time at ivabradine − diastolic time at ivabr-pace).
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Fig. 2. Box-plots of maximal hyperaemia (h) time-averaged peak coronary flow velocity (APV cm/s) at baseline (Baseline) and after one week’s ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that at baseline (Ivabr-pace).
4.1. Previous studies To the best of our knowledge, there are only two invasive studies that showed an improvement of CFR in response to pharmacological intervention in patients with stable coronary artery disease. One involved metoprolol [21] and the other nebivolol [22]. These studies (from the same research group) used different methodologies. Both were carried out in the post-stenting
artery of patients with coronary artery disease; significant changes in rate pressure were detected after treatment, since heart rate was not stable, and vasodilating actions were allowed because intracoronary nitroglycerine was not used—at least in the second study. Consequently, the observed increase in CFR could be explained by differences in heart rate, endothelial function and/or coronary artery diameter, and not as a result of an improvement in microvas-
Fig. 3. Box-plots of coronary flow velocity reserve (CFR) at baseline (Baseline) and after one week’s ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that at baseline (Ivabr-pace).
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cular function. In support of this are the control group of the latter study, but also the control group from a study recently published from our department [23]. In both of these, no changes in hyperaemic coronary flow velocity were observed with b-blocker treatment. 4.2. Limitations In the present study, coronary blood flow was assessed using intracoronary Doppler measurements of flow velocity. Although flow velocity does not actually represent volumetric flow, extensive animal studies have proved the accuracy of this technique in the assessment of changes of coronary flow [24,25]. Consequently, given that flow velocities were measured at the same location under the three different conditions (baseline, ivabradine, ivabrpace), while changes in coronary artery diameter were avoided by intracoronary nitroglycerine administration, it seems reasonable to assume that flow velocity at maximal hyperaemia provided a valid means of comparing coronary flow at the three different conditions. Nevertheless, minimal changes in cross-sectional area could not be excluded. Unfortunately, we have no data on ventricular relaxation. Such data would be very helpful in confirming our hypothetical underlying mechanism of improved ventricular relaxation with ivabradine . This could be the object of a future study. Given the short and long-term reproducibility (repeatability) of baseline and hyperaemic myocardial blood flow measurements [26,27], the absence of a control group in this study does not weaken our conclusions. 4.3. Possible implications Although the pathophysiological explanation of our findings remains to be elucidated by other studies, if the effect of ivabradine on microvascular function is confirmed in similar studies then we have an additional therapeutic approach for patients with coronary artery disease, targeting the microvascular function, with profound clinical implications [4,5]. 4.4. Conclusions This study shows for the first time that ivabradine treatment significantly improves hyperaemic coronary flow velocity and CFR in patients with stable CAD. These effects remain even after heart rate correction, indicating improved microvascular function. Conflict of interest No financial support was received for this study and none of the authors has a conflict of interest. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.atherosclerosis.2010.11.035. Fig. 4. Comparison of maximal hyperaemia time-averaged peak coronary flow velocity recordings. (A) After one week’s ivabradine treatment at the intrinsic heart rate, (B) the missing diastolic flow after heart rate correction and (C) at a paced rate identical to that of baseline.
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