Heart rate reduction and coronary flow reserve: mechanisms and treatment






Panos E. VARDAS,MD, PhD
Hellenic Cardiovascular Research Society
Chalandri, GREECE

Heart rate reduction and coronary flow reserve: mechanisms and treatment


by P. E. Vardas , Greece



Heart rate is a major determinant of myocardial oxygen consumption and therefore myocardial blood flow and coronary flow reserve. Consequently, heart rate reduction is an established important therapeutic strategy in the prevention of ischemia. Ivabradine reduces heart rate by inhibition of the If-channels in the sinus node. Treatment with ivabradine not only reduces resting myocardial blood flow, but also significantly improves hyperemic coronary flow and coronary flow reserve in patients with stable coronary artery disease. These effects remain even after heart rate correction, indicating improved microvascular function. Although the pathophysiological explanation of our findings remains to be elucidated, 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 microvascular function.

Medicographia. 2012;34:460-465 (see French abstract on page 465)


Coronary blood flow control

The heart, like all other organs, cannot function without blood flowing through its vessels. Coronary vessels carrying 5% to 10% of the cardiac output run over the surface of the heart, giving rise to branches which penetrate the heart muscle and which in turn branch into smaller vessels (microcirculation) that supply the heart’s capillary network (vessels only 5 μm in diameter) with blood.

This coronary blood flow is regulated by the heart, changing according to the heart’s metabolic needs, and maintained near the minimum level required for the supply of oxygen. Under normal conditions, the heart extracts roughly 70% of all the oxygen from the blood. Increases in myocardial oxygen consumption which occur during exercise must be accommodated by an increase in coronary blood flow through changes in microvascular resistance.1 The microcirculation (vessels <200 μm in diameter) consists of a channel of passive networks, but it is also an active site for blood flow control through a number of metabolic, myogenic, and other mechanisms. Capillary hydrostatic pressure is held constant within the myocardium at approximately 30 mm Hg, made possible by the strong and immediate myogenic response (auto-regulation) of arteriolar smooth muscle. At rest (baseline), the ability to regulate blood flow is high, since 60% of total myocardial vascular resistance is offered by arterioles.2,3 However, when hyperemia is induced, smooth muscle vasodilatation results in dilatation of the arterioles and venules with no change in the capillaries. Total myocardial vascular resistance decreases and capillary resistance now accounts for 75% of the total myocardial vascular resistance. Thus, capillaries offer the most resistance to coronary blood flow during hyperemia and provide a ceiling to hyperemic blood flow.2,3

It is clear that under normal circumstances, coronary blood flow is much lower than maximum, which allows the coronary control vessels to be able to adapt the flow to an increased level of metabolism. The extent to which coronary blood flow can increase above control is generally referred to as coronary flow reserve (CFR).

Physiological and pathophysiological disturbances of coronary blood flow

Coronary blood flow is subject to physiological disturbances created by the contraction of the heart. When pressure is generated in the left ventricle, the vessels in the heart muscle are compressed as well, impeding coronary blood flow (often referred to as extravascular resistance). Consequently, coronary blood flow occurs predominantly during diastole, paralleling the large changes in input impedance caused by ventricular contraction and relaxation of intra-myocardial vessels.

Heart rate is one of the major determinants of myocardial oxygen consumption and myocardial blood flow. An increase in heart rate does more than increase metabolic demand for blood flow, it also increases extravascular resistance by decreasing myocardial perfusion time. Thus, by increasing heart rate, arteriolar dilatation must compensate for both increase in demand and increase in extravascular resistance. Balance between demand and supply may also be disturbed by (patho)- physiological factors such as perfusion pressure (defined as the difference between central aortic pressure and left ventricular pressure).1

Atherosclerosis is a well-recognized pathophysiological mechanism negatively affecting the supply of blood. This disease process can lead to local or more diffuse narrowing of the larger coronary arteries, adding to the resistance of the coronary system. Such obstruction, interpreted by local flow control processes as a reduction in pressure, would lead to a vasodilatory response. The added resistance to flow reduces the range of oxygen demand that the coronary circulation is able to accommodate, thus the need to compensate for the arterial narrowing would overwhelm the vasodilatory capability of the coronary resistance vessels and bring the control system to the limit of its working range.1




Heart rate reduction as an important therapeutic strategy

Heart rate, as previously mentioned, is a main determinant of myocardial oxygen consumption and heart rate reduction is an established and important therapeutic strategy in the prevention of ischemia. A strong association between elevated heart rate and increased risk of total and cardiovascular mortality has been shown in the general population, as well as in patients with hypertension, diabetes, and coronary artery disease (CAD).4

BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) has provided significant data relating to the prognostic importance of heart rate,5 and to the importance of heart rate reduction with ivabradine6 for reduction of coronary events in CAD patients with left ventricular dysfunction. The results showed that elevated resting heart rate (>70 bpm) is a strong predictor of outcome in patients with stable CAD and left ventricular dysfunction. Patients in the subgroup with resting heart rate >70 bpm were 34% more likely to die from cardiovascular causes and 53% more likely to be hospitalized for new or worsening heart failure. Similarly, elevated heart rate was associated with a 46% increased risk of fatal and nonfatal myocardial infarction and a 38% increase in the need for coronary revascularization. Also, BEAUTIFUL investigated the effect of ivabradine on outcomes in stable CAD patients.6 Although ivabradine did not affect the primary composite end point, in patients with a heart rate of 70 bpm or greater, ivabradine had a significant impact on all end points linked to coronary events. There was a 36% reduction in the relative risk of hospitalization for fatal and nonfatal myocardial infarction in the patients treated with ivabradine and a 30% relative risk reduction for coronary revascularization. Nevertheless, the underlying mechanism remains unknown.

Effects of ivabradine on coronary blood flow and coronary flow reserve

Although CFR predicts long-term adverse cardiovascular outcome7,8 and decisions for coronary revascularization are based on a physiological assessment of coronary artery lesions,9,10 there were previously no data in humans concerning the effect of ivabradine on coronary hemodynamics. In a recently published study from my department,11 we examined the effects of ivabradine on coronary blood flow and flow reserve in patients with stable CAD. In this study, we assessed 21 patients with stable CAD of one or two vessels, amenable for percutaneous coronary intervention. Immediately following coronary angiography, the culprit vessel/s for coronary intervention were defined according to guidelines and a nonculprit vessel was selected for coronary flow measurements. The nonculprit vessel was selectively engaged with a guide catheter. Intracoronary nitroglycerin (200 μg) was given every 15 minutes of the procedure to prevent catheter-induced coronary artery spasm and to avoid changes in coronary artery diameter. A 0.014-in, 15-MHz Doppler guide wire (FloWire, Volcano Therapeutics Inc) was advanced through the catheter to the nonculprit vessel.


Figure 1
Figure 1. Resting (r) and maximal hyperemia (h) time-averaged peak coronary flow velocity (APV) recordings at baseline (Baseline) and after one week’s ivabradine treatment, both at the intrinsic heart rate (Ivabradine) and at a paced rate similar to that of baseline (Ivabradine-pace).

Abbreviation: CFR, coronary flow reserve.
From reference 11 supplementary data: Skalidis et al. Atherosclerosis. 2011; 215(1):160-165. © 2010 Elsevier Ireland Ltd.



Figure 2
Figure 2. Mean values with 95% confidence intervals of coronary
flow reserve at baseline (Baseline) and after one week’s ivabradine
treatment, both at the intrinsic heart rate (Ivabradine) and at a
paced rate similar to that of baseline (Ivabradine-pace).

Abbreviation: CFR, coronary flow reserve.
After reference 11: Skalidis et al. Atherosclerosis. 2011;215(1):160-165.
© 2010 Elsevier Ireland Ltd.



Once resting flow-velocity data had been collected, a 30-μg bolus injection of intracoronary adenosine was given to obtain data during hyperemia. To confirm that maximal hyperemia had been achieved, doses increasing in 30-μg increments were infused until a plateau in flow velocity was reached.

All measurements were made in the nonculprit vessel: i) during diagnostic coronary angiography (baseline); ii) during programmed coronary intervention in the culprit vessel/s (before the procedure), 1 week after treatment with ivabradine (5 mg twice daily) at the same location at the intrinsic heart rate (ivabradine); and iii) at a pacing heart rate similar to baseline (ivabradine-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 hyperemia (h-APV) to APV at rest (r-APV).

Since at the beginning of the diastolic period extravascular compressive forces are minimized and coronary perfusion pressure is highest, maximum coronary blood flow occurs in the early diastolic period.12 Consequently, changes in maximum diastolic peak coronary flow velocity (MPV cm/s) at maximal hyperemia were used as an index of early diastolic blood flow alterations. As expected, heart rate was significantly lower after treatment with ivabradine (78±14 bpm vs 65±9 bpm, P<0.001). There was a significant effect of ivabradine treatment on both r-APV and h-APV hyperemia APV. With ivabradine treatment (non-paced heart rate), r-APV was significantly lower than at baseline. However, there was no significant difference in r-APV with ivabradine treatment + pacing and baseline. In contrast, h-APV with ivabradine treatment (non-paced heart rate) was significantly higher than at baseline. Similarly, h-APV with ivabradine + pacing was significantly higher than at baseline. Ivabradine treatment also had a significant effect on CFR. CFR after ivabradine was significantly higher than at baseline. Similarly, CFR with ivabradine + pacing was significantly higher than at baseline (Figures 1 and 2).11

In summary, we found that ivabradine treatment significantly reduces resting coronary blood flow and increases hyperemic coronary flow, leading to CFR improvement in patients with stable CAD. Also, although resting coronary blood flow returns to the pretreatment values after heart rate correction, the enhancement of hyperemic coronary blood flow remains. Therefore, even after heart rate correction, CFR remains significantly higher than the pretreatment values, indicating improved microvascular function with ivabradine treatment. As heart rate is a major determinant of myocardial oxygen consumption, it thus influences myocardial blood flow and CFR. However, hyperemic coronary blood flow in the absence of hemodynamically significant epicardial coronary artery stenosis is not heart rate dependent and is associated with the integrity (either functional or structural) of the microcirculation.13

How does ivabradine affect r-APV and h-APV?

Ivabradine is a selective inhibitor of the If-channel and reduces heart rate by inhibiting these 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 the pacing rate similar to that before treatment.

However, changes in h-APV are more complicated. Hyperemic coronary blood flow increases after ivabradine treatment because the diastolic period is prolonged (per cardiac beat and per minute) as expected. The most possible explanation behind h-APV enhancement after heart rate correction may be the improvement of ventricular relaxation caused by ivabradine treatment which in turn enhances coronary blood flow during hyperemia. As mentioned earlier, Ivabradine is an If channel inhibitor. The gene for the If-channel was first discovered in the mouse brain, and four isoforms of this hyperpolarization- activated, cyclic nucleotide-gating channel protein (HCN 1, 2, 3, and 4) have been identified in animal hearts.14,15

In the animal heart, HCN4 levels are higher than HCN1 in the sinus node, while HCN2 levels are lower in ventricular myocardium. Despite that, HCN2 is considered to be the dominant isoform because of the larger mass of ventricular myocytes compared with sinus tissue.16 Nevertheless, HCN channels expressed in other cardiac tissues seem to be nonfunctional at these locations under normal conditions. The most positive activation is in the sinoatrial node and is associated with the highest pacing rate, whereas the most negative activation (ventricular myocytes) normally exhibits no diastolic depolarization at all.16 Ivabradine, by blocking If-channels reduces entry of Na+ into the myocytes, leading to reduced cytosolic calcium. Moreover, ivabradine improves reuptake of calcium by the sarcoplasmic reticulum. The cumulative effect of those ivabradine actions is improvement of ventricular relaxation.17,18 Furthermore, Heusch et al19 and Fox et al20 have previously reported a beneficial effect of ivabradine that was at least in part heart rate independent and supports the pleiotropic actions of ivabradine.21,22 In addition, it is possible that enhanced diastolic relaxation may increase early diastolic coronary blood flow by a “suction effect.”23 In fact, the increase in h-APV after ivabradine treatment is related not only to the increase in 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 Figure 3 (page 463),11 despite the shortening of the diastolic period after heart rate correction by pacing, the improvement of flow remains because the average flow (C) which will replace the missing period per minute is not less than the average flow during the missing period (B).


Figure 3
Figure 3. Comparison of maximal hyperemia 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; C) At a paced rate similar to that of baseline.
After reference 11: Skalidis et al. Atherosclerosis. 2011; 215(1):160-165. © 2010 Elsevier Ireland Ltd.

Other studies showing improvement of coronary flow reserve with pharmacological intervention in stable CAD patients

To the best of our knowledge, there are only two invasive studies showing improvement of CFR with pharmacological intervention in patients with stable CAD. One involved metoprolol24 and the other nebivolol.25 These studies (from the same research group) used different methodologies. Both were carried out in the stented artery of patients with CAD; significant changes in rate pressure were detected after treatment, since heart rate was not stable, and vasodilating actions were allowed because intracoronary nitroglycerin 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 microvascular function. In support of this is the control group of the latter study, but also the control group from a study recently published from our department.26 In both of these, no changes in hyperemic coronary flow were observed with β-blocker treatment.

Conclusion

Ivabradine treatment significantly improves hyperemic coronary flow and CFR in patients with stable CAD. These effects remain even after heart rate correction, indicating improved microvascular function. Although the pathophysiological explanation remains to be elucidated, if the effect of ivabradine on microvascular function is confirmed in similar studies, then we have an additional therapeutic approach for patients with CAD, targeting the microvascular function, with profound clinical implications.7,8 _

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Keywords: coronary artery disease; coronary blood flow; coronary flow reserve; heart rate; ivabradine