Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High-Fidelity Cardiovascular Phenotyping

Abstract

Background: Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact.

Methods and results: We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading.

Conclusions: HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.

Keywords: autonomic nervous system; baroreflex control; funny channel; heart rate; hemodynamics; inhibitor; microneurography; pharmacology; physiology; sinoatrial node.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1

HR normalization procedure. The example assumes lower SBP on ivabradine than on placebo (118 vs 122 mm Hg). Related RRIs are labeled “raw RRI.” The solid vertical line represents mean SBP (120 mm Hg), which determines “normalized RRI” values. Without normalization, ivabradine's effect on HR would have been underestimated, as demonstrated by the smaller difference between the 2 raw RRI values compared with the normalized RRI values. HR indicates heart rate; RRI, RR interval; SBP, systolic blood pressure.

Figure 2

CONSORT flow diagram of participant enrollment, allocation, and analysis. IC indicates informed consent; IVA, ivabradine; PLC, placebo

Figure 3

Individual effects of HCN4 inhibition on HR. A, Effects of HCN4 inhibition on resting HR. Solid and dashed lines denote HR decreases and increases, respectively. B, Ivabradine's use dependence: HR lowering is more pronounced in participants with higher resting HR. With resting values of ≈56.5 bpm, ivabradine has no effect (unresponsive HR). C, Effects of HCN4 inhibition on HR during parasympathetic activation (HRP) through baroreflex loading with phenylephrine. HRP was assessed as HR at the largest individual phenylephrine dose that was reached on both study days. Solid and dashed lines denote HRP decreases and increases, respectively. D, Participants with lower HRP on placebo exhibited a smaller reduction in HRP with ivabradine. The observation is consistent with ivabradine's use‐dependent pharmacology; however, parasympathetic activation shifted the unresponsive HR to ≈44.2 bpm, which is ≈12 bpm lower compared with resting conditions (see panel B). bpm indicates beats per minute; HR, heart rate.

Figure 4

Effects of HCN4 inhibition on MSNA. A, Original recordings of 2 participants. B, Individual changes in MSNA burst frequency, burst incidence, and total MSNA by ivabradine compared with placebo. Total MSNA has been rescaled (×20) for visual range harmonization among the 3 MSNA measures (also see Table). au indicates arbitrary units; hb, heart beats; MSNA, muscle sympathetic nerve activity.

Figure 5

BP sensitivity to vasoactors. Effects of HCN4 inhibition on BP sensitivity to infusion of the vasoconstrictor phenylephrine (upper panel) and the vasodilator sodium nitroprusside (lower panel) during placebo (open circles) and ivabradine (closed circles). Note the trend toward improved baroreflex buffering of BP increases on ivabradine (upper panel). BP indicates blood pressure.

Figure 6

Interactions between ivabradine and arterial baroreflexes. A, Sympathetic baroreflex: Although ivabradine may dampen the increase in MSNA burst frequency during nitroprusside infusion (ie, when high vasoconstrictor activity and elevated HR co‐occur), baroreflex curves are virtually identical if HR‐independent MSNA measures (burst incidence and total activity) are used (curves not shown). B, Cardiac baroreflex: Ivabradine shifts (“offsets”) the baroreflex curve upward (to longer RRIs) with virtually no effect on slope or range. Shaded areas indicate 95% confidence bands. Note that the bands do not overlap with high blood pressure, indicating that baroreflex‐mediated HR slowing is intensified by ivabradine. DBP indicates diastolic blood pressure; HR, heart rate; MSNA, muscle sympathetic nerve activity; RRI, RR interval; SBP, systolic blood pressure.