New Therapeutic Targets in Cardiology

Roubille, François; Tardif, Jean‐Claude

doi:10.1161/circulationaha.112.000145

Cited by 59 publications

(21 citation statements)

References 105 publications

(106 reference statements)

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“…generated in areas of myocardial scarring) compared with I f blockade, the effect of which is focused on the SAN. Therefore, BB and ivabradine can be considered complementary drugs [25]. Beta-blockers may be considered as a reasonable therapeutic option to prevent arrhythmogenic effects of DOB, especially by beta-receptor blockage.…”

Section: Discussionmentioning

confidence: 99%

Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias

Mert

Mert²,

Morrad³

et al. 2017

Kardiol Pol

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A b s t r a c tBackground: Indirect evidences suggest that the I f blocker ivabradine may exert an antiarrhythmic effect in ventricular myocardium in heart failure (HF) patients by inhibiting spontaneous depolarisations, but the clinical relevance of this mechanism is not known. Dobutamine (DOB) has been known to increase heart rate and the incidence of cardiac arrhythmias. Aim:In this study, we evaluated the effects of ivabradine on DOB-induced ventricular arrhythmias and compared them with those of beta-blocker (BB) therapy. Methods:Patients with decompensated HF requiring inotropic support, left ventricular ejection fraction < 35%, and in sinus rhythm were included in the study (ivabradine group -29 patients, control group -29 patients, BB group -15 patients). All patients underwent Holter recording for 6 h before the initiation of DOB infusion. Following baseline recording, DOB was administered at incremental doses of 5, 10, and 15 µg/kg/min, with 6-h steps. Holter monitoring was continued during 18 h of DOB infusion and analysed for the median number of ventricular premature contractions (VPC), ventricular couplets, episodes of non-sustained ventricular tachycardia, and total ventricular arrhythmias in each step of the study protocol. Results:The positive chronotropic effect of incremental DOB doses was blunted by beta-blockade and was totally abolished by ivabradine. The median number of VPCs, ventricular couplets, and total ventricular arrhythmias significantly increased with incremental doses of DOB in the control group (p = 0.018) and, to a lesser extent, in the ivabradine group (p = 0.015). In the BB group the absolute VPCs numbers were smaller than in the control or the ivabradine group, with the on-ivabradine VPCs numbers falling between those seen in control and BB groups. A numeric increase in VPCs with incremental DOB doses occurred in the BB group but did not reach statistical significance (p > 0.05), consistent with a protective effect of beta-blockade. Ivabradine reduced VPCs by 43% at 5 µg/kg/min DOB and by 38% at 10 µg/kg/min DOB against the control group (VPCs median 256 vs. 147 and 251 vs. 158) in the absence of significant differences at 15 µg/kg/min DOB between the control and ivabradine groups (overall p > 0.05). Thus, ivabradine administered without background beta-blockade attenuated the arrhythmogenic effect of increasing doses of DOB in the low and moderate DOB dose but not in the high DOB dose. Conclusions:In patients with decompensated HF, ivabradine appears to reduce the incidence of VPCs in response to low and medium DOB dose. Whether the anti-arrhythmic effect of ivabradine is additive to the anti-arrhythmic effect of beta-blockade requires further investigation; this should also determine the clinical significance of ventricular arrhythmia attenuation with ivabradine.

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Section: Discussionmentioning

confidence: 99%

Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias

Mert

Mert²,

Morrad³

et al. 2017

Kardiol Pol

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“…There is evidence that expression may vary also across species ([15, 22] and references therein). HCN4 is the main isoform in the SAN of humans, rabbits, mice and dogs, where also HCN1 (in rabbits), and HCN2 (in humans and mice) are substantially expressed [6, 15, 39-40]. In humans and rabbits HCN4 is the main isoform also in atrioventricular node and Purkinje fibers [15, 41], while HCN2 and HCN4 are the most abundant isoforms in most mammalian atria and ventricles [40, 42-43], which also display a minor presence of HCN1.…”

Section: Structure Function and Distributionmentioning

confidence: 99%

HCN Channels Modulators: The Need for Selectivity

Romanelli

Sartiani²,

Masi³

et al. 2016

CTMC

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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (I f /I h ), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks I f . Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects.HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators.

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“…First, I f has become a target for pharmacological reduction of heart rate, which may be beneficial for heart failure patients. This reduction is achieved through the specific I f blocker ivabradine, which has become available for clinical use, and represents a new approach in selective heart rate reduction [15]. Second, mutations in the HCN4 gene, encoding the major HCN isoform of the human SA node [16], have been associated with hereditary SA nodal dysfunction in several families [17–23].…”

Section: A Funny Currentmentioning

confidence: 99%

Hyperpolarization-Activated Current, , in Mathematical Models of Rabbit Sinoatrial Node Pacemaker Cells

Verkerk

Wilders

2013

BioMed Research International

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A typical feature of sinoatrial (SA) node pacemaker cells is the presence of an ionic current that activates upon hyperpolarization. The role of this hyperpolarization-activated current, I f, which is also known as the “funny current” or “pacemaker current,” in the spontaneous pacemaker activity of SA nodal cells remains a matter of intense debate. Whereas some conclude that I f plays a fundamental role in the generation of pacemaker activity and its rate control, others conclude that the role of I f is limited to a modest contribution to rate control. The ongoing debate is often accompanied with arguments from computer simulations, either to support one's personal view or to invalidate that of the antagonist. In the present paper, we review the various mathematical descriptions of I f that have been used in computer simulations and compare their strikingly different characteristics with our experimental data. We identify caveats and propose a novel model for I f based on our experimental data.

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New Therapeutic Targets in Cardiology

Cited by 59 publications

References 105 publications

Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias

Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias

HCN Channels Modulators: The Need for Selectivity

Hyperpolarization-Activated Current, , in Mathematical Models of Rabbit Sinoatrial Node Pacemaker Cells

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