New Therapeutic Targets in Cardiology

Roubille, François; Tardif, Jean‐Claude

doi:10.1161/circulationaha.112.000145

Cited by 62 publications

(22 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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“…However, certain components of the pacemaking machinery exert clear and quantifiable contributions to heart rate maintenance and/or acceleration because their removal or inactivation causes loss of basal heart rate or impairs heart rate increases. The drug ivabradine slows heart rate, at least in part, by antagonist actions on HCN4 24 . Loss of the Na + /Ca 2+ exchanger 25-27 , inhibition of the mitochondrial Ca 2+ uniporter 17 and application of toxins that prevent SR Ca 2+ uptake (thapsigargin) 16, 28 and release (ryanodine) 16, 28 reduce or eliminate heart rate acceleration.…”

Section: Discussionmentioning

confidence: 99%

A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca ²⁺ Clock

Valdivia

Wehrens

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background Fight or flight heart rate (HR) increases depend on protein kinase A (PKA) and calmodulin kinase II (CaMKII) mediated enhancement of Ca2+ uptake and release from sarcoplasmic reticulum (SR) in sinoatrial nodal cells (SANC). However, the impact of specific PKA and CaMKII phosphorylation sites on HR is unknown. Methods and Results We systematically evaluated validated PKA and CaMKII target sites on phospholamban (PLN) and the ryanodine receptor (RyR2) using genetically modified mice. We found that knockin alanine replacement of RyR2 PKA (S2808) or CaMKII (S2814) target sites failed to affect HR responses to isoproterenol or spontaneous activity in vivo or in SANC. Similarly, selective mutation of PLN amino acids critical for enhancing SR Ca2+ uptake by PKA (S16) or CaMKII (T17) to alanines did not affect HR in vivo or in SANC. In contrast, CaMKII inhibition by expression of AC3-I has been shown to slow SANC rate responses to isoproterenol and decrease SR Ca2+ content. PLN deficiency rescued SR Ca2+ content and SANC rate responses to isoproterenol in mice with AC3-I expression, suggesting CaMKII affects HR by modulation of SR Ca2+ content. Consistent with this, mice expressing a superinhibitory PLN mutant had low SR Ca2+ content and slow HR in vivo and in SANC. Conclusions SR Ca2+ depletion reduces HR and SR Ca2+ repletion restores physiological SANC rate responses despite CaMKII inhibition. PKA and CaMKII do not affect HR by a unique target site governing SR Ca2+ uptake or release. HR acceleration may require an SR Ca2+ content threshold.

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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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New Therapeutic Targets in Cardiology

Cited by 62 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

A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca ²⁺ Clock

HCN Channels Modulators: The Need for Selectivity

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New Therapeutic Targets in Cardiology

Cited by 62 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

A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca 2+ Clock

HCN Channels Modulators: The Need for Selectivity

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Product

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A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca ²⁺ Clock