Heart Rate Reduction by Ivabradine: Slowly but Surely?
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ABSTRACT:
SUBMITTER: Kojonazarov B
PROVIDER: S-EPMC7790139 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cardiac fibroblast (CF) proliferation and activation play important roles in cardiac fibrosis and diastolic dysfunction (DD), which are involved in fibrosis-associated cardiovascular diseases. A previous study showed that ivabradine, a specific heart rate (HR)-lowering agent, significantly ameliorated DD in diabetic db/db mice by reducing HR. Herein, we attempted to determine whether ivabradine has antifibrotic and cardioprotective effects in diabetic mice by directly suppressing CF proliferation and activation, independent of a reduction in HR. We found that knockdown of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase (MAPK), or treatment with ivabradine, reduced JNK and p38 MAPK phosphorylation and the protein expression of proliferating cell nuclear antigen, collagen I, collagen III, tissue inhibitor of matrix metalloproteinase 2, and α-smooth muscle actin, accompanied with upregulation of matrix metalloproteinase 2 both in high glucose-treated neonatal rat CFs and left ventricular CFs isolated from db/db mice. However, zatebradine (a HR-lowering agent) did not have these effects in vitro or in vivo. In addition, cardiac fibrosis and DD were ameliorated in db/db mice that were intravenously administered lentiviruses carrying short hairpin RNAs targeting JNK and p38 MAPK or administered ivabradine. Taken together, these findings demonstrate that the ivabradine-induced amelioration of cardiac fibrosis, and DD in db/db mice may be at least in part attributable to the suppression of CF proliferation and activation, through the inhibition of JNK and p38 MAPK.
| S-EPMC8259788 | biostudies-literature
Project description:BACKGROUND AND PURPOSE: High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with coronary artery disease. We tested the hypothesis that a reduction of resting heart rate with the cardiac pacemaker I(f) current inhibitor ivabradine prevents the endothelial dysfunction associated with dyslipidaemia. EXPERIMENTAL APPROACH: Three-month-old dyslipidaemic (DL) male mice expressing the human ApoB-100 were assigned or not (DL, n=16), to treatment for 3 months with ivabradine (10 mg kg(-1) d(-1), n=17). Wild-type C57Bl/6 mice (WT, n=15) were used as controls. Heart rate was measured at 3, 4.5 and 6 months. Dilatation to acetylcholine (ACh) of isolated cerebral and renal arteries was investigated at 6 months. KEY RESULTS: Heart rate remained stable in anaesthetized WT mice, increased (25%, P<0.05) with age in DL mice but was limited (11%, P<0.05) by ivabradine. At 6 months, left ventricular maximal pressure was similar in all groups. The minimal and end-diastolic left ventricular pressures were increased (P<0.05) in DL (10.2+/-1.0 and 18.7+/-1.4 mm Hg) compared to WT (-0.4+/-0.7 and 6.3+/-1.0 mm Hg) and reduced (P<0.05) by ivabradine (4.2+/-1.3 and 11.5+/-1.5 mm Hg). ACh-induced maximal dilatation was impaired (P<0.05) in renal and cerebral arteries isolated from DL compared to WT (56+/-7 versus 83+/-3% in renal arteries; 22+/-2 versus 42+/-2% in cerebral arteries). Ivabradine completely prevented (P<0.05) this dysfunction in renal and cerebral arteries. CONCLUSIONS AND IMPLICATIONS: Selective heart rate reduction with ivabradine limits cardiac dysfunction and prevents the renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia.
| S-EPMC2439858 | biostudies-other
Project description:Heart rates during ischaemia and reperfusion are possible determinants of reperfusion arrhythmias. We used ivabradine, a selective If current inhibitor, to assess the effects of heart rate reduction (HRR) during ischaemia-reperfusion on reperfusion ventricular arrhythmias and assessed potential anti-arrhythmic mechanisms by optical mapping. Five groups of rat hearts were subjected to regional ischaemia by left anterior descending artery occlusion for 8min followed by 10min of reperfusion: (1) Control n=10; (2) 1?M of ivabradine perfusion n=10; (3) 1?M of ivabradine+5Hz atrial pacing throughout ischaemia-reperfusion n=5; (4) 1?M of ivabradine+5Hz pacing only at reperfusion; (5) 100?M of ivabradine was used as a 1ml bolus upon reperfusion. For optical mapping, 10 hearts (ivabradine n=5; 5Hz pacing n=5) were subjected to global ischaemia whilst transmembrane voltage transients were recorded. Epicardial activation was mapped, and the rate of development of ischaemia-induced electrophysiological changes was assessed. HRR observed in the ivabradine group during both ischaemia (195±11bpm vs. control 272±14bpm, p<0.05) and at reperfusion (168±13bpm vs. 276±14bpm, p<0.05) was associated with reduced reperfusion ventricular fibrillation (VF) incidence (20% vs. 90%, p<0.05). Pacing throughout ischaemia-reperfusion abolished the protective effects of ivabradine (100% VF), whereas pacing at reperfusion only partially attenuated this effect (40% VF). Ivabradine, given as a bolus at reperfusion, did not significantly affect VF incidence (80% VF). Optical mapping experiments showed a delay to ischaemia-induced conduction slowing (time to 50% conduction slowing: 10.2±1.3min vs. 5.1±0.7min, p<0.05) and to loss of electrical excitability in ivabradine-perfused hearts (27.7±4.3min vs. 14.5±0.6min, p<0.05). Ivabradine administered throughout ischaemia and reperfusion reduced reperfusion VF incidence through HRR. Heart rate during ischaemia is a major determinant of reperfusion arrhythmias. Heart rate at reperfusion alone was not a determinant of reperfusion VF, as neither a bolus of ivabradine nor pacing immediately prior to reperfusion significantly altered reperfusion VF incidence. This anti-arrhythmic effect of heart rate reduction during ischaemia may reflect slower development of ischaemia-induced electrophysiological changes.
| S-EPMC3654199 | biostudies-literature
Project description:AimsThe SHIFT echocardiographic substudy evaluated the effects of ivabradine on left ventricular (LV) remodelling in heart failure (HF).Methods and resultsEligible patients had chronic HF and systolic dysfunction [LV ejection fraction (LVEF) ?35%], were in sinus rhythm, and had resting heart rate ?70 bpm. Patients were randomly allocated to ivabradine or placebo, superimposed on background therapy for HF. Complete echocardiographic data at baseline and 8 months were available for 411 patients (ivabradine 208, placebo 203). Treatment with ivabradine reduced LVESVI (primary substudy endpoint) vs. placebo [-7.0 ± 16.3 vs. -0.9 ± 17.1 mL/m(2); difference (SE), -5.8 (1.6), 95% CI -8.8 to -2.7, P< 0.001]. The reduction in LVESVI was independent of beta-blocker use, HF aetiology, and baseline LVEF. Ivabradine also improved LV end-diastolic volume index (-7.9 ± 18.9 vs. -1.8 ± 19.0 mL/m(2), P= 0.002) and LVEF (+2.4 ± 7.7 vs. -0.1 ± 8.0%, P< 0.001). The incidence of the SHIFT primary composite outcome (cardiovascular mortality or hospitalization for worsening HF) was higher in patients with LVESVI above the median (59 mL/m2) at baseline (HR 1.62, 95% CI 1.03-2.56, P= 0.04). Patients with the largest relative reductions in LVESVI had the lowest event rates.ConclusionIvabradine reverses cardiac remodelling in patients with HF and LV systolic dysfunction.
| S-EPMC3195263 | biostudies-literature
Project description:The heart rate lowering drug Ivabradine was shown to improve cardiac outcome in patients with previous heart failure. However, in patients without heart failure, no beneficial effect of Ivabradine was observed. Animal studies suggested a preventive effect of Ivabradine on atherosclerosis which was due to an increase in wall shear stress (WSS), the blood flow-induced frictional force exerted on the endothelium, triggering anti-inflammatory responses. However, data on the effect of Ivabradine on WSS is sparse. We aim to study the effect of Ivabradine on (i) the 3D WSS distribution over a growing plaque and (ii) plaque composition. We induced atherosclerosis in ApoE-/- mice by placing a tapered cast around the right common carotid artery (RCCA). Five weeks after cast placement, Ivabradine was administered via drinking water (15 mg/kg/day) for 2 weeks, after which the RCCA was excised for histology analyses. Before and after Ivabradine treatment, animals were imaged with Doppler Ultrasound to measure blood velocity. Vessel geometry was obtained using contrast-enhanced micro-CT. Time-averaged WSS during systole, diastole and peak WSS was subsequently computed. Ivabradine significantly decreased heart rate (459 ± 28 bpm vs. 567 ± 32 bpm, p < 0.001). Normalized peak flow significantly increased in the Ivabradine group (124.2% ± 40.5% vs. 87.3% ± 25.4%, p < 0.05), reflected by an increased normalized WSS level during systole (110.7% ± 18.4% vs. 75.4% ± 24.6%, p < 0.05). However, plaque size or composition including plaque area, relative necrotic core area and macrophage content were not altered in mice treated with Ivabradine compared to controls. We conclude that increased WSS in response to Ivabradine treatment did not affect plaque progression in a murine model.
| S-EPMC6143553 | biostudies-literature
Project description:Abstract Background Achieving pharmacologic rate control in patients with atrial fibrillation (AF) with rapid ventricular response (RVR) can be tricky when the patient’s underlying cardiac function is decreased. We present a case illustrating how ivabradine can be useful in this clinical scenario. Case summary A 95-year-old woman with a history of systolic heart failure (HF) presented with acute decompensated HF in AF with RVR. Beta blockade and calcium channel blockade were avoided given her cardiac history, and diuresis with high doses of furosemide was ineffective. Her ventricular response slowed with ivabradine, allowing for rapid decongestion and a safe discharge home. Discussion Ivabradine acts on the If current of cardiac pacemaker cells to slow heart rate (HR), and it currently carries a class IIa recommendation to reduce the risk of HF hospitalization and cardiac death in patients with left ventricular ejection fraction ≤35% and a symptomatic HR ≥70 b.p.m. Although current recommendations are for patients in sinus rhythm, ivabradine has a theoretical benefit in patients with AF given its mechanism of action. Because it does not negatively affect inotropy or blood pressure, ivabradine was used in our patient with a good clinical outcome. Our case provides an example of ivabradine’s usefulness in patients with AF in RVR with a history of depressed systolic function.
| S-EPMC8877172 | biostudies-literature
Project description:Degenerative mitral valve disease (DMVD) is a common cardiac disease in geriatric dogs characterized by the degeneration of the mitral valve, leading to decreased cardiac output and activation of the sympathetic and renin-angiotensin-aldosterone system. This disease results in an increased resting heart rate (HR) and myocardial oxygen consumption (MVO2). A recent publication demonstrated that dogs with asymptomatic DMVD had a significantly higher HR and systemic blood pressure (BP) than age-matched control dogs. This higher HR will eventually contribute to increased MVO2. This study aimed to determine the effects of a single oral dose of ivabradine on the HR, MVO2 as assessed by the rate-pressure product, and BP in dogs with asymptomatic DMVD. Seven beagles with naturally occurring DMVD were instrumented by the Holter recorder and an oscillometric device to measure electrocardiogram and BP for 24 and 12 h, respectively. Each dog was randomly subjected to receive either placebo or ivabradine (0.5, 1.0 and 2.0 mg/kg). The results revealed that oral administration of ivabradine significantly decreased the HR and rate-pressure product in a dose-dependent manner without adverse effects. The highest dose of 2.0 mg/kg significantly reduced systolic and mean BP. Therefore, the findings imply that a single oral ivabradine administration at a dose of 1.0 mg/kg is suitable for dogs with asymptomatic DMVD to reduce the HR and MVO2 without marked effects on BP. This may potentially make ivabradine promising for management of an elevated HR in DMVD dogs.
| S-EPMC6219887 | biostudies-literature
Project description:Intervention1: Tablet Ivabradine: Oral Ivabradine 5mg was given one hour before surgery
Control Intervention1: tablet multivitamin: oral multivitamin(one tablet) one hour before surgery
Primary outcome(s): Haemodynamics changesTimepoint: up to 10 min after laryngoscopy and intubation
Study Design: Randomized, Parallel Group, Placebo Controlled Trial
Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:Sequentially numbered, sealed, opaque envelopes Blinding and masking:Participant, Investigator and Outcome Assessor Blinded
| 2757961 | ecrin-mdr-crc
Project description:BACKGROUND:Postural tachycardia syndrome (POTS) is a common form of chronic orthostatic intolerance. The remarkable increase in heart rate (HR) upon standing is the hallmark of this syndrome. Treatment of POTS patients is challenging and includes drugs that slow the HR. Ivabradine is a selective If channel blocker designed to slow the HR, as an anti-anginal agent. In view of its ability to slow the HR, we posited that ivabradine may be an ideal medication for treating POTS patients. This report provides the results of an investigation in which we studied ivabradine's effect on the hemodynamics and sympathovagal balance in POTS patients. METHODS:An open-label trial, without a placebo control, was performed in eight patients with POTS of two years' standing. Characterization of symptoms, hemodynamics, autonomic function tests, and HR and blood pressure (BP) variability were determined while patients were in a supine position and during a 20-minute head-up tilt before and after a single oral dose of 7.5 mg ivabradine. RESULTS:Ivabradine slowed the HR of POTS patients at rest by 4±1 bpm (P<0.05). During a 5-minute head-up tilt, the HR decreased from 118±4 bpm to 101±5 bpm (P<0.01). Ivabradine did not affect the BP when patients were at rest in a supine position or in head-up tilt position. Cardiovascular vagal and sympathetic tone, extrapolated from the time and frequency domains of the HR and BP variability, were also not affected by ivabradine. CONCLUSIONS:Ivabradine is an effective drug for slowing the HR of POTS patients at rest and during tilting, without producing significant adverse effects. Moreover, ivabradine exerts its effects without influencing the sympathovagal balance.
| S-EPMC4524401 | biostudies-other
Project description:Control of ventricular rate is recommended for patients with paroxysmal, persistent, or permanent atrial fibrillation (AF). Existing rate-control options, including beta-blockers, nondihydropyridine calcium channel blockers, and digoxin, are limited by adverse hemodynamic effects and their ability to attain target heart rate (HR). Ivabradine, a novel HR-controlling agent, decreases HR through deceleration of conduction through If ('funny') channels, and is approved for HR reduction in heart failure patients with ejection fraction less than 35% and elevated HR, despite optimal pharmacological treatment. Because If channels were thought to be expressed solely in sinoatrial (SA) nodal tissue, ivabradine was not investigated in heart failure patients with concomitant AF. Subsequent identification of hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4), the primary gene responsible for If current expression throughout the myocardium, stimulated interest in the potential role of ivabradine for ventricular rate control in AF. Preclinical studies of ivabradine in animal models with induced AF demonstrated a reduction in HR, with no significant worsening of QT interval or mean arterial pressure. Preliminary human data suggest that ivabradine provides HR reduction without associated hemodynamic complications in patients with AF. Questions remain regarding efficacy, safety, optimal dosing, and length of therapy in these patients. Prospective, randomized studies are needed to determine if ivabradine has a role as a rate-control treatment in patients with AF.
| S-EPMC5933550 | biostudies-literature