Heart rate lowering treatment leads to a reduction in vulnerable plaque features in atherosclerotic rabbits

Abstract

ObjectiveTo investigate the effect of a heart rate (HR) lowering agent (Ivabradine) on features of atherosclerotic plaque vulnerability with magnetic resonance imaging (MRI), ultrasound imaging, and histology.Approach and resultsAtherosclerosis was induced in the abdominal aorta of 19 rabbits. Nine rabbits were treated with Ivabradine (17 mg/kg/day) during the entire study period. At week 14, imaging was performed. Plaque size was quantified on contrast-enhanced T1-weighted MR images. Microvascular flow, density, and permeability was studied with dynamic contrast-enhanced MRI. Plaque biomechanics was studied by measuring the aortic distension with ultrasound. After, animals were sacrificed and histology was performed.HR was reduced by 16% (p = 0.026) in Ivabradine-treated animals. No differences in absolute and relative vessel wall beat-to-beat distension were found, but due to the reduction in HR, the frequency of the biomechanical load on the plaque was reduced. Plaque size (MR and histology) was similar between groups. Although microvessel density (histology) was similar between groups, AUC and Ktrans, indicative for plaque microvasculature flow, density, and permeability, were decreased by 24% (p = 0.029) and 32% (p = 0.037), respectively. Macrophage content (relative RAM11 positive area) was reduced by 44% (p<0.001) on histology in Ivabradine-treated animals.ConclusionsHR lowering treatment with Ivabradine in an atherosclerotic rabbit model is associated with a reduction in vulnerable plaque features. The current study suggests that HR reduction may be beneficial for inducing or maintaining a more stable plaque phenotype.

The effect of the heart rate lowering drug Ivabradine on hemodynamics in atherosclerotic mice

“…Heart rate in mice treated with Ivabradine was 18.1% lower than the control mice, comparable to the values observed in other studies 15 – 20 , 26 . The control group showed an increase in heart rate.…”

“…Ivabradine treatment for 6 weeks in LDLR −/− mice resulted in a reduction in endothelial inflammation 21 , suggesting that although the increase in TAWSS is of short duration, it is sufficient to affect vascular biology. Pre-treatment with Ivabradine has been shown to prevent plaque growth in animal models of atherosclerosis in some 16 , 17 but not all 20 studies. Custodis et al .…”

“… 13 , 14 . Animal studies have shown that Ivabradine reduced heart rate and decreased oxidative stress, prevented endothelial dysfunction and thus reduced atherosclerosis 15 – 20 . These studies suggested that the effect of Ivabradine was exerted via alteration of the hemodynamic environment.…”

Cardiovascular outcomes related to social defeat stress: New insights from resilient and susceptible rats

“…Mice exposed to chronic variable psychological stress showed resting tachycardia and reduced endothelial function, which increased ischemic damage in a model of stroke (cerebral artery occlusion) (Custodis et al, 2011). In non-human primates treated with an atherogenic diet (Beere et al, 1984; Kaplan et al, 1987) and in rabbits with surgically induced atherosclerosis (van Hoof et al, 2017), HR reduction retarded the formation of atherosclerotic plaques.…”

Using imaging photoplethysmography for heart rate estimation in non-human primates

“…Heart rate is an important indicator of the functional status and psycho-emotional state for humans, non-human primates (NHP) [1][2][3] and other animals [4,5]. A common and the most direct tool for measuring heart rate is the electrocardiogram (ECG) [6].…”