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Background and aims: The anti-inflammatory agent colchicine is gaining interest as a treatment for coronary artery disease. However, the effects of colchicine in atherosclerotic animal models are mostly unknown. This study aimed to evaluate colchicine in a rabbit model of atherosclerosis. Methods: Twenty-two rabbits were fed a 0.5% cholesterol-enriched diet for 10 weeks and then randomized to receive either oral saline (n=11) or colchicine (350 μg/kg/day; n=11) for 6 weeks, with 0.2% cholesterol-diet during the treatment period. We performed intravascular ultrasound imaging (at start and end of treatment) and histology analyses of the descending thoracic aorta. Leucocyte activation was assessed in vitro on blood samples obtained during treatment. Results: Colchicine prevented positive aortic vascular remodelling (p=0.029 vs placebo). This effect was even more marked at high plasma cholesterol level (third quartile of plasma cholesterol, p=0.020). At high cholesterol level, both atherosclerotic plaque and media areas on histomorphology were reduced by colchicine compared to placebo (p=0.031 and p=0.039, respectively). Plaque fibrosis and macrophage area were reduced by colchicine (Masson's trichrome stain: p=0.038; RAM-11: p=0.026). The plaque vulnerability index, assessed by histology, was reduced by colchicine (p=0.040). Elastin/type I collagen ratio in media was significantly higher with colchicine compared to placebo (p=0.013). At a high level of plasma cholesterol, in vitro LPS challenge revealed a decrease in monocyte activation following treatment with colchicine (p

Background We previously demonstrated that high-density lipoprotein (HDL) infusions may improve left ventricular diastolic dysfunction (LVDD) in an aortic valve stenosis (AVS) model. Whether the benefit was direct or mediated by the observed reduction in AVS severity is not clear. Here, we aimed to test the direct effect of an ApoA-I mimetic on LVDD in the absence of AVS. Methods Rabbits were exposed to three different protocols to develop LVDD. First, rabbits were exposed to 0.5% cholesterol-rich diet for an average of 17 weeks. Second, rabbits were subjected to surgical ascending aortic constriction (AAC), to mimic the effect of fixed reduced aortic valve area, and studied after 10 weeks. The third model combined both cholesterol-enriched diet (for 12 weeks) and surgical AAC. The control group consisted of age-matched rabbits under normal diet. After development of LVDD, rabbits were randomized to receive infusions of saline or apoA-I mimetic (25 mg/kg) 3 times per week for 4 weeks. Detailed cardiac structure and function measurements were assessed at baseline and weekly during treatment period. Histological and molecular analyses were performed on LV samples. Results In the three models, echocardiographic results showed development of LVDD over time, with preserved LV systolic and aortic valve functions versus controls. ApoA-I mimetic infusions did not significantly improve echocardiographic parameters nor molecular markers of cardiac inflammation, oxidative stress and fibrosis. Conclusion ApoA-I mimetic therapy did not directly improve LVDD. These results indicate that previously observed changes of LVDD were caused by AVS improvement induced by this treatment.

BackgroundLeft ventricular diastolic dysfunction (LVDD) is present in more than 50% of patients suffering from heart failure. LVDD animal models are limited and its underlying mechanisms remain largely unknown. Aortic valve stenosis (AVS) may cause LVDD, and we recently reported LVDD in an AVS rabbit model. Here we aimed to develop a rabbit model of LVDD without AVS.MethodsRabbits were fed with a 0.5% cholesterol-enriched diet (n = 9) or normal diet (n = 8) until they developed LVDD defined by a value of the echocardiographic parameter E/Em ratio higher than the mean at baseline + 2SD. Rabbits were then fed a 0.2% cholesterol-enriched diet for 4 weeks (average total diet duration: 20 weeks). Detailed cardiac structure and function measurements were assessed by echocardiography at baseline, weeks 8, 12 and 14 to 20, when applicable. Histological analyses and RT-qPCR were performed on LV samples.ResultsThe hypercholesterolemic diet induced LVDD without systolic dysfunction or AVS, as shown by multiple echocardiographic parameters, including early filling mitral peak velocity and deceleration rate, Em/Am ratio and E/Em ratio (all pConclusionRabbits fed with a cholesterol-enriched diet develop LVDD with preserved systolic function and evidence of cardiac inflammation and oxidative stress. This rabbit model may be used in future studies to test treatment strategies against LVDD.

Aortic valve stenosis (AVS) is the most common valvular heart disease in the Western world. Therapy based on apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins, results in AVS regression in experimental models. Nevertheless, apoA-I degradation by proteases might lead to suboptimal efficacy of such therapy. An activatable probe using a quenched fluorescently labeled full-length apoA-I protein was generated to assess apoA-I-degrading protease activity in plasma derived from 44 men and 20 women with severe AVS (age 65.0 ± 10.4 years) as well as from a rabbit model of AVS. In human and rabbit AVS plasma, apoA-I-degrading protease activity was significantly higher than in controls (humans: 0.038 ± 0.009 vs 0.022 ± 0.005 RFU/s, p

Background Infusions of apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins (HDL), result in aortic valve stenosis (AVS) regression in experimental models. Severe AVS can be complicated by acquired von Willebrand syndrome, a haemorrhagic disorder associated with loss of high-molecular-weight von Willebrand factor (vWF) multimers (HMWM), the latter being a consequence of increased shear stress and enhanced vWF-cleaving protease (ADAMTS-13) activity. Although antithrombotic actions of HDL have been described, its effects on ADAMTS-13 and vWF in AVS are unknown. Methods and Results We assessed ADAMTS-13 activity in plasma derived from a rabbit model of AVS (n = 29) as well as in plasma collected from 64 patients with severe AVS (age 65.0 ± 10.4 years, 44 males) undergoing aortic valve replacement (AVR). In both human and rabbit AVS plasma, ADAMTS-13 activity was higher than that in controls (p Conclusion Our data indicate that HDL levels are associated with reduced ADAMTS-13 activity and increased HMWM. HDL-based therapies may reduce the haematologic abnormalities of the acquired von Willebrand syndrome in AVS.

Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high-resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level with a large variety of biomarkers. In this work, we present a system enabling automated volumetric histology imaging of excised aortas that can spatially correlate results with combined IVUS/NIRF imaging of lipid-rich atheroma in cholesterol-fed rabbits. Pullbacks in the rabbit aortas were performed with a dual modality IVUS/NIRF catheter developed by our group. Ex vivo three-dimensional (3D) histology was performed combining optical coherence tomography (OCT) and confocal fluorescence microscopy, providing high-resolution anatomical and molecular information, respectively, to validate in vivo findings. The microscope was combined with a serial slicer allowing for the imaging of the whole vessel automatically. Colocalization of in vivo and ex vivo results is demonstrated. Slices can then be recovered to be tested in conventional histology.

Objectives: To determine if heart rate (HR) reduction with ivabradine (IVA), a selective inhibitor of the pacemaker If current, prevents cardiac dysfunction associated with dyslipidemia. Methods: New Zealand White rabbits received either a standard diet, a 0.5% cholesterol-enriched diet only (CD), or a 0.5% CD with IVA (17 mg/kg/day) for 12 weeks. HR, left ventricular (LV) systolic function, diastolic function and LV regional myocardial performance index (MPI) were studied using echocardiography. Histological analysis included cardiac interstitial fibrosis and collagen type I fibers. Plasma levels of angiotensin II and aldosterone were quantified by immunoassays. Results: IVA reduced HR by approximately 11%. IVA improved MPI and attenuated LV diastolic dysfunction (DD) (92% mild and 8% moderate DD with IVA vs. 54% mild and 46% moderate DD in CD group). IVA also reduced atrial fibrosis (p = 0.027), ventricular fibrosis (p = 0.0002) and ventricular collagen type I (p = 0.0042). IVA decreased plasma angiotensin II levels (p = 0.042), and both angiotensin II and aldosterone levels were correlated with HR (p = 0.038 and 0.008). Conclusion: Selective HR reduction with IVA reduces DD and cardiac fibrosis in hypercholesterolemic rabbits. These beneficial effects of IVA support testing pure HR reduction in patients with diastolic heart failure.

Background and purpose: Aortic valve stenosis (AVS) is the most common valvular heart disease, and standard curative therapy remains open heart surgical valve replacement. The aim of our experimental study was to determine if apolipoprotein A-I (ApoA-I) mimetic peptide infusions could induce regression of AVS. Experimental approach: Fifteen New Zealand White male rabbits received a cholesterol-enriched diet and vitamin D2 until significant AVS was detected by echocardiography. The enriched diet was then stopped to mimic cholesterol-lowering therapy and animals were allocated randomly to receive saline (control group, n=8) or an ApoA-I mimetic peptide (treated group, n=7), three times per week for 2 weeks. Serial echocardiograms and post mortem valve histology were performed. Key results: Aortic valve area increased significantly by 25% in the treated group after 14 days of treatment (P=0.012). Likewise, aortic valve thickness decreased by 21% in the treated group, whereas it was unchanged in controls (P=0.0006). Histological analysis revealed that the extent of lesions at the base of valve leaflets and sinuses of Valsalva was smaller in the treated group compared with controls (P=0.032). The treatment also reduced calcification, as revealed by the loss of the positive relationship observed in the control group (r=0.87, P=0.004) between calcification area and aortic valve thickness. Conclusions and implications: Infusions of ApoA-I mimetic peptide lead to regression of experimental AVS. These positive results justify the further testing of high-density lipoprotein (HDL)-based therapies in patients with valvular aortic stenosis. Regression of aortic stenosis, if achieved safely, could transform the clinical treatment of this disease. British Journal of Pharmacology (2008) 154, 765–773; doi:10.1038/bjp.2008.122; published online 14 April 2008

Background and Purpose We have shown that infusions of apolipoprotein A-I (ApoA-I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA-I mimetic therapy in mice with calcific or fibrotic AVS. Experimental Approach Apolipoprotein E-deficient (ApoE−/−) mice and mice with Werner progeria gene deletion (WrnΔhel/Δhel) received high-fat diets for 20 weeks. After developing AVS, mice were randomized to receive saline (placebo group) or ApoA-I mimetic peptide infusions (ApoA-I treated groups, 100 mg·kg−1 for ApoE−/− mice; 50 mg·kg−1 for Wrn mice), three times per week for 4 weeks. We evaluated effects on AVS using serial echocardiograms and valve histology. Key Results Aortic valve area (AVA) increased in both ApoE−/− and Wrn mice treated with the ApoA-I mimetic compared with placebo. Maximal sinus wall thickness was lower in ApoA-I treated ApoE−/− mice. The type I/III collagen ratio was lower in the sinus wall of ApoA-I treated ApoE−/− mice compared with placebo. Total collagen content was reduced in aortic valves of ApoA-I treated Wrn mice. Our 3D computer model and numerical simulations confirmed that the reduction in aortic root wall thickness resulted in improved AVA. Conclusions and Implications ApoA-I mimetic treatment reduced AVS by decreasing remodelling and fibrosis of the aortic root and valve in mice.

Purpose: High-density lipoprotein (HDL) infusions induce rapid improvement of atherosclerosis and aortic valve stenosis (AVS) in animals but their effect on left ventricular diastolic dysfunction (LVDD) remains unknown. Our study aimed at evaluating the effects of the HDL mimetic peptide CER-522 on LVDD in a rabbit model of AVS. Methods: Thirty-five (35) male New-Zealand White rabbits were fed with a 0.5% cholesterol- and vitamin D2-enriched diet until mild AVS was detected by echocardiography (mean duration of diet: 16 weeks). Animals were then randomized to receive saline (control group, n = 11) or the HDL mimetic peptide CER-522 at doses of 10 mg/kg (n = 12) or 30 mg/kg (n = 12) 3 times per week for 2 weeks. Serial echocardiograms and end-of-study histological examination of the aortic valve and left ventricle were performed. Results: Aortic valve area increased at day 10 in the CER-522 10 mg/kg group (P = 0.016) and at day 14 in both the CER-522 10 and 30 mg/kg treated groups compared to controls (P = 0.011 and P = 0.033, respectively). Aortic root strain index was higher in both CER-522 treated groups vs controls at 14 days of treatment (P = 0.007 and P = 0.047, respectively). At day 14, compared to controls, CER-522 normalized early filling deceleration time (P < 0.001 for both treated groups) and E wave deceleration rate (P < 0.001 for both treated groups), decreased E/Em ratio (P < 0.001 and P = 0.001 for the 10 and 30 mg/kg groups, respectively) and increased Em/Am ratio (P < 0.001 and P = 0.025). Although all groups had similar amount of global LVDD before treatment, moderate LVDD was present in 36.4, 16.7 and 0% of animals in the control, CER-522 10 and 30 mg/kg groups respectively at study end (P = 0.216 and P < 0.001 for 10 and 30 mg/kg groups vs controls). Histological analyses showed that RAM-11 positive cells (macrophages) in LV myocardium and pericoronary fibrosis were reduced with CER-522 10 mg/kg compared to controls (P = 0.006 and P = 0.018). The number of apoptotic cardiomyocytes was reduced by CER-522 30 mg/kg vs controls (P = 0.010; P=NS for 10 mg/kg). Coronary artery atheroma area was decreased in both CER-522 groups vs controls (P = 0.028 and P = 0.044 for 10 and 30 mg/kg groups), as was the case for the coronary external/internal elastic lamina area ratio (P = 0.003 and P = 0.010). Conclusions: The HDL mimetic peptide CER-522 improves LVDD in rabbits while also reducing cardiomyocyte apoptosis, mild AVS, aortic root rigidity and coronary atherosclerosis.