ApoA-I mimetic does not improve left ventricular diastolic dysfunction in rabbits without aortic valve stenosis

https://doi.org/10.1016/j.ijcard.2020.12.089Get rights and content

Highlights

  • •

    ApoA-I mimetic infusions have no direct beneficial effect on diastolic dysfunction.

  • •

    3 different rabbit models were used to test the effects of ApoA-I mimetic on diastolic dysfunction.

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    Cardiac diastolic dysfunction was assessed by echography and molecular analysis.

Abstract

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.

Introduction

Left ventricular diastolic dysfunction (LVDD) is a complex disease which affects ventricular relaxation and compliance [1]. Numerous underlying diseases have been reported to cause LVDD, including left ventricular (LV) hypertrophy, cardiac ischemia and aortic valve stenosis (AVS) [2]. Mechanisms altered in LVDD are still not well known, but cardiac fibrosis, inflammation and oxidative stress are frequently mentioned [[3], [4], [5], [6]]. Yet, no effective treatment is available and patients with LVDD are treated for the associated diseases rather than the pathology itself [7].

High-density lipoproteins (HDL) have several favourable cardiovascular effects including those on reverse cholesterol transport, inflammation and oxidative stress [8]. Nevertheless, clinical results of several therapies targeting HDL, including CETP (cholesteryl ester transfer protein) inhibitors, have been disappointing [[9], [10], [11]]. In fact, extremely high HDL-C levels may even exert a detrimental effect [12]. As a result, attention has shifted toward strategies to improve HDL functionality, rather than simply increasing endogenous levels of HDL-C per se. Infusions with reconstituted HDL or apolipoprotein A-I (apoA-I) mimetic peptides have demonstrated pleiotropic effects, generally reducing endothelial dysfunction [13], inflammation [14] and fibrosis [15]. Circulating levels of HDL-cholesterol have been inversely correlated to LVDD in the general population [[16], [17], [18]]. Conversely, high HDL-cholesterol levels caused by overexpression of the apoA-I gene via adenoviral vector use, demonstrated beneficial effects on cardiac remodeling and diastolic function in infarcted mice [19,20]. In a previous study, we reported that the HDL mimetic CER-522 improved LVDD in a rabbit model of AVS [21]. However, beneficial effects of treatment were simultaneously found on both LVDD and AVS parameters. Whether HDL mimetics might have direct effects on LVDD, or the beneficial effects on LVDD were due to AVS improvement, or both, could not be addressed in that study. In the present investigation, we developed different rabbit models of LVDD, without the presence of valvular stenosis, and aimed to test the direct effects of an HDL mimetic on LVDD.

Section snippets

Experimental design

Animal care and procedures complied with the Canadian Council on Animal Care guidelines and were approved by the Montreal Heart Institute Research Center ethics committee for animal research.

Three rabbit LVDD models using a cholesterol-enriched diet and/or a surgical procedure were developed (Fig. S1). A first model consisted in rabbits fed with a 0.5% cholesterol-enriched diet (Teklad Global Rabbit Diet 2030, Harlan Laboratories, Madison, WI, USA) until the lateral mitral echocardiographic

Rabbits submitted to a hypercholesterolemic diet alone, aortic constriction alone, or the combination developed LVDD

Progression of LV diastolic function parameters was evaluated by Doppler-echocardiography as the change (Δ) between the last value in the LVDD-development period and baseline value. The mitral peak E-wave velocity remained stable in control (p=0.325) and AAC rabbits (p=0.359; Fig. 1A), while it significantly increased over time in both HCD and HCD-AAC rabbits (p=0.004 and p=0.003 versus baseline; p=0.002 and p=0.003 versus controls, respectively). The mitral E/A ratio did not change

Discussion

Diastolic dysfunction is a complex disease that remains poorly understood and for which there are no specific treatments available to date. Indeed, patients suffering from LVDD are only treated for associated conditions such as hypertension or myocardial ischemia. We previously reported improvement of LVDD with apoA-I mimetic infusions in an AVS rabbit model [22]. However, we could not evaluate whether those beneficial effects on cardiac function were direct or mediated by AVS improvement. In

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.

Limitations

LVDD was assessed by echocardiography in anaesthetised rabbits. Anesthesia reduces the heart rate (HR) which may affect the diastolic properties and filling pressures (ex. pulse wave transmitral and pulmonary vein flows). However, the same dose of anesthesia was given and the same HR pattern was observed between the different groups. Although echocardiography is reliable, we did not perform invasive hemodynamic monitoring which is widely used to validate LVDD. Indeed, in our present protocol,

Source of funding

Dr. Tardif holds the Canada Research Chair in translational and personalized medicine and the Université de Montréal Pfizer-endowed research chair in atherosclerosis.

Declaration of Competing Interest

Patents on the theme of HDL and both aortic valve stenosis and diastolic dysfunction were submitted by the Montreal Heart Institute and Drs Tardif and Rhéaume are mentioned as authors.

Acknowledgments

The authors would like to thank Craig Selzman, MD, and Amanda Szucsik, MSc, from University of Utah, Salt Lake City, UT, USA, for their kind advice about the microclip applier. We are also thankful to Dr. Ismail El-Hamamsy, at the Montreal Heart Institute, for his precious time and advice about the surgical procedure.

Special thanks to Lucie Lefebvre for editing the current manuscript. No funding other than Dr Tardif's own contribution and research chairs was obtained for this project.

References (31)

  • L. Ma et al.

    Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat

    Am. J. Physiol. Heart Circ. Physiol.

    (2012)
  • T. Murase et al.

    Cardiac remodeling and diastolic dysfunction in DahlS.Z-Lepr(fa)/Lepr(fa) rats: a new animal model of metabolic syndrome

    Hypertens. Res.

    (2012)
  • R.S. Rosenson et al.

    Dysfunctional HDL and atherosclerotic cardiovascular disease

    Nat. Rev. Cardiol.

    (2016)
  • P.J. Barter et al.

    Effects of torcetrapib in patients at high risk for coronary events

    N. Engl. J. Med.

    (2007)
  • M.J. Landray et al.

    Effects of extended-release niacin with laropiprant in high-risk patients

    N. Engl. Med.

    (2014)

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    1

    Authors contributed equally to this work.

    2

    This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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