Large animal model of functional tricuspid regurgitation in pacing induced end-stage heart failure

Malinowski, Marcin; Proudfoot, Alistair G.; Langholz, David; Eberhart, Lenora; Brown, Mary Jane; Schubert, H.; Wodarek, Jeremy; Timek, Tomasz A.

doi:10.1093/icvts/ivx012

Cited by 23 publications

(18 citation statements)

References 24 publications

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“…In fact, 85-90% of severe TR cases are functional, resulting predominantly from left heart disease (1). Our model, with which we have years of experience, demonstrates all salient features of biventricular disease such as reduced left and right ventricular EF, dilated ventricles, mitral and tricuspid annular dilation, and regurgitation in both valves (24). However, our ovine model develops biventricular heart failure within weeks as opposed to years as in patients.…”

Section: Limitationsmentioning

confidence: 90%

“…The TIC ovine model used in this study has been previously described in detail and validated as a reliable and repeatable model of biventricular heart failure in sheep (24). In short, we randomly assigned adult male Dorset sheep to either control (CTL, n=17, 59.9 ± 4.6 kg) or disease (TIC, n=33, 60.1 ± 5.3 kg) groups.…”

Section: Animal Modelmentioning

confidence: 99%

“…In turn, a better understanding of TR may inform improved surgical strategies or provide alternative treatment routes. Therefore, our objective was to fill this gap in knowledge and investigate whether the tricuspid valve anterior leaflet (TVAL), similarly to the mitral valve, (mal)adapts in an ovine, tachycardia-induced cardiomyopathy (TIC) biventricular heart failure model that we have previously used to study valvular disease (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

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The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

Meador

Mathur

Sugerman

et al. 2020

Preprint

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ObjectivesWe set out to determine the tricuspid valve’s propensity to (mal)adapt in disease.BackgroundTricuspid regurgitation (TR) is generally considered secondary to right and/or left ventricular disease without organic failure. Interestingly, we and others have previously shown the mitral valve (mal)adapts in functional mitral regurgitation, which may warrant reconsideration of its functional etiology. Whether the tricuspid valve similarly (mal)adapts is mostly unknown.MethodsWe evaluated the (mal)adaptive response of tricuspid valve anterior leaflets (TVALs) from an ovine model in which over-pacing (19 ± 6 days) induced biventricular heart failure and TR (tachycardia-induced cardiomyopathy, TIC, n=33) and compared findings to those from a control group (n=17). In both groups, we performed proteomics, immunohistochemistry, histology, two-photon microscopy, collagen assays, leaflet thickness and morphology measurements, and biaxial mechanical tests.ResultsWe found metabolically active resident valvular cells in TIC TVALs which expressed activation and turnover markers. In TIC TVALs, we observed a 140% increase in collagen content (p=0.016), increased collagen dispersion regionally (p=0.017), a 130% increase in leaflet area (p=0.002), a 140% increase in thickness (p=0.006), and a 130% increase in radial stiffness (p=0.006).ConclusionsOur data suggest that TVALs (mal)adapt during TIC on all scales. This response is likely initiated by activated valvular cells, resulting in collagen turnover, and ultimately leading to thickening, area increase, and stiffening. Our data motivates future studies on the exact pathways leading to tricuspid (mal)adaptation and pharmacological therapeutic strategies for TR.Condensed AbstractIn most cases, tricuspid regurgitation is presumed to originate from valve extrinsic factors. We challenge this paradigm and hypothesize that the tricuspid valve maladapts, rendering the valve at least partially culpable for its dysfunction. As such, we set out to demonstrate that the tricuspid valve, indeed, maladapts in an ovine model of heart disease. In the anterior leaflets, we found alterations on the protein and cell-level, leading to maladaptation in the form of tissue growth, thickening, and stiffening. Our findings may initially motivate mechanistic pathway studies, and in the future, leaflet-targeted pharmacological therapeutic options for tricuspid regurgitation.

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Section: Limitationsmentioning

confidence: 90%

Section: Animal Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

Meador

Mathur

Sugerman

et al. 2020

Preprint

Self Cite

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“…This leads to biventricular dilatation, increased wedge pressure and an increase in systemic vascular resistance within 2 to 3 weeks (66). Different iterations of this model vary in their placement of the pacing wires in the atria or ventricles, with some even placing multiple leads to test various stimulation patterns (66–69, 73). Tachycardic pacing has been successfully used in canine, porcine, and ovine models (70–72).…”

Section: Pacing Models Of Hfrefmentioning

confidence: 99%

Large Animal Models of Heart Failure With Reduced Ejection Fraction (HFrEF)

Spannbauer

Traxler

Zlabinger

et al. 2019

Front. Cardiovasc. Med.

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Heart failure with reduced ejection fraction (HFrEF) is defined by an ejection fraction (EF) below 40%. Many distinct disease processes culminate in HFrEF, among them acute and chronic ischemia, pressure overload, volume overload, cytotoxic medication, and arrhythmia. To study these different etiologies the development of accurate animal models is vital. While small animal models are generally cheaper, allow for larger sample sizes and offer a greater variety of transgenic models, they have important limitations in the context of HFrEF research. Small mammals have much higher heart rates and distinct ion channels. They also have much higher basal metabolic rates and their physiology in many ways does not reflect that of humans. The size of their organs also puts practical constraints on experiments. Therefore, large animal models have been developed to accurately simulate human HFrEF. This review aims to give a short overview of the currently established large animal models of HFrEF. The main animal models discussed are dogs, pigs, and sheep. Furthermore, multiple approaches for modeling the different etiologies of HF are discussed, namely models of acute and chronic ischemia, pressure overload, volume overload as well as cytotoxic, and tachycardic pacing approaches.

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“…We have recently developed several acute tricuspid regurgitation sheep models to study changes in the dynamics of the diseased annulus . In an acute pulmonary hypertension model, for example, we calculated classic clinical metrics of annular dynamics reported in the medical literature, such as annular area, perimeter, height, and eccentricity .…”

Section: Dynamics Of the Tricuspid Annulusmentioning

confidence: 99%

Biomechanics of the tricuspid annulus: A review of the annulus' in vivo dynamics with emphasis on ovine data

2019

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The tricuspid annulus forms the boundary between the tricuspid valve leaflets and their surrounding perivalvular tissue of the right atrioventricular junction. Its shape changes throughout the cardiac cycle in response to the forces from the contracting right heart myocardium and the blood‐valve interaction. Alterations to annular shape and dynamics in disease lead to valvular dysfunctions such as tricuspid regurgitation from which millions of patients suffer. Successful treatment of such dysfunction requires an in‐depth understanding of the normal shape and dynamics of the tricuspid annulus and of the changes following disease and subsequent repair. In this manuscript we review what we know about the shape and dynamics of the normal tricuspid annulus and about the effects of both disease and repair based on noninvasive imaging studies and invasive fiduciary marker‐based studies. We further show, by means of ovine data, that detailed engineering analyses of the tricuspid annulus provide regionally resolved insight into the kinematics of the annulus which would remain hidden if limiting analyses to simple geometric metrics.

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Large animal model of functional tricuspid regurgitation in pacing induced end-stage heart failure

Abstract: : Biventricular dysfunction, tricuspid annular dilatation and significant FTR were observed in our model of ovine tachycardia induced cardiomyopathy. This animal model reflects the clinical situation of end-stage heart failure patients presenting for mechanical support.

Cited by 23 publications

References 24 publications

The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

Large Animal Models of Heart Failure With Reduced Ejection Fraction (HFrEF)

Biomechanics of the tricuspid annulus: A review of the annulus' in vivo dynamics with emphasis on ovine data

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