Heterotopic abdominal heart transplantation in rats for functional studies of ventricular unloading

Ibrahim, Michael; Navaratnarajah, Manoraj; Kukadia, Punam; Rao, Christopher; Siedlecka, Urszula; Cartledge, James; Soppa, Gopal; Doorn, Carin van; Yacoub, Magdi H.; Terracciano, Cesare M.

doi:10.1016/j.jss.2012.01.053

Cited by 15 publications

(12 citation statements)

References 13 publications

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“…This study shows that MT contribution to cell YM is reversible upon unloading. The unlMI mimics several features of left ventricular assist devices in patients (16). This therapy has been questioned in some cases as prolonged unloading can attenuate cardiac function (17).…”

Section: Resultsmentioning

confidence: 99%

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Microtubules regulate cardiomyocyte transversal Young’s modulus

Swiatlowska

Sanchez-Alonso

Wright

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The field of cardiomyocyte mechanobiology is gaining significant attention, due to accumulating evidence concerning the significant role of cellular mechanical effects on the integrated function of the heart. To date, the protein titin has been demonstrated as a major contributor to the cardiomyocytes Young’s modulus (YM). The microtubular network represents another potential regulator of cardiac mechanics. However, the contribution of microtubules (MTs) to the membrane YM is still understudied and has not been interrogated in the context of myocardial infarction (MI) or mechanical loading and unloading. Using nanoscale mechanoscanning ion conductance microscopy, we demonstrate that MTs contribute to cardiomyocyte transverse YM in healthy and pathological states with different mechanical loading. Specifically, we show that posttranslational modifications of MTs have differing effects on cardiomyocyte YM: Acetylation provides flexibility, whereas detyrosination imparts rigidity. Further studies demonstrate that there is no correlation between the total protein amount of acetylated and detyrosinated MT. Yet, in the polymerized-only populations, an increased level of acetylation results in a decline of detyrosinated MTs in an MI model.

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Section: Resultsmentioning

confidence: 99%

“…Age-matched male Sprague-Dawley rats were used for control and MI models, generated according to previously published studies (18). Agematched male Lewis rats were used for the MI and partial unlMI studies, with respective controls (16). MI experiments were performed 16 wk after coronary ligation, when end-stage heart failure (HF) develops.…”

Section: Methodsmentioning

confidence: 99%

Microtubules regulate cardiomyocyte transversal Young’s modulus

Swiatlowska

Sanchez-Alonso

Wright

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The degree and duration of mechanical load variation caused by hHTX also regulates cardiomyocyte Ca 2+ handling ( 13 ): Ca 2+ release synchronicity was reduced at 8 weeks in partially unloaded hearts only. Moderate partial unloading had milder effects compared with complete unloading in cell volume reduction and did not cause depression and delay of the Ca 2+ transient, increased Ca 2+ spark frequency, or impaired t-tubule and cell surface structure.…”

Section: Heterotopic Heart Transplantation Models and Their Limitatiomentioning

confidence: 99%

Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

Segiser

Carrel

et al. 2016

Front. Cardiovasc. Med.

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Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under “reloaded” conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients.

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“…Heterotopic abdominal heart transplantation (HAHT) using normal hearts (Ibrahim et al . a ) results in a normally perfused and beating heart which does not contribute to cardiac output and is therefore mechanically unloaded. Analysis of the t‐tubule density and regularity using Di‐8‐ANEPPS membrane labelling demonstrated intact t‐tubule density but impaired regularity (Ibrahim et al .…”

Section: Mechanical Load and The T‐tubulesmentioning

confidence: 99%

“…One challenge in understanding the influence of mechanical load on t-tubule structure was whether normal t-tubule physiology depends on either (i) the absence of overload or (ii) a physiological range of loads. Heterotopic abdominal heart transplantation (HAHT) using normal hearts (Ibrahim et al 2013a) results in a normally perfused and beating heart which does not contribute to cardiac output and is therefore mechanically unloaded. Analysis of the t-tubule density and regularity using Di-8-ANEPPS membrane labelling demonstrated intact t-tubule density but impaired regularity (Ibrahim et al 2010), paralleling the changes seen initially after mechanical overload (Ibrahim et al 2012a).…”

Section: Mechanical Load and The T-tubulesmentioning

confidence: 99%

Manipulation of sarcoplasmic reticulum Ca²⁺ release in heart failure through mechanical intervention

Ibrahim

Nader

Yacoub

et al. 2015

The Journal of Physiology

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Left ventricular assist devices (LVADs) were developed as a means of temporary circulatory support, but the mechanical unloading they offer also results in significant reverse remodelling. In selected patients, these improvements are sufficient to allow ultimate device explantation without requiring transplantation; this represents a fundamental shift in our understanding of heart failure. Like heart failure itself, LVADs influence multiple biological systems. The transverse tubules are a system of membrane invaginations in ventricular cardiomyocytes which allow rapid propagation of the action potential throughout the cell. Through their dense concentration of L-type Ca 2+ channels in close proximity to intracellular ryanodine receptors, the t-tubules enable synchronous Ca 2+ release throughout the cell. The t-tubules' structure appears to be specifically regulated by mechanical load, such that either the overload of heart failure (or the spontaneously hypertensive rat model) or the profound unloading in a chronically unloaded heart result in impaired t-tubule structure, with ineffective Ca 2+ release. While there are multiple molecular pathways which underpin t-tubule regulation, Telethonin (Tcap) appears to be important in regulating the effect of altered loading on the t-tubule system.

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Heterotopic abdominal heart transplantation in rats for functional studies of ventricular unloading

Cited by 15 publications

References 13 publications

Microtubules regulate cardiomyocyte transversal Young’s modulus

Microtubules regulate cardiomyocyte transversal Young’s modulus

Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

Manipulation of sarcoplasmic reticulum Ca²⁺ release in heart failure through mechanical intervention

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Heterotopic abdominal heart transplantation in rats for functional studies of ventricular unloading

Cited by 15 publications

References 13 publications

Microtubules regulate cardiomyocyte transversal Young’s modulus

Microtubules regulate cardiomyocyte transversal Young’s modulus

Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

Manipulation of sarcoplasmic reticulum Ca2+ release in heart failure through mechanical intervention

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Product

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Manipulation of sarcoplasmic reticulum Ca²⁺ release in heart failure through mechanical intervention