Hemodynamic and transcriptomic studies suggest early left ventricular dysfunction in a preclinical model of severe mitral regurgitation

Corporan, Daniella; Onohara, Daisuke; Amedi, Alan; Saadeh, Maher; Guyton, Robert A.; Kumar, Sandeep; Padala, Muralidhar

doi:10.1016/j.jtcvs.2020.08.119

Cited by 8 publications

(13 citation statements)

References 39 publications

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“…In a rodent model of severe MR (11), we recently reported similar findings as in human patients, with rapid and significant ventricular dilatation upon MR onset, preservation of ejection fraction for up to 14 weeks, followed by a gradual but persistent decline in ejection fraction (9). However, end-systolic volume and load-independent parameters of contractility were significantly worsened prior to the decline in ejection fraction, indicating the ineffectiveness in capturing LV dysfunction using traditional cardiac function indices (9).…”

Section: Introductionmentioning

confidence: 56%

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Ultrastructural Adaptation of the Cardiomyocyte to Chronic Mitral Regurgitation

Corporan

Segura²,

Padala

2021

Front. Cardiovasc. Med.

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Introduction: Mitral regurgitation (MR) imposes volume overload on the left ventricle (LV) and elevates wall stress, triggering its adverse remodeling. Pronounced LV dilation, minimal wall thinning, and a gradual decline in cardiac ejection fraction (EF) are observed. The structural changes in the myocardium that define these gross, organ level remodeling are not known. Cardiomyocyte elongation and slippage have both been hypothesized, but neither are confirmed, nor are the changes to the cardiomyocyte structure known. Using a rodent model of MR, we used immunohistochemistry and transmission electron microscopy (TEM) to describe the ultrastructural remodeling of the cardiomyocyte.Methods: Twenty-four male Sprague-Dawley rats (350–400 g) were assigned to two groups: group (1) rats induced with severe MR (n = 18) and group (2) control rats that were healthy and age and weight matched (n = 6). MR was induced in the beating heart using a 23-G ultrasound-guided, transapical needle to perforate the anterior mitral leaflet, and the rats were followed to 2, 10, and 20 weeks (n = 6/time-point). Echocardiography was performed to quantify MR severity and to measure LV volume and function at each time-point. Explanted myocardial tissue were examined with TEM and immunohistochemistry to investigate the ultrastructural changes.Results: MR induced rapid and significant increase in end-diastolic volume (EDV), with a 50% increase by 2 weeks, compared with control. Rise in end-systolic volume (ESV) was more gradual; however, by 20 weeks, both EDV and ESV in MR rats were increased by 126% compared with control. A significant decline in EF was measured at 10 weeks of MR. At the ultrastructural level, as early as 2 weeks after MR, cardiomyocyte elongation and increase in cross-sectional area were observed. TEM depicted sarcomere shortening, with loss of Z-line and I-band. Desmin, a cytoskeletal protein that is uniformly distributed along the length of the cardiomyocyte, was disorganized and localized to the intercalated disc, in the rats induced with MR and not in the controls. In the rats with MR, the linear registry of the mitochondrial arrangement along the sarcomeres was lost, with mitochondrial fragmentation, aggregation around the nucleus, and irregularities in the cristae.Discussion: In the setting of chronic mitral regurgitation, LV dilatation occured by cardiomyocyte elongation, which manifests at the subcellular level as distinct ultrastructural alterations of the sarcomere, cytoskeleton, and mitochondria. Since the cytoskeleton not only provides tensegrity but has functional consequences on myocyte function, further investigation into the impact of cytoskeletal remodeling on progressive heart failure or recovery of function upon correcting the valve lesion are needed.

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Section: Introductionmentioning

confidence: 56%

“…Ventricular remodeling secondary to MR has been studied at the organ level in preclinical rodent and dog models, and in humans (5)(6)(7)(8)(9). At the organ level, rapid and profound chamber dilation occurs upon the onset of MR, with a gradual decline in cardiac function, in animal models and in patients.…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural Adaptation of the Cardiomyocyte to Chronic Mitral Regurgitation

Corporan

Segura²,

Padala

2021

Front. Cardiovasc. Med.

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“…Based on the experimental data presented by Corporan and colleagues 6 in this issue of the Journal, these fears may not be unfounded. The investigators from Emory University performed an elegant hemodynamic and molecular study on rats induced with severe primary mitral regurgitation through guided disruption of the mitral valve with a 23-G needle.…”

Section: Commentary: the Mitral Matrixmentioning

confidence: 99%

“…5 Even in the most experienced hands, a repair rate of >95% appears to be difficult to achieve. Although excellent results with complex mitral valve repair have been reported, 6 it would still be not easy to recommend mitral valve repair in all asymptomatic patients with severe mitral insufficiency. Or would it?…”

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confidence: 99%

Commentary: The mitral matrix

Timek

2021

The Journal of Thoracic and Cardiovascular Surgery

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“…1,2 Furthermore, it has been observed that patients with preserved LV function who undergo mitral repair frequently have postoperative LV dysfunction. 1 An interesting article by Corporan and colleagues 3 describes an experimental rat model of MR, achieved by surgically perforating the anterior mitral leaflet. Over a period of 40 weeks, they observed that ventricular dilatation, impaired LV contractility, transcriptomic changes, myocardial remodeling, and oxidative stress pathways activation preceded a fall in LV ejection fraction.…”

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confidence: 99%