An Image Guided Transapical Mitral Valve Leaflet Puncture Model of Controlled Volume Overload from Mitral Regurgitation in the Rat

Corporan, Daniella; Kono, Takanori; Onohara, Daisuke; Padala, Muralidhar

doi:10.3791/61029

Cited by 4 publications

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“…The procedure to induce MR with ultrasound guidance was previously described ( 9 , 11 ). In this model, the procedural survival is 92% ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

“…In patients, symptomatic heart failure occurs nearly 5-10 years after the onset of MR, if it is not reversed (10). 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: 99%

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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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“…The procedure to induce MR with ultrasound guidance was previously described ( 9 , 11 ). In this model, the procedural survival is 92% ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ultrastructural Adaptation of the Cardiomyocyte to Chronic Mitral Regurgitation

Corporan

Segura²,

Padala

2021

Front. Cardiovasc. Med.

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“…Techniques to induce severe MR, were described previously in detail (Corporan et al, 2020 , 2018 ; Corporan, Kono, et al, 2020 , 2018 ; Onohara et al, 2019 ). Rats were sedated with 5% isoflurane in 100% oxygen for 5 min, intubated, and mechanically ventilated with 2.5% isoflurane in 100% oxygen, with a tidal volume of 1 ml/100 g body weight and a ventilation rate of 66 breaths per minute.…”

Section: Methodsmentioning

confidence: 99%

Passive mechanical properties of the left ventricular myocardium and extracellular matrix in hearts with chronic volume overload from mitral regurgitation

Corporan

Saadeh

Yoldas

et al. 2022

Physiological Reports

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Cardiac volume overload from mitral regurgitation (MR) is a trigger for left ventricular dilatation, remodeling, and ultimate failure. While the functional and structural adaptations to this overload are known, the adaptation of myocardial mechanical properties remains unknown. Using a rodent model of MR, in this study, we discern changes in the passive material properties of the intact and decellularized myocardium. Eighty Sprague‐Dawley rats (350–400 g) were assigned to two groups: (1) MR ( n = 40) and (2) control ( n = 40). MR was induced in the beating heart by perforating the mitral leaflet with a 23G needle, and rats were terminated at 2, 10, 20, or 40 weeks ( n = 10/time‐point). Echocardiography was performed at baseline and termination, and explanted hearts were used for equibiaxial mechanical testing of the intact myocardium and after decellularization. Two weeks after inducing severe MR, the myocardium was more extensible compared to control, however, stiffness and extensibility of the extracellular matrix did not differ from control at this timepoint. By 20 weeks, the myocardium was stiffer with a higher elastic modulus of 1920 ± 246 kPa, and a parallel rise in extracellular matrix stiffness. Despite some matrix stiffening, it only contributed to 31% and 36% of the elastic modulus of the intact tissue in the circumferential and longitudinal directions. At 40 weeks, similar trends of increasing stiffness were observed, but the contribution of extracellular matrix remained relatively low. Chronic MR induces ventricular myocardial stiffening, which seems to be driven by the myocyte compartment of the muscle, and not the extracellular matrix.

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“…Then, the needle was withdrawn, and appropriate pressure was applied to the LV to stop the bleeding and allow coagulation. Subsequently, transthoracic echocardiography was done to ensure that MR significantly existed through the right parasternal long-axis view with color mapping flow displaying a regurgitant jet area > 30% of the LA 49 . After the successful creation of MR, the thoracic wall and skin were anatomically closed with suitable suture materials.…”

Section: Surgical Induction Of Mitral Regurgitationmentioning

confidence: 99%

Sacubitril/valsartan mitigates cardiac remodeling, systolic dysfunction, and preserves mitochondrial quality in a rat model of mitral regurgitation

Tantisuwat

Saengklub

Boonpala

et al. 2023

Sci Rep

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Sacubitril/valsartan (SAC/VAL), an angiotensin receptor blocker-neprilysin inhibitor, has been widely used to treat several types of heart failure. Nevertheless, the effects of drugs in mitral regurgitation patients, from the molecular level to therapeutic effects, remain unclear. This study investigates the roles of SAC/VAL on cardiac function, mitochondrial quality, autophagy, mitophagy, and natriuretic peptides in a rat model of chronic mitral regurgitation. Male Sprague–Dawley rats underwent MR induction (n = 16) and sham surgeries (n = 8). Four weeks post-surgery confirmed MR rats were randomly divided into MR (n = 8) and SAC/VAL (n = 8) groups. The SAC/VAL group was administered SAC/VAL, whereas the MR and the sham rats received vehicle via oral gavage daily for 8 weeks. Cardiac geometry, function, and myocardial fibrosis were assessed by echocardiography and histopathology. Spectrophotometry and real-time PCR were performed to assess the pharmacological effects on mitochondrial quality, autophagy, mitophagy, and natriuretic peptides. MR rats demonstrated significant left heart dilation and left ventricular systolic dysfunction compared with the sham group, which could be significantly improved by SAC/VAL. In addition, SAC/VAL significantly reduced myocardial cardiac remodeling and fibrosis in MR rats. SAC/VAL improved the mitochondrial quality by attenuating mitochondrial reactive oxygen species production and mitochondrial depolarization compared with the MR group. Also, the upregulation of autophagy-related, mitophagy-related, and natriuretic peptide system gene expression in MR rats was attenuated by SAC/VAL treatment. In conclusion, this study demonstrated that SAC/VAL treatment could provide numerous beneficial effects in MR conditions, suggesting that this drug may be an effective treatment for MR.

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An Image Guided Transapical Mitral Valve Leaflet Puncture Model of Controlled Volume Overload from Mitral Regurgitation in the Rat

Cited by 4 publications

References 0 publications

Ultrastructural Adaptation of the Cardiomyocyte to Chronic Mitral Regurgitation

Ultrastructural Adaptation of the Cardiomyocyte to Chronic Mitral Regurgitation

Passive mechanical properties of the left ventricular myocardium and extracellular matrix in hearts with chronic volume overload from mitral regurgitation

Sacubitril/valsartan mitigates cardiac remodeling, systolic dysfunction, and preserves mitochondrial quality in a rat model of mitral regurgitation

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