Characterization of Coronary Flow Reserve and Left Ventricular Remodeling in a Mouse Model of Chronic Aortic Regurgitation With Carvedilol Intervention

Wang, Xiangfei; Wu, Jian; Zhu, Dan; You, J. Q.; Zou, Yunzeng; Qian, Juying; Ge, Junbo

doi:10.7863/ultra.34.3.483

Cited by 4 publications

(8 citation statements)

References 39 publications

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“…The center frequencies of the transducers were 30 MHz, providing resolutions of 115 m (lateral) ϫ 55 m (axial) (39,45). Echocardiographic assessment had good intra-and interobserver agreement, as reported in our previous studies (35,39,41,42). During echocardiographic study, the mouse was positioned on a heating pad to maintain normothermia and anesthetized with isoflurane (3% for induction).…”

Section: Echocardiographymentioning

confidence: 82%

“…Volume overload was induced by AR, a recently developed murine model for volume overload study. AR surgery was performed under the guidance of ultrasound imaging in 10 mice, according to methods we have previously described (35,42). Briefly, after mice were anesthetized as described above, a plastic catheter containing a metal wire was inserted in the right common carotid artery, and the metal wire was then advanced through the catheter to puncture the aortic valves until the Doppler ultrasound showed significant diastolic retrograde flow in the aortic arch.…”

Section: Mice and Surgerymentioning

confidence: 99%

“…Moreover, an arteriovenous fistula confers biventricular overload that differs from valvular regurgitation and thus causes bias and controversy in studies of hypertrophymediating signaling pathways. We have recently created a murine model of aortic regurgitation (AR) to induce volume overload (35,42,46). This novel model provides a helpful platform to study a preload cardiac phenotype and its underlying mechanisms during volume overload.…”

Section: Introductionmentioning

confidence: 99%

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Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.

You

Zhang

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Mechanical overload can be classified into pressure overload and volume overload, causing concentric and eccentric cardiac hypertrophy, respectively. Here, we aimed to differentiate the load-mediated signaling pathways involved in pressure versus volume overload cardiac hypertrophy. Pressure or volume overload was imposed on C57BL/6J mice by transverse aortic constriction (TAC) or aortic regurgitation (AR), respectively. After surgery (2 wk), left ventricular structure and function were evaluated by echocardiographic, hemodynamic, and histological analyses. Signaling pathways related to hypertrophy, fibrosis, angiogenesis, and apoptosis were studied by histological analysis, RT-PCR, and Western blot analysis. Although mean wall stress was similar in both TAC and AR mice, systolic wall stress was significantly increased in TAC and diastolic wall stress was mainly elevated in AR. TAC or AR induced concentric or eccentric compensated hypertrophy, respectively. TAC was associated with more significant fibrosis and apoptosis, whereas AR was associated with more significant angiogenesis. MAPK kinase family, β-arrestin-2, Akt, and Ca-related signaling pathways were markedly activated in TAC but mildly upregulated or unchanged in AR. Pressure overload and volume overload induce different phenotypic and molecular adaptations in cardiac hypertrophy. Most load-related signaling pathways assessed in this study predominate in pressure but not volume overload. The stimulus-specific heterogeneity in the signaling pathways requires distinct manipulations for further mechanistic and pharmacological studies. NEW & NOTEWORTHY Using the transverse aortic constriction mouse model and the newly developed aortic regurgitation mouse model, we delineated the prominent differences between concentric and eccentric cardiac hypertrophy on morphological, functional, and molecular levels. Our findings are important for the precise diagnosis and treatment of these two types of cardiac hypertrophy. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/chinese-english-language-podcast-on-differential-cardiac-remodeling-in-tac-vs-ar/ .

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Section: Echocardiographymentioning

confidence: 82%

Section: Mice and Surgerymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.

You

Zhang

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…AR surgery was performed under the guidance of ultrasound imaging, according to the methods we have previously described (13,14). Briefly, after the mice were anesthetized with 2% isoflurane, a plastic catheter containing a metal wire was inserted into the right common carotid artery, then the metal wire was advanced through the catheter to puncture the aortic valve until the Doppler ultrasound showed significant diastolic retrograde flow (>200 mm/s) in the aortic arch (Figure 1).…”

Section: Creation Of the Ar Modelmentioning

confidence: 99%

“…Taking these issues into consideration, we have previously established an AR model to induce volume overload in mice, by disrupting the aortic valve cusps. In this context, we focused initially on macrovascular hemodynamic profiles (13,14). Compared with arteriovenous fistulae models, this novel volume overload model induced by AR has clinically distinct stress on the heart characterized by back flow versus pure forward flow, and shows less stress on veins.…”

Section: Introductionmentioning

confidence: 99%

Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation

You

Wang

et al. 2020

Ann Transl Med

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Background: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles of some potentially relevant molecules in an animal model of surgically induced AR.Methods: AR was induced by puncturing the aortic valve leaflets in C57BL/6J mice under echocardiographic guidance.Results: As early as 1 week following AR, the left ventricles (LV) displayed marked impairments in diastolic function and coronary flow reserve (CFR), as well as cardiac hypertrophy and chamber dilatation at both end-systole and end-diastole. LV free wall thickening and cardiomyocyte hypertrophy in LV were observed 2 weeks following of AR while a decline in ejection fraction was not seen until after 4 weeks. Nppa (natriuretic peptide A) and Nppb (natriuretic peptide B) increased over time, in conjunction with prominent Akt activation as well as slight CaMKII (Ca 2+ /calmodulin-dependent protein kinase II) activation and biphasic changes in β-arrestin-2 expression. Treatment of AR mice with Akt inhibition exacerbated the eccentric hypertrophy, while neither inhibition of CaMKII nor β-arrestin-2 overexpression influenced the response to AR.Conclusions: Our structural, functional, molecular and therapeutic analyses reveal that Akt, but not CaMKII or β-arrestin-2, plays a regulatory role in the development of LV remodeling after AR in Mice.These results may shed important light on therapeutic targets for volume overloaded cardiomyopathy.

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Angiotensin II blockers improve cardiac coronary flow under hemodynamic pressure overload

et al. 2021

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Characterization of Coronary Flow Reserve and Left Ventricular Remodeling in a Mouse Model of Chronic Aortic Regurgitation With Carvedilol Intervention

Abstract: In mice with chronic severe aortic regurgitation, carvedilol therapy significantly improves the impaired coronary flow reserve and sufficiently attenuates adverse LV remodeling. Sustained coronary flow reserve impairment indicates progressive LV remodeling.

Cited by 4 publications

References 39 publications

Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.

Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.

Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation

Angiotensin II blockers improve cardiac coronary flow under hemodynamic pressure overload

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