Effects of .BETA.-Blocker on Left Ventricular Remodeling in Rats with Volume Overload Cardiac Failure

Kobayashi, Masayuki; Motomura, Noboru; Tanaka, Ryou; Yamane, Yoshihisa

doi:10.1292/jvms.70.1231

Cited by 13 publications

(12 citation statements)

References 20 publications

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“…The prevalence of sustained VO is increasing with the aging of populations, mainly due to the development of valvular diseases including mitral and aortic valve diseases [4]. Unfortunately, despite major advances in cardiac surgery and intervention, [5][6][7][8] as well as in medical pharmacological therapy used in the treatment of VO-induced cardiac hypertrophy [9][10][11], valvular insufficiency, particularly mitral regurgitation, remains in the aging population one of the main etiologies of VO with subsequent HFrEF in the aging population [12]. Therefore, there is great need for novel effective noninvasive therapy that may attenuate the VO-mediated remodeling process and prevent or delay the need for surgery.…”

mentioning

confidence: 99%

Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody

Cohen

Sagi²,

Bigelman

et al. 2020

PLoS ONE

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ObjectiveMonoclonal antibody derivatives are promising drugs for the treatment of various diseases due to their high matrix metalloproteinases (MMP) active site specificity. We studied the effects of a novel antibody, SDS3, which specifically recognizes the mature active site of MMP9/2 during ventricular remodeling progression in a mouse model of chronic volume overload (VO). MethodsVO was induced by creating an aortocaval fistula (ACF) in 10-to 12-week-old C57BL male mice. The VO-induced mice were treated with either vehicle control (PBS) or with SDS3 twice weekly by intraperitoneal (ip) injection. The relative changes in cardiac parameters between baseline (day 1) and end-point (day 30), were evaluated by echocardiography. The effects of SDS3 treatment on cardiac fibrosis, cardiomyocyte volume, and cardiac inflammation were tested by cardiac staining with Masson's trichrome, wheat Germ Agglutinin (WGA), and CD45, respectively. Serum levels of TNFα and IL-6 with and without SDS3 treatment were tested by ELISA. ResultsSDS3 significantly reduced cardiac dilatation, left ventricular (LV) mass, and cardiomyocyte hypertrophy compared to the vehicle treated animals. The antibody also reduced the heartto-body weight ratio of the ACF animals to values comparable to those of the controls. Interestingly, the SDS3 group underwent significant reduction of cardiac inflammation and proinflammatory cytokine production, indicating a regulatory role for MMP9/2 in tissue remodeling, possibly by tumor necrosis factor alpha (TNFα) activation. In addition, significant changes in the expression of proteins related to mitochondrial function were observed in ACF animals, these changes were reversed following treatment with SDS3. , et al. (2020) Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody. PLoS ONE 15(4): e0231202. https://doi. ConclusionThe data suggest that MMP9/2 blockage with SDS3 attenuates myocardial remodeling associated with chronic VO by three potential pathways: downregulating the extracellular matrix proteolytic cleavage, reducing the cardiac inflammatory responses, and preserving the cardiac mitochondrial structure and function. PLOS ONESpecific MMP9/2 antibody attenuates volume overload PLOS ONE | https://doi.org/10.

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confidence: 99%

Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody

Cohen

Sagi²,

Bigelman

et al. 2020

PLoS ONE

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“…A 28-d postaortocaval shunt has been shown to result in increased venous return and lead to the development of VOinduced cardiac hypertrophy without affecting systolic blood pressure (22,23). Removal of VO by closure of the aortocaval shunt has been reported to significantly regress cardiac hypertrophy (24).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Arrests and Regresses the Development of Pressure Overload- but Not Volume Overload-Induced Cardiac Hypertrophy in Rats

Wojciechowski

Juric

Louis

et al. 2010

The Journal of Nutrition

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Cardiac hypertrophy is a compensatory enlargement of the heart due to either volume overload (VO) and/or pressure overload (PO) that develops into heart failure if left untreated. The polyphenol resveratrol has been reported to regress PO-induced cardiac hypertrophy in rats. Our aim in this study was to assess the effectiveness of resveratrol on VO-induced cardiac hypertrophy. Sprague Dawley rats were subjected to aortocaval shunt and abdominal aortic banding surgeries to create VO and PO, respectively; sham-operated rats served as controls. To arrest the development of cardiac hypertrophy, daily resveratrol treatment (2.5 mg/kg body weight) was started 2 d postsurgery for 26 d and assessed by echocardiography at 2, 14, and 28 d postsurgery. Similarly, to regress cardiac hypertrophy resveratrol treatment was started after structural and functional abnormalities developed (14 d postsurgery) for 14 d and assessed by echocardiography at 14 and 28 d postsurgery. VO surgeries induced eccentric hypertrophy characterized by increased left ventricle internal dimensions (LVID) without wall thickening. Conversely, PO induced concentric hypertrophy with increased wall thickness without change in LVID. Lipid peroxidation, a marker for oxidative stress, was significantly elevated in both PO and VO rats. Resveratrol treatment arrested the development and regressed abnormalities in cardiac structure and function in PO but not VO rats. Treatment with resveratrol also significantly reduced oxidative stress in cardiac tissue of PO and VO rats. The results on cardiac structure and function demonstrate a potential for resveratrol in the treatment of cardiac hypertrophy due to PO but not VO.

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“…25,26 Furthermore, in a prior study of volume overload caused by aortocaval shunt, LV weight was significantly greater in rats treated with a β-blocker than those without β-blocker treatment. 27 These findings suggest that the pathophysiology of LV remodeling caused by primary volume overload, such as organic MR, may be different from other forms of congestive heart failure in which myocardial damage (ischemic heart disease, cardiomyopathy) is the primary insult.…”

Section: β-Blockade In Chronic Organic Mrmentioning

confidence: 96%

Effects of Early, Late, and Long-term Nonselective β-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation

Gao

et al. 2013

Circ: Heart Failure

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Background-Mitral regurgitation (MR) produces sympathetic nervous system activation which is detrimental in other causes of heart failure. However, whether β-blockade is beneficial in MR has not been determined. Methods and Results-Eighty-seven rats with significant organic MR were randomized to the β-blockade group (n=43) or the control group (n=44). Carvedilol was started in week 2 post MR induction and given for 23 to 35 weeks in the β-blockade group. Echocardiography was performed at baseline and at weeks 2, 6, 12, 24, 30, and 36 after MR induction. After 23 weeks of β-blockade, heart rates were significantly reduced by carvedilol (308±25 versus 351±31 beats per minute; P<0.001). Left ventricular end-diastolic (2.2±0.7 versus 1.59±0.6 mL; P<0.001), end-systolic volumes (0.72±0.42 versus 0.40±0.19 mL; P<0.001), and mass index (2.40±0.55 versus 2.06±0.62 g/kg; P<0.001) were significantly higher, and left ventricular fraction shortening (33±7% versus 38±7%; P<0.001) and ejection fraction (69±11% versus 75±7%; P<0.001) were significantly lower in the β-blockade group than in the control group. Systolic blood pressure was lower in the β-blockade group than in the control group (114±10 versus 93±12 mm Hg; P<0.005). Survival probability was significantly lower in the early β-blockade group than in the control group (88% versus 96%; P=0.03). 14 This dissociation creates a possible pathophysiological contradiction because adverse LV remolding is often associated with LV dysfunction and poor long-term outcome in all forms of congestive heart failure. Therefore, it is important to determine whether beneficial effects of β-blockade could be demonstrated if chronic organic MR was treated in the early stages before the development of LV dysfunction and if treatment is long-term. It is also imperative to determine whether LV remodeling associated with β-blocker therapy could ultimately have a negative impact on LV function in chronic organic MR or if the early improvement in LV function and myocardial contractility observed in prior studies could lead to improvement in LV remodeling if treatment was initiated early and long-term. To clarify this important issue, we performed a prospective study to determine the effects of early, late, and long-term β-blockade on LV remodeling, systolic function, and survival in experimental chronic MR. The study design had the following unique characteristics: (1) the study used a unique rat model of chronic MR developed in our laboratory, 15 allowing us to use a large numbers of animals to test the hypothesis; (2) carvedilol (a nonselective β-adrenergic blocking agent with α 1 -blocking activity) was administered early before the development of LV systolic dysfunction; and (3) a long-term treatment strategy was applied. Conclusions-Early Methods Rat Model of MRThe study protocol was approved by the Institution's Animal Care and Use Committee of the Pennsylvania State University College of Medicine (assurance number A3045-01). The study was performed according to the guidelines of the Amer...

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Effects of .BETA.-Blocker on Left Ventricular Remodeling in Rats with Volume Overload Cardiac Failure

Cited by 13 publications

References 20 publications

Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody

Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody

Resveratrol Arrests and Regresses the Development of Pressure Overload- but Not Volume Overload-Induced Cardiac Hypertrophy in Rats

Effects of Early, Late, and Long-term Nonselective β-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation

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