scholarly journals A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure

2018 ◽  
Vol 315 (3) ◽  
pp. H563-H570 ◽  
Author(s):  
Jessica M. Bradley ◽  
Pablo Spaletra ◽  
Zhen Li ◽  
Thomas E. Sharp ◽  
Traci T. Goodchild ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Ventricular Ejection Fraction ◽  
Failing Heart

Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-β. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.

scholarly journals Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure

2020 ◽  
Author(s):  
Salva R. Yurista ◽  
Timothy R. Matsuura ◽  
Herman H.W. Silljé ◽  
Kirsten T. Nijholt ◽  
Kendra S. McDaid ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ventricular Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Ventricular Ejection Fraction ◽  
Failure Models ◽  
Ketone Ester

Background: Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models. Methods: Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet. Results: The KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P =0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P <0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2–treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values. Conclusions: Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.

ACCESSMENT OF RIGHT VENTRICULAR SYSTOLIC FUNCTION USING TAPSE

2011 ◽  
pp. 62-70
Author(s):  
Lien Nhut Nguyen ◽  
Anh Vu Nguyen
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Systolic Function ◽  
Systolic Heart Failure ◽  
Left Ventricular ◽  
Ventricular Ejection ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Background: The prognostic importance of right ventricular (RV) dysfunction has been suggested in patients with systolic heart failure (due to primary or secondary dilated cardiomyopathy - DCM). Tricuspid annular plane systolic excursion (TAPSE) is a simple, feasible, reality, non-invasive measurement by transthoracic echocardiography for evaluating RV systolic function. Objectives: To evaluate TAPSE in patients with primary or secondary DCM who have left ventricular ejection fraction ≤ 40% and to find the relation between TAPSE and LVEF, LVDd, RVDd, RVDd/LVDd, RA size, severity of TR and PAPs. Materials and Methods: 61 patients (36 males, 59%) mean age 58.6 ± 14.4 years old with clinical signs and symtomps of chronic heart failure which caused by primary or secondary DCM and LVEF ≤ 40% and 30 healthy subject (15 males, 50%) mean age 57.1 ± 16.8 were included in this study. All patients and controls were underwent echocardiographic examination by M-mode, two dimentional, convensional Dopler and TAPSE. Results: TAPSE is significant low in patients compare with the controls (13.93±2.78 mm vs 23.57± 1.60mm, p<0.001). TAPSE is linearly positive correlate with echocardiographic left ventricular ejection fraction (r= 0,43; p<0,001) and linearly negative correlate with RVDd (r= -0.39; p<0.01), RVDd/LVDd (r=-0.33; p<0.01), RA size (r=-0.35; p<0.01), TR (r=-0.26; p<0.05); however, no correlation was found with LVDd and PAPs. Conclusions: 1. Decreased RV systolic function as estimated by TAPSE in patients with systolic heart failure primary and secondary DCM) compare with controls. 2. TAPSE is linearly positive correlate with LVEF (r= 0.43; p<0.001) and linearly negative correlate with RVDd (r= -0.39; p<0.01), RVDd/LVDd (r=-0.33; p<0.01), RA size (r=-0.35; p<0.01), TR (r=-0.26; p<0.05); however, no correlation is found with LVDd and PAPs. 3. TAPSE should be used routinely as a simple, feasible, reality method of estimating RV function in the patients systolic heart failure DCM (primary and secondary).

Combination of Huangqi Granule and Rosuvastatin Improves the Cardiac Function in Heart Failure

2020 ◽  
Vol 19 (2) ◽  
pp. 181-187
Author(s):  
Jing Li ◽  
Yun Zhang ◽  
Weizhong Huangfu ◽  
Yuhong Ma
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Wall Thickness ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Model Group ◽  
Ventricular Ejection Fraction ◽  
Posterior Wall Thickness

Using rat models of heart failure, we evaluated the effects of rosuvastatin and Huangqi granule alone and in combination on left ventricular end-diastolic dimension, left ventricular end-systolic dimension, left ventricular ejection fraction, left ventricular posterior wall thickness at end-diastole, and left ventricular posterior wall thickness at end-systole. Results showed that left ventricular end-diastolic dimension, left ventricular end-systolic dimension in the rosuvastatin + Huangqi granule group were significantly decreased (P ‹ 0.01), while left ventricular ejection fraction, left ventricular posterior wall thickness at end-diastole and left ventricular posterior wall thickness at end-systole were significantly increased (P ‹ 0.05). The serum IL-2, IFN-β, and TNF-α in rosuvastatin + Huangqi granule group were significantly lower than those in model group (P ‹ 0.05). However, the levels of S-methylglutathione and superoxide dismutase in rosuvastatin + Huangqi granule group were significantly higher, while nitric oxide was significantly lower than that in the model group (P ‹ 0.05). Also, compared to the model group, the apoptosis rate, and the autophagy protein LC3-II in the cardiomyocytes of rosuvastatin + Huangqi granule group was significantly decreased (P ‹ 0.01), while the level of p62 protein was significantly increased (P ‹ 0.01). The levels of AMPK and p-AMPK in cardiomyocytes were significantly lower in rosuvastatin + Huangqi granule group; however, the levels of mTOR and p-mTOR showed an opposite trend (P ‹ 0.05). To sum up, rosuvastatin + Huangqi granule could improve the cardiac function, decrease the level of oxidative stress, and inflammatory cytokines in rats with HF. The possible underlying mechanism might be inhibition of autophagy and reduced apoptosis in cardiomyocytes by regulating AMPK-mTOR signaling pathway.

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