The Effects of Frequency of Voluntary Exercise on Cardiac Function in Dilated Cardiomyopathy Model Mice

AbstractWe investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.

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Heart rate as a marker of relapse during withdrawal of heart failure therapy in patients with recovered dilated cardiomyopathy: an analysis from TRED-HF

European Heart Journal ◽

10.1093/ehjci/ehaa946.1057 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

B Halliday ◽

A Vazir ◽

R Owen ◽

J Gregson ◽

R Wassall ◽

...

Keyword(s):

Heart Rate ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Funding Source ◽

End Point ◽

Therapy Withdrawal ◽

The Mean ◽

Withdrawal Of Therapy ◽

Continue Therapy

Abstract Introduction In TRED-HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short-term during phased withdrawal of drug therapy. Non-invasive markers of relapse may be used to monitor patients who wish a trial of therapy withdrawal and provide insights into the pathophysiological drivers of relapse. Purpose To investigate the relationship between changes in heart rate (HR) and relapse amongst patients with recovered DCM undergoing therapy withdrawal in TRED-HF. Methods Patients with recovered DCM were randomised to phased withdrawal of therapy or to continue therapy for 6 months. After 6 months of continued therapy, those in the control arm underwent withdrawal of therapy in a single arm crossover phase. HR was measured at each study visit. Mean HR and 95% confidence intervals (CI) were calculated at baseline, 45 days after baseline, 45 days prior to the end of the study or relapse and at the end of the study or relapse. Patients were stratified by treatment arm and the occurrence of the primary relapse end-point. Heart rate at follow-up was compared amongst patients who had therapy withdrawn and relapsed versus those who had therapy withdrawn and did not. ANCOVA was used to adjust for differences in HR at baseline between the two groups. Results Of 51 patients randomised, 26 were assigned to continue therapy and 25 to withdraw therapy. In the randomised and cross-over phases, 20 patients met the primary relapse end-point; one patient withdrew from the study and one patient completed follow-up in the control arm but did not enter the cross-over phase. Mean HR (standard deviation) at baseline and follow-up for (i) patients in the control arm was 69.9 (9.8) & 65.9 (9.1) respectively; (ii) for those who had therapy withdrawn and did not relapse was 64.6 (10.7) & 74.7 (10.4) respectively; and (iii) for those who had therapy withdrawn and relapsed was 68.3 (11.3) & 86.1 (11.8) respectively [all beats per minute]. The mean change in HR between the penultimate visit and the final visit for those who had therapy withdrawn and did not relapse was −2.4 (9.7) compared to 3.1 (15.5) for those who relapsed. After adjusting for differences in HR at baseline, the mean difference in HR measured at follow-up between patients who underwent therapy withdrawal and did, and did not relapse was 10.4bpm (95% CI 4.0–16.8; p=0.002) (Figure 1 & Table 1). Conclusion(s) A larger increase in HR may be a simple and effective marker of relapse for patients with recovered DCM who have insisted on a trial of therapy withdrawal. Whether HR control is crucial to the maintenance of remission amongst patients with improved cardiac function, or is simply a marker of deteriorating cardiac function, warrants further investigation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation

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Adipose-derived mesenchymal stem cells preserve cardiac function via ANT-1 in dilated cardiomyopathy hamster model

Regenerative Therapy ◽

10.1016/j.reth.2021.06.006 ◽

2021 ◽

Vol 18 ◽

pp. 182-190

Author(s):

Daisuke Mori ◽

Shigeru Miyagawa ◽

Takashi Kido ◽

Hiroki Hata ◽

Takayoshi Ueno ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Hamster Model

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Evaluation of ventricular wall stress and cardiac function in patients with dilated cardiomyopathy

Proceedings of the Institution of Mechanical Engineers Part H Journal of Engineering in Medicine ◽

10.1177/0954411915617984 ◽

2015 ◽

Vol 230 (1) ◽

pp. 71-74 ◽

Cited By ~ 4

Author(s):

Francesco Scardulla ◽

Antonino Rinaudo ◽

Salvatore Pasta ◽

Cesare Scardulla

Keyword(s):

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Wall Stress ◽

Ventricular Wall

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Prediction of improvement in cardiac function by high dose dobutamine stress echocardiography in patients with recent onset idiopathic dilated cardiomyopathy

International Journal of Cardiology ◽

10.1016/j.ijcard.2012.11.021 ◽

2013 ◽

Vol 167 (4) ◽

pp. 1649-1650 ◽

Cited By ~ 4

Author(s):

Ju Hwan Lee ◽

Dong Heon Yang ◽

Won Seok Choi ◽

Kyun Hee Kim ◽

Sun Hee Park ◽

...

Keyword(s):

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Stress Echocardiography ◽

Dobutamine Stress Echocardiography ◽

Dobutamine Stress ◽

Idiopathic Dilated Cardiomyopathy ◽

High Dose ◽

Recent Onset ◽

High Dose Dobutamine

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Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac function.

Circulation ◽

10.1161/01.cir.81.3.959 ◽

1990 ◽

Vol 81 (3) ◽

pp. 959-969 ◽

Cited By ~ 142

Author(s):

K Schulze ◽

B F Becker ◽

R Schauer ◽

H P Schultheiss

Keyword(s):

Cardiac Function ◽

Dilated Cardiomyopathy

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Ifetroban Reduces Coronary Artery Dysfunction in a Mouse Model of Duchenne Muscular Dystrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00180.2021 ◽

2021 ◽

Author(s):

Ray Mitchell ◽

Norman E Frederick ◽

Emily R Holzman ◽

Francesca Agobe ◽

Heather C M Allaway ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Coronary Arteries ◽

Oral Treatment ◽

Mdx Mice ◽

Muscarinic Agonist ◽

Therapeutic Implications

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne Muscular Dystrophy (DMD), an inheritable muscle wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A2/prostanoid receptor (TPr) antagonist, ifetroban. Further, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceutical) is currently recruiting subjects to determine if ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (~3-5 months) and aged (~9-12 months) mdx mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619(U4) was enhanced in young mdx mice versus controls. Additionally, young mdx mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mdx mice, U4-mediated vasoconstriction was measured in the absence and presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD.

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P6348Phospholamban antisense oligonucleotides drive the reversal of cardiac dysfunction and multiple heart failure parameters during murine dilated cardiomyopathy

European Heart Journal ◽

10.1093/eurheartj/ehz746.0944 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

D Spaeter ◽

A Hidalgo Gonzalez ◽

Z Elbeck ◽

S T Yeh ◽

H Siga ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Transcriptome Profiling ◽

Bioinformatic Analysis ◽

Systolic Volume ◽

Genetic Ablation ◽

Gene Therapy Approach ◽

End Diastolic Volume

Abstract Background Mice lacking muscle LIM protein (Mlp/Cspr3 −/−) develop dilated cardiomyopathy (DCM). Previous work established this model to be amenable to improvements in cardiac function by genetic ablation of phospholamban (PLN). Purpose To test the hypothesis that therapeutic reductions of PLN would similarly improve cardiac function, Mlp KO mice were administered an antisense oligonucleotide (ASO) targeting PLN. Methods Echocardiography measurements of ejection fraction (EF), end-diastolic volume (EDV) and end-systolic volume (ESV) were performed before and after treatment. In addition, global transcriptome profiling using 3'RNA-seq was performed to identify gene expression changes in diseased Mlp KO mice and following PLN ASO treatments. Mlp KO mice with ejection fraction (EF%) of less than 45% (median, 37.6%; interquartile range, 32.2–42.0%) were treated with vehicle (n=10) or PLN ASO (n=9) for 4 weeks. Results Three subcutaneous injections of PLN ASO were administered to Mlp KO mice resulting in 50–70% PLN reductions. Echocardiography performed at study end revealed improvements of EF (60±8 vs. 46±12%), ESV (31±11 vs. 56±21μl) and EDV (79±22 vs. 100±25μl) with PLN ASO treatment. Corrected for baseline values, PLN ASO treatment improved all echocardiographic measurements (p<0.001). Transcriptional analyses revealed that PLN ASO treatment reduced expression of heart failure related markers, such as Myh7 (−70%), Nppa (−72%), Nppb (−71%), Acta1 (−84%) and Ankrd1 (−40%), p<0.05 vs. vehicle. In addition, genes not previously known to be dysregulated in this model, Edn3 and Xirp2, were identified and shown to be reduced following PLN ASO treatment by 71% and 67%, respectively (p<0.001). Bioinformatic analysis suggested improvement of known and novel heart failure associated pathways by PLN inhibition in this model. In conclusion, antisense inhibition of PLN reduced functional and transcriptional indices of heart failure in a DCM model. In view of the failed CUPID trials, a gene therapy approach to improve SERCA2a activity, targeting PLN with ASO may be advantageous due to a likely more robust pharmacological profile.

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