scholarly journals Chronic low-intensity exercise attenuates cardiomyocyte contractile dysfunction and impaired adrenergic responsiveness in aortic-banded mini-swine

2018 ◽  
Vol 124 (4) ◽  
pp. 1034-1044 ◽  
Author(s):  
Jessica A. Hiemstra ◽  
Adam B. Veteto ◽  
Michelle D. Lambert ◽  
T. Dylan Olver ◽  
Brian S. Ferguson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Pressure Overload ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction ◽  
Low Intensity ◽  
Low Intensity Exercise

Exercise improves clinical outcomes in patients diagnosed with heart failure with reduced ejection fraction (HFrEF), in part via beneficial effects on cardiomyocyte Ca2+ cycling during excitation-contraction coupling (ECC). However, limited data exist regarding the effects of exercise training on cardiomyocyte function in patients diagnosed with heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to investigate cardiomyocyte Ca2+ handling and contractile function following chronic low-intensity exercise training in aortic-banded miniature swine and test the hypothesis that low-intensity exercise improves cardiomyocyte function in a large animal model of pressure overload. Animals were divided into control (CON), aortic-banded sedentary (AB), and aortic-banded low-intensity trained (AB-LIT) groups. Left ventricular cardiomyocytes were electrically stimulated (0.5 Hz) to assess Ca2+ homeostasis (fura-2-AM) and unloaded shortening during ECC under conditions of baseline pacing and pacing with adrenergic stimulation using dobutamine (1 μM). Cardiomyocytes in AB animals exhibited depressed Ca2+ transient amplitude and cardiomyocyte shortening vs. CON under both conditions. Exercise training attenuated AB-induced decreases in cardiomyocyte Ca2+ transient amplitude but did not prevent impaired shortening vs. CON. With dobutamine, AB-LIT exhibited both Ca2+ transient and shortening amplitude similar to CON. Adrenergic sensitivity, assessed as the time to maximum inotropic response following dobutamine treatment, was depressed in the AB group but normal in AB-LIT animals. Taken together, our data suggest exercise training is beneficial for cardiomyocyte function via the effects on Ca2+ homeostasis and adrenergic sensitivity in a large animal model of pressure overload-induced heart failure. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show chronic low-intensity exercise training can prevent cardiomyocyte dysfunction and impaired adrenergic responsiveness in a translational large animal model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

scholarly journals Effectiveness of Growth Hormone–Releasing Hormone Agonists (GHRH-A) in Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction

2020 ◽  
Author(s):  
Angela C. Rieger ◽  
Luiza L Bagno ◽  
Alessandro Salerno ◽  
Victoria Florea ◽  
Jose Rodriguez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Growth Hormone ◽  
Animal Model ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Large Animal Model ◽  
Large Animal ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction

ABSTRACTBackgroundTherapies that improve morbidity and mortality in heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone releasing hormone analogues (GHRH-A) reverse fibrosis and improve cardiac function in ischemic and non-ischemic animal models. We tested the hypothesis that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large animal model.MethodsFemale Yorkshire pigs (n=16) underwent 5/6 nephrectomy via renal artery embolization, which induced HFpEF, and 12-weeks later received daily subcutaneous injections of GHRH-A (n=8) or placebo (n=8). Kidney function, renal and cardiac MRI, pressure-volume loops, and electrical stimulation were assessed at baseline, 12-weeks, and 16-18 weeks post-embolization.ResultsThe CKD model was confirmed by increased creatinine and BUN. HFpEF was demonstrated at 12 weeks by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickening, end-diastolic pressure (EDP), end-diastolic pressure-volume relationship (EDPVR), and tau. After 6 weeks of treatment, diastolic function improved in the GHRH-A group, evidenced by normalization of EDP (p=0.03) associated with improved diastolic compliance as measured by EDP/EDV ratio (p=0.018).ConclusionA beneficial effect of GHRH-A in diastolic function was observed in a CKD large animal model that manifests the characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.

scholarly journals Developing a Large Animal Model of Heart Failure with Preserved Ejection Fraction

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Charlotte Hamilton ◽  
Bindu George ◽  
Julia Shanks ◽  
Rohit Ramchandra
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Ejection Fraction ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction

A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction

2015 ◽  
Vol 309 (9) ◽  
pp. H1407-H1418 ◽  
Author(s):  
Michael Schwarzl ◽  
Nazha Hamdani ◽  
Sebastian Seiler ◽  
Alessio Alogna ◽  
Martin Manninger ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Right Atrial ◽  
Large Animal Model ◽  
Large Animal ◽  
Atrial Pacing ◽  
Preserved Ejection Fraction ◽  
Lv Ejection Fraction

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs ( n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls ( n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.

scholarly journals Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction

2021 ◽  
Vol 118 (4) ◽  
pp. e2019835118
Author(s):  
Angela C. Rieger ◽  
Luiza L. Bagno ◽  
Alessandro Salerno ◽  
Victoria Florea ◽  
Jose Rodriguez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Growth Hormone ◽  
Animal Model ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Large Animal Model ◽  
Large Animal ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction

Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; n = 8; 30 µg/kg) or placebo (n = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP (P = 0.03), reduced EDP/EDV ratio (P = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca2+] transient amplitude (P = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio (P = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.

Abstract 8: Effectiveness of Combination Allogeneic Stem Cells in a Novel Large Animal Model of Chronic Kidney Disease-induced Heart Failure With Preserved Ejection Fraction (HFpEF)

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Angela Castellanos Rieger ◽  
Bryon A Tompkins ◽  
Makoto Natsumeda ◽  
Victoria Florea ◽  
Kevin Collon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Animal Model ◽  
Cell Therapy ◽  
Renal Artery ◽  
Cardiorenal Syndrome ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction ◽  
Lv Mass

Background: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular morbidity and mortality. Left ventricular (LV) hypertrophy and heart failure with preserved ejection fraction (HFpEF) are the primary manifestations of the cardiorenal syndrome in 60 to 80% of CKD patients. Therapies that improve morbidity and mortality in HFpEF are lacking. Stem cell therapy reduces fibrosis, increases neovascularization, and promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that stem cell treatment ameliorates HFpEF in a CKD model. Methods: Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization and 4-weeks later received either: allogeneic (allo-) MSC (10х10 6 ), allo-kidney c-kit + cells (c-kit; 10х10 6 ), combination (MSC+c-kit; 1:1 ratio [5х10 6 each]), or placebo (each n=5). Cell therapy was delivered via the patent renal artery. Kidney function, renal and cardiac MRI, and PV loops were measured at baseline, and at 4- and 12-weeks (euthanasia) post-embolization. Results: The CKD model was confirmed by increased creatinine and BUN and decreased GFR. Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks (p=0.7). HFpEF was demonstrated at 4 weeks by increased LV mass (20.3%; p= 0.0001), wall thickening (p<0.008), EDP (p=0.01), EDPVR (p=0.005), and arterial elastance (p=0.03), with no change in EF. Diffuse intramyocardial fibrosis was evident in histological analysis and delayed enhancement MRI imaging. After 12 weeks, there was a significant difference in MAP between groups (p=0.04), with an increase in the placebo group (19.97± 8.65 mmHg, p=0.08). GFR significantly improved in the combination group (p=0.033). EDV increased in the placebo (p=0.009) and c-kit (p=0.004) groups. ESV increased most in the placebo group (7.14±1.62ml; p=0.022). EF, wall thickness, and LV mass did not differ between groups at 12 weeks. Conclusion: A CKD large animal model manifests the characteristics of HFpEF. Intra-renal artery allogeneic cell therapy was safe. A beneficial effect of cell therapy was observed in the combination and MSC groups. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

scholarly journals Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine

2018 ◽  
Vol 125 (1) ◽  
pp. 86-96 ◽  
Author(s):  
T. Dylan Olver ◽  
Jenna C. Edwards ◽  
Brian S. Ferguson ◽  
Jessica A. Hiemstra ◽  
Pamela K. Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Interval Exercise

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca2+-activated K+ (BKCa) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BKCa channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BKCa channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BKCa channel-mediated coronary vascular dysfunction, it did not change BKCa channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BKCa channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BKCa channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

scholarly journals Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O2 balance and diastolic function

2013 ◽  
Vol 114 (1) ◽  
pp. 131-147 ◽  
Author(s):  
Kurt D. Marshall ◽  
Brittany N. Muller ◽  
Maike Krenz ◽  
Laurin M. Hanft ◽  
Kerry S. McDonald ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Diastolic Function ◽  
Myocardial Oxygen Consumption ◽  
Preserved Ejection Fraction ◽  
Miniature Swine ◽  
Interval Exercise ◽  
Low Intensity ◽  
Physiol Heart Circ

We have previously reported chronic low-intensity interval exercise training attenuates fibrosis, impaired cardiac mitochondrial function, and coronary vascular dysfunction in miniature swine with left ventricular (LV) hypertrophy (Emter CA, Baines CP. Am J Physiol Heart Circ Physiol 299: H1348–H1356, 2010; Emter CA, et al. Am J Physiol Heart Circ Physiol 301: H1687–H1694, 2011). The purpose of this study was to test two hypotheses: 1) chronic low-intensity interval training preserves normal myocardial oxygen supply/demand balance; and 2) training-dependent attenuation of LV fibrotic remodeling improves diastolic function in aortic-banded sedentary, exercise-trained (HF-TR), and control sedentary male Yucatan miniature swine displaying symptoms of heart failure with preserved ejection fraction. Pressure-volume loops, coronary blood flow, and two-dimensional speckle tracking ultrasound were utilized in vivo under conditions of increasing peripheral mean arterial pressure and β-adrenergic stimulation 6 mo postsurgery to evaluate cardiac function. Normal diastolic function in HF-TR animals was characterized by prevention of increased time constant of isovolumic relaxation, normal LV untwisting rate, and enhanced apical circumferential and radial strain rate. Reduced fibrosis, normal matrix metalloproteinase-2 and tissue inhibitors of metalloproteinase-4 mRNA expression, and increased collagen III isoform mRNA levels ( P < 0.05) accompanied improved diastolic function following chronic training. Exercise-dependent improvements in coronary blood flow for a given myocardial oxygen consumption ( P < 0.05) and cardiac efficiency (stroke work to myocardial oxygen consumption, P < 0.05) were associated with preserved contractile reserve. LV hypertrophy in HF-TR animals was associated with increased activation of Akt and preservation of activated JNK/SAPK. In conclusion, chronic low-intensity interval exercise training attenuates diastolic impairment by promoting compliant extracellular matrix fibrotic components and preserving extracellular matrix regulatory mechanisms, preserves myocardial oxygen balance, and promotes a physiological molecular hypertrophic signaling phenotype in a large animal model resembling heart failure with preserved ejection fraction.

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