Thyroid function in heart failure with preserved ejection fraction (HFpEF) - evaluation of serum and myocardial thyroid hormones in an animal model of HFpEF

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.

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Thyroid hormones and modulation of diastolic function: a promising target for heart failure with preserved ejection fraction

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018820958331 ◽

2020 ◽

Vol 11 ◽

pp. 204201882095833

Author(s):

João Sérgio Neves ◽

Catarina Vale ◽

Madalena von Hafe ◽

Marta Borges-Canha ◽

Ana Rita Leite ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Thyroid Hormones ◽

Cardiovascular Effects ◽

Clinical Syndrome ◽

Prognostic Impact ◽

Preserved Ejection Fraction ◽

Iodothyronine Deiodinase ◽

Promising Target ◽

Increased Risk

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with high mortality for which there is no proven therapy to improve its prognosis. Thyroid dysfunction is common in heart failure (HF) and is associated with worse prognosis. In this review, we discuss the cardiovascular effects of thyroid hormones, the pathophysiology of HFpEF, the prognostic impact of thyroid function, and the potential of thyroid hormones for treatment of HFpEF. Thyroid hormones have a central role in cardiovascular homeostasis, improving cardiac function through genomic and non-genomic mechanisms. Both overt and subclinical hypothyroidism are associated with increased risk of HF. Even when plasmatic thyroid hormones levels are normal, patients with HF may have local cardiac hypothyroidism due to upregulation of type 3 iodothyronine deiodinase. Thyroid hormones improve several pathophysiological mechanisms of HFpEF, including diastolic dysfunction and extra-cardiac abnormalities. Supplementation with thyroid hormones (levothyroxine and/or liothyronine), modulation of deiodinase activity, and heart-specific thyroid receptor agonists are potential therapeutic approaches for the treatment of HFpEF. Further preclinical and clinical studies are needed to clarify the role of thyroid hormones in the treatment of HFpEF.

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An Animal Model of Heart Failure with Preserved Ejection Fraction in Hypertension by Chronic Angiotensin II Infusion

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2014.07.223 ◽

2014 ◽

Vol 20 (10) ◽

pp. S170

Author(s):

Keiki Sugi ◽

Shinichiro Iida ◽

Jun Tanno ◽

Shintaro Nakano ◽

Yasumori Sujino ◽

...

Keyword(s):

Heart Failure ◽

Animal Model ◽

Angiotensin Ii ◽

Ejection Fraction ◽

Preserved Ejection Fraction

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.00840.2017 ◽

2018 ◽

Vol 124 (4) ◽

pp. 1034-1044 ◽

Cited By ~ 7

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.

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

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.00355 ◽

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

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P586Effectiveness of combination allogeneic stem cells in a novel large animal model of chronic kidney disease-induced heart failure with preserved ejection fraction (HFpEF)

European Heart Journal ◽

10.1093/eurheartj/ehx501.p586 ◽

2017 ◽

Vol 38 (suppl_1) ◽

Author(s):

A.M. Castellanos ◽

B.A. Tompkins ◽

M. Natsumeda ◽

V. Florea ◽

K. Collon ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Stem Cells ◽

Animal Model ◽

Kidney Disease ◽

Ejection Fraction ◽

Large Animal Model ◽

Large Animal ◽

Preserved Ejection Fraction

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00542.2015 ◽

2015 ◽

Vol 309 (9) ◽

pp. H1407-H1418 ◽

Cited By ~ 38

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2019835118 ◽

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.

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