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

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

scholarly journals UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension

2021 ◽  
Vol 10 (18) ◽  
Author(s):  
Xu Chen ◽  
Sadia Ashraf ◽  
Nadia Ashraf ◽  
Romain Harmancey
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Uncoupling Protein ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Uncoupling Protein 3 ◽  
Ventricular Diastolic Dysfunction

Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3 +/‐ ) to test the hypothesis that decreased UCP3 promotes left ventricular diastolic dysfunction during hypertension. Methods and Results Ucp3 +/‐ rats and ucp3 +/+ littermates fed a high‐salt diet (HS; 2% NaCl) and treated with angiotensin II (190 ng/kg per min for 28 days) experienced a similar rise in blood pressure (158±4 versus 155±7 mm Hg). However, UCP3 insufficiency worsened diastolic dysfunction according to echocardiographic assessment of left ventricular filling pressures (E/e’; 18.8±1.0 versus 14.9±0.6; P <0.05) and the isovolumic relaxation time (24.7±0.6 versus 21.3±0.5 ms; P <0.05), as well as invasive monitoring of the diastolic time constant (Tau; 15.5±0.8 versus 12.7±0.2 ms; P <0.05). Exercise tolerance on a treadmill also decreased for HS/angiotensin II‐treated ucp3 +/‐ rats. Histological and molecular analyses further revealed that UCP3 insufficiency accelerated left ventricular concentric remodeling, detrimental interstitial matrix remodeling, and fetal gene reprogramming during hypertension. Moreover, UCP3 insufficiency increased oxidative stress and led to greater impairment of protein kinase G signaling. Conclusions Our findings identified UCP3 insufficiency as a cause for increased incidence of left ventricular diastolic dysfunction during hypertension. The results add further support to the use of antioxidants targeting mitochondrial reactive oxygen species as an adjuvant therapy for preventing heart failure with preserved ejection fraction in individuals with obesity.

P3789Circulating biomarkers of myocardial fibrosis and cellular apoptosis in patients with atrial fibrillation and heart failure with preserved ejection fraction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M S Dzeshka ◽  
E Shantsila ◽  
V A Snezhitskiy ◽  
G Y H Lip
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Angiotensin Ii ◽  
Ejection Fraction ◽  
Matrix Metalloproteinase ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Myocardial Fibrosis ◽  
Volume Index ◽  
Preserved Ejection Fraction

Abstract Introduction Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. AF is associated with left atrial (LA) and ventricular (LV) myocardial fibrosis, contributing to diastolic dysfunction in HFpEF. Many profibrotic pathways have been studied in AF and HFpEF, but scarce data are available on the role of circulating microparticles (MPs). Purpose To evaluate association of circulating biomarkers of fibrosis and MPs subsets with Doppler-derived parameters of diastolic function in AF and HFpEF. Methods We studied 274 patients with non-valvular AF and HFpEF (median age 62 years, 37% females). Paroxysmal AF was diagnosed in 150 patients (55%) and non-paroxysmal AF (persistent or permanent) in 124 (45%). Median CHA2DS2-VASc score was 3 in males and 4 in females. Transthoracic echocardiography was performed to assess LV diastolic function, including early mitral inflow velocity (E), E/A velocities ratio (on sinus rhythm), early mitral annular diastolic velocity (E') for LV septal and lateral basal regions, E/E' ratio, LA maximum volume index (LAVi), E-wave velocity deceleration time (DT), flow propagation velocity (Vp). Average values from ten consecutive cardiac cycles were calculated. E/E' ratio was chosen as valid and reproducible index of diastolic function in AF patients for regression analysis. Blood levels of galectin 3, interleukin-1 receptor-like 1 (ST2), transforming growth factor beta 1 (TGF-β1), procollagen type III aminoterminal propeptide (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), angiotensin II and aldosterone level were assayed as surrogate biomarkers of myocardial fibrosis and profibrotic signaling. Using microflow cytometry, numbers of platelet-derived (CD42b+), monocyte-derived (CD14+), endothelial (CD144+), and apoptotic MPs (Annexin V+) were quantified in plasma samples. Linear regression was used to reveal parameters associated with diastolic function assessed as E/E' ratio. Data were normalized with Box-Cox transformation. Results Grade I diastolic dysfunction was found in 149 (54%); 94 (34%), and 31 (11%) patients had grade II and grade III diastolic dysfunction, respectively. On univariate analysis, age (β=0.23, p=0.0001); male gender (β=-0.19, p=0.02); history of hypertension (β=0.15, p=0.02); AF type, i.e. progression from paroxysmal to permanent (β=0.14, p=0.02); AnV+ MPs (β=0.19, p=0.01); angiotensin II (β=0.13, p=0.04); ST2 (β=0.1, p=0.04); and TIMP-1 (β=0.13, p=0.03) were associated with E/E' ratio. Using stepwise multivariate regression, AnV+ MPs (β=0.15, p=0.01) and TIMP-1 (β=0.3, p=0.04) remained significant predictors of E/E' ratio, adjusted for age, gender, hypertension and AF type. Relation of E/E' to TIMP-1 and AnV+ MPs Conclusion Apoptotic (AnV+) MPs and TIMP-1 were independently associated with diastolic dysfunction in AF and HFpEF. These may contribute to the pathophysiology of AF and HFpEF, and complications related to the presence of both. Acknowledgement/Funding ESC Research Grant, EHRA Academic Research Fellowship Programme

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 A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

2015 ◽  
Vol 309 (5) ◽  
pp. H771-H778 ◽  
Author(s):  
Jessica A. Regan ◽  
Adolfo Gabriele Mauro ◽  
Salvatore Carbone ◽  
Carlo Marchetti ◽  
Rabia Gill ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Relaxation Time ◽  
Angiotensin Ii ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Low Dose ◽  
Preserved Ejection Fraction ◽  
Arterial Blood ◽  
Chronic Infusion

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (ATII) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the ATII (0.2 mg·kg−1·day−1) or volume-matched vehicle ( N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. ATII infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.

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 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
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