Chronic Sildenafil Therapy in the ZSF1 Obese Rat Model of Metabolic Syndrome and Heart Failure With Preserved Ejection Fraction

2021 ◽  
pp. 107424842110342
Author(s):  
Sara Leite ◽  
Liliana Moreira-Costa ◽  
Rui Cerqueira ◽  
Cláudia Sousa-Mendes ◽  
António Angélico-Gonçalves ◽  
...  
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Ejection Fraction ◽  
Rat Model ◽  
Young Male ◽  
Left Ventricular ◽  
Systemic Hypertension ◽  
Endurance Capacity ◽  
Preserved Ejection Fraction ◽  
Atp Levels

Although decreased protein kinase G (PKG) activity was proposed as potential therapeutic target in heart failure with preserved ejection fraction (HFpEF), randomized clinical trials (RCTs) with type-5 phosphodiesterase inhibitors (PDE5i) showed neutral results. Whether specific subgroups of HFpEF patients may benefit from PDE5i remains to be defined. Our aim was to test chronic sildenafil therapy in the young male ZSF1 obese rat model of HFpEF with severe hypertension and metabolic syndrome. Sixteen-week-old ZSF1 obese rats were randomly assigned to receive sildenafil 100 mg·Kg−1·d−1 dissolved in drinking water (ZSF1 Ob SIL, n = 8), or placebo (ZSF1 Ob PL, n = 8). A group of Wistar-Kyoto rats served as control (WKY, n = 8). Four weeks later animals underwent effort tests, glucose metabolism studies, hemodynamic evaluation, and samples were collected for aortic ring preparation, left ventricular (LV) myocardial adenosine triphosphate (ATP) quantification, immunoblotting and histology. ZSF1 Ob PL rats showed systemic hypertension, aortic stiffening, impaired LV relaxation and increased LV stiffness, with preserved ejection fraction and cardiac index. Their endurance capacity was decreased as assessed by maximum workload and peak oxygen consumption (V˙O2) and respiratory quotient were increased, denoting more reliance on anaerobic metabolism. Additionally, ATP levels were decreased. Chronic sildenafil treatment attenuated hypertension and decreased LV stiffness, modestly enhancing effort tolerance with a concomitant increase in peak, ATP levels and VASP phosphorylation. Chronic sildenafil therapy in this model of HFpEF of the young male with extensive and poorly controlled comorbidities has beneficial cardiovascular effects which support RCTs in HFpEF patient subgroups with similar features.

scholarly journals A Preclinical Rat Model of Heart Failure With Preserved Ejection Fraction With Multiple Comorbidities

2022 ◽  
Vol 8 ◽  
Author(s):  
Géraldine Hubesch ◽  
Aliénor Hanthazi ◽  
Angela Acheampong ◽  
Laura Chomette ◽  
Hélène Lasolle ◽  
...  
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
High Fat Diet ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Preserved Ejection Fraction ◽  
High Fat

Heart failure with preserved ejection fraction (HFpEF) is a common complex clinical syndrome for which there are currently few evidence-based therapies. As patients with HFpEF very often present with comorbidities comprising the metabolic syndrome, we hypothesized, that metabolic syndrome could lead over time to the development of diastolic dysfunction and HFpEF. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 (the interleukin-1 receptor-like) markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

Abstract P490: Vascular Rarefaction And Decreased Angiogenic Potential In The Development Of Left Ventricular Diastolic Dysfunction In Heart Failure With Preserved Ejection Fraction

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Katie Anne Fopiano ◽  
Yanna Tian ◽  
Vadym Buncha ◽  
Liwei Lang ◽  
Zsolt Bagi
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Rat Model ◽  
Ex Vivo ◽  
Diastolic Heart Failure ◽  
Left Ventricular ◽  
Coronary Microvascular Dysfunction ◽  
Preserved Ejection Fraction ◽  
Angiogenic Potential

Coronary microvascular dysfunction (CMD) develops in patients with heart failure with preserved ejection fraction (HFpEF, also known as diastolic heart failure), but the nature of the underlying pathomechanisms behind this prevalent disease remain poorly understood. The hypothesis tested was that coronary microvascular rarefaction contributes to left ventricle (LV) diastolic function in HFpEF. The obese ZSF1 rat model of human HFpEF was employed and using transthoracic echocardiography it was found that 18-week-old male obese ZSF1 rats exhibited a significantly reduced E/A ratio (E=early, A=late mitral inflow peak velocities) and increased DT (E wave deceleration time) with no change in ejection fraction, indicating diastolic dysfunction. Coronary arteriolar and capillary trees were labeled using Tomato Lectin (Lycopersicon esculentum) DyLight®594 and were imaged by fluorescent confocal microscopy to generate image stacks for 3D reconstruction. Unbiased automated tracing of the microvasculature was done using VesselLucida360 software (MBF) followed by a morphometric analysis (VesselLucida Explorer). It was found that total vessel length and the number of vessel’s branching nodes were reduced in the obese ZSF1 rats, whereas the total vessel’s volumes remained consistent, when compared to the lean ZSF1 controls. These changes in the microvasculature were accompanied by decreased angiogenesis in the coronary arteries in the obese ZSF1 rats when compared to the lean ZSF1 rats using an ex vivo endothelial sprouting assay. From these results, it was concluded that vascular rarefaction and decreased angiogenesis both play a role in the development of LV diastolic dysfunction in the obese ZSF1 rat model of human HFpEF.

P5995A novel biased S1P1 agonist improves renal and cardiac functions in ZSF1 rats, a model of metabolic syndrome-associated Heart Failure with preserved Ejection Fraction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M F Evaristi ◽  
B Poirier ◽  
F Gillot ◽  
S Beeske ◽  
M P Pruniaux ◽  
...  
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Creatinine Ratio ◽  
Control Groups ◽  
Compound A ◽  
Cardiac Functions ◽  
And Function

Abstract Background/Introduction Heart Failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with currently no approved treatment. Diastolic dysfunction, dyspnea, intolerance to effort, high cardiac filling pressure, and lung congestion coexist with normal ejection fraction in this clinical syndrome. Ageing, obesity, type 2 diabetes, hypertension and renal dysfunction are the main comorbidities found in this heterogeneous group of patients. Microvascular endothelial dysfunction, driven by these risk factors, may be a common link with other aspects of the HFpEF pathogenesis that include oxidative stress, inflammation, cardiomyocyte stiffness/hypertrophy, and myofibroblast accumulation. Sphingosine-1-phosphate type-1 receptor (S1P1), a G protein–coupled receptor highly expressed in endothelial cells, regulates vascular integrity, vascular development and immune cell trafficking. Compound A is a novel G protein-biased S1P1 agonist that lacks functional antagonism and has endothelial-protective properties. Purpose S1P1 activation could promote phosphorylation of endothelial nitric oxide synthase, restoration of endothelial structure and function, and thus diminish cardiac and vascular stiffness, hypertrophy and fibrosis. The aim of this study was to investigate if compound A could improve renal and cardiac functions in a rat model of HFpEF with metabolic syndrome. Methods 65-week-old obese ZSF1 rats were fed a chow diet containing compound A (8 mg/kg/day) or no compound for 4 weeks. Lean ZSF1 and Wistar rats were included in the study as control groups. Urinary protein/creatinine ratio was measured as an index of glomerular injury. Cardiac hypertrophy and function were assessed by two-dimensional and Doppler echocardiography. Total cardiac and atrial weights and pulmonary edema were assessed. Results The obese ZSF1 rat was confirmed as a relevant model of HFpEF with advanced renal dysfunction. These rats showed severe glomerular filtration impairment, left ventricular and atrial hypertrophy and pulmonary edema. Cardiac systolic function, cardiac output and chamber volumes were preserved, diastolic function was impaired, and left ventricular posterior walls and septal thicknesses were increased compared to control groups. Four weeks of compound A treatment reduced urinary protein/creatinine ratio, blunted cardiac and atrial hypertrophy, and partially restored diastolic function. Circulating lymphocytes were not reduced by compound A, confirming that these pharmacological effects were not associated with S1P1 desensitization. Conclusion Compound A, a novel S1P1 agonist with endothelial properties, improves cardiac and renal functions in a rat model of metabolic syndrome-associated HFpEF. Sustained S1P1 activation with compound A may be a promising strategy for HFpEF treatment.

scholarly journals Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction

2021 ◽  
pp. 153537022110350
Author(s):  
Di Chang ◽  
Ting-Ting Xu ◽  
Shi-Jun Zhang ◽  
Yu Cai ◽  
Shu-Dan Min ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Factor ◽  
Ejection Fraction ◽  
Diastolic Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Male Rats ◽  
Preserved Ejection Fraction ◽  
Collagen Iii

Chronic kidney disease (CKD) is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF), whereas the underlying mechanism of cardiorenal HFpEF is still elusive. The aim of this study was to investigate the role of cardiac fibrosis in a rat model of cardiorenal HFpEF and explore whether treatment with Telmisartan, an inhibitor of renin-angiotensin-aldosterone system (RAAS), can ameliorate cardiac fibrosis and preserve diastolic function in cardiorenal HFpEF. Male rats were subjected to 5/6 subtotal nephrectomy (SNX) or sham operation (Sham), and rats were allowed four weeks to recover and form a stable condition of CKD. Telmisartan or vehicle was then administered p.o. (8 mg/kg/d) for 12 weeks. Blood pressure, brain natriuretic peptide (BNP), echocardiography, and cardiac magnetic resonance imaging were acquired to evaluate cardiac structural and functional alterations. Histopathological staining, real-time polymerase chain reaction (PCR) and western blot were performed to evaluate cardiac remodeling. SNX rats showed an HFpEF phenotype with increased BNP, decreased early to late diastolic transmitral flow velocity (E/A) ratio, increased left ventricular (LV) hypertrophy and preserved ejection fraction (EF). Pathology revealed increased cardiac fibrosis in cardiorenal HFpEF rats compared with the Sham group, while chronic treatment with Telmisartan significantly decreased cardiac fibrosis, accompanied by reduced markers of fibrosis (collagen I and collagen III) and profibrotic cytokines (α-smooth muscle actin, transforming growth factor-β1, and connective tissue growth factor). In addition, myocardial inflammation was decreased after Telmisartan treatment, which was in a linear correlation with cardiac fibrosis. Telmisartan also reversed LV hypertrophy and E/A ratio, indicating that Telmisartan can improve LV remodeling and diastolic function in cardiorenal HFpEF. In conclusion, cardiac fibrosis is central to the pathology of cardiorenal HFpEF, and RAAS modulation with Telmisartan is capable of alleviating cardiac fibrosis and preserving diastolic dysfunction in this rat model.

scholarly journals P1113Relationship between left atrium and hypertensive retinopathy in patients with systemic hypertension: a real-time three-dimensional echocardiography-based studyP1114Detection of early left ventricular systolic dysfunction in hypertensive patients with preserved ejection fraction using deformation imagingP1115Left ventricular strain in systemic sclerosis with and without pulmonary hypertension; a cardiac magnetic resonance studyP1116End-stage chronic kidney disease and routine annual transthoracic echocardiograpyP1117arrhythmogenic right ventricular cardiomyopathy or athlete's heart adaptations ?P1118Reduced left ventricular function in long term follow-up in women with previous severe preeclampsiaP1119Preload dependent changes of left ventricular twisting and torsion during pregnancy: a three-dimensional strain studyP1120Pre-procedural renal resistive index predicts contrast-induced acute kidney injury following coronary angiographyP1121Simplified 10 point ultrasound in diagnosis of pulmonary congestion in heart failureP1122Pulmonary and systemic vascular resistance during graded exercise in patients with ventricular septal defect repair versus healthy controlsP1123Effect of percutaneous stent implantation on arterial hypertension and aortic flow dynamics in patients with aortic coarctation: identification of responders and non respondersP1124The use of vitamin k antagonists is associated with increased levels of vascular calcification in low-risk patients with atrial fibrillationP1125Stress echo positivity predicts cancer deathP1126Assessment of the agreement between instantaneous wave-free ratio (iFR) and dobutamine stress echo in real world stable angina patientsP1127Impact of AVAproj on severity reclassification of LFLG AS with persistent area - gradient discordanceP1128 The prognostic value of rest and exercise- induced B-lines in heart failure patientsP1129Stress-induced worsening of left ventricular diastolic function as a new marker of myocardial ischemia: a retrospective observational studyP1130Prediction and management of stable angina in senior populationP1131Risk assessment of coronary heart desease in men before revascularization of non-coronary arteriesP1132Relation of elevated C - reactive protien level to left atrial size and left atrial thrombus in patients with valvular and non-valvular atrial fibrillationP1133Transesophageal echocardiographic assessment of left atrial appendage function as a cardioembolic source in atrial fibrillationP1134Correlations of three-dimensional mitral valve geometry with chronic ischemic mitral regurgitation severity in compliance with tethering phenotypesP1135Aortic root physiology in patients with aortic valvulopathyP1136Comparison of layer-specific strain to other contemporary deformation parameters for coronary artery disease prediction in patients with non-ST-segment elevation acute coronary syndromeP1137Machine-learning based diagnosis of heart failure with preserved ejection fraction: how much do we agree with the guidelines?

2016 ◽  
Vol 17 (suppl 2) ◽  
pp. ii234-ii241
Author(s):  
B. Kanar ◽  
RM. Hamdy ◽  
A. Lindholm ◽  
L. Puga ◽  
A. Zaroui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Stable Angina ◽  
Left Atrial ◽  
Three Dimensional ◽  
Resistive Index ◽  
Left Ventricular ◽  
Systemic Hypertension ◽  
Hypertensive Retinopathy ◽  
Preserved Ejection Fraction

scholarly journals The Giraffe as a Natural Animal Model for Resistance to Heart Failure with Preserved Ejection Fraction

2020 ◽  
Author(s):  
Barbara N. Horowitz ◽  
Basil Baccouche ◽  
Tejas Shivkumar ◽  
Mads Frost Bertelsen ◽  
Christian Aalkjær ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Ejection Fraction ◽  
Pressure Overload ◽  
Brain Perfusion ◽  
Left Ventricular ◽  
Exercise Intolerance ◽  
Systemic Hypertension ◽  
Preserved Ejection Fraction ◽  
Diastolic Relaxation

Heart failure with preserved ejection fraction (HFpEF) is a leading form of human cardiovascular disease and commonly associated with systemic hypertension. Unique evolved adaptations in giraffe myocardia may be a natural animal model of resistance to HFpEF. In humans, pressure-overload induced left ventricular thickening (PLVT) impairs diastolic relaxation, elevates left atrial pressures and may progress to heart failure with symptoms including exercise intolerance. In healthy giraffe, the left ventricle thickens as developmental neck lengthening widens the vertical distance between the heart and head increasing pressures needed to maintain constant brain perfusion. Yet, diastolic relaxation and exercise capacity are unimpaired, a critical adaptation for prey species such as giraffe. The proximate mechanisms underlying this unique cardiovascular physiology are not yet characterized. Developmental PLVT in giraffe emerges as a species-specific evolved adaptation which offers a roadmap for identifying innovations in therapeutic and prevention strategies for HFpEF.

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