Animal Model Of Heart Failure With Preserved Ejection Fraction Research Articles

Characterization of a novel ovine model of hypertensive heart failure with preserved ejection fraction.

The lack of animal models which accurately represent heart failure with preserved ejection fraction (HFpEF) has been a major barrier to the mechanistic understanding and development of effective therapies for this prevalent and debilitating syndrome characterized by multisystem impairments. Herein, we describe the development and characterization of a novel large animal model of HFpEF in older, female sheep with chronic 2-kidney, 1-clip hypertension. At six weeks post-unilateral renal artery clipping, hypertensive HFpEF sheep had higher mean arterial pressure compared to similarly aged ewes without unilateral renal artery clipping (mean arterial pressure = 112.7±15.9 vs 76.0±10.1 mmHg, P < 0.0001). The hypertensive HFpEF sheep were characterized by (i) echocardiographic evidence of diastolic dysfunction (lateral e' = 0.11±0.02 vs 0.14±0.04 m/s, P = 0.011; lateral E/e' = 4.25±0.77 vs 3.63±0.54, P = 0.028) and concentric left ventricular hypertrophy without overt systolic impairment, (ii) elevated directly measured left ventricular end-diastolic pressure (13±5 vs 0.5±1 mmHg, P = 2.1x10-6), and (iii) normal directly measured cardiac output. Crucially, these hypertensive HFpEF sheep had impaired exercise capacity as demonstrated by their (i) attenuated cardiac output (P = 0.001), (ii) augmented pulmonary capillary wedge pressure (P = 0.026), and (iii) attenuated hindlimb blood flow (P = 3.4x10-4) responses, during graded treadmill exercise testing. In addition, exercise renal blood flow responses were also altered. Collectively, our data indicates that this novel ovine model of HFpEF may be a useful translational research tool since it exhibits similar and clinically relevant impairments as that of HFpEF patients.

RNA Sequencing Screens the Key Genes and Pathways in a Mouse Model of HFpEF

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality but without available evidence-based therapies. It is essential to investigate changes in gene expression profiles in preclinical HFpEF animal models, with the aim of searching for novel therapeutic targets. Methods: Wild-type male C57BL/6J mice were administrated with a combination of high-fat diet (HFD) and inhibition of constitutive nitric oxide synthase using N-nitro-l-arginine methyl ester (l-NAME) for 5 and 7 weeks. RNA sequencing was conducted to detect gene expression profiles, and bioinformatic analysis was performed to identify the core genes, pathways, and biological processes involved. Results: A total of 1,347 genes were differentially expressed in the heart at week 5 and 7 post-intervention. Gene Ontology enrichment analysis indicated that these greatly changed genes were involved mainly in cell adhesion, neutrophil chemotaxis, cell communication, and other functions. Using hierarchical cluster analysis, these differentially expressed genes were classified into 16 profiles. Of these, three significant profiles were ultimately identified. Gene co-expression network analysis suggested troponin T type 1 (Tnnt1) directly regulated 31 neighboring genes and was considered to be at the core of the associated gene network. Conclusion: The combined application of RNA sequencing, hierarchical cluster analysis, and gene network analysis identified Tnnt1 as the most important gene in the development of HFpEF.

Vibrational spectroscopy identifies myocardial chemical modifications in heart failure with preserved ejection fraction

BackgroundVibrational spectroscopy can be a valuable tool to monitor the markers of cardiovascular diseases. In the present work, we explored the vibrational spectroscopy characteristics of the cardiac tissue in an experimental model of heart failure with preserved ejection fraction (HFpEF). The goal was to detect early cardiac chemical modifications associated with the development of HFpEF.MethodsWe used the Fourier-transform infrared (FTIR) and Raman micro-spectroscopic techniques to provide complementary and objective tools for the histological assessment of heart tissues from an animal model of HFpEF. A new sampling technique was adopted (tissue print on a CaF2 disk) to characterize the extracellular matrix.ResultsSeveral spectroscopic markers (lipids, carbohydrates, and glutamate bands) were recognized in the cardiac ventricles due to the comorbidities associated with the pathology, such as obesity and diabetes. Besides, abnormal collagen cross-linking and a decrease in tryptophan content were observed and related to the stiffening of ventricles and to the inflammatory state which is a favourable condition for HFpEF.ConclusionsBy the analyses of tissues and tissue prints, FTIR and Raman techniques were shown to be highly sensitive and selective in detecting changes in the chemistry of the heart in experimental HFpEF and its related comorbidities. Vibrational spectroscopy is a new approach that can identify novel biomarkers for early detection of HFpEF.

Abstract P1024: Cardiomyocyte Mechanics In Animal Models Of Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) has few effective therapies yet exacts substantial mortality. Its multi-system nature has made animal modeling difficult, but recent efforts combining diet-induced obesity and hemodynamic stress are popular: mouse - L-NAME/high-fat diet (HFD) and ovariectomized (OVX) females with HFD-induced obesity/cardiac pressure overload (PO) (HFD+OVX+PO), ZSF1 rat, and obese/hypertensive Göttingen minipigs. We reported human HFpEF myocyte defects including reduced Ca 2+ -activated maximum tension (T max ) negatively correlate with body mass index, reduced Hill coefficient (n H, e.g., cooperativity) and Ca 2+ at 50% T max (EC 50 ), and higher resting tension. Here we tested whether such deficits are found in HFpEF animal models. The L-NAME/HFD mouse had no differences in Ca 2+ -activated (p=0.20) or resting (p=0.75) tension. In obese ZSF-1 rats, while T max (p=0.23) and resting tension (p=0.39) were not different, n H was reduced (2±1 vs. 4±2 p=0.01). In HFD+OVX+PO mice, T max (15±2 vs. 20±2 mN/mm 2 , p=0.006) and EC 50 (1.9±0.6 vs. 2.4±0.7 μM, p=0.008) were reduced, but resting tension (p=0.70) was not different. In the Göttingen minipig HFpEF model, EC 50 (p=0.93) and n H (p=0.35) were not different, whereas T max was reduced (17±3 vs. 27±3 mN/mm 2 , p=2x10 -6 ) and tension less at physiologic Ca 2+ . Resting tension was lower (not greater) in this model (p=0.001). The HFD+OVX+PO and minipig HFpEF models recapitulate depressed Ca 2+ -activated tension as in obese human HFpEF, whereas none manifested increased resting tension ( Table 1 ). Studies investigating HFpEF sarcomere dysfunction should consider these findings in model selection.

Evaluation of large animal models for preclinical studies of heart failure with preserved ejection fraction using clinical score systems.

Heart failure with preserved ejection fraction (HFpEF) is characterized by a complex, heterogeneous spectrum of pathologic features combined with average left ventricular volume and diastolic dysfunction. HFpEF is a significant public health problem associated with high morbidity and mortality rates. Currently, effective treatments for HFpEF represent the greatest unmet need in cardiovascular medicine. A lack of an efficient preclinical model has hampered the development of new devices and medications for HFpEF. Because large animal models have similar physiologic traits as humans and appropriate organ sizes, they are the best option for limiting practical constraints. HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach. Here, we review the large animal models of HFpEF reported to date and describe the methods that have been used to create HFpEF, including surgery-induced pressure overloading, medicine-induced pressure overloading, and diet-induced metabolic syndrome. In addition, for the first time to our knowledge, we use two established clinical HFpEF algorithms (HFA-PEFF and H2FPEF scores) to evaluate the currently available large animal models. We also discuss new technologies, such as continuous remote pressure monitors and inflatable aortic cuffs, as well as how the models could be improved. Based on current progress and our own experience, we believe an efficient large animal model of HFpEF should simultaneously encompass multiple pathophysiologic factors, along with multiorgan dysfunction. This could be fully evaluated through available methods (imaging, blood work). Although many models have been studied, only a few studies completely meet clinical score standards. Therefore, it is critical to address the deficiencies of each model and incorporate novel techniques to establish a more reliable model, which will help facilitate the understanding of HFpEF mechanisms and the development of a treatment.

HFpEF animal models display differences in myofibril mechanics.

Heart Failure with preserved Ejection Fraction (HFpEF) is a complex, multi-organ disease historically defined by cardiac aberrations including diastolic dysfunction with normal resting systolic function and depressed systolic reserve, hypertrophy, and impaired relaxation. Though diastolic dysfunction is a hallmark of HFpEF, it is unknown whether organ-level deficiencies in relaxation persist down to the myofibrils, the contractile organelles within cells. Here, we performed mechanics analysis on cardiac myofibrils from three common HFpEF animal models to assess potential differences in myofibrillar force and relaxation kinetics, independent of higher-order deficits associated with the disease. The Göttingen minipig (GM) HFpEF model recapitulates the spectrum of human HFpEF multiorgan pathophysiology, including severe diastolic dysfunction, myocardial hypertrophy, fibrosis, and pulmonary and systemic hypertension. We found that GM-HFpEF myofibrils produced significantly less maximal force versus controls, with no change in either the slow or fast relaxation phases. Therefore, impaired myofibril relaxation likely does not contribute to the diastolic dysfunction in this model. Another model assessed was the Zucker spontaneously hypertensive heart failure F1 (ZSF1) rat, which exhibits elevated E/e′, insulin resistance, elevated end-diastolic pressure, and preserved ejection fraction. Our preliminary data indicate that ZSF1 myofibrils produce normal maximal force, but have a slower initial rate of relaxation compared to controls. These data suggest that impaired myofibril relaxation may contribute to diastolic dysfunction in the ZSF1 model. Moreover, the distinct responses of myofibrils from these models appear to recapitulate cell-level behavior in human cardiomyocytes isolated from patients with different HFpEF subphenotypes. Therefore, certain animal models may mimic unique HFpEF characteristics at the cellular and/or myofibril levels and be better-suited for investigating specific aspects of this extremely complex syndrome, and aid in the design of effective pharmacological or device-based treatments.

PS-B10-4: AFFERENT RENAL NERVOUS SIGNALS CONTRIBUTE TO THE DEVELOPMENT OF HFPEF WITH SYMPATHOEXCITATION IN DAHL SALT-SENSITIVE HYPERTENSIVE RATS

Objective: Sympathetic activation is involved in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Renal nerves contain sympathetic efferent and sensory afferent fibers. Excitation of the renal efferent nerves increases renal renin release and sodium/water retention. On the other hand, the renal afferent nerves are activated by the renal injury associated with hypertension, and acute stimulation of the afferent nerves increases sympathetic output from the brain. In this study, we investigated whether the signals from the renal afferent nerves contribute to the development of hypertensive HFpEF using a novel method of selective afferent renal nerve denervation (ARDN) in Dahl salt-sensitive rats, a widely used animal model of HFpEF. Design and method: Male Dahl salt-sensitive rats were fed 0.3% low-salt diet (LS) or 8% high-salt diet (HS) from 7 weeks of age. At 9 weeks, LS-fed rats received sham operation (LS-Sham), and HS-fed rats were randomly divided into ARDN (HS-ARDN) or sham operation (HS-Sham). At 19 weeks, blood pressure, echocardiographic parameters, organ weights, and plasma norepinephrine levels were measured, and the histological and biochemical analysis of the heart were performed. Results: Systolic blood pressure was significantly increased in HS-Sham compared to LS-Sham, and this increase was not affected in HS-ARDN. By echocardiography, left ventricular (LV) fractional shortening did not differ between the three groups; however, E/e’ ratio was significantly increased in HS-Sham compared to LS-Sham and was attenuated in HS-ARDN. LV weight / body weight ratio and lung weight / body weigh ratio were significantly increased in HS-Sham compared to LS-Sham, and were decreased in HS-ARDN. Plasma norepinephrine levels were significantly higher in HS-Sham than LS-Sham, and this increase tended to be inhibited in HS-ARDN. LV fibrosis evaluated by Masson trichrome staining was significantly increased in HS-Sham compared to LS-Sham and was attenuated in HS-ARDN. ANP mRNA expression in LV tissue was extremely increased in HS-Sham compared to LS-Sham and was significantly attenuated in HS-ARDN. Conclusion: The signals from afferent renal nerves contribute to the development of HFpEF with sympathoexcitation in Dahl salt-sensitive hypertensive rats.

Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction.

Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor-deficient db/db mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium-glucose cotransporter-2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B-type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone-treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.

OR19-2 Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) with Low and High Dose of Triiodothyronine: an Animal Model of Metabolic Syndrome with HFpEF

Abstract Introduction Low levels of triiodothyronine (T3) are common in patients with heart failure (HF). It has been proposed that the decreased levels of T3 contribute to metabolic and cardiac dysfunction in HF. We aimed to evaluate the effects of treatment with low dose and high dose of T3 in an animal model of HF with preserved ejection fraction (HFpEF). Materials and Methods We evaluated four groups: ZSF1 Lean (Lean-Ctrl, n=8), ZSF1 obese (rat model of metabolic syndrome with HFpEF, HFpEF-Ctrl, n=13), ZSF1 obese supplemented with a replacement dose of T3 (initially 0.04mg/ml, increased to 0.06mg/ml after 4 weeks; HFpEF-T3high, n=8), and ZSF1 Obese supplemented with a low-dose of T3 (0.03mg/mL; HFpEF-T3low, n=8). T3 was supplemented in drinking water from week 13 to 24. The animals were submitted to anthropometric and metabolic evaluation, echocardiography, VO2max evaluation, hemodynamic evaluation, single cardiomyocyte evaluation, and myocardial tissue collection at 24 weeks. Results HFpEF-Ctrl animals had lower serum and myocardial thyroid hormone levels than Lean-Ctrl. Treatment with low dose and high dose of T3 did not correct serum T3 levels, but increased myocardial T3 levels, with normalization of myocardial T3 levels in the HFpEF-T3high group. In comparison to HFpEF-Ctrl, body weight was significantly decreased in HFpEF-T3low and HFpEF-T3high groups (616±39g, 572±24g and 535±18g respectively, p&amp;lt;0.001). An improvement in glucose metabolism was observed only in HFpEF-T3high, with a decreased AUC of glucose during OGTT and insulin tolerance test. Both treated groups presented an improvement in diastolic function (with decreased isovolumetric relaxation time) and systolic function (with increased peak systolic velocity and decreased ejection time) comparing to HFpEF-Ctrl. These results were supported by enhanced Ca2+ transients during diastole and sarcomere relaxation. Comparing with HFpEF-Ctrl, animals treated with T3 had higher myocardial expression of the calcium transporter RYR2, of the transcriptional coactivator PGC-1α, and of the α-myosin heavy chain (MHC), with a lower expression of β-MHC. VO2max was improved with low-dose and high-dose T3 compared with HFpEF-Ctrl. Comparing with HFpEF-Ctrl, heart rate was increased with high-dose (277.9±30.2 vs 313.5±35.8, p=0.049) but not significantly with low-dose (277.9±30.2 vs 299.8±30.9 bpm, p=0.13). Mortality was increased in the HFpEF-T3high comparing with the other groups (no animals died during the protocol in the Lean-Ctrl, HFpEF-Ctrl and HFpEF-T3low groups; three animals had sudden death in the HFpEF-T3high group). Conclusion Treatment with T3 improves metabolic function, myocardial calcium handling, diastolic and systolic function, and exercise capacity in this animal model of HFpEF. While the low dose was well tolerated and safe, the high dose was associated with increased heart rate and a higher risk of sudden death. Modulation of thyroid hormones may be a potential therapeutic target in HFpEF; however such approaches must take into account a narrow therapeutic window of T3 in HFpEF. Presentation: Monday, June 13, 2022 11:15 p.m. - 11:30 a.m.

Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF.

Approximately 50% of all heart failure (HF) diagnoses can be classified as HF with preserved ejection fraction (HFpEF). HFpEF is more prevalent in females compared with males, but the underlying mechanisms are unknown. We previously showed that pressure overload (PO) in male felines induces a cardiopulmonary phenotype with essential features of human HFpEF. The goal of this study was to determine if slow progressive PO induces distinct cardiopulmonary phenotypes in females and males in the absence of other pathological stressors. Female and male felines underwent aortic constriction (banding) or sham surgery after baseline echocardiography, pulmonary function testing, and blood sampling. These assessments were repeated at 2 and 4 mo postsurgery to document the effects of slow progressive pressure overload. At 4 mo, invasive hemodynamic studies were also performed. Left ventricle (LV) tissue was collected for histology, myofibril mechanics, extracellular matrix (ECM) mass spectrometry, and single-nucleus RNA sequencing (snRNAseq). The induced pressure overload (PO) was not different between sexes. PO also induced comparable changes in LV wall thickness and myocyte cross-sectional area in both sexes. Both sexes had preserved ejection fraction, but males had a slightly more robust phenotype in hemodynamic and pulmonary parameters. There was no difference in LV fibrosis and ECM composition between banded male and female animals. LV snRNAseq revealed changes in gene programs of individual cell types unique to males and females after PO. Based on these results, both sexes develop cardiopulmonary dysfunction but the phenotype is somewhat less advanced in females.NEW & NOTEWORTHY We performed a comprehensive assessment to evaluate the effects of slow progressive pressure overload on cardiopulmonary function in a large animal model of heart failure with preserved ejection fraction (HFpEF) in males and females. Functional and structural assessments were performed at the organ, tissue, cellular, protein, and transcriptional levels. This is the first study to compare snRNAseq and ECM mass spectrometry of HFpEF myocardium from males and females. The results broaden our understanding of the pathophysiological response of both sexes to pressure overload. Both sexes developed a robust cardiopulmonary phenotype, but the phenotype was equal or a bit less robust in females.

A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs

More than half of heart failure (HF) cases are classified as heart failure with preserved ejection fraction (HFpEF) worldwide. Large animal models are limited for investigating the fundamental mechanisms of HFpEF and identifying potential therapeutic targets. This work provides a detailed description of the surgical procedure of descending aortic constriction (DAC) in Tibetan minipigs to establish a large animal model of HFpEF. This model used a precisely controlled constriction of the descending aorta to induce chronic pressure overload in the left ventricle. Echocardiography was used to evaluate the morphological and functional changes in the heart. After 12 weeks of DAC stress, the ventricular septum was hypertrophic, but the thickness of the posterior wall was significantly reduced, accompanied by dilation of the left ventricle. However, the LV ejection fraction of the model hearts was maintained at >50% during the 12-week period. Furthermore, the DAC model displayed cardiac damage, including fibrosis, inflammation, and cardiomyocyte hypertrophy. Heart failure marker levels were significantly elevated in the DAC group. This DAC-induced HFpEF in minipigs is a powerful tool for investigating molecular mechanisms of this disease and for preclinical testing.

A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs

More than half of heart failure (HF) cases are classified as heart failure with preserved ejection fraction (HFpEF) worldwide. Large animal models are limited for investigating the fundamental mechanisms of HFpEF and identifying potential therapeutic targets. This work provides a detailed description of the surgical procedure of descending aortic constriction (DAC) in Tibetan minipigs to establish a large animal model of HFpEF. This model used a precisely controlled constriction of the descending aorta to induce chronic pressure overload in the left ventricle. Echocardiography was used to evaluate the morphological and functional changes in the heart. After 12 weeks of DAC stress, the ventricular septum was hypertrophic, but the thickness of the posterior wall was significantly reduced, accompanied by dilation of the left ventricle. However, the LV ejection fraction of the model hearts was maintained at >50% during the 12-week period. Furthermore, the DAC model displayed cardiac damage, including fibrosis, inflammation, and cardiomyocyte hypertrophy. Heart failure marker levels were significantly elevated in the DAC group. This DAC-induced HFpEF in minipigs is a powerful tool for investigating molecular mechanisms of this disease and for preclinical testing.

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

Objective Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome representing more than 50% of heart failure cases. Currently, available treatment options do not improve patient outcomes and the mechanics of HFpEF remain largely misunderstood. This makes animal models of HFpEF a valuable resource and currently there are few animal models that replicate the clinical characteristics of this disease. Previous studies have replicated associated cardiac hypertrophy and diastolic dysfunction, however exercise intolerance is a cardinal sign of HFpEF but is rarely investigated in animal models. The aim of this study was to develop a clinically relevant large animal model of HFpEF using the two-kidney-one-clip renovascular hypertension method and investigate exercise intolerance. We hypothesized that chronic hypertension would lead to a reduced cardiac output (CO) and stunted heart rate (HR) response during exercise. Methods Hypertension (HTN) was induced by clipping of the renal artery in adult female sheep (N=4), while the contralateral kidney remained intact. Sheep were left to develop HTN for 6 weeks, after which sheep were instrumented to record cardiac output (CO), heart rate (HR) and mean arterial pressure (MAP). A normal cohort (N=3) of sheep also underwent this same instrumentation surgery. After recovery from surgery, the animals were acclimatized to walk on a treadmill and following acclimatization, they entered a treadmill protocol where the incline and speed was increased every 3 min. Results Renal artery clipping caused a significant rise in MAP (123±6 mmHg from 77±9 mmHg) while CO was not different. In normotensive sheep exercise led to large changes in CO (17±2 L/min from 9+/-0.7 L/min) and HR (153±15 bpm from 107±14 bpm). Exercise in the hypertensive sheep led to attenuated increases in CO (11+/-1 L/min from 6±0.4 L/min) and HR (137±7 bpm from 115±8 bpm). Interestingly, the hypertensive sheep reached their maximum heart rates earlier than the normotensive sheep. Discussion/Conclusion Our data suggest that chronic hypertension leads to a decrease in the maximum cardiac output reached during exercise suggesting a loss of cardiac reserve. Overall this indicates that the 2-kidney-1-clip renovascular HTN model may be a good method to induce HFpEF.

Novel Göttingen Miniswine Model of Heart Failure With Preserved Ejection Fraction Integrating Multiple Comorbidities

A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, andvascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt-induced hypertension in the Göttingen miniswine led to the developmentof a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

Effects of Cardiomyocyte-Specific Deletion of STAT3-A Murine Model of Heart Failure With Preserved Ejection Fraction.

Aims: There is a high incidence of heart failure with preserved ejection fraction (HFpEF), but the options of treatment are limited. A new animal model of HFpEF is urgently needed for in-depth research on HFpEF. Signal transducer and activator of transcription 3 (STAT3) may affect the passive stiffness of myocardium, which determines cardiac diastolic function. We hypothesized that cardiomyocyte-specific deletion of STAT3 increases cardiac passive stiffness, which results the murine features of HFpEF.Methods and Results: Cardiomyocyte-specific deletion of STAT3 (STAT3cKO) mice was generated by the Cre/FLOXp method. The STAT3cKO mice showed heavier cardiac fibrosis and cardiac hypertrophy comparing with wild-type (WT) mice. Furthermore, STAT3cKO mice showed increased serum brain natriuretic peptide (BNP) level, and growth stimulation expressed gene 2 (ST2) level. Other indicators reflecting cardiac passive stiffness and diastolic function, including end diastolic pressure volume relation, MV A value, MV E value, E/A and E/E' had different fold changes. All these changes were accompanied by decreasing levels of protein kinase G (PKG). Bioinformatic analysis of STAT3cKO mice hearts suggested cGMP-PKG signaling pathway might participate in the pathogenesis of HFpEF by means of adjusting different biological functions.Conclusions: Cardiomyocyte-specific deletion of STAT3 results in a murine HFpEF model which imitates the clinical characteristics partly by affecting cardiac PKG levels. Better understanding of the factors influencing HFpEF may finally provided innovative therapies.

Effects of Endurance Training on Detrimental Structural, Cellular, and Functional Alterations in Skeletal Muscles of Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is underpinned by detrimental skeletal muscle alterations that contribute to disease severity, yet underlying mechanisms and therapeutic treatments remain poorly established. This study used a nonhuman animal model of HFpEF to better understand whether skeletal muscle abnormalities were (1) fiber-type specific and (2) reversible by various exercise training regimes. Lean control rats were compared with obese ZSF1 rats at 20 weeks and then 8 weeks after sedentary, high-intensity interval training, or moderate continuous treadmill exercise. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were assessed for fiber size, capillarity, glycolytic metabolism, autophagy, and contractile function. HFpEF reduced fiber size and capillarity by 20%-50% (P < .05) in both soleus and EDL, but these effects were not reversed by endurance training. In contrast, both endurance training regimes in HFpEF attenuated the elevated lactate dehydrogenase activity observed in the soleus. Autophagy was down-regulated in EDL and up-regulated in soleus (P < .05), with no influence of endurance training. HFpEF impaired contractile forces of both muscles by ∼20% (P < .05), and these were not reversed by training. Obesity-related HFpEF was associated with detrimental structural, cellular, and functional alterations to both slow-oxidative and fast-glycolytic skeletal muscles that could not be reversed by endurance training.

A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function

Heart Failure with preserved Ejection Fraction (HFpEF) represents a major public health problem. The causative mechanisms are multifactorial and there are no effective treatments for HFpEF, partially attributable to the lack of well-established HFpEF animal models. We established a feline HFpEF model induced by slow-progressive pressure overload. Male domestic short hair cats (n = 20), underwent either sham procedures (n = 8) or aortic constriction (n = 12) with a customized pre-shaped band. Pulmonary function, gas exchange, and invasive hemodynamics were measured at 4-months post-banding. In banded cats, echocardiography at 4-months revealed concentric left ventricular (LV) hypertrophy, left atrial (LA) enlargement and dysfunction, and LV diastolic dysfunction with preserved systolic function, which subsequently led to elevated LV end-diastolic pressures and pulmonary hypertension. Furthermore, LV diastolic dysfunction was associated with increased LV fibrosis, cardiomyocyte hypertrophy, elevated NT-proBNP plasma levels, fluid and protein loss in pulmonary interstitium, impaired lung expansion, and alveolar-capillary membrane thickening. We report for the first time in HFpEF perivascular fluid cuff formation around extra-alveolar vessels with decreased respiratory compliance. Ultimately, these cardiopulmonary abnormalities resulted in impaired oxygenation. Our findings support the idea that this model can be used for testing novel therapeutic strategies to treat the ever growing HFpEF population.

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

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Characterisation of a Large Animal Model of Heart Failure with Preserved Ejection Fraction (HFpEF)

Background: The failure of the development of treatment for HFpEF is the result of key factors: critically, HFpEF is a disease of ageing in combination with other factors including atrial fibrillation, and the effect of potential treatments for HFpEF can only be validated pre-clinically in-vivo using large animal models, to effectively prove effects on heart function. Aim: To characterise a large animal model of HFpEF and determine applicability for pre-clinical therapeutic research. Methods: Eight aged and eight young female sheep (ewes) were anaesthetised and underwent transthoracic echocardiography and were instrumented with a left ventricular pressure transducer catheter. Left ventricular biopsies were taken for histological and molecular analysis. Results: Sheep (ewes) aged >6yrs had a preserved LVEF 73 ±8% vs young, with marked LV hypertrophy, significant myocardial fibrosis compared to young animals and elevated LVEDP (aged: 10.3 ± 1.5 vs young: 3.8 ± 0.9 mmHg, p<0.05). Conclusions: This acute study has characterised a clinically relevant, large animal model of HFpEF.

Animal models of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) constitutes a clinical syndrome in which the diagnostic criteria of heart failure are not accompanied by gross disturbances of systolic function, as assessed by ejection fraction. In turn, under most circumstances, diastolic function is impaired. Although it now represents over 50 % of all patients with heart failure, the mechanisms of HFpEF remain understood, precluding effective therapy. Understanding the pathophysiology of HFpEF has been restricted by both limited access to human myocardial biopsies and by the lack of animal models that fully mimic human pathology. Animal models are valuable research tools to clarify subcellular and molecular mechanisms under conditions where the comorbidities and other confounding factors can be precisely controlled. Although most of the heart failure animal models currently available represent heart failure with reduced ejection fraction, several HFpEF animal models have been proposed. However, few of these fulfil all the features present in human disease. In this review we will provide an overview of the currently available models to study HFpEF from rodents to large animals as well as present advantages and disadvantages of these models.