Abstract 74: Cardioprotective Effect of Growth Hormone Releasing Hormone in Mouse Model of Heart Failure with Preserved Ejection Fraction

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Rosemeire M Kanashiro-Takeuchi ◽  
Lauro M Takeuchi ◽  
Raul A Dulce ◽  
Darrell Hardin ◽  
Marilia Zuttion ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Chronic Administration ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Receptor Signaling ◽  
Ghrh Receptor

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, ventricular stiffening and fibrosis. We previously showed that activation of GHRH receptor markedly reduces fibrosis in rat and swine models of ischemic myocardial injury. Therefore, we hypothesized that activation of GHRH receptor signaling can improve diastolic dysfunction in a mouse model of HFpEF. C57BL6N mice (n=4-5) were implanted with a mini-osmotic pump to deliver angiotensin-II (Ang-II: 0.8 mg/kg/day) for 4 weeks and randomly assigned to receive daily injections of GHRH-Agonist (GHRH-A [MR-409]: 100 μg/kg) or vehicle (DMSO+propylene-glycol). Cardiac performance was assessed by serial echocardiography and hemodynamic analysis. Chronic administration of Ang-II resulted in increased end-diastolic pressure (EDP, p=0.0186) with no changes in EF (p=ns) or end-systolic pressure (ESP, p=ns) in comparison to control mice. Isovolumetric relaxation time (IVRT, p<0.05) and end-diastolic pressure-volume relationship (EDPVR, p=0.0229) were markedly increased in the Ang-II group consistent with increased ventricular stiffness and poor myocardial relaxation. MR-409 treatment reset these parameters to normal levels (table 1). Our findings demonstrate that chronic administration of Ang-II mediates structural and functional changes that mimic HFpEF. Importantly, MR-409 treatment reduces Ang-II-induced elevation of EDP, EDPVR and IVRT; thus preventing HFpEF–like effects, suggesting that activation of the GHRH receptor signaling pathways represents a potential new therapeutic approach for HFpEF.

Abstract 56: Growth Hormone Releasing Hormone Improves Sarcomere Relaxation and Calcium Decline in Cardiomyocyte From a Mouse Model of Heart Failure With Preserved Ejection Fraction

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Raul A Dulce ◽  
Rosemeire M Kanashiro-Takeuchi ◽  
Lauro M Takeuchi ◽  
Wayne Balkan ◽  
Renzhi Cai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Sarcomere Length ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Calcium Decline ◽  
Ghrh Receptor

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone (GHRH) agonists reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their effect on cardiomyocytes is not known. We hypothesized that activation of GHRH receptor signaling improves impaired cardiomyocyte relaxation in a mouse model of HFpEF. C57BL6N mice (n=4-5) were implanted with a mini-osmotic pump to deliver angiotensin-II (Ang-II: 0.8 mg/kg/day) for 4 weeks and received daily injections of GHRH-Agonist (GHRH-A [MR-409]: 100 μg/kg) or vehicle (DMSO+propylene-glycol). Cardiomyocytes were isolated and calcium and sarcomere shortening assessed. Ang-II-treated cardiomyocytes exhibited reduced sarcomere length, indicating an inability to completely relax, despite lower resting calcium. These cardiomyocytes also exhibited impaired ability to contract with no changes in calcium transient amplitude, deficient relaxation and delayed calcium decay. MR-409 treatment restored resting calcium and resting sarcomere length; improved sarcomere shortening and completely abrogated Ang-II-induced delay in calcium decline and relaxation (see figure 1). Our findings demonstrate that chronic administration of Ang-II mediates structural and functional changes consistent with HFpEF and suggest that activation of the GHRH receptor signaling pathways prevents HFpEF-associated cardiomyocyte performance alterations.

Abstract 12325: Compensatory Increase of Left Atrial External Work to Left Ventricular Dysfunction During Afterload Increase: Insights Into the Mechanism of Decompensation in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Katsuji Inoue ◽  
Toshihiko Asanuma ◽  
Kasumi Masuda ◽  
Daisuke Sakurai ◽  
Masamichi Oka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Strain Curve ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
External Work ◽  
Reservoir Function ◽  
Left Pulmonary Vein

Introduction: Afterload mismatch is considered as a cause of acute decompensation in patients with heart failure with preserved ejection fraction (HFPEF). However, behaviors of left atrium (LA) and ventricle (LV) to afterload increase have not been fully elucidated. We investigated how LA and LV acted to acute increase in afterload using speckle tracking echocardiography. Methods: Serial echocardiographic and hemodynamic data were acquired in 10 dogs during banding of the descending aorta (AoB). LA pressure was measured by a micromanometer via left pulmonary vein. As shown in Figure, peak negative strain during LA contraction and strain change during LA relaxation (early reservoir strain) and that during systole (late reservoir strain) were generated by simultaneous acquisition of LA longitudinal strain and volume. Pressure-strain curve showed 2 loops (A-loop, V-loop) and areas in A-loop and V-loop were computed as the work during active contraction and relaxation (A-work) and that during passive filling and emptying (V-work), respectively. Results: AoB increased LV systolic pressure by about 60 mmHg, mean LA pressure (3.8±1.3 vs. 7.1±2.0 mmHg) and LV end-diastolic pressure (4.5±1.7 vs. 10.7±4.0 mmHg, all p < 0.01). LV global circumferential strain decreased (-18.8±3.5 vs. -13.2±3.5%, p < 0.01) but LV stroke volume was maintained (8.4±2.3 vs. 9.6±3.6 ml). LA peak negative strain (-2.9±2.3 vs. -9.8±4.0%, p < 0.01) and early reservoir strain (3.4±1.1 vs. 7.8±2.6%, p < 0.01) increased substantially by AoB, but late reservoir function did not change (9.3±3.5 vs. 6.1±2.0%). A-work significantly increased (3.2±2.0 to 19.2±15.1 mmHg %, p < 0.01), while V-work did not change (13.3±7.1 vs. 13.6±8.0 mmHg %). Conclusions: During aortic banding, LA contraction, early reservoir function and thereby external work during the phase increased as a compensation to LV dysfunction. The failure of this mechanism may lead to decompensation in HFPEF.

scholarly journals Synthetic Growth Hormone-Releasing Hormone Agonist as Novel Treatment for Heart Failure with Preserved Ejection Fraction

2020 ◽  
Author(s):  
Raul A. Dulce ◽  
Rosemeire M. Kanashiro-Takeuchi ◽  
Lauro M. Takeuchi ◽  
Alessandro G. Salerno ◽  
Shathiyah Kulandavelu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Calcium Handling ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Releasing Hormone ◽  
Ghrh Receptor

AbstractObjectiveTo test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signaling pathway within the myocardium both prevents and reverses heart failure with preserved ejection fraction (HFpEF).BackgroundHFpEF is characterized by impaired myocardial relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing prevalence of HFpEF, no effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, hypertrophy and improve performance, independently of the growth-hormone axis.MethodsWe generated a HFpEF-like phenotype with continuous infusion of angiotensin-II (Ang-II) in CD1 mice. Mice were injected with either vehicle or a potent synthetic agonist of the growth hormone-releasing hormone, MR-356.ResultsAng-II treated animals had diastolic dysfunction, ventricular hypertrophy, and normal ejection fraction and isolated cardiomyocytes (ex vivo) exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice with HFpEF. MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo.ConclusionThese findings indicate that the GHRH receptor signaling pathway represents a new molecular target to counteract HFpEF-associated cardiomyocyte dysfunction by targeting myofilament phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH agonists may provide a novel therapeutic approach to management of the HFpEF syndrome.Condensed abstractHeart failure with preserved ejection fraction (HFpEF) is characterized by a remodeled myocardium conferring ventricular stiffness and diastolic dysfunction. There are no effective therapies. Agonists of growth hormone-releasing hormone (GHRH) receptors have beneficial effects on the heart. We hypothesize that activation of GHRH receptors suppresses this HFpEF phenotype. Treatment with a synthetic agonist of GHRH, prevented the development of the pathological phenotype in a murine model of HFpEF-induced by chronic angiotensin-II infusion. These findings indicate that activation of GHRH receptors represents a novel molecular strategy to counteract HFpEF-associated cardiomyocyte dysfunction and provide a potential approach to management of HFpEF syndrome.HighlightsA synthetic growth hormone-releasing hormone agonist (GHRH-A) prevents and reverses the pathological remodeling in a mouse model of HFpEF induced by infusion of low dose Ang II.GHRH-A improves intracellular calcium handling by reducing the sarcoplasmic reticulum calcium leakage and enhancing phospholamban phosphorylation.GHRH-A treatment prevents and reverses diastolic dysfunction by enhancing the rate of sarcomere re-lengthening.Activation of the GHRH receptor with the GHRH-A, MR-356, leads to targeting myofibrillar proteins and desensitizing myofilaments in response to calcium.

Abstract 397: Chronic Infusion of Growth Hormone Releasing Hormone Prevents Heart Failure with Preserved Ejection Fraction Phenotype Development in Murine Cardiomyocytes by Reducing Myofilament Sensitivity to Calcium

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Raul A Dulce ◽  
Rosemeire M Kanashiro-Takeuchi ◽  
Lauro M Takeuchi ◽  
Alessandro G Salerno ◽  
Wayne Balkan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Sarcomere Length ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Releasing Hormone ◽  
Ghrh Receptor ◽  
Cd1 Mice

Introduction: Heart failure with preserved ejection fraction (HFpEF) represents ~50% of heart failure cases and is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone agonists (GHRH-A) reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their effect on failing cardiomyocytes (CMs) is unknown. We hypothesized that activation of GHRH receptor signaling targets proteins associated with excitation-contraction coupling, reduces affinity of myofilaments for Ca 2+ and prevents the development of HFpEF. Methods: CD1 mice, implanted with mini-osmotic pump (Alzet) to deliver angiotensin-II (Ang-II) for 4 weeks, received daily injections of GHRH-A (MR-356; n=8) or vehicle (n=8). CMs were isolated and Ca 2+ and sarcomere length recorded. Expression and phosphorylation of Ca 2+ handling and sarcomeric proteins were assessed. Unmanipulated CD1 mice (n=7) acted as normal controls. Results: Ang-II-treated CMs exhibited reduced sarcomere length consistent with shorter cell length, indicating an inability to completely relax. These CMs also exhibited impaired contractility that correlated with reduced myosin binding protein C (cMyBPC) expression with no changes in phosphorylation. Response of [Ca 2+ ] transient amplitude to increasing pacing rate was depressed and Ca 2+ decay was delayed and associated with lower expression of SERCA2 and NCX1, increased SR Ca 2+ leak but no change in phospholamban phosphorylation (p-PLB) at Ser16. Slower sarcomere re-lengthening and reduced phospho-cTnI (p-cTnI) at Ser 23/24 were observed in HFpEF CMs. MR-356 treatment maintained resting sarcomere length as well as sarcomere shortening at control values, and completely abrogated Ang-II-induced delay in Ca 2+ decay and sarcomere relaxation. SR Ca 2+ leak was reduced. p-PLB was further enhanced by MR-356, and cMyBPC and p-cTnI were maintained at control levels. Conclusion: Our findings demonstrate that chronic administration of Ang-II mediates functional changes in CMs consistent with HFpEF and suggest that activation of the GHRH receptor signaling pathways desensitizes myofilaments and prevents HFpEF-associated alterations in Ca 2+ handling and dysfunctional CM relaxation.

Abstract 15998: Therapeutic Effectiveness Against Heart Failure With Preserved Ejection Fraction by the Activation of the Growth Hormone-releasing Hormone Receptor in a Murine Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Raul A Dulce ◽  
Rosemeire M Kanashiro-takeuchi ◽  
Lauro Takeuchi ◽  
Alessandro Salerno ◽  
Wayne Balkan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Sarcomere Length ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Ghrh Receptor

Introduction: Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of heart failure cases and is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone-agonists (GHRH-As) reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their therapeutic effect in HFpEF is unknown. Hypothesis: We hypothesized that activation of GHRH receptor signaling prevents pathological remodeling and targets cardio-myocyte (CM) excitation-contraction coupling, ameliorating the compromised myocardial performance associated with HFpEF. Methods: CD1 mice implanted with a mini-osmotic pump (Alzet) to deliver angiotensin-II (Ang-II) for 8 weeks, were randomized at week 4 to receive daily injections of either GHRH-A (MR-356; n=12) or vehicle (n=12). Echocardiographic data and pressure-volume loops were recorded. Biometric measurements and fibrosis were assessed. CMs were isolated and intracellular Ca2 + and sarcomere length acquired. Results: Ang-II-treated mice exhibited functional and morphologic features consistent with HFpEF. CMs exhibited reduced sarcomere length, indicating an inability to relax. The Ca2 + decay rate and sarcomere re-lengthening were delayed. MR-356 treatment reverted the structural remodeling, including fibrosis, improving diastolic function (Figure Top panel). This treatment also abrogated the HFpEF-associated delay in Ca2 + decay and further enhanced sarcomere re-lengthening rate (Figure Bottom panel). Conclusions: Our findings confirm that chronic infusion of Ang-II mediates functional changes in CMs consistent with HFpEF and demonstrate that activation of GHRH receptor signaling pathways targets mechanisms of excitation-contraction coupling, inflammation and fibrosis, thereby preventing HFpEF-associated dysfunctional CM relaxation and myocardial remodeling.

Abstract 13570: Diabetes is Probably Associated With Larger Fluid Retention in Patients With Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Katsuomi IWAKURA ◽  
Toshinari Onishi ◽  
Koichi Inoue ◽  
Masato Okada ◽  
Yasushi Koyama ◽  
...  
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Ejection Fraction ◽  
Hospital Stay ◽  
Diastolic Pressure ◽  
Fluid Retention ◽  
Repeated Measure ◽  
Diabetic Patients ◽  
Preserved Ejection Fraction ◽  
Patients With Heart Failure

Introduction: Diabetes is observed in about third of patients with heart failure with preserved ejection fraction (HFpEF), and it is not well elucidated how it would affect the clinical conditions of HFpEF. We investigated the physical and echocardiographic characteristics of diabetes patients in a large-scale, registration study of HFpEF. Methods: We analyzed clinical and echocardiography data obtained at admission and just before hospital discharge in the PURSUIT-HFpEF (Prospective, Multicenter, Observational Study of Patients with Heart Failure with Preserved Ejection Fraction), which is a multicenter registration study of patients who were hospitalized for HFpEF. Results: We enrolled 862 patients who were hospitalized for HFpEF between June, 2016 and December, 2019 (Age 81±9 years, male gender 44.5%) for the present study. Diabetes was observed in 287 patients (33.3%), and their age was higher (82±8 years vs. 80±9 years, p=0.003) and body mass index before discharge was larger (23.2±4.7 kg/m2 vs. 21.1±4.6 kg/m2, p<0.0001) than those without diabetes. Diabetic patients had higher body weight at admission (63.2±14.9 kg vs. 55.9±13.4 kg, p<0.0001) and before discharge (56.8±13.3 vs. 50.7±12.1 kg, p<0.0001) than non-diabetic patients. Reduction of body weight during hospital stay was higher in diabetic patients (6.4±4.5 kg) than in non-diabetic patients (5.2±4.0 kg) even after correction of body weight discharge or estimated GFR (p<0.001 by ANCOVA). Body weight reduction was significantly associated with HbA1c (p=0.01). There was no difference in use of intravenous diuretics (69.3% vs. 66.6%, p=0.44) and in hospital stay (21.4±15.3 days vs. 19.9±13.7 days, p=0.14) between diabetic- and non-diabetic patients. Whereas no differences were observed in echocardiographic parameters at admission and before discharge between two arms, the diabetic arm showed significantly higher reduction in septal E/e’ ratio during hospital stay (19.0±8.7 to 17.1±7.6) than non-diabetic arm (16.6±8.3 to 16.4±8.2)(p=0.01 by repeated measure ANOVA). Conclusions: The present study implied that diabetic patients with HFpEF have more fluid retention before hospitalization than non-diabetic ones, which could affect the changes in diastolic pressure.

scholarly journals Preload-corrected dynamic Starling mechanism in patients with heart failure with preserved ejection fraction

2018 ◽  
Vol 124 (1) ◽  
pp. 76-82 ◽  
Author(s):  
Michinari Hieda ◽  
Erin Howden ◽  
Shigeki Shibata ◽  
Takashi Tarumi ◽  
Justin Lawley ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Dynamic Modulation ◽  
Power Spectral ◽  
Ventricular Diastolic Dysfunction

The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume (SV) because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. The purpose of this study was to test whether the LVEDP-SV relationship remained impaired in heart failure with preserved ejection fraction (HFpEF) patients after normalization of LVEDP. Right heart catheterization and model-flow analysis of the arterial pressure waveform were performed while preload was manipulated using lower-body negative pressure to alter LVEDP. The DSM was compared at similar levels of LVEDP between HFpEF patients ( n = 10) and age-matched healthy controls ( n = 12) (HFpEF vs. controls: 10.9 ± 3.8 vs. 11.2 ± 1.3 mmHg, P = 1.00). Transfer function analysis between diastolic pulmonary artery pressure (PAD) representing dynamic changes in LVEDP vs. SV index was applied to obtain gain and coherence of the DSM. The DSM gain was significantly lower in HFpEF patients than in the controls, even at a similar level of LVEDP (0.46 ± 0.19 vs. 0.99 ± 0.39 ml·m−2·mmHg−1, P = 0.0018). Moreover, the power spectral density of PAD, the input variability, was greater in the HFpEF group than the controls (0.75 ± 0.38 vs. 0.28 ± 0.26 mmHg2, P = 0.01). Conversely, the power spectral density of SV index, the output variability, was not different between the groups ( P = 0.97). There was no difference in the coherence, which confirms the reliability of the linear transfer function between the two groups (0.71 ± 0.13 vs. 0.77 ± 0.19, P = 0.87). The DSM gain in HFpEF patients is impaired compared with age-matched controls even at a similar level of LVEDP, which may reflect intrinsic LV diastolic dysfunction and incompetence of ventricular-arterial coupling. NEW & NOTEWORTHY The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. Although the DSM gain is impaired in heart failure with preserved ejection fraction (HFpEF) patients, it is not clear whether this is because of higher LVEDP or left-ventricular diastolic dysfunction. The DSM gain in HFpEF patients is severely impaired, even at a similar level of LVEDP, which may reflect intrinsic left-ventricular diastolic dysfunction.

Abstract 14648: Interleukin-18 Blockade Prevents Diastolic Dysfunction in a Mouse Model of Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jessica A Regan ◽  
Adolofo G Mauro ◽  
Salvatore Carbone ◽  
Carlo Marchetti ◽  
Eleonora Mezzaroma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Low Dose ◽  
Preserved Ejection Fraction ◽  
Interleukin 18 ◽  
Lv Diastolic Function

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left ventricular (LV) filling pressures due to impaired LV diastolic function. Low-dose infusion of angiotensin 2 (AT2) in the mouse induces a HFpEF phenotype without increasing blood pressure. AT2 infusion induces expression of Interleukin-18 (IL-18) in the heart. We therefore tested whether IL-18 mediated AT2-induced LV diastolic dysfunction in this model. Methods: We infused subcutaneously AT2 (0.2 mg/Kg/day) or a matching volume of vehicle via osmotic pumps surgically implanted in the interscapular space in adult wild-type (WT) male mice and IL-18 knock-out mice (IL-18KO). We also treated WT mice with daily intraperitoneal injections of recombinant murine IL-18 binding protein (IL-18bp, a naturally occurring IL-18 blocker) at 3 different doses (0.1, 0.3 and 1.0 mg/kg) or vehicle for 25 days starting on day 3. We performed a Doppler-echocardiography study before implantation and at 28 days to measure LV dimensions, mass, and systolic and diastolic function in all mice. LV catheterization was performed prior to sacrifice to measure LV end-diastolic pressure (LVEDP) using a Millar catheter. Results: AT2 induces a significant increase in isovolumetric relaxation time (IRT) and myocardial performance index (MPI) at Doppler echocardiography and elevation of LVEDP at catheterization, indicative of impaired LV diastolic function, in absence of any measurable effects on systolic blood pressure nor LV dimensions, mass, or systolic function. Mice with genetic deletion of IL-18 (IL-18 KO) or WT mice treated with IL-18bp had no significant increase in IRT, MPI or LVEDP with AT2 infusion. Conclusion: Genetic or pharmacologic IL-18 blockade prevent diastolic dysfunction in a mouse model of HFpEF induced by low dose AT2 infusion, suggesting a critical role of IL-18 in the pathophysiology of HFpEF.

Abstract 420: Characterization of Dahl Salt-Sensitive Rat Model for Heart Failure with Preserved Ejection Fraction Research: Defining Diagnostic Criteria

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Natale Rolim ◽  
Jose B Moreira ◽  
Alessandra Medeiros ◽  
Marcia Alves ◽  
Xiaojuan Yang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diagnostic Criteria ◽  
Diastolic Pressure ◽  
Control Group ◽  
Chronic Hypertension ◽  
Preserved Ejection Fraction ◽  
Cross Sectional ◽  
Criteria For Diagnosis ◽  
Novel Therapeutic Strategies

Heart failure with preserved ejection fraction (HFpEF) is a condition that accounts for approximately 50 % of heart failure cases with the prevalence increased with advancing age. As of now, no effective treatment is available for HFpEF, which calls for continued efforts towards novel therapies. Dahl salt-sensitive (Dahl SS) rats have recently been reported as an experimental model of HFpEF, although a specific diagnostic criteria for HFpEF is still unclear in rodents. We aimed to provide clear criteria to identify HFpEF in Dahl SS rats. After a follow-up of 28 weeks, adult female Dahl SS rats receiving high salt (HS, 8 % NaCl) diet developed chronic hypertension (209 ± 80 vs. 147 ± 55 mm Hg; P <0.05 vs. low salt-fed control group (LS, 0.3 % NaCl) with consistent left ventricle (LV) remodeling compared to LS rats (LV hypertrophy index: 2.62 ± 0.07 vs. 1.79 ± 0.03 mg/mm, and cardiomyocyte cross-sectional area: 497 ± 38.9 vs. 290 ± 8.15 μm 2 , respectively; P < 0.05) and EF > 50 % (67.7 ± 1.5 %). Evidence that HS rats have developed HFpEF was observed only in rats with left atrial dimension (LAD)/body weight (BW), E/A, and E/E’ ratios above the 75 th percentile of the LS group (17.50 mm/kg, 1.53, and 14.25, respectively). In addition, HS rats diagnosed with HFpEF had increased LV end-diastolic pressure and plasma NT-proBNP compared to LS rats (12.8 ± 3.4 vs. 5.8 ± 0.8 mm Hg, and 78.7 ± 18.0 vs. 17.7 ± 3.5 pg/mL, respectively; P < 0.05), while no significant changes in LAD/BW, E/A, E/E’, and plasma NT-proBNP were demonstrated in HS rats not matching the suggested criteria for HFpEF. Distance run was not different between HS and LS groups. Survival rate was 39.9 % in HS compared to 94.7 % in LS rats ( P = 0.0001), with stroke as the main cause of death (69.6 % incidence in HS rats). These results provide the first clear criteria for diagnosis of HFpEF in Dahl SS rats. Our findings have important implications for future preclinical studies aiming to develop novel therapeutic strategies targeting diastolic dysfunction in HFpEF.

Abstract 15172: Murf1 Inhibitor Embl205 is a New Approach for Treatment of Heart Failure With Preserved Ejection Fraction in an Animal Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anett Jannasch ◽  
Antje Schauer ◽  
Virginia Kirchhoff ◽  
Runa Draskowsi ◽  
Claudia Dittfeld ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Skeletal Muscle Atrophy ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
The Impact ◽  
Peak Gradient

Background: The novel MuRF1 inhibitor EMBL205 attenuates effectively developing skeletal muscle atrophy and dysfunction in animals with heart failure with preserved ejection fraction (HFpEF, ZSF1 rat model). The impact of EMBL205 on myocardial function in the HFpEF setting is currently unknown and was evaluated in ZSF1 rats. Methods: 20 wks-old female obese ZSF1 rats received EMBL205 (12 wks, conc. of 0.1% in chow; HFpEF-EMBL205). Age-matched untreated lean (con) and obese (HFpEF) ZSF1 rats served as controls. At 32 wks of age left ventricular (LV)-, aortic valve (AV) function and LV end diastolic pressure (LVEDP) was determined by echocardiography and invasive hemodynamic measurements. LV expression of collagen 1A (Col1A) and 3A (Col3A) was assessed by qRT-PCR, MMP2 expression was obtained by zymography and perivascular fibrosis was quantified in histological sections. Results: Development of HFpEF in ZSF1 obese animals is associated with cardiac enlargement and hypertrophy, as evident by increased myocardial weight, an increase in end diastolic volume (EDV) and LV anterior and posterior wall diameters. Diastolic LV-function is disturbed with elevation of E/é, an increased LVEDP and a preserved LV ejection fraction. AV peak velocity and peak gradient are significantly increased and AV opening area (AVA) significantly decreased. Col1A and Col3A expression are increased in HFpEF animals. EMBL205 treatment results in a significant reduction of myocardial weight and a trend towards lower EDV compared to HFpEF group. EMBL205 attenuates the increase in E/é, LVEDP, AV peak gradient and the decrease of AVA. EMBL205 significantly reduces Col3A expression and a trend for Col1A expression is seen. Increased perivascular fibrosis and MMP2 expression in HFpEF is extenuated by EMBL205 treatment (table 1). Conclusions: Application of EMBL205 attenuated the development of pathological myocardial alterations associated with HFpEF in ZSF1rats due to antifibrotic effects.

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