scholarly journals In silico identification of potential calcium dynamics and sarcomere targets for recovering left ventricular function in rat heart failure with preserved ejection fraction

2021 ◽  
Vol 17 (12) ◽  
pp. e1009646
Author(s):  
Stefano Longobardi ◽  
Anna Sher ◽  
Steven A. Niederer
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Rat Heart ◽  
Cardiac Mechanics ◽  
Thick Filament ◽  
Cellular Level ◽  
Left Ventricular ◽  
Lv Function ◽  
Calcium Dynamics ◽  
Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a complex disease associated with multiple co-morbidities, where impaired cardiac mechanics are often the end effect. At the cellular level, cardiac mechanics can be pharmacologically manipulated by altering calcium signalling and the sarcomere. However, the link between cellular level modulations and whole organ pump function is incompletely understood. Our goal is to develop and use a multi-scale computational cardiac mechanics model of the obese ZSF1 HFpEF rat to identify important biomechanical mechanisms that underpin impaired cardiac function and to predict how whole-heart mechanical function can be recovered through altering cellular calcium dynamics and/or cellular contraction. The rat heart was modelled using a 3D biventricular biomechanics model. Biomechanics were described by 16 parameters, corresponding to intracellular calcium transient, sarcomere dynamics, cardiac tissue and hemodynamics properties. The model simulated left ventricular (LV) pressure-volume loops that were described by 14 scalar features. We trained a Gaussian process emulator to map the 16 input parameters to each of the 14 outputs. A global sensitivity analysis was performed, and identified calcium dynamics and thin and thick filament kinetics as key determinants of the organ scale pump function. We employed Bayesian history matching to build a model of the ZSF1 rat heart. Next, we recovered the LV function, described by ejection fraction, peak pressure, maximum rate of pressure rise and isovolumetric relaxation time constant. We found that by manipulating calcium, thin and thick filament properties we can recover 34%, 28% and 24% of the LV function in the ZSF1 rat heart, respectively, and 39% if we manipulate all of them together. We demonstrated how a combination of biophysically based models and their derived emulators can be used to identify potential pharmacological targets. We predicted that cardiac function can be best recovered in ZSF1 rats by desensitising the myofilament and reducing the affinity to intracellular calcium concentration and overall prolonging the sarcomere staying in the active force generating state.

scholarly journals Application of the current HFA-ESC consensus guidelines on diagnosis of heart failure with preserved ejection fraction to a population referred for echocardiography

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
K Liang ◽  
R Hearse-Morgan ◽  
S Fairbairn ◽  
Y Ismail ◽  
AK Nightingale
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Ejection Fraction ◽  
Diastolic Function ◽  
Global Longitudinal Strain ◽  
Diagnostic Algorithm ◽  
Left Ventricular ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
Consensus Guidelines

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND The recent Heart Failure Association (HFA) of the European Society of Cardiology (ESC) consensus guidelines on diagnosis of heart failure with preserved ejection fraction (HFpEF) have developed a simple diagnostic algorithm for clinical use. PURPOSE To assess whether echocardiogram (echo) parameters needed to assess diastolic function are routinely collected in patients referred for assessment of heart failure symptoms. METHODS Retrospective analysis of echo referrals in January 2020 were assessed for parameters of diastolic function as per step 2 of the HF-PEFF diagnostic algorithm.  Echo images and clinical reports were reviewed. Electronic records were utilised to obtain clinical history, blood results (NT-proBNP) and demographic data. RESULTS 1330 patients underwent an echo in our department during January 2020. 83 patients were referred with symptoms of heart failure without prior history of cardiac disease; 20 patients found to have impaired left ventricular (LV) function were excluded from analysis. Of the 63 patients with possible HFpEF, HF-PEFF score was low in 18, intermediate in 33 and high in 12. Median age was 68 years (range 32 to 97 years); 25% had a BMI >30. There was a high prevalence of hypertension (52%), diabetes (19%) and atrial fibrillation (40%) (cf. Table 1). Body surface area (BSA) was documented in 65% of echo reports. Most echo parameters were recorded with the exception of global longitudinal strain (GLS) and indexed LV mass (cf. image 1). NT-proBNP was recorded in only 20 patients (31.7%). 12 patients with an intermediate HF-PEFF score could have been re-categorised to a high score depending on GLS and NT-proBNP (which were not recorded). CONCLUSION More than three quarters of echoes acquired in our department obtained the relevant parameters to assess diastolic function. The addition of BSA, and inclusion of NT-proBNP, and GLS would have been additive to a third of ‘intermediate’ patients to determine definite HFpEF. Our study demonstrates that the current HFA-ESC diagnostic algorithm and HF-PEFF scoring system are easy to use, highly relevant and applicable to current clinical practice. Age >70 years 29 (46.0%) Obesity (BMI >30) 16 (25.4%) Diabetes 12 (19%) Hypertension 33 (52.4%) Atrial Fibrillation 25 (39.7%) ECG abnormalities 18 (28.5%) Table 1. Prevalence of Clinical Risk Factors Abstract Figure. Image 1. HFPEFF score & echo parameters

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.

scholarly journals Exercise Training Improved Longitudinal Intrinsic Left Ventricle Function in Heart Failure with Preserved Ejection Fraction

2019 ◽  
Vol 28 (01) ◽  
pp. 044-049
Author(s):  
Sidhi Purwowiyoto ◽  
Budhi Purwowiyoto ◽  
Amiliana Soesanto ◽  
Anwar Santoso
Keyword(s):  
Quality Of Life ◽  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
World Health ◽  
Volume Index ◽  
Lv Function ◽  
Preserved Ejection Fraction

Exercise improves morbidity, fatality rate, and quality of life in heart failure with low ejection fraction, but fewer data available in heart failure with preserved ejection fraction (HFPEF).The purpose of this study is to test the hypothesis that exercise training might improve the longitudinal intrinsic left ventricular (LV) function in HFPEF patients.This quasi-experimental study had recruited 30 patients with HFPEF. Exercise training program had been performed for a month with a total of 20 times exercise sessions and evaluated every 2 weeks. Echocardiography was performed before sessions, second week and fourth week of exercise training. Six-minute walk tests (6MWTs) and quality-of-life variables using Minnesota living with HF scoring and the 5-item World Health Organization Well-Being Index scoring were measured before and after exercise as well.Left ventricular filling pressure, represented by the ratio of early diastolic mitral flow velocity/early diastolic annular velocity and left atrial volume index, improved during exercise. The longitudinal intrinsic LV function, represented by four-chamber longitudinal strain, augmented during exercise (p < 0.001). Aerobic capacity, measured by 6MWT, increased significantly (p = 0.001). Quality of life improved significantly during exercise (p < 0.001).Exercise training was suggested to improve the longitudinal intrinsic LV function and quality of life in HFPEF. Clinical Trial Registration: ACTRN12614001042639.

Abstract 87: Alterations to Cardiac Mechanics Do Not Preserve Normal Cardiac Function in a Novel Ossabaw Swine Model of Heart Failure with Preserved Ejection Fraction

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jenna C Edwards ◽  
Madeleine Dionne ◽  
T. D Olver ◽  
Jan R Ivey ◽  
Pamela K Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Strain Rate ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Volume Index ◽  
Lv Function ◽  
Swine Model ◽  
Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is clinically characterized by an increased incidence in females and many comorbidities including type 2 diabetes (T2D) and obesity. Animal models accurately representing clinical HFpEF are lacking; thus, the purpose of this study was to examine left ventricular (LV) mechanics in a novel Ossabaw swine model of chronic pressure-overload (aortic-banding; AB) and T2D (Western diet; WD) using two dimensional speckle tracking echocardiography (2D-STE). We hypothesized that global LV strain would be decreased primarily in the longitudinal direction in WD-AB animals. Methods: Female Ossabaws were randomly divided into 2 groups: CON (n=5) and WD-AB (n=5). LV function and strain were measured at 1 year of age after 6 mo. of AB and 9 mo. of WD via pressure-volume relations and 2D-STE. Significance was set at P < 0.05 using t-test vs. CON. Results: In the WD-AB group, ejection fraction (EF%) and end diastolic volume were normal (>50%), and observed in parallel with increased LV weight, lung weight, and LV diastolic wall thickness (i.e. concentric hypertrophy). WD-AB group had increased HOMA-IR and body surface area, two common features in T2D. In WD-AB animals, although global longitudinal systolic strain rate and end systolic displacement were increased, stroke volume index was decreased. Early diastolic rotation rate was decreased, while global longitudinal late diastolic strain rate was increased in the WD-AB group. These changes, considered in parallel with an increased end diastolic pressure-volume relationship in WD-AB animals, are consistent with diastolic dysfunction. In contrast, longitudinal, radial, and circumferential early diastolic strain rates increased in the WD-AB group. Conclusion: Contrary to our hypothesis, LV longitudinal strain was increased during both systole and diastole, and observed in parallel with decreased early diastolic untwisting in WD-AB animals. Our results suggest alterations to LV mechanics do not preserve normal systolic and diastolic cardiac function, despite normal resting EF%, in this novel translational model of pressure-overload HF with potential relevance to human HFpEF including associated clinical comorbidities (sex, obesity, and T2D).

P935 Association of intracellular iron status with left ventricular systolic function response to exercise in heart failure with preserved ejection fraction

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
M Przewlocka-Kosmala ◽  
E Jasic-Szpak ◽  
E A Jankowska ◽  
P Ponikowski ◽  
W Kosmala
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Systolic Function ◽  
Iron Status ◽  
Left Ventricular ◽  
Exercise Intolerance ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
Intracellular Iron ◽  
The Impact

Abstract The intracellular iron depletion has been recognized to contribute to the dysregulation of cell energetics. The soluble transferrin receptor (sTfR) is regarded as a marker of cellular iron balance, and its elevated level reflects an insufficient iron delivery to target tissues. Despite the strong pathophysiological link, there is a scarcity of data on the impact of intracellular iron status on myocardial performance. Aim To investigate the association between the intracellular iron status, as assessed by sTfR, and left ventricular (LV) function in a well-characterized population with heart failure and preserved ejection fraction (HFpEF). Methods A complete echocardiogram including evaluation of LV global longitudinal deformation by speckle tracking (GLS) was performed at rest and immediately post-exercise in 83 pts (age 66 ± 8 yrs) with symptomatic HFpEF. Results Pts with the highest sTfR concentrations (from the 3rd sTfR tertile) demonstrated significantly lower exertional GLS than their peers from the other 2 tertiles and lower resting GLS vs. the 2nd tertile (Table). Exercise GLS was inversely correlated with sTfR (r=-0.27, p = 0.01), and this association remained significant after adjustment for age, sex, BMI, LV mass, exercise blood pressure, hemoglobin and serum galectin-3 – a marker of fibrosis (beta=-0.24, p = 0.04). Conclusions In HFpEF, higher sTfR reflecting a decreased global intracellular iron content is independently associated with reduced LV longitudinal contractility response to exertion. This might represent another mechanism of exercise intolerance and should be considered in management strategies in this condition. Abstract P935 Figure.

Abstract 15164: Impact of Conventional Right Ventricular Pacing in Patients With Heart Failure With Preserved Ejection Fraction: Insights From Pursuit-hfpef Registry

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tetsuya Watanabe ◽  
Shungo Hikoso ◽  
Daisaku D Nakatani ◽  
Masamichi Yano ◽  
Shunsuke Tamaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Pacemaker Implantation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
Ventricular Ejection Fraction ◽  
Patients With Heart Failure

Introduction: Previous studies suggest that conventional right ventricular (RV) pacing may have a deleterious effect on left ventricular (LV) function. However, there are no reports examining the effects of permanent pacemakers (PM) in patients with heart failure with preserved ejection fraction (HFpEF) admitted with acute decompensated heart failure (ADHF). Methods and Results: Patients' data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a prospective multicenter observational registry for ADHF patients with LVEF ≥50% in Osaka. Echocardiographic measurements were performed just before and 1 year after discharge. We analyzed 623 patients (median age: 81[30-101] years) after exclusion of patients on dialysis. At the admission, 55 of 623 patients had a previously implanted pacemaker (PM(+)). There were no significant differences in baseline clinical characteristics before discharge such as age, gender, renal function, echocardiographic parameters between PM(+) and PM(-) groups. One year after discharge, left ventricular ejection fraction (LVEF) in PM(+) group was significantly lower (58.3±8.6 vs 62.3±8.4%, p=0.005) than those in PM(-) group. During a mean follow-up period of 1.25±0.84years, 171patients had heart failure hospitalization (HFH). At the multivariate Cox analysis, pacemaker was significantly associated with HFH, independently of age, serum NT-proBNP level, and LVEF after the adjustment with NYHA functional class, sex, and hemoglobin. Kaplan-Meier curve analysis revealed that patients in PM(+) group had a significantly higher risk of HFH than those in PM(-) group. Conclusion: The development of cardiac systolic and diastolic dysfunction occurred in patients with HFpEF with a RV pacemaker implantation, which would be associated with poor outcome.

Abstract P135: Is Heart Failure With Preserved Ejection Fraction a Gut Disorder?

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
YanFei Qi ◽  
Ruby Goel ◽  
Avinash S Mandloi ◽  
Seungbum Kim ◽  
Gilberto O Lobaton ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Intestinal Permeability ◽  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Intestinal Barrier Function ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
Barrier Dysfunction ◽  
Human Coronary Artery

Background and Objective: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for ~50% of HF hospitalizations, is associated with poor quality of life and, has a mortality rate comparable with many cancers. To date, no therapies have proven effective in slowing disease progression, mainly due to limited understanding of underlying mechanisms. Mounting evidence suggests the intestine and gut microbiota play an important role in chronic inflammation in HF, and also hypertension, a history of which is present in most HFpEF patients. However, information about intestinal involvement in HFpEF is limited. Accordingly, we investigated the hypothesis that disturbed intestinal barrier function contributes to translocation of endotoxin and inflammation activation in HFpEF. Method and Results: Left ventricular (LV) function, intestinal permeability, circulating lipopolysaccharide (LPS, an endotoxin and strong inducer of pro-inflammatory cytokines) and high-mobility group box protein (HMGB1, a nuclear protein that triggers inflammation) were examined in a mouse model of HFpEF [4w continuous infusion of subpressor dose of angiotensin II (0.2mg/kg/d)] and 4 patients with HFpEF and 4 reference subjects. Impaired LV diastolic function (increase in LVEDP and Tau, both p<0.05) occurred in the mice with 3-fold increased intestinal permeability, 1.8-fold elevated LPS levels (137±7 vs control 77±6 pg/ml, p<0.005) and 4-fold increased HMGB1 levels (238±42 vs control 56±16 ng/ml, p<0.05). Stimulating human coronary artery endothelial cells with 10μg/ml LPS for 48h resulted in 3-fold elevation of HMGB1 (29±4 vs control 12±3 ng/ml, p<0.05) that was suppressed by butyrate (17±3 ng/ml). Patients with HFpEF had a 2-fold increase in zonulin (31±3 vs 14±2 ng/ml) and 4-fold LPS elevation (152±18 vs 32±3 pg/ml), (both p<0.05 vs reference subjects), confirming gut barrier dysfunction with translocation of endotoxin. Conclusions: HFpEF is associated with increased gut permeability that facilitates LPS translocation activating inflammation resulting in endothelial damage. Thus, the gut could be a novel target for therapeutic interventions in patients with HFpEF.

Abstract 17249: Impacts of Isometric Handgrip Exercise and Post-Exercise Circulatory Arrest on Hemodynamics and Left Ventricular Function in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Keishi Moriwaki ◽  
Naoki Fujimoto ◽  
So Miyahara ◽  
Shusuke Fukuoka ◽  
Masaki Ishiyama ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Circulatory Arrest ◽  
Left Ventricular ◽  
Voluntary Contraction ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
Isometric Handgrip ◽  
Post Exercise

Introduction: Isometric handgrip (IHG) training at 30% maximal voluntary contraction (MVC) lowers blood pressure (BP) in patients with hypertension and healthy individuals. However, impacts of IHG and post-exercise circulatory arrest (PECA), which isolates the metaboreflex control, on left ventricular (LV) function and hemodynamics have been unclear in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Methods: Sixteen patients with HF (age 63±13 years, 5M:11F, 10HFpEF:6HFrEF) underwent invasive LV pressure-volume assessments using conductance catheter with microtip-manometer during 3min of IHG exercise at 30% MVC, followed by 3 min of PECA. Impacts of IHG and PECA on LV function and hemodynamics were evaluated and compared between HFpEF and HFrEF. Results: During 3 min of IHG at 30% MCV, heart rate increased by 10±8 bpm in HFpEF and by 14±6 bpm in HFrEF. IHG elevated LV end-systolic BP in both HFpEF (134±21 vs. 158±30 mmHg, p<0.01) and HFrEF (119±30 vs. 142±31 mmHg, p<0.01) with no change in stroke volume. There was a trend towards an increase in LV end-diastolic pressure in both groups (HFpEF:14±5 vs. 19±10 mmHg, HFrEF: 15±12 vs. 23±11 mmHg). Time constant of LV relaxation was unchanged by 3 min of IHG in HFpEF (52±14 vs. 54±15 ms), while it was prolonged in HFrEF (48±7 vs. 60±9 ms, p<0.01, groupхtime interaction effect p=0.08). During PECA, LV end-systolic BP decreased in both groups and was maintained higher than baseline throughout PECA only in HFpEF. Conclusions: Although IHG exercise at 30% MVC for 3 min would elevate LV end-systolic and end-diastolic pressures, this IHG exercise has no detrimental effect on LV systolic and diastolic function, especially in HFpEF patients. Chronic effect of IHG training on BP and hemodynamics will need to be evaluated in HFpEF patients who often suffer from arterial hypertension.

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