Abstract MP03: Immunophenotyping A Heart Failure With Preserved Ejection Fraction (HFpEF) Mouse Model With Cellular Indexing Of Transcriptomes And Epitopes (CITE)-seq

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Charles D Smart ◽  
Vineet Agrawal ◽  
Anna R Hemnes ◽  
Meena S Madhur
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Gene Set Enrichment Analysis ◽  
Heart Weight ◽  
Time To Exhaustion ◽  
Type I ◽  
Preserved Ejection Fraction ◽  
Pulmonary Congestion

Deoxycorticosterone acetate (DOCA)-salt is a common hypertension model in mice and has recently been used to study heart failure with preserved ejection fraction (HFpEF) in rats. Our goal was to validate DOCA-salt as a mouse model of HFpEF and determine how DOCA-salt alters the cardiac immunological landscape to identify novel therapeutic targets for this disease. DOCA-salt mice underwent uninephrectomy, implantion of a DOCA pellet, and supplementation of the drinking water with 1% NaCl water for three weeks. Control mice underwent a sham procedure and received normal water. Compared to control mice, DOCA-salt mice exhibited elevated systolic BP, increased heart weight to body weight ratios (5.6 vs 7.1), increased lung wet to dry weight ratios (4.4 vs 4.8) indicative of pulmonary congestion, and decreased time to exhaustion upon treadmill exercise testing (23.0 vs. 18.5 seconds). On conscious echocardiography, DOCA-salt mice exhibited a preserved ejection fraction. Invasive hemodynamic studies revealed an increased tau constant (5.7 vs 8.2) and increased end-diastolic pressures in DOCA-salt mice (1.7 vs 2.6), consistent with diastolic dysfunction. CITE-seq, a novel technique to obtain transcriptomic and surface marker expression on single cells, was performed on a total of 4,359 and 7,600 cells sorted live CD45+ leukocytes from four sham and four DOCA-salt left ventricles, respectively. Unsupervised computational analysis revealed 29 clusters of immune cells. Six clusters containing natural killer, T lymphocyte and myeloid cell populations were overrepresented and five B cell clusters were underrepresented in DOCA-salt samples. Differential expression analysis of CD11b+CD64+ cardiac macrophages revealed transcriptional changes between groups with 146 significantly upregulated and 111 downregulated genes. Gene set enrichment analysis showed upregulation of leukocyte migration, response to type I interferon, and cytokine-mediated signaling pathways in DOCA-salt macrophages. In conclusion, the DOCA-salt mouse model recapitulates key features of HFpEF including diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, and pulmonary congestion and is associated with an altered cardiac immune cell profile.

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 P389: Free Fatty Acid Receptor 4 Is Necessary For An Adaptive Response Following Heart Failure Induced By Metabolic Syndrome In Mice

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Naixin Zhang ◽  
Katherine A Murphy ◽  
Dylan J Gyberg ◽  
Timothy D O'Connell
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Preserved Ejection Fraction ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor

Non-resolving inflammation is central to the pathogenesis of heart failure (HF). Heart failure preserved ejection fraction (HFpEF) is a type of HF that is particularly associated with inflammation provoked by metabolic syndrome (MetS). The G-protein coupled receptor, free fatty acid receptor 4 (Ffar4), is a receptor for medium and long chain fatty acids (FA) that regulates metabolism and attenuates inflammation. Ffar4 is expressed in the human heart, and downregulated in heart failure. Furthermore, polymorphisms in Ffar4 have been associated with eccentric remodeling in a patient cohort. Previously, Ffar4 was shown to protect the heart from pathologic stress by attenuating oxidative stress in a mouse model of pressure overload. Here, we tested the hypothesis that Ffar4 would attenuate the development of heart failure using a mouse model of MetS-induced HFpEF. Metabolic syndrome was induced in mice by feeding a high-fat, high-sucrose diet (42% fat, 30% sucrose) to produce obesity and delivering the nitric oxide synthase inhibitor, L-NAME, in the drinking water to induce hypertension. The combined intervention (referred to as HFpEF diet) resulted in mice developing excessive adiposity, glucose intolerance (in males only), and mild hypertension. After 20 weeks on the HFpEF diet, both male and female WT mice, developed diastolic dysfunction (increased E/A and E/e’) and preserved ejection fraction (EF), consistent with clinical HFpEF. In Ffar4KO male mice HFpEF diet induced a greater degree of diastolic dysfunction compared to WT mice, despite equivalent metabolic parameters. Female Ffar4KO mice fed the HFpEF diet had a greater increase in weight gain and adiposity compared to WT female mice. Surprisingly, diastolic function was equivalent between WT and FFAR4KO female mice, suggesting a sex-based difference in FFAR4 cardioprotection. Our data show that Ffar4 attenuates HFpEF secondary to MetS.

Abstract 266: Is the Col4a3 -/- Alport Mouse a Novel Model for Heart Failure With Preserved Ejection Fraction?

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Keyvan Yousefi ◽  
Wen Ding ◽  
Jayanti Singh ◽  
Lina Shehadeh
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Interventricular Septum ◽  
Early Death ◽  
Heart Weight ◽  
Preserved Ejection Fraction ◽  
Cardiovascular Pathology ◽  
Galectin 3 ◽  
Novel Model

Heart failure with preserved ejection fraction (HFpEF) accounts for more than 50% of all HF cases. HFpEF patients manifest normal or mildly reduced left ventricle (LV) ejection fraction (LVEF), LV hypertrophy, diastolic dysfunction, myocardial stiffness, cardiac fibrosis, hypertension, nephropathy and sudden death. There is no appropriate animal model for HFpEF. The Alport Col4a3 -/- mouse, a model of nephropathy, hypertension and early death, develops a cardiovascular pathology that is yet to be well characterized. We elected to analyze the cardiovascular pathology of the Alport mouse and investigate any commonalities with HFpEF. Male Alport and wild type (WT) littermates of mixed background at 2 months of age were subjected to echocardiographic and 2D speckle tracking analyses and heart tissues were used for histopathological examinations (N=6 mice per group). Circulating Galectin-3, a marker of HFpEF, was measured by Elisa in plasma samples. Data are shown as mean±SEM. Normalized heart weight increased in Alport relative to WT mice - p<0.01, indicative of cardiac hypertrophy. Consistently, echocardiography showed interventricular septum (IVS) thickening -p<0.05. Reduced stroke volume p<0.01, and impaired global longitudinal and circumferential strain (GLS and GCS) indicated systolic dysfunction in Alport mice. No significant reduction in LVEF was observed. Alport mice developed diastolic dysfunction evidenced by a prolonged Isovolumetric relaxation time -P<0.05, and a reduced E/A, a marker of LV relaxation and stiffness -p<0.01. Elevated LV filling pressure and pulmonary artery wedge pressure were demonstrated by an increase in E/E’ - p<0.01. Galectin-3 increased in Alport relative to WT plasma (P<0.01). Alport hearts had more Fibronectin protein - P<0.05 and increased number of fibroblasts with “activated” phenotype as demonstrated by increased mass of rough endoplasmic reticulum in EM cross sections. Our study suggests that the cardiovascular pathologies of the Alport mouse are similar to HFpEF, specifically preserved ejection fraction, diastolic dysfunction, hypertension, early death and cardiac stiffness and fibrosis. Further study of this multi-factorial pathology may render the Alport mouse as a useful novel model for HFpEF.

scholarly journals Combined Risk Factors Induce T Cell‐Mediated Diastolic Dysfunction in a Novel Mouse Model of Heart Failure with Preserved Ejection Fraction (HFpEF)

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Sasha Smolgovsky ◽  
Francisco Carrillo‐Salinas ◽  
Marina Anastasiou ◽  
Kuljeet Kaur ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
T Cell ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Preserved Ejection Fraction

scholarly journals Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction

2018 ◽  
Vol 315 (4) ◽  
pp. H934-H949 ◽  
Author(s):  
Linda Alex ◽  
Ilaria Russo ◽  
Volodymir Holoborodko ◽  
Nikolaos G Frangogiannis
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Cardiomyocyte Hypertrophy ◽  
Metabolic Dysfunction ◽  
Preserved Ejection Fraction ◽  
Male And Female ◽  
Microvascular Rarefaction

Heart failure with preserved ejection fraction (HFpEF) is caused, or exacerbated by, a wide range of extracardiac conditions. Diabetes, obesity, and metabolic dysfunction are associated with a unique HFpEF phenotype, characterized by inflammation, cardiac fibrosis, and microvascular dysfunction. Development of new therapies for HFpEF is hampered by the absence of reliable animal models. The leptin-resistant db/ db mouse has been extensively studied as a model of diabetes-associated cardiomyopathy; however, data on the functional and morphological alterations in db/ db hearts are conflicting. In the present study, we report a systematic characterization of the cardiac phenotype in db/ db mice, focusing on the time course of functional and histopathological alterations and on the identification of sex-specific cellular events. Although both male and female db/ db mice developed severe obesity, increased adiposity, and hyperglycemia, female mice had more impressive weight gain and exhibited a modest but significant increase in blood pressure. db/ db mice had hypertrophic ventricular remodeling and diastolic dysfunction with preserved ejection fraction; the increase in left ventricular mass was accentuated in female mice. Histological analysis showed that both male and female db/ db mice had cardiomyocyte hypertrophy and interstitial fibrosis, associated with marked thickening of the perimysial collagen, and expansion of the periarteriolar collagen network, in the absence of replacement fibrosis. In vivo and in vitro experiments showed that fibrotic changes in db/ db hearts were associated with increased collagen synthesis by cardiac fibroblasts, in the absence of periostin, α-smooth muscle actin, or fibroblast activation protein overexpression. Male db/ db mice exhibited microvascular rarefaction. In conclusion, the db/ db mouse model recapitulates functional and histological features of human HFpEF associated with metabolic dysfunction. Development of fibrosis in db/ db hearts, in the absence of myofibroblast conversion, suggests that metabolic dysfunction may activate an alternative profibrotic pathway associated with accentuated extracellular matrix protein synthesis. NEW & NOTEWORTHY We provide a systematic analysis of the sex-specific functional and structural myocardial alterations in db/ db mice. Obese diabetic C57BL6J db/ db mice exhibit diastolic dysfunction with preserved ejection fraction, associated with cardiomyocyte hypertrophy, interstitial/perivascular fibrosis, and microvascular rarefaction, thus recapitulating aspects of human obesity-related heart failure with preserved ejection fraction. Myocardial fibrosis in db/ db mice is associated with a matrix-producing fibroblast phenotype, in the absence of myofibroblast conversion, suggesting an alternative mechanism of activation.

scholarly journals Gut Dysbiosis and Barrier Disruption Are Associated with Diastolic Dysfunction in a Novel Mouse Model of Heart Failure with Preserved Ejection Fraction

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Francisco Carrillo‐Salinas ◽  
Sasha Smolgovsky ◽  
Marina Anastasiou ◽  
Kuljeet Kaur ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Preserved Ejection Fraction ◽  
Barrier Disruption ◽  
Gut Dysbiosis

The relationship between the key markers of myocardial fibrosis and gut microbiota composition in patients with heart failure and preserved ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.N Kaburova ◽  
O.M Drapkina ◽  
S.M Uydin ◽  
M.S Pokrovskaya ◽  
S.N Koretsky ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Gut Microbiota ◽  
Myocardial Fibrosis ◽  
Interquartile Range ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Microbiota Composition ◽  
Preserved Ejection Fraction ◽  
Gut Microbiota Composition

Abstract Background Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The current gold standard for the diagnosis and assessment of myocardial fibrosis is endomyocardial biopsy. A number of circulating biomarkers have been proposed for the assessment of myocardial fibrosis, however the most consistent results have been found for C-terminal propeptide of procollagen type I (PICP) and N-terminal propeptide of pro-collagen type III (PIIINP). Some evidence suggests the possible link between the gut microbiota composition and myocardioal fibrosis. Purpose The aim of the study was to investigate the association between the serum markers of myocardial fibrosis (PICP and PIIINP) with gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index &lt;35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide &gt;125 pg/ml and symptoms of HF). The levels of PICP and PIIINP were evaluated in patients' serum using enzyme-linked immunosorbent assay. The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. Results The mediana and interquartile range in PICP was 918 [700; 1044] pg/ml, in PIIINP it was 6.215 [3.99; 8.29] pg/ml. The analysis revealed significant correlations between PICP and the following bacterial genera of Firmicutes:Ruminococcus (r=−0,36); Gemmiger (r=−0,35), Allisonella (r=0,32) and Howardella (r=−0,30). PIIINP significantly correlated with 2 genera: Blautia which belongs to Firmicutes phylum (r=0,36) and Bilophila which belongs to Proteobacteria phylum (r=−0,33). All values with p&lt;0,05. Conclusion Both PICP and PIIINP had negative significant correlations with beneficial bacterial genera and positive correlations with several potencially harmful gut bacterial genera. This type of relationship might become the novel field of research in the group of patients with HF-pEF due to myocardial fibrosis. Funding Acknowledgement Type of funding source: None

Subclinical Pulmonary Congestion and Abnormal Hemodynamics in Heart Failure With Preserved Ejection Fraction

2021 ◽  
Author(s):  
C. Charles Jain ◽  
Juerg Tschirren ◽  
Yogesh N.V. Reddy ◽  
Vojtech Melenovsky ◽  
Margaret Redfield ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Preserved Ejection Fraction ◽  
Pulmonary Congestion

scholarly journals Opportunistic screening models for high-risk men and women to detect diastolic dysfunction and heart failure with preserved ejection fraction in the community

2018 ◽  
Vol 26 (6) ◽  
pp. 613-623 ◽  
Author(s):  
Aisha Gohar ◽  
Rogier F Kievit ◽  
Gideon B Valstar ◽  
Arno W Hoes ◽  
Evelien E Van Riet ◽  
...  
Keyword(s):  
Heart Failure ◽  
High Risk ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Preserved Ejection Fraction ◽  
Men And Women ◽  
Ventricular Diastolic Dysfunction

Background The prevalence of undetected left ventricular diastolic dysfunction is high, especially in the elderly with comorbidities. Left ventricular diastolic dysfunction is a prognostic indicator of heart failure, in particularly of heart failure with preserved ejection fraction and of future cardiovascular and all-cause mortality. Therefore we aimed to develop sex-specific diagnostic models to enable the early identification of men and women at high-risk of left ventricular diastolic dysfunction with or without symptoms of heart failure who require more aggressive preventative strategies. Design Individual patient data from four primary care heart failure-screening studies were analysed (1371 participants, excluding patients classified as heart failure and left ventricular ejection fraction <50%). Methods Eleven candidate predictors were entered into logistic regression models to be associated with the presence of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in men and women separately. Internal-external cross-validation was performed to develop and validate the models. Results Increased age and β-blocker therapy remained as predictors in both the models for men and women. The model for men additionally consisted of increased body mass index, moderate to severe shortness of breath, increased pulse pressure and history of ischaemic heart disease. The models performed moderately and similarly well in men (c-statistics range 0.60–0.75) and women (c-statistics range 0.51–0.76) and the performance improved significantly following the addition of N-terminal pro b-type natriuretic peptide (c-statistics range 0.61–0.80 in women and 0.68–0.80 in men). Conclusions We provide an easy-to-use screening tool for use in the community, which can improve the early detection of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in high-risk men and women and optimise tailoring of preventive interventions.

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