Abstract 16434: Temporal Metabolomic and Transcriptomic Changes in a Large-Animal Model of Hfpef

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Andrew A Gibb ◽  
Emma K Murray ◽  
Deborah M Eaton ◽  
Anh T Huynh ◽  
Dhanendra Tomar ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Disease Progression ◽  
Mitochondrial Function ◽  
Pulmonary Mechanics ◽  
Pathway Enrichment Analysis ◽  
Sham Operation ◽  
Large Animal ◽  
Aortic Banding ◽  
Metabolomics Data ◽  
Lipid Species

Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of HF cases, with no effective treatments. We previously reported that a feline aortic banding model recapitulates many of the multi-factorial features of HFpEF, including: LV hypertrophy, left atrial enlargement, elevated LV filling pressures, impaired pulmonary mechanics and fibrosis. Importantly, this model lacks obesity and hypertension enabling the discovery of cardiac centric targets independent of comorbidities. We examined early changes in metabolism and transcription to gain mechanistic insight into HFpEF development. Male short-hair kittens (2mo old) underwent aortic banding or sham operation. Cardiac function was assessed at baseline and 1mo post-banding prior to tissue collection and downstream analyses. Following banding, we observed significant cardiac hypertrophy and initiation of LV fibrosis in the absence of changes in cardiac function. We observed LV mitochondrial dysfunction, indicated by impaired complex-I and -II respiration prompting the examination of cardiac metabolism by unbiased metabolomics. 82 metabolites were significantly different (≥ 1.25 fold, p ≤ 0.1) between 1mo banded and sham hearts, with an overrepresentation of amino acid (aa) and lipid species. Pathway enrichment analysis highlighted an increase in aa metabolism (e.g. serine, proline) that is associated with ECM remodeling and tissue fibrosis. Additionally, an increase in lipid species (i.e. acyl-carnitines) suggests reduced fatty acid utilization and a shift towards glycolysis. Correlations of metabolomics data with mitochondrial function and cardiac phenotyping revealed strong associations between mitochondrial function and the cardiac energy state, as well as aa and LV fibrosis. RNA-seq and enrichment analyses revealed a significant inflammatory response early in disease progression and a decrease in protein/histone acetylation. Collectively, this systems-based approach provides new insights into the cellular biology underlying HFpEF-like disease progression. The metabolic and transcriptional signature that precede the clinical features of HFpEF, will provide new pre-clinical research directions and may yield novel therapeutic targets.

scholarly journals Homoarginine Treatment of Rats Improves Cardiac Function and Remodeling in Response to Pressure Overload

2021 ◽  
Author(s):  
Vitali Koch ◽  
Marco Ochs ◽  
Christophe Weber ◽  
Kristina Buchner ◽  
Derliz Mereles ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Myocardial Function ◽  
Synergistic Effects ◽  
Sham Operation ◽  
Inverse Association ◽  
Synthesis Inhibitor ◽  
Aortic Banding ◽  
Dose Dependent

Abstract Purpose Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on myocardial function and remodeling in rats undergoing aortic banding or given the nitric oxide synthesis inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Methods Male Wistar rats (n = 136) underwent sham operation (SH) or aortic banding (AB) and were equally divided into fourteen subgroups, receiving different doses of HA alone or in combination with either lisinopril, spironolactone or L-NAME over a 4-week period. Results HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg− 1·day− 1. Combining 800 mg·kg− 1·day− 1 HA with spironolactone or lisinopril yielded synergistic effects, showing a positive correlation with LV ejection fraction (+ 27%, p < 0.05), fractional shortening (+ 37%, p < 0.05) and an inverse association with collagen area fraction (-56%, p < 0.05), myocyte cross-sectional area (-22%, p < 0.05) and the molecular markers atrial natriuretic factor (-78%, p = 0.04), brain natriuretic peptide (-28%, p = 0.22), beta-myosin heavy chain (-42%, p = 0.19) and collagen type V alpha 1 chain (-73%, p = 0.06) compared to placebo treated AB animals. Even co-administration of HA and L-NAME was found to attenuate cardiac remodeling and to prevent NO-deficient hypertension following AB. Conclusion HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes of cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in synergistic beneficial effects boosting the direct impact of HA on heart failure pathophysiology.

Abstract 084: Dkk1 Knock out Leads To Augmentation Of Cardiac Hypertrophy Following Aortic Banding

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Johannes H Riffel ◽  
Elmar Bernhold ◽  
Marco Hagenmueller ◽  
Min Zhang ◽  
Christof Niehrs ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Wnt Signaling ◽  
Histological Evaluation ◽  
Heart Weight ◽  
Sham Operation ◽  
Aortic Banding ◽  
Knock Out ◽  
Hypertrophic Growth ◽  
Knock Out Mice

Background: Myocardial hypertrophy is an important risk factor for cardiac morbidity and mortality. In the normal adult heart, Wnt signaling remains quiescent. However, recent studies have demonstrated reactivation of Wnt signaling in hypertrophic growth of cardiomyocytes. Under such conditions Wnt signaling may be beneficial or maladaptive depending on the context. The Wnt coreceptors LRP5 and LRP6 are important for signal transmission via the β-catenin pathway and are negatively regulated by Dkk1, a member of a small family of secretory proteins. Dkk1 binds to LRP6 and thereby acts as a Wnt antagonist. In our study we investigated the cardiovascular phenotype of Dkk1 knock-out mice following aortic banding. Study Design and Results: Dkk1 (+/-) knock-out mice were subjected to aortic banding (AB) or sham operation. After 4 weeks echocardiographic and invasive measurements were performed. After that the mice were euthanized, heart weight was measured and myocardial samples were snap frozen for biochemical measurements or fixed in formalin for further histological evaluation. Under baseline conditions there were no differences in cardiomyocyte size, heart weight and cardiac function in Dkk1 knock-out animals compared to wild type animals. 4 weeks after aortic banding we observed a significant increase in heart weight/body weight ratio in Dkk1 knock out animals compared to the control group (7.3 ± 0.3 mg/g vs. 6.4 ± 0.3 mg/g, p < 0.05). Furthermore cardiomyocyte size was highly elevated in Dkk1 knock out mice compared to control animals, suggesting an augmentation in cardiac hypertrophy. Transcription levels of the pro-hypertrophic markers atrial natriuretic factor (ANF) and beta-MHC were increased in Dkk1 knock out animals. Interestingly echocardiographic data revealed an aggravation of cardiac function in Dkk1 knock out mice following aortic banding (Ejection fraction (EF): 62 ± 3 % vs. 74 ± 1 %, p < 0.05). Summary: Our findings suggest that Dkk1 knock out aggravates cardiac hypertrophy following aortic banding. The underlying molecular mechanisms remain to be further explored.

scholarly journals Glial Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

2021 ◽  
pp. 1-9
Author(s):  
Patricia Cassina ◽  
Ernesto Miquel ◽  
Laura Martínez-Palma ◽  
Adriana Cassina
Keyword(s):  
Motor Neuron ◽  
Disease Progression ◽  
Glial Cells ◽  
Mitochondrial Function ◽  
Neurodegenerative Disorder ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
Neuron Death ◽  
Energy Demands ◽  
Aberrant Glial Cells

ALS is a human neurodegenerative disorder that induces a progressive paralysis of voluntary muscles due to motor neuron loss. The causes are unknown, and there is no curative treatment available. Mitochondrial dysfunction is a hallmark of ALS pathology; however, it is currently unknown whether it is a cause or a consequence of disease progression. Recent evidence indicates that glial mitochondrial function changes to cope with energy demands and critically influences neuronal death and disease progression. Aberrant glial cells detected in the spinal cord of diseased animals are characterized by increased proliferation rate and reduced mitochondrial bioenergetics. These features can be compared with cancer cell behavior of adapting to nutrient microenvironment by altering energy metabolism, a concept known as metabolic reprogramming. We focus on data that suggest that aberrant glial cells in ALS undergo metabolic reprogramming and profound changes in glial mitochondrial activity, which are associated with motor neuron death in ALS. This review article emphasizes on the association between metabolic reprogramming and glial reactivity, bringing new paradigms from the area of cancer research into neurodegenerative diseases. Targeting glial mitochondrial function and metabolic reprogramming may result in promising therapeutic strategies for ALS.

SUMO-1 Gene Transfer Improves Cardiac Function in a Large-Animal Model of Heart Failure

2013 ◽  
Vol 5 (211) ◽  
pp. 211ra159-211ra159 ◽  
Author(s):  
L. Tilemann ◽  
A. Lee ◽  
K. Ishikawa ◽  
J. Aguero ◽  
K. Rapti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Large Animal Model ◽  
Large Animal

Abstract 2883: Retroinfusion-facilitated Inotropic AAV9-S100A1 Gene Therapy Restores Global Cardiac Function In A Clinically Relevant Pig Heart Failure Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sven T Pleger ◽  
Changguang Shan ◽  
Jan Kziencek ◽  
Oliver Mueller ◽  
Raffi Bekeredjian ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Large Animal ◽  
Circumflex Artery ◽  
Cell Counts ◽  
Clinical Conditions

Background: Cardiac expression of the Ca-dependent inotropic protein S100A1 is decreased in human end-stage heart failure (HF) and cardiomyocyte-targeted viral-based S100A1 gene transfer rescued failing myocardium in small animal models in vivo and in vitro via improved systolic and diastolic sarcoplasmic reticulum Ca-handling. We therefore hypothesized that cardioselective AAV9-S100A1 gene therapy will improve cardiac performance in a large animal experimental HF model under clinical conditions. Methods and Results: Left ventricular (LV) posterolateral myocardial infarction (MI) was induced in pigs by occlusion of the left coronary circumflex artery and resulted in LV failure (HF) 2 weeks post-MI reflected by a 40% and 27% reduction in LV +dp/dt max. and EF, respectively, as assessed by LV catheterization and echocardiography. Post-MI HF pigs were then randomized for retroinfusion of AAV9-luciferase (luc; n=6, 1.5×10 13 total viral particles, tvp) and AAV9-S100A1 (S100A1; n=6, 1.5×10 13 tvp) driven by a cardioselective promoter via the anterior cardiac vein while the left anterior descending artery was temporarily occluded. 14 weeks after cardiac gene transfer, the S100A1-treated HF group showed significantly enhanced S100A1 protein expression (+46.7±17.9%, P<0.05 vs. control groups) in targeted remote LV myocardium and improved indices of cardiac function and remodeling (luc vs. S100A1: +dp/dtmax: 983±81 vs. 1526±83 mmHg/s, EF: 39±2.1 vs. 61±3.7 %, P<0.05 S100A1 vs. luc, LV endsystolic diameter: luc 4.45±0.1 vs. S100A1 3.43 ±0.1 cm, P<0.05 S100A1 vs. luc, HR: 72±4 vs. 69±2, beats/min, P=n.s. S100A1 vs. luc). Importantly, analyses of renal, hepatic and hematopoetic function showed no alteration as assessed by unchanged transaminases, retention values and white blood cell counts compared to sham pigs. Conclusions: Our translational study provides proof of concept that AAV9-S100A1 based HF gene therapy is feasible and restores cardiac function in a large animal HF model under clinical conditions. Next, certified toxicological analysis and different AAV9-S100A1 dosage protocols will be assessed to eventually advance to first phase I/II clinical studies determining therapeutic efficiency of cardiac S100A1 gene therapy in HF patients.

Abstract 10: Disparate Temporal Regulation of Blood Pressure by Estrogens During Systemic Lupus Erythematosus.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Emily L Gilbert ◽  
Keisa W Mathis ◽  
Marcia Venegas-Pont ◽  
Michael J Ryan
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Progression ◽  
Lupus Erythematosus ◽  
Population Based ◽  
Protective Role ◽  
Young Female ◽  
Sham Operation ◽  
Systemic Lupus ◽  
Temporal Regulation ◽  
And Control

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects young women. Due to this partiality towards women, estrogen is commonly implicated in disease development. The potential for estrogens to promote SLE disease progression stems from data showing that removal of estrogens in young female mice with SLE (6-8 week old NZBWF1 mice) delays the development of renal injury and mortality. The primary cause of mortality in women with SLE is cardiovascular disease, and hypertension, a major cardiovascular risk factor, is highly prevalent in this patient population. Based on the presumed role of estrogen to promote SLE, we hypothesized that estrogen promotes hypertension during SLE. To test this, 30 week old SLE mice (NZBWF1) and control mice (NZW/LacJ) were subjected to either ovariectomy (OVX) or a sham operation and a subset of these mice were replete with 17β-estradiol (E2, 5μg/mouse, s.c., 2x/week). At 34 weeks of age, mean arterial pressure (MAP in mmHg) was measured by carotid catheter in conscious freely moving mice. MAP was higher in SLE sham mice compared to control shams (133±3, n=17 vs. 120±3, n=13, p<0.05). Contrary to our hypothesis, OVX at 30 weeks exacerbated the hypertension (154±3, n=9, p<0.05 vs. SLE sham) and prevalence of albuminuria in mice with SLE (83%, 10 of 12 vs 36%, 5 of 14 measured by dipstick > 100 mg/dL). OVX did not alter MAP (115±3, n=9) or albuminuria in control mice. The hypertensive response to OVX was prevented in OVX SLE mice replete with E2 (133±4, n=3) suggesting a protective role for E2 against SLE-associated hypertension. Because previous studies showed that estrogen removal in young mice delayed SLE disease progression, we tested whether OVX starting at 8 weeks of age delayed the development of hypertension. OVX in young SLE mice did not significantly alter the progression of SLE-associated hypertension (141±4, n=4 measured at 34 weeks of age). Consistent with previous work of others, OVX in young SLE mice reduced the prevalence of albuminuria (20%, 1 of 5 vs 33%, 1 of 3). These data suggest that estrogen has a complex temporal role in the pathogenesis of SLE with the potential to promote disease early in life, but protect against the progression of SLE associated hypertension later in the course of the disease.

Assessment of cardiac function in large animal telemetry studies: Model sensitivity and historical results

2015 ◽  
Vol 75 ◽  
pp. 178
Author(s):  
Lewis Buchanan ◽  
William Warner ◽  
Susan Arthur ◽  
Geoff Lewen ◽  
Paul Levesque ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Large Animal ◽  
Model Sensitivity

Effects of Blood Purification on Serum Levels of Inflammatory Cytokines and Cardiac Function in a Rat Model of Sepsis

2017 ◽  
Vol 44 (1) ◽  
pp. 40-50
Author(s):  
Cong-Meng Lin ◽  
Cun-Rong Chen ◽  
Xue-Qiong Wu ◽  
Jin-Hua Ren ◽  
Shao-Zhen Chen ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Inflammatory Cytokines ◽  
Rat Model ◽  
Serum Levels ◽  
Blood Purification ◽  
Sham Operation ◽  
Sham Treatment ◽  
Treatment Groups ◽  
Myocardial Apoptosis ◽  
Cardiac Functions

Objective: The study aimed to explore the effects of blood purification (BP) on serum levels of inflammatory cytokines and cardiac function in a rat model of sepsis. Methods: A rat model of sepsis was established by cecal ligation and puncture. All rats were divided into the normal control, sham operation, model, sham treatment, and BP treatment groups. Cardiac functions, inflammatory cytokines, myocardial enzymes, pathological score of cardiac muscle tissue, and myocardial apoptosis of rats in each group were compared. Results: Sepsis rats had higher serum levels of inflammatory cytokines and lower cardiac function than those in the normal control and sham operation groups. Compared with the model and sham treatment groups, improved cardiac functions, decreased inflammatory cytokines, myocardial enzymes, pathological score, and myocardial apoptosis and mortality were observed in the BP treatment group. Conclusion: BP may reduce serum levels of inflammatory cytokines and improve cardiac function of sepsis rats.

scholarly journals Scar Formation with Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1 Month Old Swine

2019 ◽  
Vol 7 (1) ◽  
pp. 1 ◽  
Author(s):  
Emma J Agnew ◽  
Nivedhitha Velayutham ◽  
Gabriela Matos Ortiz ◽  
Christina M Alfieri ◽  
Luis Hortells ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mitotic Activity ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Cardiac Regeneration ◽  
Scar Formation ◽  
Sham Operation ◽  
Large Mammals

Studies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation, but less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs to assess regenerative repair in young large mammals at a stage when cardiomyocyte (CM) mitotic activity is still detected. Female and male P30 pigs were subjected to cardiac ischemia (1 h) by occlusion of the left anterior descending artery followed by reperfusion, or to a sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 h post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated CM cell cycling, detectable by phospho-histone H3 staining, at 2 months of age in multinucleated CMs in both sham-operated and IR pigs. Inflammation and regional scar formation in the epicardial region proximal to injury were observed 4 weeks post-IR. Thus, pigs subjected to cardiac IR at P30 show myocardial damage with a prolonged decrease in cardiac function, formation of a regional scar, and increased inflammation, but do not regenerate myocardium even in the presence of CM mitotic activity.

Sign in / Sign up

Export Citation Format

Share Document