Molecular Signature of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model.
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ABSTRACT:
SUBMITTER: Gibb AA
PROVIDER: S-EPMC8385567 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1 month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.
2021-09-01 | GSE181184 | GEO
Project description:Molecular Signatures of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model
| PRJNA759257 | ENA
Project description: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.
| S-EPMC9550571 | biostudies-literature
Project description:BackgroundAnoxic brain injuries represent the main determinant of poor outcome after cardiac arrest (CA). Large animal models have been described to investigate new treatments during CA and post-resuscitation phase, but a detailed model that includes extensive neuromonitoring is lacking.MethodBefore an electrically-induced 10-minute CA and resuscitation, 46 adult pigs underwent neurosurgery for placement of a multifunctional probe (intracranial pressure or ICP, tissue oxygen tension or PbtO2 and cerebral temperature) and a bolt-based technique for the placement and securing of a regional blood flow probe and two sEEG electrodes; two modified cerebral microdialysis (CMD) probes were also inserted in the frontal lobes and accidental misplacement was prevented using a perforated head support.Result42 animals underwent the CA procedure and 41 achieved the return of spontaneous circulation (ROSC). In 4 cases (8.6%) an adverse event took place during preparation, but only in two cases (4.3%) this was related to the neurosurgery. In 6 animals (13.3%) the minor complications that occurred resolved after probe repositioning.ConclusionHerein we provide a detailed comprehensive neuromonitoring approach in a large animal model of CA that might help future research.
| S-EPMC8879632 | biostudies-literature
Project description:BackgroundSeptic shock, in humans and in our well-established animal model, is associated with increases in biventricular end diastolic volume (EDV) and decreases in ejection fraction (EF). These abnormalities occur over 2 days and reverse within 10 days. Septic non-survivors do not develop an increase in EDV. The mechanism for this cardiac dysfunction and EDV differences is unknown.MethodsPurpose-bred beagles randomized to receive intrabronchial Staphylococcus aureus (n=27) or saline (n=6) were provided standard ICU care including sedation, mechanical ventilation, and fluid resuscitation to a pulmonary arterial occlusion pressure of over 10mmHg. No catecholamines were administered. Over 96h, cardiac magnetic resonance imaging, echocardiograms, and invasive hemodynamics were serially performed, and laboratory data was collected. Tissue was obtained at 66h from six septic animals.ResultsFrom 0-96h after bacterial challenge, septic animals vs. controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%) which was more pronounced at 48h in non-survivors than survivors. On histology, edema was located predominantly in myocytes, the interstitium, and endothelial cells. Edema was associated with significantly worse biventricular function (lower EFs), ventricular-arterial coupling, and circumferential strain. In septic animals, from 0-24h, the EDV decreased from baseline and, despite cardiac filling pressures being similar, decreased significantly more in non-survivors. From 24-48h, all septic animals had increases in biventricular chamber sizes. Survivors biventricular EDVs were significantly greater than baseline and in non-survivors, where biventricular EDVs were not different from baseline. Preload, afterload, or HR differences did not explain these differential serial changes in chamber size.ConclusionSystolic and diastolic cardiac dysfunction during sepsis is associated with ventricular wall edema. Rather than differences in preload, afterload, or heart rate, structural alterations to the ventricular wall best account for the volume changes associated with outcome during sepsis. In non-survivors, from 0-24h, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part explain, the EDV increases from 24-48h. However, these changes continued and even accelerated into the recovery phase consistent with a reparative process rather than ongoing injury.
| S-EPMC11188083 | biostudies-literature
Project description:Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown multiple inflammatory mechanisms causing cardiac remodeling, dysfunction and chronic failure. Therapeutics in trials targeting the immune response in heart failure and its effects did not result in evident benefits regarding clinical endpoints and mortality. This review elaborates pathways of immune cytokines in pathogenesis and worsening of heart failure in clinical and cellular settings. Besides the well-known mechanisms of immune activation and inflammation in atherosclerosis causing ischemic cardiomyopathy or myocarditis, attention is focused on other mechanisms leading to heart failure such as transthyretin (TTR) amyloidosis or heart failure with preserved ejection fraction. The knowledge of the pathogenesis in heart failure and amyloidosis on a molecular and cellular level might help to highlight new disease defining biomarkers and to lead the way to new therapeutic targets.
| S-EPMC6540104 | biostudies-literature
Project description:AimsThe prevalence of heart failure with preserved ejection fraction (HFpEF) is still increasing, and so far, no pharmaceutical treatment has proven to be effective. A key obstacle for testing new pharmaceutical substances is the availability of suitable animal models for HFpEF, which realistically reflect the clinical picture. The aim of the present study was to characterize the development of HFpEF and skeletal muscle (SM) dysfunction in ZSF1 rats over time.Methods and resultsEchocardiography and functional analyses of the SM were performed in 6-, 10-, 15-, 20-, and 32-week-old ZSF1-lean and ZSF1-obese. Furthermore, myocardial and SM tissue was collected for molecular and histological analyses. HFpEF markers were evident as early as 10 weeks of age. Diastolic dysfunction, confirmed by a significant increase in E/e', was detectable at 10 weeks. Increased left ventricular mRNA expression of collagen and BNP was detected in ZSF1-obese animals as early as 15 and 20 weeks, respectively. The loss of muscle force was measurable in the extensor digitorum longus starting at 15 weeks, whereas the soleus muscle function was impaired at Week 32. In addition, at Week 20, markers for aortic valve sclerosis were increased.ConclusionsOur measurements confirmed the appearance of HFpEF in ZSF1-obese rats as early as 10 weeks of age, most likely as a result of the pre-existing co-morbidities. In addition, SM function was reduced after the manifestation of HFpEF. In conclusion, the ZSF1 rat may serve as a suitable animal model to study pharmaceutical strategies for the treatment of HFpEF.
| S-EPMC7524062 | biostudies-literature
Project description:Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer's ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans.
| S-EPMC6912636 | biostudies-literature
Project description:As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (AAV)-S100A1 gene therapy in a preclinical large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and animals, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca(2+)) handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered, by retrograde coronary venous delivery, AAV serotype 9 (AAV9)-S100A1 to the left ventricular, non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed these functional and structural changes by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca(2+) cycling, sarcoplasmic reticulum calcium handling, and energy homeostasis. Transgene expression was restricted to cardiac tissue, and extracardiac organ function was uncompromised. This translational study shows the preclinical feasibility of long-term therapeutic effectiveness of and a favorable safety profile for cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.
| S-EPMC4095769 | biostudies-literature
Project description:Dissolution-dynamic nuclear polarization (dissolution-DNP) for magnetic resonance (MR) spectroscopic imaging has recently emerged as a novel technique for noninvasive studies of the metabolic fate of biomolecules in vivo. Since acetate is the most abundant extra- and intracellular short-chain fatty acid, we focused on [1-(13) C]acetate as a promising candidate for a chemical probe to study the myocardial metabolism of a beating heart. The dissolution-DNP procedure of Na[1-(13) C]acetate for in vivo cardiac applications with a 3 T MR scanner was optimized in pigs during bolus injection of doses of up to 3 mmol. The Na[1-(13) C]acetate formulation was characterized by a liquid-state polarization of 14.2% and a T1Eff in vivo of 17.6 ± 1.7 s. In vivo Na[1-(13) C]acetate kinetics displayed a bimodal shape: [1-(13) C]acetyl carnitine (AcC) was detected in a slice covering the cardiac volume, and the signal of (13) C-acetate and (13) C-AcC was modeled using the total area under the curve (AUC) for kinetic analysis. A good correlation was found between the ratio AUC(AcC)/AUC(acetate) and the apparent kinetic constant of metabolic conversion, from [1-(13) C]acetate to [1-(13) C]AcC (kAcC ), divided by the AcC longitudinal relaxation rate (r1 ). Our study proved the feasibility and the limitations of administration of large doses of hyperpolarized [1-(13) C]acetate to study the myocardial conversion of [1-(13) C]acetate in [1-(13) C]acetyl-carnitine generated by acetyltransferase in healthy pigs.
| S-EPMC4362963 | biostudies-literature