scholarly journals Reactive fibrosis precedes doxorubicin‐induced heart failure through sterile inflammation

2020 ◽  
Vol 7 (2) ◽  
pp. 588-603 ◽  
Author(s):  
Ryo Tanaka ◽  
Masanari Umemura ◽  
Masatoshi Narikawa ◽  
Mayu Hikichi ◽  
Kohei Osaw ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sterile Inflammation ◽  
Reactive Fibrosis

scholarly journals Mitochondrial fission process 1 (MTFP1) controls bioenergetic efficiency and prevents inflammatory cardiomyopathy and heart failure in mice

2021 ◽  
Author(s):  
Erminia Donnarumma ◽  
Michael Kohlhaas ◽  
Elodie Vimont ◽  
Etienne Kornobis ◽  
Thibaut Chaze ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cell Death ◽  
Knockout Mice ◽  
Mitochondrial Permeability Transition ◽  
Mitochondrial Fission ◽  
Sterile Inflammation ◽  
Mitochondrial Morphology ◽  
Fission Process ◽  
General Decline

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling.

Abstract 333: AAV9 Serca2a Gene Transfer Reverses Some but Not All Electrophysiological Deficits in a Chronic Model of Congestive Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Chaoqin Xie ◽  
Jiqiu Chen ◽  
Jun Hu ◽  
Antoine H Chaanine ◽  
Dongtak Jeong ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Transfer ◽  
Regional Differences ◽  
Mechanical Function ◽  
Aortic Banding ◽  
Cx43 Expression ◽  
Treatment Groups ◽  
Chronic Model ◽  
To Receive ◽  
Reactive Fibrosis

SERCA2a gene transfer (GT) to the failing heart improves it mechanical function. The electrophysiological (EP) consequences of SERCA2a GT are less clear. We investigated the EP substrate, total (t) and phosphorylated (p) Cx43 expression in a chronic model of heart failure (HF) with & without SERCA2a GT. Methods: After 2 mo of aortic banding rats underwent 30min LAD occlusion & reperfusion for another 2 mo. Rats developed widespread proliferation of reactive fibrosis in ischemic & remote zones and were randomized to receive AAV9 GFP (HF) or AAV9 SERCA2a (HF treatment) at the time of LAD occlusion/reperfusion. Hearts from normal (Sham, N=6), HF (AAV9.GFP, N=7), and HF treatment (AAV9.SERCA2a, N=9) rats were studied using optical mapping. Cx43 levels (t & p) were measured. Results: HF rats exhibited significant APD prolongation (by 50%) & CV slowing (by 30%). More importantly APD heterogeneity was increased 2.5 fold (p=0.006). The ratio of S368 p-to-t Cx43 was reduced in the ischemic zone of HF rats where SERCA2a expression was decreased (Fig). AAV9 SERCA2a GT increased SERCA2a levels in the ischemic and remote zones. Surprisingly, APD & CV were comparable (p=NS each) in HF and HF treatment groups. In contrast SERCA2a GT reduced APD heterogeneity by 30% relative to untreated rats (p=0.03), fully restored pCx43 expression to sham levels in the ischemic zone and abolished regional differences in p-to-t Cx43 (Fig). Conclusions: AAV9 SERCA2a GT reverses key EP and molecular deficits that are causally related to arrhythmias in HF. This therapy, however, fails to reverse other hallmark features of HF, which are likely dependent on widespread ion channel and structural remodeling, namely fibrosis.

Female sex, atrial fibrillation, and heart failure, but not ageing, are associated with endomysial fibrosis in atrial myocardium: results from the CATCH ME consortium

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
J Winters ◽  
S Zeemering ◽  
A Isaacs ◽  
B Casadei ◽  
L Fabritz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Clinical Parameter ◽  
Atrial Fibrosis ◽  
Mixed Effect ◽  
Structural Remodeling ◽  
Horizon 2020 ◽  
Female Sex ◽  
Public Grant ◽  
Reactive Fibrosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME Horizon 2020, EU-H2020-PHC-RIA (633196) CVON2014-09, RACE V: Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF Background Atrial fibrosis is one of the most important aspects of structural remodeling in the atria and largely increases the inducibility and sustainability of AF. The main risk factors for recurrent AF, such as ageing, heart failure, and history of AF, partly enhance AF propensity by inducing atrial fibrosis. A distinction should be made between replacement fibrosis following myocyte death and reactive fibrosis, which often occurs in the absence of myocyte death.  Endomysial fibrosis, a type of reactive fibrosis in between cardiomyocytes, is  poorly studied as a result of limitations and labor intensiveness of traditional histochemical quantification. Purpose We examined the contributions of age, sex, AF and heart failure to the development of overall and endomysial fibrosis in the context of concurrent pathologies. Methods We developed an algorithm for automated quantification of multiple features of structural remodeling following myocardial staining with wheat germ agglutinin (WGA).  We studied the type, quantity and distribution of fibrosis in left (LAA, n = 95) and right (RAA, n = 76) atrial appendage biopsies in a large European cohort of patients with varying indications for cardiac surgery. Linear mixed effect models were constructed to predict endomysial fibrosis quantity and clustering as a function of AF, heart failure, sex, age and 4 principle components that accounted for potential confounding due to other clinical characteristics. Results Persistent AF, heart failure and female sex were independently associated with endomysial fibrosis, age was not. AF and age were not associated with overall fibrosis. Clustering of endomysial fibrosis was observed in females (LAA), paroxysmal AF (RAA), persistent AF and heart failure (LAA) patients (table 1).  Conclusions Female sex, AF, and heart failure are associated with the quantity and distribution of endomysial fibrosis, the effects of age are limited. summary of results Clinical parameter Overall fibrosis Endomysial fibrosis Clustering of endomysial fibrosis LAA RAA LAA RAA LAA RAA Paroxysmal AF +1.6%±1.5; p = 0.29 +2.1%±2.2; p = 0.34 -0.7μm ± 0.5; p = 0.19 +1.0μm ± 0.6; p = 0.10 -0.8%±3.6; p = 0.82 +7.4%±4.1; p = 0.04 Persistent AF +1.6%±1.5; p = 0.26 +2.2%±2.1; p = 0.30 +1.1μm ± 0.5; p = 0.04 +1.3μm ± 0.6; p = 0.03 +5.7%±0.03; p = 0.04 +6.9%±3.9, p = 0.04 Heart failure +4.8%±1.5; p = 0.01 +2.3%±2.0; p = 0.24 +2.5μm ± 0.5; p < 0.001 +0.3μm ± 0.5; p = 0.53 +16.9%±3.4; p < 0.001 +0.8%±3.6; p = 0.82 Female sex +4.5%±1.8; p = 0.01 +0.8%±2.5; p = 0.76 +1.5μm ± 0.6; p = 0.01 -0.4μm ± 0.7; p = 0.58 +12.9%±3.9; p< 0.01 -3.3%±4.8; p = 0.49 Age +0.5%±0.3; p = 0.17 +0.4%±0.4; p = 0.34 +0.1μm ± 0.1; p = 0.39 +0.05μm ± 0.1; p = 0.97 +0.9%±0.8; p = 0.11 -0.02%±0.8; p = 0.49 Values presented are effect estimates ± SD as obtained from the described linear mixed models. P-values were estimated using the Kenward-Roger approximation. The effect of age is presented as increase per 5 years of age.

Abstract 482: Beta-catenin Activation in Cardiac Fibroblasts Modulates the Immune Micro-environment to Promote Fibrosis and Heart Failure Following Chronic Injury

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Meiling Melzer ◽  
Dina Hassan ◽  
David Beier ◽  
Pampee P Young ◽  
Sarika Saraswati
Keyword(s):  
Heart Failure ◽  
Wnt Signaling ◽  
Immune Cell ◽  
Interstitial Fibrosis ◽  
Diastolic Heart Failure ◽  
Expression Patterns ◽  
Beta Catenin ◽  
Chronic Injury ◽  
Reactive Fibrosis

Almost 6.5 million people in United States suffer from heart failure (HF). Diastolic HF following non-ischemic cardiac insult is a progressive condition with limited effective therapies underscoring the urgency to invest in identifying novel therapeutic targets for treatment. Reactive fibrosis in response to pathological stress is one of the major causes of diastolic HF. Emerging data suggest an association of systemic inflammation with reactive fibrosis and HF. Canonical Wnt/beta-catenin signaling has been linked to HF and fibrosis with limited understanding of the precise cellular and molecular mechanism. We utilized thoracic aortic constriction (TAC), a well-defined model of HF, to study Wnt signaling mediated reactive fibrosis. TAC was induced in a transgenic mouse model with stabilized beta-catenin (Wnt signaling) in fibroblasts (Bcat/Postn). Wnt activation following TAC resulted in increased maladaptive reactive fibrosis, HF marker ANP, and cardiac hypertrophy with preserved Ejection Fraction (pEF) suggesting Wnt-mediated progression of diastolic heart failure with pEF. TAC also resulted in increased macrophage activation and recruitment of CD8+ cytotoxic T-cells. In vitro co-culture of Wnt3a-overexpressing fibroblasts with activated myeloid cells promoted fibroblast proliferation and collagen synthesis. Therefore, we hypothesize that Wnt signaling activation promotes interstitial fibrosis via recruitment of specific inflammatory cells. Genomic analysis further supports this by demonstrating distinct chemokine gene expression patterns in fibroblasts resulting from Wnt activation in these injury models. Our future goal is to elucidate the role of Wnt signaling in modulating the fibroblast-immune cell crosstalk in modulating interstitial fibrosis induced diastolic HFpEF. Currently, there is no approved therapy to specifically target reactive fibrosis to avert diastolic dysfunction. Our study is aiming to identify targetable cellular and molecular players that improve, prevent or avert reactive fibrosis mediated HFpEF in order to reduce the incidence and severity of pathology resulting from HF.

scholarly journals Sterile Inflammation and Degradation Systems in Heart Failure

2017 ◽  
Vol 81 (5) ◽  
pp. 622-628 ◽  
Author(s):  
Kazuhiko Nishida ◽  
Kinya Otsu
Keyword(s):  
Heart Failure ◽  
Sterile Inflammation

scholarly journals The Role of Anti-Inflammatory Cytokines in Heart Failure

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Rachel Pathimagaraj
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Immune Complex ◽  
Therapeutic Potential ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Ischaemia Reperfusion Injury ◽  
Pyrin Domain

Coronary occlusion promotes a state of ischaemia that results in myocardial infarction; it  is  a  major  cause  of  mortality  accounting  for  one  hospital  admission  every  three minutes. At the site of infarct, sterile inflammation is initiated due to pro-inflammatory secretions from cardiac and innate immune cells. The focus of this review is to explore the role of a newly discovered innate immune complex, the nod-like receptor family pyrin domain containing 3 inflammasome. This review discusses the potential of this immune  complex  in  decreasing  the  proportion  of  functional  myocardium  during ischaemia   and   ischaemia-reperfusion   injury.   Due   to   the   central   role   of   this inflammasome  in  promoting  cardiac  dysfunction  following  an  acute  myocardial infarction,  the  risk  of  port-infarction  heart  failure  increases.  With  an  intention  of highlighting the importance of improving current management of patients with acute myocardial  infarction,  this  review  addresses  novel  therapeutic  agents  that  have demonstrated  cardioprotective  outcomes  in  recent  studies.  This  follows  discussion concerning the therapeutic potential of these agents, intending to form the basis of heart failure therapy.

Mitochondria in Cardiomyopathy: Alterations in Size, Number and Internal Structures

1968 ◽  
Vol 26 ◽  
pp. 126-127
Author(s):  
George Hug ◽  
William K. Schubert
Keyword(s):  
Heart Failure ◽  
Biochemical Analysis ◽  
Left Ventricular ◽  
Size Number ◽  
Internal Structures ◽  
Left Ventricular Outflow ◽  
Chest X Ray ◽  
Myocardial Fibers ◽  
Muscle Biopsies ◽  
Needle Liver Biopsy

A white boy six months of age was hospitalized with respiratory distress and congestive heart failure. Control of the heart failure was achieved but marked cardiomegaly, moderate hepatomegaly, and minimal muscular weakness persisted.At birth a chest x-ray had been taken because of rapid breathing and jaundice and showed the heart to be of normal size. Clinical studies included: EKG which showed biventricular hypertrophy, needle liver biopsy which showed toxic hepatitis, and cardiac catheterization which showed no obstruction to left ventricular outflow. Liver and muscle biopsies revealed no biochemical or histological evidence of type II glycogexiosis (Pompe's disease). At thoracotomy, 14 milligrams of left ventricular muscle were removed. Total phosphorylase activity in the biopsy specimen was normal by biochemical analysis as was the degree of phosphorylase activation. By light microscopy, vacuoles and fine granules were seen in practically all myocardial fibers. The fibers were not hypertrophic. The endocardium was not thickened excluding endocardial fibroelastosis. Based on these findings, the diagnosis of idiopathic non-obstructive cardiomyopathy was made.

Localization of endothelial nitric oxide synthase in the normal and failing human atrial myocardium

1996 ◽  
Vol 54 ◽  
pp. 786-787
Author(s):  
Chi-Ming Wei ◽  
Margarita Bracamonte ◽  
Shi-Wen Jiang ◽  
Richard C. Daly ◽  
Christopher G.A. McGregor ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Cardiac Tissues ◽  
Mammalian Tissues ◽  
End Stage Heart Failure ◽  
End Stage ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Nitric oxide (NO) is a potent endothelium-derived relaxing factor which also may modulate cardiomyocyte inotropism and growth via increasing cGMP. While endothelial nitric oxide synthase (eNOS) isoforms have been detected in non-human mammalian tissues, expression and localization of eNOS in the normal and failing human myocardium are poorly defined. Therefore, the present study was designed to investigate eNOS in human cardiac tissues in the presence and absence of congestive heart failure (CHF).Normal and failing atrial tissue were obtained from six cardiac donors and six end-stage heart failure patients undergoing primary cardiac transplantation. ENOS protein expression and localization was investigated utilizing Western blot analysis and immunohistochemical staining with the polyclonal rabbit antibody to eNOS (Transduction Laboratories, Lexington, Kentucky).

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