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Pubblicazioni recenti - cardiac fibrosis
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Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease.
Nat Commun2022 Dec;13(1):7497. doi: 10.1038/s41467-022-35306-1.
Widjaja Anissa A, Viswanathan Sivakumar, Shekeran Shamini G, Adami Eleonora, Lim Wei-Wen, Chothani Sonia, Tan Jessie, Goh Joyce Wei Ting, Chen Hui Mei, Lim Sze Yun, Boustany-Kari Carine M, Hawkins Julie, Petretto Enrico, Hübner Norbert, Schafer Sebastian, Coffman Thomas M, Cook Stuart A,
Abstract
The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3? inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGF? reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.
© 2022. The Author(s).
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Docosahexaenoic acid administration improves diabetes-induced cardiac fibrosis through enhancing fatty acid oxidation in cardiac fibroblast.
J Nutr Biochem2022 Dec;():109244. doi: 10.1016/j.jnutbio.2022.109244.
Qin Linhui, Mei Yingwu, An Chengcheng, Ning Rui, Zhang Haifeng,
Abstract
Diabetes mellitus can lead to various complications, including organ fibrosis. Metabolic remodeling often occurs during the development of organ fibrosis. Docosahexaenoic acid (DHA), an essential ?-3 polyunsaturated fatty acid, shows great benefits in improving cardiovascular disease and organ fibrosis, including regulating cellular metabolism. In this study, we investigated whether DHA can inhibit diabetes-induced cardiac fibrosis by regulating the metabolism of cardiac fibroblasts. Type I diabetic mice were induced by streptozotocin and after supplementation with DHA for 16 weeks, clinical indicators of serum and heart were evaluated. DHA administration significantly improved serum lipid levels, cardiac function and cardiac interstitial fibrosis, but not blood glucose levels. Subsequently, immunofluorescences, western blot and label-free quantitative proteomics methods were used to study the mechanism. The results showed that the anti-fibrotic function of DHA was achieved through regulating extracellular matrix homeostasis including ECM synthesis and degradation. Our research demonstrated DHA regulated the energy metabolism of cardiac fibroblasts, especially fatty acid oxidation, and then affected the balance of ECM synthesis and degradation. It suggested that DHA supplementation could be considered an effective adjuvant therapy for cardiac fibrosis caused by hyperglycemia.
Copyright © 2022. Published by Elsevier Inc.
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GSK126 an Inhibitor of Epigenetic Regulator EZH2 Suppresses Cardiac Fibrosis by Regulating EZH2-PAX6-CXCL10 Pathway.
Biochem Cell Biol2022 Dec;():. doi: 10.1139/bcb-2022-0224.
Aziz Shireen, Yalan Li, Raza Muhammad Ahmer, Lemin Jiao, Akram Hafiz Muhammad Bilal, Zhao Wen,
Abstract
Myocardial fibrosis is a common pathological companion of various cardiovascular diseases. To date, the role of enhancer of zeste homolog 2 (EZH2) in cancer has been well demonstrated including in renal carcinoma and its inhibitors have entered the stage of phase I/II clinical trials. However, the precise mechanism of EZH2 in cardiac diseases is largely unclear. In the current study, we first found that EZH2 expression was increased in Ang-II treated cardiac fibroblasts (CFs) and mouse heart homogenates following isoproterenol (ISO) administration for 21 days, respectively. Ang-II induces CFs activation and increased collagen-I, collagen-III, ?-SMA, EZH2, and trimethylates lysine 27 on histone 3 (H3K27me3) expressions can be reversed by EZH2 inhibitor (GSK126) and EZH2 siRNA. The ISO induced-cardiac hypertrophy, and fibrosis in vivo which were also related to the upregulation of EZH2 and its downstream target, H3K27me3, could be recovered by GSK126. Furthermore, the upregulation of EZH2 induces the decrease of paired box 6 (PAX6) and C-X-C motif ligand 10 (CXCL10) "which" was also reversed by GSK126 treatment. In summary, the present evidence strongly suggests that GSK126 could be a therapeutic intervention blunting the development and progression of myocardial fibrosis in an EZH2-PAX6-CXCL10-dependent manner.
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Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers.
Front Physiol2022 ;13():1057200. doi: 1057200.
Ernault Auriane C, Kawasaki Makiri, Fabrizi Benedetta, Montañés-Agudo Pablo, Amersfoorth Shirley C M, Al-Shama Rushd F M, Coronel Ruben, De Groot Joris R,
Abstract
Atrial fibrosis plays an important role in the development and persistence of atrial fibrillation by promoting reentry. Primary cilia have been identified as a regulator of fibroblasts (FB) activation and extracellular matrix (ECM) deposition. We hypothesized that selective reduction of primary cilia causes increased fibrosis and facilitates reentry. The aim of this study was to disrupt the formation of primary cilia in FB and examine its consequences on ECM and conduction in a co-culture system of cardiomyocytes (CM) and FB. Using short interfering RNA (siRNA), we removed primary cilia in neonatal rat ventricular FB by reducing the expression of gene required for ciliary assembly. We co-cultured neonatal rat ventricular cardiomyocytes (CM) with FB previously transfected with siRNA (siIft88) or negative control siRNA (siNC) for 48 h. We examined the consequences of ciliated fibroblasts reduction on conduction and tissue remodeling by performing electrical mapping, microelectrode, and gene expression measurements. Transfection of FB with siIft88 resulted in a significant 60% and 30% reduction of relative expression in FB and CM-FB co-cultures, respectively, compared to siNC. Knockdown of significantly increased the expression of ECM genes , and by 38%, 30% and 18%, respectively, in comparison to transfection with siNC. Conduction velocity (CV) was significantly decreased in the siIft88 group in comparison to siNC [11.12 ± 4.27 cm/s ( = 10) vs. 17.00 ± 6.20 ( = 10) respectively,
Copyright © 2022 Ernault, Kawasaki, Fabrizi, Montañés-Agudo, Amersfoorth, Al-Shama, Coronel and De Groot.
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Myocardial fibrosis in congenital heart disease.
Front Pediatr2022 ;10():965204. doi: 965204.
Gordon Blanca, González-Fernández Víctor, Dos-Subirà Laura,
Abstract
Myocardial fibrosis resulting from the excessive deposition of collagen fibers through the myocardium is a common histopathologic finding in a wide range of cardiovascular diseases, including congenital anomalies. Interstitial fibrosis has been identified as a major cause of myocardial dysfunction since it distorts the normal architecture of the myocardium and impairs the biological function and properties of the interstitium. This review summarizes current knowledge on the mechanisms and detrimental consequences of myocardial fibrosis in heart failure and arrhythmias, discusses the usefulness of available imaging techniques and circulating biomarkers to assess this entity and reviews the current body of evidence regarding myocardial fibrosis in the different subsets of congenital heart diseases with implications in research and treatment.
© 2022 Gordon, González-Fernández and Dos-Subirà.
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Mending a broken heart-targeting cardiomyocyte regeneration: a literature review.
Ann Transl Med2022 Nov;10(21):1179. doi: 1179.
Jin Chunna, Zhu Shiyu, Zhao Tingting, Deng Jiewen, Xiang Meixiang, Ma Hong,
Abstract
BACKGROUND AND OBJECTIVES:
Cardiovascular diseases have been the leading cause of death globally for decades. Pharmacological advances targeting the sympathetic nervous system, renin-angiotensin-aldosterone system, and fibrosis slow the progression of diverse cardiovascular diseases. However, ongoing cardiomyocyte loss is inevitable in divergent cardiovascular diseases, eventually leading to heart failure as the end stage. In this review, we focused on the key biomedical findings and underlying principles of cardiomyocyte regeneration.
METHODS:
Literature regarding the key findings in cardiomyocyte regeneration research, including controversies on the origins of newly formed cardiomyocytes, potential barriers and strategies to heart regeneration, and the key animals, models, and methods applied in the study of heart regeneration, were broadly researched using the PubMed and Web of Science databases.
KEY CONTENT AND FINDINGS:
In the mammalian heart, cardiomyocytes proliferate during the embryonic and early postnatal stages, while the capability of proliferation disappears in the adult stage. An increasing amount of evidence suggests that cardiomyocytes self-renew at a very limited level and that most newly formed cardiomyocytes originate from pre-existing cardiomyocytes and not cardiac progenitor cells (CPCs). Several potential barriers to heart regeneration have been addressed, including metabolic switch, a large increase in multinucleated and polyploid cardiomyocytes, and alteration in the epigenome and transcriptome. In addition, immune system evolution is also associated with the loss of regenerative capacity. However, the activation of resident cardiomyocytes, somatic cell reprogramming, and direct reprogramming, in addition to the promotion of neovascularization and immune modulation, constitute the new insights into those strategies that can boost cardiac regeneration.
CONCLUSIONS:
Heart regeneration is one of the most popular fields in cardiovascular research and represents a promising avenue of therapeutics for mending a broken heart. Despite the controversies and challenges, a clearer picture of adult mammalian cardiac regeneration is emerging.
2022 Annals of Translational Medicine. All rights reserved.
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Blocking VCAM-1 ameliorates hypertensive cardiac remodeling by impeding macrophage infiltration.
Front Pharmacol2022 ;13():1058268. doi: 1058268.
Qiu Ze-Yang, Yu Wei-Jia, Bai Jie, Lin Qiu-Yue,
Abstract
Cardiac remodeling is an important mechanism of heart failure, which frequently results from leukocyte infiltration. Vascular cellular adhesion molecule-1 (VCAM-1) plays a critical role in leukocyte adhesion and transmigration. However, the importance of VCAM-1 in the development of angiotensin II (Ang II)-induced cardiac remodeling remains unclear. Wild-type (WT) mice were infused with Ang II (1,000 ng/kg/min) for 14 days and simultaneously treated with VCAM-1 neutralizing antibody (0.1 or 0.2 mg) or IgG control. Systolic blood pressure (SBP) and cardiac function were detected by a tail-cuff and echocardiography. Cardiac remodeling was evaluated by histological staining. Adhesion and migration of bone marrow macrophages (BMMs) were evaluated . Our results indicated that VCAM-1 levels were increased in the serum of patients with heart failure (HF) and the hearts of Ang II-infused mice. Furthermore, Ang II-caused hypertension, cardiac dysfunction, hypertrophy, fibrosis, infiltration of VLA-4+ BMMs and oxidative stress were dose-dependently attenuated in mice administered VCAM-1 neutralizing antibody. In addition, blocking VCAM-1 markedly alleviated Ang II-induced BMMs adhesion and migration, therefore inhibited cardiomyocyte hypertrophy and fibroblast activation. In conclusion, the data reveal that blocking VCAM-1 ameliorates hypertensive cardiac remodeling by impeding VLA-4+ macrophage infiltration. Selective blockage of VCAM-1 may be a novel therapeutic strategy for hypertensive cardiac diseases.
Copyright © 2022 Qiu, Yu, Bai and Lin.
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Work-up for Incidentally Detected NAFLD: How Far is It Worth?
Euroasian J Hepatogastroenterol2022 Jul;12(Suppl 1):S26-S36. doi: 10.5005/jp-journals-10018-1364.
Mishra Saurabh, Bhujade Harish, Butt Amna Subhan, Kamani Lubna, Premkumar Madhumita,
Abstract
UNLABELLED:
The incidence of nonalcoholic fatty liver disease (NAFLD) has seen a steep rise in parallel with the global obesity and metabolic syndrome epidemic. The presence of NAFLD contributes to significant socioeconomic burden due to healthcare costs, progression of liver disease as non-alcoholic steatohepatitis (NASH), and later cirrhosis and hepatocellular carcinoma (HCC). With the advent of widely available imaging, it is also being detected as an incidental diagnosis in individuals with systemic disease like metabolic syndrome, diabetes, chronic cardiac disease, polycystic ovarian syndrome, etc. or in asymptomatic persons on presurgical evaluation or even annual health assessments. Gastroenterologists, hepatologists, physicians and surgeons need to be updated about the new diagnostic criteria of Metabolic (dysfunction)-associated fatty liver disease, noninvasive tests (NITs) of liver fibrosis, new tools of elastography, and identification of those with high-risk disease. In this review, we appraise the relevance of new diagnostic definitions, steatosis and fibrosis estimation tests, advanced imaging like magnetic resonance elastography and proton density fat fraction and discuss the diagnostic algorithm for incidentally detected NAFLD.
HOW TO CITE THIS ARTICLE:
Mishra S, Bhujade H, Butt AS, . Work-up for Incidentally Detected NAFLD: How Far is It Worth? Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S26-S36.
Copyright © 2022; Jaypee Brothers Medical Publishers (P) Ltd.
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Cardiac magnetic resonance imaging parameters show association between myocardial abnormalities and severity of chronic kidney disease.
Front Cardiovasc Med2022 ;9():1053122. doi: 1053122.
Jia Xi, Han Xiaoyu, Wang Yuqin, He Fangfang, Zhou Xiaoyue, Zheng Yuting, Guo Yingkun, Xu Rong, Liu Jia, Li Yumin, Gu Jin, Cao Yukun, Zhang Chun, Shi Heshui,
Abstract
BACKGROUND:
Chronic kidney disease patients have increased risk of cardiovascular abnormalities. This study investigated the relationship between cardiovascular abnormalities and the severity of chronic kidney disease using cardiac magnetic resonance imaging.
METHODS:
We enrolled 84 participants with various stages of chronic kidney disease (group I: stages 1-3, = 23; group II: stages 4-5, = 20; group III: hemodialysis patients, = 41) and 32 healthy subjects. The demographics and biochemical parameters of the study subjects were evaluated. All subjects underwent non-contrast cardiac magnetic resonance scans. Myocardial strain, native T1, and T2 values were calculated from the scanning results. Analysis of covariance was used to compare the imaging parameters between group I-III and the controls.
RESULTS:
The left ventricular ejection fraction (49 vs. 56%, = 0.021), global radial strain (29 vs. 37, = 0.019) and global circumferential strain (-17.4 vs. -20.6,
CONCLUSIONS:
Our study showed that myocardial strain, native T1, and T2 values progressively got worse with advancing chronic kidney disease stage. The increased T1 values and decreased T2 values of hemodialysis patients might be due to increasing myocardial fibrosis but with reduction in oedema following effective fluid management.
TRIAL REGISTRATION NUMBER:
ChiCTR2100053561 (http://www.chictr.org.cn/edit.aspx?pid=139737&htm=4).
Copyright © 2022 Jia, Han, Wang, He, Zhou, Zheng, Guo, Xu, Liu, Li, Gu, Cao, Zhang and Shi.
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Loss of AKAP12 aggravates rheumatoid arthritis-like symptoms and cardiac damage in collagen-induced arthritis mice.
Exp Anim2022 Dec;():. doi: 10.1538/expanim.22-0103.
Ni Yanhui, Cao Jingjing, Yuan Jing, Ning Xiaoran,
Abstract
A-kinase anchoring protein 12 (AKAP12) has been identified as an anti-inflammatory and anti-fibrotic regulator in chronic inflammation and cardiovascular disease. However, the potential of AKAP12 in autoimmune disorders, rheumatoid arthritis (RA) and associated cardiac complications remains elusive. Here, a murine model of collagen-induced arthritis (CIA) was successfully induced, followed by adenovirus-mediated AKAP12 short hairpin RNA (shRNA) treatment. AKAP12 silenced mice displayed elevated clinical arthritis scores and significant ankle joint swelling. AKAP12 loss in CIA mice increased inflammatory cell infiltration and cartilage erosion, increased the levels of anti-IIC IgG and inflammatory cytokines IL-1?, IL-6, TNF-? in serum, and upregulated the expression of cartilage-degrading enzymes MMP-1, MMP-3, MMP-13 in synovium, but reduced IL-10. The number of M1 macrophages and the expression of the markers (CCR7, IL-6, TNF-? and iNOS) was enhanced in synovial tissues, while M2 polarized macrophages and the makers (IL-10 and arginase-1) were reduced in response to AKAP12 loss. Moreover, low expression of AKAP12 was detected in the hearts of CIA mice. Loss of AKAP12 results in increased cardiac inflammation and fibrosis. This work suggests that AKAP12 loss aggravates joint inflammation likely through the promotion of M1 macrophage polarization and exacerbates inflammation-caused cardiac fibrosis.
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Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator.
EBioMedicine2022 Nov;86():104384. doi: 10.1016/j.ebiom.2022.104384.
Vanherle Lotte, Lidington Darcy, Uhl Franziska E, Steiner Saskia, Vassallo Stefania, Skoug Cecilia, Duarte Joao M N, Ramu Sangeetha, Uller Lena, Desjardins Jean-François, Connelly Kim A, Bolz Steffen-Sebastian, Meissner Anja,
Abstract
BACKGROUND:
Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI).
METHODS:
MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention.
FINDINGS:
Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window.
INTERPRETATION:
Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI.
FUNDING:
Knut and Alice Wallenberg Foundation [F 2015/2112]; Swedish Research Council [VR; 2017-01243]; the German Research Foundation [DFG; ME 4667/2-1]; Hjärnfonden [FO2021-0112]; The Crafoord Foundation; Åke Wibergs Stiftelse [M19-0380], NMMP 2021 [V2021-2102]; the Albert Påhlsson Research Foundation; STINT [MG19-8469], Lund University; Canadian Institutes of Health Research [PJT-153269] and a Heart and Stroke Foundation of Ontario Mid-Career Investigator Award.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
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Membrane Estrogen Receptor Beta is Sufficient to Mitigate Cardiac Cell Pathology.
Endocrinology2022 Dec;():. doi: bqac200.
Ahluwalia Amrita, Hoa Neil, Moreira Debbie, Aziz Daniel, Singh Karanvir, Patel Khushin N, Levin Ellis R,
Abstract
Estrogen acting through estrogen receptor beta has been shown to oppose the stimulation of cardiac myocytes and cardiac fibroblasts that results in cardiac hypertrophy and fibrosis. Previous work has implicated signal transduction from ER? as being important to the function of estrogen in these regards. Here we address whether membrane ER? is sufficient to oppose key mechanisms by which Angiotensin II stimulates cardiac cell pathology. To do this we first defined essential structural elements within ER? that are necessary for membrane or nuclear localization in cells. We previously determined that cysteine 418 is the site of palmitoylation of ER? that is required and sufficient for cell membrane localization in mice and is the same site in humans. Here we determined in CHO cells, and mouse and rat myocytes and cardiac fibroblasts, the impact on multiple aspects of signal transduction by expressing wild type or a C418A mutant ER?. To test the importance of the nuclear receptor, we determined a four amino acid deletion in the E domain of ER? that strongly blocked nuclear localization. Using these tools, we expressed wild type and mutant ER? constructs into cardiomyocytes and cardiac fibroblasts from ER? deleted mice. We determined the ability of estrogen to mitigate cell pathology stimulated by Angiotensin II and whether the membrane ER? is necessary and sufficient.
Published by Oxford University Press on behalf of the Endocrine Society 2022.
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Eplerenone inhibits the macrophage-to-myofibroblast transition in rats with UUO-induced type 4 cardiorenal syndrome through the MR/CTGF pathway.
Int Immunopharmacol2022 Dec;113(Pt A):109396. doi: 10.1016/j.intimp.2022.109396.
Han Yutong, Xian Yunqian, Gao Xiaomeng, Qiang Panpan, Hao Juan, Yang Fan, Shimosawa Tatsuo, Chang Yi, Xu Qingyou,
Abstract
Cardiovascular complications are the leading causes of death in patients with chronic kidney disease (CKD), accounting for approximately 50% of deaths. Despite significant advances in the understanding of cardiac disease due to CKD, the underlying mechanisms involved in many pathological changes have not been fully elucidated. In our previous study, we observed severe fibrosis in the contralateral kidney of a 6-month-old rat UUO model. In the present experiment, we also observed severe fibrosis in the hearts of rats subjected to UUO and the macrophage-to-myofibroblast transition (MMT). These effects were inhibited by the mineralocorticoid receptor (MR) blocker eplerenone. Notably, in vitro, aldosterone-activated MR induced the MMT and subsequently promoted the secretion of CTGF, the target of MR, from macrophages; these changes were inhibited by eplerenone. The CTGF also induced the MMT and both the aldosterone and CTGF-induced MMT could be alleviated by the CTGF blocker. In conclusion, our results suggest that targeting the MR/CTGF pathway to inhibit the MMT may be an effective therapeutic strategy for the treatment of cardiac fibrosis.
Copyright © 2022 Elsevier B.V. All rights reserved.
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The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner.
Geroscience2022 Dec;():. doi: 10.1007/s11357-022-00695-0.
Li Ping, Newhardt Maria F, Matsuzaki Satoshi, Eyster Craig, Pranay Atul, Peelor Frederick F, Batushansky Albert, Kinter Caroline, Subramani Kumar, Subrahmanian Sandeep, Ahamed Jasimuddin, Yu Pengchun, Kinter Michael, Miller Benjamin F, Humphries Kenneth M,
Abstract
SIRT3 is a longevity factor that acts as the primary deacetylase in mitochondria. Although ubiquitously expressed, previous global SIRT3 knockout studies have shown primarily a cardiac-specific phenotype. Here, we sought to determine how specifically knocking out SIRT3 in cardiomyocytes (SIRTcKO mice) temporally affects cardiac function and metabolism. Mice displayed an age-dependent increase in cardiac pathology, with 10-month-old mice exhibiting significant loss of systolic function, hypertrophy, and fibrosis. While mitochondrial function was maintained at 10 months, proteomics and metabolic phenotyping indicated SIRT3 hearts had increased reliance on glucose as an energy substrate. Additionally, there was a significant increase in branched-chain amino acids in SIRT3cKO hearts without concurrent increases in mTOR activity. Heavy water labeling experiments demonstrated that, by 3 months of age, there was an increase in protein synthesis that promoted hypertrophic growth with a potential loss of proteostasis in SIRT3cKO hearts. Cumulatively, these data show that the cardiomyocyte-specific loss of SIRT3 results in severe pathology with an accelerated aging phenotype.
© 2022. The Author(s).
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Cardiomyopathy Induced by Artificial Cardiac Pacing: To Whom, When, Why, and How? Insights on Heart Failure Development.
Braz J Cardiovasc Surg2022 Dec;():. doi: 10.21470/1678-9741-2021-0629.
Ferrari Andres Di Leoni, Oliveira Eduardo Bartholomay, Tagliari Ana Paula, Kochi Adriano Nunes, Beuren Thaís Mariel Andara, Cabral Gustavo Chiari, Ferreira Flávio Vinicius Costa, Danzmann Luiz Cláudio,
Abstract
Coordinated and harmonic (synchronous) ventricular electrical activation is essential for better left ventricular systolic function. Intraventricular conduction abnormalities, such as left bundle branch block due to artificial cardiac pacing, lead to electromechanical "dyssynchronopathy" with deleterious structural and clinical consequences. The aim of this review was to describe and improve the understanding of all the processes connecting the several mechanisms involved in the development of artificially induced ventricular dyssynchrony by cardiac pacing, most known as pacing-induced cardiomyopathy (PiCM). The chronic effect of abnormal impulse conduction and nonphysiological ectopic activation by artificial cardiac pacing is suspected to affect metabolism and myocardial perfusion, triggering regional differences in the activation/contraction processes that cause electrical and structural remodeling due to damage, inflammation, and fibrosis of the cardiac tissue. The effect of artificial cardiac pacing on ventricular function and structure can be multifactorial, and biological factors underlying PiCM could affect the time and probability of developing the condition. PiCM has not been included in the traditional classification of cardiomyopathies, which can hinder detection. This article reviews the available evidence for pacing-induced cardiovascular disease, the current understanding of its pathophysiology, and reinforces the adverse effects of right ventricular pacing, especially right ventricular pacing burden (commonly measured in percentage) and its repercussion on ventricular contraction (reflected by the impact on left ventricular systolic function). These effects might be the main defining criteria and determining mechanisms of the pathophysiology and the clinical repercussion seen on patients.
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Prognostic value of multiparametric cardiac magnetic resonance in sickle cell patients.
Ann Hematol2022 Dec;():. doi: 10.1007/s00277-022-05057-6.
Meloni Antonella, Pistoia Laura, Quota Alessandra, Messina Giuseppe, Ricchi Paolo, Bagnato Sergio, Gerardi Calogera, Lisi Roberto, Cuccia Liana, Renne Stefania, Vallone Antonino, Righi Riccardo, Positano Vincenzo, Pepe Alessia, Cademartiri Filippo,
Abstract
The aim of this multicenter study was to prospectively assess the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in sickle cell disease (SCD) patients. Among all patients with hemoglobinopathies consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network, we selected 102 SCD patients (34.38?±?12.67 years, 49 females). Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect focal myocardial fibrosis. At baseline CMR, only two patients had significant MIO (global heart T2*?20 ms). During a mean follow-up of 63.01?±?24.95 months, 11 cardiovascular events (10.8%) were registered: 3 pulmonary hypertension, 2 supraventricular arrhythmias, 1 heart failure, 1 death for heart failure, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, and 1 death after acute chest syndrome. In the multivariate analysis, the independent CMR predictors of cardiovascular events were left ventricular (LV) ejection fraction (hazard ratio-HR?=?0.88; p?=?0.025) and right ventricular (RV) mass index (HR?=?1.09; p?=?0.047). According to the receiver-operating characteristic curve analysis for adverse events, an LV ejection fraction?58.9% and an RV mass index?>?31 g/m were optimal cut-off values. Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that CMR may be added as a screening tool for identifying SCD patients at high risk for cardiopulmonary and vascular diseases.
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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Beneficial effects of nintedanib on cardiomyopathy in patients with systemic sclerosis: a pilot study.
Rheumatology (Oxford)2022 Dec;():. doi: keac674.
Ninagawa Keita, Kato Masaru, Tsuneta Satonori, Ishizaka Suguru, Ujiie Hideyuki, Hisada Ryo, Kono Michihito, Fujieda Yuichiro, Ito Yoichi M, Atsumi Tatsuya,
Abstract
OBJECTIVES:
Nintedanib is an inhibitor of tyrosine kinases that has been shown to slow the progression of interstitial lung disease (ILD), including ILD associated with systemic sclerosis (SSc). The aim of this study was to explore the effect of nintedanib on cardiomyopathy associated with SSc.
METHODS:
Twenty consecutively hospitalized patients with SSc-ILD were enrolled and prospectively followed. The rate of change at six months in cardiac magnetic resonance (CMR) parametric mapping, including myocardial extracellular volume, was primarily evaluated. Other endpoints included changes in CMR functional parameters, echocardiographic parameters, modified Rodnan skin score, serum biomarkers, and pulmonary function test.
RESULTS:
Nintedanib was administered in 10 patients, whereas the other 10 were treated without nintedanib or watched, according to ILD severity and progression. Baseline values of CMR parametric mapping were not different between the two groups. The rate of change at six months in myocardial extracellular volume was largely different, almost divergent between the nintedanib group and the control group (-1.62% vs. +2.00%, p= 0.0001). Among other endpoints, the change in right ventricular ejection fraction was significantly different between the two groups (p= 0.02), with a preferential change in the nintedanib group.
CONCLUSION:
Our data indicate beneficial signals of nintedanib on cardiomyopathy associated with SSc. The anti-fibrotic effect of nintedanib might not be limited to the lung.
© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Intrapericardial cardiosphere-derived cells hinder epicardial dense scar expansion and promote electrical homogeneity in a porcine post-infarction model.
Front Physiol2022 ;13():1041348. doi: 1041348.
Carta-Bergaz Alejandro, Ríos-Muñoz Gonzalo R, Crisóstomo Verónica, Sánchez-Margallo Francisco M, Ledesma-Carbayo María J, Bermejo-Thomas Javier, Fernández-Avilés Francisco, Arenal-Maíz Ángel,
Abstract
The arrhythmic substrate of ventricular tachycardias in many structural heart diseases is located in the epicardium, often resulting in poor outcomes with currently available therapies. Cardiosphere-derived cells (CDCs) have been shown to modify myocardial scarring. A total of 19 Large White pigs were infarcted by occlusion of the mid-left anterior descending coronary artery for 150 min. Baseline cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement sequences was obtained 4 weeks post-infarction and pigs were randomized to a treatment group (intrapericardial administration of 300,000 allogeneic CDCs/kg), ( = 10) and to a control group ( = 9). A second CMR and high-density endocardial electroanatomical mapping were performed at 16 weeks post-infarction. After the electrophysiological study, pigs were sacrificed and epicardial optical mapping and histological studies of the heterogeneous tissue of the endocardial and epicardial scars were performed. In comparison with control conditions, intrapericardial CDCs reduced the growth of epicardial dense scar and epicardial electrical heterogeneity. The relative differences in conduction velocity and action potential duration between healthy myocardium and heterogeneous tissue were significantly smaller in the CDC-treated group than in the control group. The lower electrical heterogeneity coincides with heterogeneous tissue with less fibrosis, better cardiomyocyte viability, and a greater quantity and better polarity of connexin 43. At the endocardial level, no differences were detected between groups. Intrapericardial CDCs produce anatomical and functional changes in the epicardial arrhythmic substrate, which could have an anti-arrhythmic effect.
Copyright © 2022 Carta-Bergaz, Ríos-Muñoz, Crisóstomo, Sánchez-Margallo, Ledesma-Carbayo, Bermejo-Thomas, Fernández-Avilés and Arenal-Maíz.
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Residual Lung Abnormalities Following COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID Study.
Am J Respir Crit Care Med2022 Dec;():. doi: 10.1164/rccm.202203-0564OC.
Stewart Iain, Jacob Joseph, George Peter M, Molyneaux Philip L, Porter Joanna C, Allen Richard J, Aslani Shahab, Baillie J Kenneth, Barratt Shaney L, Beirne Paul, Bianchi Stephen M, Blaikley John F, Chalmers James D, Chambers Rachel C, Chaudhuri Nazia, Coleman Christopher, Collier Guilhem, Denneny Emma K, Docherty Annemarie, Elneima Omer, Evans Rachel A, Fabbri Laura, Gibbons Michael A, Gleeson Fergus V, Gooptu Bibek, Greening Neil J, Guillen Guio Beatriz, Hall Ian P, Hanley Neil A, Harris Victoria, Harrison Ewen M, Heightman Melissa, Hillman Toby E, Horsley Alex, Houchen-Wolloff Linzy, Jarrold Ian, Johnson Simon R, Jones Mark G, Khan Fasihul, Lawson Rod, Leavy Olivia, Lone Nazir, Marks Michael, McAuley Hamish, Mehta Puja, Parekh Dhruv, Piper Hanley Karen, Platé Manuela, Pearl John, Poinasamy Krisnah, Quint Jennifer K, Raman Betty, Richardson Matthew, Rivera-Ortega Pilar, Saunders Laura, Saunders Ruth, Semple Malcolm G, Sereno Marco, Shikotra Aarti, Simpson A John, Singapuri Amisha, Smith David Jf, Spears Mark, Spencer Lisa G, Stanel Stefan, Thickett David, Thompson A A Roger, Thorpe Mathew, Walsh Simon Lf, Walker Samantha, Weatherley Nicholas David, Weeks Mark, Wild Jim M, Wootton Dan G, Brightling Chris E, Ho Ling-Pei, Wain Louise V, Jenkins R Gisli,
Abstract
RATIONALE:
Shared symptoms and genetic architecture between COVID-19 and lung fibrosis suggests SARS-CoV-2 infection may lead to progressive lung damage.
OBJECTIVES:
The UKILD Post-COVID study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 based on risk strata.
METHODS:
The Post-HOSPitalisation COVID Study (PHOSP-COVID) was used for capture of routine and research follow-up within 240 days from discharge. Thoracic CTs linked by PHOSP-COVID identifiers were scored for percentage of residual lung abnormalities (ground glass opacities and reticulations). Risk factors in linked CT were estimated with Bayesian binomial regression and risk strata were generated. Numbers within strata were used to estimate post-hospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol driven research follow-up.
MEASUREMENTS AND MAIN RESULTS:
The interim cohort comprised 3700 people. Of 209 subjects with linked CTs (median 119 days, interquartile range 83-155), 166 people (79.4%) had >10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (RR 1·21 95%CrI 1·05; 1·40), percent predicted DLco
CONCLUSIONS:
Residual lung abnormalities were estimated in up to 11% of people discharged following COVID-19 related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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Methamphetamine-associated heart failure: a systematic review of observational studies.
Heart2022 Dec;():. doi: heartjnl-2022-321610.
Manja Veena, Nrusimha Ananya, Gao Ya, Sheikh Aleesha, McGovern Mark, Heidenreich Paul A, Sandhu Alex Tarlochan Singh, Asch Steven,
Abstract
OBJECTIVE:
To conduct a systematic review of observational studies on methamphetamine-associated heart failure (MethHF) .
METHODS:
Six databases were searched for original publications on the topic. Title/abstract and included full-text publications were reviewed in duplicate. Data extraction and critical appraisal for risk of bias were performed in duplicate.
RESULTS:
Twenty-one studies are included in the final analysis. Results could not be combined because of heterogeneity in study design, population, comparator, and outcome assessment. Overall risk of bias is moderate due to the presence of confounders, selection bias and poor matching; overall certainty in the evidence is very low. MethHF is increasing in prevalence, affects diverse racial/ethnic/sociodemographic groups with a male predominance; up to 44% have preserved left-ventricular ejection fraction. MethHF is associated with significant morbidity including worse heart failure symptoms compared with non-methamphetamine related heart failure. Female sex, methamphetamine abstinence and guideline-directed heart failure therapy are associated with improved outcomes. Chamber dimensions on echocardiography and fibrosis on biopsy predict the extent of recovery after abstinence.
CONCLUSIONS:
The increasing prevalence of MethHF with associated morbidity underscores the urgent need for well designed prospective studies of people who use methamphetamine to accurately assess the epidemiology, clinical features, disease trajectory and outcomes of MethHF. Methamphetamine abstinence is an integral part of MethHF treatment; increased availability of effective non-pharmacological interventions for treatment of methamphetamine addiction is an essential first step. Availability of effective pharmacological treatment for methamphetamine addiction will further support MethHF treatment. Using harm reduction principles in an integrated addiction/HF treatment programme will bolster efforts to stem the increasing tide of MethHF.
© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
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