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Pubblicazioni recenti - cardiac fibrosis
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Is Pulmonary Hypertension a Rare Condition Associated to Angiostrongylosis in Naturally Infected Dogs?
Top Companion Anim Med2021 Jan;():100513. doi: S1938-9736(21)00006-4.
Paradies Paola, Sasanelli Mariateresa, Capogna Antonio, Mercadante Angelica, Rubino Giuseppe Tommaso Roberto, Bussadori Claudio Maria,
Abstract
Canine angiostrongylosis due to Angiostrongylus vasorum is one of the cardiopulmonary parasitic diseases in dogs and it can manifest with very different clinical pictures, which often make diagnosis very difficult. Based on the nature of the vascular and parenchymal lesions induced by the infection (thrombo-arteritis and fibrosis), it is not surprising that cases of pulmonary arterial hypertension (PAH) associated with angiostrongylosis have been reported in the literature, although it seems to represent a rare condition. The aim of the present work is to describe the clinical and instrumental aspects referred to cases of canine angiostrongylosis before and after treatment then to evaluate even mild conditions of PAH using echocardiography. PAH was not only conventionally investigated based on characteristic cardiac changes that occur secondary to PAH and by estimating pulmonary pressure from spectral Doppler tracings, but also by using a combination of further selected echocardiographic parameters (AT/ET, PA/Ao, Pulmonary flow profile pattern) able also to reveal PAH in the absence of tricuspid or pulmonary regurgitation. Clinical and instrumental aspects of 17 cases of angiostrongylosis, divided into respiratory cases (n?=?6), non-respiratory (n?=?5) and asymptomatic (n?=?6), are here described. Radiographic alterations were recorded in 90% of patients despite the reason for clinical presentation. A state of mild to severe PAH was diagnosed in 58.8% of cases. Although the return to a normal clinical condition was achieved 2 months after treatment in almost all patients, radiographic and echocardiographic alterations were persistent for longer. The cases presented reinforce the evidence on the complexity of the clinical picture of angiostrongylosis. PAH associated with canine angiostrongylosis could be a more common condition than previously reported in naturally infected dogs. In some cases, echocardiographic findings suggestive of PAH could be the starting point to address the clinical diagnosis toward angiostrongylosis. PAH may be responsible for worsening of the clinical picture of patients; thus, a careful evaluation is suggested before and after anthelmintic treatment in order to optimize the therapeutic management of each case.
Copyright © 2021. Published by Elsevier Inc.
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Presence of fragmented QRS is associated with left ventricular systolic dysfunction after surgery in patients with severe aortic regurgitation.
J Card Surg2021 Jan;():. doi: 10.1111/jocs.15370.
Celik Mehmet, Yilmaz Yusuf, Karagöz Ali, Kahyaoglu Muzaffer, Kup Ayhan, Celik Fatma Betul, Izci Servet, Candan Ozkan, Gecmen Cetin, Kirma Cevat, Kirali Mehmet Kaan,
Abstract
BACKGROUND AND AIM OF THE STUDY:
Chronic severe aortic regurgitation (AR) is associated with progressive accumulation of interstitial fibrosis and disruption of myocardial structure. After aortic valve replacement (AVR), the negative remodeling process reverses, and left ventricular ejection fraction (LVEF) improves but not in all patients. In this study, we aimed to investigate the association of fragmented QRS (F-QRS), which is a possible marker of myocardial fibrosis, with postoperative left ventricular (LV) systolic dysfunction.
METHODS:
A total of 147 consecutive patients with AVR were included in this study. F-QRS was identified by the presence of various RSR' patterns (QRS duration?<120?ms) such as additional R wave (R prime)or notching of the R or S wave in at least two consecutive leads. Patients were compared in two groups based on the presence or absence of F-QRS. A logistic regression model was used to determine independent predictors of postoperative LV systolic dysfunction (LVEF?<50%).
RESULTS:
Patients with F-QRS were associated with poor recovery of LV systolic function after AVR compared to the patients without F-QRS, regardless of preoperative LVEF (p?=?.008). F-QRS was found to be an independent predictor of postoperative LV systolic dysfunction (LVEF?<50%). Lower preoperative LVEF and increased LV end diastolic diameter index were also found as independent risk factors for postoperative LV systolic dysfunction.
CONCLUSIONS:
As a possible marker of myocardial fibrosis, F-QRS was associated with postoperative LV systolic dysfunction. Therefore, as a simple and convenient clinical parameter, F-QRS may be used to predict poor recovery of LVEF after AVR.
© 2021 Wiley Periodicals LLC.
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Possible value of galectin-3 on follow-up of cardiac remodeling during glucocorticoid treatment.
J Biochem Mol Toxicol2021 Jan;():e22717. doi: 10.1002/jbt.22717.
Akin Senay, Kubat Gokhan B, Guray Umit, Akin Yesim, Demirel Haydar A,
Abstract
Glucocorticoids are among the most prescribed drugs globally due to their potent anti-inflammatory and immunosuppressive properties. Although they have positive effects on the treatment of various disease states; long-term administration is associated with high blood pressure, insulin resistance, and susceptibility to type 2 diabetes. The heart attempts to cope with increased blood pressure and a decrease in glucose utilization by developing pathological cardiac remodeling. However, in this process, cardiac fibrosis formation and deterioration in heart structure and functions occur. Galectin-3, a member of the ?-galactoside binding lectins, is consistently associated with inflammation and fibrosis in the pathogenesis of various disease states including insulin resistance and heart failure. Galectin-3 expression is markedly increased in activated macrophages and a subset of activated fibroblasts and vascular cells. Also, failing and remodeling myocardium show increased Gal-3 expression and elevated Gal-3 levels are related to heart failure severity and prognosis. Furthermore, Gal-3-related pathways are recently suggested as therapeutic targets both pharmacologically and genetically to increase insulin sensitivity in vivo. The objective of this review is to provide a summary of our current understanding of the role of glucocorticoid-associated insulin resistance, which is important for some cardiac events, and the potential role of galectin in this pathophysiological process.
© 2021 Wiley Periodicals LLC.
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Multi-organ damage by covid-19: congestive (cardio-pulmonary) heart failure, and blood-heart barrier leakage.
Mol Cell Biochem2021 Jan;():. doi: 10.1007/s11010-021-04054-z.
Tyagi Suresh C, Singh Mahavir,
Abstract
Corona virus disease-19 (covid-19) is caused by a coronavirus that is also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and is generally characterized by fever, respiratory inflammation, and multi-organ failure in susceptible hosts. One of the first things during inflammation is the response by acute phase proteins coupled with coagulation. The angiotensinogen (a substrate for hypertension) is one such acute phase protein and goes on to explain an association of covid-19 with that of angiotensin-converting enzyme-2 (ACE2, a metallopeptidase). Therefore, it is advisable to administer, and test the efficacy of specific blocker(s) of angiotensinogen such as siRNAs or antibodies to covid-19 subjects. Covid-19 activates neutrophils, macrophages, but decreases T-helper cells activity. The metalloproteinases promote the activation of these inflammatory immune cells, therefore; we surmise that doxycycline (a metalloproteinase inhibitor, and a safer antibiotic) would benefit the covid-19 subjects. Along these lines, an anti-acid has also been suggested for mitigation of the covid-19 complications. Interestingly, there are three primary vegetables (celery, carrot, and long-squash) which are alkaline in their pH-range as compared to many others. Hence, treatment with fresh juice (without any preservative) from these vegies or the antioxidants derived from purple carrot and cabbage together with appropriate anti-coagulants may also help prevent or lessen the detrimental effects of the covid-19 pathological outcomes. These suggested remedies might be included in the list of putative interventions that are currently being investigated towards mitigating the multi-organ damage by Covid-19 during the ongoing pandemic.
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Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice.
Cardiovasc Res2021 Jan;():. doi: cvab019.
Mighiu Alexandra S, Recalde Alice, Ziberna Klemen, Carnicer Ricardo, Tomek Jakub, Bub Gil, Brewer Alison C, Verheule Sander, Shah Ajay M, Simon Jillian N, Casadei Barbara,
Abstract
AIMS:
Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility.
METHODS AND RESULTS:
NOX2-Tg mice showed a 2-2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (2-fold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P?=?0.004 and P?=?0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P?=?0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1?, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype.
CONCLUSIONS:
Together, these data indicate that whilst atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.
TRANSLATIONAL PERSPECTIVE:
Atrial NOX2-derived superoxide is an independent predictor of postoperative AF in humans and contributes to atrial oxidative stress early after AF induction. Whilst experimental models have reported an association of NOX2 with AF-induced remodelling, a causal link between NOX2 activity and AF remains to be established. Here we show that overexpression of the human NOX2 gene in mice resulted in a 2-fold higher atrial superoxide production and a modest increase in AF susceptibility, independent of atrial electrical or structural remodelling. Short-term treatment with atorvastatin normalized atrial superoxide in NOX2-Tg mice without affecting AF susceptibility. Together these findings indicate that atrial NOX2-derived superoxide is more likely a biomarker of AF risk than a primary driver of AF development, and that NOX2 inhibition is unlikely to prevent the new-onset of AF.
© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
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A new player in the game: treatment with antagomiR-21a-5p significantly attenuates histological and echocardiographic effects of experimental autoimmune myocarditis.
Cardiovasc Res2021 Jan;():. doi: cvab015.
Mirna Moritz, Paar Vera, Topf Albert, Kraus Theo, Sotlar Prof Karl, Aigner Prof Achim, Ewe Dr Rer Nat Alexander, Watzinger Simon, Podesser Prof Bruno K, Hackl Matthias, Pistulli Rudin, Hoppe Prof Uta C, Kiss Attila, Lichtenauer Assoc Prof Michael,
Abstract
AIMS:
Myocarditis is associated with formidable symptoms and increased risk of adverse outcomes. Current approaches mostly rely on symptomatic treatments, warranting novel concepts for clinical practice. The aim of this study was to investigate the microRNA (miRNA) expression profile of Balb/c mice with experimental autoimmune myocarditis (EAM), choose a representative miRNA to antagonize after review of available literature and test its effects on myocardial inflammation in vitro and in vivo.
METHODS AND RESULTS:
Methods: Phase 1: EAM was induced in 12 male Balb/c mice, 10 animals served as controls. After sacrifice, next-generation sequencing (NGS) of the microRNA expression profile was performed. Based on these results, H9C2 cells and human ventricular cardiac fibroblasts exposed to lipopolysaccharide (LPS) were treated with the selected candidate antagomiR-21a-5p. Phase 2: EAM was induced in 48 animals. Thereof, 24 animals were either treated with antagomiR-21a-5p or negative control oligonucleotide in a nanoparticle formulation. Transthoracic echocardiography (TTE) was performed on days 0,7,14 and 21. Histopathological examination was performed after sacrifice. Results: Phase 1: EAM resulted in a significant upregulation of 27 miRNAs, including miR-21a-5p (log2FC: 2.23, adj. p?=?0.0026). Transfection with antagomiR-21a-5p resulted in a significant reduction of TNF?, IL-6 and collagen I in vitro. Phase 2: Treatment with antagomiR-21a-5p, formulated in polymeric nanoparticles for systemic injection, significantly attenuated myocardial inflammation (p?=?0.001) and fibrosis (p?=?0.013), as well as myocardial "hypertrophy" on TTE.
CONCLUSIONS:
Silencing of miR-21a-5p results in a significant reduction of the expression of pro-inflammatory cytokines in vitro, as well as a significant attenuation of inflammation, fibrosis and echocardiographic effects of EAM in vivo.
TRANSLATIONAL PERSPECTIVE:
Based on the findings of our study, silencing of miR-21a-5p by synthetic antagomiR could constitute a novel therapeutic approach in myocarditis. Hence, research on this matter certainly warrants further scientific attention and investigation.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions please email: journals.permissions@oup.com.
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Endothelial Cell Metabolic Memory Causes Cardiovascular Dysfunction In Diabetes.
Cardiovasc Res2021 Jan;():. doi: cvab013.
Yao Yufeng, Song Qixue, Hu Changqing, Da Xingwen, Yu Yubing, He Zuhan, Xu Chengqi, Chen Qiuyun, Wang Qing K,
Abstract
AIMS:
The aim of this study was to identify the molecular mechanism for hyperglycemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes.
METHODS AND RESULTS:
Hyperglycemia induces increased nuclear factor-?B (NF-?B) signaling, upregulation of miR-27a-3p, downregulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-? (TGF-?) signaling, downregulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction. Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs. The observed metabolic memory effects in ECs are blocked by NRF2 activator tert-butylhydroquinone and a miR-27a-3p inhibitor. In vivo, the NRF2 activator and miR-27a-3p inhibitor block cardiac perivascular fibrosis and restore cardiovascular function by decreasing NF-?B signaling, downregulating miR-27a-3p, upregulating NRF2 expression, reducing TGF-? signaling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin (STZ)-induced diabetic mice, whereas insulin alone does not improve cardiac function.
CONCLUSIONS:
Our data indicate that disruption of hyperglycemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signaling pathway of NF-?B/miR-27a-3p/NRF2/ROS/TGF-?/EndMT involved in metabolic memory.
TRANSLATIONAL PERSPECTIVE:
Controversy exists on whether high blood glucose (hyperglycemia) induces metabolic memory that may cause long-lasting damaging cardiovascular complications in diabetic patients. Here, we demonstrate that hyperglycemia-induced metabolic memory in endothelial cells causes cardiac perivascular fibrosis and cardiac dysfunction in diabetes in mice, and identify NF-kB/miR-27a-3p/NRF2/ROS/TGF-?-EndMT as the signaling mechanism. We show that disruption of metabolic memory by a NRF2 activator or miR-27a-3p inhibitor is required to achieve therapeutic effect on cardiac dysfunction by insulin treatment of diabetes. Thus, inhibition of metabolic memory is a novel strategy to better prevent cardiovascular complications and improve the clinical outcome of diabetic patients.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions please email: journals.permissions@oup.com.
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Kcnk3 Dysfunction Exaggerates The Development Of Pulmonary Hypertension Induced By Left Ventricular Pressure Overload.
Cardiovasc Res2021 Jan;():. doi: cvab016.
Lambert Mélanie, Mendes-Ferreira Pedro, Ghigna Maria-Rosa, LeRibeuz Hélène, Adão Rui, Boet Angèle, Capuano Véronique, Rucker-Martin Catherine, Brás-Silva Carmen, Quarck Rozenn, Domergue Valérie, Vachiéry Jean-Luc, Humbert Marc, Perros Frédéric, Montani David, Antigny Fabrice,
Abstract
AIMS:
Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, group 2?PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, group 1?PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown.
METHODS AND RESULTS:
We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial (LA) emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in RV and LV. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular edema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, RV, LV, and LA of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular edema in AAC-Kcnk3-mutated rats.
CONCLUSIONS:
Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions please email: journals.permissions@oup.com.
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Obstructive sleep apnea during acute coronary syndrome is related to myocardial necrosis and wall stress.
Sleep Med2021 Jan;79():79-82. doi: S1389-9457(21)00007-1.
Cheong Crystal Sj, Aung Aye-Thandar, Wong Raymond Cc, Yeo Tee Joo, Chan Siew-Pang, Lee Chi-Hang,
Abstract
BACKGROUND:
The relative contribution of pathophysiological mechanisms in acute coronary syndrome (ACS) towards obstructive sleep apnea (OSA) is not well-studied. We examined the correlation between severity of OSA and inflammation, myocardial necrosis, wall stress, and fibrosis.
METHODS:
A total of 89 patients admitted with ACS underwent a sleep study during index admission. Plasma levels of high-sensitivity C-reactive protein (hs-CRP), troponin I, N-terminal pro-brain natriuretic peptide (NT-proBNP), and suppression of tumorigenicity 2 (ST2) were prospectively analyzed. Two patients diagnosed with central sleep apnea were excluded.
RESULTS:
The recruited patients were divided into no (AHI <5 events/hour, 9.2%), mild (5-<15, 27.6%), moderate (15-<30, 21.8%), and severe (?30, 41.4%) OSA. Compared to the no, mild and moderate OSA groups, the severe OSA group had a higher body mass index (p = 0.005). They were also more likely to present with ST-segment elevation ACS (versus non-ST-segment elevation ACS) (p = 0.041), have undergone previous coronary artery bypass grafting (p = 0.013), demonstrate complete coronary occlusion during baseline coronary angiography (p = 0.049), and have a larger left atrial diameter measured on echocardiography (p = 0.029). Likewise, the severe OSA group had higher plasma levels of hs-CRP (p = 0.004), troponin I (p = 0.017), and NT-proBNP (p = 0.004), but not ST2 (p = 0.10). After adjustment for the effects of confounding variables, OSA was independently associated with troponin I (ie, myocardial necrosis; p = 0.001) and NT-proBNP (ie, myocardial wall stress; p = 0.008).
CONCLUSION:
Severe OSA during the acute phase of ACS was associated with extensive myocardial necrosis and high myocardial wall stress, but not with inflammation and myocardial fibrosis.
Copyright © 2021 Elsevier B.V. All rights reserved.
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Value of 3D mapping guided endomyocardial biopsy in cardiac sarcoidosis.
Eur J Clin Invest2021 Jan;():e13497. doi: 10.1111/eci.13497.
Haanschoten D M, Adiyaman A, 't Hart N A, Jager P L, Elvan A,
Abstract
AIM:
Integration of endomyocardial biopsy (EMB) in the diagnostic work-up of cardiac sarcoidosis (CS) is under-recognized in current clinical practice, since capturing focal granulomas is challenging. Our aim was to describe our experience with electro-anatomic mapping (EAM) guided EMB and provide a comprehensive review of the literature.
METHODS AND RESULTS:
Five patients (age 49.4 ± 11.4) with suspected CS underwent EAM-guided EMB in Isala Heart Center (Zwolle, the Netherlands) between 2017-2019. In all patients a 3D bipolar voltage map (<0.5 mV-1.5mV) and unipolar voltage map (LV <8.3 mV, RV <5.5 mV) was created using a high-density mapping catheter. The bioptome was connected to the mapping system to guide targeted EMB. Biopsy samples (2-9 samples) were taken from both LV and RV sites, guided by EAM and areas with abnormal electrograms, without complications. CS diagnosis was based on EMB in 2/5 patients. A granuloma was captured in one patient at the LV basal septum with normal bipolar and abnormal unipolar voltage. All patients with delayed enhancement on cardiac magnetic resonance, revealed fibrosis in the biopsy sample. In one patient with suspected isolated cardiac sarcoidosis, diagnosis could not be confirmed by histopathology analysis, while unipolar voltage mapping was abnormal and diastolic potentials were present. Literature search revealed 7 reports (18 patients) describing EAM-guided EMB in CS patients, with 100% of the EMB taken form the RV.
CONCLUSION:
Unipolar voltage mapping may be superior to target active inflamed tissue and should be evaluated in future research regarding EAM guided EMB in CS.
This article is protected by copyright. All rights reserved.
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HFpEF without elevated right ventricular systolic pressure is a favorable prognostic indicator in patients with IPF requiring hospitalization for heart failure.
PLoS One2021 ;16(1):e0245778. doi: 10.1371/journal.pone.0245778.
Yamazaki Ryo, Nishiyama Osamu, Yoshikawa Kazuya, Saeki Sho, Sano Hiroyuki, Iwanaga Takashi, Tohda Yuji,
Abstract
BACKGROUND:
Some patients with idiopathic pulmonary fibrosis (IPF) must be hospitalized because of heart failure (HF), including HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF). The association between IPF and HF has not been clarified. We retrospectively investigated the clinical features and outcomes of patients with IPF who required nonelective hospitalization because of HF.
METHODS:
We examined data from IPF patients who required nonelective hospitalization for HF at the Kindai University Hospital from January 2008 to December 2018. We divided the patients into 3 groups: those with HFpEF without elevated right ventricular systolic pressure (RVSP), those with HFpEF and elevated RVSP, and those with HFrEF. The recurrence rates of HF after discharge and the 30- and 90-day mortality rates of the patients were evaluated.
RESULTS:
During the study period, 37 patients with IPF required hospitalization because of HF. Among the 34 patients included in the study, 17 (50.0%) were diagnosed with HFpEF without elevated RVSP, 11 (32.3%) with HFpEF and elevated RVSP, and 6 (17.6%) with HFrEF. Patients with HFrEF had significantly higher values for B-type natriuretic peptide (BNP) and left ventricular (LV) end-systolic and end-diastolic diameters than patients with the 2 types of HFpEF (BNP: P = 0.01 and P = 0.0004, LV end-systolic diameter: P <0.0001 and P <0.0001, and LV end-diastolic diameter: P = 0.01 and P = 0.0004, respectively). Notably, the difference between the LVEFs of the patients with 2 types of HFpEF was not significant. The patients with HFpEF without elevated RVSP had the lowest 30- and 90-day mortality rates (0%, P = 0.02 and 11.7%, P = 0.11, respectively).
CONCLUSIONS:
Among patients with IPF, HFpEF without elevated RVSP was the most common type of HF that required hospitalization. Patients with HFpEF without elevated RVSP survived longer than the patients with the other 2 types of HF.
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Incidence and risk factors for respiratory tract bacterial colonization and infection in lung transplant recipients.
Eur J Clin Microbiol Infect Dis2021 Jan;():. doi: 10.1007/s10096-021-04153-1.
Paglicci L, Borgo V, Lanzarone N, Fabbiani M, Cassol C, Cusi M G, Valassina M, Scolletta S, Bargagli E, Marchetti L, Paladini P, Luzzi L, Fossi A, Bennett D, Montagnani F,
Abstract
To evaluate incidence of and risk factors for respiratory bacterial colonization and infections within 30 days from lung transplantation (LT). We retrospectively analyzed microbiological and clinical data from 94 patients transplanted for indications other than cystic fibrosis, focusing on the occurrence of bacterial respiratory colonization or infection during 1 month of follow-up after LT. Thirty-three percent of patients developed lower respiratory bacterial colonization. Bilateral LT and chronic heart diseases were independently associated to a higher risk of overall bacterial colonization. Peptic diseases conferred a higher risk of multi-drug resistant (MDR) colonization, while longer duration of aerosol prophylaxis was associated with a lower risk. Overall, 35% of lung recipients developed bacterial pneumonia. COPD (when compared to idiopathic pulmonary fibrosis, IPF) and higher BMI were associated to a lower risk of bacterial infection. A higher risk of MDR infection was observed in IPF and in patients with pre-transplant colonization and infections. The risk of post-LT respiratory infections could be stratified by considering several factors (indication for LT, type of LT, presence of certain comorbidities, and microbiologic assessment before LT). A wider use of early nebulized therapies could be useful to prevent MDR colonization, thus potentially lowering infectious risk.
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Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension.
Sci Rep2021 Jan;11(1):2012. doi: 10.1038/s41598-021-81244-1.
Oh Seyeon, Jang Albert Y, Chae Sehyun, Choi Seungbum, Moon Jeongsik, Kim Minsu, Spiekerkoetter Edda, Zamanian Roham T, Yang Phillip C, Hwang Daehee, Byun Kyunghee, Chung Wook-Jin,
Abstract
Despite the advancement of targeted therapy for pulmonary arterial hypertension (PAH), poor prognosis remains a reality. Mesenchymal stem cells (MSCs) are one of the most clinically feasible alternative treatment options. We compared the treatment effects of adipose tissue (AD)-, bone marrow (BD)-, and umbilical cord blood (UCB)-derived MSCs in the rat monocrotaline-induced pulmonary hypertension (PH) model. The greatest improvement in the right ventricular function was observed in the UCB-MSCs treated group. The UCB-MSCs treated group also exhibited the greatest improvement in terms of the largest decrease in the medial wall thickness, perivascular fibrosis, and vascular cell proliferation, as well as the lowest levels of recruitment of innate and adaptive immune cells and associated inflammatory cytokines. Gene expression profiling of lung tissue confirmed that the UCB-MSCs treated group had the most notably attenuated immune and inflammatory profiles. Network analysis further revealed that the UCB-MSCs group had the greatest therapeutic effect in terms of the normalization of all three classical PAH pathways. The intravenous injection of the UCB-MSCs, compared with those of other MSCs, showed superior therapeutic effects in the PH model for the (1) right ventricular function, (2) vascular remodeling, (3) immune/inflammatory profiles, and (4) classical PAH pathways.
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Lung transplantation for sarcoidosis: outcome and prognostic factors.
Eur Respir J2021 Jan;():. doi: 2003358.
Le Pavec Jérôme, Valeyre Dominique, Gazengel Pierre, Holm Are M, Schultz Hans Henrik, Perch Michael, Le Borgne Aurélie, Reynaud-Gaubert Martine, Knoop Christiane, Godinas Laurent, Hirschi Sandrine, Bunel Vincent, Laporta Rosalia, Harari Sergio, Blanchard Elodie, Magnusson Jesper M, Tissot Adrien, Mornex Jean-François, Picard Clément, Savale Laurent, Bernaudin Jean-François, Brillet Pierre-Yves, Nunes Hilario, Humbert Marc, Fadel Elie, Gottlieb Jens,
Abstract
STUDY QUESTION:
In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant, and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation.
PATIENTS AND METHODS:
We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres.
RESULTS:
Patient survival was the main outcome measure. At transplantation, median age was 52 [46-59] years; 71 (64%) were male. Lung phenotypes were individualised as follows (i) extended fibrosis only; (ii) airflow obstruction; (iii) severe pulmonary hypertension (sPH) and airflow obstruction; (iv) sPH, airflow obstruction, and fibrosis, (v) sPH and fibrosis, (vi) airflow obstruction and fibrosis, (vii) sPH and (viii) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Posttransplant survival rates after 1, 3, and 5?years were 86%, 76%, and 69%, respectively. During follow-up (median, 46 [16-89] months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications.
ANSWER TO THE STUDY QUESTION:
Posttransplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive preoperative lung fibrosis.
©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.
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The not so innocent bystander: an unusual cause of progressive breathlessness.
Thorax2021 Jan;():. doi: thoraxjnl-2020-216290.
Lyon Max, Whiteway Alastair, Darby Michael, Bhatt Nidhi, Barratt Shaney L,
Abstract
This case report discusses a 76-year-old man who presented with symptomatic diffuse alveolar-septal and tracheobronchial amyloidosis with a low-grade monoclonal gammopathy. This patient had a combination of both symptomatic diffuse alveolar-septal interstitial disease and tracheobronchial amyloidosis, features that contradict the widely accepted presentations seen in this disease. First, tracheobronchial amyloidosis has been documented as localised disease without systemic involvement. Second, diffuse alveolar-septal interstitial disease is rarely identified with clinical symptoms unless there is significant cardiac involvement. This case highlights a number learning points in the diagnosis and management of systemic amyloid light chain amyloidosis;(1) There is a need for a high index of suspicion for diagnosis due to the potential subtlety of a plasma cell clone underlying AL amyloidosis, requiring serum-free light chain assays to increase sensitivity; (2) Haematological response and recovery of organ dysfunction are not a linear relationship due to the slower reversal of amyloid deposition; therefore, ongoing monitoring is required to identify those in need of repeated therapy. However, haematological response is a marker of overall survival and (3) Multisystem assessment and multidisciplinary collaboration are critical in optimising the care of patients with systemic AL amyloidosis.
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
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MR Elastography of the Abdomen: Basic Concepts.
Methods Mol Biol2021 ;2216():301-323. doi: 10.1007/978-1-0716-0978-1_18.
Serai Suraj D, Yin Meng,
Abstract
Magnetic resonance elastography (MRE) is an emerging imaging modality that maps the elastic properties of tissue such as the shear modulus. It allows for noninvasive assessment of stiffness, which is a surrogate for fibrosis. MRE has been shown to accurately distinguish absent or low stage fibrosis from high stage fibrosis, primarily in the liver. Like other elasticity imaging modalities, it follows the general steps of elastography: (1) apply a known cyclic mechanical vibration to the tissue; (2) measure the internal tissue displacements caused by the mechanical wave using magnetic resonance phase encoding method; and (3) infer the mechanical properties from the measured mechanical response (displacement), by generating a simplified displacement map. The generated map is called an elastogram.While the key interest of MRE has traditionally been in its application to liver, where in humans it is FDA approved and commercially available for clinical use to noninvasively assess degree of fibrosis, this is an area of active research and there are novel upcoming applications in brain, kidney, pancreas, spleen, heart, lungs, and so on. A detailed review of all the efforts is beyond the scope of this chapter, but a few specific examples are provided. Recent application of MRE for noninvasive evaluation of renal fibrosis has great potential for noninvasive assessment in patients with chronic kidney diseases. Development and applications of MRE in preclinical models is necessary primarily to validate the measurement against "gold-standard" invasive methods, to better understand physiology and pathophysiology, and to evaluate novel interventions. Application of MRE acquisitions in preclinical settings involves challenges in terms of available hardware, logistics, and data acquisition. This chapter will introduce the concepts of MRE and provide some illustrative applications.This publication is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by another separate chapter describing the experimental protocol and data analysis.
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Targeting 5-HT Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling after Myocardial Infarction.
Circulation2021 Jan;():. doi: 10.1161/CIRCULATIONAHA.120.051517.
Snider J Caleb, Riley Lance A, Mallory Noah T, Bersi Matthew R, Umbarkar Prachi, Gautam Rekha, Zhang Qinkun, Mahadevan-Jansen Anita, Hatzopoulos Antonis K, Maroteaux Luc, Lal Hind, Merryman W David,
Abstract
Myocardial infarction (MI) induces an intense injury response which ultimately generates a collagen-dominated scar. While required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process post-MI. Serotonin 2B receptor (5-HT) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI. We employed two pharmacologic antagonists to explore the effect of 5-HT inhibition on outcomes post-MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible, 5-HT ablation driven by and were used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT, respectively. RNA sequencing was used to motivate subsequent analyses to explore cardiac fibroblast phenotype. 5-HT antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT antagonism resulted in collagen fiber redistribution to thinner collagen fibers which were more anisotropic, enhancing left ventricular contractility, while fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT from -lineage resident cardiac fibroblasts and saw similar improvements to the pharmacologic approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT after onset of injury in -lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in expression and Src phosphorylation. Together, our findings illustrate that 5-HT expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI.
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Comparison of Ga-FAPI imaging and cardiac magnetic resonance in detection of myocardial fibrosis in a patient with chronic thromboembolic pulmonary hypertension.
J Nucl Cardiol2021 Jan;():. doi: 10.1007/s12350-020-02517-2.
Xing Hai-Qun, Gong Juan-Ni, Chen Bi-Xi, Guo Xiao-Juan, Yang Yuan-Hua, Huo Li, Yang Min-Fu,
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Long noncoding RNA regulates cardiac fibrosis.
Mol Ther Nucleic Acids2021 Mar;23():377-392. doi: 10.1016/j.omtn.2020.11.013.
Zhang Feng, Fu Xuyang, Kataoka Masaharu, Liu Ning, Wang Yingchao, Gao Feng, Liang Tian, Dong Xiaoxuan, Pei Jianqiu, Hu Xiaoyun, Zhu Wei, Yu Hong, Cowan Douglas B, Hu Xinyang, Huang Zhan-Peng, Wang Jian'an, Wang Da-Zhi, Chen Jinghai,
Abstract
Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (), which is significantly elevated after MI. Silencing expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the interacting proteins. Mechanistically, competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-? receptor-associated protein 1), which enhances TGF-? signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress. could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.
© 2020 The Author(s).
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Identification of Celastrol As a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A).
Arterioscler Thromb Vasc Biol2021 Jan;():ATVBAHA120315731. doi: 10.1161/ATVBAHA.120.315731.
Kurosawa Ryo, Satoh Kimio, Nakata Takashi, Shindo Tomohiko, Kikuchi Nobuhiro, Satoh Taijyu, Siddique Mohammad A H, Omura Junichi, Sunamura Shinichiro, Nogi Masamichi, Takeuchi Yutaro, Miyata Satoshi, Shimokawa Hiroaki,
Abstract
OBJECTIVE:
Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs.
CONCLUSIONS:
These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA.
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