DONA ORA
Pubblicazioni recenti - cardiac fibrosis
-
A tangled tale of microRNA and cardiac fibrosis.
Clin Sci (Lond)2019 Nov;133(21):2217-2220. doi: 10.1042/CS20190866.
Chandy Mark,
Abstract
Cardiac fibrosis is important for wound healing, regeneration and producing the extracellular matrix (ECM) that provides the scaffold for cells. In pathological situations, fibroblasts are activated and remodel the ECM. In volume 133, issue 17 of Clinical Science, Yang et al. discovered that the miR-214-3p/NLRC5 axis is important for fibroblast-to-myofibroblast transition (FMT) and ECM remodelling in a pressure overload model of fibrosis [Clin. Sci. (2019) 133(17), 1845-1856]. This discovery helps to explain the complicated regulation of cardiac fibrosis. It also underscores the need for more investigation into the mechanisms of cardiac fibrosis to develop better diagnostic modalities and therapeutic options in heart failure.
© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
Guarda su PubMed
-
Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis.
Clin Drug Investig2019 Nov;():. doi: 10.1007/s40261-019-00861-x.
Gomez Carla Cristina Souza, Parazzi Paloma Lopes Francisco, Clinckspoor Karl Jan, Mauch Renan Marrichi, Pessine Francisco Benedito Teixeira, Levy Carlos Emilio, Peixoto Andressa Oliveira, Ribeiro Maria Ângela Gonçalves Oliveira, Ribeiro Antônio Fernando, Conrad Douglas, Quinton Paul Marquis, Marson Fernando Augusto Lima, Ribeiro José Dirceu,
Abstract
BACKGROUND:
Among the many consequences of loss of CFTR protein function, a significant reduction of the secretion of bicarbonate (HCO) in cystic fibrosis (CF) is a major pathogenic feature. Loss of HCO leads to abnormally low pH and impaired mucus clearance in airways and other exocrine organs, which suggests that NaHCO inhalation may be a low-cost, easily accessible therapy for CF.
OBJECTIVE:
To evaluate the safety, tolerability, and effects of inhaled aerosols of NaHCO solutions (4.2% and 8.4%).
METHODS:
An experimental, prospective, open-label, pilot, clinical study was conducted with 12 CF volunteer participants over 18 years of age with bronchiectasis and pulmonary functions classified as mildly to severely depressed. Sputum rheology, pH, and microbiology were examined as well as spirometry, exercise performance, quality-of-life assessments, dyspnea, blood count, and venous blood gas levels.
RESULTS:
Sputum pH increased immediately after inhalation of NaHCO at each clinical visit and was inversely correlated with rheology when all parameters were evaluated: [G' (elasticity of the mucus)?=?- 0.241; G? (viscosity of the mucus)?=?- 0.287; G* (viscoelasticity of the mucus)?=?- 0.275]. G* and G' were slightly correlated with peak flow, forced expiratory volume in 1 s (FEV), and quality of life; G? was correlated with quality of life; sputum pH was correlated with oxygen consumption (VO) and vitality score in quality of life. No changes were observed in blood count, venous blood gas, respiratory rate, heart rate, peripheral oxygen saturation of hemoglobin (SpO), body temperature, or incidence of dyspnea. No adverse events associated with the study were observed.
CONCLUSION:
Nebulized NaHCO inhalation appears to be a safe and well tolerated potential therapeutic agent in the management of CF. Nebulized NaHCO inhalation temporarily elevates airway liquid pH and reduces sputum viscosity and viscoelasticity.
Guarda su PubMed
-
Transforming growth factor-? promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke.
Geroscience2019 Nov;():. doi: 10.1007/s11357-019-00118-7.
Howe Matthew D, Furr J Weldon, Munshi Yashasvee, Roy-O'Reilly Meaghan A, Maniskas Michael E, Koellhoffer Edward C, d'Aigle John, Sansing Lauren H, McCullough Louise D, Urayama Akihiko,
Abstract
Aging and stroke alter the composition of the basement membrane and reduce the perivascular distribution of cerebrospinal fluid and solutes, which may contribute to poor functional recovery in elderly patients. Following stroke, TGF-? induces astrocyte activation and subsequent glial scar development. This is dysregulated with aging and could lead to chronic, detrimental changes within the basement membrane. We hypothesized that TGF-? induces basement membrane fibrosis after stroke, leading to impaired perivascular CSF distribution and poor functional recovery in aged animals. We found that CSF entered the aged brain along perivascular tracts; this process was reduced by experimental stroke and was rescued by TGF-? receptor inhibition. Brain fibronectin levels increased with experimental stroke, which was reversed with inhibitor treatment. Exogenous TGF-? stimulation increased fibronectin expression, both in vivo and in primary cultured astrocytes. Oxygen-glucose deprivation of cultured astrocytes induced multiple changes in genes related to astrocyte activation and extracellular matrix production. Finally, in stroke patients, we found that serum TGF-? levels correlated with poorer functional outcomes, suggesting that serum levels may act as a biomarker for functional recovery. These results support a potential new treatment strategy to enhance recovery in elderly stroke patients.
Guarda su PubMed
-
[Atrial fibrillation : Recent studies and new treatment options].
Herzschrittmacherther Elektrophysiol2019 Nov;():. doi: 10.1007/s00399-019-00657-8.
Bergau Leonard, Sohns Christian, Sommer Philipp,
Abstract
Catheter ablation by pulmonary vein isolation (PVI) is established in patients suffering from drug-refractory symptomatic atrial fibrillation (AF). According to recent guidelines, it can also be offered to AF patients as a first-line treatment. The CASTLE-AF study randomized AF patients with severely impaired left ventricular (LV) function to catheter ablation or drug therapy. The patients in the ablation group experienced a significantly lower all-cause mortality and hospitalization rate compared to the conservatively managed group. This result is supported by the CAMERA-MRI trial. The benefit of AF ablation in heart failure was not reproducible in the large randomized CABANA trial. Due to a high cross-over rate, the results are vigorously being discussed and the consequences for clinical practice remain unclear. The DECAAF study described a positive correlation with left atrial fibrosis and the risk for recurrence following PVI. Whether those fibrotic areas should be targeted during the first ablation attempt is now part of the ongoing DECAAF-II trial. Its results might affect the preprocedural planning phase and future ablation strategies. Finally, new ablation techniques are being investigated. In this context, high-power short-duration ablation (HPSD) is of growing interest. In the QDOT-FAST trial, the procedure and fluoroscopy times could be significantly reduce using HPSD catheter technology. However, future studies are still required to evaluate the long-term performance of this novel ablation approach.
Guarda su PubMed
-
Ventilator settings and outcome of respiratory failure in paraquat-induced pulmonary injury.
Sci Rep2019 Nov;9(1):16541. doi: 10.1038/s41598-019-52939-3.
Khazraei Seyedehparvin, Marashi Sayed Mahdi, Sanaei-Zadeh Hossein,
Abstract
Paraquat is a nonselective contact herbicide that has significant importance in clinical toxicology due to its high mortality rate. The cause of mortality in the acute phase of poisoning is a multi-organ failure while in the sub-acute phase is alveolar injury and lung fibrosis. The aim of this study was to evaluate the advantages and drawbacks of mechanical ventilation (MV) in paraquat-induced pulmonary injury and its consequential respiratory failure (PIPI-CRF). This retrospective descriptive analytical study was done to investigate the outcome of patients who had developed PIPI-CRF and underwent conventional treatments with invasive MV in three teaching hospitals in Shiraz, Iran, from March 2010 to February 2015. In total, 44 patients (mean age of 27.9?±?9.98 years) had undergone MV due to PIPI-CRF. None of the patients had a successful wean off from the ventilator. Although all the patients' were on aggressive life support and full efforts to resuscitate were carried out in case of cardiac arrest, all of them expired. We suggest that in the case of conventional treatment of paraquat poisoning, only noninvasive ventilation should be applied. However, considering the chance of patient's survival performing novel treatments, such as extracorporeal membrane oxygenation (ECMO), lung protective ventilation with optimal positive end-expiratory pressure (PEEP) could be applied only in such circumstances.
Guarda su PubMed
-
TGF-?- and lipopolysaccharide-induced upregulation of circular RNA PWWP2A promotes hepatic fibrosis via sponging miR-203 and miR-223.
Aging (Albany NY)2019 Nov;11():. doi: 10.18632/aging.102405.
Liu Wentao, Feng Ruo, Li Xingxing, Li Dingyang, Zhai Wenlong,
Abstract
Both transforming growth factor-beta (TGF-?) and lipopolysaccharide (LPS) can activate hepatic stellate cells (HSCs), thus increasing expressions of alpha smooth muscle actin (?-SMA) and type I collagen alpha 1 (Col1?1) and promoting liver fibrosis. However, whether TGF-? and LPS have a common downstream reactor remains unclear. Recently, a strong relationship of circular RNAs (circRNAs) and fibrogenesis has been elucidated. In this study, we compared the expressions of several circRNAs in TGF-?- and LPS-activated HSCs, and found that circ-PWWP2A was upregulated in both TGF-?- and LPS-activated HSCs and in mouse fibrotic liver tissues. Meanwhile, circ-PWWP2A was positively correlated with HSC activation and proliferation. Two microRNAs, miR-203 and miR-223, were identified to be the downstream targets of circ-PWWP2A using luciferase reporter assay and pull-down interaction assay. Circ-PWWP2A was suggested to promote HSC activation and proliferation via sponging miR-203 and miR-223, and subsequently increasing Fstl1 and TLR4, respectively. Furthermore, downregulating circ-PWWP2A was indicated to alleviate hepatic fibrosis in vivo. In conclusion, our findings indicated that circ-PWWP2A is the common downstream reactor of TGF-? and LPS in HSC activation, and that circ-PWWP2A plays a critical role in hepatic fibrogenesis via sponging miR-203 and miR-223.
Guarda su PubMed
-
The matrikine acetyl-proline-glycine-proline and clinical features of COPD: findings from SPIROMICS.
Respir Res2019 Nov;20(1):254. doi: 10.1186/s12931-019-1230-8.
Wells J Michael, Xing Dongqi, Viera Liliana, Burkes Robert M, Wu Yixin, Bhatt Surya P, Dransfield Mark T, Couper David J, O'Neal Wanda, Hoffman Eric A, Gaggar Amit, Barjaktarevic Igor, Curtis Jeffrey L, Labaki Wassim W, Han Mei Lan K, Freeman Christine M, Putcha Nirupama, Schlange Thomas, Blalock J Edwin, ,
Abstract
BACKGROUND:
Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD.
METHODS:
Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation.
RESULTS:
The 182 COPD participants in the analysis were 66?±?8?years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61?±?1.89?ng/mL (mean?±?SD) in sputum and 0.60?±?1.13?ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk.
CONCLUSIONS:
In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up.
TRIAL REGISTRATION:
ClinicalTrials.gov: NCT01969344 (SPIROMICS).
Guarda su PubMed
-
Cardiomyocyte-Specific Prevents Inflammation in the Heart.
J Am Heart Assoc2019 Nov;8(22):e012792. doi: 10.1161/JAHA.119.012792.
Thirugnanam Karthikeyan, Cossette Stephanie M, Lu Qiulun, Chowdhury Shreya R, Harmann Leanne M, Gupta Ankan, Spearman Andrew D, Sonin Dmitry L, Bordas Michelle, Kumar Suresh N, Pan Amy Y, Simpson Pippa M, Strande Jennifer L, Bishop Erin, Zou Ming-Hui, Ramchandran Ramani,
Abstract
Background The SNRK (sucrose-nonfermenting-related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed in cardiac conditional knockout mouse is unknown. Methods and Results Previously, 6-month adult mice knocked out for in cardiomyocytes (CMs) displayed left ventricular dysfunction. Here, 4-month adult mice, on angiotensin II (Ang II) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor ? light chain enhancer of activated B cells (NF-?B), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang II infusion, mice knocked out for in endothelial cells did not show significant systolic or diastolic dysfunction. Although an NF-?B inflammation signaling pathway was increased in knockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out for in CMs, we also observed NF-?B pathway activation in CMs, and an increased presence of Mac2 macrophages was observed in basal and Ang II-infused states. In vitro analysis of knockdown HL-1 CMs revealed similar upregulation of the NF-?B signaling proteins and proinflammatory proteins that was exacerbated on Ang II treatment. The Ang II-induced NF-?B pathway-mediated proinflammatory effects were mediated in part through protein kinase B or AKT, wherein AKT inhibition restored the proinflammatory signaling protein levels to baseline in knockdown HL-1 CMs. Conclusions During heart failure, SNRK acts as a cardiomyocyte-specific repressor of cardiac inflammation and fibrosis.
Guarda su PubMed
-
Improved Biomarker and Imaging Analysis for Characterizing Progressive Cardiac Fibrosis in a Mouse Model of Chronic Chagasic Cardiomyopathy.
J Am Heart Assoc2019 Nov;8(22):e013365. doi: 10.1161/JAHA.119.013365.
Hoffman Kristyn A, Reynolds Corey, Bottazzi Maria Elena, Hotez Peter, Jones Kathryn,
Abstract
Background Chronic chagasic cardiomyopathy (CCC), caused by infection, is an important public health problem attributable to progressive cardiomyopathy in patients, for which there is no cure. Chronic chagasic cardiomyopathy is characterized by myocarditis and cardiac fibrosis, which leads to life-threatening arrhythmogenic and circulatory abnormalities. This study aimed to investigate cardiac fibrosis progression in a mouse model of chronic chagasic cardiomyopathy. Methods and Results Cardiac cells infected with produced significantly higher concentrations of transforming growth factor-? (TGF-?), connective tissue growth factor, endothelin-1, and platelet-derived growth factor-D than noninfected controls. Female Balb/c mice infected with were compared with naïve mice. TGF-? genes and other TGF-? superfamily genes, as well as connective tissue growth factor, endothelin-1, and platelet-derived growth factor, were upregulated in infected mouse hearts. Serum concentrations of TGF-?, connective tissue growth factor, and platelet-derived growth factor-D were higher in infected mice and correlated with cardiac fibrosis. Strain analysis performed on magnetic resonance images at 111 and 140 days postinfection and echocardiography images at 212 days postinfection revealed significantly elevated left ventricular strain and cardiac fibrosis and concomitantly significantly decreased cardiac output in infected mice. Conclusions TGF-?, connective tissue growth factor and platelet-derived growth factor-D are potentially useful biomarkers of cardiac fibrosis, as they correlate with cardiac fibrosis. Strain analysis allows for use of noninvasive methods to measure fibrosis in the chronic stages of chagasic cardiomyopathy in a mouse model. These findings can be applied as noninvasive tools to study the effects of interventions and/or therapeutics on cardiac fibrosis development when using a mouse model of chronic chagasic cardiomyopathy.
Guarda su PubMed
-
Early Treatment of Coxsackievirus B3-Infected Animals With Soluble Coxsackievirus-Adenovirus Receptor Inhibits Development of Chronic Coxsackievirus B3 Cardiomyopathy.
Circ Heart Fail2019 Nov;12(11):e005250. doi: 10.1161/CIRCHEARTFAILURE.119.005250.
Pinkert Sandra, Dieringer Babette, Klopfleisch Robert, Savvatis Konstantinos, Van Linthout Sophie, Pryshliak Markian, Tschöpe Carsten, Klingel Karin, Kurreck Jens, Beling Antje, Fechner Henry,
Abstract
BACKGROUND:
Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model.
METHODS:
NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3 infection. Chronic myocarditis was analyzed on day 28 after infection.
RESULTS:
Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm?Hg, =0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, =0.02; dP/dt, 7275.2±1674 versus 4432.6±1107 mm?Hg/s, =0.004; dP/dt, -4046.9±776 versus -3146.3±642 mm?Hg/s, =0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury.
CONCLUSIONS:
Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.
Guarda su PubMed
-
A Role for the Biological Clock in Liver Cancer.
Cancers (Basel)2019 Nov;11(11):. doi: E1778.
Mazzoccoli Gianluigi, Miele Luca, Marrone Giuseppe, Mazza Tommaso, Vinciguerra Manlio, Grieco Antonio,
Abstract
The biological clock controls at the molecular level several aspects of mammalian physiology, by regulating daily oscillations of crucial biological processes such as nutrient metabolism in the liver. Disruption of the circadian clock circuitry has recently been identified as an independent risk factor for cancer and classified as a potential group 2A carcinogen to humans. Hepatocellular carcinoma (HCC) is the prevailing histological type of primary liver cancer, one of the most important causes of cancer-related death worldwide. HCC onset and progression is related to B and C viral hepatitis, alcoholic and especially non-alcoholic fatty liver disease (NAFLD)-related milieu of fibrosis, cirrhosis, and chronic inflammation. In this review, we recapitulate the state-of-the-art knowledge on the interplay between the biological clock and the oncogenic pathways and mechanisms involved in hepatocarcinogenesis. Finally, we propose how a deeper understanding of circadian clock circuitry-cancer pathways' crosstalk is promising for developing new strategies for HCC prevention and management.
Guarda su PubMed
-
The Role of the Lung's Microbiome in the Pathogenesis and Progression of Idiopathic Pulmonary Fibrosis.
Int J Mol Sci2019 Nov;20(22):. doi: E5618.
Spagnolo Paolo, Molyneaux Philip L, Bernardinello Nicol, Cocconcelli Elisabetta, Biondini Davide, Fracasso Federico, Tiné Mariaenrica, Saetta Marina, Maher Toby M, Balestro Elisabetta,
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease that commonly affects older adults and is associated with the histopathological and/or radiological patterns of usual interstitial pneumonia (UIP). Despite significant advances in our understanding of disease pathobiology and natural history, what causes IPF remains unknown. A potential role for infection in the disease's pathogenesis and progression or as a trigger of acute exacerbation has long been postulated, but initial studies based on traditional culture methods have yielded inconsistent results. The recent application to IPF of culture-independent techniques for microbiological analysis has revealed previously unappreciated alterations of the lung microbiome, as well as an increased bacterial burden in the bronchoalveolar lavage (BAL) of IPF patients, although correlation does not necessarily entail causation. In addition, the lung microbiome remains only partially characterized and further research should investigate organisms other than bacteria and viruses, including fungi. The clarification of the role of the microbiome in the pathogenesis and progression of IPF may potentially allow its manipulation, providing an opportunity for targeted therapeutic intervention.
Guarda su PubMed
-
Combinatorial inhibition of Angiotensin converting enyme, Neutral endopeptidase and Aminopeptidase N by N-methylated peptides alleviates blood pressure and fibrosis in rat model of dexamethasone-induced hypertension.
Peptides2019 Nov;():170180. doi: S0196-9781(19)30158-5.
Natarajan Savitha Mysuru, Nagaraj Suvilesh Kanve, Mariswamy Siddesha Jalahalli, Milan Gowda M D, Choudhury Manisha, Velmurugan Devadasan, Umashankar Muddegowda, Sannanaik Vishwanath Bannikuppe,
Abstract
Angiotensin converting enzyme (ACE), neutral endopeptidase (NEP) and aminopeptidase N (APN) are responsible for generation of vasoactive peptides that regulates vasoconstriction, vasodilation and natriuresis, which altogether regulate blood pressure. Cumulative inhibition of ACE, NEP and APN effectively blocks the progression of respective pathways. In this study, N-methylated peptide inhibitors F-N(Me)H-L, V-N(Me)F-R and R-N(Me)V-Y were synthesized against ACE, NEP and APN respectively, using their respective physiological substrates. F-N(Me)H-L inhibited ACE activity with an IC of 83?nmol/L, V-N(Me)F-R inhibited NEP activity with an IC of 1.173?µmol/L and R-N(Me)V-Y inhibited APN activity with an IC of 3.94?nmol/L respectively. Further, the anti-hypertensive effect of N-methylated peptides was evaluated using rat model of dexamethasone-induced hypertension. Individual peptides and their cocktail treatment were started from day 6 of the study period and blood pressure was measured on every alternate day during 15 day study. Administration of F-N(Me)H-L (138?±?3?mmHg) and cocktail of all the three peptides at a dose of 100?mg/kg significantly reduced systolic blood pressure (SBP) compared to dexamethasone group (SBP of Groups-dexamethasone; (167?±?5?mmHg), F-N(Me)H-L (138?±?3?mmHg), and Cocktail (122?±?3?mmHg). Anti-hypertensive, anti-hypertrophic and anti-fibrotic effects of N-methylated peptides and cocktail was further reflected by the decreased levels of circulating Ang II and increased ANP levels in sera of hypertensive rats along with decrease in collagen deposition in heart and kidney. Though, ACE inhibition is adequate to reduce SBP, targeting NEP and APN along with ACE is beneficial in tackling hypertension and associated fibrosis of heart.
Copyright © 2019. Published by Elsevier Inc.
Guarda su PubMed
-
Mucus, mucins, and cystic fibrosis.
Pediatr Pulmonol2019 Nov;54 Suppl 3():S84-S96. doi: 10.1002/ppul.24530.
Morrison Cameron Bradley, Markovetz Matthew Raymond, Ehre Camille,
Abstract
Cystic fibrosis (CF) is both the most common and most lethal genetic disease in the Caucasian population. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by the accumulation of thick, adherent mucus plaques in multiple organs, of which the lungs, gastrointestinal tract and pancreatic ducts are the most commonly affected. A similar pathogenesis cascade is observed in all of these organs: loss of CFTR function leads to altered ion transport, consisting of decreased chloride and bicarbonate secretion via the CFTR channel and increased sodium absorption via epithelial sodium channel upregulation. Mucosa exposed to changes in ionic concentrations sustain severe pathophysiological consequences. Altered mucus biophysical properties and weakened innate defense mechanisms ensue, furthering the progression of the disease. Mucins, the high-molecular-weight glycoproteins responsible for the viscoelastic properties of the mucus, play a key role in the disease but the actual mechanism of mucus accumulation is still undetermined. Multiple hypotheses regarding the impact of CFTR malfunction on mucus have been proposed and are reviewed here. (a) Dehydration increases mucin monomer entanglement, (b) defective Ca chelation compromises mucin expansion, (c) ionic changes alter mucin interactions, and (d) reactive oxygen species increase mucin crosslinking. Although one biochemical change may dominate, it is likely that all of these mechanisms play some role in the progression of CF disease. This article discusses recent findings on the initial cause(s) of aberrant mucus properties in CF and examines therapeutic approaches aimed at correcting mucus properties.
© 2019 Wiley Periodicals, Inc.
Guarda su PubMed
-
Highly effective treatment response and well tolerability by all oral direct acting antivirals for chronic hepatitis C patients post organ transplantation.
J Chin Med Assoc2019 Nov;():. doi: 10.1097/JCMA.0000000000000222.
Wu Sih-Hsien, Loong Che-Chuan, Chu Chi-Jen, Su Chien-Wei, Lin Chung-Chi, Hsia Cheng-Yuan, Liu Chinsu, Lee Shou-Dong, Wang Yuan-Jen, Lee Fa-Yauh, Lin Niang-Cheng, Chen Cheng-Yen, Huang Yi-Hsiang, Hou Ming-Chih,
Abstract
BACKGROUND:
Immunosuppressant-related acceleration of fibrosis has been documents in chronic hepatitis C (CHC) patients who receive organ transplantation (Tx), sustained virological response (SVR) rates for these patients by pegylated interferon (IFN)-based therapy are generally poor and associated with unfavorable safety profiles. In addition IFN treatment varies by patient and poses a high risk of post-renal Tx graft rejection. This study was aimed to investigate the efficacy and safety of all oral direct acting antivirals (DAAs) for CHC patients following organ Tx.
METHODS:
32 organ Tx (liver: 17, kidney: 13, kidney then liver: 1, heart: 1) patients with CHC on an oral DAA (paritaprevir/ritonavir, ombitasvir and dasabuvir: 11, daclatasvir and asunaprevir: 4, sofosbuvir-based: 17) were enrolled in the study. DAAs regimen was based by genotype/subtype, patient characteristics, drug interaction profiles, and health insurance coverage.
RESULTS:
Mean patient age was 61.4±9.5 years, 50.0%, male, and 15.6% with cirrhosis. 14 (43.7%) experienced unsuccessful IFN treatment. Genotype distribution was as follows: 1a: 6, 1b: 17, 2: 7, 3: 1 and 6: 1. Mean time between Tx and DAAs therapy was 77.3±11.0 months. Baseline HCV RNA before DAAs was 6.20±0.19 log10 IU/mL. After DAAs, the distribution of week 2 HCV RNA was as follows: < 15 IU/mL (53.1%), 15 to 50 IU/mL (15.6%), 50 to 100 IU/mL (6.3%), and > 100 IU/mL (25.0%), respectively. The rates of undetectable HCV RNA (< 15 IU/mL) at week 4 and end-of-treatment were 93.8% and 100%. Subjective adverse events during therapy were generally mild, which no treatment terminations. After post-treatment follow-up, all 32 patients (100%) achieved SVR12.
CONCLUSION:
Highly responsive treatment and favorable tolerability were achieved by all oral DAAs in this difficult-to-treat patient population.
Guarda su PubMed
-
Atrial fibrillation and cardiac fibrosis.
Eur Heart J2019 Nov;():. doi: ehz786.
Sohns Christian, Marrouche Nassir F,
Abstract
The understanding of atrial fibrillation (AF) evolved from a sole rhythm disturbance towards the complex concept of a cardiomyopathy based on arrhythmia substrates. There is evidence that atrial fibrosis can be visualized using late gadolinium enhancement cardiac magnetic resonance imaging and that it is a powerful predictor for the outcome of AF interventions. However, a strategy of an individual and fibrosis guided management of AF looks promising but results from prospective multicentre trials are pending. This review gives an overview about the relationship between cardiac fibrosis and AF focusing on translational aspects, clinical observations, and fibrosis imaging to emphasize the concept of personalized paths in AF management taking into account the individual amount and distribution of fibrosis.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
Guarda su PubMed
-
Structural and Functional Properties of the Left Atrium in Healthy Volunteers and Patients With Atrial Fibrillation: Data of Magnetic Resonance Imaging.
Kardiologiia2018 Nov;57(9):5-13. doi: 10.18087/cardio.2017.9.10029.
Aparina Olga P, Stukalova O V, Parkhomenko D V, Mironova N A, Strazdenj E Yu, Ternovoy S K ', Golitsyn S P,
Abstract
BACKGROUND:
In the recent years, there has been an increasing number of publications postulating that data on left atrial (LA) structure obtained by late gadolinium enhancement magnetic resonance imaging (LGE MRI) can improve the management of patients with atrial fibrillation (AF). At the same time, similar data regarding healthy LA myocardium is limited.
AIM:
To assess structural and functional properties of LA in healthy volunteers (HV) using cardiac magnetic resonance (CMR) (including LGE MRI); to compare these properties in patients with AF and HV.
MATERIALS AND METHODS:
We included in this study 53 patients with AF (28 without signs of cardiovascular disease, 28 with hypertension) and 23 HV of similar age. All enrolled persons underwent MRI. Cine-MRI was used to assess end diastolic volume of LA (LA EDV), LA ejection fraction (LA EF), left ventricular diastolic index (LV DI). High resolution LGE MRI was performed 15-20 min after gadoversetamide injection using IR 3D gradient echo pulse sequence with fat saturation (TI 290-340 ms, TE 2.44 ms, TR 610-1100ms). On obtained images LA was segmented semiautomatically. LA fibrosis quantification was performed using developed software LGE Heart Analyzer. The extent of fibrosis was represented as percent of LA myocardium volume. Fibrosis location was determined on reconstructed rotating 3D LA model.
RESULTS:
Compared with patients HV had lower LA EDV (59 [54; 78] ml and 79 [65.5; 86.6] ml, ?=0.043, respectively), higher LA EF (56.1 [49; 63.2] % and 44.5 [34.5, 54.5] %, ?=0.03, respectively), and lower extent of LA fibrosis (0.7 [0.05; 3.5] % and 9.1 [1.7; 18] %, ?.
Guarda su PubMed
-
Astragaloside-IV protects H9C2(2-1) cardiomyocytes from high glucose-induced injury via miR-34a-mediated autophagy pathway.
Artif Cells Nanomed Biotechnol2019 Dec;47(1):4172-4181. doi: 10.1080/21691401.2019.1687492.
Zhu Yaobin, Qian Xin, Li Jingjing, Lin Xing, Luo Jiewei, Huang Jianbin, Jin Zhao,
Abstract
Diabetic cardiomyopathy (DCM) is an important cardiac disorder in patients with diabetes. High glucose (HG) levels lead to inflammation of cardiomyocytes, oxidative stress, and long-term activation of autophagy, resulting in myocardial fibrosis and remodelling. Astragaloside-IV (AS-IV) has a wide range of pharmacological effects. This study aimed to investigate the effects of AS-IV on injury induced by HG in rat cardiomyocytes (H9C2(2-1)) and the involvement of the miR-34a-mediated autophagy pathway. An AS-IV concentration of 100??M was selected based on H9C2(2-1) cell viability using the cell counting kit-8 (CCK-8). We found that 33?mM HG induced a morphologic change in cells and caused excessive oxidative stress, whereas AS-IV inhibited lipid peroxidation and increased superoxide dismutase activity. In terms of mRNA expression, HG increased miR-34a and inhibited Bcl2 and Sirt1, whereas AS-IV and miR-34a-inhibitor reversed the above effects. Further, LC3-GFP adenovirus infection and western blotting showed that HG increased autophagy, which was reversed synergistically by AS-IV and miR-34a-inhibitor. Bcl2 and pAKT/AKT protein expressions in the HG group was significantly lower than that in controls, but AS-IV and miR-34a-inhibitor antagonized the process. Thus, AS-IV inhibits HG-induced oxidative stress and autophagy and protects cardiomyocytes from injury via the miR-34a/Bcl2/(LC3II/LC3I) and pAKT/Bcl2/(LC3II/LC3I) pathways.
Guarda su PubMed
-
BMP10 preserves cardiac function through its dual-activation of SMAD-mediated and STAT3-mediated pathways.
J Biol Chem2019 Nov;():. doi: jbc.RA119.010943.
Qu Xiuxia, Liu Ying, Cao Dayan, Chen Jinghai, Liu Zhuo, Ji Hongrui, Chen Yuwen, Zhnag Wenjun, Zhu Ping, Xiao Deyong, Li Xiaohui, Shou Weinian, Chen Hanying,
Abstract
Bone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor, belonging to the transforming growth factor beta (TGF?) superfamily, that critically controls cardiovascular development, growth, and maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 (ALK1) with morphogenetic protein receptor type II (BMPR2A) or activin receptor type-2A (ActR2A). Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the ?-myosin heavy chain gene promoter (?MHC-Bmp10), and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the ?-adrenoceptor agonist isoproterenol (ISO). We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 (rhBMP10) was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway both in vivo and in vitro. Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
Guarda su PubMed
-
Usefulness of Cardiac Magnetic Resonance for Recurrent Pericarditis.
Am J Cardiol2019 Oct;():. doi: S0002-9149(19)31094-X.
Imazio Massimo, Pivetta Emanuele, Palacio Restrepo Sara, Sormani Paola, Pedrotti Patrizia, Quarta Giovanni, Brucato Antonio, Bubbico Elisa, Dal Corso Maria, Milazzo Angela, Quattrocchi Giuseppina, Andriani Monica, Lobetti Bodoni Luisa, Davini Ottavio, Sironi Sandro, Giannattasio Cristina, Giustetto Carla, Bogaert Jan, Adler Yehuda, Bucciarelli Ducci Chiara, De Ferrari Gaetano Maria,
Abstract
Cardiac magnetic resonance (CMR) offers the capability to objectively detect pericarditis by identifying pericardial thickening, edema/inflammation by Short-TI Inversion Recovery-T2 weighted (STIR-T2w) imaging, edema/inflammation or fibrosis by late gadolinium enhancement (LGE), and presence of pericardial effusion. This is especially helpful for the diagnosis of recurrent pericarditis. Aim of the present paper is to assess the diagnostic accuracy of CMR findings as well as their potential prognostic value for the diagnosis of recurrent pericarditis. Multicenter cohort study of consecutive patients with recurrent pericarditis evaluated by CMR. We included 128 consecutive cases (60 males, 47%; mean age 48 ± 14 years). CMR was performed at a mean time of 12 days (95% confidence interval 15 to 21) after the clinical diagnosis. We evaluated the diagnostic accuracy and areas under the receiver operating characteristic (ROC) curve for CMR diagnostic criteria and complications (additional recurrences, cardiac tamponade, and constrictive pericarditis). Areas under the ROC curve were respectively 64% for pericardial thickening, 84% for pericardial edema, 82% for pericardial LGE, and 71% for pericardial effusion. After a mean follow-up of 34 months, recurrences occurred in 52% of patients, tamponade in 6%, and constrictive pericarditis in 11%. Using a multivariable Cox model, elevation of CRP and presence of CMR pericardial thickening were predictors of adverse events, whereas the presence of CMR LGE was associated with a lower risk. The prognostic model for adverse events using gender, age, CRP level, and all CMR variables showed a C-index of 0.84. In conclusion, CMR findings show high diagnostic accuracy and may help identifying patients at higher risk of complications.
Copyright © 2019 Elsevier Inc. All rights reserved.
Guarda su PubMed
