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Pubblicazioni recenti - cardiac fibrosis
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Myocardial Tissue Characterization and Fibrosis by Imaging.
JACC Cardiovasc Imaging2019 Sep;():. doi: S1936-878X(19)30711-9.
Karamitsos Theodoros D, Arvanitaki Alexandra, Karvounis Haralambos, Neubauer Stefan, Ferreira Vanessa M,
Abstract
Myocardial fibrosis, either focal or diffuse, is a common feature of many cardiac diseases and is associated with a poor prognosis for major adverse cardiovascular events. Although histological analysis remains the gold standard for confirming the presence of myocardial fibrosis, endomyocardial biopsy is invasive, has sampling errors, and is not practical in the routine clinical setting. Cardiac imaging modalities offer noninvasive surrogate biomarkers not only for fibrosis but also for myocardial edema and infiltration to varying degrees, and have important roles in the diagnosis and management of cardiac diseases. This review summarizes important pathophysiological features in the development of commonly encountered cardiac diseases, and the principles, advantages, and disadvantages of various cardiac imaging modalities (echocardiography, single-photon emission computer tomography, positron emission tomography, multidetector computer tomography, and cardiac magnetic resonance) for myocardial tissue characterization, with an emphasis on imaging focal and diffuse myocardial fibrosis.
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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The Interstitium in the Hypertrophied Heart.
JACC Cardiovasc Imaging2019 Sep;():. doi: S1936-878X(19)30714-4.
Halliday Brian P, Prasad Sanjay K,
Abstract
Pathological left ventricular hypertrophy is a common feature of many cardiac diseases. It results from both myocyte hypertrophy and interstitial expansion. Interstitial expansion is most commonly secondary to the accumulation of mature cross-linked collagen fibers due to dysregulated metabolism, known as interstitial fibrosis. This occurs secondary to a variety of stimuli including ischemic, toxic, metabolic, infective, genetic, and hemodynamic factors. Less commonly, interstitial expansion may occur because of the accumulation of misfolded amyloid protein or interstitial edema. It is now well recognized that the presence and extent of interstitial disease are associated with adverse outcomes. There is therefore interest in the development of novel therapies that target the pathways that drive these disease processes. With the emergence of such therapies, it is becoming increasingly important to be able to characterize the type and extent of interstitial disease to enable the use of such targeted therapies in a personalized manner.
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Do Drugs That Ameliorate Epicardial Adipose Tissue Inflammation Have Concordant Benefits on Atrial Fibrillation and on Heart Failure with a Preserved Ejection Fraction?
J Card Fail2019 Sep;():. doi: S1071-9164(19)30529-9.
Packer Milton,
Abstract
Heart failure with a preserved ejection fraction (HFpEF) and heart failure with a reduced ejection fraction (HFrEF) have distinctive pathophysiologies, and thus, therapeutic approaches to the two disorders should differ. Neurohormonal activation drives the progression of HFrEF, and neurohormonal antagonists are highly effective in HFrEF, but not in HFpEF. Conversely, a broad range of chronic systemic inflammatory or metabolic disorders cause an expansion and inflammation of epicardial adipose tissue; the secretion of adipocytokines may lead to microvascular dysfunction and fibrosis of the underlying myocardium, which (if the left atrium is affected) may lead to atrial fibrillation (AF) and (if the left ventricle is affected) may lead to HFpEF. Anti-inflammatory drugs (such as statins and anticytokine agents) can ameliorate epicardial adipose tissue dysfunction. Statins appear to ameliorate the development of atrial myopathy (both experimentally and clinically), and in randomized controlled trials, they reduce the incidence of new-onset and recurrent AF and decrease the risk of heart failure with the features of HFpEF; yet, they have no benefits in HFrEF. Similarly, anticytokine agents appear to prevent heart failure in patients with or prone to HFpEF, but adversely affect HFrEF. Several antihyperglycemic agents also reduce epicardial fat mass and inflammation, but this benefit may be offset by additional actions to cause sodium retention and neurohormonal activation. Thiazolidinediones have favorable effects on experimental AF and HFpEF, but their antinatriuretic actions negate these benefits, and they worsen the clinical course of HFrEF. Glucagon-like peptide-1 receptor agonists also ameliorate AF and HFpEF in laboratory models, but their positive inotropic and chronotropic effects may be deleterious in HFrEF. By contrast, metformin and sodium-glucose cotransporter 2 inhibitors alleviate epicardial adipose tissue dysfunction and may reduce the risk of AF and HFpEF; yet, they may have additional actions to promote cardiomyocyte survival that are useful in HFrEF. The concordance of the benefits of anti-inflammatory and antihyperglycemic drugs on AF and HFpEF (but not on HFrEF) supports the paradigm that epicardial adipose tissue is an central pathogenetic mechanism and therapeutic target for both AF and HFpEF in patients with chronic systemic inflammatory or metabolic diseases.
Copyright © 2019. Published by Elsevier Inc.
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Nerolidol attenuates cyclophosphamide-induced cardiac inflammation, apoptosis and fibrosis in Swiss Albino mice.
Eur J Pharmacol2019 Sep;():172666. doi: S0014-2999(19)30618-1.
Iqubal Ashif, Sharma Sumit, Ansari Mohd Asif, Najmi Abul Kalam, Syed Mansoor Ali, Ali Javed, Alam M Mumtaz, Ahmad Shaniya, Haque Syed Ehtaishamul,
Abstract
Incidence and prevalence of cancer is an alarming situation globally. For the treatment of cancer many anticancer drugs have been developed but, unfortunately, their potential cardiotoxic side effects raised serious concerns about their use among clinicians. Cyclophosphamide is a potent anticancer and immunosuppressant drug but its use is limited due to cardiotoxic side effect. Thus, there is a need for the development of certain drug which can reduce cardiotoxicity and can be used as an adjuvant therapy in cancer patients. In this direction we, therefore planned to evaluate nerolidol (NER) for its cardioprotective potential against cyclophosphamide-induced cardiotoxicity in Swiss Albino mice. Animals were divided into 6 groups. Vehicle control; Cyclophosphamide (CP 200); NER 400 per se; NER 200 + CP 200; NER 400 + CP 200; and fenofibrate (FF 80) + CP 200. Dosing was done for 14 days along with a single dose of CP 200 on the 7th day. On 15th day animals were sacrificed and various biochemical parameters pertaining to oxidative stress, nitrative stress, inflammation, apoptosis and fibrosis were estimated in the blood and heart tissues. Histopathological analysis (H & E and Masson's trichrome staining); ultrastructural analysis (transmission electron microscopy) and immunohistochemical analysis were also performed along with mRNA expression and molecular docking to establish the cardioprotective potential of nerolidol. Nerolidol acted as a potent cardioprotective molecule and attenuated CP-induced cardiotoxicity.
Copyright © 2019. Published by Elsevier B.V.
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Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion.
Sci Rep2019 Sep;9(1):13664. doi: 10.1038/s41598-019-50221-0.
Zhuang Aowen, Yap Felicia Y T, McCarthy Domenica, Leung Chris, Sourris Karly C, Penfold Sally A, Thallas-Bonke Vicki, Coughlan Melinda T, Schulz Benjamin L, Forbes Josephine M,
Abstract
The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48?kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n?=?9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUC observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinary-renal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.
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Cigarette Smoke Exposure Induces Retrograde Trafficking of CFTR to the Endoplasmic Reticulum.
Sci Rep2019 Sep;9(1):13655. doi: 10.1038/s41598-019-49544-9.
Marklew Abigail J, Patel Waseema, Moore Patrick J, Tan Chong D, Smith Amanda J, Sassano M Flori, Gray Michael A, Tarran Robert,
Abstract
Chronic obstructive pulmonary disease (COPD), which is most commonly caused by cigarette smoke (CS) exposure, is the third leading cause of death worldwide. The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane anion channel that is widely expressed in epithelia throughout the body. In the airways, CFTR plays an important role in fluid homeostasis and helps flush mucus and inhaled pathogens/toxicants out of the lung. Inhibition of CFTR leads to mucus stasis and severe airway disease. CS exposure also inhibits CFTR, leading to the decreased anion secretion/hydration seen in COPD patients. However, the underlying mechanism is poorly understood. Here, we report that CS causes CFTR to be internalized in a clathrin/dynamin-dependent fashion. This internalization is followed by retrograde trafficking of CFTR to the endoplasmic reticulum. Although this internalization pathway has been described for bacterial toxins and cargo machinery, it has never been reported for mammalian ion channels. Furthermore, the rapid internalization of CFTR is dependent on CFTR dephosphorylation by calcineurin, a protein phosphatase that is upregulated by CS. These results provide new insights into the mechanism of CFTR internalization, and may help in the development of new therapies for CFTR correction and lung rehydration in patients with debilitating airway diseases such as COPD.
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FGF23-Mediated Activation of Local RAAS Promotes Cardiac Hypertrophy and Fibrosis.
Int J Mol Sci2019 Sep;20(18):. doi: E4634.
Böckmann Ineke, Lischka Jonas, Richter Beatrice, Deppe Jennifer, Rahn Anja, Fischer Dagmar-Christiane, Heineke Jörg, Haffner Dieter, Leifheit-Nestler Maren,
Abstract
Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin-angiotensin-aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced and , which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.
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High-Resolution CT Change over Time in Patients with Idiopathic Pulmonary Fibrosis on Antifibrotic Treatment.
J Clin Med2019 Sep;8(9):. doi: E1469.
Balestro Elisabetta, Cocconcelli Elisabetta, Giraudo Chiara, Polverosi Roberta, Biondini Davide, Lacedonia Donato, Bazzan Erica, Mazzai Linda, Rizzon Giulia, Lococo Sara, Turato Graziella, Tinè Mariaenrica, Cosio Manuel G, Saetta Marina, Spagnolo Paolo,
Abstract
Antifibrotic treatment slows down functional decline and disease progression in idiopathic pulmonary fibrosis (IPF). High-resolution computed tomography (HRCT) is useful to diagnose IPF; however, little is known about whether and to what extent HRCT changes reflect functional changes during antifibrotic therapy. The aim of this study was, therefore, to assess HRCT change over time after 1 year of treatment and to evaluate whether these changes correlate with functional decline over the same period of time. Sixty-eight IPF patients on antifibrotic treatment (i.e., pirfenidone or nintedanib) were functionally categorized as stable or progressors based on whether (or not) they had a decline in forced vital capacity (FVC) >5% predicted/year, and their HRCT were scored blindly and independently by two expert thoracic radiologists at treatment initiation (HRCT1) and after 1 year of treatment (HRCT2). Ground glass opacities (Alveolar Score, AS), reticulations (Interstitial Score, IS) and honeycombing (HC) were quantified and correlated with FVC decline between HRCT1 and HRCT2. At treatment initiation, HRCT scores were similar in both stable patients and progressors. After one year of treatment, in the entire population, AS and HC increased significantly, while IS did not. However, when stratified by the rate of functional decline, in stable patients, HC increased significantly while AS and IS did not. On the other hand, among progressors AS and HC increased significantly whereas IS did not. In the entire population, the combined score of fibrosis (IS + HC) correlated significantly with FVC decline. In conclusion, IPF patients on antifibrotic treatment exhibit different patterns of HRCT change over time based on their rate of functional decline. HRCT data should be integrated to lung function data when assessing response to antifibrotic treatment in patients with IPF.
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Interaction Between Sacubitril and Valsartan in Preventing Heart Failure Induced by Aortic Valve Insufficiency in Rats.
J Card Fail2019 Sep;():. doi: S1071-9164(19)30491-9.
Maslov M Y, Foianini S, Mayer D, Orlov M V, Lovich M A,
Abstract
BACKGROUND:
Synergistic interactions between neprilysin inhibition (NEPi) with sacubitril and angiotensin receptor type1 blockade (ARB) with valsartan have been implicated in improvement of left ventricular (LV) contractility, relaxation, exercise tolerance, and fibrosis in preexisting heart failure induced by aortic valve insufficiency (AVI). It is not known whether this pharmacologic synergy can prevent cardiovascular pathology in a similar AVI model.
AIM:
To investigate pharmacology of sacubitril/valsartan in an experimental setting with therapy beginning immediately after creation of AVI.
METHODS:
HF was induced through partial disruption of the aortic valve in rats. Therapy began 3 hours after valve disruption and lasted 8 weeks. Sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg), or vehicle were administered daily via oral gavage (N=8 in each group). Hemodynamic assessments were conducted using Millar technology, and an exercise tolerance test was conducted using a rodent treadmill.
RESULTS:
Only sacubitril/valsartan increased total arterial compliance and ejection fraction (EF). Therapies with sacubitril/valsartan and valsartan similarly improved load dependent (dP/dt) and load independent indices (Ees) of LV contractility, and exercise tolerance while sacubitril did not. None of the therapies improved LV relaxation (dP/dt) while all reduced myocardial fibrosis.
CONCLUSIONS:
1) The synergistic interaction between NEPi and ARB in early therapy with sacubitril/valsartan leads to increased total arterial compliance and EF. 2) Improvement in indices of LV contractility, and exercise tolerance with sacubitril/valsartan is likely due to ARB effect of valsartan. 3) All three therapies provided antifibrotic effects, suggesting both ARB and NEPi are capable of reducing myocardial fibrosis.
Copyright © 2019. Published by Elsevier Inc.
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MicroRNA-150 alleviates acute myocardial infarction through regulating cardiac fibroblasts in ventricular remodeling.
Eur Rev Med Pharmacol Sci2019 Sep;23(17):7611-7618. doi: 18884.
Tian H-B, Li S-H, Hu K-Q, Zan Y-S, Zhang X-L, Su G-H,
Abstract
OBJECTIVE:
The aim of this study was to investigate the effect of microRNA-150 on the regulation of myocardial fibrosis and ventricular remodeling in rats with acute myocardial infarction (AMI).
MATERIALS AND METHODS:
The AMI rats model was established by the ligation of the left anterior descending coronary artery (LAD) in vivo. After AMI procedures, the rats were injected with microRNA-150 lentivirus overexpression or negative control, respectively. Cardiac function of rats was evaluated by echocardiography. Hematoxylin and eosin (HE) staining and Masson trichrome were performed to evaluate myocardial fibrosis in each rat. Meanwhile, cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method. The expression levels of microRNA-150, col1?1, col1?2, col3 and ? smooth muscle actin (?-SMA) in the border zone of rat infarct myocardium were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively.
RESULTS:
MicroRNA-150 expression in the border zone of infarct myocardium decreased significantly at day 28 after AMI (p<0.05). Overexpressing microRNA-150 significantly improved cardiac function, decreased collagen volume fraction (CVF) and attenuated cardiomyocyte apoptosis in rats. Furthermore, the expression levels of col1?1, col1?2, col3 and ?-SMA in the border zone of infarct myocardium were remarkably down-regulated in rats overexpressing microRNA-150 compared with those of controls (p<0.001).
CONCLUSIONS:
MicroRNA-150 expression in the border zone of rat infarct myocardium decreased at day 28 after AMI. In addition, the upregulation of microRNA-150 in myocardial tissue could inhibit myocardial fibrosis and improve ventricular remodeling at post-AMI.
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Prognostic value of ST2 in myocardial infarction.
Tunis Med2019 Feb;97(2):335-343.
Mzoughi Khadija, Chouaieb Sonia, Zairi Ihsen, Fredj Soumaya, Ben Kilani Mouna, Berriri Soumaya, Zili Mohamed, Kraiem Sondos,
Abstract
INTRODUCTION:
Soluble Suppression of Tumorigenicity 2 (ST2) is a biomarker of myocardial fibrosis increasingly recognized as a predictor of morbidity and mortality in heart failure. Its role in the prognosis after a myocardial infarction has not been validated to date.
AIM:
To evaluate the prognostic value of ST2 for in-hospital morbidity and mortality after myocardial infarction.
METHODS:
We conducted a longitudinal prospective study including 74 patients admitted for an acute uncomplicated cardiac myocardial infarction at Habib Thameur hospital between April and October 2016. ST2 blood samples were drawn until 72 hours post admission .The primary endpoint was the occurrence of a major cardiovascular event during hospitalization.
RESULTS:
Patients' mean age was 61.28 ± 13 years-old with a sex ratio of 1.8. The reason for admission was acute coronary syndrome with persistent ST segment elevation in 54% of cases and non-ST segment elevation acute myocardial infarction in 46% of cases. The ST2 assay was positive in 78% of cases with a mean value of 122.43 ± 95.72 ng/ ml. Left ventricular dysfunction was observed in 47% of cases. Fifteen per cent of the patients had a 3 vessel-disease, 24% a 2 vessel-disease and 34% a 1 vessel-disease. Twenty-six percent had at least one major cardiovascular event. In-hospital mortality was 10%. In multivariate analysis, ST2 was an independent factor associated with the occurrence of major cardiovascular events (RR = 2, p = 0.04). The cutoff value of ST2 of 35 ng/ml had a sensitivity of 95%, a specificity of 30% (AUC = 0.672, CI 0.546-0.798, p = 0.024), a negative predictive value of 100% and a positive value of 33%. A significant correlation was found between ST2 and troponin, blood glucose on admission, CRP and left ventricular ejection fraction (respectively: r = 0.398, p <0.0001, r = 0.281, p = 0.015, r = 0.245, p = 0.039, r = -0.401, p <0.0001).
CONCLUSION:
The measurement of ST2 after a myocardial infarction constitutes a new prognostic indicator of in-hospital morbidity and mortality.
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Elastomeric cardiopatch scaffold for myocardial repair and ventricular support.
Eur J Cardiothorac Surg2019 Sep;():. doi: ezz252.
Chachques Juan Carlos, Lila Nermine, Soler-Botija Carolina, Martinez-Ramos Cristina, Valles Ana, Autret Gwennhael, Perier Marie-Cecile, Mirochnik Nicolas, Monleon-Pradas Manuel, Bayes-Genis Antoni, Semino Carlos E,
Abstract
OBJECTIVES:
Prevention of postischaemic ventricular dilatation progressing towards pathological remodelling is necessary to decrease ventricular wall deterioration. Myocardial tissue engineering may play a therapeutic role due to its capacity to replace the extracellular matrix, thereby creating niches for cell homing. In this experimental animal study, a biomimetic cardiopatch was created with elastomeric scaffolds and nanotechnologies.
METHODS:
In an experimental animal study in 18 sheep, a cardiopatch was created with adipose tissue-derived progenitor cells seeded into an engineered bioimplant consisting of 3-dimensional bioabsorbable polycaprolactone scaffolds filled with a peptide hydrogel (PuraMatrix?). This patch was then transplanted to cover infarcted myocardium. Non-absorbable poly(ethyl) acrylate polymer scaffolds were used as controls.
RESULTS:
Fifteen sheep were followed with ultrasound scans at 6?months, including echocardiography scans, tissue Doppler and spectral flow analysis and speckle-tracking imaging, which showed a reduction in longitudinal left ventricular deformation in the cardiopatch-treated group. Magnetic resonance imaging (late gadolinium enhancement) showed reduction of infarct size relative to left ventricular mass in the cardiopatch group versus the controls. Histopathological analysis at 6?months showed that the cardiopatch was fully anchored and integrated to the infarct area with minimal fibrosis interface, thereby promoting angiogenesis and migration of adipose tissue-derived progenitor cells to surrounding tissues.
CONCLUSIONS:
This study shows the feasibility and effectiveness of a cardiopatch grafted onto myocardial infarction scars in an experimental animal model. This treatment decreased fibrosis, limited infarct scar expansion and reduced postischaemic ventricular deformity. A capillary network developed between our scaffold and the heart. The elastomeric cardiopatch seems to have a positive impact on ventricular remodelling and performance in patients with heart failure.
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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Cardiac abnormalities in patients with nonalcoholic fatty liver disease : Insights from auxiliary examinations.
Herz2019 Sep;():. doi: 10.1007/s00059-019-04855-5.
Dong Yu, Li Guangsen,
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease in developed countries and is associated with type 2 diabetes mellitus, obesity, hypertension, dyslipidemia, and metabolic syndrome. It is defined as steatosis in over 5% of hepatocytes. The disease spectrum of NAFLD ranges from simple fatty liver to nonalcoholic steatohepatitis, liver fibrosis, even hepatic cirrhosis. The disease affects various extra-hepatic systems such as the cardiovascular system and urinary system. Heart-related disease is identified as the leading cause of mortality in NAFLD patients rather than liver-related disease. In this review, we summarize the cardiac abnormalities (structural, functional, arrhythmic cardiac complications etc.) seen in NAFLD patients with the assistance of auxiliary examinations, such as electrocardiography, echocardiography, computed tomography, magnetic resonance imaging etc. In addition, the epidemiology of NAFLD and how NAFLD affects the myocardium are also discussed.
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Functional aging in fibrotic interstitial lung disease: The impact of frailty on adverse health outcomes.
Eur Respir J2019 Sep;():. doi: 1900647.
Guler Sabina A, Kwan Joanne M, Leung Janice M, Khalil Nasreen, Wilcox Pearce G, Ryerson Christopher J,
Abstract
BACKGROUND:
Accelerated biological and functional aging is common in fibrotic interstitial lung disease (ILD); however, their impact on adverse health outcomes has not been evaluated in this population.
METHODS:
Patients were prospectively recruited from a specialised ILD clinic. Functional aging was determined by the frailty index (FI), and biological age by measurement of absolute telomere length (aTL) from patients' peripheral blood leukocytes. Adverse health outcomes included health-related quality of life (St George's Respiratory Questionnaire), number and length of respiratory and non-respiratory hospitalisations, medication tolerability, and time to death or lung transplantation. Multivariable models were used to determine the risks and rates of adverse health outcomes associated with the FI and aTL.
RESULTS:
540 patients with fibrotic ILD, including 100 with idiopathic pulmonary fibrosis (IPF), provided 749 FI assessments, with 189 patients providing blood samples. The FI was strongly associated with quality of life, rate of hospitalisation, time to hospital discharge, and mortality, including with adjustment for age, sex, disease severity, and IPF diagnosis. Mortality prognostication was improved by the addition of the FI to commonly used clinical parameters and previously validated composite indices. Conversely, aTL was not associated with most adverse health outcomes. The effect of chronological age on outcomes was mediated primarily by the FI and to a lesser extent by aTL.
CONCLUSIONS:
Functional aging is associated with adverse health outcomes in patients with fibrotic ILD, indicating the need for consideration of the individual functional age into clinical decision-making.
Copyright ©ERS 2019.
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Sex Differences in Circulating Biomarkers of Cardiovascular Disease.
J Am Coll Cardiol2019 Sep;74(12):1543-1553. doi: S0735-1097(19)36181-9.
Lau Emily S, Paniagua Samantha M, Guseh James Sawalla, Bhambhani Vijeta, Zanni Markella V, Courchesne Paul, Lyass Asya, Larson Martin G, Levy Daniel, Ho Jennifer E,
Abstract
BACKGROUND:
Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD).
OBJECTIVES:
This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants.
METHODS:
The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD.
RESULTS:
Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q < 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (p <0.05 for all).
CONCLUSIONS:
In a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development.
Copyright © 2019 American College of Cardiology Foundation. All rights reserved.
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Cardioprotective Effect of Danhong Injection against Myocardial Infarction in Rats Is Critically Contributed by MicroRNAs.
Evid Based Complement Alternat Med2019 ;2019():4538985. doi: 10.1155/2019/4538985.
Chen Jingrui, Wei Jing, Orgah John, Zhu Yan, Ni Jingyu, Li Lingyan, Zhang Han, Gao Xiumei, Fan Guanwei,
Abstract
Background:
Danhong injection (DHI) has been mainly used for the treatment of myocardial infarction, atherosclerosis, and coronary heart disease in clinical practice. Our previous studies have shown that DHI improves ventricular remodeling and preserves cardiac function in rats with myocardial infarction (MI). In this study, we focused on the potential mechanism of DHI in protecting cardiac function in MI rats.
Methods:
Sprague-Dawley rats were subjected to ligation of the left anterior descending coronary artery (LAD) to prepare a myocardial infarction (MI) model. After 14?day DHI intervention, cardiac function was measured by echocardiography and myocardial fibrosis was assessed by Masson staining. Differentiated miRNAs were screened using rat immunopathology miScript miRNA PCR arrays, and their results were verified by RT-PCR, immunofluorescence, and immunoblotting.
Results:
DHI treatment significantly reduced infarct size and improved cardiac function and hemodynamics in MI rats by echocardiography and morphology. miRNA PCR array results showed that DHI reversed 25 miRNAs known to be associated with inflammation and apoptosis. Moreover, the expression of inflammatory factors TNF-, IL-1, and IL-6 was significantly reduced in the treated DHI group. Mechanistically, DHI downregulated the inflammatory transcription factor NF-B (as reflected by inhibition of NF-B p65 nuclear translocation and phosphorylation of the IB).
Conclusions:
DHI is effective in mitigating inflammation associated with MI by preventing NF-B nuclear translocation and regulating miRNAs, thereby improving cardiac function in myocardial infarction rats.
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Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarction.
JCI Insight2019 Sep;4(18):. doi: 10.1172/jci.insight.131545.
Schroer Alison K, Bersi Matthew R, Clark Cynthia R, Zhang Qinkun, Sanders Lehanna H, Hatzopoulos Antonis K, Force Thomas L, Majka Susan M, Lal Hind, Merryman W David,
Abstract
Over one million Americans experience myocardial infarction (MI) annually, and the resulting scar and subsequent cardiac fibrosis gives rise to heart failure. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not been studied in myocardium after MI. MI was induced by ligation of the left anterior descending artery in mice with either heterozygous or homozygous knockout of CDH11, wild-type mice receiving bone marrow transplants from Cdh11-deficient animals, and wild-type mice treated with a functional blocking antibody against CDH11 (SYN0012). Flow cytometry revealed significant CDH11 expression in noncardiomyocyte cells after MI. Animals given SYN0012 had improved cardiac function, as measured by echocardiogram, reduced tissue remodeling, and altered transcription of inflammatory and proangiogenic genes. Targeting CDH11 reduced bone marrow-derived myeloid cells and increased proangiogenic cells in the heart 3 days after MI. Cardiac fibroblast and macrophage interactions increased IL-6 secretion in vitro. Our findings suggest that CDH11-expressing cells contribute to inflammation-driven fibrotic remodeling after MI and that targeting CDH11 with a blocking antibody improves outcomes by altering recruitment of bone marrow-derived cells, limiting the macrophage-induced expression of IL-6 by fibroblasts and promoting vascularization.
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The Potential Role of Undercarboxylated Osteocalcin Upregulation in Microvascular Insufficiency in a Rat Model of Diabetic Cardiomyopathy.
J Cardiovasc Pharmacol Ther2019 Sep;():1074248419876632. doi: 10.1177/1074248419876632.
Sadek Nermeen B, Gamal Sarah M, Aboulhoda Basma E, Rashed Laila A, Shawky Heba M, Gamal El-Din Maha M,
Abstract
BACKGROUND:
Diabetic cardiomyopathy (DCM) is accompanied by microvascular complications that lead to myocardial dysfunction and heart failure. Most conventional therapies cannot ameliorate the microvascular insufficiency in DCM. In this study, we tested the hypothesis that undercarboxylated osteocalcin (ucOC) may be a new adjuvant therapy against the progression of DCM and its underlying microvascular pathology.
MATERIALS AND METHODS:
Diabetes was induced in Wistar rats with a high-fat diet combined with streptozotocin injections, and ucOC was upregulated after warfarin administration in the treated group. After 8 weeks, cardiac functions were assessed using a Langendorff apparatus. Cardiac tissue samples were also extracted to assess the ucOC receptor and vascular endothelial growth factor (VEGF) for histopathological studies.
RESULTS:
Both the systolic and the diastolic dysfunction observed in the DCM group were significantly improved after the increase in ucOC blood levels. Significant improvement in VEGF and CD31 expression after warfarin injection was associated with increased capillary density, neovascularization, and decreased myocardial fibrosis together with the reestablishment of myocardial structural and ultrastructural patterns.
CONCLUSION:
Undercarboxylated osteocalcin may have a promising effect in improving microvascular insufficiency and myocardial dysfunction in DCM.
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Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy.
Circulation2019 Sep;():. doi: 10.1161/CIRCULATIONAHA.119.040676.
Chelko Stephen P, Asimaki Angeliki, Lowenthal Justin, Bueno-Beti Carlos, Bedja Djahida, Scalco Arianna, Amat-Alarcon Nuria, Andersen Peter, Judge Daniel P, Tung Leslie, Saffitz Jeffrey E,
Abstract
Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. To define the role of inflammation in the pathogenesis of ACM, we characterized NF?B signaling in ACM models in vitro and in vivo, and in cardiac myocytes from patient induced pluripotent stem cells (hiPSCs). Activation of NF?B signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of in neonatal rat ventricular myocytes), and in a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2; ) that recapitulates the cardiac manifestations seen in ACM patients. Bay 11-7082, a small molecule inhibitor of NF?B signaling, prevented development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, LV contractile dysfunction, ECG abnormalities). Hearts of mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules which were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. NF?B signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. Inflammatory signaling is activated in ACM and it drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.
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Genetic profiling of fatty acid desaturase polymorphisms identifies patients who may benefit from high-dose omega-3 fatty acids in cardiac remodeling after acute myocardial infarction-Post-hoc analysis from the OMEGA-REMODEL randomized controlled trial.
PLoS One2019 ;14(9):e0222061. doi: 10.1371/journal.pone.0222061.
Kwong Raymond Y, Heydari Bobak, Ge Yin, Abdullah Shuaib, Fujikura Kana, Kaneko Kyoichi, Harris William S, Jerosch-Herold Michael, Antman Elliott M, Seidman Jonathan G, Pfeffer Marc A,
Abstract
BACKGROUND:
The double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes.
METHODS AND RESULTS:
We tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, p<0.0001; vs. AG: 1.76±0.35, p = 0.03). When randomized to 6-months of O-3FA treatment, GG patients demonstrated significant lowering of LV end-systolic volume index (LVESVi), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and galectin-3 levels compared to placebo (-4.4 vs. 1.2 ml/m2, -733 vs. -181 pg/mL, and -2.0 vs. 0.5 ng/mL; p = 0.006, 0.006, and 0.03, respectively). In contrast, patients with either AA or AG genotype did not demonstrate significant lowering of LVESVi, NT-proBNP, or galectin-3 levels from O-3FA treatment, compared to placebo. The odds ratios for improving LVESVi by 10% with O-3FA treatment was 7.2, 1.6, and 1.2 in patients with GG, AG, and AA genotypes, respectively.
CONCLUSION:
Genetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI.
CLINICAL TRIAL REGISTRATION INFORMATION:
clinicaltrials.gov Identifier: NCT00729430.
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