Publications by authors named "Fernando Dominguez"

112 Publications

Checkpoint inhibitor-induced fulminant myocarditis, complete atrioventricular block and myasthenia gravis-a case report.

Cardiovasc Diagn Ther 2021 Aug;11(4):1013-1019

Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy over the last decade. Pembrolizumab, a humanized monoclonal IgG4 antibody, binds to the programmed death 1 (PD-1) receptor, blocking its interaction with programmed death-ligand 1 (PD-L1) and thereby increasing the anti-tumor activity of the host immune system. These drugs are associated with immune-mediated side effects that can be life threatening, and myocarditis is among the most serious events. We present a 48-year-old woman with a history of progressive thymoma who developed complete atrioventricular block associated with fulminant myocarditis and myasthenia gravis 2 weeks after starting treatment with pembrolizumab. She had also presented a couple of days before to the emergency department due to dyspnea that was related to pleural effusion. Electrocardiogram (ECG) and echocardiogram were unremarkable, but she had very mildly increased troponin levels that were attributed to acute respiratory compromise, so she was discharged after successful thoracentesis. Despite aggressive treatment combination of high-dose corticosteroids, immunosuppressive agents and anti-thymocyte globulin, the disease rapidly progressed to the fatal outcome. This report remarks on the importance of rapid consideration of ICI-induced myocarditis even if cardiac biomarkers are slightly elevated, as a mild presentation can go unnoticed and progress to a severe case. Therefore, a high index of suspicion is warranted in these patients and cardiac imaging techniques such as magnetic resonance could have a role diagnosing incipient cardiac inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/cdt-21-147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410500PMC
August 2021

Early Preventive Treatment With Enalapril Improves Cardiac Function and Delays Mortality in Mice With Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.

Circ Heart Fail 2021 Sep 20;14(9):e007616. Epub 2021 Aug 20.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (F.D., L.L., M.L.-O., M.V.-O., L.P.-B., M.R., E.B.-A., E.L.-P.).

Background: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice.

Methods: TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed.

Results: TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; =0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; =0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice.

Conclusions: Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007616DOI Listing
September 2021

A Simple Entropic-Driving Separation Procedure of Low-Size Silver Clusters, Through Interaction with DNA.

ChemistryOpen 2021 Aug;10(8):760-763

Department of Physical Chemistry, Lab. Nanomag University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.

Synthesis and purification of metal clusters without strong binding agents by wet chemical methods are very attractive for their potential applications in many research areas. However, especially challenging is the separation of uncharged clusters with only a few number of atoms, which renders the usual techniques very difficult to apply. Herein, we report the first efficient separation of Ag and Ag clusters using the different entropic driving forces when such clusters interact with DNA, into which Ag selectively intercalates. After sequential dialysis of the samples and denaturalizing the DNA-Ag complex, pure Ag can be found in the dialysate after extensive dialysis. Free Ag is recovered after DNA denaturation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/open.202100028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340070PMC
August 2021

Saw-Tooth Cardiomyopathy: Try Not to Stumble Twice Over the Same Stone.

JACC Case Rep 2020 Jul 15;2(8):1210-1211. Epub 2020 Jul 15.

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaccas.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311887PMC
July 2020

Hospital-acquired infective endocarditis during Covid-19 pandemic.

Infect Prev Pract 2020 Sep 30;2(3):100080. Epub 2020 Jul 30.

Servicio de Medicina Preventiva, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.

Background: The COVID pandemic has had a major impact on healthcare in hospitals, including the diagnosis and treatment of infections. Hospital-acquired infective endocarditis (HAIE) is a severe complication of medical procedures that has shown a progressive increase in recent years.

Objectives: To determine whether the incidence of HAIE during the first two months of the epidemic (March-April 2020) was higher than previously observed and to describe the clinical characteristics of these cases. The probability of the studied event (HAIE) during the study period was calculated by Poisson distribution.

Results: Four cases of HAIE were diagnosed in our institution during the study period. The incidence of HAIE during the study period was 2/patient-month and 0.3/patient-month during the same calender months in the previous 5 years (p=0.033). Two cases presented during admission for COVID-19 with pulmonary involvement treated with methylprednisolone and tocilizumab. The other two cases were admitted to the hospital during the epidemic. All cases underwent central venous and urinary catheterization during admission. The etiology of HAIE was (2 cases), and (one case each). A source of infection was identified in three cases (central venous catheter, peripheral venous catheter, sternal wound infection, respectively). One patient was operated on. Two patients died during hospital admission.

Conclusions: The incidence of HAIE during COVID-19 pandemic in our institution was higher than usual. In order to reduce the risk of this serious infection, optimal catheter care and early treatment of every local infection should be prioritized during coronavirus outbreaks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.infpip.2020.100080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391975PMC
September 2020

Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.

J Biol Chem 2021 07 5;297(1):100854. Epub 2021 Jun 5.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address:

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260873PMC
July 2021

Nanomechanical Phenotypes in Cardiac Myosin-Binding Protein C Mutants That Cause Hypertrophic Cardiomyopathy.

ACS Nano 2021 06 1;15(6):10203-10216. Epub 2021 Jun 1.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain.

Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C domains targeted by HCM mutations that do not induce RNA splicing alterations or protein thermodynamic destabilization. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, nonpathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.1c02242DOI Listing
June 2021

Prevalence and clinical outcomes of dystrophin-associated dilated cardiomyopathy without severe skeletal myopathy.

Eur J Heart Fail 2021 08 9;23(8):1276-1286. Epub 2021 Jun 9.

Leviev Heart Center, Sheba Medical Center and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Aims: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy.

Methods And Results: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up.

Conclusions: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.2250DOI Listing
August 2021

Chloroplast dismantling in leaf senescence.

J Exp Bot 2021 Aug;72(16):5905-5918

Instituto de Bioquímica Vegetal y Fotosíntesis, Universidad de Sevilla and Consejo Superior de Investigaciones Científicas, Avda. Américo Vespucio 49, 41092-Sevilla, Spain.

In photosynthetic plant cells, chloroplasts act as factories of metabolic intermediates that support plant growth. Chloroplast performance is highly influenced by environmental cues. Thus, these organelles have the additional function of sensing ever changing environmental conditions, thereby playing a key role in harmonizing the growth and development of different organs and in plant acclimation to the environment. Moreover, chloroplasts constitute an excellent source of metabolic intermediates that are remobilized to sink tissues during senescence so that chloroplast dismantling is a tightly regulated process that plays a key role in plant development. Stressful environmental conditions enhance the generation of reactive oxygen species (ROS) by chloroplasts, which may lead to oxidative stress causing damage to the organelle. These environmental conditions trigger mechanisms that allow the rapid dismantling of damaged chloroplasts, which is crucial to avoid deleterious effects of toxic by-products of the degradative process. In this review, we discuss the effect of redox homeostasis and ROS generation in the process of chloroplast dismantling. Furthermore, we summarize the structural and biochemical events, both intra- and extraplastid, that characterize the process of chloroplast dismantling in senescence and in response to environmental stresses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jxb/erab200DOI Listing
August 2021

Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy.

Nefrologia (Engl Ed) 2021 Mar 10. Epub 2021 Mar 10.

Red de Investigación Renal (REDinRen), Fondos FEDER, Spain; Servicio de Nefrología de la Fundación Jimenez Diaz, Spain.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT.

Study Design: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120).

Results: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models.

Conclusions: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nefro.2021.01.002DOI Listing
March 2021

Infective endocarditis in patients with solid organ transplantation. A nationwide descriptive study.

Eur J Intern Med 2021 May 6;87:59-65. Epub 2021 Mar 6.

Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid. Instituto de Investigación Sanitaria Gregorio Marañón. CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058). Facultad de Medicina, Universidad Complutense de Madrid.

Background: Solid organ transplantation (SOT) implies immunosuppression and frequent health care contact. Our aim was to compare the characteristics of patients with infective endocarditis (IE) and SOT against those without SOT.

Methods: We used data from the Spanish Collaboration on Endocarditis during the period 2008-2018.

Results: We identified 4794 cases of IE, 85 (1.8%) in SOT (56 kidney, 18 liver, 8 heart, 3 lung). Thirteen patients with other transplantation types (bone marrow, hematopoietic precursors, and cornea) were excluded from the analysis. Compared with patients without SOT, patients with SOT had lower median age (61 vs. 69 years, p<0.001), more comorbidities (mean age-adjusted Charlson index 5.7±2.9 vs. 4.9±2.9, p=0.004), a lower prevalence of native valvular heart disease (29.4 vs. 45.4%, p=0.003), more in-hospital and healthcare-related IE (70.5% vs. 36.3%, p<0.001) and staphylococcal etiology (57.7% vs. 39.7%, p=0.001). Patients with SOT had more frequent kidney function worsening (47.1% vs. 34.6%, p=0.02), septic shock (25.9% vs. 12.1 %, p<0.001), sepsis (27.1% vs. 17.2%, p=0.02), and less surgery indication (54.1% vs 66.3%, p=0.02) and surgery (32.9% vs. 46.3%, p=0.01) than patients without SOT. There were no significant differences in mortality: inhospital (30.6% SOT vs. 25.6% without SOT, p=0.31), 1-year (38.8% SOT vs. 31.9% without SOT, p=0.18).

Conclusions: Most IE in SOT recipients are nosocomial and over 70% are health care-related. Half have previously normal heart valves and almost 60% are due to Staphylococcus spp. infections. Mortality seems to be similar to non-SOT counterparts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejim.2021.02.017DOI Listing
May 2021

Benefits of cardiac pacing in ICD recipients with hypertrophic cardiomyopathy.

J Interv Card Electrophysiol 2021 Feb 16. Epub 2021 Feb 16.

Electrophysiology Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Calle Manuel de Falla 1, 28222 Majadahonda, Madrid, Spain.

Purpose: Implantable cardiac defibrillator (ICD) is the only definitive therapy for prevention of sudden cardiac death in hypertrophic cardiomyopathy (HCM). Conventional transvenous ICDs can provide cardiac pacing unlike new subcutaneous ICD, but the usefulness of cardiac pacing in HCM patients is not well defined. We sought to assess the usefulness of ICD pacing in HCM.

Methods: We retrospectively analyzed 93 HCM patients who had undergone ICD implantation at our center. Usefulness of pacing was defined as follows: 1) need of pacing due to bradycardia or AV conduction disturbances, 2) improvement of LV outflow tract obstruction by sequential AV pacing, 3) need for CRT pacing, or 4) successful antitachycardia pacing without a subsequent shock. Independent predictors of useful pacing were investigated by multivariable analysis.

Results: During a mean follow-up of 91.3 ± 5.5 months, 43 patients (46.2%) reached the composite endpoint. Independent predictors of pacing usefulness were older age (HR 1.36; 95%CI: 1.088-1.709; p=0.007) and NYHA functional class ≥ II (HR 2.15; 95%CI: 1.083-4.301; p=0.029). Twenty-eight (30.1%) patients had appropriate ICD interventions, triggered by a monomorphic ventricular tachycardia (MVT) in 22 of them (78.5%). In 17 individuals with MVT (77%), antitachycardia pacing successfully treated MVT.

Conclusions: In our HCM series of patients with ICD, 46% of individuals benefitted from cardiac pacing. MVT were documented in nearly 80% of the patients with ventricular arrhythmias and antitachycardia pacing successfully treated them in 77% of cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10840-021-00961-9DOI Listing
February 2021

Role of somatic mutations and chromosomal aberrations in the prognosis of uveal melanoma in a Spanish patient cohort.

Acta Ophthalmol 2021 Jan 9. Epub 2021 Jan 9.

Tumores Intraoculares en el Adulto, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.

Background: Uveal melanoma (UM) has a high tendency to cause liver metastases. Metastatic disease is fatal, with a low survival rate. There are two large groups of UMs that, according to their risk of metastatic disease, can be divided into risk subgroups based on histopathological, cytogenetic and molecular characteristics. The presence of somatic mutations in certain genes may explain the origin and prognosis of these tumours.

Methods: Forty-six UM samples previously classified as high or low metastatic risk according to chromosome 3 copy number status were tested for somatic mutations. A multi-gene targeting strategy was adopted, and sequencing was performed using AmpliSeq technology.

Results: Mutations were found in all major UM-related genes. BAP1 mutations confer an increased risk of metastases in high-risk tumours; thus, this gene acts as a strong prognostic predictor in UM. The presence of somatic mutations in LZTS1 did not show significant differences in the risk of metastases.

Conclusions: This result supports the idea that exploring mutations and copy number variations in UM provides insights into patient outcomes. Genetic tests allow the determination of accurate personalized molecular profiles with a fundamental prognostic purpose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aos.14760DOI Listing
January 2021

Current use of cardiac magnetic resonance in tertiary referral centres for the diagnosis of cardiomyopathy: the ESC EORP Cardiomyopathy/Myocarditis Registry.

Eur Heart J Cardiovasc Imaging 2021 06;22(7):781-789

Members of the European Reference Network on Heart Diseases (ERN GUARD-HEART), Coordinating Centre: Academic Medical Center, Amsterdam, the Netherlands.

Aims: Cardiac magnetic resonance (CMR) is recommended in the diagnosis of cardiomyopathies, but it is time-consuming, expensive, and limited in availability in some European regions. The aim of this study was to determine the use of CMR in cardiomyopathy patients enrolled into the European Society of Cardiology (ESC) cardiomyopathy registry [part of the EURObservational Research Programme (EORP)].

Methods And Results: Three thousand, two hundred, and eight consecutive adult patients (34.6% female; median age: 53.0 ± 15 years) with cardiomyopathy were studied: 1260 with dilated (DCM), 1739 with hypertrophic (HCM), 66 with restrictive (RCM), and 143 with arrhythmogenic right ventricular cardiomyopathy (ARVC). CMR scans were performed at baseline in only 29.4% of patients. CMR utilization was variable according to cardiomyopathy subtypes: from 51.1% in ARVC to 36.4% in RCM, 33.8% in HCM, and 20.6% in DCM (P < 0.001). CMR use in tertiary referral centres located in different European countries varied from 1% to 63.2%. Patients undergoing CMR were younger, less symptomatic, less frequently had implantable cardioverter-defibrillator (ICD)/pacemaker implanted, had fewer cardiovascular risk factors and comorbidities (P < 0.001). In 28.6% of patients, CMR was used along with transthoracic echocardiography (TTE); 67.6% patients underwent TTE alone, and 0.9% only CMR.

Conclusion: Less than one-third of patients enrolled in the registry underwent CMR and the use varied greatly between cardiomyopathy subtypes, clinical profiles of patients, and European tertiary referral centres. This gap with current guidelines needs to be considered carefully by scientific societies to promote wider availability and use of CMR in patients with cardiomyopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjci/jeaa329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219354PMC
June 2021

Gas chromatography-mass spectrometry based untargeted volatolomics for smoked seafood classification.

Food Res Int 2020 11 18;137:109698. Epub 2020 Sep 18.

Enviromental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water (IUPA), University Jaume I, Av. Sos Baynat S/N, 12071 Castellón de la Plana, Spain.

With the increase of the demand of low flavouring smoked seafood products, there is a need of methodologies able to distinguish between different seafood treatments, as not all of them are allowed in all markers. Following this objective, in the present work an untargeted volatolomics approach was applied to identify volatile markers that demonstrate that Cold smoked products can be distinguished from Tasteless smoke neither Carbon monoxide treated seafood, which are prohibited in the European Union. The use of dynamic headspace for the volatile extraction followed by thermal desorption in combination with Gas Chromatography (GC) coupled to single quadrupole Mass Spectrometry (MS) has been employed for the determination of volatile composition of smoked fish. Data processing consisted on the use of PARADISe software, applied for GC/MS data treatment, followed by the multivariate analysis with PLS_Toolbox (MATLAB), and finally the creation and validation of statistical classification model. All 107 variables obtained allowed the construction of a model reaching the correct classification of 97% of the blind samples, while a simplified model with only 11 variables correctly classified up to 93% of the blind samples. These 11 compounds were elucidated to develop subsequent target volatolomics approaches, if needed. Ordered according to the importance in the classification model, the elucidated compounds were: 3-methyl-cyclopentanone, ethylbenzene, 2-methyl-2-cyclopenten-1-one, 2-methyl-benzofuran, furfuryl alcohol, 2-acetylfuran, acetophenone, guaiacol, 1-hydroxy-2-butanone, 4-vinylguaicol and acetoin. The results demonstrated the great potential of untargeted volatolomics for smoked seafood treatments classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.foodres.2020.109698DOI Listing
November 2020

Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences.

Eur Heart J 2021 01;42(2):162-174

Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Aims: The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups.

Methods And Results: We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping.

Conclusion: The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813623PMC
January 2021

Transthyretin amyloid cardiomyopathy.

Med Clin (Barc) 2021 02 31;156(3):126-134. Epub 2020 Oct 31.

Unidad de Insuficiencia Cardíaca y Cardiopatías Familiares, Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, España; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, España.

Transthyretin (TTR) cardiac amyloidosis is a severe, progressive, infiltrative disease caused by the deposition of TTR at cardiac level. It may be due to a genetic alteration in its hereditary form (ATTRv) or as a consequence of an age-related degenerative process (ATTRwt). Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that ATTR is more frequent than traditionally considered and that it is particularly relevant in patients over 65 years with heart failure or with aortic stenosis. With the appearance of several treatment options capable of modifying the natural history of ATTR, it is necessary for clinicians to be familiar with the diagnostic process and treatment of this disease. This review will cover the clinical spectrum of presentation of ATTR, its diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.medcli.2020.06.064DOI Listing
February 2021

Reducing Catheter-associated Urinary Tract Infections via Cost-saving Diagnostic Stewardship.

Clin Infect Dis 2021 06;72(11):e883-e886

Los Angeles County + University of Southern California Medical Center, Los Angeles, California, USA.

We conducted a quality improvement project at our large, public, tertiary-care, academic hospital to reduce the standardized infection ratio (SIR) of hospital-acquired catheter-associated urinary tract infections (CAUTIs). Our diagnostic stewardship program, based on education and audit and feedback, significantly reduced inpatient urine culture orders and CAUTI SIR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1512DOI Listing
June 2021

Four weeks versus six weeks of ampicillin plus ceftriaxone in Enterococcus faecalis native valve endocarditis: A prospective cohort study.

PLoS One 2020 3;15(8):e0237011. Epub 2020 Aug 3.

Infectious Diseases Service, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain.

Enterococcus faecalis infective endocarditis (EFIE) is a severe disease of increasing incidence. The objective was to analyze whether the outcome of patients with native valve EFIE (NVEFIE) treated with a short course of ampicillin plus ceftriaxone (4wAC) was similar to patients treated according to international guidelines (6wAC). Between January 2008 and June 2018, 1,978 consecutive patients with definite native valve IE were prospectively included in a national registry. Outcomes of patients with NVEFIE treated with 4wAC were compared to those of patients who received 6wAC. Three hundred and twenty-two patients (16.3%) had NVEFIE. One hundred and eighty-three (56.8%) received AC. Thirty-nine patients (21.3%) were treated with 4wAC for four weeks and 70 patients (38.3%) with 6wAC. There were no differences in age or comorbidity. Patients treated 6wAC presented a longer duration of symptoms before diagnosis (21 days, IQR 7-60 days vs. 7 days, IQR 1-22 days; p = 0.002). Six patients presented perivalvular abscess and all of these received 6wAC. Surgery was performed on 14 patients (35.9%) 4wAC and 34 patients (48.6%) 6wAC (p = 0.201). In-hospital mortality, one-year mortality and relapses among 4wAC and 6wAC patients were 10.3% vs. 11.4% (p = 0.851); 17.9% vs. 21.4% (p = 0.682) and 5.1% vs. 4.3% (p = 0.833), respectively. In conclusion, a four-week course of AC may be considered as an alternative regimen in NVEFIE, notably in patients with shorter duration of symptoms and those without perivalvular abscess. These results support the performance of a randomized clinical trial to evaluate the efficacy of this short regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237011PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398509PMC
October 2020

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

J Am Coll Cardiol 2020 07;76(2):186-197

Algarve Biomedical Center, Faro, Portugal; Hospital Universitário do Algarve, Faro, Portugal; Biomedical and Medicine Department, University of Algarve, Faro, Portugal.

Background: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood.

Objectives: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.

Methods: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied.

Results: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died.

Conclusions: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2020.05.029DOI Listing
July 2020

Multidrug-resistant bacteria in lung transplantation.

Curr Opin Organ Transplant 2020 08;25(4):348-350

Division of Infectious Diseases, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.

Purpose Of Review: The review of infections in lung transplantation is beyond the scope of this article as it is a comprehensive topic, however we aim to focus on infections with multidrug-resistant (MDR) microorganisms in this patient population.

Recent Findings: New emerging clinical studies have provided data regarding outcomes in lung transplant recipients with MDR bacterial infections.

Summary: Isolation of MDR bacteria from lung donors preoperatively has not been associated with worse outcomes in recipients. Patients with cystic fibrosis colonized with MDR bacteria do not have increased 1 year mortality rates compared to those without MDR bacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MOT.0000000000000782DOI Listing
August 2020

Pericardial variant of Austrian syndrome.

Rev Esp Cardiol (Engl Ed) 2021 02 25;74(2):184. Epub 2020 Jun 25.

Servicio de Cardiología, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rec.2020.03.021DOI Listing
February 2021

Mutations in cause an autosomal-recessive form of hypertrophic cardiomyopathy.

Heart 2020 09 25;106(17):1342-1348. Epub 2020 May 25.

Centre for Inherited Cardiac Diseases. Barts Heart Centre, Saint Bartholomew's Hospital, London, United Kingdom.

Objective: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in and the development of HCM.

Methods: was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls.

Results: Sixteen index cases with rare homozygous or compound heterozygous variants in (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15-69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%).

Conclusion: appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2020-316913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476281PMC
September 2020

Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center.

Rev Esp Cardiol (Engl Ed) 2021 Feb 18;74(2):149-158. Epub 2020 Apr 18.

Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Universidad Autónoma de Madrid, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain. Electronic address:

Introduction And Objectives: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center.

Methods: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival.

Results: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02).

Conclusions: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rec.2019.12.020DOI Listing
February 2021

Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5.

Heart Rhythm 2020 06 13;17(6):945-954. Epub 2020 Feb 13.

Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; CIBERCV, Madrid, Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain. Electronic address:

Background: Arrhythmogenic right ventricular cardiomyopathy type V (ARVC-5) is the most aggressive heterozygous form of ARVC. It is predominantly caused by a fully penetrant mutation (p.S358L) in the nondesmosomal gene TMEM43-endemic to Newfoundland, Canada. To date, all familial cases reported worldwide share a common ancestral haplotype. It is unknown whether the p.S358L mutation by itself causes ARVC-5 or whether the disease is influenced by genetic or environmental factors.

Objective: The purpose of this study was to examine the phenotype, clinical course, and the impact of exercise on patients with p.S358L ARVC-5 without the Newfoundland genetic background.

Methods: We studied 62 affected individuals and 73 noncarriers from 3 TMEM43-p.S358L Spanish families. The impact of physical activity on the phenotype was also evaluated.

Results: Haplotype analysis revealed that the 3 Spanish families were unrelated to patients with ARVC-5 with the Newfoundland genetic background. Two families shared 10 microsatellite markers in a 4.9 cM region surrounding TMEM43; the third family had a distinct haplotype. The affected individuals showed a 38.7% incidence of sudden cardiac death, which was higher in men. Left ventricular involvement was common, with 40% of mutation carriers showing a left ventricular ejection fraction of <50%. Compared with noncarriers, the R-wave voltage in lead V was lower (3.2 ± 2.8 mV vs 7.5 ± 3.6 mV; P < .001) and QRS complex in right precordial leads wider (104.7 ± 24.0 ms vs 88.2 ± 7.7 ms; P = .001). A history of vigorous exercise showed a trend toward more ventricular arrhythmias only in women (P = .053).

Conclusion: ARVC-5 is associated with a high risk of sudden cardiac death and characteristic clinical and electrocardiographic features irrespective of geographical origin and genetic background. Our data suggest that, as in desmosomal ARVC, vigorous physical activity could aggravate the phenotype of TMEM43 mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2020.01.035DOI Listing
June 2020

Peripheral microRNA panels to guide the diagnosis of familial cardiomyopathy.

Transl Res 2020 04 29;218:1-15. Epub 2020 Jan 29.

Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, Puerta del Mar University Hospital University of Cádiz, Spain; Medicine Department, School of Medicine, University of Cádiz, Cádiz, Spain. Electronic address:

Etiology-based diagnosis of dilated cardiomyopathy (DCM) is challenging. We evaluated whether peripheral microRNAs (miRNAs) could be used to characterize the DCM etiology. We investigated the miRNA plasma profiles of 254 subjects that comprised 5 groups: Healthy subjects (n = 70), idiopathic DCM patients (n = 55), ischemic DCM patients (n = 60) and 2 groups of patients with pathogenic variants responsible for familial DCM in the LMNA (LMNA, n = 37) and BAG3 (BAG3, n = 32) genes. Diagnostic performance was assessed using receiver operating characteristic curves. In a screening study (n = 30), 179 miRNAs robustly detected in plasma samples were profiled in idiopathic DCM and carriers of pathogenic variants. After filtering, 26 miRNA candidates were selected for subsequent quantification in the whole study population. In the validation study, a 6-miRNA panel identified familial DCM with an AUC (95% confidence interval [CI]) of 87.8 (82.0-93.6). The 6-miRNA panel also distinguished between specific DCM etiologies with AUCs ranging from 85.9 to 89.9. Only 1 to 10 of the subjects in the first and second tertiles of the 6-miRNA panel were patients with familial DCM. Additionally, a 5-miRNA panel showed an AUC (95% CI) of 87.5 (80.4-94.6) for the identification of carriers with pathogenic variants who were phenotypically negative for DCM. The 5-miRNA panel discriminated between carriers and healthy controls with AUCs ranging from 83.2 to 90.8. Again, only 1 to 10 of the subjects in the lowest tertiles of the 5-miRNA panel were carriers of pathogenic variants. In conclusion, miRNA signatures could be used to rule out patients with pathogenic variants responsible for DCM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trsl.2020.01.003DOI Listing
April 2020

Multiparametric Echocardiography Scores for the Diagnosis of Cardiac Amyloidosis.

JACC Cardiovasc Imaging 2020 04 18;13(4):909-920. Epub 2019 Dec 18.

Fondazione Toscana Gabriele Monasterio, Pisa, Italy; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.

Objectives: This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or those with increased heart wall thickness who had amyloid was suspected. We also aimed to further characterize the structural and functional changes associated with amyloid infiltration.

Background: Cardiac amyloidosis (CA) is a serious but increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool.

Methods: We studied 1,187 consecutive patients evaluated at 3 referral centers for CA and analyzed morphological, functional, and strain-derived echocardiogram parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified by using extracellular volume measurements at cardiac magnetic resonance.

Results: A total of 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin CA. Concentric remodeling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E wave/e' wave ratio, longitudinal strain, and tricuspid annular plane systolic excursion had the greatest diagnostic performance in AL amyloidosis (area under the curve: 0.90; 95% confidence interval: 0.87 to 0.92), whereas the addition of septal apical-to-base ratio yielded the best diagnostic accuracy in the increased heart wall thickness group (area under the curve: 0.80; 95% confidence interval: 0.85 to 0.90).

Conclusions: Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances and enable the definition of 2 scores that are sensitive and specific tools with which diagnose or exclude CA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmg.2019.10.011DOI Listing
April 2020

Predictive model of in-hospital mortality in left-sided infective endocarditis.

Rev Esp Cardiol (Engl Ed) 2019 Dec 14. Epub 2019 Dec 14.

Servicio de Cardiología, Instituto de Ciencias del Corazón (ICICOR), Hospital Clínico Universitario Valladolid, Valladolid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.

Introduction And Objectives: Infective endocarditis (IE) is a complex disease with high in-hospital mortality. Prognostic assessment is essential to select the most appropriate therapeutic approach; however, international IE guidelines do not provide objective assessment of the individual risk in each patient. We aimed to design a predictive model of in-hospital mortality in left-sided IE combining the prognostic variables proposed by the European guidelines.

Methods: Two prospective cohorts of consecutive patients with left-sided IE were used. Cohort 1 (n=1002) was randomized in a 2:1 ratio to obtain 2 samples: an adjustment sample to derive the model (n=688), and a validation sample for internal validation (n=314). Cohort 2 (n=133) was used for external validation.

Results: The model included age, prosthetic valve IE, comorbidities, heart failure, renal failure, septic shock, Staphylococcus aureus, fungi, periannular complications, ventricular dysfunction, and vegetations as independent predictors of in-hospital mortality. The model showed good discrimination (area under the ROC curve=0.855; 95%CI, 0.825-0.885) and calibration (P value in Hosmer-Lemeshow test=0.409), which were ratified in the internal (area under the ROC curve=0.823; 95%CI, 0.774-0.873) and external validations (area under the ROC curve=0.753; 95%CI, 0.659-0.847). For the internal validation sample (observed mortality: 29.9%) the model predicted an in-hospital mortality of 30.7% (95%CI, 27.7-33.7), and for the external validation cohort (observed mortality: 27.1%) the value was 26.4% (95%CI, 22.2-30.5).

Conclusions: A predictive model of in-hospital mortality in left-sided IE based on the prognostic variables proposed by the European Society of Cardiology IE guidelines has high discriminatory ability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rec.2019.11.003DOI Listing
December 2019

Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β.

Circulation 2019 10 5;140(14):1188-1204. Epub 2019 Sep 5.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (L.P.-B., M.V.-O., J.M.G.-S., F.D., J.L.-A., P.O.-S., F.M., M.L.-O., E.B.-K., J.V., C.M.-G., D.J.S., B.P., G.G., S.P., E.L.-P.).

Background: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5.

Methods: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter.

Results: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition.

Conclusions: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784777PMC
October 2019

POT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas.

J Am Heart Assoc 2019 09 12;8(18):e012875. Epub 2019 Sep 12.

Human Genetics Group Spanish National Cancer Research Center (CNIO) Madrid Spain.

Background Mutations in the gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the gene has been studied. Patients with CAS and nonfunctional did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway ( gene). The same observation was made in mutation carriers with tumors different from CAS and also in CAS patients without mutations in the gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.012875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818007PMC
September 2019
-->