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1.
J Interv Card Electrophysiol ; 62(2): 427-439, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34609691

RESUMO

PURPOSE: We present the preliminary results of the STRA-MI-VT Study (NCT04066517), a spontaneous, phase Ib/II study, designed to prospectively test the safety and efficacy of stereotactic body radiotherapy (SBRT) in patientswith advanced cardiac disease and intractable ventricular tachycardia (VT). METHODS: Cardiac computed tomography (CT) integrated by electroanatomical mapping was used for substrate identification and merged with dedicated CT scans for treatment plan preparation. A single 25-Gy radioablation dose was delivered by a LINAC-based volumetric modulated arc therapy technique in a non-invasive matter. The primary safety endpoint was treatment-related adverse effects during acute and long-term follow-up (FU), obtained by regular in-hospital controls and implantable cardioverter defibrillator (ICD) remote monitoring. The primary efficacy endpoint was the reduction at 3 and 6 months of VT episodes and ICD shocks. RESULTS: Seven out of eight patients (men; age, 70 ± 7 years; ejection fraction, 27 ± 11%; 3 ischemic, 4 non-ischemic cardiomyopathies) underwent SBRT. At a median 8-month FU, no treatment-related serious adverse event occurred. Three patients died from non-SBRT-related causes. Four patients completed the 6-month FU: the number of VT decreased from 29 ± 33 to 11 ± 9 (p = .05) and 2 ± 2 (p = .08), at 3 and 6 months, respectively; shocks decreased from 11 to 0 and 2, respectively. At 6 months, all patients. showed a significant reduction of VT episodes and no electrical storm recurrence, with the complete regression of iterative VTs in 2/2 patients. CONCLUSION: The STRA-MI-VT Study suggests that SBRT can be considered an alternative option for the treatment of VT in patients with structural heart disease and highlights the need for further clinical investigation addressing safety and efficacy.


Assuntos
Ablação por Cateter , Desfibriladores Implantáveis , Taquicardia Ventricular , Idoso , Arritmias Cardíacas , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dados Preliminares , Taquicardia Ventricular/diagnóstico por imagem , Taquicardia Ventricular/cirurgia , Resultado do Tratamento
2.
Front Cardiovasc Med ; 8: 709795, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552966

RESUMO

In the last decades, various non-pharmacological solutions have been tested on top of medical therapy for the treatment of patients affected by refractory angina (RA). Among these therapeutics, neuromodulation, external counter-pulsation and coronary sinus constriction have been recently introduced in the guidelines for the management of RA in United States and Europe. Notably and paradoxically, although a consistent body of evidence has proposed cell-based therapies (CT) as safe and salutary for RA outcome, CT has not been conversely incorporated into current international guidelines yet. As a matter of fact, published randomized controlled trials (RCT) and meta-analyses (MTA) cumulatively indicated that CT can effectively increase perfusion, physical function and well-being, thus reducing angina symptoms and drug assumption in RA patients. In this review, we (i) provide an updated overview of novel non-pharmacological therapeutics included in current guidelines for the management of patients with RA, (ii) discuss the Level of Evidence stemmed from available clinical trials for each recommended treatment, and (iii) focus on evidence-based CT application for the management of RA.

3.
Pharmaceuticals (Basel) ; 14(9)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34577636

RESUMO

In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis' many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34556432

RESUMO

An 81-year-old female presented with chronic coronary disease (Canadian Cardiovascular Society angina severity grading III). The patient underwent coronary computed tomography angiography (CCTA) that revealed three-vessel coronary artery disease (3VD). This case illustrates that in a patient with 3VD, planning and execution of coronary artery bypass grafting (CABG) were successfully performed based solely on CCTA combined with fractional flow reserve derived from computed tomography angiography (FFRCT). Coronary artery bypass grafting (CABG) was planned and executed as follows: left internal mammary artery grafted to the left anterior descending artery (LAD), saphenous vein graft (SVG) to the right coronary artery (RCA), and SVG to the obtuse marginal artery (OM). Repeat imaging assessment with non-invasive CCTA and FFRCT at 30-day follow-up confirmed the safety of this approach. The FFRCT values of the RCA and LAD were normalized, whereas a borderline pressure drop was observed in the distal run-off of the OM (FFRCT=0.79). Notably, this is the first case in which post-CABG FFRCT assessment was performed. Post-CABG FFRCT is an investigational novel non-invasive tool for assessing the functional improvement of the epicardial conductance vessels following surgical revascularization.

5.
Int J Cardiol ; 343: 164-170, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34517017

RESUMO

BACKGROUND: Despite the low spatial resolution of 2D-multisegment late gadolinium enhancement (2D-MSLGE) sequences, it may be useful in uncooperative patients instead of standard 2D single segmented inversion recovery gradient echo late gadolinium enhancement sequences (2D-SSLGE). The aim of the study is to assess the feasibility and comparison of 2D-MSLGE reconstructed with artificial intelligence reconstruction deep learning noise reduction (NR) algorithm compared to standard 2D-SSLGE in consecutive patients with ischemic cardiomyopathy (ICM). METHODS: Fifty-seven patients with known ICM referred for a clinically indicated CMR were enrolled in this study. 2D-MSLGE were reconstructed using a growing level of NR (0%,25%,50%,75%and 100%). Subjective image quality, signal to noise ratio (SNR) and contrast to noise ratio (CNR) were evaluated in each dataset and compared to standard 2D-SSLGE. Moreover, diagnostic accuracy, LGE mass and scan time were compared between 2D-MSLGE with NR and 2D-SSLGE. RESULTS: The application of NR reconstruction ≥50% to 2D-MSLGE provided better subjective image quality, CNR and SNR compared to 2D-SSLGE (p < 0.01). The best compromise in terms of subjective and objective image quality was observed for values of 2D-MSLGE 75%, while no differences were found in terms of LGE quantification between 2D-MSLGE versus 2D-SSLGE, regardless the NR applied. The sensitivity, specificity, negative predictive value, positive predictive value and accuracy of 2D-MSLGE NR 75% were 87.77%,96.27%,96.13%,88.16% and 94.22%, respectively. Time of acquisition of 2D-MSLGE was significantly shorter compared to 2D-SSLGE (p < 0.01). CONCLUSION: When compared to standard 2D-SSLGE, the application of NR reconstruction to 2D-MSLGE provides superior image quality with similar diagnostic accuracy.


Assuntos
Cardiomiopatias , Aprendizado Profundo , Algoritmos , Inteligência Artificial , Meios de Contraste , Estudos de Viabilidade , Gadolínio , Humanos , Imageamento por Ressonância Magnética
6.
Artigo em Inglês | MEDLINE | ID: mdl-34542612

RESUMO

OBJECTIVES: The aim of this study was to determine Syntax scores based on coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) and to assess whether heavy coronary calcification significantly limits the CCTA evaluation and the impact of severe calcification on heart team's treatment decision and procedural planning in patients with three-vessel coronary artery disease (CAD) with or without left main disease. METHODS: SYNTAX III was a multicentre, international study that included patients with three-vessel CAD with or without left main disease. The heart teams were randomized to either assess coronary arteries with coronary CCTA or ICA. We stratified the patients based on the presence of at least 1 lesion with heavy calcification defined as arc of calcium >180° within the lesion using CCTA. Agreement on the anatomical SYNTAX score and treatment decision was compared between patients with and without heavy calcifications. RESULTS: Overall, 222 patients with available CCTA and ICA were included in this trial subanalysis (104 with heavy calcification, 118 without heavy calcification). The mean difference in the anatomical SYNTAX score (CCTA derived-ICA derived) was lower in patients without heavy calcifications [mean (-1.96 SD; +1.96 SD) = 1.5 (-19.3; 22.4) vs 5.9 (-17.5; +29.3), P = 0.004]. The agreement on treatment decision did not differ between patients with (Cohen's kappa 0.79) or without coronary calcifications (Cohen's kappa 0.84). The agreement on the treatment planning did not differ between patients with (concordance 80.3%) or without coronary calcifications (concordance 82.8%). CONCLUSIONS: An overall good correlation between CCTA- and ICA-derived Syntax score was found. The presence of heavy coronary calcification moderately influenced the agreement between CCTA and ICA on the anatomical SYNTAX score. However, agreement on the treatment decision and planning was high and irrespective of the presence of calcified lesions.

7.
J Am Heart Assoc ; 10(19): e021370, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34569251

RESUMO

Background Endomyocardial biopsy (EMB) is part of 2010 Task Force Criteria (TFC) for arrhythmogenic right ventricular cardiomyopathy (ARVC). However, its usage has been curtailed because of its low presumed diagnostic yield, and it is now a poorly used tool. This study aims to analyze the contribution of EMB to the final diagnosis of ARVC. Methods and Results We included 104 consecutive patients evaluated for a suspicion of ARVC, who were referred for EMB. Patients with suspected left dominant pattern were excluded from the primary analysis. Subjects were initially stratified according to TFC without considering EMB. After EMB, patients were reclassified accordingly, and the reclassification rate was calculated. EMB yielded a diagnostic finding in 92 patients (85.5%). After including EMB evaluation, 20 (43%) more patients "at risk" received a definite diagnosis of ARVC. Overall, 59 patients received a definite diagnosis of ARVC, 34% only after EMB. EMB appeared to be the better-performing exam with respect to the final diagnosis (ß, 2.2; area uder the curve, 0.73; P<0.05). The reclassification improvement after EMB measured 28%. TFC score increased from 3.5±1.3 to 4.3±1.4 (P<0.001). Notably, active inflammation was present in 6 (10%) patients. Minor complications were reported in only 2% of the cohort. In patients with suspected left-dominant disease, conventional TFC performed poorly. Conclusions Electroanatomic voltage mapping-guided EMB was safe and yielded an optimal diagnostic yield. It allowed upgrading of the diagnosis of nearly one-third of the patients considered "at risk." Classical TFC without EMB performed poorly in patients with the left dominant form of ARVC.

8.
EMBO Mol Med ; 13(9): e14365, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34337880

RESUMO

Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro-adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low-density lipoprotein (oxLDL)-dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient-derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock-out mice through high-fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies.


Assuntos
Displasia Arritmogênica Ventricular Direita , Animais , Arritmias Cardíacas/etiologia , Displasia Arritmogênica Ventricular Direita/genética , Humanos , Lipoproteínas LDL , Camundongos , Fenótipo
9.
Int J Cardiol ; 342: 94-102, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34400166

RESUMO

BACKGROUND: Arrhythmogenic Cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes. AC hearts show fibro-fatty myocardial replacement, which favors stress-related life-threatening arrhythmias, predominantly in the young and athletes. AC lacks effective therapies, as its pathogenesis is poorly understood. Recently, we showed that cardiac Mesenchymal Stromal Cells (cMSCs) contribute to adipose tissue in human AC hearts, although the underlying mechanisms are still unclear. PURPOSE: We hypothesize that the sympathetic neurotransmitter, Neuropeptide Y (NPY), participates to cMSC adipogenesis in human AC. METHODS: For translation of our findings, we combined in vitro cytochemical, molecular and pharmacologic assays on human cMSCs, from myocardial biopsies of healthy controls and AC patients, with the use of existing drugs to interfere with the predicted AC mechanisms. Sympathetic innervation was inspected in human autoptic heart samples, and NPY plasma levels measured in healthy and AC subjects. RESULTS: AC cMSCs expressed higher levels of pro-adipogenic isotypes of NPY-receptors (i.e. Y1-R, Y5-R). Consistently, NPY enhanced adipogenesis in AC cMSCs, which was blocked by FDA-approved Y1-R and Y5-R antagonists. AC-associated PKP2 reduction directly caused NPY-dependent adipogenesis in cMSCs. In support of the involvement of sympathetic neurons (SNs) and NPY in AC myocardial remodeling, patients had elevated NPY plasma levels and, in human AC hearts, SNs accumulated in fatty areas and were close to cMSCs. CONCLUSIONS: Independently from the disease origin, AC causes in cMSCs a targetable gain of responsiveness to NPY, which leads to increased adipogenesis, thus playing a role in AC myocardial remodeling.


Assuntos
Cardiomiopatias , Células-Tronco Mesenquimais , Adipogenia , Humanos , Neuropeptídeo Y , Receptores de Neuropeptídeo Y
10.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445659

RESUMO

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.


Assuntos
Cardiomiopatias/patologia , Biologia Computacional/métodos , Distrofina/deficiência , Genoma , Proteoma/análise , Transcriptoma , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Humanos
11.
Cardiovasc Res ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34254111

RESUMO

Alterations in the DMD gene, which codes for the protein dystrophin, cause forms of dystrophinopathies such as Duchenne muscular dystrophy, an X-linked disease. Cardiomyopathy linked to DMD mutations is becoming the leading cause of death in patients with dystrophinopathy. Since phenotypic pathophysiological mechanisms are not fully understood, the improvement and development of new disease models, considering their relative advantages and disadvantages, is essential. The application of genetic engineering approaches on induced pluripotent stem cells, such as gene editing technology, enables the development of physiologically relevant human cell models for in vitro dystrophinopathy studies. The combination of induced pluripotent stem cells-derived cardiovascular cell types and 3 D bioprinting technologies hold great promise for the study of dystrophin-linked cardiomyopathy. This combined approach enables the assessment of responses to physical or chemical stimuli, and the influence of pharmaceutical approaches. The critical objective of in vitro microphysiological systems is to more accurately reproduce the microenvironment observed in vivo. Ground-breaking methodology involving the connection of multiple microphysiological systems comprised of different tissues would represent a move toward precision body-on-chip disease modelling could lead to a critical expansion in what is known about inter-organ responses to disease and novel therapies that have the potential to replace animal models. In this review, we will focus on the generation, development, and application of current cellular, animal and potential for bio-printed models, in the study of the pathophysiological mechanisms underlying dystrophin-linked cardiomyopathy in the direction of personalized medicine.

12.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204386

RESUMO

The "Extreme Exercise Hypothesis" states that when individuals perform training beyond the ideal exercise dose, a decline in the beneficial effects of physical activity occurs. This is due to significant changes in myocardial structure and function, such as hemodynamic alterations, cardiac chamber enlargement and hypertrophy, myocardial inflammation, oxidative stress, fibrosis, and conduction changes. In addition, an increased amount of circulating biomarkers of exercise-induced damage has been reported. Although these changes are often reversible, long-lasting cardiac damage may develop after years of intense physical exercise. Since several features of the athlete's heart overlap with arrhythmogenic cardiomyopathy (ACM), the syndrome of "exercise-induced ACM" has been postulated. Thus, the distinction between ACM and the athlete's heart may be challenging. Recently, an autoimmune mechanism has been discovered in ACM patients linked to their characteristic junctional impairment. Since cardiac junctions are similarly impaired by intense physical activity due to the strong myocardial stretching, we propose in the present work the novel hypothesis of an autoimmune response in endurance athletes. This investigation may deepen the knowledge about the pathological remodeling and relative activated mechanisms induced by intense endurance exercise, potentially improving the early recognition of whom is actually at risk.


Assuntos
Atletas , Autoanticorpos/sangue , Biomarcadores/sangue , Resistência Física , Adaptação Fisiológica , Animais , Displasia Arritmogênica Ventricular Direita/etiologia , Displasia Arritmogênica Ventricular Direita/metabolismo , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Autoimunidade , Suscetibilidade a Doenças , Exercício Físico , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Remodelação Ventricular
13.
Int J Biol Sci ; 17(10): 2399-2416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326683

RESUMO

Myocardial aging increases the cardiovascular risk in the elderly. The Receptor for Advanced Glycation End-products (RAGE) is involved in age-related disorders. The soluble isoform (sRAGE) acts as a scavenger blocking the membrane-bound receptor activation. This study aims at investigating RAGE contribution to age-related cardiac remodeling. We analyzed the cardiac function of three different age groups of female Rage-/- and C57BL/6N (WT) mice: 2.5- (Young), 12- (Middle-age, MA) and 21-months (Old) old. While aging, Rage-/- mice displayed an increase in left ventricle (LV) dimensions compared to age-matched WT animals, with the main differences observed in the MA groups. Rage-/- mice showed higher fibrosis and a larger number of α-Smooth Muscle Actin (SMA)+ cells with age, along with increased expression of pro-fibrotic Transforming Growth Factor (TGF)-ß1 pathway components. RAGE isoforms were undetectable in LV of WT mice, nevertheless, circulating sRAGE declined with aging and inversely associated with LV diastolic dimensions. Human cardiac fibroblasts stimulated with sRAGE exhibited a reduction in proliferation, pro-fibrotic proteins and TGF-beta Receptor 1 (TGFbR1) expression and Smad2-3 activation. Finally, sRAGE administration to MA WT animals reduced cardiac fibrosis. Hence, our work shows that RAGE associates with age-dependent myocardial changes and indicates sRAGE as an inhibitor of cardiac fibroblasts differentiation and age-dependent cardiac fibrosis.

14.
J Am Coll Cardiol ; 78(4): 384-407, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34294273

RESUMO

Over the last 4 decades, percutaneous coronary intervention has evolved dramatically and is now an acceptable treatment option for patients with advanced coronary artery disease. However, trialists have struggled to establish the respective roles for percutaneous coronary intervention and coronary artery bypass graft surgery, especially in patients with multivessel disease and unprotected left-main stem coronary artery disease. Several pivotal trials and meta-analyses comparing these 2 revascularization strategies have enabled the relative merits of each technique to be established with regard to the type of ischemic syndrome, the coronary anatomy, and the patient's overall comorbidity. Precision medicine with individualized prognosis is emerging as an important method of selecting treatment. However, the never-ending advancement of technology, in conjunction with the emergence of novel pharmacological agents, will in the future continue to force us to reconsider the evolving question: "Which treatment strategy is better and for which patient?"

15.
BMC Biol ; 19(1): 124, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134693

RESUMO

BACKGROUND: Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA breaks. It is highly effective against several types of tumours; however, it also has adverse effects on regenerative populations of normal cells, such as human cardiac mesenchymal progenitor cells (hCmPCs), and its clinical use is limited by cardiotoxicity. Another known effect of Dox is nucleolar disruption, which triggers the ubiquitously expressed nucleolar phosphoprotein Nucleophosmin (NPM) to be released from the nucleolus into the cell, where it participates in the orchestration of cellular stress responses. NPM has also been observed in the extracellular space in response to different stress stimuli; however, the mechanism behind this and its functional implications are as yet largely unexplored. The aim of this study was to establish whether Dox could elicit NPM secretion in the extracellular space and to elucidate the mechanism of secretion and the effect of extracellular NPM on hCmPCs. RESULTS: We found that following the double-strand break formation in hCmPCs caused by Dox, NPM was rapidly secreted in the extracellular space by an active mechanism, in the absence of either apoptosis or necrosis. Extracellular release of NPM was similarly seen in response to ultraviolet radiation (UV). Furthermore, we observed an increase of NPM levels in the plasma of Dox-treated mice; thus, NPM release also occurred in vivo. The treatment of hCmPCs with extracellular recombinant NPM induced a decrease of cell proliferation and a response mediated through the Toll-like receptor (TLR)4. We demonstrated that NPM binds to TLR4, and via TLR4, and nuclear factor kappa B (NFkB) activation/nuclear translocation, exerts proinflammatory functions by inducing IL-6 and COX-2 gene expression. Finally, we found that in hCmPCs, NPM secretion could be driven by an autophagy-dependent unconventional mechanism that requires TLR4, since TLR4 inhibition dramatically reduced Dox-induced secretion. CONCLUSIONS: We hypothesise that the extracellular release of NPM could be a general response to DNA damage since it can be elicited by either a chemical agent such as Dox or a physical genotoxic stressor such as UV radiation. Following genotoxic stress, NPM acts similarly to an alarmin in hCmPCs, being rapidly secreted and promoting cell cycle arrest and a TLR4/NFκB-dependent inflammatory response.

16.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800912

RESUMO

Arrhythmogenic Cardiomyopathy (ACM) is characterized by the replacement of the myocardium with fibrotic or fibro-fatty tissue and inflammatory infiltrates in the heart. To date, while ACM adipogenesis is a well-investigated differentiation program, ACM-related fibrosis remains a scientific gap of knowledge. In this study, we analyze the fibrotic process occurring during ACM pathogenesis focusing on the role of cardiac mesenchymal stromal cells (C-MSC) as a source of myofibroblasts. We performed the ex vivo studies on plasma and right ventricular endomyocardial bioptic samples collected from ACM patients and healthy control donors (HC). In vitro studies were performed on C-MSC isolated from endomyocardial biopsies of both groups. Our results revealed that circulating TGF-ß1 levels are significantly higher in the ACM cohort than in HC. Accordingly, fibrotic markers are increased in ACM patient-derived cardiac biopsies compared to HC ones. This difference is not evident in isolated C-MSC. Nevertheless, ACM C-MSC are more responsive than HC ones to TGF-ß1 treatment, in terms of pro-fibrotic differentiation and higher activation of the SMAD2/3 signaling pathway. These results provide the novel evidence that C-MSC are a source of myofibroblasts and participate in ACM fibrotic remodeling, being highly responsive to ACM-characteristic excess TGF-ß1.


Assuntos
Displasia Arritmogênica Ventricular Direita/fisiopatologia , Endocárdio/patologia , Células-Tronco Mesenquimais/patologia , Miofibroblastos/patologia , Fator de Crescimento Transformador beta1/fisiologia , Adulto , Displasia Arritmogênica Ventricular Direita/sangue , Displasia Arritmogênica Ventricular Direita/patologia , Diferenciação Celular , Endocárdio/metabolismo , Feminino , Fibrose , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , Transdução de Sinais/fisiologia , Proteína Smad2/fisiologia , Proteína Smad3/fisiologia , Fator de Crescimento Transformador beta1/sangue
17.
Metabolites ; 11(4)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805952

RESUMO

Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibro-fatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Recent studies on human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) obtained from ACM individuals showed a dysregulated metabolic status, leading to the hypothesis that ACM pathology is characterized by an impairment in the energy metabolism. However, despite efforts having been made for the identification of ACM specific biomarkers, there is still a substantial lack of information regarding the whole metabolomic profile of ACM patients. The aim of the present study was to investigate the metabolic profiles of ACM patients compared to healthy controls (CTRLs). The targeted Biocrates AbsoluteIDQ® p180 assay was used on plasma samples. Our analysis showed that ACM patients have a different metabolome compared to CTRLs, and that the pathways mainly affected include tryptophan metabolism, arginine and proline metabolism and beta oxidation of fatty acids. Altogether, our data indicated that the plasma metabolomes of arrhythmogenic cardiomyopathy patients show signs of endothelium damage and impaired nitric oxide (NO), fat, and energy metabolism.

18.
Diagnostics (Basel) ; 11(4)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924082

RESUMO

The 2019 Coronavirus disease (COVID-19) outbreak had detrimental effects on essential medical services such as organ and tissue donation. Lombardy, one of the most active Italian regions in organ/tissue procurement, has been strongly affected by the COVID-19 pandemic. To date, data concerning the risk of SARS-CoV-2 transmission after tissue transplantation are controversial. Here, we aimed to evaluate the presence/absence of SARS-CoV-2 in different cardiac tissues eligible for transplantation obtained from Lombard donors. We used cardiovascular tissues from eight donors potentially suitable for pulmonary valve transplantation. All donor subjects involved in the study returned negative results for the SARS-CoV-2 RNA molecular tests (quantitative real-time reverse-transcription PCR, qRT-PCR, and chip-based digital PCR) in nasopharyngeal swabs (NPS) or bronchoalveolar lavage (BAL). None of the eight donors included in this study revealed the presence of the SARS-CoV-2 viral genome. However, evaluation of the protein content of pulmonary vein wall (PVW) tissue revealed variable levels of SARS-CoV-2 nucleoprotein signal in all donors. Our study demonstrated for the first time, to the best of our knowledge, that viral nucleoprotein but not viral RNA was present in the examined tissue bank specimens, suggesting the need for caution and in-depth investigations on implantable tissue specimens collected during the COVID-19 pandemic period.

20.
ESC Heart Fail ; 8(3): 2306-2309, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33652498

RESUMO

The concept that cell-based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.


Assuntos
Regeneração , Transplante de Células-Tronco , Terapia Baseada em Transplante de Células e Tecidos , Coração , Humanos
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