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1.
Dis Model Mech ; 16(5)2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35481478

RESUMO

Modifier genes contribute significantly to our understanding of pathophysiology in human diseases; however, effective approaches to identify modifier genes are still lacking. Here, we aim to develop a rapid F0-based genetic assay in adult zebrafish using the bag3 gene knockout (bag3e2/e2) cardiomyopathy model as a paradigm. First, by utilizing a classic genetic breeding approach, we identified dnajb6b as a deleterious modifier gene for bag3 cardiomyopathy. Next, we established an F0-based genetic assay in adult zebrafish through injection of predicted microhomology-mediated end joining (MMEJ)-inducing single guide RNA/Cas9 protein complex. We showed that effective gene knockdown is maintained in F0 adult fish, enabling recapitulation of both salutary modifying effects of the mtor haploinsufficiency and deleterious modifying effects of the dnajb6b gene on bag3 cardiomyopathy. We finally deployed the F0-based genetic assay to screen differentially expressed genes in the bag3 cardiomyopathy model. As a result, myh9b was identified as a novel modifier gene for bag3 cardiomyopathy. Together, these data prove the feasibility of an F0 adult zebrafish-based genetic assay that can be effectively used to discover modifier genes for inherited cardiomyopathy.


Assuntos
Cardiomiopatias , Peixe-Zebra , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Cardiomiopatias/genética , Técnicas de Inativação de Genes , Genes Modificadores , RNA Guia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
2.
Gene ; 851: 146984, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36270459

RESUMO

BACKGROUND: Splice prediction algorithms currently used in routine DNA diagnostics have limited sensitivity and specificity, therefore many potential splice variants are classified as variants of uncertain significance (VUSs). However, functional assessment of VUSs to test splicing is labour-intensive and time-consuming. We developed a decision tree to prioritise potential splice variants for functional studies and functionally verified the outcome of the decision tree. MATERIALS AND METHODS: We built the decision tree, SEPT-GD, by setting thresholds for the splice prediction programs implemented in Alamut. A set of 343 variants with known effects on splicing was used as control for sensitivity and specificity. We tested SEPT-GD using variants from a Dutch cardiomyopathy cohort of 2002 patients that were previously classified as VUS and predicted to have a splice effect according to diagnostic rules. We then selected 12 VUSs ranked by SEPT-GD to functionally verify the predicted effect on splicing using a minigene assay: 10 variants predicted to have a strong effect and 2 with a weak effect. RT-PCR was performed for nine variants. Variant classification was re-evaluated based on the functional test outcome. RESULTS: Compared to similar individually tested algorithms, SEPT-GD shows higher sensitivity (91 %) and comparable specificity (88 %) for both consensus (dinucleotides at the start and end of the intron, GT at the 5' end and AG at the 3' end) and non-consensus splice-site variants (excluding middle of exon variants). Using clinical diagnostic criteria, 1295 unique variants in our cardiomyopathy cohort had originally been classified as VUSs, with 57 predicted by Alamut to have an effect on splicing. Using SEPT-GD, we prioritised 31 variants in 40 patients. In the minigene assay, all 12 variants showed results concordant with SEPT-GD predictions. RT-PCR confirmed the minigene results for two variants, TMEM43 c.1000 + 5G > T and TTN c.25922-6 T > G. Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were reclassified as likely pathogenic. CONCLUSION: SEPT-GD outperforms the tools commonly used for RNA splicing prediction and improves prioritisation of variants in cardiomyopathy genes for functional splicing analysis in a diagnostic setting.


Assuntos
Cardiomiopatias , Sítios de Splice de RNA , Humanos , Sítios de Splice de RNA/genética , Árvores de Decisões , Variação Genética , Splicing de RNA , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética
3.
Curr Probl Cardiol ; 48(1): 101414, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36155200

RESUMO

Atrial fibrillation (AF) is associated with profound structural and functional changes in the atrium. Inflammation mediated atrial fibrosis is one of the key mechanisms in the pathogenesis of AF. The collagen deposition in extracellular matrix (ECM) is mainly mediated by transforming growth factor ß1 (TGF-ß1) which promotes AF via controlling smads mediated-collagen gene transcription and regulating the balance of metalloproteinases (MMPs)/ tissue inhibitor of metalloproteinases (TIMPs). Although many processes can alter atrial properties and promote AF, animal models and clinical studies have provided insights into 2 major forms of atrial remodeling: Atrial tachycardia remodeling (ATR), which occurs with rapid atrial tachyarrhythmia's such as AF and atrial flutter, and atrial structural remodeling (ASR), which is associated with CHF and other fibrosis-promoting conditions. The mechanism of atrial remodeling such as atrial enlargement, ultra-structural changes of atrial muscle tissue and myocardial interstitial fibrosis in AF is still unclear. At present, many studies focus on calcium overload, renin angiotensin aldosterone system and transforming growth factor ß1, that effect on atrial structural remodeling. Recent experimental studies and clinical investigations have provided structural remodeling is important contributor to the AF. This paper reviews the current understanding of the progresses about mechanism of atrial structural remodeling, and highlights the potential therapeutic approaches aimed at attenuating structural remodeling to prevent AF. Now some recent advancements of this area are reviewed in this paper.


Assuntos
Fibrilação Atrial , Remodelamento Atrial , Cardiomiopatias , Animais , Humanos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Átrios do Coração/patologia , Fibrilação Atrial/patologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Inibidores Teciduais de Metaloproteinases/farmacologia , Fibrose , Cardiomiopatias/complicações , Colágeno/metabolismo , Colágeno/farmacologia
4.
Methods Mol Biol ; 2596: 377-395, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36378452

RESUMO

Following large-scale protein separation by two-dimensional gel electrophoresis or liquid chromatography, mass spectrometry-based proteomics can be used for the swift identification and characterization of cardiac proteins and their various proteoforms. Comparative cardiac proteomics has been widely applied for the systematic analysis of heart disease and the establishment of novel diagnostic protein biomarkers. The X-linked neuromuscular disorder Duchenne muscular dystrophy is a multisystemic disease that is characterized by late-onset cardiomyopathy. This chapter outlines the bioinformatic analysis of the subproteomic profile of cardiac tissue from wild-type versus the dystrophic mdx-4cv mouse model of dystrophinopathy.


Assuntos
Cardiomiopatias , Distrofia Muscular de Duchenne , Camundongos , Animais , Camundongos Endogâmicos mdx , Biologia Computacional , Distrofia Muscular de Duchenne/metabolismo , Proteômica/métodos , Cardiomiopatias/metabolismo , Proteínas/metabolismo , Músculo Esquelético/metabolismo , Distrofina/genética , Distrofina/metabolismo
5.
Curr Probl Cardiol ; 48(1): 101425, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36181782

RESUMO

There is limited data on the impact of atrial fibrillation (Afib) on hospital outcomes in females with peripartum cardiomyopathy (PPCM). The National Inpatient Sample (NIS) 2011-2019 was used to find patients with PPCM. PPCM patients were divided into 2 groups: with and without Afib. Baseline characteristics were compared between both groups. Logistic regression was used to find independent predictors of Afib. Out of 13,840 PPCM patients, 249 (1.8%) also had a diagnosis of Afib. The Afib group was older and had a high burden of comorbidities. PPCM patients with Afib had higher in-hospital mortality (4-vs-0.7%, P=0.02), mean length of stay (11.3-vs-4.3 days, P<0.001) and healthcare resource utilization. Old age, low-income quartile, liver disease, obstructive sleep apnea, and acute posthemorrhagic anemia were significant predictors of Afib. In conclusion, Afib is associated with higher in-hospital mortality and worse outcomes in females with PPCM. Further research is needed to improve these outcomes.


Assuntos
Fibrilação Atrial , Cardiomiopatias , Humanos , Feminino , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/terapia , Período Periparto , Pacientes Internados , Cardiomiopatias/complicações , Cardiomiopatias/epidemiologia , Cardiomiopatias/terapia , Hospitais , Atenção à Saúde
6.
Phytomedicine ; 108: 154523, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36332385

RESUMO

BACKGROUND: Chronic and persistent obesity can lead to various complications, including obesity cardiomyopathy. Inhibition of the inflammatory response is an effective measure for the intervention of obesity cardiomyopathy. Numerous studies indicate that costunolide (Cos) can reduce inflammation. However, the role of Cos in obesity cardiomyopathy and its molecular targets remains unknown. HYPOTHESIS/PURPOSE: We aimed to clarify potential cardioprotective effects and mechanism of Cos against obesity cardiomyopathy. METHODS: The model of obesity cardiomyopathy was established by feeding mice with a high-fat diet for 24 weeks. Cos at 10 and 20 mg/kg or vehicle (1% CMCNa solution) was administered once every two days via oral gavage from the 17th to 24th week. Body weight, heart weight/tibia length, cardiac function, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers, inflammatory factors were assessed. The targets of Cos were predicted through molecular docking. Pull-down assay and biolayer interferometry were used to confirm the target of Cos. RESULTS: Cos effectively reduces obesity-induced cardiomyocyte inflammation, cardiac hypertrophy and fibrosis, thereby improving cardiac function. We confirmed that Cos can interact with TAK1 and inhibit downstream NF-κB pathway activation by blocking the formation of the TAK1/TAB2 complex, thus inhibiting inflammatory cytokine release in cardiomyocytes. CONCLUSION: Our results demonstrated that Cos significantly improved myocardial remodeling and cardiac dysfunction against obesity cardiomyopathy by reducing myocardial inflammation. Therefore, Cos may serve as a promising therapeutic agent in obesity cardiomyopathy.


Assuntos
Cardiomiopatias , NF-kappa B , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inflamação/patologia , MAP Quinase Quinase Quinases/metabolismo , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Transdução de Sinais
7.
Ultrasound Med Biol ; 49(1): 45-61, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36184393

RESUMO

Adaptive Bayesian regularized cardiac strain imaging (ABR-CSI) uses raw radiofrequency signals to estimate myocardial wall contractility as a surrogate measure of relative tissue elasticity incorporating regularization in the Bayesian sense. We determined the feasibility of using ABR-CSI -derived strain for in vivo longitudinal monitoring of cardiac remodeling in a murine ischemic injury model (myocardial infarction [MI] and ischemia-reperfusion [IR]) and validated the findings against ground truth histology. We randomly stratified 30 BALB/CJ mice (17 females, 13 males, median age = 10 wk) into three surgical groups (MI = 10, IR = 12, sham = 8) and imaged pre-surgery (baseline) and 1, 2, 7 and 14 d post-surgery using a pre-clinical high-frequency ultrasound system (VisualSonics Vevo 2100). We then used ABR-CSI to estimate end-systolic and peak radial (er) and longitudinal (el) strain estimates. ABR-CSI was found to have the ability to serially monitor non-uniform cardiac remodeling associated with murine MI and IR non-invasively through temporal variation of strain estimates post-surgery. Furthermore, radial end-systole (ES) strain images and segmental strain curves exhibited improved discrimination among infarct, border and remote regions around the myocardium compared with longitudinal strain results. For example, the MI group had significantly lower (Friedman's with Bonferroni-Dunn test, p = 0.002) ES er values in the anterior middle (infarcted) region at day 14 (n = 9, 9.23 ± 7.39%) compared with the BL group (n = 9, 44.32 ± 5.49). In contrast, anterior basal (remote region) mean ES er values did not differ significantly (non-significant Friedman's test, χ2 = 8.93, p = 0.06) at day 14 (n = 6, 33.05 ± 6.99%) compared with baseline (n = 6, 34.02 ± 6.75%). Histology slides stained with Masson's trichrome (MT) together with a machine learning model (random forest classifier) were used to derive the ground truth cardiac fibrosis parameter termed histology percentage of myocardial fibrosis (PMF). Both radial and longitudinal strain were found to have strong statistically significant correlations with the PMF parameter. However, radial strain had a higher Spearman's correlation value (εresρ = -0.67, n = 172, p < 0.001) compared with longitudinal strain (εlesρ = -0.60, n = 172, p < 0.001). Overall, the results of this study indicate that ABR-CSI can reliably perform non-invasive detection of infarcted and remote myocardium in small animal studies.


Assuntos
Cardiomiopatias , Infarto do Miocárdio , Masculino , Feminino , Camundongos , Animais , Remodelação Ventricular , Teorema de Bayes , Coração , Infarto do Miocárdio/diagnóstico por imagem , Miocárdio
8.
J Cardiovasc Magn Reson ; 24(1): 67, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36451214

RESUMO

BACKGROUND: Methamphetamine-associated cardiomyopathy (MA-CMP) is an increasingly recognised aetiology of cardiomyopathy. Cardiovascular magnetic resonance (CMR) is a specialised cardiac imaging modality commonly used in assessment of cardiomyopathy. We aimed to identify specific CMR features associated with MA-CMP. METHODS: A retrospective cohort study of CMR scans was performed in a single centre between January 2015 and December 2020. Thirty patients with MA-CMP who had undergone CMR were identified. MA-CMP was defined as those with a history of significant methamphetamine use hospitalised with acute decompensated heart failure (other causes of cardiomyopathy excluded). A retrospective analysis of index admission CMRs was performed. All studies were performed on a 1.5 T CMR scanner. RESULTS: The mean age of MA-CMP patients was 43.7 ± 7.5 years, and 86.7% were male. The mean left ventricular (LV) volume obtained in this cohort was consistent with severe LV dilatation (LV end-diastolic volume (334 ± 99 ml); LV end-systolic volume: 269 ± 98 ml), whilst the right ventricular (RV) volume indicated moderate-to-severe dilatation (RV end-diastolic volume: 272 ± 91 ml; RV end-systolic volume: 173 ± 82 ml). Mean LV ejection fraction (20.9 ± 9.2%) indicated severe LV dysfunction, with moderate-to-severe RV dysfunction also detected (RV ejection fraction: 29.4 ± 13.4%). 22 patients (73.3%) had myocardial late gadolinium enhancement (LGE), of which 59.1% were located in the mid-wall, with all of these involving the interventricular septum. 22.7% displayed localised regions of sub-endocardial LGE in a variety of locations, and 18.2% had transmural regions of LGE that were located in the inferior and inferolateral segments. 6 patients (20%) had intracardiac thrombus (4 LV, 2 both LV and RV). CONCLUSION: MA-CMP was associated with severe biventricular dilatation and dysfunction, with a high prevalence of intraventricular thrombus. This cohort study highlights that MA-CMP patients have a high prevalence of CMR findings.


Assuntos
Cardiomiopatias , Insuficiência Cardíaca , Metanfetamina , Septo Interventricular , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Metanfetamina/efeitos adversos , Estudos de Coortes , Meios de Contraste/efeitos adversos , Gadolínio , Valor Preditivo dos Testes , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Ventrículos do Coração , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico por imagem , Citidina Monofosfato
9.
Arq Bras Cardiol ; 119(5): 689-690, 2022 11.
Artigo em Inglês, Português | MEDLINE | ID: mdl-36453759
10.
Circ Cardiovasc Imaging ; 15(11): e014645, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36378779

RESUMO

BACKGROUND: Echocardiographic deformation-based ratios and novel multi-parametric scores have been suggested to discriminate transthyretin cardiac amyloidosis (ATTR-CM) from other causes of increased left ventricular wall thickness among patients referred for ATTR-CM evaluation. Their relative predictive accuracy has not been well studied. We sought to (1) identify echocardiographic parameters predictive of ATTR-CM and (2) compare the diagnostic accuracy of these parameters in patients with suspected ATTR-CM referred for technetium-99m-pyrophosphate scintigraphy. METHODS: Echocardiograms from 598 patients referred to 3 major amyloidosis centers for technetium-99m-pyrophosphate to detect ATTR-CM were analyzed, including longitudinal strain (LS) analysis. Deformation ratios (septal apex to base ratio, relative apical sparing, ejection fraction to global LS), a multi-center European increased wall thickness score, and Mayo Clinic derived ATTR score (transthyretin cardiac amyloidosis score) were calculated. A logistic regression model was used to identify the parameters that best associated with a diagnosis of ATTR-CM. Comparison of the diagnostic capacity of the parameters was performed by receiver operating characteristic curves and the area under the curve (AUC). RESULTS: Over half of the subjects (54.2%) were diagnosed with ATTR-CM (78% were men, median age of 76 years). Age, inferolateral wall thickness, and basal LS were the strongest predictors of ATTR-CM, AUC of 0.87 (95% CI: 0.83, 0.90), superior to the increased wall thickness score AUC of 0.78 (95% CI: 0.73, 0.83; P=0.004). An inferolateral wall thickness of ≥14 mm (AUC: 0.73) was as accurate as the published cut-offs for transthyretin cardiac amyloidosis score and septal apex to base (AUC: 0.72 and 0.69, P=0.8 and P=0.1, respectively), and was superior to ejection fraction to global LS and relative apical sparing (AUC: 0.64 and 0.53, P<0.001, respectively). A cut-off of ≥-8% for average basal LS (AUC: 0.76, CI: 0.72-0.79) had a similar area under the curve to transthyretin cardiac amyloidosis score (TCAS) (P=0.2); outperforming the other indices (P<0.01). CONCLUSION: Inferolateral wall thickness and average basal LS performed as well as or better than more complex echo ratios and multiparametric scores to predict ATTR-CM.


Assuntos
Neuropatias Amiloides Familiares , Cardiomiopatias , Masculino , Humanos , Idoso , Feminino , Pré-Albumina , Neuropatias Amiloides Familiares/complicações , Tecnécio , Difosfatos , Pirofosfato de Tecnécio Tc 99m , Ecocardiografia , Cintilografia
11.
J Transl Med ; 20(1): 522, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371290

RESUMO

BACKGROUND: Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium (Ca2+) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown. Thus, we aim to ascertain whether intracellular Ca2+ oscillations and the Ca2+ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes. METHODS AND RESULTS: ACM C-MSC show enhanced spontaneous Ca2+ oscillations and concomitant increased Ca2+/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca2+ Entry (SOCE), which leads to enhanced Ca2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca2+ handling machinery or CaMKII activity, we demonstrated a causative link between Ca2+ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca2+ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca2+ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE. CONCLUSIONS: Altogether, our results extend the knowledge of Ca2+ dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM.


Assuntos
Cardiomiopatias , Células-Tronco Mesenquimais , Camundongos , Animais , Humanos , Flecainida , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Miócitos Cardíacos , Cálcio , Cardiomiopatias/genética
12.
JACC Cardiovasc Imaging ; 15(11): 1944-1955, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36357136

RESUMO

BACKGROUND: Patients with suspected cardiac sarcoidosis frequently undergo fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging to assess disease activity at baseline and after treatment initiation. OBJECTIVES: This study investigated the effect of immunosuppressive therapy and biopsy status to achieve complete treatment response (CTR), partial treatment response (PTR), or no response (NR) on myocardial FDG-PET/CT. METHODS: This study analyzed 83 patients with suspected cardiac sarcoidosis (aged 53 ± 1.8 years, 71% were male, 69% were White, 61% had a history of biopsy-confirmed sarcoidosis) who were treatment naive, had evidence of myocardial FDG at baseline, and underwent repeat PET imaging after treatment initiation. CTR was graded visually, and PTR/NR were measured both visually and quantitatively using the total glycolytic activity. Patients were also evaluated for the occurrence of death, sustained ventricular arrhythmias, and heart failure admissions. RESULTS: Overall, 59 patients (71%) achieved CTR/PTR (30%/41%) at follow-up scan (P = 0.04). Total glycolytic activity and visual estimate of PTR/NR had excellent agreement (κ = 0.86 [95% CI: 0.72-0.99]; P < 0.0001). In patients receiving prednisone only, the highest rates of CTR/PTR were observed in patients initiated on moderate or high dose (P < 0.01). In a regression model, moderate prednisone start dose (P = 0.03) was more strongly associated with achieving CTR/PTR than was high prednisone start dose. However, the latter patients were tapered faster between start dose and follow-up scan (P < 0.01). After a median follow-up of 4.7 (IQR: 3.1-7.8) years, patients who were biopsy-proven (vs non-biopsy-proven; P = 0.029) and with preserved left ventricular function (P = 002) were less likely to experience major adverse cardiac events. Outcomes based on treatment response status (CTR vs PTR vs NR; P = 0.23) were not significantly different. CONCLUSIONS: Among patients with suspected sarcoidosis and evidence of myocardial inflammation, treatment response by serial FDG-PET was variable, but a favorable response was more common when using moderate-to-high intensity prednisone dose. Biopsy-proven individuals and those with preserved systolic function were less likely to experience adverse outcomes during follow-up.


Assuntos
Cardiomiopatias , Miocardite , Sarcoidose , Humanos , Masculino , Feminino , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Prednisona , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/patologia , Valor Preditivo dos Testes , Sarcoidose/diagnóstico por imagem , Sarcoidose/tratamento farmacológico , Sarcoidose/patologia , Tomografia por Emissão de Pósitrons/métodos , Terapia de Imunossupressão
13.
Sci Rep ; 12(1): 19670, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36385157

RESUMO

Cardiomyopathies are progressive disease conditions that give rise to an abnormal heart phenotype and are a leading cause of heart failures in the general population. These are complex diseases that show co-morbidity with other diseases. The molecular interaction network in the localised disease neighbourhood is an important step toward deciphering molecular mechanisms underlying these complex conditions. In this pursuit, we employed network medicine techniques to systematically investigate cardiomyopathy's genetic interplay with other diseases and uncover the molecular players underlying these associations. We predicted a set of candidate genes in cardiomyopathy by exploring the DIAMOnD algorithm on the human interactome. We next revealed how these candidate genes form association across different diseases and highlighted the predominant association with brain, cancer and metabolic diseases. Through integrative systems analysis of molecular pathways, heart-specific mouse knockout data and disease tissue-specific transcriptomic data, we screened and ascertained prominent candidates that show abnormal heart phenotype, including NOS3, MMP2 and SIRT1. Our computational analysis broadens the understanding of the genetic associations of cardiomyopathies with other diseases and holds great potential in cardiomyopathy research.


Assuntos
Cardiomiopatias , Humanos , Camundongos , Animais , Cardiomiopatias/genética , Fenótipo , Algoritmos , Coração
14.
Card Electrophysiol Clin ; 14(4): 657-677, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36396183

RESUMO

Percutaneous epicardial ventricular tachycardia ablation can decrease implanted cardioverter defibrillator shocks and hospitalizations; proper patient selection and procedural technique are imperative to maximize the benefit-risk ratio. The best candidates for epicardial ventricular tachycardia will depend on history of prior ablation, type of cardiomyopathy, and specific electrocardiogram and cardiac imaging findings. Complications include hemopericardium, hemoperitoneum, coronary vessel injury, and phrenic nerve injury. Modern epicardial mapping techniques provide new understandings of the 3-dimensional nature of reentrant ventricular tachycardia circuits across cardiomyopathy etiologies. Where epicardial access is not feasible, alternative techniques to reach epicardial ventricular tachycardia sources may be necessary.


Assuntos
Cardiomiopatias , Taquicardia Ventricular , Humanos , Seleção de Pacientes , Resultado do Tratamento , Mapeamento Epicárdico/efeitos adversos , Arritmias Cardíacas/complicações , Cardiomiopatias/complicações
15.
Card Electrophysiol Clin ; 14(4): 793-799, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36396194

RESUMO

Surgery for ventricular tachycardia (VT) is indicated in patients in whom pharmacotherapy or catheter ablation is ineffective or frequent VT attacks are not suppressed or with frequent activation of implantable cardioverter defibrillator. In ischemic VT, resection of fibrous endocardium combined with encircling cryothermia at the border between the infarcted and normal myocardium is performed. In surgery for VT associated with cardiomyopathy, close collaboration between the physician and surgeon is important and intraoperative mapping using electro-anatomic mapping system is helpful. In VT associated with cardiac tumors, cryothermia of the thinned subepicardial myocardium at the edge of the tumor is recommended in addition to resection of tumors.


Assuntos
Cardiomiopatias , Ablação por Cateter , Desfibriladores Implantáveis , Taquicardia Ventricular , Humanos , Taquicardia Ventricular/cirurgia , Endocárdio/cirurgia , Cardiomiopatias/cirurgia
16.
Emerg Med Clin North Am ; 40(4): 651-662, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36396213

RESUMO

Sudden cardiac death (SCD) describes the unexpected natural death from a cardiac cause within a short time period, generally 1 hour or lesser from the onset of symptoms, often due to a cardiac dysrhythmia. Overall, the most common cause of SCD is coronary artery disease but for patients aged younger than 35 years, the most common cause of SCD is a dysrhythmia in the setting of a structurally normal heart. This article will review the background, diagnosis, and management of the common hereditary channelopathies and cardiomyopathies associated with an increased risk of SCD in patients without ischemic heart disease.


Assuntos
Cardiomiopatias , Morte Súbita Cardíaca , Humanos , Idoso , Síndrome , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Cardiomiopatias/complicações
18.
J Cardiovasc Magn Reson ; 24(1): 60, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36404313

RESUMO

BACKGROUND: Myocardial fibrosis is a common pathophysiological process involved in many cardiovascular diseases. However, limited prior studies suggested no association between focal myocardial fibrosis detected by cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) and disease severity in Eisenmenger syndrome (ES). This study aimed to explore potential associations between myocardial fibrosis evaluated by the CMR LGE and T1 mapping and risk stratification profiles including exercise tolerance, serum biomarkers, hemodynamics, and right ventricular (RV) function in these patients. METHODS: Forty-five adults with ES and 30 healthy subjects were included. All subjects underwent a contrast-enhanced 3T CMR. Focal replacement fibrosis was visualized on LGE images. The locations of LGE were recorded. After excluding LGE in ventricular insertion point (VIP), ES patients were divided into myocardial LGE-positive (LGE+) and LGE-negative (LGE-) subgroups. Regions of interest in the septal myocardium were manually contoured in the T1 mapping images to determine the diffuse myocardial fibrosis. The relationships between myocardial fibrosis and 6-min walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-pro BNP), hematocrit, mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), RV/left ventricular end-systolic volume (RV/LV ESV), RV ejection fraction (RVEF), and risk stratification were analyzed. RESULTS: Myocardial LGE (excluding VIP) was common in ES (16/45, 35.6%), and often located in the septum (12/45, 26.7%). The clinical characteristics, hemodynamics, CMR morphology and function, and extracellular volume fraction (ECV) were similar in the LGE+ and LGE- groups (all P > 0.05). ECV was significantly higher in ES patients (28.6 ± 5.9% vs. 25.6 ± 2.2%, P < 0.05) and those with LGE- ES (28.3 ± 5.9% vs. 25.6 ± 2.2%, P < 0.05) than healthy controls. We found significant correlations between ECV and log NT-pro BNP, hematocrit, mPAP, PVRI, RV/LV ESV, and RVEF (all P < 0.05), and correlations trends between ECV and 6MWT (P = 0.06) in ES patients. An ECV threshold of 29.0% performed well in differentiating patients with high-risk ES from those with intermediate or low risk (area under curve 0.857, P < 0.001). CONCLUSIONS: Myocardial fibrosis is a common feature of ES. ECV may serve as an important imaging marker for ES disease severity.


Assuntos
Cardiomiopatias , Complexo de Eisenmenger , Cardiopatias Congênitas , Humanos , Adulto , Gadolínio , Meios de Contraste , Complexo de Eisenmenger/complicações , Complexo de Eisenmenger/diagnóstico por imagem , Valor Preditivo dos Testes , Fibrose , Espectroscopia de Ressonância Magnética
19.
J Cardiovasc Magn Reson ; 24(1): 52, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329520

RESUMO

BACKGROUND: Although Chagas cardiomyopathy is related to thromboembolic stroke, data on risk factors for cerebrovascular events in Chagas disease is limited. Thus, we assessed the relationship between left ventricular (LV) impairment and cerebrovascular events and sources of thromboembolism in patients with Chagas cardiomyopathy. METHODS: This retrospective cohort included patients with chronic Chagas cardiomyopathy who underwent cardiovascular magnetic resonance (CMR). CMR was performed with a 1.5 T scanner to provide LV volumes, mass, ejection fraction (LVEF), and myocardial fibrosis. The primary outcome was a composite of incident ischemic cerebrovascular events (stroke or transient ischemic attack-TIA) and potential thromboembolic sources (atrial fibrillation (AF), atrial flutter, or intracavitary thrombus) during the follow-up. RESULTS: A total of 113 patients were included. Median age was 56 years (IQR: 45-67), and 58 (51%) were women. The median LVEF was 53% (IQR: 41-62). LV aneurysms and LV fibrosis were present in 38 (34%) and 76 (67%) individuals, respectively. The median follow-up time was 6.9 years, with 29 events: 11 cerebrovascular events, 16 had AF or atrial flutter, and two had LV apical thrombosis. In the multivariable model, only lower LVEF remained significantly associated with the outcomes (HR: 0.96, 95% CI: 0.93-0.99). Patients with reduced LVEF lower than 40% had a much higher risk of cerebrovascular events and thromboembolic sources (HR: 3.16 95% CI: 1.38-7.25) than those with normal LVEF. The combined incidence rate of the combined events in chronic Chagas cardiomyopathy patients with reduced LVEF was 13.9 new cases per 100 persons-year. CONCLUSIONS: LV systolic dysfunction is an independent predictor of adverse cerebrovascular events and potential sources of thromboembolism in patients with chronic Chagas cardiomyopathy.


Assuntos
Fibrilação Atrial , Flutter Atrial , Cardiomiopatias , Cardiomiopatia Chagásica , Cardiopatias , Acidente Vascular Cerebral , Tromboembolia , Disfunção Ventricular Esquerda , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Cardiomiopatia Chagásica/complicações , Cardiomiopatia Chagásica/diagnóstico por imagem , Cardiomiopatia Chagásica/epidemiologia , Estudos Retrospectivos , Valor Preditivo dos Testes , Função Ventricular Esquerda , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/etiologia , Volume Sistólico , Tromboembolia/diagnóstico por imagem , Tromboembolia/epidemiologia , Tromboembolia/etiologia
20.
Cell Death Dis ; 13(11): 948, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357371

RESUMO

Genetic mutations in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common cause of hypertrophic cardiomyopathy (HCM). Myocardial fibrosis (MF) plays a critical role in the development of HCM. However, the mechanism for mutant MYBPC3-induced MF is not well defined. In this study, we developed a R495Q mutant pig model using cytosine base editing and observed an early-onset MF in these mutant pigs shortly after birth. Unexpectedly, we found that the "cardiac-specific" MYBPC3 gene was actually expressed in cardiac fibroblasts from different species as well as NIH3T3 fibroblasts at the transcription and protein levels. CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated nuclear factor κB (NF-κB) signaling pathway, which increased the expression of transforming growth factor beta (TGF-ß1) and other pro-inflammatory genes. The upregulation of TGF-ß1 promoted the expression of hypoxia-inducible factor-1 subunit α (HIF-1α) and its downstream targets involved in glycolysis such as GLUT1, PFK, and LDHA. Consequently, the enhanced aerobic glycolysis with higher rate of ATP biosynthesis accelerated the activation of cardiac fibroblasts, contributing to the development of HCM. This work reveals an intrinsic role of MYBPC3 in maintaining cardiac fibroblast homeostasis and disruption of MYBPC3 in these cells contributes to the disease pathogenesis of HCM.


Assuntos
Cardiomiopatias , Cardiomiopatia Hipertrófica , Camundongos , Suínos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células NIH 3T3 , Cardiomiopatia Hipertrófica/genética , Mutação , Cardiomiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas do Citoesqueleto/metabolismo , Fibrose
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