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1.
Clin Cardiol ; 47(5): e24278, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38767024

RESUMO

Olanzapine, an atypical antipsychotic medication, has gained prominence in the treatment of schizophrenia and related psychotic disorders due to its effectiveness and perceived safety profile. However, emerging evidence suggests a potential link between olanzapine use and adverse cardiovascular effects, including cardiomyopathy. This narrative review explores the mechanisms, clinical implications, and management strategies associated with olanzapine-induced cardiomyopathy. A comprehensive review of the literature was conducted to investigate the relationship between olanzapine and cardiomyopathy. The search included epidemiological studies, clinical case reports, and mechanistic research focusing on the pathophysiology of olanzapine-induced cardiomyopathy. The review also examined treatment strategies for managing this potential complication. Olanzapine-induced cardiomyopathy is hypothesized to be associated with metabolic disturbances and receptor antagonism. The metabolic effects of olanzapine, such as weight gain, insulin resistance, and dyslipidemia, share similarities with obesity-related cardiomyopathy. Additionally, olanzapine's antagonism of certain receptors may contribute to cardiovascular stress. The review highlighted that patients with new-onset heart failure and significant weight gain while on olanzapine should be closely monitored for signs of cardiomyopathy. Early detection and prompt withdrawal of olanzapine, along with initiation of goal-directed medical therapy, are crucial for mitigating this potentially life-threatening condition. The relationship between olanzapine and cardiomyopathy is complex and not yet fully understood. However, the potential for significant cardiovascular risk necessitates vigilance among healthcare providers. Early identification and management of olanzapine-induced cardiomyopathy can improve patient outcomes. Further research is needed to elucidate the precise mechanisms behind this adverse effect and to develop optimized treatment strategies for patients requiring antipsychotic therapy.


Assuntos
Antipsicóticos , Cardiomiopatias , Obesidade , Olanzapina , Humanos , Olanzapina/efeitos adversos , Antipsicóticos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Obesidade/complicações , Esquizofrenia/tratamento farmacológico , Diagnóstico Diferencial , Fatores de Risco
2.
Circ Cardiovasc Imaging ; 17(5): e015996, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38771906

RESUMO

BACKGROUND: Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECVCT), and has prognostic utility in several diseases. This study aims to map out regional differences in ECVCT to obtain greater insights into the pathophysiological mechanisms of ECV expansion and its clinical implications. METHODS: Three prospective cohorts were included: patients with aortic stenosis (AS) and coexisting AS and transthyretin cardiac amyloidosis were referred for a transcatheter aortic valve replacement and had ECG-gated CT angiography and Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy to differentiate between the 2 cohorts. Controls had CT angiography and cardiac magnetic resonance demonstrating no significant coronary artery disease or infarction. Global and regional ECVCT was analyzed, and its association with mortality was assessed for patients with AS. RESULTS: In 199 patients, controls (n=65; 66% male), AS (n=115), and coexisting AS and transthyretin cardiac amyloidosis (n=19) had a global ECVCT of 26.1 (25.0-27.8%) versus 29.1 (27.5-31.1%) versus 37.4 (32.5-46.6%), respectively; P<0.001. Across cohorts, ECVCT was higher at the base (versus apex), the inferoseptum (versus anterolateral wall), and the subendocardium (versus subepicardium); P<0.05 for all. Among patients with AS, epicardial ECVCT, rather than any other regional value or global ECVCT, was the strongest predictor of mortality at a median of 3.9 (max 6.3) years (adjusted hazard ratio, 1.21 [95% CI, 1.08-1.36]; P=0.002). CONCLUSIONS: Regional differences in ECVCT suggest a predilection for fibrosis and amyloid infiltration at the base, subendocardium, inferior wall, and septum more than the anterior and lateral myocardium. ECVCT can predict long-term mortality with the subepicardium demonstrating the strongest discriminatory power. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03029026 and NCT03094143.


Assuntos
Neuropatias Amiloides Familiares , Estenose da Valva Aórtica , Angiografia por Tomografia Computadorizada , Fibrose , Miocárdio , Humanos , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/mortalidade , Masculino , Feminino , Idoso , Estudos Prospectivos , Angiografia por Tomografia Computadorizada/métodos , Idoso de 80 Anos ou mais , Miocárdio/patologia , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/mortalidade , Valor Preditivo dos Testes , Prognóstico , Angiografia Coronária/métodos , Substituição da Valva Aórtica Transcateter , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Pessoa de Meia-Idade
4.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732138

RESUMO

D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.


Assuntos
Proteína Mitocondrial Trifuncional/deficiência , Proteína Multifuncional do Peroxissomo-2 , Humanos , Proteína Multifuncional do Peroxissomo-2/deficiência , Proteína Multifuncional do Peroxissomo-2/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Recém-Nascido , Lactente , Masculino , Feminino , Sequenciamento do Exoma , Mutação da Fase de Leitura , 17-Hidroxiesteroide Desidrogenases/deficiência , 17-Hidroxiesteroide Desidrogenases/genética , Região de Recursos Limitados , Miopatias Mitocondriais , Cardiomiopatias , Doenças do Sistema Nervoso , Rabdomiólise
5.
Int J Mol Sci ; 25(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38731929

RESUMO

Sepsis-induced cardiomyopathy (SICM) is one of the leading indicators for poor prognosis associated with sepsis. Despite its reversibility, prognosis varies widely among patients. Mitochondria play a key role in cellular energy production by generating adenosine triphosphate (ATP), which is vital for myocardial energy metabolism. Over recent years, mounting evidence suggests that severe sepsis not only triggers mitochondrial structural abnormalities such as apoptosis, incomplete autophagy, and mitophagy in cardiomyocytes but also compromises their function, leading to ATP depletion. This metabolic disruption is recognized as a significant contributor to SICM, yet effective treatment options remain elusive. Sepsis cannot be effectively treated with inotropic drugs in failing myocardium due to excessive inflammatory factors that blunt ß-adrenergic receptors. This review will share the recent knowledge on myocardial cell death in sepsis and its molecular mechanisms, focusing on the role of mitochondria as an important metabolic regulator of SICM, and discuss the potential for developing therapies for sepsis-induced myocardial injury.


Assuntos
Cardiomiopatias , Sepse , Sepse/complicações , Sepse/metabolismo , Humanos , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Animais , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitofagia , Metabolismo Energético , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Apoptose , Trifosfato de Adenosina/metabolismo
6.
BMC Cardiovasc Disord ; 24(1): 243, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724901

RESUMO

BACKGROUND: The aim of this study was to evaluate the recovery rate of the left ventricular systolic function of women diagnosed with peripartum cardiomyopathy receiving specialized care in rural Tanzania. METHODS: In this observational study, women diagnosed with peripartum cardiomyopathy at a referral center in rural Tanzania between December 2015 and September 2021 were included. Women diagnosed between February and September 2021 were followed prospectively, those diagnosed between December 2015 and January 2021 were tracked back for a follow-up echocardiography. All participants received a clinical examination, a comprehensive echocardiogram, and a prescription of guideline-directed medical therapy. The primary outcome was recovery of the left ventricular systolic function (left ventricular ejection fraction > 50%). RESULTS: Median age of the 110 participants was 28.5 years (range 17-45). At enrolment, 49 (45%) participants were already on cardiac medication, 50 (45%) had severe eccentric hypertrophy of the left ventricle, and the median left ventricular ejection fraction was 30% (range 15-46). After a median follow-up of 8.98 months (IQR 5.72-29.37), 61 (55%) participants were still on cardiac medication. Full recovery of the left ventricular systolic function was diagnosed in 76 (69%, 95% CI 59.6-77.6%) participants. In the multivariate analysis, a higher left ventricular ejection fraction at baseline was positively associated with full recovery (each 5% increase; OR 1.7, 95% CI 1.10-2.62, p = 0.012), while higher age was inversely associated (each 10 years increase; OR 0.40, 95% CI 0.19-0.82, p = 0.012). CONCLUSION: Left ventricular systolic function recovered completely in 69% of study participants with peripartum cardiomyopathy from rural Tanzania under specialized care.


Assuntos
Cardiomiopatias , Período Periparto , Complicações Cardiovasculares na Gravidez , Recuperação de Função Fisiológica , Volume Sistólico , Sístole , Função Ventricular Esquerda , Humanos , Feminino , Adulto , Tanzânia/epidemiologia , Adulto Jovem , Adolescente , Gravidez , Cardiomiopatias/fisiopatologia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/diagnóstico , Fatores de Tempo , Pessoa de Meia-Idade , Complicações Cardiovasculares na Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Resultado do Tratamento , Estudos Prospectivos , Saúde da População Rural , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico , Transtornos Puerperais/fisiopatologia , Transtornos Puerperais/diagnóstico , Transtornos Puerperais/terapia , Transtornos Puerperais/tratamento farmacológico
7.
Int J Med Sci ; 21(6): 983-993, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38774750

RESUMO

Previous studies have highlighted the protective effects of pyruvate kinase M2 (PKM2) overexpression in septic cardiomyopathy. In our study, we utilized cardiomyocyte-specific PKM2 knockout mice to further investigate the role of PKM2 in attenuating LPS-induced myocardial dysfunction, focusing on mitochondrial biogenesis and prohibitin 2 (PHB2). Our findings confirmed that the deletion of PKM2 in cardiomyocytes significantly exacerbated LPS-induced myocardial dysfunction, as evidenced by impaired contractile function and relaxation. Additionally, the deletion of PKM2 intensified LPS-induced myocardial inflammation. At the molecular level, LPS triggered mitochondrial dysfunction, characterized by reduced ATP production, compromised mitochondrial respiratory complex I/III activities, and increased ROS production. Intriguingly, the absence of PKM2 further worsened LPS-induced mitochondrial damage. Our molecular investigations revealed that LPS disrupted mitochondrial biogenesis in cardiomyocytes, a disruption that was exacerbated by the absence of PKM2. Given that PHB2 is known as a downstream effector of PKM2, we employed PHB2 adenovirus to restore PHB2 levels. The overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and promoted mitochondrial function. Overall, our results underscore the critical role of PKM2 in regulating the progression of septic cardiomyopathy. PKM2 deficiency impeded mitochondrial biogenesis, leading to compromised mitochondrial integrity, increased myocardial inflammation, and impaired cardiac function. The overexpression of PHB2 mitigated the deleterious effects of PKM2 deletion. This discovery offers a novel insight into the molecular mechanisms underlying septic cardiomyopathy and suggests potential therapeutic targets for intervention.


Assuntos
Cardiomiopatias , Camundongos Knockout , Mitocôndrias Cardíacas , Miócitos Cardíacos , Proibitinas , Piruvato Quinase , Sepse , Animais , Cardiomiopatias/patologia , Cardiomiopatias/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/etiologia , Camundongos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Sepse/metabolismo , Sepse/patologia , Sepse/genética , Piruvato Quinase/metabolismo , Piruvato Quinase/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Humanos , Biogênese de Organelas , Lipopolissacarídeos/toxicidade , Masculino , Modelos Animais de Doenças
8.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167208, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38701956

RESUMO

OBJECTIVE: This study aims to investigate the cardiac protective effects and molecular mechanisms of electroacupuncture (EA) pre-treatment in lipopolysaccharide (LPS)-Induced Cardiomyopathy. METHODS AND RESULTS: Pre-treatment with EA was performed 30 min before intraperitoneal injection of LPS. Cardiac function changes in mice of the EA + LPS group were observed using electrocardiography, echocardiography, and enzyme linked immunosorbent assay (ELISA) and compared with the LPS group. The results demonstrated that EA pre-treatment significantly improved the survival rate of septic mice, alleviated the severity of endotoxemia, and exhibited notable cardiac protective effects. These effects were characterized by a reduction in ST-segment elevation on electrocardiography, an increase in ejection fraction (EF) and fraction shortening (FS) on echocardiography and a decrease in the expression of serum cardiac troponin I (cTn-I) levels. Serum exosomes obtained after EA pre-treatment were extracted and administered to septic mice, revealing significant cardiac protective effects of EA-derived exosomes. Furthermore, the antagonism of circulating exosomes in mice markedly suppressed the cardiac protective effects conferred by EA pre-treatment. Analysis of serum exosomes using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed a significant upregulation of miR-381 expression after EA pre-treatment. Inhibition or overexpression of miR-381 through serotype 9 adeno-associated virus (AAV9)-mediated gene delivery demonstrated that overexpression of miR-381 exerted a cardiac protective effect, while inhibition of miR-381 significantly attenuated the cardiac protective effects conferred by EA pre-treatment. CONCLUSIONS: Our research findings have revealed a novel endogenous cardiac protection mechanism, wherein circulating exosomes derived from EA pre-treatment mitigate LPS-induced cardiac dysfunction via miR-381.


Assuntos
Cardiomiopatias , Eletroacupuntura , Exossomos , Lipopolissacarídeos , MicroRNAs , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Exossomos/metabolismo , Exossomos/genética , Eletroacupuntura/métodos , Camundongos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/terapia , Cardiomiopatias/patologia , Cardiomiopatias/genética , Cardiomiopatias/prevenção & controle , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
10.
J Korean Med Sci ; 39(19): e163, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769922

RESUMO

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We sought to characterize the clinical characteristics of ATTR-CM in Asia. METHODS: Data from a nationwide cohort of patients with ATTR-CM from six major tertiary centres in South Korea were analysed between 2010 and 2021. All patients underwent clinical evaluation, biochemical laboratory tests, echocardiography, and transthyretin (TTR) genotyping at the time of diagnosis. The study population comprised 105 Asian ATTR-CM patients (mean age: 69 years; male: 65.7%, wild-type ATTR-CM: 41.9%). RESULTS: Among our cohort, 18% of the patients had a mean left ventricular (LV) wall thickness < 12 mm. The diagnosis of ATTR-CM increased notably during the study period (8 [7.6%] during 2010-2013 vs. 22 [21.0%] during 2014-2017 vs. 75 [71.4%] during 2018-2021). Although the duration between symptom onset and diagnosis did not differ, the proportion of patients with HF presenting mild symptoms increased during the study period (25% NYHA class I/II between 2010-2013 to 77% between 2018-2021). In contrast to other international registry data, male predominance was less prominent in wild-type ATTR-CM (68.2%). The distribution of TTR variants was also different from Western countries and from Japan. Asp38Ala was the most common mutation. CONCLUSION: A nationwide cohort of ATTR-CM exhibited less male predominance, a proportion of patients without increased LV wall thickness, and distinct characteristics of genetic mutations, compared to cohorts in other parts of the world. Our results highlight the ethnic variation in ATTR-CM and may contribute to improving the screening process for ATTR-CM in the Asian population.


Assuntos
Neuropatias Amiloides Familiares , Cardiomiopatias , Ecocardiografia , Pré-Albumina , Humanos , Masculino , Feminino , Idoso , República da Coreia , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/patologia , Cardiomiopatias/genética , Cardiomiopatias/diagnóstico , Pré-Albumina/genética , Pessoa de Meia-Idade , Estudos de Coortes , Povo Asiático/genética , Genótipo , Mutação , Insuficiência Cardíaca/diagnóstico , Idoso de 80 Anos ou mais
11.
Dis Model Mech ; 17(5)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38770680

RESUMO

Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.


Assuntos
Distrofina , Camundongos Endogâmicos mdx , Camundongos Knockout , Receptores de Glucocorticoides , Animais , Receptores de Glucocorticoides/metabolismo , Distrofina/metabolismo , Distrofina/genética , Distrofina/deficiência , Miocárdio/patologia , Miocárdio/metabolismo , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Camundongos , Cardiomiopatias/patologia , Cardiomiopatias/metabolismo , Camundongos Endogâmicos C57BL , Distrofia Muscular Animal/patologia , Distrofia Muscular Animal/metabolismo , Fenótipo , Sístole/efeitos dos fármacos
13.
J Clin Invest ; 134(10)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38747296

RESUMO

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac condition characterized by cardiac remodeling and life-threatening ventricular arrhythmias. In this issue of the JCI, Chelko, Penna, and colleagues mechanistically addressed the intricate contribution of immune-mediated injury in ACM pathogenesis. Inhibition of nuclear factor κ-B (NF-κB) and infiltration of monocyte-derived macrophages expressing C-C motif chemokine receptor-2 (CCR2) alleviated the phenotypic ACM features (i.e., fibrofatty replacement, contractile dysfunction, and ventricular arrhythmias) in desmoglein 2-mutant (Dsg2mut/mut) mice. These findings pave the way for efficacious and targetable immune therapy for patients with ACM.


Assuntos
Desmogleína 2 , Macrófagos , Receptores CCR2 , Animais , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Humanos , Desmogleína 2/genética , Desmogleína 2/metabolismo , Desmogleína 2/imunologia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores CCR2/antagonistas & inibidores , NF-kappa B/metabolismo , NF-kappa B/genética , Arritmias Cardíacas/patologia , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/patologia , Displasia Arritmogênica Ventricular Direita/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/imunologia , Cardiomiopatias/metabolismo
14.
PLoS One ; 19(5): e0296440, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691571

RESUMO

BACKGROUND: Chronic myocardial injury is a condition defined by stably elevated cardiac biomarkers without acute myocardial ischemia. Although studies from high-income countries have reported that chronic myocardial injury predicts adverse prognosis, there are no published data about the condition in sub-Saharan Africa. METHODS: Between November 2020 and January 2023, adult patients with chest pain or shortness of breath were recruited from an emergency department in Moshi, Tanzania. Medical history and point-of-care troponin T (cTnT) assays were obtained from participants; those whose initial and three-hour repeat cTnT values were abnormally elevated but within 11% of each other were defined as having chronic myocardial injury. Mortality was assessed thirty days following enrollment. RESULTS: Of 568 enrolled participants, 81 (14.3%) had chronic myocardial injury, 73 (12.9%) had acute myocardial injury, and 412 (72.5%) had undetectable cTnT values. Of participants with chronic myocardial injury, the mean (± sd) age was 61.5 (± 17.2) years, and the most common comorbidities were CKD (n = 65, 80%) and hypertension (n = 60, 74%). After adjusting for CKD, thirty-day mortality rates (38% vs. 36%, aOR 1.03, 95% CI: 0.52-2.03, p = 0.931) were similar between participants with chronic myocardial injury and those with acute myocardial injury, but significantly greater (38% vs. 13.6%, aOR 3.63, 95% CI: 1.98-6.65, p<0.001) among participants with chronic myocardial injury than those with undetectable cTnT values. CONCLUSION: In Tanzania, chronic myocardial injury is a poor prognostic indicator associated with high risk of short-term mortality. Clinicians practicing in this region should triage patients with stably elevated cTn levels in light of their increased risk.


Assuntos
Serviço Hospitalar de Emergência , Troponina T , Humanos , Masculino , Feminino , Tanzânia/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Troponina T/sangue , Idoso , Prognóstico , Adulto , Biomarcadores/sangue , Doença Crônica , Cardiomiopatias/sangue , Cardiomiopatias/epidemiologia , Cardiomiopatias/mortalidade
15.
Sci Adv ; 10(19): eadh0798, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38718107

RESUMO

Mutations in the LMNA gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis underlying cardiac dysfunction remains elusive. Using a novel conditional deletion model capable of translatome profiling, we observed that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Before cardiac dysfunction, Lmna-deleted cardiomyocytes displayed nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation. Translatome profiling identified MED25 activation, a transcriptional cofactor that regulates Golgi stress. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the Golgi. Systemic administration of modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the LMNA cardiomyopathy development.


Assuntos
Cardiomiopatias , Lamina Tipo A , Miócitos Cardíacos , Membrana Nuclear , Animais , Lamina Tipo A/metabolismo , Lamina Tipo A/genética , Camundongos , Membrana Nuclear/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Cardiomiopatias/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Autofagia , Estresse Fisiológico , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Complexo de Golgi/metabolismo , Camundongos Knockout
16.
J Am Heart Assoc ; 13(10): e034518, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38761073

RESUMO

BACKGROUND: Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes. METHODS AND RESULTS: In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P=0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P<0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes. CONCLUSIONS: Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.


Assuntos
Neuropatias Amiloides Familiares , Benzoxazóis , Biomarcadores , Cardiomiopatias , Peptídeo Natriurético Encefálico , Troponina T , Humanos , Masculino , Feminino , Biomarcadores/sangue , Peptídeo Natriurético Encefálico/sangue , Idoso , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/mortalidade , Neuropatias Amiloides Familiares/diagnóstico , Benzoxazóis/uso terapêutico , Troponina T/sangue , Cardiomiopatias/sangue , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/mortalidade , Cardiomiopatias/diagnóstico , Resultado do Tratamento , Fatores de Tempo , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Estudos Retrospectivos , Pré-Albumina/metabolismo
17.
J Am Heart Assoc ; 13(10): e030467, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38761081

RESUMO

BACKGROUND: Many cardiomyopathy-associated FLNC pathogenic variants are heterozygous truncations, and FLNC pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood. METHODS AND RESULTS: We describe an individual with biallelic FLNC pathogenic variants, p.Arg650X and c.970-4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with FLNC variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970-4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. The FLNC truncation, Arg650X/c.970-4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous FLNC disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC-CMs for response to the proteasome inhibitor bortezomib. After exposure to low-dose bortezomib, FLNC-null iPSC-CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II. FLNC null iPSC-CMs had prolonged electric field potential, which was further prolonged in the presence of low-dose bortezomib. FLNC null engineered heart tissues had impaired function after low-dose bortezomib. CONCLUSIONS: FLNC pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC-CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib-induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.


Assuntos
Filaminas , Proteostase , Filaminas/genética , Filaminas/metabolismo , Humanos , Feminino , Células-Tronco Pluripotentes Induzidas/metabolismo , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/etiologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Masculino , Adulto , Mutação , Bortezomib/farmacologia
18.
Pediatr Transplant ; 28(4): e14742, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38702926

RESUMO

BACKGROUND: As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. METHODS: Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. RESULTS: In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. CONCLUSIONS: Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.


Assuntos
Rejeição de Enxerto , Sobrevivência de Enxerto , Cardiopatias Congênitas , Transplante de Coração , Humanos , Criança , Masculino , Feminino , Pré-Escolar , Lactente , Adolescente , Cardiopatias Congênitas/cirurgia , Cardiopatias Congênitas/patologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Seguimentos , Cardiomiopatias/cirurgia , Cardiomiopatias/patologia , Reoperação , Recém-Nascido , Análise de Sobrevida
19.
PLoS One ; 19(5): e0297914, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691546

RESUMO

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.


Assuntos
Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/diagnóstico , Canalopatias/genética , Canalopatias/diagnóstico , Testes Genéticos/métodos , Variação Genética , Cardiomiopatias/genética , Cardiomiopatias/diagnóstico , Síndrome do QT Longo/genética , Síndrome do QT Longo/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico
20.
Kardiologiia ; 64(4): 54-60, 2024 Apr 30.
Artigo em Russo, Inglês | MEDLINE | ID: mdl-38742516

RESUMO

AIM: To estimate the prevalence of amyloid cardiomyopathy (CM) caused by transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) amyloidosis among patients aged >65 years with interventricular septal (IVS) hypertrophy of ≥14 mm. MATERIAL AND METHODS: From January through August 2023, 60 patients (mean age 7.2±7.3 years, 34 (56.67%) men) were enrolled. Patients meeting the inclusion criteria underwent an echocardiographic study with determining the myocardial longitudinal strain, myocardial scintigraphy with 99mTc-pyrfotech, myocardial single-photon emission computed tomography, measurement of N-terminal fragment of brain natriuretic peptide and troponin I, and the immunochemical study of serum and urine proteins with measurement of free light chains. In the presence of grades 2 and 3 radiopharmaceutical uptake according to scintigraphy, a molecular genetic study was performed for differential diagnosis of wild-type transthyretin amyloidosis (wtATTR) and hereditary/variant (hATTR) ATTR-CM. RESULTS: According to data of myocardial scintigraphy with 99mTc-pyrfotech, grade 3 uptake in the absence of monoclonal secretion was detected in 5 (8.3%) cases and grade 2 radiotracer uptake in the absence of monoclonal secretion was detected in 6 (10%) patients. Myeloma complicated by AL amyloidosis and primary AL amyloidosis were found in 5 (8.3%) patients. CONCLUSION: Among patients aged ≥65 years with IVS hypertrophy ≥14 mm, amyloid CM was detected in 20% of cases (12 patients), including 5 cases (8.3%) of AL amyloidosis and 7 cases (11.7%) of ATTR amyloidosis.


Assuntos
Neuropatias Amiloides Familiares , Ecocardiografia , Hipertrofia Ventricular Esquerda , Humanos , Masculino , Feminino , Federação Russa/epidemiologia , Idoso , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Prevalência , Hipertrofia Ventricular Esquerda/epidemiologia , Ecocardiografia/métodos , Amiloidose de Cadeia Leve de Imunoglobulina/epidemiologia , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Cardiomiopatias/epidemiologia
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