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1.
Am J Cardiol ; 160: 99-105, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610875

RESUMO

Cardiac amyloidosis is an important clinical entity associated with significant morbidity and mortality. Although the signs and symptoms can be apparent early in the disease course, diagnoses are often made late because of inadequate recognition. A diagnosis of cardiac amyloidosis requires careful scrutiny of a patient's symptoms, an electrocardiogram, and imaging studies, including echocardiography and magnetic resonance imaging. Further evaluation is required through the measurement of serum and urine light chains and the use of bone scintigraphy imaging to differentiate transthyretin amyloidosis from light-chain cardiac amyloidosis. The available treatments have expanded tremendously in recent years and have improved outcomes in the population with this disorder. Thus, it has become increasingly important to diagnose cardiac amyloidosis and provide timely therapies. This article will clarify the various misconceptions about cardiac amyloidosis and provide a framework for primary care providers to better identify this disease in their practice.


Assuntos
Amiloidose/diagnóstico , Cardiomiopatias/diagnóstico , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/fisiopatologia , Neuropatias Amiloides Familiares/terapia , Amiloidose/epidemiologia , Amiloidose/fisiopatologia , Amiloidose/terapia , Compostos de Anilina , Circulação Assistida , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Técnicas de Imagem Cardíaca , Cardiomiopatias/epidemiologia , Cardiomiopatias/fisiopatologia , Cardiomiopatias/terapia , Diagnóstico Diferencial , Ecocardiografia , Eletrocardiografia , Etilenoglicóis , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/epidemiologia , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Estilbenos
2.
PLoS One ; 16(8): e0255022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34339435

RESUMO

Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.


Assuntos
Cardiomiopatias/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Obesidade/tratamento farmacológico , Inibidores de Prolil-Hidrolase/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Biomarcadores/sangue , Cardiomegalia/sangue , Cardiomegalia/complicações , Cardiomegalia/fisiopatologia , Cardiomiopatias/sangue , Cardiomiopatias/complicações , Cardiomiopatias/fisiopatologia , Glucose/metabolismo , Hemoglobinas/metabolismo , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/fisiopatologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Rim/fisiopatologia , Nefropatias/sangue , Nefropatias/complicações , Nefropatias/fisiopatologia , Masculino , Obesidade/sangue , Obesidade/complicações , Obesidade/fisiopatologia , Inibidores de Prolil-Hidrolase/farmacologia , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia
3.
J Exp Med ; 218(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34325467

RESUMO

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células Mieloides/metabolismo , Idoso , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Células Mieloides/patologia , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Miocardite/metabolismo , Miocardite/patologia
4.
Neurology ; 97(11): e1150-e1158, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34315782

RESUMO

BACKGROUND AND OBJECTIVES: We aimed to determine the genetic and clinical phenotypes of patients with desmin-related myopathy and long-term outcomes after cardiac transplantation. METHODS: We performed a retrospective review of cardiac and neurologic manifestations of patients with genetically confirmed desmin-related myopathy (January 1, 1999-January 1, 2020). RESULTS: Twenty-five patients in 20 different families were recognized. Median age at onset of symptoms was 20 (range 4-50) years; median follow-up time was 36 (range 1-156) months. Twelve patients initially presented with skeletal muscle involvement, and 13 presented with cardiac disease. Sixteen patients had both cardiac and skeletal muscle involvement. Clinically muscle weakness distribution was distal (n = 11), proximal (n = 4), or both (n = 7) in 22 patients. Skeletal muscle biopsy from patients with missense and splice site variants (n = 12) showed abnormal fibers containing amorphous material in Gomori trichrome-stained sections. Patients with cardiac involvement had atrioventricular conduction abnormalities or cardiomyopathy. The most common ECG abnormality was complete atrioventricular block in 11 patients, all of whom required a permanent pacemaker at a median age of 25 (range 16-48) years. Sudden cardiac death resulting in implantable cardioverter-defibrillator (ICD) shocks or resuscitation was reported in 3 patients; a total of 5 patients had ICDs. Orthotopic cardiac transplantation was performed in 3 patients at 20, 35, and 39 years of age. DISCUSSION: Pathogenic variants in desmin can lead to varied neurologic and cardiac phenotypes beginning at a young age. Two-thirds of the patients have both neurologic and cardiac symptoms, usually starting in the third decade. Heart transplantation was tolerated with improved cardiac function and quality of life.


Assuntos
Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Transplante de Coração , Distrofias Musculares/genética , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
Am J Cardiol ; 154: 86-91, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233837

RESUMO

Methamphetamine-associated cardiomyopathy (MACM) in an increasingly prevalent disease yet presenting clinical characteristics have not been well studied. We studied consecutive patients with MACM presenting between June 2018 and March 2020 who were interviewed for drug use and medical history. We retrospectively identified an age- and gender-matched cohort of Non-MACM (NMACM) patients and compared clinical characteristics. 140 patients (70 MACM and 70 NMACM) were studied. MACM patients were young (49.6 ± 10 years) and predominantly male (94%). Compared to NMACM, MACM patients were more likely to be Caucasian (21% vs 6%, p = 0.007) and homeless (47% vs 7%, p = 0.001). MACM was characterized by lower left ventricular ejection fraction (EF) (p <0.001) and greater LV end diastolic volume (LVEDV) (p = 0.024). Right ventricular (RV) dilation was present more often (p = s0.001) and was more often severe (p = 0.03). Among MACM cases, half of the cohort developed MACM within 5 years of starting MA (18% within 1 year). There was no apparent relationship between frequency or amount of MA used weekly with time until heart failure onset. Drug use patterns were not clearly related to the degree of LV structural change however there were more consistent, significant associations with RV and right atrial (RA) size parameters. In conclusion, patients with MACM have more severe myocardial impairment with lower EF, greater LVEDV and RV dilation. Drug use patterns do not clearly impact degree of LV structural changes by echocardiography however may be related to RV and RA size.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Cardiomiopatias/fisiopatologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Administração Intranasal , Adulto , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/epidemiologia , Cardiotoxicidade , Estudos de Casos e Controles , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar , Volume Sistólico , Disfunção Ventricular Esquerda
7.
J Am Heart Assoc ; 10(12): e020205, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34096318

RESUMO

Background Dietary Mg intake is associated with a decreased risk of developing heart failure, whereas low circulating Mg level is associated with increased cardiovascular mortality. We investigated whether Mg deficiency alone could cause cardiomyopathy. Methods and Results C57BL/6J mice were fed with a low Mg (low-Mg, 15-30 mg/kg Mg) or a normal Mg (nl-Mg, 600 mg/kg Mg) diet for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with nl-Mg diet for another 6 weeks. Low-Mg diet significantly decreased mouse serum Mg (0.38±0.03 versus 1.14±0.03 mmol/L for nl-Mg; P<0.0001) with a reciprocal increase in serum Ca, K, and Na. Low-Mg mice exhibited impaired cardiac relaxation (ratio between mitral peak early filling velocity E and longitudinal tissue velocity of the mitral anterior annulus e, 21.1±1.1 versus 15.4±0.4 for nl-Mg; P=0.011). Cellular ATP was decreased significantly in low-Mg hearts. The changes were accompanied by mitochondrial dysfunction with mitochondrial reactive oxygen species overproduction and membrane depolarization. cMyBPC (cardiac myosin-binding protein C) was S-glutathionylated in low-Mg mouse hearts. All these changes were normalized with Mg repletion. In vivo (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride treatment during low-Mg diet improved cardiac relaxation, increased ATP levels, and reduced S-glutathionylated cMyBPC. Conclusions Mg deficiency caused a reversible diastolic cardiomyopathy associated with mitochondrial dysfunction and oxidative modification of cMyBPC. In deficiency states, Mg supplementation may represent a novel treatment for diastolic heart failure.


Assuntos
Cardiomiopatias/etiologia , Deficiência de Magnésio/complicações , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Função Ventricular Esquerda , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/farmacologia , Sinalização do Cálcio , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Proteínas de Transporte/metabolismo , Diástole , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Piperidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
8.
BMC Cardiovasc Disord ; 21(1): 302, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130633

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) associated cardiomyopathy is a major cause of morbidity and mortality. In an in vitro DMD cardiomyocyte model, nicorandil reversed stress-induced cell injury through multiple pathways implicated in DMD. We aimed to test the efficacy of nicorandil on the progression of cardiomyopathy in mdx mice following a 10-day treatment protocol. METHODS: A subset of mdx mice was subjected to low-dose isoproterenol injections over 5 days to induce a cardiac phenotype and treated with vehicle or nicorandil for 10 days. Baseline and day 10 echocardiograms were obtained to assess cardiac function. At 10 days, cardiac tissue was harvested for further analysis, which included histologic analysis and assessment of oxidative stress. Paired student's t test was used for in group comparison, and ANOVA was used for multiple group comparisons. RESULTS: Compared to vehicle treated mice, isoproterenol decreased ejection fraction and fractional shortening on echocardiogram. Nicorandil prevented isoproterenol induced cardiac dysfunction. Isoproterenol increased cardiac fibrosis, which nicorandil prevented. Isoproterenol increased gene expression of NADPH oxidase, which decreased to baseline with nicorandil treatment. Superoxide dismutase 2 protein expression increased in those treated with nicorandil, and xanthine oxidase activity decreased in mice treated with nicorandil during isoproterenol stress compared to all other groups. CONCLUSIONS: In conclusion, nicorandil is cardioprotective in mdx mice and warrants continued investigation as a therapy for DMD associated cardiomyopathy.


Assuntos
Cardiomiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Nicorandil/farmacologia , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Feminino , Fibrose , Isoproterenol , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/complicações , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Xantina Oxidase/metabolismo
10.
Circ Cardiovasc Imaging ; 14(6): e012549, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34102857

RESUMO

BACKGROUND: Current risk assessment approaches fail to identify the majority of patients at risk of sudden cardiac arrest (SCA). Noninvasive imaging of the cardiac sympathetic nervous system using single-photon emission computed tomography and positron emission tomography offers the potential for refining SCA risk assessment. While various [11C]meta-hydroxyephedrine quantification parameters have been proposed, it is currently unknown whether regional denervation or global innervation yields greater SCA risk discrimination. The aim of the study was to determine whether the global innervation parameters yield any independent and additive prognostic value over the regional denervation alone. METHODS: In a post hoc competing-risks analysis of the PAREPET trial (Prediction of Arrhythmic Events With Positron Emission Tomography), we compared global innervation and regional denervation parameters using the norepinephrine analog [11C]meta-hydroxyephedrine for SCA risk discrimination. Patients with ischemic cardiomyopathy (n=174) eligible for an implantable cardioverter-defibrillator for the primary prevention of SCA were recruited into the trial. [11C]meta-hydroxyephedrine uptake and clearance rates were measured to assess global (left ventricle mean) retention index and volume of distribution. Regional defects were quantified as the percentage of the left ventricle having values <75% of the maximum. RESULTS: During a median follow-up of 4.2 years, there were 56 cardiac-related deaths, of which 26 were SCAs. For any given regional denervation volume, there was substantial heterogeneity in global innervation scores. Global retention index and distribution volume did not decrease until regional defects exceeded 40% left ventricle. Global scale parameters, retention index, and distribution volume (area under the curve=0.61, P=0.034, P=0.046, respectively), yielded inferior SCA risk discrimination compared to regional heterogeneity (area under the curve=0.74). CONCLUSIONS: Regional denervation volume has superior cause-specific mortality prediction for SCA versus global parameters of sympathetic innervation. These results have widespread implications for future cardiac sympathetic imaging, which will greatly simplify innervation analysis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01400334.


Assuntos
Cardiomiopatias/diagnóstico , Isquemia Miocárdica/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Sistema Nervoso Simpático/fisiopatologia , Função Ventricular Esquerda/fisiologia , Idoso , Cardiomiopatias/fisiopatologia , Feminino , Humanos , Masculino , Isquemia Miocárdica/fisiopatologia , Prognóstico
11.
Am J Cardiol ; 152: 125-131, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34127248

RESUMO

Cardiac sarcoidosis (CS) is frequently complicated by fatal ventricular arrhythmias. T-peak to T-end interval to QT interval ratio (TpTe/QT) on electrocardiograms (ECG) was proposed as a marker of ventricular repolarization dispersion. Although this ratio could be associated with the incidence of ventricular arrhythmias in cardiovascular diseases, its prognostic implication in patients with CS is unclear. We sought to investigate whether TpTe/QT was associated with long-term clinical outcomes in patients with CS. Ninety consecutive patients with CS in 2 tertiary hospitals who had ECG data before initiation of immunosuppressive therapy between November 1995 and March 2019 were examined. The primary outcome was a composite of advanced atrioventricular block, ventricular tachycardia or ventricular fibrillation (VT/VF), heart failure hospitalization, and all-cause death. During a median follow-up period of 4.70 (interquartile range 2.06-7.23) years, the primary outcome occurred in 21 patients (23.3%). Survival analyses revealed that the primary outcome (p < 0.001), especially VT/VF or sudden cardiac death (p = 0.002), occurred more frequently in patients with higher TpTe/QT (≥ 0.242, the median) than in those with lower TpTe/QT. Multivariable Cox regression analysis showed that a higher TpTe/QT was independently associated with increased subsequent risk of adverse events (hazard ratio1.11, 95% confidence interval 1.03-1.20, p = 0.008) even after adjustment for the significant covariates. In conclusion, a higher TpTe/QT was associated with worse long-term clinical outcomes, especially fatal ventricular arrhythmic events, in patients with cardiac sarcoidosis, suggesting the importance of assessing TpTe/QT as a surrogate for risk stratification in these patients.


Assuntos
Bloqueio Atrioventricular/epidemiologia , Cardiomiopatias/fisiopatologia , Morte Súbita Cardíaca/epidemiologia , Sarcoidose/fisiopatologia , Taquicardia Ventricular/epidemiologia , Fibrilação Ventricular/epidemiologia , Idoso , Causas de Morte , Eletrocardiografia , Feminino , Insuficiência Cardíaca/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais
12.
J Stroke Cerebrovasc Dis ; 30(8): 105933, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34157668

RESUMO

OBJECTIVES: The study aimed to investigate whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration and/or left atrial volume index (LAVI), as atrial cardiopathy biomarkers, were associated with infarct patterns on diffusion-weighted imaging in patients with embolic strokes of undetermined source (ESUS). MATERIALS AND METHOD: We retrospectively evaluated patient with ESUS from our stroke registry between January 2018 and November 2019. Cut-off values for atrial cardiopathy biomarkers were defined as >250 pg/mL for NT-proBNP and >34 mL/m2 for LAVI. Eligible patients were then assigned to 3 groups and infarct patterns were compared according to their atrial cardiopathy markers: Group 1 (no atrial cardiopathy markers), Group 2 (one marker), and Group 3 (both markers). RESULTS: Among 194 eligible patients with ESUS (76 women; mean age, 69.2 years), simultaneous increases of NT-proBNP concentration and LAVI were identified in 39 (20.1%). Group 3 had a significantly larger infarct volume, relative to Group 1 and Group 2 (P=0.043) Multivariable logistic regression analyses revealed that these patients (Group 3) were significantly more likely to have multi-territorial infarcts (adjusted odds ratio [aOR]: 3.03, 95% confidence interval [CI]: 1.05-8.72; P=0.04), a maximal lesion diameter >15mm (aOR: 4.51, 95% CI: 1.70-11.93; P=0.001), and large cortical infarctions (aOR: 4.17, 95% CI: 1.75-9.96; P=0.001). CONCLUSION: We found that simultaneously increased values for NT-proBNP concentration and LAVI were independently associated with multi-territorial and large cortical infarct patterns in patients with ESUS. These findings suggest that NT-proBNP and LAVI may be useful biomarkers for identifying cardioembolic subtypes and guiding treatment selection in patients with ESUS.


Assuntos
Função do Átrio Esquerdo , Remodelamento Atrial , Infarto Encefálico/diagnóstico por imagem , Cardiomiopatias/complicações , Imagem de Difusão por Ressonância Magnética , Ecocardiografia , AVC Embólico/diagnóstico por imagem , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Infarto Encefálico/etiologia , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , AVC Embólico/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de Registros , Estudos Retrospectivos , Fatores de Tempo
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071707

RESUMO

Cardiac connexins (Cxs) are proteins responsible for proper heart function. They form gap junctions that mediate electrical and chemical signalling throughout the cardiac system, and thus enable a synchronized contraction. Connexins can also individually participate in many signal transduction pathways, interacting with intracellular proteins at various cellular compartments. Altered connexin expression and localization have been described in diseased myocardium and the aim of this study is to assess the involvement of Cx43, Cx26, and some related molecules in ponatinib-induced cardiac toxicity. Ponatinib is a new multi-tyrosine kinase inhibitor that has been successfully used against human malignancies, but its cardiotoxicity remains worrisome. Therefore, understanding its signaling mechanism is important to adopt potential anti cardiac damage strategies. Our experiments were performed on hearts from male and female mice treated with ponatinib and with ponatinib plus siRNA-Notch1 by using immunofluorescence, Western blotting, and proteomic analyses. The altered cardiac function and the change in Cxs expression observed in mice after ponatinib treatment, were results dependent on the Notch1 pathway and sex. Females showed a lower susceptibility to ponatinib than males. The downmodulation of cardiac Cx43, Cx26 and miR-122, high pS368-Cx43 phosphorylation, cell viability and survival activation could represent some of the female adaptative/compensatory reactions to ponatinib cardiotoxicity.


Assuntos
Cardiomiopatias , Conexina 26 , Conexina 43 , Imidazóis , Piridazinas , Fatores Sexuais , Anormalidades Induzidas por Medicamentos , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Cardiomiopatias/etiologia , Cardiomiopatias/fisiopatologia , Cardiotoxicidade , Conexina 26/efeitos dos fármacos , Conexina 26/metabolismo , Conexina 43/efeitos dos fármacos , Conexina 43/metabolismo , Modelos Animais de Doenças , Feminino , Junções Comunicantes/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteômica , Piridazinas/efeitos adversos , Piridazinas/farmacologia , Receptor Notch1/metabolismo , Transdução de Sinais
14.
Circ Heart Fail ; 14(5): e008223, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33980039

RESUMO

Heart failure (HF) is a leading cause of morbidity and mortality in pregnant women in the United States. Although peripartum cardiomyopathy is the most common diagnosis for pregnant women with HF, women with preexisting cardiomyopathies and systolic dysfunction are also at risk as the hemodynamic demands of pregnancy can lead to decompensation, arrhythmia, and rarely death. The differential diagnosis of HF in pregnancy is broad and includes Takotsubo or stress cardiomyopathy, exacerbation of a preexisting cardiomyopathy, such as familial cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or left ventricular noncompaction. This review will explore the implications of pregnancy in women with preexisting cardiomyopathies and de novo HF, risk assessment and preconception planning, decisions about contraception, the safety of HF medications and implantable cardioverter-defibrillators during pregnancy, pregnancy in women with left ventricular assist devices and following heart transplantation.


Assuntos
Cardiomiopatias/fisiopatologia , Insuficiência Cardíaca/etiologia , Período Periparto/fisiologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Cardiomiopatias/etiologia , Cardiomiopatia Hipertrófica/complicações , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Gravidez , Complicações Cardiovasculares na Gravidez/etiologia , Medição de Risco
15.
BMC Cardiovasc Disord ; 21(1): 234, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964872

RESUMO

BACKGROUND: 8-28% of patients infected with COVID-19 have evidence of cardiac injury, and this is associated with an adverse prognosis. The cardiovascular mechanisms of injury are poorly understood and speculative. We aim to use multimodality cardiac imaging including cardiac magnetic resonance (CMR) imaging, computed tomography coronary angiography (CTCA) and positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG-PET/CT) to identify the cardiac pathophysiological mechanisms related to COVID-19 infections. METHODS: This is a single-centre exploratory observational study aiming to recruit 50 patients with COVID-19 infection who will undergo cardiac biomarker sampling. Of these, 30 patients will undergo combined CTCA and 18F-FDG-PET/CT, followed by CMR. Prevalence of obstructive and non-obstructive atherosclerotic coronary disease will be assessed using CTCA. CMR will be used to identify and characterise myocardial disease including presence of cardiac dysfunction, myocardial fibrosis, myocardial oedema and myocardial infarction. 18F-FDG-PET/CT will identify vascular and cardiac inflammation. Primary endpoint will be the presence of cardiovascular pathology and the association with troponin levels. DISCUSSION: The results of the study will identify the presence and modality of cardiac injury associated COVID-19 infection, and the utility of multi-modality imaging in diagnosing such injury. This will further inform clinical decision making during the pandemic. TRIAL REGISTRATION: This study has been retrospectively registered at the ISRCTN registry (ID ISRCTN12154994) on 14th August 2020. Accessible at https://www.isrctn.com/ISRCTN12154994.


Assuntos
COVID-19/complicações , Cardiomiopatias/diagnóstico por imagem , Doença das Coronárias/diagnóstico por imagem , COVID-19/fisiopatologia , Cardiomiopatias/fisiopatologia , Cardiomiopatias/virologia , Angiografia por Tomografia Computadorizada , Doença das Coronárias/fisiopatologia , Doença das Coronárias/virologia , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética , Imagem Multimodal , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Compostos Radiofarmacêuticos
16.
Circ Cardiovasc Imaging ; 14(5): e012256, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34000818

RESUMO

BACKGROUND: Long-term right ventricular (RV) pacing leads to heart failure or a decline in left ventricular (LV) function in up to a fifth of patients. We aimed to establish whether patients with focal fibrosis detected on late gadolinium enhancement cardiovascular magnetic resonance (CMR) have deterioration in LV function after RV pacing. METHODS: We recruited 84 patients with LV ejection fraction ≥40% into 2 observational CMR studies. Patients (n=34) with a dual-chamber device and preserved atrioventricular conduction underwent CMR in 2 asynchronous pacing modes (atrial asynchronous and dual-chamber asynchronous) to compare intrinsic atrioventricular conduction with forced RV pacing. Patients (n=50) with high-grade atrioventricular block underwent CMR before and 6 months after pacemaker implantation to investigate the medium-term effects of RV pacing. RESULTS: The key findings were (1) initiation of RV pacing in patients with fibrosis, compared with those without, was associated with greater immediate changes in both LV end-systolic volume index (5.3±3.5 versus 2.1±2.4 mL/m2; P<0.01) and LV ejection fraction (-5.7±3.4% versus -3.2±2.6%; P=0.02); (2) medium-term RV pacing in patients with fibrosis, compared with those without, was associated with greater changes in LV end-systolic volume index (8.0±10.4 versus -0.6±7.3 mL/m2; P=0.008) and LV ejection fraction (-12.3±7.9% versus -6.7±6.2%; P=0.012); (3) patients with fibrosis did not experience an improvement in quality of life, biomarkers, or functional class after pacemaker implantation; (4) after 6 months of RV pacing, 10 of 50 (20%) patients developed LV ejection fraction <35% and were eligible for upgrade to cardiac resynchronization according to current guidelines. All 10 patients had fibrosis on their preimplant baseline scan and were identified by >1.1 g of fibrosis with 90% sensitivity and 70% specificity. CONCLUSIONS: Fibrosis detected on CMR is associated with immediate- and medium-term deterioration in LV function following RV pacing and could be used to identify those at risk of heart failure before pacemaker implantation.


Assuntos
Estimulação Cardíaca Artificial/métodos , Cardiomiopatias/terapia , Miocárdio/patologia , Função Ventricular Direita/fisiologia , Idoso , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Eletrocardiografia , Fibrose/diagnóstico , Fibrose/tratamento farmacológico , Fibrose/fisiopatologia , Seguimentos , Humanos , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
18.
Am J Cardiol ; 151: 100-104, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34024627

RESUMO

Multiple observational studies have demonstrated an association with cannabis use and acute myocardial infarction, especially among young adults. However, little is known about the connection with subclinical or electrocardiographic myocardial injury. We hypothesized that cannabis use would be associated with an increased risk of myocardial injury as defined by the cardiac infarction and/or injury score (CIIS). This analysis included 3,634 (age 48.0 ± 5.9 years, 47.1% male, 68.7% Caucasians) participants from the Third National Health and Examination Survey. Cannabis use was defined by self-report. Those with history of cardiovascular disease were excluded. Myocardial injury was defined as electrocardiographic CIIS ≥ 10. Multivariable logistic regression was used to examine the association between cannabis use and myocardial injury. The consistency of this association was tested among subgroups stratified by race, gender, tobacco smoking status, and comorbidities. About 26.0% (n = 900) of participants were ever-cannabis users and 15.5% (n = 538) had myocardial injury. In a model adjusted for potential confounders, ever-cannabis users had 43% increased odds of myocardial injury compared to never users (Odds ratio (95% confidence interval): 1.43 (1.14, 1.80); p = 0.002). This association was stronger among participants with a history of hypertension versus those without (Odds ratio (95% confidence interval): 1.83 (1.36, 2.47) vs 1.17 (0.83, 1.64), respectively; interaction p value 0.04). Cannabis use is associated with an increased risk of myocardial injury among those without cardiovascular disease with effect modification by co-existent hypertension. These novel findings underscore the harmful effects of cannabis use on cardiovascular health and also merit a personalized risk assessment when counseling patients with hypertension on its use.


Assuntos
Cardiomiopatias/epidemiologia , Uso da Maconha/epidemiologia , Adulto , Afro-Americanos , Cardiomiopatias/fisiopatologia , Diabetes Mellitus/epidemiologia , Eletrocardiografia , Feminino , Humanos , Hiperlipidemias , Hipertensão/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/epidemiologia , Razão de Chances , Fatores de Risco , Fatores Sexuais , Fumar Tabaco/epidemiologia
19.
J Cardiovasc Magn Reson ; 23(1): 39, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33789682

RESUMO

BACKGROUND: To differentiate effects of ventricular asynchrony from an underlying hypocontractile cardiomyopathy this study aimed to enhance the understanding of functional impairment and structural remodeling in idiopathic left bundle-branch block (LBBB). We hypothesize, that functional asynchrony with septal flash volume effects alone might not entirely explain the degree of functional impairment. Hence, we suggest the presence of a superimposed contractile cardiomyopathy. METHODS: In this retrospective study, 53 patients with idiopathic LBBB were identified and matched to controls with and without cardiovascular risk factors. Cardiovascular magnetic resonance (CMR) was used to evaluate cardiac function, volumes and myocardial fibrosis using native T1 mapping and late gadolinium enhancement (LGE). Septal flash volume was assessed by CMR volumetric measurements and allowed to stratify patients with systolic dysfunction solely due to isolated ventricular asynchrony or superimposed contractile impairment. RESULTS: Reduced systolic LV-function, increased LV-volumes and septal myocardial fibrosis were found in patients with idiopathic LBBB compared to healthy controls. LV-volumes increased and systolic LV-function declined with prolonged QRS duration. Fibrosis was typically located at the right ventricular insertion points. Subgroups with superimposed contractile impairment appeared with pronounced LV dilation and increased fibrotic remodeling compared to individuals with isolated ventricular asynchrony. CONCLUSIONS: The presence of superimposed contractile impairment in idiopathic LBBB is crucial to identify patients with enhanced structural remodeling. This finding suggests an underlying cardiomyopathy. Future studies are needed to assess a possible prognostic impact of this entity and the development of heart failure. TRIAL REGISTRATION: This study was retrospectively registered.


Assuntos
Bloqueio de Ramo/fisiopatologia , Cardiomiopatias/fisiopatologia , Contração Miocárdica , Função Ventricular Esquerda , Remodelação Ventricular , Adulto , Idoso , Bloqueio de Ramo/diagnóstico por imagem , Bloqueio de Ramo/etiologia , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico por imagem , Bases de Dados Factuais , Feminino , Fibrose , Septos Cardíacos/diagnóstico por imagem , Septos Cardíacos/fisiopatologia , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
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