RESUMO
Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.
Assuntos
Antineoplásicos Imunológicos , Função do Átrio Esquerdo , Neoplasias da Mama , Cardiotoxicidade , Receptor ErbB-2 , Trastuzumab , Função Ventricular Esquerda , Humanos , Trastuzumab/efeitos adversos , Feminino , Neoplasias da Mama/tratamento farmacológico , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Estudos Prospectivos , Antineoplásicos Imunológicos/efeitos adversos , Função Ventricular Esquerda/efeitos dos fármacos , Função do Átrio Esquerdo/efeitos dos fármacos , Adulto , Fatores de Tempo , Fatores de Risco , Resultado do Tratamento , Idoso , Valor Preditivo dos Testes , Medição de Risco , Remodelamento Atrial/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Cardiopatias/fisiopatologia , Cardiopatias/diagnóstico por imagem , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Átrios do Coração/diagnóstico por imagem , Volume Sistólico/efeitos dos fármacosRESUMO
AIMS: Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial anti-arrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. METHODS AND RESULTS: Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs. HFpEF: 0.21 ± 0.02 vs. 0.38 ± 0.04â mmol/L/min (N = 7 vs. 18); P = 0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. CONCLUSION: We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to anti-arrhythmic effects in patients with HFpEF.
Assuntos
Potenciais de Ação , Compostos Benzidrílicos , Glucosídeos , Insuficiência Cardíaca , Miócitos Cardíacos , Inibidores do Transportador 2 de Sódio-Glicose , Volume Sistólico , Humanos , Glucosídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/enzimologia , Masculino , Feminino , Idoso , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Pessoa de Meia-Idade , Compostos Benzidrílicos/farmacologia , Volume Sistólico/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Sódio/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Átrios do Coração/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Células Cultivadas , Função do Átrio Esquerdo/efeitos dos fármacos , Trocador 1 de Sódio-HidrogênioAssuntos
Antineoplásicos , Função do Átrio Esquerdo , Cardiotoxicidade , Valor Preditivo dos Testes , Humanos , Função do Átrio Esquerdo/efeitos dos fármacos , Feminino , Fatores de Risco , Antineoplásicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Medição de Risco , Idoso , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologiaRESUMO
Survivors of childhood cancer are at risk of cancer therapy-related cardiac dysfunction (CTRCD) characterized by systolic impairment, with little known about diastolic function. Left atrial strain (LAS) is a surrogate measure of left ventricular filling. We hypothesized that survivors (1) have lower LAS versus controls, and (2) survivors exposed to higher anthracycline dosage have even lower LAS. Cross-sectional study of 45 survivors exposed to anthracyclines ≥ 1 year after chemotherapy and 45 healthy controls. Echo variables included mitral spectral and tissue Doppler, left ventricular ejection fraction (LV EF), LV dimension, LA volume, LV global longitudinal strain (GLS), and LAS. Peak strain (Æ) and strain rate (SR) at three phases were obtained: atrial contraction (ac), reservoir (res), and conduit (con). Two sub-analyses of cancer survivors were performed: (1) those with anthracycline dosage ≥ 250 mg/m2, and (2) those with Æres in the lowest quartile. On the whole, survivors had lower Æres and Æcon values. The majority of survivors had relatively normal LAS, while a subset had very low LAS values and were more likely to be older. Survivors exposed to ≥ 250 mg/m2 anthracycline also had lower Æres than those < 250 mg/m2. There were no differences in mitral spectral/tissue Doppler, LV dimension, left atrial volume, or GLS. A subset of childhood cancer survivors have lower LAS than their healthy counterparts, while most are essentially normal. Those exposed to higher anthracycline dosage have even lower Æres. Longitudinal study of LAS may prove useful in monitoring for CTRCD.
Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Função do Átrio Esquerdo/efeitos dos fármacos , Sobreviventes de Câncer , Ecocardiografia Doppler , Átrios do Coração/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Neoplasias/tratamento farmacológico , Adolescente , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Humanos , Masculino , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. METHODS: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. RESULTS: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P<0.0001). CONCLUSIONS: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/toxicidade , Fibrilação Atrial/induzido quimicamente , Função do Átrio Esquerdo/efeitos dos fármacos , Proteína Tirosina Quinase CSK/antagonistas & inibidores , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Piperidinas/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Potenciais de Ação/efeitos dos fármacos , Adenina/toxicidade , Tirosina Quinase da Agamaglobulinemia/deficiência , Tirosina Quinase da Agamaglobulinemia/genética , Animais , Fibrilação Atrial/enzimologia , Fibrilação Atrial/fisiopatologia , Proteína Tirosina Quinase CSK/genética , Proteína Tirosina Quinase CSK/metabolismo , Bases de Dados Genéticas , Átrios do Coração/enzimologia , Átrios do Coração/fisiopatologia , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Previous studies demonstrated impaired lipid metabolism and augmented aerobic glycolysis in AF. The authors aimed to investigate whether the use of metformin, an AMPK activator, could reverse this metabolic remodeling in chronic AF and to explore the underlying mechanisms. METHODS: We conducted chronic AF animal models with 18 beagle dogs and divided them into SR (pacemaker implanted without pacing), AF (pacemaker implanted with sustained pacing at a frequency of 400 beats/min for 6 weeks), and metformin+AF group (daily oral administration of metformin was initiated 1 week before surgery and continued throughout the study period). After electrophysiological measurements, the left atrial appendage tissue samples were taken from the beating heart for further analysis. Protein expression, histological analysis, and biochemical measurements were conducted. RESULTS: The AF groups showed decreased expression of FAT/CD36, CPT-1, VLCAD, increased concentration of free fatty acid and triglyceride, and increased lipid deposition. The activation of AMPK/PGC-1α/PPARα pathway was decreased. The key factors of the Warburg effect, including HIF-1α, GLUT-1, PDK1, HK, and LDH, increased in AF group compared to SR group. The expression of PDH decreased significantly, accompanied by increased atrial lactate production. The extent of fibrosis increased significantly in the left atrial appendage of AF group. dERP, ∑WOV, and AF inducibility increased while ERP decreased in AF group compared to SR group. The use of metformin attenuated all these changes effectively. CONCLUSIONS: Metformin improves lipid metabolism and reverses the Warburg effect in chronic AF via AMPK activation. It attenuates atrial electrical and structural remodeling.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apêndice Atrial/efeitos dos fármacos , Fibrilação Atrial/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metformina/farmacologia , Animais , Apêndice Atrial/enzimologia , Apêndice Atrial/fisiopatologia , Fibrilação Atrial/enzimologia , Fibrilação Atrial/fisiopatologia , Função do Átrio Esquerdo/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Cães , Ativação Enzimática , Frequência Cardíaca/efeitos dos fármacos , MasculinoRESUMO
Background: Left atrial (LA) function is an important determinant of the left ventricular (LV) filling, playing a key role in maintaining optimal cardiac performance. Pimobendan is a phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. The present study aims to investigate the effects of pimobendan on LA function in dogs with stage B2 myxomatous mitral valve disease (MMVD). Aim: The aim of this investigation was to study the effects of pimobendan on LA function in dogs with preclinical MMVD. Methods: Twenty-seven dogs with stage B2 MMVD were retrospectively included. LA function was assessed before and 1-6 months following pimobendan initiation. For each dog, two-dimensional (2D) echocardiography was performed to assess LA diameter and volume for each phase of the LA cycle and to assess complete, passive, and active LA function. Pulsed-wave tissue Doppler imaging (TDI) of the left ventricular longitudinal myocardial velocity associated with atrial contraction (A'), both at the level of the interventricular septum and the LV free wall, was also used as an indicator of LA function. Results: There were no significant differences in any of the left atrial variables pre- and posttreatment. Conclusion: Echocardiographic estimates of LA function by 2D diameters and volumes and TDI A' in dogs with MMVD do not change after treatment with pimobendan.
Assuntos
Função do Átrio Esquerdo/efeitos dos fármacos , Doenças do Cão/tratamento farmacológico , Doenças das Valvas Cardíacas/veterinária , Piridazinas/farmacologia , Vasodilatadores/farmacologia , Animais , Cardiotônicos/farmacologia , Cães , Feminino , Doenças das Valvas Cardíacas/tratamento farmacológico , Masculino , Inibidores de Fosfodiesterase/farmacologiaRESUMO
Background This study assessed the effect of blockading neural transmission in the ganglionated plexi by injecting lidocaine into fat pads in the vagal nerve stimulation canine model and patients with persistent atrial fibrillation ( AF ). Methods and Results An efficacy test of lidocaine injection was performed in 7 canines. During vagal nerve stimulation, AF was sustained for >5 minutes. The lidocaine was injected into ganglionated plexi during sinus rhythm and reinduction of AF was attempted. Six patients with persistent AF were studied at open heart surgery. Lidocaine was injected into ganglionated plexi. Atrial electrograms were recorded from 96 epicardial electrodes covering Bachmann's bundle and atrial appendages. In the canine vagal nerve stimulation AF model, AF was not inducible in 4 of 7 after lidocaine injection. In patients with persistent AF , during baseline AF , there was a left atrium ( LA )-to-right atrium ( RA ) frequency gradient ( LA , mean cycle length [ CL ] 175±17 ms; RA , mean CL 192±17 ms; P<0.01). After lidocaine injection, AF persisted in all patients, and the LA -to- RA frequency gradient disappeared ( LA , mean CL 186±13 ms; RA , mean CL 199±23 ms; P=0.08). Comparison of mean CL s before and after lidocaine demonstrated prolongation of LA CL s ( P<0.05) with no effect on RA CL s. Conclusions In the canine vagal nerve stimulation AF model, lidocaine injection decreased inducibility of AF . In patients with persistent AF , atrial electrograms from the LA had shorter CL s than RA , indicating an LA -to- RA frequency gradient. Lidocaine injection significantly prolonged only LA CL s, explaining disappearance of the LA -to- RA frequency gradient. The mechanism of localized atrial electrogram CL prolongation in patients with persistent AF is uncertain.
Assuntos
Antiarrítmicos/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Função do Átrio Esquerdo/efeitos dos fármacos , Gânglios Autônomos/efeitos dos fármacos , Átrios do Coração/inervação , Frequência Cardíaca/efeitos dos fármacos , Lidocaína/administração & dosagem , Potenciais de Ação , Idoso , Idoso de 80 Anos ou mais , Animais , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Cães , Técnicas Eletrofisiológicas Cardíacas , Feminino , Gânglios Autônomos/fisiopatologia , Humanos , Injeções , Lidocaína/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure. METHODS AND RESULTS: The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin. CONCLUSIONS: Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.
Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Hipertensão/complicações , Miocárdio/patologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fibrose , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/fisiopatologia , Masculino , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Recuperação de Função Fisiológica , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The left atrium (LA) modulates left ventricular filling pressure and is a strong prognosticator in heart failure. Although anthracycline exposure may lead to impaired left ventricular (LV) function, the effects on LA function are not well-described in the younger population. We aim to evaluate LA function in children exposed to anthracyclines. METHODS: Children exposed to anthracyclines with pre- and post-treatment echocardiographic imaging were enrolled. Measures of LA function (LA ejection fraction [LA EF], global longitudinal strain [GLS], and peak GLS rate) were quantified using 2D speckle tracking echocardiography pre- and post-anthracycline therapy and were compared. Segments with poor tracking were excluded. RESULTS: Fifty-five children (age 13 [SD 5] years) treated with anthracyclines were evaluated. LA EF, GLS, and peak GLS rate were lower after anthracycline exposure. Mean changes were as follows: LA EF (pre-73.5 [SD 7.7]% vs post-70.6 [SD 8.2]%, P = 0.06), GLS (-34.2 [SD 8.4]% vs -31.9 [SD 7.1]%, P = 0.09), peak GLS rate (2.2 [SD 0.8] s-1 vs 2.0 [SD 0.6] s-1 , P = 0.18). When stratified by pre- (≤12 years old) vs post-puberty (>12 years old), prepubescent patients (n = 21) had statistically significant changes in pre/post LA GLS (P = 0.01) and LA EF (P = 0.01). In models adjusted for radiation dose, age, gender, body surface area, or cumulative anthracycline dose, there were no significant relationships in the absolute difference between pre/post LA EF (P = 0.34) or LA GLS (P = 0.18). CONCLUSIONS: In children exposed to anthracyclines, short-term effects on LA function were minimal in those with preserved LV EF. Age-dependent LA susceptibility to anthracycline requires further study.
Assuntos
Antraciclinas/efeitos adversos , Função do Átrio Esquerdo/efeitos dos fármacos , Sobreviventes de Câncer/estatística & dados numéricos , Ecocardiografia/métodos , Adolescente , Adulto , Função do Átrio Esquerdo/fisiologia , Criança , Pré-Escolar , Feminino , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To evaluate atrial and ventricular parameters using real time three-dimensional transthoracic echocardiography (RT3DTTE) in women treated with nifedipine in the early third trimester (III-T) of pregnancy. METHODS: A prospective single-subject design study in a university-affiliated hospital, where each participant served as her own control. We studied 25 pregnant women at a gestational age of 25-33 weeks with TPTL prior to vs 48 hours postnifedipine treatment. Two-dimensional transthoracic echocardiography (2DTTE) and RT3DTTE were used to study 3D left atrial (LA) volumes and indexes, emptying fraction, left ventricular and LA cavities, and total vascular resistance (TVR). RESULTS: Two-dimensional transthoracic echocardiography showed a significant increase in LA area (from 15.2 ± 2.62 to 16.16 ± 2.21 mm2 , P = .02) before vs after nifedipine; RT3DTTE showed a significant change in LA end-diastolic volume index (from 23.7 ± 4.2 to 26.75 ± 3.8 mL/m2 , P = .008). LA end-systolic volume and index were not significantly different before vs after nifedipine (from 24.56 ± 8 to 25.3 ± 5.5 mL, from 13.6 ± 5.3 to 14.8 ± 3.4 mL/m2 ); P > .05, respectively. E/a ratio, E-tdi, and E/E-tdi did not change significantly ([from 2.54 ± 4.46 to 2.54 ± 4.1], [from 11.9 ± 1.9 to 11.9 ± 2], [from 7.8 ± 1.4 to 7.6 ± 1.1], respectively, P > .05). Tricuspid annular plane systolic excursion (TAPSE) did not change significantly from 23.77 ± 4.2 to 23.9 ± 3.3, P = .1. There was a significant decrease in pulmonary pressure (from 25.4 ± 4.2 to 23 ± 2.5 mm Hg, P = .02), in mean arterial pressure (from 80 ± 4 to 76 ± 3 mm Hg, P < .001) and in TVR (from 1160 ± 260 to 1050 ± 206 dyne s/cm-5 , P = .04). CONCLUSIONS: According to RT3DTTE measurements, in pregnant women treated with nifedipine for tocolysis, there were no detrimental cardiovascular effects detected 48 hours postnifedipine treatment. RT3DTTE could show accurately the compensatory response of the left heart to the cardiovascular changes induced by treatment with nifedipine.
Assuntos
Ecocardiografia Tridimensional/métodos , Átrios do Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Nifedipino/administração & dosagem , Trabalho de Parto Prematuro/prevenção & controle , Tocólise/métodos , Ultrassonografia Pré-Natal/métodos , Adulto , Função do Átrio Esquerdo/efeitos dos fármacos , Função do Átrio Esquerdo/fisiologia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Relação Dose-Resposta a Droga , Ecocardiografia Doppler de Pulso , Feminino , Seguimentos , Idade Gestacional , Átrios do Coração/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Humanos , Gravidez , Terceiro Trimestre da Gravidez , Prognóstico , Estudos Prospectivos , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
PURPOSE: Anthracyclines (ANTs) are a class of active antineoplastic agents with topoisomerase-interacting activity that are considered the most active agents for the treatment of breast cancer. We investigated the efficacy of carvedilol in the inhibition of ANT-induced cardiotoxicity. METHODS: In this randomized, single-blind, placebo-controlled study, 91 women with recently diagnosed breast cancer undergoing ANT therapy were randomly assigned to groups treated with either carvedilol (n = 46) or placebo (n = 45). Echocardiography was performed before and at 6 months after randomization, and absolute changes in the mean left ventricular ejection fraction, left ventricular end diastolic volume, and left ventricular end systolic volume were determined. Furthermore, the percentage change in the left atrial (LA) diameter and other variables of left ventricular (LV) diastolic function, such as transmitral Doppler parameters, including early (E wave) and late (A wave) diastolic velocities, E/A ratio and E wave deceleration time, pulmonary venous Doppler signals, including forward systolic (S wave) and diastolic (D wave) velocities into LA, late diastolic atrial reversal velocity, and early diastolic tissue Doppler mitral annular velocity (e') were measured. In addition, tissue Doppler mitral annular systolic (s') velocity, as a marker of early stage of LV systolic dysfunction, E/e' ratio, as a determinant of LV filling pressure, and troponin I level, as a marker of myocardial necrosis were measured. RESULTS: At the end of follow-up period, left ventricular ejection fraction did not change in the carvedilol group. However, this parameter was significantly reduced in the control group (P < 0.001). Echocardiography showed that both left ventricular end systolic volume and LA diameter were significantly increased compared with the baseline measures in the control group. In pulse Doppler studies, pulmonary venous peak atrial reversal flow velocity was significantly increased in the control group. Moreover, a significant decrease in the mitral annuli early diastolic (e') and peak systolic (s') velocities and a significant increase in the E (the peak early diastolic velocity)/e' ratio in the control group were also observed. However, none of these variables were adversely changed at the end of follow-up in the carvedilol group. Furthermore, the TnI level was significantly higher in the control group than in the carvedilol group (P = 0.036) at 30 days after the initiation of chemotherapy. CONCLUSIONS: Prophylactic use of carvedilol may inhibit the development of anthracycline-induced cardiotoxicity, even at low doses.
Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Carbazóis/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Cardiopatias/prevenção & controle , Propanolaminas/uso terapêutico , Adulto , Idoso , Função do Átrio Esquerdo/efeitos dos fármacos , Biomarcadores/sangue , Carbazóis/efeitos adversos , Cardiotoxicidade , Fármacos Cardiovasculares/efeitos adversos , Carvedilol , Ecocardiografia Doppler de Pulso , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Humanos , Irã (Geográfico) , Pessoa de Meia-Idade , Propanolaminas/efeitos adversos , Medição de Risco , Fatores de Risco , Método Simples-Cego , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Troponina I/sangue , Função Ventricular Esquerda/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: The study goal was to compare the effect of epinephrine in different doses on pulmonary gas exchange in a rat model of bupivacaine-induced cardiac depression. METHODS: Twenty-four adult male Sprague-Dawley rats were divided into 4 groups (n = 6), and each group received a bupivacaine infusion (2.5 mg/kg per minute, 6 minutes) via the left femoral vein to induce cardiac depression. At the end of the bupivacaine infusion, each group was immediately given either isotonic sodium chloride solution (normal saline; NS group), 5-µg/kg epinephrine (Epi5 group), 10-µg/kg epinephrine (Epi10 group), or 20 µg/kg epinephrine (Epi20 group). Left atrial pressures were monitored for 20 minutes after epinephrine was administered (as was the NS group). Arterial blood gas analyses were performed before bupivacaine infusion and at the end of the 20-minute monitoring period. RESULTS: The Epi10 and Epi20 groups had lower pH (P = 0.02 and P < 0.001, respectively) and PaO2 (P = 0.049 and P < 0.001, respectively), and a higher PaCO2 (P < 0.001 and P < 0.001, respectively) compared with the NS group. There were no statistical differences between the Epi5 and NS groups in pH, PaCO2, or PaO2. Left atrial systolic pressure was higher in the Epi10 group (P = 0.002) and the Epi20 group (P < 0.001) within 2 minutes of epinephrine administration. There was no statistical difference between the Epi5 and NS groups in left atrial systolic pressure. CONCLUSION: A single injection of 10 µg/kg epinephrine or greater was associated with deterioration of pulmonary gas exchange in our rat model of bupivacaine induced cardiac depression.
Assuntos
Anestésicos Locais/toxicidade , Bupivacaína/toxicidade , Cardiotoxinas/toxicidade , Epinefrina/toxicidade , Troca Gasosa Pulmonar/efeitos dos fármacos , Vasoconstritores/toxicidade , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Função do Átrio Esquerdo/fisiologia , Masculino , Modelos Animais , Troca Gasosa Pulmonar/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Rhodiola, a popular plant in Tibet, has been proven to decrease arrhythmia. The aim of this study was to elucidate the molecular mechanism and electrophysiological properties of rhodiola in the suppression of atrial fibrillation. METHODS: This study consisted of 3 groups as follows: Group 1: normal control rabbits (n = 5); Group 2: rabbits with heart failure (HF) created by coronary ligation and who received 2 weeks of water orally as a placebo (n = 5); and Group 3: rabbits with HF who received 2 weeks of a rhodiola 270 mg/kg/day treatment orally (n = 5). The monophasic action potential, histology, and real-time polymerase chain reaction (RT-PCR) analysis of ionic channels and PI3K/AKT/eNOS were examined. RESULTS: Compared with the HF group, attenuated atrial fibrosis (35.4 ± 17.4% vs. 16.9 ± 8.4%, P = 0.05) and improved left ventricular (LV) ejection fraction (51.6 ± 3.4% vs. 68.0 ± 0.5%, P = 0.001) were observed in the rhodiola group. The rhodiola group had a shorter ERP (85.3 ± 6.8 vs. 94.3 ± 1.2, P = 0.002), APD90 (89.3 ± 1.5 vs. 112.7 ± 0.7, P < 0.001) in the left atrium (LA), and decreased AF inducibility (0.90 ± 0.04 vs. 0.42 ± 0.04, P < 0.001) compared with the HF group. The mRNA expressions of Kv1.4, Kv1.5, Kv4.3, KvLQT1, Cav1.2, and SERCA2a in the HF LA were up-regulated after rhodiola treatment. The rhodiola-treated HF LA demonstrated higher mRNA expression of PI3K-AKT compared with the HF group. CONCLUSIONS: Rhodiola reversed LA electrical remodeling, attenuated atrial fibrosis and suppressed AF in rabbits with HF. The beneficial electrophysiological effect of rhodiola may be related to upregulation of Kv1.4, Kv1.5, Kv4.3, KvLQT1, Cav1.2, SERCA2a, and activation of PI3K/AKT signaling.
Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/prevenção & controle , Átrios do Coração/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rhodiola , Potenciais de Ação , Animais , Antiarrítmicos/isolamento & purificação , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Função do Átrio Esquerdo/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Fibrose , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Rhodiola/química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Real-time three-dimensional echocardiography(RT-3DE) has allowed a better assessment of LA volumes and function. We sought to assess the early change in left atrial size and function in patients treated with anthracyclines using RT-3DE. 61 patients aged 44.9 ± 11.9 years with large B-cell non-Hodgkin lymphoma treated with doxorubicin were studied. Blood collection and echocardiography were performed at baseline and 1 day after completion of the chemotherapy. Global longitudinal strain (GLS), maximum, minimum and pre-atrial contraction LA volumes were measured and reservoir, conduit and booster pump function were assessed. Despite normal LVEF, passive emptying percent of total emptying (0.51 ± 0.14 vs. 0.40 ± 0.12, P < 0.001) and passive emptying index (0.29 ± 0.10 vs. 0.23 ± 0.06, P < 0.001) were remarkably reduced compared to baseline values, while active emptying percent of total emptying (0.49 ± 0.14 vs. 0.60 ± 0.12, P < 0.001) and active emptying index (0.41 ± 0.16 vs. 0.47 ± 0.16, P = 0.048) were increased. GLS (-21.64 ± 2.83 vs. -17.30 ± 2.50) was markedly reduced, cTnT levels was elevated from 0.005 ± 0.004 to 0.020 ± 0.026 ng/mL at the completion of chemotherapy (P all < 0.001). Early LA functional change occur after doxorubicin exposure in patients with preserved LVEF, which could be detected by RT-3DE.
Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Função do Átrio Esquerdo/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Átrios do Coração/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Ecocardiografia Tridimensional , Feminino , Átrios do Coração/fisiopatologia , Testes de Função Cardíaca , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab , Vincristina/administração & dosagem , Vincristina/efeitos adversosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Função do Átrio Esquerdo/efeitos dos fármacos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Função do Átrio Esquerdo/fisiologia , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Ecocardiografia , Feminino , Humanos , Pessoa de Meia-Idade , Miocárdio , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Resultado do TratamentoRESUMO
Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.
Assuntos
Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Cardiotônicos/farmacologia , Doxorrubicina , Cardiopatias/prevenção & controle , Morfolinas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Naftalenos/farmacologia , Oxazóis/farmacologia , PPAR alfa/antagonistas & inibidores , Tirosina/análogos & derivados , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Cardiotoxicidade , Citoproteção , Modelos Animais de Doenças , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , PPAR alfa/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/farmacologiaRESUMO
OBJECTIVE: In Turkey, a type of smokeless tobacco called Maras powder (MP) is widely used in the south-eastern region. Smokeless tobacco is found in preparations for chewing and for absorption by the nasal and oral mucosae. The purpose of this study was to investigate whether MP damages intra- and inter-atrial conduction delay and left atrial (LA) mechanical function as much as cigarette smoking. METHOD: A total of 150 chronic MP users (50 males, 32.5 ± 5.4 years), smokers (50 males, 32.1 ± 6.0 years) and controls (50 males, 30.1 ± 5.8 years) were included in the study. LA volumes were measured echocardiographically according to the biplane area-length method. Atrial electromechanical coupling was measured with tissue Doppler imaging and LA mechanical function parameters were calculated. RESULTS: The LA passive emptying fraction was significantly decreased and LA active emptying volume (LAAEV) was significantly increased in the MP group (p = 0.012 and p = 0.024, respectively), and the LA active emptying fraction (LAAEF) was significantly increased in the smokers (p = 0.003). There was a positive correlation between the amount of MP used and smoking (pack years) with LAAEV and LAAEF (r = 0.26, p = 0.009 and r = 0.25, p = 0.013, respectively). Lateral atrial electromechanical intervals (PA) were significantly higher in MP users, and the septal mitral PA was statistically higher in the smokers (p = 0.05 and p = 0.04, respectively). CONCLUSION: We suggest that atrial electromechanical coupling intervals were prolonged and LA mechanical function was impaired in MP users and smokers, but there was no significant difference between the MP users and smokers. These findings may be markers of subclinical cardiac involvement and tendency for atrial fibrillation.
Assuntos
Fibrilação Atrial/induzido quimicamente , Função do Átrio Esquerdo/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Tabaco sem Fumaça/efeitos adversos , Adulto , Fibrilação Atrial/diagnóstico por imagem , Estudos de Casos e Controles , Estudos Transversais , Ecocardiografia Doppler de Pulso , Feminino , Sistema de Condução Cardíaco/diagnóstico por imagem , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pós , Valor Preditivo dos Testes , Fatores de Risco , TurquiaRESUMO
Fenoterol, a ß2-adrenoceptor agonist, has anti-apoptotic action in cardiomyocytes and induces a specific pattern of downstream signaling. We have previously reported that exposure to fenoterol (5 µM) results in a delayed positive inotropic effect which is related to changes in both Ca2+ transient and NO. Here, the changes in reactive oxygen species (ROS) production in response to the fenoterol administration and the involvement of ROS in effect of this agonist on contractility were investigated in mouse isolated atria. Stimulation of ß2-adrenoceptor increases a level of extracellular ROS, while intracellular ROS level rises only after removal of fenoterol from the bath. NADPH-oxidase inhibitor (apocynin) prevents the increase in ROS production and the Nox2 isoform is immunofluorescently colocalized with ß2-adrenoceptor at the atrial myocytes. Treatments with antioxidants (N-acetyl-L-cysteine, NADPH inhibitors, exogenous catalases) significantly inhibit the fenoterol induced increase in the contraction amplitude, probably by attenuating Ca2+ transient and up-regulating NO production. ROS generated in a ß2-adrenoceptor-dependent manner can potentiate the activity of some Ca2+ channels. Indeed, inhibition of ryanodine receptors, TRPV-or L-type Ca2+- channels shows a similar efficacy in reduction of positive inotropic effect of both fenoterol and H2O2. In addition, detection of mitochondrial ROS indicates that fenoterol triggers a slow increase in ROS which is prevented by rotenone, but rotenone has no impact on the inotropic effect of fenoterol. We suggest that stimulation of ß2-adrenoceptor with fenoterol causes the activation of NADPH-oxidase and after the agonist removal extracellularly generated ROS penetrates into the cell, increasing the atrial contractions probably via Ca2+ channels.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Função do Átrio Esquerdo/fisiologia , Cardiotônicos/farmacologia , Contração Miocárdica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Masculino , Camundongos , Contração Miocárdica/fisiologia , Técnicas de Cultura de ÓrgãosRESUMO
INTRODUCTION: The pleiotropic effects of glitazones may favorably affect atrial remodeling. We sought to investigate the effects of peroxisome proliferator-activated receptor-γ (PPAR-γ) activator rosiglitazone on atrial structural remodeling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits. METHODS: Twenty alloxan-induced diabetic rabbits were randomly divided into two groups (10 animals in each group), namely the diabetic rosiglitazone group (treated with rosiglitazone 2 mg/day/kg for 4 weeks) and the nontreated diabetic group, while 10 additional healthy rabbits served as controls. Moreover, isolated Langendorff-perfused rabbit hearts were used to evaluate atrial electrophysiological parameters and vulnerability to AF, examined by burst pacing. Histological examination was also performed, whereas plasma oxidative stress and inflammatory biomarkers were measured. RESULTS: The duration of induced AF was significantly prolonged in the alloxan-induced diabetic rabbits compared with controls (1.6 ± 0.4 s vs. 0 s; P < 0.05). Rosiglitazone treatment significantly reduced the duration of induced AF in the treated rabbits (1.6 ± 0.4 s vs. 1.2 ± 0.05 s; P < 0.05). Moreover, rosiglitazone attenuated atrial structural remodeling reducing the interatrial activation time (35.4 ± 12.1 ms vs. 24.2 ± 10.8 ms, P < 0.05; control 23.3 ± 10.4 ms) and the atrial interstitial fibrosis as well (collagen volume fraction: 5.6 ± 3.9% vs. 2.4 ± 2.1%, P < 0.05; control 1.6 ± 0.8%). Rosiglitazone increased plasma superoxide dismutase (SOD) activity and, on the other hand, decreased malondialdehyde (MDA), hs-C-reactive protein, and tumor necrosis factor-α levels. CONCLUSION: Rosiglitazone attenuates arrhythmogenic atrial structural remodeling and AF promotion in alloxan-induced diabetic rabbits. Also, it seems to modulate oxidative stress and inflammation in this experimental model.