Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51
Filtrar
1.
J Intern Med ; 294(3): 347-357, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37340835

RESUMO

BACKGROUND: Optogenetics could offer a solution to the current lack of an ambulatory method for the rapid automated cardioversion of atrial fibrillation (AF), but key translational aspects remain to be studied. OBJECTIVE: To investigate whether optogenetic cardioversion of AF is effective in the aged heart and whether sufficient light penetrates the human atrial wall. METHODS: Atria of adult and aged rats were optogenetically modified to express light-gated ion channels (i.e., red-activatable channelrhodopsin), followed by AF induction and atrial illumination to determine the effectivity of optogenetic cardioversion. The irradiance level was determined by light transmittance measurements on human atrial tissue. RESULTS: AF could be effectively terminated in the remodeled atria of aged rats (97%, n = 6). Subsequently, ex vivo experiments using human atrial auricles demonstrated that 565-nm light pulses at an intensity of 25 mW/mm2 achieved the complete penetration of the atrial wall. Applying such irradiation onto the chest of adult rats resulted in transthoracic atrial illumination as evidenced by the optogenetic cardioversion of AF (90%, n = 4). CONCLUSION: Transthoracic optogenetic cardioversion of AF is effective in the aged rat heart using irradiation levels compatible with human atrial transmural light penetration.


Assuntos
Fibrilação Atrial , Adulto , Humanos , Animais , Ratos , Fibrilação Atrial/terapia , Optogenética/métodos , Cardioversão Elétrica , Iluminação , Átrios do Coração/efeitos da radiação
2.
PLoS Comput Biol ; 17(10): e1009476, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34624017

RESUMO

Interruptions in nonlinear wave propagation, commonly referred to as wave breaks, are typical of many complex excitable systems. In the heart they lead to lethal rhythm disorders, the so-called arrhythmias, which are one of the main causes of sudden death in the industrialized world. Progress in the treatment and therapy of cardiac arrhythmias requires a detailed understanding of the triggers and dynamics of these wave breaks. In particular, two very important questions are: 1) What determines the potential of a wave break to initiate re-entry? and 2) How do these breaks evolve such that the system is able to maintain spatiotemporally chaotic electrical activity? Here we approach these questions numerically using optogenetics in an in silico model of human atrial tissue that has undergone chronic atrial fibrillation (cAF) remodelling. In the lesser studied sub-threshold illumination régime, we discover a new mechanism of wave break initiation in cardiac tissue that occurs for gentle slopes of the restitution characteristics. This mechanism involves the creation of conduction blocks through a combination of wavefront-waveback interaction, reshaping of the wave profile and heterogeneous recovery from the excitation of the spatially extended medium, leading to the creation of re-excitable windows for sustained re-entry. This finding is an important contribution to cardiac arrhythmia research as it identifies scenarios in which low-energy perturbations to cardiac rhythm can be potentially life-threatening.


Assuntos
Estimulação Elétrica , Átrios do Coração , Sistema de Condução Cardíaco , Modelos Cardiovasculares , Fibrilação Atrial/fisiopatologia , Biologia Computacional , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Sistema de Condução Cardíaco/fisiologia , Sistema de Condução Cardíaco/efeitos da radiação , Humanos , Optogenética
3.
Cancer Radiother ; 25(3): 229-236, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33423965

RESUMO

PURPOSE: This study aimed to assess radiation dose distribution to cardiac subvolumes in left-sided breast cancer radiotherapy (LBCRT) and to clarify whether the mean heart dose (MHD) reliably reflects cardiac substructures exposure. MATERIALS AND METHODS: Fifty women referred for adjuvant LBCRT were prospectively evaluated. All patients received 3D-conformal hypofractionated radiotherapy (40Gy delivered in 15 fractions of 2.67Gy±boost of 13.35Gy). Cardiac substructures were contoured using the F. Duane's cardiac atlas. Dose distribution to cardiac chambers, left main (LM), left anterior descending (LAD), left circumflex (LCx) and right coronary artery (RCA)) was assessed. Dosimetric associations were analysed. RESULTS: The mean MHD was 3.08Gy (EQD2=3.67Gy). The mean Dmean/Dmax LAD was 11.45Gy (EQD2=13.64Gy)/29.5Gy (EQD2=35.15Gy). Low doses were delivered to LM, LCx, and RCA (Dmean≤1.3Gy). The left ventricle (LV) was the most exposed cardiac chamber with Dmean/Dmax of 4.78Gy/37Gy. The strongest correlation with MHD was found for Dmean LAD (r=0.81). For every 1Gy increase in MHD, Dmean LAD rose by 3.4Gy. However, the proportion of variance in Dmean LAD predictable from MHD was moderate (R2=0.65). For all other cardiac substructures, R2 values were<0.7. CONCLUSION: Our study showed high exposure of LAD and LV in LBCRT. With poor predictive value, MHD may underestimate doses to cardiac substructures. For optimal heart sparing radiotherapy, we recommend to consider LV and LAD as separate organ at risk.


Assuntos
Cardiotoxicidade/etiologia , Coração/efeitos da radiação , Radioterapia Conformacional/efeitos adversos , Neoplasias Unilaterais da Mama/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/radioterapia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/radioterapia , Vasos Coronários/efeitos da radiação , Feminino , Átrios do Coração/efeitos da radiação , Ventrículos do Coração/efeitos da radiação , Humanos , Irradiação Linfática , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Estudos Prospectivos , Doses de Radiação , Hipofracionamento da Dose de Radiação , Reirradiação , Neoplasias Unilaterais da Mama/tratamento farmacológico
4.
Int J Radiat Oncol Biol Phys ; 108(4): 1073-1081, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32585334

RESUMO

PURPOSE: For patients with lung cancer treated with radiation therapy, a dose to the heart is associated with excess mortality; however, it is often not feasible to spare the whole heart. Our aim is to define cardiac substructures and dose thresholds that optimally reduce early mortality. METHODS AND MATERIALS: Fourteen cardiac substructures were delineated on 5 template patients with representative anatomies. One thousand one hundred sixty-one patients with non-small cell lung cancer were registered nonrigidly to these 5 template anatomies, and their radiation therapy doses were mapped. Mean and maximum dose to each substructure were extracted, and the means were evaluated as input to prediction models. The cohort was bootstrapped into 2 variable reduction techniques: elastic net least absolute shrinkage and selection operator and the random survival forest model. Each method was optimized to extract variables contributing most to overall survival, and model coefficients were evaluated to select these substructures. The most important variables common to both models were selected and evaluated in multivariable Cox-proportional hazard models. A threshold dose was defined, and Kaplan-Meier survival curves plotted. RESULTS: Nine hundred seventy-eight patients remained after visual quality assurance of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery, and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, a hazard ratio of 1.01/Gy, and P = .03 after accounting for tumor volume (P < .001), N stage (P < .01), and performance status (P = .01). The optimal threshold for the maximum dose, equivalent dose in 2-Gy fractions, was 23 Gy. Kaplan-Meier survival curves showed a significant split (log-rank P = .008). CONCLUSIONS: The maximum dose to the combined cardiac region encompassing the right atrium, right coronary artery, and ascending aorta was found to have the greatest effect on patient survival. A maximum equivalent dose in 2-Gy fractions of 23 Gy was identified for consideration as a dose limit in future studies.


Assuntos
Aorta/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Vasos Coronários/efeitos da radiação , Átrios do Coração/efeitos da radiação , Neoplasias Pulmonares/radioterapia , Órgãos em Risco/efeitos da radiação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Coração/efeitos da radiação , Ventrículos do Coração/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Doses de Radiação
5.
Exp Mol Pathol ; 114: 104409, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32088192

RESUMO

BACKGROUND: Noise is an important environmental risk factor. Industrial environments are rich in high-intensity infrasound (hi-IFS), which we have found to induce myocardial and coronary perivascular fibrosis in rats. The effects of exposure to IFS on the ventricles have been studied, but not on the atria. We hypothesized that rats exposed to hi-IFS develop atrial remodeling involving fibrosis and connexin 43, which we sought to evaluate. MATERIAL AND METHODS: Seventy-two Wistar rats, half exposed to hi-IFS (120 dB, <20 Hz) during a maximum period of 12 weeks and half age-matched controls, were studied. Atrial fibrosis was analyzed by Chromotrope-aniline blue staining. The immunohistochemical evaluation of Cx43 was performed using the polyclonal antibody connexin-43 m diluted 1:1000 at 4 °C overnight. Digitized images were obtained with an optical microscope using 400× magnifications. The measurements were performed using image J software. A two-way ANOVA model was used to compare the groups. RESULTS: The mean values of the ratio "atrial fibrosis / cardiomyocytes" increased to a maximum of 0.1095 ± 0,04 and 0.5408 ± 0,01, and of the ratio "CX43 / cardiomyocytes" decreased to 0.0834 ± 0,03 and 0.0966 ± 0,03, respectively in IFS-exposed rats and controls. IFS-exposed rats exhibited a significantly higher ratio of fibrosis (p < .001) and lower ratio of Cx43 (p = .009). CONCLUSION: High-intensity infrasound exposure leads to an increase in atrial interstitial fibrosis and a decrease in connexin 43 in rat hearts. This finding reinforces the need for further experimental and clinical studies concerning the effects of exposure to infrasound.


Assuntos
Conexina 43/genética , Fibrose/genética , Coração/fisiopatologia , Ruído/efeitos adversos , Animais , Modelos Animais de Doenças , Fibrose/etiologia , Fibrose/fisiopatologia , Regulação da Expressão Gênica/efeitos da radiação , Coração/efeitos da radiação , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Wistar , Fatores de Risco
6.
Int J Radiat Biol ; 96(6): 759-766, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31977276

RESUMO

Purpose: Hepatocellular carcinoma (HCC) involving the inferior vena cava (IVC) and/or right atrium (RA) can affect systemic circulation, causing fatal complications. Standard treatment is yet to be established due to its rarity and intractability. We sought to determine the clinical efficacy of external beam radiotherapy (EBRT) in HCC treatment.Patients and methods: Our group designed this multicenter trial and recruited patients with HCC and IVC and/or RA involvement. Forty-nine patients from six institutions received EBRT with median dose of 46.7 (range: 35.4-71.5) Gy during 2009-2016. The primary outcome was overall survival (OS), and relevant predictors were evaluated.Results: Median follow-up length was 9.3 (range: 1.1-119) months. Median survival, 1-, and 2- year OS rates were 10.1 months (95% confidence interval [CI]: 7.5-12.7 months), 43.5%, and 30.1%, respectively. Significant factors affecting OS were alpha-fetoprotein level ≥300 ng/mL (risk ratio [RR]: 2.34, p = .025), tumor multiplicity (RR: 2.56, p = .028), and patient volume of institutions (high- vs. middle volume centers) (RR: 3.58, p = .001). Local control rates were 88.7% and 74.5% at 1 and 2 years, respectively. The most common first failure site was the lung (21/49, 42.9%) followed by liver outside the EBRT field (17/49, 34.7%). One case of possible radiation-induced liver disease was noted, with transient alkaline phosphatase elevation.Conclusion: EBRT can yield favorable local control in HCC with IVC and/or RA involvement. Systemic treatment may be more indicated as factors reflecting tumor aggressiveness were significant, and first distant failure is common.


Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/radioterapia , Átrios do Coração/efeitos da radiação , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/radioterapia , Veia Cava Inferior/efeitos da radiação , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Átrios do Coração/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , República da Coreia , Veia Cava Inferior/patologia
7.
Echocardiography ; 36(10): 1806-1813, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31573712

RESUMO

AIMS: Cardiotoxicity is a possible complication of cancer treatment, particularly with anthracyclines and anti-HER2 drugs. Systolic dysfunction has already been described. Diastolic dysfunction and left atrial function are less studied. We sought to analyze the impact of cardiotoxic treatments on left ventricular diastolic function and left atrial (LA) function. METHODS AND RESULTS: Retrospective study of 100 patients (all women, with a mean age of 54 ± 12 years) with three exams in the span of 1 year during treatment for breast cancer. Patients with previous cancer treatment, coronary artery disease, significant valvular disease, and atrial arrhythmias were excluded. Diastolic dysfunction was classified according to international guidelines and left atrial strain was analyzed by two-dimensional speckle tracking. In our sample, 74% received anthracyclines, 83% anti-HER2, and 76% radiation treatment. In the follow-up, 20% developed new or worsening diastolic dysfunction. Age was the only independent predictor (OR 1.93, 95% CI 1.04-3.58, P = .037). In left atrial function, only the contractile function was significantly reduced in 20.8% of the patients and age was also the only independent predictor, but with a protective effect (OR 0.51, 95% CI 0.28-0.91, P = .023). CONCLUSIONS: During breast cancer treatment, 20% of the patients develop new or worsening diastolic dysfunction, being age the main determinant, suggesting higher impact of chemotherapy in older patients. Contractile left atrial function is also compromised but, in this case, age seems to be protective. Our results support a stricter surveillance in older patients together to eventually adjust chemotherapy regimens.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Neoplasias da Mama/terapia , Cardiotoxicidade/diagnóstico por imagem , Ecocardiografia/métodos , Lesões por Radiação/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Diástole , Feminino , Seguimentos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Disfunção Ventricular Esquerda/etiologia
8.
Acta Oncol ; 58(9): 1250-1258, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31219359

RESUMO

Background: In this study, we evaluate the evolution of cardiac changes during a three-year follow-up after adjuvant breast radiotherapy (RT). Methods: Sixty patients with left-sided and 20 patients with right-sided early stage breast cancer without chemotherapy were included in this prospective study. Echocardiography and cardiac biomarkers were evaluated before, immediately after and 3 years after RT. Radiation doses to cardiac structures were calculated. Results: In echocardiography, left ventricle (LV) systolic measurements had impaired at 3 years compared to baseline: the mean global longitudinal strain (GLS) worsened from -18 ± 3 to -17 ± 3 (p = .015), LV ejection fraction from 62 ± 5% to 60 ± 4% (p = .003) and the stroke volume from 73 ± 16 mL to 69 ± 15 mL (p = .015). LV diastolic function was also negatively affected: the isovolumetric relaxation time was prolonged (p = .006) and the first peak of diastole decreased (p = .022). Likewise, left atrial (LA) measurements impaired. These changes in echocardiography were more prominent in left-sided than in right-sided patients. The concurrent aromatase inhibitor (AI) use was associated with GLS impairment. In all patients, the N-terminal pro-brain natriuretic peptide (proBNP) values were median (interquartile range) 74 (41-125) ng/L at baseline, 75 (41-125) ng/L at the end of RT and 96 (56-162) ng/L at 3 years (p < .001 from baseline to 3 years). However, proBNP did not increase in right-sided patients. Conclusion: During the 3-year follow-up after RT, negative subclinical changes in cardiac biomarkers and in LV systolic and diastolic function were observed. The measured changes were more pronounced in left-sided patients. In addition, AI use was associated with impaired cardiac systolic function.


Assuntos
Carcinoma Intraductal não Infiltrante/radioterapia , Coração/efeitos da radiação , Neoplasias Unilaterais da Mama/radioterapia , Adulto , Idoso , Biomarcadores/análise , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Ecocardiografia , Feminino , Seguimentos , Átrios do Coração/efeitos da radiação , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/efeitos da radiação , Humanos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Doses de Radiação , Radioterapia Adjuvante/efeitos adversos , Volume Sistólico/efeitos da radiação , Fatores de Tempo , Neoplasias Unilaterais da Mama/patologia , Neoplasias Unilaterais da Mama/cirurgia , Função Ventricular Esquerda/efeitos da radiação
9.
Nat Commun ; 10(1): 1281, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894542

RESUMO

The standard technique for investigating adrenergic effects on heart function is perfusion with pharmaceutical agonists, which does not provide high temporal or spatial precision. Herein we demonstrate that the light sensitive Gs-protein coupled receptor JellyOp enables optogenetic stimulation of Gs-signaling in cardiomyocytes and the whole heart. Illumination of transgenic embryonic stem cell-derived cardiomyocytes or of the right atrium of mice expressing JellyOp elevates cAMP levels and instantaneously accelerates spontaneous beating rates similar to pharmacological ß-adrenergic stimulation. Light application to the dorsal left atrium instead leads to supraventricular extrabeats, indicating adverse effects of localized Gs-signaling. In isolated ventricular cardiomyocytes from JellyOp mice, we find increased Ca2+ currents, fractional cell shortening and relaxation rates after illumination enabling the analysis of differential Gs-signaling with high temporal precision. Thus, JellyOp expression allows localized and time-restricted Gs stimulation and will provide mechanistic insights into different effects of site-specific, long-lasting and pulsatile Gs activation.


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Átrios do Coração/metabolismo , Ventrículos do Coração/metabolismo , Transdução de Sinal Luminoso , Miócitos Cardíacos/metabolismo , Optogenética/métodos , Animais , Cálcio/metabolismo , Cátions Bivalentes , Diferenciação Celular , AMP Cíclico/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Átrios do Coração/citologia , Átrios do Coração/efeitos da radiação , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos da radiação , Luz , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/efeitos da radiação , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos da radiação
10.
J Cardiothorac Surg ; 13(1): 116, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30445977

RESUMO

BACKGROUND: It is still difficult to create a secure linear conduction block on a beating heart from the epicardial side. To overcome this drawback we developed an infrared coagulator equipped with a cuboid light-guiding quartz rod. This study was designed to electrophysiologically confirm the efficacy of a new ablation probe using infrared energy in a clinical case. METHODS: The infrared light from a lamp is focused into the newly developed cuboid quartz rod, which has a rectangular distal exit-plane that allows 30 mm × 10 mm linear photocoagulation. Two pairs of electrodes were attached to the right atrium of a patient who was undergoing surgery. Each pair of electrodes was placed 10 mm from an ablation line. The change in conduction time between the two pairs of electrodes was measured during ablation. The predicted conduction time delay ratio was 1.54. RESULTS: The actual conduction time after ablation was 1.38-1.43 times longer than the pre-ablation conduction time. CONCLUSIONS: The infrared ablation using a newly developed cuboid probe made it possible to create a linear conduction block on the beating right atrial free wall clinically.


Assuntos
Fibrilação Atrial/cirurgia , Átrios do Coração/cirurgia , Sistema de Condução Cardíaco/cirurgia , Raios Infravermelhos/uso terapêutico , Pericárdio/cirurgia , Animais , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Ablação por Cateter , Galinhas , Eletrodos , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Sistema de Condução Cardíaco/patologia , Sistema de Condução Cardíaco/fisiopatologia , Sistema de Condução Cardíaco/efeitos da radiação , Humanos , Modelos Animais , Pericárdio/patologia , Pericárdio/fisiopatologia , Pericárdio/efeitos da radiação
11.
JACC Clin Electrophysiol ; 4(4): 467-479, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-30067486

RESUMO

OBJECTIVES: This study sought to examine the biophysical properties of high-power and short-duration (HP-SD) radiofrequency ablation for pulmonary vein isolation. BACKGROUND: Pulmonary vein isolation is the cornerstone of atrial fibrillation ablation. However, pulmonary vein reconnection is frequent and is often the result of catheter instability, tissue edema, and a reversible nontransmural injury. We postulated that HP-SD ablation increases lesion-to-lesion uniformity and transmurality. METHODS: This study included 20 swine and a novel open-irrigated ablation catheter with a thermocouple system able to record temperature at the catheter-tissue interface (QDOT Micro Catheter). Step 1 compared 3 HP-SD ablation settings: 90 W/4 s, 90 W/6 s, and 70 W/8 s in a thigh muscle preparation. Ablation at 90 W/4 s was identified as the best compromise between lesion size and safety parameters, with no steam-pop or char. In step 2, a total of 174 single ablation applications were performed in the beating heart and resulted in 3 (1.7%) steam-pops, all occurring at catheter-tissue interface temperature ≥85°C. Additional 233 applications at 90 W/4 s and temperature limit of 65°C were applied without steam-pop. Step 3 compared the presence of gaps and lesion transmurality in atrial lines and pulmonary vein isolation between HP-SD (90 W/4 s, T ≤65°C) and standard (25 W/20 s) ablation. RESULTS: HP-SD ablation resulted in 100% contiguous lines with all transmural lesions, whereas standard ablation had linear gaps in 25% and partial thickness lesions in 29%. Ablation with HP-SD produced wider lesions (6.02 ± 0.2 mm vs. 4.43 ± 1.0 mm; p = 0.003) at similar depth (3.58 ± 0.3 mm vs. 3.53 ± 0.6 mm; p = 0.81) and improved lesion-to-lesion uniformity with comparable safety end points. CONCLUSIONS: In a preclinical model, HP-SD ablation (90 W/4 s, T ≤65°C) produced an improved lesion-to-lesion uniformity, linear contiguity, and transmurality at a similar safety profile of conventional ablation.


Assuntos
Ablação por Cateter/instrumentação , Ablação por Cateter/métodos , Veias Pulmonares/cirurgia , Animais , Desenho de Equipamento , Átrios do Coração/efeitos da radiação , Humanos , Segurança do Paciente , Suínos , Temperatura
12.
J Physiol ; 596(17): 3841-3858, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29989169

RESUMO

KEY POINTS: Although optogenetics has clearly demonstrated the feasibility of cardiac manipulation, current optical stimulation strategies lack the capability to react acutely to ongoing cardiac wave dynamics. Here, we developed an all-optical platform to monitor and control electrical activity in real-time. The methodology was applied to restore normal electrical activity after atrioventricular block and to manipulate the intraventricular propagation of the electrical wavefront. The closed-loop approach was also applied to simulate a re-entrant circuit across the ventricle. The development of this innovative optical methodology provides the first proof-of-concept that a real-time all-optical stimulation can control cardiac rhythm in normal and abnormal conditions. ABSTRACT: Optogenetics has provided new insights in cardiovascular research, leading to new methods for cardiac pacing, resynchronization therapy and cardioversion. Although these interventions have clearly demonstrated the feasibility of cardiac manipulation, current optical stimulation strategies do not take into account cardiac wave dynamics in real time. Here, we developed an all-optical platform complemented by integrated, newly developed software to monitor and control electrical activity in intact mouse hearts. The system combined a wide-field mesoscope with a digital projector for optogenetic activation. Cardiac functionality could be manipulated either in free-run mode with submillisecond temporal resolution or in a closed-loop fashion: a tailored hardware and software platform allowed real-time intervention capable of reacting within 2 ms. The methodology was applied to restore normal electrical activity after atrioventricular block, by triggering the ventricle in response to optically mapped atrial activity with appropriate timing. Real-time intraventricular manipulation of the propagating electrical wavefront was also demonstrated, opening the prospect for real-time resynchronization therapy and cardiac defibrillation. Furthermore, the closed-loop approach was applied to simulate a re-entrant circuit across the ventricle demonstrating the capability of our system to manipulate heart conduction with high versatility even in arrhythmogenic conditions. The development of this innovative optical methodology provides the first proof-of-concept that a real-time optically based stimulation can control cardiac rhythm in normal and abnormal conditions, promising a new approach for the investigation of the (patho)physiology of the heart.


Assuntos
Arritmias Cardíacas/terapia , Bloqueio Atrioventricular/terapia , Terapia por Estimulação Elétrica/métodos , Átrios do Coração/citologia , Ventrículos do Coração/citologia , Optogenética/instrumentação , Potenciais de Ação , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Bloqueio Atrioventricular/genética , Bloqueio Atrioventricular/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Imagem Óptica
13.
J Physiol ; 596(2): 181-196, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29193078

RESUMO

KEY POINTS: Optogenetics has emerged as a potential alternative to electrotherapy for treating heart rhythm disorders, but its applicability for terminating atrial arrhythmias remains largely unexplored. We used computational models reconstructed from clinical MRI scans of fibrotic patient atria to explore the feasibility of optogenetic termination of atrial tachycardia (AT), comparing two different illumination strategies: distributed vs. targeted. We show that targeted optogenetic stimulation based on automated, non-invasive flow-network analysis of patient-specific re-entry morphology may be a reliable approach for identifying the optimal illumination target in each individual (i.e. the critical AT isthmus). The above-described approach yields very high success rates (up to 100%) and requires dramatically less input power than distributed illumination We conclude that simulations in patient-specific models show that targeted light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT if the human atria can be successfully light-sensitized via gene delivery of ChR2. ABSTRACT: Optogenetics has emerged as a potential alternative to electrotherapy for treating arrhythmia, but feasibility studies have been limited to ventricular defibrillation via epicardial light application. Here, we assess the efficacy of optogenetic atrial tachycardia (AT) termination in human hearts using a strategy that targets for illumination specific regions identified in an automated manner. In three patient-specific models reconstructed from late gadolinium-enhanced MRI scans, we simulated channelrhodopsin-2 (ChR2) expression via gene delivery. In all three models, we attempted to terminate re-entrant AT (induced via rapid pacing) via optogenetic stimulation. We compared two strategies: (1) distributed illumination of the endocardium by multi-optrode grids (number of optrodes, Nopt  = 64, 128, 256) and (2) targeted illumination of the critical isthmus, which was identified via analysis of simulated activation patterns using an algorithm based on flow networks. The illuminated area and input power were smaller for the targeted approach (19-57.8 mm2 ; 0.6-1.8 W) compared to the sparsest distributed arrays (Nopt  = 64; 124.9 ± 6.3 mm2 ; 3.9 ± 0.2 W). AT termination rates for distributed illumination were low, ranging from <5% for short pulses (1/10 ms long) to ∼20% for longer stimuli (100/1000 ms). When we attempted to terminate the same AT episodes with targeted illumination, outcomes were similar for short pulses (1/10 ms long: 0% success) but improved for longer stimuli (100 ms: 54% success; 1000 ms: 90% success). We conclude that simulations in patient-specific models show that light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT in atria light-sensitized via gene delivery. We show that targeted optogenetic stimulation based on analysis of AT morphology may be a reliable approach for defibrillation and requires less power than distributed illumination.


Assuntos
Potenciais de Ação , Simulação por Computador , Átrios do Coração/citologia , Optogenética/métodos , Taquicardia/terapia , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Humanos
15.
Int J Radiat Oncol Biol Phys ; 99(2): 434-441, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28871994

RESUMO

PURPOSE: To evaluate whether inclusion of incidental radiation dose to the cardiac atria and ventricles improves the prediction of grade ≥3 radiation pneumonitis (RP) in advanced-stage non-small cell lung cancer (AS-NSCLC) patients treated with intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). METHODS AND MATERIALS: Using a bootstrap modeling approach, clinical parameters and dose-volume histogram (DVH) parameters of lungs and heart (assessing atria and ventricles separately and combined) were evaluated for RP prediction in 188 AS-NSCLC patients. RESULTS: After a median follow-up of 18.4 months, 26 patients (13.8%) developed RP. Only the median mean lung dose (MLD) differed between groups (15.3 Gy vs 13.7 Gy for the RP and non-RP group, respectively; P=.004). The MLD showed the highest Spearman correlation coefficient (Rs) for RP (Rs = 0.21; P<.01). Most Rs of the lung DVH parameters exceeded those of the heart DVH parameters. After predictive modeling using a bootstrap procedure, the MLD was always included in the predictive model for grade ≥3 RP, whereas the heart DVH parameters were seldom included in the model. CONCLUSION: Incidental dose to the cardiac atria and ventricles did not improve RP risk prediction in our cohort of 188 AS-NSCLC patients treated with IMRT or VMAT.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Órgãos em Risco/efeitos da radiação , Pneumonite por Radiação/etiologia , Radioterapia de Intensidade Modulada/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Átrios do Coração/efeitos da radiação , Ventrículos do Coração/efeitos da radiação , Humanos , Pulmão/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Doses de Radiação , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Fatores de Tempo
16.
Int J Radiat Oncol Biol Phys ; 99(1): 51-60, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28816160

RESUMO

PURPOSE: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy. METHODS AND MATERIALS: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression. RESULTS: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model. CONCLUSIONS: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Coração/efeitos da radiação , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Órgãos em Risco/efeitos da radiação , Lesões por Radiação/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Causas de Morte , Fracionamento da Dose de Radiação , Eletrocardiografia/efeitos da radiação , Feminino , Coração/diagnóstico por imagem , Coração/fisiologia , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/efeitos da radiação , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Órgãos em Risco/diagnóstico por imagem , Órgãos em Risco/fisiologia , Pericárdio/efeitos da radiação , Análise de Componente Principal , Estudos Prospectivos , Doses de Radiação , Lesões por Radiação/fisiopatologia , Planejamento da Radioterapia Assistida por Computador
17.
Can J Physiol Pharmacol ; 95(9): 985-992, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28301729

RESUMO

The objective of this study was to study the functional changes of the left atrium after radiofrequency ablation treatment for atrial fibrillation and the therapeutic effect of atorvastatin. Fifty-eight patients undergoing radiofrequency ablation for atrial fibrillation were randomly divided into non-atorvastatin group and atorvastatin group. Patients in the atorvastatin group were treated with atorvastatin 20 mg p.o. per night in addition to the conventional treatment of atrial fibrillation; patients in the non-atorvastatin group received conventional treatment of atrial fibrillation only. Echocardiography was performed before radiofrequency ablation operation and 1 week, 2 weeks, 3 weeks, and 4 weeks after operation. Two-dimensional ultrasound speckle tracking imaging system was used to measure the structural indexes of the left atrium. Results indicated that there was no significant change for indexes representing the structural status of the left atrium within a month after radiofrequency ablation (P > 0.05); however, there were significant changes for indexes representing the functional status of the left atrium. There were also significant changes in indexes reflecting left atrial strain status: the S and SRs of atorvastatin group were higher than those of non-atorvastatin group (P < 0.05). In summary, atorvastatin could improve left atrial function and shorten the duration of atrial stunning after radiofrequency ablation of atrial fibrillation.


Assuntos
Atorvastatina/farmacologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Miocárdio Atordoado/tratamento farmacológico , Miocárdio Atordoado/etiologia , Adulto , Idoso , Atorvastatina/uso terapêutico , Fibrilação Atrial/complicações , Feminino , Átrios do Coração/patologia , Átrios do Coração/efeitos da radiação , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio Atordoado/complicações , Miocárdio Atordoado/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/efeitos da radiação , Sístole/efeitos dos fármacos
18.
J Radiat Res ; 56(6): 927-37, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26386255

RESUMO

We compared two intensity-modulated radiotherapy techniques for left-sided breast treatment, involving lymph node irradiation including the internal mammary chain. Inverse planned arc-therapy (VMAT) was compared with a forward-planned multi-segment technique with a mono-isocenter (MONOISO). Ten files were planned per technique, delivering a 50-Gy dose to the breast and 46.95 Gy to nodes, within 25 fractions. Comparative endpoints were planning target volume (PTV) coverage, dose to surrounding structures, and treatment delivery time. PTV coverage, homogeneity and conformality were better for two arc VMAT plans; V95%(PTV-T) was 96% for VMAT vs 89.2% for MONOISO. Homogeneity index (HI)(PTV-T) was 0.1 and HI(PTV-N) was 0.1 for VMAT vs 0.6 and 0.5 for MONOISO. Treatment delivery time was reduced by a factor of two using VMAT relative to MONOISO (84 s vs 180 s). High doses to organs at risk were reduced (V30(left lung) = 14% using VMAT vs 24.4% with MONOISO; dose to 2% of the volume (D2%)(heart) = 26.1 Gy vs 32 Gy), especially to the left coronary artery (LCA) (D2%(LCA) = 34.4 Gy vs 40.3 Gy). However, VMAT delivered low doses to a larger volume, including contralateral organs (mean dose [Dmean](right lung) = 4 Gy and Dmean(right breast) = 3.2 Gy). These were better protected using MONOISO plans (Dmean(right lung) = 0.8 Gy and Dmean(right breast) = 0.4 Gy). VMAT improved PTV coverage and dose homogeneity, but clinical benefits remain unclear. Decreased dose exposure to the LCA may be clinically relevant. VMAT could be used for complex treatments that are difficult with conventional techniques. Patient age should be considered because of uncertainties concerning secondary malignancies.


Assuntos
Neoplasias da Mama/radioterapia , Coração , Vasos Coronários/efeitos da radiação , Feminino , Coração/efeitos da radiação , Átrios do Coração/efeitos da radiação , Humanos , Doses de Radiação , Radiometria/instrumentação , Radiometria/métodos , Neoplasias Unilaterais da Mama/radioterapia
19.
Cardiovasc Res ; 104(1): 194-205, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25082848

RESUMO

AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia and often involves reentrant electrical activation (e.g. spiral waves). Drug therapy for AF can have serious side effects including proarrhythmia, while electrical shock therapy is associated with discomfort and tissue damage. Hypothetically, forced expression and subsequent activation of light-gated cation channels in cardiomyocytes might deliver a depolarizing force sufficient for defibrillation, thereby circumventing the aforementioned drawbacks. We therefore investigated the feasibility of light-induced spiral wave termination through cardiac optogenetics. METHODS AND RESULTS: Neonatal rat atrial cardiomyocyte monolayers were transduced with lentiviral vectors encoding light-activated Ca(2+)-translocating channelrhodopsin (CatCh; LV.CatCh∼eYFP↑) or eYFP (LV.eYFP↑) as control, and burst-paced to induce spiral waves rotating around functional cores. Effects of CatCh activation on reentry were investigated by optical and multi-electrode array (MEA) mapping. Western blot analyses and immunocytology confirmed transgene expression. Brief blue light pulses (10 ms/470 nm) triggered action potentials only in LV.CatCh∼eYFP↑-transduced cultures, confirming functional CatCh-mediated current. Prolonged light pulses (500 ms) resulted in reentry termination in 100% of LV.CatCh∼eYFP↑-transduced cultures (n = 31) vs. 0% of LV.eYFP↑-transduced cultures (n = 11). Here, CatCh activation caused uniform depolarization, thereby decreasing overall excitability (MEA peak-to-peak amplitude decreased 251.3 ± 217.1 vs. 9.2 ± 9.5 µV in controls). Consequently, functional coresize increased and phase singularities (PSs) drifted, leading to reentry termination by PS-PS or PS-boundary collisions. CONCLUSION: This study shows that spiral waves in atrial cardiomyocyte monolayers can be terminated effectively by a light-induced depolarizing current, produced by the arrhythmogenic substrate itself, upon optogenetic engineering. These results provide proof-of-concept for shockless defibrillation.


Assuntos
Fibrilação Atrial/terapia , Luz , Miócitos Cardíacos/efeitos da radiação , Optogenética , Potenciais de Ação , Animais , Animais Recém-Nascidos , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Western Blotting , Estimulação Cardíaca Artificial , Células Cultivadas , Channelrhodopsins , Estudos de Viabilidade , Imunofluorescência , Vetores Genéticos , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Lentivirus/genética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Ratos Wistar , Fatores de Tempo , Transdução Genética , Transfecção , Imagens com Corantes Sensíveis à Voltagem
20.
Artigo em Inglês | MEDLINE | ID: mdl-25570272

RESUMO

Intermittent vagal nerve stimulation (VNS) has emerged as a potential therapy to treat cardiovascular diseases by delivering electrical stimulation to the vagus nerves. The purpose of this study was to investigate the electrophysiological changes in the atrium resulting from long-term intermittent VNS therapy in the chronic myocardial infarction (MI) rat model. MI was induced via left anterior descending coronary artery (LAD) ligation in male Sprague-Dawley rats, randomized into two groups: MI (implanted with nonfunctional VNS stimulators) and MI-VNS (implanted with functional VNS stimulators and received chronic intermittent VNS treatment) groups. Further, a sham group was used as control in which MI was not performed and received nonfunctional VNS stimulators. At 12 weeks, optical mapping of right atrium (RA) of sinus rhythm was performed. Our results demonstrated that chronic MI changed the electrical properties of the atrium action potentials and resulted in reduced action potential duration at 50% (APD50) and 80% (APD80) repolarization. Chronic right cervical VNS restored the APD back to healthy heart APD values. Additionally, APD heterogeneity index increased as a result of the chronic MI. Chronic VNS was not found to alter this increase. By calculating PR intervals from weekly ECG recordings of anaesthetized rats, we demonstrated that chronic MI and intermittent VNS did not affect the AV conduction time from the atria to the ventricles. From our study, we conclude the MI decreased the APD and increased APD spatial dispersion. VNS increased the APD back to healthy normal values but did change the APD spatial dispersion and the electrical conduction in the RA.


Assuntos
Coração/efeitos da radiação , Infarto do Miocárdio/fisiopatologia , Estimulação do Nervo Vago , Potenciais de Ação/efeitos da radiação , Animais , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Masculino , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...