RESUMEN
BACKGROUND: The 12-month follow-up (F/U) efficacy of CBA PVI performed at community hospitals for treatment of symptomatic paroxysmal and persistent atrial fibrillation (AF) is unknown. This study determined the 12-month efficacy of pulmonary vein isolation (PVI) using cryoballoon ablation (CBA) performed at community hospitals with limited annual case numbers. METHODS: This registry study included 983 consecutive patients (pts) from 19 hospitals, each with an annual procedural volume of < 100 PVI procedures/year. Pts underwent CBA PVI for paroxysmal AF (n = 520), persistent AF (n = 423), or redo PVI (n = 40). The primary endpoint was frequency of documented recurrent AF, the occurrence of atrial flutter or tachycardia following a 90-day period after the index ablation and up to 12 months. The frequency of repeat ablation was determined. RESULTS: Isolation of all PVs was documented in 98% of pts at the end of the procedure. Twelve-month F/U data could be obtained in 916 pts. A 24-h ECG registration was performed in 641 pts (70.0%); in 107 pts (16.7%) of them, recurrent AF was documented. The primary endpoint was met in 193 F/U pts (21.1%). It occurred in 80/486 F/U pts with paroxysmal AF (16.4%), and in 107/390 F/U pts with persistent AF (27.4%). Redo PVI was performed in 71 pts (7.8%), and atrial flutter ablation was performed in 12 pts (1.4%). CONCLUSIONS: CBA PVI for paroxysmal or persistent AF can be performed at community hospitals with adequate rates of 12-month symptom freedom and arrhythmia recurrence. The study was registered at the German register of clinical studies (DRKS00016504).
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Fibrilación Atrial , Aleteo Atrial , Ablación por Catéter , Criocirugía , Venas Pulmonares , Humanos , Fibrilación Atrial/cirugía , Hospitales Comunitarios , Aleteo Atrial/cirugía , Resultado del Tratamiento , Criocirugía/métodos , Venas Pulmonares/cirugía , Ablación por Catéter/métodos , RecurrenciaRESUMEN
AIMS: Pulmonary vein isolation (PVI) using cryoballoon ablation (CBA) is an established procedure for treating symptomatic paroxysmal and persistent atrial fibrillation (AF). The safety and efficacy of PVI performed at community hospitals are unknown. We aimed to determine the safety and acute efficacy of PVI using CBA performed at community hospitals with limited annual case numbers. METHODS AND RESULTS: This registry study included 1004 consecutive patients who had PVI performed for symptomatic paroxysmal (n = 563) or persistent AF (n = 441) from January 2019 to September 2020 at 20 hospitals. Each hospital performed fewer than 100 CBA-PVI procedures/year according to local standards. Procedural data, efficacy, and complication rates were determined. The mean number of CBA procedures performed/year at each centre was 59 ± 25. The average procedure time was 90.1 ± 31.6 min and the average fluoroscopy time was 19.2 ± 11.4 min. Isolation of all pulmonary veins was documented in 97.9% of patients. The most frequent reason for not achieving complete isolation was development of phrenic nerve palsy. No hospital deaths were observed. Two patients (0.2%) suffered a clinical stroke. Pericardial effusion occurred in six patients (0.6%), two of whom (0.2%) required pericardial drainage. Vascular complications occurred in 24 patients (2.4%), two of whom (0.2%) required vascular surgery. Phrenic nerve palsy occurred in 48 patients (4.8%) and persisted up to hospital discharge in six patients (0.6%). CONCLUSION: Pulmonary vein isolation procedures for paroxysmal or persistent AF using CBA can be performed at community hospitals with high acute efficacy and low complication rates.
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Fibrilación Atrial , Ablación por Catéter , Criocirugía , Venas Pulmonares , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Criocirugía/efectos adversos , Criocirugía/métodos , Hospitales Comunitarios , Humanos , Venas Pulmonares/cirugía , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: Implantable cardioverter/defibrillator (ICD) shocks can cause myocardial injury, contributing to the progression of the underlying heart disease. The aim was to evaluate whether internal electrical cardioversion (int-CV) via the ICD or conventional external CV (ext-CV) of persistent atrial fibrillation (AF) in heart failure (HF) patients induces myocardial injury and initiates inflammation. METHODS AND RESULTS: A total of 115 HF patients with an ejection fraction between 20% and 45% were prospectively enrolled. Fifty-one patients were excluded due to failure of electrical CV at the first attempt as well as early relapse of AF within 8h after CV. The int-CV group consisted of 22 and the ext-CV group of 42 patients. Baseline values of high sensitive troponin T (hsTnT), interleukin (IL)-6, and C-reactive protein (CRP) did not differ significantly in both groups, whereas baseline N-terminal pro B-type natriuretic peptide (NT-pro BNP) was significantly lower in the ext-CV group. Eight hours after CV, the level of hsTnT increased significantly in the int-CV group, whereas no significant change was observed in the ext-CV group. Furthermore, CV significantly increased IL-6 and CRP in the int-CV group, whereas an insignificant increase could be documented in the ext-CV group. Due to electrical CV in both groups, the NT-pro BNP levels significantly declined in approximately the same content (int-CV 29% vs. ext-CV 36%). CONCLUSIONS: The significant increase in hsTnT, IL-6, and CRP in patients who underwent int-CV compared to those undergoing ext-CV may suggest that int-CV causes significant myocardial damage and induces systemic inflammation.
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Fibrilación Atrial/terapia , Cardioversión Eléctrica/métodos , Insuficiencia Cardíaca/terapia , Anciano , Fibrilación Atrial/sangre , Proteína C-Reactiva/análisis , Desfibriladores Implantables , Femenino , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Troponina T/sangreRESUMEN
The aim of this paper is to identify predictors of serum muscle damage marker (MDM) response following mixed martial arts (MMA) matches. Creatine kinase activity (CK) and myoglobin concentration (Mb) were measured in ten male elite MMA fighters (aged 28±5.7 years) prior to, 2 h, 24 h, and 96 h following 9 different MMA matches. The number of performed upright punches and kicks (UKF) that failed the opponent, the number of obtained hits to the upper and lower body (LBH), as well as the total fight duration (TFD) were evaluated as potential predictors from video recordings. CK peaked 24 h (829±753 U/L(-1)) and Mb peaked 2 h (210±122 µg/L(-1)) post matches. Almost 80% of the peak CK variance could be explained by LBH and UKF, whereas 87% of the Mb variation was explained by TFD and LBH. MMA result in a significant skeletal muscle damage, which largely depends on LBH. Furthermore, eccentric contractions to decelerate kicks that missed the opponent and the TFD seem to contribute to the MDM response.
RESUMEN
We performed a comparative literature review, to elucidate the major features of the Takotsubo (stress) cardiomyopathy (TCM) collected in last 25 years. TCM is characterized by left- or biventricular apical ballooning with a clinical presentation, electrocardiographic abnormalities, and biomarker profils similar to those seen in acute myocardial infarction. Epidemiological studies have shown that TCM is more common in postmenopausal women; however exact figures are not available. The underlying aetiology is still largely undetermined. Elevated catecholamine levels, lack of estrogen, disturbed myocardial fatty acid metabolism and plaque rupture with spontaneous thrombolysis are potentially discussed mechanisms responsible for inducing a prolonged stunned myocardium. Strong emotional or physical stress is the most frequently described trigger in the literature. Therapy recommendations include appropriate antiplatelet treatment, ß-blockers and ACE inhibitors. The abnormal kinetics usually resolve or improve within a month and carry a favorable prognosis in most cases. However, all the suspected complications of an acute myocardial infarction, including cardiogenic shock or lethal arrhythmias, may still occur.
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Cardiomiopatía de Takotsubo , Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Arritmias Cardíacas/complicaciones , Femenino , Humanos , Masculino , Menopausia , Infarto del Miocardio/metabolismo , Pronóstico , Factores Sexuales , Cardiomiopatía de Takotsubo/diagnóstico , Cardiomiopatía de Takotsubo/etiología , Cardiomiopatía de Takotsubo/fisiopatología , Cardiomiopatía de Takotsubo/terapia , Factores de TiempoRESUMEN
BACKGROUND: Autoantibodies have been identified as major predisposing factors for dilated cardiomyopathy (DCM). Patients with DCM show elevated serum levels of vascular endothelial growth factor (VEGF) whose source is unknown. Besides its well-investigated effects on angiogenesis, evidence is present that VEGF signaling is additionally involved in fibroblast proliferation and cardiomyocyte hypertrophy, hence in cardiac remodeling. Whether autoimmune effects in DCM impact cardiac VEGF signaling needs to be elucidated. METHODS: Five DCM patients were treated by the immunoadsorption (IA) therapy on five consecutive days. The eluents from the IA columns were collected and prepared for cell culture. Cardiomyocytes from neonatal rats (NRCM) were incubated with increasing DCM-immunoglobulin-G (IgG) concentrations for 48 h. Polyclonal IgG (Venimmun N), which was used to restore IgG plasma levels in DCM patients after the IA therapy was additionally used for control cell culture purposes. RESULTS: Elevated serum levels of VEGF decreased significantly after IA (Serum VEGF (ng/ml); DCM pre-IA: 45 ± 9.1 vs. DCM post-IA: 29 ± 6.7; P < 0.05). In cell culture, pretreatment of NRCM by DCM-IgG induced VEGF expression in a time and dose dependent manner. Biologically active VEGF that was secreted by NRCM significantly increased BNP mRNA levels in control cardiomyocytes and induced cell-proliferation of cultured cardiac fibroblast (Fibroblast proliferation; NRCM medium/HC-IgG: 1 ± 0.0 vs. NRCM medium/DCM-IgG 100 ng/ml: 5.6 ± 0.9; P < 0.05). CONCLUSION: The present study extends the knowledge about the possible link between autoimmune signaling in DCM and VEGF induction. Whether this observation plays a considerable role in cardiac remodeling during DCM development needs to be further elucidated.
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Autoanticuerpos/farmacología , Cardiomiopatía Dilatada/genética , Fibroblastos/efectos de los fármacos , Inmunoglobulina G/farmacología , Miocitos Cardíacos/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Animales Recién Nacidos , Autoanticuerpos/sangre , Cardiomiopatía Dilatada/inmunología , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/terapia , Proliferación Celular/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Expresión Génica , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Humanos , Inmunoglobulina G/sangre , Técnicas de Inmunoadsorción , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Cultivo Primario de Células , Ratas , Ratas Sprague-Dawley , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Subthreshold electrical stimulation (SES) has been shown to induce an improvement of angiogenesis in ischemic and nonischemic skeletal muscles, mediated by increased VEGF expression. VEGF plays a key role in physiological and pathological angiogenesis. Cardiomyocytes possess the ability to synthesize and secrete VEGF. Thus, we thought to investigate the effect of SES on VEGF regulation in cultured neonatal rat ventricular myocytes (NRVMs), in the aim to reveal new techniques for therapeutic angiogenesis in ischemic heart disease. Cell cultures of NRVMs were electrically stimulated with field strengths below the myocyte depolarization threshold (0.5 V/cm with 1 ms bipolar impulse duration). Frequencies ranging from 5 Hz up to 25, 50, and 99 Hz were applied over a period of 48 h. The expression of VEGF and its receptor KDR was determined with Western blot and ELISA. To reveal the biological activity of the secreted VEGF amount, cultured human coronary artery endothelial cells (HCAECs) were treated with the cell culture supernatant of NRVMs exposed to SES. A dominant effect of SES was observed at 25 Hz. Within this particular frequency the VEGF protein amount in the cytoplasm as well as in the cell culture supernatant increased significantly. In parallel, the protein expression of the KDR receptor decreased in a significant manner. Moreover, cell culture supernatant of NRVMs exposed to SES augmented the growth of HCAECs. Cardiomyocytes respond to SES with an increase in biologically active VEGF expression that promotes cell proliferation of HCAECs. This mechanism may provide new approaches to develop therapeutic angiogenesis in the ischemic heart.
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Estimulación Eléctrica , Miocitos Cardíacos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Vasos Coronarios/citología , Medios de Cultivo Condicionados/farmacología , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Miocitos Cardíacos/citología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factor A de Crecimiento Endotelial Vascular/análisis , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Neurofilament light chain (NF-L) is the major intermediate filament specifically expressed in neurons and their axons. No data are available concerning serum levels of NF-L after global cerebral ischemia due to cardiac arrest. To find a specific neuronal marker of long-term neurological outcome, we examined serum levels of NF-L in patients after cardiac arrest. METHODS: A prospective observational cohort study was conducted. Blood samples for the measurement of NF-L were analyzed from 85 patients within 2h after admission, as well as on 2nd, 3rd, 5th, and 7th day. Neurological outcome was assessed 6 months after cardiac arrest by employing the Modified Glasgow Outcome Score (MGOS). RESULTS: The serum course of NF-L in patients with poor neurological outcome (MGOS 1+2) was significantly augmented compared to patients with good neurological outcome (MGOS 3+4+5) (on admission (pg/ml): good: 125 ± 11.7 vs. poor: 884.4 ± 86.2 pg/ml; 3rd day: good: 153.1 ± 13.2 vs. poor: 854.4 ± 119.1; 7th day: good: 112.5 ± 10.4 vs. poor: 1011.8 ± 100.8; P<0.001). Intermediate NF-L serum values were found in patients with MGOS 0, which represents a mixture of patients who died with and without certified brain damage (on admission (pg/dl): 433.7 ± 49.8; 3rd day: 598.3 ± 86.6; 7th day: 474 ± 77.4). A prediction power of 0.93 (c-statistic, 95%-CI 0.87-0.99) on 1st, 0.85 (0.81-0.95) on 2nd, 0.92 (0.85-0.99) on 3rd, 0.97 (0.92-1) on 5th and 0.99 (0.98-1) on 7th day was achieved for NF-L predicting poor neurological outcome. CONCLUSIONS: The present data suggest that within 7 days after cardiac arrest serum NF-L is a valuable marker of long-term neurological outcome.
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Paro Cardíaco/sangre , Paro Cardíaco/diagnóstico , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/diagnóstico , Proteínas de Neurofilamentos/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Diagnóstico Precoz , Femenino , Paro Cardíaco/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/epidemiología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The Glasgow-Pittsburgh cerebral performance categories (GP-CPC) and the Glasgow Outcome Score (GOS) have been used to categorize patients according to their neurological outcome for prognostic predictors in patients after cardiac arrest (CA). We postulated that inclusion of deaths without knowing the cerebral status into the group of patients with poor outcome after CA using the GP-CPC and GOS will lead to dilution of the prognostic power of the investigated biochemical marker. The present study was conducted to verify this issue by employing a modified outcome score, which we termed as Modified Glasgow Outcome Score (MGOS). In the present study, 97 patients were enrolled in a prospective manner. Serum NSE and S100B levels were measured daily for 7 days after admission to the intensive care unit. Neurological outcome was assessed by employing the GOS and MGOS after 6 months. By employing the GOS, 46 patients were categorized into the group of patients with poor outcome and 51 patients survived with good neurological outcome. Patients who died without certified brain damage or with unknown cerebral status after CA (n = 20) were separated from patients with poor outcome in the MGOS. The magnitude of NSE (S100B) elevation in patients with poor outcome categorized by the MGOS was approximately 1.7-fold (1.5) higher as compared with patients divided by the GOS. The mean calculated sensitivities and area under the curve values of NSE and S100B predicting poor outcome classified by the MGOS were significantly higher as compared with the GOS. Conclusively, inclusion of deaths without certified brain damage or with unknown cerebral status into the group of patients with poor outcome will lead to underestimation of the prognostic power of investigated biochemical markers such as NSE and S100B. The MGOS will help to avoid this bias.
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Escala de Consecuencias de Glasgow , Paro Cardíaco/diagnóstico , Hipoxia Encefálica/diagnóstico , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Biomarcadores/sangre , Reanimación Cardiopulmonar , Causas de Muerte , Evaluación de la Discapacidad , Femenino , Alemania , Paro Cardíaco/sangre , Paro Cardíaco/complicaciones , Paro Cardíaco/mortalidad , Paro Cardíaco/fisiopatología , Paro Cardíaco/terapia , Humanos , Hipoxia Encefálica/sangre , Hipoxia Encefálica/etiología , Hipoxia Encefálica/mortalidad , Hipoxia Encefálica/fisiopatología , Hipoxia Encefálica/terapia , Masculino , Persona de Mediana Edad , Factores de Crecimiento Nervioso/sangre , Examen Neurológico , Fosfopiruvato Hidratasa/sangre , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Curva ROC , Recuperación de la Función , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteínas S100/sangre , Factores de TiempoRESUMEN
An irregular ventricular response during atrial fibrillation (AF) has been shown to mediate an increase in sympathetic nerve activity in human subjects. The molecular mechanisms remain unclear. This study aimed to investigate the impact of rate and irregularity on nerve growth factor (NGF) expression in cardiomyocytes, since NGF is known to be the main contributor to cardiac sympathetic innervation density. Cell cultures of neonatal rat ventricular myocytes were electrically stimulated for 48 h with increasing rates (0, 5 and 50 Hz) and irregularity (standard deviation (SD)=5%, 25% and 50% of mean cycle length). Furthermore, we analyzed the calcineurin-NFAT and the endothelin-1 signalling pathways as possible contributors to NGF regulation during arrhythmic stimulation. We found that the increase of NGF expression reached its maximum at the irregularity of 25% SD by 5 Hz (NGF: 5 Hz 0% SD=1 vs. 5Hz 25% SD=1.57, P<0.05). Specific blockade of the ET-A receptor by BQ123 could abolish this NGF increase (NGF: 5 Hz 25% SD+BQ123=0.66, P<0.05). High frequency electrical field stimulation (HFES) with 50 Hz decreased the NGF expression in a significant manner (NGF: 50Hz=0.55, P<0.05). Inhibition of calcineurin-NFAT signalling with cyclosporine-A or 11R-VIVIT abolished the HFES induced NGF down-regulation (NGF: 50 Hz+CsA=1.14, P<0.05). In summary, this study reveals different signalling routes of NGF expression in cardiomyocytes exposed to increasing rates and irregularity. Whether this translates into different degrees of NGF expression and possibly neural sympathetic growth in various forms of ventricular rate control during AF remains to be elucidated in further studies.
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Fibrilación Atrial/fisiopatología , Ventrículos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Factor de Crecimiento Nervioso/genética , Transducción de Señal , Animales , Fibrilación Atrial/metabolismo , Factor Natriurético Atrial/metabolismo , Calcineurina/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Medios de Cultivo Condicionados/química , Estimulación Eléctrica , Antagonistas de los Receptores de la Endotelina A , Endotelina-1/metabolismo , Regulación de la Expresión Génica , Factores de Transcripción NFATC/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Neuritas/fisiología , Péptidos Cíclicos/farmacología , Cultivo Primario de Células , Ratas , Transcripción GenéticaRESUMEN
Age has been identified as an independent risk factor for cardiovascular diseases. A shift of the cardiac autonomic nervous system towards an increase in sympathetic tone has been reported in the elderly. Nerve growth factor (NGF) is the main neurotrophic factor that increases the sympathetic activity of the heart. If there is a shift of NGF expression in old compared to young cardiomyocytes and whether there are regional differences in the heart still remain unclear. Therefore, we chose a rat model of different-aged rats (3-4 days = neonatal, 6-8 weeks = young, 20-24 months = old), and isolated cardiomyocytes from the left and the right atrium (LA, RA), as well as from the left and the right ventricle (LV, RV), were used to determine NGF expression on mRNA and protein levels. In neonatal, young, and old rats, NGF amount in LA and RA was significantly lower as compared to LV and RV. In young and old rats, we found significant higher NGF protein levels in LA compared to RA. In addition, both atria showed an increase in NGF expression between age groups neonatal, young, and old. In both ventricles, we observed a significant decrease in NGF expression from neonatal to young rats and a significant increase from young to old rats. The highest NGF amount in LV and RV was observed in neonatal rats. Regarding tyrosine kinase A receptor (TrkA) expression, the main receptor for NGF signaling, both atria showed the largest expression in old rats; while in LV and RV, TrkA was expressed mainly in young rats. These results point to a contribution of nerve growth factors to the change of autonomic tone observed in elderly patients.
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Envejecimiento/genética , Sistema Nervioso Autónomo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Corazón/inervación , Factor de Crecimiento Nervioso/genética , ARN/genética , Envejecimiento/metabolismo , Animales , Animales Recién Nacidos , Sistema Nervioso Autónomo/citología , Sistema Nervioso Autónomo/crecimiento & desarrollo , Western Blotting , Células Cultivadas , Corazón/crecimiento & desarrollo , Masculino , Factor de Crecimiento Nervioso/biosíntesis , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Recently, increased cardiac norepinephrine levels were observed in patients who were exposed to irregular stimulation during electrophysiological testing. The molecular mechanisms remain unclear. Intrinsic cardiac adrenergic (ICA) cells are present in mammalian hearts and contain catecholamine-synthesizing enzymes sufficient to produce biologically active norepinephrine levels. Thus, we aimed to investigate the expression of catecholamine-synthesizing enzymes by ICA cells exposed to irregular pacing. METHODS: Co-cultures of cardiomyocytes and ICA cells were exposed to irregular pacing for 48h (standard deviation (SD)=5%, 25% and 50% of mean cycle length) at a constant rate of 5Hz. The expression of catecholamine-synthesizing enzymes including tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) were analyzed on mRNA and protein levels. RESULTS: First, immunolabeling identified ICA cells presenting TH and DBH staining around the cell nucleus. Irregular pacing with 25% SD at a constant rate of 5Hz significantly increased the expression of TH and DBH enzyme synthesis. Pharmacological approaches have shown that both metoprolol and losartan reversed the irregular pacing induced DBH increase, whereas the expression of TH was only blocked by metoprolol in a significant manner. Blockade of the endothelin-A receptor by BQ123 or the calcineurin-NFAT pathway by cyclosporine-A, 11R-VIVIT or FK506 revealed a potential role of both cascades in irregular pacing induced catecholamine-synthesizing enzyme expression. CONCLUSIONS: ICA cells respond to irregular electrical activation with an increase in catecholamine-synthesizing enzymes. Drugs commonly used in clinical routine significantly influence the expression of TH and DBH by ICA cells via different signaling routes.
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Dopamina beta-Hidroxilasa/biosíntesis , Epinefrina/fisiología , Miocardio/citología , Miocardio/enzimología , Miocitos Cardíacos/fisiología , Tirosina 3-Monooxigenasa/biosíntesis , Animales , Inhibidores de la Calcineurina , Catecolaminas/biosíntesis , Técnicas de Cocultivo , Ciclosporina/farmacología , Dopamina beta-Hidroxilasa/genética , Estimulación Eléctrica , Antagonistas de los Receptores de la Endotelina A , Losartán/farmacología , Metoprolol/farmacología , Miocitos Cardíacos/enzimología , Factores de Transcripción NFATC/antagonistas & inhibidores , Péptidos Cíclicos/farmacología , Ratas , Transducción de Señal , Tacrolimus/farmacología , Tirosina 3-Monooxigenasa/genéticaRESUMEN
Mechanical stretch has been shown to increase vascular endothelial growth factor (VEGF) expression in cultured myocytes. Sympathetic neurons (SN) also possess the ability to express and secrete VEGF, which is mediated by the NGF/TrkA signaling pathway. Recently, we demonstrated that SN respond to stretch with an upregulation of nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). Whether stretch increases neuronal VEGF expression still remains to be clarified. Therefore, SN from the superior cervical ganglia of neonatal Sprangue Dawley rats were exposed to a gradual increase of stretch from 3% up to 13% within 3days (3%, 7% and 13%). Under these conditions, the expression and secretion of VEGF was analyzed. Mechanical stretch significantly increased VEGF mRNA and protein expression (mRNA: control=1 vs. stretch=3.1; n=3/protein: control=1 vs. stretch=2.7; n=3). ELISA experiments to asses VEGF content in the cell culture supernatant showed a time and dose dependency in VEGF increment due to stretch. NGF and CNTF neutralization decreased stretch-induced VEGF augmentation in a significant manner. This response was mediated in part by TrkA receptor activation. The stretch-induced VEGF upregulation was accompanied by an increase in HIF-1α expression. KDR levels remained unchanged under conditions of stretch, but showed a significant increase due to NGF neutralization. In summary, SN respond to stretch with an upregulation of VEGF, which is mediated by the NGF/CNTF and TrkA signaling pathway paralleled by HIF-1α expression. NGF signaling seems to play an important role in regulating neuronal KDR expression.
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Factor Neurotrófico Ciliar/metabolismo , Mecanotransducción Celular , Factor de Crecimiento Nervioso/metabolismo , Neuronas/metabolismo , Estrés Mecánico , Sistema Nervioso Simpático/citología , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Animales , Células Cultivadas , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Miocitos Cardíacos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
INTRODUCTION: Cardiac resynchronization therapy (CRT) provides a therapeutic option for patients with congestive heart failure (CHF) and left bundle-branch block. Structural myocardial remodelling due to CRT has been described extensively. We hypothesized that CRT might also induce electrical remodelling, thus decreasing the intrinsic QRS duration. METHODS: In 38 patients with CHF (ejection fraction (EF): 26 +/- 7%) a CRT device was implanted. 18 patients suffered from ischaemic cardiomyopathy (ICM) and 20 from dilated cardiomyopathy (DCM). Echocardiography and 12-lead ECGs without pacing were obtained prior to implantation and after 6 and 12 months. Patients were classified as responders in case of an increase in EF > or = 25% in combination with an increase in NYHA class > or = 1. Variance analysis was performed to determine the impact of response or underlying heart disease (ICM/DCM) on the extent of change in QRS duration (delta QRS duration). RESULTS: The EF increased to 36 +/- 10% (P < 0.0001) after 6 months and 40 +/- 12% (P < 0.0001) after 12 months of CRT. Intrinsic QRS duration decreased from 171 +/- 18 ms before CRT to 164 +/- 23 ms (P = 0.027) after 6 months and 161 +/- 25 ms (P = 0.002) after 12 months of CRT. 22 patients (58%) were classified as responders. Whereas a significant decrease in intrinsic QRS duration was observed in responders, only a slight decrease was seen in non-responders. However, two-factorial variance analyses did not show a significant influence of response or underlying heart disease (ICM/DCM) on delta QRS duration (P = 0.7). CONCLUSION: CRT results in an electrical remodelling with a reduction of the intrinsic QRS duration.
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Terapia de Resincronización Cardíaca , Cardiomiopatía Dilatada/terapia , Sistema de Conducción Cardíaco/fisiopatología , Insuficiencia Cardíaca/terapia , Isquemia Miocárdica/terapia , Remodelación Ventricular/fisiología , Anciano , Análisis de Varianza , Cardiomiopatía Dilatada/fisiopatología , Ecocardiografía , Electrocardiografía , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Isquemia Miocárdica/fisiopatología , Resultado del TratamientoRESUMEN
RATIONALE: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off. OBJECTIVE: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. METHODS AND RESULTS: In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, ß-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. CONCLUSIONS: HFES of cardiac neurons in vivo and in vitro causes neuronal cellular hypertrophy, which is mediated by NGF and boosters cellular function by NT-3-mediated acetylcholine upregulation. This knowledge may contribute to develop HFES techniques to augment cardiac parasympathetic tone.
Asunto(s)
Función del Atrio Derecho/fisiología , Factores de Crecimiento Nervioso/fisiología , Neuronas/fisiología , Neurotrofina 3/fisiología , Fibras Parasimpáticas Posganglionares/fisiología , Regulación hacia Arriba/fisiología , Animales , Células Cultivadas , Perros , Estimulación Eléctrica/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Biochemical markers, e.g. NSE or S100B, and somatosensory evoked potentials (SSEP) are considered promising candidates for neurological prognostic predictors in patients after cardiac arrest (CA). The Utstein Templates recommend the use of the Glasgow-Pittsburgh Cerebral Performance Categories (GP-CPC) to divide patients according to their neurological outcome. However, several studies investigating biochemical markers and SSEP are based on the Glasgow Outcome Score (GOS). We noticed that many studies failed to exclude patients who died without certified brain damage from patients classified as poor outcome, instead including all patients who died into this category. Therefore, we summarized the published NSE cut-off values and the derived sensitivity and specificity to predict poor outcome of those studies which only included patients with certified brain death in GOS-1 or GP-CPC-5 (group A) vs. those studies which did not differentiate between death from any cause or death due to primary brain damage (group B). On average, mean NSE cut-off values and sensitivity were higher (56 ± 35 ng/ml, 56 ± 18%) in group A than in group B (41 ± 17 ng/ml, 44 ± 25%), respectively. The specificity remained equally high in both groups. In analogy, the average sensitivity of SSEP to predict poor outcome was higher in group A (76 ± 11%) than in group B (50 ± 15%), while the specificity was similar in both groups. Conclusively, inclusion of deaths without certified brain damage after CA in neurological outcome studies will lead to underestimation of the prognostic power of biochemical or electrophysiological markers for brain damage. A modified GOS and GP-CPC score might help to avoid this bias.
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Potenciales Evocados Somatosensoriales/fisiología , Paro Cardíaco/complicaciones , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/fisiopatología , Fosfopiruvato Hidratasa/análisis , Biomarcadores/metabolismo , Escala de Consecuencias de Glasgow/normas , Humanos , Hipoxia Encefálica/etiología , Fosfopiruvato Hidratasa/metabolismo , Valor Predictivo de las Pruebas , PronósticoRESUMEN
BACKGROUND: Several studies have shown that mild hypothermia (32-34°C) markedly mitigates brain damage after cardiac arrest (CA). This study aimed to compare the efficacy of the non-invasive cooling device Hilotherm Clinic (Hilotherm GmbH, Germany) with conventional cooling to induce and maintain mild hypothermia in patients after out-of-hospital CA. METHODS: 50 adult patients with an indication for controlled mild hypothermia were prospectively assigned to conventional cooling (n=20) or cooling with the Hilotherm system (n=30). Patients receiving a cooling therapy by Hilotherm were treated either with 0.35 m(2) (n=20) or with 0.7 m(2) (n=10) surface area of cooling sleeves. RESULTS: The speed of cooling was significantly higher in both Hilotherm groups compared to conventional cooling (Hilotherm 0.7 m(2): 0.91 ± 0.08°C/h, Hilotherm 0.35 m(2): 0.47 ± 0.04°C/h, and conventional: 0.3 ± 0.04°C/h, p ≤ 0.003). Temperature deviation from the target temperature of 33°C was significantly higher in the conventional group compared to both Hilotherm groups. During induction of mild hypothermia a significant reduction of the mean arterial blood pressure and the heart rate was observed without significant differences between the groups. However, the speed of cooling (range 0.3-0.91°C/h) did not correlate to the decrease of blood pressure and heart rate. Norepinephrine dosing during induction of mild hypothermia and re-warming (1st-2nd day) was significantly increased compared to the 3rd day after admission in all groups. Dobutamine dosing and 30 days in-hospital mortality did not differ significantly between the groups. CONCLUSIONS: Rapid and reliable mild hypothermia can be better achieved by the non-invasive cooling system Hilotherm compared to conventional cooling with ice packs and cold infusion.
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Hipotermia Inducida/métodos , Paro Cardíaco Extrahospitalario/fisiopatología , Paro Cardíaco Extrahospitalario/terapia , Presión Sanguínea/fisiología , Femenino , Frecuencia Cardíaca/fisiología , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Persona de Mediana Edad , Paro Cardíaco Extrahospitalario/mortalidadRESUMEN
Recently, we have shown that high frequency electrical field stimulation (HFES) of sympathetic neurons (SN) induces nerve sprouting by up-regulation of nerve growth factor (NGF) which targets the tyrosine kinase A receptor (TrkA) in an autocrine/paracrine manner. There is increasing evidence that matrix metalloproteinase-2 (MMP-2) is not only involved in extracellular matrix (ECM) turnover but may also exert beneficial effects during neuronal growth. Therefore, this study aimed to investigate the regulation and function of MMP-2 and its major activator membrane type 1-matrix metalloproteinase (MT1-MMP) as well its inhibitor TIMP-1 in SN under conditions of HFES. Moreover, we analyzed molecular mechanisms of the beneficial effect of losartan, an angiotensin II type I receptor (AT-1)blocker on HFES-induced nerve sprouting. Cell cultures of SN from the superior cervical ganglia (SCG) of neonatal rats were electrically stimulated for 48 h with a frequency of 5 or 50 Hz. HFES increased MMP-2 and MT1-MMP mRNA and protein expression, whereas TIMP-1 expression remained unchanged. Under conditions of HFES, we observed a shift from pro- to active-MMP-2 indicating an increase in MMP-2 enzyme activity. Specific pharmacological MMP-2 inhibition contributed to an increase in pro-NGF amount in the cell culture supernatant and significantly reduced HFES-induced neurite outgrowth. Losartan abolished HFES-induced nerve sprouting in a significant manner by preventing HFES-induced NGF, MMP-2, and MT1-MMP up-regulation. In summary, specific MMP-2 blockade prevents sympathetic nerve sprouting (SNS) by inhibition of pro-NGF conversion while losartan abolishes HFES-induced SNS by reducing total NGF, MMP-2 and MT1-MMP expression.
Asunto(s)
Metaloproteinasa 14 de la Matriz/fisiología , Metaloproteinasa 2 de la Matriz/fisiología , Factores de Crecimiento Nervioso/metabolismo , Neuritas/fisiología , Precursores de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional/genética , Sistema Nervioso Simpático/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , Animales , Animales Recién Nacidos , Células Cultivadas , Estimulación Eléctrica/métodos , Losartán/farmacología , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Neuritas/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/fisiologíaRESUMEN
In the heart, acetylcholine (ACh) slows pacemaker activity, depresses contractility and slows conduction in the atrioventricular node. Beside these cardiovascular effects, ACh has also been associated with an anti-inflammatory and anti-apoptotic pathway. There is no evidence for ACh synthesis and excretion in other cell types than neuronal cells in the heart. Therefore, this study investigates whether cardiomyocytes are able to synthesize, transport and excrete ACh in the heart. We chose a rat model of different aged rats (neonatal, 6-8 week = young, 20-24 month = old). By real-time PCR, Western blot and immunofluorescence experiments we could demonstrate that adult, but not neonatal cardiomyocytes, express the choline acetyltransferase (ChAT). The expression level of ChAT is down-regulated in old cardiomyocytes. Furthermore, we found that young and old cardiomyocytes express the ACh transport proteins choline transporter-1 (CHT-1) and the vesicular acetylcholine transporter (VAChT). The amount of ACh excretion detected by high performance liquid chromatography (HPLC) is significantly down-regulated in old cardiomyocytes. Bromo-acetylcholine (BrACh), a specific ChAT inhibitor, significantly decreased ACh concentrations in cardiomyocyte supernatants demonstrating that ChAT is the main ACh synthesizing enzyme in cardiomyocytes. In conclusion, we could demonstrate that adult, but not neonatal, cardiomyocytes are able to synthesize, transport and excrete ACh in the rat heart. The expression level of ChAT and the ACh excretion amount are significantly down-regulated in old cardiomyocytes. This finding may provide new physiological/pathological aspects in the communication between cardiomyocytes and other cell types in the myocardium, e.g. fibrocytes, neurocytes or endothelial cells.