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1.
Eur J Clin Microbiol Infect Dis ; 30(1): 59-63, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20878199

RESUMEN

Antibacterial therapy may enhance the risk of symptomatic vulvo-vaginal candidosis in susceptible women. We addressed the question whether oral antifungal treatment for vulvo-vaginal candidosis also influences the bacterial vaginal microflora. One hundred and forty-two patients with a culture-proven acute episode of recurrent vulvo-vaginal candidosis (RVC) were treated with fuconazole according to the ReCiDiF regimen (induction dose of 600 mg orally per week followed by 200 mg per week) or with a single dose of 200 mg pramiconazole, a new potent oral triazole. At inclusion, 1 week and 1 month after the end of antifungal treatment, the bacterial microflora was assessed by microscopy of vaginal fluid to detect lactobacillary grades and bacterial vaginosis (BV). The presence of BV was studied in these patients with vulvo-vaginal candidosis after treatment with antifungal medication. At the start of oral antifungal treatment, 6.3% of women with Candida were co-infected with BV. Of the BV-negative women, 10 out of 133 (8%) developed BV after 1 week and after 1 month 8 of them (7%) were still BV-positive. Although no patients received antibacterial treatment at any moment of the study, 6 out of 9 (66%) of the women with Candida and BV at inclusion no longer had BV 1 week after antifungal treatment and 6 out of 7 (86%) lacked BV after 1 month. Treatment with antifungals may have a beneficial effect on women with concurrent BV, but does not prevent BV from occurring in BV-negative women with Candida vaginitis.


Asunto(s)
Antifúngicos/uso terapéutico , Bacterias/crecimiento & desarrollo , Candidiasis Vulvovaginal/tratamiento farmacológico , Vaginosis Bacteriana/inducido químicamente , Administración Oral , Antifúngicos/administración & dosificación , Femenino , Fluconazol/administración & dosificación , Fluconazol/uso terapéutico , Humanos , Imidazoles/administración & dosificación , Imidazoles/uso terapéutico , Triazoles/administración & dosificación , Triazoles/uso terapéutico
2.
Aliment Pharmacol Ther ; 29(3): 315-28, 2009 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-19035970

RESUMEN

BACKGROUND: Chronic constipation may result in disabling symptoms, is often unsatisfactorily treated by laxatives and negatively impacts quality of life (QoL). AIM: A randomized, double-blind, placebo-controlled, phase III trial to evaluate the efficacy and safety of a selective, high-affinity 5-HT(4) receptor agonist, prucalopride, in patients with chronic constipation [or=3 SCBMs/week, averaged over 12 weeks. Other assessments included BM frequency, constipation-related QoL and symptoms and tolerability. RESULTS: Among 641 patients, significantly more patients taking prucalopride 2 or 4 mg (24%) than placebo (12%), achieved the primary efficacy endpoint (>or=3 SCBMs/week) or an increase of >or=1 SCBMs/week; 43% and 47% vs. 28% respectively. Prucalopride-treated patients also achieved significantly greater satisfaction with treatment and bowel function, and improved perception of constipation severity and constipation-related QoL, compared with placebo. Most frequent treatment-related adverse events were headache, abdominal pain, nausea and diarrhoea (mainly during day 1). There were no differences in comparison to placebo in the incidence of serious adverse effects or cardiovascular events. CONCLUSION: Over 12 weeks, prucalopride was effective and well tolerated in chronic constipation.


Asunto(s)
Benzofuranos/administración & dosificación , Estreñimiento/tratamiento farmacológico , Placebos/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benzofuranos/efectos adversos , Enfermedad Crónica , Estreñimiento/psicología , Defecación/efectos de los fármacos , Método Doble Ciego , Femenino , Tránsito Gastrointestinal/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Placebos/efectos adversos , Calidad de Vida/psicología , Agonistas de Receptores de Serotonina/efectos adversos , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto Joven
5.
Skin Pharmacol Physiol ; 19(1): 50-6, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16247249

RESUMEN

BACKGROUND: R126638 is a novel triazole exhibiting potent in vitro and in vivo antifungal activity against fungal pathogens including dermatophytes and yeasts. OBJECTIVE: To determine the antifungal activity in time in the stratum corneum of healthy volunteers after oral intake of R126638 at a daily dose of 100 or 200 mg for 1 week. METHOD: Sixteen male volunteers were randomly allocated to oral treatment with either 100 or 200 mg of R126638 once daily for 1 week. Five cyanoacrylate skin surface strippings (CSSS) were obtained from the forearm of each subject before drug intake at day 1. CSSS were also collected during treatment at day 2 (24 h after the first drug intake, before the second drug intake), at day 4 (before the fourth drug intake) and at day 7 (10 h after the last drug intake). The post-treatment lingering effect was assessed at day 10 (3 days after treatment) and at day 14 (7 days after treatment). The corneofungimetry bioassay was performed on these CSSS to assess the antifungal profile of R126638. Cells of different fungal species (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Candida albicans and Malassezia globosa) were deposited and cultured for 10 days on CSSS in a sterile and controlled environment. The extent of fungal growth on the stratum corneum was determined using computerized image analysis. RESULTS: R126638 clearly reduced the growth of all tested fungal species. The onset of effects of R126638 was evidenced at day 4 when it reached statistical significance for 3 of 5 species. At day 7, significance was reached for 4 of 5 species. During the posttreatment period, R126638 remained effective for 4 of 5 species at day 10, and this activity persisted until day 14 for 2 of 5 species. CONCLUSION: A broad spectrum antifungal activity was rapidly expressed in the stratum corneum after oral intake of R126638. The drug likely reached the upper layers of the stratum corneum by diffusion and persisted in this location for at least 7 days after treatment.


Asunto(s)
Antifúngicos/farmacología , Dermatomicosis/tratamiento farmacológico , Epidermis/microbiología , Imidazoles/farmacología , Triazoles/farmacología , Administración Oral , Adolescente , Adulto , Bioensayo , Hongos/efectos de los fármacos , Hongos/crecimiento & desarrollo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Adhesivos Tisulares
6.
Antimicrob Agents Chemother ; 48(2): 388-91, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14742185

RESUMEN

R126638 is a new triazole agent with potent antifungal activity in vitro against various dermatophytes, Candida spp., and Malassezia spp. Its activity against Malassezia spp. in vitro was superior to that of ketoconazole, the agent currently used for the treatment of Malassezia-related infections. R126638 showed activity comparable to or lower than that of itraconazole against dermatophytes in vitro; however, in guinea pig models of dermatophyte infections, R126638 given orally consistently showed antifungal activity superior to that of itraconazole, with 50% effective doses (ED(50)s) three- to more than eightfold lower than those of itraconazole, depending on the time of initiation and the duration of treatment. The ED(50) of R126638 in a mouse dermatophytosis model was more than fivefold lower than that of itraconazole. These data indicate that if the effects of R126638 seen when it is used to treat animals can be extrapolated to humans, the novel compound would be expected to show effects at doses lower than those of existing drugs and, hence, present a lower risk for side effects.


Asunto(s)
Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Dermatomicosis/tratamiento farmacológico , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Microsporidios/efectos de los fármacos , Tiña/tratamiento farmacológico , Triazoles/síntesis química , Triazoles/uso terapéutico , Trichophyton/efectos de los fármacos , Animales , Candida/efectos de los fármacos , Dermatomicosis/microbiología , Relación Dosis-Respuesta a Droga , Cobayas , Itraconazol/farmacología , Itraconazol/uso terapéutico , Cetoconazol/farmacología , Cetoconazol/uso terapéutico , Ratones , Pruebas de Sensibilidad Microbiana , Piel/microbiología , Tiña/microbiología
7.
J Mol Cell Cardiol ; 33(12): 2083-94, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11735256

RESUMEN

BACKGROUND: Previously we documented cellular structural changes of a non-degenerative nature in atrial myocytes after atrial fibrillation (AF) in the goat. The time course of these changes was not studied. METHODS AND RESULTS: Cellular structural changes were studied by light- and electron microscopy and immunohistochemistry in goat atria after 0-16 weeks AF. The first sign of cellular structural remodeling was a more homogeneous chromatin distribution, at 1 week of AF. Sub-structural changes in mitochondria and sarcoplasmic reticulum occurred gradually. Cellular degeneration was absent. The degree of myolysis and glycogen accumulation increased till 8 weeks of AF and did not increase further from thereon. After 16 weeks of AF, 42% of the myocytes in the right atrial free wall were affected by myolysis. The diameter of the atrial myocytes increased. Dedifferentiation of the atrial myocytes was suggested by altered expression patterns of structural proteins, such as the disappearance of cardiotin (1 week), the A-I junctional part of titin (4 weeks), desmin at the intercalated disk (ID) (8 weeks) and a gradual re-expression of alpha-smooth muscle actin. CONCLUSION: Remodeling of the cellular ultrastructure in atrial myocardium of the goat develops progressively during AF. Re-expression of fetal proteins indicate dedifferentiation of atrial myocytes, analogous to observations in hibernating myocardium of the ventricle.


Asunto(s)
Fibrilación Atrial/fisiopatología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/metabolismo , Proteínas/metabolismo , Actinina/metabolismo , Actinas/metabolismo , Animales , Fibrilación Atrial/metabolismo , Moléculas de Adhesión Celular/metabolismo , Tamaño de la Célula , Conectina , Tejido Conectivo/diagnóstico por imagen , Modelos Animales de Enfermedad , Cabras , Atrios Cardíacos/patología , Proteínas Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Proteínas Quinasas/metabolismo , Factores de Tiempo , Ultrasonografía
8.
Cardiovasc Res ; 52(1): 14-24, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11557230

RESUMEN

Atrial fibrillation is the most common cardiac arrhythmia with an overall prevalence of almost 1%. Increasing prevalence and associated risks such as stroke and mortality have increased the need for better and more reliable therapeutic treatment. This has stimulated research to elucidate the pathophysiological mechanisms underlying atrial fibrillation. Atrial fibrillation is primarily characterised by electrical remodelling and functional deterioration. Both phenomena are reversible but after prolonged duration of atrial fibrillation, a discrepancy occurs between rapid electrical remodelling and slow recovery of contractile function. Recent studies have indicated that morphological remodelling might underlie this incongruity. In experimental models of lone atrial fibrillation, the remodelling involves cellular changes that are reminiscent of dedifferentiation and are characterised by cellular volume increase, myolysis, glycogen accumulation, mitochondrial changes and chromatin redistribution. The absence of clear signs of degeneration in these models points towards cardiomyocyte adaptation or a mechanism of programmed cell survival. In patients with atrial fibrillation cardiomyocyte degeneration does occur along with dedifferentiation which might be the result of underlying cardiac pathologies or longer duration of atrial fibrillation. In this review we focus on structural remodelling during atrial fibrillation. The different aspects of histological and ultrastructural changes as well as their role in atrial dysfunction and cardiomyocyte survival are discussed. We briefly describe the underlying molecular remodelling. and possible mechanisms responsible for remodelling involving calcium overload and stretch are presented.


Asunto(s)
Fibrilación Atrial/patología , Miocardio/patología , Remodelación Ventricular , Animales , Apoptosis , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Calcio/metabolismo , Canales de Calcio/metabolismo , Muerte Celular , Enfermedad Crónica , Conexinas/metabolismo , Proteínas Contráctiles/metabolismo , Fibrosis , Cabras , Atrios Cardíacos , Humanos , Microscopía Electrónica , Modelos Animales , Miocardio/metabolismo , Miocardio/ultraestructura
9.
Circulation ; 103(17): 2201-6, 2001 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-11331263

RESUMEN

BACKGROUND: Structural and phenotypic changes of cardiomyocytes characterize atrial fibrillation. We investigated whether changes in the glucose-regulated protein GRP94, which is essential for cell viability, occur in the presence of chronic atrial fibrillation. METHODS AND RESULTS: Samples of fibrillating atrial myocardium obtained from both goat and human hearts were analyzed for GRP94 expression by an immunologic approach. In goats, atrial fibrillation was induced and maintained for 2, 4, 8, and 16 weeks. After 16 weeks of atrial fibrillation, cardioversion was applied and followed by 8 weeks of sinus rhythm. GRP94 levels doubled in goat atrial myocytes after 4 to 16 weeks of fibrillation with respect to normal atria and returned to control levels in atrial myocardium of cardioverted goats. Immunohistochemical analyses confirm that GRP94 increase occurred within cardiomyocytes. Significantly, increased levels of GRP94 were also observed in samples from human fibrillating atria. In the absence of signs of myocyte irreversible damage, the GRP94 increase in fibrillating atria is comparable to GRP94 levels observed in perinatal goat myocardium. However, calreticulin, another endoplasmic reticulum protein highly expressed in perinatal hearts, does not increase in fibrillating atria, whereas inducible HSP70, a cytoplasm stress protein that is expressed in perinatal goat hearts at levels comparable to those observed in the adult heart, shows a significant increase in chronic fibrillating atria. CONCLUSIONS: Our data demonstrate a large, reversible increase in GRP94 in fibrillating atrial myocytes, which may be related to the appearance of a protective phenotype.


Asunto(s)
Fibrilación Atrial/metabolismo , Regulación de la Expresión Génica , Proteínas HSP70 de Choque Térmico/biosíntesis , Proteínas de la Membrana/biosíntesis , Proteínas Musculares/biosíntesis , Miocardio/metabolismo , Adaptación Fisiológica , Adulto , Animales , Animales Recién Nacidos , Fibrilación Atrial/genética , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/terapia , Calcio/metabolismo , Diferenciación Celular , Enfermedad Crónica , Cardioversión Eléctrica , Retículo Endoplásmico/metabolismo , Femenino , Cabras , Proteínas HSP70 de Choque Térmico/genética , Corazón/fisiopatología , Humanos , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mitocondrias Cardíacas/metabolismo , Proteínas Musculares/genética , Fenotipo , Retículo Sarcoplasmático/metabolismo
10.
Circulation ; 103(5): 691-8, 2001 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-11156881

RESUMEN

BACKGROUND: After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood. METHODS AND RESULTS: Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (>/=3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. ss-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca(2+), isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca(2+) was maintained, and the postrest potentiation was preserved. Beta-adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients. CONCLUSIONS: After prolonged AF, atrial contractility was reduced by 75%. The impairment of beta-adrenergic modulation of contractile force cannot be explained by downregulation of ss-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca(2+) channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca(2+) shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.


Asunto(s)
Fibrilación Atrial/fisiopatología , Contracción Miocárdica , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Fibrilación Atrial/metabolismo , Western Blotting , Agonistas de los Canales de Calcio/farmacología , Enfermedad Crónica , Femenino , Humanos , Masculino , Microscopía , Persona de Mediana Edad , Contracción Miocárdica/efectos de los fármacos , Receptores Adrenérgicos beta/metabolismo , Transducción de Señal
11.
Cardiovasc Res ; 47(4): 788-96, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10974227

RESUMEN

OBJECTIVE: Prolonged atrial fibrillation (AF) results in (ultra)structural remodelling of atrial cardiomyocytes resembling alterations seen in ischemia-induced ventricular hibernation. The mechanisms underlying these changes are incompletely understood. In the present study we explored the hypothesis that a profound imbalance in energy status during chronic AF acts as a stimulus for structural remodelling. METHODS AND RESULTS: The content of high energy-phosphates and related compounds together with a selected number of mitochondrial enzymes, known to be altered under ischemic conditions, were determined in tissue samples taken from atria of goats in sinus rhythm (SR) and after 1, 2, 4, 8 and 16 weeks of AF maintained by burst pacing. Atrial remodelling was quantified by counting the percentage of cells with >10% myolysis. During AF structural remodelling developed progressively, after 8 weeks about 40% of the atrial myocytes were affected. The concentration of adenine nucleotides and their degradation products did not change significantly during AF. Also the activity of mitochondrial cytochrome c oxidase activity was similar during AF and SR. Mitochondrial NADH-oxidase and proton-translocating ATPase activities were not induced by AF. The tissue content of phosphocreatine decreased during the first week by 60%, but completely recovered between 8 and 16 weeks of AF. CONCLUSIONS: The analysis of adenine nucleotides during AF provided no indication for the development of severe atrial ischemia. This notion is supported by enzyme cytochemical findings. However, AF-induced atrial remodelling was associated with a transient lowering of phosphocreatine content, suggesting an increase in energy demand during the early phase of AF. The subsequent recovery of the phosphocreatine pool indicates restoration of the balance between energy demand and supply in chronically fibrillating atria.


Asunto(s)
Adenosina Trifosfatasas/análisis , Apéndice Atrial/metabolismo , Fibrilación Atrial/metabolismo , Mitocondrias Cardíacas/enzimología , Fosfatos/metabolismo , Animales , Fibrilación Atrial/patología , Estimulación Cardíaca Artificial , Enfermedad Crónica , Creatina/análisis , Perros , Femenino , Cabras , Atrios Cardíacos , Inmunohistoquímica , Microscopía Electrónica , Complejos Multienzimáticos/análisis , Miocardio/metabolismo , Miocardio/ultraestructura , NADH NADPH Oxidorreductasas/análisis , Fosfocreatina/análisis , Estadísticas no Paramétricas
12.
Cardiovasc Res ; 46(3): 476-86, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10912458

RESUMEN

OBJECTIVE: It has been postulated that high atrial rate induced changes at the level of the gap junctions ('gap junctional remodeling', i.e. changes in distribution, intercellular orientation and expression of gap junction proteins), could be part of the vicious circle of electrophysiologic and structural changes leading to sustained atrial fibrillation (AF). To obtain experimental evidence in favour of such a postulate the timing of this remodeling process was studied in relation to the development of sustained AF in a goat model. METHODS AND RESULTS: Thin sections from the left (LAA) and right atrial appendage (RAA) from goats in sinus rhythm (SR) or AF, induced through programmed endocardial burst pacing for time periods between 0 and 16 weeks, were immunolabeled with antibodies against connexin(Cx)40 and Cx43 and analysed by immunofluorescence and confocal laser scanning microscopy. During SR the distribution pattern for Cx43 was completely homogeneous (LAA and RAA) and for Cx40 mostly homogeneous (LAA: all five goats, RAA: three out of five goats). The distribution pattern for Cx43 remained stable during AF, while the Cx40 distribution pattern became increasingly heterogeneous, both in the LAA and RAA, with increasing duration of pacing. This increase in heterogeneity in Cx40 distribution correlated (Spearman rank order) with an increase in stability of AF and the occurrence of structural changes (myolysis) in atrial myocytes. The Cx40/Cx43 immunofluorescence signal ratio in both the LAA and RAA appeared to be significantly lower in AF (1-16 weeks) as compared to SR (0 weeks); going from 0 to 16 weeks average ratios decreased 54.5% (n=5; P=0.026) in the LAA and 35.8 (n=5; P=0.034) in the RAA. Western blot analyses revealed similar decreases in the total Cx40/Cx43 protein ratio, on average 50.0% (n=5; P=0.008) and 47.8% (n=5; P=0.02) in the LAA and RAA, respectively. No changes were measured in the levels of Cx40 or Cx43 mRNA, as was assessed through RT-PCR. CONCLUSION: The time course of changes in the distribution and content of Cx40 gap junctions as observed during endocardial burst pacing of the goat atrium suggests that Cx40 gap junctional remodeling might be involved in the pathogenesis of sustained atrial fibrillation.


Asunto(s)
Apéndice Atrial/metabolismo , Fibrilación Atrial/metabolismo , Conexinas/metabolismo , Animales , Apéndice Atrial/química , Western Blotting , Estimulación Cardíaca Artificial , Conexina 43/análisis , Conexina 43/metabolismo , Conexinas/análisis , Femenino , Cabras , Inmunohistoquímica , Microscopía Confocal , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Proteína alfa-5 de Unión Comunicante
13.
Cardiovasc Pathol ; 9(1): 17-28, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10739903

RESUMEN

Of all known arrhythmia's, atrial fibrillation (AF) is the most often met in the clinical setting and it is associated with an increase in mortality risk. Several risk factors for AF have been described and several mechanisms of induction and maintenance have been proposed. Studies in patients with AF have shown that structural changes occur in the atria, but the relationship between the structural remodelling and the chronicity of the arrhythmia are not well understood. The changes mainly concern adaptive (dedifferentiation of cardiomyocytes) and maladaptive (degeneration of cells with replacement fibrosis) features. In order to characterise the time course of the structural remodelling the need for animal models which adequately mimic chronic atrial fibrillation in humans is felt essential. In this review, the structural changes that are observed during prolonged sustained AF in patients and animal models, are described. Furthermore, the time course and potential mechanisms of structural remodelling are discussed and methods for elucidation of the underlying molecular mechanisms are presented.


Asunto(s)
Fibrilación Atrial/patología , Atrios Cardíacos/patología , Miocardio/patología , Actinas/metabolismo , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Perros , Cabras , Atrios Cardíacos/metabolismo , Humanos , Miocardio/metabolismo , Remodelación Ventricular/fisiología
14.
J Mol Cell Cardiol ; 32(3): 355-64, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10731435

RESUMEN

It has been suggested that Ca(2+)content of atrial cardiomyocytes is increased at the onset of atrial fibrillation (AF). Whether this phenomenon is transient is currently unknown. Therefore, in this study the time-related changes in Ca(2+)location in atrial myocytes from goats with chronic AF have been investigated. The distribution of calcium was assessed with the electron microscope using the cytochemical phosphate-pyroantimonate and oxalate-pyroantimonate methods in atrial biopsies from goats in sinus rhythm and goats with 1-16 weeks of burst-pacing-induced AF. In atrial myocytes from control goats in sinus rhythm, a normal Ca(2+)distribution was observed, with regular deposits along the sarcolemma (an average of 3.4 deposits per microm at a regular distance). The number of sarcolemma-bound Ca(2+)deposits substantially increased after 1 and 2 weeks of atrial fibrillation. After this period the amount of Ca(2+)precipitate decreased at 4 and 8 weeks, and became below control level at 16 weeks. A similar time-related redistribution of Ca(2+)occurred in mitochondria. Whereas mitochondria from control goats displayed very few Ca(2+)deposits (average 4.0 deposits per micro m(2)), their number markedly increased after 1 and 2 weeks of atrial fibrillation, which indicates cellular Ca(2+)overload. From 4 weeks, Ca(2+)deposits reached control levels and were below control level after 16 weeks of atrial fibrillation (2.5 deposits per microm(2)). Our findings are consistent with the previously observed Ca(2+)overload early after the onset of atrial fibrillation. The present study shows that this overload persists for at least 2 weeks, after which the cardiomyocytes apparently adapt to a new Ca(2+)homeostasis, thereby avoiding Ca(2+)overload. This protection against Ca(2+)overload co-occurs with dedifferentiation like cellular remodeling.


Asunto(s)
Fibrilación Atrial/metabolismo , Calcio/metabolismo , Atrios Cardíacos/metabolismo , Animales , Fibrilación Atrial/patología , Femenino , Cabras , Atrios Cardíacos/patología , Atrios Cardíacos/ultraestructura , Factores de Tiempo
15.
Cardiovasc Res ; 43(4): 947-57, 1999 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10615422

RESUMEN

OBJECTIVE: Similar structural changes in the myocardium can be observed in chronic hibernating myocardium and in myocardium taken from hearts suffering chronic atrial fibrillation. We investigated whether or not these changes are indicative of apoptosis. METHODS: Myocardial biopsies from 28 strictly selected patients with chronic hibernating myocardium and heart samples from 13 goats with pacing-induced chronic atrial fibrillation were used. Special attention was paid to processing the tissues immediately (fixation/freezing) in order to prevent artificial degenerative changes, thereby excluding false positive identification of apoptosis. Infarcted areas or infarcted border zones were excluded from our study. Apoptosis was detected with light and electron microscopy and terminal deoxynucleotidyl transferase nick end-labelling. Immunohistochemistry was used for detecting Bcl-2, P53 and PCNA-proteins associated with apoptosis/DNA damage. RESULTS: The results obtained for chronic hibernating left ventricular myocardium were similar to those for chronic fibrillating atrial myocardium. No apoptotic nuclei, as characterised by extensive chromatin clumping, could be observed in normal or dedifferentiated cardiomyocytes under the electron microscope. The end-labelling assay did not reveal any cardiomyocytes with damaged DNA. Nor could we find any evidence of substantial expression of Bcl-2, P53 or PCNA, a result indicative of the absence of apoptotic threat or DNA damage. CONCLUSION: Cardiomyocyte dedifferentiation, but not extensive degeneration through apoptosis, can be observed in chronic hibernating myocardium and chronic fibrillating atrium. Dedifferentiation may be the best way to survive prolonged exposure to the unfavourable conditions imposed by increased wall stress, a relative lowered oxygen environment, or both.


Asunto(s)
Apoptosis , Fibrilación Atrial/patología , Aturdimiento Miocárdico/patología , Miocardio/patología , Animales , Fibrilación Atrial/metabolismo , Biomarcadores/análisis , Femenino , Cabras , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Microscopía Electrónica , Aturdimiento Miocárdico/metabolismo , Miocardio/química , Antígeno Nuclear de Célula en Proliferación/análisis , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteína p53 Supresora de Tumor/análisis
16.
Mol Cell Biochem ; 186(1-2): 159-68, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9774197

RESUMEN

Left ventricular biopsies from 21 patients with clinically diagnosed chronic hibernating myocardium (CHM) were examined by light- and electron microscopy. A mean of 27% of cardiomyocytes were structurally altered and were characterized as hibernating, because of reduced amount of myofibrils and increased glycogen content. Electron microscopy of these cells showed reduction of T-tubules and numerous small mitochondria, but few changes associated with degeneration, acute ischemia or apoptosis. The structural changes found in CHM are reminiscent of dedifferentiation rather than degeneration. The expression patterns of some structural proteins show resemblance with those in embryonic cardiomyocytes. Histochemically, mitochondrial NADH-oxidase and proton translocating ATPase activities were absent, whereas cytochrome c activity was present. Intracellular calcium distribution indicated normally bound sarcolemmal calcium and absence of excess mitochondrial calcium accumulation. Nuclear chromatin ranged from normal to dispersed with only a few nuclei that were clumped. These results suggest that cardiomyocytes from human CHM hearts are structurally altered, but viable, and lack morphologic and cytochemical characteristics suggestive of apoptosis or acute ischemia.


Asunto(s)
Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Miocardio/patología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Apoptosis , Calcio/metabolismo , Estudios de Casos y Controles , Diferenciación Celular , Núcleo Celular/ultraestructura , Complejo IV de Transporte de Electrones/metabolismo , Hibernación , Humanos , Microscopía Electrónica , Complejos Multienzimáticos/metabolismo , Miocardio/metabolismo , Miocardio/ultraestructura , NADH NADPH Oxidorreductasas/metabolismo
17.
Circulation ; 96(9): 3157-63, 1997 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-9386188

RESUMEN

BACKGROUND: After cardioversion of sustained atrial fibrillation (AF), the electrical and contractile functions of the atria are impaired, and recurrences of AF frequently occur. Whether remodeling of the structure of atrial myocardium is the basis for this problem is not known. METHODS AND RESULTS: Sustained AF was induced by electrical pacing in 13 goats instrumented long-term. The goats were killed after 9 to 23 weeks, and the atrial myocardium was examined by light and electron microscopy. The changes were quantified in left and right atrial free walls, appendages, trabeculae, the interatrial septum, and the bundle of Bachmann. A substantial proportion of the atrial myocytes (up to 92%) revealed marked changes in their cellular substructures, such as loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were accompanied by an increase in size of the myocytes (up to 195%). There were virtually no signs of cellular degeneration, and the interstitial space remained unaltered. The duration of sustained AF did not significantly affect the degree of myolytic cell changes. CONCLUSIONS: Sustained AF in goats leads to predominantly structural changes in the atrial myocytes similar to those seen in ventricular myocytes from chronic hibernating myocardium. These structural changes may explain the depressed contractile function of atrial myocardium after cardioversion. This goat model of AF offers a new approach to study the cascade of events leading to sustained AF and its maintenance.


Asunto(s)
Fibrilación Atrial/patología , Atrios Cardíacos/patología , Animales , Enfermedad Crónica , Femenino , Cabras , Atrios Cardíacos/ultraestructura , Microscopía Electrónica , Aturdimiento Miocárdico/etiología
18.
Am J Pathol ; 151(4): 985-97, 1997 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9327732

RESUMEN

Chronic atrial fibrillation was induced in goats by electrical pacing. After 9 to 23 weeks of sustained atrial fibrillation, the morphology of the atrial structures was examined. The majority of the cardiomyocytes exhibited marked changes in their cellular substructures, with the replacement of sarcomeres by glycogen as the main characteristic. Using immuno-histochemical staining procedures, we assessed the expression and organization of contractile and cytoskeletal proteins in these cases and compared them with the expression and organization of these proteins in normal atria. Part of the atrial cardiomyocytes acquired a dedifferentiated phenotype, as deduced from the re-expression of alpha-smooth muscle actin, the disappearance of cardiotin, and the staining patterns of titin, which resembled those of embryonic cardiomyocytes. From these results we conclude that chronic atrial fibrillation induces myocardial dedifferentiation. This model of chronic atrial fibrillation in goats offers the possibility to study the time course of changes in cardiac structure during sustained atrial fibrillation and after cardioversion.


Asunto(s)
Fibrilación Atrial/patología , Atrios Cardíacos/patología , Miocardio/patología , Animales , Fibrilación Atrial/etiología , Fibrilación Atrial/metabolismo , Biomarcadores , Estimulación Cardíaca Artificial/efectos adversos , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular , Núcleo Celular , Enfermedad Crónica , Conectina , Proteínas Contráctiles/metabolismo , Proteínas del Citoesqueleto/metabolismo , Femenino , Cabras , Atrios Cardíacos/metabolismo , Inmunohistoquímica , Proteínas Musculares/metabolismo , Músculo Liso/metabolismo , Miocardio/metabolismo , Proteínas Quinasas/metabolismo , Retículo Sarcoplasmático/metabolismo
19.
J Am Coll Cardiol ; 29(1): 62-8, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8996296

RESUMEN

OBJECTIVES: The value of 99mTc-sestamibi (2-methoxy-isobutyl isonitrile [MIBI]) as a viability tracer was investigated in patients undergoing coronary artery bypass graft surgery. BACKGROUND: Initial studies claim that rest MIBI single-photon emission computed tomographic (SPECT) studies can be used to assess myocardial viability. METHODS: Thirty patients with a severely stenosed left anterior descending coronary artery and wall motion abnormalities were prospectively included. The patients underwent a MIBI rest study, a positron emission tomographic (PET) flow (13NH3) and metabolism (18F-deoxyglucose) study and nuclear angiography before undergoing bypass surgery. A preoperative transmural biopsy specimen was taken from the left ventricular anterior wall. Morphometry was performed to assess percent fibrosis. After 3 months, radionuclide angiography was repeated. RESULTS: Statistically significant higher MIBI values were found in the group with myocardial viability as assessed by PET than in the group with PET-assessed nonviability (p < 0.01). Significantly higher MIBI values were found in the group with enhanced contractility at 3 months (76 +/- 13% vs. 53 +/- 22%, p < 0.01). A linear relation was found between MIBI uptake and percent fibrosis in the biopsy specimen (r = 0.78, p < 0.00001). When maximizing the threshold for assessment of viability with MIBI by using functional improvement as the reference standard, a cutoff value of 50% was found, with positive and negative predictive values of 82% and 78%, respectively. CONCLUSIONS: 99mTc MIBI uptake was significantly higher in PET-assessed viable areas and in regions with enhanced contractility at 3 months. A linear relation was found between percent fibrosis and MIBI uptake. An optimal threshold of 50% was found for prediction of functional recovery.


Asunto(s)
Enfermedad Coronaria/diagnóstico por imagen , Corazón/diagnóstico por imagen , Tecnecio Tc 99m Sestamibi , Tomografía Computarizada de Emisión de Fotón Único , Amoníaco , Angiografía Coronaria , Puente de Arteria Coronaria , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/fisiopatología , Enfermedad Coronaria/cirugía , Desoxiglucosa/análogos & derivados , Femenino , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Imagen de Acumulación Sanguínea de Compuerta , Humanos , Masculino , Persona de Mediana Edad , Contracción Miocárdica , Miocardio/patología , Radioisótopos de Nitrógeno , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y Especificidad , Tomografía Computarizada de Emisión
20.
Circulation ; 94(3): 308-15, 1996 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-8759070

RESUMEN

BACKGROUND: The aims of this study were to identify hibernating myocardium (hypocontractile, hypoperfused viable myocardium that regains contractility after revascularization) in the clinical setting and to predict functional outcome in patients with coronary artery disease after coronary revascularization. METHODS AND RESULTS: Preoperative data related to the anterior free wall of the left ventricle were collected in 50 coronary bypass surgery candidates (positron emission tomography [PET], [13N]NH3 for flow, and [18F]FDG for metabolism [MET]; equilibrium-gated nuclear angiography [EGNA] for regional ejection fraction [REF]; and histological data from myocardial biopsies for percentage fibrosis and viable myocytes). Three months after surgery, the patients had follow-up PET and EGNA investigations. A principal-components analysis identified four patient clusters. Cluster 1 (n = 9) had normal viable myocardium. Cluster 2 (n = 18) had viable hypocontractile myocardium (REF, 39 +/- 12%) showing a PET mismatch pattern. Cluster 3 (n = 16) had viable hypocontractile myocardium associated with morphological myocyte injury showing a matched moderate decrease in flow (66 +/- 11%) and MET (70 +/- 11%). Cluster 4 (n = 7) had hypocontractile myocardium with mainly scar tissue (fibrosis, 74 +/- 12%). After surgery, only cluster 2, with hibernating myocardium, showed significant improvement in REF (from 39 +/- 12% to 50 +/- 13%, P < .05). Cluster 3, with sites of morphological myocyte injury, showed no recovery. The stepwise logistic regression showed a combination of low preoperative REF and high MET to be the best predictor of functional recovery (P < .008). CONCLUSIONS: Multivariate analysis identifies hibernating myocardium showing early postrevascularization recovery, as opposed to viable but myolytic myocardium with no early recovery. Postrevascularization recovery can be predicted (combination of low REF and high MET) by noninvasive techniques.


Asunto(s)
Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/cirugía , Revascularización Miocárdica , Adulto , Anciano , Biopsia con Aguja , Cateterismo Cardíaco , Femenino , Fibrosis , Humanos , Periodo Intraoperatorio , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Análisis Multivariante , Isquemia Miocárdica/diagnóstico , Miocardio/patología , Periodo Posoperatorio , Angiografía por Radionúclidos , Tomografía Computarizada de Emisión
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