RESUMO
A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Ritmo Circadiano , Glucocorticoides/metabolismo , Hipocampo/citologia , Células-Tronco Neurais/metabolismo , Animais , Encéfalo/citologia , Proliferação de Células , Masculino , Camundongos , Neurogênese , Receptores de Glucocorticoides/metabolismoRESUMO
Early during their maturation, adult-born dentate granule cells (aDGCs) are particularly excitable, but eventually develop the electrophysiologically quiet properties of mature cells. However, the stability versus plasticity of this quiet state across time and experience remains unresolved. By birthdating two populations of aDGCs across different animal ages, we found for 10-month-old rats the expected reduction in excitability across cells aged 4-12 weeks, as determined by Egr1 immunoreactivity. Unexpectedly, cells 35 weeks old (after genesis at an animal age of 2 months) were as excitable as 4-week-old cells, in the dorsal hippocampus. This high level of excitability at maturity was specific for cells born in animals 2 months of age, as cells born later in life did not show this effect. Importantly, excitability states were not fixed once maturity was gained, but were enhanced by enriched environment exposure or LTP induction, indicating that any maturational decrease in excitability can be compensated by experience. These data reveal the importance of the animal's age for aDGC excitability, and emphasize their prolonged capability for plasticity during adulthood.
Assuntos
Envelhecimento/fisiologia , Comportamento Animal , Giro Denteado/fisiologia , Neurogênese , Plasticidade Neuronal , Neurônios/fisiologia , Potenciais de Ação , Fatores Etários , Animais , Biomarcadores/metabolismo , Senescência Celular , Giro Denteado/citologia , Giro Denteado/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Abrigo para Animais , Potenciação de Longa Duração , Masculino , Atividade Motora , Neurônios/metabolismo , Ratos Sprague-Dawley , Comportamento SocialRESUMO
AIMS: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. METHODS: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. RESULTS: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. CONCLUSIONS: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.
Assuntos
Encéfalo/patologia , Degeneração Neural/patologia , Ataxias Espinocerebelares/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/metabolismoRESUMO
GABA(B) receptors play a critical neuromodulatory role in the central nervous system. It has been suggested that both the functional role and the cellular distribution of GABA(B) receptors in the neuronal network change during post-natal maturation. In the present study, the cellular and subcellular distribution patterns of the GABA(B) R1a/b receptors have been analysed in different brain regions of the mouse using immunocytochemistry with isoform-specific antisera. GABA(B) R1-immunoreactivity (IR) was present from the first post-natal day (P0) on in most regions of the brain. Neurones exhibited diffuse GABA(B) R1-IR labelling throughout somata and larger proximal dendrites as well as some fine neuronal processes. After P5, distinct punctuated staining was apparent. The number of such GABA(B) IR granules per cell increased with age in a sigmoidal manner from P5 to P60. Electron microscopy revealed GABA(B) IR as clusters of small clear vesicles of 30-50 nm diameter within the cytoplasm and close to the cell membrane at extrasynaptic locations, as well as at pre-synaptic and post-synaptic specialisations. The increase in GABA(B) R1-IR punctuate staining during brain maturation points to increasing functional participation and heterogeneity of GABA(B) receptors as the complexity of the central nervous system expands with growth and development.
Assuntos
Envelhecimento/fisiologia , Química Encefálica/fisiologia , Vesículas Citoplasmáticas/metabolismo , Neurônios/metabolismo , Receptores de GABA-B/análise , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Vesículas Citoplasmáticas/ultraestrutura , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Neurônios/ultraestrutura , Receptores de GABA-B/metabolismoAssuntos
Calcinose/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Calcinose/patologia , Doença da Artéria Coronariana/patologia , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Tomografia Computadorizada por Raios X/métodosRESUMO
Respiration-related membrane potential fluctuations were recorded in hypoglossal (XII) motoneurons and pre-Bötzinger complex (pre-BötC) interneurons in medullary slices from perinatal rats. Bath application of serotonin (5-HT) evoked a ketanserine-sensitive depolarization (approximately 11 mV) and tonic spike discharge in XII motoneurons, whereas pre-BötC neurons responded with a <6 mV depolarization and no tonic discharge. The membrane effects were accompanied by an increase in respiratory frequency by up to 260% in 64% of preparations. A frequency decrease leading to block of respiratory activity could also occur (20%) as well as an initial acceleration that turned into a frequency depression (16%). In contrast, iontophoresis of 5-HT into the pre-BötC exclusively increased respiratory frequency by 30-220%, whereas iontophoresis into the XII nucleus did not change respiratory frequency but induced tonic nerve discharge. The effects of local iontophoretic administration of 5-HT on membrane properties of XII and pre-BötC cells were very similar to those upon bath application. Bath application and iontophoresis of the 5-HT2 receptor agonist -methyl-hydroxytryptamine mimicked the effects of 5-HT. Bath application of the 5-HT1A receptor agonist 8-hydroxydipropylaminotetralin hydrobromide did not affect XII nerve bursting or pre-BötC neurons. Iontophoresis of 8-hydroxydipropylaminotetralin hydrobromide had almost no effect on respiratory frequency and induced in the interneurons either a depolarization or hyperpolarization (<5 mV) which was blocked by the 5-HT1A receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)N-2-pyridinylcyclohexane carboxamide. In conclusion, 5-HT-evoked tonic excitation of respiratory XII motoneurons is mediated by postsynaptic 5-HT2 receptors. The excitatory effects on respiratory rhythm are also primarily attributable to postsynaptic 5-HT2 receptors of pre-BötC neurons. Additional modulatory effects on the interneurons appear to be mediated by postsynaptic 5-HT1A receptors.
Assuntos
Nervo Hipoglosso/fisiologia , Interneurônios/fisiologia , Bulbo/fisiologia , Neurônios Motores/fisiologia , Núcleos da Rafe/fisiologia , Centro Respiratório/fisiologia , Serotonina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Nervo Hipoglosso/efeitos dos fármacos , Nervo Hipoglosso/crescimento & desenvolvimento , Interneurônios/efeitos dos fármacos , Bulbo/efeitos dos fármacos , Bulbo/crescimento & desenvolvimento , Neurônios Motores/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/crescimento & desenvolvimento , Rede Nervosa/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/fisiologia , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/crescimento & desenvolvimento , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Centro Respiratório/efeitos dos fármacos , Centro Respiratório/crescimento & desenvolvimento , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
AIMS: To investigate whether intravascular ultrasound provides additional information regarding the prediction of stent thrombosis, a retrospective multicentre registry was designed to enrol patients with stent thrombosis following stent deployment under ultrasound guidance. METHODS AND RESULTS: A total of 53 patients were enrolled (mean age 61+/-9 years) with stable angina (43%), unstable angina (36%), and post-infarct angina (21%) who underwent intracoronary stenting. The majority had balloon angioplasty alone prior to stenting (94%) with 6% also undergoing rotational atherectomy. The indication for stenting was elective (53%), suboptimal result (32%) and bailout (15%). There were 1.6+/-0.8 stents/artery with 87% undergoing high-pressure dilatation (> or =14 atmospheres). The minimum stent area was 7.7+/-2.8 mm(2)with a mean stent expansion of 81.5+/-21.9%. Overall, 94% of cases demonstrated one abnormal ultrasound finding (stent under-expansion, malapposition, inflow/outflow disease, dissection, or thrombus). Angiography demonstrated an abnormality in only 32% of cases (chi-square=30.0, P<0.001). Stent thrombosis occurred at 132+/-125 h after deployment. Myocardial infarction occurred in 67% and there was an overall mortality of 15%. CONCLUSION: On comparison with angiography, the vast majority of stents associated with subsequent thrombosis have at least one abnormal feature by intravascular ultrasound at the time of stent deployment.
Assuntos
Stents/efeitos adversos , Trombose/diagnóstico por imagem , Trombose/etiologia , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Trombose/terapia , Ultrassonografia de IntervençãoAssuntos
Doença da Artéria Coronariana/fisiopatologia , Fatores de Crescimento Endotelial/fisiologia , Linfocinas/fisiologia , Animais , Circulação Coronária/fisiologia , Progressão da Doença , Humanos , Camundongos , Camundongos Knockout , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Nitric oxide (NO) generated by inducible NO synthase (iNOS) enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle cells (VSMC) and both NO and modified low density lipoprotein (LDL) augment VEGF production in macrophages. Oxidized LDL (oxLDL) are known inhibitors of NO generation in the cells of vascular wall. As the relationship between VEGF, iNOS and oxLDL has not been well elucidated, we studied the effect of two main components of oxLDL, 7-ketocholesterol (7-Kchol) and lysophosphatidylcholine (LPC), on VEGF and NO synthesis in rat VSMC and on VEGF synthesis in human VSMC. Both LPC and 7-Kchol significantly augmented VEGF production in rat and human VSMC. Increase in VEGF generation was related to the activation of VEGF promoter by both 7-Kchol and LPC and enhancement of VEGF mRNA transcription. In rat, VSMC IL-1beta-induced NO generation and enhanced VEGF synthesis. 7-Kchol decreased rat iNOS promoter activity, iNOS expression and NO generation, but it did not impair IL-1beta-induced VEGF synthesis. LPC did not significantly influence IL-1beta-induced NO production in rat VSMC and VEGF synthesis was significantly enhanced by combined treatment with IL-1beta and LPC in comparison to the effect of either compound alone. The results indicate that VEGF and NO synthesis in VSMC can be modulated by oxLDL. Those interactions might have an effect on the plaque growth and might be of relevance for the physiology of vascular wall cells.
Assuntos
Fatores de Crescimento Endotelial/biossíntese , Cetocolesteróis/farmacologia , Linfocinas/biossíntese , Linfocinas/efeitos dos fármacos , Lisofosfatidilcolinas/farmacologia , Óxido Nítrico/metabolismo , Análise de Variância , Animais , Humanos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Óxido Nítrico/análise , Probabilidade , RNA Mensageiro/análise , Ratos , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Inappropriate therapy of supraventricular tachyarrhythmias by an ICD is still a common problem. Dual chamber (DDD) ICDs provide additional atrial sensing and should result in higher specificity for detection of supraventricular tachyarrhythmias. However, a direct comparison of different dual chamber algorithms has not been reported. The detection algorithms of four different DDD ICDs were tested: Phylax AV, Defender IV, Ventak AV III DR, and Gem DR 7271. Based on arrhythmias recorded from patients undergoing invasive electrophysiological studies and in many cases of catheter ablation at our institution, a library consisting of 71 supraventricular and 15 ventricular tachyarrhythmias was created. The library consists of episodes of atrial fibrillation, atrial flutter with different AV conduction, typical and atypical AV nodal reentrant tachycardia, AV reentrant tachycardia, sinus tachycardia, and ventricular tachycardia with and without ventriculoatrial conduction. Atrial fibrillation was appropriately classified by all four algorithms. However, the specificity for detection of other supraventricular tachyarrhythmias achieved by the Biotronik (12%) and the Guidant (11%) devices was significantly lower compared to the specificity of the ELA (28%) and the Medtronic DDD ICD (20%). This is due to the fact that the Biotronik and the Guidant algorithm classified all supraventricular tachyarrhythmias resulting in a stable ventricular rate as ventricular tachycardia, whereas the ELA and Medtronic algorithms performed a more detailed analysis by assessment of PR association, atrial onset, or timing of the atrial event relative to the ventricular event, respectively. Atrial fibrillation, the most common supraventricular tachyarrhythmia in patients with ICD, was detected by all devices.
Assuntos
Algoritmos , Desfibriladores Implantáveis , Taquicardia Supraventricular/diagnóstico , Desfibriladores Implantáveis/efeitos adversos , Erros de Diagnóstico , Humanos , Sensibilidade e Especificidade , Taquicardia Supraventricular/classificação , Taquicardia Supraventricular/terapiaRESUMO
This study provides biochemical evidence that ultraendurance exercise may cause subclinical myocardial damage, even in well-trained cyclists. The cellular nature of this damage and its clinical relevance remain unknown at present.
Assuntos
Exercício Físico/fisiologia , Resistência Física/fisiologia , Troponina T/sangue , Adulto , Ciclismo/fisiologia , Humanos , MasculinoRESUMO
Intravascular stents increase long-term patency but their effects on the vascular mechanics of adjacent segments have not been studied. In this study, stents were deployed in the rabbit abdominal aorta after 1 week of normal diet, 1% cholesterol diet or 1% cholesterol diet with L-nitro arginine (L-NA 60 mg/l water). Intravascular ultrasound showed a small distal decrease in vessel distensibility (area/pressure * 100) before stenting. Distensibility was almost abolished by stenting (0.12 +/- 0.01, p < 0.001), but was increased proximal to the stent and decreased distal to the stent both acutely (proximal: 1.18 +/- 0.10 vs distal: 0.65 +/- 0.06, p < 0.001), and at 4 weeks (proximal: 1.05 +/- 0.08 vs distal: 0.37 +/- 0.07, p < 0.001). Nitric oxide (NO) activity was enhanced proximal to and within the stent, and remained constant distal to the stent, (versus control, proximal: 57 +/- 23%, stent: 136 +/- 35%, distal: 2 +/- 12%, p < 0.01). The I/M ratio was significantly higher proximal to and within the stent than in the distal segment (proximal: 0.40 +/- 0.10, stent: 0.37 +/- 0.12, distal: 0.12 +/- 0.11, p < 0.01). NO blockade with L-NA prevented hyperdistensibility proximally, and significantly increased the I/M ratio within the stent and distally (stent: 0.81 +/- 0.19, distal: 0.30 +/- 0.10, p < 0.05) but not proximally (0.38 +/- 0.09). In conclusion, aortic stenting increases proximal vascular distensibility and intimal lesion formation. Nitric oxide blockade augments intimal growth within but not proximal to the stent.
Assuntos
Óxido Nítrico/fisiologia , Stents , Túnica Íntima/fisiologia , Sistema Vasomotor/fisiopatologia , Animais , Aorta/patologia , Hemodinâmica/fisiologia , Técnicas In Vitro , Masculino , Coelhos , Valores de Referência , Túnica Íntima/patologia , Túnica Média/patologiaRESUMO
Hypertension is a well-known risk factor for coronary artery disease and carotid and lower extremity occlusive disease. Surgically induced hypertension in hypercholesterolemic animals results in increased aortic wall motion and increased plaque formation. We tested the hypothesis that reduction in aortic wall motion, despite continued hypertension, could reduce plaque formation. New Zealand White rabbits (n=26) underwent thoracic aortic banding to induce hypertension and were fed an atherogenic diet for 3 weeks. In 13 rabbits, a segment of aorta proximal to an aortic band was externally wrapped to reduce wall motion. All animals were fed an atherogenic diet for 3 weeks. Four groups were studied: 1, coarctation control (no wrap, n=7); 2, coarctation with loose wrap (n=6); 3, coarctation with firm wrap (n=7); and 4, control (noncoarcted, n=6). Wall motion, blood pressure, and pulse pressure were measured at standard reference sites proximal and distal to the coarctation by use of intravascular ultrasound. Quantitative morphometry was used to measure intimal plaque. Mean arterial pressure and cyclic aortic wall motion were equally increased proximal to the aortic coarctation in all 3 coarcted rabbit groups compared with the control group (P:<0.001). Wall motion in the segment of aorta under the loose and firm wraps was no different from the control value. The external wrap significantly reduced intimal thickening in the 4 groups by the following amounts: group 1, 0.30+/-0.03 mm(2); group 2, 0.06+/-0.02 mm(2); group 3, 0. 04+/-0.02 mm(2); and group 4, 0.01+/-0.01 mm(2) (P:<0.001). Localized inhibition of aortic wall motion in the lesion-prone hypertensive aorta resulted in significant reduction in intimal plaque formation. These data suggest that arterial wall cyclic motion may stimulate cellular proliferation and lipid uptake in experimental atherosclerosis.
Assuntos
Aorta Torácica/fisiopatologia , Arteriosclerose/etiologia , Hipertensão/complicações , Animais , Aorta Torácica/patologia , Arteriosclerose/patologia , Fenômenos Biomecânicos , Dieta , Modelos Animais de Doenças , Hemodinâmica , Masculino , Coelhos , Túnica Íntima/patologia , Túnica Média/patologiaRESUMO
BACKGROUND: Perioperative diagnosis of myocardial ischemia following cardiac surgical procedures remains a challenging problem. Particularly, the role of new conduction disturbances as markers of postoperative ischemia is still questionable. The goal of this study was to elucidate the diagnostic significance of new postoperative right bundle branch block (RBBB) for the detection of perioperative myocardial ischemia in patients undergoing elective coronary artery bypass grafting (CABG). METHODS: In 169 consecutive patients, three-channel Holter monitoring and serial assessment of serum enzymes were performed for 48 h, and 12-lead ECG repeated for up to 5 days postoperatively. Postoperative events were classified as either myocardial infarction (MI), transient ischemic events (TIE) or various conduction disturbances. RESULTS: Transient (n=9) or permanent (n=4) RBBB occurred in 13 patients (8%); 14 patients (8%) showed signs of perioperative MI and 18 patients (11%) evidence of TIE. Peak activity of creatine-kinase (CK, 561+/-135 vs. 316+/-19, P<0.05) and CK-MB (22.7+/-3.2 vs. 13.4+/-0.8, P<0.01) were higher in patients with RBBB than in patients without perioperative ischemic events. Peak CK-MB levels were significantly higher in patients with MI as compared to those with RBBB (33.4+/-7.6 vs. 22.7+/-3.2, P<0. 05). Patients with TIE had similar perioperative enzyme levels as patients with no events. CONCLUSION: It is concluded that the combined assessment of repeated 12-lead ECG, continuous Holter monitoring and enzyme analysis allows a reliable diagnosis of perioperative myocardial ischemia and conduction disturbances. The occurrence of new RBBB following elective CABG is indicative of perioperative myocardial necrosis and thus serves as a valuable tool for the diagnosis of new, perioperative ischemic events.
Assuntos
Bloqueio de Ramo/etiologia , Ponte de Artéria Coronária , Creatina Quinase/sangue , Eletrocardiografia Ambulatorial , Infarto do Miocárdio/diagnóstico , Biomarcadores/sangue , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/fisiopatologia , Feminino , Humanos , Isoenzimas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/cirurgia , Prognóstico , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Coronary remodeling plays a significant role in lumen loss in transplant allograft vasculopathy (TxCAD), but the determinants of remodeling are unknown. We assessed the relationship between remodeling and plaque topography, coronary compliance, and blood flow in TxCAD. METHODS AND RESULTS: One artery in each of 27 transplant patients was investigated with simultaneous intravascular ultrasound and coronary flow measurements (basal and hyperemic by Doppler flow wire). At 4 to 8 different cross sections (mean 5.1+/-1. 2), plaque topography (concentric or eccentric) was determined, and total vessel area, lumen area, and intimal/medial area (IMA) were measured. Mean remodeling ratio (vessel area/IMA) in eccentric lesions (E, n=28) was significantly larger than that in concentric lesions (C, n=70) (E 5.87+/-0.93 versus C 3.58+/-0.62; P<0.001), despite similar IMA (E 3.89+/-0.68 versus C 3.90+/-0.41; P=NS) and distribution of imaged segments. Remodeling ratio was consistently larger in eccentric lesions in all 3 vessel segments when analyzed separately, and mean remodeling ratio for each artery was larger in vessels with predominantly eccentric lesions. Coronary compliance ([Delta lumen area/diastolic lumen area]/Delta mean arterial pressure x 10(3)) was also significantly greater in eccentric lesions versus concentric lesions (proximal 1.00+/-0.39 versus 0.22+/-0.04; mid 0.71+/-0.17 versus 0.21+/-0.10; distal 0.43+/-0.13 versus 0. 01+/-0.08; all P<0.01). Coronary flow reserve was also significantly higher in coronary arteries with primarily eccentric lesions (E 2. 49+/-0.64 versus C 1.87+/-0.28; P<0.01). CONCLUSIONS: Vessel remodeling in transplant vasculopathy is significantly greater in eccentric lesions than in concentric lesions, possibly due to greater coronary compliance and resistive vessel function.
Assuntos
Doença das Coronárias/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiologia , Transplante de Coração , Reologia/métodos , Ultrassonografia de Intervenção , Complacência (Medida de Distensibilidade) , Circulação Coronária/fisiologia , Doença das Coronárias/etiologia , Doença das Coronárias/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-OperatóriasRESUMO
We used intravascular ultrasound to show that outward remodeling predominates in lesions responsible for acute myocardial infarction, whereas negative remodeling is far more prevalent in lesions responsible for chronic stable angina. The total cholesterol:high-density lipoprotein ratio was also strongly correlated with outward remodeling.
Assuntos
Angina Pectoris/diagnóstico por imagem , Infarto do Miocárdio/diagnóstico por imagem , Ultrassonografia de Intervenção , Idoso , Estudos de Casos e Controles , Vasos Coronários/diagnóstico por imagem , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Local administration of L-arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of L-arginine inhibits lesion formation. METHODS AND RESULTS: New Zealand White rabbits (n=56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either L-arginine (800 mg/5 mL with and without 100 microCi L-[2,3-(3)H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled L-arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676+/-223 versus 453+/-93 cpm/mg; P<0.02); this was associated with significantly higher NO levels in the L-arginine-treated segments (394.4+/-141.6 versus 86.3+/-34.3 nmol/mg; P<0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with L-arginine as compared with saline infusion (P<0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of L-arginine as compared with the saline-treated segments (P<0.05). CONCLUSIONS: Intramural delivery of L-arginine immediately after angioplasty causes a sustained increase in tissue L-arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.
Assuntos
Angioplastia com Balão/métodos , Apoptose , Arginina/farmacologia , Endotélio Vascular/fisiologia , Monócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Arginina/administração & dosagem , Adesão Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Sistemas de Liberação de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Masculino , Monócitos/efeitos dos fármacos , Óxido Nítrico/metabolismo , CoelhosRESUMO
BACKGROUND: We have recently found that administration of L-arginine to hypercholesterolemic rabbits induces regression of preexisting lesions. Others have previously shown that activation of the L-arginine/nitric oxide (NO) synthase pathway can induce apoptosis of vascular cells in vitro. Accordingly, the current study was designed to determine if dietary supplementation of L-arginine induces apoptosis of intimal lesions and if this effect is mediated through the NO synthase pathway. METHODS AND RESULTS: Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 weeks and subsequently placed on 2.5% L-arginine HCl in the drinking water, and the cholesterol diet was continued for 2 weeks, at which time the aortas were harvested for histological studies. L-Arginine treatment increased the number of apoptotic cells (largely macrophages) in the intimal lesions by 3-fold (11.9+/-3.9 vs 3.9+/-1. 4 apoptotic cells/mm2, P<0.01). In subsequent studies, aortas were harvested for ex vivo studies. Aortic segments were incubated in cell culture medium for 4 to 24 hours with modulators of the NO synthase pathway. The tissues were then collected for histological studies and the conditioned medium collected for measurement of nitrogen oxides by chemiluminescence. Addition of sodium nitroprusside (10(-5) mol/L) to the medium caused a time-dependent increase in apoptosis of vascular cells (largely macrophages) in the intimal lesion. L-Arginine (10(-3) mol/L) had an identical effect on apoptosis, which was associated with an increase in nitrogen oxides released into the medium. These effects were not mimicked by D-arginine, and they were antagonized by the NO synthase inhibitor L-nitro-arginine (10(-4) mol/L). The effect of L-arginine was not influenced by an antagonist of cGMP-dependent protein kinase, nor was the effect mimicked by the agonist of protein kinase G or 8-BR cGMP. CONCLUSIONS: These results indicate that supplemental L-arginine induces apoptosis of macrophages in intimal lesions by its metabolism to NO, which acts through a cGMP-independent pathway. These studies are consistent with our previous observation that supplementation of dietary arginine induces regression of atheroma in this animal model. These studies provide a rationale for further investigation of the therapeutic potential of manipulating the NO synthase pathway in atherosclerosis.
Assuntos
Apoptose/fisiologia , Arteriosclerose/patologia , Arteriosclerose/prevenção & controle , Óxido Nítrico/fisiologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Apoptose/efeitos dos fármacos , Arginina/administração & dosagem , Arteriosclerose/dietoterapia , Arteriosclerose/metabolismo , GMP Cíclico/farmacologia , Suplementos Nutricionais , Masculino , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/fisiologia , Técnicas de Cultura de Órgãos , CoelhosRESUMO
Routine follow-up investigation methods after peripheral arterial bypass surgery, such as arteriography and colour duplex sonography, do not always allow correct analysis of moderate alterations in the vessel wall, e.g. initial stages of distal anastomotic intimal hyperplasia (DAIH). The aim of this study was to evaluate the efficiency of angioscopy and intravascular ultrasound compared to the named routine methods regarding detection of early DAIH. Eight months after bilateral femoropopliteal bypass surgery with venous grafts in 18 sheep, we investigated the distal anastomotic sites using the named methods. The findings were then correlated to histologic specimens. Intravascular ultrasound presented the highest sensitivity followed by angioscopy, with results markedly different from the findings arrived at by conventional methods.