RESUMO
BACKGROUND: Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease that occurs in previously healthy women. We identified prolactin, mainly its 16-kDa angiostatic and proapoptotic form, as a key factor in PPCM pathophysiology. Previous reports suggest that bromocriptine may have beneficial effects in women with acute onset of PPCM. METHODS AND RESULTS: A prospective, single-center, randomized, open-label, proof-of-concept pilot study of women with newly diagnosed PPCM receiving standard care (PPCM-Std; n=10) versus standard care plus bromocriptine for 8 weeks (PPCM-Br, n=10) was conducted. Because mothers receiving bromocriptine could not breast-feed, the 6-month outcome of their children (n=21) was studied as a secondary end point. Blinded clinical, hemodynamic, and echocardiographic assessments were performed at baseline and 6 months after diagnosis. Cardiac magnetic resonance imaging was performed 4 to 6 weeks after diagnosis in PPCM-Br patients. There were no significant differences in baseline characteristics, including serum 16-kDa prolactin levels and cathepsin D activity, between the 2 study groups. PPCM-Br patients displayed greater recovery of left ventricular ejection fraction (27% to 58%; P=0.012) compared with PPCM-Std patients (27% to 36%) at 6 months. One patient in the PPCM-Br group died compared with 4 patients in the PPCM-Std group. Significantly fewer PPCM-Br patients (n=1, 10%) experienced the composite end point of poor outcome defined as death, New York Heart Association functional class III/IV, or left ventricular ejection fraction <35% at 6 months compared with the PPCM-Std patients (n=8, 80%; P=0.006). Cardiac magnetic resonance imaging revealed no intracavitary thrombi. Infants of mothers in both groups showed normal growth and survival. CONCLUSIONS: In this trial, the addition of bromocriptine to standard heart failure therapy appeared to improve left ventricular ejection fraction and a composite clinical outcome in women with acute severe PPCM, although the number of patients studied was small and the results cannot be considered definitive. Larger-scale multicenter and blinded studies are in progress to test this strategy more robustly.
Assuntos
Bromocriptina/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Antagonistas de Hormônios/administração & dosagem , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Cardiomiopatias/diagnóstico por imagem , Catepsina D/sangue , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Parto , Projetos Piloto , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Resultado da Gravidez , Prolactina/sangue , Tromboembolia/diagnóstico , Resultado do Tratamento , Ultrassonografia , Função Ventricular Esquerda/efeitos dos fármacos , Adulto JovemRESUMO
AIMS: We report our single-centre experience with the Solitaire AB self-expanding retrievable stent system in patients with acute ischaemic stroke. METHODS AND RESULTS: Demographic, clinical, and angiographic findings of thirty-eight consecutive patients with acute ischaemic stroke who underwent mechanical thrombectomy were evaluated retrospectively. The mean initial National Institutes of Health Stroke Scale (NIHSS) score was 17.8±4.6. Nearly half of the patients had a middle cerebral artery (MCA) occlusion (45%). Both internal carotid artery and MCA occlusions were detected in five patients. Successful revascularisation (Thrombolysis in Cerebral Infarction [TICI] 2b and 3) was achieved in 34 of 38 (89%) patients; a TICI 3 state was observed in 24 (63%) patients. Almost three quarters of the patients (74.3%) improved by >5 points on the NIHSS at discharge, and 57.9% showed a modified Rankin Scale (mRS) score of ≤2 at 90 days. CONCLUSIONS: This single-centre experience with mechanical thrombectomy devices demonstrated that the procedure could be performed safely with high success rates by experienced interventional cardiologists in suitably equipped cathlabs.
Assuntos
Isquemia Encefálica/terapia , Procedimentos Endovasculares/métodos , Trombólise Mecânica , Acidente Vascular Cerebral/terapia , Trombectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiologia , Feminino , Humanos , Masculino , Trombólise Mecânica/instrumentação , Trombólise Mecânica/métodos , Pessoa de Meia-Idade , StentsRESUMO
Peripartum/postpartum cardiomyopathy (PPCM) is a potentially life-threatening disease of uncertain aetiology in previously healthy women. Clinical and experimental data suggested inflammation, autoimmune processes, apoptosis and endothelial dysfunction as typical pathophysiological features of PPCM. Recent data discovered that unbalanced peri/postpartum oxidative stress linked to proteolytic cleavage of the nursing hormone prolactin into a potent anti-angiogenic, pro-apoptotic and pro-inflammatory 16-kDa subform as a potential pathomechanism for the development of PPCM. Consistent with these idea, blockade of prolactin by bromocriptine, a dopamine D2 receptor agonist, prevented the onset of disease in an experimental model of PPCM and appeared successful in small pilot trials with respect to prevention or treatment of PPCM in patients. Here we highlight the current state of knowledge on diagnosis of PPCM, provide novel insights into the pathophysiology behind the disease and outline potential consequences for the clinical management and treatment options for patients at risk for or with PPCM.
Assuntos
Cardiomiopatias/fisiopatologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Prolactina/fisiologia , Transtornos Puerperais/fisiopatologia , Animais , Bromocriptina/uso terapêutico , Cardiomiopatias/diagnóstico , Cardiomiopatias/prevenção & controle , Modelos Animais de Doenças , Feminino , Antagonistas de Hormônios/uso terapêutico , Humanos , Camundongos , Estresse Oxidativo/fisiologia , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/prevenção & controle , Prolactina/antagonistas & inibidores , Transtornos Puerperais/diagnóstico , Transtornos Puerperais/prevenção & controleRESUMO
The abundance of the transcription factor hypoxia-inducible factor is regulated through hydroxylation of its alpha-subunits by a family of prolyl-hydroxylases (PHD1-3). Enzymatic activity of these PHDs is O2-dependent, which enables PHDs to act as cellular O2 sensor enzymes. Herein we studied endogenous PHD activity that was induced in cells grown under hypoxia or in the presence of nitric oxide. Under such conditions nuclear extracts contained much higher PHD activity than the respective cytoplasmic extracts. Although PHD1-3 were abundant in both compartments, knockdown experiments for each isoenzyme revealed that nuclear PHD activity was only due to PHD2. Maximal PHD2 activity was found between 120 and 210 microm O2. PHD2 activity was strongly decreased below 100 microm O2 with a half-maximum activity at 53 +/- 13 microm O2 for the cytosolic and 54 +/- 10 microm O2 for nuclear PHD2 matching the physiological O2 concentration within most cells. Our data suggest a role for PHD2 as a decisive oxygen sensor of the hypoxia-inducible factor degradation pathway within the cell nucleus.
Assuntos
Núcleo Celular/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Hipóxia Celular , Linhagem Celular , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Humanos , Pró-Colágeno-Prolina Dioxigenase/genéticaRESUMO
The transcription factor complex hypoxia-inducible factor 1 (HIF-1) plays a crucial role in cellular adaptation to low oxygen availability. O(2)-dependent HIF prolyl hydroxylases (PHDs) modify HIF-1alpha, which is sent to proteasomal degradation under normoxia. Reduced activity of PHDs under hypoxia allows stabilization of HIF-1alpha and induction of HIF-1 target gene expression. Like hypoxia, nitric oxide (NO) was found to inhibit normoxic PHD activity leading to HIF-1alpha accumulation. In contrast under hypoxia, NO reduced HIF-1alpha levels due to enhanced PHD activity. Herein, we studied the role of NO in regulating PHD expression and the consequences thereof for HIF-1alpha degradation. We report a biphasic response of HIF-1alpha and PHDs to NO treatment both under normoxia and hypoxia. In the early phase, NO inhibits PHD activity that leads to HIF-1alpha accumulation, whereas in the late phase, increased PHD levels reduce HIF-1alpha. NO induces expression of PHD2 and -3 mRNA and protein under normoxia and hypoxia in a strictly HIF-1-dependent manner. NO-treated cells with elevated PHD levels displayed delayed HIF-1alpha accumulation and accelerated degradation of HIF-1alpha upon reoxygenation. Subsequent suppression of PHD2 and -3 expression using small interfering RNA revealed that PHD2 was exclusively responsible for regulating HIF-1alpha degradation under NO treatment. In conclusion, we identified the induction of PHD2 as an underlying mechanism of NO-induced degradation of HIF-1alpha.