RESUMO
AIMS: Neovascularization is an important element of long-term functional recovery during chronic ischaemia. We postulated that haeme oxygenase (HO) is required for progenitor cell recruitment, neovascularization, and blood flow recovery after critical hindlimb ischaemia (HLI). METHODS AND RESULTS: The femoral artery was ligated in FVB/N mice proximal to its superficial and deep branches. Blood flow in the ischaemic hindlimb was determined by laser Doppler perfusion imaging. Capillary density was measured by isolectin staining, and mobilization of Sca-1(+)/Kdr(+) progenitor cells by FACS analysis. Progenitor cell recruitment to the ischaemic hindlimb was assessed after Tie2-lacZ transgenic bone marrow transplantation. Blood flow recovery after femoral artery ligation was significantly blunted in mice treated with the HO inhibitor tin protoporphyrin-IX (25 mg/kg i.p., every other day). HO-inhibited mice developed more pronounced limb necrosis, associated with impaired hindlimb motor function. Capillary density in the ischaemic hindlimb and mobilization of Sca-1(+)/Kdr(+) progenitor cells were significantly reduced after HO inhibition. After transplantation of Tie2-lacZ transgenic bone marrow cells into lethally irradiated wild-type mice, fewer LacZ(+) cells were detected in the ischaemic hindlimb muscle of HO-inhibited mice. Mechanistically, HO inhibition prevented the establishment of a stromal cell-derived factor-1 gradient for progenitor cell mobilization between the ischaemic hindlimb and bone marrow. CONCLUSION: HOs are required for progenitor cell recruitment, neovascularization, and functional recovery after HLI.
Assuntos
Movimento Celular , Células Endoteliais/enzimologia , Heme Oxigenase-1/metabolismo , Isquemia/enzimologia , Proteínas de Membrana/metabolismo , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Células-Tronco/enzimologia , Inibidores da Angiogênese/farmacologia , Animais , Velocidade do Fluxo Sanguíneo , Transplante de Medula Óssea , Capilares/metabolismo , Capilares/fisiopatologia , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Membro Posterior , Isquemia/diagnóstico por imagem , Isquemia/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Proteínas de Membrana/antagonistas & inibidores , Metaloporfirinas/farmacologia , Camundongos , Camundongos Transgênicos , Neovascularização Fisiológica/efeitos dos fármacos , Protoporfirinas/farmacologia , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Fluxo Sanguíneo Regional , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Fatores de Tempo , UltrassonografiaRESUMO
BACKGROUND: In patients with severe pulmonary hypertension (PH), right ventricular function is a main determinant of clinical stability and outcome. Supraventricular tachyarrhythmias (SVTs) may compromise cardiac function and threaten prognosis in patients with PH, but the incidence and clinical relevance of SVTs in PH and chronic right ventricular failure have not been evaluated. METHODS: In a 6-year retrospective single-center analysis, 231 consecutive patients followed for pulmonary arterial hypertension, or inoperable chronic thromboembolic PH were studied for SVTs. Analysis included incidence, clinical consequences, treatment, and outcome. RESULTS: Thirty-one episodes of SVT were observed in 27 of 231 patients (cumulative incidence 11.7%, annual risk 2.8% per patient), including atrial flutter (n = 15), atrial fibrillation (n = 13), and AV nodal reentry tachycardia (n = 3). Supraventricular tachyarrhythmia onset was almost invariably associated with marked clinical deterioration and right ventricular failure (84% of SVT episodes). Outcome was strongly associated with the type of SVT and restoration of sinus rhythm. During follow-up, cumulative mortality was low (6.3%, follow-up 26 +/- 23 months) when sinus rhythm was restored (all cases of AV nodal reentry tachycardia and atrial flutter). In contrast, 9 of 11 patients with sustained atrial fibrillation died from right ventricular failure (cumulative mortality 82%, follow-up 11 +/- 8 months). CONCLUSIONS: In patients with PH, SVTs constitute a relevant problem, often resulting in clinical deterioration. Sustained atrial fibrillation may be associated with a high risk of death from right ventricular failure.