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Biochem Biophys Res Commun ; 524(1): 50-56, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-31980166


Pulmonary arterial hypertension (PAH) is a rare, but progressive and devastating vascular disease with few treatment options to prevent the advancement to right ventricular dysfunction hypertrophy and failure. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, enhances urinary glucose excretion as well as reduces cardiovascular events and mortality in individuals with type 2 diabetes. While empagliflozin has been reported to lower systemic hypertension due to increased diuresis, the effect of empagliflozin on PAH is unknown. We used monocrotaline (MCT)-treated Sprague-Dawley rats to determine if empagliflozin alters PAH-associated outcomes. Compared to vehicle control, daily empagliflozin administration significantly improved survival in rats with severe MCT-induced PAH. Hemodynamic assessments showed that empagliflozin treatment significantly reduced mean pulmonary artery pressure, right ventricular systolic pressure, and increased pulmonary acceleration time. Empagliflozin treatment resulted in reduced right ventricular hypertrophy and fibrosis. Histological and molecular assessments of lung vasculature revealed significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles after empagliflozin treatment compared to vehicle-treated rats. In summary, SGLT2 inhibition with empagliflozin lowered mortality, reduced right ventricle systolic pressure, and attenuated maladaptive pulmonary remodeling in MCT-induced PAH. Clinical studies evaluating the efficacy of SGLT-2 inhibition should be considered for patients with PAH.

Cell Metab ; 30(4): 609-613, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31477497


Hess et al. quantified circulating aldehyde dehydrogenase-expressing (ALDHhi) cell subsets in people with T2DM given either empagliflozin (EMPA) or placebo. EMPA treatment increased circulating pro-angiogenic CD133+ progenitor cells, decreased pro-inflammatory ALDHhi granulocyte precursors, and increased ALDHhi monocytes with M2 polarization. EMPA treatment improved T2DM-associated "regenerative cell depletion" contributing to enhanced vascular health.

CMAJ Open ; 7(2): E379-E384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31147379


BACKGROUND: Recent years have seen centralization of vascular surgery services in Ontario. We sought to examine the trends in overall and approach-specific elective and ruptured abdominal aortic aneurysm repair by hospital type (teaching v. community). METHODS: We conducted a population-based time-series analysis of elective and ruptured abdominal aortic aneurysm repairs in Ontario, Canada, from 2003 to 2016. Quarterly cumulative incidences of repairs per 100 000 Ontarians aged 40 years and older were calculated. We fit exponential smoothing models to the data stratified by approach and hospital type to examine repair trends. RESULTS: We identified 19 219 elective and 2722 ruptured repairs between 2003 and 2016. The cumulative incidences of overall elective repair and elective open surgical repair decreased by 1.15% (p = 0.008) and 67% (p < 0.001), respectively, in teaching hospitals and by 23% (p < 0.001) and 60% (p < 0.001), respectively, in community hospitals. The cumulative incidence of elective endovascular repair increased 667% in teaching hospitals (p < 0.001). Elective endovascular repair began in community centres after 2010 and increased to 0.98/100 000 (p < 0.001), resulting in a rebound in overall elective repair in the community. Overall ruptured repairs and ruptured open repairs decreased by 84% (p < 0.001) and 88% (p = 0.002), respectively, at community hospitals. Ruptured endovascular repairs at community hospitals increased from no procedures before 2006 to 0.03/100 000 in 2016 (p = 0.005). INTERPRETATION: There has been substantial uptake of endovascular aortic repair in teaching and community hospitals in Ontario, and community hospital uptake of endovascular repair has begun decentralization of abdominal aortic aneurysm repair. Increased experience and training in endovascular repair and reduced specialized care requirements will probably lead to continued decentralization.

Can J Physiol Pharmacol ; 96(11): 1184-1187, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30265814


Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to prevent heart failure and reduce cardiovascular death in patients with type 2 diabetes (T2DM) and cardiovascular disease (CVD). Whether or not SGLT2 inhibitors improve indices of cardiorespiratory fitness (CRF), an independent predictor of mortality in patients with CVD, remains unknown. We evaluated the effects of empagliflozin on indices of CRF in patients with T2DM. Twenty patients with T2DM received either empagliflozin 10 mg or usual care. Baseline and 3- to 6-month post-treatment measurements of CRF were evaluated using cardiopulmonary exercise testing on a cycle ergometer. Treatment with empagliflozin led to an increased peak oxygen consumption (VO2), reduction in VE/VCO2 slope, and improvement in heart rate recovery. Our results suggest that SGLT2 inhibitors may improve markers of CRF in patients with T2DM. This may help provide important clues into the mechanism of benefit of SGLT2 inhibitors in clinical trials and provide a translational framework for the ongoing large studies of SGLT2 inhibitors in the treatment of heart failure.

Compostos Benzidrílicos/farmacologia , Aptidão Cardiorrespiratória , Diabetes Mellitus Tipo 2/fisiopatologia , Glucosídeos/farmacologia , Insuficiência Cardíaca/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Idoso , Compostos Benzidrílicos/uso terapêutico , Biomarcadores , Teste de Esforço , Feminino , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Resultado do Tratamento
Can J Physiol Pharmacol ; 94(9): 1007-14, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27434139


Hyperglycemia-related endothelial dysfunction is believed to be the crux of diabetes-associated micro- and macro-vascular complications. We conducted a systematic transcriptional survey to screen for human endothelial long non-coding RNAs (lncRNAs) regulated by elevated glucose levels. lncRNAs and protein-coding transcripts from human umbilical vein endothelial cells (HUVECs) cultured under high (25 mmol/L) or normal (5 mmol/L) glucose conditions for 24 h were profiled with the Arraystar Human LncRNA Expression Microarray V3.0. Of the 30 586 lncRNAs screened, 100 were significantly upregulated and 186 appreciably downregulated (P < 0.05) in response to high-glucose exposure. In the same HUVEC samples, 133 of the 26 109 mRNAs screened were upregulated and 166 downregulated. Of these 299 differentially expressed mRNAs, 26 were significantly associated with 28 differentially expressed long intergenic non-coding RNAs (P < 0.05). Bioinformatics analyses indicated that the mRNAs most upregulated are primarily enriched in axon guidance signaling pathways; those most downregulated are notably involved in pathways targeting vascular smooth muscle cell contraction, dopaminergic signaling, ubiquitin-mediated proteolysis, and adrenergic signaling. This is the first lncRNA and mRNA transcriptome profile of high-glucose-mediated changes in human endothelial cells. These observations may prove novel insights into novel regulatory molecules and pathways of hyperglycemia-related endothelial dysfunction and, accordingly, diabetes-associated vascular disease.

Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Perfilação da Expressão Gênica , Glucose/farmacologia , RNA Longo não Codificante/genética , Transcriptoma/efeitos dos fármacos , Células Cultivadas , Humanos , Transdução de Sinais/genética