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1.
Endocrinology ; 161(8)2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428240

RESUMO

Selective inhibitors of sodium glucose cotransporter-2 (SGLT2) are widely used for the treatment of type 2 diabetes and act primarily to lower blood glucose by preventing glucose reabsorption in the kidney. However, it is controversial whether these agents also act on the pancreatic islet, specifically the α cell, to increase glucagon secretion. To determine the effects of SGLT2 on human islets, we analyzed SGLT2 expression and hormone secretion by human islets treated with the SGLT2 inhibitor dapagliflozin (DAPA) in vitro and in vivo. Compared to the human kidney, SLC5A2 transcript expression was 1600-fold lower in human islets and SGLT2 protein was not detected. In vitro, DAPA treatment had no effect on glucagon or insulin secretion by human islets at either high or low glucose concentrations. In mice bearing transplanted human islets, 1 and 4 weeks of DAPA treatment did not alter fasting blood glucose, human insulin, and total glucagon levels. Upon glucose stimulation, DAPA treatment led to lower blood glucose levels and proportionally lower human insulin levels, irrespective of treatment duration. In contrast, after glucose stimulation, total glucagon was increased after 1 week of DAPA treatment but normalized after 4 weeks of treatment. Furthermore, the human islet grafts showed no effects of DAPA treatment on hormone content, endocrine cell proliferation or apoptosis, or amyloid deposition. These data indicate that DAPA does not directly affect the human pancreatic islet, but rather suggest an indirect effect where lower blood glucose leads to reduced insulin secretion and a transient increase in glucagon secretion.


Assuntos
Compostos Benzidrílicos/farmacologia , Células Secretoras de Glucagon/efeitos dos fármacos , Glucosídeos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Adolescente , Adulto , Animais , Células Cultivadas , Feminino , Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Xenoenxertos , Humanos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Especificidade da Espécie , Adulto Jovem
2.
J Am Heart Assoc ; 7(10)2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29728013

RESUMO

BACKGROUND: Coronary microvascular dysfunction may contribute to myocardial ischemia during mental stress (MS). However, the role of coronary epicardial and microvascular function in regulating coronary blood flow (CBF) responses during MS remains understudied. We hypothesized that coronary vasomotion during MS is dependent on the coronary microvascular endothelial function and will be reflected in the peripheral microvascular circulation. METHODS AND RESULTS: In 38 patients aged 59±8 years undergoing coronary angiography, endothelium-dependent and endothelium-independent coronary epicardial and microvascular responses were measured using intracoronary acetylcholine and nitroprusside, respectively, and after MS induced by mental arithmetic testing. Peripheral microvascular tone during MS was measured using peripheral arterial tonometry (Itamar Inc, Caesarea, Israel) as the ratio of digital pulse wave amplitude compared to rest (peripheral arterial tonometry ratio). MS increased the rate-pressure product by 22% (±23%) and constricted epicardial coronary arteries by -5.9% (-10.5%, -2.6%) (median [interquartile range]), P=0.001, without changing CBF. Acetylcholine increased CBF by 38.5% (8.1%, 91.3%), P=0.001, without epicardial coronary diameter change (0.1% [-10.9%, 8.2%], P=not significant). The MS-induced CBF response correlated with endothelium-dependent CBF changes with acetylcholine (r=0.38, P=0.03) but not with the response to nitroprusside. The peripheral arterial tonometry ratio also correlated with the demand-adjusted change in CBF during MS (r=-0.60, P=0.004), indicating similarity between the microcirculatory responses to MS in the coronary and peripheral microcirculation. CONCLUSIONS: The coronary microvascular response to MS is determined by endothelium-dependent, but not endothelium-independent, coronary microvascular function. Moreover, the coronary microvascular responses to MS are reflected in the peripheral microvascular circulation.


Assuntos
Circulação Coronária , Vasos Coronários/fisiopatologia , Microcirculação , Microvasos/fisiopatologia , Estresse Psicológico/fisiopatologia , Vasodilatação , Idoso , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Conceitos Matemáticos , Microcirculação/efeitos dos fármacos , Microvasos/diagnóstico por imagem , Microvasos/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Prospectivos , Estresse Psicológico/psicologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem
3.
JACC Cardiovasc Interv ; 11(20): 2072-2080, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30268874

RESUMO

OBJECTIVES: This study investigated the relationship between low wall shear stress (WSS) and severe endothelial dysfunction (EDFx). BACKGROUND: Local hemodynamic forces such as WSS play an important role in atherogenesis through their effect on endothelial cells. The study hypothesized that low WSS independently predicts severe EDFx in patients with coronary artery disease (CAD). METHODS: Forty-four patients with CAD underwent coronary angiography, fractional flow reserve, and endothelial function testing. Segments with >10% vasoconstriction after acetylcholine (Ach) infusion were defined as having severe EDFx. WSS, calculated using 3-dimensional angiography, velocity measurements, and computational fluid dynamics, was defined as low (<1 Pa), intermediate (1 to 2.5 Pa), or high (>2.5 Pa). RESULTS: Median age was 52 years, 73% were women. Mean fractional flow reserve was 0.94 ± 0.06. In 4,510 coronary segments, median WSS was 3.67 Pa. A total of 24% had severe EDFx. A higher proportion of segments with low WSS had severe EDFx (71%) compared with intermediate WSS (22%) or high WSS (23%) (p < 0.001). Segments with low WSS demonstrated greater vasoconstriction in response to Ach than did intermediate or high WSS segments (-10.7% vs. -2.5% vs. +1.3%, respectively; p < 0.001). In a multivariable logistic regression analysis, female sex (odds ratio [OR]: 2.44; p = 0.04), diabetes (OR: 5.01; p = 0.007), and low WSS (OR: 9.14; p < 0.001) were independent predictors of severe EDFx. CONCLUSIONS: In patients with nonobstructive CAD, segments with low WSS demonstrated more vasoconstriction in response to Ach than did intermediate or high WSS segments. Low WSS was independently associated with severe EDFx.


Assuntos
Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Endotélio Vascular/fisiopatologia , Reserva Fracionada de Fluxo Miocárdico , Hemodinâmica , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Endotélio Vascular/diagnóstico por imagem , Feminino , Humanos , Hidrodinâmica , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Sistema de Registros , Estresse Mecânico , Vasoconstrição
4.
JACC Cardiovasc Interv ; 10(10): 999-1007, 2017 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28521932

RESUMO

OBJECTIVES: The aim of this study was to investigate the epicardial and microvascular substrates associated with discordances between fractional flow reserve (FFR) and coronary flow reserve (CFR) values. BACKGROUND: Discordances between FFR and CFR remain poorly characterized. METHODS: FFR, hyperemic stenosis resistance (HSR), and intravascular ultrasound were performed as indexes of epicardial function and CFR and hyperemic microvascular resistance (HMR) as measures of microvascular function in 94 patients with moderate coronary stenosis. Maximal plaque burden (PBmax), HSR, and HMR were calculated in 4 quadrants based on values of FFR ≤0.80 and CFR ≤2.0 as follows: concordant normal (preserved FFR and CFR), concordant abnormal (low FFR and CFR), discordant low FFR and preserved CFR, and discordant preserved FFR and low CFR. RESULTS: Sixty-four patients (68%) had concordant FFR and CFR findings, and 30 patients (32%) had discordant FFR and CFR. Compared with patients with preserved FFR and CFR, those with low FFR and CFR had higher PBmax (p = 0.003), higher HSR (p < 0.001), and similar HMR. Among patients with preserved FFR, those with reduced CFR had similar PBmax and HSR but a trend toward higher HMR (p = 0.058) compared with patients with preserved CFR. Among patients with reduced FFR, those with preserved CFR had lower PBmax (p = 0.004), a trend toward lower HSR (p = 0.065), and lower HMR (p = 0.03) compared with patients with reduced CFR. Furthermore, compared with patients with preserved FFR and low CFR, those with low FFR and preserved CFR had higher HSR (p = 0.022) but lower HMR (p = 0.003). CONCLUSIONS: In patients with moderate coronary stenosis, preserved FFR and low CFR is associated with increased microvascular resistance, while low FFR and preserved CFR has modest epicardial stenosis and preserved microvascular function.


Assuntos
Cateterismo Cardíaco , Estenose Coronária/diagnóstico , Vasos Coronários/diagnóstico por imagem , Reserva Fracionada de Fluxo Miocárdico , Ultrassonografia de Intervenção , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/fisiopatologia , Vasos Coronários/fisiopatologia , Ecocardiografia Doppler , Feminino , Humanos , Hiperemia/fisiopatologia , Masculino , Microcirculação , Pessoa de Meia-Idade , Placa Aterosclerótica , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Resistência Vascular , Vasodilatadores/administração & dosagem
5.
JACC Cardiovasc Interv ; 9(7): 728-41, 2016 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-27056313

RESUMO

OBJECTIVES: The purpose of this study was to assess and compare in vivo the restoration of vasomotor function following Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) and metallic Xience V (XV) (Abbott Vascular, Santa Clara, California) stent implantations in porcine coronary arteries at 1 and 2 years. BACKGROUND: Drug-eluting metallic coronary stents induce sustained vasomotor dysfunction, and preliminary observations from arteries with bioresorbable scaffolds have indicated partially restored vasoreactivity. METHODS: A total of 15 Absorb BVS (3.0 × 18.0 mm) and 14 XV (3.0 × 18.0 mm or 3.0 × 12.0 mm) stents were randomly implanted in the main coronaries of 12 nonatherosclerotic swine. The effect of implant on vasomotor performance (constrictive and expansive) was measured in the stented/scaffolded segments and the 5-mm proximal and distal adjacent segments in vivo by angiography assessing mean luminal diameter changes following infusion of vasoactive agents at 1 year (n = 6) and 2 years (n = 6) as well as ex vivo at 2 years using a tissue chamber apparatus. Endothelial cell function and smooth muscle cell phenotype gene marker levels were evaluated with quantitative real-time polymerase chain reaction. RESULTS: The scaffolded Absorb BVS segments showed fully restored constrictive response compared with XV implanted vessels at 1 year: -24.30 ± 14.31% versus -1.79 ± 6.57% (p < 0.004) and at 2 years: -28.13 ± 14.60% versus -3.90 ± 6.44% (p < 0.004). The early restoration of vasomotor function within the scaffolded segments reached a peak at 1 year and did not significantly change up to 2 years. The vasoactive responses of Absorb BVS-implanted vessels within the scaffolded segments were similar to those observed within the proximal and distal edge segments at both time points. Conversely, the stented XV segments demonstrated significantly impaired constrictive response compared with the distal XV edges at 1 year: -1.79 ± 6.57% versus -21.89 ± 7.17% (p < 0.0002) and at 2 years: -3.90 ± 6.44% versus -21.93 ± 15.60% (p < 0.03). Ex vivo assessment of contraction induced by PGF2α and relaxation induced by substance P of isolated BVS segments compared with XV-treated segments generated greater contraction force of 3.94 ± 0.97 g versus 1.83 ± 1.03 g (p < 0.05), and endothelial-dependent relaxation reached 35.91 ± 24.74% versus 1.20 ± 3.79% (p < 0.01). Quantitative real-time polymerase chain reaction gene analysis at 2 years demonstrated increased Connexin 43 messenger ribonucleic acid levels of Absorb BVS-treated vessels compared with XV-treated vessels: 1.92 ± 0.23 versus 0.77 ± 12 (p < 0.05). CONCLUSIONS: Absorb BVS-implanted coronary arteries demonstrate early functional restoration of the scaffolded and adjacent segments at 1 year, which is preserved up to 2 years.


Assuntos
Cateteres Cardíacos , Fármacos Cardiovasculares/administração & dosagem , Materiais Revestidos Biocompatíveis , Angiografia Coronária , Vasos Coronários/efeitos dos fármacos , Stents Farmacológicos , Everolimo/administração & dosagem , Metais , Intervenção Coronária Percutânea/instrumentação , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Regulação da Expressão Gênica , Técnicas In Vitro , Modelos Animais , Intervenção Coronária Percutânea/efeitos adversos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Recuperação de Função Fisiológica , Suínos , Porco Miniatura , Fatores de Tempo
6.
Glob Cardiol Sci Pract ; 2015(5): 63, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26925408

RESUMO

The impetus for developing drug-eluting bioresorbable scaffolds (BRS) has been driven by the need for elastic and transient platforms instead of stiff and permanent metallic implants in diseased coronary anatomies. This endeavor would prevent acute recoil or occlusion, allow sealing of post-procedural dissections following acute barotrauma, provide inhibition of in-segment restenosis through efficient drug-elution and would further prepare the vessel to enter a reparative phase following scaffold resorption. Biocorrodible metallic platforms have been introduced as alternatives to bioresorbable polymeric scaffolds for the treatment of significant atherosclerosis and in view of the body of evidence derived from recent clinical trials we elaborate on the clinical safety and efficacy of these devices in interventional cardiology.

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