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2.
Artigo em Inglês | MEDLINE | ID: mdl-32130021

RESUMO

The mechanism by which the kidney senses changes in hemoglobin concentration (Hb) may inform decisions regarding the optimal fluid for intravascular volume resuscitation in critical care settings where starch solution may be nephrotoxic. We hypothesized that hemodilution with starch solutions would reduce renal PktO2 to a more severe degree than other diluents. Anesthetized Sprague Dawley rats (n=61) were block-randomized to undergo hemodilution with either colloid (6% hydroxyethyl starch or 5% albumin), crystalloid (saline), or a sham procedure (control) (n=6-12 rats/group). We measured mean arterial pressure (MAP), arterial blood gases, Hb (cooximetry), cardiac output (CO, echocardiography), renal PktO2 and hypoxic gene expression (mRNA qRT-PCR). Following hemodilution, MAP decreased in the saline group while Hb and blood oxygen content (CaO2) decreased in all groups. Cardiac output increased (~50%) after colloid, but not after saline hemodilution. Renal PktO2 decreased in proportion to the reduction in Hb in all treatment groups. At comparably reduced Hb and PaO2 values, hemodilution with starch resulted in a larger decrease in kidney PktO2 relative to animals hemodiluted with albumin or saline (p<0.008). Renal erythropoietin (EPO) mRNA levels increased after hemodilution in all groups, but other HIF-dependent molecules did not increase (Glut-1, GAPDH, VEGF). This suggests that EPO expression is highly responsive to changes in CaO2 and demonstrates the capacity for the kidney as a biosensor of CaO2. Our data demonstrates that PktO2 reflects proportional changes in CaO2 and supports the hypothesis that hemodilution with starch colloid solution impairs renal PktO2, relative to hemodilution with albumin and saline.

4.
Cardiovasc Diabetol ; 19(1): 13, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32035482

RESUMO

BACKGROUND AND AIMS: Sodium-glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions. METHODS: Pressure-volume (P-V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later. RESULTS: The circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy. CONCLUSION: Empagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.

6.
Lancet Diabetes Endocrinol ; 7(11): 820-821, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495650
7.
Circulation ; 140(21): 1693-1702, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31434508

RESUMO

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. METHODS: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m2. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). RESULTS: Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m2, LV mass indexed to body surface area 60.7 [11.9] g/m2), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m2 and 0.01 g/m2 for those assigned empagliflozin and placebo, respectively (adjusted difference -3.35 g/m2; 95% CI, -5.9 to -0.81g/m2, P=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference -6.8mmHg, 95% CI -11.2 to -2.3mmHg, P=0.003), diastolic blood pressure (adjusted difference -3.2mmHg; 95% CI, -5.8 to -0.6mmHg, P=0.02) and elevation of hematocrit (P=0.0003). CONCLUSIONS: Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02998970.

8.
Physiol Rep ; 7(9): e14044, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31087539

RESUMO

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD+ -dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age-related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1Y/Y ) mice had lower GFRs and fewer glomeruli than their wild-type (Sirt1+/+ ) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1Y/Y mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1Y/Y mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.

9.
Diabetes Obes Metab ; 21(8): 1996-2000, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31050116

RESUMO

Three, multicentre, large-scale, randomized, placebo-controlled trials of cardiovascular outcomes with sodium-glucose co-transporter-2 (SGLT2) inhibitors have each shown substantial reductions in rates of hospitalization for heart failure and progression of chronic kidney disease in people with type 2 diabetes. However, safety concerns remain for this ostensibly paradigm-shifting drug class. In particular, the US Food and Drug Administration has highlighted the risk of acute kidney injury (AKI), a condition associated with high morbidity and mortality. To investigate this further, we conducted a meta-analysis of the three trials to compare the frequency of AKI adverse event reports between participants treated with placebo and those who had received an SGLT2 inhibitor. Rather than an increase, we noted a consistent and robust reduction in the likelihood of AKI among those participants who had been randomized to receive an SGLT2 inhibitor (hazard ratio 0.66, 95% confidence interval 0.54-0.80). We further noted that the reports of AKI were similar in frequency to those of kidney disease progression. The caveats of the non-adjudicated reporting of AKI in the trials notwithstanding, these data suggest that SGLT2 inhibitors may protect vulnerable patients with type 2 diabetes from AKI and that prospective studies to evaluate this additional aspect of kidney protection are warranted.

10.
JACC Basic Transl Sci ; 4(1): 27-37, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30847416

RESUMO

Recent studies send an unambiguous signal that the class of agents known as sodium-glucose-linked co-transporter-2 inhibitors (SGLT2i) prevent heart failure hospitalization in patients with type 2 diabetes. However, the mechanisms remain unclear. Herein the authors utilize a rodent model of heart failure with preserved ejection fraction (HFpEF), and demonstrate that treatment with the SGLT2i empagliflozin, reduces left ventricular mass, improving both wall stress and diastolic function. These findings extend the observation that the main mechanism of action of empagliflozin involves improved hemodynamics (i.e., reduction in preload and afterload) and provide a rationale for upcoming trials in patients with HFpEF irrespective of glycemic status.

12.
Am J Pathol ; 188(12): 2763-2773, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30273603

RESUMO

The excessive accumulation of extracellular matrix material in the kidney is a histopathologic hallmark of diabetic kidney disease that correlates closely with declining function. Although considerable research has focused on the role of profibrotic factors, comparatively little attention has been paid to the possibility that a diminution in endogenous antifibrotic factors may also contribute. Among the latter, the ELR- CXC chemokines, CXCL9, CXCL10, and CXCL11, have been shown to provide a stop signal to prevent excessive fibrosis. Although the plasma concentrations of CXCL9 and CXCL11 were similar, those of CXCL10 were markedly lower in diabetic db/db mice compared with control db/m mice. In cell culture, CXCL10 inhibited kidney fibroblast collagen production in response to high glucose and the prosclerotic growth factor, transforming growth factor-ß. In vivo, recombinant murine CXCL10 reduced mesangial and peritubular matrix expansion, albuminuria, and glomerular hypertrophy in db/db mice. In bone marrow, a major source of circulating chemokines, the concentration of CXCL10 was lower in cells derived from diabetic mice than from their nondiabetic counterparts. Silencing of CXCR3, the cognate receptor for CXCL10, abrogated the antifibrotic effects of bone marrow-derived secretions. In conclusion, experimental diabetes is a state of CXCL10 deficiency and that restoration of CXCL10 abundance prevented fibrosis and the development of diabetic kidney disease in mice.


Assuntos
Quimiocina CXCL10/administração & dosagem , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Modelos Animais de Doenças , Fibrose/prevenção & controle , Animais , Quimiocina CXCL10/deficiência , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Fibrose/etiologia , Fibrose/patologia , Masculino , Camundongos
13.
Sci Rep ; 8(1): 13972, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228292

RESUMO

The NAD+-dependent lysine deacetylase, Sirtuin 1 (SIRT1), plays a central role in metabolic regulation. With type 1 diabetes a disease that is characterised by metabolic dysregulation, we sought to assess the impact of SIRT1 activation in experimental, streptozotocin (STZ)-induced diabetes. CD1 mice with and without STZ-induced diabetes were randomized to receive the SIRT1 activating compound, SRT3025, or vehicle over 20 weeks. Vehicle treated STZ-CD1 mice developed severe hyperglycaemia with near-absent circulating insulin and widespread beta cell loss in association with hyperglucagonaemia and expanded islet alpha cell mass. Without affecting ß-cell mass or circulating insulin, diabetic mice that received SRT3025 had substantially improved glycaemic control with greatly reduced islet α cell mass and lower plasma glucagon concentrations. Consistent with reduced glucagon abundance, the diabetes-associated overexpression of key gluconeogenic enzymes, glucose-6-phosphatase and PEPCK were also lowered by SRT3025. Incubating cultured α cells with SRT3025 diminished their glucagon secretion and proliferative activity in association with a reduction in the α cell associated transcription factor, Aristaless Related Homeobox (Arx). By reducing the paradoxical increase in glucagon, SIRT1 activation may offer a new, α-cell centric approach to the treatment of type 1 diabetes.


Assuntos
Diabetes Mellitus Experimental/complicações , Glucagon/metabolismo , Hiperglicemia/prevenção & controle , Hiperplasia/prevenção & controle , Sirtuína 1/metabolismo , Anilidas/farmacologia , Animais , Glicemia/análise , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperplasia/etiologia , Hiperplasia/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Tiazóis/farmacologia
14.
Cardiovasc Diabetol ; 17(1): 99, 2018 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-29981571

RESUMO

BACKGROUND: Inhibiting both type 1 and 2 sodium-glucose linked cotransporter (SGLT1/2) offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby also stimulate glucagon-like peptide 1 secretion. However, beyond the kidney and gut, SGLT1 is expressed in a range of other organs particularly the heart where it potentially assists GLUT-mediated glucose transport. Since cardiac myocytes become more reliant on glucose as a fuel source in the setting of stress, the present study sought to compare the effects of dual SGLT1/2 inhibition with selective SGLT2 inhibition in the normal and diseased heart. METHODS: Fischer F344 rats underwent ligation of the left anterior descending coronary artery or sham ligation before being randomized to receive the dual SGLT1/2 inhibitor, T-1095, the selective SGLT2 inhibitor, dapagliflozin or vehicle. In addition to measuring laboratory parameters, animals also underwent echocardiography and cardiac catheterization to assess systolic and diastolic function in detail. RESULTS: When compared with rats that had received either vehicle or dapagliflozin, T-1095 exacerbated cardiac dysfunction in the post myocardial infarction setting. In addition to higher lung weights, T-1095 treated rats had evidence of worsened systolic function with lower ejection fractions and reduction in the rate of left ventricle pressure rise in early systole (dP/dtmax). Diastolic function was also worse in animals that had received T-1095 with prolongation of the time constant for isovolumic-pressure decline (Tau) and an increase in the end-diastolic pressure volume relationship, indices of the active, energy-dependent and passive phases of cardiac relaxation. CONCLUSIONS: The exacerbation of post myocardial infarction cardiac dysfunction with T-1095 in the experimental setting suggests the need for caution with the use of dual SGLT1/2 inhibitors in humans.


Assuntos
Compostos Benzidrílicos/farmacologia , Carbonatos/toxicidade , Glucosídeos/farmacologia , Glucosídeos/toxicidade , Hipertrofia Ventricular Esquerda/induzido quimicamente , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Disfunção Ventricular Esquerda/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Infarto do Miocárdio/fisiopatologia , Ratos Endogâmicos F344 , Transportador 1 de Glucose-Sódio/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
15.
Can J Cardiol ; 34(5): 506-525, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29731013

RESUMO

Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately. For 2018, 5 new guidelines are introduced, and 1 existing guideline on the blood pressure thresholds and targets in the setting of thrombolysis for acute ischemic stroke is revised. The use of validated wrist devices for the estimation of blood pressure in individuals with large arm circumference is now included. Guidance is provided for the follow-up measurements of blood pressure, with the use of standardized methods and electronic (oscillometric) upper arm devices in individuals with hypertension, and either ambulatory blood pressure monitoring or home blood pressure monitoring in individuals with white coat effect. We specify that all individuals with hypertension should have an assessment of global cardiovascular risk to promote health behaviours that lower blood pressure. Finally, an angiotensin receptor-neprilysin inhibitor combination should be used in place of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in individuals with heart failure (with ejection fraction < 40%) who are symptomatic despite appropriate doses of guideline-directed heart failure therapies. The specific evidence and rationale underlying each of these guidelines are discussed.


Assuntos
Determinação da Pressão Arterial , Monitorização Ambulatorial da Pressão Arterial , Doenças Cardiovasculares/prevenção & controle , Hipertensão , Serviços Preventivos de Saúde/métodos , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/classificação , Determinação da Pressão Arterial/instrumentação , Determinação da Pressão Arterial/métodos , Determinação da Pressão Arterial/normas , Monitorização Ambulatorial da Pressão Arterial/instrumentação , Monitorização Ambulatorial da Pressão Arterial/métodos , Canadá , Doenças Cardiovasculares/etiologia , Criança , Prática Clínica Baseada em Evidências , Feminino , Promoção da Saúde/métodos , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/terapia , Masculino , Medição de Risco/métodos
16.
Cardiovasc Res ; 114(12): 1629-1641, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800064

RESUMO

Aims: Transforming growth factor ß1 (TGF-ß1) is a prosclerotic cytokine involved in cardiac remodelling leading to heart failure (HF). Acetylation/de-acetylation of specific lysine residues in Smad2/3 has been shown to regulate TGF-ß signalling by altering its transcriptional activity. Recently, the lysine de-acetylase sirtuin 1 (SIRT1) has been shown to have a cardioprotective effect; however, SIRT1 expression and activity are paradoxically reduced in HF. Herein, we investigate whether pharmacological activation of SIRT1 would induce cardioprotection in a pressure overload model and assess the impact of SIRT1 activation on TGF-ß signalling and the fibrotic response. Methods and results: Eight weeks old male C57BL/6 mice were randomized to undergo sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Post-surgery, animals were further randomized to receive SRT1720 or vehicle treatment. Echocardiography, pressure-volume loops, and histological analysis revealed an impairment in cardiac function and deleterious left ventricular remodelling in TAC-operated animals that was improved with SRT1720 treatment. Genetic ablation and cell culture studies using a Smad-binding response element revealed SIRT1 to be a specific target of SRT1720 and identified Smad2/3 as a SIRT1 specific substrate. Conclusion: Overall, our data demonstrate that Smad2/3 is a specific SIRT1 target and suggests that pharmacological activation of SIRT1 may be a novel therapeutic strategy to prevent/reverse HF via modifying Smad activity.


Assuntos
Ativadores de Enzimas/farmacologia , Insuficiência Cardíaca/prevenção & controle , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Acetilação , Animais , Células Cultivadas , Modelos Animais de Doenças , Ativação Enzimática , Fibrose , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Histonas/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Fosforilação , Processamento de Proteína Pós-Traducional , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/genética , Fator de Crescimento Transformador beta/metabolismo
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