RESUMO
BACKGROUND: Empagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness. METHODS: Our analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial ( http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis. RESULTS: As previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.6 ± 12.1 vs 118.6 ± 12.9 mmHg, p < 0.001), central pulse pressure (39.1 ± 10.2 vs 41.9 ± 10.7 mmHg, p = 0.027) forward (27.1 ± 5.69 vs 28.7 ± 6.23 mmHg, p = 0.031) as well as reflected wave amplitude (18.9 ± 5.98 vs 20.3 ± 5.97 mmHg, p = 0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta = - 0.259, p = 0.054), sex (beta = 0.292, p = 0.040) and change in systolic 24-h ambulatory blood pressure (beta = 0.364, p = 0.019), the change of hsCRP (beta = 0.305, p = 0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta = 0.347, p = 0.017) on arterial stiffness parameters was found. CONCLUSION: Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms. Trial registration http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered.
Assuntos
Anti-Inflamatórios/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Adolescente , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Alemanha , Glucosídeos/efeitos adversos , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The sodium-glucose cotransporter 2 inhibitor, dapagliflozin, has been shown to improve diabetic control and reduce blood pressure in patients with type 2 diabetes mellitus. Its effects on micro- and macrovascular structure and function have not yet been reported. METHODS: This was a prospective, single-centre, placebo-controlled, double-blind, randomised crossover phase IIIb study conducted between March 2014 and February 2015. After a 4-week run-in/washout phase, patients (N = 59) received 6 weeks of either dapagliflozin 10 mg or placebo once daily. They then underwent a 1-week washout before crossing over to the other treatment. Changes in retinal capillary flow (RCF) and arteriole remodelling were evaluated using scanning laser Doppler flowmetry, while micro- and macrovascular parameters in the systemic circulation were assessed using pulse wave analysis. RESULTS: Six weeks of dapagliflozin treatment resulted in improvements in diabetes control, including blood glucose and insulin resistance, and reduced office and 24-h ambulatory blood pressure values. RCF decreased from 324 AU at baseline to 308 AU after treatment with dapagliflozin (p = 0.028), while there was little difference after the placebo (318 AU; p = 0.334). Furthermore, the arteriole remodelling that was seen after the placebo phase was not evident after the dapagliflozin phase. Central systolic and diastolic blood pressure values were significantly lower after 6 weeks of dapagliflozin, by 3.0 and 2.2 mmHg, respectively (p = 0.035 and 0.020, respectively vs. baseline). CONCLUSIONS: Six weeks of dapagliflozin treatment resulted in numerous beneficial effects. In addition to achieving superior diabetes control and blood pressure, parameters associated with the early stages of vascular remodelling were also improved. Trial registration http://www.clinicaltrials.gov (NCT02383238).
Assuntos
Compostos Benzidrílicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Microcirculação/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Glucosídeos/farmacologia , Humanos , Resistência à Insulina/fisiologia , Fluxometria por Laser-Doppler/métodos , Masculino , Microcirculação/fisiologia , Microvasos/fisiologia , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Case numbers in central emergency departments (EDs) have risen during the past decade in Germany, leading to recurrent overcrowding, increased risks in emergency care, and elevated costs. Particularly the fraction of outpatient emergency treatments has increased disproportionately. Within the framework of the Optimization of emergency care by structured triage with intelligent assistant service (OPTINOFA, Förderkennzeichen [FKZ] 01NVF17035) project, an intelligent assistance service was developed. PATIENTS AND METHODS: New triage algorithms were developed for the 20 most frequent leading symptoms on the basis of established triage systems (emergency severity index, ESI; Manchester triage system, MTS) and provided as web-based intelligent assistance services on mobile devices. To evaluate the validity, reliability, and safety of the new OPTINOFA triage instrument, a pilot study was conducted in three EDs after ethics committee approval. RESULTS: In the pilot study, nâ¯= 718 ED patients were included (age 59.1⯱ 22 years; 349 male, 369 female). With respect to disposition (out-/inpatient), a sensitivity of 91.1% and a specificity of 40.7%, and a good correlation with the OPTINOFA triage levels were detected (Spearman's rank correlation ρâ¯= 0.41). Furthermore, the area under the curve (AUC) for prediction of disposition according to the OPTINOFA triage level was 0.73. The in-hospital mortality rate of OPTINOFA triage levels 4 and 5 was 0%. The association between the length of ED stay and the OPTINOFA triage level was shown to be significant (pâ¯< 0.001). CONCLUSION: The results of the pilot study demonstrate the safety and validity of the new triage system OPTINOFA. By definition of both urgency and emergency care level, new customized perspectives for load reduction in German EDs via a closer cooperation between out- and inpatient sectors of emergency care could be established.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Rigidez Vascular/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Estudos Cross-Over , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: Epidemiological studies found a link between aircraft noise exposure and increased incidence of arterial hypertension and cardiovascular disease, but the underlying pathophysiological mechanisms are not fully understood. Clinical studies have shown that mental stress affects the systemic and renal haemodynamic, but no such study was performed with noise exposure as stress factor. We analysed systemic and renal effects of 25 min standardized aircraft noise in a sham controlled clinical study including 80 healthy men and 34 male patients with hypertension. METHODS AND RESULTS: Systemic haemodynamic parameters were measured using electrocardiography and impedance cardiography. The renal haemodynamic was assessed using steady state input clearance with infusion of para-aminohippuric acid and inulin for glomerular filtration rate and renal plasma flow, respectively. In the systemic circulation of hypertensive patients, there was an increase in total peripheral resistance (TPR) (1420 ± 387 vs. 1640 ± 516 dyn·s·cm-5, P = 0.001) and a decrease in cardiac index (CI) (2.9 ± 0.8 vs. 2.6 ± 0.8 L/(min·m2, P < 0.001) 25 min after the start of noise exposure, which was not present during sham procedure (P = 0.10, P = 0.86). In healthy individuals a procedure induced increase in TPR and decrease in CI was present after noise (TPR: 995 ± 239 vs. 1106 ± 308 dyn·s·cm-5, P = 0.001, CI: 3.6 ± 0.7 vs. 3.3 ± 0.9 L/(min·m2, P < 0.001) and sham application (TPR: P = 0.002, CI: P < 0.001). However, in healthy individuals changes in TPR (P = 0.450) and CI (P = 0.605) from baseline until 25 min after the start of the intervention did not differ between noise and sham exposure. In the renal circulation of hypertensive patients and healthy individuals the response did not differ between noise and sham procedure. CONCLUSIONS: In hypertensive but not healthy men we observed a systemic vasoconstrictive response after aircraft noise exposure accompanied by a decrease in CI. No significant changes were observed in the renal circulation. Our results suggest that male hypertensive patients are more susceptible for noise-induced changes of vascular resistance in the systemic circulation.
Assuntos
Rim , Circulação Renal , Aeronaves , Taxa de Filtração Glomerular , Hemodinâmica , Humanos , MasculinoRESUMO
BACKGROUND: Copeptin, the C-terminal peptide of provasopressin, is released from the neurohypophysis and reflects the activity of the hormone arginine vasopressin in patients with hypertension. Elevated copeptin levels are associated with increased cardiovascular and all-cause mortality. The aim of this study is to compare copeptin levels in patients with treatment-resistant hypertension (TRH) before and 6 months after renal denervation (RDN). METHODS: Copeptin was measured in 34 patients with TRH and 30 patients with primary hypertension stage 1 or 2 (HT). In addition, copeptin levels were measured in patients with TRH at 6-month follow-up visit after RDN. RDN was performed by an experienced interventionalist applying at least 4 ablations longitudinally and rotationally within the lengths of each renal artery to cover a full 4-quadrant ablation. RESULTS: In patients with TRH 24-hour ambulatory blood pressure (BP) decreased from 154 ± 15/87 ± 12 mm Hg to 146 ± 13/83 ± 7.9 mm Hg after RDN (systolic: P = 0.001, diastolic: P = 0.034). There was no significant change in copeptin levels in these 34 patients with TRH before vs. 6 months after RDN (median 8.4 [interquartile range 3.6-14] vs. 8.5 [4.5-13] pmol/l, P = 0.334). Patients with TRH had higher copeptin levels (P = 0.024) than patients with HT (24-hour ambulatory BP: 142 ± 11/91 ± 8.3 mm Hg, copeptin: 4.2 [2.8-6.3] pmol/l). CONCLUSION: Patients with TRH showed 2-fold higher copeptin levels than patients with HT. RDN did not lead to any change of copeptin levels in patients with TRH 6 months after procedure despite significant fall in BP. CLINICAL TRIAL REGISTRATION: NCT01318395, NCT01687725.
Assuntos
Pressão Sanguínea , Ablação por Cateter , Glicopeptídeos/sangue , Hipertensão/sangue , Hipertensão/cirurgia , Rim/irrigação sanguínea , Artéria Renal/inervação , Simpatectomia , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Resistência a Medicamentos , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Regulação para CimaRESUMO
AIMS: Preserved vascular function represents a key prognostic factor in type 2 diabetes mellitus (T2DM), but data on vascular parameters in this patient cohort are scarce. Patients with T2DM often need more than one drug to achieve optimal glucose control. The aim of this study was to analyse the efficacy of two combination therapies on vascular function in subjects with T2DM. METHODS AND RESULTS: This prospective, randomized study included 97 subjects with T2DM. Subjects were randomized to either the combination therapy empagliflozin (E) 10 mg with linagliptin (L) 5 mg once daily or metformin (M) 850 or 1000 mg twice daily with insulin glargine (I) once daily. At baseline and after 12 weeks, subjects had peripheral office and 24-h ambulatory blood pressure (BP) measurement and underwent vascular assessment by pulse wave analysis under office and ambulatory conditions. Office, 24-h ambulatory and central BP as well as pulse pressure (PP) decreased after 12 weeks of treatment with E + L, whereas no change was observed in M + I. There were greater decreases in 24-h ambulatory peripheral systolic (between-group difference: -5.2 ± 1.5 mmHg, P = 0.004), diastolic BP (-1.9 ± 1.0 mmHg, P = 0.036), and PP (-3.3 ± 1.0 mmHg, P = 0.007) in E + L than M + I. Central office systolic BP (-5.56 ± 1.9 mmHg, P = 0.009), forward pressure height of the pulse wave (-2.0 ± 0.9 mmHg, P = 0.028), 24-h ambulatory central systolic (-3.6 ± 1.4 mmHg, P = 0.045), diastolic BP (-1.95 ± 1.1 mmHg, P = 0.041), and 24-h pulse wave velocity (-0.14 ± 0.05m/s, P = 0.043) were reduced to a greater extent with E + L. CONCLUSION: Beyond the effects on glycaemic control, the combination therapy of E + L significantly improved central BP and vascular function compared with the classic combination of M + I. CLINICALTRIALS.GOV: NCT02752113.
Assuntos
Pressão Arterial/efeitos dos fármacos , Compostos Benzidrílicos/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Linagliptina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Idoso , Compostos Benzidrílicos/efeitos adversos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Quimioterapia Combinada , Feminino , Alemanha , Glucosídeos/efeitos adversos , Humanos , Insulina Glargina/uso terapêutico , Linagliptina/efeitos adversos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Tissue sodium content by 23Na magnetic resonance imaging (MRI) has been found to be increased in arterial hypertension. We analyzed whether tissue sodium content is increased in patients with type-2 diabetes (T2DM). METHODS: Patients with T2DM were compared to those with primary hypertension. Patients with T2DM were off any antidiabetic and hypertensive patients off any antihypertensive therapy for at least 4â¯weeks. Skin and muscle sodium content was assessed non-invasively with a 3.0â¯T clinical MRI system (Magnetom Verio, Siemens Health Care, Erlangen, Germany) in each patient. RESULTS: In patients with T2DM (Nâ¯=â¯59) we observed significantly greater muscle sodium content (diabetes: 20.6⯱â¯3.5 vs hypertension: 16.3⯱â¯2.5â¯mmol/l, pâ¯<â¯0.001) and skin sodium content (diabetes: 24.5⯱â¯7.2 vs hypertension: 20.6⯱â¯5.7â¯mmol/l, pâ¯=â¯0.01) than in those with primary hypertension (Nâ¯=â¯33). When potential confounders (age, body mass index, gender, systolic and diastolic blood pressure, estimated glomerular filtration rate) were entered in a covariance analysis, both skin sodium content (pâ¯=â¯0.037) and muscle sodium content (pâ¯<â¯0.001) were still clearly elevated. CONCLUSION: Patients with T2DM have greater skin and muscle sodium content. These are the first known data to demonstrate increased tissue sodium content in patients with T2DM, measured by 23Na magnetic resonance imaging. Since tissue sodium content is related to organ damage, therapeutic intervention should aim at reducing tissue sodium content.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Músculos/metabolismo , Pele/metabolismo , Isótopos de Sódio/farmacocinética , Sódio/metabolismo , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Alemanha , Taxa de Filtração Glomerular , Humanos , Hipertensão/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Músculos/química , Fatores Sexuais , Pele/química , Sódio/análise , Isótopos de Sódio/análise , Distribuição TecidualRESUMO
OBJECTIVE: In patients with resistant hypertension, percutaneous placement of an iliac arteriovenous coupler device leads to a reduction of blood pressure (BP) via decreased total vascular resistance and improved arterial compliance. However, long-term efficacy and safety need to be further explored. We report on the first case of 3.5-year follow-up in a patient who underwent implantation of an iliac arteriovenous coupler device. RESULTS: A patient with resistant hypertension was admitted to hospital. Despite treatment with six anti-hypertensive drugs, his BP was poorly controlled. Previously, he had undergone renal denervation, which did not cause a significant BP decrease. Therefore, an arteriovenous coupler device was implanted, leading to an immediate and significant BP decrease. The patient was discharged with an office BP of 122/71âmmHg. After 3 months, there was a sustained BP decrease (-14/9âmmHg), whereas later, it was fluctuant (office BP: 147-173/85-95âmmHg, ABPM: 153-166/81-94âmmHg) probably due to medication non-adherence confirmed by a urinary toxicological screening test. Follow-up right heart catheterization showed changes in hemodynamic parameters related to volume congestion, which were accompanied by progressive dyspnea and weight gain. This was controlled by an optimized diuretic therapy. Additionally, an invasive closure maneuver was performed, leading to an immediate BP increase after closure and a similar decrease after re-opening of the anastomosis, verifying its proper long-term function. CONCLUSION: The implantation of an iliac arteriovenous coupler device appears to be a promising and effective method to decrease BP and therefore reduce cardiovascular risk in patients with severe, treatment-resistant hypertension.
Assuntos
Derivação Arteriovenosa Cirúrgica/instrumentação , Pressão Sanguínea , Vasoespasmo Coronário/cirurgia , Hipertensão/cirurgia , Anti-Hipertensivos/uso terapêutico , Vasoespasmo Coronário/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Artéria Ilíaca/cirurgia , Veia Ilíaca/cirurgia , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Mineralocorticoid receptor antagonists are increasingly used in patients with treatment-resistant hypertension (TRH). There is experimental evidence for blood pressure (BP) independent effects of mineralocorticoid receptor blockade on cardiovascular target organ damage. We hypothesized that low-dose eplerenone (50âmg) will reduce left ventricular mass (LVM) beyond its BP-lowering effects. METHODS: We performed a randomized, double-blind, placebo-controlled, parallel group study in 51 patients with TRH. Patients were allocated to receive either eplerenone 50âmg or placebo for 6 months, while other antihypertensive agents could be added in both groups to achieve a BP target of less than 140/90âmmHg. LVM was assessed by MRI before and after treatment. RESULTS: Baseline office BP was similar in the eplerenone and the placebo group (166â±â21/91â±â15 versus 159â±â19/94â±â8âmmHg, n.s.). BP was similarly reduced in the eplerenone versus the placebo group (-35â±â20/-15â±â11 versus -30â±â19/-13â±â7âmmHg, n.s.). However, LVM was reduced only in the eplerenone group (from 155â±â33 to 136â±â33âg, Pâ<â0.001), but not in the placebo group (152â±â32 versus 148â±â38âg, Pâ=â0.45). CONCLUSIONS: Despite similar BP-lowering, only patients with TRH who were allocated to eplerenone experienced a reduction of LVM. Thus, our data suggest that in patients with TRH, mineralocorticoid receptor antagonists should be used preferentially in order to achieve an effective reduction of LVM along with the improvement of BP control.