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Oral L-Arginine (5 g/day) for 14 Days Improves Microcirculatory Function in Healthy Young Women and Healthy and Type 2 Diabetes Mellitus Elderly Women.
Costa, G, Shushanof, M, Bouskela, E, Bottino, D
Journal of vascular research. 2022;(1):24-33
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Abstract
OBJECTIVE The aim of this study was to investigate the effect of oral supplementation with L-arginine on serum biochemical profile, blood pressure, microcirculation, and vasoreactivity/endothelial function in young controls, and elderly women with and without type 2 diabetes mellitus (T2DM). METHODS Healthy young (n = 25), healthy elderly (n = 25), and elderly women with type 2 diabetes mellitus (T2DME, n = 23, glycated Hb ≥6.4% and mean of 7.7 years for duration of the disease), aged 18-30 and older than 65 years, respectively, were included in the study. All patients underwent biochemical analysis (fasting glycemia and lipidogram), arterial blood pressure, nailfold videocapillaroscopy (capillary diameters, functional capillary density [FCD], peak red blood cell velocity [RBCVmax] after 1 min ischemia, time to reach peak RBCV [TRBCVmax]), and venous occlusion plethysmography (vasoreactivity), before and after 14 days of oral supplementation with L-arginine (5 g/day). RESULTS L-Arginine did not change fasting glycemia and lipidogram, but it decreased systolic, diastolic, and mean arterial pressure in elderly women, increased RBCVmax in all groups, and did not decrease TRBCVmax in T2DME. Capillary diameters and FCD remained unchanged in all groups. L-Arginine improved vasoreactivity during reactive hyperemia and after sublingual nitroglycerin (0.4 mg) in all groups. CONCLUSION L-Arginine supplementation (5g/day during 14 days) was able to improve vascular/microvascular health in the elderly women with or without T2DM.
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First-Line Vasopressor and Mortality Rates in ED Patients with Acute Drug Overdose.
Clifford, C, Sethi, M, Cox, D, Manini, AF
Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2021;(1):1-9
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INTRODUCTION While emergency department (ED) visits for acute drug overdose are at an all-time high, the importance of vasopressors to treat circulatory shock in this patient population remains unclear. This study investigated the association between first-line vasopressor and mortality, for both push-dose and infusion, in this patient population. METHODS From a prospective cohort of consecutive ED patients with drug overdose at two urban teaching centers over 5 years, we performed a secondary data analysis of patients with circulatory shock, defined as hypotension requiring either vasopressors, high-dose insulin euglycemia therapy, or both. The first-line vasopressor (push-dose and infusion) was analyzed for associations with the primary outcome (in-hospital mortality) and secondary outcomes (24-hour mortality, ICU LOS). Subgroup analysis of beta-/calcium-channel blocker overdose was performed to evaluate impact of antidotal therapies. Data analysis included multivariable regression. RESULTS Fifty-five patients with circulatory shock were analyzed, in whom there was 20% 24-hour mortality, 42% in-hospital mortality, 730-minute mean vasopressor duration, and 53.4-hour median ICU LOS. On multivariable analysis, there was significantly decreased adjusted odds of in-hospital mortality with first-line push-dose phenylephrine (aOR 0.06, CI 0.01-0.55), and significantly increased adjusted odds of in-hospital mortality with first-line push-dose epinephrine (aOR 60.8, CI 6.1-608). Of the first-line infusions, norepinephrine had the lowest odds of in-hospital mortality (aOR 0.80, CI 0.2-3.1). CONCLUSIONS In ED patients with undifferentiated drug overdose and circulatory shock, the first-line vasopressor is associated with in-hospital mortality. First-line push-dose phenylephrine was associated with the lowest odds of in-hospital mortality. Future randomized studies are warranted for validation.
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Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors.
Scholtes, RA, van Baar, MJB, Kok, MD, Bjornstad, P, Cherney, DZI, Joles, JA, van Raalte, DH
Nephrology (Carlton, Vic.). 2021;(5):377-390
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Diabetic kidney disease remains the leading cause of end-stage kidney disease and a major risk factor for cardiovascular disease. Large cardiovascular outcome trials and dedicated kidney trials have shown that sodium-glucose cotransporter (SGLT)2 inhibitors reduce cardiovascular morbidity and mortality and attenuate hard renal outcomes in patients with type 2 diabetes (T2D). Underlying mechanisms explaining these renal benefits may be mediated by decreased glomerular hypertension, possibly by vasodilation of the post-glomerular arteriole. People with T2D often receive several different drugs, some of which could also impact the renal vasculature, and could therefore modify both renal efficacy and safety of SGLT2 inhibition. The most commonly prescribed drugs that could interact with SGLT2 inhibitors on renal haemodynamic function include renin-angiotensin system inhibitors, calcium channel blockers and diuretics. Herein, we review the effects of these drugs on renal haemodynamic function in people with T2D and focus on studies that measured glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) with gold-standard techniques. In addition, we posit, based on these observations, potential interactions with SGLT2 inhibitors with an emphasis on efficacy and safety.
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Inorganic nitrate supplementation attenuates conduit artery retrograde and oscillatory shear in older adults.
Casey, DP, Bock, JM
American journal of physiology. Heart and circulatory physiology. 2021;(3):H991-H998
Abstract
Aging causes deleterious changes in resting conduit artery shear patterns and reduced blood flow during exercise partially attributable to reduced nitric oxide (NO). Inorganic nitrate increases circulating NO bioavailability and may, therefore, improve age-associated changes in shear rate as well as exercise hyperemia. Ten older adults (age: 67 ± 3 yr) consumed 4.03 mmol nitrate and 0.29 mmol nitrite (active) or devoid of both (placebo) daily for 4 wk in a randomized, double-blinded, crossover fashion. Brachial artery diameter (D) and blood velocity (Vmean) were measured via Doppler ultrasound at rest for the characterization of shear profile as well as during two handgrip exercise trials (4 and 8 kg) for calculation of forearm blood flow (Vmean × cross-sectional area, FBF) and conductance [FBF/mean arterial pressure, forearm vascular conductance (FVC)]. Plasma [nitrate] and [nitrite] increased following active (P < 0.05 for both) but not placebo (P = 0.68 and 0.40, respectively) supplementation. Neither mean nor antegrade shear rate changed following either supplement (beverage-by-time P = 0.14 and 0.21, respectively). Retrograde (-13.4 ± 7.0 to -9.7 ± 6.8·s-1) and oscillatory (0.20 ± 0.08 to 0.15 ± 0.09 A.U., P < 0.05 for both) shear decreased following active, but not placebo (P = 0.81 and 0.70, respectively), supplementation. The FBF response (Δ from rest) to neither 4-kg nor 8-kg trials changed following either supplement (beverage-by-time P = 0.53 and 0.11, respectively). Similarly, no changes were observed in FVC responses to 4-kg or 8-kg trials (beverage-by-time P = 0.23 and 0.07, respectively). These data indicate that inorganic nitrate supplementation improves conduit artery shear profiles, but not exercise hyperemia, in older adults.NEW & NOTEWORTHY We report for the first time, to our knowledge, that 4 wk of inorganic nitrate supplementation attenuates retrograde and oscillatory shear in the brachial artery of older adults. However, this was not associated with greater hyperemic or vasodilatory responses to exercise. In sum, these data highlight favorable changes in shear patterns with aging, which may reduce the risk of atherosclerotic cardiovascular disease.
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Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine.
Ott, C, Jung, S, Korn, M, Kannenkeril, D, Bosch, A, Kolwelter, J, Striepe, K, Bramlage, P, Schiffer, M, Schmieder, RE
Cardiovascular diabetology. 2021;(1):178
Abstract
BACKGROUND Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. METHODS Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. RESULTS Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups. CONCLUSIONS In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. TRIAL REGISTRATION The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016.
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No Effects of Different Doses of New Zealand Blackcurrant Extract on Cardiovascular Responses During Rest and Submaximal Exercise Across a Week in Trained Male Cyclists.
Montanari, S, Şahin, MA, Lee, BJ, Blacker, SD, Willems, MET
International journal of sport nutrition and exercise metabolism. 2021;(1):66-72
Abstract
Supplementation with anthocyanin-rich blackcurrant increases blood flow, cardiac output, and stroke volume at rest. It is not known whether cardiovascular responses can be replicated over longer timeframes in fed trained cyclists. In a randomized, double-blind, crossover design, 13 male trained cyclists (age 39 ± 10 years, V˙O2max 55.3 ± 6.7 ml·kg-1·min-1) consumed two doses of New Zealand blackcurrant (NZBC) extract (300 and 600 mg/day for 1 week). Cardiovascular parameters were measured during rest and submaximal cycling (65% V˙O2max) on day 1 (D1), D4, and D7. Data were analyzed with an RM ANOVA using dose (placebo vs. 300 vs. 600 mg/day) by time point (D1, D4, and D7). Outcomes from placebo were averaged to determine the coefficient of variation within our experimental model, and 95% confidence interval (CI) was examined for differences between placebo and NZBC. There were no differences in cardiovascular responses at rest between conditions and between days. During submaximal exercise, no positive changes were observed on D1 and D4 after consuming NZBC extract. On D7, intake of 600 mg increased stroke volume (3.08 ml, 95% CI [-2.08, 8.26]; d = 0.16, p = .21), cardiac output (0.39 L/min, 95% CI [-1.39, .60]; d = 0.14, p = .40) (both +2.5%), and lowered total peripheral resistance by 6.5% (-0.46 mmHg·min/ml, 95% CI [-1.80, .89]; d = 0.18, p = .46). However, these changes were trivial and fell within the coefficient of variation of our study design. Therefore, we can conclude that NZBC extract was not effective in enhancing cardiovascular function during rest and submaximal exercise in endurance-trained fed cyclists.
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Intradialytic exercise with blood flow restriction: Something to add to hemodialysis adequacy? Findings from a crossover study.
Dias, EC, Orcy, R, Antunes, MF, Kohn, R, Rombaldi, AJ, Ribeiro, L, Oses, JP, Ferreira, GD, Araújo, AM, Boff, IF, et al
Hemodialysis international. International Symposium on Home Hemodialysis. 2020;(1):71-78
Abstract
INTRODUCTION Hemodialysis (HD) increases the lifespan of chronic kidney disease (CKD) patients. However, HD is only partially effective in replacing renal function. The aim of this study is to compare HD adequacy between sessions with intradialytic exercise with or without blood flow restriction (BFR) with sessions without exercise. METHODS A crossover study including 22 adult CKD patients on HD. The patients were assigned to BFR (n = 11) or exercise alone group (n = 11). Each patient was submitted to four HD sessions (two with exercise and two control sessions). HD adequacy was assessed by equilibrated Kt/V-urea (eKT/V), single-pool Kt/V-urea (sp-Kt/V), urea and phosphorus rebound, urea reduction ratio (URR) and removal of urea and phosphorus in dialysate. FINDINGS BFR exercise improved eKt/V and sp-Kt/V (1.32 ± 0.21 vs. 1.10 ± 0.16 for control, P < 0.001; 1.53 ± 0.26 vs. 1.27 ± 0.19 for control, P < 0.001, respectively) and URR (72.5 ± 5.4% vs. 66.1 ± 7.7% for control, P < 0.001). No difference in eKt/V, sp-Kt/V or URR could be detected between exercise alone and control HD sessions. Urea rebound was lower in BFR exercise vs. control sessions (-8.9 ± 9.1% vs. 30.7 ± 12.8%, P < 0.01) and exercise alone vs. control sessions (13.3 ± 29.0% vs. 42.4 ± 15.3%, P < 0.01). Phosphorus rebound was marginally lower in exercise vs. control sessions (14.4 ± 19.1% vs. 28.4 ± 22.1%, P = 0.18). Urea and phosphorus mass removal in dialysate were marginally higher in exercise vs. control sessions (42.2 ± 19.4 g vs. 35.7 ± 12.5 g, P = 0.24; 912.1 ± 360.9 mg vs. 778.6 ± 245.1 mg, P = 0.28). CONCLUSIONS Intradialytic exercise with BFR was more effective than standard exercise in increasing HD adequacy.
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Role of Terlipressin in Cirrhotic Patients with Ascites and without Hepatorenal Syndrome: A Systematic Review of Current Evidence.
Bai, Z, An, Y, Guo, X, Teschke, R, Méndez-Sánchez, N, Li, H, Qi, X
Canadian journal of gastroenterology & hepatology. 2020;:5106958
Abstract
Ascites, a common complication in cirrhosis, is prone to the development of acute kidney injury or hepatorenal syndrome and can be complicated by circulatory dysfunction after paracentesis. Terlipressin has not been considered as the mainstay treatment option for ascites in cirrhosis yet. The present work aimed to systematically review the current evidence regarding the use of terlipressin in cirrhosis with ascites and without hepatorenal syndrome. PubMed, EMBASE, and Cochrane Library databases were searched for relevant studies. Twelve studies were eligible. In 3 studies (1 randomized controlled trial and 2 single-arm studies without controls) involving 32 patients who received terlipressin for nonrefractory ascites, terlipressin improved hemodynamics by decreasing the heart rate and cardiac output and increasing the mean arterial pressure and systemic vascular resistance. In 5 studies (1 randomized controlled trial, 2 single-arm studies without controls, and 2 comparative studies with controls) involving 67 patients who received terlipressin for refractory ascites, terlipressin improved renal function by increasing the glomerular filtration rate, renal blood flow, urinary sodium, and urine output and decreasing serum creatinine. In 4 studies (4 randomized controlled trials) involving 71 patients who received terlipressin for preventing from paracentesis-induced circulatory dysfunction, terlipressin prevented from paracentesis-induced circulatory dysfunction by increasing the mean arterial pressure and systemic vascular resistance and decreasing plasma renin. Terlipressin may improve hemodynamics, severity of ascites, and renal function and prevent from paracentesis-induced circulatory dysfunction in cirrhosis with ascites and without hepatorenal syndrome. However, no study has evaluated the effect of terlipressin for prevention of acute kidney injury.
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CK (Creatine Kinase) Is Associated With Cardiovascular Hemodynamics: The HELIUS Study.
Brewster, LM, Haan, YC, Zwinderman, AH, van den Born, BJ, van Montfrans, GA
Hypertension (Dallas, Tex. : 1979). 2020;(2):373-380
Abstract
The ATP-regenerating enzyme CK (creatine kinase) is strongly associated with blood pressure, which lowers upon experimental CK inhibition. The enzyme is thought to affect cardiovascular hemodynamics through enhanced systemic vascular resistance, stroke volume, and cardiac contractility, but data on these parameters are lacking. We hereby report hemodynamics by CK levels in the multiethnic, cross-sectional HELIUS study (Healthy Life in an Urban Setting). Physical examination included sitting brachial blood pressure and noninvasively assessed supine systemic vascular resistance, stroke volume, cardiac output, and cardiac contractility, which we associated with resting plasma CK. Data from 14 937 men and women (mean age, 43.3; SD, 12.9) indicated that per log CK increase, blood pressure increased with 20.2 (18.9-21.4) mm Hg systolic/13.0 (12.2-13.7) diastolic, an odds ratio for hypertension of 6.1 (5.1-7.2). Outcomes were similar by sex, body mass index, and ancestry, although higher blood pressures in men, with overweight/obesity, and West-African ancestry were partially explained by higher CK, with an adjusted increase in systolic/diastolic pressure of 10.5 (10.0-10.9)/6.4 (6.0-6.7) mm Hg per log CK increase. Systemic vascular resistance, stroke volume, cardiac output, and cardiac contractility (n=7876), increased by respectively 20%, 39%, 14%, and 23% SD per log CK increase. This study indicates that the association of CK with blood pressure likely results from an increase in systemic vascular resistance and stroke volume. These data expand the knowledge on the nature of hypertension associated with CK and may inform further experiments on CK inhibition as a means to lower blood pressure.
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Omega-3 polyunsaturated fatty acid supplementation versus placebo on vascular health, glycaemic control, and metabolic parameters in people with type 1 diabetes: a randomised controlled preliminary trial.
O'Mahoney, LL, Dunseath, G, Churm, R, Holmes, M, Boesch, C, Stavropoulos-Kalinoglou, A, Ajjan, RA, Birch, KM, Orsi, NM, Mappa, G, et al
Cardiovascular diabetology. 2020;(1):127
Abstract
BACKGROUND The role of omega-3 polyunsaturated fatty acids (n-3PUFA), and the potential impact of n-3PUFA supplementation, in the treatment and management of type 1 diabetes (T1D) remains unclear and controversial. Therefore, this study aimed to examine the efficacy of daily high-dose-bolus n-3PUFA supplementation on vascular health, glycaemic control, and metabolic parameters in subjects with T1D. METHODS Twenty-seven adults with T1D were recruited to a 6-month randomised, double-blind, placebo-controlled trial. Subjects received either 3.3 g/day of encapsulated n-3PUFA or encapsulated 3.0 g/day corn oil placebo (PLA) for 6-months, with follow-up at 9-months after 3-month washout. Erythrocyte fatty acid composition was determined via gas chromatography. Endpoints included inflammation-associated endothelial biomarkers (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], E-selectin, P-selectin, pentraxin-3, vascular endothelial growth factor [VEGF]), and their mediator tumor necrosis factor alpha [TNFα] analysed via immunoassay, vascular structure (carotid intima-media thickness [CIMT]) and function (brachial artery flow mediated dilation [FMD]) determined via ultrasound technique, blood pressure, glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial metabolism. RESULTS Twenty subjects completed the trial in full. In the n-3PUFA group, the mean ± SD baseline n-3PUFA index of 4.93 ± 0.94% increased to 7.67 ± 1.86% (P < 0.001) after 3-months, and 8.29 ± 1.45% (P < 0.001) after 6-months. Total exposure to n-3PUFA over the 6-months (area under the curve) was 14.27 ± 3.05% per month under n-3PUFA, and 9.11 ± 2.74% per month under PLA (P < 0.001). VCAM-1, ICAM-1, E-selectin, P-selectin, pentraxin-3, VEGF, TNFα, CIMT, FMD, blood pressure, HbA1c, FPG, and postprandial metabolism did not differ between or within groups after treatment (P > 0.05). CONCLUSIONS This study indicates that daily high-dose-bolus of n-3PUFA supplementation for 6-months does not improve vascular health, glucose homeostasis, or metabolic parameters in subjects with T1D. The findings from this preliminary RCT do not support the use of therapeutic n-3PUFA supplementation in the treatment and management of T1D and its associated complications. Trial Registration ISRCTN, ISRCTN40811115. Registered 27 June 2017, http://www.isrctn.com/ISRCTN40811115 .