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1.
Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.
Blagojevic, J, Abignano, G, Avouac, J, Cometi, L, Frerix, M, Bellando-Randone, S, Guiducci, S, Bruni, C, Huscher, D, Jaeger, VK, et al
Clinical rheumatology. 2020;(1):27-36
Abstract
INTRODUCTION DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.
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2.
Folic acid ingestion improves skeletal muscle blood flow during graded handgrip and plantar flexion exercise in aged humans.
Romero, SA, Gagnon, D, Adams, AN, Moralez, G, Kouda, K, Jaffery, MF, Cramer, MN, Crandall, CG
American journal of physiology. Heart and circulatory physiology. 2017;(3):H658-H666
Abstract
Skeletal muscle blood flow is attenuated in aged humans performing dynamic exercise, which is due, in part, to impaired local vasodilatory mechanisms. Recent evidence suggests that folic acid improves cutaneous vasodilation during localized and whole body heating through nitric oxide-dependent mechanisms. However, it is unclear whether folic acid improves vasodilation in other vascular beds during conditions of increased metabolism (i.e., exercise). The purpose of this study was to test the hypothesis that folic acid ingestion improves skeletal muscle blood flow in aged adults performing graded handgrip and plantar flexion exercise via increased vascular conductance. Nine healthy, aged adults (two men and seven women; age: 68 ± 5 yr) performed graded handgrip and plantar flexion exercise before (control), 2 h after (acute, 5 mg), and after 6 wk (chronic, 5 mg/day) folic acid ingestion. Forearm (brachial artery) and leg (superficial femoral artery) blood velocity and diameter were measured via Duplex ultrasonography and used to calculate blood flow. Acute and chronic folic acid ingestion increased serum folate (both P < 0.05 vs. control). During handgrip exercise, acute and chronic folic acid ingestion increased forearm blood flow (both conditions P < 0.05 vs. control) and vascular conductance (both P < 0.05 vs. control). During plantar flexion exercise, acute and chronic folic acid ingestion increased leg blood flow (both P < 0.05 vs. control), but only acute folic acid ingestion increased vascular conductance (P < 0.05 vs. control). Taken together, folic acid ingestion increases blood flow to active skeletal muscle primarily via improved local vasodilation in aged adults.NEW & NOTEWORTHY Our findings demonstrate that folic acid ingestion improves blood flow via enhanced vascular conductance in the exercising skeletal muscle of aged humans. These findings provide evidence for the therapeutic use of folic acid to improve skeletal muscle blood flow, and perhaps exercise and functional capacity, in human primary aging.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/folic-acid-and-exercise-hyperemia-in-aging/.
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3.
Endothelial dysfunction markers as a therapeutic target for Sildenafil treatment and effects on metabolic control in type 2 diabetes.
Mandosi, E, Giannetta, E, Filardi, T, Lococo, M, Bertolini, C, Fallarino, M, Gianfrilli, D, Venneri, MA, Lenti, L, Lenzi, A, et al
Expert opinion on therapeutic targets. 2015;(12):1617-22
Abstract
OBJECTIVE Endothelial dysfunction (ED) plays a role in diabetic cardiovascular complications. Hyperglycemia increases cytockines involved in vascular inflammation. Inhibition of phosphodiesterase type 5 (PDE5) exerts a relaxation on corpora cavernosa and has cardioprotective properties. The effect of chronic sildenafil treatment, on ED markers and metabolic parameters in a non-randomized study on men with type 2 diabetes (T2DM), was investigated. RESEARCH DESIGN AND METHODS Twenty-eight T2DM patients (61.2 ± 7.8 years, hemoglobin A1c (HbA1c) 7.9 ± 1.3%, duration of diabetes 11.5 ± 7.8 years) were treated with sildenafil 100 mg/d for 3 months. Baseline and postprandial glycemia, insulin, HbA1c, HOMA index, lipids, glomerular filtration rate, homocysteine were assessed at each visit. P-selectin (CD62P), CD14/42b, CD14/41, ICAM (CD54), PECAM (CD31) and CD11b/CD18, were evaluated, after monocyte isolation with flow-cytometry, before and after treatment. RESULTS After 3 months, sildenafil decreased P-selectin (p < 0.05), post-prandial glycemia (p < 0.01), HbA1c (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and increased high-density lipoprotein (p < 0.05). CONCLUSIONS PDE5 inhibition, in T2DM patients, reduces the endothelial function marker P-selectin and exerts a beneficial effect on glycometabolic control.
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4.
Differences in hemodynamic responses between intravenous carperitide and nicorandil in patients with acute heart failure syndromes.
Hattori, H, Minami, Y, Mizuno, M, Yumino, D, Hoshi, H, Arashi, H, Nuki, T, Sashida, Y, Higashitani, M, Serizawa, N, et al
Heart and vessels. 2013;(3):345-51
Abstract
While recent guidelines for the treatment of acute heart failure syndromes (AHFS) recommend pharmacotherapy with vasodilators in patients without excessively low blood pressure (BP), few reports have compared the relative efficiency of vasodilators on hemodynamics in AHFS patients. The present study aimed to assess the differences in hemodynamic responses between intravenous carperitide and nicorandil in patients with AHFS. Thirty-eight consecutive patients were assigned to receive 48-h continuous infusion of carperitide (n = 19; 0.0125-0.05 μg/kg/min) or nicorandil (n = 19; 0.05-0.2 mg/kg/h). Hemodynamic parameters were estimated at baseline, and 2, 24, and 48 h after drug administration using echocardiography. After 48 h of infusion, systolic BP was significantly more decreased in the carperitide group compared with that in the nicorandil group (22.1 ± 20.0 % vs 5.3 ± 10.4 %, P = 0.003). While both carperitide and nicorandil significantly improved hemodynamic parameters, improvement of estimated pulmonary capillary wedge pressure was greater in the carperitide group (38.2 ± 14.5 % vs 26.5 ± 18.3 %, P = 0.036), and improvement of estimated cardiac output was superior in the nicorandil group (52.1 ± 33.5 % vs 11.4 ± 36.9 %, P = 0.001). Urine output for 48 h was greater in the carperitide group, but not to a statistically significant degree (4203 ± 1542 vs 3627 ± 1074 ml, P = 0.189). Carperitide and nicorandil were differentially effective in improving hemodynamics in AHFS patients. This knowledge may enable physicians in emergency wards to treat and manage patients with AHFS more effectively and safely.
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5.
The effects of fluid balance and colloid administration on outcomes in patients with aneurysmal subarachnoid hemorrhage: a propensity score-matched analysis.
Ibrahim, GM, Macdonald, RL
Neurocritical care. 2013;(2):140-9
Abstract
BACKGROUND Delayed ischemic neurological deficit (DIND) following aneurysmal subarachnoid hemorrhage (SAH) remains a significant cause of mortality and disability. The administration of colloids and the induction of a positive fluid balance during the vasospasm risk period remain controversial. Here, we compared DIND and outcomes among propensity score-matched cohorts who did and did not receive colloids and also tested the effect of a positive fluid balance on these endpoints. METHODS Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Propensity score matching was performed on the basis of age, gender, pre-existing heart conditions, hypertension, nicotine use, World Federation of Neurosurgical Societies scores, aneurysm location, clazosentan treatment, subarachnoid clot burden, and severity of angiographic vasospasm. Inferential statistics were used for group-wise comparisons. RESULTS One hundred twenty-three subjects were matched (41 received colloids, whereas 82 did not). The covariate balance and propensity score distributions were acceptable. There was no difference between the groups with respect to DIND (17 vs. 22%; p = 0.64) or the presence (48 vs. 51%; p = 0.71) or volume of delayed infarcts (volume >7.5 cm3; 62 vs. 48%; p = 0.41). Similarly, no differences were found on multivariate analysis between patients who did and did not have a positive fluid balance, although patients with severe angiographic vasospasm had more delayed infarcts with a negative fluid balance (p = 0.01). Among all subjects, the administration of colloids and a positive fluid balance were associated with worse outcomes on the NIHSS (p = 0.04) and modified Rankin (p = 0.02) scales, respectively. CONCLUSIONS Colloid administration and induction of a positive fluid balance during the vasospasm risk period may be associated with poor outcomes in specific patient groups. Patient selection is of utmost importance when managing the fluid status of patients with aneurysmal SAH.
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6.
Oral treatment with nicorandil at discharge is associated with reduced mortality after acute myocardial infarction.
Sakata, Y, Nakatani, D, Shimizu, M, Suna, S, Usami, M, Matsumoto, S, Hara, M, Sumitsuji, S, Kawano, S, Iwakura, K, et al
Journal of cardiology. 2012;(1):14-21
Abstract
BACKGROUND Previous studies showed that nicorandil can reduce coronary events in patients with coronary artery disease. However, it is unclear whether oral nicorandil treatment may reduce mortality following acute myocardial infarction (AMI). METHODS AND RESULTS We examined the impact of oral nicorandil treatment on cardiovascular events in 1846 AMI patients who were hospitalized within 24 h after AMI onset, treated with emergency percutaneous coronary intervention (PCI), and discharged alive. Patients were divided into those with (Group N, n=535) and without (Group C, n=1311) oral nicorandil treatment at discharge. No significant differences in age, gender, body mass index, prevalence of coronary risk factors, or history of myocardial infarction existed between the two groups; however, higher incidences of multi-vessel disease, and a lower rate of successful PCI were observed in Group N. During the median follow-up of 709 (340-1088) days, all-cause mortality rate was 43% lower in Group N compared with Group C (2.4% vs. 4.2%, stratified log-rank test: p=0.0358). Multivariate Cox regression analysis revealed that nicorandil treatment was associated with all-cause death after discharge (Hazard ratio 0.495, 95% CI: 0.254-0.966, p=0.0393), but not for other cardiovascular events such as re-infarction, admission for heart failure, stroke and arrhythmia. CONCLUSIONS The results suggest that oral administration of nicorandil is associated with reduced incidence of death in the setting of secondary prevention after AMI.
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7.
Efficacy and safety of cinnarizine in the prophylaxis of migraine headaches in children: an open, randomized comparative trial with propranolol.
Togha, M, Malamiri, RA, Rashidi-Ranjbar, N, Asa, S, Mahvelati, F, Ashrafi, MR
Acta neurologica Belgica. 2012;(1):51-5
Abstract
Migraine headaches are common in children. Early diagnosis and appropriate interventions are mandatory to prevent decades of suffering and diminished quality of life. There is need for data regarding the efficacy and safety of prophylactic agents in children with migraine; therefore, we designed a randomized clinical trial to compare the efficacy and safety of cinnarizine with that of a well-known prophylactic agent (propranolol) in the prophylaxis of pediatric migraine headache. A total of 120 patients aged between 6 and 17 years were recruited and 113 patients succeeded in completing all phases of the trial. Of them, 57 patients were given cinnarizine, and propranolol was administered in 56 patients. Reduction in headache frequency was the main response to treatment. Cinnarizine reduced the baseline headache frequency by more than 50% in 74.6% of patients and the mean headache frequency per month was reduced from 11.851 ± 0.739 (mean ± SEM) to 3.358 ± 0.739 (mean ± SEM) attacks per month (P < 0.001). In the propranolol group, more than 50% reduction of the baseline headache frequency was seen in 72.5% of patients and the mean headache frequency per month was reduced from 10.264 ± 0.830 (mean ± SEM) to 2.774 ± 0.830 (mean ± SEM) attacks per month (P < 0.001). No significant difference was seen in 50% reduction of the baseline headache frequency between treatment groups (P = 0.358). No significant adverse effects were reported. In this open study, cinnarizine appeared thus as effective as propranolol and safe for the prophylaxis of migraine in children, but this remains to be confirmed in a double-blind placebo-controlled trial.
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8.
The association between microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional study.
Sandoo, A, Carroll, D, Metsios, GS, Kitas, GD, Veldhuijzen van Zanten, JJ
Arthritis research & therapy. 2011;(3):R99
Abstract
INTRODUCTION Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). One of the earliest manifestations of CVD is endothelial dysfunction (ED). ED can occur in both the microcirculation and the macrocirculation, and these manifestations might be relatively independent of each other. Little is known about the association between endothelial function in the microcirculation and the macrocirculation in RA. The objectives of the present study were to examine the relationship between microvascular and macrovascular endothelial function in patients with RA. METHODS Ninety-nine RA patients (72 females, mean age (± SD) 56 ± 12 years), underwent assessments of endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) microvascular vasodilatory function (laser Doppler imaging with iontophoresis), as well as endothelial-dependent (flow-mediated dilation) and endothelial-independent (glyceryl trinitrate-mediated dilation) macrovascular vasodilatory function. Vasodilatory function was calculated as the percentage increase after each stimulus was applied relative to baseline values. RESULTS Pearson correlations showed that microvascular endothelial-dependent function was not associated with macrovascular endothelial-dependent function (r (90 patients) = 0.10, P = 0.34). Similarly, microvascular endothelial-independent function was not related to macrovascular endothelial-independent function (r (89 patients) = 0.00, P = 0.99). CONCLUSIONS Microvascular and macrovascular endothelial function were independent of each other in patients with RA, suggesting differential regulation of endothelial function in these two vascular beds. Assessments of both vascular beds may provide more meaningful clinical information on vascular risk in RA, but this hypothesis needs to be confirmed in long-term prospective studies.
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9.
The role of nebivolol in the prevention of contrast-induced nephropathy in patients with renal dysfunction.
Avci, E, Yeşil, M, Bayata, S, Postaci, N, Arikan, E, Cirit, M
Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology. 2011;(7):613-7
Abstract
OBJECTIVE This prospective study was designed to evaluate the potential protective effect of nebivolol compared with metoprolol on the development of contrast-induced nephropathy (CIN) following coronary angiography in patients with renal dysfunction. METHODS Ninety patients with stable coronary angina pectoris with renal insufficiency (creatinine value ≥1.2 mg/dl) were included for this prospective study. Patients were divided into two groups. Patients in group 1 (n=55) received oral administration of nebivolol 5 mg/daily for coronary artery disease and/or hypertension. Group 2 consisted of 35 patients who received metoprolol 50 mg/daily for the same indications. All patients were hydrated with 0.9% NaCl at a rate of 1 mL/kg/hr for 12 hours before and 24 hours after the procedure. Patients were also given N-acetylcysteine (NAC) 600 mg twice a day, beginning 24 hours before and continuing 48 hours after the procedure. All patients underwent routine coronary angiography. Serum creatinine was assessed just before, immediately after and 48 hours after the procedure. CIN was defined as an increase in serum creatinine concentration of ≥25% within 48 hours after the procedure compared to the patient's baseline value. Tests for significance between groups were conducted using the independent sample t-test for continuous variables and Chi-square test for categorical variables. RESULTS Baseline serum creatinine levels were statistically comparable in two groups. Following angiography, serum creatinine levels increased in both groups. Post-angiographic creatinine levels were not statistically different in the nebivolol and the metoprolol groups. Contrast induced nephropathy developed in 13 patients (24%) of the nebivolol group and in 12 patients (33%) of the metoprolol group. The incidence of CIN was statistically significantly lower in the nebivolol group comparing with the metoprolol group (p=0.03). CONCLUSION The use of oral nebivolol for one week at a dose of 5 mg per day may decrease the incidence of contrast-induced nephropathy in patients who underwent coronary angiography with renal dysfunction. The small numbers of this study do not allow to draw final conclusion on the use of nebivolol in the prevention of CIN. Therefore, larger studies may be necessary to address the definite role of nebivolol in this setting.
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10.
Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure.
Tanaka, K, Kato, K, Takano, T, Katagiri, T, Asanoi, H, Nejima, J, Nakashima, M, Kamijo, T, Sakanashi, M
Journal of cardiology. 2010;(3):291-9
Abstract
BACKGROUND Nicorandil injection, a potent vasodilator with K(ATP) channel opening action and nitrate-like action, has been used for treatment of unstable angina. In the present investigation, we examined the effect of intravenous nicorandil on hemodynamics in patients with acute decompensated heart failure (ADHF). METHODS ADHF patients admitted to hospital with pulmonary artery wedge pressure (PAWP)≥18 mm Hg were enrolled. Patients received nicorandil by an intravenous bolus injection of 0.2mg/kg/5 min followed by continuous infusion at a rate of 0.05, 0.10, or 0.20mg/kg/h for 6h. RESULTS Nicorandil administration caused a significant decrease in PAWP and increase in the cardiac index (CI) that began immediately after the injection and were maintained during the continuous infusion. After 6h, nicorandil administration at 0.2mg/kg/5 min followed by 0.20mg/kg/h resulted in a decrease in PAWP (26.5%, p<0.01), an increase in CI (15.8%, p<0.05), and a decrease in total peripheral resistance (13.8%, p<0.01) in a dose-dependent manner. Nicorandil decreased blood pressure significantly, without an excessive decrease or negative impact even in patients with lower systolic blood pressure. CONCLUSION Intravenous administration of nicorandil, by bolus injection followed by continuous infusion, improves PAWP and CI in ADHF patients immediately and continuously as a potent vasodilator with combined preload and afterload reduction. These results demonstrate that nicorandil is a safe and effective new medication for the treatment of ADHF.