Peripheral Endothelial Function In Patients Research Articles

63 Peripheral endothelial function in patients affected by pulmonary hypertension. Relationship between endothelial function, haemodynamic parameters, and therapy response

Abstract Aims Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) of 25 mmHg or greater at rest, confirmed by right heart catheterization (RHC). The World Health Organization has classified PH into five clinical subgroups. Pulmonary arterial hypertension (PAH) (group 1) is characterized by loss and obstructive remodelling of the pulmonary vascular bed. These patients are characterized haemodynamically by the presence of precapillary PH, defined as an mPAP of 25 mm Hg or greater, pulmonary artery wedge pressure (PAWP) of 15 mm Hg or less, and pulmonary vascular resistance (PVR) of three Wood units (WU) or greater. Pulmonary hypertension due to left-sided heart disease (LHD) (PH-LHD) (group 2) occurs in HF. Patients with PH-LHD usually have isolated postcapillary PH (PAWP >15 mm Hg and PVR <3 WU), although some of them have combined postcapillary and precapillary PH (PAWP >15 mm Hg and PVR ≥3 WU). PH due to chronic lung disease (CLD) (PH-CLD) and/or hypoxia (group 3) can occur in many lung diseases. These patients have precapillary PH. Chronic thromboembolic PH (CTEPH) (group 4) is characterized by obstruction of the pulmonary vasculature by organized thromboembolic material and vascular remodelling, resulting from prior pulmonary embolism. Patients with unclear and/or multifactorial mechanisms are listed as group 5. Specific pulmonary vasodilators are approved only in PAH patients. While research was predominantly focused on pulmonary vasculature, little is known about the peripheral endothelial damage in different vascular beds in PH patients. To evaluate the relationship between the peripheral endothelial function and the haemodynamic parameters, in order to provide a non-invasive method for the indirect evaluation of mean pulmonary pressure and vascular resistance, to predict if the PH is a precapillary or postcapillary, to select more accurately the patients who should undergo RHC. Moreover, we investigate if there is a possible correlation between endothelial dysfunction and response to specific PH therapies. Methods and results Patients with suspected PH, based on symptoms, medical history, and clinics will undergo physical examination, ECG, echocardiography, and RHC. In all patients, endothelial function was assessed by FMD. Medical history, heart rate, systolic blood pressure, body mass index, WHO functional class, and medications were recorded. All patients underwent blood analysis, erythrocyte sedimentation rate (ERS), high sensitivity C-reactive protein (CRP), and NT-proBNP levels were assayed. Increased peripheral endothelial dysfunction in patients with precapillary PH, with a linear correlation between endothelium dysfunction and increased PVR at the right catheterization. To differentiate pre and post capillary PH forms by cut-off values of the FMD. The degree of endothelial dysfunction could be a marker of therapy response. Sequential combination therapy in the pre-capillary PH forms could be the one with a worst endothelial response than up-front combination therapy.

Acute effects of oral triglyceride load on dynamic changes in peripheral endothelial function in heart failure patients with reduced ejection fraction and healthy controls

BachgroundPostprandial hyperlipaemia impairs endothelial function, possibly via oxidative-stress-mediated mechanisms. The aim of this study was to evaluate the acute effects of an oral triglyceride load (OTGL) on peripheral endothelial function in heart failure patients with reduced ejection fraction (HFrEF) compared to healthy controls. DesignProspective cross-sectional. MethodsWe enrolled 47 patients with HFrEF and 20 healthy controls. Peripheral endothelial function was assessed with EndoPAT2000 technology using a reactive hyperaemia index (RHI) and pulse wave amplitude (PWA) at baseline (after 8-h overnight fasting) as well as 1, 2, 3 and 4-h post-OTGL consumption (250-ml cream drink). Pulse wave amplitude index (PWAI) was calculated as a ratio of PWA at each time point to the baseline PWA. ResultsRHI at baseline was lower in HFrEF patients compared to controls (1.7 ± 0.3 and 2.3 ± 0.6, respectively; P = 0.001). The OTGL accounted for a physiologic increase in PWA in healthy controls (p = 0.01), but this change was not observed in HFrEF patients. After 4 h, vasodilator response was significantly increased in healthy controls but not patients with HFrEF (2.3 ± 1.3 vs. 1.3 ± 0.8 respectively, P < 0.05). ConclusionsThe main finding of this study was the impaired postprandial dynamic changes in peripheral endothelial function in patients with HFrEF compared to healthy controls. A high-fat load that caused acute hypertriglyceridaemia significantly increased resting blood flow and peak flow at reactive hyperaemia in healthy subjects. By contrast, patients with HFrEF exhibited impaired dynamic changes in peripheral endothelial function after oral triglyceride load.

Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome.

AimsMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem disease. Evidence for disturbed vascular regulation comes from various studies showing cerebral hypoperfusion and orthostatic intolerance. The peripheral endothelial dysfunction (ED) has not been sufficiently investigated in patients with ME/CFS. The aim of the present study was to examine peripheral endothelial function in patients with ME/CFS.Methods and resultsThirty‐five patients [median age 40 (range 18–70) years, mean body mass index 23.8 ± 4.2 kg/m2, 31% male] with ME/CFS were studied for peripheral endothelial function assessed by peripheral arterial tonometry (EndoPAT2000). Clinical diagnosis of ME/CFS was based on Canadian Criteria. Nine of these patients with elevated antibodies against β2‐adrenergic receptor underwent immunoadsorption, and endothelial function was measured at baseline and 3, 6, and 12 months follow‐up. ED was defined by reactive hyperaemia index ≤1.81. Twenty healthy subjects of similar age and body mass index were used as a control group. Peripheral ED was found in 18 of 35 patients (51%) with ME/CFS and in 4 healthy subjects (20%, P < 0.05). Patients with ED, in contrast to patients with normal endothelial function, reported more severe disease according to Bell score (31 ± 12 vs. 40 ± 16, P = 0.04), as well as more severe fatigue‐related symptoms (8.62 ± 0.87 vs. 7.75 ± 1.40, P = 0.04) including a higher demand for breaks [9.0 (interquartile range 7.0–10.0) vs. 7.5 (interquartile range 6.0–9.25), P = 0.04]. Peripheral ED showed correlations with more severe immune‐associated symptoms (r = −0.41, P = 0.026), such as sore throat (r = −0.38, P = 0.038) and painful lymph nodes (r = −0.37, P = 0.042), as well as more severe disease according to Bell score (r = 0.41, P = 0.008) and symptom score (r = −0.59, P = 0.005). There were no differences between the patient group with ED and the patient group with normal endothelial function regarding demographic, metabolic, and laboratory parameters. Further, there was no difference in soluble vascular cell adhesion molecule and soluble intercellular adhesion molecule levels. At baseline, peripheral ED was observed in six patients who underwent immunoadsorption. After 12 months, endothelial function had improved in five of these six patients (reactive hyperaemia index 1.58 ± 0.15 vs. 2.02 ± 0.46, P = 0.06).ConclusionsPeripheral ED is frequent in patients with ME/CFS and associated with disease severity and severity of immune symptoms. As ED is a risk factor for cardiovascular disease, it is important to elucidate if peripheral ED is associated with increased cardiovascular morbidity and mortality in ME/CFS.

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study.

In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel [mean difference 2.13, 95% confidence interval (CI) 0.68-3.58; P = 0.0047] and ticagrelor (mean difference 1.57, 95% CI 0.31-2.83; P = 0.0155), but this difference was limited to patients who received the study therapy 2 h before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference 0.55, 95% CI -0.73 to 1.82; P = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (P = 0.02 and P = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (P = 0.002 and P = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group. As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting. 2011-005305-73.

Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection Fraction: A Single-Center, Randomized Double-Blind Placebo-Controlled Crossover Pilot Study

Endothelial dysfunction is reportedly associated with worse outcomes in patients with chronic heart failure. Ubiquinol is a reduced form of coenzyme Q10 (CoQ10) that may improve endothelial function. We assessed the hypothesis that ubiquinol improves peripheral endothelial function in patients with heart failure with reduced ejection fraction (HFrEF). In this randomized, double-blind, placebo-controlled, crossover pilot study, 14 patients with stable HFrEF were randomly and blindly allocated to ubiquinol 400mg/day or placebo for 3months. After a 1-month washout period, patients were crossed over to the alternative treatment. Before and after each treatment, we assessed peripheral endothelial function using the reactive hyperemia index (RHI) and analyzed it using the natural logarithm of RHI (LnRHI). Peripheral endothelial function as assessed by LnRHI tended to improve with ubiquinol 400mg/day for 3months (p = 0.076). Original RHI values were also compared, and RHI significantly improved with ubiquinol treatment (pre-RHI 1.57 [interquartile range (IQR) 1.39-1.80], post-RHI 1.74 [IQR 1.63-2.02], p = 0.026), but not with placebo (pre-RHI 1.67 [IQR 1.53-1.85], post-RHI 1.51 [IQR 1.39-2.11], p = 0.198). Ubiquinol 400mg/day for 3months led to significant improvement in peripheral endothelial function in patients with HFrEF. Ubiquinol may be a therapeutic option for individuals with HFrEF. Large-scale randomized controlled trials of CoQ10 supplementation in patients with HFrEF are needed. Japanese University Hospital Medical Information Network (UMIN-ICDR). Clinical Trial identifier number UMIN000012604.

Attenuated peripheral endothelial function among women treated with aromatase inhibitors for breast cancer.

Data on long-term cardiovascular effects of aromatase inhibitors (AIs) are limited and conflicting. We sought to evaluate the effect of AIs on peripheral endothelial function in patients with breast cancer. This is an observational, prospective study of postmenopausal women with breast cancer who were enrolled at the initiation of cancer treatment. All participants underwent baseline and 6-12 months of follow-up, with peripheral endothelial function testing to measure reactive hyperemia index (RHI). The primary aim was to assess endothelial function deterioration between baseline and follow-up. The secondary aim was to assess the correlation of cardiovascular risk factors with RHI change in women treated with versus without AIs. Among 97 patients, mean (SD) age was 66 (7) years; 59 (61%) women had AI treatment, and 38 women did not (control group). There were no significant differences in baseline characteristics between the groups. Mean (SD) RHI at baseline in the treatment group did not differ significantly from that in the control group [2.2 (0.6) vs. 2.1 (0.5); P=0.15]. The mean (SD) time between baseline and follow-up studies was 262 (60) days. RHI deterioration, evaluated as a dichotomous variable with a 20% cutoff, was significantly more common in the AI group [17 (29%) vs. 4 (11%); P=0.04]. After adjusting for age, treatment with AIs was significantly associated with an RHI deterioration of at least 20% from baseline (odds ratio: 3.6; 95% confidence interval: 1.10-12.07; P=0.03). Further, in the intervention group, women with at least three traditional cardiovascular risk factors were more likely to have RHI deterioration compared to women with λ2 risk factors [10 (42%) vs. 7 (20%); P=0.04]. Amongst women with three or more cardiovascular risk factors, the percentage with RHI deterioration was higher in the AI group than the control group [10/24 (42%) vs. 3/22 (14%); P=0.04], whereas in women with up to two risk factors, the percentage with RHI deterioration was similar between the groups [7/35 (20%) vs. 1/16 (6%); P=0.21]. This study suggests that AIs may be associated with vascular injury. The effect is more pronounced among women with a higher baseline cardiovascular risk factor burden. These findings have potentially important implications, particularly among women at high risk for cardiovascular disease who are treated with AIs for hormone receptor-positive breast cancer.

Effects of bosentan on peripheral endothelial function in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

Endothelin receptor antagonists (ERAs) have been shown to improve the prognosis of patients with pulmonary arterial hypertension (PAH). However, the effect of the oral dual ERA bosentan on peripheral endothelial dysfunction (PED), as assessed by flow-mediated vasodilation (FMD), in patients with pulmonary hypertension is not well characterized. We investigated the effect of bosentan on PED in patients with PAH or inoperable chronic thromboembolic pulmonary hypertension (CTEPH). A total of 18 patients with PAH and 8 with CTEPH were treated with bosentan. All patients underwent FMD assessment before and after 3 months of bosentan treatment. Whereas FMD increased from 6.01% ± 2.42% at baseline to 8.07% ± 3.18% after 3 months (P < 0.0001) in patients with PAH, those with CTEPH showed no change in FMD after bosentan therapy. In addition, FMD at baseline showed no correlation with pulmonary vascular resistance (r = 0.09) or plasma brain natriuretic peptide levels (r = -0.23) in patients with PAH. Bosentan treatment ameliorated PED in patients with PAH but not in those with inoperable CTEPH. In addition, FMD did not correlate with PAH severity.

Effect of Moderate Aerobic Exercise Training on Endothelial Function and Arterial Stiffness in CKD Stages 3-4: A Randomized Controlled Trial

Evidence of a beneficial effect of exercise training on mediators of vascular disease is accumulating in chronic kidney disease (CKD), but its effect on vascular function in vivo still has to be established. The present study was designed to investigate whether a formal aerobic exercise training program improves peripheral endothelial function in patients with CKD stages 3 to 4. Randomized controlled trial with a parallel-group design. 48 patients with CKD stages 3 to 4 without established cardiovascular disease were randomly assigned to either an exercise training program or usual care. 40 patients completed the study (exercise training, 19; usual care, 21). The 3-month home-based aerobic training program consisted of 4 daily cycling sessions of 10 minutes each at a target heart rate, calculated as 90% of the heart rate achieved at the anaerobic threshold. Patients in the usual-care group were given standard therapy. The primary outcome was peripheral endothelial function. Secondary outcomes were aerobic capacity, arterial stiffness, numbers of endothelial (EPCs) and osteogenic progenitor cells (OPCs), migratory function of circulatory angiogenic cells, and health-related quality of life. Endothelial function was assessed with flow-mediated dilation of the brachial artery, aerobic capacity by peak oxygen uptake (VO(2peak)), arterial stiffness by carotid-femoral pulse wave velocity, numbers of EPCs and OPCs by flow cytometry, circulatory angiogenic cell function by an in vitro migratory assay, and quality of life by the Kidney Disease Quality of Life-Short Form questionnaire. Exercise training significantly improved VO(2peak) and quality of life, but not in vivo vascular function (flow-mediated dilation and carotid-femoral pulse wave velocity) or cellular markers for vascular function (EPC and OPC count and circulatory angiogenic cell migratory function). Short duration and intermittent nature of the exercise intervention. In patients with CKD stages 3 to 4 without overt cardiovascular disease, 3 months of aerobic exercise training improved VO(2peak) and quality of life, without altering endothelial function or arterial stiffness.

Ischemic postconditioning does not improve peripheral endothelial function in ST-segment elevation myocardial infarction patients.

The purpose of this study was to determine whether ischemic postconditioning (IPC) could improve peripheral endothelial function in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Of 102 patients randomly assigned to an IPC or standard protocol to study infarct size utilizing cardiovascular magnetic resonance imaging, 84 patients had peripheral endothelial function assessed with brachial ultrasound measures and peripheral arterial tonometry (PAT) during reactive hyperemia 3 days after PCI. Overall IPC was not associated with a smaller infarct size compared to controls, though there was a trend towards greater myocardial salvage with IPC. Patients randomized to IPC (n=43; age 56 ± 11 years; 85% male) and standard protocol (n=41; age 56 ± 10 years; 88% male) underwent endothelial function assessment. Flow mediated vasodilatation was not significantly greater in the IPC group than in the standard group (7.4 ± 4.9% versus 6.6 ± 4.0% respectively, p=0.40) nor was peak hyperemic velocity-time integral (78 ± 26 cm versus 71 ± 30 cm respectively, p=0.28). Similarly, the PAT hyperemic ratio was not significantly greater in the IPC group than in the standard group (2.0 ± 0.9 versus 1.8 ± 0.6 respectively, p=0.14). In conclusion, IPC did not improve early peripheral endothelial function in patients with STEMI undergoing primary PCI.

The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial

Endothelial dysfunction is important in the development of vascular complications in diabetes. Patients with type 2 diabetes have increased production of the vasoconstrictor and pro-inflammatory peptide, endothelin-1. Short-term intra-arterial administration of endothelin antagonists improves endothelium-dependent vasodilatation in patients with type 2 diabetes. We tested the hypothesis that oral administration of the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. This placebo-controlled and double-blind study was performed on 46 patients with type 2 diabetes and microalbuminuria (urine albumin/creatinine ratio >3 mg/mmol) at a medical university department. Patients were randomised to bosentan, 125 mg two times per day (n = 28), or placebo (n = 28) for 4 weeks. The computer-generated randomisation code was kept in sealed envelopes. Patients and people doing examinations or assessing outcomes were blinded. The primary endpoint was change in microvascular endothelium-dependent vasodilatation, based on change in digital reactive hyperaemia index. The secondary endpoint was change in brachial artery flow-mediated vasodilatation. Reactive hyperaemia index increased from 1.73 ± 0.43 (mean ± SD) at baseline to 2.08 ± 0.59 at follow-up (p < 0.05) in the bosentan group (n = 22), but did not change in the placebo group (1.84 ± 0.49 to 1.87 ± 0.47; n = 24). The change in reactive hyperaemia index from baseline was greater in the bosentan group than in the placebo group (p < 0.05). Nitroglycerine-induced digital hyperaemia was not affected. Brachial artery flow-mediated vasodilatation and blood pressure did not change during treatment. Oral treatment of 4 weeks duration with the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria.

Impact of Mind Body Therapies on Vascular Endothelial Dysfunction and Implications for Cardiovacular Disease Management

Mind body therapies appear to reduce morbidity and mortality in patients with cardiovascular diseases, but there is limited understanding of the mechanisms that mediate this effect. Vascular endothelial dysfunction is a central feature of atherogenesis that is adversely impacted by mental stress. We conducted a systematic review and meta-analysis of the effect of mind body therapies on peripheral endothelial function in patients with and without established cardiovascular disease. The search included Medline, Cochrane Library, Scopus and Embase to identify studies up to November 2009. Eligible studies were randomized controlled trials that compared the effects of mind body therapies and placebo on endothelial function. Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus. Three eligible trials enrolled a total of 258 patients. Sixty one (24 percent) were women and 53 percent had established cardiovascular disease. The trials had good methodological quality. Meta-analysis using random-effects model showed a non significant improvement of endothelial function by mind body therapies (standardized mean difference 0.15; 95% CI, -0.36 to 0.67, P=0.56). The analysis was underpowered due to small sample size. Circumstantial evidence indicates that mind body therapies may have a therapeutic benefit on endothelial dysfunction, however, the aggregate data from the three small randomized trials to date do not support this hypothesis. This biologically plausible effect requires additional investigation in adequately powered studies.

Repetitive bouts of mechanical compression improve systemic markers of endothelial function in patients with coronary artery disease

We hypothesized that repetitive mechanical compression (MC) of the lower limbs would lead to favorable changes in peripheral endothelial function in patients with coronary artery disease (CAD). To test this hypothesis, 35 1‐hour sessions of MC were administered to CAD patients (n=12). Each session consisted of sequential inflation and deflation of compressible cuffs wrapped around the calves and lower and upper thighs. Compressed air pressure (300mmHg) was applied in a sequence synchronized with the cardiac cycle. Eight (n=8) CAD patients served as sham controls (CON). Brachial (b) and femoral (f) artery flow‐mediated dilation (FMD) and plasma levels of nitric oxide metabolites (NOx) and asymmetric dimethylarginine (ADMA) were assessed pre and post intervention. The MC group demonstrated increases in b‐FMD (3.7 ± 0.2 vs. 5.7 ± 0.4 %, P &lt; 0.05) and f‐FMD (2.7 ± 0.2 vs. 3.5 ± 0.3%, P &lt; 0.05). Additionally, a 40% increase in NOx (22.8 ± 2.2 vs. 31.9 ± 4.5 [mu]mol/L, P &lt; 0.05) and a 26% decrease in ADMA (0.62 ± 0.06 vs. 0.46 ± 0.03 [mu]mol/L, P &lt; 0.05) were observed in the MC group. There were no significant changes in any outcome measures for the CON group. These results suggest that external mechanical compression of the lower limbs improves markers of peripheral endothelial function in CAD patients. This effect is likely attributed to increases in shear stress on the endothelium.Supported by NIH R01 HL‐077571‐01

AT1-receptor blockade with irbesartan improves peripheral but not coronary endothelial dysfunction in patients with stable coronary artery disease

Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis. Studies evaluating the effect of AT1-receptor blockers on endothelial dysfunction in patients with coronary artery disease (CAD) revealed mixed results. Studies addressing the effects of AT1-receptor blockers on the coronary and peripheral function in the same study population, are still lacking. We therefore aimed to test the effects of long-term therapy with the AT1-receptor blocker irbesartan (IRB) on both, the coronary and peripheral endothelial function in patients with CAD. Seventy-two patients with CAD were randomly assigned to double-blinded treatment for 6 months with IRB 300 mg per day or placebo, respectively. Coronary and peripheral endothelial function were measured by intracoronary infusion of acetylcholine (final intracoronary concentration 10 −7.3 to 10 −5.6 M) and by determining flow-dependent dilation (FMD) of the brachial artery, respectively. IRB significantly improved FMD, while no change of coronary endothelial function was observed. Interestingly, plasma levels of N G, N G-dimethyl-arginine, and the isoprostane excretion rate were not modified. IRB treatment improves peripheral but not coronary endothelial dysfunction in patients with CAD. Since reduced FMD of the brachial artery has been shown to be associated with a high-cardiovascular event rate, improvement of FMD by IRB may lead to better prognosis of patients with CAD.

Nifedipine improves coronary and peripheral endothelial function in patients with coronary artery disease: Are calcium channel blockers acquitted on the charges?

We have read with great enthusiasm the recently published article by Takase et al. [1]. This meticulously designed study helped us to refocus on calcium channel blockers in the prevention of endothelial dysfunction and atherosclerosis. Takase et al. revealed that acute administration of nifedipine improves not only coronary but also brachial artery vasodilator responses to acetylcholine by using invasive tests in patients with coronary artery disease (CAD). They concluded that nifedipine improves coronary and peripheral endothelial function in patients with CAD. Endothelial dysfunction is thought to play a pivotal role in the development, progression and clinical complications of atherosclerosis [2]. The vascular endothelium has emerged as an attractive treatment target, given accumulating data suggesting an important role of endothelial dysfunction for prognosis in vascular disease including coronary arterial tree. Although calcium channel blockers (CCBs) were developed as vasodilators, with the evolution of second and thirdgeneration CCBs, pleitropic effects have been noticed, and at least some of CCBs' benefit is attributable to these mechanisms [3]. CCBs have been shown to enhance the effects of nitric oxide and diminish those of endothelin-1 on vascular smooth muscle cell improving endothelial function. This phenomenon might be related to the antioxidant properties of some CCBs like amlodipine and nisoldipine [4]. Effect of Nifedipine and Cerivastatin on Coronary Endothelial Function in Patients with Coronary Artery Disease (ENCORE) study showed that combination of nifedipine and cerivastatin improved endothelial function [5].

Beneficial effects of nifedipine on vasodilator response to acetylcholine in coronary and brachial arteries in the patients with coronary artery disease

Background Nifedipine has been reported to improve endothelial function. However, there are few simultaneous studies on the effects of nifedipine on coronary and peripheral endothelial function in humans. Methods To investigate the effects of nifedipine on endothelial function in coronary artery (CA) and brachial artery (BA) in coronary artery disease (CAD), we measured vasodilator responses of CA and BA to acetylcholine (ACh, endothelium-dependent dilation) in 13 patients (63 ± 10 years old) with CAD before and after sublingual administration of nifedipine 10 mg. To measure blood flow, a Doppler guidewire was inserted into the major branch of CA and the left BA. ACh was infused at 10 − 7 mol/l for 3 min into CA and at 15.0 μg/ml for 5 min into BA, respectively. The vasodilator response to ACh was assessed by the ratio of ACh-induced flow / baseline flow (CAVR index, the ratio of CA flow changed by ACh; BAVR index, the ratio of BA flow changed by ACh). Results Nifedipine significantly increased both the CAVR and BAVR index : CAVR index, from 1.33 ± 0.54 to 1.76 ± 0.52 (32%) and BAVR index, from 1.74 ± 0.83 to 2.18 ± 0.93 (25%), respectively, p < 0.05. In addition, nifedipine-induced changes in CAVR tended to correlate with those of BAVR ( r = 0.42. p = 0.06). Conclusions Acute administration of nifedipine improves both coronary and brachial artery vasodilator responses to ACh. Nifedipine improves coronary and peripheral endothelial function in patients with CAD.

Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease

Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65 ± 8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and nonelevated uric acid levels (233 ± 10 μM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10 −7 to 10 −5 μM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051 ± 0.001 vs 0.019 ± 0.005 μU/mg protein; p < 0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh ( n = 13), oxypurinol markedly attenuated ACh-induced vasoconstriction (−23 ± 4 vs −15 ± 4% at ACh 10 −5 μM, p < 0.05) and significantly increased CBF (16 ± 17 vs 62 ± 18% at ACh 10 −5 μM, p < 0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8 ± 4.2 vs 5.2 ± 0.7%, p > 0.05) or CBF (135 ± 75 vs 154 ± 61%, p > 0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1 ± 1.5 before to 7.6 ± 1.5% after oxypurinol administration ( p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.

Early effects of statin therapy on endothelial function and microvascular reactivity in patients with coronary artery disease

Recent data suggest an early outcome benefit with reduction in cholesterol using statin therapy in patients with coronary artery disease (CAD). This may be caused by effects of low-density lipoprotein cholesterol (LDL-C) reduction on endothelial function and vascular reactivity in the coronary bed. The aim of this randomized placebo-controlled study was to examine the early effects of important reductions in LDL-C on myocardial perfusion and peripheral endothelial function. Seventy-two patients with CAD and LDL-C between 3.0 and 5.9 mmol/L (116-228 mg/dL) were randomized to receive simvastatin 20 mg daily, pravastatin 40 mg daily, or placebo for 8 weeks. At baseline, 2 weeks, and 8 weeks, patients underwent dynamic positron emission tomography perfusion imaging to quantify the retention of rubidium-82 as a measure of myocardial flow at rest and after dipyridamole stress. Patients also underwent brachial artery ultrasound to measure endothelium-dependent flow-mediated vasodilatation. At 2 and 8 weeks, the simvastatin and pravastatin groups showed a significant reduction (P < .001) in LDL-C compared with placebo. At 8 weeks, simvastatin led to an improvement in flow-mediated vasodilatation compared with placebo (6.86% +/- 4.4% vs 3.44% +/- 4.0%, P < .05), whereas pravastatin was not significantly different than placebo (5.62% +/- 4.1% vs 3.44% +/- 4.0%, P = NS). Despite this improvement in peripheral endothelial function with simvastatin, there were no significant differences observed in global stress flow and coronary flow reserve at 8 weeks with either drug. Short-term LDL reduction with simvastatin therapy improves peripheral endothelial function in patients with stable CAD, although an early effect on coronary vascular reactivity could not be demonstrated.

Impaired myocardial perfusion reserve but preserved peripheral endothelial function in patients with Fabry disease

Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder due to deficient alpha-galactosidase A activity, which leads to accumulation of glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. The effect of this accumulation on peripheral and cardiac vascular function is poorly known. We studied 15 Fabry patients (mean age 35 years and mean BMI 24.8 kg/m2) and 30 age- and BMI-matched healthy controls to examine whether myocardial perfusion reserve and peripheral artery endothelial function are altered. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and H2(15)O. Myocardial blood flow reserve was calculated as the ratio between the dipyridamole-induced maximal blood flow and resting blood flow. Peripheral artery endothelial function was assessed by measuring the brachial artery flow-mediated dilatation using ultrasound at rest and during reactive hyperaemia. The myocardial perfusion reserve was significantly lower in Fabry patients than in controls (3.3+/-1.2 vs 4.4+/-1.6, p=0.02), while the brachial artery flow-mediated dilatation was similar (5.9%+/-3.9% vs 4.5%+/-3.6%, p=0.27). Thus, inFabry disease, myocardial perfusion reserve is reduced while the peripheral artery endothelial function is preserved.

Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy

The aim of this study was to assess the relation between peripheral endothelial function and myocardial perfusion reserve in patients with mild heart failure due to idiopathic dilated cardiomyopathy (IDC). Myocardial perfusion and brachial artery flow mediated dilation (FMD) were measured in 20 clinically stable patients with IDC (New York Heart Association classes I to III, ejection fraction 35 ± 9%) and 13 apparently healthy subjects who were matched for age and lipid profile. Resting and hyperemic (dipyridamole; 0.56 mg/kg/min) perfusion were measured using oxygen-15-labeled water and positron emission tomography (PET). Perfusion reserve was calculated as the ratio of hyperemic to resting perfusion. FMD was assessed by measuring the change in brachial artery diameter in response to reactive hyperemia. Patients with IDC had lower hyperemic perfusion (1.73 ± 0.83 vs 3.01 ± 1.20 ml/min/g, p <0.001) and perfusion reserve (2.01 ± 0.91 vs 3.08 ± 1.35, p <0.01) compared with healthy subjects. Brachial artery FMD, however, was not different from that of the healthy subjects. Furthermore, neither hyperemic perfusion nor perfusion reserve was correlated with FMD in the patients with IDC, whereas the healthy subjects demonstrated a positive correlation between FMD and perfusion reserve (r = 0.57; p = 0.04). Thus, abnormal myocardial perfusion characterizes patients with IDC. Myocardial perfusion reserve and peripheral endothelial function do not parallel each other in patients with IDC.

Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease, ischemic, and dilated cardiomyopathy

Background Endothelial dysfunction has been described in patients with coronary artery disease (CAD) or chronic heart failure (CHF). Vitamin C administration leads to an improvement of endothelial function by reducing elevated levels of reactive oxygen species. It remains unclear, however, whether the degree of endothelial dysfunction caused by oxidative stress differs between CAD and CHF because of ischemic (ICM) or dilated cardiomyopathy (DCM). Methods In patients with CAD (n = 9; left ventricular ejection fraction [LVEF], 64% ± 3%), ICM (n = 9; LVEF, 25% ± 4%), DCM (n = 9; LVEF, 25% ± 3%), and healthy subjects (HS; n = 5; LVEF, 66% ± 5%) a change in internal radial artery diameter in response to acetylcholine (Ach; 15 and 30 μg/min) was measured with high-resolution ultrasound scanning during a co-infusion of normal saline or vitamin C (25 mg/min). Results Ach-mediated vasodilation was blunted in patients with CHF (DCM, 90 ± 20 μm; ICM, 86 ± 20 μm) and patients with CAD (336 ± 20 μm) as compared with HS (496 ± 43 μm; P <.05 vs patients with DCM, ICM, CAD). Vitamin C co-infusion increased Ach-mediated vasodilation by 180 ± 35 μm (to 270 ± 30 μm) in DCM ( P <.05 vs CAD, HS) and by 294 ± 40 μm (to 380 ± 20 μm) in ICM ( P <.05 vs DCM, CAD, HS). In patients with CAD, vitamin C increased Ach-mediated vasodilation by 146 ± 35 μm to normal values, whereas vascular diameter remained unchanged in HS (14 ± 20 μm; P = not significant). Conclusions Acute vitamin C administration restored peripheral endothelial function in patients with CAD to normal values, whereas endothelial function remained attenuated in CHF, in particular in patients with DCM. These results suggest that in patients with CHF, factors other than oxidative stress (eg, cytokines) contribute to the pathologic endothelial function.