Rémy Chenevard

Anti–Tumor Necrosis Factor-α Treatment Improves Endothelial Function in Patients With Rheumatoid Arthritis

Background— Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Striking similarities exist in the inflammatory and immunologic response in RA and atherosclerosis. Indeed, adhesion molecules and cytokines, tumor necrosis factor (TNF)-α in particular, are key mediators of joint inflammation and of vascular dysfunction and progression of atherosclerotic vascular disease. Hence, the aim of the present study was to assess the effect of chronic antiinflammatory treatment with the anti-TNF-α antibody infliximab on disease activity and endothelial function in patients with active RA. Methods and Results— Eleven RA patients (mean age 46±5 years; disease duration 9±2 years) with high disease activity despite treatment with stable doses of methotrexate (≤25 mg/wk) and prednisone (≤10 mg/d) were investigated. Clinical status and endothelium-dependent and -independent vasodilation of the brachial artery as assessed by high-resolution ultrasoun...

Selective COX-2 Inhibition Improves Endothelial Function in Coronary Artery Disease

Background—There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined. Methods and Results—Fourteen male patients (mean age, 66±3 years) with severe coronary artery disease (average of 2.6 vessels with stenosis >75%) undergoing stable background therapy with aspirin and statins were included. The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. After each treatment period, flow-mediated dilation of the brachial artery, high-sensitivity C-reactive protein, oxidized LDL, and prostaglandins were measured. Celecoxib significantly improved endothelium-dependent vasodilation compared with placebo (3.3±0.4% versus 2.0±0.5%, P =0.026), whereas endothelium-independent vasodilation, as assessed by nitroglycerin, remained unchanged (9.0±1.6% versus 9.5±1.3%, P =0.75). High-sensitivity C-reactive protein was significantly lower after celecoxib (1.3±0.4 mg/L) than after placebo (1.8±0.5 mg/L, P =0.019), as was oxidized LDL (43.6±2.4 versus 47.6±2.6 U/L, P =0.028), whereas prostaglandins did not change. Conclusions—This is the first study to demonstrate that selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease. Thus, selective COX-2 inhibition holds the potential to beneficially impact outcome in patients with cardiovascular disease.

Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia

Background: Reduced availability of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide (NO) synthase (NOS), decreases NO production and increases reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH4 improves endothelial dysfunction, the effect of chronic BH4 in humans is unknown. Objective: To investigate the effect of chronic BH4 supplementation on endothelial function and oxidative stress in hypercholesterolaemia. Design: Randomised double-blind, placebo-controlled trial. Setting: University Hospital. Patients: 22 hypercholesterolaemic patients (low-density lipoprotein (LDL) >4.5 mmol/l) were randomised to 4 weeks of oral BH4 (400 mg twice daily) or placebo. Age-matched healthy volunteers served as controls. Main outcome measures: Endothelium-dependent and -independent vasodilatation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH4 effect, NO release and superoxide anion (O2−) production were measured in human aortic endothelial cells exposed to native LDL (2.6 mmol cholesterol/l). Results: BH4 plasma levels were significantly increased by oral supplementation. NO-mediated vasodilatation to acetylcholine was reduced in patients compared with controls and restored by BH4. No effect of BH4 on endothelium-independent vasodilatation was seen. Furthermore, 8-F2 isoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH4. In LDL-treated endothelial cells, BH4 levels and NO release were reduced and O2− production increased compared with control cells. Exogenous BH4 normalised NO and O2− production. Conclusions: In hypercholesterolaemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH4. Thus, BH4 availability is essential for maintaining NO synthesis and low O2− production by endothelial NOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.

Dysfunctional Baroreflex Regulation of Sympathetic Nerve Activity in Patients With Vasovagal Syncope

Background—The interplay of resting muscle sympathetic nerve activity (MSA) and the baroreceptor reflex in patients with vasovagal syncope remains elusive. Hence, the aim of the present study was to investigate MSA, baroreceptor sensitivity, heart rate, and blood pressure under resting conditions and during orthostatic stress in patients with a history of vasovagal syncope. Methods and Results—MSA was measured using microneurography at rest and during lower body negative pressure (LBNP) to mimic orthostatic stress in patients with a history of vasovagal syncope (n=10) and in age-matched healthy controls (n=8). Heart rate and blood pressure were simultaneously recorded. Cardiac baroreceptor sensitivity was calculated with the spectral technique (&agr; coefficient). Resting MSA in the patients with syncope was significantly increased as compared with controls (42.4±2.3 versus 26.5±3.6 bursts/min, P =0.001), whereas activation of MSA during orthostatic stress in the patient group was significantly blunted (5.1±1.6 versus 15.2±2.1 bursts/min at LBNP −50 mm Hg, P =0.002). In the patients with syncope, cardiac baroreceptor sensitivity was significantly reduced under supine resting conditions (8.5±0.7 versus 13.0±1.1 ms/mm Hg, P =0.001), as well as under orthostatic stress (7.3±0.7 versus 13.4±1.5 ms/mm Hg, P =0.003). Conclusions—This study shows that in patients with vasovagal syncope, resting MSA is increased and baroreflex regulation during orthostatic stress is blunted, thus leading to impaired MSA adaptation. These results provide new insights into mechanisms of vasovagal syncope and suggest that pharmacological modulation of baroreceptor sensitivity may represent a promising treatment of neuromediated syncope.

Effects of statins on endothelial function and lipid profile in HIV infected persons receiving protease inhibitor-containing anti-retroviral combination therapy: a randomised double blind crossover trial

Introduction of anti-retroviral combination therapy has profoundly altered both the course and prognosis of the disease in HIV infected persons. Recent data, however, have raised concerns that anti-retroviral combination therapy is associated with premature manifestation of coronary artery disease.1 In particular, protease inhibitors have been linked to metabolic changes such as insulin resistance, abnormalities in lipid metabolism and lipodystrophy, and increased coronary artery calcification. While previous studies have reached conflicting conclusions about the incidence of myocardial infarction, the most substantial database recently provided by Friis-Moller and co-workers demonstrated an increased incidence in HIV infected persons receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitor-containing therapy.2 One of the postulated mechanisms of pro-atherogenic effects of protease inhibitors is the promotion of atherosclerotic lesion formation by an increase in CD36-dependent cholesteryl ester accumulation in macrophages. Additionally, hypercholesterolaemia promotes a CD36-dependent and endothelial nitric oxide synthase mediated endothelial dysfunction. Endothelial dysfunction is associated with future risk of adverse cardiovascular events.3 Impaired endothelial function was previously shown in HIV infected persons receiving protease inhibitor therapy.4 The effect of statins (hydroxy-methyl-glutaryl coenzyme A reductase inhibitors) in anti-retroviral combination therapy associated dyslipidaemia remains to be determined. As most statins are metabolised by the cytochrome P450 3A4 isoform, and thus interfere with the metabolism of many anti-retroviral drugs, resulting in increased toxicity, cytochrome P450 independent statins, such as pravastatin, may be advantageous. Hence, the present study aimed to evaluate the effects of pravastatin on endothelial function and plasma lipid profile in …

Selective COX-2 Inhibitors and Renal Injury in Salt-Sensitive Hypertension

In view of the ongoing controversy of cardiorenal safety of selective COX-2 inhibitors (coxibs), the present study was designed to examine the effects of 2 different coxibs, celecoxib and rofecoxib, compared with a traditional NSAID, diclofenac, and placebo on renal morphology and function in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl-enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib), or placebo was added to chow from weeks 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. Renal cortex mRNA was isolated for determination of COX-2, eNOS, and CRP mRNA by real-time reverse-transcriptase polymerase chain reaction. Untreated hypertensive animals showed glomerular injury including collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops, and an especially high grade of glomerulosclerosis (P<0.05 versus DR-placebo) and CD8-positive and ED1-positive cells (P<0.01 versus DR-placebo), which was improved by celecoxib but not by diclofenac and rofecoxib. C-reactive protein mRNA in renal cortex was increased in DS-placebo animals (P<0.05 versus DR-placebo) and normalized by celecoxib (P<0.05 versus DS-placebo), whereas eNOS mRNA was decreased in the DS-rofecoxib group (P<0.05 versus DR-placebo, DS-celecoxib, and DS-diclofenac). Proteinuria was observed in hypertensive animals (P<0.0001 versus DR-placebo), increased by rofecoxib (P<0.05 versus DS-placebo), and normalized by celecoxib (P=0.0015 versus DS-placebo). This head-to-head comparison of selective and nonselective COX inhibitors demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertension.

Reconstituted HDL in Acute Coronary Syndromes

OBJECTIVES The strong inverse relationship between plasma high-density lipoprotein (HDL)-cholesterol and atherosclerotic cardiovascular disease provides the epidemiological basis that HDL is atheroprotective. Since HDL enhances cholesterol efflux and exhibits potent antiinflammatory properties, the aim of the present study was to investigate whether infusion of reconstituted HDL (rHDL) impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with acute coronary syndromes (ACS). METHODS Twenty-nine patients with ACS were randomized to double-blind treatment with rHDL or albumin. Endothelium-dependent and independent vasodilatation to intraarterial acetylcholine and sodium nitroprusside were measured by forearm venous occlusion plethysmography. In addition, oxidized LDL and high-sensitivity C-reactive protein were determined as markers of oxidative stress and vascular inflammation. RESULTS rHDL infusion increased plasma HDL (P < 0.0001) and decreased LDL (P < 0.0001). Oxidized LDL (P= 0.11), high-sensitivity C-reactive protein (P= 0.12) and the response to endothelium-dependent and -independent vasodilatators remained unchanged after rHDL compared to albumin infusion (14.9 ± 9.2 versus 14.5 ± 12.4, P= 0.93 and 12.8 ± 7.1 versus 13.2 ± 9.6, P= 0.27, respectively). CONCLUSIONS An increase of HDL and a reduction of LDL notwithstanding, human rHDL did not improve vascular function in patients with ACS thus further challenging the clinical benefit of interventions, which rapidly raise HDL in ACS, particularly with the infusion of reconstituted HDL.

Persistent endothelial dysfunction in calcified aortic stenosis beyond valve replacement surgery

The leading cause of aortic valve morbidity in industrialised nations is degenerative calcified aortic stenosis. A convincing body of evidence suggests the concept that degenerative aortic stenosis represents a form of atherosclerotic vascular disease.1 Endothelial dysfunction promoting abnormal vasomotion, increased leucocyte adhesion, platelet dysfunction and vascular inflammation, which have been shown extensively in atherosclerosis, was recently found in degenerative aortic valve disease.2 Decreased nitric oxide (NO) bioavailability has a pivotal role in this process, and is largely determined by the expression of endothelial nitric oxide synthase (eNOS). Interestingly, eNOS expression is markedly influenced by haemodynamic factors, as shear stress is the main physiological trigger to enhance eNOS expression and activity.3 In the study by Poggianti et al,2 the effects of haemodynamic parameters have not been discussed as only patients with aortic valve sclerosis but without relevant haemodynamic stenosis were studied. We hypothesised that altered haemodynamics in aortic stenosis may at least partly be responsible for endothelial dysfunction and thus potentially normalise after aortic-valve replacement. Increased low-grade systemic inflammation has also been shown in aortic stenosis4 and consequently would be expected to influence vascular function similar to that described in coronary artery disease. Thus, we investigated endothelial dysfunction and signs of inflammation in haemodynamically relevant degenerative aortic stenosis before and after valve replacement. Patients …

Folic Acid improves baroreceptor sensitivity in hypertension.

In hypertension baroreceptor-mediated modulation of heart rate is impaired, resulting in a decreased vagal control. Reactive oxygen species produced locally in the vasculature decrease baroreceptor sensitivity. Folic acid has antioxidant properties. Therefore, the aim of this study was to test whether folic acid improves baroreceptor function in hypertension. Twenty-one male patients with hypertension not taking any drugs for 2 weeks participated in the study and were randomized to folic acid 5 mg or matching placebo. Cardiac and vascular sympathetic baroreceptor functions were tested before and after a single dose of folic acid or placebo with two different methods: the α-coefficient method and the phenylephrine (PE) and sodium nitroprusside (SNP) bolus method. In the folic acid group both methods showed significantly improved cardiac and vascular sympathetic baroreceptor sensitivity compared with placebo. This study provides evidence that folic acid improves cardiac and vascular sympathetic baroreceptor sensitivity in hypertensive patients, which suggests an improved vagal control and an enhanced baroreceptor modulation of sympathetic vasomotor tone. Thus, folic acid may represent a novel treatment for prevention of orthostatic dysregulation and/or arrhythmic complications resulting from baroreceptor dysfunction.

Anxiolytic therapy with alprazolam increases muscle sympathetic activity in patients with panic disorders

Anxiolytic therapy with the benzodiazepine alprazolam is an established therapy in patients with panic disorder. Normally, panic-like anxiety and its concomitant physical symptoms quickly disappear under such treatment. Therefore we investigated whether there is a difference in sympathetic nervous system in patients with panic disorder compared to healthy controls. Three groups of subjects were included: ten patients with panic disorder, who received alprazolam and 20 healthy control subjects who were given either alprazolam (n=10) or matching placebo (n=10). Muscle sympathetic nerve activity (MSNA) and heart rate did not differ at baseline but significantly increased both in patients and healthy controls after intake of alprazolam (1 mg). However, in both groups both MSNA and heart rate were significantly elevated when compared to both baseline and the placebo control group. This study demonstrates (1) that anxiolytic therapy with alprazolam increases muscle sympathetic nerve activity and heart rate not only in patients with panic disorder but also in healthy controls and (2) that a significant difference in sympathetic nervous system activity between patients and controls, at baseline and during the therapy with alprazolam could not be demonstrated.