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.

Effects of the heart-lung machine on melatonin metabolism and mood disturbances.

OBJECTIVE: Cardiothoracic surgery using the heart-lung machine (HLM) provokes a pronounced endocrine-metabolic response leading to circadian rhythm disturbances that affect postoperative morbidity. Focus has been laid on changes in melatonin metabolism. The effects of an extra-corporal artificial circulation have not been adequately addressed. METHODS: Seventeen patients scheduled for open heart surgery using the HLM were compared with 15 patients undergoing major surgery without cardiopulmonary bypass (non-HLM). Late afternoon and night urinary 6-sulfatoxymelatonin were measured at baseline, immediately after the operation and on return to the normal ward. Mood disturbances were assessed at baseline and final sampling times using a standardized questionnaire (arbitrary units). RESULTS: Vital signs were comparable between groups. The difference (delta) between day and night melatonin levels was similar at baseline (HLM group 1.1 ng/ml, non-HLM group 1.4 ng/ml, p=0.25). Immediately following surgery melatonin day-night deltas were unchanged to baseline (HLM 1.0 ng/ml, p=0.67; non-HLM 0.8 ng/ml, p=0.46) but at final sampling normal circadian melatonin profile was abolished (-0.3 ng/ml, p=0.001 and 0.0 ng/ml, p=0.07). However, this effect was not different between the two studied groups (p=0.17). No mood disorders were detectable at baseline (HLM 8.0 vs non-HLM 7.0, p=0.97) and no changes occurred after surgery (7.0 vs 6.5, p=0.33). Overall, patients with a worsening psychological score had pronounced postoperative washout of afternoon-night melatonin delta (p=0.04). CONCLUSIONS: We found no relevant influence of the HLM on perioperative circadian melatonin profiles. Additionally, no alterations in mood assessment before and after surgery were observed. However, worsening of psychological score was associated with a pronounced disruption of the normal circadian melatonin profile.

Effect of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension.

OBJECTIVE: It has been shown that angiotensin-converting enzyme inhibition or angiotensin receptor blockade may improve endothelial dysfunction, an early manifestation of atherosclerosis, in patients with diabetes. Whether this protective effect is mediated through blood pressure-lowering effects or other specific mechanisms such as a reduction in oxidative stress is not clear. We investigated the influence of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension. METHODS: Thirteen patients were included in this randomized, double-blind, crossover study; they received losartan 50 mg twice daily for 4 weeks followed by atenolol 50 mg twice daily or vice versa. Concomitant medication with renin-angiotensin blocking agents or beta-blockers was withdrawn, whereas other medication remained unchanged. At baseline and after each treatment period, flow-mediated dilation of the brachial artery and oxidative stress were measured in serum samples. RESULTS: Flow-mediated dilation was increased significantly after 4 weeks' treatment with losartan (3.4 +/- 0.44%) compared with atenolol (2.58 +/- 0.42%; P = 0.01). 8-Isoprostanes, a marker of oxidative stress, were significantly reduced in the losartan group compared with baseline (0.039 +/- 0.007 versus 0.067 +/- 0.006 ng/ml; P = 0.01), but did not differ from baseline with atenolol. Glucose, hemoglobin A1c, highly sensitive C-reactive protein, lipids and systolic blood pressure remained unaltered, whereas diastolic blood pressure tended to be lower in the atenolol group. CONCLUSIONS: This study demonstrates that losartan significantly improved endothelial function in type 2 diabetes patients with hypertension compared with atenolol. This must be independent of the blood pressure-lowering effect of losartan and is probably caused by an antioxidative effect of the angiotensin receptor blocker.

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.

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.

Effect of losartan on muscle sympathetic activity and baroreceptor function in systemic hypertension.

Angiotensin II directly stimulates muscle sympathetic nerve activity and facilitates adrenergic sympathetic transmission. The hypotheses that the chronic blockade of angiotensin II receptors (AT(1) type) reduces muscle sympathetic activity and that there is an interaction with baroreceptor function in patients with mild to moderate hypertension were investigated. Muscle sympathetic nerve activity decreased from 51.7 +/- 3.5 to 45.9 +/- 4.2 bursts/min (p = 0.022), and cardiac baroreceptor sensitivity increased from 3.2 +/- 1.3 to 4.9 +/- 1.8 ms/mm Hg (p = 0.007). This study for the first time demonstrates that in hypertensive patients, chronic AT(1) receptor antagonism inhibits muscle sympathetic nerve activity and that baroreceptor function is improved under these conditions.

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 alpha-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.

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 (alpha 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.

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.

Anti-tumor necrosis factor-alpha 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)-alpha 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-alpha 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 (