Daniel Périat

Acetaminophen Increases Blood Pressure in Patients With Coronary Artery Disease

Background— Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. Methods and Results— The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. Conclusions— This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Angiotensin-Converting Enzyme Inhibition Improves Vascular Function in Rheumatoid Arthritis

Background— The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis. Methods and Results— Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85±1.49% to 4.00±1.81% (P=0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85±1.49% to 2.84±2.47%; P=0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78±7 to 74±6 mm Hg (P=0.03). Tumor necrosis factor-&agr; showed a significant inverse correlation with flow-mediated dilation (r=−0.408, P=0.02), and CD40 significantly decreased after ramipril therapy (P=0.049). Conclusions— Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.

Cardiovascular effects of flavanol-rich chocolate in patients with heart failure

AIMS Flavanol-rich chocolate (FRC) is beneficial for vascular and platelet function by increasing nitric oxide bioavailability and decreasing oxidative stress. Congestive heart failure (CHF) is characterized by impaired endothelial and increased platelet reactivity. As statins are ineffective in CHF, alternative therapies are a clinical need. We therefore investigated whether FRC might improve cardiovascular function in patients with CHF. METHODS AND RESULTS Twenty patients with CHF were enrolled in a double-blind, randomized placebo-controlled trial, comparing the effect of commercially available FRC with cocoa-liquor-free control chocolate (CC) on endothelial and platelet function in the short term (2 h after ingestion of a chocolate bar) and long term (4 weeks, two chocolate bars/day). Endothelial function was assessed non-invasively by flow-mediated vasodilatation of the brachial artery. Flow-mediated vasodilatation significantly improved from 4.98 ± 1.95 to 5.98 ± 2.32% (P = 0.045 and 0.02 for between-group changes) 2h after intake of FRC to 6.86 ± 1.76% after 4 weeks of daily intake (P = 0.03 and 0.004 for between groups). No effect on endothelial-independent vasodilatation was observed. Platelet adhesion significantly decreased from 3.9 ± 1.3 to 3.0 ± 1.3% (P = 0.03 and 0.05 for between groups) 2 h after FRC, an effect that was not sustained at 2 and 4 weeks. Cocoa-liquor-free CC had no effect, either on endothelial function or on platelet function. Blood pressure and heart rate did not change in either group. CONCLUSION Flavanol-rich chocolate acutely improves vascular function in patients with CHF. A sustained effect was seen after daily consumption over a 4-week period, even after 12 h abstinence. These beneficial effects were paralleled by an inhibition of platelet function in the presence of FRC only.

Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study

AIMS Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive. METHODS AND RESULTS Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 (P < 0.0001), while no change was observed with placebo (5.4 ± 2.4 to 4.7 ± 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F(2t)-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo. CONCLUSION This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.

Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia.

INTRODUCTION While elevated plasma HDL levels are inversely correlated with cardiovascular events, raising HDL with the CETP inhibitor torcetrapib, however, was associated with increased cardiovascular morbidity and mortality in the ILLUMINATE trial. Whether the deleterious clinical effects of torcetrapib represent a molecule specific off-target effect, a class effect of CETP inhibitors or both is matter of ongoing debate. As such, the aim of the present study was to investigate whether CETP-inhibition with JTT-705, a molecule distinctly different from torcetrapib, impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with type II hyperlipidemia. METHODS AND RESULTS Eighteen patients were randomized to receive JTT-705 600 mg/d or matching placebo for 4 weeks. Flow-mediated dilation (FMD) was measured using ultrasonography of the brachial artery. HDL-C increased by 26% from 1.14 mmol/l to 1.44 mmol/l (p=0.01) in the JTT-705 group, while triglycerides decreased from 2.52 mmol/l to 1.97 mmol/l (p=0.03). CETP- inhibition with JTT-705, however, did not change FMD (3.1+/-0.6% to 3.6+/-0.4%; p=0.48). Interestingly, in a sub group analysis of patients with lower than median HDL-C (<1.19 mmol/l), FMD increased by 41% in patients vs. patients with higher than median HDL-C (>1.19 mmol/l; p=0.01). Markers of vascular inflammation (CRP, ICAM-1, IL-6, TNF alpha), as well as plasma endothelin-1 levels all remained unchanged throughout the study. CONCLUSION In patients with type II hyperlipidemia, CETP inhibition with JTT-705 increased HDL-C and lowered triglycerides but improved endothelial function in the subgroup of patients with low baseline HDL-C levels only.

Progression of human carotid and femoral atherosclerosis: a prospective follow-up study by magnetic resonance vessel wall imaging

AIMS The time course of atherosclerosis burden in distinct vascular territories remains poorly understood. We longitudinally evaluated the natural history of atherosclerotic progression in two different arterial territories using high spatial resolution magnetic resonance imaging (HR-MRI), a powerful, safe, and non-invasive tool. METHODS AND RESULTS We prospectively studied a cohort of 30 patients (mean age 68.3, n = 9 females) with high Framingham general cardiovascular disease 10-year risk score (29.5%) and standard medical therapy with mild-to-moderate atherosclerosis intra-individually at the level of both carotid and femoral arteries. A total of 178 HR-MRI studies of carotid and femoral arteries performed at baseline and at 1- and 2-year follow-up were evaluated in consensus reading by two experienced readers for lumen area (LA), total vessel area (TVA), vessel wall area (VWA = TVA - LA), and normalized wall area index (NWI = VWA/TVA). At the carotid level, LA decreased (-3.19%/year, P = 0.018), VWA increased (+3.83%/year, P = 0.019), and TVA remained unchanged. At the femoral level, LA remained unchanged, VWA and TVA increased (+5.23%/year and +3.11%/year, both P < 0.01), and NWI increased for both carotid and femoral arteries (+2.28%/year, P = 0.01, and +1.8%/year, P = 0.033). CONCLUSION The atherosclerotic burden increased significantly in both carotid and femoral arteries. However, carotid plaque progression was associated with negative remodelling, whereas the increase in femoral plaque burden was compensated by positive remodelling. This finding could be related to anatomic and flow differences and/or to the distinct degree of obstruction in the two arterial territories.

Vascular Effects of Eplerenone in Coronary Artery Disease With Preserved Ejection Fraction: A Double-Blind, Randomized, Placebo-Controlled Trial

Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). Their role in patients without heart failure, particularly in patients with coronary artery disease (CAD) and preserved EF, is still a matter of debate.

Das Endocannabinoid-System

Das Endocannabinoidsystem ist ein physiologisches System, welches unter anderem fur die Kontrolle des Energiegleichgewichtes, den Glukose- und Lipidmetabolismus sowie fur die Regulation des Korpergewichtes verantwortlich ist. Die Endocannabinoid- Rezeptoren sind sowohl im zentralen Nervensystem als auch in der Peripherie verteilt. Durch verschiedene Studien wird belegt, dass ein hyperaktives Endocannabinoidsystem fur die Entwicklung verschiedener kardialer und metabolischer Risikofaktoren von Bedeutung ist. Die medikamentose Blockierung des Cannabinoid-1- Rezeptors kann einen neuen Ansatz zur Beeinflussung von kardiometabolischer Risikofaktoren darstellen.

Response to Letter Regarding Article, “Acetaminophen Increases Blood Pressure in Patients With Coronary Artery Disease”

We thank Dr Nguyen for his interest in our study and share his view that the findings may have major public health implications. As is usual for multiple end points, a Bonferroni correction was made at the end of the study. Bonferroni corrections for an interim analysis are important to decide whether to stop a study preliminarily, but are not necessarily useful for extending a study that is not dependent on statistical significance values alone but rather on trends and power analysis. We disagree with Dr Nguyens statement about P values, given that statistical significance was defined as P <0.05, and P values of 0.021 and 0.024 for systolic and diastolic blood pressure (BP), respectively, were observed.1 Of note, the crossover design allowed for exposing all 33 patients to acetaminophen, thus substantially …

Response to Letter Regarding Article, “Angiotensin-Converting Enzyme Inhibition Improves Vascular Function in Rheumatoid Arthritis”

We would like to thank Drs Popa and Netea for their interest in our study1 and their comments. It is a prerequisite of clinical studies investigating endothelial function that patients remain clinically stable throughout the course of the study to allow the assessment of the potential impact of the study drug. Clinically stable patients, however, present with low disease activity and demonstrate low markers of inflammation, thus explaining the relatively low …