Matthias Hermann

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.

Dark Chocolate Improves Coronary Vasomotion and Reduces Platelet Reactivity

Background— Dark chocolate has potent antioxidant properties. Coronary atherosclerosis is promoted by impaired endothelial function and increased platelet activation. Traditional risk factors, high oxidative stress, and reduced antioxidant defenses play a crucial role in the pathogenesis of atherosclerosis, particularly in transplanted hearts. Thus, flavonoid-rich dark chocolate holds the potential to have a beneficial impact on graft atherosclerosis. Methods and Results— We assessed the effect of flavonoid-rich dark chocolate compared with cocoa-free control chocolate on coronary vascular and platelet function in 22 heart transplant recipients in a double-blind, randomized study. Coronary vasomotion was assessed with quantitative coronary angiography and cold pressor testing before and 2 hours after ingestion of 40 g of dark (70% cocoa) chocolate or control chocolate, respectively. Two hours after ingestion of flavonoid-rich dark chocolate, coronary artery diameter was increased significantly (from 2.36±0.51 to 2.51±0.59 mm, P<0.01), whereas it remained unchanged after control chocolate. Endothelium-dependent coronary vasomotion improved significantly after dark chocolate (4.5±11.4% versus −4.3±11.7% in the placebo group, P=0.01). Platelet adhesion decreased from 4.9±1.1% to 3.8±0.8% (P=0.04) in the dark chocolate group but remained unchanged in the control group. Conclusions— Dark chocolate induces coronary vasodilation, improves coronary vascular function, and decreases platelet adhesion 2 hours after consumption. These immediate beneficial effects were paralleled by a significant reduction of serum oxidative stress and were positively correlated with changes in serum epicatechin concentration.

Dark chocolate improves endothelial and platelet function

The effects of chocolate on cardiovascular health are still a matter of debate. Chocolate may adversely affect cardiovascular risk because of its effects on glucose, lipids, and body weight or potentially favour cardiovascular health through antioxidative effects of chocolate ingredients, such as flavonoids (present in dark but not white chocolate). Endothelial dysfunction and platelet activation are cornerstones in the pathogenesis of atherothrombosis, leading to vasoconstriction, thrombus formation, and inflammation. Smoking is a major cardiovascular risk factor. The mechanisms promoting atherothrombosis in smokers primarily include increased oxidative stress that enhances proatherogenic processes such as low density lipoprotein oxidation and inactivation of endothelium derived nitric oxide. Platelets contribute both to acute coronary syndromes and to the progression of atherothrombosis. Both active and passive cigarette smoking has consistently been shown to induce endothelial dysfunction. Therefore, smokers serve as an ideal model to study the beneficial vascular effects of antioxidant strategies such as dark chocolate.1 The goal of the present study was to investigate whether the beneficial antioxidant effect of polyphenol-rich dark chocolate can induce an improvement of endothelial and platelet function in healthy volunteers with known endothelial dysfunction and platelet hyperreactivity. Twenty five male smokers were enrolled in the study after giving written informed consent. Women were excluded for known sex hormone induced differences in vascular tone and reactivity. All study participants did not take any medication, including vitamins or dietary supplements. The local institutional ethical review board approved the protocol. To assess the effect of dark …

Nitric oxide in hypertension

Hypertension is a major risk factor for cardiovascular disease, and reduction of elevated blood pressure significantly reduces the risk of cardiovascular events. Endothelial dysfunction, which is characterized by impairment of nitric oxide (NO) bioavailability, is an important risk factor for both hypertension and cardiovascular disease and may represent a major link between the conditions. Evidence suggests that NO plays a major role in regulating blood pressure and that impaired NO bioactivity is an important component of hypertension. Mice with disruption of the gene for endothelial NO synthase have elevated blood pressure levels compared with control animals, suggesting a genetic component to the link between impaired NO bioactivity and hypertension. Clinical studies have shown that patients with hypertension have a blunted arterial vasodilatory response to infusion of endothelium‐dependent vasodilators and that inhibition of NO raises blood pressure. Impaired NO bioactivity is also implicated in arterial stiffness, a major mechanism of systolic hypertension. Clarification of the mechanisms of impaired NO bioactivity in hypertension could have important implications for the treatment of hypertension.

Differential Effects of Selective Cyclooxygenase-2 Inhibitors on Endothelial Function in Salt-Induced Hypertension

Background—In view of the ongoing controversy about potential differences in cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors (coxibs), we compared the effects of 2 different coxibs and a traditional NSAID on endothelial dysfunction, a well-established surrogate of cardiovascular disease, in salt-induced hypertension. Methods and Results—Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed a high-sodium diet (4% NaCl) for 56 days. From days 35 to 56, diclofenac (6 mg · kg−1 · d−1; DS-diclofenac), rofecoxib (2 mg · kg−1 · d−1; DS-rofecoxib), celecoxib (25 mg · kg−1 · d−1; DS-celecoxib) or placebo (DS-placebo) was added to the chow. Blood pressure increased with sodium diet in the DS groups, which was more pronounced after diclofenac and rofecoxib treatment (P <0.005 versus DS-placebo) but was slightly decreased by celecoxib (P <0.001 versus DS-placebo). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (10−10-10−5 mol/L) in aortic rings of untreated hypertensive rats (P <0.005 versus DR-placebo). Relaxation to acetylcholine improved after celecoxib (P <0.005 versus DS-placebo and DS-rofecoxib) but remained unchanged after rofecoxib and diclofenac treatment. Vasoconstriction after nitric oxide synthase inhibition, indicating basal NO release, with N&ohgr;-nitro-l-arginine methyl ester (10−4 mol/L) was blunted in DS rats (P <0.05 versus DR-placebo), normalized by celecoxib, but not affected by rofecoxib or diclofenac. Indicators of oxidative stress, 8-isoprostane levels, were elevated in untreated DS rats on 4% NaCl (6.55±0.58 versus 3.65±1.05 ng/mL, P <0.05) and normalized by celecoxib only (4.29±0.58 ng/mL). Conclusions—These data show that celecoxib but not rofecoxib or diclofenac improves endothelial dysfunction and reduces oxidative stress, thus pointing to differential effects of coxibs in salt-induced hypertension.

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.

Celecoxib Decreases Endothelial Tissue Factor Expression Through Inhibition of c-Jun Terminal NH2 Kinase Phosphorylation

Background—Despite potential antiinflammatory properties, the use of selective cyclooxygenase-2 inhibitors (coxibs) in patients with cardiovascular diseases has been questioned because of a possibly increased thrombotic risk. Tissue factor (TF), a key protein for initiation of coagulation, has been implicated in the pathogenesis of atherosclerosis and thrombosis. Hence, we examined the effect of different coxibs on TF expression. Methods and Results—Celecoxib (10−5 mol/L), but not rofecoxib (10−7 to 10−5 mol/L) or the experimental coxib NS-398 (10−7 to 10−5 mol/L), decreased tumor necrosis factor-α–induced TF expression and activity in human aortic endothelial cells. Celecoxib (10−5 mol/L) reduced activation of c-jun terminal NH2 kinase (JNK), whereas it did not affect p38 mitogen-activated protein (MAP) kinase or p44/42 MAP kinase; in contrast, JNK activation was not affected by rofecoxib (10−5 mol/L) or NS-398 (10−5 mol/L). TF expression was reduced in a concentration-dependent manner by pretreatment with SP600125 (10−7 to 10−6 mol/L), a specific inhibitor of JNK, which confirms that JNK regulates tumor necrosis factor-α–induced TF expression. Conclusions—Celecoxib reduced TF expression and activity in human aortic endothelial cells. Because neither rofecoxib nor the experimental coxib NS-398 affected TF expression, this effect occurs independently of COX-2 inhibition; it is rather mediated through inhibition of JNK phosphorylation. These data indicate a distinct heterogeneity within this class of drugs, which may be clinically relevant, especially for patients with atherosclerotic vascular diseases.

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.

Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice.

The endothelium controls blood flow and pressure by releasing several vasoactive factors, among them the vasodilator nitric oxide (NO) and the potent vasoconstrictor endothelin‐1 (ET‐1). Although increased NO levels have been found in excessive erythrocytosis, little is known concerning ET‐1 expression in this condition. Thus, we examined the endothelin system in transgenic mice that due to constitutive overexpression of erythropoietin (Epo) reached hematocrit levels of ~80%. Surprisingly, despite generalized vasodilatation, polycythemic mice exhibited a two‐ to fivefold elevation in ET‐1 mRNA levels in aorta, liver, heart, and kidney. In line with this, increased expression of ET‐1 protein was detected in the pulmonary artery by immunohistochemical analysis. Compared with their wild‐type littermates, aortic rings of Epo transgenic animals exhibited a marked reduction in vascular reactivity to ET‐1 and big ET‐1, but this effect was abrogated upon preincubation with the NO synthase inhibitor N‐nitro‐l‐arginine methyl ester (L‐NAME). Pretreatment of polycythemic mice with the ETA receptor antagonist darusentan for 3 wk significantly prolonged their survival upon acute exposure to L‐NAME. Taken together, these results demonstrate for the first time that excessive erythrocytosis induces a marked activation of the tissue endothelin system that results in increased mortality upon blockade of NO‐mediated vasodilatation. Because ETA antagonism prolonged survival after acute blockade of NO synthesis, endothelin may be regarded as a contributor to the adverse cardiovascular effects of erythrocytosis and may thus represent a new target in the treatment of cardiovascular disease associated with erythrocytosis.

Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis--an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks.

BackgroundThere are several guidelines addressing the issues around the use of NSAIDs. However, none has specifically addressed the upper versus lower gastrointestinal (GI) risk of COX-2 selective and non-selective compounds nor the interaction at both the GI and cardiovascular (CV) level of either class of drugs with low-dose aspirin. This Consensus paper aims to develop statements and guidance devoted to these specific issues through a review of current evidence by a multidisciplinary group of experts.MethodsA modified Delphi consensus process was adopted to determine the level of agreement with each statement and to determine the level of agreement with the strength of evidence to be assigned to the statement.ResultsFor patients with both low GI and CV risks, any non-selective NSAID (ns-NSAID) alone may be acceptable. For those with low GI and high CV risk, naproxen may be preferred because of its potential lower CV risk compared with other ns-NSAIDs or COX-2 selective inhibitors, but celecoxib at the lowest approved dose (200 mg once daily) may be acceptable. In patients with high GI risk, if CV risk is low, a COX-2 selective inhibitor alone or ns-NSAID with a proton pump inhibitor appears to offer similar protection from upper GI events. However, only celecoxib will reduce mucosal harm throughout the entire GI tract. When both GI and CV risks are high, the optimal strategy is to avoid NSAID therapy, if at all possible.ConclusionsTime is now ripe for offering patients with osteoarthritis the safest and most cost-effective therapeutic option, thus preventing serious adverse events which could have important quality of life and resource use implications.Please see related article: http://dx.doi.org/10.1186/s12916-015-0291-x.