[Show abstract][Hide abstract] ABSTRACT: Purpose: Atherosclerotic plaques progress in a highly individual manner. Plaque eccentricity has been associated with a rupture-prone phenotype and adverse coronary events in humans. Endothelial shear stress (ESS) critically determines plaque growth and low ESS leads to high-risk lesions. However, the factors responsible for rapid disease progression with increasing plaque eccentricity have not been studied. We investigated in vivo the effect of local hemodynamic and plaque characteristics on progressive luminal narrowing with increasing plaque eccentricity in humans.
Methods: Three-dimensional coronary artery reconstruction using angiographic and intravascular ultrasound data was performed in 374 patients at baseline (BL) and 6-10 months later (FU) to assess plaque natural history as part of the PREDICTION Trial. A total of 874 coronary arteries were divided into consecutive 3-mm segments. We identified 408 BL discrete luminal narrowings with a throat in the middle surrounded by gradual narrowing proximal and distal to the throat. Local BL ESS was assessed by computational fluid dynamics. The eccentricity index (EI) at BL and FU was computed as the ratio of max to min plaque thickness at the throat. Mixed-effects logistic regression was used to investigate the effect of BL variables on the combined endpoint of substantial worsening of luminal narrowing (decrease in lumen area >1.8 mm2 or >20%) with an increase in plaque EI.
Results: Lumen worsening with an increase in plaque EI was evident in 73 luminal narrowings (18%). Independent predictors of worsening lumen narrowing with plaque EI increase were low BL ESS (<1 Pa) distal to the throat (odds ratio [OR] =2.2 [95% CI: 1.3-3.7]; p=0.003) and large BL plaque burden (>51%) at the throat (OR=1.7 [95% CI: 1.0-2.8]; p=0.051). The incidence of worsening lumen narrowing with increasing plaque eccentricity was 30% in the presence of both predictors versus 15% in luminal narrowings without this combination of characteristics (OR=2.4 [95% CI: 1.4-4.3]; p=0.002).
Conclusions: Low local ESS independently predicts areas with rapidly progressive luminal narrowing and increasing plaque eccentricity. Coronary regions manifesting an abrupt anatomic change, i.e., at highest risk to cause an adverse event, can be identified early by assessment of ESS and plaque burden.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.
European Heart Journal 01/2012; 33(13):1589-97. DOI:10.1093/eurheartj/ehr482 · 15.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
European Heart Journal 12/2011; 33(17):2172-80. DOI:10.1093/eurheartj/ehr448 · 15.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
European Heart Journal 09/2011; 33(2):230-7. DOI:10.1093/eurheartj/ehr332 · 15.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.
[Show abstract][Hide abstract] ABSTRACT: Cardiac cachexia including fat loss is detrimental for advanced aged heart failure patients. Advanced heart failure is characterized by neurohormonal and oxidative stress imbalance. This study evaluated in old male spontaneously hypertensive rats (SHR), developing heart failure, the effects of long-term inhibition of NAD(P)H oxidase with Apocynin on subcutaneous white adipose tissue lipid metabolism and sympathetic turnover, expressed by interstitial norepinephrine release (NE) and presynaptic NE reuptake evaluation (through desipramine microdialysis probe perfusion). Blood pressure, heart rate and body weight were measured on 51 SHR from 72 weeks old until the development of overt heart failure. Thirteen age-matched Wistar-Kyoto rats (WKY) were normotensive controls. At 72 weeks, SHR underwent a basal microdialysis procedure which showed a higher interstitial subcutaneous glycerol level, expressing an increased local triglyceride breakdown and lipolysis, and higher NE level associated with a reduced presynaptic reuptake as compared to WKY. SHRs were then separated: 1) untreated SHR (n = 27) and 2) SHR (n = 24) treated with Apocynin (2.5 mg/kg/d in drinking water) until death or 88 weeks of age, when the rats repeated the microdialysis procedure.Thirty-three % of untreated SHR showed a body weight reduction of more than 15% (at 88 weeks of age) whereas in Apocynin-treated SHR only 4 (16%) developed cachexia. Glycerol interstitial levels were higher in cachectic than non-cachectic untreated SHR. Cachectic SHR showed higher NE level and a blunted response to desipramine, indicating a marked reduction of presynaptic reuptake. Non-cachectic apocynin-treated SHR showed a reduced interstitial level of glycerol and NE and improved presynaptic NE reuptake. These results suggest that chronic Apocynin treatment could improve subcutaneous NE reuptake and reduce interstitial NE concentrations and NE-induced lipolysis, as expressed by lower interstitial glycerol level. This drug seems to be able to attenuate cachexia development in this animal model of heart failure.
Journal of Hypertension 06/2010; 28. DOI:10.1097/01.hjh.0000378240.06072.2c · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Cyclosporine represents a milestone in immunosuppression following organ transplantation. Its use, however, comes at the cost of significant side effects, such as arterial hypertension which is rarely controllable by currently available anti-hypertensive drugs. The aim was to investigate the effect of acute administration of nitroglycerin in heart-transplanted patients with cyclosporine-induced hypertension. METHODS: The sample included 18 cyclosporine-induced hypertensive patients (HTX group) scheduled for elective cardiac catheterization following heart transplantation, as well as 6-matched essential hypertensive patients (HT group). The blood pressure (BP) in the aorta and pulmonary artery, before and after administration of nitroglycerin, was measured simultaneously. RESULTS: After injection of 50 microg and 100 microg nitroglycerin, BP significantly decreased both in HTX (systolic (s) BP p = 0.0001; diastolic (d) BP p = 0.0001) and in controls (sBP p = 0.006; dBP p = 0.05). This reduction was more pronounced in HTX (sBP p = 0.022; dBP p = 0.018 for group-comparison). Following analysis of the data in relation to its individual baseline, a significantly higher reduction of the BP induced by 100 microg nitroglycerin was observed in the HTX group compared to the HT group (p = 0.02 for sBP and p = 0.03 for dBP). 8 +/- 3 minutes after the last nitrate infusion, BP remained significantly reduced compared to baseline in HTX (p <0.001), whereas it came back to baseline in controls. The reduction in sBP was correlated to cyclosporine A levels (p = 0.04 after 50microg nitroglycerin; p = 0.05 after 100 microg nitroglycerin). CONCLUSION: After application of nitroglycerin, sBP is reduced immediately in HTX with uncontrolled cyclosporine-induced hypertension. Further studies are needed to evaluate the long-term effect of nitrates in these patients.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Thrombosis Research 10/2008; 123(3):460-5. DOI:10.1016/j.thromres.2008.06.022 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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-alpha 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).
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.
[Show abstract][Hide abstract] ABSTRACT: The endocannabinoid system is a physiological system, which is responsible for the control of glucose and lipid-metabolism, as well as for the regulation of the body weight. The endocannabinoid receptors are distributed both in the central and peripher nervous system. Different studies provide evidence that an hyperactive endocannabinoid system is involved in the development of different cardiovascular risk factors. The pharmacological blockade of these cannabinoid receptors may represent a new approach for cardiometabolic risk management.
[Show abstract][Hide abstract] ABSTRACT: Das Endocannabinoidsystem ist ein physiologisches System, welches unter anderem für die Kontrolle des Energiegleichgewichtes, den Glukose- und Lipidmetabolismus sowie für die Regulation des Körpergewichtes 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 für die Entwicklung verschiedener kardialer und metabolischer Risikofaktoren von Bedeutung ist. Die medikamentöse Blockierung des Cannabinoid-1- Rezeptors kann einen neuen Ansatz zur Beeinflussung von kardiometabolischer Risikofaktoren darstellen.
[Show abstract][Hide abstract] ABSTRACT: Bei Patienten mit arterieller Hypertonie liegt eine Endotheldysfunktion vor. Eine reduzierte Verfügbarkeit von gefäßerweiterndem
Stickstoffmonoxid (NO) sowie ein Überschuss an vasokonstriktiven Substanzen (z.B. Endothelin oder Angiotensin II) sind als
Ursache der gestörten endothelabhängigen Vasodilatation anzusehen. Das Vorhandensein einer Endotheldysfunktion korreliert
mit kardiovaskulären Ereignissen und hat auch prognostische Bedeutung. Die Reduktion des Blutdrucks per se ist nicht ausreichend,
um die Endothelfunktion zu verbessern. Die verschiedenen Substanzklassen der Antihypertensiva beeinflussen die Gefäßfunktion
in unterschiedlicher Art und Weise.
Essential hypertension is associated with reduced endothelium-dependent vasodilation, mainly due to reduced nitric oxide and
an increase in vasoconstrictors such as endothelin-1 and angiotensin II. Endothelial dysfunction has been shown to be associated
with an increased incidence of cardiovascular events and to have prognostic significance. The reduction of blood pressure
per se is insufficient for improving endothelial function, and antihypertensive drugs show contrasting effects in terms of
improvement or restoration of endothelial function.
Der Diabetologe 11/2007; 3(6):430-438. DOI:10.1007/s11428-007-0169-4 · 0.17 Impact Factor