[Show abstract][Hide abstract]ABSTRACT: Coronary artery disease continues to be the leading cause of death in developed countries. As coronary atherosclerosis worsens, luminal narrowing caused by coronary plaque mass may result in haemodynamic
obstruction and subsequently, angina pectoris symptoms may occur. To avoid redundant invasive procedures
and minimize its complications, noninvasive Imaging is often performed for an initial assessment of patients with suspected coronary artery disease, serving as a gatekeeper for invasive coronary angiography. The diagnostic accuracy and prognostic value of These strategies have been confirmed in many single-Center or multi-center trials. In 2013 the updated ESC Guidelines on the management on stable coronary artery disease were released, highlighting the aspect that the diagnostic algorithm is based on the pre-test-probability of coronary artery disease. The consideration of new imaging modalities such as cardiovascular magnetic resonance imaging and coronary CT angiography however, makes it harder for the referring physician to
choose the right imaging modality for a patient. This article reviews the clinical utility and the limitations of the most widely used noninvasive imaging modalities and summarizes the diagnostic work-up according to
the current ESC guidelines.
[Show abstract][Hide abstract]ABSTRACT: Objectives
The aim of the study was to examine frequency, size, and localization of peri-device leaks after percutaneous left atrial appendage (LAA)-closure with the AMPLATZER-Cardiac-Plug (ACP) by using a multimodal imaging approach, i.e. combined cardiac-CT and TEE follow-up. Background
Catheter-based LAA-occlusion using ACP aims to reduce the risk of stroke in patients with atrial fibrillation. Detection of peri-device leaks after ACP implantation by TEE is challenging, the few available data are inconsistent and the frequency of LAA leaks after ACP implantation remains therefore unclear. Methods
Cardiac-CT using a multi-phase protocol and a second-generation dual-source-CT-system was performed in 24 patients with non-valvular atrial fibrillation starting 3 months after LAA-closure by ACP. Color Doppler multiplane TEE was used to evaluate peri-device flow. ResultsCardiac-CT follow-up detected any persistent LAA contrast filling in 62% of patients (n=15), but leak-sizes were small (1.51.4 mm). Peri-device leaks were almost exclusively localized at the posterior portion of the LAA-orifice (>90%). TEE follow-up revealed peri-device flow in 36% of patients (jet-sizes:4 mm). ACP-lobe compression (>10%) and perpendicular ACP-lobe orientation to the LAA-neck axis, that was also dependent on LAA anatomy, were substantially more frequent in patients with complete LAA closure. Conclusion
The present study evaluates for the first time peri-device flow after LAA closure by ACP using a combined cardiac-CT and TEE follow-up. Persistent LAA-perfusion was frequently detected, leak-sizes were small and were less frequent when lobe compression was >10% and lobe orientation was perpendicular to the LAA-neck axis, that was also related to the LAA anatomy. The clinical significance of these small leaks after LAA-closure using ACP needs to be further evaluated in future studies. (c) 2014 Wiley Periodicals, Inc.
No preview · Article · Feb 2015 · Catheterization and Cardiovascular Interventions
[Show abstract][Hide abstract]ABSTRACT: Background: Endothelial injury is thought to promote progression of atherosclerotic vascular disease. Early outgrowth cells (EOCs) are known to support endothelial repair and microRNAs are important regulators of vascular cells by modulating their gene expression at the post-transcriptional level. We therefore hypothesized that differential expression of microRNAs in EOCs may impact on their capacity to promote endothelial repair. Here we evaluate the role of the endothelial microRNAs miR-126 and miR-130a that are dysregulated in EOCs from patients with coronary artery disease for the in vivo endothelial repair response of EOCs.
Methods and results: Carotid injury was performed in a nude mouse model for the assessment of in vivo endothelial repair capacity of anti-miR-126/anti-miR-130a transfected EOCs from healthy subjects (HS) as compared to scrambled-miR transfected EOCs. Combined inhibition of miR-126 and miR-130a markedly impaired the endothelial repair response mediated by EOCs. By using single anti-miR transfections, only anti-miR-130a transfected EOCs showed a significantly reduced EOC-mediated endothelial repair response. Consistently, anti-miR-130a transfection of EOCs from HS impaired endothelial cell (EC) –migration as compared to scrambled-miR transfected EOCs in an in vitro wound scratch assay. Adhesion and apoptosis of anti-miR-130a transfected EOCs were not altered as compared to scrambled-miR transfected EOCs. However, concentrated supernatant of anti-miR-130a transfected EOCs demonstrated an impaired stimulation of EC migration in vitro. Moreover miR-130a was released into the supernatant of cultured EOCs.
Conclusion: The present study suggests a novel role of miR-130a as an important regulator of the endothelial repair response after vascular injury mediated by EOCs, likely by regulating their paracrine functions.
Full-text · Article · Aug 2013 · European Heart Journal
[Show abstract][Hide abstract]ABSTRACT: Background
The heart is subject to structural and functional changes with advancing age. However, the magnitude of cardiac age-dependent transformation has not been conclusively elucidated.
This retrospective cardiac magnetic resonance (CMR) study included 183 subjects with normal structural and functional ventricular values. End systolic volume (ESV), end diastolic volume (EDV), and ejection fraction (EF) were obtained from the left and the right ventricle in breath-hold cine CMR. Patients were classified into four age groups (20–29, 30–49, 50–69, and ≥70 years) and cardiac measurements were compared using Pearson’s rank correlation over the four different groups.
With advanced age a slight but significant decrease in ESV (r=−0.41 for both ventricles, P<0.001) and EDV (r=−0.39 for left ventricle, r=−0.35 for right ventricle, P<0.001) were observed associated with a significant increase in left (r=0.28, P<0.001) and right (r=0.27, P<0.01) ventricular EF reaching a maximal increase in EF of +8.4% (P<0.001) for the left and +6.1% (P<0.01) for the right ventricle in the oldest compared to the youngest patient group. Left ventricular myocardial mass significantly decreased over the four different age groups (P<0.05).
The aging process is associated with significant changes in left and right ventricular EF, ESV and EDV in subjects with no cardiac functional and structural abnormalities. These findings underline the importance of using age adapted values as standard of reference when evaluating CMR studies.
Full-text · Article · Feb 2013 · BMC Medical Imaging
[Show abstract][Hide abstract]ABSTRACT: Background:
MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34(+) cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34(+) cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity.
Methods and results:
Angiogenic EOCs and CD34(+) cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34(+) cells. Anti-miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function.
The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34(+) cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection.
[Show abstract][Hide abstract]ABSTRACT: Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1- and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.
Full-text · Article · Jun 2011 · The Journal of clinical investigation
[Show abstract][Hide abstract]ABSTRACT: The aim of this study was to investigate whether nebivolol has added effects on left ventricular (LV) dysfunction and remodeling early after myocardial infarction (MI) beyond its β₁-receptor-blocking properties.
Nebivolol is a third-generation selective β₁-adrenoreceptor antagonist that stimulates endothelial cell nitric oxide (NO) production and prevents vascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Both endothelial NO synthase-derived NO production and NADPH oxidase activation are critical modulators of LV dysfunction early after MI.
Mice with extensive anterior MI (n = 90) were randomized to treatment with nebivolol (10 mg/kg/day), metoprolol-succinate (20 mg/kg/day), or placebo for 30 days starting on day 1 after surgery.
Infarct size was similar among the groups. Both β₁-adrenergic receptor antagonists caused a similar decrease in heart rate. Nebivolol therapy improved endothelium-dependent vasorelaxation and increased early endothelial progenitor cells 4 weeks after MI compared with metoprolol and placebo. Nebivolol, but not metoprolol, inhibited cardiac NADPH oxidase activation after MI, as detected by electron spin resonance spectroscopy analysis. Importantly, nebivolol, but not metoprolol, improved LV dysfunction 4 weeks after MI (LV ejection fraction: nebivolol vs. metoprolol vs. placebo: 32 ± 4% vs. 17 ± 6% vs. 19 ± 4%; nebivolol vs. metoprolol: p < 0.05) and was associated with improved survival 4 weeks post-MI compared with placebo. Nebivolol had a significantly more pronounced inhibitory effect on cardiomyocyte hypertrophy after MI compared with metoprolol.
Nebivolol improves LV dysfunction and survival early after MI likely beyond the effects provided by conventional β₁-receptor blockade. Nebivolol induced effects on NO-mediated endothelial function, early endothelial progenitor cells and inhibition of myocardial NADPH oxidase likely contribute to these beneficial effects of nebivolol early after MI.
Full-text · Article · Feb 2011 · Journal of the American College of Cardiology
[Show abstract][Hide abstract]ABSTRACT: Prehypertension is a highly frequent condition associated with an increased cardiovascular risk. Endothelial dysfunction is thought to promote the development of hypertension and vascular disease; however, underlying mechanisms remain to be further determined. The present study characterizes for the first time the in vivo endothelial repair capacity of early endothelial progenitor cells (EPCs) in patients with prehypertension/hypertension and examines its relation with endothelial function. Early EPCs were isolated from healthy subjects and newly diagnosed prehypertensive and hypertensive patients (n=52). In vivo endothelial repair capacity of EPCs was examined by transplantation into a nude mouse carotid injury model. EPC senescence was determined (RT-PCR of telomere length). NO and superoxide production of EPCs were measured using electron spin resonance spectroscopy analysis. CD34(+)/KDR(+) mononuclear cells and circulating endothelial microparticles were examined by fluorescence-activated cell sorter analysis. Endothelium-dependent and -independent vasodilations were determined by high-resolution ultrasound. In vivo endothelial repair capacity of EPCs was substantially impaired in prehypertensive/hypertensive patients as compared with healthy subjects (re-endothelialized area: 15+/-3%/13+/-2% versus 28+/-3%; P<0.05 versus healthy subjects). Senescence of EPCs in prehypertension/hypertension was substantially increased, and NO production was markedly reduced. Moreover, reduced endothelial repair capacity of early EPCs was significantly related to an accelerated senescence of early EPCs and impaired endothelial function. The present study demonstrates for the first time that in vivo endothelial repair capacity of early EPCs is reduced in patients with prehypertension and hypertension, is related to EPC senescence and impaired endothelial function, and likely represents an early event in the development of hypertension.
[Show abstract][Hide abstract]ABSTRACT: High-density lipoprotein (HDL)-raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL.
HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell-mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy.
HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important.
clinicaltrials.gov. Identifier: NCT00346970.
[Show abstract][Hide abstract]ABSTRACT: Xanthine oxidase (XO), a major source of superoxide, has been implicated in endothelial dysfunction in atherosclerosis. Mechanisms, however, leading to endothelial XO activation remain poorly defined. We tested the effect of angiotensin II (Ang II) on endothelial XO and its relevance for endothelial dysfunction in patients with coronary disease.
XO protein levels and XO-dependent superoxide production were determined in cultured endothelial cells in response to Ang II. In patients with coronary disease, endothelium-bound XO activity as determined by ESR spectroscopy and endothelium-dependent vasodilation were analyzed before and after 4 weeks of treatment with the AT1-receptor blocker losartan, the XO inhibitor allopurinol, or placebo. Ang II substantially increased endothelial XO protein levels and XO-dependent superoxide production in cultured endothelial cells, which was prevented by NAD(P)H-oxidase inhibition. In vivo, endothelium-bound XO activity was reduced by losartan and allopurinol, but not placebo therapy in patients with coronary disease. XO inhibition with oxypurinol improved endothelium-dependent vasodilation before, but not after losartan or allopurinol therapy.
These findings suggest a novel mechanism whereby Ang II promotes endothelial oxidant stress, ie, by redox-sensitive XO activation. In patients with coronary disease, losartan therapy reduces endothelium-bound XO activity likely contributing to improved endothelial function.
Full-text · Article · May 2007 · Arteriosclerosis Thrombosis and Vascular Biology
[Show abstract][Hide abstract]ABSTRACT: Accumulating evidence suggests a critical role of increased reactive oxygen species production for left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). An increased myocardial activity of the NAD(P)H oxidase, a major oxidant enzyme system, has been observed in human heart failure; however, the role of the NAD(P)H oxidase for LV remodeling and dysfunction after MI remains to be determined. MI was induced in wild-type (WT) mice (n=46) and mice lacking the cytosolic NAD(P)H oxidase component p47 (p47 mice) (n=32). Infarct size was similar among the groups. NAD(P)H oxidase activity was markedly increased in remote LV myocardium of WT mice after MI as compared with sham-operated mice (83±8 versus 16.7±3.5 nmol of O2μg·min; P<0.01) but not in p47 mice after MI (13.5±3.6 versus 15.5±3.5 nmol of O2μg·min), as assessed by electron-spin resonance spectroscopy using the spin probe CP-H. Furthermore, increased myocardial xanthine oxidase activity was observed in WT, but not in p47 mice after MI, suggesting NAD(P)H oxidase-dependent xanthine oxidase activation. Myocardial reactive oxygen species production was increased in WT mice, but not in p47 mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47 mice as compared with WT mice, as assessed by echocardiography (LV end-diastolic diameter: 4.5±0.2 versus 6.3±0.3 mm, P<0.01; LV ejection fraction, 35.8±2.5 versus 22.6±4.4%, P<0.05). Furthermore, cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis were substantially reduced in p47 mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47 mice as compared with WT mice after MI (72% versus 48%; P<0.05). These results suggest a pivotal role of NAD(P)H oxidase activation and its subunit p47 for LV remodeling/dysfunction and survival after MI. The NAD(P)H oxidase system represents therefore a potential novel therapeutic target to prevent cardiac failure after MI.
Full-text · Article · Mar 2007 · Circulation Research
[Show abstract][Hide abstract]ABSTRACT: Statins may exert important pleiotropic effects, ie, improve endothelial function, independently of their impact on LDL cholesterol. In humans, however, pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels. We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe, a novel cholesterol absorption inhibitor, result in different effects on endothelial function.
Twenty patients with chronic heart failure were randomized to 4 weeks of simvastatin (10 mg/d) or ezetimibe (10 mg/d) treatment. Flow-dependent dilation (FDD) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals (DeltaFDD-VC). Activity of extracellular superoxide dismutase, a major vascular antioxidant enzyme system, was determined after release from the endothelium by a heparin bolus injection. Endothelial progenitor cells were analyzed with an in vitro assay. Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent (15.6% versus 15.4%; P=NS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (Deltamevalonate-simvastatin, -1.04+/-0.62 versus Deltamevalonate-ezetimibe, 1.79+/-0.94 ng/mL; P<0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5+/-0.6% versus 5.1+/-0.7%; P<0.01) but not after ezetimibe treatment (5.6+/-0.5% versus 5.8+/-0.6%; P=NS). DeltaFDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by >100% (P<0.05) after simvastatin but not ezetimibe treatment. Simvastatin treatment increased the number of functionally active endothelial progenitor cells, whereas ezetimibe had no effect.
Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering, at least in part by reducing oxidant stress. Simvastatin may thereby exert important pleiotropic effects in humans.