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1.  Dual Role of Endothelial Nitric Oxide Synthase in Oxidized LDL-Induced, p66Shc-Mediated Oxidative Stress in Cultured Human Endothelial Cells 
PLoS ONE  2014;9(9):e107787.
Background
The aging gene p66Shc, is an important mediator of oxidative stress-induced vascular dysfunction and disease. In cultured human aortic endothelial cells (HAEC), p66Shc deletion increases endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) bioavailability via protein kinase B. However, the putative role of the NO pathway on p66Shc activation remains unclear. This study was designed to elucidate the regulatory role of the eNOS/NO pathway on p66Shc activation.
Methods and Results
Incubation of HAEC with oxidized low density lipoprotein (oxLDL) led to phosphorylation of p66Shc at Ser-36, resulting in an enhanced production of superoxide anion (O2-). In the absence of oxLDL, inhibition of eNOS by small interfering RNA or L-NAME, induced p66Shc phosphorylation, suggesting that basal NO production inhibits O2- production. oxLDL-induced, p66Shc-mediated O2- was prevented by eNOS inhibition, suggesting that when cells are stimulated with oxLDL eNOS is a source of reactive oxygen species. Endogenous or exogenous NO donors, prevented p66Shc activation and reduced O2- production. Treatment with tetrahydrobiopterin, an eNOS cofactor, restored eNOS uncoupling, prevented p66Shc activation, and reduced O2- generation. However, late treatment with tetrahydropterin did not yield the same result suggesting that eNOS uncoupling is the primary source of reactive oxygen species.
Conclusions
The present study reports that in primary cultured HAEC treated with oxLDL, p66Shc-mediated oxidative stress is derived from eNOS uncoupling. This finding contributes novel information on the mechanisms of p66Shc activation and its dual interaction with eNOS underscoring the importance eNOS uncoupling as a putative antioxidant therapeutical target in endothelial dysfunction as observed in cardiovascular disease.
doi:10.1371/journal.pone.0107787
PMCID: PMC4172699  PMID: 25247687
2.  Feasibility of second-generation bioresorbable vascular scaffold implantation in complex anatomical and clinical scenarios 
Background
Bioresorbable vascular scaffolds (BVS) have become an emerging tool to treat coronary artery disease. However, the current use of BVS is still widely restricted to stable patients and non-complex lesions. In real-world practice patients are far more complex than those with simple type A lesions and the extended use of BVS to complex lesions and high-risk patients needs to be evaluated. Therefore, we sought to investigate the feasibility and performance of BVS in a broad spectrum of patients.
Methods
106 patients underwent in total 193 BVS implantations. We assessed the device-related (cardiac death, target vessel myocardial infarction, ischemia-driven target lesion revascularization) and patient-related (all-cause death, any reinfarction and any revascularization) composite outcomes.
Results
90 % of patients (n = 95) had at least one of the following characteristics: >65 years (35 %), ACS (42 %), tortuous vessels (13 %), calcified (17 %) or thrombotic lesions (12 %), lesions defined as AHA type B2/C (42 %), bifurcations (16 %), chronic total occlusions (9 %) or restenosis (14 %). There was no evidence of significant edge dissection, huge thrombus load or incidence of scaffold dislodgement or scaffold disruption in optical coherence tomography pullbacks. Out of 10,157 struts evaluated within 1,117 cross-sections, 302 were classified as malapposed (2.9 %). During a mean follow-up of 147 ± 119 days the rate of device-related events was 2.0 %, whereas patient-related composite events occurred in 6.1 %.
Conclusions
Our results strongly suggest that BVS implantation is feasible in a wide spectrum of patients and complex anatomy of coronary lesions. Long-term outcome of BVS should be further investigated in unrestricted settings in randomized controlled trials.
Electronic supplementary material
The online version of this article (doi:10.1007/s00392-014-0757-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s00392-014-0757-4
PMCID: PMC4315475  PMID: 25173111
Bioresorbable vascular scaffold; Optical coherence tomography
3.  Congenital coronary anomalies detected by coronary computed tomography compared to invasive coronary angiography 
Background
As coronary computed tomography angiography (CCTA) has emerged as a non-invasive alternative for evaluation of coronary anatomy with a lower referral threshold than invasive coronary angiography (ICA), the prevalence of coronary anomalies in CCTA may more closely reflect the true prevalence in the general population. Morphological features of coronary anomalies can be evaluated more precisely by CCTA than by ICA, which might lead to a higher identification of congenital coronary anomalies in CCTA compared to ICA.
To evaluate the incidence, clinical and morphological features of the anatomy of patients with coronary anomalies detected either by coronary computed tomography angiography (CCTA) with prospective ECG-triggering or invasive coronary angiography (ICA).
Methods
Consecutive patients underwent 64-slice CCTA (n = 1′759) with prospective ECG-triggering or ICA (n = 9′782) and coronary anatomy was evaluated for identification of coronary anomalies to predefined criteria (origin, course and termination) according to international recommendations.
Results
The prevalence of coronary anomalies was 7.9% (n = 138) in CCTA and 2.1% in ICA (n = 203; p < 0.01). The most commonly coronary anomaly detected by CCTA was myocardial bridging 42.8% (n = 59) vs. 21.2% (n = 43); p < 0.01, while with ICA an absent left main trunk was the most observed anomaly 36.0% (n = 73; p < 0.01). In 9.4% (n = 13) of identified coronary anomalies in CCTA 9.4% were potentially serious coronary anaomalies, defined as a course of the coronary artery between aorta and pulmonary artery were identified.
Conclusion
The prevalence of coronary anomalies is substantially higher with CCTA than ICA even after exclusion of patients with myocardial bridging which is more frequently found with CCTA. This suggests that the true prevalence of coronary anomalies in the general population may have been underestimated based on ICA.
doi:10.1186/1471-2261-14-81
PMCID: PMC4118645  PMID: 25004927
Coronary anomalies; Computed coronary tomography angiography; Invasive coronary angiography
4.  Characterization of Pulmonary Vein Dimensions Using High-Definition 64-Slice Computed Tomography prior to Radiofrequency Catheter Ablation for Atrial Fibrillation 
Background. Contrast-enhanced computed tomography is commonly acquired before radiofrequency catheter ablation (RFCA) for atrial fibrillation (AFib) to guide the procedure. We analyzed pulmonary vein (PV) ostial diameter and volumes on a high-definition 64-slice CT (HDCT) scanner in patients with AFib prior to RFCA. Methods and Results. This retrospective study included 50 patients (mean age 60.2 ± 11.4 years, 30 males) undergoing cardiac HDCT scanning before RFCA for drug refractory AFib and 50 age-, BMI-, and sex-matched controls with normal sinus rhythm undergoing HDCT. PV ostial diameter and volume were measured and calculated using a semiautomatic calliper tool. Total ostial PV volume was significantly increased in patients with AFib as compared to controls (P < 0.005). Similarly, total ostial PV diameter was significantly increased in AFib compared to controls (P < 0.001). In AFib, the largest PV volume and diameters were measured in right superior PV (P < 0.05 versus controls). The difference in PV volume between patients and controls was most pronounced in right superior PVs (P = 0.015). Right middle PVs were found more often in patients with AFib (16/50; 32%) than in normal subjects (7/50; 14%). Conclusion. Enlargement of PV ostial area and enlargement of volume are frequent findings in patients with drug refractory AFib. These parameters may add to the risk stratification for AFib recurrence following RFCA.
doi:10.1155/2014/179632
PMCID: PMC4096392  PMID: 25089213
5.  Welcome to the ESC journal family 
doi:10.1177/2048872612444365
PMCID: PMC3760551  PMID: 24062882
6.  Alternatively Spliced Tissue Factor Is Not Sufficient for Embryonic Development 
PLoS ONE  2014;9(5):e97793.
Tissue factor (TF) triggers blood coagulation and is translated from two mRNA splice isoforms, encoding membrane-anchored full-length TF (flTF) and soluble alternatively-spliced TF (asTF). The complete knockout of TF in mice causes embryonic lethality associated with failure of the yolk sac vasculature. Although asTF plays roles in postnatal angiogenesis, it is unknown whether it activates coagulation sufficiently or makes previously unrecognized contributions to sustaining integrity of embryonic yolk sac vessels. Using gene knock-in into the mouse TF locus, homozygous asTF knock-in (asTFKI) mice, which express murine asTF in the absence of flTF, exhibited embryonic lethality between day 9.5 and 10.5. Day 9.5 homozygous asTFKI embryos expressed asTF protein, but no procoagulant activity was detectable in a plasma clotting assay. Although the α-smooth-muscle-actin positive mesodermal layer as well as blood islands developed similarly in day 8.5 wild-type or homozygous asTFKI embryos, erythrocytes were progressively lost from disintegrating yolk sac vessels of asTFKI embryos by day 10.5. These data show that in the absence of flTF, asTF expressed during embryonic development has no measurable procoagulant activity, does not support embryonic vessel stability by non-coagulant mechanisms, and fails to maintain a functional vasculature and embryonic survival.
doi:10.1371/journal.pone.0097793
PMCID: PMC4039448  PMID: 24879059
7.  Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial† 
European Heart Journal  2014;35(46):3277-3286.
Aim
High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo.
Objective
To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA).
Design and setting
A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2–5) weeks after the last study infusion.
Patients
Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively.
Intervention
Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001.
Main outcome measures
The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints.
Results
The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups.
Conclusion
CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study.
Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; Trial registration number: NCT01201837.
doi:10.1093/eurheartj/ehu171
PMCID: PMC4258222  PMID: 24780501
Atherosclerosis; Coronary disease; High-density lipoproteins; Clinical trial
8.  Two-year outcomes after percutaneous mitral valve repair with the MitraClip system: durability of the procedure and predictors of outcome 
Open Heart  2014;1(1):e000056.
Objective
Analyse 2-year outcomes after MitraClip therapy and identify predictors of outcome.
Methods
Consecutive patients (n=74) undergoing MitraClip therapy were included in the MitraSWISS registry and followed prospectively.
Results
A reduction of mitral regurgitation (MR) to ≤ mild was achieved in 32 (43%) patients and to moderate in 31 (42%) patients; 16/63 (25%) patients with initially successful treatment developed recurrent moderate to severe or severe MR during the first year and only 1 patient did so during the second year. At 2 years, moderate or less MR was more frequently present in patients with a transmitral mean gradient <3 mm Hg at baseline (73% vs 23%, p < 0.01) and in patients with a left atrial volume index (LAVI) <50 mL/m2 at baseline (86% vs 52%, p=0.03). More than mild MR post MitraClip, N-terminal probrain natriuretic peptide ≥5000 ng/L at baseline, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) were associated with reduced survival.
Conclusions
A mean transmitral gradient <3 mm Hg at baseline, an LAVI <50 mL/m2, the absence of COPD and CKD, and reduction of MR to less than moderate were associated with favourable outcome. Given a suitable anatomy, such patients may be excellent candidates for MitraClip therapy. Between 1 and 2 years follow-up, clinical and echocardiographic outcomes were stable, suggesting favourable, long-term durability of the device.
doi:10.1136/openhrt-2014-000056
PMCID: PMC4195933  PMID: 25332799
VALVULAR DISEASE; INTERVENTIONAL CARDIOLOGY
9.  Inhibition of Nicotinamide Phosphoribosyltransferase Reduces Neutrophil-Mediated Injury in Myocardial Infarction 
Antioxidants & Redox Signaling  2013;18(6):630-641.
Abstract
Aims: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD+) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed. Results: Treatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD+-dependent deacetylase in the production of this chemokine. Innovation: The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation- and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction. Conclusions: Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice. Antioxid. Redox Signal. 18, 630–641.
doi:10.1089/ars.2011.4487
PMCID: PMC3549207  PMID: 22452634
10.  Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development 
Basic Research in Cardiology  2013;109(1):399.
Sirt3 is a mitochondrial NAD+-dependent deacetylase that governs mitochondrial metabolism and reactive oxygen species homeostasis. Sirt3 deficiency has been reported to accelerate the development of the metabolic syndrome. However, the role of Sirt3 in atherosclerosis remains enigmatic. We aimed to investigate whether Sirt3 deficiency affects atherosclerosis, plaque vulnerability, and metabolic homeostasis. Low-density lipoprotein receptor knockout (LDLR−/−) and LDLR/Sirt3 double-knockout (Sirt3−/−LDLR−/−) mice were fed a high-cholesterol diet (1.25 % w/w) for 12 weeks. Atherosclerosis was assessed en face in thoraco-abdominal aortae and in cross sections of aortic roots. Sirt3 deletion led to hepatic mitochondrial protein hyperacetylation. Unexpectedly, though plasma malondialdehyde levels were elevated in Sirt3-deficient mice, Sirt3 deletion affected neither plaque burden nor features of plaque vulnerability (i.e., fibrous cap thickness and necrotic core diameter). Likewise, plaque macrophage and T cell infiltration as well as endothelial activation remained unaltered. Electron microscopy of aortic walls revealed no difference in mitochondrial microarchitecture between both groups. Interestingly, loss of Sirt3 was associated with accelerated weight gain and an impaired capacity to cope with rapid changes in nutrient supply as assessed by indirect calorimetry. Serum lipid levels and glucose tolerance were unaffected by Sirt3 deletion in LDLR−/− mice. Sirt3 deficiency does not affect atherosclerosis in LDLR−/− mice. However, Sirt3 controls systemic levels of oxidative stress, limits expedited weight gain, and allows rapid metabolic adaptation. Thus, Sirt3 may contribute to postponing cardiovascular risk factor development.
Electronic supplementary material
The online version of this article (doi:10.1007/s00395-013-0399-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00395-013-0399-0
PMCID: PMC3898152  PMID: 24370889
SIRTUIN 3; Atherosclerosis; Metabolism; Oxidative stress
11.  A Novel Electrocardiographic Index for the Diagnosis of Diastolic Dysfunction 
PLoS ONE  2013;8(11):e79152.
Background
Although the assessment of diastolic dysfunction (DD) is an integral part of routine cardiologic examinations, little is known about associated electrocardiographic (ECG) changes. Our aim was to investigate a potential role of ECG indices for the recognition of patients with DD.
Methods and Results
ECG parameters correlating with echocardiographic findings of DD were retrospectively assessed in a derivation group of 172 individuals (83 controls with normal diastolic function, 89 patients with DD) and their diagnostic performance was tested in a validation group of 50 controls and 50 patients. The patient group with a DD Grade 1 and 2 showed longer QTc (422±24ms and 434±32ms vs. 409±25ms, p<0.0005) and shorter Tend–P and Tend–Q intervals, reflecting the electrical and mechanical diastole (240±78ms and 276±108ms vs. 373±110ms, p<0.0001; 409±85ms and 447±115ms vs. 526±119ms, p<0.0001). The PQ–interval was significantly longer in the patient group (169±28ms and 171±38ms vs. 153±22ms, p<0.005). After adjusting for possible confounders, a novel index (Tend–P/[PQxAge]) showed a high performance for the recognition of DD, stayed robust in the validation group (sensitivity 82%, specificity 93%, positive predictive value 93%, negative predictive value 82%, accuracy 88%) and proved a substantial added value when combined with the indexed left atrial volume (LAESVI, sensitivity 90%, specificity 92%, positive predictive value 95%, negative predictive value 86%, accuracy 91%).
Conclusions
A novel electrocardiographic index Tend–P/(PQxAge) demonstrates a high diagnostic accuracy for the diagnosis of DD and yields a substantial added value when combined with the LAESVI.
doi:10.1371/journal.pone.0079152
PMCID: PMC3818461  PMID: 24223898
12.  A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction 
European Heart Journal  2013;35(15):999-1006.
Aims
Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI.
Methods and results
After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733–0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793–0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05).
Conclusion
The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.
doi:10.1093/eurheartj/eht392
PMCID: PMC3985061  PMID: 24046434
Takotsubo cardiomyopathy; Biomarker; Endothelin-1; MicroRNA
13.  The Assessment of Endothelial Function – From Research into Clinical Practice 
Circulation  2012;126(6):753-767.
The discovery of the endothelium as a crucial organ for the regulation of the vasculature to physiological needs and the recognition of endothelial dysfunction as a key pathological condition - which is associated with most if not all cardiovascular risk factors - led to a tremendous boost of endothelial research in the past 3 decades. Despite the possibility to measure endothelial function in the individual and its widespread use in research, its use as a clinical tool in daily medicine is not established yet. We review the most common methods to assess vascular function in humans and discuss their advantages and disadvantages. Furthermore we give an overview about clinical settings were endothelial function measurements may be valuable in individual patients. Specifically, we provide information why endothelial function is not only a risk marker for cardiovascular risk but may also provides prognostic information beyond commonly used risk scores in primary prevention, and in patients with already established coronary disease.
We conclude, that non-invasive endothelial function measurements provide valuable additional information, however, to ascertain its use for daily clinical practice, future research should determine whether endothelial function can be used to guide treatment in the individual and if this translates into better outcomes.
doi:10.1161/CIRCULATIONAHA.112.093245
PMCID: PMC3427943  PMID: 22869857
endothelial function; risk factors; atherosclerosis
14.  Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial 
European Journal of Heart Failure  2013;15(11):1267-1276.
Aims
Therapy with i.v. iron in patients with chronic heart failure (CHF) and iron deficiency (ID) improves symptoms, functional capacity, and quality of life. We sought to investigate whether these beneficial outcomes are independent of anaemia.
Methods and results
FAIR-HF randomized 459 patients with CHF [NYHA class II or III, LVEF ≤40% (NYHA II) or ≤45% (NYHA III)] and ID to i.v. iron as ferric carboxymaltose (FCM) or placebo in a 2:1 ratio. We analysed the efficacy and safety according to the presence or absence of anaemia (haemoglobin ≤120 g/L) at baseline. Of 459 patients, 232 had anaemia at baseline (51%). The effect of FCM on the primary endpoints of self-reported Patient Global Assessment (PGA) and NYHA class at week 24 was similar in patients with and without anaemia [odds ratio (OR) for improvement, 2.48 vs. 2.60, P = 0.97 for PGA and 1.90 vs. 3.39, P = 0.51 for NYHA). Results were also similar for the secondary endpoints, including PGA and NYHA at weeks 4 and 12, 6 min walk test distance, Kansas City Cardiomyopathy Questionnaire overall score, and European Quality of Life-5 Dimensions Visual Analogue Scale at most time points. Regarding safety, no differences were noticed in the rates of death or first hospitalization between FCM and placebo both in anaemic and in non-anaemic patients.
Conclusions
Treatment of ID with FCM in patients with CHF is equally efficacious and shows a similar favourable safety profile irrespective of anaemia. Iron status should be assessed in symptomatic CHF patients both with and without anaemia and treatment of ID should be considered.
doi:10.1093/eurjhf/hft099
PMCID: PMC3806282  PMID: 23787722
Anaemia; Iron deficiency; Heart failure; Intravenous iron; Ferric carboxymaltose
15.  Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: pre- and post-procedural comparison with the Simplicity® catheter system and the EnligHTN™ multi-electrode renal denervation catheter 
European Heart Journal  2013;34(28):2141-2148.
Aims
Catheter-based renal nerve ablation (RNA) using radiofrequency energy is a novel treatment for drug-resistant essential hypertension. However, the local endothelial and vascular injury induced by RNA has not been characterized, although this importantly determines the long-term safety of the procedure. Optical coherence tomography (OCT) enables in vivo visualization of morphologic features with a high resolution of 10–15 µm. The objective of this study was to assess the morphological features of the endothelial and vascular injury induced by RNA using OCT.
Methods and results
In a prospective observational study, 32 renal arteries of patients with treatment-resistant hypertension underwent OCT before and after RNA. All pre- and post-procedural OCT pullbacks were evaluated regarding vascular changes such as vasospasm, oedema (notches), dissection, and thrombus formation. Thirty-two renal arteries were evaluated, in which automatic pullbacks were obtained before and after RNA. Vasospasm was observed more often after RNA then before the procedure (0 vs. 42%, P < 0.001). A significant decrease in mean renal artery diameter after RNA was documented both with the EnligHTN™ (4.69 ± 0.73 vs. 4.21 ± 0.87 mm; P < 0.001) and with the Simplicity® catheter (5.04 ± 0.66 vs. 4.57 ± 0.88 mm; P < 0.001). Endothelial-intimal oedema was noted in 96% of cases after RNA. The presence of thrombus formations was significantly higher after the RNA then before ablation (67 vs. 18%, P < 0.001). There was one evidence of arterial dissection after RNA with the Simplicity® catheter, while endothelial and intimal disruptions were noted in two patients with the EnligHTN™ catheter.
Conclusion
Here we show that diffuse renal artery constriction and local tissue damage at the ablation site with oedema and thrombus formation occur after RNA and that OCT visualizes vascular lesions not apparent on angiography. This suggests that dual antiplatelet therapy may be required during RNA.
doi:10.1093/eurheartj/eht141
PMCID: PMC3717310  PMID: 23620498
Optical coherence tomography; Catheter-based renal nerve ablation; Vascular lesions; Simplicity catheter system; EnligHTN multi-electrode renal denervation catheter
16.  Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity 
European Heart Journal  2013;34(45):3515-3524.
Received 22 July 2012; revised 29 January 2013; accepted 4 March 2013
Aims
Aldosterone plays a crucial role in cardiovascular disease. ‘Systemic’ inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the ‘endothelial’ MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis.
Methods and results
C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high ‘endogenous’ aldosterone) and in ‘exogenous’ aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR.
Conclusion
Obesity-induced endothelial dysfunction depends on the ‘endothelial’ MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.
doi:10.1093/eurheartj/eht095
PMCID: PMC3844149  PMID: 23594590
Obesity; Endothelial; Aldosterone; Mineralocorticoid receptor
17.  Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial 
European Heart Journal  2012;33(7):857-865.
Aims
High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538).
Methods and results
Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA2 mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo).
Conclusion
The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.
doi:10.1093/eurheartj/ehs019
PMCID: PMC3345558  PMID: 22345126
High-density; Lipoprotein; Cholesterol (HDL-C); Torcetrapib; Dalcetrapib
18.  Aortic regurgitation after transcatheter aortic valve implantation: mechanisms and implications 
In recent years, transcatheter aortic valve implantation (TAVI) has become an established treatment option for selected high-risk patients with severe aortic stenosis (AS). Favorable results with regard to both hemodynamics and clinical outcome have been achieved with transcatheter valves.
Aortic regurgitation (AR) remains a major concern after TAVI. Echocardiography is the imaging modality of choice to assess AR in these patients due to its wide accessibility and low cost. Mostly mild residual AR has been observed in up to 70% of patients. However, as even a mild degree of AR has been associated with a decreased survival up to two years after TAVI, accurate evaluation and classification of AR is important. AR in transcatheter valves can be divided into three types according to different pathophysiological mechanisms. Besides the well-known transvalvular and paravalvular forms of regurgitation, a third form termed supra-skirtal has recently been observed. A thorough understanding of AR in transcatheter valves may allow to improve device design and implantation techniques to overcome this complication.
The aim of this review is to provide an overview of the three types of AR after TAVI focussing on the different pathophysiological mechanisms.
doi:10.3978/j.issn.2223-3652.2013.02.01
PMCID: PMC3839218  PMID: 24282741
Transcatheter aortic valve implantation; aortic regurgitation; echocardiography
19.  Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis  
The Journal of Clinical Investigation  2013;123(3):1323-1334.
Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr–/–) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3+ Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3+ Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.
doi:10.1172/JCI63891
PMCID: PMC3582120  PMID: 23426179
20.  Peripheral Blood Monocyte Sirt1 Expression Is Reduced in Patients with Coronary Artery Disease 
PLoS ONE  2013;8(1):e53106.
Background
Inflammation plays a key role in atherosclerosis. Sirt1 regulates transcription factors involved in inflammatory processes and blunts atherosclerosis in mice. However, its role in humans remains to be defined. This study was therefore designed to investigate the role of Sirt1 in the development of atherosclerosis.
Methods and Results
48 male subjects admitted for cardiac catheterization were subdivided into healthy subjects, patients with stable coronary artery disease (CAD), and with acute coronary syndromes (ACS). Monocytes were isolated and Sirt1 mRNA levels were determined. Sirt1 gene expression was higher in healthy subjects as compared to patients with CAD or ACS (P<0.05), respectively. Interestingly, HDL levels correlated positively with Sirt1 expression. Thus, HDL from the three groups was isolated and incubated with THP-1 monocytes to determine the effects of HDL on Sirt1 protein in controlled experimental conditions. HDL from healthy subjects stimulated Sirt1 expression in THP-1 monocytes to a higher degree than HDL from CAD and ACS patients (P<0.05). Paraoxonase-1 (PON-1), a HDL-associated enzyme, showed a reduced activity in HDL isolated from CAD and ACS patients as compared to the controls (P<0.001).
Conclusions
Monocytic Sirt1 expression is reduced in patients with stable CAD and ACS. Experiments on THP-1 monocytes suggest that this effect is HDL-dependent and is mediated by a reduced activity of HDL-associated enzyme PON1.
doi:10.1371/journal.pone.0053106
PMCID: PMC3558418  PMID: 23382833
21.  Antibody Phage Display Assisted Identification of Junction Plakoglobin as a Potential Biomarker for Atherosclerosis 
PLoS ONE  2012;7(10):e47985.
To date, no plaque-derived blood biomarker is available to allow diagnosis, prognosis or monitoring of atherosclerotic vascular diseases. In this study, specimens of thrombendarterectomy material from carotid and iliac arteries were incubated in protein-free medium to obtain plaque and control secretomes for subsequent subtractive phage display. The selection of nine plaque secretome-specific antibodies and the analysis of their immunopurified antigens by mass spectrometry led to the identification of 22 proteins. One of them, junction plakoglobin (JUP-81) and its smaller isoforms (referred to as JUP-63, JUP-55 and JUP-30 by molecular weight) were confirmed by immunohistochemistry and immunoblotting with independent antibodies to be present in atherosclerotic plaques and their secretomes, coronary thrombi of patients with acute coronary syndrome (ACS) and macrophages differentiated from peripheral blood monocytes as well as macrophage-like cells differentiated from THP1 cells. Plasma of patients with stable coronary artery disease (CAD) (n = 15) and ACS (n = 11) contained JUP-81 at more than 2- and 14-fold higher median concentrations, respectively, than plasma of CAD-free individuals (n = 13). In conclusion, this proof of principle study identified and verified JUP isoforms as potential plasma biomarkers for atherosclerosis. Clinical validation studies are needed to determine its diagnostic efficacy and clinical utility as a biomarker for diagnosis, prognosis or monitoring of atherosclerotic vascular diseases.
doi:10.1371/journal.pone.0047985
PMCID: PMC3480477  PMID: 23110151
22.  Falls and Fractures in the Elderly with Sinus Node Disease: The Impact of Pacemaker Implantation 
Background. Falls and fractures in the elderly are among the leading causes of disability. We investigated whether pacemaker implantation prevents falls in patients with SND in a large cohort of patients. Methods. Patient demographics and medical history were collected prospectively. Fall history was retrospectively reconstituted from available medical records. The 10-year probability for major osteoporotic fractures was calculated retrospectively from available medical records using the Swiss fracture risk assessment tool FRAX-Switzerland. Results. During a mean observation period of 2.3 years after implantation, the rates of fallers and injured fallers with fracture were reduced to 15% and 6%, respectively. This corresponds to a relative reduction in the number of fallers of 75% (P < 0.001) and of injured fallers of 63% (P = 0.014) after pacemaker implantation. Similarly, the number of falls was reduced from 60 (48%) before pacemaker implantation to 22 (18%) thereafter (relative reduction 63%, P = 0.035) and the number of falls with injury from 22 (18%) to 7 (6%), which corresponds to a relative reduction of 67%, P = 0.013. Conclusion. In patients with SND, pacemaker implantation significantly reduces the number of patients experiencing falls, the total number of falls, and the risk for osteoporotic fractures.
doi:10.1155/2012/498102
PMCID: PMC3488401  PMID: 23150844
23.  Predictors of Appropriate ICD Therapy in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy: Long Term Experience of a Tertiary Care Center 
PLoS ONE  2012;7(9):e39584.
Introduction
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically transmitted disease prone to ventricular arrhythmias. We therefore investigated the clinical, echocardiographical and electrophysiological predictors of appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ARVC.
Methods
A retrospective analysis was performed in 26 patients (median age of 40 years at diagnosis, 21 males and 5 females) with ARVC who underwent ICD implantation.
Results
Over a median (range) follow-up period of 10 (2.7, 37) years, appropriate ICD therapy for ventricular arrhythmias was documented in 12 (46%) out of 26 patients. In all patients with appropriate ICD therapy the ICD was originally inserted for secondary prevention. Median time from ICD implantation to ICD therapy was 9 months (range 3.6, 54 months). History of heart failure was a significant predictor of appropriate ICD therapy (p = 0.033). Left ventricular disease involvement (p = 0.059) and age at implantation (p = 0.063) were borderline significant predictors. Patients with syncope at time of diagnosis were significantly less likely to receive ICD therapy (p = 0.02). Invasive electrophysiological testing was not significantly associated with appropriate ICD therapy.
Conclusion
In our cohort of patients with ARVC, history of heart failure was a significant predictor of appropriate ICD therapy, whereas left ventricular involvement and age at time of ICD implantation were of borderline significance. These predictors should be tested in larger prospective cohorts to optimize ICD therapy in this rare cardiomyopathy.
doi:10.1371/journal.pone.0039584
PMCID: PMC3459957  PMID: 23028419
24.  Correction: Globotriaosylceramide Accumulation and Not Alpha-Galactosidase-A Deficiency Causes Endothelial Dysfunction in Fabry Disease 
PLoS ONE  2012;7(9):10.1371/annotation/7b2c04df-8592-4fb7-8608-3039db28b504.
doi:10.1371/annotation/7b2c04df-8592-4fb7-8608-3039db28b504
PMCID: PMC3464302
25.  Correction: Carotid Artery Stenting: A Single Center “Real World” Experience 
PLoS ONE  2012;7(8):10.1371/annotation/42028902-fdcd-4e2c-9ec0-62f01edc30fa.
doi:10.1371/annotation/42028902-fdcd-4e2c-9ec0-62f01edc30fa
PMCID: PMC3437795

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