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AIMS: Degenerative aortic valve stenosis (AVS) is independently associated with endothelial dysfunction and increased levels of circulating endothelium-derived microparticles (EMPs) as a marker of compromised endothelial integrity. The aim of this study was to investigate whether therapy for severe AVS by transcatheter aortic valve implantation (TAVI) improves endothelial function and decreases EMPs. METHODS AND RESULTS: Fifty-six patients with indication for TAVI due to symptomatic severe AVS were prospectively enrolled. Brachial wall shear stress (WSS), endothelial function and circulating microparticles (MPs) were measured before and three months following TAVI. Endothelial function was assessed as flow-mediated dilation (FMD) using ultrasound. MP subpopulations were discriminated by flow cytometry according to the expression of established surface antigens: CD31+/CD41-, CD144+ and CD62E+ as EMPs and CD41+ as platelet-derived MPs (PMPs). In patients with severe AVS, decreased brachial WSS was an independent predictor of low FMD. At three-month follow-up after TAVI, WSS and FMD increased along with decreased levels of EMPs as compared to pre TAVI. Decrease of CD31+/CD41-, CD144+ and CD62E+ EMP levels correlated with the increase of FMD. CONCLUSIONS: Therapy for AVS by TAVI was associated with improved endothelial function and integrity indicating beneficial effects of TAVI on systemic arterial function.

Dietary intervention studies suggest that flavan-3-ol intake can improve vascular function and reduce the risk of cardiovascular diseases (CVD). However, results from prospective studies failed to show a consistent beneficial effect. Associations between flavan-3-ol intake and CVD risk in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) were investigated. Data were available from 24,885 (11,252 men; 13,633 women) participants, recruited between 1993 and 1997 into the EPIC-Norfolk study. Flavan-3-ol intake was assessed using 7-day food diaries and the FLAVIOLA Flavanol Food Composition database. Missing data for plasma cholesterol and vitamin C were imputed using multiple imputation. Associations between flavan-3-ol intake and blood pressure at baseline were determined using linear regression models. Associations with CVD risk were estimated using Cox regression analyses. Median intake of total flavan-3-ols was 1034 mg/d (range: 0–8531 mg/d) for men and 970 mg/d (0–6695 mg/d) for women, median intake of flavan-3-ol monomers was 233 mg/d (0–3248 mg/d) for men and 217 (0–2712 mg/d) for women. There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure (BP). After 286,147 person-years of follow-up, there were 8463 cardiovascular events and 1987 CVD related deaths; no consistent association between flavan-3-ol intake and CVD risk (HR 0.93, 95% CI: 0.87; 1.00; Q1 vs Q5) or mortality was observed (HR 0.93, 95% CI: 0.84; 1.04). Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk., Graphical abstract, Highlights • Median intake of total flavan-3-ol monomers in EPIC Norfolk was 233 mg/d for men and 217 mg/d for women. • There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure in EPIC Norfolk. • There were no consistent association between flavan-3-ol intake and CVD risk in EPIC Norfolk. • Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk.

Orthotopic aortic transplantation using the sleeve technique reduces injury to the aorta with failure rate of only 10-20%. The time to anastomose the aorta in mice using the sleeve method was short and easy averaging 20 min, permitting studies of iso/allo grafts. The following article describes the aortic transplantation procedure used in our laboratory. The mice were anesthetized with a mixture of 1.5% volume isoflurane and 100% oxygen through a face mask. At this point, the segment of the aorta between the renal arteries and its bifurcation was separated from the vena cava, freely prepared and clampedat the proximal and distal segments with a single silk suture. Prior to the removal of the aorta, a saline solution containing heparin was injected into the inferior vena cava. Then the aorta was cut between the clamps and a saline heparin solution was used to flush the lumen. The sleeve technique with monofilament sutures was used in order to transplant the abdominal aorta in the orthotopic position.

The anticancer efficacy of anthracyclines is limited by congestive heart failure. Clinically established markers of early onset of cardiotoxicity following anthracycline treatment and preventive measures are missing. Although statins are reported to alleviate anthracycline-induced cardiotoxicity in vivo, the molecular mechanisms involved remain elusive. In vitro data point to Rac1 as major target of the cytoprotective statin effects. Here we investigated whether specific inhibition of Rac1 by NSC23766 is as effective as lovastatin in preventing subacute cardiotoxicity following doxorubicin treatment. C57BL/6 mice were treated over 3 weeks with multiple low doses of doxorubicin (6 × 3 mg/kg BW, i.p.) and the level of DNA damage, apoptosis and regenerative proliferation as well as pro-inflammatory, pro-fibrotic and oxidative stress responses were investigated. Moreover, heart function was monitored by echocardiography. Doxorubicin induced subacute cardiotoxicity which was reflected on the level of residual DNA damage, frequency of apoptotic and mitotic cells as well as elevated mRNA expression of markers of heart failure, remodeling and mitochondrial biogenesis. These molecular markers of cardiotoxicity were mitigated to a similar extent by co-treatment with either lovastatin (10 mg/kg BW, p.o.) or NSC23766 (5 mg/kg BW, i.p.) three times a week. Moreover, doxorubicin caused diastolic dysfunction as reflected by increased E-wave acceleration time (EAT), which again was prevented by pharmacological inhibition of Rac1. Inhibition of Rac1 signaling is of major relevance for the cardioprotective effects of lovastatin in the context of anthracycline-induced cardiotoxicity. Moreover, EAT is a useful marker of subacute cardiotoxicity caused by persisting harmful effects of doxorubicin.

Pulmonary vein isolation (PVI) as a cornerstone for catheter ablation of atrial fibrillation (AF) remains a complex and time-consuming procedure.To assess feasibility, safety, and acute efficacy of a novel irrigated multielectrode ablation catheter guided by an electroanatomic mapping system for PVI in patients with paroxysmal AF.Twenty-five consecutive patients (60 ± 10 years) with paroxysmal AF underwent PVI by using a novel decapolar mapping and ablation catheter (nMARQ catheter, Biosense Webster Inc, Diamond Bar, CA). Ablation was guided by electroanatomic mapping allowing radiofrequency (RF) energy delivery in the antral region of pulmonary veins (PVs) from 10 irrigated electrodes simultaneously. The day after ablation, cardiac magnetic resonance imaging was performed routinely in order to assess for potential acute PV stenosis.Overall, 97 of 97 (100%) targeted PVs could be isolated with a mean of 27 ± 11 RF applications and a mean total burning time of 15 ± 6 minutes per patient. The total procedure time from femoral vein access to catheter withdrawal was 110 ± 31 minutes, including a mean total fluoroscopy time of 23 ± 9 minutes. On average, 6 ± 3 RF impulses with a maximum of 25 W were applied per vein. After a short learning curve, procedure, fluoroscopy, and total burning times decreased to 94 ± 16, 16 ± 3, and 9 ± 2 minutes, respectively (P.05). Entrance and exit blocks could be verified by placing the ablation catheter into 90 of 97 (93%) PVs in 18 of 25 (72%) patients. No procedure-related complications were observed, especially no acute PV stenosis could be detected.The use of a novel irrigated multielectrode ablation system for PVI is feasible and safe, resulting in acute isolation of all targeted PVs with no complications and short procedure times. Sustainability of these initial results has to be confirmed in long-term efficacy and follow-up trials.

Einfuhrung Murine arterielle Transplantatmodelle werden angewandt, die entzundliche Reaktion der Gefaswand und die dabei beteiligten Faktoren genauer aufzuschlusseln. Das Ziel der vorliegenden Studie war es, ein Modell der Transplantatarteriosklerose nach Aortentransplantation zu etablieren.

To determine the impact of red blood cell distribution width on outcome in anemic patients undergoing transcatheter aortic valve implantation (TAVI).In a retrospective single center cohort study we determined the impact of baseline red cell distribution width (RDW) and anemia on outcome in 376 patients with aortic stenosis undergoing TAVI. All patients were discussed in the institutional heart team and declined for surgical aortic valve replacement due to high operative risk. Collected data included patient characteristics, imaging findings, periprocedural in hospital data, laboratory results and follow up data. Blood samples for hematology and biochemistry analysis were taken from every patient before and at fixed intervals up to 72 h after TAVI including blood count and creatinine. Descriptive statistics were used for patient's characteristics. Kaplan-Meier survival curves were used for time to event outcomes. A recursive partitioning regression and classification was used to investigate the association between potential risk factors and outcome variables.Mean age in our study population was 81 ± 6.1 years. Anemia was prevalent in 63.6% (n = 239) of our patients. Age and creatinine were identified as risk factors for anemia. In our study population, anemia per se did influence 30-d mortality but did not predict longterm mortality. In contrast, a RDW14% showed to be highly predictable for a reduced short- and longterm survival in patients with aortic valve disease after TAVI procedure.Age and kidney function determine the degree of anemia. The anisocytosis of red blood cells in anemic patients supplements prognostic information in addition to that derived from the WHO-based definition of anemia.

SummaryS-nitrosation of macrophage migration inhibitory factor (MIF) has been shown to be cytoprotective in myocardial ischaemia/reperfusion (I/R) injury. Since the exact mechanism of action is unknown, we here characterise the cardioprotective effects of targeted intracellular accumulation of MIF in myocardial I/R injury. We used different in vivo, ex vivo and in vitro models of myocardial I/R and hypoxia/reoxyge-nation (H/R) injury to determine MIF levels by immunoblots and ELISA in different phases of reperfusion and reoxygenation, respectively. We discovered a rapid decrease of cardiac MIF that was specific to the early phase of reperfusion. Posttranslational modification of MIF via S-nitrosation – proofed by a modified version of the Biotin Switch Assay – prevented this rapid decrease, leading to a targeted intracellular accumulation of MIF in the early phase of reperfusion. Intracellular MIF accumulation preserved the intracellular ability of MIF to reduce oxidative stress as shown by hydrogen peroxide and aconitase activity measurements. Infarct size measurements by TTC staining showed an overall enhanced cardioprotective effect of this protein by reduction of reperfusion injury. In summary, we have unravelled a novel mechanism of MIF-mediated cardioprotection. Targeted intra-cellular accumulation of MIF by S-nitrosation may offer a novel therapeutic approach in the treatment of myocardial I/R-injury.

Cell-based therapy is considered a novel and potentially new strategy in regenerative medicine. But the efficacy of cell-based therapy has been limited by the poor survival of the transplanted cells in an ischaemic environment. The goal of the present study is to present a possibility to increase survival of the transplanted cardiomyocytes, by increasing the vascularization of the infarcted area. First, we injected endothelial progenitor cells (EPCs) to augment the vascular density in infarcted areas and to improve the benefit of a subsequent Tx of foetal cardiomyocytes. Serial echocardiography indeed showed significant improvement of the left ventricular function after application of EPC and a significant additive improvement after Tx of foetal cardiomyocytes. In contrast, repetitive EPC transplantation as a control group did not show an additional improvement after the second transplantation. Histologically, cells could be readily detected after Tx by BrdU-staining for EPC and by carboxy-fluorescein diacetate succinimidyl ester (CFSE)-staining for foetal cardiomyocytes. Staining for CD31 revealed a significant increase in vessel density in the infarction area compared with medium controls, possibly contributing to the benefit of transplanted foetal cardiomyocytes. Notably, a significant increase in the number of apoptotic cells was observed in cell-transplanted hearts accompanied by an increase in proliferation, collagen content and neutrophil infiltration, suggesting an active remodelling concomitant with sustained inflammatory processes. In conclusion, repetitive Tx of different cell types after myocardial infarction in rat hearts significantly improved left ventricular function and could represent a feasible option to enhance the benefit of cell therapy.

Innerhalb der letzten Jahre wurde die kathetergestutzte Aortenklappenimplantation (TAVI) bei alteren Hochrisikopatienten in vielen klinischen Studien evaluiert. In diesen konnte gezeigt werden, dass die TAVI einer medikamentosen Therapie bei inoperablen Patienten mit hochgradiger Aortenklappenstenose hinsichtlich einer Prognoseverbesserung uberlegen ist. Auserdem liefert die TAVI bei operablen Risikopatienten mit Aortenklappenstenose ebenso gute Ergebnisse wie der konventionelle Aortenklappenersatz. Ein weiteres Anwendungsgebiet der TAVI stellt die Therapie degenerierter Aortenklappenbioprothesen dar, die in kleineren Studien machbar und sicher erscheint. Die Valvuplastie der degenerierten, hochgradigen Aortenklappenstenose sollte nur noch unter palliativem Ansatz bzw. als „bridge to TAVI/bridge to surgery“ zum Einsatz kommen.

Objectives Here we assess the intrinsic functions of the chemokine receptor CXCR4 in remodeling after myocardial infarction (MI) using Cxcr4 heterozygous (Cxcr(4+/-)) mice. Background Myocardial necrosis triggers complex remodeling and inflammatory changes. The chemokine CXCL12 has been implicated in protection and therapeutic regeneration after MI through recruiting angiogenic outgrowth cells, improving neovascularization and cardiac function, but the endogenous role of its receptor CXCR4 is unknown. Methods MI was induced by ligation of the left descending artery. Langendoff perfusion, echocardiography, quantitative immunohistochemistry, flow cytometry, angiogenesis assays, and cardiomyocyte analysis were performed. Results After 4 weeks, infarct size was reduced in Cxcr4(+/-) mice compared with wild-type mice and in respective bone marrow chimeras compared with controls. This was associated with altered inflammatory cell recruitment, decreased neutrophil content, delayed monocyte infiltration, and a predominance of Gr1(low) over classic Gr1(high) monocytes. Basal coronary flow and its recovery after MI were impaired in Cxcr4(+/-)mice, paralleled by reduced angiogenesis, myocardial vessel density, and endothelial cell count. Notably, no differences in cardiac function were seen in Cxcr4(+/-)mice compared with wild-type mice. Despite defective angiogenesis, Cxcr4(+/-) mouse hearts showed no difference in CXCL12, vascular endothelial growth factor or apoptosis-related gene expression. Electron microscopy revealed lipofuscin-like lipid accumulation in Cxcr4(+/-) mouse hearts and analysis of lipid extracts detected high levels of phosphatidylserine, which protect cardiomyocytes from hypoxic stress in vitro. Conclusions CXCR4 plays a crucial role in endogenous remodeling processes after MI, contributing to inflammatory/progenitor cell recruitment and neovascularization, whereas its deficiency limits infarct size and causes adaptation to hypoxic stress. This should be carefully scrutinized when devising therapeutic strategies involving the CXCL12/CXCR4 axis. (J Am Coll Cardiol 2011;58:2415-23)

Desmosomes are cell–cell adhesion sites and part of the intercalated discs, which couple adjacent cardiomyocytes. The connection is formed by the extracellular domains of desmosomal cadherins that are also linked to the cytoskeleton on the cytoplasmic side. To examine the contribution of the desmosomal cadherin desmoglein 2 to cardiomyocyte adhesion and cardiac function, mutant mice were prepared lacking a part of the extracellular adhesive domain of desmoglein 2. Most live born mutant mice presented normal overall cardiac morphology at 2 weeks. Some animals, however, displayed extensive fibrotic lesions. Later on, mutants developed ventricular dilation leading to cardiac insufficiency and eventually premature death. Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed. Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue. Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure. Taken together, the desmoglein 2-mutant mice display features of dilative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, an inherited human heart disease with pronounced fibrosis and ventricular arrhythmias that has been linked to mutations in desmosomal proteins including desmoglein 2. Electronic supplementary material The online version of this article (doi:10.1007/s00395-011-0175-y) contains supplementary material, which is available to authorized users.

Objectives The aim of this study was to investigate the effect of diagnostic transradial catheterization on vascular function of upstream brachial artery (BA). Background The transradial access has recently become an alternative to transfemoral cardiac catheterization. A potential caveat of this approach lies in possible sustained physical radial artery (RA) damage. Methods We studied 30 patients (age 61 ± 11 years) undergoing diagnostic coronary angiography with the transradial access (5-F). Endothelium-dependent, flow-mediated vasodilation (FMD) was measured before and at 6 and 24 h after catheterization of the right-sided RA and BA with high-resolution ultrasound. The left-sided RA served as a control. Results Transradial catheterization significantly decreased FMD in the RA (overall mean 8.5 ± 1.7% to 4.3 ± 1.6%) and the upstream BA (overall mean 4.4 ± 1.6% to 2.9 ± 1.6%) at 6 h. Subgroup analysis showed that FMD of both arteries at 6 h was significantly lower in active smokers and that it only remained impaired at 24 h in this group, whereas nonsmoker FMD fully recovered. The degree of BA but not RA FMD dysfunction was related to the number of catheters used, with no change after 2 catheters, 1.9 ± 1.2% decrease (6 h) and recovery (24 h) after 3 catheters, and 3.9 ± 1.2% decrease (6 h) without recovery (24 h) after 4 to 5 catheters. The RA dysfunction correlated with the baseline diameter. The contralateral control RA exhibited no change ruling out systemic effects. Conclusions Transradial catheterization not only leads to dysfunction of the RA but also the upstream BA, which is more severe and sustained in smokers and with increasing numbers of catheters.

The occurrence of ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy (DCM) who are treated with an implantable cardioverter-defibrillator (ICD) for primary or secondary prevention is not fully understood.In this nonrandomized, two-centre, observational study we analyzed the occurrence of ventricular arrhythmias in a total of 105 DCM patients (age, 53 ± 13 years) treated with an ICD. Fifty-one patients with a left ventricular ejection fraction ≤ 35% did not have prior sustained ventricular arrhythmias (primary prevention). The secondary prevention group consisted of 54 patients with documented sustained ventricular tachycardia (n = 25) or aborted sudden cardiac death (n = 29). During 32 ± 7 months follow-up the number of patients with appropriate defibrillator therapies (n = 51) was comparable between the two groups (HR 0.79, 95% CI 0.454 to 1.361, P = 0.389). Importantly, less primary prevention patients experienced appropriate ICD shocks for any arrhythmic event (HR 0.35, 95% CI 0.186 to 0.777, P = 0.008), as well as appropriate ICD shocks for ventricular fibrillation (HR 0.31, 95% CI 0.167 to 0.737, P = 0.006). In contrast, antitachycardia pacing was more often observed in the primary prevention group (HR 2.75, 95% CI 1.031 to 6.238, P = 0.043). Two primary prevention and 6 secondary prevention patients received multiple ICD therapies in consequence of incessant ventricular tachycardia.The characteristics of ventricular arrhythmias in patients with DCM who are treated with an ICD for primary or secondary prevention vary according to the underlying indication. Therefore, different device programming according to the patient’s history might improve ventricular tachyarrhythmia management.

Objectives Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients. Background Even in fully medicated diabetic patients, overall prognosis is unfavorable due to deteriorated cardiovascular function. Based on epidemiological data, diets rich in flavanols are associated with a reduced cardiovascular risk. Methods In a feasibility study with 10 diabetic patients, we assessed vascular function as flow-mediated dilation (FMD) of the brachial artery, plasma levels of flavanol metabolites, and tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-masked fashion. Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively. Results A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 h: from 3.7 0.2% to 5.5 0.4%, p 0.001). A 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30% (p 0.0001), while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxia. Endothelium-independent responses, blood pressure, heart rate, and glycemic control were unaffected. Conclusions Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovascular disease. (J Am Coll Cardiol 2008;51:2141‐9) © 2008 by the American College of Cardiology Foundation

Myocardial necrosis triggers inflammatory changes and a complex cytokine cascade that are only incompletely understood. The chemokine receptor CCR1 mediates inflammatory recruitment in response to several ligands released by activated platelets and up-regulated after myocardial infarction (MI). Here, we assess the effect of CCR1 on remodelling after MI using Ccr1-deficient (Ccr1(-)(/-)) mice. MI was induced in Ccr1(-/-) or wild-type mice by proximal ligation of the left anterior descending (LAD). Mice were sacrificed and analysed at day 1, 4, 7, 14 and 21 after MI. While initial infarct areas and areas at risk did not differ between groups, infarct size increased to 20.6+/-8.4% of the left ventricle (LV) in wild-type mice by day 21 but remained at 11.2+/-1.2% of LV (P

Cell transplantation has recently emerged as a novel therapy for ischemic heart disease. The presented study investigated the effect of intramyocardial transfer of human endothelial progenitor cells (EPCs) and stromal-cell derived factor-1alpha (SDF-1alpha) on left ventricular function in a chronic setting after myocardial infarction in cyclosporine treated rats. BrdU-labeled EPCs (10(6)), 10 microg SDF-1alpha, EPCs+SDF-1alpha or placebo medium were injected directly into the border infarct zone 4 weeks after acute myocardial infarction. Eight weeks after transplantation, echocardiography identified significantly improved fractional shortening after EPC or EPCs+SDF-1alpha injection as compared with injection of placebo medium. Investigating isolated hearts revealed a significant increase in left ventricular developing pressure after transplantation of SDF-1alpha or EPCs+SDF-1alpha. Furthermore, coronary flow rates were significantly elevated, especially after transplantation of EPCs+SDF-1alpha (under catecholamine stress 24.2 +/- 1.55 ml/min vs. 13.1 +/- 1 ml/min in the control) correlating with increased density of CD31+ vessel structures in the EPC as well as EPCs+SDF-1alpha groups, thus defining a higher rate of neovascularization. Notably, SDF-1alpha injected hearts showed only a trend towards improvement in coronary flow. BrdU+ signals were detected in infarct areas, partially integrating into vascular networks. The rate of apoptotic cells as well as the amount of inflammatory cells was significantly elevated in the placebo control group. In conclusion, transplantation of EPCs as well as EPCs+SDF-1alpha associated with improvement in cardiac function after infarction, which was attributable to enhanced neovascularization and decreased inflammation. These results imply a combined benefit of EPCs+SDF-1alpha in the treatment of myocardial infarction.

Increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension are hallmarks of vascular aging. Regular cocoa flavanol (CF) intake can improve vascular function in healthy young and elderly at-risk individuals. However, the mechanisms underlying CF bioactivity remain largely unknown. We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history, signs, or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging. In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 22 young (

PURPOSE:Nitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI. METHODS:To analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining. RESULTS:Three weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5) and end-diastolic volumes (82.7±5.6 μl; *p

Cocoa flavanol (CF) intake improves endothelial function in patients with cardiovascular risk factors and disease. We investigated the effects of CF on surrogate markers of cardiovascular health in low risk, healthy, middle-aged individuals without history, signs or symptoms of CVD. In a 1-month, open-label, one-armed pilot study, bi-daily ingestion of 450 mg of CF led to a time-dependent increase in endothelial function (measured as flow-mediated vasodilation (FMD)) that plateaued after 2 weeks. Subsequently, in a randomised, controlled, double-masked, parallel-group dietary intervention trial (Clinicaltrials.gov: NCT01799005), 100 healthy, middle-aged (35–60 years) men and women consumed either the CF-containing drink (450 mg) or a nutrient-matched CF-free control bi-daily for 1 month. The primary end point was FMD. Secondary end points included plasma lipids and blood pressure, thus enabling the calculation of Framingham Risk Scores and pulse wave velocity. At 1 month, CF increased FMD over control by 1·2 % (95 % CI 1·0, 1·4 %). CF decreased systolic and diastolic blood pressure by 4·4 mmHg (95 % CI 7·9, 0·9 mmHg) and 3·9 mmHg (95 % CI 6·7, 0·9 mmHg), pulse wave velocity by 0·4 m/s (95 % CI 0·8, 0·04 m/s), total cholesterol by 0·20 mmol/l (95 % CI 0·39, 0·01 mmol/l) and LDL-cholesterol by 0·17 mmol/l (95 % CI 0·32, 0·02 mmol/l), whereas HDL-cholesterol increased by 0·10 mmol/l (95 % CI 0·04, 0·17 mmol/l). By applying the Framingham Risk Score, CF predicted a significant lowering of 10-year risk for CHD, myocardial infarction, CVD, death from CHD and CVD. In healthy individuals, regular CF intake improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular health even in low-risk subjects.

Dual antiplatelet therapy (DAPT) is recommended early after transcatheter aortic valve implantation (TAVI) procedure at the moment despite the lack of evidence. Two small randomized trials failed to demonstrate DAPT to be superior to aspirin alone in TAVI patients. However, it is known that there are substantial response variabilities to antiplatelet medication. We aimed to investigate high on-treatment platelet reactivity (HTPR), low on-treatment platelet reactivity (LTPR) to clopidogrel as well as HTPR to aspirin in patients undergoing TAVI procedure. We analyzed data of 140 TAVI patients in a real world observational study. Platelet function assays (clopidogrel-vasodilator-stimulated protein phosphorylation assay; aspirin-light-transmission aggregometry) have been performed during hospital course. Clinical complications were investigated during 30 days follow-up and defined using the valve academic research consortium standardized criteria. HTPR to clopidogrel occurred in 87 (62%) patients and LTPR in 9 (6.4%) patients. Aspirin antiplatelet effects were insufficient in 25 (18%) patients. Clinical complications were observed in 35 (25%) patients. Ischemic events occurred in 6 (4%), bleeding complications in 28 (20%) patients. There were no differences regarding the incidence of HTPR/LTPR in patients with overall complications, ischemic events or bleeding events. HTPR to clopidogrel is very frequent in TAVI patients. However bleeding complications are frequent and ischemic events are rare. Therefore, future clinical trials investigating the optimal antithrombotic regiment in TAVI patients should consider this high incidence of HTPR to clopidogrel and monitor clopidogrel antiplatelet effects carefully.

SummaryWe have recently shown that dipyrone (metamizole), a non-opioid analgesic, can nullify aspirin (acetylsalicylic acid; ASA) antiplatelet effects in patients with coronary artery disease (CAD). In this study, we analysed the aspirin and dipyrone drug-drug interaction in order to identify strategies to prevent the dipyrone induced inhibition of asprin antiplatelet effects. Platelet function was measured by arachidonic acid-induced light-transmission aggregometry, thromboxane (TX) B2–formation by immunoassay. Dipyrone metabolite plasma levels were determined by high-performance-liquid-chromatography (HPLC). In seven healthy individuals, in vitro ASA (30 μM/ 100 μM/ 300 μM/ 1,000 μM) and dipyrone (10 μM) coincubation revealed, that the aspirin and dipyrone interaction can be overcome by increasing doses of aspirin. In 36 aspirin and dipyrone comedicated CAD patients, addition of ASA (30 μM/ 100 μM) in vitro inhibited, but did not completely overcome the dipyrone induced reduction of aspirin antiplatelet effects. Notably, the inhibition of thromboxane formation in aspirin and dipyrone comedicated CAD patients coincided with dipyrone plasma levels. In a cross-over designed study in four healthy individuals, we were able to prove that inhibition of aspirin (100 mg/ day) effects by dipyrone (750 mg/ day) was reversible. Furthermore, aspirin (100 mg/ day) medication prior to dipyrone (750 mg/ day) intake prevented the inhibition of antiplatelet effects by dipyrone in 12 healthy individuals. In conclusion, aspirin medication prior to dipyrone intake preserves antiplatelet effects, circumventing the pharmacodynamic drug-drug interaction at the level of cyclooxygenase-1.Clinical Trial Registration: NCT01402804; http://clinicaltrials.gov/ct2/show/NCT01402804.

Pulmonary vascular injury is a rare but life-threatening complication of Swan-Ganz catheterization. We report an 82-year old patient who underwent right heart catheterization by a balloon-tipped catheter because of suspected pulmonary hypertension. After deflation of the catheter in the wedge position, hemoptoe appeared associated with acute respiratory insufficiency requiring respiratory support by intubation and mechanical ventilation. Pulmonary angiography showed the formation of a false aneurysm of a segment artery of the left lower lobe. Immediate interventional therapy was performed by the implantation of two coated coronary stent grafts into the injured pulmonary artery thereby excluding the false aneurysm. Bleeding was stopped by this interventional approach while antegrade blood flow was maintained. Long term follow-up after 3 months showed an effective treatment with a completely thrombotic false aneurysm. However, despite oral anticoagulation and dual antiplatelet therapy, graft patency could not be achieved after 3 months. In summary, implantation of coated stents is a feasible and safe approach for the acute and long term treatment of potentially life-threatening condition of a pulmonary artery false aneurysm while treatment to achieve long term patency of the affected vessel still remains an issue to be resolved.

Background— HMG-CoA-reductase inhibitors have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering. We have recently demonstrated that pretreatment with simvastatin profoundly improves survival in a cecal ligation and perforation (CLP) model of sepsis. Here, we studied whether treatment with simvastatin after onset of sepsis-induced hemodynamic alterations is beneficial and whether prolonged survival can also be achieved with other statins. Methods and Results— Mice were rendered septic by CLP. At 6 hours after sepsis induction, when profound hemodynamic alterations were manifest, treatment with atorvastatin, fluvastatin, pravastatin, simvastatin, or placebo was initiated. Except for fluvastatin (27±2.3 hours), survival time was extended from 23±1.2 hours for placebo-treated mice to 37±3.6 hours for simvastatin-treated, to 40±4.2 hours for atorvastatin-treated, and to 39±3.9 hours for pravastatin-treated mice. This profound improvement is based on the preservation of cardiac function and hemodynamic status in statin-treated animals, both of which are severely impaired in untreated CLP mice. As underlying mechanisms, improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes could be demonstrated after statin treatment. Conclusions— Well established in the treatment of lipid disorders and coronary artery disease, statins harbor the additional and novel potential of effective sepsis treatment. This benefit extends to several but not all statins tested.

Although cell-based therapy after myocardial infarction (MI) may be beneficial in improving cardiac dysfunction, the underlying mechanisms remain to be clarified. Since human umbilical vein endothelial cells (HUVEC) harbor the potential for transdifferentiation, we studied the functional effects of HUVEC transplantation in a rat model of MI.HUVEC labeled with BrdU or medium alone were injected into the infarcted area and its margin 4 weeks after ligation of the left coronary artery in cyclosporine-treated rats. BrdU(+) signals could be detected in the area of MI at two weeks and two months after injection only in hearts transplanted with HUVEC. While no signs of transdifferentiation into cardiomyocytes were evident, staining for the rat macrophage marker ED-1, adjacent to or colocalized with BrdU(+) signals, revealed an in.ltration with macrophages and implied the phagocytosis of injected HUVEC. In the vicinity of BrdU(+) signals, the density of CD31(+) microvessels was significantly increased in HUVEC-transplanted as compared to medium-treated hearts after two months. HUVEC transplantation led to improved contractility as assessed by echocardiography and to higher coronary flow rates as well as to improved response to volume strain and catecholamine stress in Langendorff perfused hearts.After MI, transplanted HUVEC persist in the host myocardium and trigger an infiltration with macrophages. The ensuing increase in neovascularization and improvement in global left ventricular function may be attributable to the associated inflammatory response.

Background— HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis. Methods and Results— Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24±0.09 to 0.87±0.11 mL · min −1 · g −1 in untreated mice ( P −1 · g −1 at baseline and 1.15±0.1 mL · min −1 · g −1 20 hours after CLP, P =NS, n=12) in CLP mice treated with simvastatin]. Untreated CLP mice remained refractory to β-stimulation, whereas the responsiveness to dobutamine was restored by treatment with simvastatin. Susceptibility of coronary flow to endothelial nitric oxide synthase (eNOS) stimulation by bradykinin was close to 3 times as pronounced in untreated CLP mice as in untreated sham-operated mice, indicating a high level of eNOS activation secondary to sepsis. In addition, treatment with simvastatin reversed inflammatory alterations in CLP mice, namely, increased monocyte adhesion to endothelium. Conclusions— Simvastatin, which is well established in the treatment of lipid disorders and coronary artery disease, might have the additional potential of being an effective agent in sepsis treatment.

Background: Raised concentrations of endotoxin (lipopolysaccharide, LPS) are found in patients with chronic heart failure (CHF). Tolerance of monocytes to LPS can be induced by LPS itself resulting in a downregulation of cytokine response to LPS challenge. This phenomenon of LPS desensitization has also been suggested for CHF. Methods: We investigated whether CHF patients really show a desensitization to LPS stimuli at rest or after physical exercise, which was used as a model of limited inflammatory reaction. Thirty-five patients with CHF (59±12 years, 8 women) and 30 healthy control subjects were prospectively studied with cardiopulmonary exercise testing. At rest and directly after exercise blood samples were taken for the quantitative determination of HLA-DR expression of monocytes as a measure for immune competence and for the measurement of TNFα generation after ex vivo stimulation by LPS. Results: HLA-DR expression was comparable in CHF patients and controls at rest as well as after exercise. TNFα production by LPS-stimulated monocytes ex vivo was higher in CHF patients compared to controls at rest and after exercise. Conclusions: Thus, our data are the first to show that patients with stable CHF show a cellular hypersensitivity to LPS with a higher TNFα generation capacity at rest and after exercise compared to controls. CHF patients seem to have a marked susceptibility to low inflammatory stimuli and no desensitization to LPS.

Aim Inflammation is a hallmark of cardiac healing after myocardial infarction and it determines subsequent cardiovascular morbidity and mortality. The aim of the present study was to explore whether inflammation imaging with two perfluorocarbon (PFC) nanoemulsions and fluorine magnetic resonance imaging (19F MRI) is feasible at 3.0 T with sufficient signal-to-noise ratio (SNR) using explanted hearts, an 19F surface coil and dedicated MR sequences. Methods and results Acute myocardial infarction (AMI) was induced by balloon angioplasty (50 min) of the distal left anterior descending artery in 12 pigs. One day thereafter, PFCs were injected intravenously to label circulating monocytes. Either emulsified perfluoro-15-crown-5 ether or already clinically applied perfluorooctyl bromide (PFOB) was applied. Four days after AMI and immediately after gadolinium administration, hearts were explanted and imaged with a 3.0 T Achieva MRI scanner. 19F MRI could be acquired with an SNR of >15 using an in-plane resolution of 2 × 2 mm2 within

PLoS one 9(7), e102648 (2014). doi:10.1371/journal.pone.0102648, Published by PLoS [u.a.], Lawrence, Kan.

Dietary interventions with flavan-3-ols have shown beneficial effects on vascular function. The translation of these findings into the context of the health of the general public requires detailed information on habitual dietary intake. However, only limited data are currently available for European populations. Therefore, in the present study, we assessed the habitual intake of flavan-3-ol monomers, proanthocyanidins (PA) and theaflavins in the European Union (EU) and determined their main food sources using the EFSA (European Food Safety Authority) Comprehensive European Food Consumption Database. Data for adults aged 18–64 years were available from fourteen European countries, and intake was determined using the FLAVIOLA Flavanol Food Composition Database, developed for the present study and based on the latest US Department of Agriculture and Phenol-Explorer databases. The mean habitual intake of flavan-3-ol monomers, theaflavins and PA ranged from 181 mg/d (Czech Republic) to 793 mg/d (Ireland). The highest intakes of flavan-3-ol monomers and theaflavins were observed in Ireland (191/505 mg/d) and the lowest intakes in Spain (24/9 mg/d). In contrast, the daily intake of PA was highest in Spain (175 mg/d) and lowest in The Netherlands (96 mg/d). Main sources were tea (62 %), pome fruits (11 %), berries (3 %) and cocoa products (3 %). Tea was the major single contributor to monomer intake (75 %), followed by pome fruits (6 %). Pome fruits were also the main source of PA (28 %). The present study provides important data on the population-based intake of flavanols in the EU and demonstrates that dietary intake amounts for flavan-3-ol monomers, PA and theaflavins vary significantly across European countries. The average habitual intake of flavan-3-ols is considerably below the amounts used in most dietary intervention studies.

OBJECTIVES We sought to evaluate whether transthoracic contrast echocardiography using second harmonic imaging (SHI) is a diagnostic alternative to transesophageal contrast echocardiography (TEE) for the detection of atrial right to left shunt. BACKGROUND Paradoxic embolism is considered to be the major cause of cerebral ischemic events in young patients. Contrast echocardiography using TEE has proven to be superior to transthoracic echocardiography (TTE) for the detection of atrial shunting; SHI is a new imaging modality that enhances the visualization of echocardiographic contrast agents. METHODS We evaluated 111 patients with an ischemic cerebral embolic event for the presence of atrial right to left shunt using an intravenous (IV) contrast agent in combination with three different echocardiographic imaging modalities: 1) TTE using fundamental imaging (FI); 2) TTE using SHI; and 3) TEE. The severity of atrial shunting and the duration of contrast visibility within the left heart chambers were evaluated for each imaging modality. Image quality was assessed separately for each modality by semiquantitative scoring (0 = poor to 3 = excellent). Presence of atrial right to left shunt was defined as detection of contrast bubbles in the left atrium within the first three cardiac cycles after contrast appearance in the right atrium either spontaneously or after the Valsalva maneuver. RESULTS A total of 57 patients showed evidence of atrial right to left shunt with either imaging modality. Fifty-one studies were positive with TEE, 52 studies were positive with SHI, and 32 were positive with FI (p CONCLUSIONS In combination with IV contrast injections, TEE and SHI have a comparable yield for the detection of atrial right to left shunt. Both modalities may miss patients with atrial shunting. In young patients with an unexplained cerebrovascular event and no clinical evidence of cardiac disease, a positive SHI study may obviate the need to perform a TEE study to search for cardiac sources of emboli.

The goal of this study was to validate 3-dimensional echocardiography by multiplane transesophageal transducer for the determination of left ventricular volumes and ejection fraction in an in vitro experiment and to compare the method in vivo with biplane angiography and the continuous thermodilution method. In the dynamic in vitro experiment, we scanned rubber balloons in a water tank by using a pulsatile flow model. Twenty-nine measurements of volumes and ejection fractions were performed at increasing heart rates. Three-dimensional echocardiography showed a very high accuracy for volume measurements and ejection fraction calculation (correlation coefficient, standard error of estimate, and mean difference for end-diastolic volume 0.998, 2.3 mL, and 0.1 mL; for end-systolic volume 0.996, 2.7 mL, and 0.5 mL; and for ejection fraction 0.995, 1.0%, and -0.4%, respectively). However, with increasing heart rate there was progressive underestimation of ejection fraction calculation (percent error for heart rate below and above 100 bpm 0.59% and -8.6%, P.001). In the in vivo study, left ventricular volumes and ejection fraction of 24 patients with symmetric and distorted left ventricular shape were compared with angiography results. There was good agreement for the subgroup of patients with normal left ventricular shape (mean difference +/-95% confidence interval for end-diastolic volume 5.2+/-6.7 mL, P.05; for end-systolic volume -0.5+/-8.4 mL, P = not significant; for ejection fraction 2.4%+/-7.2%, P = not significant) and significantly more variability in the patients with left ventricular aneurysms (end-diastolic volume 23.1+/-56.4 mL, P.01; end-systolic volume 5.6+/-41.0 mL, P = not significant; ejection fraction 4.9%+/-16.0%, P.05). Additionally, in 20 critically ill, ventilated patients, stroke volume and cardiac output measurements were compared with measurement from continuous thermodilution. Stroke volume as well as cardiac output correlated well to thermodilution (r = 0.89 and 0.84, respectively, P.001), although both parameters were significantly underestimated by 3-dimensional echocardiography (mean difference +/-95% confidence interval = -6.4+/-16.0 mL and -0.6+/-1.6 L/min, respectively, P.005).

Background Fractional flow reserve (FFR) is a valid surrogate for hemodynamic significance in stenotic native coronary arteries. The aim of this study was to examine the value of FFR compared to stress perfusion myocardial scintigraphy (SPMS) in patients with coronary stent restenosis. Methods We studied 42 patients, aged 62 ± 10 years, with stent restenosis 5.3 ± 1.6 months after coronary stent implantation. All patients had a single coronary lesion of intermediate severity (diameter stenosis 40–70%). FFR measurement, SPMS, and quantitative angiography of the stent stenosis were performed in all patients. Results The mean percentage in stent diameter stenosis was 53 ± 9%. FFR was 0.77 ± 0.15. In 20 patients FFR was below 0.75. Nineteen patients had reversible perfusion defects in SPMS. FFR showed good diagnostic accuracy for the detection of reversible perfusion defects in SPMS (AUROC 0.86, 95% CI 0.74–0.98). The percentage of agreement of SPMS and FFR was 88%, with the best cutoff value of 0.75 for FFR. Conclusions A FFR value of 0.75 is not only valid for diagnosing significant native coronary stenosis, but also for stent restenosis. Thus, FFR measurement should be taken into account when making decisions regarding patients with stent restenosis.

Background Transcatheter aortic valve implantation (TAVI) offers a minimal invasive option for the treatment of patients with severe aortic stenosis at high risk for conventional surgery. The objective of this study was to investigate whether there is a positive effect on the left ventricular remodeling 6 month after transcatheter aortic valve implantation (TAVI) using cardiac magnetic resonance imaging (cMRI). Methods 20 patients with severe aortic stenosis (aortic valve area

Background Imaging of the aortic annulus is paramount for the success of transcatheter aortic valve implantation (TAVI) to obviate prosthesis size mismatch. The aortic annulus is a dynamic structure with alterations of its ellipsoid shape during the cardiac cycle. The objective of this study was to investigate with cine-MRI the changes of the sagittal and coronal diameter of the aortic annulus and whether the point in time of measurement is relevant for prosthesis size selection.

Background— Transcatheter aortic valve implantation (TAVI) using the Medtronic CoreValve (MCV) system might represent an alternative to conventional redo surgery in older high-risk patients with a failing aortic valve bioprosthesis. Methods and Results— Symptomatic patients with failing aortic valve bioprosthesis, aged ≥65 years with a logistic EuroSCORE ≥10 % were considered for treatment. Local anesthesia was used to retrogradely implant the MCV system into the failing bioprosthetic valve. Clinical events were recorded and a transthoracic echocardiography was performed to evaluate the impact of MCV on hemodynamics after transcatheter aortic valve implantation. A total of 27 patients (aged 74.8±8 years, logistic EuroSCORE of 31±17%) were treated. In those with AS and AS and AR (n=25), the mean gradient declined from 42±16 mm Hg before to 18±8 mm Hg after MCV implantation ( P Conclusions— These results suggest that transfemoral MCV implantation into a wide range of degenerated aortic bioprosthetic valves—irrespective of the failure mode—is feasible, safe, and improves hemodynamics in older patients with higher risk for conventional aortic valve redo surgery.

Background In contrast to surgical aortic valve replacement pre procedural assessment of aortic, aortic annulus diameter and prosthesis size is essential for successful percutaneous interventional valve therapy. Among different imaging modalities multislice-computed tomography (MSCT) and transesophageal echocardiography (TEE) are routinely used for patient screening. We sought to evaluate the diagnostic performance of cardiac magnetic resonance tomography (CMR) in this setting, and the difference in diameter measurements between all 3 imaging modalities. Methods

Aims To characterize the time course of tumor necrosis factor-α (TNF-α) serum levels along with myocardial perfusion and contractile function in patients with ST-segment elevation myocardial infarction (STEMI) and successful primary percutaneous coronary intervention (PCI). Methods Serum levels of TNF-α, interleukin 6 (IL-6), and C-reactive protein (CRP) were measured in 42 patients with STEMI before, one and 6 days after successful PCI. Myocardial perfusion was assessed by contrast-enhanced echocardiography (ceEcho), contractile function by unenhanced two-dimensional (2DE) and real-time three-dimensional echocardiography. In a subset of 18 patients, infarct size was quantified by late gadolinium enhancement cardiovascular magnetic resonance imaging (LGE-CMR) on day six. Results TNF-α serum levels were in the upper normal range within the first 12 h from symptom onset and increased continuously until day six, while IL-6 and CRP increased subsequently with a peak on day one after STEMI. Serum TNF-α on day one after PCI correlated with perfusion defects, wall motion abnormalities, and infarct size (ceEcho: r = 0.52, p = 0.005; 2DE: r = 0.56, p = 0.002; LGE-CMR: r = 0.83–0.86; p < 0.0001). Using multiple regression linear analysis, infarct size on day six was predicted by serum TNF-α 1 day after PCI (p = 0.006, adjusted R 2 0.638). Conclusion Our data reflect the clinical significance of early TNF-α elevation in patients with STEMI and primary PCI (Controlled Clinical Trials number, NCT00529607).

Temporary cardiac pacing may become necessary as treatment or as prophylaxis of hemodynamic instability resulting from tachy- or bradyarrhythmia. The goal is to restore effective cardiac depolarization until the dysrhythmia either can be resolved or until a long-term therapy is initiated.

Background Peripheral chemoreceptors residing predominantly in the carotid body monitor changes in arterial blood oxygen and are mechanistically linked to the cardiorespiratory control by the autonomic nervous system. Enhanced sympathetic activation is common in end-stage renal disease and kidney transplantation has been shown to improve cardiorespiratory reflex measures of autonomic function. Objective The aim of the present study was to test whether improvement in renal function following kidney transplantation is related to an improvement in chemosensory function. Methods and Results We compared hyperoxic chemoreflex sensitivity (CHRS) in patients after renal transplantation (RTX) to that in patients on maintenance hemodialysis (HD), and that of age- and gender-matched healthy controls. In addition, we investigated the impact of common confounding factors including pharmacological neurohumoral modulation and diabetes mellitus. The difference in the R-R intervals divided by the difference in the oxygen pressures before and after deactivation of the chemoreceptors by 5-min inhalation of 7 L oxygen was calculated as the hyperoxic CHRS. Autonomic activity was characterized by 24-h time-domain heart rate variability (HRV) parameters. CHRS was improved in RTX patients as compared to HD patients being related to HRV. CHRS was related to the concomitant presence of diabetes and medication with cyclosporine. Conclusion Our findings indicate that chemosensory activity following kidney transplantation is related to cardiac autonomic control, but functional testing might only be useful to characterize the time course and extent of sympathetic activation in selected patients due to existing co-morbidities and immunosuppressive medication in this population.

As yet, murine aortic grafts have merely been monitored histopathologically. The aim of our study was to examine how these grafts can be monitored in vivo and non-invasively by using high-resolution ultrasound microimaging to evaluate function and morphology. A further aim was to prove if this in vivo monitoring can be correlated to immunohistological data that indicates graft integrity.Murine infrarenal aortic isografts were orthotopically transplanted into 14 female mice (C57BL/6-Background) whereas a group of sham-operated animals (n = 10) served as controls. To assess the graft morphology and hemodynamics, we examined the mice over a post-operative period of 8 weeks with a sophisticated ultrasound system (Vevo 770, Visual Sonics).The non-invasive graft monitoring was feasible in all transplanted mice. We could demonstrate a regular post-transplant graft function and morphology, such as anterior/posterior wall displacement and wall thickness. Mild alterations of anterior wall motion dynamics could only be observed at the site of distal graft anastomosis (8 weeks after grafting (transplant vs. sham mice: 0.02 mm ± 0.01 vs. 0.03 mm ± 0.01, p0.05). However, the integrity of the entire graft wall could be confirmed by histopathological evaluation of the grafts.With regard to graft patency, function and morphology, high resolution ultrasound microimaging has proven to be a valuable tool for longitudinal, non-invasive, in vivo graft monitoring in this murine aortic transplantation model. Consequently, this experimental animal model provides an excellent basis for molecular and pharmacological studies using genetically engineered mice.

Cardiovascular mortality is markedly increased in chronic kidney disease (CKD) and may be explained in part by sympathetic hyperactivity. Impaired hyperoxic chemoreflex sensitivity (CHRS) has been attributed to an increased sympathetic tone. The aim of the present study was to examine whether chemosensor function is altered in patients with CKD.We assessed CHRS in 20 patients with stage 3 CKD [glomerular filtration rate (GFR) 30-59 ml/min/1.73 m(2)], in 15 patients with stage 4 CKD [GFR 15-29 ml/min/1.73 m(2)], as well as in 35 age and gender matched patients without any evidence of CKD. The difference in the R-R intervals divided by the difference in the oxygen pressures before and after deactivation of the chemoreceptors by inhalation of pure oxygen was calculated as the CHRS. A CHRS below 3.0 ms/mmHg was defined as pathological. CHRS was significantly depressed in patients with stage 3 CKD (2.9 ± 0.9 ms/mmHg, P=0.005) and in patients with stage 4 CKD (2.1 ± 0.6 ms/mmHg, P0.001), as compared with patients without CKD (6.7 ± 0.9 ms/mmHg). There was a negative correlation between serum creatinine and CHRS (r=-0.51; P0.001). In patients with CKD, chemosensor deactivation decreased mean arterial pressure from 91 ± 4 mmHg to 87 ± 3 mmHg (P=0.03). Multivariate analysis showed that GFR (P=0.001) was the only independent predictor of a pathological CHRS.Using a relatively non-invasive bedside test we provide evidence for a blunted peripheral chemosensor function in chronic kidney disease. We thereby lay the basis for interventional studies assessing chemosensor function in chronic kidney disease.

Age-dependent alterations of the vessel wall may predispose older individuals to increased cardiovascular pathology. Aging is associated with an impaired bioactivity of nitric oxide (NO). Plasma nitrite reflects NO-synthase activity under fasting conditions and is an important storage pool of NO. To test the hypothesis that aging is associated with an impaired capacity of the vasculature to increase plasma nitrite during exercise, 29 young and 28 old healthy individuals (25 +/- 1 years and 58 +/- 2 years; P < 0.001) without major cardiovascular risk factors were enrolled. Exercise stress was similar in both groups. Baseline nitrite did not differ (107 +/- 8 vs. 82 +/- 10 nmol/l, young vs. old; n.s.) although a trend toward higher nitrite levels in young individuals was seen. In young subjects, exercise increased plasma nitrite by 38 +/- 7% (P < 0.001) compared to only 13 +/- 8% (P = n.s.) in older subjects. L-NMMA blocked increases of nitrite. Endothelial function, as defined by flow-mediated-dilation (FMD) of the brachial artery via ultrasound, was impaired in older subjects (5.4 +/- 0.4% vs. 6.7 +/- 0.3%; P < 0.01). Multivariate analysis showed that age (P = 0.007), BMI (P = 0.010), and LDL (P = 0.021) were independent predictors of nitrite increase. The fact that aging is associated with an impaired capacity of the vasculature to adequately increase nitrite to physiological stimuli may contribute to attenuated maintenance and further deterioration of vascular homeostasis with aging.

Nitrite plays an eminent role in cardiovascular physiology and pathology, mediating hypoxic vasodilation, reducing ischemia-reperfusion injury, and regulating cardiac energetics and function. The role of circulating nitrite in critically ill patients has not been examined so far. To investigate whether whole blood nitrite can be determined reproducibly in an intensive care setting, 30 patients from a cardiology intensive care unit were enrolled in this study, no matter what the underlying disease. Blood was drawn from an arterial catheter and whole blood nitrite was determined, using a tri-iodide/ozone-based chemiluminescence assay after incubation with a ferricyanide-containing stabilization solution. Whole blood nitrite levels ranged from 35 to 1193 nmol/L (mean+/-SEM: 220+/-20 nmol/L). Myocardial infarction was associated with lower whole blood nitrite levels (200+/-53 nmol/L for elevated serum CK MB levels vs 432+/-95 nmol/L in the normal CK MB range, p=0.039). Neither impaired kidney function nor an inflammatory state was associated with higher or lower whole blood nitrite levels. In conclusion, whole blood nitrite can be measured easily and reproducibly in critically ill patients, regardless of renal function and inflammation. The origin of decreased nitrite levels in myocardial infarction is currently unclear and needs to be further elucidated.

Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.

Stefanie Keymel,1 Katharina Hellhammer,1 Tobias Zeus,1 Marc Merx,2 Malte Kelm,1 Stephan Steiner3 1Department of Cardiology, Pneumology, and Vascular Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, 2Department of Cardiology, Vascular Diseases and Intensive Care Medicine, KRHKlinikum Robert Koch Gehrden, Gehrden, 3Department of Cardiology, Pneumology and Intensive Care Medicine, St Vincenz Hospital, Limburg, Germany Background: Aortic valve stenosis is common in the elderly, with a prevalence of nearly 3% in patients aged 75 years or older. Despite the fact that sleep-related breathing disorders (SRBD) are thought to be associated with cardiac disease, little is known about their prevalence in this patient cohort. The purpose of this study was to evaluate the prevalence of SRBD in older patients with aortic valve stenosis admitted for transcatheter aortic valve implantation.Methods: Forty-eight consecutive patients (mean age 81±6 years; 37.5% male) with symptomatic aortic valve stenosis and considered for transcatheter aortic valve replacement were screened for SRBD. Sleep studies were performed by in-hospital unattended cardiorespiratory polygraphy measuring nasal air flow, chest and abdominal efforts, as well as oxygen saturation and body position. The patients were divided in subgroups dependent on the documented apnea–hypopnea index (AHI; no SRBD was defined as an AHI of

Statins are effective lipid-lowering agents used extensively in medical practice. This review summarizes the evidence for statin treatment of cardiovascular patients in the intensive care unit and briefly discusses the role of statins in prevention and treatment of sepsis as a potential future application of statins in critical care.Recent studies have extended the use of statin therapy to the acute manifestations of cardiovascular disease and have suggested cholesterol-independent therapeutic benefits, termed pleiotropic effects, which have added a wide scope of potential targets for statin therapy.Statin therapy should be continued in intensive-care patients in whom statin therapy is warranted due to underlying cardiovascular disease or significant risk thereof. In acute coronary syndromes, statin therapy should be initiated within 24-96 h regardless of pretreatment cholesterol levels. Patients undergoing vascular surgery should receive peri-operative statin therapy. Placebo-controlled clinical trials are required to consolidate the experimental and observational evidence for prevention and treatment of sepsis.

Accelerated atherosclerosis in dialysis patients is characterized by severe vascular calcification, and the magnitude of vascular calcification is associated with increased cardiovascular mortality. Calcification-dependent arterial stiffness is considered to be a major determinant of cardiac failure in uremia. Fetuin-A/alpha(2)-Heremans-Schmid glycoprotein is an abundant serum protein with powerful calcification inhibitory properties. Fetuin-A deficiency was recently linked to cardiovascular mortality in dialysis patients. Fetuin-A knockout (fetuin-KO) mice spontaneously develop widespread soft tissue calcification, including significant myocardial calcification, whereas larger arteries are spared. Therefore, this investigation offers the unique opportunity to study the functional role of isolated myocardial calcification independent of arterial stiffness by assessing the hemodynamics of fetuin-KO mice. Cardiac output in fetuin-KO mice was lower than in wild-type mice (fetuin-KO 1.81 +/- 0.18 versus WT 2.45 +/- 0.29 ml/min per g; P0.005), and fetuin-KO mice were refractory to dobutamine stimulation. Left ventricular relaxation was significantly impaired in fetuin-KO hearts with the relaxation index reduced by 23% (P0.005). After ischemia, fetuin-KO hearts displayed a continuous decline in left ventricular developed pressure after the initial phase of reperfusion, resulting in 77 +/- 15% of preischemic left ventricular developed pressure (P0.05 versus wild-type). In fetuin-KO mice, dystrophic cardiac calcification, with myocardial calcium contents increased 60-fold, was associated with profound induction of profibrotic TGF-beta and downstream collagen and fibronectin mRNA synthesis. In conclusion, independent of arterial stiffness, calcification-associated "myocardial stiffness" characterized by cardiac fibrosis, diastolic dysfunction, impaired tolerance to ischemia, and catecholamine resistance thus may constitute an underestimated cardiovascular risk factor that contributes to cardiac failure in calcification-prone states.