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Background Animal studies demonstrated that serelaxin lessens fibrosis in heart failure. This study assessed its effect on myocardial deformation using cardiac magnetic resonance and elucidated its relationship to gene regulation and histology in a mouse heart failure model. Methods and Results C57 BL /6J mice were subjected to SHAM (n=4) or transverse aortic constriction ( TAC ). At week 10, TAC mice were randomized to receive either serelaxin (0.5 mg/kg per day; n=11) or vehicle (n=13) for 4 weeks. Cardiac magnetic resonance imaging was performed at baseline and repeated at the end of the study (week 14). Cine images were used to calculate left ventricular ( LV ) global longitudinal, circumferential, and radial strain. Hearts were examined for histology and gene expression. Compared with SHAM , mice 10 weeks after TAC showed increased LV mass with significant decreases in LV deformation parameters, indicating subclinical deterioration of myocardial function. At week 14, TAC mice given serelaxin demonstrated significant improvements in all LV strain parameters and no decrease in LV stroke volume and ejection fraction compared with TAC mice given vehicle. A significant positive correlation between global circumferential strain and the extent of myocardial fibrosis was found, and global circumferential strain correlated significantly with the expression of heart failure genes in serelaxin‐treated mice. Conclusions Serelaxin improved cardiac magnetic resonance–derived myocardial deformation parameters as well as histomorphometric and gene expression findings in mice with heart failure. Cardiac magnetic resonance–derived myocardial mechanics correlate with histology and gene expression, stressing its utilization in myocardial remodeling.

Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH.

Objective: Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction. Methods: Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj−/− (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake. Results: High-fat diet fed-Ptprj−/− mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj−/− mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj−/− mice. Conclusion: Together, these data establish DEP-1 as novel negative regulator of insulin signaling.

Zusammenfassung: Die koronare Herzerkrankung ist eine chronisch entzündliche Veränderung der Herzkranzgefäße. Sie ist aktuell die häufigste Todesursache in Deutschland. Der 27. Herzbericht 2015 stellt die aktuelle Prävalenz und die sektorübergreifende Versorgung in Deutschland dar. Der Beitrag beleuchtet ausgewählte Daten und diskutiert sie im Kontext aktueller wissenschaftlicher Evidenz. Aktuelle Entwicklungen in der präventiven und akutmedizinischen Versorgung der koronaren Herzerkrankung werden diskutiert.

Aims The effectiveness of stress cardiac magnetic resonance (CMR) as a gatekeeper for coronary angiography (CA) has been established. Level five HTA studies according to the hierarchical model of diagnostic test evaluation are not available. Methods This cohort study included 1,158 consecutive patients (mean age 63 ± 11 years, 42 % women) presenting at our institution between January 1, 2003 and December 31, 2004 with suspected coronary artery disease (CAD) for an elective CA. The patients were assessed for eligibility and propensity score matching was applied to address selection bias regarding the patients’ allocation to CMR or direct CA. Median patient follow-up was 7.9 years (95 % CI 7.8–8.0 years). The primary effect was calculated as relative survival difference. The cost unit calculation (per patient) at our institute was the source of costs. Results Survival was similar in CMR and CA (p = 0.139). Catheterizations ruling out CAD were significantly reduced by the CMR gate-keeper strategy. Patients with prior CMR had significantly lower costs at the initial hospital stay and at follow-up (CMR vs. CA, initial: 2,904€ vs. 3,421€, p = 0.018; follow-up: 2,045€ vs. 3,318€, p = 0.037). CMR was cost-effective in terms of a contribution of 12,466€ per life year to cover a part of the CMR costs. Conclusion Stress CMR prior to CA was saving 12,466€ of hospital costs per life year. Lower costs at follow-up suggest sustained cost-effectiveness of the CMR-guided strategy. Electronic supplementary material The online version of this article (doi:10.1007/s00392-014-0793-0) contains supplementary material, which is available to authorized users.

AimTo study the effects of RD on renal artery wall function non-invasively using magnetic resonance.Methods and results32 patients undergoing RD were included. A 3.0 Tesla magnetic resonance of the renal arteries was performed before RD and after 6-month. We quantified the vessel sharpness of both renal arteries using a quantitative analysis tool (Soap-Bubble®). In 17 patients we assessed the maximal and minimal cross-sectional area of both arteries, peak velocity, mean flow, and renal artery distensibility. In a subset of patients wall shear stress was assessed with computational flow dynamics. Neither renal artery sharpness nor renal artery distensibility differed significantly. A significant increase in minimal and maximal areas (by 25.3%, p = 0.008, and 24.6%, p = 0.007, respectively), peak velocity (by 16.9%, p = 0.021), and mean flow (by 22.4%, p = 0.007) was observed after RD. Wall shear stress significantly decreased (by 25%, p = 0.029). These effects were observed in blood pressure responders and non-responders.ConclusionsRD is not associated with adverse effects at renal artery level, and leads to an increase in cross-sectional areas, velocity and flow and a decrease in wall shear stress.

BACKGROUND Endomyocardial remodeling is characterized by progressive fibrosis and scars and may develop after heart transplantation. The role of everolimus in preventing this process has not been evaluated as yet. METHODS We prospectively studied 132 patients at baseline pretransplant and at 4 weeks, 1 year, and 3 years after heart transplantation. Fibrosis, scars (Zeiss Vision, in Sirius), and acute cellular rejection (hematoxylin-eosin) were studied in biopsy. Transplant vasculopathy was assessed by coronary angiography (focal stenoses, peripheral obliterations, negative vascular remodeling defined by peripheral obliterations, and diffusely narrowed proximal and mid vessel segments). RESULTS Patients on everolimus versus patients on mycophenolate mofetil presented with significantly less fibrosis at 4 weeks (3.8%±0.3% vs. 5.5%±0.3%, P=0.007), 1 year (4.1%±0.3% vs. 4.8%±0.3%, P=0.015), and 3 years (4.2%±0.3% vs. 5.5%±0.7%, P=0.049) posttransplant and showed less scarring at 3 years posttransplant (19.9±1.9% vs. 31.9±4.6% vs. baseline biopsy 26.0±2.8%; P=0.017). Angiographic peripheral obliterations correlated with higher amounts of endomyocardial fibrosis. The negative correlation of everolimus and the positive correlation of peripheral obliterations with fibrosis were confirmed by regression analysis. Angiographic stenoses or acute cellular rejection had no effect on the development of fibrosis. Negative vascular remodeling in 1-year follow-up tended to be less frequent in everolimus-treated patients (24% vs. 76%; P=0.053). CONCLUSIONS Everolimus prevents endomyocardial remodeling after heart transplantation and might have beneficial effects on vascular remodeling of epicardial coronary arteries too. Angiographic peripheral obliterations correlate with increased amounts of endomyocardial fibrosis, suggesting a relevant effect on microvascular perfusion.

Aims: Blood flow, vascular shape and size and local remodeling of the vascular wall are linked through wall shear stress (WSS) signaling. Inter-individual comparison of shape and WSS is hampered by large differences in size of flow and shape. We performed non-dimensional modeling to discriminate different types of coronary artery remodeling based on WSS patterns and vessel morphology. Methods and results: Blood flow was simulated in three-dimensional reconstructed right coronary artery trees from seven controls, five patients with coronary artery disease (CAD) and five patients with aneurysmatic CAD (AnCAD) classified by expert visual diagnosis. A discriminant model using low WSS area, a remodeling index, and cross-correlation of WSS in main trunks and complete trees (K) as non-dimensional parameters classified CAD and AnCAD correctly and identified three patients with high risk profile and functional disease in controls. The new model was compared with discriminant analysis of identical cases simulated without side-branches. The inclusion of K (information from side-branches) and replacement of the mean diameter by a non-dimensional remodeling index improved the model. We found significant (p < 0.005) gender differences in the remodeling index. Conclusion: The combination of non-dimensional modeling and WSS profiling should be further investigated as a novel diagnostic tool in CAD beyond local stenosis.

This study tests the correlation of coronary angiographic findings with the extent of microvascular reaction in right ventricular endomyocardial biopsies (EMBs) in transplanted hearts. In EMBs (n = 209) of 30 heart transplant patients (8 female, 22 male, mean age 48 years) microvascular reaction, i.e. endothelial cell swelling and vascular wall thickening (both grade 0-2), was graded by light microscopy at ×200. Patients' first and last coronary angiography (CA) (mean time after heart transplantation [HTx] 8 and 44 months) were graded according to the Stanford Classification and the presence of diameter irregularities was evaluated semi-quantitatively. We found a correlation of angiographic type B lesions with endothelial cell swelling during the first 5 months and vascular wall thickening during the fifth to fourteenth month after HTx (p

ObjectivesThe aim of this study was to assess the long-term value of high-dose dobutamine cardiac magnetic resonance (DCMR) for the prediction of cardiac events in a large cohort of patients with known or suspected coronary artery disease.BackgroundHigh-dose DCMR has been shown to be a useful technique for diagnosis and intermediate-term prognostic stratification.MethodsClinical data and DCMR results were analyzed in 1,463 consecutive patients undergoing DCMR between 2000 and 2004. Ninety-four patients were lost to follow-up. The remaining 1,369 patients were followed up for a mean of 44 ± 24 months. Cardiac events, defined as cardiac death and nonfatal myocardial infarction, were related to clinical and DCMR results.ResultsThree-hundred fifty-two patients underwent early revascularization (≤3 months of DCMR) and were excluded from analysis. Of the remaining 1,017 patients, 301 patients (29.6%) experienced inducible wall motion abnormalities (WMA). Forty-six cardiac events were reported. In those with and without inducible WMA, the proportion of patients with cardiac events was 8.0% versus 3.1%, respectively, p = 0.001 (hazard ratio: 3.3; 95% confidence interval: 1.8 to 5.9 for the presence of inducible WMA; p < 0.001). A DCMR without inducible WMA carried an excellent prognosis, with a 6-year cardiac event-free survival of 96.8%. In all 1,369 patients in the patient group with stress-inducible WMA, those patients with medical therapy demonstrated a trend to a higher cardiac event rate (8.0%) than those with early revascularization (5.4%) (p = 0.234). Patients with normal DCMR and medical therapy or early revascularization demonstrated similar cumulative cardiac event rates (3.1% vs. 3.2%, p = 0.964).ConclusionsIn a large cohort of patients, DCMR has an added value for predicting cardiac events during long-term follow-up, improving the differentiation between high-risk and low-risk patients. Patients with inducible WMA and following early revascularization, demonstrate lower cardiac event rates than patients with medical therapy alone.

Objectives The purpose of the present study was to directly compare the diagnostic accuracy of magnetic resonance imaging (MRI) and multislice computed tomography (CT) for the detection of coronary artery stenosis. Background Both imaging modalities have emerged as potential noninvasive coronary imaging modalities; however, CT—unlike MRI—exposes patients to radiation and iodinated contrast agent. Methods One hundred twenty consecutive patients with suspected or known coronary artery disease prospectively underwent 32-channel 3.0-T MRI and 64-slice CT before elective X-ray angiography. The diagnostic accuracy of the 2 modalities for detecting significant coronary stenosis (≥50% luminal diameter stenosis) in segments ≥1.5 mm diameter was compared with quantitative invasive coronary angiography as the reference standard. Results In the patient-based analysis MRI and CT angiography showed similar diagnostic accuracy of 83% (95% confidence interval [CI]: 75 to 87) versus 87% (95% CI: 80 to 92), p = 0.38; sensitivity of 87% (95% CI: 76 to 93) versus 90% (95% CI: 80 to 95), p = 0.16; and specificity of 77% (95% CI: 63 to 87) versus 83% (95% CI: 70 to 91), p = 0.06, respectively. All cases of left main or 3-vessel disease were correctly diagnosed by MRI and CT angiography. In the patient-based analysis MRI and CT angiography were similar in their ability to identify patients who subsequently underwent revascularization: the area under the receiver-operator characteristic curve was 0.78 (95% CI: 0.69 to 0.87) for MRI and 0.82 (95% CI: 0.74 to 0.90) for CT angiography. Conclusions Thirty-two channel 3.0-T MRI and 64-slice CT angiography similarly identify significant coronary stenosis in patients with suspected or known coronary artery disease scheduled for elective coronary angiography. However, CT angiography showed a favorable trend toward higher diagnostic performance.

We compared coronary magnetic resonance angiography (CMRA) and coronary multislice computed tomography angiography (CTA) for prediction of cardiac events in patients with suspected or known coronary artery disease (CAD) scheduled for elective coronary angiography (ICA). We included 110 consecutive

Summary Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty-four coronary angiograms from 11 hospitals were circulated. One hundred eighty-eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa = 0.371, P

The accurate assessment of pulmonary vein (PV) anatomy is important in planning radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). The aim of the present study was to perform a head-to-head comparison of magnetic resonance imaging (MRI) and multislice computed tomography (CT) for the evaluation of PV morphology before RFCA of AF. Contrast-enhanced MRI (on a 1.5-T system) and multislice CT (on a dual-source system) were performed for the evaluation of the PVs in 44 consecutive patients (31 men, mean age 56 +/- 10 years) admitted for RFCA of drug-refractory AF. Data on PV anatomy, ostial branching pattern, and ostial dimensions were compared between MRI and multislice CT. Variant PV anatomy was observed in 21 patients (48%) with the 2 imaging approaches. The incidence of PV ostial branching, as assessed with MRI and multislice CT, was higher on the right and more common in the inferior than superior vein. Agreement between the 2 imaging modalities for the evaluation of variant PV anatomy (kappa = 0.87, 95% confidence interval 0.77 to 0.97) and ostial branching pattern (kappa = 0.84, 95% confidence interval 0.75 to 0.93) was nearly perfect. Assessment of PV ostial cross-sectional area as well as maximal and minimal ostial diameters resulted in strong agreement and correlation (r(2) = 0.75 to 0.99, p0.001 for all) between the 2 imaging approaches. In conclusion, MRI and multislice CT of the PVs appear to provide similar and detailed anatomic and quantitative information before RFCA of AF.

Purpose To define the reproducibility of strain-encoded (SENC) magnetic resonance imaging (MRI) for assessment of regional left ventricular myocardial strain and timing of contraction in a 3T MRI system. Materials and Methods The study population consisted of 16 healthy subjects. SENC measurements were performed in three short-axis (SA) slices (apical, mid, and basal) and three long-axis (LA) views (two-, three-, and four-chamber) for assessment of maximal transmural systolic strain and time to peak strain. To assess the interobserver and interstudy reproducibility, analysis of SENC MRI was performed by two independent observers who were blinded to each other's results and four studies were repeated on a different day. Results Maximal longitudinal strain was highest at the apex, as was maximal circumferential strain. Peak longitudinal strain occurred earliest at the base, as did peak circumferential strain. Interclass correlation coefficient between observers and repeated studies ranged from 0.92 to 0.98 (P < 0.001 for all). Conclusion The present study demonstrates the ability of SENC MRI to define regional left ventricular strain and the time sequence of regional strain. SENC MRI may represent a highly objective method for quantifying regional left ventricular function. J. Magn. Reson. Imaging 2009;29:799–808. © 2009 Wiley-Liss, Inc.

Computational fluid dynamics (CFD) methods based on three-dimensional (3D) vessel reconstructions have recently been shown to provide prognostically relevant hemodynamic data. However, the geometry reconstruction and the assessment of clinically relevant hemodynamic parameters may depend on the used imaging modality. In this study, the silicon model of the left coronary artery (LCA) was acquired with a biplane angiography. The geometry reconstruction was done using commercial CAAS 5.2 QCA 3D software and compared with an original geometry. The original model is an optically digitized post-mortem vessel cast. The biplane angiography reconstruction achieved a Hausdorff surface distance of 0.236 mm to the original geometry that is comparable with results obtained in our earlier study for computed tomography (CT) and magnetic resonance imaging (MRI) reconstructions. Steady flow simulations were performed with a commercial CFD program FLUENT. A comparison of the calculated wall shear stress (WSS) shows good correlation for histograms (r = 0.97) and good agreement among the four modalities with a mean WSS of 0.65 Pa in the original model, of 0.68 Pa in the CT-based model, of 0.67 Pa in the MRI based model, and of 0.69 Pa in the biplane angiography-based model. We can conclude that the biplane angiography-based reconstructions can be used for the WSS profiling of the coronary arteries.

Cardiac allograft vasculopathy (CAV) in patients who have undergone heart transplantation leads to graft dysfunction and is still the major concern for long-term survival. Evaluation of coronary flow velocity reserve (CFR) has been established for diagnosis of CAV. Systemic application of adenosine vs intracoronary testing for CFR has been validated in adults; however, its accuracy in pediatric patients has not yet been proven.CFR was prospectively measured in 33 clinically asymptomatic pediatric heart transplant recipients. CFR measurements were made in the left anterior descending (LAD) artery using a 0.014-inch Doppler FloWire (Cardiometrics). CFR was defined as the ratio of hyperemic (after adenosine injection) to basal (before adenosine) average peak velocity (APV). Adenosine (Adrekar) was administered by intracoronary (15 or 30 mug bolus) and systemic (0.1 mg/kg) injection in each patient. Epicardial CAV was evaluated in coronary angiograms (Stanford criteria) and microvasculopathy was diagnosed in endomyocardial biopsies (evidence of luminal stenosis) blinded to clinical data.Thirty-three patients were included in this study. Their median age (range) was 11.9 (1.4 to 17) years and median post-transplant time 4.3 (1 to 11.7) years. Seventeen of the 33 patients had epicardial CAV (mainly peripheral obliterations or B1 and B2 lesions) and microvascular CAV. Epicardial CAV only was found in 4 patients and microvasculopathy only was present in only 1 patient. CFR was significantly reduced in patients with epicardial CAV and microvasculopathy when compared with patients without any signs of CAV: 206 +/- 53 vs 276 +/- 39 (p0.001) for the systemic application and 213 +/- 50 vs 271 +/- 45 (p = 0.004) for the intracoronary application.CFR and coronary vasoreactivity to adenosine are decreased in pediatric patients with CAV and correlate with histopathologic and angiographic evidence of microvascular disease. Measurement of CFR with intracoronary and systemic application of adenosine is comparable, while systemic application is necessary for non-invasive measurement of CFR in pediatric patients.

Background— Epicardial vasculopathy has been shown to be associated with poor outcome after heart transplantation. We demonstrate that histologically proven stenotic microvasculopathy is a novel prognostic factor for long-term survival. Methods and Results— In 9713 biopsies harvested within the first posttransplantation year from 873 patients (83% male; mean age, 49.1±0.6 years), light microscopic evaluations (×200) were performed for microvasculopathy, defined as stenotic endothelial and/or medial disease. Prevalence of severe epicardial vasculopathy was defined by presence of ≥75% luminal stenosis in coronary angiography (available in 611 of 873 patients), which was present in 118 of 611 patients (19%). For Kaplan-Meier analysis, we defined fatal cardiac events as lethal acute myocardial infarction, sudden cardiac death, and graft failure. Stenotic microvasculopathy was present in 379 of 873 patients (43%) and was due to medial (345/379; 91%) rather than endothelial disease (2/379; 1%) or a combination of both (31/379; 8%; P P =0.3329) and nonstenotic medial disease (12.44 [11.14 to 13.74] versus 12.43 years [10.51 to 14.35]; P =0.4047) did not decrease overall survival or time to fatal cardiac event. Stenotic microvasculopathy was associated with poor overall survival (10.90 [9.16 to 12.60] versus 13.40 years [11.79 to 15.07]; P =0.0374) and decreased freedom from fatal cardiac events (1, 5, 10 years, 95.6±1.4%, 86.9±2.3%, 75.5±3.1% versus 99.1±0.5%, 96.8±1.0%, 89.8±1.9%; P P =0.0031). Conclusions— Stenotic microvasculopathy is frequent in routinely processed biopsies and a new prognostic factor for long-term survival after heart transplantation.

We assessed the value of deceleration time (dt) of diastolic wave of pulmonary venous flow (PVF) (PVF_dt) as noninvasive estimation of pulmonary wedge pressure (PWP) in candidates for and recipients of heart transplantation.We prospectively recruited 51 patients with end-stage congestive heart failure (group A) and 49 recipients of heart transplantation (group B). PWP and PVF_dt were measured using a Swan-Ganz catheter and Doppler echocardiography, respectively. We performed regression analyses to assess interrelationships. Moreover, we used the area under the receiver operating characteristic curve to assess how clearly PVF_dt could discriminate between normal and elevated PWP values.In both study groups, PWP was inversely associated with PVF_dt (R(2) = 0.785 and 0.797, respectively, P.001). A cut-off value of less than 187 milliseconds was predictive of an elevated PWP value (or =12 mm Hg) in both study groups. Specificity and sensitivity were between 90% and 100%, respectively, in both study groups. The area under the receiver operating characteristic curve was 0.961 (0.908-1.013; P.001) for group A and 0.998 (0.992-1.04; P.001) for group B.In recipients of heart transplantation and patients with end-stage congestive heart failure, the noninvasive measuring of PVF_dt distinguishes between normal and elevated PWP values.

Background Previous studies in patients and in dogs with experimentally induced heart failure (HF) showed that electrical signals applied to the failing myocardium during the absolute refractory period improved left ventricular (LV) function. We examined the effects these same cardiac contractility modulating (CCM) electrical signals on myocardial oxygen consumption (MVO 2 ) in both patients and dogs with chronic HF. Methods and Results Six dogs with microembolizations-induced HF and 9 HF patients underwent CCM leads and generator (OPTIMIZER II) implantation. After baseline measurements, CCM signals were delivered continuously for 2 hours in dogs and for 30 minutes in patients. MVO 2 was measured before and after CCM therapy. In dogs, CCM therapy increased LV ejection fraction at 2 hours (26 ± 1 versus 31 ± 2 %, P = .001) without increasing MVO 2 (257 ± 41 versus 180 ± 34 μmol/min). In patients, CCM therapy increased LV peak +dP/dt by 10.1 ± 1.5 %. As with dogs, the increase in LV function after 30 minutes of CCM therapy was not associated with increased MVO 2 (13.6 ± 9.7 versus 12.5 ± 7.2 mL O 2 /min). Conclusions The study results suggest that unlike cAMP-dependent positive inotropic drugs, the increase in LV function during CCM therapy is elicited without increasing MVO 2 .

Target temperature management (TTM) after cardiac arrest (CA) improves outcome in patients with acute coronary syndrome (ACS). Previous data point to an interaction between hypothermia and drug metabolism, potentially impacting on platelet function in patients on antiplatelet therapy.To compare clopidogrel metabolism and platelet function in clopidogrel naïve ACS patients treated with TTM (33°C, n=15) and in ACS patients (troponin positive) without TTM (n=18).Platelet function was measured by multiple electrode platelet aggregometry (MEA), light transmittance aggregometry (LTA) and VASP analysis before and after administration of a 600mg clopidogrel loading dose. Plasma levels of clopidogrel and its metabolites were measured. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. TTM was carried out for 24h at a target temperature of 33°C using a computer feedback surface cooling device in cardiac arrest patients.Plasma concentration of clopidogrel and metabolites was lower in the TTM group after 2 and 4h, respectively (all p0.005 vs. controls), and platelet function tests revealed an attenuated response to clopidogrel with respect to baseline platelet activity in the TTM group. This was significant for MEA, LTA and VASP analysis (all p0.05). Moreover, there was no significant difference in genotype and platelet function determined ex vivo at 33 or 37°C, respectively.Inhibition of platelet function is significantly lessened in TTM at 33°C, likely due to reduced clopidogrel absorption. Patients with TTM might thus have a higher risk for further cardiovascular events despite antiplatelet therapy with clopidogrel.

Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases.

Information regarding the flow properties in bubble columns with a three-phase flow is of great interest for research into its performance, as well as for the validation of computer models. In an earlier paper, we proposed an X-ray based particle tracking velocimetry (PTV), called XPTV. This method allows not only the measurement of the velocities of both solid and fluid phases in a three-phase flow, but also the assessment of the time-averaged local solid phase content. In this paper, we are concerned with the statistical significance of the obtained measurements.

Information regarding the flow in multi-phase systems, such as bubble columns, is necessary for the design of improved devices, as well as for the validation of computer models. Common optical methods are limited in bubble columns with a large void fraction. The reason that this should be is the difference in the refraction indices of liquid and gaseous phases, which leads to reflection and refraction of light. In addition, in flows without optical access, optical methods cannot be used. The method proposed by these authors in their previous paper regarding X-ray based particle tracking velocimetry (PTV)–called XPTV–resolves these problems. It allows us to measure the velocity three-dimensionally, non-invasive, and in devices without optical access. In bubble columns, X-rays are neither reflected nor refracted at the phase boundaries and the flow is penetrated in straight lines. Therefore, it works independently from the void fraction. This has been proved to be a reliable and useful measurement technique, circumventing the limitations of optical methods. This paper reports the latest improvements in the algorithms designed to track and reconstruct particles, a feature which is explained here in detail. The improved algorithms are applied to measure the hydrodynamic parameters in a bubble column under two different flow conditions.

Background Mortality in severe congestive heart failure rises with the incidence of an inter- and intraventricular conduction delay and doubles if atrial fibrillation (AF) occurs. Electrical cardioversion (CV) is frequently regarded as less promising in these patients. Encouraged by first conversions during defibrillation threshold (DFT) testing we consecutively attempted electrical cardioversion in 30 patients selected for cardiac resynchronization therapy (CRT). Methods After successful CV an additional atrial electrode was placed during implantation of a CRT device (ICD or pacemaker) to ensure AV sequential biventricular pacing. Regular clinical follow-up examinations up to 2 years were performed. Results In 23 (75%) of 30 patients (onset of AF at least 6 months earlier), sinus rhythm (SR) could successfully be restored. Under antiarrhythmic medication in 21 patients SR was still present after 333±142 days. Furthermore, a significant increase of EF from 22% to 31% (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P{

Aims: The scope of this study was to assess the potential value of pulmonary venous flow diastolic deceleration time to predict end-diastolic pressure and stratify patients with regard to elevation of left ventricular end-diastolic pressures. Methods and Results: In 174 consecutive patients, pulmonary venous flow diastolic deceleration time was determined and compared with left ventricular end-diastolic pressures measured invasively. The sample was randomly divided into two subgroups of equal size for modelling of prediction and independent testing of the model. Predicted left ventricular end-diastolic pressures calculated from pulmonary venous flow diastolic deceleration time (left ventricular end-diastolic pressures = −10.87 + 5261/pulmonary venous flow diastolic deceleration time) agreed well with measured left ventricular end-diastolic pressures (mean difference: -1.3 ± 3.4 mmHg). The correlation of left ventricular end-diastolic pressures with pulmonary venous flow diastolic deceleration time is fair (r=0.73989). A value of pulmonary venous flow diastolic deceleration time

The measurement of the local solid velocity and the local solid hold-up in three-phase flows (gas, liquid, solid) is of great interest with regard to the design of three-phase reactors. Moreover, such measurements are necessary for the validation of flow simulations of three-phase flows. The optical methods usually applied for velocity measurements such as particle image velocimetry do not work in three-phase flows. This is due to the opacity of the solid phase or/and because of the reflections and refractions that occur on phase boundaries. Other measurement methods are intrusive and very time consuming. The measurement of the local solid hold-up is even more difficult. The new X-ray based particle tracking velocimetry (XPTV), described in this paper, measures the solid velocity and the solid content simultaneously. This fast working and non-intrusive technique has already been successfully applied in a bubble column to measure the liquid velocity. XPTV is a three-dimensional three-component method. It works independently from void fraction and solid hold-up.

AIMS The purpose of this three-dimensional intracoronary ultrasound (ICUS) study was to assess longitudinal plaque distribution patterns in patients with angiographically silent coronary artery disease (CAD) after heart transplantation (HTX). METHODS AND RESULTS Out of 334 patients without diameter stenosis >/=25% determined by coronary angiography, 321 underwent successful three-dimensional ICUS (30 MHz) of the left main coronary artery (LMCA) and all segments of the left anterior descending coronary artery (LAD). Early plaque formation was found in 296 patients (92.2%). Single (focal CAD, n = 65) or multiple (polyfocal CAD, n = 77), discrete coronary lesions were found in 142 patients and continuous plaque formation of at least one entire coronary segment (diffuse CAD) in 154 patients. Using multivariate regression analysis, male sex (P = 0.01), increasing post-transplantation time (P = 0.003) and increasing donor age (P = 0.001) were independent clinical predictors for diffuse CAD. Both focal and diffuse CAD most frequently affected the proximal LAD (88% compared with 89.6%, NS). The mean intimal index of each LAD segment was significantly higher in patients with diffuse CAD (P < 0.001) and showed a proximal-to-distal decline in patients with focal/polyfocal (LMCA, 10.1 +/- 14.3, LAD-6, 30.1 +/- 17.4%, LAD-7, 16.3 +/- 14.1%, LAD-8, 4.6 +/- 11.1%; P < 0.001) and diffuse (LMCA, 27.0 +/- 16.0, LAD-6, 47.8 +/- 16.1%, LAD-7, 41.9 +/- 14.5%, LAD-8, 24.9 +/- 23.3%; P < 0.01) CAD. CONCLUSION Evaluation of longitudinal plaque distribution after HTX by three-dimensional ICUS revealed a time-dependent increase in the incidence of diffuse CAD and a proximal-to-distal decline in frequency and magnitude of early plaque formation.

Information concerning continuous or discreet phase flow in multiphase systems is desired for various practical and analytical applications. The potential of X-ray-based flow visualization and measurement of multiphase flow is demonstrated here by two non-intrusive methods: (1) Measurement of the three-dimensional (3D) velocity field of the continuous liquid phase in a bubble column by X-ray-based particle tracking velocimetry (PTV) of seeded particles. (2) Liquid flow visualization in a bubble column by injecting an X-ray absorbing liquid into the bubble column. X-rays have the advantage that they are not affected by the various refraction indices of the multiphase system and penetrate the multiphase flow in undistorted straight lines. Hence, in contrast to optical methods, both of these X-ray-based methods are independent of the void fraction and are applicable to opaque liquids.

Objectives: Quantitative measurements on three-dimensional (3-D) reconstructed coronary trees permit accurate evaluation of vascular volumes, lengths and diameters. We applied this technique to investigate diffuse luminal narrowing in patients with the clinical manifestation of progressive atherosclerosis. Methods: In 13 patients who presented repeatedly for coronary angioplasty (at least 4 years of invasive follow-up), left coronary arteries were reconstructed in 3-D from biplane coronary angiograms. Mean diameter, cross-sectional areas, total length, and volume were calculated for segments and branches. Five patients without coronary artery disease served as controls. Results: Patients with progressive coronary atherosclerosis demonstrated a significant reduction of total vascular volumes, mean diameters and cross-sectional areas at the initial investigation when compared with controls. Progressive luminal shrinkage occurred during follow-up (−0.04±0.13 mm per year and per segmental diameter). The progress of luminal narrowing in patients with coronary artery disease is related to the number of coronary risk factors and the duration of follow-up. Conclusion: Quantitative measurements on 3-D reconstructed coronary trees are a useful investigative tool for the assessment of progression of coronary atherosclerosis.

Introduction: Pulmonary vein isolation (PVI) has been established as effective interventional treatment in chronic atrial fibrillation (AF). Impairment of left atrial strain is considered a surrogate parameter of fibrosis. There is considerable variance of strain among different atrial wall segments. We hypothesized that early impairment of strain affects mobile segments and thus reduces inter-segmental variance of strain. Methods: We evaluated 89 consecutive PVI patients and 28 controls (mean age 60 ± 12 y, 33 female). The longitudinal strain of the left atrium in a 4-chamber apical window was determined by speckle tracking (Philips IE33 offline analysis by QLAB™). Success was defined as maintenance of sinus rhythm until last follow-up (minimum 3 months elapsed since PVI). Follow-up comprised repeated Holter-monitoring and echocardiography. Variance was evaluated as standard deviation of segmental strain before PVI (STD). Results: Atrial fibrillation recurred in 40 of 89 patients. STD was 16.5±7.9 in controls, 8.1±5.3 in PVI with persisting success and 4.6±2.2 in late PVI failure (see also box-plot). The group differences between controls, PVI success and PVI failure were all significant (p Conclusions: Standard deviation of segmental left atrial strain is impaired in patients treated by pulmonary vein isolation with late failure and should be further evaluated as predictor for recurrence.

Aims We sought to evaluate the impact of ischemic burden for the prediction of hard cardiac events (cardiac death or nonfatal myocardial infarction) in patients with known or suspected CAD who undergo dobutamine stress cardiac magnetic resonance imaging (DCMR) Methods We included 3166 patients (pts.), mean age 63±12 years, 27% female, who underwent DCMR in 3 tertiary cardiac centres (University Hospital Heildelberg, German Heart Institute and Kings College London). Pts. were separated in groups based on the number of ischemic segments by wall motion abnormalities (WMA) as follows: 1. no ischemic segment, 2. one ischemic segment, 3. two ischemic segments and 4. ≥three ischemic segments. Cardiac death and nonfatal myocardial infarction were registered as hard cardiac events. Pts. with an “early” revascularization procedure (in the first three months after DCMR) were not included in the final survival analysis. Results Pts. were followed for a median of 3.1 years (iqr 2–4.5 years). 187 (5.9%) pts. experienced hard cardiac events. 2349 (74.2%) had no inducible ischemia, 189 (6%) had ischemia in 1 segment, 292 (9.2%) in 2 segments and 336 (10.6%) ≥3 segments. Patients with only 1 ischemic segment showed a high rate of hard cardiac events of ∼6% annually, which was 10-fold higher compared to those without ischemia (0.6% annually, p

Aims Sympathetic stimulation induces left ventricular hypertrophy and is associated with increased cardiovascular risk. Catheter-based renal denervation (RDN) has been shown to reduce sympathetic outflow and blood pressure (BP). The present multi-centre study aimed to investigate the effect of RDN on anatomic and functional myocardial parameters, assessed by cardiac magnetic resonance (CMR), in patients with resistant hypertension. Methods and results Cardiac magnetic resonance was performed in 72 patients (mean age 66 ± 10 years) with resistant hypertension (55 patients underwent RDN, 17 served as controls) at baseline and after 6 months. Clinical data and CMR results were analysed blindly. Renal denervation significantly reduced systolic and diastolic BP by 22/8 mm Hg and left ventricular mass index (LVMI) by 7.1% (46.3 ± 13.6 g/m1.7 vs. 43.0 ± 12.6 g/m1.7, P < 0.001) without changes in the control group (41.9 ± 10.8 g/m1.7 vs. 42.0 ± 9.7 g/m1.7, P = 0.653). Ejection fraction (LVEF) in patients with impaired LVEF at baseline (