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Luzern, Switzerland

Leenders G.E.,University Utrecht | Lumens J.,Cardiovascular Research Institute Maastricht | Cramer M.J.,University Utrecht | De Boeck B.W.L.,Kantonsspital Luzern | And 3 more authors.
Circulation: Heart Failure

Background-Response to cardiac resynchronization therapy depends both on dyssynchrony and (regional) contractility. We hypothesized that septal deformation can be used to infer integrated information on dyssynchrony and regional contractility, and thereby predict cardiac resynchronization therapy response. Methods and Results-In 132 cardiac resynchronization therapy candidates with left bundle branch block (LBBB)-like electrocardiogram morphology (left ventricular ejection fraction 19=6%; QRS width 170=23 ms), longitudinal septal strain was assessed by speckle tracking echocardiography. To investigate the effects of dyssynchronous activation and differences in septal and left ventricular free wall contractility on septal deformation pattern, we used the CircAdapt computer model of the human heart and circulation. In the patients, 3 characteristic septal deformation patterns were identified: LBBB-1=double-peaked systolic shortening (n=28); LBBB-2=early systolic shortening followed by prominent systolic stretching (n=34); and LBBB-3=pseudonormal shortening with less pronounced late systolic stretch (n=70). LBBB-3 revealed more scar (2 [2-5] segments) compared with LBBB-1 and LBBB-2 (both 0 [0-1], P<0.05). In the model, imposing a time difference of activation between septum and left ventricular free wall resulted in pattern LBBB-1. This transformed into pattern LBBB-2 by additionally simulating septal hypocontractility, and into pattern LBBB-3 by imposing additional left ventricular free wall or global left ventricular hypocontractility. Improvement of left ventricular ejection fraction and reduction of left ventricular volumes after cardiac resynchronization therapy were most pronounced in LBBB-1 and worst in LBBB-3 patients. Conclusions-A double-peaked systolic septal deformation pattern is characteristic for LBBB and results from intraventricular dyssynchrony. Abnormal contractility modifies this pattern. A computer model can be helpful in understanding septal deformation and predicting cardiac resynchronization therapy response. © 2011 American Heart Association, Inc. Source

Winterhalder R.,Kantonsspital Luzern | Hoesli P.,Etablissements Hospitaliers Nord Vaudois | Delmore G.,Kantonsspital Frauenfeld | Pederiva S.,Kantonsspital Baden | And 3 more authors.

Objectives: While oral anticancer treatment has increased the convenience for patients with no risk of venous access complications compared to intravenous drug administration, a high level of compliance cannot always be assumed. The aim of the present report was to evaluate real-life drug adherence in a prospective cohort analysis of patients with gastrointestinal or breast cancer treated with capecitabine-based chemotherapy. Methods: Twenty-nine Swiss oncologists recruited patients receiving capecitabine, either as monotherapy or in combination with other chemotherapeutic agents, in a prospective fashion. Patients recorded both their capecitabine intake and any adverse effects each day in patient diaries. Results: A total of 177 patients were included, 143 (81%) with gastrointestinal tumours and 34 (19%) with breast cancer. Overall, 161 patients (91%) were considered as fully compliant, while 16 patients (9%) reported some kind of compliance error. Reasons for non-compliance included forgetting to take treatment (n = 9), side effects (n = 4) and misunderstanding instructions (n = 3). Self-reported compliance was not influenced by age or Eastern Cooperative Oncology Group performance status, but there was a trend towards better compliance with capecitabine therapy if fewer adverse effects occurred (p = 0.07, simple logistic regression). Conclusions: Self-reported compliance with capecitabine-based therapy in clinical practice is high and seems to be adversely affected by side effects. © 2011 S. Karger AG, Basel. Source

Fussen S.,University of Basel | De Boeck B.W.L.,University of Basel | Zellweger M.J.,University of Basel | Bremerich J.,University of Basel | And 4 more authors.
European Heart Journal

AimsTo evaluate the diagnostic accuracy of cardiovascular magnetic resonance (CMR) imaging from a risk-stratification and therapeutic-management perspective in patients with suspected cardiac tumours.Methods and resultsCardiovascular magnetic resonance exams of 41 consecutive patients (aged 61 ± 14 years, 21 men) referred for evaluation of a suspected cardiac mass were reviewed for tumour morphology and signal characteristics in various unenhanced and contrast-enhanced sequences. Cardiovascular magnetic resonance-derived diagnosis and treatment were compared with clinical outcome and histology in patients undergoing surgery or autopsy (n 20). In 18 of 41 patients, CMR excluded masses or reclassified them as normal variants; all were treated conservatively. In 23 of 41 patients, CMR diagnosed a neoplasm (14 'benign', 8 'malignant', and 1 'equivocal'); 18 of these patients were operated on, 2 managed conservatively, and 3 by palliation. During follow-up of 705 (inter-quartile range 3031472) days, 13 patients died. No tumour-related deaths occurred in conservatively managed patients. Patients with a CMR-based diagnosis and treatment of benign tumour had a similar survival as patients without detectable tumour. Compared with histology, CMR correctly classified masses as 'benign or malignant' in 95 of the cases. Tumour perfusion, invasiveness, localization, and pericardial fluid were valuable to distinguish between malignant and benign tumours. Soft tissue contrast and signal intensity patterns in various sequences were valuable for excluding neoplastic lesions and helped to obtain tissue characterization at the histological level in selected tumour cases, respectively.ConclusionComprehensive CMR provides a confident risk-stratification and clinical-management tool in patients with suspected tumours. Patients where CMR excludes tumours can be managed conservatively. © 2010 The Author. Source

Philippova M.,University of Basel | Joshi M.B.,University of Basel | Pfaff D.,University of Basel | Kyriakakis E.,University of Basel | And 3 more authors.
Cardiovascular Research

Aims: T-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin family member. Experimental, clinical, and genomic studies suggest a role for T-cad in vascular disorders such as atherosclerosis and hypertension, which are associated with endothelial dysfunction and insulin resistance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that T-cad is a regulatory component of insulin signalling in EC and therefore a determinant of the development of endothelial InsRes. Methods and results: We investigated T-cad-dependent effects on insulin sensitivity using human EC stably transduced with respect to T-cad overexpression or T-cad silencing. Responsiveness to insulin was examined at the level of effectors of the insulin signalling cascade, EC nitric oxide synthase (eNOS) activation, and angiogenic behaviour. Overexpression and ligation of T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely, T-cad silencing enhances these actions of insulin. Attenuation of EC responsiveness to insulin results from T-cad-mediated chronic activation of the Akt/mTOR-dependent negative feedback loop of the insulin cascade and enhanced degradation of the insulin receptor (IR) substrate. Co-immunoprecipitation experiments revealed an association between T-cad and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling, demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and protein levels in EC. Conclusion: T-cad expression modulates signalling and functional responses of EC to insulin. We have identified a novel signalling mechanism regulating insulin function in the endothelium and attribute a role for T-cad up-regulation in the pathogenesis of endothelial InsRes. © The Author 2011. Source

Lumens J.,Maastricht University | Leenders G.E.,University Utrecht | Cramer M.J.,University Utrecht | De Boeck B.W.L.,Kantonsspital Luzern | And 3 more authors.
Circulation: Cardiovascular Imaging

Background-The power of echocardiographic dyssynchrony indices to predict response to cardiac resynchronization therapy (CRT) appears to vary between indices and between studies. We investigated whether the variability of predictive power between the dyssynchrony indices can be explained by differences in their operational definitions. Methods and Results-In 132 CRT-candidates (left ventricular [LV] ejection fraction, 19±6%; QRS width, 170±22 ms), 4 mechanical dyssynchrony indices (septal systolic rebound stretch [SRSsept], interventricular mechanical dyssynchrony [IVMD], septal-to-lateral peak shortening delay [Strain-SL], and septal-to-posterior wall motion delay [SPWMD]) were quantified at baseline. CRT response was quantified as 6-month percent change of LV end-systolic volume. Multiscale computer simulations of cardiac mechanics and hemodynamics were used to assess the relationships between dyssynchrony indices and CRT response within wide ranges of dyssynchrony of LV activation and reduced contractility. In patients, SRSsept showed best correlation with CRT response followed by IVMD, Strain-SL, and SPWMD (R=?0.56, ?0.50, ?0.48, and ?0.39, respectively; all P<0.01). In patients and simulations, SRSsept and IVMD showed a continuous linear relationship with CRT response, whereas Strain-SL and SPWMD showed discontinuous relationships characterized by data clusters. Model simulations revealed that this data clustering originated from the complex multipeak pattern of septal strain and motion. In patients and simulations with (simulated) LV scar, SRSsept and IVMD retained their linear relationship with CRT response, whereas Strain-SL and SPWMD did not. Conclusions-The power to predict CRT response differs between indices of mechanical dyssynchrony. SRSsept and IVMD better represent LV dyssynchrony amenable to CRT and better predict CRT response than the indices assessing time-to-peak deformation or motion. © 2012 American Heart Association, Inc. Source

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