L. Van Bortel

Multiple-dose pharmacodynamics and pharmacokinetics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the heteroexchange of cholesteryl esters from high‐density lipoprotein (HDL) and triglycerides to apolipoprotein B–containing lipoproteins, especially very low–density lipoproteins (LDL‐C). 1, 2

Determining carotid artery pressure from scaled diameter waveforms: comparison and validation of calibration techniques in 2026 subjects

Calibrated diameter distension waveforms could provide an alternative for local arterial pressure assessment more widely applicable than applanation tonometry. We compared linearly and exponentially calibrated carotid diameter waveforms to tonometry readings. Local carotid pressures measured by tonometry and diameter waveforms measured by ultrasound were obtained in 2026 subjects participating in the Asklepios study protocol. Diameter waveforms were calibrated using a linear and an exponential calibration scheme and compared to measured tonometry waveforms by examining the mean root-mean-squared error (RMSE), carotid systolic blood pressure (SBPcar) and augmentation index (AIx) of calibrated and measured pressures. Mean RMSE was 5.2(3.3) mmHg (mean(stdev)) for linear and 4.6(3.6) mmHg for exponential calibration. Linear calibration yielded an underestimation of SBPcar by 6.4(4.1) mmHg which was strongly correlated to values of brachial pulse pressure (PPbra) (R = 0.4, P < 0.05). Exponential calibration underestimated true SBPcar by 1.9(3.9) mmHg, independent of PPbra. AIx was overestimated by linear calibration by 1.9(10.1)%, the difference significantly increasing with increasing AIx (R = 0.25, P < 0.001) and by exponential calibration by 5.4(10.6)%, independently of the value of AIx. Properly calibrated diameter waveforms offer a viable alternative for local pressure estimation at the carotid artery. Compared to linear calibration, exponential calibration significantly improves the pressure estimation.

Three- and four-element Windkessel models: Assessment of their fitting performance in a large cohort of healthy middle-aged individuals

Lumped-parameter models are used to estimate the global arterial properties by fitting the model to measured (aortic) pressure and flow. Different model configurations coexist, and it is still an open question as to which model optimally reflects the arterial tree and leads to correct estimates of arterial properties. An assessment was made of the performance of (a) the three-element Windkessel model (WK3) consisting of vascular resistance R, total arterial compliance C, and characteristic impedance Zc; (b) a four-element model with an inertance element L placed in parallel with Zc (WK4-p); and (c) a four-element model with L placed in series with Zc (WK4-s). Models were fitted to data measured non-invasively in 2404 healthy subjects, aged between 35 and 55 years. It was found that model performance segregated into two groups. In a group containing 20 per cent of the dataset (characterized by low blood pressure and wave reflection) the WK4-p model outperformed the other models, with model behaviour as envisioned by its promoters. In these cases, the WK3 and WK4-s models led to increased overestimation of total arterial compliance and underestimation of characteristic impedance. However, in about 80 per cent of the cases, the WK4-p model showed a behaviour that was very similar to that of the WK3 and WK4-s models. Here, the WK4-s model yielded the best quality of fit, although model parameters reached physically impossible values for L in about 12 per cent of all cases. The debate about which lumped-parameter model is the better approximation of the arterial tree is therefore still not fully resolved.

CARDIAC TOXICITY OF TRASTUZUMAB: EXPERIENCE AT THE GHENT UNIVERSITY HOSPITAL, BELGIUM

Abstract Introduction Trastuzumab (TRAS) is a humanised monoclonal antibody that is targeted against the HER2 growth factor receptor. Over-expression of the receptor occurs in around 15-25% of women with early breast cancer (CA). Four major adjuvant trials compared trastuzumab treatment with observation after neoadjuvant or adjuvant chemotherapy in women with high risk HER2-positive breast cancer. Results of these trials showed that trastuzumab treatment given every 3 weeks for 1 year achieved a significant improvement of disease free survival and overall survival. However, cardiac toxicity occurred more in the trastuzumab arm than in the observation arm resulting in symptomatic congestive heart failure and a significant drop in left ventricular ejection function (LVEF). Aim of the study The purpose of this analysis is to evaluate cardiac toxicity of adjuvant trastuzumab treatment in 30 breast cancer patients. Study parameters were cardiac toxicity assessed by LV function, disease free survival and overall survival. Materials and methods Based on the adjuvant trials and in expectation of the reimbursement of trastuzumab in the adjuvant setting, a convention was set up between the Belgian National Institute for Health and Disability Insurance and hospital centres specialized in the treatment of breast cancer. In this convention, trastuzumab was offered to patients diagnosed with invasive, non-metastatic breast cancer with an over-expression of HER2 proven by a positive FISH test. Metastatic lymph nodes or a tumour measuring more than 10 mm had to be present. At least 4 cycles of adjuvant or neoadjuvant chemotherapy had to be given to the patient. Radiotherapy could be administered. The time interval between chemotherapy or radiotherapy and treatment with trastuzumab could not be more than 6 months. LVEF determined by MUGA scan or by ultrasonography at the start of trastuzumab treatment had to be more than 55%. Results 30 breast cancer patients were treated with adjuvant trastuzumab in our hospital between June 2006 and July 2007. All patients met the inclusion criteria. Six patients stopped trastuzumab treatment because of cardiac toxicity. All these patients had received prior anthracycline neoadjuvant or adjuvant chemotherapy. Five of these patients were found to have a LVEF < 55%, one showing symptoms of congestive cardiomyopathy. The sixth patient was diagnosed with a newly developed tricuspid valve insufficiency grade 3. Follow-up data of 20 months since the start of trastuzumab treatment showed that 27 patients were disease-free. Two patients died because of progressive breast cancer disease. One patient was lost of follow-up. Conclusion In this small group of breast cancer patients, treated with adjuvant trastuzumab, cardiac toxicity expressed as a decreased left ventricular function seems to have a higher incidence compared to the other adjuvant trials. Therefore, a close cardiac monitoring for several years should be recommended in patients treated with trastuzumab.