P3492Carvedilol and its analogue VK-II-86 attenuate stretch-induced manifestations of mechanoelectric feedback

Background Mechanical stretch modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. The store-overload-induced Ca2+ release (SOICR) through the ryanodine receptor (RyR2) seems to be implicated in this deleterious effect. Carvedilol and its analogue VK-II-86 (which does not have significant beta-blocking effects) suppress SOCIR by directly reducing the open duration of the cardiac RyR2, and could modulate calcium-related changes produced by myocardial stretch. Purpose The aim of this study was to investigate, by the ventricular fibrillation (VF) spectral analysis, whether carvedilol and VK-II-86 prevents stretch-induced arrhythmogenic effects. Methods The VF modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=10), during carvedilol infusion (0.1 and 1 μM) (n=10) and during VK-II-86 infusion (0.1 and 1 μM) (n=10). Spectral techniques were used to establish the baseline and stretch characteristics in the three series above mentioned: VF dominant frequency (DF) and VF spectral concentration (SpC) were determined. A two-factor ANOVA test was used and significance was reached when p<0.05. Results Myocardial stretch significantly increased DF with respect to pre-stretch values in control conditions (13.3±1.2 vs. 16.1±3.0 Hz, p<0.05) and during the perfusion of 0.1μM carvedilol (11.6±1.5 vs. 13.6±2.9 Hz, p<0.05) and 0.1μM VK-II-86 (13.2±2.2 vs. 16.2±4.1 Hz, p<0.05). However, the maximum concentration of both drugs (1μM) abolished this stretch-induced VF acceleration (carvedilol: 6.9±2.2 vs. 7.3±2.6 Hz, ns; VK-II-86: 7.0±1.4 vs. 7.1±0.6 Hz, ns). The significant stretch-induced decrease in SpC in control conditions (31.4±8.6 vs. 23.2±6.4%, p<0.01) was attenuated under 0.1μM carvedilol (0.1μM: 27.6±8.4 vs. 23.5±6.1%, ns) and 0.1μM VK-II-86 (24.7±5.4 vs. 21.2±3.9%, ns), but not under 1μM of both drugs (carvedilol: 41.3±11.3 vs. 30.3±5.7%, p<0.05; VK-II-86: 34.7±7.2 vs. 28.3±3.9%, p<0.01). Nevertheless, during stretch, arrhythmia regularity and organization was greater (higher SpC) under the highest concentration of carvedilol (p<0.01) and VK-II-86 (p<0.05) than in control conditions (control: 23.2±6.4%, carvedilol 1μM: 30.3±5.7%, VK-II-86 1μM: 28.3±3.9%). Conclusion Carvedilol and its analogue VK-II-86 abolished the changes in VF activation frequency produced by myocardial stretch at the highest studied concentration, and also attenuated the stretch-induced activation heterogeneity at the lowest concentration. The similarity in the effects of both drugs on the stretch-induced alterations would imply that its protective effect is due to its ability to inhibit store-overload-induced calcium release.

Cardiovascular Comorbidities Common in Patients with Metastatic Colorectal Cancer

Aim: As comorbidities may impact treatment decisions, prognoses and quality of care, this study determined the rate of comorbid cardiovascular diseases in patients with metastatic colorectal cancer (mCRC). Methods: From the PHARMO Record Linkage System in The Netherlands, all patients with a hospital discharge code for CRC and distant metastasis from 2000–2008 were selected. Prevalent cardiovascular comorbidities were assessed during the 12 months prior to the index date (the first discharge diagnosis defining metastases). Cardiovascular comorbidities were captured using cardiovascular drug use and hospital admission data. 2964 patients with mCRC were included in the analysis. Mean (± standard deviation) age at diagnosis was 68 (± 12) years and 53% were male. Results: Cardiovascular comorbidities were observed in 52% of patients. Of patients identified by drug use, the most commonly used agents were antithrombotic agents (54%), beta-blocking agents (46%), and agents acting on the renin-angiotensin system (45%). Of patients hospitalised for cardiovascular comorbidities, about one-third were hospitalised for cardiac dysrhythmia (39%), followed by congestive heart failure (19%) and hypertension (18%). Conclusions: Cardiovascular comorbidities are common in patients with mCRC, which is likely to be explained by the high mean age at diagnosis. Consideration of these conditions should be integral to the treatment strategy in individual patients with mCRC.

Extended Release Micro-pellets of Chiral Molecule of Metoprolol Succinate by Fluid Bed Technology

The objective is to prepare extended release micro-pellets of the s-Metoprolol Succinate which is chirally pure molecules. Commercially Metoprolol Succinate is available the racemic mixture of the s and r isomers. Out of both the isomers s-isomer is predominantly responsible for the cardiac beta blocking activity. So to use the more desirable beta blocking activity of s-Metoprolol Succinate, extended release micro-pellets of the s-Metoprolol Succinate was prepared. Due to pure chiral molecules the dose was also reduced to half to that of the racemic mixture. Extended release micro-pellets of the s-Metoprolol Succinate was prepared by the fluid bed technology, in which s-Metoprolol Succinate along with binder and anti-adherent material was sprayed on the inert core. These drug loaded pellets of the s-Metoprolol Succinate was than coated with ethyl cellulose as extended release polymer, hypromellose as pore former and acetyl tri butyl as novel plasticizer and talc as an anti-adherent. The formulation was further optimized for drug release, as per USP recommended dissolution condition, using central composite design (CC). Results shows that at level of 58-66% w/w extended release coating with any studied concentration of acetyl tri butyl citrate and hypromellose gives desired drug release profile.

Preoperative Antihypertensive Medication in Relation to Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery: A Meta-Analysis

Background. We undertake a systematic review and meta-analysis to evaluate the effect of preoperative hypertension and preoperative antihypertensive medication to postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. Methods. We searched PubMed, Embase, and Cochrane Library (from inception to March 2016) for eligible studies. The outcomes were the effects of preoperative hypertension, preoperative calcium antagonists regimen, preoperative ACE inhibitors regimen, and preoperative beta blocking agents regimen with POAF. We calculated pooled risk ratios (OR) and 95% CIs using random- or fixed-effects models. Results. Twenty-five trials involving 130087 patients were listed. Meta-analysis showed that the number of preoperative hypertension patients in POAF group was significantly higher (P<0.05), while we found that there are no significant differences between two groups in Asia patients by subgroup analysis, which is in contrast to other outcomes. Compared with the Non-POAF group, the number of patients who used calcium antagonists and ACE inhibitors preoperatively in POAF group was significantly higher (P<0.05). And we found that there were no significant differences between two groups of preoperative beta blocking agents used (P=0.08). Conclusions. Preoperative hypertension and preoperative antihypertensive medication in patients undergoing cardiac operations seem to be associated with higher risk of POAF.