The Role of the Frank–Starling Law in the Transduction of Cellular Work to Whole Organ Pump Function: A Computational Modeling Analysis

We have developed a multi-scale biophysical electromechanics model of the rat left ventricle at room temperature. This model has been applied to investigate the relative roles of cellular scale length dependent regulators of tension generation on the transduction of work from the cell to whole organ pump function. Specifically, the role of the length dependent Ca2+ sensitivity of tension (Ca50), filament overlap tension dependence, velocity dependence of tension, and tension dependent binding of Ca2+ to Troponin C on metrics of efficient transduction of work and stress and strain homogeneity were predicted by performing simulations in the absence of each of these feedback mechanisms. The length dependent Ca50 and the filament overlap, which make up the Frank-Starling Law, were found to be the two dominant regulators of the efficient transduction of work. Analyzing the fiber velocity field in the absence of the Frank-Starling mechanisms showed that the decreased efficiency in the transduction of work in the absence of filament overlap effects was caused by increased post systolic shortening, whereas the decreased efficiency in the absence of length dependent Ca50 was caused by an inversion in the regional distribution of strain

A physicochemical descriptor-based scoring scheme for effective and rapid filtering of kinase-like chemical space

<p>Abstract</p> <p>Background</p> <p>The current chemical space of known small molecules is estimated to exceed 10⁶⁰structures. Though the largest physical compound repositories contain only a few tens of millions of unique compounds, virtual screening of databases of this size is still difficult. In recent years, the application of physicochemical descriptor-based profiling, such as Lipinski's rule-of-five for drug-likeness and Oprea's criteria of lead-likeness, as early stage filters in drug discovery has gained widespread acceptance. In the current study, we outline a kinase-likeness scoring function based on known kinase inhibitors.</p> <p>Results</p> <p>The method employs a collection of 22,615 known kinase inhibitors from the ChEMBL database. A kinase-likeness score is computed using statistical analysis of nine key physicochemical descriptors for these inhibitors. Based on this score, the kinase-likeness of four publicly and commercially available databases, i.e., National Cancer Institute database (NCI), the Natural Products database (NPD), the National Institute of Health's Molecular Libraries Small Molecule Repository (MLSMR), and the World Drug Index (WDI) database, is analyzed. Three of these databases, i.e., NCI, NPD, and MLSMR are frequently used in the virtual screening of kinase inhibitors, while the fourth WDI database is for comparison since it covers a wide range of known chemical space. Based on the kinase-likeness score, a kinase-focused library is also developed and tested against three different kinase targets selected from three different branches of the human kinome tree.</p> <p>Conclusions</p> <p>Our proposed methodology is one of the first that explores how the narrow chemical space of kinase inhibitors and its relevant physicochemical information can be utilized to build kinase-focused libraries and prioritize pre-existing compound databases for screening. We have shown that focused libraries generated by filtering compounds using the kinase-likeness score have, on average, better docking scores than an equivalent number of randomly selected compounds. Beyond library design, our findings also impact the broader efforts to identify kinase inhibitors by screening pre-existing compound libraries. Currently, the NCI library is the most commonly used database for screening kinase inhibitors. Our research suggests that other libraries, such as MLSMR, are more kinase-like and should be given priority in kinase screenings.</p

Repair of Rare Direct Gerbode Defect Secondary to Aortic and Tricuspid Valve Endocarditis

<p>Direct Gerbode defects (GD) are rare, especially those secondary to endocarditis. Only 10.7% involve both the aortic and tricuspid valves. The authors present a direct GD secondary to aortic and tricuspid valve endocarditis and discuss the surgical management of the defect with sliding tricuspid valve annuloplasty.<br></p><p>The preoperative echocardiogram shows what was thought to be a perimembranous ventricular septal defect (VSD), a large amount of endocarditis involving the aortic and tricuspid valves, and significant tricuspid regurgitation. GDs are depicted as left ventricle (LV) to right atrium (RA) communication.</p><p>As mentioned, the preoperative working provisional diagnosis was a perimembranous VSD. The authors felt that the endocarditis was slightly secondary to this congenital defect. They explored the aortic valve first as part of the procedure. Upon examination, the valve had an extremely significant amount of pannus involving all three leaflets, which was carefully resected. It was a very considerable burden of endocarditis on the valve, which was grossly incompetent.</p><p>The leaflets were resected sequentially, and after resection the authors progressively found a significant amount of pannus involving the left ventricle outflow tract. This was carefully debrided. The vegetation was gelatinous and friable, and as it was gently resected, the authors saw that it extended down into the septum. They carefully debrided the entire area to ensure that an adequate margin of good tissue was available to sew the valve into and confidently have a good repair. After seeing the GD and how friable and necrotic the tissue was, the authors further debrided the area.</p><p>Next, the RA was opened to look under the tricuspid valve, where the authors expected to find a communication at that level. They planned to subsequently repair it and the tricuspid valve. After approaching through the aortic valve, the authors turned to the RA, which revealed a defect that communicated with the RA as opposed to the right ventricle. The septum on the right side was intact, so this was a direct GD from the LV into the RA through erosion. The original diagnosis was wrong, but that is what GDs do; the defect is a great masquerader.</p><p>The authors observed the GD and repaired it with a patch, then examined the tricuspid valve. The posterior and septal leaflets of the tricuspid valve were badly involved with the endocarditis process, so this tissue was resected. The authors began to adequately mobilize the valve in order to obtain a satisfactory repair rather than replacement. They used a sliding annuloplasty of the septal leaflet of the tricuspid valve. A bit more was incised in order to provide better mobilization and ultimately better coaptation of the valve without any undue tension on the repaired valve. The authors then repaired the septal leaflet back to the annulus using 5-0 Prolene® sutures in two layers.</p><p>After the septal leaflet was reattached and the GD repaired, the repair was checked to ensure the tricuspid valve was functional. By inflating the RV with a red rubber catheter, the authors could see that the valve itself functioned well and would likely provide the patient with good repair. In the video, the patched GD can again be seen with the completed valve repair after the septal leaflet tricuspid valve mobilization and reattachment to the annulus.</p><p>The next part of the procedure involved aortic valve replacement. The authors sewed in a bioprosthesis. The patient also had ischemic heart disease involving left anterior descending arteries, which was not associated with this endocarditis but was revascularized with left internal mammary artery harvest. The patient was weaned from cardiopulmonary bypass.</p><p>The patient showed very good ventricular function. A postoperative echocardiogram was done, which demonstrated a competent aortic bioprosthesis with no evidence of leak. Additionally, the septum was intact with no evidence of GD or any VSD, and the tricuspid valve function was normal.</p><p><strong>Suggested Reading</strong></p><ol><li>Yuan SM. A systematic review of acquired left ventricle to right atrium shunts (Gerbode defects). <em><a href="https://www.ncbi.nlm.nih.gov/pubmed/26429364">Hellenic J Cardiol.</a></em><a href="https://www.ncbi.nlm.nih.gov/pubmed/26429364"> 2015;56(5):357-372</a>.</li><li>Alphonso N, Dhital K, Chambers J, Shabbo F. Gerbode’s defect resulting from infective endocarditis. <em><a href="https://www.ncbi.nlm.nih.gov/pubmed/12754046">Eur J Cardiothorac Surg</a></em><a href="https://www.ncbi.nlm.nih.gov/pubmed/12754046">. 2003;23(5):844-846</a>.</li><li>Roughneen PT, Conti VR. Tricuspid septal leaflet detachment for ventricular septal defect repair in adults. <em><a href="https://doi.org/10.1016/j.athoracsur.2016.01.032">Ann Thorac Surg</a></em><a href="https://doi.org/10.1016/j.athoracsur.2016.01.032">. 2016;102(2):e93-95</a>.</li></ol