Increased Mortality among Survivors of Myocardial Infarction with Kidney Dysfunction: the Contribution of Gaps in the use of Guideline-Based Therapies

Abstract Background We assessed the degree to which differences in guideline-based medical therapy for acute myocardial infarction (AMI) contribute to the higher mortality associated with kidney disease. Methods In the PREMIER registry, we evaluated patients from 19 US centers surviving AMI. Cox regression evaluated the association between estimated glomerular filtration rate (GFR) and time to death over two years, adjusting for demographic and clinical variables. The contribution of variation in guideline-based medical therapy to differences in mortality was then assessed by evaluating the incremental change in the hazard ratios after further adjustment for therapy. Results Of 2426 patients, 26% had GFR ≥ 90, 44% had GFR = 60- < 90, 22% had GFR = 30- < 60, and 8% had GFR < 30 ml/min/1.73 m2. Greater degrees of renal dysfunction were associated with greater 2-year mortality and lower rates of guideline-based therapy among eligible patients. For patients with severely decreased GFR, adjustment for differences in guideline-based therapy did not significantly attenuate the relationship with mortality (HR 3.82, 95% CI 2.39–6.11 partially adjusted; HR = 3.90, 95% CI 2.42–6.28 after adjustment for treatment differences). Conclusion Higher mortality associated with reduced GFR after AMI is not accounted for by differences in treatment factors, underscoring the need for novel therapies specifically targeting the pathophysiological abnormalities associated with kidney dysfunction to improve survival.Peer Reviewe

Anticancer activity of a sub-fraction of dichloromethane extract of Strobilanthes crispus on human breast and prostate cancer cells in vitro

<p>Abstract</p> <p>Background</p> <p>The leaves of <it>Strobilanthes crispus </it>(<it>S. crispus</it>) which is native to the regions of Madagascar to the Malay Archipelago, are used in folk medicine for their antidiabetic, diuretic, anticancer and blood pressure lowering properties. Crude extracts of this plant have been found to be cytotoxic to human cancer cell lines and protective against chemically-induced hepatocarcinogenesis in rats. In this study, the cytotoxicity of various sub-fractions of dichloromethane extract isolated from the leaves of <it>S. crispus </it>was determined and the anticancer activity of one of the bioactive sub-fractions, SC/D-F9, was further analysed in breast and prostate cancer cell lines.</p> <p>Methods</p> <p>The dichloromethane extract of <it>S. crispus </it>was chromatographed on silica gel by flash column chromatography. The ability of the various sub-fractions obtained to induce cell death of MCF-7, MDA-MB-231, PC-3 and DU-145 cell lines was determined using the LDH assay. The dose-response effect and the EC₅₀values of the active sub-fraction, SC/D-F9, were determined. Apoptosis was detected using Annexin V antibody and propidium iodide staining and analysed by fluorescence microscopy and flow cytometry, while caspase 3/7 activity was detected using FLICA caspase inhibitor and analysed by fluorescence microscopy.</p> <p>Results</p> <p>Selected sub-fractions of the dichloromethane extract induced death of MCF-7, MDA-MB-231, PC-3 and DU-145 cells. The sub-fraction SC/D-F9, consistently killed breast and prostate cancer cell lines with low EC₅₀values but is non-cytotoxic to the normal breast epithelial cell line, MCF-10A. SC/D-F9 displayed relatively higher cytotoxicity compared to tamoxifen, paclitaxel, docetaxel and doxorubicin. Cell death induced by SC/D-F9 occurred via apoptosis with the involvement of caspase 3 and/or 7.</p> <p>Conclusions</p> <p>A dichloromethane sub-fraction of <it>S. crispus </it>displayed potent anticancer activities <it>in vitro </it>that can be further exploited for the development of a potential therapeutic anticancer agent.</p

Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C

PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Imaging cardiac SCN5A using the novel F-18 radiotracer radiocaine

The key function of the heart, a well-orchestrated series of contractions, is controlled by cardiac action potentials. These action potentials are initiated and propagated by a single isoform of voltage gated sodium channels - SCN5A. However, linking changes in SCN5A expression levels to human disease in vivo has not yet been possible. Radiocaine, an F-18 radiotracer for positron emission tomography (PET), is the first SCN5A imaging agent in the heart. Explants from healthy and failing human hearts were compared using radiocaine autoradiography to determine that the failing heart has ~30% lower SCN5A levels - the first evidence of changes in SCN5A expression in humans as a function of disease. Paving the way for translational imaging, radiocaine proved to exhibit high in vivo specific binding to the myocardium of non-human primates. We envision that SCN5A measurements using PET imaging may serve as a novel diagnostic tool to stratify arrhythmia risk and assess for progression of heart failure in patients with a broad spectrum of cardiovascular diseases.status: publishe