A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1-5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia-reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

Calcium Modification Techniques in Complex Percutaneous Coronary Intervention.

Percutaneous coronary intervention is the most common mode of revascularization and is increasingly undertaken in high-risk subsets, including the elderly. The presence of coronary artery calcification is increasingly observed and significantly limits technical success. The mechanisms for this are multi-factorial, including increased arterial wall stiffness and impaired delivery of devices, leading to suboptimal stent delivery, deployment, and expansion which are harbingers for increased risk of in-stent restenosis and stent thrombosis. Although conventional balloon pretreatment techniques aim to mitigate this risk by modifying the lesion before stent placement, many lesions remain resistant to conventional strategies, due to the severity of calcification. There have been several substantial technological advancements in calcium modification methods in recent years, which have allowed improved procedural success with low periprocedural complication rates. This review will summarize the current adjunctive modification technologies that can be employed to improve technical outcomes in percutaneous coronary intervention in calcific disease and the evidence supporting these tools.

Where to now in cardiovascular disease prevention.

Clinical trials have been instrumental in reducing the morbidity and mortality associated with cardiovascular disease, especially in the developed world. Recently however this improvement has plateaued, highlighting the importance of optimising current strategies and considering alternative practises. Inequalities in global healthcare, the changing patient profile as a result of an obesity and diabetes epidemic, and inadequate utilisation of evidence-based treatments are partly responsible. Despite pharmacotherapies such as statins having substantial evidence for cardiovascular benefit, patient response may be variable with genetic factors thought to be partly responsible. Although randomised controlled trials remain the backbone of clinical research, they have limitations including time taken to complete a trial and the financial costs associated with it. In this opinion-based paper, we discuss some of the key considerations for the future of cardiovascular disease prevention.

Familial Hypercholesterolemia: a Review of the Natural History, Diagnosis, and Management.

Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism characterized by premature cardiovascular disease. It is one of the most common metabolic disorders affecting humans. There are two clinical manifestations: the milder heterozygous form and more severe homozygous form. Despite posing a significant health risk, FH is inadequately diagnosed and managed. As the clinical outcome is related to the degree and duration of exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels, early treatment is vital. Diagnosis can usually be made using a combination of clinical characteristics such as family history, lipid levels, and genetic testing. Mutations in the gene encoding the LDL receptor (LDLR), apolipoprotein B, the pro-protein convertase subtilisin/kexin 9 (PCSK9), and LDLR adaptor protein are the commonest abnormalities. Early identification and treatment of patients, as well as screening of relatives, helps significantly reduce the risk of premature disease. Although statins remain the first-line therapy in most cases, monotherapy is usually inadequate to control elevated LDL-C levels. Additional therapy with ezetimibe and bile acid sequestrants may be required. Newer classes of pharmacotherapy currently under investigation include lomitapide, mipomersen, and monoclonal antibodies to PCSK9. Lipoprotein apheresis may be required when multiple pharmacotherapies are inadequate, especially in the homozygous form. Effective early detection and treatment of the index individual and initiation of cascade screening will help reduce the complications associated with FH. In this article, we review the disease of FH, complexity of diagnosis and management, and the challenges faced in preventing the significant morbidity and mortality associated with it.

Closed suction drainage improves clinical outcome in patients undergoing endoscopic vein harvesting for coronary artery bypass grafting.

BACKGROUND: Endoscopic vein harvesting (EVH) is a widely accepted technique for coronary artery bypass grafting, with well-reported benefits. However, EVH is associated with severe hematoma formation at incision sites, resulting in postoperative pain. We hypothesized that the use of a leg wound drain at the incision site may reduce these comorbidities. METHODS: One hundred consecutive patients were prospectively randomly allocated into two groups of 50: group 1 with leg wound drains, and group 2 without drains. Group 1 patients underwent EVH followed by closure with a size 10 high vacuum leg wound drain (20 kPa), whereas group 2 underwent EVH followed by closure without a leg wound drain. Patients were assessed for postoperative pain, wound infection, and satisfaction using validated scoring systems immediately after surgery. RESULTS: Pain at rest (p < 0.001) and with movement (p < 0.001), incidence of hematoma (p < 0.001), and patient satisfaction (p < 0.001) were significantly improved in the drain group at days 1 to 7 and remained significant at week 6 after surgery. Interestingly, the use of antibiotics (6% versus 24%, p = 0.012) and the number of general practitioner visits (6% versus 26%, p = 0.012) were lower in the drain group compared with the no-drain group. However, there were no differences in the length of hospital stay between the two groups after surgery. CONCLUSIONS: Our findings indicate that the use of a high vacuum leg drain after EVH for long saphenous vein is of clear therapeutic benefit in the early postoperative period. We also report that this technique may reduce antibiotic administration and general practitioner visits after patient discharge.

Scrotal distension after endoscopic harvesting of the saphenous vein in patients with inguinal hernia.

The great saphenous vein remains the most commonly used conduit for coronary artery bypass grafting. The endoscopic vein harvesting technique is widely used due to reduced postoperative complications. We present the case of 5 patients with a history of inguinal hernia undergoing coronary artery bypass grafting, which resulted in CO2 infiltration through the deep inguinal ring and into the scrotum leading to acute scrotal enlargement. Due to the risk of impediment of vascular blood supply and necrosis, endoscopic vein harvesting was withdrawn, and the vein was harvested by using the bridging technique. Postoperatively, severe contusion, inflammation, and erythematous vesicular eruption resulted in a lengthened hospital stay.

The usefulness of chronic heart failure treatments in chronic cardiac graft failure.

Following cardiac transplantation, registry data has demonstrated a gradual improvement in survival over the last several decades, which is testament to continual improvement in aftercare strategy. However, a significant number of patients will eventually develop a new syndrome of chronic heart failure, owing to the multitude of physiological processes that occur after transplantation. This condition, referred to as chronic graft failure (CGF) should be regarded as a unique illness rather than one that is simply analogous with chronic heart failure. In particular, the unique pathophysiological (and pharmacological) environment in the setting of CGF presents a challenging situation to the transplant physician. There is uncertainty over which treatments to offer given a paucity of clinical trial data to support the use of standard heart failure treatments in CGF. In this review, we discuss which chronic heart failure treatments could be considered in the setting of CGF based on their mechanisms of action, benefits within the native heart failure setting, and the relevant issues within the posttransplant environment.

A comparative analysis of saphenous vein conduit harvesting techniques for coronary artery bypass grafting--standard bridging versus the open technique.

Coronary artery bypass graft (CABG) surgery involves harvesting the great saphenous vein (GSV) using the traditional open technique (TOT). This can be associated with significant leg morbidity and patient dissatisfaction. Alternatively, the standard bridging technique (SBT) is a minimally invasive procedure of vein retrieval that uses smaller frequent incisions along the length of the leg and may reduce postoperative complications. This study was designed to compare the success of SBT in reducing leg morbidity and increasing patient satisfaction. One hundred patients were recruited into the study and computer randomised into two groups of 50 undergoing SBT or TOT. Leg morbidity and patient satisfaction were analysed by assessment of pain scores, wound development and scar formation. Closure and harvesting time were also compared between the two groups. SBT was associated with better wound development (P<0.001) and a significantly higher patient satisfaction (P<0.001). Leg pain was significantly reduced amongst SBT group at rest and with movement (P<0.001). There was also a reduction in saphenous neuropathy with the use of SBT (P<0.001). No difference in closure or harvesting time was demonstrated (P=0.26 and P=0.23, respectively). This study demonstrates that harvesting the GSV by the minimally invasive SBT reduces postoperative leg morbidity and increases patient satisfaction without the need of costly equipment. SBT represents a safe, effective and financially viable technique for vein harvesting.

Randomized prospective study comparing conventional subcuticular skin closure with Dermabond skin glue after saphenous vein harvesting.

BACKGROUND: Dermabond (Ethicon UK, Edinburgh, United Kingdom) is a topical skin adhesive used for surgical wound closure, with purported advantages over conventional sutures on cosmetic outcomes, cost benefits, and operative times. This study compared results of skin closure using Dermabond and subcuticular sutures after coronary artery bypass grafting (CABG). METHODS: The study prospectively enrolled and randomized 106 patients who underwent CABG. The groups received closure with Dermabond skin glue or subcuticular sutures (n = 53 each) after saphenous vein harvesting using the bridging technique. Wound closure time for the two methods was recorded. Cosmetic appearance was assessed using the Hollander, the Vancouver, and the visual analog scale. Patient satisfaction was recorded before discharge and at week 6. RESULTS: There were no significant differences in the total operative time between the two groups (p = 0.43). Closure time was significantly shorter in the Dermabond group (p = 0.017). Patients in the Dermabond group also reported superior cosmetic outcome at weeks 1 (p < 0.001) and 6 (p = 0.001) and improved patient satisfaction (p < 0.001). CONCLUSIONS: Dermabond has demonstrated superiority over traditional subcuticular skin sutures in terms of closure time, cosmetic appearance, and patient satisfaction. This technique provides a novel method of wound closure after CABG.

Ezetimibe and atorvastatin both immunoregulate CD4+ T cells from cardiac transplant recipients invitro.

BACKGROUND: Statins are LDL lowering agents that reduce cardiac allograft vasculopathy (CAV) incidence after cardiac transplantation. Furthermore, 'pleiotropic effects' including immunomodulation have been demonstrated by statins following transplantation. It has also been previously suggested that ezetimibe may exert specific effects on the innate immune system in vitro. We compared the effects of ezetimibe and atorvastatin on T lymphocytes in vitro on the justification that these cells are implicated in the pathogenesis of atherosclerosis, allograft rejection and CAV. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 30 cardiac transplant recipients and co-cultured with the study drug (or placebo) over 48 h. In total, 150 cultures were performed (5 per patient). Drug concentrations were calculated to simulate 10 mg or 100 mg daily in a 70 kg adult. Flow cytometry was performed to analyse T lymphocyte counts and functional characteristics. RESULTS: Ezetimibe reduced the standard CD3+CD4+ T cell count and CD3+CD4+CD45ro T memory count by dose linear effect (p < 0.001). Atorvastatin also reduced the CD3+CD4+ T cell count and CD3+CD4+CD45ro T memory count by dose linear effect (p = 0.005). Neither drug affected CD3+CD8+ cytotoxic T cells. DISCUSSION: Both atorvastatin and ezetimibe may have selective immunomodulatory properties independent of their mechanisms of LDL lowering, given that both drugs affect CD4 T helper cells but have no effect on CD8 cytotoxic lymphocytes in vitro. Although speculative, both of these agents could potentially offer benefits to the transplant patient by modulating important components of the adaptive immune system. CD4+ cells in particular are implicated in both CAV and rejection processes.