Gonzalo Martínez

Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome

Background Interleukin (IL)-1β, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1β and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production. Methods and Results Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1β, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1β, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1β, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1β, IL-18, and IL-6, respectively). Conclusions ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines.

Extracorporeal Membrane Oxygenation for Very High-risk Transcatheter Aortic Valve Implantation

BACKGROUND Transcatheter aortic valve implantation (TAVI) can cause profound haemodynamic perturbation in the peri-operative period. Veno-arterial extracorporeal membrane oxygenation (ECMO) can be used to provide cardiorespiratory support during this time, either prophylactically or emergently. METHOD 100 TAVI procedures were performed between 2009 and 2013 in our institution. ECMO was used in 11 patients, including eight prophylactic and three rescue cases. Rescue ECMO was required for ventricular fibrillation after valvuloplasty, and aortic annulus rupture. The criteria for prophylactic ECMO included heart failure requiring stabilisation pre-TAVI, haemodynamic instability with balloon aortic valvuloplasty performed to improve heart function pre-TAVI, moderate or severe left and/or right ventricular failure, or borderline haemodynamics at procedure. Differences in preoperative characteristics and postoperative outcomes between ECMO and non-ECMO TAVI patients were compared, and significant results were further assessed controlling for EuroSCORE. RESULTS Compared to TAVI patients who did not require ECMO, ECMO patients had significantly higher mean EuroSCORE (51 vs. 30%, p<.05). Postoperative outcomes, however, were largely comparable between the two groups. All-cause mortality occurred in nil prophylactic ECMO patients, one rescue ECMO patient, and two non-ECMO patients. The difference in mortality between ECMO and non-ECMO patients was not significantly different (9 vs. 2%; p>.05). ECMO patients were more likely to develop acute renal failure than non-ECMO patients (36 vs. 8%, p<.05), which was most likely due to haemodynamic collapse and end-organ dysfunction in patients that required ECMO rescue. CONCLUSIONS Instituting prophylactic ECMO in selected very high-risk patients may help avoid consequences of intra-operative complications and the need for emergent rescue ECMO.

The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation

Atherosclerosis is considered a chronic inflammatory disease of the arterial wall. Recently, compelling evidence has arisen for the role of monocytes and neutrophils and a particular protein complex that resides within these cells - the NLRP3 inflammasome - in atherosclerosis-associated inflammation. It is now also known that cholesterol crystals are present through all stages of atherosclerosis and can activate the NLRP3 inflammasome within these inflammatory cells to produce interleukin 1β and interleukin 18 - key mediators in the inflammatory cascade that drive plaque progression and instability. In this review, we describe the role of monocytes/macrophages and neutrophils in atherosclerosis, outline mechanisms of activation of the NLRP3 inflammasome in the setting of atherosclerosis-associated inflammation and discuss potential therapies that specifically target the NLRP3 inflammasome and/or its downstream mediators in atherosclerosis, with a particular focus on the emerging role of colchicine.

Basal autophagy protects cardiomyocytes from doxorubicin-induced toxicity

Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability. Here we investigated the effect of Doxo 1uM for 24h of stimulation on cultured neonatal rat cardiomyocytes. We showed that Doxo inhibits basal autophagy. This inhibition is due to both Akt/mTOR signaling pathway activation and Beclin 1 level decrease. To assess the role of autophagy on Doxo-induced cardiomyocyte death, we evaluated the effects 3-methyladenine (3-MA), bafilomycin A1 (BafA), siRNA Beclin 1 (siBeclin 1) and rapamycin (Rapa) on cell viability. Inhibition of autophagy with 3-MA, BafA and siBeclin 1 increased lactate dehydrogenase (LDH) release but, when autophagy was induced by Rapa, Doxo-induced cardiomyocyte death was decreased. These results suggest that Doxo inhibits basal autophagy and contributes to cardiomyocyte death. Activation of autophagy could be used as a strategy to protect the heart against Doxo toxicity.

Introduction of an interdisciplinary heart team-based transcatheter aortic valve implantation programme: short and mid-term outcomes.

Transcatheter aortic valve implantation (TAVI) has been developed to treat symptomatic aortic stenosis in patients deemed too high risk for open‐heart surgery. To address this complex population, an interdisciplinary heart team approach was proposed.

Transapical Aortic Valve Implantation—An Australian Experience

BACKGROUND The aim of this study was to report our initial experience with the transapical approach to transcatheter aortic valve implantation (TAVI) at an Australian institution. METHODS All patients with severe, symptomatic aortic stenosis were assessed by our multidisciplinary team. A total of 32 patients received a transapical TAVI using an Edwards SAPIEN prosthesis. Data were prospectively collected and analysed according to the Valve Academic Research Consortium version 2 guidelines. RESULTS Intraoperative outcomes included: 100% device success with no conversion to surgical valve replacement, extracorporeal membrane oxygenation was used electively in 15.6% and emergently in 6.3%, and no valve migration or malpositioning requiring prosthesis retrieval and re-implantation. Outcomes at 30 days post-TAVI included: No mortality, 3.1% myocardial infarction, no disabling stroke, 3.1% non-disabling stroke, no transient ischaemic attacks, 6.3% life-threatening bleeding, 15.6% major bleeding, 3.1% major vascular complications, and 12.5% postoperative acute kidney injury requiring renal replacement therapy. Mild paravalvular regurgitation was present in 29%, and there was no moderate or severe regurgitation. Mean follow-up time was 28.8±12.9 months. Cumulative results included: 9.4% mortality, 6.3% stroke, 6.3% myocardial infarction, and no repeat procedures. At one year postoperation, echocardiography demonstrated that the mean pressure across the prosthesis was 10.1±1.7mmHg, and the mean aortic valve area was 1.4±0.2cm(2). CONCLUSION Good short-term outcomes and low or zero mortality are achievable with transapical TAVI at an Australian institution.

Neutrophil-derived microparticles are released into the coronary circulation following percutaneous coronary intervention in acute coronary syndrome patients

To evaluate (i) local coronary and systemic levels of microparticles (MP) in acute coronary syndrome (ACS) and stable angina pectoris (SAP) patients and (ii) their release after plaque disruption with percutaneous coronary intervention (PCI). MP are small vesicles originating from plasma membranes of cells after activation or apoptosis and are implicated in the pathogenesis of atherosclerosis. Neutrophils play a role in plaque destabilization and shed neutrophil-derived MP that have the potential to drive significant proinflammatory and thrombotic downstream effects. Eight ACS and eight SAP patients were included. Coronary sinus (CS) samples pre-intervention (CS1), 45 s following balloon angioplasty (CS2) and at 45 s intervals following stent deployment (CS3, CS4 and CS5), together with peripheral vein samples, pre- and post-PCI were analysed for neutrophil-derived (CD66b+), endothelial-derived (CD144+), platelet-derived (CD41a+), monocyte-derived (CD14+) and apoptotic (Annexin V+) MP. ELISA for interleukin (IL)-6, myeloperoxidase (MPO) and P-selectin was also performed. CD66b+ MP levels were similar in both groups pre-intervention. Post-PCI, CS levels rose significantly in ACS but not SAP patients (ACS area under the curve (AUC): 549 ± 83, SAP AUC: 24 ± 29, P<0.01). CS CD41a+, CD144+, CD14+ and Annexin V+ MP levels did not differ between groups. Acute neutrophil-derived MP release post-PCI occurs in ACS compared with stable patients, likely to be reflective of plaque MP content in vulnerable lesions.

Capataz: a framework for distributing algorithms via the World Wide Web

In recent years, some scientists have embraced the distributed computing paradigm. As experiments and simulations demand ever more computing power, coordinating the eorts of many dierent processors is often the only reasonable resort. We developed an open-source distributed computing framework based on web technologies, and named it Capataz. Acting as an HTTP server, web browsers running on many dierent devices can connect to it to contribute in the execution of distributed algorithms written in Javascript. Capataz takes advantage of architectures with many cores using web workers. This paper presents an improvement in Capataz’ usability and why it was needed. In previous experiments the total time of distributed algorithms proved to be susceptible to changes in the execution time of the jobs. The system now adapts by bundling jobs together if they are too simple. The computational experiment to test the solution is a brute force estimation of pi. The benchmark results show that by bundling jobs, the overall perfomance is greatly increased.

A safe and easy technique to sample the coronary sinus — Facilitating a closer look at cardiac disease

Step 1 The catheter is advanced from the right groin to the right atrium over a 0.035′′ guidewire, which is then removed, allowing the catheter to adopt its pre-formed configuration. The catheter tip might be either in the right ventricle or in the low right atrium, near the tricuspid valve (Fig. 1A and B). Step 2 Using a haemostatic valve, a 0.014′′ coronary wire (Balance middleweight, Abbott vascular, Santa Clara, USA) is advanced

Combined total-arterial, off-pump coronary artery bypass grafting and transaortic transcatheter aortic valve implantation

a Sydney Medical School, The University of Sydney, Sydney, Australia b The Baird Institute of Applied Heart & Lung Surgical Research, Sydney, Australia c Cardiothoracic Surgery Unit, The Royal Prince Alfred Hospital, Sydney, Australia d Cardiology Unit, The Royal Prince Alfred Hospital, Sydney, Australia e Catholic University School of Medicine, Santiago, Chile f Radiology Department, The Royal Prince Alfred Hospital, Sydney, Australia