Colchicine in Cardiac Surgery: The COCS Randomized Clinical Trial.

BACKGROUND: In patients who underwent cardiac surgery, first-time postoperative atrial fibrillation (POAF) is associated with increased incidence of hospital-acquired complications and mortality. Systemic inflammation is one of confirmed triggers of its development. The anti-inflammatory properties of colchicine can be effective for the POAF prevention. However, the results of several studies were questionable and required further investigation. Hence, we aimed to evaluate the effectiveness of low-dose short-term colchicine administration for POAF prevention in patients after the open-heart surgery. This double-blind randomized placebo-controlled trial included 267 patients, but 27 of them dropped out in the course of the study. Study subjects received the test drug on the day before the surgery and on postoperative days 2, 3, 4 and 5. The rhythm control was conducted immediately after the operation and until the discharge from the hospital. The final analysis included 240 study subjects: 113 in the colchicine group and 127 in the placebo group. POAF was observed in 21 (18.6%) patients of the colchicine group vs. 39 (30.7%) control patients (OR 0.515; 95% Cl 0.281-0.943; p = 0.029). We observed no statistically significant differences between the patient groups in the secondary endpoints of the study (hospital mortality, respiratory failure, stroke, bleeding, etc.). For other parameters characterizing the severity of inflammation (pericardial effusion, pleural effusion, WBC count, neutrophil count), there were statistically significant differences between the groups in the early postoperative period (days 3 and 5). Also, statistically significant differences between the groups in the frequency of adverse events were revealed: the incidence of diarrhea in the colchicine group was 25.7% vs. 11.8% in the placebo group (OR 2.578; 95% Cl 1.300-5.111; p = 0.005); for abdominal pain, incidence values were 7% vs. 1.6%, correspondingly (OR 4.762; 95% Cl 1.010-22.91; p = 0.028). Thus, there were statistically significant differences between groups in the primary endpoint, thereby confirming the effectiveness of short-term colchicine use for the POAF prevention after coronary artery bypass grafting and/or aortic valve replacement. Also, we detected statistically significant differences between groups in the frequency of side effects to colchicine: diarrhea and abdominal pain were more common in the colchicine group. This clinical trial is registered with ClinicalTrials database under a unique identifier: NCT04224545.

Colchicine for Prevention of Atrial Fibrillation after Cardiac Surgery in the Early Postoperative Period.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery. It has been proven to be associated with an increase in the incidence of early complications and mortality, an increase in the rate of hospital stay duration, and economic costs of their treatment. One of the pharmaceutical drugs recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) for preventing POAF is colchicine (class IIB). However, the results of research on the efficacy and safety of colchicine are ambiguous and, consequently, require further study. OBJECTIVE: Evaluating the efficacy of short-term colchicine administration in the prevention of POAF in patients after open-heart surgery. MATERIALS AND METHODS: Double-blind, randomized, placebo-controlled clinical trial. The subjects were randomly assigned to two groups: treatment group (n = 50) with subjects receiving 1 mg of colchicine 24 h before the surgery, as well as on days 2, 3, 4, and 5 in the postoperative period; and the control group (n = 51), receiving placebo on the same schedule. The primary endpoint was the frequency of POAF in both groups within 7 days after surgery. RESULTS: The study included 101 patients (82 men, 19 women). Baseline clinical, laboratory, instrumental, and intraoperative data did not differ statistically significantly between the groups. POAF was detected in 9 patients (18%) of the treatment group and 15 subjects (29.4%) of the control group, which had no statistical significance (odds ratio, OR 0.527; 95% Cl 0.206-1.349; p = 0.178). No statistically significant differences were revealed for most secondary endpoints, as well as between the groups for all laboratory parameters. There were statistically significant differences between the groups solely in the frequency of diarrhea: 16 (32%) patients in the treatment group and 6 (11.8%) subjects in the control group (OR 3.529; 95% Cl 1.249-9.972; p = 0.010). CONCLUSIONS: We did not detect any statistical differences between the groups in terms of primary endpoints, which could be due to the insufficient volume of the sample of the study. However, we detected some trends of statistical differences among the groups in terms of some parameters. CLINICALTRIALS: Unique identifier: NCT04224545.

Hemolytic Performance in Two Generations of the Sputnik Left Ventricular Assist Device: A Combined Numerical and Experimental Study.

BACKGROUND: Currently, left ventricular assist devices (LVADs) are a successful surgical treatment for patients with end-stage heart failure on the waiting list or with contraindicated heart transplantation. In Russia, Sputnik 1 LVAD was also successfully introduced into clinical practice as a bridge-to-transplant and a destination therapy device. Development of Sputnik 2 LVAD was aimed at miniaturization to reduce invasiveness, optimize hemocompatibility, and improve versatility for patients of various sizes. METHODS: We compared hemolysis level in flow path of the Sputnik LVADs and investigated design aspects influencing other types of blood damage, using predictions of computational fluid dynamics (CFD) and experimental assessment. The investigated operating point was a flow rate of 5 L/min and a pressure head of 100 mm Hg at an impeller rotational speed of 9100 min-1. RESULTS: Mean hemolysis indices predicted with CFD were 0.0090% in the Sputnik 1 and 0.0023% in the Sputnik 2. Averaged values of normalized index of hemolysis obtained experimentally for the Sputnik 1 and the Sputnik 2 were 0.011 ± 0.003 g/100 L and 0.004 ± 0.002 g/100 L, respectively. CONCLUSIONS: Obtained results indicate obvious improvements in hemocompatibility and sufficiently satisfy the determined miniaturization aim for the Sputnik 2 LVAD development.

Local Use of Hydrogel with Amiodarone in Cardiac Surgery: Experiment and Translation to the Clinic.

The objective of this study was to study the use of the hydrogel biopolymer based on sodium alginate ("Colegel") with a drug substance-amiodarone-for the prevention of postoperative atrial fibrillation (POAF) in cardiac surgery. The experimental part of the study was performed on 46 rabbits. Five groups were formed: in the first group, the dose of amiodarone in hydrogel was 1 mg; in the second group-3 mg; in the third group-6 mg; in the fourth group, hydrogel was used without amiodarone; in the fifth group, 60 mg amiodarone was administered intravenously. The animals from each group were removed from the experiment for the pathomorphological study of the heart after 3, 7 and 14 days. The studied endpoints were: the heart rate control; the development of the blockades of the conduction system of the heart; and the development of inflammation according to laboratory pathomorphological studies. The translational clinical part involved a randomized clinical trial which included 60 patients, with an average age of 62 ± 8.5 years. All patients were randomized into two groups: the study group (n = 30, with the application of amiodarone hydrogel) and the control group (n = 30, without the application of amiodarone hydrogel). The dose of amiodarone in the hydrogel material was 60 mg for all patients. The heart rhythm was monitored during 5 days. The primary endpoint was the development of POAF. Secondary endpoints were: the dynamics of heart rate; the duration of the QT and PQ intervals; the development of blockades of the cardiac conduction system; as well as the dynamics of AST and ALT. According to the results of the experimental part, it was found that the method of the local epicardial delivery of amiodarone by the hydrogel material was safe. Hydrogel with amiodarone is effective for reducing the heart rate in the animal experiment in comparison to the control group and the group with the intravenous administration of the drug. The optimal dose of amiodarone in hydrogel was 1 mg per 1 kg. According to the results of the clinical part, it was found that the method of the local epicardial delivery of amiodarone as a hydrogel material proved its safety. Hydrogel with amiodarone at a dose of 60 mg was effective in preventing POAF in patients after coronary artery bypass grafting (CABG) operations in comparison to the control group (p < 0.001). The age and procedure of application of the amiodarone gel were significantly associated with POAF (p = 0.009 and p = 0.011, respectively). The use of hydrogel with amiodarone reduced the probability of developing POAF 18.9-fold. The method of the local epicardial delivery of amiodarone in the form of a hydrogel material is safe. The use of hydrogel with amiodarone after CABG reduced the probability of developing POAF.

Additional superior vena cava combined with abnormal inflow of the hepatic vein.

We represent a case of successful surgical treatment of a rare congenital heart disease: abnormal inflow of an additional superior vena cava into the left atrium, combined with atrial septal defect, mitral and tricuspid valve regurgitation, and abnormal inflow of the left hepatic vein into a roofless coronary sinus.

Endometrial regenerative cells for treatment of heart failure: a new stem cell enters the clinic.

Heart failure is one of the key causes of morbidity and mortality world-wide. The recent findings that regeneration is possible in the heart have made stem cell therapeutics the Holy Grail of modern cardiovascular medicine. The success of cardiac regenerative therapies hinges on the combination of an effective allogeneic "off the shelf" cell product with a practical delivery system. In 2007 Medistem discovered the Endometrial Regenerative Cell (ERC), a new mesenchymal-like stem cell. Medistem and subsequently independent groups have demonstrated that ERC are superior to bone marrow mesenchymal stem cells (MSC), the most widely used stem cell source in development. ERC possess robust expansion capability (one donor can generate 20,000 patients doses), key growth factor production and high levels of angiogenic activity. ERC have been published in the peer reviewed literature to be significantly more effect at treating animal models of heart failure (Hida et al. Stem Cells 2008).Current methods of delivering stem cells into the heart suffer several limitations in addition to poor delivery efficiency. Surgical methods are highly invasive, and the classical catheter based techniques are limited by need for sophisticated cardiac mapping systems and risk of myocardial perforation. Medistem together with Dr. Amit Patel Director of Clinical Regenerative Medicine at University of Utah have developed a novel minimally invasive delivery method that has been demonstrated safe and effective for delivery of stem cells (Tuma et al. J Transl Med 2012). Medistem is evaluating the combination of ERC, together with our retrograde delivery procedure in a 60 heart failure patient, double blind, placebo controlled phase II trial. To date 17 patients have been dosed and preliminary analysis by the Data Safety Monitoring Board has allowed for trial continuation.The combined use of a novel "off the shelf" cell together with a minimally invasive 30 minute delivery method provides a potentially paradigm-shifting approach to cardiac regenerative therapy.