Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Stem Cell Therapy for Congestive Heart Failure

IntroductionHeart failure is a major cardiovascular health problem. Coronary artery disease is the leading cause of congestive heart failure (CHF) [1]. Cardiac transplantation remains the most effective long-term treatment option, however is limited primarily by donor availability, rejection and infections. Mechanical circulatory support has its own indications and limitations [2]. Therefore, there is a need to develop more effective therapeutic strategies.Recently, regenerative medicine has received considerable scientific attention in the cardiovascular arena. We report here our experience demonstrating the beneficial effects of cardiac stem cell therapy on left ventricular functions in a patient with Hodgkin’s lymphoma (HL) who developed CHF due to ischemic heart disease during the course of lymphoma treatment. Case reportA 58-year-old male with relapsed HL was referred to our bone marrow transplantation unit in October 2009. He was given 8 courses of combination chemotherapy with doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) between June 2008 and February 2009 and achieved complete remission. However, his disease relapsed 3 months after completing the last cycle of ABVD and he was decided to be treated with DHAP (cisplatin, cytarabine, dexamethasone) followed autologous stem cell transplantation (SCT). After the completion of first course of DHAP regimen, he developed acute myocardial infarction (AMI) and coronary artery bypass grafting (CABG) was performed. After his cardiac function stabilized, 3 additional courses of DHAP were given and he was referred to our centre for consideration of autologous SCT. Computed tomography scans obtained after chemotherapy confirmed complete remission. Stem cells were collected from peripheral blood after mobilization with 10 µg/kg/day granulocyte colony-stimulating factor (G-CSF) subcutaneously. Collection was started on the fifth day of G-CSF and performed for 3 consecutive days. Flow cytometric analysis of CD 34 was used to identify hematopoietic stem cells. During the last evaluation before stem cell transplantation, conventional echocardiogram (ECHO) revealed left ventricular systolic dysfunction with an ejection fraction of ALEF: 44%, MODEF: 45%, MUGA scan showed a decreased left ventricular ejection fraction (LVEF: 43%) (Figure 1). In view of these findings, the patient was found ineligible for SCT and he was offered to give his peripheral blood stem cells for the treatment of heart failure. After receiving the patient’s signed informed consent form, a total number of 3.49x106/kg CD 34+ cells were infused via antecubital vein. Echocardiographic studies performed 2 months after stem cell therapy revealed a similar ejection fraction rate while a significant improvement in left ventricular ejection fraction (ALEF: 55%, MODEF: 57%) was noticed in ECHO performed 7 months after stem cell therapy (Figure 2).EF values at various time periods are shown on Table 1. Myocardial perfusion scintigraphy was also performed and showed infarction containing viable tissue in inferior wall (Figure 3). Myocardial positron emission tomography revealed that glucose metabolism was conserved in inferior wall.HL was in complete remission in the 2 months follow up after SCT but SCT for HL was not contemplated because renal failure due to chemotherapy developed later. Discussion Here, we reported a patient with HL who was ineligible for SCT because of low LVEF due to AMI. LVEF was low despite CABG. Collected stem cells were used as a stem cell therapy for heart failure since he was ineligible for SCT directed to treat HL. Although intravenous infusion of stem/progenitor cells are not favoured any more and intracoronary infusion or intramyocardial injections are preferred in latest reports [3] our data supports this route can still be effective. The objective of stem cell therapy in CHF due to ischemic heart disease is to repopulate post-infarction scar tissue with contractile cells that can engraft in sufficient numbers to differentiate to the cardiac myocytes and restore functionality in these akinetic areas. Hematopoietic stem cells consist can differentiate to skeletal and myocardial cells when cultured under appropriate conditions [4]. Strauer et al [5] reported that intracoronary bone marrow stem cell therapy improves ventricular performance, quality of life and survival in patients with chronic heart failure. Hamano et al [6] showed in 5 patients that autologous bone marrow cells can be injected safely during a by-pass operation into areas of ischemic myocardium. Brehm et al [7] have treated 23 patients with acute cardiac infarction using autologous mononuclear bone marrow cells. Ozbaran et al [8] transplanted peripheral blood stem cells into areas of injury with open-heart surgery in six patients with ischemic cardiomyopathy. There are also meta-analysis on ongoing clinical trials performed. Abdel-Latif et al [9] described a statistically significant improvement in ejection fraction, reduction in infarct size and left ventricular end-systolic volume in 18 patients treated with either unseparated bone marrow cells, bone marrow mesenchymal and mobilized peripheral blood cells. Martin-Rendon et al ­­ focused on 13 randomized studies encompassing 811 participants on bone marrow therapy for post acute infarction. Improvement in LVEF, decrease in left ventricular and systolic and end diastolic volumes and infarct size were observed. The reason for choice of intravenous route was being the standard way of giving hematopoietic stem cells by hematologists. We tried to decide the availibility of this route for indications other than hematological diseases. Although trapping of stem cells in the pulmonary vascular bed is a drawback of intravenous route and the question of whether the patient would have been more benefited by intracoronary or intramyocardial route remains unanswered, we think intravenous route may still have some role according to our own experience from this patient. ConclusionStudies in the era of cardiac stem cell therapy are heterogenous. It is not yet possible to comment on the most appropriate stem cell type and route of administration. When we assess the results from literature and the improvement in our own patient we think stem cell therapy can be an option for bridging to heart transplantation or an adjuvant therapy for CHF.References1.Ohnishi S, Ohgushi H, Kitamura S, Nagaya N. Mesenchymal stem cells for the treatment of heart failure. Int J Hematol 2007; 86: 17-21.2.Bukharovich IF, Kukin M. Optimal medical therapy for heart failure. Prog Cardiovasc Dis 2006; 48: 372-385.3.Tongers J, Losordo DW, Landmesser U. Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties and challenges. Eur Heart J 2011. Epub ahead of print.4.Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105:369-377.5.Strauer BE, Yousef M, Schannwell CM. the acute and long term effects of intracoronary stem cell transplantation in 191 patients with chronic heart failure: the STAR-heart study. Eur J Heart Fail 2010; 12:721-729.6.Hamano K, Nishida M, Mirata K, Mikarno A, Li TS, Harada M, Miura T, Matsuzaki M, Esato K. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ishemic heart disease: clinical trial and preliminary results Jpn Circ J. 2001; 65:845-847.7.Brehm M, Zeus T, Strauer BE. Stem cells-clinical application and perspectives. Herz 2002; 27:611-620.8.Ozbaran M, Omay SB, Nalbantgil S, Kultursay H, Kumanlioglu K, Nart D, Pektok E. Autologous peripheral stem cell transplantation in patients with congestive heart failure due to ischemic heart disease. Eur J Cardiothorac Surg. 2004; 25:342-350.9.Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, Zuba-Surma EK, Al-Mallah M, Dawn B. Adult bone marrow derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007; 167:989-997.10.Martin-Rendon E, Brunskill S, Doree C, Hyde C, Watt S, Mathur A, Stanworth S. Stem cell treatment for acute myocardial infarction. Cochrane database Syst Rev 2008; CD006536

Right ventricular thrombus with Behçet's syndrome successful treatment with warfarin and immunosuppressive agents

Behçet's syndrome is a chronic multisystem disease that presents with recurrent oral and genital ulceration and recurrent uveitis. Cardiac involvement is an extremely rare manifestation of this disorder. A 33-year-old man with Behçet's syndrome was admitted to our department with a history of cough, fever, chest pain, hemoptysis, and weight loss. Transthoracic and transesophageal echocardiography revealed a right ventricular thrombus. After 1 month of treatment with warfarin, cyclophosphamide, and corticosteroid, the intracardiac thrombus resolved. © 2007 by the Texas Heart® Institute

INVESTIGATION OF THE CYP3A4 AND PON1 GENE VARIANTS IN TURKISH PATIENTS WITH FAMILIAL CORONARY ARTERY DISEASE

Ozbayer, Cansu/0000-0002-1120-1874;WOS: 000440358702255Objective: Coronary artery disease (CAD), a complex multifactorial disorder, has been suggested to be associated by the interaction of both environmental and genetic risk factors

The Plasma Levels Of Prostanoids And Plasminogen Activator Inhibitor-1 In Primary And Secondary Thrombocytosis

An elevated platelet count is a common finding in both hospitalized and ambulatory patients. Thrombosis and bleeding complications are more frequently observed in patients with clonal thrombocytosis than secondary thrombocytosis. The aim of this study was to investigate the behaviors of plasminogen activator inhibitor type 1 (PAI-1), the inhibitor of fibrinolysis; and thromboxane A2 and 6-keto-PGF1 alpha, the products of endoperoxides, in 16 patients affected with clonal thrombocytemia as compared with 16 patients with reactive thrombocytosis and 15 normal controls. In the clonal thrombocytemia group, plasma levels of PAI-1 antigen and activity were significantly higher than both reactive thrombocytosis and control group. Plasma levels of 6-keto-PGF1 alpha were significantly higher in the clonal thrombocytemia group than the other two groups and also higher in the reactive thrombocytosis group than the control group, which was also significant. This study confirms that arachidonate metabolism is frequently deranged in patients with thrombocytosis and hypofibrinolysis due to increased PAI-1 plasma levels as shown in the clonal thrombocytosis group. This may explain the thrombotic tendency in myeloproliferative disorders.WoSScopu

Plasminogen Activator İnhibitor Type-1 Gene 4G/5G Polymorphism is Associated With Hypertensive Patients in the Turkish Population

PubMed ID: 20392162This study has been performed on hypertensive patients in the Turkish population to determine the frequency of 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene and with the aim of examining the role of this polymorphism in hypertension development. Genomic DNA obtained from 284 persons (176 patients with hypertension and 108 healthy controls) was used in the study. DNA was multiplied by polymerase chain reaction using 4G and 5G allele-specific primers. Polymerase chain reaction products were assessed by being exposed to 2% agarose gel electrophoresis. Results were evaluated with the chi-square test. The 4G allele frequency was 31.25% and the 5G allele frequency was 68.75% in patients, whereas it was 49/51% in a control group. 5G5G genotype was found statistically high (p<0.001) in patients relative to controls. This study showed that the plasminogen activator inhibitor type-1 gene 4G/5G polymorphism and the 5G5G genotype appear to be associated with an elevated risk of developing hypertension in a representative sample of Turkish population. © Copyright 2010, Mary Ann Liebert, Inc. 2010

Effects of vitamin E and prednisolone on some oxidative stress markers in endotoxemic rabbits

Effects of prednisolone (PR) and vitamin E (VE) on oxidative stress and antioxidant systems were investigated in endotoxemic rabbits. Forty rabbits were used and divided into four equal groups. Group I served as the control group. In group II, lipopolysaccharide (LPS, 100 µg/kg/h) was infused for 6 hours, whereas rabbits of groups III and IV received prior treatments with subcutaneous injection of prednisolone (10 mg/kg) (group III) or with intra-peritoneous injections of vitamin E (10 mg/kg) for 4 consecutive days (group IV). Serum, liver, heart and kidney samples were obtained at 8 hours after infusion. Malonedialdehyde (MDA), glutathione (GSH) concentrations and superoxide dismutase (SOD), catalase (CAT) activities were spectrophotometrically determined in tissues plus in serum (for MDA). LPS caused statistically significant (p<0.05) increases of MDA and antioxidants in serum and in all tissues. PR and VE significantly (p<0.05) suppressed increases of MDA, SOD, CAT and GSH. As a consequence, prednisolone and vitamin E had protective effects on oxidative stress in endotoxemic rabbits

An observational study to evaluate factors responsible and actions taken for hypertensive patients who are not at blood pressure goal: I-target Goal Study

PubMed ID: 22318207To evaluate the percentage of hypertensive patients who could achieve target blood pressure (TBP) according to the guidelines in the context of recommended measures and the factors responsible for failure. A total of 589 hypertensive patients (59.0% female; mean age: 57.7±10.4 years) were assessed twice for TBP achievement based on 2007 ESH/ESC guidelines and the investigators' view, in addition to the recommended measures and possible causes of failure in hypertension management in this national multi-center (n=99), non-interventional observational study. Only 29.5% of the patients at the first visit and 46.8% at the second visit achieved the TBP levels specified by the guidelines. However, the investigators' evaluation indicated a higher achievement rate at the first (43.5%) as well as the second (69.1%) visit when compared with the guideline-based assessments (P<0.001). The primary reasons identified by the investigators for the failure to reach TBP were non-compliance with dietary recommendations (61.6%) at the first visit and non-compliance with treatment (63.92%) at the second visit. Recommendations for lifestyle were the most commonly identified treatment plan by the investigators at both visits (62.9% and 66.1%, respectively). Although more patients achieved the TBP levels specified by the guidelines for the second visit compared with the first, effective blood pressure control was achieved only in 29.5% of our patients. Interestingly, the investigators had a more optimistic view about their patients' control of hypertension, which may have contributed to a poor achievement of TBP. © 2012 The Japanese Society of Hypertension All rights reserved