Insulin growth-factor 1Ea gene transfer therapy after myocardial infarction

Cardiovascular diseases (CVD) are the major cause of death globally with myocardial infarction (MI) being one of the main causes of mortality. The limited regenerative capacity of adult human tissues is particularly pertinent to the heart, which cannot repair itself fully after injury; instead, the damaged myocardium is replaced by fibrotic scar tissue and the heart progressively decrement in function. To date, efforts to develop interventions for alleviation of this inevitable destructive progression have proven largely ineffective. Although over the past decades, treatment for myocardial ischemia has made significant progress, myocardial infarction remains an unsolved therapeutic target. In attempting to address this problem, insulin growth factor splicing variant 4 (IGF-1Ea) has been extensively tested for its therapeutic properties in the resolution of tissue injury. In the heart, constitutive overexpression of IGF-1Ea (αMHC.IGF-1Ea) restored heart functionality post-infarct, reducing scar formation and increased anti-apoptotic signalling. This thesis provides deeper understanding on the role of IGF-1Ea in early modulation of the inflammatory process after myocardial infarction in αMHC.IGF-1Ea transgenic mice. In fact, the enhanced repair in αMHC.IGF-1Ea after myocardial infarction is due to IGF-1Ea modulating several aspects of the cellular repair process after MI, including immune cell recruitment, cytokine expression, and reduction of the extracellular matrix turnover. However, the heart-specific transgene is constitutively expressed from birth and does not simulate delivery to humans in the clinic. With a better understanding of IGF-1Ea in cardiac repair, this thesis also focused on the design of both cell- and gene-based approaches to deliver the IGF-1Ea therapeutic payload into the heart by (i) adoptive immunotherapy approach using bone-marrow derived-macrophages mediated cell delivery of IGF-1Ea and (ii) IGF-1Ea gene transfer to the heart using a cardiotropic adeno-associated viral vector (AAV9) after ischemia/reperfusion. Of the two approaches, only the gene-based approach was able to deliver IGF-1Ea into the heart achieving therapeutically relevant levels. AAV9-mediated IGF1Ea gene transfer proved to be a potential therapeutic clinical approach to prevent the adverse ventricular remodeling after myocardial infarct. The knowledge acquired in this thesis will be relevant to inform and design future therapeutic approaches for the treatment of patients suffering from myocardial infarction.Open Acces

Pacemaker lead endocarditis: A rare cause of relapsing brucellosis

Implantable cardioverter-defibrillator endocarditis is a rare and potentially life threatening complication of brucellosis of difficult management for clinicians. We report an unusual case of pacemaker-related endocarditis due to Brucella melitensis in a patient with previous history of neurobrucellosis. Our patient was admitted to a hospital with severe swelling of his pacemaker pocket implanted 8 years earlier for sick sinus syndrome. Although pocket site cultures were positive for Brucella but blood cultures were not and serologic titer by the Rose Bengal test was positive. Transesophageal echocardiography showed two vegetations on the pacemaker leads. The patient was treated with doxycycline, rifampin and gentamicin with full recovery and the entire pacemaker apparatus was surgically explanted.Interestingly, two year prior this admission, the patient presented with meningoencephalitis diagnosed with neurobrucellosis proven by positive growth of Brucella mellitensis from the CSF. The patient was treated with doxycycline, rifampin and gentamicin with full recovery and the pacemaker had been removed. Reports of Brucella infection of prosthetic implants and devices have increased over the past decade. Consequently, potential relapsing of the disease and occupational exposure to Brucella should be considered in the differential diagnosis and management of cardiac device infection. Keywords: Brucella melitensis, Relapsing brucellosis, Neurobrucellosis, Pacemaker induced endocarditis, Sick sinus syndrom

Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction.

Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1α1 and Col 1α3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function. Mediators Inflamm 2015; 2015:484357

Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction.

Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1α1 and Col 1α3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function. Mediators Inflamm 2015; 2015:484357

Cardiology on the cutting edge: updates from the\ua0European Society of Cardiology (ESC) Congress 2020

The 2020 annual Congress of the European Society of Cardiology (ESC) was the first ever to be held virtually. Under the spotlight of 'the cutting edge of cardiology', exciting and ground-breaking cardiovascular (CV) science was presented both in basic and clinical research. This commentary summarizes essential updates from ESC 2020-The Digital Experience. Despite the challenges that coronavirus disease 2019 (COVID-19) has posed on the conduct of clinical trials, the ESC Congress launched the results of major studies bringing innovation to the field of general cardiology, cardiac surgery, heart failure, interventional cardiology, and atrial fibrillation. In addition to three new ESC guidelines updates, the first ESC Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease were presented. As former ESC president, Professor Casadei undoubtedly pointed out theESC Congress 2020 was a great success. During the ESC 2020 Congress, BMC Cardiovascular Disorders updated to seven journal sections including Arrhythmias and Electrophysiology, CV Surgery, Coronary Artery Disease, Epidemiology and Digital health, Hypertension and Vascular biology, Primary prevention and CV Risk, and Structural Diseases, Heart Failure, and Congenital Disorders. To conclude, an important take-home message for all CV health care professionals engaged in the COVID-19 pandemic is that we must foresee and be prepared to tackle the dramatic, long-term CV complications of COVID-19 patients

Low High-Density Lipoprotein Cholesterol Predisposes to Coronary Artery Ectasia

Coronary Artery Ectasia (CAE) is a phenomenon characterized by locally or diffuse coronary artery dilation of one or more coronary arteries. In the present study, the prevalence of acquired coronary ectasia and coronary risk factors for CAE was analyzed in patients undergoing cardiac catheterization for suspected ischemic heart disease. We retrospectively analyzed 4000 patients undergoing coronary angiography for suspected coronary artery disease at our cardiac catheterization unit, and a total of 171 patients were selected. The study group was divided into three groups, 65 patients with CAE, 62 patients with significant obstructive coronary artery disease, and 44 patients with normal coronary angiograms as a control group. A negative correlation was observed between high-density lipoprotein cholesterol (HDL-C) and the presence of CAE (r = −0.274, p < 0.001). In addition, HDL-C (OR, 0.858; CI, 0.749–0.984; p = 0.029), low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio (OR, 1.987; CI, 1.542–2.882; p = 0.034), and hemoglobin (OR, 2.060; CI, 1.114–3.809; p = 0.021) were identified as independent risk factors for the development of CAE. In fact, we observed that a one-unit increase in HDL-C corresponded to a 15% risk reduction in CAE development and that each unit increase in hemoglobin could potentially increase the CAE risk by 2-fold. Low HDL-C could significantly increase the risk of developing CAE in healthy individuals. Elevated hemoglobin could predispose to subsequent dilation and aneurysm of the coronary artery. This work suggests that disordered lipoprotein metabolism or altered hemoglobin values can predispose patients to aneurysmal coronary artery disease

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for β-galactosides. The galectin–glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins’ action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer

Exenatide modulates tumor–endothelial cell interactions in human ovarian cancer cells

Diabetes and cancer are prevalent diseases whose incidence is increasing globally. Diabetic women have a moderate risk increase in ovarian cancer, suggested to be due to an interaction between these two disorders. Furthermore, patients manifesting both diseases have associated worse prognosis, reduced survival and shorter relapse-free survival. According to current recommendations, incretin drugs such as Exenatide, a synthetic analog of Exendin-4, and Liraglutide are used as therapy for the type 2 diabetes (T2D). We studied the effects of GLP-1 and Exendin-4 on migration, apoptosis and metalloproteinase production in two human ovarian cancer cells (SKOV-3 and CAOV-3). Exendin-4 inhibited migration and promoted apoptosis through caspase 3/7 activation. Exendin-4 also modulated the expression of key metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). Vascular endothelial cells, which contribute to the formation and progression of metastasis, were also analyzed. TNF-α-stimulated endothelial cells from iliac artery after Exendin-4 treatment showed reduced production of adhesion molecules (ICAM-1 and VCAM-1). Additionally, incretin treatment inhibited activation of apoptosis in TNF-α-stimulated endothelial cells. In the same experiment, MMPs (MMP-1 and MMP-9), which are relevant for tumor development, were also reduced. Our study demonstrated that incretin drugs may reduce cancer cell proliferation and dissemination potential, hence limiting the risk of metastasis in epithelial ovarian cancer