Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil e ective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA. Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients' aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall. Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF- 1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients' TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC. Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment

Pharmacological agents affecting mitophagy and inflammation

Mitochondria are cellular organelles providing energy to the cells. Due to the nature of mitochondrial enzymatic repair systems, mitochondrial DNA tends to generate mutations that are repaired less efficiently than nuclear DNA mutations. There is a certain relationship between the accumulation of mitochondria with mutated DNA in tissues, the development of oxidative stress, and several pathological conditions, from specific mitochondrial diseases to an increased risk of cancer, atherosclerosis, neurodegeneration, and non-systemic inflammation. Mitophagy is the biological mechanism responsible for the degradation of dysfunctional, damaged, and mutant mitochondria. Presumably, the stimulation of mitophagy can lead to tissue cleansing from dysfunctional mitochondria, which can have a powerful therapeutic effect on the root cause of the pathology. This review examines the relationship between mitochondrial mutations and the development of oxidative stress, the mechanisms of mitophagy, and a group of chemicals that stimulate mitophagy

Sex-Specific Features of Calcific Aortic Valve Disease

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in developed countries predominantly affecting the elderly population therefore posing a large economic burden. It is a gradually progressive condition ranging from mild valve calcification and thickening, without the hemodynamic obstruction, to severe calcification impairing leaflet motion, known as aortic stenosis (AS). The progression of CAVD occurs over many years, and it is extremely variable among individuals. It is also associated with an increased risk of coronary events and mortality. The recent insights into the CAVD pathophysiology included an important role of sex. Accumulating evidence suggests that, in patients with CAVD, sex can determine important differences in the relationship between valvular calcification process, fibrosis, and aortic stenosis hemodynamic severity between men and women. Consequently, it has implications on the development of different valvular phenotypes, left ventricular hypertrophy, and cardiovascular outcomes in men and women. Along these lines, taking into account the sex-related differences in diagnosis, prognosis, and treatment outcomes is of profound importance. In this review, the sex-related differences in patients with CAVD, in terms of pathobiology, clinical phenotypes, and outcomes were discussed

CEM immediately after contrast-enhanced CT: a one-step staging of breast cancer

Background Contrast-enhanced mammography (CEM) is a promising technique. We evaluated the diagnostic potential of CEM performed immediately after contrast-enhanced computed tomography (CE-CT). Methods Fifty patients with breast cancer underwent first CE-CT and then CEM without additional contrast material injection. Two independent radiologists evaluated CEM images. The sensitivity of CEM for detecting index and additional malignant lesions was compared with that of mammography/ultrasonography by the McNemar test, using histopathology as a reference standard. Interobserver agreement for detection of malignant lesions, for classifying index tumors, and for evaluating index tumor size and extent was assessed using Cohen kappa. Pearson correlation was used for correlating index tumor size/extent at CEM or mammography/ultrasonography with histopathology. Results Of the 50 patients, 30 (60%) had unifocal disease while 20 (40%) had multicentric or multifocal disease; 5 of 20 patients with multicentric disease (25%) had bilateral involvement, for a total of 78 malignant lesions, including 72 (92%) invasive ductal and 6 (8%) invasive lobular carcinomas. Sensitivity was 63/78 (81%, 95% confidence interval 70.27-88.82) for unenhanced breast imaging and 78/78 (100%, 95.38-100) for CEM (p < 0.001). The interobserver agreement for overall detection of malignant lesions, for classifying index tumor, and for evaluating index tumor size/extent were 0.94, 0.95, and 0.86 kappa, respectively. For index tumor size/extent, correlation coefficients as compared with histological specimens were 0.50 for mammography/ultrasonography and 0.75 for CEM (p <= 0.010). Conclusions CEM acquired immediately after CE-CT without injection of additional contrast material showed a good performance for local staging of breast cancer. Relevance statement When the CEM suite is near to the CE-CT acquisition room, CEM acquired immediately after, without injection of additional contrast material, could represent a way for local staging of breast cancer to be explored in larger prospective studies

From Diabetes to Atherosclerosis: Potential of Metformin for Management of Cardiovascular Disease

Atherosclerosis is a common cause of cardiovascular disease, which, in turn, is often fatal. Today, we know a lot about the pathogenesis of atherosclerosis. However, the main knowledge is that the disease is extremely complicated. The development of atherosclerosis is associated with more than one molecular mechanism, each making a significant contribution. These mechanisms include endothelial dysfunction, inflammation, mitochondrial dysfunction, oxidative stress, and lipid metabolism disorders. This complexity inevitably leads to difficulties in treatment and prevention. One of the possible therapeutic options for atherosclerosis and its consequences may be metformin, which has already proven itself in the treatment of diabetes. Both diabetes and atherosclerosis are complex metabolic diseases, the pathogenesis of which involves many different mechanisms, including those common to both diseases. This makes metformin a suitable candidate for investigating its efficacy in cardiovascular disease. In this review, we highlight aspects such as the mechanisms of action and targets of metformin, in addition to summarizing the available data from clinical trials on the effective reduction of cardiovascular risks

Red Flags, Prognostic Impact, and Management of Patients With Cardiac Amyloidosis and Aortic Valve Stenosis: A Systematic Review and Meta-Analysis

BACKGROUND: Cardiac amyloidosis (CA) has been recently recognized as a condition frequently associated with aortic stenosis (AS). The aim of this study was to evaluate: the main characteristics of patients with AS with and without CA, the impact of CA on patients with AS mortality, and the effect of different treatment strategies on outcomes of patients with AS with concomitant CA. MATERIALS AND METHODS: A detailed search related to CA in patients with AS and outcomes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seventeen studies enrolling 1,988 subjects (1,658 AS alone and 330 AS with CA) were included in the qualitative and quantitative analysis of main patients with AS characteristics with and without CA, difference in mortality, and treatment strategy. RESULTS: The prevalence of CA resulted in a mean of 15.4% and it was even higher in patients with AS over 80 years old (18.2%). Patients with the dual diagnosis were more often males, had lower body mass index (BMI), were more prone to have low flow, low gradient with reduced left ventricular ejection fraction AS phenotype, had higher E/A and E/e', and greater interventricular septum hypertrophy. Lower Sokolow–Lyon index, higher QRS duration, higher prevalence of right bundle branch block, higher levels of N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were significantly associated with CA in patients with AS. Higher overall mortality in the 178 patients with AS + CA in comparison to 1,220 patients with AS alone was observed [odds ratio (OR) 2.25, p = 0.004]. Meta-regression analysis showed that younger age and diabetes were associated with overall mortality in patients with CS with CA (Z-value −3.0, p = 0.003 and Z-value 2.5, p = 0.013, respectively). Finally, patients who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) had a similar overall mortality risk, but lower than medication-treated only patients. CONCLUSION: Results from our meta-analysis suggest that several specific clinical, electrocardiographic, and echocardiographic features can be considered “red flags” of CA in patients with AS. CA negatively affects the outcome of patients with AS. Patients with concomitant CA and AS benefit from SAVR or TAVI

Purinergic Receptor P2Y2 Stimulation Averts Aortic Valve Interstitial Cell Calcification and Myofibroblastic Activation

Rationale—Calcific aortic valve stenosis (CAVS) is a pathological condition of the aortic valve with a prevalence of 3% in the general population. It is characterized by massive rearrangement of the extracellular matrix, mostly due to the accumulation of fibro-calcific deposits driven by valve interstitial cells (VIC), and no pharmacological treatment is currently available. The aim of this study was to evaluate the effects of P2Y2 receptor (P2RY2) activation on fibro-calcific remodeling of CAVS. Methods—We employed human primary VICs isolated from CAVS leaflets treated with 2-thiouridine-5′-triphosphate (2ThioUTP, 10 µM), an agonist of P2RY2. The calcification was induced by inorganic phosphate (2 mM) and ascorbic acid (50 µg/mL) for 7 or 14 days, while the 2ThioUTP was administered starting from the seventh day. 2ThioUTP was chronically administered for 5 days to evaluate myofibroblastic activation. Results—P2RY2 activation, under continuous or interrupted pro-calcific stimuli, led to a significant inhibition of VIC calcification potential (p < 0.01). Moreover, 2ThioUTP treatment was able to significantly reduce pro-fibrotic gene expression (p < 0.05), as well as that of protein α-smooth muscle actin (p = 0.004). Conclusions—Our data suggest that P2RY2 activation should be further investigated as a pharmacological target for the prevention of CAVS progression, acting on both calcification and myofibroblastic activation