Oxidative stress is widely accepted as a key factor of doxorubicin (doxo)-induced cardiotoxicity. There is evidence to indicate that nitrosative stress is involved in this process, and that doxo interacts by amplifying cell damage. Mitochondrial connexin 43 (mitocx43) can confer cardioprotective effects through the reduction of mitochondrial reactive oxygen species production during doxo-induced cardiotoxicity. The present study aimed to evaluate the involvement of mitocx43 in doxo-induced nitrosative stress. Rat H9c2 cardiomyoblasts were treated with doxo in the absence or presence of radicicol, an inhibitor of Hsp90, the molecular chaperone involved in cx43 translocation to the mitochondria that underlies its role in cardioprotection. FAcS analysis and RT-qPcR revealed that doxo increased superoxide dismutase, and catalase gene and protein expression. As shown by hypodiploid nuclei and confirmed by western blot analysis, Doxo increased caspase 9 expression and reduced procaspase 3 levels, which induced cell death. Moreover, a significant increase in the activation of the NF-κB signaling pathway was observed. It is well known that the increased expression of inducible nitric oxide synthase results in nitric oxide overproduction, which then rapidly reacts with hydrogen peroxide or superoxide generated by the mitochondria, to form highly reactive and harmful peroxynitrite, which ultimately induces nitrotyrosine formation. Herein, these interactions were confirmed and increased effects were observed in the presence of radicicol. On the whole, the data of the present study indicate that an interplay between oxidative and nitrosative stress is involved in doxo-induced cardiotoxicity, and that both aspects are responsible for the induction of apoptosis. Furthermore, it is demonstrated that the mechanisms that further increase mitochondrial superoxide generation (e.g., the inhibition of cx43 translocation into the mitochondria) significantly accelerate the occurrence of cell death.

Background Coronary Artery Aneurysms (CAA) are defined as localized coronary artery dilations more than 1.5 times the diameter of the adjacent segments. Giant CAA (GCAAs) are rare coronary diseases and the presence of multiple CAAs, located in more than one coronary artery, is even more uncommon. The pathophysiology is unknown but the majority are due to atherosclerosis. There is currently no consensus concerning the management. Case presentation: We report the case of a 72–year–old man, referred to our emergency department due to chest pain. The patient’s electrocardiogram was consistent with myocardial infarction with inferior leads ST–segment elevation. Two-dimensional echocardiography showed hypertrophic Left Ventricle (LV) with akinesia of the infero–postero-lateral LV wall and hypokinesia of the remaining LV segments (LVEF = 40%). Coronary angiography and computed tomography revealed multiple CAAs, some of them giant, associated with significant coronary artery disease: two CAAs on the right coronary artery, including a giant one (Dmax 11 mm and Dmax 32 mm); one large aneurism on the circumflex artery (D max 20.5 mm) and one on the left main descendent artery (D max 8 mm). The patient had a previous history of hypertension, dyslipidemia and abdominal aortic aneurysm. He had no history of percutaneous coronary intervention or cardiac surgical procedures. Serological studies for vasculitis or connective tissue disease were all negative. The patient underwent surgical exclusion of the giant right CAA with ligation of the proximal and distal ends of the aneurysm and double bypass surgery to the obtuse marginal and right posterior descending coronary arteries. Conclusions CAAs’ treatment options include medical treatment, interventional or surgical management. No clear evidence about the better option exists, but it seems that surgical option should be favored in cases of bigger, more tortuous and more calcified CAAs. Based on these evidences and the anatomic lesions of our patient, we opted for surgery and he successfully underwent CAAs resection with coronary bypasses. We reported our experience and we examined the current knowledge on CAA/GCAA. Overall, management is hampered by lack of evidence. We need prospective studies and registries to further our knowledge in the management of this disorder and prognosis. From our attitude, surgical treatment should be performed for multiple GCAA to prevent fatal complications.

Introduction Pulmonary arterial hypertension (PAH) is a rare form of pulmonary hypertension (PH) that may also be associated with connective tissue diseases (CTD). In particular, PAH may affect from 5 to 19% of patients with systemic sclerosis (SSc), leading to a significant prognostic worsening. The current challenge is an early detection of PAH in such patients, in order to provide an early referral to PH centers to supply specific therapies as soon as possible. In the latest ESC guidelines for PH, cardiopulmonary exercise testing (CPET) has been included in the diagnostic algorithm for patients with unexplained exertional dyspnoea and/or suspected PH. Patients with PAH show a typical pattern, with a low end-tidal partial pressure of carbon dioxide (PETCO2), high ventilatory equivalent for carbon dioxide (VE/VCO2), low oxygen pulse (VO2/ HR) and low peak oxygen uptake (VO2). CPET may identify patients with SSc at low risk of PAH, to avoid unnecessary right heart catheterization (RHC). However, CPET is not available in all centers. So, we designed a preliminary study to identify new biomarkers that correlate with CPET's parameters. Material and Methods We enrolled 62 SSc patients [53 females, median age 52 years] with no other comorbidities and asymptomatic for dyspnea or other symptoms. 56% and 44% of them presented limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), respectively. For all patients we performed serum analysis for sST2, Galectine-3, pro-ANP, BNP and IL6, diagnostic imaging with echocardiography and cardiac MRI, CPET and pulmonary functionality test (PFT). Results All patients presented normal echocardiographic and RMI imaging findings. Galectin-3, sST2, pro-ANP, BNP and IL6 presented respectively the following median value: 13.45 ng/mL [11.78; 18.70], 23.25 ng/mL [13.04; 43.35], 1897 fmol/ml [1487; 2445], 12.18 pg/mL [9.34; 15.01]. Both Galectin-3 and sST2 showed a linear correlation with VE/VCO2 slope with R 0.339 (P-value 0.018) and 0.355 (P-value 0.013) respectively. After linear regression analysis, Galectin-3 and sST2 were overall statistically significant with R2 of 0.115 and 0.126, F of 5.97 and 6.62 and P-value of 0.018 and 0.013, respectively. It was found that Galectin-3 and SST2 significantly predicted VE/VCO2 slope with β = 0.364 [0,064; 0,665] for Galectin-3 and 0.137 [0,030; 0,244] for SST2. All other CPET parameters did not show correlation with the biomarkers. Conclusion Our preliminary results suggest that Galectine-3 and sST2 may be useful biomarkers for predicting increasing VE/VCO2 slope. Future analysis may confirm the role of these new biomarkers for early detection of pulmonary vascular involvement in SSc patients to allow an early referral and treatment and, conversely, to avoid unnecessary RHC.