To evaluate the impact of 3D printed models (3D models) on surgical planning in complex congenital heart disease (CHD). A prospective case-crossover study involving 10 international centres and 40 patients with complex CHD (median age 3 years, range 1 month–34 years) was conducted. Magnetic resonance imaging and computed tomography were used to acquire and segment the 3D cardiovascular anatomy. Models were fabricated by fused deposition modelling of polyurethane filament, and dimensions were compared with medical images. Decisions after the evaluation of routine clinical images were compared with those after inspection of the 3D model and intraoperative findings. Subjective satisfaction questionnaire was provided. 3D models accurately replicate anatomy with a mean bias of −0.27 ± 0.73 mm. Ninety-six percent of the surgeons agree or strongly agree that 3D models provided better understanding of CHD morphology and improved surgical planning. 3D models changed the surgical decision in 19 of the 40 cases. Consideration of a 3D model refined the planned biventricular repair, achieving an improved surgical correction in 8 cases. In 4 cases initially considered for conservative management or univentricular palliation, inspection of the 3D model enabled successful biventricular repair. 3D models are accurate replicas of the cardiovascular anatomy and improve the understanding of complex CHD. 3D models did not change the surgical decision in most of the cases (21 of 40 cases, 52.5% cases). However, in 19 of the 40 selected complex cases, 3D model helped redefining the surgical approach.

We compared efficacy and safety of tacrolimus (Tac)‐based vs. cyclosporine (CyA) microemulsion‐based immunosuppression in combination with azathioprine (Aza) and corticosteroids in heart transplant recipients. During antibody induction, patients were randomized (1:1) to oral treatment with Tac or CyA. Episodes of acute rejection were assessed by protocol biopsies, which underwent local and blinded central evaluation. The full analysis set comprised 157 patients per group. Patient/graft survival was 92.9% for Tac and 89.8% for CyA at 18 months. The primary end point, incidence of first biopsy proven acute rejection (BPAR) of grade ≥ 1B at month 6, was 54.0% for Tac vs. 66.4% for CyA (p = 0.029) according to central assessment. Also, incidence of first BPAR of grade ≥ 3A at month 6 was significantly lower for Tac vs. CyA; 28.0% vs. 42.0%, respectively (p = 0.013). Significant differences (p < 0.05) emerged between groups for these clinically relevant adverse events: new‐onset diabetes mellitus (20.3% vs. 10.5%); post‐transplant arterial hypertension (65.6% vs. 77.7%); and dyslipidemia (28.7% vs. 40.1%) for Tac vs. CyA, respectively. Incidence and pattern of infections over 18 months were comparable between groups, as was renal function. Primary use of Tac during antibody induction resulted in superior prevention of acute rejection without an associated increase in infections.

Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca²⁺)-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca²⁺ entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation. We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca²⁺ mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca²⁺ concentration ([Ca²⁺]_i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd³⁺-sensitive current with similar features of the Ca²⁺ release-activated Ca²⁺ current (I_CRAC). Additionally, UII stimulated VSMCs proliferation and Ca²⁺/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca²⁺/calmodulin-dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca²⁺ influx, CREB activation and VSMCs proliferation. Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.

Cardiac, skeletal, and smooth muscle cells shared the common feature of contraction in response to different stimuli. Agonist-induced muscle's contraction is triggered by a cytosolic free Ca²⁺ concentration increase due to a rapid Ca²⁺ release from intracellular stores and a transmembrane Ca²⁺ influx, mainly through L-type Ca²⁺ channels. Compelling evidences have demonstrated that Ca²⁺ might also enter through other cationic channels such as Store-Operated Ca²⁺ Channels (SOCCs), involved in several physiological functions and pathological conditions. The opening of SOCCs is regulated by the filling state of the intracellular Ca²⁺ store, the sarcoplasmic reticulum, which communicates to the plasma membrane channels through the Stromal Interaction Molecule 1/2 (STIM1/2) protein. In muscle cells, SOCCs can be mainly non-selective cation channels formed by Orai1 and other members of the Transient Receptor Potential-Canonical (TRPC) channels family, as well as highly selective Ca²⁺ Release-Activated Ca²⁺ (CRAC) channels, formed exclusively by subunits of Orai proteins likely organized in macromolecular complexes. This review summarizes the current knowledge of the complex role of Store Operated Calcium Entry (SOCE) pathways and related proteins in the function of cardiac, skeletal, and vascular smooth muscle cells.

Urocortin 1 and 2 (Ucn-1 and Ucn-2) have established protective actions against myocardial ischemia-reperfusion (I/R) injuries. However, little is known about their role in posttranscriptional regulation in the process of cardioprotection. Herein, we investigated whether microRNAs play a role in urocortin-induced cardioprotection. Administration of Ucn-1 and Ucn-2 at the beginning of reperfusion significantly restored cardiac function, as evidenced ex vivo in Langendorff-perfused rat hearts and in vivo in rat subjected to I/R. Experiments using microarray and qRT-PCR determined that the addition of Ucn-1 at reperfusion modulated the expression of several miRNAs with unknown role in cardiac protection. Ucn-1 enhanced the expression of miR-125a-3p, miR-324-3p; meanwhile it decreased miR-139-3p. Similarly, intravenous infusion of Ucn-2 in rat model of I/R mimicked the effect of Ucn-1 on miR-324-3p and miR-139-3p. The effect of Ucn-1 involves the activation of corticotropin-releasing factor receptor-2, Epac2 and ERK1/2. Moreover, the overexpression of miR-125a-3p, miR-324-3p and miR-139-3p promoted dysregulation of genes expression involved in cell death and apoptosis (BRCA1, BIM, STAT2), in cAMP and Ca²⁺ signaling (PDE4a, CASQ1), in cell stress (NFAT5, XBP1, MAP3K12) and in metabolism (CPT2, FoxO1, MTRF1, TAZ). Altogether, these data unveil a novel role of urocortin in myocardial protection, involving posttranscriptional regulation with miRNAs.