Bruno Trimarco

Calmodulin-Dependent Kinase II Mediates Vascular Smooth Muscle Cell Proliferation and Is Potentiated by Extracellular Signal Regulated Kinase

Vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling in atherosclerosis and hypertension. Calcium-dependent signaling through calcium/calmodulin-dependent kinase II (CaMKII) and ERK1/2 activation plays an important role in the regulation of VSMC proliferation by agents such as alpha-adrenergic receptor agonists. Nevertheless, how the CaMKII and ERK pathways interact in VSMCs has yet to be characterized. The aim of the present study was to clarify this interaction in response to alpha(1)-adrenergic receptor-mediated VSMC proliferation. We discovered that phenylephrine stimulation resulted in complex formation between CaMKII and ERK in a manner that facilitated phosphorylation of both protein kinases. To assess the effects of CaMKII/ERK association on VSMC proliferation, we inhibited endogenous CaMKII either pharmacologically or by adenoviral-mediated gene transfer of a kinase-inactive CaMKII mutant. Inhibition of CaMKII activation but not CaMKII autonomous activity significantly decreased formation of the CaMKII/ERK complex. On the contrary, the expression of constitutively active CaMKII enhanced VSMC growth and CaMKII/ERK association. In addressing the mechanism of this effect, we found that CaMKII could not directly phosphorylate ERK but instead enhanced Raf1 activation. By contrast, ERK interaction with CaMKII facilitated CaMKII phosphorylation and promoted its nuclear localization. Our results reveal a critical role for CaMKII in VSMC proliferation and imply that CaMKII facilitates assembly of the Raf/MEK/ERK complex and that ERK enhances CaMKII activation and influences its subcellular localization.

Early stent thrombosis with bivalirudin in patients undergoing percutaneous coronary intervention: A meta-analysis of randomised clinical trials

Although bivalirudin has been shown to reduce bleeding events in patients undergoing percutaneous coronary intervention, residual concerns remain about a possible higher risk of early (within 30 days) stent thrombosis (ST). Therefore, we performed a meta-analysis of randomised trials reporting ST events with bivalirudin compared to other antithrombotic therapies (heparins ± glycoprotein IIb/IIIa inhibitors). A systematic literature search of electronic resources was performed through May, 2014. The primary endpoint was definite early ST, according to Academic Research Consortium criteria. Secondary endpoints included: all-cause death, myocardial infarction and major bleeding. A total of 11 trials, including 16,415 patients, were accrued. Compared to other regimens, bivalirudin significantly increased the risk of early ST (odds ratio [OR]=1.80; 95u2009% confidence interval [CI], 1.28-2.52; p=0.0007) and reduced the risk of major bleeding (OR [95u2009%CI]=0.64 [0.51-0.82], p=0.0003), with a comparable risk of mortality or myocardial infarction. The higher risk of early ST was mainly attributable to acute (OR [95u2009% CI] =4.33 [2.33-8.05], p <u20090.001) than subacute (OR [95u2009% CI] =0.89 [0.53-1.50], p =0.67) ST events (p for interaction <u20090.001). Non-fatal myocardial infarction was the most common presentation (83u2009%) of early ST events, while death occurred infrequently (about 5u2009%). In conclusion, in patients undergoing PCI, bivalirudin compared to heparins is associated with a higher risk of early ST, which is mainly related to more frequent acute events. Further studies are required to evaluate alternative strategies to mitigate this risk, without hampering the benefits derived from the reduction in bleeding events with bivalirudin.

New Insights in Cardiac Calcium Handling and Excitation-Contraction Coupling

Excitation-contraction (EC) coupling denotes the conversion of electric stimulus in mechanic output in contractile cells. Several studies have demonstrated that calcium (Ca2+) plays a pivotal role in this process. Here we present a comprehensive and updated description of the main systems involved in cardiac Ca2+ handling that ensure a functional EC coupling and their pathological alterations, mainly related to heart failure.

Functional role of mitochondria in arrhythmogenesis

Growing evidence indicate that mitochondria play a functional role in arrhythmogenesis. We report here the molecular mechanisms underlying the action of these highly dynamic organelles in the regulation of cell metabolism, action potential and, overall, heart excitability. In particular, we examine the role of cardiac mitochondria in linking metabolism and cell excitability. The importance of the main mitochondrial channels is evaluated as well, including the recently identified calcium uniporter. Promises and pitfalls of potential therapeutic strategies targeting mitochondrial pathways are also assessed.

Percutaneous Coronary Intervention in a Patient with Acute Thrombosis of Saphenous Vein Graft and Patent Native Coronary Artery: Which is the Vessel to Approach?

We describe a case of a patient with a clinical history of coronary artery disease, previously treated by coronary surgery and, one year later, by percutaneous coronary intervention plus stenting for sub-occlusive disease of the saphenous vein graft to first obtuse marginal (OM) branch. The patient, admitted to our emergency room with chest pain, nausea, hypotension and diaphoresis, had elevated blood levels of cardiac troponin T and EKG showed elevation of the ST segment in the in lateral leads, suggesting a diagnosis of ST elevated myocardial infarction (STEMI). Thus, coronary angiography was immediately performed, showing the massive thrombosis of the saphenous vein graft previously treated by stenting and the slight patency of the native vessel. We decided to approach the native vessel instead of clashing to the massive thrombus of the saphenous vein graft, overcoming the actual guidelines indications.