Teresa Strisciuglio

β2-Adrenergic Receptor Stimulation Improves Endothelial Progenitor Cell–Mediated Ischemic Neoangiogenesis

Rationale: Endothelial progenitor cells (EPCs) are present in the systemic circulation and home to sites of ischemic injury where they promote neoangiogenesis. &bgr;2-Adrenergic receptor (&bgr;2AR) plays a critical role in vascular tone regulation and neoangiogenesis. Objective: We aimed to evaluate the role of &bgr;2AR on EPCs’ function. Methods and Results: We firstly performed in vitro analysis showing the expression of &bgr;2AR on EPCs. Stimulation of wild-type EPCs with &bgr;-agonist isoproterenol induced a significant increase of Flk-1 expression on EPCs as assessed by fluorescence-activated cell sorter. Moreover, &bgr;2AR stimulation induced a significant increase of cell proliferation, improved the EPCs migratory activity, and enhanced the EPCs’ ability to promote endothelial cell network formation in vitro. Then, we performed in vivo studies in animals model of hindlimb ischemia. Consistent with our in vitro results, in vivo EPCs’ treatment resulted in an improvement of impaired angiogenic phenotype in &bgr;2AR KO mice after induction of ischemia, whereas no significant amelioration was observed when &bgr;2AR knock out (KO) EPCs were injected. Indeed, wild-type–derived EPCs’ injection resulted in a significantly higher blood flow restoration in ischemic hindlimb and higher capillaries density at histological analysis as compared with not treated or &bgr;2AR KO EPC-treated mice. Conclusions: The present study provides the first evidence that EPCs express a functional &bgr;2AR. Moreover, &bgr;2AR stimulation results in EPCs proliferation, migration, and differentiation, enhancing their angiogenic ability, both in vitro and in vivo, leading to an improved response to ischemic injury in animal models of hindlimb ischemia.

No-Reflow Phenomenon Pathophysiology, Diagnosis, Prevention, and Treatment. A Review of the Current Literature and Future Perspectives

No-reflow is responsible for 40% of the primary percutaneous coronary intervention without complete myocardial reperfusion despite successful reopening of the infarct-related artery. This review describes the main pathophysiological mechanisms of no-reflow, its clinical manifestation, including the strong association with increased in-hospital mortality, malignant arrhythmias, and cardiac failure as well as the diagnostic methods. The latter ranges from simple angiographic thrombolysis in myocardial infarction grade score to more complex angiographic indexes, imaging techniques such as myocardial contrast echo or cardiac magnetic resonance, and surrogate clinical end points such as ST-segment resolution. This review also summarizes the strategies of prevention and treatment of no-reflow, considering the most recent studies results regarding medical therapy and devices.

Endothelial Dysfunction: Its Clinical Value and Methods of Assessment

Endothelial dysfunction (ED) is a systemic disorder characterized by reduced production of nitric oxide. This pathologic condition, which impairs vascular homeostasis, leads to the loss of protective properties of endothelial cells and is related to the pathogenesis of cardiovascular diseases. ED may affect every vascular bed, accounting for several clinical implications, particularly when the coronary bed is affected. Although the reliability of ED as a cardiovascular disease surrogate is still debated, many methods for its assessment have been proposed. In this review, we underline the clinical value of ED in the cardiovascular field and summarize the principal methods currently available for its assessment.

Pharmacotherapeutic considerations for the use of prasugrel and ticagrelor to reduce stent thrombosis in patients with acute coronary syndrome.

Despite the improvement in stent technology, stent thrombosis (ST), a potentially catastrophic event, still occurs. Among several risk factors for ST, high on-treatment platelet reactivity to clopidogrel has been demonstrated to play a role, occurring in about one-third of the patients. In order to overcome this limitation, prasugrel and ticagrelor, newer P2Y12 inhibitors, have been developed and approved for clinical use. Two large clinical trials, TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-thrombolysis in myocardial infarction (TRITON-TIMI) 38 and Study of Platelet Inhibition and Patient Outcomes (PLATO), evaluated these drugs in patients with acute coronary syndrome (ACS), showing a significant improvement in efficacy end points (including a prominent reduction in ST occurrence) compared to clopidogrel. In contrast, the TRILOGY ACS trial found no benefit with prasugrel compared to clopidogrel in patients with medically treated ACS. The aim of this review is to consider decision-making strategies between prasugrel and ticagrelor in daily clinical practice.

Atrial Dilatation Development in Hypertensive Treated Patients: The Campania-Salute Network

BACKGROUND Left atrial (LA) dilatation is associated with unfavorable outcome in hypertension. However, there are few data on clinical, demographic, and echocardiographic findings correlated with LA dilatation development. METHODS From the Campania-Salute Network registry, we identified 5,375 hypertensive patients (52±11 years, 38% women) in normal sinus rhythm, with normal LA diameter (parasternal short-axis <24.0 in women and <25.4mm/m in men), with normal left ventricular (LV) ejection fraction, and with at least 12 months of echocardiographic follow-up. We included in the clinic evaluation type of antihypertensive drugs. RESULTS Follow-up duration was of 70±48 months. During follow-up, 647 patients (12%) showed LA dilatation. Patients with incident LA dilatation were older, most likely to be women, more obese, more diabetics, with lower Modification of Diet in Renal Disease, higher total cholesterol, lower uric acid, higher pulse pressure, lower heart rate, higher LV mass, concentric geometry and lower E/A ratio at mitral level, longer E deceleration time, and higher intima-media carotid thickness. They take more drugs, and follow-up was longer (overall P < 0.05). In the Cox analysis, age, female gender, obesity, higher LV mass, LA diameter at baseline, and longer E deceleration time were determinants of LA dilatation. Furthermore, the use of diuretics protected against LA dilatation. CONCLUSIONS Our data identify a risk profile for LA dilatation, characterized by older age, female sex, obesity, higher LV mass, and worse diastolic function. In this subgroup of patients, the use of diuretics seems to protect against LA dilatation.

Reperfusion Correlates and Clinical Outcomes of Right Ventricular Dysfunction in Patients With Inferior ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention

We evaluated the relation between reperfusion indexes and right ventricular (RV) dysfunction in patients with inferior ST-segment elevation myocardial infarction (STEMI). We included patients with inferior STEMI undergoing percutaneous coronary intervention and right coronary artery as infarct-related artery. Myocardial reperfusion was evaluated by Thrombolysis In Myocardial Infarction (TIMI) flow, TIMI frame count, myocardial blush grade, and ST-segment resolution. RV dysfunction was defined as tricuspid annular plane systolic excursion≤16 mm in M-mode imaging. RV dysfunction was present in 58 of 141 patients (41.1%) and was more frequent in patients achieving suboptimal postprocedural TIMI flow grade (66.7% vs 36.7%, grades 0 to 2 vs 3, p=0.01), TIMI frame count (63.2% vs 37.7%, ≥40 vs <40 frames, p=0.04), and myocardial blush grade (33.3% vs 56.2%, grade 0 or 1 vs 2 or 3, p=0.001). RV dysfunction rates did not differ according to ST-segment resolution. Patients with RV dysfunction had increased rates of cardiac death (13.2% vs 2.6%, p=0.03), reinfarction (24.5% vs 10.3%, p=0.03), and stent thrombosis (22.6% vs 6.4%, p=0.01) at 2-year follow-up. Postprocedural TIMI flow grade 3 (odds ratio 0.25, 95% confidence interval 0.09 to 0.68, p=0.007) was the only reperfusion correlate of RV dysfunction at multivariate analysis. In an independent cohort of 84 patients with STEMI, postprocedural TIMI flow grade 3 had a limited sensitivity (52%), with a high specificity (74.5%) and negative predictive value (71%) for excluding RV dysfunction. In conclusion, in patients with inferior STEMI undergoing coronary revascularization, RV dysfunction is associated with a worse long-term prognosis. Postprocedural TIMI flow grade may be a useful tool to predict RV dysfunction.

Adenosine-induced torsade de pointes complicating a fractional flow reserve measurement in a right coronary artery intermediate stenosis

We present the case of a 57 year-old patient that presented to our Institution with a positive treadmill stress test. Coronary angiography revealed an intermediate stenosis of the right coronary artery evaluated with a fractional flow reserve (FFR), complicated by torsade de pointes. Despite this being a very rare arrhythmic complication during FFR, its prompt recognition and treatment are of utmost importance.

T2238C Atrial Natriuretic Peptide Gene Variant and the Response to Antiplatelet Therapy in Stable Ischemic Heart Disease Patients

The T2238C variant of the ANP gene is associated with higher risk of major cardiovascular events. The purpose of this study is to investigate if this polymorphism influences the response to antiplatelet agents and it is responsible of increased platelet reactivity, thus contributing to the adverse outcome. In patients undergoing elective percutaneous coronary intervention (PCI), loaded with antiplatelets, blood samples were withdrawn for genotyping, platelet reactivity assessment and for troponin T measurement to investigate the association between the polymorphism with residual platelet reactivity and with the incidence of PPMI. No significant differences in platelet reactivity nor in PPMI incidence were observed between groups. Nevertheless, higher ARU, PRU, and % PI were detected in diabetic patients, with PRU significantly higher in carriers versus non-carriers. We observed increased residual platelet reactivity exclusively in diabetic carriers of the T2238C variant undergoing elective PCI, suggesting the need of a more effective platelet inhibition in this category of patients.

C2238 ANP gene variant promotes increased platelet aggregation through the activation of Nox2 and the reduction of cAMP

Subjects carrying the C2238 variant of the atrial natriuretic peptide (ANP) gene have a higher occurrence of stroke and acute coronary syndrome, suggesting an increased predisposition to acute thrombotic events in these subjects. We evaluated for the first time the direct effects of mutant ANP (C2238/αANP) on platelet activation in vitro and in human subjects. In vitro, platelets were incubated with no peptide, with T2238/αANP (WT) or with C2238/αANP at different concentrations. C2238/αANP (10−10 M) induced higher collagen-induced platelet aggregation with respect to both control without ANP and T2238/αANP. This effect was even stronger at a higher concentration (10−6 M). Mechanistically, C2238/αANP significantly lowered platelet cAMP levels, increased ROS production and activated Nox2, with respect to both control and T2238/αANP. Forskolin, a cAMP activator, and sNOX2-tat, a Nox2 inhibitor, significantly reduced the pro-aggregant effects of C2238/αANP. In vivo, we found that platelet aggregation resulted to be higher in patients with atrial fibrillation carrying the C2238 ANP gene variant with respect to non-carriers. In conclusions, C2238/αANP promotes platelet aggregation through the activation of Nox2 and the reduction of cAMP.

Genetically Determined Platelet Reactivity and Related Clinical Implications

AbstractMany drugs are nowadays available to inhibit platelet activation and aggregation, especially in patients with acute coronary syndromes and undergoing percutaneous coronary intervention with stent implantation. Primary targets are represented by enzymes or receptors involved in platelet activation. Genetic mutations in these targets contribute to the inter-individual variability in platelet responses therefore weakening the efficacy of antiplatelet agents. High on treatment platelet reactivity is a condition characterized by low levels of platelet inhibition despite the use of antiplatelet drugs. This could be responsible for re-infarction, stent-thrombosis and strokes, affecting short and long-term prognosis after coronary revascularization. So far, to test antiplatelet resistance either the assessment of platelet function or the identification of genetic carriers of poly morphisms have been pursued. Although several methods are now available to test platelet reactivity, it is still debated whether its routine assessment gives real benefits in clinical practice. The present review aims at examining current evidences on genetic polymorphisms affecting optimal platelet inhibition.