Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hcpcs) is regulated by clinically relevant dose of ticagrelor (1 μM), an oral selective and reversible non-thienopyridine P2Y 12 inhibitor. ticagrelorinduced enhancement of exosome levels is related to increased mitotic activity of hcpcs. We show a drug-response threshold above which the effects on hCPCs are lost due to higher dose of ticagrelor and larger adenosine levels. While it is known that pan-Aurora kinase inhibitor halts cell proliferation through dephosphorylation of histone H3 residue Ser10, we demonstrate that it also prevents ticagrelor-induced effects on release of cardiac progenitor cell-derived exosomes delivering antiapoptotic HSP70. Indeed, sustained pre-treatment of cardiomyocytes with exosomes released from explant-derived hcpcs exposed to low-dose ticagrelor attenuated hypoxia-induced apoptosis through acute phosphorylation of ERK42/44. Our data indicate that ticagrelor can be leveraged to modulate release of anti-hypoxic exosomes from resident hcpcs. Acute myocardial infarction (AMI) is an adverse cardiac event leading to high risk of morbidity and mortality worldwide 1. Indeed, it has been demonstrated that a significant residual microvascular perfusion deficit remains after coronary revascularization 2 , which leads to cardiac cell death and progressive ventricular remodeling 3. Post-ischemic left ventricular (LV) remodeling is a complex scenario mainly characterized by progressive loss of cardiomyocytes due to apoptosis and alteration of intercellular cross talk following prolonged exposure to hypoxic microenvironment 3. In order to improve AMI care, adequate pharmacological approach to safely increase hypoxic tolerance of cardiomyocytes remains a critical need. Numerous experimental 4-8 and clinical 9-12 studies have shown that long-term antagonism of P2Y 12 , a G protein-coupled (GPCR) purinergic receptor, protects the myocardium against ischemic LV remodeling. Chronic administration of ticagrelor, a selective and reversible P2Y 12 receptor antagonist that does not require metabolic activation, is more cardioprotective than clopidogrel 13,14 , a prodrug that irreversibly inhibits P2Y 12. The non-thienopyridine P2Y 12 inhibitor such as ticagrelor enhances cardiomyocyte tolerance against ischemic microenvironment 4,7,8,15 beyond its clinical efficacy in preventing intracoronary platelet aggregation. Although previous studies suggested that cardioprotective pleiotropic effects of ticagrelor are dependent on the enhanced levels of adenosine 16 , this mechanistic relationship was recently questioned by others 17. In particular, recent study demonstrated that higher dose of ticagrelor (10 μM/L), which potentiates extracellular adenosine concentration compared to lower dose 18 , failed to protect ischemic reperfused rodent heart 19. Although suc...
Background The echocardiographic evaluation of cardiac output relies on the product of the flow across the left ventricular outflow tract (LVOT), estimated through its velocity time integral (LVOT-VTI), and its cross-sectional area, estimated through the formula πr2. Considering the geometrical assumption behind such formula, LVOT-VTI has been proposed as a more reproducible surrogate of cardiac systolic function and showed prognostic value in the critical care setting. However, the role of such measure in patients with chronic heart failure (HF) remains unexplored. Objective To assess the clinical and prognostic significance of LVOT-VTI in a contemporary cohort of patients with chronic HF. Methods Outpatients with chronic HF with a LV ejection fraction <50% were prospectively enrolled to undergo a clinical, echocardiographic, and biohumoral assessment, and were followed-up for the endpoint of all-cause death. Results Finally, 971 patients were enrolled (71±12 years, 72% men, 50% ischemic etiology, LVEF 35±9%). Most patients showed a NYHA class I-II (74%) and were treated with ACE-inhibitors/ARBs or ARNI (81%), beta-blockers (95%), and mineralocorticoid receptor antagonists (71%). Patients were distinguished in three subgroups according to LVOT-VTI tertiles <19 (n=324), 19–24 (n=324), or ≥24 (n=323). Compared with the other two subgroups, patients with LVOT-VTI <19 showed worse NYHA class, lower LVEF and tricuspid annular plane systolic excursion (TAPSE), and higher E/e', left atrial volume index (LAVi), estimated systolic pulmonary arterial pressure (sPAP), and NT-proBNP concentration (all p<0.001). No differences were observed as for patients' age, HF etiology, and therapies (all p>0.05). Over a median follow-up of 22 (9–34) months, 103 (11%) patients met the primary endpoint. LVOT-VTI significantly stratified the risk of death, observing 65 (20%), 21 (7%), and 17 (5%) events across the subgroups with values <19, 19–24, or ≥24 (log-rank 33, p<0.001). At multivariable regression analysis, LVOT-VTI <19 (HR 2.06 [95% 1.21–3.49], p=0.008), but not LVEF <30% (p=0.614) was an independent predictor of all-cause death in a model adjusted for age, sex, ischemic etiology, renal function, hemoglobin, E/e', LAVi, TAPSE, sPAP, and NT-proBNP. Conclusion LVOT-VTI is associated with disease severity and is a strong predictor of all-cause death in patients with chronic HF. Funding Acknowledgement Type of funding sources: None.
Background Cardiac amyloidosis (CA) may affect all cardiac structures, including the valves. Methods From 423 patients undergoing a diagnostic workup for CA we selected 2 samples of 20 patients with amyloid transthyretin (ATTR-) or light-chain (AL-) CA, and age- and sex-matched controls. We chose 31 echocardiographic items related to the mitral, aortic and tricuspid valves, giving a value of 1 to each abnormal item. Results Patients with ATTR-CA displayed more often a shortened/hidden and restricted posterior mitral valve leaflet (PMVL), thickened mitral chordae tendineae and aortic stenosis than those with AL-CA, and less frequent PMVL calcification than matched controls. Score values were 15.8 (13.6–17.4) in ATTR-CA, 11.0 (9.3–14.9) in AL-CA, 12.8 (11.1–14.4) in ATTR-CA controls, and 11.0 (9.1–13.0) in AL-CA controls (p=0.004 for ATTR- vs. AL-CA, 0.009 for ATTR-CA vs. their controls, and 0.461 for AL-CA vs. controls). Area under the curve values to diagnose ATTR-CA were 0.782 in patients with ATTR-CA or matched controls, and 0.773 in patients with LV hypertrophy. Conclusions Patients with ATTR-CA have a prominent impairment of mitral valve structure and function, and higher score values. The valve score is quite effective in identifying patients with ATTR-CA among patients with CA or unexplained hypertrophy. Funding Acknowledgement Type of funding sources: None.
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