Antiplatelet Therapy for Secondary Prevention of Vascular Disease Complications.

PURPOSE OF REVIEW: Platelets are activated upon interaction with injured vascular endothelium to form a primary hemostatic plug. Pathogenic thrombosis driven by platelet aggregation can occur in the setting of vascular disease leading to ischemic events. The use of antiplatelet agents has become a mainstay for prevention of the secondary complications of vascular disease. This review summarizes seminal and recent literature related to this area. RECENT FINDINGS: Aspirin is a cornerstone of antiplatelet therapy for coronary artery disease and cerebrovascular disease for prevention of myocardial infarction, stroke, and vascular death. Alternative antiplatelet agents have shown promise for use in patients with peripheral artery disease though further validation is necessary. Dual antiplatelet therapy (DAPT) with clopidogrel, prasugrel, or ticagrelor, and aspirin demonstrates benefit in patients with higher thrombotic risk. However, use of DAPT predictably increases bleeding risk, thus limiting mortality benefit. Individualization of DAPT to patient-specific features is an area of active research with the development the DAPT score and pharmacogenomic approaches. Application of pharmacogenetic data could allow for a precision medicine approach to tailoring antiplatelet therapy. Recommendations for management of cardiovascular, cerebrovascular, and peripheral artery disease are largely based on large-scale randomized control trials and meta-analyses. Seminal trials have largely focused on prevention of vascular events including non-fatal MI, stroke, and vascular death in subsets of patients with cardiovascular disease. Data from these trials along with smaller studies have driven recommendations for secondary prevention management in patients with cerebrovascular and peripheral artery disease.

PGC-1α dictates endothelial function through regulation of eNOS expression.

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1α (PGC-1α) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1α in vascular function using mice with endothelial specific loss of function (PGC-1α EC KO) and endothelial specific gain of function (PGC-1α EC TG). Here we report that endothelial PGC-1α is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1α sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1α EC TG mice were protected. Mechanistically, PGC-1α promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1α expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor α (ERRα) is required to coordinate the PGC-1α -induced eNOS expression. In conclusion, endothelial PGC-1α expression protects from vascular dysfunction by promoting NO• bioactivity through ERRα induced expression of eNOS.