Diabetes and the Platelet Phenotype: Influence of Sex, Cholesterol Lowering and Cardiovascular Events

Project: SFRN

Investigators

  • Jeffrey Stuart Berger (PI)

Description

It is estimated that over 35 million United States (US) adults have diabetes, of which 90-95% of cases are type 2 diabetes (T2D). Alarmingly, more than 90 million US adults have prediabetes. Compared to those without disease, T2D is associated with double the risk for death and a 10-fold increase in hospitalizations for coronary heart disease, and this risk is magnified in women with T2D leading to disparities by sex. Women and men with increased risk of CVD are generally treated with moderate to high intensity statins to lower LDL cholesterol. However, even with statin treatment, subjects with T2D have residual cardiovascular risk and a greater incidence of heart attack and stroke than subjects without T2D. This residual cardiovascular risk in patients with T2D has been under investigation with limited success. We have previously reported that patients with T2D have more reticulated thrombocytosis, a marker of young and more active platelets, than subjects without T2D. We have also found that women have increased platelet activity and a more thrombogenic platelet transcriptome than men. We hypothesize that heightened platelet activity is a significant contributor to the excess risk observed in T2D, and that this difference in the platelet phenotype will explain the sex disparity observed in patients with T2D. As part of this SFRN investigating REPAIR (non-progression of clinical events or regression of atherosclerosis) in T2D, this project will reveal mechanisms behind the platelet mediated increased cardiovascular risk in patients with T2D by focusing on the platelet transcriptome in those with clinical progression and subsequent cardiovascular events versus those without clinical progression. A prospective clinical study will investigate platelet activity and transcriptome before and after significant cholesterol reduction to better understand mechanisms of increased residual risk observed in patients with T2D, even when cholesterol is not elevated. By combining prospective studies on the platelet phenotype in humans with T2D, mechanistic mouse models of diabetes-accelerated atherosclerosis in the Fisher, Basic Project, and the human plaque and genomic data available data from the Giannarelli, Population Project, we believe we are in an excellent position to fill an important and clinically significant gap in our understanding of how diabetes attenuates cardiovascular repair and to identify new treatment and prevention strategies.
Award amount$954,360.00
Award date01/01/2020
Program typeStrategically Focused Research Network
Award ID20SFRN35210609
Effective start/end date01/01/202012/31/2023
StatusActive