Current Research Areas:

Vascular Effects of Antiplatelet Therapy: The key To Understanding harmfuL Bleeding?

Antiplatelet therapy involving the administration of P2Y₁₂ receptor antagonists is the standard of care for managing patients at risk for thrombotic events. The therapeutic efficacy of this routine treatment strategy is coupled with an increased risk of devastating adverse bleeding events, including intracerebral hemorrhage (ICH). Clopidogrel, a widely used P2Y₁₂ antagonist, is administered as the standard of care, despite carrying this substantial bleeding liability. Each year, approximately 1.9 million U.S. patients on clopidogrel therapy will develop adverse bleeding. This bleeding risk is accepted clinically as an unavoidable consequence of achieving ‘on-target’ antiplatelet effects. Our studies directly challenge this dogma and suggest that observed ICH caused by clopidogrel is caused by previously unrecognized mechanisms of action on cerebral arteries that are P2Y₁₂-dependent and P2Y₁₂-independent. Uncovering how these mechanisms combine with the antiplatelet effects of clopidogrel to increase bleeding risk has real potential to limit the incidence and severity of ICH and improve the risk-benefit ratio for patients taking this common therapy.

Despite its routine use, the biological actions of nearly all clopidogrel metabolites are not known. The field has focused on the specific metabolite inhibiting the platelet P2Y₁₂ receptor, largely ignoring any pharmacologic potential of the numerous other clopidogrel metabolites that accumulate at even higher plasma concentrations. Indeed, a significant and actionable knowledge gap is a comprehensive map of clopidogrel pharmacology. Our overall objective is to discover how clopidogrel metabolites perturb cerebral artery function to cause bleeding. Our central hypothesis is that clopidogrel disrupts cerebral artery function by inhibiting receptor-mediated vasoconstriction and reducing arterial distensibility by inhibiting P2Y₂ and P2Y₁₂, respectively. This hypothesis is supported by exciting preliminary data demonstrating worsened bleeding with the clopidogrel parent compound compared to administration of the active metabolite of clopidogrel alone, even while retaining antiplatelet efficacy via inhibition of platelet P2Y₁₂. Our laboratory recently demonstrated that clopidogrel inhibited endothelium-dependent P2Y₂-mediated vasoconstriction in cerebral arteries. Subsequent pilot experiments have revealed that clopidogrel administration also reduces cerebral artery distensibility. However, it is unclear whether these observed vascular effects result from direct drug actions on the vasculature or are secondary effects resulting from platelet inhibition and the subsequent loss of platelet-vessel interaction. We postulate that these vascular changes are a crucial determinant of clopidogrel-driven ICH.

Modeling Approaches to Predicting Proarrhythmia in Drug Discovery and Development

Drug-induced prolongation of the QT interval, resulting from inhibiting hERG potassium channels, can result in serious ventricular arrhythmias and sudden death.  These adverse effects on cardiac repolarization have directly led to the withdrawal of 14 medications from global markets.  In the past decade, more than $5 Billion has been spent by the pharmaceutical industry on assessing proarrhythmia at various stages of drug development.  While this investment has eliminated the appearance of arrhythmia in recently approved drugs, it has done so at the expense of many non-toxic drugs that may have been falsely identified as unsafe by existing testing methods. 

While preclinical risk assessment of drug-induced arrhythmias is critical for drug development, it relies on heart rate corrected QT interval prolongation as a biomarker for arrhythmia risk. The methods used to correct QT, however, vary in complexity and don't account for all changes in the QT-rate relationship. Thus, we developed the novel Ratio QT correction method, which characterizes that relationship at each timepoint using the ratio between QT, adjusted for a species-specific constant, and rate (RR interval). This ratio represents the slope between the intercept and the data point being corrected, which is then used in a linear regression equation. A unique correction coefficient for each data point avoids assuming static QT-rate relationships. We hypothesize that the simple and dynamic nature of the Ratio method will provide more consistent rate correction and error reduction compared to population-based and individual regression methods.

Perivascular Adipose Tissue as a Central Integrator of Vascular Health

Perivascular adipose tissue (PVAT) surrounds every peripheral blood vessel. Its presence on the ~60,000 miles of blood vessels in the adult human body, as well as in all mammalian species, raises the question as to its purpose in normal vascular function (homeostasis) and in disease. PVAT’s ability to act as an ‘anti-contractile’ component of blood vessels was first appreciated in 1991. Since this time, dozens of studies have supported the anti-contractile nature of PVAT in health and loss of this ability in diseases such as obesity-associated hypertension in humans and adiposity-associated hypertension in laboratory animals. These studies consider PVAT almost exclusively as a tissue that secretes vasoactive substances and, as such, are limited. Though important, they provide an incomplete view of the potential functions of PVAT as they pertain to vascular homeostasis in health and disease.

PVAT is far behind in the intensity of study and understanding of its contributions to health and disease. It is the most diverse vascular layer, home to multiple cell types that include adipocytes, preadipocytes, fibroblasts, mesenchymal stem-like cells, immune cells, as well as multiple tissues including vasa vasorum and capillaries. In collaboration with a group of investigators at MSU, we will expand the currently narrow view of PVAT by studying new, important functions and mechanisms of PVAT. We ‘reverse’ the focus/direction of PVAT research by proposing studies that investigate how the blood vessel (intima, media, adventitia) informs the PVAT of its status and correspondingly influences PVAT function.