Cardiovascular Disease Research
Heart disease remains the number one cause of death in the United States AND worldwide, accounting for over 15 million deaths annually. With a globally aging population, we expect to see a rise in the incidence of cardiovascular diseases in the coming years. With our research, we hope to increase lifespans and the quality of life of our loved ones as they age.
suPAR as a Subclinical Marker of Atherosclerosis
A secondary use clinical study investigating suPAR levels in the progression of atherosclerosis in high risk populations, using the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
The MESA cohort is an NHLBI-sponsored prospective cohort with over 6000 participants of various ethnicities, who, at the beginning of the study, were free of cardiovascular disease. Samples collected from these partcipiants underwent extensive characterization for subclinical markers of atherosclersosis, as well as measures of renal function, at baseline and with periodic follow-ups.
The MESA study allowed many traditional biomarkers, such as C-reactive protein (CRP), high sensitivity (hs) troponin I, B-type natriuretic peptides, and coronary artery calcium to be studied in this general population, and these biomarkers have long been used as predictors of cardiovascular disease, though arguably with limited clinical usefulness.
suPAR is a non-cardiac biomarker of inflammation and thus may be a better indicator of risk prior to any cardiac involvement than previously used biomarkers, and unlike other measures of inflammation, suPAR remains stable during acute episodes of stress such as surgery or acute myocardial infarction. suPAR is strongly prognostic of outcomes across patient populations, genders, and ethnicities.
Using the MESA cohort, this study will characterize the association between suPAR and subclinical markers of cardiovascular disease, including endothilial function assessed by flow-mediated dilation, carotid intima-media thickness, arterial stiffness, ankle-brachial index, cardiac function, and most importantly cornonary calcification. The ability of suPAR to discriminate cardiovascular risk will be compared with that of other biomarkers, including coronary calcium and hs-CRP, looking specifically at cardiovascular death, non-fatal myocardial infarction, stroke, and hospitalization for heart failure.
Our goal is to determine whether suPAR levels can be used to identify patients who may benefit from statin therapy, and who would have otherwise been classified as low risk.
Learn more about the original MESA trial.
For more information on coronary artery disease and atherosclerosis, click here.
suPAR as a guide for the Management of Multi-Vessel Coronary Artery Disease
Coronary Artery Disease (also known as atherosclerosis) is the hardening or narrowing of coronary arteries, the arteries that supply blood to the heart, which can leave the heart muscle without an adequate blood supply or enough oxygen to continue pumping as normal.
Over 800,000 patients with high-risk coronary artery disease (CAD) undergo coronary artery bypass grant (CABG) surgery every year, an open-heart surgery in which a section of a blood vessel is grafted from the aorta to the coronary artery to bypass the blocked section of the coronary artery and improve the blood supply to the heart. While it revolutionized the treated of heart disease and saves thousands of lives every year, the complications can be serious. There is a 2% risk of death and 1.5% risk of stroke with every procedure performed, as well as potential for cognitive decline and wound infections. The surgery takes 3-4 hours and patients usually remain in the hospital for 5-7 days following the procedure, with an additional 6-12 weeks of recovery after discharge.
Percutaneous coronary interventions (PCI), also known as "stenting," is a non-surgical procedure that uses a catheter inserted in a wrist or groin artery to access the coronary arteries and relieve the obstruction in the blood vessel by inflating a balloon and placing a stent. The procedure can be completed in as little as an hour and patients are often discharged the day of the procedure. Stenting is much less invasive, is less costly, and has lower risk of morbidity or complications, with less than 0.1% risk of death during the procedure and 0.4% risk of stroke following the procedure.
We know that patients prefer to undergo PCI procedures over CABG, but studies examining the differences in outcomes between bypass surgery and stenting have shown a decreased need for repeat procedures when patients undergo open-heart surgery the first time. But physicians don't have a reliable guide to determine patients which patients will do just as well with the stent as with the surgery.
Our goal is to find a non-invasive, cost-effective and reliable method to accurately predict a patient's long-term risk to guide the decision toward bypass surgery or a coronary stent.
With the samples collected prior to patients undergoing either CABG or PCI procedures, in a clinical trial known as "BARI-2D," we will be able to measure biomarkers, including suPAR, to derive a clinical algorithm to guide cardiologists' approach to revascularization. We hope the creation of an algorithm incorporating baseline suPAR levels into pre-surgical assessments will increase the number of patients who can successfully undergo percutaneous interventions and limit the number of individuals sent for open-heart surgery.
The ability to personalize therapy with simple diagnostic assays is the mark of the future.
Mouse models of Atherosclerosis
Patients with diffuse atherosclerosis have very high suPAR levels, and suPAR levels strongly predict adverse cardiovascular outcomes, outperforming the traditional methods used for prediction. suPAR levels are increased in atherosclerotic plaques and correlate with intra-plaque pro-inflammatory cytokines; whether suPAR plays a causal role in atherosclerosis is still unknown.
Using our mouse models of induced atherosclerosis, and mice overexpressing suPAR, we're identifying the role of suPAR in the pathogenesis of the disease. Comparing the overexpressing mice to their wild-type littermates, we use echocardiography to asses atherosclerotic plaque formation and cardiac function, as well as blood pressure monitoring to non-invasively track disease progression.
Serial blood collections for analysis of suPAR as well as other biomarkers throughout the course of disease begin to tease out the effects of high suPAR levels on the cardiovascular system during atherosclerosis. Histopathological examination and immunofluorescent imaging of inflammatory markers and plaque vulnerability in aortic lesions show the outcomes of suPAR overexpression.
Our research, along with previous studies in humans showing endothelial involvement in suPAR regulation, and increased suPAR levels in the dysfunctional coronary endothelium, has led us to look at vascular endothelial cells in vitro, examining the role of integrins and suPAR in the activation of endothelial cells, upregulation of matrix metalloproteinases, increase in vascular permeability, and production of the inflammatory cytokines seen in our atherosclerosis models.
Quick overview to research on suPAR inflammation and pathogenic processes.