FIRST LOOK: Targeting Vascular Calcification to Prevent Cardiovascular Disease
Vascular calcification is the abnormal deposition of calcium phosphate crystals within the blood vessel wall, is one of the strongest risk factors for cardiovascular disease, and predicts clinical events such as myocardial infarction and stroke. The following approaches are being utilized in our laboratory to target vascular calcification:
Human Genetics: Approximately 50% of cardiovascular disease is driven by genetic causes. We have identified novel genes associated with vascular calcification by performing a multi-center genome-wide association study in >9000 individuals, as part of the Framingham Heart Study.
Cell-based Assays: Vascular smooth muscle cells (VSMC) and endothelial cells (EC) reside in the vessel wall and play critical roles in the development of vascular calcification. These cells first undergo a process of transdifferentiation, changing to a different cell phenotype, before calcification occurs. Our laboratory has optimized assays to model vascular calcification in vitro. Using this technique, we have discovered novel inhibitors of VSMC and EC transdifferentiation and calcification.
In vivo Imaging: Our laboratory utilizes near-infrared fluorescent imaging probes that specifically target calcium phosphate crystals and macrophages, to precisely characterize the temporal and spatial relationships between vascular calcification and vascular inflammation in models of atherosclerosis. These tools provide mechanistic insights into the development of vascular calcification in vivo and allow for the assessment of potential new drug therapies.
Biomarkers and Clinical Trials: Our laboratory has created a prospective registry of patients who suffer from a severe form of diffuse vascular calcification known as calciphylaxis. We have identified abnormal serum matrix Gla protein (MGP) levels as a hallmark for this disease. MGP is an endogenous inhibitor of vascular calcification that requires vitamin K-dependent carboxylation for activation. We have determined that the majority of patients with calciphylaxis have vitamin K deficiency and are enrolling calciphylaxis patients in a randomized trial to determine if vitamin K therapy improves disease outcomes.
In summary, our work combines these investigational strategies in the hopes of defining novel mechanisms and developing new treatments for vascular calcification and cardiovascular disease.
For more information about Dr. Malhotra’s research, please contact Partners HealthCare Innovation by clicking here.
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