CAUSE Trial: Patient Specific-Cellular Characterization of Fibromuscular Dysplasia and High-Risk Atherosclerotic Endothelium

Overview

The purpose of this project is to see if heritable alterations in the function, biology and vascular repair capacity of vascular cells make a major contribution to the burden of coronary artery disease (CAD), fibromuscular dysplasia (FMD), and other vascular diseases. In more detail, FMD is a nonatherosclerotic vascular disease that primarily affects women aged 20 to 60. It commonly affects the renal and carotid arteries but may involve almost every artery in the body. At the cellular level, FMD is characterized by increased fibroblast proliferation and collagen deposition. This study aims to define some of these cellular problems by directly studying fibroblast cells from FMD patients and healthy control subjects. Similarly, CAD is among the leading causes of death worldwide. However, a large part of the risk for CAD is unexplained. It is thought that a major but undefined risk factor may be gene (genomic) variations causing a change in vascular cell function. Here, we will study important vascular cell types in patients with severe and early onset CAD in an attempt to define these problems. Therefore, in summary, this study will look to define the various cellular-level problems that occur in patients with both in CAD and FMD. These data will be linked to DNA-level analyses to ultimately attempt to define the cause of these conditions.

The purpose of this project is to see if heritable alterations in the function, biology and vascular repair capacity of vascular cells make a major contribution to the burden of coronary artery disease (CAD), fibromuscular dysplasia (FMD), and other vascular diseases. Patients will be referred for this study by their physician if he/she feels that the patient qualifies for entry into the study based upon the Inclusion/Exclusion Criteria and is expected by their physician to be a suitable candidate. This will include: 1) patients with FMD and non-affected control subjects, 2) patients with early onset CAD in the absence of significant CAD risk factors, or matching healthy controls those with ≥2 cardiovascular risk factors and no CAD (those with angiographically 'normal' coronary arteries). Also, as an extension of this study, patients with rare, undiagnosed or unusual forms of CAD (e.g. unexplained dissection, fulminant calcification, aneurysms etc.) and appropriate controls, will be recruited, particularly if there is a strong family pedigree. This study will include collection of whole blood for subsequent DNA isolation and sequencing, a plasma sample, and a skin biopsy. Blood will be handled in a standard fashion to obtain DNA from leukocytes and plasma. These will be stored pending later batched analysis. Once the skin biopsy tissue is collected, the tissue will be sent to the lab for further processing. The initial step is that we will derive fibroblasts from the skin biopsies. In brief, the biopsies are washed, cut into small fragments are distributed on a culture dish with growth medium and incubated at 37°C. Over the next 4 - 6 weeks, fibroblasts progressively grow and can be collected. We may then induce these fibroblasts to undergo changes so that they become stem cells (called "induced pluripotent stem cells" or iPSCs). Once we have made iPSCs, we can then make endothelial cells (iPSC-ECs), or in fact, many other cell types. The cells can be frozen until analysis, or until experiments are done in the future. All of the derived cells (fibroblasts, iPSCs and iPSC-ECs) generated under this protocol will be kept indefinitely, and may be used for future studies into the causes and other aspects of FMD or CAD. This study is not concerned with any clinical events after patient enrollment. Only clinical events that have occurred prior to enrollment (e.g. prior myocardial infarction, stroke, dissection) will be recorded. Once we have obtained these cells, detailed cellular and molecular analyses will be performed to study the particular cellular defects that are associated with these differing conditions. This data will be combined with the DNA- and plasma-derived data in an attempt to define the underlying basis for these disorders. As this is not a treatment, no alternative treatment options apply. The subject can decide not to participate in the trial. No benefit can be promised to any subject in this study. The information gained may benefit others with the same condition.