Improved detection of cardiac fibrosis : Biomarkers and novel imaging techniques

Abstract

Cardiac cells are embedded in a collagen network that provides strength in the heart against tension that occurs during contraction and relaxation. In almost every cardiac disease increased collagen (fibrosis) is observed. Fibrosis has adverse effects on cardiac pump function and increases the risk for cardiac arrhythmias. At current, detection of cardiac fibrosis is challenging. One method to determine cardiac fibrosis is analysing cardiac tissue acquired by a biopsy. However, this method is not without risk and provides only local information. Current clinical standard to detect cardiac fibrosis is contrast based MRI. Unfortunately, this technique requires the use of a contrast agent, which may affect kidney function and is therefore contra-indicated in patients suffering from kidney failure. In addition to imaging techniques, circulating biomarkers to assess cardiac fibrosis have become of specific interest. However, it is not yet elucidated whether they give a proper reflection of the amount of fibrosis present in the heart. Current research focuses on the potential of microRNAs (miRs) as circulating biomarkers. Several miRs have already been shown to play a role in collagen synthesis. However, whether these miRs are useful as a circulating biomarker to reflect cardiac fibrosis is not yet elucidated.

Although tools are already available to assess cardiac fibrosis, further improvement of detecting cardiac fibrosis is required. Improving current techniques should focus on non-invasiveness, no use of a contrast agent, and the ability to determine smaller patches of fibrosis. Research described in this thesis aims to improve fibrosis detection by the development of 1) novel imaging techniques and 2) determination and validation of circulating biomarkers.

In part 1 a study investigating labelled CNA35, a molecule that specifically binds to collagen, is presented. This study showed that CNA35 is able to enter cardiac tissue and to specifically bind to cardiac collagen after intravenous administration. Additionally in part 1, research is presented that investigated two MRI techniques assessing cardiac fibrosis without using a contrast agent: UTE and T1ρ MRI. UTE MRI has been studied in isolated infarcted rat hearts and was compared to microscopy. UTE MRI signal nicely corresponded to microscopically observed fibrosis. To investigate T1ρ MRI, T1ρ signal was measured in fibrotic human hearts and compared to microscopy. T1ρ signal correlated moderately to fibrosis.

Part 2 describes research involving circulating biomarkers. One study focused on expression of four miRs (involved in cardiac collagen synthesis) in both healthy mice and mice with increased cardiac fibrosis. MiR levels in both cardiac tissue and plasma were determined and compared to the amount of cardiac fibrosis, measured by microscopy. MiR levels differed between fibrotic hearts and healthy hearts. High correlation is observed between the cardiac miR levels and fibrosis. MiRs were detectable in the murine circulation; however, no relation is observed between the circulating miRs and fibrosis. Part 2 also describes the rationale of a patient study in which circulating biomarker levels are validated with contrast based MRI in patients with a myocardial infarction.

All studies are put into perspective in the general discussion.