Detecting the Vulnerable Plaque

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Myocardial infarction and stroke, mainly caused by a rupture of an atherosclerotic plaque, are two of the most
common causes of mortality and morbidity in the world. Previous studies have pointed out inflammation, driven
by inflammatory lipids, as the keystone in the formation of the rupture prone vulnerable plaque. The risk for a
plaque rupture is greatly enhanced in the diabetic population and increased inflammation has been suggested as the
contributing factor. However, the mechanism remains unknown. One of the current greatest challenges in the
atherosclerotic field is to identify subjects with plaques that are vulnerable before the occurrence of a plaque
rupture.
In this thesis we provide evidence that the enzyme lipoprotein associated phospholipase A2 (LpPLA2) and the
lipids lysophosphatidylcholines and sphingolipids (ceramides, lactosylceramides, glucosylceramides) contribute to
the inflammatory process and that they are associated with the vulnerable plaque. This suggests that the synthesis
of these lipids may be possible therapeutic targets. We also show that the inflammatory process in the plaque is
reflected in the peripheral blood, as measured by cytokines, whereas no association was found for soluble
urokinase-type plasminogen activator receptor. The inflammatory cytokines MIP-1β, TNF-α and fractalkine
predict the inflammatory plaque with high sensitivity and specificity, proposing that these inflammatory cytokines
could be used as plasma markers for plaque inflammation. Finally, we provide novel data regarding the biology of
the diabetic plaque. According to our data the inflammatory activity is not increased in the diabetic plaque tissue.
Diabetic plaques contained less stabilizing extracellular matrix proteins (collagen and elastin). Additionally the
plaque levels of the inflammation regulating cytokine IL-10 and the growth factor platelet derived growth factor
as well as the smooth muscle cell stimulating matrix metalloproteinase 2 were significantly decreased in diabetic
plaque tissue. These findings were independent of the presence of symptoms.
In summary, this thesis shows that lipids as LysoPCs and glycosphingolipids are important inducers of plaque
inflammation and may be possible therapeutic targets. In the general population the inflammatory activity is an
important factor for the formation of a vulnerable plaque and this inflammatory process is reflected in blood,
hinting a role for fractalkine, MIP-1β and TNF-α as future biomarkers. In the diabetic population, however, an
impaired tissue repair mechanism seems to be the keystone of plaque vulnerability, rather than inflammation,
emphasizing the need for new therapeutic approaches for diabetics.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems

Keywords

  • Atherosclerosis, Carotid plaque, Inflammation, Diabetes, LpPLA2, suPAR, Cytokines, Lipids
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2013 Nov 15
Publisher
  • Experimental Cardiovascular Research Unit, Lund University
Print ISBNs978-91-87449-89-5
Publication statusPublished - 2013
Publication categoryResearch

Bibliographic note

Defence details Date: 2013-11-15 Time: 13:00 Place: Föreläsningssalen på Kvinnokliniken, Jan Waldenströmsgata 47, ingång 74, Skånes Universitetssjukhus i Malmö External reviewer(s) Name: Pasterkamp, Gerard Title: MD, PhD Affiliation: University Medical Centre Utrecht, the Netherlands ---

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