Inflammation and coronary microvascular dysfunction in middle-aged women, a pilot study

Coronary microvascular dysfunction (CMD) consists of abnormalities in the
regulation of myocardial blood flow (MBF) and coronary flow reserve (CFR) that
cannot be attributed to epicardial coronary arterial disease (CAD). It is
considered an early manifestation of a mismatch of myocardial blood flow and
myocardial metabolic demand (1). Although CMD is a type of ischemic heart
disease (IHD), myocardial ischemia is not apparent in all CMD patients but
occurs with longer duration of exposure to this mismatch (2). This disease
relatively frequently occurs in middle aged women with multiple cardiovascular
risk factors but no obstructive coronary artery disease of the large
coronaries. CMD is not a benign disease, but it is associated with increased
rates of hospitalization and adverse cardiovascular events, including sudden
cardiac death, myocardial infarction, congestive heart failure, and coronary
revascularization (3). Although the exact pathophysiologic mechanisms
underlying CMD are poorly understood, both endothelial and non-endothelial
dependent impaired vasoreactivity plays an important role. Other leading
contenders are inappropriate sympathetic tone, microvascular atherosclerosis
and inflammation (1, 3, 4).
Both CMD and systemic autoimmune diseases (SAD) occur more often in women than
in men and several studies have found that SAD patients exhibit inflammatory
mediators in the perivascular layers more frequent than in the general
population (2). Chronic inflammation and immune dysregulation play a
pathogenetic role in the development of atherosclerosis adding as an additional
risk for CVD even in the absence of traditional risk factors (5).
There are numerous studies that indicate that inflammation plays a pivotal role
in atherogenesis (5-7) and Increasing data indicate that there are important
gender differences in immune mechanisms that play a role in the development of
atherosclerosis (8). However, there is little evidence when it comes to CMD.

It is now widely accepted that the innate immune system plays a central role in
the development of atherosclerosis. Recently, it has been reported that
monocytes/macrophages can adopt a long-term pro-inflammatory phenotype after
microbial stimulation via epigenetic reprogramming; this mechanism is termed
*trained immunity* (9). Importantly, endogenous atherogenic substances such as
oxidized LDL particles (10) or lipoprotein (a) (unpublished data) can also skew
monocytes into this long-term activated phenotype. The trained phenotype is
associated with increased production of pro-atherogenic cytokines and
chemokines and increased foam cell formation. Therefore, we speculated that
trained innate immunity contributes to the development of atherosclerosis.
Through this mechanism, monocyte-derived macrophages that are the most abundant
immune cells in atherosclerotic plaques, can adopt this long-term
proinflammatory phenotype leading to excessive production of cytokines. There
are also some reports demonstrating that platelet adhesion and activation not
only account for the increased incidence of thrombosis that is associated with
acute and chronic inflammatory conditions, but also intensifies, via
contact-dependent and-independent mechanisms, the activation of vascular
endothelial cells and leucocytes in inflamed microvessels, promoting vascular
remodeling (8). Additionally, the members of the matrix metalloproteinase (MMP)
family directly modulate platelet activation and thrombus formation under flow
and are capable of degrading the underlying collagen matrix, thereby
restricting future thrombus formation (4).

The goal of this pilot study is to investigate whether circulating monocytes of
patients with MCD are characterized by a trained phenotype, so we can ascertain
whether trained innate immunity may contribute to microvascular wall
inflammation in these patients.

case-control, pilot study

a single venapuncture of 30cc blood