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UvA-DARE (Digital Academic Repository)
The inflammatory response in myocarditis and acute myocardial infarction
Emmens, R.W.
Publication date2016Document VersionFinal published version
Link to publication
Citation for published version (APA):Emmens, R. W. (2016). The inflammatory response in myocarditis and acute myocardialinfarction.
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Download date:14 Apr 2021
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Chapter 1
General Introduction
10
11
INTRODUCTION
Worldwide cardiovascular disease (CVD) is a major cause of mortality and
morbidity, in which acute myocardial infarction (AMI) is playing an important
role. Over the years it has become clear that myocarditis, an inflammatory
condition of the heart mostly related to a viral infection, is playing a considerable
role in CVD morbidity and mortality as well. In both myocarditis and AMI,
inflammation is essential in the development of the disease, but also in its
outcome. This thesis encompasses eight original studies related to myocarditis
and AMI. The aim of this general introduction section is to give a summarized
overview of myocarditis and AMI and to provide the rationale for each study.
MYOCARDITIS
The term ‘myocarditis’ literally means ‘inflammation (‐itis) of the heart muscle
(myocardium)’. Myocarditis as a clinical entity is a cardiomyopathy (disease of
the myocardium associated with cardiac dysfunction), and in the context of
cardiomyopathies is categorized as ‘inflammatory cardiomyopathy’.1 Myocarditis
is primarily recognized by its distinct histopathological appearance in the
myocardium, which was defined by Aretz et al. as: ‘Inflammatory infiltrates
within the myocardium associated with myocyte degeneration and necrosis of
non‐ischaemic origin’.2 In Western Europe and North America, myocarditis is
most often caused by a viral infection (viral myocarditis), although a wide array
of other aetiologies have been described, including bacterial infection, fungal
infection, protozoal infection, stress, hypersensitivity reactions, metal poisoning,
adverse drug reactions and autoimmune disorders.3‐5 This wide array of
aetiologies also results in several distinctive patterns of inflammatory cell
infiltrations of the heart, by which myocarditis is often subcategorized.
Disease progression of viral myocarditis
Viral myocarditis is not only the most common form of myocarditis, but also the
most widely investigated. It is generally accepted that both environmental
(culprit virus) and genetic factors influence the way viral myocarditis manifests
itself, although the precise underlying mechanisms are not yet fully determined. 3, 6 Coxsackievirus B3 (CVB3) is one of the more common viruses associated with
myocarditis.3 CVB3‐induced myocarditis is a widely used mouse model to study
disease mechanisms of viral myocarditis. A simplified representation of viral
myocarditis, largely based on knowledge from CVB3‐induced myocarditis
models3, 7, 8, is displayed in figure 1. In the acute phase, viral infiltration and
replication occurs in the myocardium, resulting in cell death of cardiomyocytes,
although this can be quite limited. This triggers activation of macrophages,
followed by infiltration of natural killer cells and lymphocytes (the subacute
phase), after which the virus and the necrotic cardiomyocytes are eliminated.
12
Figure 1. Simplified schematic representation of the disease course of viral myocarditis
In patients, several clinical scenarios are known to follow after the (sub)acute
phase of viral myocarditis.5
In some patients, the inflammation subsides following viral clearance and
the myocardium restores to its normal situation (recovery). In other patients, the
virus does not get cleared, resulting in a chronic viral infection (viral persistence).
Finally, in some patients molecular mimicry occurs. Here, antibodies created to
bind viral proteins cross‐react with endogenous cardiac proteins such as α‐
myosin, resulting in a chronic autoimmune response targeting cardiomyocytes
(autoimmune myocarditis).9 Viral persistence and autoimmune myocarditis
phases can result in several different clinical complications (see below).
Diagnosis of myocarditis
Myocarditis is a notoriously difficult condition to diagnose. The clinical
symptoms vary greatly per patient, ranging from asymptomatic disease to heart
13
failure symptoms such as chest pain, palpitations, exercise intolerance, fatigue
and shortness of breath. Often, symptoms suggestive of viral infection are found,
including fever, muscle / joint pain and respiratory symptoms.4 Myocarditis can
also result in alterations of the electrocardiogram (ECG: usually ST‐elevation or
T‐wave inversion4, 10) or an increase in serological markers (f.i. Cardiac
Troponins11, 12). However, ECG and serology lack sufficient sensitivity and
specificity to provide a clear diagnosis of myocarditis.
Cardiac magnetic resonance imaging (CMR) is becoming a standardized
part of the diagnostic process for myocarditis. Combining different CMR
techniques (T2‐weighted imaging, late gadolinium enhancement and global
relative enhancement) has been demonstrated to diagnose myocarditis with 85%
accuracy.13 Even though CMR is a rapidly advancing field, there are still some
limitations. For instance, borderline myocarditis (an increase of inflammatory
cells without cardiomyocyte damage or a limited increase of inflammatory cells)
is difficult to detect using CMR.14 Therefore, analysing cardiac tissue samples,
obtained via an endomyocardial biopsy (EMB), remains the golden standard to
determine the underlying cause of the disease.14 Current guidelines require >14
inflammatory cells per mm2 tissue to confirm myocarditis.15 However,
inflammatory cells are often present in the myocardium as focal pockets and
random tissue samples may miss such pockets, resulting in a false negative
diagnosis. Furthermore, EMB is an invasive procedure with the risk of
complications like ventricular wall perforation, arrhythmia and damage to the
heart valves.16 Several case reports have demonstrated that cardiotropic viruses
can infect not only cardiac but also skeletal muscle tissue.17, 18 In chapter 2, we
have investigated quadriceps muscle tissue analysis as alternative for EMB in
lymphocytic myocarditis patients.
Clinical complications of myocarditis
Inflammatory damage to the myocardium as result of myocarditis can result in
different complications. On the long term it might result in a so‐called dilated
cardiomyopathy (DCM).19 In DCM, the loss of cardiomyocytes and the coinciding
increase in cardiac fibrosis is so extensive that it results in a decreased
contractility of the heart and thus heart failure.20 Despite advances in heart failure
therapeutics, DCM remains a common cause for cardiac transplantation,21 with a
population‐wide transplant‐free survival rate after 4 years of 88%.22
A more acute complication of myocarditis is sudden cardiac death (SCD). SCD is
defined as a death that occurs within one hour of symptom onset. Especially in
young patients (<35 years old), myocarditis is a common cause of SCD.23 SCD is
mostly attributed to ventricular arrhythmia,24 although it has also been related to
atrial fibrillation (AF).25 It is unknown however what the mechanisms are that
underlie the incidence of AF in myocarditis patients. In chapter 3, we have
studied atrial inflammation in myocarditis patients as a possible underlying
cause of AF.
14
Treatment of myocarditis
Treatment of myocarditis is dependent on the clinical symptoms of the particular
patient. Patients with heart‐failure symptoms are treated with a standard heart
failure treatment regimen, which usually consist of angiotensin converting
enzyme (ACE) inhibitors and beta(β)‐blockers.26 ACE inhibitors inhibit the renin‐
angiotensin system, which results in reduced activity of the sympathetic nervous
system, vasoconstriction and a reduction in adverse cardiac remodeling.27 β‐
blockers block adrenergic stimulation of beta‐adrenergic receptors in the heart,
resulting in a decreased heart rate.28 Acute myocarditis patients with ventricular
arrhythmia or AF are treated according to standardized anti‐arrhythmogenic
treatment protocols.29, 30 Anti‐arrhythmogenic drugs generally interfere with ion
channels on atrial cardiomyocytes, increasing electrical excitability and
prolonging action potential length, thereby reducing the chance of abnormal
signal transduction across the tissue.
Even though these treatment regimens serve as a symptom reliever and
prevent further decline of cardiac function, they do not target the underlying
disease. Therefore, the potential application of anti‐inflammatory therapy in
myocarditis patients is a widely researched topic. Lymphocyte inhibitors such as
prednisone and azathioprine have shown promising results in clinical trials.
However, the efficacy of these compounds is largely diminished when
myocarditis is accompanied by an ongoing viral infection.31‐33 An anti‐
inflammatory agent that can be applied despite an ongoing viral infection would
be highly beneficial for the management of myocarditis.
Clinical trials on pericarditis, a disease which is also often caused by viral
infection,34 have indicated that colchicine is an effective treatment in pericarditis
patients.35 Colchicine prevents polymerisation of microtubules, thereby
interfering both with inflammatory cell migration across the endothelial cell
barrier, as well as the release of inflammatory cytokines from macrophages.36 In
chapter 4, we have studied whether colchicine is also effective in the treatment of
acute CVB3‐induced myocarditis in mice.
ACUTE MYOCARDIAL INFARCTION
In Europe, acute myocardial infarction (AMI) is responsible for 20% of all
deaths.37 In AMI, part of the coronary circulation is obstructed, resulting in
cardiac ischemia. This is usually caused by thrombus formation in one or more of
the coronary arteries, in majority triggered by the rupture of an unstable
atherosclerotic plaque.38 Alternatively, the coronary circulation can also be
dysfunctional as result of vasospasm or coronary embolism.39
15
Figure 2. A. The three histopathological phases of AMI. Lactate dehydrogenase decolouration
(yellow‐brownish areas) showing ischemia in the left ventricle (acute phase). Haematoxylin and
Eosin staining revealing neutrophil infiltration of the infarcted myocardium (polymorphonuclear
leukocyte or PMN phase). Haematoxylin and Eosin staining showing replacement fibrosis
(granulation tissue) in the infarcted myocardium (chronic phase).
Post‐AMI inflammation and remodelling.
The histopathological alterations in the human myocardium following AMI have
been described in detail already in the 1930s.40 Based on histopathology, AMI can
be divided in three different phases (figure 2A). The acute phase (0‐12 hours after
AMI) is the period of cardiac ischemia immediately following the occlusion of a
coronary artery. In the core of the ischemic area of the myocardium,
cardiomyocytes become irreversibly damaged, forming a necrotic infarct core.
Blood supply to the ischemic areas can be restored with reperfusion therapy (see
following section) or it restores naturally due to the outgrowth of pre‐existing
collateral arteries (arteriogenesis),41 or by natural thrombolysis.42 This restoration
of blood flow coincides with extravasation of inflammatory cells, which infiltrate
the infarcted area. Initially, the inflammatory infiltrate consists of neutrophils.
Later on monocytes/macrophages and lymphocytes also appear. The neutrophil
infiltration hallmarks the start of the polymorphonuclear leukocyte (PMN) phase
(12 hours – 5 days after AMI). The inflammatory response of the PMN phase is
needed for clearance of necrotic cell debris and the initiation of reparative
pathways. However, simultaneously the inflammatory response also results in
enlargement of the necrotic infarct core partly through production of reactive
oxygen species and lytic enzymes, and via pro‐inflammatory changes of the
plasma membrane of cardiomyocytes, which especially occurs in the border zone
of the infarction area, and as such increases the area of cell death (figure 2B).43
In the chronic phase (5‐14 days after AMI), the inflammation subsides and
cardiac fibroblasts turn into myofibroblasts, producing extracellular matrix
proteins that stimulates the formation of a collagen scar in the regions of
cardiomyocyte loss.44
16
Treatment of acute myocardial infarction
An important aspect of post‐AMI treatment is reperfusion therapy, which limits
the ischemic damage to the myocardium. Artificial reperfusion can be achieved
either by enzymatically dissolving the blocking thrombus (thrombolytic
therapy45), mechanical clearance of the obstruction (coronary angioplasy46) or
creating a bypass around the obstruction (coronary artery bypass grafting47).
Although developments in reperfusion therapies have decreased AMI‐related
mortality, heart failure remains a common complication of AMI at present day.48
As post‐AMI inflammation results in infarct size expansion and an increased risk
of post‐AMI complications such as heart failure, a large amount of research has
been carried out on inhibiting post‐AMI inflammation as therapeutic strategy.
Anti‐inflammatory therapy is not yet part of common clinical practice, although a
number of therapeutic compounds have been studied thus far in clinical trials.
These include glucocorticoids (inhibits NF‐κB and MAPK‐mediated production
of pro‐inflammatory cytokines), non‐steroidal anti‐inflammatory drugs (NSAIDs,
inhibit Cyclooxygenase‐2‐mediated production of pro‐inflammatory cytokines),
disabling antibodies targeting Interleukin(IL)‐1β or Tumour Necrosis
Factor(TNF)‐α, and inhibitors of the complement system.49
The complement system
An important component of the post‐AMI inflammatory response is the
complement system. The complement system is part of the humoral immune
response and forms a cascade network consisting of over 30 extracellular and
membrane‐bound proteins.50, 51 Complement components are found in the
necrotic infarct core specifically during the PMN phase (figure 3).52 Complement
activation here appears to be tightly regulated. We and others have found C‐
reactive protein, IgM52 (activate the classical complement pathway), C4b‐binding
protein53 (induces dissociation and decay of C3b and C4b), clusterin, vitronectin
and C8‐binding protein54, 55 (prevent assembly of the membrane‐attack complex)
present in the infarcted human myocardium at the same time and location as
complement activation products. Despite the presence of endogenous inhibitors,
activation of the complement system results in lysis of damaged cardiomyocytes
through the membrane‐attack complex, and production of anaphylatoxins. In the
context of AMI, anaphylatoxins (C5a in particular) in the infarcted myocardium
are considered primarily to function as a chemoattractant for neutrophils,
stimulate neutrophil production of reactive oxygen species (ROS) and pro‐
inflammatory cytokines and stimulate leukocyte extravasation by up regulation
of adhesion molecules on vascular endothelial cells (figure 3).56
In 1971, a landmark paper was published which demonstrated that
disabling the complement system significantly decreases AMI‐related damage to
the myocardium.57 This discovery triggered a great deal of interest in the
complement system as possible therapeutic target for AMI patients. While
showing promising results in animal models, the effect of complement inhibitors
17
Figure 3. Simplified representation of the complement cascade (grey boxes). Endogenous
activators (+) and inhibitors (‐) coinciding with complement activation in the infarcted
myocardium are depicted in blue. Effects of the complement cascade in the infarcted myocardium
are depicted in red. Top‐left image: Immunohistochemical staining of complement component
C3d (brown) in the necrotic infarct core, while adjacent tissue (the border zone) is negative. ).
Image was kindly supplied by dr. PAJ Krijnen.
Abbreviations: BZ: Border zone. C4b‐BP: C4b‐binding protein. CRP: C‐reactive protein. IC:
Infarct core. IgM: Type M immunoglobulin. MAC: Membrane attack complex. MBL: Mannose‐
binding lectin. PMN: Polymorphonuclear leukocytes (neutrophils). ROS: Reactive oxygen
species.
in clinical trials was limited. In chapter 5, a systematic overview of studies
investigating various complement inhibitors as treatment for AMI in both animal
models and clinical trials is discussed.
C1‐inhibitor
One of the complement inhibitors of interest is C1‐inhibitor (C1‐inh). C1‐inh is an
endogenous plasma protein which is primarily synthesized in hepatocytes, but
can also be produced by other cell types, including monocytes, fibroblasts and
endothelial cells.58 Besides inhibiting complement activation, C1‐inh is also
known to inhibit the coagulation system and has been suggested to interfere with
leukocyte binding to endothelial cells.59 As mentioned above, a number of
18
endogenous complement activators and inhibitors have been described to
coincide with complement in the post‐AMI myocardium, indicating their
involvement in post‐AMI complement regulation. Even though C1‐inh is a well‐
known complement inhibitor, it has never been investigated whether
endogenous C1‐inh would also play a role in post‐AMI complement regulation.
In chapter 6 we have studied the production and expression of endogenous C1‐
inh in the heart following AMI.
In clinical practice, plasma‐derived human C1‐inh is used as therapy for
patients with hereditary angioedema (HAE), which is caused by a genetic
deficiency in functional C1‐inh.60 C1‐inh is administered in those patients
intravenously. In the past several years the possibility of subcutaneous C1‐inh
administration was also approached, as this would make it easier for patients to
self‐administer C1‐inh.61, 62 For rodent models, subcutaneous administration
would also be beneficial, as repeated intravenous injections causes considerable
damage to the tail veins. In chapter 7 we have therefore compared subcutaneous
C1‐inh administration with intravenous C1‐inh administration in rats.
Acute myocardial infarction and atrial fibrillation
Similar to myocarditis (see above section ‘clinical complications of myocarditis’),
AMI is a known precursor of AF.63 Unknown is whether AMI coincides with
atrial inflammation. In chapter 8, we have studied if AMI coincides with atrial
inflammation in patients. At the same time we have studied whether C1‐inh
administration would have an effect hereon in a rat AMI model.
Adipose‐derived stem cells
Reperfusion therapy and anti‐inflammatory drugs can limit post‐AMI damage to
the myocardium, but they cannot restore lost cardiomyocytes. In recent years
studies have been published in which the effect of stem cell therapy was analysed
in AMI. Adipose tissue derived stem cells (ASCs) theoretically have the potential
to repair lost tissue,64, 65 as ASCS can differentiate into cardiomyocytes.66 In
addition, ASC can secrete cytokines that inhibit inflammation, such as IL‐10
(stimulates regulatory T‐lymphocytes) and Galectin1/3 (deactivates inflammatory
monocytes/macrophages and lymphocytes).67 In addition , ASCs can limit the
amount of permanently damaged myocardium by production of vascular
endothelial growth factor (VEGF, stimulates neovascularization) and
mobilization of local cardiomyocyte progenitor cells.68
An unresolved problem of ASC therapy however is the low amount of
ASCs that reach to infarcted myocardium following administration. For this, we
have previously developed a technique called ‘StemBells’‐technique (figure 2C).
For this, ASCs are coupled to gas‐filled microbubbles. These microbubbles are
used to target the ASC‐microbubble complex to the infarct area in the heart by
binding an antibody to the microbubble that is directed against intercellular
19
Figure 4. An adipose‐derived stem cell (ASC) coated with gas‐filled microbubbles that bind
activated endothelial cells (EC) in the infarcted myocardium through Intercellular Adhesion
Molecule 1 (ICAM‐1). Image was kindly supplied by dr. LJM Juffermans.
adhesion molecule 1 (ICAM‐1), which is present on activated endothelial cells
and cardiomyocytes in the infarcted myocardium.69 Theoretically, in this way
more ASCs could infiltrate the infarcted area, and as such could improve stem
cell therapy of the heart. Even more, using ultrasound, StemBells can be pushed
against the vessel wall to facilitate binding (acoustic radiation force), via a direct
effect on the microbubbles.70 We have previously found that StemBells
administered 7 days post‐AMI in rats improve post AMI heart function
(unpublished results). However, administering StemBells at an earlier time point
(1 day post‐AMI) theoretically might result in an additional anti‐inflammatory
effect early after AMI. In chapter 9, we have compared the therapeutic efficacy of
both time points of StemBell administration (1 and 7 days post‐AMI) in a rat
model of AMI.
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