INDIVIDUAL ASSIGNMENT

Cardiovascular
2 year / 4 Semester / 2021 / FMUI 2020
st st

Mohamad Arbian Karim

2006489400 – Group A

PBL Trigger 3

Pathophysiology of Myocardial Infarction

Introduction

A myocardial infarction (MI), sometimes known as a "heart attack," occurs when blood
supply to a region of the myocardium is reduced or completely stopped. Myocardial
infarction can be "silent" and go unnoticed, or it can be a catastrophic occurrence that causes
hemodynamic decline and rapid death. The vast majority of myocardial infarctions are caused
by underlying coronary artery disease. The myocardium is deprived of oxygen due to
coronary artery blockage. Prolonged oxygen deprivation of the myocardium can result in
cardiac cell death and necrosis. Patients may complain of chest pain or pressure that spreads
to the neck, jaw, shoulder, or arm.1

Over the last 40 years, our understanding of the causes, diagnosis, and treatment of acute
myocardial infarction (AMI) has advanced dramatically. In the early twentieth century, AMI
was typically seen as a deadly occurrence that could only be diagnosed at postmortem. Until
the 1970s, it was conservatively controlled with extended bed rest and, later, a sedentary
lifestyle, with a proper awareness of its common clinical presentation and diagnosis. Since
then, there has been a flood of information that has revolutionized our understanding of its
pathophysiology and significantly altered our treatment choices, resulting in drastically
improved results.2

In this LTM, I will be discussing about the pathophysiology of Myocardial Infarction based
on the symptoms of the patient.

Topics Discussion
A. Introduction

AMI, often known as a heart attack in simple words, is most commonly caused by a
reduction or interruption of blood flow to a segment of the heart, resulting in necrosis
of heart muscle. This is usually caused by a blood clot in the epicardial artery, which
supplies that area of heart muscle. It is now acknowledged that, depending on how
AMI is defined, not all cases need an etiological blood clot. The blood supply must
meet the oxygen demands of every living tissue, including heart muscle. This is
referred to as the supply–demand ratio. It is now recognized that an imbalance in this
ratio (too little supply or too much demand), such as that caused by a very fast heart
rate (too much demand) or a drop in blood pressure (too little supply), can cause
cardiac injury without the presence of a blood clot.2

Over the last decade, a global definition of AMI has been provided to assist clinicians
in its diagnosis . According to this criteria, there must be an increase or decrease (or
both) in a blood test sensitive to heart muscle injury (troponin I or T) with at least one
value over the 99th percentile of the upper reference limit, as well as clinical evidence
for an AMI diagnosis. This clinical evidence comprises ischemic symptoms, such as
ST segment alterations or new left bundle branch block on electrocardiogram (ECG),
the development of pathological Q waves on ECG, or new wall motion abnormalities
on cardiac tests, or a combination of these.2

Fig 1. Universal Definition of Myocardial Infarction3

MI is pathologically characterized as myocardial cell death caused by persistent

ischemia. The first ultrastructural alterations include reduced cellular glycogen,
relaxed myofibrils, and sarcolemmal disruption, which can be evident as early as 10–
15 minutes following the beginning of ischemia. Mitochondrial abnormalities can be
seen by electron microscopy as early as 10 minutes after cardiac blockage and worsen
over time. In humans, postmortem examination can take hours to identify myocyte
necrosis; in animal models, biochemical evidence of myocardial cell death owing to
 apoptosis can be discovered within 10 minutes of induced myocardial ischemia in
combination with myocyte death. In the laboratory, necrosis develops over many
hours from the subendocardium to the subepicardium. Increased collateral flow,
lowered drivers of myocardial oxygen demand, and intermittent
occlusion/reperfusion, which might precondition the heart, can all lengthen the time
course. When used appropriately, timely initiation of reperfusion treatment minimizes
myocardial ischemia damage.3

Myocardial damage is defined as the presence of cTn levels in the blood that exceed
the 99th percentile upper reference range (URL). The injury might be either acute, as
shown by a newly found dynamic rising and/or falling pattern of cTn values above the
99th percentile URL, or chronic, as evidenced by continuously increased cTn levels.
Cardiac troponins I (cTnI) and T (cTnT) are contractile apparatus components of
myocardial cells that are almost exclusively expressed in the heart. Increases in cTnI
readings have not been recorded following noncardiac tissue damage. Other
biomarkers, such as wwm (CK-MB), are both less sensitive and specific.3

Figure 2 depicts myocardial ischemia or nonischemic situations linked with elevated

cTn levels. The complexities of clinical settings may make it difficult to distinguish
certain unique mechanisms of myocardial damage at times. In this case, the
multifarious factors that resulted in myocardial damage should be documented in the
patient's medical record.3

Fig 2. Spectrum of myocardial injury, ranging from no injury to myocardial infarction.

Reasons for the Elevation of Cardiac Troponin Values Because of Myocardial Injury:3

1. Myocardial injury related to acute myocardial ischemia

a. Atherosclerotic plaque disruption with thrombosis
2. Myocardial injury related to acute myocardial ischemia because of oxygen
supply/demand imbalance
a. Reduced myocardial perfusion, eg,
i. Coronary artery spasm, microvascular dysfunction
ii. Coronary embolism
iii. Coronary artery dissection
iv. Sustained bradyarrhythmia
v. Hypotension or shock
vi. Respiratory failure
vii. Severe anemia
b. Increased myocardial oxygen demand, eg,
i. Sustained tachyarrhythmia
ii. Severe hypertension with or without left ventricular hypertrophy
3. Other causes of myocardial injury
a. Cardiac conditions, eg,
i. Heart failure
ii. Myocarditis
iii. Cardiomyopathy (any type)
iv. Takotsubo syndrome
v. Coronary revascularization procedure
vi. Cardiac procedure other than revascularization
vii. Catheter ablation
viii. Defibrillator shocks
ix. Cardiac contusion
b. Systemic conditions, eg,
i. Sepsis, infectious disease
ii. Chronic kidney disease
iii. Stroke, subarachnoid hemorrhage
iv. Pulmonary embolism, pulmonary hypertension
v. Infiltrative diseases, eg, amyloidosis, sarcoidosis
vi. Chemotherapeutic agents
vii. Critically ill patients
viii. Strenuous exercise

It is common practice to designate MI in patients with chest discomfort or other

ischemic symptoms who develop new ST-segment elevations in 2 contiguous leads or
new bundle branch blocks with ischemic repolarization patterns as an ST-elevation
MI for the purposes of immediate treatment strategies such as reperfusion therapy
(STEMI). Patients who do not have ST-segment elevation at the time of presentation,
on the other hand, are commonly classified as non–ST-elevation MI (NSTEMI).
Patients with STEMI, NSTEMI, or unstable angina are often included in the notion of
ACS. MI can also be categorized into distinct forms based on pathological, clinical,
and prognostic characteristics, as well as different therapeutic options.3
B. Pathophysiology of Myocardial Infarction
Acute MI is primarily caused by the rapid cessation of blood flow via an epicardial
coronary artery caused by plaque rupture, followed by the development of an
occlusive thrombus, which results in cardiac myocyte death and reduced heart
function. Although early reperfusion methods have lowered acute mortality associated
with MI, greater patient survival has increased the prevalence of chronic heart failure,
owing in part to unfavorable remodeling of the injured left ventricle (LV) following
the first ischemic event. As a result, despite surviving an initial MI, many patients
endure a substantial decline in quality of life with the beginning of heart failure, a
disease for which there are presently few therapy options that address the core
problem of cardiomyocyte loss. This paradigm change has redirected translational
research efforts toward investigating the aftereffects of MI in the hopes of discovering
innovative techniques to limit unfavorable LV remodeling and avoid the onset of
heart failure.4

The innate immune system orchestrates a sequence of time-dependent processes in

heart healing following MI, according to research in this field. During the first few
days after MI, there is significant sterile inflammation and myocardial infiltration of a
number of immune cell subtypes, including neutrophils and monocytes. Following
that, there is a transition to a reparative and proliferative phase in which inflammation
resolves, myofibroblasts multiply, and collagen deposition results in scar formation.
Finally, the scar undergoes maturation, which is characterized by extracellular matrix
(ECM) cross-linking and myofibroblast quiescence. The innate immune system
orchestrates a sequence of time-dependent processes in heart healing following MI,
according to research in this field. During the first few days after MI, there is
significant sterile inflammation and myocardial infiltration of a number of immune
cell subtypes, including neutrophils and monocytes. Following that, there is a
transition to a reparative and proliferative phase in which inflammation resolves,
myofibroblasts multiply, and collagen deposition results in scar formation. Finally,
the scar undergoes maturation, which is characterized by extracellular matrix (ECM)
cross-linking and myofibroblast quiescence.4
Fig. 3 Cardiac repair after myocardial infarction. (A) The three phases of repair. (B)
Temporal changes in leukocyte populations during repair phase.4

1. Inflammatory Phase of Post-infarction Repair

Although many different cell types are implicated in post-MI inflammation,

circulating leukocytes play a particularly important role. Prolonged ischemia and
reperfusion damage causes cardiomyocyte mortality, mostly by necrosis, but also
via apoptosis and autophagy. Myocyte death and ECM damage cause the
production of danger-associated molecular patterns (DAMPs), which attract
circulating immune cells by attaching to pattern recognition receptors (PRRs).
DAMPs and pro-inflammatory cytokines may be produced by stressed or
reversibly wounded myocytes surrounding the infarct core, in addition to passive
release from necrotic myocytes and damaged ECM, to induce recruitment of
circulating granulocytes and monocytes. These signals also cause endothelial
activity and fast upregulation of cellular adhesion molecules like P- and E-
selectin, which aid in leukocyte attachment, endothelial rolling, and, eventually,
extravasation into injured tissue.4

Neutrophils are the first immune cell type to infiltrate the infarcted heart, and they
do so by expressing selectin ligands, which cause adherence to activated
endothelial cells. Slow rolling over the endothelium surface helps neutrophils to
detect chemokines linked to glycosaminoglycans, which promotes integrin
activation, firm adhesion, and transmigration at endothelial junctions. To
deconstruct extracellular matrix and trigger the wound healing response,
extravasated neutrophils phagocytize cellular debris, release proteolytic enzymes,
and create reactive oxygen species. These activities, however, promote additional
inflammation and can have direct cytotoxic effects on viable myocytes and blood
vessels, increasing cardiac damage associated with reperfusion injury. Excessive
intravascular neutrophil accumulation also increases capillary damage and
microvascular clogging, which can lead to microvascular blockage and the "no-
reflow" phenomenon, decreasing reperfusion quality and lengthening the duration
of ischemia injury. Furthermore, neutrophil-mediated endothelial cell damage
promotes the formation of interstitial edema, which can compromise
microvascular perfusion even further via extravascular compression. The negative
effects of neutrophil infiltration can extend beyond the early post-reperfusion
period, as disproportionate neutrophil accumulation can interfere with the
recruitment of additional leukocyte populations and the transition from the
inflammatory to proliferative phase of cardiac repair, which is a necessary
component of tissue healing. Nonetheless, experimental neutrophil depletion
studies have revealed that neutrophils play a critical role in orchestrating post-
infarction repair by influencing macrophage polarization toward a reparative
phenotype, reinforcing the notion that an appropriately tempered inflammatory
response is required after MI. Indeed, whereas abrupt abrogation of integrin
CD11/CD18 and P-selectin produced spectacular results in experimental animal
investigations, it failed to enhance human outcomes substantially. This
emphasizes the importance of better understanding MI etiology, particularly in
humans.4

Monocytes are recruited to the site of injury shortly after neutrophil infiltration
peaks at 24 hours post-MI and begin to play a significant role in infarct wound
healing and tissue repair. Monocyte infiltration is aided by enhanced mobilization
of monocytes into the circulation from bone marrow as well as extramedullary
tissue such as the spleen, which has recently been identified as a monocyte
reservoir that may be activated upon injury. The monocyte chemoattractant
protein (MCP)-1/chemokine receptor (CCR)-2 axis is primarily responsible for
early recruitment of monocytes to infarcted myocardium, as pro-inflammatory
monocytes (e.g., Ly-6Chi cells in mice) expressing high levels of CCR2 are
attracted to injured tissue expressing the CCR2 ligand MCP-1.4

As a result, the initial wave of monocyte infiltration, which peaks 3 days after
reperfused MI, is characterized by an influx of pro-inflammatory monocytes,
which differentiate into tissue macrophages and promote necrotic debris removal
and tissue digestion through the release of proteolytic enzymes such as matrix
metalloproteinases and cathepsins. Following that, an inflammatory response
gives way to a reparative response, which is mediated in part by a shift in
 monocyte and macrophage function toward tissue repair via increased expression
of anti-inflammatory, pro-fibrotic, and angiogenic growth factors like interleukin
(IL)-10, transforming growth factor (TGF)-beta, and vascular endothelial growth
factor (VEGF).4

2. Proliferative Phase of Post-infarction Repair

Infiltrating leukocytes play a vital role in the timely suppression and spatial
confinement of inflammation to promote the transition to the proliferative phase
of healing, in addition to commencing the inflammatory phase of post-infarction
repair. This stage generally begins 4–7 days after reperfusion and is characterized
by inflammation resolution and fibroblast proliferation to beginning the creation
of a collagen-rich scar. Neutrophils that infiltrate the injured area early after
reperfusion undergo apoptosis and subsequent phagocytic uptake by macrophages,
resulting in a phenotypic switch toward a pro-resolving (i.e., "M2") macrophage
phenotype characterized by the release of anti-inflammatory and pro-fibrotic
cytokines such as IL-10 and TGF-. Furthermore, apoptotic neutrophils produce
chemokine and cytokine receptors that diminish tissue levels of pro-inflammatory
mediators, contributing to a shift toward an anti-inflammatory microenvironment.4

Aside from the macrophage phenotypic flip induced by phagocytosis of apoptotic

neutrophils, other leukocyte and lymphocyte populations participate to the repair
proliferative phase. During the proliferative phase of healing, CD11c+ dendritic
cells, for example, enter the infarcted heart and contribute to the resolution of
inflammation, scar formation, and angiogenesis. These effects appear to be
mediated by clearance of pro-inflammatory cell types, as experimental ablation of
dendritic cells in a rodent model of MI resulted in sustained expression of
inflammatory cytokines, persistent infiltration of pro-inflammatory monocytes and
macrophages, and worsening of left ventricular function. During the proliferative
phase of healing, anti-inflammatory T-lymphocyte populations infiltrate the
infarct region and aid in the shift to maturation. This comprises CD4+ and CD8+
T-cells, regulatory T-cells, and natural killer T-cells, which may be triggered by
yet-unidentified cardiac autoantigens and restrict unfavorable ventricular
remodeling by encouraging wound healing, inflammation resolution, and scar
formation via collagen matrix creation.4

Fibroblast growth and conversion to a synthetic myofibroblast phenotype is a

critical component of post-infarction healing. In this process, dormant fibroblasts
get awakened and begin to express contractile proteins such as -smooth muscle
actin. Although myofibroblasts contribute to the inflammatory phase of repair by
secreting pro-inflammatory cytokines and matrix metalloproteinases, they play a
more important role in the proliferative phase by producing anti-inflammatory and
pro-angiogenic factors that promote granulation tissue formation. The origin of
these cells is unknown, however it has been proposed that myofibroblasts are
derived from either local fibroblasts or circulating bone marrow progenitor cells.
Endothelial cells (through endothelial-mesenchymal transition) and epicardial
epithelial cells are two more probable origins of myofibroblasts in the infarct. The
development of a myofibroblast phenotype, regardless of the source, leads to
proliferative activity and the production of extracellular matrix proteins such as
 collagen, fibrin, and fibronectin, all of which contribute to the early stages of scar
formation.4

The activation of matricellular proteins, which predominantly guide cytokine and

growth factor responses rather than providing structural support, drives the
dynamic extracellular matrix alterations that occur during the proliferative phase
of infarct repair. Thrombospondins, tenascins, periostin, osteopontin, osteoglycin,
and proteins from the secreted protein acidic and cysteine-rich (SPARC) and CCN
families are among the matricellular proteins. These matricellular proteins,
together with proteins from the galectin and syndecan families, control protease
and growth factor activity to provide spatial and temporal modulation of various
events that characterize the transition between early inflammatory activation and
scar formation. Matricellular proteins, for example, have been shown to impact
structural matrix construction, angiogenesis, fibrinogenesis, growth factor
signaling, and inflammatory modulation. Furthermore, despite diffusion of
secreted growth factors and cytokines to remote, non-infarcted tissue, it has been
suggested that selective localization of matricellular protein expression in the
infarct border zone plays an important role in localizing inflammatory and fibrotic
responses to the site of injury. As a result, improper production of matricellular
proteins beyond the infarct boundary may contribute to infarct enlargement and
unfavorable ventricular remodeling, making it a potential therapeutic target for
improving post-infarction healing. Similarly, prolonged production of
matricellular proteins during the proliferative phase of healing may result in
excessive fibrosis following damage, as clearance of matricellular proteins is
regarded to be an essential "stop" signal to restrict pro-fibrotic signaling. Despite
the fact that the great majority of extracellular matrix proteins are glycosylated,
little is known about their involvement in controlling post-MI cell proliferation
and repair.4

3. Maturation Phase of Post-infarction Repair

Following the proliferative phase of repair, the growing scar goes through a
maturation process in which the extracellular matrix gets cross-linked and
reparative cells, including myofibroblasts, are deactivated, enter a dormant
condition, and may die. The specific processes underpinning myofibroblast
deactivation and quiescence are unknown, although they most likely entail the
withdrawal of pro-fibrotic growth hormones and the activation of inhibitory "stop"
signals via matricellular protein clearance, as previously described. Furthermore, a
time-dependent increase in anti-fibrotic factor production may reduce matrix
synthesis and accelerate scar development. Interferon-inducible protein-10, for
example, is known to be increased after MI and works to restrict the spatial spread
of the pro-fibrotic response outside the infarct location via proteoglycan-mediated
suppression of fibroblast migration.4

After scar maturation in the infarct location, late post-infarction remodeling is

frequently characterized by inflammation and fibrosis in viable non-infarcted
myocardium in distant portions of the heart. This remodeling pattern can result in
LV dilatation, global systolic dysfunction, and the beginning of heart failure.
Clinical investigations show that this sequence of events is more prevalent in
individuals with big infarcts and those with greater early inflammatory activation.
 This scenario is hypothesized to include local activation of macrophages and
fibroblasts in the distant non-infarcted myocardium as a result of increased wall
stress caused by the infarct area's lack of contractile function. Furthermore, it has
been proposed that inadequate or delayed resolution of myocardial inflammation
in the late stages of healing may result in amplification of post-MI damage over
time and promote unfavorable LV remodeling. Alternatively, new evidence
suggests that a second wave of immune activation may occur, possibly as a result
of splenic structural remodeling, increased antigen processing, and trafficking of
activated spleen-derived monocytes to the heart to induce apoptosis, fibrosis, and
dysfunction. More research is needed in this area, which could lead to a new
understanding of the mechanisms underlying immune system-mediated
remodeling of the heart in the late stages of post-infarction repair, eventually
leading to new treatments designed to inhibit this process and prevent the
development of heart failure.4

Summary

AMI, often known as a heart attack in simple words, is most commonly caused by a reduction
or interruption of blood flow to a segment of the heart, resulting in necrosis of heart muscle.
This is usually caused by a blood clot in the epicardial artery, which supplies that area of
heart muscle. It is now acknowledged that, depending on how AMI is defined, not all cases
need an etiological blood clot. The blood supply must meet the oxygen demands of every
living tissue, including heart muscle. This is referred to as the supply–demand ratio. It is now
recognized that an imbalance in this ratio (too little supply or too much demand), such as that
caused by a very fast heart rate (too much demand) or a drop in blood pressure (too little
supply), can cause cardiac injury without the presence of a blood clot.

References

1. Ojha N, Dhamoon AS. Myocardial Infarction. [Updated 2021 Aug 11]. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK537076/.
2. Saleh M, Ambrose JA. Understanding myocardial infarction. F1000Research
[Internet]. 2018 Sep 3;7:1378. Available from: https://f1000research.com/articles/7-
1378/v1
3. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth
Universal Definition of Myocardial Infarction (2018). Circulation [Internet]. 2018 Nov
13;138(20). Available from:
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000617
4. Weil BR, Neelamegham S. Selectins and Immune Cells in Acute Myocardial
Infarction and Post-infarction Ventricular Remodeling: Pathophysiology and Novel
Treatments. Front Immunol [Internet]. 2019 Feb 27;10. Available from:
https://www.frontiersin.org/article/10.3389/fimmu.2019.00300/full