Aubrey Unique M.

Evangelista

2nd Year JMCM

JOSE MARIA COLLEGE OF MEDICINE

DEPARTMENT OF PATHOLOGY

Module: Pathology of the Heart

Case 1.

Clinical Data:

A 49-year-old married male PE teacher with 2 pack/day smoking history, history of diabetes mellitus,
hyperlipidemia and obesity, and a family history of coronary artery disease. He was awakened from his sleep at
3:00 A.M. with crushing substernal chest pain which radiated to his left arm and was accompanied by shortness
of breath. When paramedics arrived, they found the patient cool, clammy, bradycardic and hypotensive. On
transport to the hospital, patient was unresponsive and eventually was declared dead on arrival at 7:30 A.M.

Discussion Points:

1. What is your probable diagnosis? How can it be differentiated from other types of angina pectoris?

 Based on the salient features of the patients, the probable diagnosis would be Acute Myocardial
Infarction. This infarction is diffusely involving the left ventricle with focal sparing of the
anterior wall. The peculiarity of Acute myocardial infarction from angina pectoris is that it is
classically associated with substernal chest pain, frequently described by the patient as crushing,
squeezing, or “elephant sitting on chest” kind of pain as opposed to a stabbing or sharp pain.
This chest pain radiates to the left arm, shoulder, or neck in 80% of cases.

 The patients commonly also have sweating, nausea, vomiting, dyspnea, low-grade fever, an S4
gallop, an S3 gallop (if the heart is failing), a friction rub (if there is pericarditis), mitral
regurgitation (if the left ventricle is severely dilated) and low-grade leukocytosis.

 Transmural infarction involves the full thickness of the heart wall and is associated with plaque
rupture in approximately 75% of cases and is associated with occlusive thrombosis superimposed
on a complicated plaque with an acute change in approximately 90% of cases. Subendocardial
infarction involves the inner portion of the heart and is associated with the risk of subsequent
extension. Subendocardial infarction is sometimes patchy or in the distribution of multiple
 coronary arteries.

2. What are the gross and microscopic pathologic features in the heart at the time of death? Discuss
the progression of the morphologic changes in the heart over time.

 The gross pathologic features of the patient’s heart at the time of death would be the
following: Heart was mildly enlarged. The epicardium was smooth. The endocardium was thin
and translucent. The heart valves were thin, pliable and free of vegetations. The heart showed
mild four-chamber dilatation and diffuse severe softening ("flabbiness") of the myocardium.
Sectioning the heart revealed extensive pallor of the myocardium, which was transmural and
maximal in the apex. The cardiac apex was focally thinned to 0.6 cm. The pallor was minimal in
the upper anterior left ventricle, and there was focal mottling of the muscle in the high portion of
the septum.

 Microscopic pathologic features in the patient’s heart are also listed as follows: The
anterior left ventricle displayed pale myocytes with fading nuclei and markedly decreased cross-
striations, with blood vessels containing basophilic debris, bordered by a thin subepicardial zone
of acute inflammation, extravasation of blood and myocyte cytoplasmic contraction banding,
leaving only a small subepicardial corner of normal myocytes above the zone of inflammation.
There was diffuse interstitial edema. The cardiac apex also showed diffuse interstitial edema and
pale myocytes with fading nuclei and decreased striations, with a thin subepicardial zone of
acute inflammation, extravasation of blood and myocyte cytoplasmic contraction banding. The
base of the posterior papillary muscle showed diffuse interstitial edema, a small area of acute
inflammation and extravasation of blood, focal myocyte cytoplasmic contraction banding and
areas of subendocardial hyper eosinophilic myocytes. The posterior left ventricle exhibited
multifocal myocyte contraction banding, diffuse interstitial edema and focal acute inflammation.
The septum had a large area of pale staining myocytes associated with a nearby necrotic small
intramyocardial coronary artery and a border of moderate acute inflammation and extravasation
of blood. Three sections of the most proximal portion of the right coronary artery showed severe
atherosclerotic intimal thickening with old sclerotic disease in the deepest portions of the intima
and areas of superimposed young atheroma resulting in 80-85% lumenal narrowing; there was
focal superimposed thrombus deposition adding approximately 5% more lumenal narrowing.
Five sections of the next most proximal right coronary artery all showed severe sclerotic intimal
thickening with superimposed atheroma producing 70-80% lumenal narrowing, one with
superimposed condensing fibrin thrombus deposition adding approximately 20% more
 narrowing (for a total of 90% lumenal stenosis), but the others with mostly postmortem thrombus
in their residual lumens. The balance of the proximal right coronary artery showed sclerotic
disease with superimposed atheroma producing 70-80% lumenal narrowing, with primarily
postmortem thrombus in the residual lumens.The left circumflex artery showed severe intimal
thickening with one section showing two-sided large young atheromas with numerous
cholesterol clefts, numerous macrophages and lymphocytes, and a few multinucleated giant cells,
resulting in approximately 95% luminal narrowing and a slit-like lumen. The proximal left
anterior descending artery showed intimal thickening with calcification and areas of young
atheroma resulting in lumenal narrowing of 60-80%.

3. Arrange in order of appearance and describe the following microscopic findings seen in the heart.
Order of Appearance: C, B, E, D, A

C. One day old Infarct

One-day-old infarct showing coagulative necrosis and wavy fibers (elongated and narrow, as compared
with adjacent normal fibers at right). Widened spaces between the dead fibers contain edema fluid and
scattered neutrophils

B. Myocardial Infarction (MI) 3-4 Days Old

Dense polymorphonuclear leukocytic infiltrate in an acute myocardial infarction that is 3 to 4 days old.

E. Myocardial Infarction (MI) 7-10 Days Old

 Removal of necrotic myocytes by phagocytosis (approximately 7 to 10 days)

D. Granulation Tissue

Granulation tissue characterized by loose collagen and abundant capillaries.

A. Healed Myocardial Infarct

Healed myocardial infarct, in which the necrotic tissue has been replaced by a dense collagenous scar. The
residual cardiac muscle cells show evidence of compensatory hypertrophy.

4. What is the pathophysiology of coronary atherosclerosis?

 Early atherosclerosis is characterized by atheromatous plaques, which are 0.3-1.5 cm raised
white-yellow fibro-fatty lesions composed of central soft yellow lipid-rich "atheroma" covered by a firm
white fibrous cap. On microscopic examination, atheromas are primarily composed of amorphous
eosinophilic debris, cholesterol clefts, fibrin and foam cells (lipid-laden macrophages and smooth
muscle cells). Their fibrous caps are primarily composed of collagen, proliferating smooth muscle cells,
macrophages, lymphocytes and foam cells. The thickening of the tunica intima causes
neovascularization, ingrowth of capillaries through the tunica adventitia and tunica media into the tunica
intima, creating abnormal vessels prone to rupture.

In the later stages of disease, atherosclerosis is complicated by calcification, ulceration, fissure,

rupture, intraplaque hemorrhage or superimposed thrombosis. Calcification causes hardening and loss of
adaptability of the arteries. Ulceration or rupture of an atherosclerotic plaque can release atheroemboli,
which can cause sudden ischemia or infarction. Intraplaque hemorrhage due to rupture of one of the
small abnormal neovascular channels can acutely expand a plaque, causing ischemia or infarction. An
acute change in a plaque, which exposes subendothelial collagen and atheroma to platelets, causes
adhesion, aggregation and activation of platelets. These platelets then release adenosine diphosphate
(ADP), aggregating more platelets. The platelets also release thromboxane A2, serotonin and platelet
factors 3 and 4, all of which predispose to coagulation and vasospasm. Release of tissue thromboplastin
from an atheroma can activate the extrinsic pathway of coagulation. Thrombosis superimposed on
atherosclerosis of a coronary artery is associated with transmural myocardial infarction, but it is a
dynamic process, with only 60% of coronary thromboses showing total occlusion after 12-24 hours.

Schematic diagram
Case 2.
Clinical Data:
A 15-year-old male comes to the ER due to dyspnea. History started 1 month prior to admission when he
developed, intermittent fever, joint pains, throat irritation accompanied by mild difficulty in breathing. He
sought consult at a private clinic and was treated as a case of “sore throat”. 1 week prior to admission, the
patient noticed that he easily gets tired and sometimes feel out of breath. Persistence of symptoms accompanied
by facial swelling and abdominal enlargement prompted consult.
On cardiopulmonary PE, there was noted S4 murmur and decreased breath sounds on both lung fields. ECG
showed 1st degree heart block.

Discussion Points:
1. What is your diagnosis? What is the basis for your diagnosis?

Based on the clinical manifestation of the patient, the probable diagnosis for this is Acute
Rheumatic Fever. Cardiac involvement in acute rheumatic fever is typically described as “pancarditis”,
underscoring the fact that the pericardium, myocardium, and endocardium can all be affected. The
salient feature, nonetheless, is valvar involvement, given its long-term ramifications. It is the hallmark of
carditis and is therefore considered a major criterion in the Jones criteria for the diagnosis of rheumatic
fever. Atrioventricular conduction abnormalities are also well recognized features of acute rheumatic
fever. The advent of ECG has allowed for precise measurement of such abnormalities, since prolonged
atrioventricular conduction, i.e., first degree heart block, is a well-recognized feature of acute rheumatic
fever, occurring in about one-fifth to three-fifths of patients. The patient’s recent medical history and its
clinical presentation and symptoms back up the diagnosis.

2. Describe the pathophysiology of your diagnosis.

Group A streptococcal (GAS) pharyngitis is the etiologic precursor of acute rheumatic fever, but
host and environmental factors are important. GAS M proteins share epitopes (antigenic-determinant
sites that are recognized by antibodies) with proteins found in synovium, heart muscle, and heart valve,
suggesting that molecular mimicry by GAS antigens from rheumatogenic strains contributes to the
arthritis, carditis, and valvular damage. Genetic host risk factors include the D8/17 B-cell antigen and
certain class II histocompatibility antigens. Undernutrition, overcrowding, and lower socioeconomic
status predispose to streptococcal infections and subsequent episodes of rheumatic fever.

Remarkably, although GAS infections of both the pharynx and of other areas of the body (skin
and soft-tissue structures, bones or joints, lungs, and bloodstream) may cause poststreptococcal
glomerulonephritis , nonpharyngitis GAS infections do not lead to ARF. The reason for this distinct
difference in complications resulting from infection by the same organism is not well understood.

The joints, heart, skin, and central nervous system (CNS) are most often affected. Pathology
varies by site.
 Symptoms and Signs of Rheumatic Fever
Joints
Migratory polyarthritis is the most common manifestation of acute rheumatic fever, occurring in
about 35 to 66% of children; it is often accompanied by fever. "Migratory" means the arthritis appears in
one or a few joints, resolves but then appears in others, thus seeming to move from one joint to another.
Occasionally monarthritis occurs in high-risk indigenous populations (eg, in Australia, India, Fiji) but
very rarely in the US. Joints become extremely painful and tender; these symptoms are often out of
proportion to the modest warmth and swelling present on examination (this is in contrast to the arthritis
of Lyme disease , in which the examination findings tend to be more severe than the symptoms).

Heart

 Heart murmurs are common and, although usually evident early, may not be heard at
initial examination; in such cases, repeated clinical examinations as well as
echocardiography are recommended to determine the presence of carditis.

 Mitral regurgitation is characterized by an apical pansystolic blowing murmur radiating

to the axilla. The soft diastolic blow at the left sternal border of aortic regurgitation, and
the presystolic murmur of mitral stenosis, may be difficult to detect. Murmurs often
persist indefinitely. If no worsening occurs during the next 2 to 3 weeks, new
manifestations of carditis seldom follow. ARF typically does not cause chronic,
smoldering carditis. Scars left by acute valvular damage may contract and change, and
secondary hemodynamic difficulties may develop in the myocardium without persistence
of acute inflammation.

 Pericarditis may be manifested by chest pain and a pericardial rub.

 Heart failure caused by the combination of carditis and valvular dysfunction may cause
dyspnea without rales, nausea and vomiting, a right upper quadrant or epigastric ache,
and a hacking, nonproductive cough. Marked lethargy and fatigue may be early
manifestations of heart failure.
Skin
 Cutaneous and subcutaneous features are uncommon and almost never occur alone,
usually developing in a patient who already has carditis, arthritis, or chorea.

 Subcutaneous nodules, which occur most frequently on the extensor surfaces of large
joints (eg, knees, elbows, wrists), usually coexist with arthritis and carditis. Fewer than
10% of children with acute rheumatic fever have nodules. Ordinarily, the nodules are
painless and transitory and respond to treatment of joint or heart inflammation.

 Erythema marginatum is a serpiginous, flat or slightly raised, nonscarring, and painless

rash. Fewer than 6% of children have this rash. The rash usually appears on the trunk and
proximal extremities but not the face. It sometimes lasts < 1 day. Its appearance is often
delayed after the inciting streptococcal infection; it may appear with or after the other
manifestations of rheumatic inflammation.

CNS
Sydenham chorea occurs in about 10 to 30% of children. It may develop along with other
manifestations but frequently arises after the other manifestations have subsided (often months after the
acute streptococcal infection) and thus may be overlooked as an indicator of acute rheumatic fever.
Onset of chorea is typically insidious and may be preceded by inappropriate laughing or crying. Chorea
consists of rapid and irregular jerking movements that may begin in the hands but often becomes
generalized, involving the feet and face.

Schematic Diagram
Case 3.
Clinical Data:
A healthy 33-year-old athletic male was evaluated in cardiology clinic for worsening exertional palpitations and
non-specific chest discomfort. About five years ago, he had similar complaints and prior ECG showed diffuse
symmetric T wave inversions in right precordial leads. Subsequently, he had extensive work up consisting of
cardiac monitor, echocardiogram, exercise stress test, and coronary angiogram, which were all unremarkable.
Patient was eventually admitted for further monitoring.
While hospitalized, he became critically hypotensive with multiple runs of non-sustained ventricular
tachycardia. Echocardiogram showed moderate left ventricular systolic dysfunction with an estimated left
ventricular ejection fraction of 40%. The right ventricle was severely dilated and severely hypokinetic. Severe
tricuspid regurgitation was present. The patient proceeded to suffer a cardiac arrest from which she could not be
resuscitated and she was pronounced dead.
Family history showed that the patient' s mother died at age 65 of congestive heart failure. His father died at age
48 of a myocardial infarction. One of his sisters died at age 46 from a cardiomyopathy. This sister had heart
failure for about two years and died suddenly. Another sister had congestive heart failure at age 38 and a history
of rapid ventricular tachycardia which prompted automatic implantable defibrillator placement, and later a heart
transplantation.
Autopsy of the heart showed the following gross and microscopic findings:

Discussion Points:
1. Describe the gross and microscopic findings.

As shown above in Figure A, it is a gross photograph exhibiting the dilation of right ventricle
and near-transmural replacement of the right ventricular free-wall by fat and fibrosis, right side of the
heart appears yellowish or whitish due to fatty or fibrofatty infiltration of the underlying myocardium. It
is also notable that the left ventricle maintained its virtually normal configuration, a paradox which
explains why these hearts are able to withstand the cardiac output of a strenuous exercise performance
and at the same time are electrically vulnerable because of fibrofatty infiltration of the right ventricle.
The right ventricular inflow outflow tract appear lardaceous / fatty and right ventricular free wall
 appears parchment like when held against a light source. Aneurysms of the right ventricular free wall,
whether single or multiple, are considered a pathognomonic feature. Right ventricular enlargement
(mild, moderate or severe) is a constant feature.

The Figure B shown above represents the significant microscopic finding, it is a histologic
section of the right ventricular free wall. It was demonstrating the replacement of myocardium (red) by
fibrosis (blue,arrow) and fat (Masson trichrome stain). To sum it up, histology of the free wall of the
right ventricle shows disappearance of the myocardium with transmural fibrofatty replacement, the
pathologic process starts from the subepicardium and extend to the endocardium as a wave front
phenomenon and patchy myocarditis with myocyte death and round cell inflammatory infiltrates may be
seen as well.

2. What is the basis for your diagnosis?

In this case, the basis of this diagnosis was the sudden onset of critical hypotension accompanied
by multiple runs of non-sustained ventricular tachycardia. Echocardiogram showed moderate left
ventricular systolic dysfunction with an estimated left ventricular ejection fraction of 40%. The right
ventricle was severely dilated and severely hypokinetic and we can conclude that this bulging is
localized to thee infundibular, apical and subtricuspid regions of right ventricle which is 90 % specific
for ARVD once we perform a right ventricular angiography, a process that is considered as the gold
standard for the diagnosis of this disease. Severe tricuspid regurgitation was present which led to sudden
cardiac death and the family history of having cardiac diseases also backed up the ARVD diagnosis
since one notable trait of ARVD is Inherited in an autosomal dominant pattern, with variable expression.

3. Differentiate the different types of cardiomyopathies.

 Dilated Hypertrophic Restrictive
Cardiomyopathy Cardiomyopathy Cardiomyopathy
(DCM) (HCM) (RCM)

Dilated cardiomyopathy is typically It is the most common inherited Restrictive cardiomyopathy

characterized by dilatation and cardiomyopathy due to mutations in (RCM) is a heart-muscle
impaired function of one or both numerous genes, encoding sarcomere disease characterized by
ventricles. Patients may develop proteins and is transmitted with an stiffness of the ventricular
heart failure, and most often the autosomal dominant pattern with walls leading to diastolic
presenting symptoms may be variable penetrance. HCM is dysfunction, raised end-
arrhythmias, atrial or ventricular,
characterized by cardiac hypertrophy, diastolic pressure, and dilated
and sudden cardiac death. This
particularly of the left ventricle (LV) atria. The ventricles are not
disease can be classified as either
primary or secondary DCM. (wall thickness ≥ 15 mm), in the absence dilated and there is
Primary DCM is considered of overload conditions (e.g., physiological wall thickness.
idiopathic and the diagnosis can hypertension, valvular disease, etc.), Therefore, systolic function
only be made after excluding which could justify this thickening. In is usually preserved.
secondary causes. Dilated particular, in an adult, HCM is defined Impairment of the ventricular
cardiomyopathy is one of the main by a wall thickness >15 mm in one or structure and its systolic
causes of heart failure. Patients with more MV=myocardial segments, as function may be present only
dilated cardiomyopathy typically measured by an imaging technique, and in the advanced stages of
present with signs of congestive is not explained solelyby loading secondary RCM]. RCM is
heart failure, such as dyspnea, conditions. As in adults, in children, the not a single disease but can
congestive edema, orthopnea. diagnosis of HCM requires wall LV be the result of multiple
thickness more than two standard inherited or acquired
deviations greater than the predicted predispositions. As in other
mean. Many patients with HCM have no cardiomyopathies, also in
or only minor symptoms throughout life. RCM there are genetic
Dyspnea on exertion, as a symptom of mutations in the genes
heart failure (HF), is present in more encoding the sarcomere
than 90% of symptomatic patients. proteins that have been
Typical chest pain on exertion occurs in associated. Epidemiology of
25 to 30% of patients with HCM. this disease in not so well
Syncopal episodes occur in about 15– represented in literature, but
25% of patients with HCM. Another RCM is the least common of
20% of these patients report pre-syncope the cardiomyopathies. An
episodes. HCM can present with both idiopathic pattern in which
supraventricular and ventricular no identifiable cause is found
arrhythmias. These can appear to the is a really rare disease. It can
patients as palpitations, dyspnea, affect people at any age.
presyncope/syncope. Children have the worst
prognosis and girls seem to
be more affected]. It can be
acquired or inherited