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When is having a big heart a problem?
Fishbein Gregory, Fishbein Michael
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Acad Forensic Pathol. 2011 Sep; 1(2): 188-193
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INVITED REVIEW
When is Having a Big Heart a Problem?
Gregory A. Fishbein MD, Michael C. Fishbein MD
Gregory A Fishbein, MD is
a resident physician in the
Department of Pathology and
Laboratory Medicine at the
University of California,
Los Angeles.
Author Affiliations: UCLA Medical
Center - Pathology and Laboratory
Medicine, Los Angeles, CA (MF)
Contact Dr. Gregory Fishbein at:
[email protected]
Acad Forensic Pathol
2011 1 (2): 188-193
https://doi.org/10.23907/2011.024
© 2017
Academic Forensic Pathology International
ABSTRACT Cardiac enlargement is a common and important post-mortem finding. The
presence of a big heart may provide a basis for determination of the mechanisms of death
in an otherwise negative autopsy. In this article we will 1) define terms used to describe the
morphology of the heart; 2) describe the ways the heart can enlarge; 3) review the reasons
the heart may enlarge and 4) discuss the consequences of that enlargement. In so doing,
we hope to assist the pathologist in evaluating cardiomegaly at autopsy and recognizing the
significance of the cardiac enlargement.
KEYWORDS: Autopsy, Cardiomyopathies, Cardiovascular diseases, Sudden death, Myocardium
INTRODUCTION
The heart is the seat of the soul. To describe
someone as having a “big heart” is to imply one
has the abilities of exceptional caring and sympathy. As autopsy pathologists, however, we tend
to focus on the heart’s other qualities and functions. To us, the heart is a pump – perhaps a sophisticated and important pump – but nevertheless a pump. Its functional component is striated
muscle. As such, the heart has a limited way to
compensate for a chronic increase in workload or
injury, namely to increase the size of the organ.
In this article we will 1) define terms used to describe the morphology of the heart; 2) describe
the ways the heart can enlarge; 3) review the
reasons the heart may enlarge and 4) discuss the
consequences of that enlargement. Since cardiac
enlargement is a common and important autopsy
finding, the hope is that this review will assist the
pathologist in evaluating individuals who have
enlarged hearts at autopsy and recognizing the
significance of the cardiac enlargement.
Page 188 • Volume 1 Issue 2
DEFINITIONS
A number of terms are used to describe the size
and shape of the heart. Cardiomegaly is a relatively nonspecific term that means “big heart”.
Cardiomegaly provides no information regarding which chambers are enlarged, or whether the
enlargement is due to hypertrophy, dilatation, or
both. Hypertrophy is more specific. Hypertrophy
indicates that there is organ enlargement due to
enlargement of individual cells. There is no increase in the number of cells. Cardiac hypertrophy can be further described by the shape of the
entire organ and its chambers. Eccentric hypertrophy describes a change in the configuration
of a hollow organ, such as the heart, in which
there is enlargement of the cavities resulting in
increased diameter of the organ. Eccentric hypertrophy of the heart is the type that shows up on
chest x-ray. On the other hand, concentric hypertrophy, most often used to describe the left ventricle, results in wall thickening without increase
in organ or chamber diameter; furthermore, there
is a decrease in cavity size. Concentric hypertrophy of the left ventricle does not cause an
increase in the cardiac silhouette on chest x-ray.
Hypertrophy can involve one or more of the cardiac chambers, but the process is most readily
detected in the ventricles first, especially the left
ventricle that makes up roughly 75% of the mass
of the heart (Image 1).
Atrophy may also affect the myocytes of the
heart causing a decrease in mass, usually related
to decreased functional demand. Hence, in hearts
with severe mitral valve stenosis, the left ventricular mass and dimensions are decreased. Hyperplasia is an increase in the number of normal
cells in an organ. Hyperplasia of the heart is a
subject of great interest, as it would be beneficial if myocytes could increase in number after
cardiac injury or in response to increased work-
RV
usual post-mortem contraction of the ventricles.
Furthermore, unless the heart is fixed while distended, at physiologic pressures, any post-mortem measurement of ventricular diameter has
serious limitations (3).
LV
LV
RV
*
*
Image 1: A) concentric hypertrophy in a patient with hypertrophic cardiomyopathy, and B) eccentric hypertrophy with
fibrosis (*) in a patient with dilated cardiomyopathy (LV = left
ventricle and RV = right ventricle)
load. Unfortunately, if hyperplasia occurs at all,
the increase in number of myocytes does not contribute substantially to the mass of the heart after
birth (1, 2).
NORMAL HEART WEIGHTS AND DIMENSIONS
Since the heart has such a limited way to respond
to increased pressure or volume load, accurately
documenting the degree of hypertrophy or dilatation should provide very useful information
regarding the status of the heart. Unfortunately,
as discussed, dilatation can not be quantified reliably at autopsy.
Wall thickness is another measure of the degree
of hypertrophy. However, wall thickness is dependent on several factors. In concentric hypertrophy, sarcomeres are laid down side-by-side, so
wall thickness increases with myocardial mass
(5). With chronic dilatation, however, sarcomeres are added end-to-end, so myocardial mass
increases while wall thickness may remain the
same. Wall thickness at autopsy will also depend
upon the degree of contraction of the post-mortem heart. Another problem is that the ventricular wall is highly trabeculated and has papillary
muscles. Thus, wall thickness in any given heart
is quite variable depending on the site where wall
thickness is measured.
Because of all these limitations and because
weight is a number that can be measured quite
precisely, heart weight is a very useful index of
the state of the heart. As luck would have it, the
heart weight measurement also has a number of
limitations. The heart has a variable amount of
epicardial adipose tissue that increases with body
weight, steroid use (or production), alcohol use,
diabetes mellitus, and other factors. The heart is
Fishbein & Fishbein • Page 189
Dilation and dilatation are terms used interchangeably to describe enlargement of the cavity
of an organ. To a cardiologist, when dilatation is
detected clinically by x-ray, ultrasound, or ventriculography, the expansion of one or more of
the cardiac chambers indicates cardiac dysfunction. Dilatation at autopsy is a different matter. If
atria appear expanded at autopsy, it is probably a
real finding. However, in our opinion, the observation of a dilated ventricle is more problematic.
At autopsy, there is no intraventricular pressure
against the walls of the ventricles as there is in
life. Rigor mortis will contract the ventricles, so
a normal heart may actually be more contracted
than in end-systole. Autolysis (decomposition),
hyperkalemia at the time of death, and acute failure of the heart just before death, may prevent the
CARDIOMEGALY
The last definition to discuss is related to the
most catastrophic consequence of cardiomegaly,
namely, sudden cardiac death. There are several
aspects to the definition of this term. Generally
speaking, sudden cardiac death is used when
death is “unexpected.” How unexpected does the
death have to be? If the individual is known to
have underlying heart disease, is an arrhythmic
death totally unexpected? How “sudden” is sudden? Some authors say death within one hour of
symptoms; others say within 4 hours; others yet
say within 24 hours (4). In the absence of clinical
electrophysiologic abnormalities and acute cardiovascular abnormalities what is the evidence
that the death was cardiac in origin? The role of
cardiomegaly in cardiac dysfunction and arrhythmogenesis will be discussed in subsequent sections of this review.
INVITED REVIEW
RV
LV
1 cm
Image 2: Isolated right ventricular hypertrophy from a patient with idiopathic pulmonary arterial hypertension.
usually preserved with some segments of great
vessels still attached. In addition, the cardiac
chambers usually contain post-mortem clots that
are often difficult and labor-intensive to remove.
Since different chambers may hypertrophy to
different degrees, total heart weight does not
provide information regarding which chamber
has increased the most. In fact, the majority of
heart weight is left ventricle, so left ventricular
hypertrophy will usually increase heart weight
the most. In practice, the one time wall thickness
measurements may be more useful than heart
weight is in the case of pure right ventricular
hypertrophy as occurs in idiopathic pulmonary
hypertension, since there will be substantial
thickening of the right ventricular wall with little
impact on overall heart weight (Image 2). There
are methods described to separate the cardiac
chambers before weighing. The Fulton method
(6) is one, but this method is used primarily for
research studies.
Page 190 • Volume 1 Issue 2
How then does one go about obtaining an accurate heart weight? First the heart must be opened
before weighing to remove post-mortem clots.
The great vessels should be transected 1-2 cm
above the semilunar valves. The inferior and
superior vena cavae and the pulmonary veins
should be cut within 1 cm of their entry into the
atria. For routine purposes, epicardial adipose
tissue with coronary arteries in place is weighed
as part of the heart.
What is normal heart weight? In most mammalian species, including human beings, normal heart
weight is 0.45% of body weight for males, and
0.40% of body weight for females, if and only
if, body weight is normal (7). Unfortunately,
obesity is currently epidemic in industrialized
societies, limiting the use of body weight to calculate normal heart weight. For example, in a
400 lb obese individual, 0.45% of body weight
would equal 810 gm. This would not be a normal sized heart. In obesity, the heart is enlarged
pathologically for a number of reasons. First,
adipose tissue is very vascular so cardiac output
is increased to supply blood to the fat. Second, in
obese individuals, “lean” body mass is increased
as muscle is added to carry the excess fat. The
increase in skeletal muscle also increases cardiac
workload. And third, obesity is associated with
diseases that also are associated with hypertrophy of the heart, such as hypertension and diabetes mellitus. Clearly there are serious limitations
in using body weight to normalize heart weight.
One popular table (8) used by pathologists lists
“normal” heart weight for a 5’8” man as 224-446
gm. This may be the “average” heart weight for
this height, but certainly “normal” could not have
such a wide range. The articles justifying the use
of body weight to normalize heart weight cite
a linear relationship between increasing body
weight and heart weight. This is precisely the
problem. Heart weight does increase with body
weight, but this is pathologic; the heart in overweight individuals is not normal.
How then is normal heart weight best estimated? In our opinion, it makes much more sense
to normalize heart weight to body height. Zeek,
in 1942 (9), did a study of heart size in men and
women without heart disease, and came up with
formulae based on body height that can readily
be used to calculate normal heart weight for adult
men and women (Table 1). Table 1 lists information on cardiac dimensions taken from the medical literature, and summarize normal dimensions
for adult hearts. Many of these data have serious
limitations.
CAUSES OF HYPERTROPHY
When the heart is enlarged, regardless of whether
it can be designated eccentric or concentric, the
hypertrophy is invariably attributed to growth at
the cellular level. The heart is an organ with exceptionally low regenerative capacity; the principle mechanism by which the heart responds
to increased workload and increased stress is by
cardiomyocyte hypertrophy. Protein expression
is up-regulated, and sarcomeres, the cell’s forcegenerating machinery, increase in size, resulting
in cellular enlargement. Furthermore, the sarcomeres become more organized, arranging themselves in a manner that cumulatively results in
either wall thickening (concentric hypertrophy)
or chamber dilatation (eccentric hypertrophy).
We tend to consider the former a result of pressure overload, and the latter a result of volume
Table 1: Normal Cardiac Dimensions
0.38-0.45
1.23-1.5**
LV free wall weight (g)6
Septal weight (g)6
Normal heart weight in males (g)9
48-123 (m=86)***
17-61 (m=39)***
1.9 x height (cm) –
2.1 ± 40†
Total ventricular weight (g)6
RV free wall weight (g)6
Normal heart weight in females (g)9
Normal heart weight in males7
Normal heart weight in females7
*
88-235 (m=171)***
23-68 (m=46)***
1.78 x height (cm)
– 21.6 ± 30†
0.45% body
weight††
0.40% body
weight††
* Higher than expected, usually normal = ~.30.
** Measured where wall is compact, excluding
papillary muscles and trabeculations.
*** Depends on gender and body size; such wide ranges
don’t seem physiologic.
† In our opinion, the preferred way to calculate normal
heart weight in adults.
†† Works well in lean individuals only.
Table 2: Common causes of hypertrophy
Cause
Phenotype
Aortic stenosis
Mitral regurgitation
Aortic regurgitation
Hypertension
Ischemia
Myocarditis
Hypertrophic cardiomyopathy
Concentric
Eccentric
Variable
Variable
Eccentric
Eccentric
Concentric
Dilated cardiomyopathy
Eccentric
Alcoholic cardiomyopathy
Eccentric
overload. However, there are many variables that
determine the hypertrophic phenotype (i.e. concentric vs. eccentric).
In pregnancy, the heart, as well as other maternal
organs, undergoes dramatic structural changes.
Maternal cardiac output may increase by 50%,
so at parturition the mother’s heart is normally
heavy. This fact is often overlooked in evaluation
of a potential cardiac cause of death of a mother
in the peripartum period. “Peripartum” cardiomyopathy can easily be overdiagnosed in this
circumstance.
The differential remodeling of pressure overload
(concentric hypertrophy) and volume overload
(eccentric hypertrophy) is well demonstrated
by aortic valve stenosis. In aortic stenosis, the
sclerotic, calcified valve causes LV outflow obstruction and increased LV pressure. Structural
proteins, such as integrins and stretch receptors,
sense pressure overload and initiate a signaling
cascade that promotes concentric hypertrophic
growth. However, concentric remodeling is not
the only pattern of hypertrophy seen in this disease. The increased pressure eventually affects
mitral valve function, leading to mitral regurgitation and left atrial volume overload. Left atrial
enlargement may be prominent. The LV also
becomes volume overloaded, in which case the
hypertrophic phenotype is eccentric, not concentric. Furthermore, as the aortic valve becomes
more and more sclerotic, it may lose the ability
to close completely, resulting in aortic regurgitation. In this case, either concentric or eccentric
hypertrophy can be seen (15).
Not all stress to the heart is biomechanical. Neurohumoral factors, such as angiotensin II, catecholamines, and sympathetic innervation, act
directly on cardiomyocytes. Neurohumoral and
biomechanical stress trigger hypertrophic growth
via independent pathways (16). That said, overstimulation of many these factors also causes
hypertension and therefore pressure overload. In
such situations, neurohumoral and biomechanical
stress act in concert. Though we tend to associate
Fishbein & Fishbein • Page 191
Before we examine various pathologic entities
leading to cardiac hypertrophy (Table 2), let us
first consider cardiac enlargement in the absence
of disease. Volume overload occurs physiologically in elite endurance athletes as well as pregnant women. This “physiologic hypertrophy”
results in an increase in LV chamber size with
little or no increase in relative wall thickness (10)
—eccentric hypertrophy. “Athlete’s heart”, as it
is known, is regarded as benign and reversible.
However, power athletes, such as professional
weight-lifters, undergo a different type of hypertrophy. It is estimated that their cardiomyocytes see transient pressures in excess of 480/350
mmHg, 5-6 days per week, for 5-15 years (11).
The result is pressure overload; their hearts
demonstrate concentric hypertrophy. While it is
generally accepted that chamber dilatation in endurance athletes is benign, it is well established
that, in general, LV wall thickening is damaging
to the myocardium, conferring increased risk of
arrhythmia and ischemia (12). Moreover, it has
been demonstrated that athletes engaging in less
extreme strength training, such as rowers, may
exhibit LV wall thickening that exceeds the
threshold for normal (13). Furthermore, there are
data suggesting that LV remodeling in both endurance and power athletes may not completely
resolve after long-term deconditioning (14).
Thus, the concept of “athlete’s heart” is somewhat controversial.
CARDIOMEGALY
RV wall thickness (cm)
LV wall thickness (cm)26
26
INVITED REVIEW
hypertension with concentric hypertrophy—being a disease of pressure overload—studies demonstrate that the geometry of the hypertensive
heart is often eccentric (17, 18), perhaps owing
to the multifactorial nature of the disease.
Myocardial injury is another important trigger of
pathologic hypertrophy—ischemia being a prime
example. When injured myocardium is functionally impaired, there is an attempt by surrounding
tissue to compensate via eccentric remodeling.
The increase in chamber size increases preload,
therefore increasing stroke volume and cardiac
output. Quite often, however, the compensation
is inadequate. As the chamber dilates, wall tension increases (law of Laplace). This increase
in stress stimulates further hypertrophic growth,
resulting in a downward spiral of maladaptive
remodeling. The etiologies of myocardial injury
are virtually endless. Important categories to
consider include ischemia (coronary artery disease, microvascular disease), myocarditis (infectious, immune-mediated), and toxins (alcohol,
chemotherapeutic agents).
Page 192 • Volume 1 Issue 2
Unlike the causes of cardiomegaly previously
mentioned, in which external influences trigger
cardiomyocyte hypertrophy, dilated and hypertrophic cardiomyopathies are diseases of the
cardiomyocyte itself. It should be noted, that
although the term cardiomyopathy is commonly
used to describe the hypertrophic heart in general
(e.g. ischemic cardiomyopathy), one could argue
the term should be reserved for intrinsic diseases
of the heart muscle (as it’s name denotes). Hypertrophic cardiomyopathy (HCM), previously
known as hypertrophic obstructive cardiomyopathy (HOCM), is an inherited cardiomyopathy
and an important cause of sudden death in young
people (19). It is a disease of the sarcomere, in
which defective proteins aberrantly trigger concentric hypertrophy (20). HCM has a peculiar
predilection for the interventricular septum,
though the entire left ventricle (and occasionally
the right) may be affected. Histologically, HCM
is characterized by myofibrillar disarray and fibrosis. In contrast to HCM, dilated cardiomyopathy (DCM) represents a diverse group of diseases
that share a common phenotype—eccentric hypertrophy. It is estimated that 20-48% of DCM
is familial (21), and a wide variety of defective
proteins have been implicated. Despite their genomic diversity, the aberrancies all manifest as
marked chamber dilatation.
Infiltrative diseases represent a group of rare
disorders associated with cardiac hypertrophy.
Some are diagnosed early in life, though others
may be revealed at autopsy. Grossly the heart
may be indistinguishable from cardiomyopa-
thies. However, the histologic appearances are
distinct. Infiltrative diseases that may mimic
HCM (i.e. concentric hypertrophy) include cardiac amyloid, glycogen storage diseases, primary
hyperoxaluria, Fabry’s disease, and mucopolysaccharidoses. Examples of infiltrative diseases
that mimic DCM (i.e. eccentric hypertrophy) are
sarcoidosis, hemochromatosis, and Wegener’s
granulomatosis (22). Other notable yet uncommon causes of cardiac hypertrophy include muscular dystrophies, neurodegenerative disorders
(e.g. Friedreich ataxia), mitochondrial disorders,
thiamine deficiency (Beri Beri), and numerous
inborn errors of metabolism.
HYPERTROPHY AS A CAUSE OF DEATH
When is cardiac hypertrophy responsible for
death? The hypertrophic heart can result in death
in only two ways: 1) failure of the heart as a pump
– heart failure, and 2) failure of the electrical system of the heart – arrhythmia or conduction abnormalities. Of course, determination of factors
responsible for death involves clinicopathologic
correlation – clinical history, laboratory studies,
toxicology, etc. If other organ systems have been
excluded, then what are the autopsy manifestations of a “cardiac death?”
If death is due to pump failure, then certain anatomic abnormalities should be apparent. If there
is left ventricular failure, the lungs should be
heavy, and microscopic examination should show
diffuse alveolar edema. One caveat is that if a patient dies after failed resuscitation attempts, the
lungs are always heavy and full of fluid, so the
pathologist can not determine whether or not left
ventricular failure was present. The presence of
hemosiderin-laden macrophages, so called “heart
failure cells” is suggestive but not very specific.
If right ventricular failure is present, there should
be acute and/or chronic passive congestion of the
liver and perhaps peripheral edema.
What if the mechanism of death is arrhythmia or
conduction abnormalities? How does a pathologist diagnose an electrical event, if no recordings were made at the time of, or soon after, collapse? Clearly, this is a diagnosis of exclusion.
Most sudden cardiac deaths, over 75%, are due
to tachyarrhythmias, namely ventricular fibrillation. Less than 25% are due to bradyarrhythmias.
The paradigm for the diagnosis of an arrhythmic
death is that there are structural abnormalities
that predispose to arrhythmias plus a trigger that
initiates the arrhythmias (23). Indeed, triggers
are often difficult to identify and document; they
include physical exertion, emotional stress, fluid/
electrolyte imbalance, hypoxia, and toxins, including pro-arrhythmic drugs.
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CARDIOMEGALY
The structural abnormalities that predispose to
arrhythmias are hypertrophy and/or fibrosis. Fibrosis can result in conduction block and re-entry
arrhythmias (23). The mechanism by which hypertrophy predisposes to arrhythmia is a complex
subject, the discussion of which is beyond the
scope of this paper. However, proposed mechanisms include changes in membrane channels,
ion pumps, cell receptor abnormalities, and other
derangements of the cellular level. Whatever
the cellular event, there is no question that hypertrophy of the heart increases the risk of sudden death. The classical Framingham Study (24)
found that, in men, hypertrophy of any cause
increases the risk of sudden death four fold. Interestingly, in women, hypertrophy only doubles
the risk of sudden death. Other studies (25) have
confirmed the increased risk of fatal arrhythmia
in the presence of cardiac hypertrophy. So finally,
having a big heart in life, despite its positive connotations, is likely problematic. However, to the
autopsy pathologist, the finding of a big heart is
less a problem than a solution. It provides a basis
for determination of the mechanisms of death –
heart failure or arrhythmia – in what may be an
otherwise negative autopsy.
Fishbein & Fishbein • Page 193