Forensic Science International 194 (2010) 1–8

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Forensic Science International

journal homepage: www.elsevier.com/locate/forsciint

Review

Insight into stress-induced cardiomyopathy and sudden cardiac death due

to stress. A forensic cardio-pathologist point of view
Vittorio Fineschi a,*, Manolis Michalodimitrakis b, Stefano D’Errico a,
Margherita Neri a, Cristoforo Pomara a, Irene Riezzo a, Emanuela Turillazzi a
a
Department of Forensic Pathology, University of Foggia, Ospedale Colonnello D’Avanzo, Viale degli Aviatori 1, 71100 Foggia, Italy
b
Department of Forensic Sciences, University of Crete, School of Medicine, 71110 Heraklion, Greece

A R T I C L E I N F O A B S T R A C T

Article history: Emotional, physiological and physical stress is associated with increased rates of cerebrovascular events
Received 25 April 2009 and sudden deaths. The pathophysiology of stress-induced cardiomyopathy is not well understood.
Received in revised form 25 September 2009 Proposed mechanisms for catecholamine-mediated stunning in stress cardiomyopathy include
Accepted 20 October 2009
epicardial vasospasm, microvascular dysfunction, hyperdynamic contractility with midventricular or
Available online 24 November 2009
outflow tract obstruction, and direct effects of catecholamines on cardiomyocytes. Studies show
evidence of significant heritable influences on individual responses to adrenergic stimulation. Data from
Keywords:
such studies may be of help for a more accurate comprehension of clinical and morphological alterations
Stress-induced cardiomyopathy
Catecholamine systems
of the heart. Irrespective of the cause, patients with the classic stress-induced cardiomyopathy
Contraction band necrosis morphology deserve special attention because this extensive distribution of wall motion abnormalities
Sudden death has implications for potential associated complications. Cardiac response may be significantly coupled to
genetic differences at candidate loci that encode components of catecholamine biosynthesis, storage,
and metabolic pathway. Given the role of the sympathetic nervous system in responses to acute stress, it
is reasonable to explore whether genetically determined alterations in catecholamine system functions
contribute to acute and chronic cardiovascular disorders such as stress-induced cardiomyopathy.
ß 2009 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Stress-induced cardiomyopathy: a pathologic characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Stress-induced cardiomyopathy: a clinical characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. Stress-induced cardiomyopathy: a forensic characterization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. Mortality . . . . . . . . . . . . . . . . . . . . ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
6. Pathophysiology. . . . . . . . . . . . . . . ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
7. Pathomorphology. . . . . . . . . . . . . . ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
8. Conclusion . . . . . . . . . . . . . . . . . . . ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
References . . . . . . . . . . . . . . . . . . . ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1. Introduction infinite stimuli from the environment with an intense psycholo-

The risk of stress causing sudden death is controversial.
Growing evidence suggests a major role of the brain, particularly
during stress and in the presence of cerebral lesions in certain
locations [1]. In permanently stressful conditions, exacerbated by
* Corresponding author. Tel.: +39 0881 733195; fax: +39 0881 736903.
E-mail address: vfinesc@tin.it (V. Fineschi).
gical response (e.g., earthquake survivors, mobbing), adrenergic
stimulation, particularly in susceptible individuals, may become a
damaging element. This is a fact apparently proven by the
effectiveness of beta-blocker therapy; by a higher frequency of
sudden death with a heart rate of 65 beats/min; by the
deleterious effects of cigarette smoking which increases sympa-
thetic outflow; by adrenergic system stimulation by exogenous
substances (e.g., cocaine) and by its role in coronary heart disease
and congestive heart failure; by effects shown in brain injury and

0379-0738/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.forsciint.2009.10.025
2 V. Fineschi et al. / Forensic Science International 194 (2010) 1–8
in many other conditions; by different alpha and beta receptors
increase in hypo-akinetic segments with respect to normal ones
[2]. The adrenergic system provides an alarm mechanism that
alerts the body to react quickly to any acute emergency. The
question is whether intense emotion, per se, is sufficient to alter
neurovegetative control or whether it needs to be associated with a
morpho-functional derangement as described for coronary cardio-
pathy, which, in turn, may also be an expression of repetitive
adrenergic stimulation. The relationship between the heart and the
brain is complex and integral in the maintenance of normal
cardiovascular function. Certain pathological conditions can
interfere with the normal brain–heart regulatory mechanisms
and result in impaired cardiovascular function [3]. Neurocardiol-
ogy has many dimensions, but it may be conceptualized as divided
into three major categories:
(1) the heart’s effects on the brain (e.g., cardiac source of embolic
stroke),
(2) the brain’s effects on the heart (e.g., neurogenic heart disease)
and
(3) neurocardiac syndromes (e.g., Friedreich disease) [4].
All of our morpho-functional data indicate that the sympathetic
nervous system may have an important role in explaining the
pathogenesis of several cardiovascular conditions [5]. We need to
understand the link between psychological factors, acting in
‘‘ischemic’’ patterns and heart/brain interaction. An impaired
balance of the vegetative nervous system may explain cardiac
arrest and coronary-like syndromes. There is powerful evidence to
suggest that overactivity of the sympathetic limb of the autonomic
nervous system is the common phenomenon that links the major
cardiac pathologies seen in neurological catastrophes [4]. A
generalized autonomic storm, which occurs as a result of a life-
threatening stressor, will have both sympathetic and parasympa-
thetic effects. Cerebral hemispheral dominance with regard to
autonomic control (right predominantly sympathetic and left
predominantly parasympathetic) probably also contributes to the
dominant mechanism of sudden death (e.g., sympathetic versus
vagal) in a given person [4].
The purpose of this article is to provide an up-to-date review of
the stress-induced sudden death and cardiomyopathy, to discuss
possible causal mechanisms and to highlight the similarities and
differences between them.
2. Stress-induced cardiomyopathy: a pathologic
characterization
The expert consensus panel [6] proposes this definition:
‘‘cardiomyopathies are a heterogeneous group of diseases of the
Table 1
Primary cardiomyopathies can be most effectively classified as primary: genetic, mixed (genetic and non-genetic), acquired from [6].
Genetic Mixed
HCM DCM
ARVC/D Restrictive (non-hypertrophied and non-dilated)
LVNC
Glycogen storage PRKAG2; Danon
Conduction defects
Mithocondrial myopathies
Ion channel disorders LQTS; Brugada
SQTS
CVPT
Asian SUNDS
Hypertrophic cardiomyopathy, HCM; catecholaminergic polymorphic ventricular tachycardia, CVPT; LV non-compaction, LVNC; long QT syndrome, LQTS; short-QT
syndrome, SQTS; dilated cardiomyopathy, DCM; sudden unexplained nocturnal death syndrome (in young Southeast Asian males), SUNDS.
myocardium associated with mechanical and/or electrical dysfunction
that usually (but not invariably) exhibit inappropriate ventricular
hypertrophy or dilatation and are due to a variety of causes that
frequently are genetic. Cardiomyopathies either are confined to the
heart or are part of generalized systemic disorders, often leading to
cardiovascular death or progressive heart failure-related disability’’.
Cardiomyopathies are divided into two major groups based on
predominant organ involvement. Primary cardiomyopathies
(genetic, non-genetic, acquired) are those solely or predominantly
confined to the heart muscle and are relatively few in number.
Secondary cardiomyopathies show pathological myocardial invol-
vement as part of a large number and variety of generalized
systemic (multiorgan) disorders. Therefore, on the basis of all these
considerations, the panel recommends that cardiomyopathies can
be most effectively classified as primary: genetic, mixed (genetic
and non-genetic), acquired, and secondary (Table 1) [6]. The
expert consensus panel proposes this definition about stress
cardiomyopathy: ‘‘. . .is a recently described clinical entity character-
ized by acute but rapidly reversible LV systolic dysfunction in the
absence of atherosclerotic coronary artery disease, triggered by
profound psychological stress. This distinctive form of ventricular
stunning typically affects older women and preferentially involves the
distal portion of the LV chamber (‘‘apical ballooning’’), with the basal
LV hypercontractile. Although presentation often mimics ST-segment–
elevation myocardial infarction, outcome is favorable with appro-
priate medical therapy’’ [6].
The stress-induced cardiomyopathy appear similar in that they
seemingly occur during times of enhanced sympathetic tone and
may be precipitated in part or entirely by excessive endogenous or
exogenous catecholamine stimulation of the myocardium.
Although significant clinical overlap exists in those presenting
with stress-associated cardiomyopathy, it is unclear whether
myocardial adrenergic hyperstimulation is the only pathophysio-
logical mechanism responsible for these syndromes.
3. Stress-induced cardiomyopathy: a clinical characterization
Stress-induced cardiomyopathy, also called transient left ven-
tricular (LV) apical ballooning syndrome, broken heart syndrome,
ampulla cardiomyopathy and, in Japan, takotsubo cardiomyopathy
(TC), is an increasingly reported syndrome characterized by
transient apical or midventricular left ventricular dysfunction that
mimics myocardial infarction (MI), but in the absence of significant
coronary artery disease [7,8]. Because of the pathophysiological
significance of stress hormones in this disorder, the term ‘‘stress-
induced cardiomyopathy’’ (SICM) appears to be the most accurate
[9]. The onset of SICM is typically triggered by an acute medical
illness or by intense emotional or physical stress (e.g., death of
relatives, particularly if unexpected, domestic abuse, arguments,
Acquired
Inflammatory (myocarditis)
Stress-provoked
Peripartum
Tachycardia-induced
Infants of insulin-dependent diabetic mothers
 V. Fineschi et al. / Forensic Science International 194 (2010) 1–8 3

Table 2 exists on the risk of recurrence after a patient experiences an

Precipitants of stress cardiomyopathy.
Acute emotional stress
Acute intracranial events
Intracranial bleeding (SAH, ICH)
Head trauma
Ischemic stroke
Acute medical illness including sepsis
Surgical procedures
Administration of exogenous cathecolamnergic agents (inhaled b-agonist,
methylxanthines, epinephrine/amphetamines, cocaine)
SAH: subarachnoid haemorrhage; ICH: intracranial haemorrhage.
catastrophic medical diagnoses, devastating financial or gambling
losses, natural disasters) [10] (Table 2).
The incidence and prevalence of SICM is uncertain. Some of the
best available estimates come from four small series of consecutive
patients presenting with a suspected acute coronary syndrome
(ACS), which were included in a larger systematic review [10].
Thus, a conservative estimate of the annual rate of SICM in the
United States may be 7000–14,000 cases [11]. A paucity of data
episode of SICM. Most published data suggest that the recurrence
rate in the first few years after presentation with SICM is likely in
the range of 2–10% [3].
SICM clinically presents like an acute myocardial infarction but is
characterized by a specific group of findings. SICM syndrome
includes a sudden onset of chest pain, EKG changes consistent with
myocardial ischemia and/or infarction, acute left ventricular systolic
dysfunction evident on echocardiography as apical ballooning,
and normal coronary arteries [12]. The Mayo Clinic criteria, which
can be applied at the time of presentation, have been proposed
for the clinical diagnosis of SICM. All four criteria must be present.
Table 3 illustrates a modified version of the criteria. In the current
version, the classification no longer excludes patients who develop
typical ballooning in the setting of intracranial bleeding, including
those with subarachnoid haemorrhage (SAH). Neurogenic stunning
in this situation has the same features as takotsubo cardiomyopathy
and is likely a manifestation of the same spectrum of disease.
The absence of obstructive coronary artery disease and the
characteristic regional wall motion abnormality are likely to lead
to the diagnosis [11]. Table 4 summarizes the clinical presentation of
patients with this syndrome.

Table 3
Proposed Mayo Clinic criteria for SICM.
1. Transient hypokinesis, akinesis, or dyskinesis of the left ventricular mild segments with or without apical involvement; the regional wall motion
abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always presenta.

2. Absence of obstructive coronary disease or angiographic evidence of acute plaque ruptureb.

3. New electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin.

4. Absence of:
Pheochromocytoma
Myocarditis

In both of the above circumstances, the diagnosis of SICM should be made with caution, and a clear stressful precipitating trigger must be sought.
a
There are rare exceptions to these criteria such as those patients in whom the regional wall motion abnormality is limited to a single coronary territory.
b
It is possible that a patient with obstructive coronary atherosclerosis may also develop SICM. However, this is very rare in the published literature, perhaps because such
cases are misdiagnosed as an acute coronary syndrome.

Table 4
Clinical presentation of stress cardiomyopathy.

Diagnostic tool Findings

Current symptom Sudden onset of chest pain/pressure.

Dyspnoea has been reported as the initial symptom.
Syncope has been the presenting symptom in isolated cases.

Onset Most frequently precipitated by acute emotional stress or a period of increased physical activity.

Medical history No pattern of patient or family history of takotsubo cardiomyopathy.

Patient history may include hypertension, hyperlipidemia, and/or trial arrhythmias.

Electrocardiography New transient ST-segment elevation or T-wave inversion.

There may be a high ratio of S-T elevation in leads V4–6 compared with V1–3.
Abnormal Q-wave formation in some patients, may be transient.
Subsequent negative T-wave inversion.
Prolonged QTc interval.
Rarely associated with malignant ventricular arrhythmias.

Echocardiography Reversible LV apical ballooning

Transient akinesis or dyskinesis of the LV apical and midventricular segments with regional wall motion abnormalities
extending beyond a single epicardial vascular distribution.*
Basal normokinesia.

Cardiac catheterization Normal coronary arteries or non-obstructive coronary disease, no evidence of acute plaque rupture.*
Minimal disturbance of microcirculation.
Low ejection fraction.
Minimal evidence of vasospasm.

Biomarkers Creatine kinase and/or cardiac troponin I have a small, rapid increase to above normal levels.
BNP levels may be elevated.
Plasma catecholamines may be elevated.

LV, left ventricular; QTc, corrected QT; BNP, brain natriuretic peptide. Proposed Mayo Criteria* for the clinical diagnosis of the transient left ventricular apical ballooning
syndrome.
4 V. Fineschi et al. / Forensic Science International 194 (2010) 1–8

4. Stress-induced cardiomyopathy: a forensic characterization 5. Mortality

Courts are interested in whether stress ‘‘caused’’ or ‘‘con-
tributed to’’ the development of a pathological condition [13].
Although many of these cases are due to known causes, such as
atherosclerosis and myocardial infarction, some cases will not
have clear findings at necropsy. Unexplained sudden death
with an unremarkable autopsy is not rare, and the coroner or
pathologist should consider genetically associated causes of
disease. Given the multiply determined nature of cardiovascular
disease, it is clear that psychological stressors contribute to
cardiovascular disease, but ‘‘how much?’’ Could a stressful
stimulus be reasonably expected to elicit a fatal arrhythmia
in the ‘‘average’’ patient with arrhythmias? [14]. Can one
assign blame/causation/contribution when the stressor was
relatively mild but the patient was singularly vulnerable (e.g.,
patients with long QT or Brugada Syndromes)? [13]. The past
decade has witnessed a rapid evolution of molecular genetics in
cardiology and the emergence of ion channelopathies as
diseases predisposing to potentially lethal ventricular tachyar-
rhythmias that are characterized by mutations in ion channel
proteins leading to dysfunctional sodium, potassium, calcium,
and other ion channels [6]. Nonetheless, we must keep in mind
the clinical consequences that stress has in actually triggering
an overt acute coronary syndrome (ACS). There are multiple
excellent articles that lend credence to the high likelihood that
stress leads to metabolic derangements that, in turn, serve as
possible trigger(s) for an ACS [15]. This is another important task
of SICM.
The overall prognosis for SICM is good without any form of
treatment, provided the patient survives the severe heart failure
period. Indeed, the reversibility of left ventricular dysfunction is a
hallmark of the syndrome. However, mortality rates range from 0%
to 8% [16]. Left-sided heart failure with and without pulmonary
oedema is the most frequently reported complication. Infre-
quently, cardiogenic shock, ventricular arrhythmias, left ventri-
cular mural thrombus, mitral valve dysfunction pulmonary
embolism, and left ventricular rupture have been reported [12].
In-hospital mortality rates have ranged from 0% to 8%, and
mortality was 1% in the largest series of 88 patients in Japan.
Patients who survive the acute episode typically recover normal
ventricular function within 1–4 weeks. Late sudden death and
recurrent disease have occurred in occasional patients (Fig. 1) [10].
6. Pathophysiology
The pathophysiology of SICM is not well understood. Proposed
mechanisms for catecholamine-mediated stunning in stress cardi-
omyopathy include epicardial vasospasm, microvascular dysfunc-
tion, hyperdynamic contractility with midventricular or outflow
tract obstruction, and direct effects of catecholamines on cardio-
myocytes [7]. Rather than ischemia, we believe that the prime cause
is a molecular/ion disorder of a small or large focus of myocardial
cells triggered by the autonomic nervous control, particularly by the
adrenergic system. In this respect a distinction must be made
between blood-borne catecholamines and catecholamines released

Fig. 1. Fatal case of a 50 years old woman with stress cardiomyopathy mobbing-related. We studied the clinical presentation with typical end-systolic (A) frames (typical
takotsubo feature indicated by the arrow) from a left ventriculogram in a woman who presented with chest pain and diffused ST-segment elevation on electrocardiogram,
non-obstructive coronary disease and no evidence of acute plaque rupture at cardiac catheterization (B-D).
 V. Fineschi et al. / Forensic Science International 194 (2010) 1–8
within the myocardium, because it has been hypothesized that
stunning is the result of epinephrine-mediated effects on cardio-
myocytes [10]. Sympathetic stimulation of adrenoceptors in the
ventricular myocardium is achieved through local release of
norepinephrine (NE) by sympathetic nerve terminals directly
innervating the myocardium (most important quantity) and by
diffusion of circulating catecholamines into the myocardium from
the coronary circulation (the smallest contribution). At physiological
and elevated concentrations, norepinephrine released from the
sympathetic nerves acts predominantly via the b1-adrenoceptors
(b1ARs) on ventricular cardiomyocytes, exerting positive inotropic
and lusitropic responses [17]. At higher ‘supraphysiological’
concentrations, epinephrine stimulates a negative inotropic effect
on myocyte contraction [17]. Plasma catecholamine and neuropep-
tide levels in patients with SCM induced by acute emotional stress
are markedly elevated compared with patients with myocardial
infarction [18]. Considering that circulating catecholamines have a
global effect on the myocardium, the magnitude of the effect will
depend on the local density of adrenoceptors in different regions
of the myocardium [19]. In normal human hearts, the basal portion
of the human left ventricle possesses the highest concentration of
sympathetic nerve endings [18].
Also, in the acute phase of SICM a role is played by the presence
of reactive oxygen species (ROS) [20,21]. These ROS, when
stimulated for example by catecholamines or ischemia, have the
potential to injure vascular cells and cardiac myocytes directly and
can initiate a series of local chemical reactions and genetic
alterations which ultimately result in an amplification of the initial
ROS-mediated cardiomyocytes’ dysfunction and/or cytotoxicity.
Exposure of normal myocardium to ROS-generating systems alters
myocardial function through persistent cellular loss of K+,
depletion of high-energy phosphates, elevated intracellular
calcium concentration, loss of systolic force development, pro-
gressive diastolic tension, and depressed metabolic function
[20,21]. Catecholamines may induce oxidative damage through
reactive intermediates resulting from their auto-oxidation, irre-
spective of their interaction with adrenergic receptors, thus
representing an important factor in the pathogenesis of catecho-
lamines induced cardiotoxicity [22]. In a previous paper we have
described the effect of ROS on the catecholamine-mediated
myocardial expressions of TNF-a (tumor necrosis factor-alpha),
MCP-1 (monocyte chemotactic protein-1), interleukins IL6, IL8,
IL10 and a significant apoptotic process randomly sparse in the
damaged myocardium [21]. The rise of the cardioinhibitory
cytokines may be interpreted as the adaptive response of
jeopardized myocardium with respect to the cardiac dysfunction
resulting from catecholamines effects [7]. Again, it has been
hypothesized that norepinephrine-mediated coronary vasospasm
could impose a secondary ischemic insult, superimposed on the
primary epinephrine-induced apical stunning [17] (Fig. 2).
7. Pathomorphology
We must consider two aspects of adrenergic stress in cardiac
disease, one that produces structural changes (including both
nerve and myocardial pathomorphology) and another involving
ionic and morphologically invisible molecular fluxes. Of the
patients who underwent endomyocardial biopsy, interstitial
infiltrates consisting primarily of mononuclear lymphocytes and
macrophages and contraction bands without myocyte necrosis
were observed. Extensive inflammatory lymphocytic infiltrate and
multiple foci of contraction band myocyte necrosis are described
too [23]. A more precise histological documentation is needed for
all cases with different kind of behavior who suddenly died
following emotional distress. ‘‘Myofibrillar degeneration’’ has been
observed in victims of assaults who had no internal injuries, and
5
Fig. 2. Catecholamines induced cardiotoxicity: coronary vasospasm could impose a
secondary ischemic insult, superimposed on the primary epinephrine-induced
apical stunning and myocyte injury.
particularly in coronary heart disease patients in whom help-
lessness or hopelessness were the basic feelings. For reasons given
above, myocardial contraction band necrosis (CBN), no matter
which of its many synonyms one cares to use, is the pathogno-
monic lesion of myocardial catecholamine damage linked with
peroxidation. The first histologic change, visible within 10 min of
onset, is an intense hypereosinophilia of the hypercontracted
myocardial cells with rhexis of the myofibrillar apparatus into
cross-fiber, anomalous, and irregular or pathological bands. The
latter are formed by segments of hypercontracted sarcomeres with
scalloped sarcolemma. Normal cells around hypercontracted ones
assume a wavy appearance. The spaces between bands are filled by
mitochondria. No evidence of platelet aggregation or other vessel
changes or of interstitial or sarcolemmal alterations exists. This
necrosis is, in general, plurifocal, formed by foci ranging from one
to thousands of myocardial cells and is found in any cardiac region.
Two patterns of this lesion can be recognized. One corresponds to
fragmentation of the whole myocell (pancellular lesion), which
ranges from early breakdown in pathological bands to a total
granular disruption (myofibrillar degeneration) (Fig. 3A and B).
This myocardial cell destruction is likely due to the action of the
contracting myocardium on these rigid elements in tetany. Repair
of the pancellular lesion is by macrophagic digestion of all
structures within the sarcolemmal tubes (alveolar pattern)
followed by a progressive collagenization. The second pattern,
associated with the previous one, is characterized by a unique band
of 10–20 hypercontracted sarcomeres close to the intercalated disc
(paradiscal lesion) (Fig. 3C and D). This band does not show rhexis of
myofibrils and may assume a dark, dense, ultrastructural aspect or
a pale, clear one, with very thin Z-lines and myofibrils, and
mitochondria ‘‘squeezed’’ in the normal portion of the myocyte.
The paradiscal lesion does not show any macrophagic infiltrates.
Two possibilities may explain this. Either the paradiscal lesion
transforms in the pancellular one, or if it is a reversible change, the
pale aspect represents a rebuilding of new sarcomeres because the
major portion of the cell is normal and maintains a normal function
without myofibrillar rhexis at the hypercontracted band level. The
concept that CBN is a result of direct catecholamine toxicity, is
based on experimental catecholamine infusion. The lesion is
visible within 5–10 min of perfusion in the presence of normal
vessels and unrelated to ischemia. Its presence in acute coronary
syndromes is probably due to catecholamines released within the
myocardium as a reflex response to regional asynergy of the
infarcted or preinfarcted zone, a hypothesis that is supported by
6 V. Fineschi et al. / Forensic Science International 194 (2010) 1–8

Fig. 3. (A and B) Sudden death due to acute mental stress in a 48 years old man: hypercontraction of the myocell with a breakdown of the whole contractile apparatus with
markedly thickened Z-lines and extremely short sarcomeres (H&E, 40). CBN ranges from foci formed by one or a few myocells to large zones of myocardium in the absence of
interstitial/intermyocellular haemorrhage (H&E, 60). (C) Paradiscal lesion: it is formed by a unique band of hypercontraction involving 10–15 sarcomeres adjacent to an
intercalated disc. The dense band can be seen histologically (Azan modified, 100). (D) A hypercontracted center induces the waviness of normal adjacent myocells seen by
electron micrography.

the abolishment of contraction bands and ventricular fibrillation
with beta-blocking agents in experimental myocardial infarction
and in reperfusion necrosis. They may trigger a catecholamine
myotoxicity linked with ventricular fibrillation and acting through
free radical mediated lipid peroxidation with intramyocellular
Ca2+ influx. Contrary to the general opinion that excess catecho-
lamines produce cardiotoxicity mainly through binding to
adrenoceptors, there is increasing evidence that catecholamine-
induced deleterious actions may also occur through oxidative
mechanisms. Recent studies have shown that oxidation of
catecholamines results in the formation of highly toxic substances
such as aminochromes (e.g., adrenochrome) and free radicals and
by virtue of the latter’s actions on different types of heart
membranes, they cause intracellular Ca2+ overload and myocardial
cell damage [24]. No systematic, quantitative studies of CBN in
human and experimental pathology were done until we quantified
this lesion in terms of number of foci and necrotic myo-
cells  100 mm2 [24,25]. Beyond a histological threshold of
37  7 foci and 322  99 myocells/100 mm2, the lesion may indicate
sympathetic overdrive in the natural history of a disease and
associated arrhythmogenic supersensitivity. The threshold for a
diagnosis of adrenergic overactivity seems to be an extent of CBN
beyond the quantified range, particularly when associated with the
coexistence of different morphological stages of the lesion [26].
Pathologists need to quantify all morphologic findings in cases of
SICM related death to establish both their significance and the real
meaning of adrenergic stress in cardiac diseases. We emphasize that
cardiopulmonary resuscitation per se – including norepinephrine
infusion, electrical defibrillation, etc. – did not seem responsible for
catecholamine damage in the cases we studied, at least when the
latter had the ‘‘threshold’’ previously reported. Higher value and the
presence of different stages of the lesion seem an acceptable post-
mortem indicator of adrenergic stress repeated over time. It remains
to be established whether the source of catecholamines is blood-
borne or intramyocardial in the different pathological conditions. In
experimental catecholamine intravenous infusion and in trans-
planted denervated hearts as well as in any similar conditions, e.g.,
pheochromocytoma, the lesion distribution was similar in both
cardiac ventricles. This suggests a blood-borne origin for the
damaging catecholamines. In particular, the transplanted heart
shows an early depletion of intramyocardial catecholamine with
possible up-regulation of b-1 and down-regulation of b-2 adrenor-
eceptors and supersensitivity to blood-borne catecholamines. In
other patterns the adrenergic damage is mainly located in the left
ventricle suggesting a prevalent intramyocardial release and reduced
uptake of catecholamines via brain stimuli, or mechanoreceptor
stimulation by local myocardial asynergy, or media neuritis at the
atherosclerotic plaque level or other still unknown mechanisms. The
increasing evidence of a sympathetic denervation in experimental
and human coronary and non-coronary conditions suggests that
arrhythmogenic sympathetic supersensitivity may depend on a local
release of catecholamines by adjacent non-denervated tissue with a
possible hyperinnervation [17,20].
Other morphological changes might be included amongst
chronic adrenergic-related effects and deserve further investigation.
One is myocardial disarray and its linkage with catecholamine
 V. Fineschi et al. / Forensic Science International 194 (2010) 1–8
Fig. 4. (A) Typical aspects of myocardial disarray with interstitial fibrosis in a 49 years old woman suffering major head trauma who died after 3 months (60). Endocardial
myoelastofibrosis; (B) moderate fibrosis mainly interstitial (20). (C and D) The majority of endocardial thickening is due to the formation of smooth muscle cell bundles with
hyperelastosis ending in fibrous replacement (Van Gieson, 40).
disorders [27]. This linkage is supported by several experiments
showing a catecholamine increase following administration of nerve
growth factors and of triac (acetic analogue of tri-iodothyronin) in
pregnant rats with disarray in fetuses and prevention of its effect by
beta-blocking, or subhypertensive doses of norepinephrine; the
cardiac directed overexpression of human b1-adrenergic receptors
in transgenic mice leading to myofibrillar disarray, marked cardiac
hypertrophy and interstitial myocardial fibrosis plus cardiac
dysfunction and sudden death in older animals. In our experience
‘‘pathologic’’ (i.e., 20% of the histological area) disarray was
observed in conditions where adrenergic stress is admitted [27].
Furthermore, it is known that catecholamines regulate myocardial
protein synthesis with an impact on growth and hypertrophy by
stimulation of a- and b-adrenoceptors [20].
The other structural change is endocardial myoelastofibrosis. In
contrast to the current opinion that endocardial thickening is
secondary to the healing of mural thrombosis, we showed that the
latter is a relatively rare event and that endocardial thickening is
the end result of a process which starts as nodular smooth muscle
cell hyperplasia followed by elastic fiber proliferation and fibrosis
[28]. This is a process which mirrors the earliest stages of the
atherosclerotic plaque. Can this change, which occurs in different
conditions, be related to adrenergic stress? Further studies are
needed to explain this hypothesis (Fig. 4).
8. Conclusion
The time for a reassessment of cause of death in SICM cases
should be a collaborative clinical–pathological effort, to under-
stand where the truth lies. A sudden cardiac arrest must have an
7
acute etiopathogenetic mechanism and the forensic pathologist
should seek acute morphological changes. Histological documen-
tation is needed in patients of different behavioral types who died
suddenly after emotional stress. We hypothesize that SICM is a
catecholamines-mediated form of myocardial stunning due to
adrenergic stress, different to those caused by transient episodes of
ischemia secondary to coronary stenosis. The concept of adrener-
gic stress is based on several facts. Whereas neural control of the
human heart remains incompletely characterized, it is likely that
the morphological patterns seen with SCM result from the complex
interplay between sympathetic innervation, beta-receptor density
and function, and catecholamine sensitivity [18]. It has been
hypothesized that high levels of circulating epinephrine trigger a
switch in intracellular signal trafficking, this change is negatively
inotropic and the effect is greatest at the apical myocardium, in
which the density of b-adrenoceptors is highest [17]. In our
previously experimental study, NE increased Kd (dissociation
constant) and myocardial b1-adrenoceptor density 1 and 4 h after
treatment [21]. A recent study demonstrates a significant
contribution of oxidative stress to the pathophysiological mechan-
ism of SICM, which is possibly triggered by catecholamine excess
[20]. Plasma catecholamines correlate with the severity of the left
ventricular dysfunction [21].
In conclusion, SICM can occur after acute mental or physical
stress, SAH, ischemic stroke, major head trauma, acute medical
illness and as a result of exogenous substance administration
having catecholamine-like effects (e.g., cocaine, ecstasy, etc.)
(Table 5). The common histological finding of contraction band
necrosis in patients with stress-induced cardiomyopathy suggests
a common catecholamine-mediated mechanism. The relative
8 V. Fineschi et al. / Forensic Science International 194 (2010) 1–8
Table 5
Pathophysiology of neurogenic heart damage.
Structural brain damage
Intensive emotional stress
# [12] Z.R. Brenner, J. Powers, Takotsubo cardiomyopathy, Heart Lung 37 (2008) 1–7.
Autonomic output from the CNS
# 51 (2008) 1237–1246.
Local catecholamine excess
# (2007) 324–329.
Cardiac receptor mediated calcium channel activation
# disease with emphasis on acute coronary syndromes, J. Am. Coll. Cardiol. 53
Free radical release
Increased cytosolic and intra-mitochondrial calcium
Peroxidation of lipid membranes
#
ECG changes, lethal arrhythmias, wall motion disorders, contraction band
necrosis seen in cardiac samples
contribution of other pathophysiological mechanisms such as
ischemia remains to be established. Takotsubo cardiomyopathy, a
distinct morphological manifestation of stress cardiomyopathy, is
characterized by transient systolic dysfunction of the apical and/or
midventricular myocardial segments in the absence of obstructive
CAD (coronary artery disease) and is unique in that it can manifest
after acute emotional stress. Given the role of the sympathetic
nervous system in responses to acute stress, it is reasonable to
explore whether genetically determined alterations in catechola-
mine system functions contribute to acute and chronic cardiovas-
cular disorders such as SICM. It is to be hoped that studies will
spur further research on genotype–phenotype linkages based on
catecholamine systems [29]. Studies show evidence of significant
heritable influences on individual responses to adrenergic stimula-
tion [30]. Cardiac response may be significantly coupled to genetic
differences at candidate loci that encode components of the
catecholamine biosynthesis, storage, and metabolic pathway. The
large interindividual differences may reflect variable responses to
sympathetic activity, it may be accounted for by genetic inheritance,
and it may play a role in the development of SICM [31]. This is a still
relatively unknown field worth investigation to understand SICM,
malignant arrhythmias and related cardiac arrest [32,33].
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