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Based upon the Veneto Region study project findings on
juvenile (£35 yrs) sudden death, cardiovascular causes accounted for more than 80%
of the collected
cases and about one third of events were due to a congenital heart defect present since birth15. In
our experience, the most common causes include premature atherosclerosis (16.7%), arrhythmogenic
right ventricular cardiomyopathy (10.8%), mitral valve prolapse (9.7%), conduction system disease
(8.9%) and myocarditis (8.2%)16.
A recent review of major series on sudden cardiac death in the young revealed that myocarditis
accounts for up to 44% of fatal events17. Among these18-26, myocarditis was the most common
cardiac diagnosis associated with sudden death in the article by Topaz and Edwards20, comprising
12 cases (24%), of which 11 were presumed to be viral and one sarcoid. Noteworthy, among the
cases of acute myocarditis was a 9-year-old boy with mumps who died suddenly on the third day
of illness. A major limitation in the autopsy diagnosis of myocarditis in several series has been the
lack of standardized histological criteria.
The strongest evidence that subclinical myocarditis can be a cause of ventricular fibrillation comes
from an autopsy series on USA army recruits in which 42% of those who died suddenly had histological
evidence of myocarditis24. Although myocarditis usually presents with signs of pump failure and
ventricular dilatation, ventricular arrhythmias have been described in patients with myocarditis and
apparently normal heart. A recent flu-like illness is common, although the symptoms may be mild and
clinical signs of heart failure subtle or absent. Cardiac involvement is unpredictable and may affect the
conduction system, causing heart block, or the ordinary myocardium, causing ventricular arrhythmias.
Sometimes the patient suffers previous syncopal episodes and/or palpitations. The electrocardiogram
may show diffuse low voltage, ST-T changes, and often heart block or ventricular arrhythmias. A recent
large-scale study that included 672672 Finnish military conscripts with a mean age of 20 years showed
that the usual presentation of acute myo-carditis in young men mimicks myocardial infarction27. The results of
echocardiography and endomyocardial biopsy are confirmatory.
Sudden death may occur both in the active or healed phases as a consequences of life-threatening
ventricular arrhythmias that develop mostly in the setting of an unstable myocardial substrate, namely
inflammatory infiltrate, interstitial edema, myocardial necrosis and fibrosis. The gross appearance of
the heart is not distinctive and its weight may be within normal values. Histology invariably discloses
either a “starry-like sky” feature (> 14 leucocytes/mm2) or a patchy inflammatory infiltrate, sometimes
no more than 3 foci at magnification 6x, and not necessarily associated with myocyte necrosis. This
subtle substrate, together with the possible inflammatory involvement of the conduction system, seems
highly arrhythmogenic and may account for unexpected arrhythmic cardiac arrest28. The inflammatory
infiltrates is usually polymorphous and less frequently purely lymphocytic. Sudden death due to patchy
giant-cell myocarditis as well as eosinophilic myocarditis in the setting of allergic condition, have also
been reported. Rheumatic carditis is nowadays an exceptional occurrence.
Evidence of myocardial infection, whether bacterial or viral, has been rarely found. Chlamydia
pneumoniae myocarditis was implicated in the sudden deaths of several young Swedish elite orienteers
after RNA from this organism was detected in the heart of one of the victims29. A subsequent paper
implicated this agent in one third of sudden cardiac deaths of the 15 Swedish orienteers who died
unexpectedly between 1979 and 199230. Awareness of the problem and modification of “training
habits and attitudes” have been effective since no further deaths in the following years have been
reported among Sweedish orienteers. Nonetheless, viral infections are the most plausible cause.
Application of gene amplification techniques is particularly useful in detecting viral nucleic acids in
biopsies, especially when characteristic cytopatic changes cannot be observed at light microscopy,
a rather frequent condition in acute fatal forms causing sudden death. Although enterovirus are the
most important causative agent in the pathogenesis of myocarditis, several studies have shown that
various other viruses, such as adenovirus, herpesvirus (cytomegalovirus, herpes simplex virus, Epstein
Barr virus) parvovirus, influenza virus A e B, and hepatitis C virus can be involved in myocardial infective
disease, particularly in the pediatric population11,31. Its frequency is not so rare, especially during
influenza epidemic occurred in 1998-99 which has been characterized by many cases of fatal cardiogenic
shock and sudden unexpected death. As far as the issue of an in vivo diagnosis of myocarditis,
endomyocardial biopsy plays a key role but its interpretation is frequently challenging. First of all, it
is important to keep in mind that lymphocytes can reside in the normal myocardium (normal myocardium
contain less than five lymphocytes/high-power field x400)32. Moreover, endomyocardial biopsy has a low
sensitivity for the detection of myocarditis because it is often focal, so that casual and insufficient number
of samples could produce false negative (sampling error), and is not performed in the acute phase33-35.
Thus, to increase diagnostic sensitivity, use of immunohistochemistry is mandatory to identify and
characterize the inflammatory infiltrate. Immunohistochemical analysis has always to be carried out by
means of CD45 (leucocyte antigen common), CD43 (T-lymphocytes), CD45RO (activated T-lymphocytes),
CD68 (macrophages), CD20 (B-lymphocytes), CD4 (T-helper), CD8 (cytotoxic T-lymphocytes) monoclonal
and policlonal antibodies.
Furthermore, classical morphology rarely identifies the etiological agent. The diagnosis of viral
myocarditis since a long time has been based on viral culture and serology. However, these
investigations are time consuming and generally fall short in specificity and sensitivity. More recently,
molecular biology techniques as PCR and nested-PCR have been shown to rapidly detect the presence
of infective agents, in specific and very sensitive way, also using very small amount of tissue such as
the fragments of endomyocardial biopsies12,13,36. To obtain a specific molecular diagnosis of infective
myocarditis, whole blood or serum is routinary analysed to exclude “blood contamination”. Different
molecular strategies are now used to detect infective status of viruses: in fact it is usually performed
RT-PCR instead of PCR to detect specific mRNA indicative of active viral replication and not only the
presence of a latent viral form. Moreover molecular biology techniques are successfully applied to
better understand the pathogenesis of myocarditis. Although until now only few papers have reported
the evidence of hyper-expression of inflammatory cytokines in endomyocardial biopsies, their detection
seems to be very important, particularly for prognostic and therapeutic implications12.
Studies in laboratory animals with myocarditis have shown a significant increase in mortality with
strenuous physical activity37,38. In particular, exercise during the acute phase of the disease leads
to increased viral replication, more extensive myocyte necrosis, and a worse chance of survival. Phillips
et al29 reported that exertion may have been a precipitating factor in seven of eight myocarditis deaths
in the Air Force recruits. In the Veneto Region experience, myocarditis accounted for 6% of fatalities
among competitive athletes16. The ventricular fibrous repair following inflammatory injury may create
an arrhythmogenic milieu that could be unmasked with exercise39. The
recent Bethesda conference40
on athletes with cardiovascular disorders recommended a convalescence period of 6 months after the
onset of symptoms. Athletic participation depends on the ventricular function as assessed by
echocardiography as well as the absence of clinically significant arrhythmias. The physician who is in
charge of the athlete following recovery from myocarditis should remember that persistence of ventricular
arrhythmia after the resolution of myocarditis has been reported in children and young adults41.
At present, there are no clinical variables available to stratify the risk of sudden death in these patients.
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