Sudden cardiac death of a 16-year-old boy with Wolff-Parkinson-White syndrome and hypertrophic cardiomyopathy

In Europe, 350,000 people die suddenly and unexpectedly every year. The majority of sudden deaths are caused by cardiac alterations and known as sudden cardiac death (SCD). The interpretation of medicolegal findings is especially difficult in those SCDs where there is no morphological correlate and no antemortem electrocardiograms or relevant medical history are available. The Wolff-Parkinson-White (WPW) syndrome, in which an accessory electrical conduction pathway exists between the atrium and the ventricle in addition to the physiological conduction system, is mostly a benign disease of the heart, which may lead to cardiac arrhythmia. A 16-year-old boy with a known history of WPW syndrome since the second year of life had consumed alcohol before death and was found sitting on the toilet fully dressed. The autopsy performed on the deceased 3 days postmortem showed a marked mass increase of the heart with left ventricular concentric hypertrophy and macroscopic signs of cardiomyopathy. In the microscopic examination, the right and left ventricles and the atria were found to have a regular structure with normal vessels. Hematoxylin-eosin (HE) and elastica-van-Gieson (EvG) staining disclosed a thin accessory muscle bridge connecting the left atrium with the left ventricle as a possible morphological correlate of a fatal cardiac arrhythmia.


Introduction
In Europe 350,000 people die suddenly and unexpectedly every year.The majority of sudden deaths are caused by cardiac alterations and known as sudden cardiac death [1].Coronary heart disease is the dominant cause of sudden cardiac death in 65-90% of cases.Independent of age, there are two groups of causes: coronary, e.g., coronary arteriosclerosis or coronary malformations, and non-coronary cardiac deaths, e.g., cardiomyopathies or valvular defects [2].
Non-ischemic cardiomyopathies (dilated, hypertrophic) are more frequently diagnosed in young athletes (10-23% of acute heart failure).Rhythm disturbances including arrhythmogenic right ventricular cardiomyopathy or Wolff-Parkinson-White (WPW) syndrome are rare and account for 0.5-5% of cases with acute heart failure [3,4].The WPW syndrome was first described in 1930 [5].It is characterized by the presence of an additional electrically conductive heart muscle pathway to the regular conduction system that connects atrium and ventricle.This accessory atrioventricular pathway causes preexcitation of the ventricular myocardium in sinus rhythm.The electrographic correlate of this mechanism is a shortened PQ interval and the so-called delta wave at the beginning of the QRS complex [6,7].The WPW syndrome may become symptomatic at any age with about half of the patients experiencing the first episode of tachycardia before the age of 20 years.A male dominance with a ratio of 2:1 has been described [8].
Diagnostic problems occur in cases without a morphological correlate of abnormal conducting fibers and no relevant medical history.In this case, the cause of death is assumed to be a functional one.Usually not only comprehensive toxicological and microbiological tests, but also histological analyses are performed in such cases systematically examining the conduction system of the heart in order to detect, e.g., whether there are any additional conduction pathways called accessory pathways [9][10][11].Previously, mutations undisclosed by molecular autopsy were considered to have a functional relevance in cardiac arrhythmia, and to partly explain the pathophysiology of these deaths [12,13]; however, not all functional events with a fatal outcome are based on genetic mutations [14].
The case reported in this article deals with the sudden death of a young boy with a history of WPW syndrome.

History
A 16-year-old boy was found dead by his brother around midnight, sitting completely dressed on the toilet.The brother started resuscitation and called an emergency doctor, who tried in vain to resuscitate the youth for 20min.
In the evening, the deceased had first gone to his girlfriend, where he had had two "Radler" (beer lemonade mix) drinks.Then he went to his brother's apartment and drank vodka.In the apartment of the brother, marijuana and amphetamine had been found.With respect to pre-existing diseases, the young man was known to have suffered from WPW syndrome since his second year of life.Moreover, hehad experienced occasional syncopes after physical exercise.

Autopsy and further investigations
A forensic autopsy was performed on the deceased 3 days postmortem at the Institute of Legal Medicine of the University of Wuerzburg, Germany.The body height was 168 cm and body weight 58 kg.The heart showed a marked mass increase (405 g) with left ventricular concentric hypertrophy (ventricular wall thickness 1.8 cm on the left, 0.5 cm on the right) and macroscopic signs of cardiomyopathy.On the cut surface, the myocardium showed a homogeneous pale brown color and discreet patchy imbibition with blood only in the region of the posterior wall (status following resuscitation).The coronary vessels and the valves were macroscopically unremarkable.The other parts of the body did not show any signs of congenital anomalies.The internal organs, particularly the liver (1590 g) and the spleen (270 g), were strongly congested with blood.The brain (1520 g) showed marked swelling with a cerebellar pressure cone.No tongue bite was discernible.
With a known history of WPW syndrome, large tissue sections of the heart were obtained and fixed in 4% formalin for microscopic examination at the Institute of Pathology of the Chemnitz Medical Center.The right and left ventricles and also the atria were found to have a regular structure with normal vessels.Hematoxylin-eosin (HE) and Elastica-van-Gieson (EvG), a connective tissue stain, disclosed a thin accessory muscle bridge connecting the left atrium with the left ventricle (see .Fig. 1a, b).
Chemical and toxicological testing did not produce any clues to an intoxication.The blood alcohol content was 1.19 g/kg (g alcohol/kg blood).The relatives refused genetic analysis.
Altogether, death seemed to have been caused by acute heart failure in the presence of an already damaged heart (WPW syndrome and hypertrophic cardiomyopathy) and the influence of alcohol.

Discussion
The most common arrhythmia in WPW patients is atrioventricular re-entry tachycardia, which occurs in 80% of cases.Ventricular fibrillation is the most common cause of sudden death in WPW patients [15].It is difficult to diagnose the pathogenesis of fatal arrhythmia at autopsy when no antemortem electrocardiograms are available.For establishing the cause of death other causes must be excluded and the history of electrocardiographic abnormalities is essential [14].
Additional pathological changes of the heart, such as a ventricular septum defect or malformation of the tricuspid valve, which is known as Ebstein anomaly [16], could be associated with WPW syndrome.A study by MacRae et al. demonstrated the mutation to a locus on chromosome 7q3, which causes WPW syndrome and familial hypertrophic cardiomyopathy (FHC) [17].These genetic data confirm earlier hypotheses that WPW syndrome and FHC are fundamentally related.Abnormal ventricular activation might result in regional myocardial hypertrophy or localized hypertrophy might disrupt normal cardiac electrical discontinuity at the atrioventricular ring [18].In the present case, the relatives refused a genetic analysis because they wanted to conclude with the death of 16-yearold boy; however, postmortem genetic testing is useful in the diagnosis of the specific etiology of sudden cardiac death.
As sudden and unexpected deaths, especially of younger people, often trigger forensic investigations, autopsies can occasionally reveal very rare diseases, for example undetected valvular defects (e.g., aortic valve stenosis), vasculitis involving the coronary arteries or high-grade stenosing fibromuscular dysplasia of the atrioventricular node artery [2].
In the reported case, no concomitant illnesses of this type were found.Apart from the macroscopic examination, it is also advisable to perform histological tests of tissue samples of the heart, as described in detail by Basso et al. [19,20].An examination of the conduction system of the heart can detect accessory pathways of the heart (bundle of Kent) that connect one of the atria with one of the ventricles [21].To the best of our knowledge, this is the only reported case of sudden death in a young boy with WPW with histological evidence of a thin accessory muscle bridge between the left atrium and the left ventricle as a possible morphological correlate of fatal cardiac arrhythmia.
To trigger a fatal arrhythmogenic event in the heart three promoting components interact: (1) a morphological correlate in the form of an underlying heart disease, e.g., myocardial infarction, (2) transient triggering factors such as electrolyte imbalance, tissue hypoxia and acidosis and (3) a mechanism of arrhythmia, for example a circular or re-entry pathway, such as a pathological connection between the atrium and the ventricle [4].
Clinical studies have documented the occurrence of cardiac arrhythmias, especially in the form of supraventricular events such as tachyarrhythmias, atrial fibrillation and extrasystoles [22,23].Excessive ethanol consumption of more than 90-100 g per day damages the cardiac muscleand changes thephysiological electrical conduction system of the heart [24].In 1978, Ettinger et al. coined the term holiday-heart syndrome referring to patients who developed supraventricular tachycardia or tachyarrhythmia after consuming higher amounts of alcohol in their leisure time [25].An additional effect of alcohol may be an electrolyte imbalance, especially of intracellular potassium and magnesium.In rats, chronic administration of alcohol lowered the threshold for the electrical induction of ventricular fibrillation, and a decrease in the myocardial potassium and magnesium concentrations was demonstrated.Moreover, one also has to consider the influence of alcohol on the autonomic nervous system, which can intensify the arrhythmogenic potency of alcohol [26].
In the deceased's blood sample a blood alcohol concentration of 1.19 g/kg was determined.According to clinical studies [24,25] the alcohol consumption may also have contributed to the development of atri-oventricular re-entry tachycardia in combination with morphological evidence of a pathological atrioventricular connection and hypertrophic cardiomyopathy in the case presented here.

Conclusion
Inthepresentcase, histological evidenceof a thin accessory muscle bridge between the left atrium and the left ventricle as a possible morphological correlate of a fatal cardiac arrhythmia could be demonstrated.The alcohol concentration measured in the deceased's blood should also be discussed as a potential trigger and be included in the interaction of promoting components of a fatal arrhythmogenic event.For forensic interpretation, the clinical history is needed in addition to detailed autopsy and histopathology examination results.

Corresponding address
Dr. med.Dipl.-Biol.Simone Bohnert Institute of Forensic Medicine, University of Wuerzburg Versbacher Str. 3, 97078 Wuerzburg, Germany simone.bohnert@uni-wuerzburg.de material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Fig. 1 9
Fig. 1 9 a, b Serial sections through a thin accessory muscle bundle (arrows) in the epicardial connective tissue found at microscopic inspection to connect the left atrium with the left ventricle.a Hematoxylineosin (HE), b elastica-van-Gieson (EvG) staining, bars in both figures correspond to 1 mm