Why do people die at the age of 27

Background: Sudden cardiac death is one of the leading causes of death in Europe. Although this essentially affects the elderly, 5 to 10% of these cases occur in young, apparently healthy people, cardiac arrest. In infants, children and young adults, sudden cardiac death is relatively rare, with an incidence of 1 to 5 per 100,000 people per year. Yet up to 7,000 asymptomatic children die each year in the United States, nearly half with no previous prodromes.
Method: Selective literature research.
Results: Although most of the sudden cardiac deaths can be explained by cardiovascular changes, no cause of death can be determined by autopsy in 10 to 30% of these cases. Potentially fatal ion channel diseases such as long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) can account for at least a third of these deaths. Most of these diseases have a familial disposition with an autosomal dominant inheritance, i.e. 50% of the offspring can be affected.
Conclusion: Genetic screening for changes in cardiac ion channels is therefore an important one
forensic aid to determine the cause of death. In this way, carriers of previously undetected, ion channel changes can be recognized within the affected families and, if the patient has a typical medical history, they can be subjected to cardiological monitoring.
Dtsch Arztebl Int 2009; 106 (4): 41-7
DOI: 10.3238 / arztebl.2009.0041
Keywords: sudden cardiac death, ion channel disease, cardiac diagnostics, molecular biology, family history
Sudden cardiac death is defined as unexpected death that leads to death within a very short time in people who previously appeared healthy - usually 1 hour after the onset of symptoms. It is one of the most common causes of death in the western world. In Germany alone, around 100,000 people die every year as a result of sudden cardiac death. Although it mainly affects the elderly, 5 to 15% of the cases are young, previously asymptomatic people.

In the elderly, coronary heart disease (approx. 80%) and dilated cardiomyopathy (approx. 10 to 15%) are the cause of the majority of sudden cardiac deaths. The most common pathological substrates in young people are hypertrophic, dilated or arrhythmogenic right ventricular cardiomyopathy, myocarditis or congenital changes in the coronary arteries. However, in 10 to 30% of cases (Figure 1), no detectable cause of death can be determined by autopsy (1).

Deaths without an autoptically identifiable cause that occur after the first year of life are referred to as "sudden unexplained death syndrome" (SUDS). If death from an unexplained cause occurs before the age of one, it is referred to as a "sudden infant death syndrome" (SIDS).

Primary electrical heart disease
Cardiac changes that can lead to sudden death in young people are often genetic but rarely diagnosed. In recent years, significant advances have been made in the elucidation of such genetic heart diseases. To date, over 40 of these diseases have been identified, many of which are associated with an increased risk of sudden cardiac death.

Genetically determined heart diseases can be divided into two groups: In diseases that are associated with a structural change in the heart, such as arrhythmogenic right ventricular dysplasia (ARVD) and hypertrophic cardiomyopathy (HCM). The second group, on the other hand, does not show any autoptically recognizable changes in the heart - their cause is primarily of an arrhythmogenic nature. These include primarily electrical heart diseases such as the complex of LQT syndromes (LQT, long QT), Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), which are the cause of a number of sudden autopsy negative deaths in young people could be.

Primary electrical heart diseases are based on pathological changes in cardiac ion channels. These are caused by mutations in genes that encode these ion channels. Ion channels are anchored transmembrane and, when pores open, enable ions to flow along an electrochemical gradient across the membrane. Many of these ion channels are involved in the creation and regulation of the action potential and thus in the generation of excitation and stimulus conduction in the heart. Mutations in these proteins can cause the channel to malfunction. As a result, cardiac arrhythmias occur that can ultimately lead to ventricular fibrillation. Many of these altered genes have already been identified and their role in the development of cardiac arrhythmias has been established (table).

The penetrance of these diseases, i.e. the probability with which the corresponding phenotype develops in a certain genotype, is very variable. The phenotypes that occur, in turn, show considerable clinical variance, which in some cases makes diagnosis more difficult. Electrocardiographic findings are often not clearly pathological. About 15% of those affected show a normal, frequency-corrected QT interval in the 12-lead ECG despite the presence of a QT syndrome (2). Likewise, the unmasking of Brugada syndrome by means of drugs does not seem to be necessarily conclusive in the case of a negative test (3).

Genetic aspects of heart disease as causes of sudden cardiac death
The LQT Syndromes
Congenital LQT syndrome is a genetically heterogeneous disease that is often, but not necessarily, characterized in the ECG by a prolonged QT time (eFigure 1). This should be differentiated from patients with acquired LQT syndromes such as those after taking medication that prolongs the QT time. In the meantime, 9 different gene locations on chromosomes 3, 4, 7, 11, 12, 17 and 21 have been identified for congenital LQT syndromes, the mutations of which have been assigned to LQT syndromes 1 to 9. Over 200 mutations are currently known: in the 5 potassium channel genes KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, in the sodium channel gene SCN5A (4) and in the adapter protein ankyrin B (5). Recently, mutations in the gene for calveolin, CAV3, and in a calcium channel have been identified that lead to prolonged QT times associated with Thimothy syndrome, a multisystem disease associated with syncope and sudden cardiac death (6).

In studies by Schwartz et al. (7) on genetic defects and their clinical manifestation (so-called genotype-phenotype relationships), it was shown that almost all patients with LQT1 syndrome develop syncope under increased sympathetic stimulation (physical or psychological stress). In a third of those affected, the disease manifests itself during childhood under physical stress situations such as swimming (7). LQT1 syndrome can therefore be concealed behind some of the cases of sudden bathing death. In patients with LQT3 syndrome (Figure 2), the symptoms usually occur at rest, often during sleep (8). Sudden cardiac death is the only clinical manifestation of the disease in 12% of all patients with any of the LQT syndromes. In around 4% of these patients, cardiac death occurs within the first year of life (9).

Short QT Syndromes
Only in the last few years, the short QT syndrome (SQTS), was another rhythmological disease associated with sudden cardiac death (10). In contrast to the LQT syndrome, the ECG of the affected person shows a shortened QT time and a change in the shape of the T waves. So far, 5 mutations in the potassium channel genes KCNH2 (SQTS1), KCNQ1 (SQTS2) and KCNJ2 (SQTS3), which have also been associated with the long QT syndrome, have been identified as the molecular basis of SQTS (11). As a result of each of these mutations, the ion flow in the affected channels increases, which leads to accelerated repolarization and thus to a shortened action potential (12). Gaita et al. (13) showed that people with SQTS have an increased familial risk of sudden cardiac death.

Catecholaminergic polymorphic ventricular tachycardias
Mutations in the gene of the ryanodine receptor RyR2 are found in around 60% of patients with catecholaminergic, polymorphic ventricular tachycardias (CPVT). Among other things, this is responsible for regulating the calcium balance of the endoplasmic reticulum. Mutations in the RyR2 gene were also found in patients with a sub-form of arrhythmogenic right ventricular cardiomyopathy (ARVC) (14). Insufficient data are available on the incidence.

The ryanodine receptor is one of the largest proteins in the human organism with 105 exons (coding regions of DNA that contain the information for proteins). Around 70 mutations are known to date, but it can be assumed that more will be discovered. Mutations in this gene lead to an altered protein and possibly to impairment of the release of calcium from the sarcoplasmic reticulum into the cytoplasm, which can lead to arrhythmias, especially under stress. The ryanodine-2 receptor (RyR2) and its accessory proteins calsequestrin-2, FKBP12.6 and triadin-1 / junctin, which together form a complex, regulate this process. If mutations occur in the RyR2 gene, adrenergic stimulation, for example due to stress, can lead to a decrease in the affinity of the accessory FKBP12.6 protein to the channel complex. This leads to an increased opening of the ryanodine receptor, which can result in an intracellular calcium excess. This Ca2 + ion overload can lead to the development of further depolarizations after the repolarization of the heart has ended and thus favor the induction of ventricular tachyarrhythmias. Patients affected by CPVT are at a significantly increased risk of syncope and sudden cardiac death. In contrast to LQT syndromes, the first syncope in untreated patients often manifests itself at the age of 40, with a death rate of 30 to 50% (14).

The Brugada Syndrome
Brugada syndrome is a major cause of sudden cardiac death. A saddle-like ST elevation on the ECG (eFigure 2) with atypical right bundle branch block in leads V1 to V3 is characteristic of Brugada syndrome (15). These changes can also only occur intermittently. By giving sodium channel blockers such as
Ajmaline (Figure 3) it is possible to partially unmask these changes (3). Approximately 15 to 20% of patients with Brugada syndrome have a mutation in the SCN5A gene, which codes for the cardiac sodium channel. Mutations in genes that regulate the sodium channel have also been found in affected patients. Mutations in the L-type of the calcium channel could also be found, which indicates that, in addition to changes in the sodium current, a reduced calcium current should also be considered as a cause of Brugada syndrome. In many cases, however, the genetic basis has not yet been adequately clarified (15). Patients with Brugada syndrome are particularly at risk from life-threatening tachyarrhythmias. It is therefore recommended that a defibrillator be implanted after cardiac arrest or syncope has occurred (16).

Molecular biological diagnostics
The steadily growing number of diseases associated with ion channel defects deserves special attention because, like hardly any other hereditary disease, the pathophysiology can be elucidated by a combination of molecular genetics and electrophysiology. Molecular genetic methods make it possible to search specifically for disease-causing mutations in the corresponding ion channel genes. For this purpose, the DNA is first extracted from EDTA blood or tissue. The coding regions of the corresponding genes are amplified using further molecular biological methods (polymerase chain reaction). The detection of sequence variants in the PCR products is usually carried out by means of a special chromatographic separation (DHPLC, "denaturating high performance liquid chromatography"). The base sequence is analyzed for all samples with an abnormal chromatogram.

If new mutations are found, electrophysiological methods can be used to examine whether these changes in the gene are actually functionally effective and thus possibly causing disease. The molecular genetic diagnosis of these diseases is currently still very complex and costly, which limits its use in routine diagnosis.

Care of affected families
The funeral talk with relatives who have lost a family member to sudden cardiac death poses a special challenge for clinicians and forensic doctors because of the sudden and unexpected death Cause of death. As recent studies have shown, the intensive dissemination of information and care of the affected family members leads in 40 to 53% to the diagnosis of the cardiac disease which is presumably responsible for sudden cardiac death. In this context, reference should be made to the procedural sequence presented by Behr and Tan (17), which provides support for the procedure after an autopsy (Figure 4).

Role of molecular autopsy
At the beginning of the care of the affected families it is important to find out all available information about the death of the loved one. In addition to the autopsy report, this includes clinical data, but also observations and symptoms before death. Often, however, death is the first sign of the disease, or symptoms appear that have never been investigated.

One of the largest epidemiological studies to date of unexpected deaths in young people found that more than half of these cases were of cardiac origin and 29% had no autopsy identifiable cause (18). Another study by the Australian military showed an incidence of non-traumatic, unexpected deaths of 13 per 100,000 recruits per year, with more than a third (35%) of which autopsy found no cause of death (19).

Based on cardiac and clinical data from families in which cases of sudden cardiac death had occurred, it was shown in two further studies that there were signs of hereditary cardiac disease in 22% and 28% of the cases, respectively. Mostly it was LQT syndromes, but also catecholamine-induced ventricular tachycardias.

More recent studies have shown that 35% of sudden deaths were caused by cardiac ion channel disease (Figure 5). These studies indicate the importance of finding potentially life-threatening mutations in determining the cause of death in people with an unclear cause of death. The molecular autopsy is therefore an important diagnostic tool in the forensic assessment of such deaths.

In this context, however, it should be pointed out that if there is no evidence of a genetic change, cardiac disease cannot be ruled out, because around 30% of these deaths cannot currently be clarified using molecular biology.

Prevention by molecular autopsy
Primary electrical heart diseases are hereditary diseases with an autosomal dominant inheritance, which means that there is a 50 percent risk for family members that they are carriers of an altered gene. For this reason, genetic testing is of the utmost importance for the affected family, especially with a view to preventing further sudden cardiac death.

From a forensic medical point of view, it is therefore essential to inform the relatives about the results of the molecular genetic examination in a personal conversation.

In such a case, there is no violation of the continuing personality rights or the obligation to maintain confidentiality, which also exists after death, because it is in the interest of the deceased that his descendants are informed about possible risks. In this case, however, the “right to be ignorant” must be observed, which must be discussed with the person concerned before the start of the explanation.

A genetic family examination is indicated if there is positive evidence of mutation in the deceased and / or a typical medical history and first clinical symptoms in family members. On the one hand, potentially threatened persons can be recorded, on the other hand, the risk of a possible illness can be excluded in this way. To what extent asymptomatic gene carriers benefit from prophylactic therapy currently appears unclear. At the latest after a suspicious finding has been made through a molecular genetic examination, the relatives should be offered advice from a human geneticist and cardiologist or pediatrician. The prognosis and, if necessary, therapy as well as information on the likelihood of the disease occurring must be discussed with the person concerned.When examining clinically healthy family members, genetic counseling should be offered prior to the examination. This is particularly advisable in the case of illnesses that manifest themselves late and are not or only partially treatable. Addresses for carrying out a molecular genetic examination can be obtained from the author.

Conclusion
In summary, it can be said that identifiable cardiac ion channel diseases are responsible for around a third of all sudden deaths that were normal at autopsy. The identification of the genes associated with these diseases and their proteins has made it clear how important it is to investigate mutations in these genes, especially with regard to sudden cardiac death. The forensic medicine institutes play an important role here, since such cases are almost exclusively recognized there and samples for further molecular genetic testing are only available here.

Molecular genetic post-mortem studies on affected ion channel genes (molecular autopsy) in cases of sudden cardiac death are therefore an important tool for the elucidation of such deaths. If the identification is positive, there is a need for further medical examination of the family. As part of genetic counseling, an individual risk analysis can be carried out and, in the case of phenotypically and genotypically positive carriers of a genetic change, life-saving prophylactic therapy, for example by implanting an ICD (implantable cardioverter defibrillator), can be achieved. It must be emphasized, however, that no randomized study is yet available for the use of the ICD.

Conflict of interest
The authors declare that there is no conflict of interest within the meaning of the guidelines of the International Committee of Medical Journal Editors.

Manuscript dates
Taken: May 21, 2008, revised version accepted: August 27, 2008

Address for the authors
Dr. rer. nat. Silke Kauferstein
Institute for Forensic Medicine
in the clinical center of the J. W. Goethe University
Kennedyallee 104, 60596 Frankfurt am Main
Email: [email protected]

Summary
Cardiac Gene Defects Can Cause Sudden Cardiac Death in Young People
Background: In Europe, sudden cardiac death (SCD) is one of the most common causes of death. Although sudden cardiac death usually happens in older people, 5% to 10% of the affected individuals are young and apparently healthy. Sudden death in infants, children, and young adults is relatively rare, with an incidence of 1 to 5 per 100,000 persons per year. Nonetheless, up to 7000 asymptomatic children die in the USA each year, almost half of them without any warning signs or symptoms.
Method: Selective literature review.
Results: Although structural cardiovascular abnormalities explain most cases of sudden cardiac death in young people, the cause of death remains unexplained after autopsy in 10% to 30% of cases. Potentially lethal ion channel disorders (channelopathies) such as the long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and the Brugada syndrome (BrS) may account for at least one-third of these unexplained cases. Most of these diseases are hereditary with autosomal dominate transmission, i.e., there is a 50% chance that the children of affected individuals will be affected themselves.
Conclusion: Post-mortem genetic screening for sequence variations in cardiac ion channel genes has become an important forensic tool for elucidating the cause of sudden cardiac death. Moreover, it allows the identification of other family members bearing the previously undiagnosed gene defect, who can then undergo a cardiological evaluation
if indicated by their clinical history.
Dtsch Arztebl Int 2009; 106 (4): 41-7
DOI: 10.3238 / arztebl.2009.0041
Key words: sudden cardiac death, ion channel disorder, cardiological diagnosis, molecular biology, family history

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Institute for Forensic Medicine, Johann Wolfgang Goethe University, Frankfurt am Main: Dr. rer. nat. Kauferstein, Dipl.-Biol. Kiehne, Prof. Dr. med. Bratzke; Kerckhoff Clinic, Department of Electrophysiology, Bad Nauheim: Dr. med. Neumann, Dr. med. Pitschner