Annals of Medicine.

2008; 40: 360375

REVIEW ARTICLE

Sudden cardiac death: Prevalence, pathogenesis, and prevention

MARTINA MONTAGNANA1, GIUSEPPE LIPPI1, MASSIMO FRANCHINI2,

GIOVANNI TARGHER3 & GIAN CESARE GUIDI1
1
Sezione di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Università degli Studi di
Verona, Italy, 2Servizio di Immunoematologia e Trasfusione, Azienda Ospedaliera di Verona, Italy, and 3Sezione di
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Endocrinologia e Malattie del Metabolismo, Dipartimento di Scienze Biomediche e Chirurgiche, Università degli Studi di
Verona, Italy

Abstract
Sudden cardiac death (SCD), also known as sudden arrest, is a major health problem worldwide. It is usually defined as an
unexpected death from a cardiac cause occurring within a short time in a person with or without preexisting heart disease.
The pathogenesis of SCD is complex and multifaceted. A dynamic triggering factor usually interacts with an underlying
heart disease, either genetically determined or acquired, and the final outcome is the development of lethal
For personal use only.

tachyarrhythmias or, less frequently, bradycardia. It has increasingly been highlighted that a reliable clinical and diagnostic
approach might be effective to unmask the most important genetic and environmental factors, allowing the construction of a
rational personalized medicine framework that can be applied in both the preclinical and clinical settings of SCD. The aim
of the present article is to provide a concise overview of prevalence, pathogenesis, clinical presentation, and diagnostic
approach to this challenging disorder.

Key words: Cardiomyopathy, genetic testing, heart, sudden cardiac death

Introduction acts with an underlying heart disease, either

genetically determined or acquired, and the final
Sudden cardiac death (SCD) (also called sudden
outcome is the development of lethal tachyarrhyth-
arrest) is defined as an unexpected death from a
mias or, less frequently, bradycardia (5). The ac-
cardiac cause occurring within a short time, generally
knowledgement of the most common precipitating
within 1 hour of symptom onset, in a person with or factors, along with the early identification of indivi-
without preexisting heart disease (1). It is a major duals at highest risk, are essential requisites to limit-
health problem worldwide, since the annual incidence ing the burden of this challenging pathology. Major
of SCD in the general population is estimated as 1 in inroads into profiling individual or population risk of
1,000 (2), and more than 3 million persons die SCD both require better understanding of each of
annually (2,3). Despite the multiple advances in the epidemiologic-clinical-physiologic interactions. The
field of cardiovascular medicine and the efforts in disciplines range from epidemiology, through clinical
medical care, neurologically intact survival rates re- medicine, membrane channel physiology, genetic
main poor, usually less than 20% (4). The prevalence determinants, and molecular biology (6). A possible
of SCD has two peaks, one between birth and 6 laboratory aid in the early identification of subjects at
months of age (sudden infant death syndrome (SIDS)) high risk might come from genetics and molecular
and the other between 45 and 75 years of age (2). biology. The so-called ‘personalized medicine’ may
The pathogenesis of SCD is complex and multi- come to play an important role, for both prevention
faceted. Basically, a dynamic triggering factor inter- and treatment of SCD cases occurring in subjects

Correspondence: Dr Martina Montagnana, Sezione di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Ospedale
Policlinico G.B. Rossi, Piazzale Scuro 10, 37134 Verona, Italy. Fax:
39-045-8201889. E-mail: [email protected]

ISSN 0785-3890 print/ISSN 1365-2060 online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.1080/07853890801964930
 Role of laboratory in sudden death 361

affected by genetic cardiovascular disease. Accord-

Key messages
ingly, the identification of subjects at major risk
through gene-based diagnosis of all family members . Sudden cardiac death, also known as sud-
should be regarded as a priority for health care den arrest, is a major health problem
practitioners. The genetic basis for cardiomyopathic worldwide.
processes vulnerable to sudden arrhythmic death* . The pathogenesis of sudden cardiac death
hypertrophic cardiomyopathy, dilated cardiomyopa- is complex and multifaceted, involving
thy, arrhythmogenic right ventricular cardiomyopa- dynamic factors that usually interact with
thy, and ion channel diseases*is now largely underlying heart diseases, and finally trig-
acknowledged (7). However, the extension to routine ger lethal tachyarrhythmias or bradycardia.
genetic testing is currently limited by technical . The implementation of preventive and
difficulties and costs. diagnostic strategies might be effective to
unmask the most important risk factors for
sudden cardiac death, constructing perso-
Pathogenesis nalized medicine frameworks that can be
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applied to limit the onset of this challenging

The pathogenesis of SCD is apparently multifactor-
disorder.
ial and incompletely clear. It has been hypothesized
that single or multiple dynamic factors, possibly
transient, interact with a disease substrate to pre- that torsade de pointes is bradycardia-dependent or
cipitate the arrhythmia. All known heart diseases can pause-dependent, bradycardia is an important trigger
be the substrate in SCD, but in 60%80% of cases of SCD (10). Patients with bradycardia can have
SCD occurs in the setting of a preexisting coronary severe tachyarrhythmias but it is unclear whether
artery disease (CAD) (2,3). Sudden cardiac death is bradycardia alone can induce arrhythmias or whether
an additional substrate is necessary (5). Depressed
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the first presentation in about one-third of the

patients with CAD, and it is three times more parasympathetic tone is also associated with an
common in men than in women. Most other SCD increased risk of SCD (11). Accordingly, involve-
events occur in non-ischemic cardiomyopathy, infil- ment of the autonomic nervous system is suggested
trative, inflammatory, and acquired valvular dis- by the occurrence of ventricular tachyarrhythmias
eases. A small percentage of SCDs manifests in the and SCD at rest or during sleep and by changes of
setting of ion channel mutations responsible for typical electrocardiogram (ECG) signs in patients
inherited abnormalities, such as the long/short QT with Brugada syndrome (12).
syndromes, Brugada syndrome, and catecholami-
nergic ventricular tachycardia (2,3). In children and
young athletes the two main causes of sudden death Potential substrate in sudden cardiac death
are long QT syndrome and hypertrophic cardiomyo- Long QT syndrome
pathy. Most instances of SCD involve ventricular
tachycardia degenerating to ventricular fibrillation Long QT Syndrome (LQTS) is an inherited disorder
and subsequent asystole. Some cardiac arrests in of the heart’s electrical system characterized by pro-
SCD are due to bradycardia. longed ventricular repolarization (QT interval) and by
Wake-up time, first day of the working week, ventricular tachyarrhythmias. The exact prevalence of
winter season, physical activity, emotional upset, LQTS remains to be determined, although an estimate
overeating, lack of sleep, social drugs (cocaine, of 1 in 10,000 has been suggested (13). LQTS causes a
marijuana), anger, and sexual activity are among sudden type of ventricular tachycardia commonly
the most common triggers (8). Dynamic factors also called ‘torsade de pointes’ (TDP), and patients are at
include transient ischemia, pH and electrolytes im- high risk of developing syncope and sudden death,
balance, inflammation, hypoxia, stretch, and ion often at a young age. TDP is a polymorphic ventricular
channel abnormalities. Other changes could also tachycardia with a peculiar electrocardiographic pat-
occur, such as plaque rupture (2). The role of tern of continuously changing morphology of the QRS
external events and the nature of the pathophysiolo- complex twisting around an imaginary baseline (14).
gical mechanisms causing SCD are still poorly In LQTS patients, cardiac arrhythmias are often
understood. A relative hyperadrenergic tone related induced by stress and emotion, although in some cases
to abnormalities of the autonomic nervous system is they may also occur at rest or during sleep (15). Several
suspected in the triggering mechanisms of SCD (9). genes have been identified and are responsible of
Moreover, in specific genetic situations, such as long different varieties of LQTS. The symptoms of LQTS
QT-3 (LQT3) syndrome, in which it is demonstrated occur only when the patient develops an episode of
 362 M. Montagnana et al.

torsade de pointes, and the degree of symptoms Short Q-T

depends on the length of time the arrhythmia persists.
The short QT syndrome (SQTS) is characterized by
Two patterns of inheritance have been identified: the
a short QT interval (QT and QTc 5 300 ms) during
more common autosomal dominant Romano-Ward an electrocardiogram (ECG), and by a high risk of
syndrome (RWS) and Timothy syndrome (16), and syncope or sudden death due to malignant ventri-
the much rarer autosomal recessive cases. Mutations in cular arrhythmia. It is a clinical entity originally
ten genes have been discovered, eight of them encod- described in 2000 (24) that usually affects young
ing cardiac ion channel subunits (17,18), and two and healthy subjects with no structural heart disease
encoding an anchoring protein that has been impli- and may be present in sporadic cases as well as in
cated in controlling ion channel targeting specific families (26). It has been associated with a gain of
membrane sites (19). The RWS is a genetically function in three distinct potassium channels
heterogeneous disease caused by mutations in at least (KCNH2, KCNQ1, and KCNJ2) (27). The possi-
four genes (LQT1 to LQT4). Three of them (LQT1 to ble substrate for the development of ventricular
LQT3) have been identified and encode for ion tachyarrhythmias in these patients may be a signifi-
channel subunits, respectively for two potassium cant transmural dispersion of the repolarization due
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channels, and one sodium channel. To date, nearly to a heterogeneous abbreviation of the action poten-
100 different mutations have been reported as respon- tial duration (27). The definitive link between short
sible for the cardiac long QT syndrome (20). There is QT syndrome and familial sudden death was de-
also a recessive form of LQTS, the Jervell and Lange- scribed by Gaita et al. in 2003, with the clinical
Nielsen syndrome (JLNS). Patients with JLNS experi- report of two families with short QT syndrome and a
ence a high rate of cardiac and fatal events from early high incidence of SCD (28). One year later, the
childhood despite medical therapy (21). genetic and biophysical basis for the disease, as well
The number of genetic carriers of LQTS as a possible therapeutic approach, was acknowl-
edged (28,29). Hereditary short QT syndrome is a
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mutations in the population is around 510 per

100,000. In the severe forms of RWS, the affected clinical ECG entity with an autosomal-dominant
subjects usually experience syncope due to ventri- mode of transmission, and it is the most recently
cular arrhythmias during the first decade of life described channelopathy. The syndrome may affect
and sometimes in early childhood, most often infants, children, or young adults with a strong
induced by physical exercise or emotion. Rarely, positive family background of SCD (26).
it can also occur at rest, and cardiac arrest can be
the first presentation of the disease. The availabil- Ion channel dysfunction
ity of genetic testing has led to an understanding of
important clinical differences between the indivi- Electrolyte depletion may represent an important
dual genetic disorders (22). Patients with LQT1 but potentially reversible factor in the development
are at particularly high risk of cardiac events of malignant ventricular arrhythmias causing SCD
during physical exercise, especially swimming. (30). Fundamental changes in calcium handling in
heart failure (HF) are thought to account for
Patients with LQT2 are susceptible to cardiac
abnormalities in excitationcontraction coupling.
events during emotional or auditory stimuli and
Although alteration of the calcium transient (CaF)
during the postpartum period (23). Unexpectedly,
is associated with and influences the static and
women affected by the common RWS mutations
dynamic changes in the ventricular action potential
are at lower risk for cardiac events during preg-
(AP), the precise relationship remains unclear, and
nancy but regional anesthesia can represent a risk the role of spatial and temporal dispersion of CaF in
factor in such forms of RWS (24). The LQT8 arrhythmogenesis in the failing heart remains to be
form of long QT syndrome, also known as clarified. The failing heart exhibits a defect in Ca2

Timothy syndrome, is a multisystem disorder cycling reserve, which may be particularly pro-
associated with gain-of-function mutations in car- nounced in the endocardium (31). A significant
diac calcium channel activity, particularly L-type association between magnesium depletion and lethal
calcium current (I(Ca,L)). The L-type Ca2
arrhythmias has also been proposed by the finding
channel plays an important role in action potential of depressed myocardial magnesium content in
generation, morphology, and duration. The result victims of SCD (32). Hypomagnesemia and deple-
of calcium channel mutations is that they remain tion of intracellular magnesium stores have been
open for much more than a millisecond at any one held responsible for a variety of cardiovascular and
time, and intracellular calcium is raised to toxic other functional abnormalities, including various
levels (25). arrhythmias, impairment of cardiac contractility,
 Role of laboratory in sudden death 363

and vasoconstriction (33). Although serum magne- risk of SCD among patients with acute coronary
sium measurement is not always a good surrogate for events is closely related to the family history. In
the magnesium body content, its measurement, as particular, SCD as a manifestation of the first acute
part of the electrolyte profile of congestive heart coronary event appears to cluster in certain families,
failure (CHF) patients, might, however, assist in the which suggests a strong genetic background (44).
early prevention and detection of magnesium deple- However, although a majority of SCD events con-
tion. This would go a long way to reducing the tinue to occur in the context of this disease etiology,
susceptibility to lethal arrhythmias and sudden risk factors for CAD appear to have relatively limited
death, though it should also be mentioned that the ability to predict risk in specific individuals and
role of intravenous magnesium, especially in the subgroups with enhanced progressive or inherited
management of acute myocardial infarction, remains susceptibility to lethal arrhythmias (45). Clinical
controversial (34). studies in patients with significant CAD without
In patients affected by sudden unexplained HF have implied that a primary arrhythmia without
nocturnal death (SUND), even if this fatal event an acute ischemic event may be the primary me-
could be a consequence of arrhythmogenic cardio- chanism of SCD in the majority of patients (45). In
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myopathies like the long QT syndromes, potassium autopsy series, however, acute coronary findings are
deficiency is probably one among the causal factors. often present in patients who die suddenly, particu-
Serum and urinary potassium have been measured larly those with CAD (46,47). In autopsy studies, a
and indicate a deficiency of the electrolyte (35). fresh thrombus, recent myocardial infarction (MI),
SCD occurs in other less frequent electrolyte dis- or plaque rupture was found in 57%73% of CAD
eases, such as Bartter and Gitelman syndromes (36). patients without HF who died suddenly (46,47).
Patients affected by these syndromes are character- Therefore, although significant progress has been
ized by hypokalemia, and QTc prolongation has made in the treatment of ischemic heart disease,
been proposed as a potential mechanism (36). SCD still remains a serious problem.
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Contrarily, exercise-induced hyperkalemia has been

suggested as a factor in SCD in young athletes (37).
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a relatively
Coronary artery disease
common primary cardiac disorder defined as the
SCD may be the first clinical manifestation of CAD presence of a hypertrophied left ventricle, correlated
in as many as one in five patients with coronary heart with diastolic dysfunction, myocardial ischemia, and
disease and about 20% of CAD patients have cardiac arrhythmias, in the absence of any other diagnosed
arrest as the first clinical manifestation (38). Many etiology. Left ventricular hypertrophy is associated
survivors of SCD suffer from concomitant CAD with myofibril disarray and interstitial fibrosis (48).
(39). Among the many manifestations of CAD, The introduction of molecular genetics during the
acute coronary syndrome (ACS), ranging from past decade has provided a new paradigm for the
unstable angina to acute myocardial infarction, is diagnosis of HCM, offering a better understanding
the most catastrophic event and, despite improved of the pathogenetic mechanisms, along with the
treatments of CAD, ACS results in sudden death or individualization of distinct anatomic and functional
permanent disability in a substantial percentage of risk patterns. HCM is the most common form of
patients (40). The presence of CAD is a major risk genetic cardiovascular disease, and it is responsible
factor for SCD usually by reducing ejection fraction for 1 case in every 500 individuals (48).
and by triggering ventricular tachycardia degenerat- In 1989, HCM was mapped to chromosome 14 in
ing into ventricular fibrillation (41). Ventricular a French-Canadian pedigree with autosomal domi-
tachycardia, on the other hand, is mostly due to a nant disease and, thereafter, mutations in cardiac b-
reentrant mechanism caused by infarct-related scar- myosin heavy chain (MHC) were shown to cause
ring (42). The progression from conventional risk HCM (49). More than 250 mutations involving 11
factors of CAD to arrhythmogenesis and SCD can disease genes have been identified so far, and 9 of
be represented as a cascade of events: atherogenesis, these encode proteins that constitute the contractile
changes in atherosclerotic plaque anatomy, disrup- apparatus of the cardiac muscle cell. Mutations
tion of active plaque, activation of the thrombotic scattered among at least ten sarcomeric genes confer
cascade and acute occlusion, followed by acute the pathogenetic substrate for this disease of the
changes in myocardial electrophysiology which be- sarcomere/myofilament (50). Recently, Ellinor et al.
come the immediate trigger for arrhythmogenesis have mapped a novel locus for cardiomyopathy,
and SCD (43). Moreover, it was observed that the diffuse myocardial fibrosis, and sudden death to
 364 M. Montagnana et al.

chromosome 10q25-q26. It is principally inherited as Congenital and acquired structural heart diseases
an autosomal dominant pattern characterized by a
One-third of sudden deaths in the young may be
considerable genetic heterogeneity, both intergenic attributable to structural defects present since birth.
and intragenic. Lately, the genetic spectrum of HCM A large spectrum of congenital heart disease
has expanded to encompass mutations in Z-disc- involves the risk of sudden death, but most
associated genes (Z-disc HCM) and glycogen storage structural defects are usually not considered to be
diseases (50). Genetic studies showed that approxi- life-threatening (54). Several studies reported on
mately 20% of genetically affected adults are healthy the incidence of sudden death in patients with a
carriers without any ECG or echocardiographic broad variety of types of valvular heart disease (55).
abnormality. The disease is caused by disorders that Studies with Holter monitoring in patients with
directly affect the generation or regulation of con- aortic valve disease have demonstrated that the
tractile energy. Recently, other proteins not related to occurrence of ventricular arrhythmias is not appar-
sarcomeres, such as the adenosine monophosphate ently correlated with the type of the lesion (steno-
(AMP)-activated protein kinase, have been identified sis, regurgitation, or combined stenosis and
as contributors to the development of similar pheno- regurgitation), nor with the transvalvular gradient
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types (51). HCM remains the main cause of sudden or degree of regurgitation, nor with the presence of
death in top-class sportsmen and women; SCD also concomitant CAD (56). However, spontaneous
represents the most devastating aspect of obstructive ventricular arrhythmias have occurred in a large
and non-obstructive HCM. Particularly, loss of number of patients, being strongly influenced by
consciousness associated with ventricular arrhythmia the presence of impaired left ventricular function
identifies patients at very high risk of SCD. Genetic (56). Supravalvular aortic stenosis is an uncommon
insights have now provided remarkable implications but well characterized congenital form of left
for a genotype-phenotype correlation. Although ventricular outflow obstruction. The severity of
supravalvular aortic stenosis varies; but if it is left
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there is substantial clinical diversity among patients

untreated, it may result in heart failure, myocardial
with the identical mutation, some polymorphisms
infarction, and sudden death (57). Other less
might be associated with significant premature death,
frequent important causes of sudden death include
whereas life expectancy appears normal with others.
ruptured aorta (due to cystic medial necrosis) and
Whether or not healthy carriers of a mutation are at
idiopathic concentric left ventricular hypertrophy
risk of developing a later form of disease is presently (48). In young athletes the second most common
unknown. category of diseases responsible for sudden death is
a spectrum of congenital malformations of the
coronary arteries; the most important of these is
Dilated non-ischemic cardiomyopathy anomalous origin of the left main coronary artery
Dilated cardiomyopathy (DCM) is associated with from the right (anterior) sinus of Valsalva (58).
a high incidence of malignant ventricular arrhyth-
mias and SCD. Abnormalities in repolarization of Arrhythmic right ventricular dysplasia
ventricular myocardium have been implicated in
the development of these arrhythmias (52). In Arrhythmic right ventricular dysplasia (ARVD) is a
particular, the heart cells of patients affected by clinical and pathological entity characterized by
DCM display significantly prolonged action poten- replacement of ventricular myocardium with fatty
and fibrous elements that preferentially involves the
tials compared with those from normal myocar-
right ventricular (RV) free wall. ARVD is one of the
dium, regardless of the mechanism involved in the
major genetic causes of juvenile sudden death, whose
development of cardiomyopathy. In the DEFI-
prevalence is about 1 in 5000 persons (59). A familial
NITE (DEFIbrillators in Non-Ischemic cardio-
occurrence in about 50% of cases has been reported,
myopathy Treatment Evaluation) study, the use characterized by autosomal dominant inheritance,
of statins was associated with a reduction in variable penetrance, and polymorphic phenotypic
mortality, probably associated with a reduction in expression (60). ARVD is a disease of desmosomal
arrhythmic sudden death (53). Patients with non- dysfunction. Desmosomes are a family of proteins
ischemic dilated cardiomyopathy and preserved the function of which is to bind the myocardial cells
heart rate variability (HRV) have an excellent to one another providing cellular contact that is
prognosis and may not benefit from prophylactic necessary for electric conduction and mechanical
implantable cardioverter defibrillator (ICD) place- contraction of the myocardial cells (61). The usual
ment (53). clinical presentation is characterized by palpitations,
 Role of laboratory in sudden death 365

non-sustained ventricular tachycardia, and sustained cases. Screening for mutations in the cardiac Na

ventricular arrhythmias. Uncommonly, SCD may be channel-encoding gene for the alpha subunit of the
the first manifestation of the disease. The onset of sodium channel (SCN5A) uncovers a mutation in
these symptoms is normally between the ages of 20 approximately 20% of Brugada syndrome cases (68).
and 40 years, and the disease shows a predisposition These genetic abnormalities cause a reduction of the
to occur in men (61). Although a potential predis- density of the sodium current and explain the
posing mutation involving the PKP2 gene has been aggravation of ECG abnormalities caused by antiar-
identified in nearly 30% of ARVD patients (62), rhythmic sodium channel blockers (10). Two addi-
there is little evidence so far to indicate that tional genetic pathways have been associated with the
identification of a disease-causing mutation has any disease over the past years. Moreover, an inflamma-
clinical or prognostic significance, but identification tory or infectious etiology has recently been linked
of disease-causing mutations facilitates rapid and with this syndrome (69). In these patients, fever is a
accurate screening of family members. ARVD is a well recognized triggering factor, since it can pre-
common finding in athletes with ventricular arrhyth- cipitate ventricular tachycardia (69). Electrocardio-
mia and an appropriate screening program may be graphically characterized by a distinct coved-type ST
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effective to prevent and reduce the incidence of SCD segment elevation in the right precordial leads, the
(63). It is a typical ‘silent’ arrhythmogenic cardio- syndrome is associated with a high risk of SCD in
myopathy, with the possibility of normal ventricular young and otherwise healthy adults, and less fre-
performance and life-threatening arrhythmias (64). quently in infants and children (69).
Prevalence of ARVD among Italian athletes with
SCD is high (about 25%), confirming the observa-
tion that ARVD is one of the major causes of SCD in Catecholaminergic polymorphic ventricular tachycardia
Italian athletes and indicating the potentiality of (CPVT)
exercise as a cause of electrical destabilization in Polymorphous ventricular tachycardia was originally
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subjects with ARVD. Therefore, in athletes with observed in 1918 by Wilson and Robinson, who
documented ARVD intense sport activity should be described a tachyarrhythmia characterized by multi-
prohibited (64). ple extrasystoles of different types at a rapid rate (70).
CPVT is hence characterized by ventricular tachyar-
Wolff-Parkinson-White syndrome rhythmias that develop during adrenergic stimulus,
such as physical activity or acute emotion in the
SCD is a rare complication of the Wolff-Parkinson- presence of an unremarkable resting ECG (71). The
White (WPW) syndrome, which might occur with- disease can be transmitted as an autosomal dominant
out any apparent environmental triggers in young, as well as a recessive trait. Half of the autosomal
previously asymptomatic persons. The most com- dominant cases are caused by mutations in the gene
mon mechanism of sudden death in WPW patients encoding the cardiac ryanodine receptor (RyR2)
is ventricular fibrillation, which is triggered by an (72). The RyR (ryanodine receptor) mediates rapid
atrial fibrillation capable of conducting rapidly over Ca2
efflux from the endoplasmic reticulum (ER)
the accessory pathway (65). Syncope, despite being and is responsible for triggering numerous Ca2
-
induced by various mechanisms, has been consid- activated physiological processes. The recessive form
ered an alarming sign of sudden death of WPW is caused by mutations in the gene encoding calse-
syndrome (66). questrin (CASQ2), a calcium-buffering protein in
the sarcoplasmic reticulum (73). The mortality rate
in untreated individuals is 30%50% by the age of 40
Brugada syndrome
(73). The molecular diagnostics of this disease have
The Brugada syndrome is a congenital syndrome of become increasingly important, since underlying
SCD first described in 1992. It is clinically char- mutations can be found in more than 60% of the
acterized by the onset of syncopes or sudden death identified CPVT patients (74).
related to ventricular tachyarrhythmias in patients
with a structurally normal heart. In Asian countries
the prevalence is 1 per 1000, and probably lower Dynamic triggering factors
elsewhere. In patients with Brugada syndrome, the
Circadian variability
clinical phenotype is 8 to 10 times more prevalent in
males than in females (67). The transmission is The observation of a circadian variation in the
autosomal dominant, with variable penetrance of incidence of SCD with a significant morning peak
 366 M. Montagnana et al.

(75) suggests causation by identifiable triggers that chronic action it contributes to creating a sort of
may act alone or synergistically with physical morn- ‘myocardial background’, altering electrophysiologi-
ing activity, mental stress, blood pressure changes, cal properties of the myocardium, whereas by an
working stress, blood viscosity, and platelet hyper- acute action it can create the transient trigger
aggregability (76). A circadian rhythm of platelet precipitating SCD, as through the actions of stress
aggregability has been acknowledged. The first hormones. Moreover, some individuals have a hy-
direct evidence of a circadian variation of SCD was perresponsivity of the sympathetic nervous system,
reported in 1987 from a retrospective analysis of the characterized by exaggerated heart rate and blood
mortality records of the Massachusetts population pressure responses, which results in accelerated
(75). In this study, 2203 individuals who presumably atherosclerosis (81). A variety of uneventful condi-
died of SCD outside of a hospital or nursing home tions have been reported to trigger SCD, including
were identified. The time of death showed a natural disasters and terrorist attacks (8). Anxiety
circadian variation, with a primary peak in the late disorders are often accompanied by an overactive
morning, from 9 to 11 AM, and a minor secondary autonomic nervous system, reflected in increased
peak in the afternoon. Contrarily, in-hospital cardiac body temperature and heart rate (HR). Moreover, it
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deaths were approximately evenly distributed over a has been postulated that cardiovascular reactivity to
24-hour period. Analysis of death time in 264 mental stress varies with tonic central sympathetic
individuals belonging to the Framingham Heart nervous system activity. For example, during normal
Study demonstrated a circadian variation with an daily activities, patients with HCM experience a
approximately 3-fold increased risk of SCD during significant autonomic alteration with decreased
the morning, and a low incidence during the night sympathetic tone (82). Sexual activity may be an
(77). The prospective database of the West Berlin additional triggering factor of acute coronary events
emergency medical services system also provides and SCD, especially in combination with organic
interesting insights into the epidemiology of SCD. It heart disease increasing the relative risk of sponta-
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has been hypothesized that the greater risk of SCD neous recurrence of sustained ventricular tachyar-
in the first hours after awakening may be at least rhythmias (83).
partially due to the morning increase in blood
pressure and heart rate, increased vascular tone,
changes in heart rate variability, elevated blood Inflammation
viscosity, and platelet hyperaggregability (77). The It has been reported that the febrile condition can
more pronounced increase of sudden death in exacerbate a Brugada-type ECG pattern, poly-
younger subjects observed in the first working day morphic ventricular tachycardia and syncope (84).
of the week (usually Mondays) might be related to In this latter case, the ECG reveals a right bundle
the employment status. In fact, employed subjects branch block and pattern of elevated ST segment in
experience a more stressful change from the week- the anterior and inferior leads similar to the Brugada
end leisure activities to work activities on Mondays syndrome. These anomalies disappear when the
(78). The frequency of disease onset also varies temperature returns to normal. The potential ex-
with the time of the year. A 20% increase of SCD planation for this process is that the function of the
was reported during the months of the climatic ion channels is reportedly temperature-dependent
winter (78). (84). SCD is usually anticipated by progressive
increases in inflammatory markers, such as neutro-
phil counts and C-reactive protein (CRP) (85). A
Psychological stress
key question is whether increase in inflammatory
Psychological stress increases SCD in populations markers and worsening in HRV may be somehow
during emotionally devastating disasters such as related. A reliable hypothesis is the link between
earthquake or war, alters induced arrhythmias, and inflammation and endothelial dysfunction (86),
precipitates spontaneous ventricular arrhythmias in which is also associated with reduced vascular nitric
patients with ICDs. Moreover, depression and social oxide. The outcome is a worsening of the autonomic
isolation predicted mortality independently of de- function as indicated by decreased HRV (85).
mographic and clinical status in heart failure out- Recent data are generally consistent with this
patients (79). One hypothesis is that autonomically assumption, in that SCD in congestive heart failure
mediated repolarization changes may be one patho- (CHF) is often but not always associated with an
physiologic link between emotion and arrhythmia identifiable acute coronary event at necropsy (87)
(80). Psychological stress can act at two levels; by a which may be preceded by inflammation-induced
 Role of laboratory in sudden death 367

endothelial dysfunction. Albert et al. (88) advanced predilection for commotio cordis is related to the
the goal of improving individual SCD prediction by precise velocity of chest-wall impact (92).
providing the first evidence that a marker of chronic
inflammation, high-sensitivity CRP, may also appear
as a long-term marker for unexpected SCD. Neuroendocrine actions
They concluded that CRP levels were highly pre- The autonomic nervous system (ANS) plays an
dictive in identifying SCD victims. Multivariate important role not only in physiological situations,
evaluation also suggested increased relative SCD but also in various pathological settings such as
risk signaled by CRP, independently of these and diabetic neuropathy, myocardial infarction (MI)
other traditional markers of CAD risk per se. and CHF. The study by Pozzati et al. suggests that
sympathovagal imbalance, associated to increased
sympathetic activity and reduced vagal tone, may
Stretch trigger fatal arrhythmias during acute myocardial
Commotio cordis, or non-penetrating chest wall ischemia, resulting in sudden death. Autonomic
dysfunction, as detected by a marked decrease in
Ann Med Downloaded from informahealthcare.com by CDL-UC San Diego on 06/07/15

impact, is a mechanical induction of heart rhythm

disturbances in the absence of corresponding struc- HRV, is commonly present in the period immediately
tural damage. Reported with increasing frequency in preceding the onset of the ST shift precipitating
young individuals participating in some sport activ- ischemic sudden death (11). Specifically, sympa-
ities, it may cause SCD by acute initiation of thetic activation can trigger malignant arrhythmias,
ventricular fibrillation (89). Commotio cordis is the whereas vagal activity may exert a protective effect.
second leading cause of death in young athletes and Data from Perticone et al. (93) confirm a delayed
most events are caused by blows from projectiles, maturation or impaired functioning of the autonomic
baseballs, or lacrosse balls, with a substantial pro- nervous system in the first weeks of life in newborns
affected by SIDS. In an established experimental
For personal use only.

portion, nearly 40%, occurring despite the use of a

chest protector (90). Particularly, baseball impacts model for sudden death involving conscious dogs
induce ventricular fibrillation when directed at the with a healed myocardial infarction, either depressed
center of the left ventricle during the vulnerable reflex chronotropic responses during a blood pres-
portion of repolarization just prior to the T wave sure rise or reduced variability of heart rate (respec-
peak (90). The electrophysiological changes have tively, markers of reflex and tonic cardiac vagal
been attributed to mechanoelectric feedback, and activity) identify dogs at greater risk of developing
particularly to the recruitment of stretch-activated malignant arrhythmias during a new ischemic epi-
ion channels. However, the underlying mechanisms sode (94). Moreover, activation of the renin-angio-
by which a mechanical impact results in ventricular tensin-aldosterone system (RAAS) in left ventricular
fibrillation remain mostly unknown (91). Li et al. systolic dysfunction is a critically important determi-
(91) demonstrated that the region of impact is nant in the pathophysiologic processes that lead to
characterized by different types of cellular responses, progression of heart failure and SCD. The changes in
including generation of a new action potential, and the autonomic tone in the clinical setting can be
shortening or lengthening of action potential dura- evaluated by means of HRV, a sensitive measure of
tion. The impact might produce sustained reentry neurocardiac autonomic regulation (95). HRV, a
only when a new activation is elicited by mechanical beat-to-beat variation in cardiac cycle length result-
stimulation (caused by activation of cation-non- ing from autonomic influence on the sinus node of
selective stretch-activated ion channels), and upon patients in sinus rhythm, has been shown to predict
return to the original region of impact, this activa- independently the risk of SCD. Reduced baroflex
tion does not encounter an extension of action sensitivity, a quantitative assessment of the ability of
potential duration (prevented by activation of po- the autonomic nervous system to react to acute
tassium-selective stretch-activated ion channels). It stimulation involving primarily vagal reflexes, was
has also been demonstrated that vagotonic and also successful in assessing the risk of SCD, alone or
sympathetic surges do not likely contribute to the in combination with HRV (96).
syndrome of SCD due to chest blows (89). An
important variable in the generation of ventricular
Drugs and illegal drug abuse
fibrillation seems to be the energy of the impact.
Impacts at 40 mph (64.4 km/h) are more likely to Both experimental studies and clinical observations
produce ventricular fibrillation than those with have shown that drugs from various indication areas,
greater or lesser velocities, suggesting that the such as psychotropic agents and antiarrhythmics can
 368 M. Montagnana et al.

induce disturbances of cardiac rhythm and ECG (103). Opioid abuse by mothers is associated with a
abnormalities. The acquired long QT syndrome is high number of infant SCD (104). The finding of an
usually associated with drugs and electrolyte imbal- association between methadone and prolongation of
ance and often causes syncopes or cardiac arrest that cardiac depolarization (QT prolongation) and TDP
represent a high risk of recurrent events, including is of great concern (105). Body-packing, a quite
SCD. Non-antiarrhythmic drugs that prolong repo- common form of carrying illicit drugs by smugglers,
larization, along with class IA antiarrhythmic agents can be a cause of SCD (106). The intentional
such as quinidine, procainamide, N-acetylprocaina- inhalation of volatile substances such as isobutane
mide, and disopyramide, can cause torsade de has been reported as a cause of SCD (107). The use
pointes (97). SCD seems to be more frequent of cannabis by parents, either alone or in combina-
following treatment with neuroleptic drugs in pa- tion with tobacco smoke, has been associated with
tients with preexisting cardiac lesions, especially SCD in infants (108). Ecstasy (methylenedioxy-
dilated and hypertrophic myocardiopathy. The ob- methamphetamine (MDMA)) has been associated
served cardiac lesions can be compared to those seen with sudden death following induction of myocardial
in toxic myocarditis. Most of antipsychotic drugs, hypertrophy, especially in young otherwise healthy
Ann Med Downloaded from informahealthcare.com by CDL-UC San Diego on 06/07/15

including clozapine, olanzapine, sertindole, risper- individuals (109). The commonest cause of sudden
idone, and haloperidol, are associated with arrhyth- death following amphetamines abuse is uninten-
mia and sudden death (98). The use of droperidol tional overdosing (110).
by emergency departments and prehospital settings
to sedate extremely agitated patients following illicit
drug-taking, has been warned of as a possible cause Ischemia
of rare SCD (99). Diuretic agents can also trigger
The ion channels have been demonstrated to be
SCD, since they generate hypokalemia, hypomagne-
sensitive to changes in oxygen tension. Because they
semia, and increased intracellular calcium concen-
For personal use only.

respond rapidly to hypoxia, it has been proposed that

tration (2). Moreover, clebopride, a class of
the channel itself is an oxygen sensor (111). Adeno-
antidopaminergic gastrointestinal prokinetic, has
sine triphosphate (ATP)-dependent potassium
been reported to increase the risk of SCD, by
(K(ATP)) channels exist in high density in the
inhibition of the potassium current I(Kr) and QT
sarcolemmal membrane of heart muscle cells. Under
prolongation (100). Antimicrobial agents, such as
fluoroquinolone, can also trigger SCD with a similar normoxic conditions these channels are closed, but
mechanism (100). Reliable scientific evidence, based they become active when the intracellular ATP level
on case reports and clinical observations, describes falls. This leads to a shortening of the action
serious cardiovascular adverse effects, including potential duration, making the heart more suscep-
SCD, from the use of performance-enhancing sub- tible to life-threatening arrhythmias. The appearance
stances. Anabolic-androgenic steroids, including two of arrhythmias is also related to the time from the
synthetic substances, tetrahydrogestrinone and an- onset of ischemia. Within the first few minutes there
drostenedione (andro), stimulants such as ephedra, is abundant ventricular arrhythmogenesis, usually
and non-steroidal agents such as recombinant hu- lasting for 30 min (112). In acute myocardial ische-
man erythropoietin, human growth hormone, crea- mia, the obstruction of coronary flow leads to the
tine, and beta-hydroxy-beta-methylbutyrate have interruption of oxygen flow. Cellular metabolism is
been implicated (101). Due to the potential side impaired, and severe electrophysiological changes in
effects (increased risk of stroke, myocardial infarc- ionic currents and concentrations ensue, which favor
tion and sudden death) of herbal medicines contain- the development of lethal cardiac arrhythmias such
ing ephedrine and guarana-derived caffeine, the US as ventricular fibrillation (113). In large animal
Food and Drug Administration (FDA) has recently hearts, regional ischemia induces two phases of
banned the sale of ephedra-containing products, ventricular arrhythmia. The first phase, associated
specifically over-the-counter dietary supplements. with membrane depolarization, mild intracellular
As previously reported, there are possible deleterious and extracellular acidification, and small membrane
effects of beta-blockers in patients with Brugada depolarization, occurs between 5 and 7 min after
syndrome (102). Drug-induced long QT syndrome, arrest of perfusion. A second phase occurs between
occurring with drugs that directly block a specific 20 and 30 minutes after arrest of perfusion, when
cardiac ion channel (KCNH2 or hERG) that carries ischemia-induced K
and pH changes are fairly
the rapidly activating delayed rectifier potassium stable. The arrhythmia is presumably related to the
current, can lead to cardiac arrhythmias and SCD process of cell-to-cell electrical uncoupling, because
 Role of laboratory in sudden death 369

a rapid increase of tissue impedance precedes the competitive athletes. Moreover, the German Society
onset of the arrhythmia (114). for Sports Medicine and Prevention recommend a
medical check to be performed before a person starts
to seriously practice sports, with the aim of identifying
Hypoglycemia and hyperglycemia
cardiovascular factors or anomalies (122). In Japan,
Abnormal cardiac repolarization occurs consistently both athletes and non-athletes have been screened for
during insulin-induced hypoglycemia. Either potas- the presence or absence of cardiovascular diseases for
sium infusion or beta-blockade were proven effective more than 20 years (123). The screening protocols
to prevent increased QT dispersion, but they only implicates different approaches: ECG is convention-
partially prevent QT lengthening. The sympathoa- ally considered a much more effective screening tool
drenal discharge induced by hypoglycemia alters than cardiac history and history/auscultation/inspec-
cardiac repolarization by both direct and indirect tion in detecting cardiovascular abnormalities (124).
(by reducing extracellular potassium) mechanisms. A standard resting 12-lead ECG not only allows the
Autonomic neuropathy might also contribute to the recognition of various congenital abnormalities asso-
clinical risk of cardiac arrhythmias during nocturnal ciated with ventricular arrhythmias and SCD, but also
Ann Med Downloaded from informahealthcare.com by CDL-UC San Diego on 06/07/15

hypoglycemia (115). Diabetes mellitus and impaired the identification of various other ECG abnormal-
glucose tolerance patients are an elevated risk of ities, such as those due to electrolyte disturbances, or
SCD (116). HRV is inversely associated with plasma
those reflecting underlying structural diseases, such
glucose levels, and it is reduced in diabetics as well as
as bundle branch block, atrio-ventricular (AV) block,
in subjects with impaired fasting glucose levels
ventricular hypertrophy, and Q waves indicative of
(117). The potential triggering mechanism is human
ischemic heart disease or infiltrative cardiomyopathy
ether-a-go-go-related gene (HERG) K
dysfunc-
(95). The resting ECG may be useful, in that it
tion, which is a typical cause of diabetic QT
prolongation (QT-P) (118). Contrarily, as reported measures several variables of prognostic value, but is
For personal use only.

by others, glycemic index might be a significant not often considered as part of SCD risk stratification.
predictor of spontaneous ventricular tachycardia Prolonged conduction creates increased dispersion of
(VT), independently of QT interval (119). depolarization and repolarization, thus promoting
ventricular arrhythmias (125). QRS duration, which
reflects intraventricular conduction time, and pre-
Severe weight reduction sence of left bundle branch block were found to be
Low QRS voltage, QT interval prolongation, and independent predictors of SCD and total mortality
both non-sustained ventricular arrhythmias and (126). A large proportion of cardiovascular diseases
SCD have been described in subjects treated with underlying sudden death in young competitive ath-
weight reduction diets. Orthostatic hypotension may letes may be detected by ECG (127). Silent but
complicate very-low-calorie protein diets because of potentially lethal conditions, distinctively manifesting
sodium depletion and depressed sympathetic ner- with ECG abnormalities, include cardiomyopathies
vous system activity (120). Moreover, the effect of (such as hypertrophic cardiomyopathy, arrhythmo-
weight loss on the electrocardiogram abnormalities genic right ventricular cardiomyopathy, and dilated
of obesity appears to be dependent upon diet cardiomyopathy), conduction system diseases, and
duration and whether protein and mineral nutri- cardiac ion channel diseases (63). Echocardiography
tional status is maintained. Copper, potassium, and and exercise stress echocardiography are therefore
magnesium deficiencies may play important roles in indicated in patients with ventricular arrhythmias
promoting an electrically unstable heart. Stress, by suspected of having structural heart disease or in
eliciting autonomic imbalance, may also act upon an acute myocardial infarction (AMI) survivors (128). A
electrically unstable heart to provoke acute arrhyth- specific behavioral follow-up should also be ad-
mias (121). dressed, as cocaine administration and doping, which
both can lead to cardiac problems and SCD in
sportsmen (129). Among AMI survivors the abnor-
Identification of the patients at risk mal Holter variables, such as all HR variability
The prevention of SCD requires detection of well indexes (except the high-frequency spectral compo-
known pathologies, which are often clinically latent nent of HR variability), predict the occurrence of
but may develop in form of sudden death. As a SCD, but only among the patients with slightly
paradigmatic example of effective prevention in high- reduced or preserved left ventricular (LV) systolic
risk categories, the European Society of Cardiology function (96). Moreover, elevated brain natriuretic
has proposed cardiovascular screening for young peptide (BNP) provides information on the risk of
 370 M. Montagnana et al.

subsequent SCD, independently of clinical variables (134). Eight of the most commonly mutated genes
and left ventricular ejection fraction (EF)(130). have been selected and clustered within three tests
panels. The panel A includes the most common
mutations. If it comes up negative, the panel B is
New hypothesis: potential role of laboratory then performed, which picks up rarer mutations. If
testing in the early identification of subjects at also the B panel is negative, panel C is performed,
high risk which tests for other causes of hypertrophy with
Basic research could be a potential aid to evaluating signs and symptoms that mimic cardiomyopathy.
specific individuals and subgroups with enhanced The reason for three smaller tests, rather than a
progressive or inherited susceptibility to lethal ar- larger one, is to cut down the costs. In case a
rhythmias. Efforts in risk stratification for SCD have patient tests positive for one or more of these
primarily focused on predicting unfavorable events in panels, other family members including younger
patients with structural heart disease, since the children who would otherwise go undiagnosed for
incidence of SCD increases 6- to 10-fold in this years can be offered with the same diagnostic
subset of patients (43). However, despite the ubi- strategy. From this perspective, genetic testing
Ann Med Downloaded from informahealthcare.com by CDL-UC San Diego on 06/07/15

quity of tests that have been purported to predict appears financially reasonable. For example, in
SCD vulnerability in these patients, there is little LQTS patients, genotyping can be very important
consensus on which test, in addition to the left for the approximately 35% of gene carriers with
ventricular ejection fraction, should be used to normal to borderline QTc intervals of 0.410.46
determine which patients will finally benefit from seconds, since they are difficult to diagnose and
an implantable cardioverter defibrillator (131). A separate from the large percentage of normals with
variety of studies demonstrated familial clustering of these same QTc values. Importantly, recent evi-
events. Allelic variation in candidate genes in a dence indicates that these gene carriers with
reduced penetrance of the QTc have essentially
For personal use only.

number of signaling systems that alter myocardial

electrical substrate or triggers, cell survival pathways, the same risk of syncope and sudden death as
and thrombotic cascades may enhance susceptibility LQTS patients as a whole (22). In this circum-
to SCD in the failing heart (132). Therefore, a first stance, a correct diagnosis allows life-saving treat-
reliable step in risk stratification might be the ment to be instituted (23). For LQTS, genotype
assessment of a genetic predisposition. The comple- phenotype correlations have been developed along
tion of the Human Genome Project in 2003 is with important improvement in risk stratification
shifting the focus of modern health care from disease and genetic-guided treatment. Genetic screening
management based on clinical signs to genomic- has shown that LQTS is more frequent than
based treatment and prevention. The personalized expected, and, interestingly, ethnic-specific poly-
medicine includes the use of genomic information to morphisms conferring increased susceptibility to
improve the diagnosis of disease, as well as the drug-induced QT prolongation and torsade de
prevention and treatment. Single-gene disorders pointes have been identified (135). Although ge-
predominate as causes of SCD in the young, and netic testing forms a part of the process of early
molecular genetic analysis may facilitate familial identification of high-risk subjects, its role varies
assessment (1). Therefore, genetics would allow not with different tests and in different conditions
only an early but a definitive diagnosis to be made in (136). At present, genetic tests are usually reserved
SCD. Accordingly, identification of the causal gene for confirming a clinically suspected diagnosis. In
mutation and additional genotypephenotype corre- fact, the standard ECG can identify patients with
lation studies will provide a fundamental insight into inherited arrhythmogenic diseases. Other diseases,
mechanisms of cardiac remodeling (132). such as familial HCM or arrhythmogenic right
Some genetic substrates confer susceptibility to ventricular cardiomyopathy, may require echocar-
development of dangerous cardiac rhythms and diography and further cardiac investigations to be
maladaptive responses to stressors (133). For ex- diagnosed correctly (137). Moreover, a number of
ample, the diagnostic utility of genetic testing for factors should be taken into consideration: sensi-
HCM or other genetic diseases predisposing to tivity and specificity of testing, a cost-efficacy
SCD is clearly evident. Identification of such high- benefit, implications of test results on patient life-
risk mutations calls for intensive evaluation and style, and the potential consequences of the screen-
possibly an implanted defibrillator. The Harvard ing on the clinical management and the prognosis
Medical School-Partners HealthCare Center for (136). Indeed, the definition of a risk status is
Genetics and Genomics (HPCGG) provides an unsuitable for the screening of large ‘healthy’
example in the diagnosis of genetic cardiomyopathy populations, but usually starts with a positive
 Role of laboratory in sudden death 371

clinical diagnosis in an affected family member. Pharmacological prevention of SCD includes the
Once the disease has been recognized, results can use of several drugs targeting the early (upstream)
be easily used to assess which other members of the processes of the complex cascade leading to SCD,
family may carry that particular genotype. These such as beta-blockers, aldosterone antagonists, an-
subjects, who might be at higher risk of developing giotensin-converting enzyme inhibitors, angiotensin
SCD, might also benefit from prevention, appro- receptor-blocker agents (41), or others drug that
priate clinical management, and early triage (136). prevent acute ischemic cardiac events (aspirin,
The second step of laboratory evaluation might statins, and omega-3 fatty acids).
be the identification of transient risk markers,
potentially triggers for SCD, such as inflammatory
markers (43), aberrant intracellular Ca handling, Conclusions
ionic imbalances, or neurohumoral changes. Re-
Systems biology attempts to elucidate the complex
cently, other laboratory markers, such as non-
interaction between genes, proteins, and metabolites
esterified fatty acids (NEFA) (138), EPA (eicosa-
to provide a mechanistic understanding of most
pentaenoic acid/arachidonic acid) (139) and plasma
Ann Med Downloaded from informahealthcare.com by CDL-UC San Diego on 06/07/15

biological functions and how the human biology is

N-terminal (NT) fragment of pro-brain natriuretic
affected by disease processes, drug toxicity, or drug
peptide (BNP) (130), have been proposed, but
efficacy effects. SCD is emerging as a major health
there is no definitive evidence on their clinical
care problem worldwide. Although the pathogenesis
usefulness in this specific circumstance so far.
is still partially unclear, a variety of predisposing and
triggering conditions have been identified, whose
interaction might discriminate a subset of patients
Prevention of SCD
characterized by a greater risk. A reliable clinical and
Primary prevention of SCD requires identification of diagnostic approach might hence be effective to
For personal use only.

potential SCD victims ahead of the first arrhythmia unmask the most important genetic and environ-
episode. For example, actions for primary preven- mental factors, allowing the construction of a rational
tion of CAD, the first cause of SCD, should be personalized medicine framework that can be applied
targeted to reduce the impact of major and inde- in both preclinical and clinical settings of SCD.
pendent risk factors (137). Patients with acute
bradyarrhythmias often retain a basal circulation,
for example due to ventricular escape rhythms.
Thereby, the appropriate treatment (often a pace- References
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