In the past 20 years, cardiovascular mortality has decreased in high-income countries, in response to the adoption of preventive measures to reduce the burden of coronary artery disease (CAD) and heart failure (HF). Approximately 1 in every 4 deaths is a direct consequence of suden cardiac arrest (SCA), which is defined as suddencardiacdeath (SCD). To prevent SCD and decrease the incidence further, risk stratification is crucial for identifying persons at increased risk. Primaryprevention of SCD focuses on individuals who are at risk of SCD but have not yet experienced an aborted cardiac arrest or life-threatening arrhythmias. However, accurate risk stratification remains challenging, because approximately 50% of cardiac arrests occur in individuals without a known heart disease and without detectable markers. Additional research is necessary to determine which further tests are effective in these patients, looking at the significance of alterations in cardiac function, signs of electrical instability identified by electrocardiogram abnormalities or by autonomic tests, and the progressive impact of genetic screening. Despite its insufficient accuracy, the only indicator that has consistently shown an association with increased risk of SCD is left ventricular ejection fraction (LVEF). Correct identification of future SCD victims is especially important as there is an effective treatment, namely defibrillation via an external or internal defibrillator. Implantable cardioverter-defibrillators (ICD) are the most widely used devices, while wearable defibrillators require additional research. The most important aspect of the successful prevention of SCD is effective management of underlying diseases and co- morbidities. Approximately 40% of the observed reduction in SCD is the direct consequence of a reduction of CAD and other cardiac conditions.
ICD follow-up data. During the follow-up period, 15 subjects (6 with ICM, 9 with NICM) received appropriate device therapies with a median time from device implanta- tion to first therapy of 211 days (IQR: 86 to 370 days). Of these 15 patients, 12 (80%) received defibrillation (7 for ventricular fibrillation and 5 for sustained ventricular tachy- cardia), with the remaining 3 receiving antitachycardia pacing for sustained ventricular tachycardia. The average rate of ventricular tachycardia was 199 beats/min (range 150 to 227 beats/min). All therapies occurred in subjects with LGE on CMRI (LGE⫹), which resulted in a significant increase in rate of device therapy in the LGE⫹ group compared with patients without LGE (21% in LGE⫹ patients vs. 0% in LGE⫺ patients, p ⫽ 0.01). Death occurred in 2 subjects in the LGE⫺ group and 1 in the LGE⫹ group, whereas 8 LGE⫹ patients received heart transplantation at a median time of 328 days (IQR: 210 to 459 days) after ICD implantation. When subjects were stratified by device therapy, there was no difference in age, LVEF, or medication use ( Table 2 ).
balance as well as monitoring of heart rhythm . However, it is common knowledge that the implantation of automatic cardioverter-defibrillators (ICD) both as a primary and secondary prevention is the only effective way of preventing SCD . Though ICD implantation decreases the risk of SCD, there are hardly any trials concerning the use of ICD in patients with advanced renal insufficiency . The ICD is a device that works symptomatically and thus it does not decrease the risk of arrhythmic events, in contrast to coronary revascular- ization, optimal pharmacotherapy or cardiac resynchro- nization in HF [65,66]. Published data (MADIT II study) show that ICD implantation contributed to reduction in total mortality in primary and secondary prevention, and reduction in mortality from arrhythmia causes in a population of patients after myocardial infarction . On the basis of the results of the aforementioned stud- ies, guidelines considering the indications for ICD im- plantation were defined . According to them, an ICD should be implanted as the secondary prevention in patients who survived cardiac arrest in the course of ma- lignant ventricular arrhythmias unless arrhythmia oc- curred within the first 24-48 h after fresh myocardial infarction (class I of recommendation, level A of evi- dence). During the first 24-48 h ventricular arrhythmia is a symptom of acute ischemia, and treatment should refer to immediate and optimal coronary revasculariza- tion . In the primaryprevention of SCD, ICD should be implanted within 40 days after MI in patients with the EF 30-40%, in NYHA class II-III, receiving optimal pharmacological treatment and with predicted survival in good functional condition for at least one year (class I of recommendation, level A of evidence) .
was the primary endpoint, whereas SCD or ICD therapy was a secondary endpoint. It is always harder to interpret results on the basis of composite end- points. The small number of events is perhaps the reason why many of these studies have used such a strategy. Still, the largest study had 30 total events, which potentially makes most models over-fitted. Also, the quantification of scar throughout studies was performed with different techniques. Furthermore, the endpoints were neither uniform nor interchangeable. Inducible VT, which was the primary endpoint of 2 studies, might not be a good endpoint, because a negative study is often not reassuring ( 27 ); indeed, Klem et al. ( 22 ) showed in a subgroup analysis that LGE was more predictive of death or ICD therapy than electrophysiologic study. The more clinically important endpoints, such as SCD or ICD shock for ventricular fibrillation or very fast VT, were limited in numbers. Finally, the role of CMR in risk-stratifying patients might be less important for secondary pre- vention as compared with primaryprevention, and stratification results on the basis of the ICD indication were unclear in all but 1 of the studies ( 16 ) ( Table 2 ).
defibrillation effectiveness (e.g. termination of 2 induced VF episodes with 25 J each in a 35 J device). However, in modern high-out- put ICDs with left pectoral implantation the primary shock success rates have been esti- mated to be as high as 95% for submaximal and 99% for maximal shocks in the setting of induced ventricular fibrillation (44). Addition- ally, the incidence of shocks has declined, be- cause most ICDs are implanted for primaryprevention indications today and antitachy- cardia pacing is used as a first-line therapy for the termination of ventricular tachycardia. Hence, it has been questioned whether rou- tine implant testing still is mandatory, and sur- vey data indicate that many implanting cen- tres have stopped this practice (44). This is- sue is still unresolved but novel data can be expected from current randomized trials (e.g. the SIMPLE trial) that prospectively test risk and benefit of routine DFT testing.
ICD implantation is currently recommended in young adults with congenital heart disease for survivors of SCD (reversible cause excluded), those with unexplained syncope and impaired ventricular function once a revers- ible cause has been excluded and for those with spontan- eous sustained VT if catheter ablation or surgical resection is not successful. 23 Khanna et al reviewed clin- ical, implantation and follow-up data on all transvenous ICDs in adults with a variety of congenital heart disease, including 12 patients with ccTGA (17%), at the Mayo Clinic from 1991 through 2008. The commonest indica- tion for ICD implantation was sustained ventricular arrhythmias or primaryprevention. They reported no major implant-related complications and found that the likelihood of an appropriate ICD discharge was asso- ciated with increased subpulmonic ventricular pressure. 24
Over the last three decades, revolutionary advances in the understanding and treatment of SCD have been accom- plished. Structural and electrical mechanisms of terminal arrhythmias have been elucidated. Over two-dozen genetic mutations and polymorphisms have been identified, which in turn have increased our understanding of ion channel struc- ture and function. At the same time, randomized trials that demonstrated harm from antiarrhythmic drugs have curtailed the use of such drugs alone in the prevention of SCD. The ICD was developed and has proved to be a highly effective therapy in the prevention of SCD to date. Although most cases of SCD occur in patients without these high-risk features, the biggest challenge still remains: to accurately identify patients at risk for SCD for primaryprevention.
the National Center for Health Statistics (NCHS), a division of the Centers for Disease Control and Prevention, maintains an online database registry, which encompasses county-level national mortality and population data. The NCHS processes and files all death certificates in the 50 states and the District of Columbia. Each year, multiple cause of death data files are created from death certificates for US residents. Available information in the database includes the following: age, sex, race and/or ethnicity, place of residence and death, a single underlying cause of death, and multiple major contributing causes of death. The underlying cause-of- death is classified in accordance with the International Classification of Diseases, 10th Revision (ICD-10) and is selected from the conditions entered by the treating physician or coroner. The study investigators obtained data through the Centers for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research platform (https:// wonder. cdc. gov/ ). All data used are deidentified; thus, institutional review board approval was not required.
yielded 3 diagnoses (HCM: n ⫽ 2; myocarditis [after revision]: n ⫽ 1). In 8 of the remaining 17 SCD cases with available pathology specimens, a primary electrical disease was identified as the most likely cause of SCD after cardiologic workup in surviving relatives. Of the other 9 autopsies, a complete revision was attempted in 1; however, we could not recover sufficient material (notably, ARVC could not be diagnosed or excluded because the right ventricular tissue had not been stored). It is conceivable that a full revision of these autopsies may have revealed a higher proportion of structural heart diseases, more comparable with earlier studies. Still, we have now established that a proportion of SCD cases in children may be explained by primary electrical diseases. Of note, these potential causes were not ana- lyzed in previous studies in which only autopsy studies were performed. These electrical diseases can only be diagnosed in survivors of aborted SCD or relatives. Over- all, it is likely that the primary electrical diseases identi- fied here may increase the overall proportion of SCD in children with a causal diagnosis.
athletes. This is, of course, very good news, because regular exercise has enormous proven potential to reduce cardiovascular morbidity and mortality. Therefore, there is a growing need to provide prac- tical, clinically relevant advice to minimize the asso- ciated risk. Among older athletes, the primary risk for sports-related SCD is CAD with acute plaque rupture. This risk is low for most endurance events, such as the marathon. Indeed, an epidemiological study has argued credibly that marathons reduce the death toll because the average number of race- associated SCDs is about one-half the number of deaths that would typically result from motor vehicle accidents if the race route were not closed to traf ﬁc (9). However, the risk associated with training is approximately 5-fold greater. Accordingly, we observe that cardiologists can intervene most effec- tively by advising noncompetitive or pre-competitive athletes. Because the most common substrate for risk is (by far) CAD, the main objective of pre-
In the children aged 1 to 18 years that we studied, SCD is, in part, caused by inherited heart disease, both struc- tural (HCM and ARVC) and primary electrical (LQTS and CPVT). These familial diseases can be identified in high proportion even after the SCD victim has died, that is, by postmortem analysis or cardiologic and genetic investigation of surviving relatives. Referral to a cardio- genetics department is encouraged, because such depart- ments offer not only cardiologic investigation and DNA analysis but also specialized genetic counseling, includ- ing psychosocial support.
cardiomyopathy (NICM) for primary and secondary prevention of SCD. (NCBI, 2015; Kuck et al., 2000; AVID, 1997; Connolly et al., 2000) Although ICD therapy has been reproducibly shown to improve mortality in eligible patients, the costs associated with this therapy warrant that it is used appropriately. To that end, a wide variety of noninvasive techniques for risk stratification are available, including LV ejection fraction assessment by echocardiography, QRS duration estimates by surface 12-lead ECG, QT interval/dispersion and heart rate variability, among others. (Goldberger et al., 2008) More recently, cardiac magnetic resonance imaging (CMRI) has been put forth as a highly sensitive and specific noninvasive diagnostic modality for delineating myocardial scar in the setting of NICM. (Gulati et al., 2013) Invasive electrophysiologic study and/or intracardiac catheter mapping also offer an alternate means of identifying and characterizing arrhythmogenic substrate, although the prognostic value of programmed stimulation remains unclear. Despite the plethora of available options, there is a paucity of randomized clinical trials and a lack of consensus in support of any one diagnostic algorithm that can consistently stratify the risk for suddencardiacdeath. The present review addresses the implications for non invasive imaging in identifying high risk of SCD in patients with dilated cardiomyopathy causing heart failure
DCM-related genetic variants have also been recently found in other genes encoding sarcomere proteins, namely α-cardiac actin, α-tropomyosin, cardiac troponin T, I, and C, β- and α-myosin heavy chains, myosin binding protein C, and α-actinin-2 .Of note, such genetic vari- ants have also been observed in HCM. Additionally, hypertrophic and dilated phenotypes may overlap in some families, emphasizing that definition of the morphological features of cardiomyopathy may also have a key role in diagnosis. Among the mutations impairing electrolyte homeostasis, PLN gene mutations may contribute to the DCM phenotype . PLN encodes phospholam- ban, a protein that modulates calcium uptake by the calcium-transporting ATPase of the sarcoplasmic reticulum (SERCA2a). Mutations in the SCN5A gene have similarly been implicated in DCM. However, this gene has also been associated with other cardiac diseases that may cause SD, confirming that examin- ation of morphological features may be necessary to clinically characterize DCM. Among structural proteins, mutations in the LMNA gene encoding the lamin-A and -C nuclear envelope proteins may account for up to 5% of all autosomal dominant DCM cases [65, 75]. These pro- teins are ubiquitously expressed and play key roles in the maintenance of proper nuclear structure. Alterations of laminin-A and -C proteins may cause dilated cardiomyop- athy, atrioventricular block, and both atrial and ventricular fibrillation . LMNA mutations are highly predictive for progressive conduction disease and SD risk. Although clinical identification of affected subjects at high risk of SCD is quite difficult, the identification of LMNA muta- tions has recognized prognostic value for the diagnosis of DCM. Overall, the genetic heterogeneity of DCM and the overlap of mutations with other cardiac diseases have pre- vented the assessment of a direct correlation between genetic features and this specific pathology. As reported above, the same mutation may be the cause of DCM or HCM in different unrelated subjects. However, heart function and morphology may be affected differently, suggesting that factors other than genetic ones (e.g., en- vironment) may influence the phenotypic expression of a primary cardiomyopathy.
This review does not allow us to surely identify the pre- ference causes of SCD in athletes. Although this etiology tends to prevail in older subjects, it seems that in com- petitive sports there is insufficient evidence regarding this matter. Acceptance of this premise may reduce the preventive approach to SCD just aiming to exclude con- genital heart in young and just deal with coronary risk factors in the elderly, considering as secondary level the prevention of other possible etiologies for the athletes, including masters in football. The qualification by age implies that as a result of age the athletes would present limitations that would hamper their performance. More- over, ages above 35 years old puts a real stigma in these athletes, thus, compromising physical performance, beyond the psychological involvement resulting on SCD risk.
A blow to the chest in the area of the heart, called commotio cordis, or cardiac concussion is a rare cause of suddendeath in athletes. This condition often occurs in children or adolescents with a non-penetrating and usually innocent appearing, blow to the middle of the chest, such as when a baseball, hockey puck, lacrosse ball, softball or karate blow strikes the athlete’s chest. The precise incidence of commotio cordis is unknown because of the absence of systematic and mandatory reporting, but on the basis of data from the National Commotio Cordis Registry in Minneapolis, it is among the most frequent cardio- vascular causes of suddendeath in young US athletes, after HCM and congenital coronary artery anomalies. 32 33 Since commotio cordis occurs in a wide variety of circumstances, it has undoubtedly been underreported. Most victims are boys or men and are white. Although cardiovascular collapse is virtually instantaneous, 20% of victims remain physically active for a few seconds after the blow (eg, continuing to walk, run, skate, throw a ball or even speak), which may reﬂect individual toler- ance for sustained ventricular tachyarrhythmias. Commotio cordis is a primary arrhythmic event that occurs when the mechanical energy generated by a blow is con ﬁned to a small area of the precordium and profoundly alters the electrical sta- bility of the myocardium, resulting in ventricular ﬁbrillation. The ﬁrst of these determinants involves the location of the blow, which must be directly over the heart ( particularly at or near the centre of the cardiac silhouette). This ﬁnding is con- sistent with clinical observations at autopsy, that precordial bruises representing the imprint of a blow are frequently evident in victims. There is no evidence in humans or in experi- mental models that blows sustained outside the precordium (eg, the back, the ﬂank or the right side of the chest) cause suddendeath. The second determinant concerns the timing of the blow, which must occur within a narrow window of 10–20 ms on the upstroke of the T-wave, just before its peak
defibrillators (ICDs) enabled prompt recognition and termi- nation of ventricular tachyarrhythmias, including sustained monomorphic ventricular tachycardia and ventricular fibril- lation (VT/VF), leading to a demonstrable survival benefit in both ischemic and non-ischemic cardiomyopathy (NICM) for primary and secondary prevention of SCD. 1116 Although ICD therapy has been reproducibly shown to improve mortality in eligible patients, the costs associated with this therapy war- rant that it is used appropriately. To that end, a wide variety of noninvasive techniques for risk stratification are available, including LV ejection fraction assessment by echocardiogra- phy, QRS duration estimates by surface 12-lead ECG, QT interval/dispersion and heart rate variability, among others. 17 More recently, cardiac magnetic resonance imaging (CMRI) has been put forth as a highly sensitive and specific non- invasive diagnostic modality for delineating myocardial scar in the setting of NICM. 18,19 Invasive electrophysiologic study
The differential diagnosis for causes of pediatric SCD includes anatomic and structural abnormalities of the heart (eg, hypertrophic cardiomyopathy, single right coronary artery with anomalous course of the left coro- nary between the aorta and pulmonary artery, arrhyth- mogenic right ventricular cardiomyopathy, etc), primary electrical cardiac disorders (including long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome), stimulant use (eg, cocaine, ephedra), and trauma (commotio cor- dis). Importantly, because many of these disorders are genetic, the identification of a first-affected family mem- ber may unravel extensive family involvement.
authors did not detail how cases with multiple International Classification of Diseases, 10th Revision codes for overlapping cardiac conditions were classified. It is thus likely that a fraction of the deaths attributed to primary arrhythmia versus other cardiac conditions may have been misclassified. An accurate diagnosis of any underlying cardiac condition is vital to evaluate prevention measures for these seemingly preventable deaths.
Clearly, FHC of adults is a disease of the sarcomere. Similarly, patients with other cardiac disorders, such as familial dilated cardiomyopathy (FDCM) and familial vent- ricular arrhythmias (i.e., LQTS and Brugada syndrome) have been shown to have mutations in genes encoding a consistent family of proteins. In familial ventricular arrhythmias, ion channel gene mutations (i.e., ion channel- opathy) have been found in all cases thus far reported. In FDCM, cytoskeletal protein-encoding genes and sarcomeric proteins have been speculated to be causative (i.e., cyto- skeletal/sarcomyopathy) . Hence, the final common pathways of these disorders include ion channels and cytoskeletal proteins, similar to the sarcomyopathy in HCM. Intermediate disorders, such as ARVD/ARVC, appear to connect the primary electrical and primary muscle disorders mechanistically. Although it is not yet certain what the underlying pathways and targets are for RCM, hints have been forthcoming. Desmin and other intermedi- ate filament proteins appear to be at play in RCM as has been shown in animal models. In addition, it appears that cascade pathways are involved directly in some cases (i.e., mitochondrial abnormalities in HCM, DCM), while sec- ondary influences are likely to result in the wide clinical spectrum seen in patients with similar mutations. In HCM, mitochondrial and metabolic influences are probably important. Additionally, molecular interactions with such molecules as calcineurin, sex hormones, growth factors, among others, are probably involved in development of clinical signs, symptoms and age of presentation. In the future, these factors are expected to be uncovered, allowing for development of new therapeutic strategies.
stress-related enzyme, myeloperoxidase (MPO), a heme peroxidase, participates in LDL oxidation mediated by radical 1e-oxidation and non-radical 2e-oxidation . Detection, quantification and imaging of MPO mass and activity are useful in cardiac risk stratification . Mean- while, urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored membrane protein that, during inflammation, becomes shedded from cell membrane and forms soluble uPAR (suPAR) . The levels of plasma suPAR were shown to correlate with pro-inflammatory markers and even outperform CRP at prognosticating CVD [68, 69]. Another protein, pentraxin-3 (PTX3) is re- leased upon primary inflammatory signals  and has been implicated as an inflammatory biomarker for CAD . In two independent clinical trials (CORONA and GISSI-HF) enrolling patients with chronic HF, PTX3 was consistently associated with adverse outcomes . Fi- nally, matrix metalloproteinases (MMP) are implicated in plaque formation and rupture, leading to coronary occlu- sion . Individuals with acute coronary syndrome and CAD were shown to possess elevated levels of MMP-1, − 2, − 8 and − 9 in their plasma [74, 75].