|Year : 2022 | Volume
| Issue : 4 | Page : 157-169
Overview of sudden cardiac deaths
Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD, USA
|Date of Submission||07-Dec-2022|
|Date of Decision||12-Dec-2022|
|Date of Acceptance||12-Dec-2022|
|Date of Web Publication||30-Dec-2022|
Dr. Allen Burke
Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD 21201
Source of Support: None, Conflict of Interest: None
Sudden cardiac death (SCD) is an unexpected cardiac death that is instantaneous or occurs within a short period of time after onset of symptoms, in a person in a stable state of health. SCD has either a certain etiology (for example, cardiac tamponade or fresh occlusive coronary thrombus), or has one or more morphologic substrates that increase the risk of electrical instability that in turn can lead to a fatal arrhythmia. The latter group of SCD has been assigned as either highly probable or uncertain etiologies, according to guidelines of the Association of European Cardiovascular Pathology. This review describes definitive causes and potential underlying substrates for SCD.
Keywords: Sudden cardiac death, pathology, cardiomegaly
|How to cite this article:|
Burke A. Overview of sudden cardiac deaths. J Forensic Sci Med 2022;8:157-69
| Introduction|| |
Sudden cardiac death (SCD) is an unexpected death due to cardiac causes that is instantaneous or occurs within a short period of time after the onset of symptoms. The cause of SCD is typically attributed to one or more morphologic substrates that increase the risk of electrical instability that can lead to a fatal arrhythmia. Because of uncertainty in the relationship between the cause of death and the individual substrate in many cases, causes of SCD have been classified as certain, highly probable, and uncertain. The Association of European Cardiovascular Pathology has issued the guidelines for what constitutes normal, uncertain, and pathologic cardiac findings in the autopsy setting.
| Epidemiology|| |
SCD has an incidence of about 0.1%–0.2% per year in the adult population, or 1–2 deaths per 1000 person-years., The incidence of sudden death in adolescents and young adults is far lower, about 0.003% per year, about 25% of which are unexplained, even with autopsy (sudden arrhythmic death syndrome [SADS])., SCD can also occur in young, otherwise healthy-appearing athletes, where the incidence ranges from 1:3000 person-years to 1:917,000 person-years, with the highest incidence seen in African American male basketball players. Men in general have been reported to have at least a 2-4-fold increased risk when compared with women.
In individuals over 40 years of age, the most causes of SCD are acquired, with coronary atherosclerosis present in more than 7 of every 10 cases. Hypertensive heart disease is the second most common cause and has appreciable overlap with atherosclerotic heart disease, given the common risk factors.
In people younger than 40 years of age, congenital disease is the most common cause of SCD, including anomalous coronary artery origin hypertrophic cardiomyopathy (HCM) and arrhythmogenic cardiomyopathy (AC).
In children, congenital coronary anomalies and myocarditis are the most common causes of SCD, followed by HCM. Rare causes include noncompaction cardiomyopathy, supra or subvalvular aortic stenosis, coronary artery dysplasia, histiocytoid cardiomyopathy, undiagnosed complex congenital heart disease, cardiac rhabdomyoma, and cardiac fibroma.
| Types of Cardiac Arrest|| |
The most common is electrical, followed by mechanical.
Sudden arrhythmic events are the most common cause of SCD. Arrhythmogenic foci can result from myocardial ischemia, scarring, or inflammation. The precise location of the arrhythmogenic focus in the ventricular myocardium is usually not definitively established by the pathologic examination, rather structural abnormalities in a broad sense are assumed to be culpable for such. In fact, there are often multiple coexisting potential substrates for arrhythmia identified in a given heart, including coronary artery disease (leading to presumed myocardial ischemia), myocyte hypertrophy (which increases the heart's oxygen demand), and scarring.
Some cases of SCD are caused by sudden catastrophic changes in hemodynamics, so-called mechanical arrest. These changes can involve the heart itself or the great arteries. These may be relatively common (e.g., cardiac tamponade as a result of ischemic myocardial rupture or ruptured aortic aneurysm, and pulmonary embolism) or rare (e.g., tumor obstructing normal blood flow).
| Sudden Coronary Death|| |
The most common acquired lesion is atherosclerosis, although there are numerous nonatherosclerotic causes of cardiac ischemia, both congenital and acquired.
Congenital coronary anomalies
These include ectopic origin and congenital narrowing by dysplasia. The most common anomaly affecting infants and young children is the anomalous left coronary artery from pulmonary artery (ALCAPA or Bland-White-Garland syndrome More Details) occurring in 1/50,000–1/300,000 autopsies, representing 0.25%–0.5% of congenital heart diseases. Most cases are identified in the 1st year of life, and sudden death occurs in approximately 40% of cases. When unrecognized, mortality resulting from this lesion is high (80%–90% in the 1st year of life). Sudden death usually occurs at rest but may occur after strenuous activity in older children. Pathologically, the aberrant artery arises in the left pulmonary sinus in 95% of cases [Figure 1]. Conventionally, the artery appears thin-walled and vein-like, and the right coronary artery, while normal in location, is tortuous. The heart is typically enlarged, with extensive scarring and thinning of the anterolateral left ventricular wall and anterolateral papillary muscle. Dilatation of the left ventricle with endocardial fibroelastosis is common, and the gross appearance of the heart may mimic dilated cardiomyopathy.
Anomalous left main coronary artery from the right aortic sinus is lethal in up to 75% of affected individuals and generally presents in adolescence or young adulthood. It has a male predilection (male: female = 4–9:1). There are often premonitory symptoms of syncope or chest pain, but stress electrocardiograms and stress echocardiograms are often negative. Almost three-fourths of individuals dying during or immediately after exertion.,
|Figure 1: ALCAPA. A probe is in the ostium of the left coronary artery in the pulmonary outflow|
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Pathologically, the ectopic ostium is typically near the commissure [Figure 2], and in some cases actually lies above the commissure between the right and left sinuses. Often, the ostium is somewhat malformed and slit-like, and an ostial ridge is present. The proximal artery lies within the aortic media and traverses between the aorta and pulmonary trunk., In a minority of cases, the left main travels anterior to the pulmonary trunk, posterior to the aorta, or posterior to the right ventricular outflow tract within the ventricular septum. Because of the relatively high frequency of the conus coronary artery arising directly from the right aortic sinus, it is not uncommon to see 2 ostia within said sinus. Therefore, two or three ostia may be seen in the setting of this anomaly.
|Figure 2: Anomalous origin of the left coronary artery from right sinus of Valsalva. Double arrow: Anomalous ostium, R: Right sinus of Valsalva, Single arrow: Normal right ostium, NC: Noncoronary sinus of Valsalva|
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The pathophysiology of sudden death in patients with aberrant left main coronary artery may be related to the compression of the left main by the pulmonary trunk and aorta, diastolic compression of the vessel lying within the aortic media, and poor filling during diastole because of ostial ridges or slit-like ostia.
Anomalous origin of the right coronary artery from the left aortic sinus is far less lethal than an anomalous left and may cause sudden death in up to one in three individuals. In contrast to anomalous left main coronary artery, anomalous right coronary artery from the left aortic sinus was thought to be an incidental finding, although cases of SCD have been attributed to this variant as well. Almost 50% of these deaths are exercise-related, and most deaths occur in individuals <35 years of age.
Grossly, there are two ostia located in the left aortic sinus [Figure 3]. The ostium supplying the right coronary artery may have similar features as anomalous left ostia located in the right sinus. Namely, there may be upward displacement, location near the commissure, and slit-like ostium with ostial ridges. The proximal anomalous right coronary generally also courses between the aorta and pulmonary trunk. The pathophysiology of sudden death is similar to that of anomalous left coronary artery, and evidence of acute or remote ischemia in the ventricular myocardium is not often found.,,, The actual focus of ischemia in the myocardium is not often identified by autopsy, but up to 50% of hearts will show areas of scarring.
|Figure 3: Anomalous origin of the right coronary artery from the left sinus of Valsalva. Left arrow: Normal left ostium, R: Right sinus of Valsalva, NC: Noncoronary sinus of Valsalva, Right arrow: Anomalous ostium in the left sinus of Valsalva (cut through)|
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Rare congenital causes of sudden coronary death include fibromuscular dysplasia of an epicardial coronary artery, and congenital ostial stenosis of the left main coronary artery.,
Acquired nonatherosclerotic coronary disease
The most common acquired cause of nonatherosclerotic SCD is spontaneous coronary artery dissection (SCAD). SCAD occurs most frequently in women of childbearing age. The specific etiology of the condition is unknown, but some authors consider a form of arterial dysplasia. In fact, there is emerging evidence that indeed there is a heritable component to this condition. Histologically, there is medial dissection [Figure 4], sometimes accompanied by a reactive eosinophilic infiltrate surrounding the dissection tract.
Coronary artery spasm (CAS) has been shown to result in life-threatening ventricular arrhythmias and sudden death. CAS is prevalent among East Asians and is associated with an aldehyde dehydrogenase 2 (ALDH2)-deficient genotype (ALDH2*2) and alcohol flushing. At autopsy, the diagnosis can only be surmised based on the clinical history and absence of significant coronary disease. If there are areas of acute and chronic ischemia in the myocardium of sudden death victims, with normal coronary arteries, then a presumptive diagnosis of CAS can be made. In a series of SCD with successful resuscitation and return of spontaneous circulation, up to 20% of patients showed spasm on follow-up coronary angiography. However, reproducibility of diagnosing spasm after injection of triggering agents is not always reliable, and over half of the patients in Lee's first study had follow-up inherited arrhythmic syndromes including early repolarization syndrome, long QT syndrome, Brugada syndrome and AC.
Epicardial coronary artery thrombosis in the absence of underlying atherosclerosis is rare and may be a complication of cocaine abuse. More frequently, coronary thrombi without atherosclerosis are the result of vasculitis.,,
Small vessel thrombosis
Thrombosis of arterioles and capillaries is a feature of thrombotic microangiopathies, such as thrombotic thrombocytopenic purpura. Cardiac arrhythmias may result from occlusion of small vessels and result in relatively rapid death. Histologically, there may be subepicardial interstitial hemorrhages and focal myocyte necrosis. Antiphospholipid syndrome may also result in small myocardial vessel occlusion, pulmonary embolism, and autonomic dysfunction, in addition to epicardial arterial thrombosis.
Myocardial bridging occurs primarily in the left anterior descending artery and refers to the presence of cardiac muscle overlying a segment of the artery, typically in the middle portion of the left anterior descending artery. Although it is well documented clinically that intramural tunneled left anterior descending may result in myocardial ischemia and infarction,, it is difficult to prove in an individual case that it is the cause of death at autopsy.
The tunneled left anterior descending coronary artery is usually an incidental finding, occurring in 30% of autopsy heart specimens, and even higher in some anatomic studies. The length and depth of an abnormal tunneled segment is not well established. Angiographically, a significant isolated bridge (without superimposed atherosclerosis) is defined functionally, as the narrowing of the vessel during systole.
Most deaths due to coronary artery anomalies are exertional; for this reason, the finding of a deep tunnel in an exercise related death is more likely significant than in a death that occurred at rest. As with other cases of anomalous origin of coronary arteries, the finding of ischemic lesions (subendocardial necrosis or fibrosis) within the distribution of the abnormal vessel is evidence that the anomaly was hemodynamically significant.
SCD is often the first manifestation of coronary atherosclerosis, occurring in more than one-third of patients with coronary atherosclerosis. This occurs despite the fact that prior symptoms were reported to be present in more than half of these individuals. Risk factors for sudden death in patients with ischemic heart disease include presence of heart failure, especially with an ejection fraction of <30%. The risk of SCD extends beyond the initial infarction with a high rate of ventricular arrhythmias persisting throughout the patient's life. Patients who have survived a prior cardiac arrest are also likely to have recurrent arrest.,, The incidence of coronary disease increases with age in all populations, but the proportion of deaths that are sudden from coronary disease actually decreases with age.,,
By convention, at least 75% cross-sectional narrowing (grade 4 stenosis) of an epicardial coronary artery needs to be found in order for the coronary lesion to be considered a likely cause of death.
Because ischemic myocardium cannot be identified at autopsy until histologic changes are manifest,,,,,,,,,,,,, the ultimate cause (myocardial ischemia) will often not be identified, but rather inferred by the identification of the thrombus.
Lesions should be graded based on extent of stenosis (0%–25%, Grade 1; 26%–50%, Grade 2; 51%–75%, Grade 3; 76%–100%, Grade 4). In case of thrombosis, plaque rupture, plaque erosion or intraplaque hemorrhage should be noted [Figure 5].
|Figure 5: (a) Occlusive thrombus, multiple levels of coronary artery that resulted in sudden death. (b) Fibrin platelet thrombus at interface with arterial intima|
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The rate of coronary thrombosis in SCD varies widely depending on the techniques of dissection, selection of patients, and presence of noncoronary cardiac pathology but is approximately 50% if careful dissection is performed.
In most cases of coronary atherosclerosis without thrombi, there are other morphologic findings that increase the risk of ventricular arrhythmias, especially healed infarcts and ventricular hypertrophy.,, Occasionally, only stable plaque (usually causing grade 3-4 stenosis) is found, in the setting of normal heart weight and no prior infarcts. In these cases, which comprise about 15% of SCDs attributed to coronary disease, the real mechanism of death remains obscure.
The estimation of the exact degree of coronary artery narrowing may become important in sudden coronary death autopsies, especially if there are no thrombi, and if there are medicolegal concerns. There are many factors that render precise morphometric measurements somewhat meaningless in arteries that are not perfusion fixed at physiologic pressures. These include processing shrinkage and collapse of the artery, which can cause gross overestimations. Furthermore, assessment of narrowing angiographically during life is determined based on a proximal reference segment. At autopsy, the percent stenosis is estimated as an area within the internal elastic lamina at the same segment, which does not take into account as positive arterial remodeling, resulting in further overestimation of luminal narrowing.
Acute myocardial infarcts are present in about 20% of SCD cases, healed infarcts in about 50% and cardiomegaly in about 40%–50%, most often due to multifactorial diseases that include hypertension and chronic ischemic changes.,
| Sudden Cardiac Death Due to Cardiomyopathy|| |
The mechanisms of sudden death due to structural heart disease are varied.
Heart failure is known to increase the risk for ventricular arrhythmias and may serve as an intermediary mechanism behind SCD. Importantly, however, it is not technically a “cause” of death. Rather, it represents a constellation of symptoms resulting from the inability of the heart muscle to effective pump blood to meet the metabolic demands of the body. This results from an underlying pathology, such as ischemic heart disease, hypertensive heart disease, valvular heart disease or a cardiomyopathic state. In most cases, there is a history of heart disease, and the patient is taking cardiac medications.
Cardiomegaly is defined as increased size which is reflected by increased weight (>50% above the expected mean, as calculated by body size). Cardiomegaly is itself a risk factor for sudden death and should warrant investigation for an underlying etiology. The most common cause of cardiomegaly is concentric left ventricular hypertrophy (LVH), a known risk for sudden death. Concentric LVH has numerous causes, including hypertensive heart disease, idiopathic forms, and aortic stenosis. Right ventricular hypertrophy (cor pulmonale) may also be the primary finding at sudden death autopsy, and is caused by pulmonary hypertension. Terminal arrhythmias in patients with pulmonary hypertension typically show pulseless electrical activity.,
Myocardial scarring is frequent in SCD, and usually seen as a consequence of cardiomyopathy, coronary artery disease, myocarditis or sarcoidosis. The pattern and size of scars is important to note, as well as the pattern of replacement or interstitial fibrosis. Small amounts of subendocardial fibrosis is common in dilated or hypertrophied hearts, and interstitial collagen is a normal finding in some areas of the myocardium, including near the central fibrous body and near insertions of papillary muscles.
Specific forms of cardiomyopathy
There are three primary genetic cardiomyopathies. HCM and AC have a high rate of arrhythmias and sudden death, whereas nonischemic dilated cardiomyopathy has a relatively low rate, although many patients required defibrillators later in the course of disease.
Hypertrophic cardiomyopathy is underlying cause of death in 4%–10% of SCD. HCM is a relatively common disease, with an estimated incidence of approximately 1 in 500 people. It is autosomal dominant with variable penetrance. The incidence of SCD in the setting of HCM is quite variable and, in large part, dependent on the disease severity and the number of defined risk factors present. Risk factors associated with SCD include young age at diagnosis, presence of symptoms, presence of hemodynamic obstruction, history of arrhythmia, and family history of SCD. Patients with no risk factors can have a relatively low risk of SCD (.83% per year), while those with multiple risk factors can have a 5% risk per year. An autopsy study showed that age at death was significantly younger in exertional (27 ± 13 years) versus nonexertional sudden deaths (40 ± 16 years), and that exertional deaths were more likely in women. The average heart weight was less in exertional sudden deaths as compared to stationary deaths.
Grossly, hearts with HCM are typically enlarged and usually show thickening of the ventricular walls. This thickening may be either symmetric or asymmetric. In the latter instance, it is the ventricular septum that is usually disproportionately hypertrophied resulting in a ventricular septal-to-free wall ratio (VS: LVFW) >1.2 [Figure 6] and [Figure 7]. Microscopically, there is myocyte hypertrophic with disarray, which can be manifest as branching [Figure 8], and cartwheel configurations.
|Figure 7: Hypertrophic cardiomyopathy, septal asymmetry, short axis section|
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Molecular autopsy demonstrates mutations in sarcomeric genes in approximately 25% of sudden death cases. This contrasts with the >75% rate in living patients.
Arrhythmogenic cardiomyopathy (arrhythmogenic right ventricular cardiomyopathy) accounts for <3% of cases of SCD but is a relatively more common cause if exertional deaths are considered., Similar to HCM, AC is familial in up to 50% of cases, in which case the mode of inheritance is autosomal dominant with variable penetrance. Most patients are <40 years old at the time of death, and some deaths occur in children. Grossly at autopsy, biventricular scars situated under the epicardium are seen in the majority of hearts from patients dying suddenly. Heart weight is increased in slightly over 50%. Histologically, there are areas of fibrofatty change with vacuolated myocytes [Figure 9].
Molecular autopsy studies show mutations in desmosomal genes in approximately 10%–15% of cases. As in the case with HCM, mutations are more common in testing done on living patients. In one study, over 50% of patients transplanted for AC had lethal mutations, slightly over one-half of which were not desmosomal.
LAMP-1 mutations can cause SCD due to massive LVH usually in adults.,
By far the most common forms of cardiomyopathy that contribute to adult SCD are secondary, usually to hypertension and/or chronic renal disease. At forensic autopsy there is often limited history, but renal vascular disease would suggest a degree of clinical hypertension. The heart shows concentric LVH appreciated best on short axis sections.
Aortic stenosis is another common cause of LVH and potentially lethal tachyarrhythmias. In children, sub-or supravalvular aortic stenosis may cause sudden death, whereas in adults both congenitally bicuspid or degenerative tricuspid valves are the cause. Aortic stenosis accounts for approximately 2% of sudden deaths in adults and the risk in living patients is <1% per year.
| Sudden Death Caused by Myocarditis|| |
Inflammation in the myocardium can take the form of diffuse mononuclear cell infiltrates, acute inflammation with abscesses, such as seen in infectious endocarditis, granulomatous inflammation, and incidental focal lesions. The presence of myocyte necrosis is important in establishing a causative link to death, especially if the lesions are focal.
Less than one percent of adult SCD are due to myocarditis. Most patients are younger than 30 and there is no strong sex predilection. Nearly half are witnessed collapses but only a small fraction are exertional.,, The diagnosis is made microscopically by diffuse inflammatory infiltrates. A grossly mottled myocardial appearance or gross fibrosis is present in 10%-20% of cases. Lymphocytic myocarditis is most common [Figure 10], followed by neutrophilic, eosinophilic, and giant cell type [Figure 11] and [Figure 12]. Myocyte necrosis is seen in all giant cell types, and in the majority of lymphocytic and neutrophilic myocarditis.
The role of focal myocarditis as a cause of sudden death is debated, and often ascribed as a contributing or possible cause., In general if the infiltrates are small (<1 mm) and not numerous, the term “myocarditis” is best avoided, unless there is unequivocal necrosis. Focal myocardial inflammation (<5 small, microscopic foci) without necrosis has been reported as an incidental finding and appears more likely in deceased who were taking oral medications, especially antibiotics.
Cardiac involvement in systemic sarcoidosis is not uncommon. Symptoms are most commonly related to high-grade atrioventricular (AV) block, followed by heart failure and ventricular arrhythmias. In one large series, 14% of patients died suddenly, most of whom had no clinical diagnosis.
Grossly, sarcoidosis that results in SCD shows large areas of scar, with no real ventricular predilection [Figure 13]. Microscopically granulomas are seen virtually anywhere, including valves, epicardial fat, and epicardial coronary arteries. The scars are somewhat random and do not usually appear similar to healed infarcts, although there are exceptions that appear aneurysmal. Microscopically, there is granulomatous inflammation in more recent areas of inflammation, progressing to acellular scars [Figure 14]. Necrotizing granulomas have not been reported as are occasionally seen in pulmonary sarcoid.
| Mixed and Multiple Arrhythmogenic Substrates|| |
In many cases of SCD there are multiple anatomic substrates found at autopsy, each of which contributes to the electrical instability of the heart. In patients with coronary artery disease, there are frequently changes of ventricular remodeling, such as cardiomegaly, ventricular dilatation, and scars from previous infarcts. It is the role of the autopsy pathologist to enumerate the potential arrhythmogenic substrates, with the most likely first. Combining terms (e.g., hypertensive and atherosclerotic cardiovascular disease) is appropriate when one entity is not favored over another.
Phenotypic-genotypic discordance occurs when there are morphologic features of a specific cardiomyopathy, for example dilated cardiomyopathy, and genetics findings of a different phenotype, for example, desmosomal mutations or mutations in myosin heavy chain gene. Channelopathy gene mutations such as SCN5A have been found in patients dying suddenly with morphologic features of dilated cardiomyopathy, representing a form of phenotype/genotype discordance with channelopathy and structural heart disease.
| Mitral Valve Prolapse|| |
SCD is a known complication of mitral valve prolapse (MVP), occurring in 0.4% to 2% per year., A subset of MVP patients are at high risk of malignant arrhythmias with a specific phenotype, namely bileaflet involvement, mid-systolic click on auscultation, T-wave abnormalities on inferior leads and right bundle branch-type or polymorphic ventricular arrhythmias. A mutation of the FLNC-encoded filamin C gene has been discovered in this syndrome.
At autopsy, SCD due to MVP tends to show bileaflet involvement by leaflet billowing, chordal elongation, and endocardial fibrosis under the posterior leaflet, which is generally most extensively involved [Figure 15] and [Figure 16]. Left atrial dilatation may be prominent. Potential mechanisms of death include small arterial disease, autonomic dysfunction, and congestive heart failure in cases with marked regurgitation.
| Cardiac Tumors|| |
Virtually any primary or cardiac tumor may result in an arrhythmia and SCD.
Cystic tumor of the atrioventricular node
A developmental rest originally believed to be of ultimobranchial origin, cystic tumor of the AV node is a collection of endoderm-derived glands in the region of the AV node [Figure 17]. The condition is congenital, and results in heart block from birth in most patients. Sudden death may occur at any age, from young childhood to late adulthood. In most patients, there is no clinical history, but when present it is generally heart block.
|Figure 17: (a) Cystic tumor of the AV node, low magnification. (b) Cystic tumor of the AV node, high magnification. AV: Atrioventricular|
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Other tumors can cause sudden death by embolization into coronary arteries (myxoma, papillary fibroelastoma) or by increasing electrical instability in the myocardium (cardiac fibroma, rhabdomyoma, histiocytoid cardiomyopathy).
| Commotio Cordis|| |
”Commotio cordis” is a fatal mechano-electric arrhythmogenic syndrome caused by a blunt impact to the chest, without the occurrence of a rupture of a vessel or hemopericardium. By definition, the autopsy is negative for potential cardiac causes of death. Autopsy criteria for diagnosis include no cardiac or other organic fatal lesions with negative toxicological screening. Most cases are accidental deaths in young men during sporting activities, but it may also be a form of homicide in instances of intentional striking with intent to harm. The first report of commotio cordis was documented in 1898, when the Sussex Express described a 13-year-old grammar school boy killed by a “not a very swift” cricket ball that struck him between the left fifth and sixth rib.
| Sudden Death without Morphologic Findings|| |
In sudden unexpected deaths when scene investigation, toxicology and autopsy have ruled out unnatural and noncardiac causes, there are three broad categories of cardiac findings. One is that of a nearly certain cause of death, most commonly coronary thrombosis, severe coronary atherosclerosis, arrhythmogenic or HCM, acute myocardial infarction, and severe cardiomegaly. The second category comprises deaths in which the heart is not normal but has chronic abnormalities (uncertain cardiac findings) such as mild to moderate cardiomegaly, focal scarring or inflammation, valve disease, and moderate coronary artery disease without thrombosis. The third category defines “normal” heart. The criteria for these categories have been proposed in a consensus statement [Table 1]. These criteria have been applied to forensic series of sudden death in terms of comparing the risk of genetic defects and family history between the normal and borderline or uncertain group., It is a common practice among forensic pathologists, whose primary task is to establish manner of death, to assign the cause of death to such uncertain cardiac findings, although some forensic pathologists would diagnose “cardiac arrhythmia” in uncertain cases.
There are several synonyms for “autopsy-negative” cardiac arrhythmias, including sudden adult death syndrome, sudden unexpected death syndrome, sudden unexpected death with negative autopsy (SUDNA) and SADS. “Sudden unexpected nocturnal death syndrome” is characterized by abnormal premortem physical activity, is prevalent in Southeast Asia and is likely a form of Brugada syndrome.
”SADS” is probably the most prevalent current designation and is defined “sudden death or been seen well within 24 h of death with no ante-mortem cardiac diagnosis, negative noncardiac autopsy, and negative toxicological analysis.” These authors then designated “true SADS” as a subgroup without pathologic or uncertain cardiac findings.
The rate of SUDNA, or “true SADS” is nearly 80% of forensic autopsies in young children dying with SCD, and up to one-third of young adults. The rate at which there is no finding in apparent lethal cardiac arrhythmias is lower in adults as age increases, and is higher in witnessed and exertional deaths, compared to deaths at rest. The reason for this increase is likely two-fold: inherited arrhythmogenic syndromes often present at a young age, and the likelihood of finding an acquired cardiac disease that would serve as an arrhythmogenic substrate increases with age. A recent series of careful complete autopsies by cardiovascular specialists on population-based SCDs reported only 10% with no structural findings.
In lieu of autopsies we can obtain information about causes of ventricular fibrillation that occurs in structurally normal hearts by cardiologic and genetic testing of survivors of SCD. Thamaree and Sunsaneewitayakul, in a study from Southeast Asia that evaluated survivors of cardiac arrest in which structural heart disease was excluded, found high rates of Brugada syndrome and other channelopathies, family history of syncope, and postarrest recurring tachycardias in patients surviving cardiac arrest. In a study from Korea, only approximately 50% of SCD survivors, with a mean age of 52 years, had obstructive lesions in angiograms, and nearly 8% had evidence of coronary spasm. Jiménez-Jáimez et al. studied cases of fatal and resuscitated SCD in Spanish young adults (mean age 30 years) and expanded molecular and cardiologic workup from probands to family members, thereby increasing the likelihood of finding abnormalities. Over three-fourths of cases yielded an arrhythmogenic syndrome in at least one family member, channelopathies somewhat more common than cardiomyopathies. Long QT syndrome was the most common channelopathy, followed by Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. Arrhythmogenic and hypertrophic were the most common cardiomyopathies, followed by dilated and noncompaction cardiomyopathy. Interestingly, coronary spasm was not found in any family.
A different study of young Australian victims of SUDNA (mean age 25) studied the genetics of first-degree relatives and included cases with borderline or uncertain cardiac findings. A small subset of the probands were genetically tested, with an unusually high rate of mutations in arrhythmogenic syndromes, most of which were long QT syndrome (interestingly, there were no ryanodine receptor mutations, and no difference between the borderline and normal hearts). In approximately 25% of the families tested cardiologically in the entire group, at least one family member was diagnosed with a channelopathy or cardiomyopathy, most commonly long QT syndrome, Brugada syndrome, and dilated cardiomyopathy.
The results of these studies demonstrate an overlap between the genetics of cardiomyopathy and channelopathies, and heterogeneity between patient populations.
Early repolarization syndrome
In 2008, Haïssaguerre et al. found that early repolarization syndrome, previously considered benign, is significantly increased in incidence in survivors of cardiac arrest. Early repolarization was defined as “elevation of the QRS-ST junction of at least 0.1 mV from the baseline in the inferior or lateral lead, manifested as QRS slurring or notching.” The notching is often termed “J-wave” or “J-deflection.” Subsequent studies on survivors of cardiac arrest have found early repolarization in a significant number of patients. Because the molecular basis appears to be heterogeneous and overlaps with potassium ion and L-type calcium channel ion disorders, early repolarization cannot be diagnosed by molecular autopsy.,
| Molecular Autopsy|| |
The use of molecular testing in medicolegal autopsy is increasing. Unfortunately, a significant proportion of SUDNA deaths show negative molecular testing. There are technical limitations to genetic testing, and other potential causes of death are undetected by current autopsy technology, such as coronary spasm and early repolarization syndrome. Furthermore, interpretation of genetic variants is constantly changing, and those deemed of uncertain significance may eventually be classified as pathologic as more data become available.
The majority of positive molecular autopsies in SUDNA involve mutations associated with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, idiopathic ventricular fibrillation, and short QT syndrome. A small proportion of mutations are typically associated with structural cardiomyopathy, despite the absence of structural abnormalities.
The number of genes implicated in SUDNA is continuously growing and are largely cardiac-specific genes implicated in ion channel disorders, including catecholaminergic polymorphous ventricular tachycardia. Fewer than 5% of SUDNA will identify genes underlying nonischemic cardiomyopathy, such as PKP2, although one study found a 25% rate of PKP2 in SUDNA. As noted above, the definition of “negative autopsy” relies partly on definitions of normal and uncertain categories. One recent molecular autopsy study included both SUDNA and sudden death. It is certain that genetic factors that contribute to myocyte electrical instability are at play in a significant proportion of sudden death victims with structural heart disease, especially uncertain categories.
Rate of genetic abnormalities in SUDNA
In only about one-third patients with SUDNA will a pathogenic mutation be found.,,,, The rate depends heavily on the section of patients, and smaller studies with selected young patients have an up to 40% positivity rate. Recently, whole exome testing has increased the rate of positive mutations, including nonexomic promoter regions. Interpretation of the significance of variants found by deep sequencing technology can be challenging.
Pathogenic mutations linked to arrhythmias are multiple in up to one-fifth of patients with SUDNA. Over one-half are channelopathy genes, one third are ryanodine receptor mutations and the remainder mutations usually seen in cardiomyopathy, including hypertrophic, dilated, arrhythmogenic, and noncompaction, [Table 2]. In series that focus on exertional deaths, a far higher proportion involves RYR2, as catecholaminergic polymorphic ventricular tachycardia occurs preferentially during exercise.
|Table 2: Postmortem identification of potentially lethal variants in series of sudden cardiac death without structural heart disease (negative autopsy)|
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In most series of SCD cases in which an underlying mutation is identified, fewer than one-third of patients had a history of cardiac events.,,,,,,, Pursuit of family member screening after the mutation is identified is generally a part of the medical examiner's investigation.
Molecular testing has also been done on sudden deaths with structural heart disease and an identified cause of death. In Williams et al.'s study, 20% of deaths due to “arrhythmia/cardiomyopathy” and 15% of deaths due to “atherosclerosis or hypertensive heart disease” had pathogenic mutations, including channelopathy KCNH2, a Long QT gene, MYH7, a HCM gene, and RYR2. These results emphasize that the actual cause of the arrhythmia that resulted in sudden death may not be identifiable and those multiple factors are often at play.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17]
[Table 1], [Table 2]