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  Table of Contents    
REVIEW ARTICLE  
Year : 2021  |  Volume : 64  |  Issue : 1  |  Page : 14-21
Sudden cardiac deaths: Role of nonischemic myocardial disorders—Part 1


1 Department of Pathology (Cardiovascular and Thoracic Division), Seth GS Medical College, Mumbai, Maharashtra, India
2 Department of Forensic Medicine and Toxicology, Seth GS Medical College, Mumbai, Maharashtra, India
3 Department of Cardiac Surgery, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA

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Date of Submission11-Jul-2020
Date of Decision01-Aug-2020
Date of Acceptance09-Aug-2020
Date of Web Publication8-Jan-2021
 

   Abstract 


Sudden death, a catastrophic event, falls within the purview of the forensic experts. It is often caused by cardiovascular diseases, which may be evident or occult. A vast majority of sudden cardiac deaths (to the extent of 90%) are due to ischemia of the working or conducting myocardial tissues consequent to coronary artery diseases. A heterogeneous group of nonischemic myocardial disorders, most producing structural abnormalities are responsible for the remainder; they predominantly represent various cardiomyopathies. This review, in two parts, covers sudden cardiac death in medicolegal autopsies with an approach to some common and uncommon nonischemic myocardial diseases that have a genetic and/or nongenetic basis.

Keywords: Cardiomyopathy, nonischemic myocardium, sudden cardiac death

How to cite this article:
Vaideeswar P, Tyagi S, Singaravel S, Marathe SP. Sudden cardiac deaths: Role of nonischemic myocardial disorders—Part 1. Indian J Pathol Microbiol 2021;64:14-21

How to cite this URL:
Vaideeswar P, Tyagi S, Singaravel S, Marathe SP. Sudden cardiac deaths: Role of nonischemic myocardial disorders—Part 1. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Jan 21];64:14-21. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/14/306538





   Introduction Top


Sudden death (SD) is a catastrophic event occurring at all ages and has a devastating socioeconomic impact. This is even more unfortunate if the deceased was young. Most of the causes of SD are of cardiac origin (to the extent of 85%), while others may be related to neurological or pulmonary diseases.[1]Hence, SD usually refers to sudden cardiac death (SCD) unless further qualified.

The diagnosis and definitions of SCD are variable; several terms, acronyms, and abbreviations are used to refer to specific types of untimely deaths. The generally recognized definition is based on the length of time between the onset of symptoms and death. SCD has been defined as “a natural, unexpected fatal event occurring within 1 h from the onset of symptoms in an apparently healthy subject or in one whose disease was not so severe as to predict an abrupt outcome.”[2]However, when un-witnessed, it refers to “the death of an individual within 24 h after being seen alive and in a normal state of health.”[3]The term also includes “sudden, rapid, and fatal deterioration in patients who have had a diagnosed stable chronic condition, or who have an illness, which would not be expected to cause death.”[3]In most cases, irrespective of the age of the individual, SCD is caused by structural cardiovascular disorders (CVD), identifiable by gross examination and/or histological preparations, aided by appropriate post-mortem investigations. However, all these deaths are not necessarily autopsied for which there is the use of another term “sudden unexplained death syndrome” (referred to in infants as “sudden unexplained death in infancy”).[3]Additionally, there is a subset where the heart and other organs are structurally normal, and the investigations (particularly toxicological) are noncontributory. These are referred to as “negative” autopsies and in about 30% of them, death is caused by genetic alterations in ion channels or their associated proteins (cardiac channelopathies), i.e., the nonstructural causes.[4]This mode is referred to as “sudden arrhythmic death syndrome” (referred to as “sudden infant death syndrome” in infants) and the diagnosis rests on genetic testing, i.e., “molecular” autopsy.[5]In many instances, channelopathies are also responsible for “sudden unexplained nocturnal death syndrome,”[3]which occurs usually in young males during sleep with symptoms such as moaning and tachypnea, lasting for few minutes before death. Arrhythmias also play a role in patients previously diagnosed with epilepsy (“sudden unexpected death in epilepsy”).[6]

SCD accounts for more than 50% of deaths in patients with CVD, which may be evident or occult. The incidence ranges from 0.36 to 1.28 per 1000 persons per year. Children have a lower incidence, while a higher incidence is seen in males among individuals especially beyond 4th decades of life.[7]This incidence is estimated from studies from North America and Europe. Few countries in the Afro-Asian regions including India have neither a standard protocol for autopsies in sudden deaths nor a national registry.[8]In our own experience, we feel that the incidence may be higher. Almost all types of CVDs are capable of producing sudden deaths. Among them, coronary artery diseases contribute to the majority of SCDs (over 90% of the cases), by producing ischemia of the working or conducting myocardial tissues.[9]Structural nonischemic myocardial disorders (NIMD) are responsible for most of the remainder and they represent cardiomyopathies (CMPs), which are “a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to the variety of causes that are frequently genetic.[10]This review in two parts will elaborate on CMPs that are more frequently associated with SCD. The CMPs are categorized into those with genetic and/or nongenetic causes. Channelopathies (which are also NIMD) and CMPs in children are not discussed. Part I deals with the CMPs that have a dominant genetic basis, while Part II (published in the next issue) focuses on NIMDs that can have nongenetic and/or genetic basis.

[TAG:2]Approach To Nimds[3][/TAG:2]

The basic approach to SCD is a thorough gross evaluation of the heart. However, this is to be performed only after procuring sufficient information of the deceased. Apart from the age and gender, it is important to be aware of the occupation/lifestyle, date/time interval/place/circumstances of death, past medical history, and use of therapeutic drugs/drugs of abuse. A family history of cardiac disease or sudden death should also be enquired. In this context, collection of a blood sample or any other DNA-friendly material for genetic analysis is beneficial to the family as many structural NIMDs also have a genetic basis.

After inspection of the external surfaces of the heart and dissection of the coronary arteries and if a myocardial pathology is suspected, a transverse section is taken from the mid-portion of the heart. The myocardium should be inspected for any alteration in the thickness, appearance, and color. Subsequently, the myocardium can be “bread-loafed” at an interval of 1 cm. The heart is then dissected in the usual “inflow-outflow” method of Virchow. If there has been a previous history of myocardial disease or if the gross appearance is suggestive of the same, the heart may be subjected to a “four-chamber” cut. It is imperative to weigh the heart and take measurements of the ventricular cavity and ventricular walls. Sections from the myocardium should be taken as shown in [Figure 1], particularly if the myocardium appears normal with additional section from the right ventricular (RV) outflow tract. Any abnormal area should be sampled with an interface of normal. If required, the conduction tissues should also be sampled. The routine staining technique of hematoxylin and eosin should be coupled with a connective tissue stain, and special stains (including immunohistochemistry) are to be used as and when required. It is also prudent to keep samples of all other organs, particularly the lungs, liver, kidneys, and spleen.
Figure 1: Bread-loafed ventricular myocardium depicting the areas of sampling in NIMDs (A: Anterior wall, IVS: Interventricular septum, L: Lateral wall, LV: Left ventricle, P: Posterior wall, RV: Right ventricle)

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Fibrosis and hypertrophy are important features in NIMDs. Interestingly, the fibrosis (streaky, focal or multi-focal) in NIMDs is frequently nonterritorial, subepicardial, and basal. This is in sharp contrast to the fibrosis occurring as an aftermath to ischemic injury. In general, ventricular tachyarrhythmias are the commonest mechanism for SCD in over 75% of the CMPs; the remainder occurs due to bradyarrhythmias. The propensity for developing life-threatening ventricular arrhythmias among all CMP subtypes rests heavily on the presence of myocardial scarring. True hypertrophy of cardiomyocytes occurs due to the induction of growth factors. The transverse diameter of the hypertrophied cells often exceeds 40 μm (reference range: 10–15 μm), accompanied by nuclear enlargement, pleomorphism, and hyperchromasia. The cardiac hypertrophy may be physiological (“athlete's heart”) or pathological, univentricular or biventricular, concentric or asymmetric, and proportionate or disproportionate to the cause. Pseudo-hypertrophy can be clinicopathologically indistinguishable and occurs due to intracellular or interstitial deposition of various substances or cells.

Genetic CMPs [Table 1]
Table 1: The Genetic Cardiomyopathies

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Hypertrophic cardiomyopathy (HCM)

Introduction[11],[12],[13]

HCM is the most common, heritable cardiac disorder with an estimated prevalence of 1 in 500 (0.16% to 0.29%) and is devoid of geographic, ethnic, and gender predilection. It is characterized by cardiac hypertrophy (left ventricular LV wall thickness of <15 mm as measured on imaging) with nondilated LV and normal or increased ejection fraction. Secondary causes of hypertrophy such as hypertension (hence the importance of kidney sections), aortic stenosis, and other infiltrative CMPs have to be ruled out. HCM is a single gene disorder that arises most commonly from mutations involving the sarcomeric protein-encoding genes. The inheritance in the majority of the cases is autosomal dominant. Mutations involving the beta-myosin heavy chain or myosin binding protein C are most common, accounting for about 60% to 70% of cases. The clinical heterogeneity and phenotypic expression are modified by the penetrance and expressivity of the genes, environmental factors, and genetic modifiers such as epigenetic factors, microRNAs, and posttranslational protein modifications.

Pathological features[14],[15]

The heart shows marked biventricular hypertrophy with weights exceeding 100% to 200% the normal [Figure 2]a. The LV is more involved than the RV with slight hypertrophy of the atria as well. In most cases, the hypertrophy is asymmetric and chiefly affects the basal interventricular septum (IVS) below the aortic valve (ratio of the thickness of the septum to the LV free wall of ≥1.3/1.0); on transverse sections, the rounded contour of the LV cavity is lost and is reduced to a slit [Figure 2]b. However, asymmetric hypertrophy can affect other portions of the septum and even LV free walls, and at times, there is only apical involvement. In about 10% of the patients, there is symmetric hypertrophy. The trabeculae and papillary muscles are enlarged and prominent. In the RV, the septal band becomes wider and muscular. Asymmetric septal hypertrophy results in dynamic LV outflow tract (LVOT) obstruction during systole in approximately 70% of HCM patients. Also, elongation and abnormal position of the mitral leaflets and papillary muscles pushes the anterior mitral leaflet (AML) into the LVOT during systole, a condition known as “systolic anterior motion.” This produces a morphologically identifiable mirror image of the AML [Figure 2]c and its attached cords over the septum. The leaflet also shows distortion and thickening with the development of mitral regurgitation. Consequently, there is left atrial dilatation with chances of stasis thrombi. Mural thrombus is rarely seen in the ventricles. Macroscopic fibrosis may show two forms. One is diffuse and interstitial producing a whorled cut surface resembling a uterine leiomyoma. The other form produces contiguous areas of fibrosis that are usually subendocardial, but may be transmural. “Burnt out” HCM shows thinning of the ventricular wall with increased fibrosis, chamber dilatation, systolic dysfunction, and pulmonary hypertension, and portends poor prognosis.
Figure 2: 40-year-old male with collapse in the bathroom showing: (a) Marked cardiomegaly. The heart weight was 520 g; (b) Hypertrophy with obvious asymmetry of the inter-ventricular septum IVS. Note near-obliteration of the ventricular cavities; (c) Band of pearly white endocardial thickening (arrow) as a result of systolic anterior motion of the anterior mitral leaflet AML (A: Anterior wall, AA: Ascending aorta, APM: Anterior papillary muscle, L: Lateral wall, LCC: Left coronary cusp, LV: Left ventricle, NCC: Noncoronary cusp, P: Posterior wall, PT: Pulmonary trunk, RCC: Right coronary cusp, RV: Right ventricle)

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Varying degrees of myocyte hypertrophy and disarray, interstitial fibrosis, and small vessel disease are important histological characteristics [Figure 3]. Disarray is considered as a reliable histopathological marker, when seen in 35% to 50% of the ventricular myocardium even in the absence of hypertrophy. From the practical point of view, it should occupy a significant part of at least one paraffin block in at least one region of the ventricle. The disarray tends to occur more extensively in the septum and posterior wall of LV and seen in interlacing, whorling, or herringbone patterns. In some cases, the disarray is out of proportion to the hypertrophy; such cases may harbor mutations in genes encoding troponin T. It should be noted that normal hearts can show nonspecific disarray in the junctional areas of the septum, the apex, and very often in the RV. The intramural coronary arteries have markedly thickened walls due to smooth muscle proliferation, collagen, and ground substance. Increased interstitial fibrosis is a common feature. Degenerating myocytes, associated focal collections of mononuclear cells, and dilated lymphatics may be present.
Figure 3: HCM characteristics: (a) Myofiber hypertrophy (H and E ×250); (b) Myofiber disarray (H and E ×400); (c) Increased in interstitial connective tissue (H and E ×250); (d) Presence of thick-walled vascular channels (H and E ×250)

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SCD is infrequent in HCM (~1% per year), but can occur due to the development of ventricular tachyarrythmias, especially in young adults. Disorganization of the myocardial architecture, increased interstitial collagen deposition, vascular abnormalities, ischemia, and scarring contribute to the production of an arrhythmogenic substrate. Abnormal intracellular calcium uptake and autonomic over-activity due to LVOT obstruction may also play a contributory role.

Arrhythmogenic cardiomyopathy (ACM)

Introduction[16],[17]

ACM is a primary inheritable myocardial disorder characterized clinically by a high degree of electrical instability and pathologically by fibro-fatty replacement of the ventricular myocardium. Though originally designated as arrhythmogenic right ventricular dysplasia, with increasing evidence of LV involvement, the term ACM is preferred. It has an estimated prevalence from 1 in 2000 to 1 in 5000, with regional variations. The actual prevalence may be greater as the diagnosis can be missed on clinical evaluation and even at autopsy. Typically, ACM is an autosomal dominant disease, largely due to mutations in genes that encode for desmosomal proteins, and hence ACM can be described as a cell-junction disease. These mutations are seen in over 60% of the affected persons, though there is an incomplete, often age-related penetrance and variable phenotype. Not surprisingly, ACM is infrequent in children and adults over 60 years of age. It may also occur as part of cardio-cutaneous disorders (Naxos disease or Carvajal syndrome), which are characteristically autosomal recessive. As with all other mutations, some of them can be sporadic and may on occasions involve nondesmosomal proteins.

Pathological features[18],[19],[20]

Depending on the degree of ventricular involvement, ACM can be classified into three subtypes:

  1. Right-dominant ACM is considered to be the classical form. The hallmark is a gradual degeneration of the cardiomyocytes with replacement by fat and fibrous tissue, the progression of which depends not only on the type of mutation, but also on epigenetic and environmental modifying factors. In some cases, despite the occurrence of SCD, the organ is structurally normal (negative autopsy) and consequently can be mistaken for channelopathies. Initially, it was thought that there can be two microscopic patterns of fatty and fibro-fatty, but now single most important feature to be identified is fibro-fatty remodeling [Figure 4]a. Subtle fibrosis is well brought out by trichrome stains. The fibro-fatty infiltration commences from the subepicardial aspect, extending inwards to become transmural. Traditionally, the remodeling was thought to occur preferentially at the sites of maximal stress, i.e., over the posterior subtricuspid region, the apex and outflow tract, constituting the “triangle of dysplasia.” But now, it should be noted that the initial area of involvement is the basal and inferior regions of the RV. In due course of time, there is formation of a trans-illuminant parchment-like wall [Figure 4]b with multiple aneurismal outpouchings. Such subtle changes can also be seen in the LV, depending on the amount of sampling. The distribution of fat and its association with fibrosis helps to differentiate ACM from an age-related or alcohol-induced increase in adipose tissue, and from adipositas cordis [Figure 5]a and [Figure 5]b.[21]At times, myocardial infarction can also show the presence of adipose tissue metaplasia [Figure 5]c. Myocyte necroses can also be present, which may be accompanied by lymphocytic infiltrate, mimicking myocarditis. However, there have also been cases of isolated RV myocarditis, the healing of which can lead to an erroneous diagnosis of ACM. The loss of contractile tissue is explained on the basis of mechanical damage produced by dysfunctional desmosomes and apoptosis. Furthermore, desmosomal aberrations can increase the expression of adipogenic/fibrogenic genes. There is trans-differentiation of the epicardial cardiac progenitors, predominantly derived from the secondary heart field (SHF). This also explains the RV dominant disease as this ventricle develops majorly from the SHF. The natural history of the classical form can be divided into four stages, based on the degree of remodeling into: a) Initial or concealed with minimal or no structural changes, but retained risk of SCD, b) Overt electrical disorder with morphologically evident changes and symptomatic life-threatening arrhythmias, c) RV failure, and later d) Biventricular failure. The proportion of SCDs in ACM can be as high as 80%, especially in males and athletes. These arrhythmias are not related to scarring but also to intracellular signaling problems and conduction heterogeneity
  2. Biventricular ACM is characterized by early and parallel involvement of both ventricles. This form simulates DCM, though the type of arrhythmias would be different
  3. Left-dominant ACM is less commonly seen and shows exclusive or dominant LV pathology with preserved global RV function. There is a predilection of the subepicardial and mid-portions of the postero-basal and postero-septal regions; posterior inter-ventricular septum can also be affected. At times, there is even an isolated nonischemic fibro-fatty scar.
Figure 4: (a) The right ventricular free wall shows adipose tissue deposition. Note attenuated cardiomyocytes with interstitial fibrosis (H and E ×250); (b) Extreme parchment-like thinning of the entire right ventricular RV wall with prominence of the trabeculae (TV tricuspid valve)

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Figure 5: Case of adipositas cordis. (a) The external morphology of the heart cannot be appreciated to extensive epicardial adiposity; (b) Serial cross-sections of the ventricles shows uniform layer of fat without infiltration of the myocardium (AA: Ascending aorta, LV: Left ventricle, PT: Pulmonary trunk, RV: Right ventricle); (c) Healed myocardial infarction with adipose tissue metaplasia (arrow)

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Idiopathic dilated cardiomyopathy (I-DCM)[22],[23],[24],[25]

Introduction

DCM is characterized by structural and functional abnormalities that result in LV or biventricular dilatation and systolic dysfunction (an ejection fraction of strictly <45%) in the absence of either pressure or volume overload and significant coronary artery disease. The exact prevalence is unknown, but may be 1 in 250. In most cases, DCM manifests in the third or fourth decades of life (usually <55 years) with a male to female ratio of 3:1. It is a heterogeneous group with genetic and nongenetic basis. I-DCM constitutes 50% of all cases and is caused by mutations in sarcomeric and nonsarcomeric proteins such as cytoskeletal, nuclear envelope, sarcolemmal, ion channel and intercellular junction proteins and also in the mitochondrial DNA, indicating a polygenetic basis. About 30% to 50% of these idiopathic cases are familial and even syndromic. The inheritance pattern often depends on the specific gene involved and on the degree of penetrance and expressivity of the concerned gene. This varies considerably among individuals of the same and/or different ethnic groups and is age dependent, with a much higher incidence of the disease and severity at older ages.

Pathological features

Grossly, the heart is enlarged, globular, and flabby [Figure 6]a with weights 50% to 100% above normal (range between 500 and 800 g). The above features are a result of four-chamber dilatation and biventricular hypertrophy, best demonstrated by the “short-axis” cut. The thickness of the ventricular myocardium may be normal or less than normal due to dilatation. The myocardium appears pale. Small scars may be seen in the subendocardial zones, which at times, can even be transmural. Diffuse endocardial fibrosis is sometimes seen as a response to ventricular dilatation. Poor cardiac function and stasis of blood often lead to thrombi in the ventricles [Figure 6]b and appendages. There may be atrioventricular valvular regurgitation, due to annular dilatation and mal-alignment of the papillary muscles. Coronary arteries are normal or can be atherosclerotic depending on the patient's age.
Figure 6: (a) Globular heart with biventricular hypertrophy; (b) Opened out left ventricle LV showing the presence of multiple polypoidal mural thrombi projecting from the intertrabecular spaces (AA: Ascending aorta, LA: Left atrium, LV: Left ventricle, MV: Mitral valve, RAA: Right atrial appendage, RV: Right ventricle); (c) Myocytes of various sizes are individually separated by increased interstitial connective tissue (H and E ×400)

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The specific feature of DCM lies in the nonspecificity of its microscopic characteristics. The changes are prominently seen in the LV. There are cases in which the changes are minimal with stretched myocytes and no increase in the interstitium, despite cardiac enlargement. In others, the myocytes display great diversity in size (either atrophy or hypertrophy) with increased interstitial and interfiber connective tissue [Figure 6]c and/or replacement fibrosis; this can vary in amount within the same case. The nuclei of the myocytes are hyperchromatic or multinucleated. Degenerative changes in the form of myofibrillar loss, myocytolyses, increased lipofuscin pigment, and basophilic degeneration are also present. Small foci of mononuclear inflammatory cells are sometimes observed. Approximately, 50% of the deaths in patients with heart failure are sudden, and this risk is inversely proportional to heart failure severity. Furthermore, the risk may persist even after improvement in ventricular function.

Fabry CMP (F-CMP)

Introduction[26]

Fabry disease (FD) or Anderson-Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alfa-galactosidase A gene. This results in the deficiency of the hydrolase enzyme alfa-galactosidase A, leading to the accumulation of glycosphingolipids (particularly its most abundant substrate globotriaosylceramide Gb3) in fluids and lysosomes throughout the body. The accumulation promotes oxidative stress and release of proinflammatory cytokines/growth-promoting factors, leading to gradual progressive multisystem disease. It usually culminates in progressive renal insufficiency, CMP (F-CMP), and cerebrovascular accidents.

The reported incidence world-wide is about 1 in 40000 to 117000 and represents the classic form seen in homozygous males, who have negligible or absent functional enzymatic activity. They are symptomatic at a young age with various manifestations including cutaneous lesions and peripheral neuropathy. This category may also include a small proportion of women with a skewed X-chromosome inactivation. As with all genetic syndromes, the genotype-phenotype relationship is altered by environmental factors and also by blood groups. Some homozygous males have mutations that permit residual enzyme activity, giving rise to an attenuated, nonclassic or delayed type of FD. In such cases, there can be organ-dominant disease forming 0.25% to 5% of men requiring hemodialysis, those diagnosed with HCM or cryptogenic strokes.

Pathological features[27],[28],[29],[30],

The accumulation of lysosomal glycosphingolipids occurs in all components of the heart; in the cardiac variant, there is an absence of the involvement of the vascular endothelium. The effects of this involvement constitute F-CMP, which in the cardiac subtype usually manifests beyond the third decade of life. Diffuse concentric LV hypertrophy is the most common manifestation; though rarely, asymmetric septal hypertrophy is also observed. The increased myocardial thickness is produced by intracellular lysosomal storage as well as “genuine” hypertrophy induced by neurohormonal activation. The papillary muscles are also prominent. The heart is enlarged with a pale yellowish appearance. On histology, the myocytes are enlarged with central perinuclear vacuoles that displace the contractile elements to the periphery, imparting a lacework appearance [Figure 7]. The vacuolations are fairly uniform in thickness, which differentiates them from artefactual clearing or subendocardial ischemic myocytolyses. The nuclei are large and hyperchromatic. The deposits, on frozen sections, are both PAS positive and sudanophilic with birefringence on polarization. They appear as concentric or parallel lamellae with periodic spacing on electron microscopy. At times, focal disarray is also present. End-stage CMP is characterized by replacement fibrosis that begins in the mid-portion of the basal postero-lateral regions. Later it may become transmural with the formation of ventricular aneurysms. The fibrosis can also have ischemia as a contributing factor due to coronary arteriopathy where smooth muscle deposits can lead to shrinkage necrosis and dystrophic calcification. Abnormalities of valves are also frequently noted, mainly in the form of left-sided valvular regurgitations, including mitral valvular prolapse, but these are seldom clinically significant. The involvement of the conduction system leads to atrioventricular blocks and various supra-ventricular/ventricular tachyarrhythmias; SCD is attributed to malignant brady- or tachy-arrhythmias.
Figure 7: Enlarged cardiomyocytes with vacuolated cytoplasm and large hyperchromatic nuclei, seen in a 28-year-old male with isolated Fabry's disease (H and E ×400)

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Other genetic CMPs

Restrictive CMP (RCM),[31],[32] the rarest of the CMPs (3% to 5%), is characterized by impaired diastolic function with restrictive filling and reduced diastolic volume of either or both ventricles. At the same time, systolic function is preserved and ventricular wall thickness is usually normal. This restrictive physiology is produced by a diverse group of conditions that include genetic and nongenetic abnormalities, leading to injury and infiltration of the myocardial and interstitial tissues. A distinct subset of RCM, albeit rare, is commonly transmitted as an autosomal dominant condition with rare examples of even autosomal recessive and X-linked patterns. This is termed as primary or idiopathic RCM, commonly seen in children and young adults in whom it pursues an aggressive course. Very surprisingly, it is multifactorial induced by a combination of synchronous multiple mutations involving sarcomeric and nonsarcomeric molecules. Heart failure is the predominant clinical presentation in this group of patients. SCD is a real problem (especially in children) with reports indicating an incidence of around 25%. These deaths can be attributed to rhythm disturbances including both tachyarrhythmias and bradyarrhythmias though the exact mechanism is unclear. The striking feature of idiopathic RCM on gross examination is biatrial dilatation and relatively normal-sized ventricles [Figure 8]a and [Figure 8]b. The microscopic changes include myocyte hypertrophy, focal disarray, and patchy or diffuse interfiber fibrosis.
Figure 8: Primary restrictive cardiomyopathy. (a) Enlarged heart with marked dilatation of the right atrium appendage (RAA); (b) The dilated right atrium (RA) is much larger than the right ventricular (RV) cavity (AO: Aorta, FO: Fossa ovalis, LV: Left ventricle, PT: Pulmonary trunk, SVC: Superior vena cava, TV: Tricuspid valve); (c) Left ventricular noncompaction scanned H and E and elastic van Gieson stained sections showing increased width of the trabecular portion of the left ventricle

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Noncompaction CMP (NCCM)[33],[34] is an idiopathic CMP characterized by failure of the process of myocardial compaction. Embryonic myocardium consists of a meshwork of interwoven myocardial fibers, which are separated by deep recesses. Between the 5th and 8th weeks of gestation, the process of myocardial compaction (or solidification) occurs from the base to the apex and coincides with the invasion of developing coronary vasculature. NCCM occurs due to the arrest of this process and mutations are found in a variety of the sarcomeric and nonsarcomeric proteins. This CMP may be accompanied by cardiac anomalies. This association is not seen in some cases and the condition is referred to as isolated NCCM. The true prevalence of NCCM is unknown, but in echocardiographic series, the incidence ranges between 0.014% and 1.3%. The diagnostic features of NCCM are a two-layered ventricular wall, comprising a thinner compact epicardial layer and an inner noncompacted layer, which exhibits prominent trabeculations and deep, intertrabecular recesses communicating with the ventricular cavity. The findings are more prominent in the apical parts of the myocardium as this is the last portion of the heart to undergo “compaction” [Figure 8]c. The prominent trabeculae are covered by a thick endocardium with focal myocytolyses of the subendocardial fibers. Later, there can be subendocardial fibrosis due to ischemic necroses. Deep inter-trabecular recesses in these patients result in sluggish blood flow, which acts as a nidus for thrombus formation. The classic clinical triad of NCCM is heart failure, arrhythmias, and embolic events. Subendocardial fibrosis acts as an arrhythmogenic substrate. These arrhythmias result in SCD, the incidence being as high as 18%.

SCDs can also occur in certain hereditary muscle disorders[35]and infiltrative lysosomal and nonlysosomal storage disorders.[36]Some of the glycogen storage disorders can show isolated cardiac involvement like the protein kinase AMP-activated noncatalytic subunit gamma 2-deficient cardiomyopathy or Danon disease due to lysosomal-associated membrane protein-2.

Acknowledgments

The authors are grateful to Dr. Harish Pathak, Professor & Head and all faculty, Department of Forensic Medicine & Toxicology, Seth GS Medical College, Mumbai, to Dr. Jayanthi Yadav, Additional Professor, Department of Forensic Medicine, All India Institute of Medical Sciences, Bhopal and to Dr. Rajesh DR, Assistant Professor, Department of Forensic Medicine, Indira Gandhi Medical College & Research Institute, Puducherry for their support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Pradeep Vaideeswar
Department of Pathology (Cardiovascular and Thoracic Division), Seth GS Medical College, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_845_20

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