Indian Journal of Pathology and Microbiology
Home About us Instructions Submission Subscribe Advertise Contact e-Alerts Ahead Of Print Login 
Users Online: 750
Print this page  Email this page Bookmark this page Small font sizeDefault font sizeIncrease font size

  Table of Contents    
Year : 2021  |  Volume : 64  |  Issue : 2  |  Page : 231-237
Sudden cardiac deaths: Role of nonischemic myocardial disorders—Part II

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

Click here for correspondence address and email

Date of Submission14-Jul-2020
Date of Decision03-Aug-2020
Date of Acceptance12-Aug-2020
Date of Web Publication9-Apr-2021


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 II. Indian J Pathol Microbiol 2021;64:231-7

How to cite this URL:
Vaideeswar P, Tyagi S, Singaravel S, Marathe SP. Sudden cardiac deaths: Role of nonischemic myocardial disorders—Part II. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 7];64:231-7. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/231/313264

Nonischemic myocardial disorders (NIMDs) are responsible for about 10% of sudden cardiac deaths (SCD). The first part of this review focused on the common and uncommon genetic myocardial disorders (mainly hypertrophic, arrhythmogenic and dilated cardiomyopathies, CMPs). This second part is devoted to some of the NIMDs that can have nongenetic and/or genetic basis [Table 1].
Table 1: The Genetic/Nongenetic Cardiomyopathies

Click here to view

[TAG:2]Inflammatory CMP (ICMP)[1][/TAG:2]

ICMP is a broad group of disorders, characterized by the “presence of cellular inflammatory infiltrate in direct association with necroses or degeneration of myocytes, not typical of ischemic necroses” [Figure 1]a and [Figure 1]b. Its precise characterization and natural history have been limited by the diversity of etiologies and extraordinary variability of its clinical presentation. The trigger (infective or noninfective) leads to innate and/or adaptive immune responses. On histology, the defining feature is the presence of >14 leukocytes/mm2 with myocardial damage. This results in a broad spectrum of clinical manifestations ranging from mild symptoms or subtle features of cardiac dysfunction to life-threatening cardiac failure, arrhythmias, and SCD. It is worth noting that the acute phase of inflammation regardless of the etiology can eventually lead to fibrosis and architectural remodeling, i.e., post-inflammatory type of DCM. It has been our experience (unpublished) that these are the most common causes of SCD.
Figure 1: Myocyte damage associated with lymphohistiocytic infiltrate in the (a) interstitial and (b) perivascular regions (H and E ×400); (c) Moderate cardiomegaly with patchy epicardial opacification and congestion; (d) There is moderate left ventricular LV dilatation with thinning of the walls (A: Anterior wall, AA: Ascending aorta, IVS: Interventricular septum, P: Posterior wall, PT: Pulmonary trunk, RV: Right ventricle)

Click here to view

Viral myocarditis


Among the various pathogens, viruses are the major causes of myocarditis, mostly affecting children and young adults, where it accounts for about 12% of sudden deaths. The true incidence is not exactly known because the condition may be clinically silent or often unrecognized. The projected estimate is 22 of 100,000 persons per year, especially males; a regional variation is also expected. The common viruses implicated are enterovirus, adenovirus, parvovirus, herpes virus, Epstein-Barr virus, influenza virus, and hepatitis C. In immunocompromised hosts, cytomegalovirus and human immunodeficiency virus are implicated. The viruses may be newly acquired or there may be reactivation of latent viruses. The viral agent, along with an underlying genetic predisposition and immune responses, produces myocardial inflammation, which is said to occur in a phased manner. The virus gains entry into the cardiomyocyte using certain receptor complexes such as the common receptor for Coxsackie and adenoviruses or into the endothelial cell via blood group P antigen as for the parvovirus. This initiates virus-dependent early myocyte injury by direct cytopathic effect, the action of macrophages/natural killer cells, or endothelial dysfunction. The second inflammatory wave with T-lymphocytes is brought about by viral proteins expressed on the cell membranes. This is followed by an autoimmune cellular and antibody-mediated damage as a reaction to molecular mimicry phenomenon or exposure of the sequestered cardiac antigens. The result is viral clearance or persistence with varying degrees of fibrosis and dysfunction.

Pathological features[4],[5],[6]

In fatal cases of myocarditis, the heart may be normal or dilated. The dilatation is usually biventricular, the left being more affected than the right [Figure 1]c and [Figure 1]d. Softening, congestion, or pallor may be present. Some cases are associated with mural thrombi (very often seen in the intertrabecular spaces), and patchy to diffuse fibrinous pericarditis. On histology, the viruses, irrespective of their type, invariably produce lymphocytic myocarditis (at least 7 CD 4+/CD 8+ T lymphocytes with 4 CD 68+ macrophages/mm2); B lymphocytes are sparse. Lymphocytes can also be a feature of toxic agents or collagen vascular disorders. A fleeting neutrophilic response may also be present, and sometimes, there can be a response in the form of eosinophils. The viral myocarditis may manifest as fulminant, acute, or chronic forms; the latter usually presents as post-inflammatory DCM. Acute fulminant myocarditis presents as an acute illness (<4 weeks of symptoms), followed by extreme hemodynamic instability that requires emergent support. In such cases, there would be extensive widespread foci of necroses that can be seen even with minimal sampling. On the other hand, in acute myocarditis, the changes are patchy and may require extensive sampling. Such patients would also have similar symptoms of a viral prodrome (<4 weeks) with acute coronary syndrome-like symptoms of chest and dyspnea. Some cases are supposedly asymptomatic, which is explained on the basis of very subtle manifestations ignored by the deceased or may have presentations unrelated to the heart such as diarrhea. Though time-consuming, viral genome search may be attempted; it may not always be successful. The inflammatory cytokine release, myocyte necrosis, and subsequent fibrosis are capable of producing electrical instability, resulting in life-threatening arrhythmias.

Giant-cell myocarditis (GCM)[7],[8]


GCM is a rare example of ICMP, commonly depicted as a fulminant process. It presents with acute heart failure, refractory ventricular arrhythmias, and conduction system abnormalities. This may be true in about 75% of the patients, but in others, the smoldering inflammation persists for years with a DCM-like phenotype and heart blocks. A primary presentation as SCD is also possible. In autopsy analysis, it has an incidence of 0.007% to 0.051%, but the true incidence is likely to be underestimated. GCM is more common in males with an average age of presentation at 42.6 years. Since it is associated with systemic autoimmune disorders or tumors (thymoma and lymphoma) in 20% of patients, dysregulated immunity related to T-cells forms the basis of the disease; the trigger is yet to be elucidated.

Pathological features

At autopsy, the heart shows a variable degree of dilatation with flabby consistency and mild-to-moderate increase in weight. The myocardium, particularly the left ventricle (LV), shows serpiginous congested foci of necroses or translucent or opaque fibrosis. Mural thrombi can also be present. The characteristic feature in the acute phase is the presence of small foci of coagulative to granular necroses [Figure 2]a bordered by multinucleated giant cells, T-lymphocytes, plasma cells, macrophages, and sprinkling of eosinophils [Figure 2]a. The giant cells have the same contour of the myocytes, i.e., they are round in areas where the myocytes are sectioned transversely and elongated when the cells are longitudinally sectioned, often appearing connected to them [Figure 2]b. There are no granulomas. Variable amounts of granulation tissue and fibrosis are seen in the healing and healed phases.
Figure 2: (a) Presence of coagulative to granular necrosis. Arrow points to an eosinophil; (b) Presence of multinucleated giant cells “connected” to a longitudinally oriented myofiber (arrow, H and E ×400)

Click here to view

Cardiac Sarcoidosis (CS)


Sarcoidosis is a chronic multisystem inflammatory disorder characterized by noncaseating granulomas in the affected organs or tissues. Although the etiology and pathogenesis are not clearly understood, geographic, seasonal and familial/occupational clustering suggests a delayed hypersensitivity reaction to a yet-to-be identified antigen in genetically susceptible individuals. The disease has a variable distribution depending on race and ethnicity with an approximate prevalence of 10 to 40 per 100000 persons. It has a slight female preponderance and the average age of presentation is 48 years. Lymph nodes and lungs are most frequently affected (>90%), but other organs, including the heart, can also be involved. By and large, cardiac involvement occurs concurrently with systemic sarcoidosis, but clinically only about 5% of these patients have the telltale features of cardiac involvement. Even more alarming are the rates at autopsy that range from 19% to 27% (a higher incidence to the tune of 58% in Japan), suggesting that a significant proportion of patients are devoid of signs and symptoms of heart disease. Also, the involvement may manifest at the time of tapering off the steroid therapy or when patients have concomitant neurosarcoidosis. However, the incidence is expected to rise in the future due to better awareness and imaging modalities. The diagnosis becomes challenging when cardiac sarcoidosis presents several years after the initial presentation and even more so when it is the sole manifestation—isolated CS (ICS). It is defined as cardiac involvement devoid of preexisting diagnosis or any evidence of systemic sarcoidosis. The rate of ICS among patients with CS appears to be approximately 25%, and this is often diagnosed at autopsy or else is treated as some other disease, particularly in patients presenting at the CMP or arrhythmia clinics. Some cases remain localized while some others may finally progress relentlessly to multisystem disease.

Pathological features[11],[12],[13]

CS in both its forms can affect any part of the heart and the inflammation is said to occur in three consecutive phases of edema, granuloma formation, and post-inflammatory fibrosis. The manifestations depend on the distribution of lesions and the extent of involvement. Histologically, there are classically noncaseating granulomas composed of tightly clustered epithelioid cells, often with Langhan's or foreign body giant cells and mainly CD4+ T-lymphocytes. Sometimes, clusters of lymphocytes with giant cells [Figure 3]a can also be present. There is usually always an associated element of fibrosis (unlike the tuberculous granuloma), which can be infiltrated by lymphocytes (both T and B). Enclosed in some of the giant cells are Schaumann bodies (laminated concretions composed of calcium and proteins) and asteroid (stellate) bodies [Figure 3]b. Some of them can also show scanty central fibrinoid necrosis. It is important to differentiate the sarcoidal granulomas from other granulomatous diseases, which have different modes of therapy and prognosis. The other granulomatous inflammations include infectious (tuberculous or fungal) and other noninfectious (drug-induced) causes, which may be ruled out by performing special stains and/or taking into consideration the appropriate clinical scenario. Clinical and histopathological features help to differentiate sarcoidosis from giant-cell myocarditis.
Figure 3: (a) Destruction and separation of the cardiomyocytes by a large collection of lymphocytes with many multinucleated giant cells (H and E ×250); (b) “Asteroid body” (arrow) within the giant cell (H and E ×400); (c) A cross-section of the mid-portion of the ventricles shows biventricular dilatation with thinned out walls and typical subepicardial translucent foci of scarring (A: Anterior wall, IVS: Interventricular septum, L: Lateral wall, LV: Left ventricle, P: Posterior wall, RV: Right ventricle)

Click here to view

The ventricular myocardium is the commonest location of the granulomas, which may appear as well-delineated gray-white opaque to translucent foci, producing localized myocardial expansion/thinning [Figure 3]c and distinct from the uninvolved myocardium. The lesions are patchy and, in the initial stages of the disease, are very classically restricted to the summit of the interventricular septum. Therefore, atrioventricular blocks ranging from first-degree block to complete heart block are the most frequently encountered clinical manifestations (12% to 62%). Such is this regularity that their occurrence even in isolation should point to the presence of CS in young patients. Similarly, it is a common predictor of the disease in elderly Japanese women. After the septum, the fibro-inflammatory lesions are seen to involve the subepicardial and mid-myocardial regions of the basal aspects of the left ventricular free wall. The scarring that follows serves as a substrate for ventricular tachyarrhythmias (2% to 42%). SCD due to ventricular tachyarrhythmia and complete heart block causes 25% to 65% of the deaths due to CS; SCD can also be the initial presentation in 40% of patients. Occasionally, the LV is spared and the RV bears the brunt of sarcoidal involvement. This process often simulates arrhythmogenic CMP, pathologically and clinically. Secondary atrial dilatation or atrial granulomatous disease can also lead to less common atrial arrhythmias in the form of supraventricular tachycardia, atrial flutter, or fibrillation.

The granulomas initially produce ventricular stiffness and consequent diastolic dysfunction. Subsequent replacement fibrosis introduces systolic dysfunction as well. Thus, the clinical features of cardiac failure may be attributed to restrictive and/or dilated cardiomyopathy. Sarcoidosis mainly tends to involve the intramural coronary arteries, where the arteries may be actively caught up in the perivascular granulomatous reaction or fibrosing processes. Papillary muscles can also be affected leading to valvular regurgitation. A combination of these factors leads to subsequent development of overt congestive heart failure seen in 10% to 40% of patients. Primary valvular infiltration, formation of ventricular aneurysms, and mass lesions are other uncommon manifestations. Granulomas can also be found in the epicardium, leading to recurrent pericardial effusions and eventually constrictive pericarditis in some cases. In this context, sampling of the lungs, mediastinal lymph nodes, liver, and kidneys become important to rule out subclinical systemic disease. Moreover, if there are sarcoidal granulomas in other organs which are associated with GCM, the diagnosis will be sarcoidosis rather than GCM.[14]

   Cardiac Amyloidosis: So-Called Amyloidotic Cardiomyopathy (AmCMP) Top


Pathologically, amyloid represents an abnormal deposition of normal or abnormal proteins (characteristically resistant to degradation) in the extracellular matrix. It appears homogeneous, amorphous, and pale pink (hyaline) on routine hematoxylin and eosin stain. Ultrastructurally, the protein moiety occurs as a nonbranching cross beta-pleated fibrillar protein bundle, which permits an intense avidity to alkaline Congo red. The stained tissue appears orange-red and also exhibits apple-green birefringence under polarized light. These fibrillar and tinctorial properties confer important criteria for the identification of the amyloid deposits. Also bound to the protein are serum amyloid P (a glycoprotein) and proteoglycans, contributing to the carbohydrate component and are responsible for the gross staining reactions with iodine and sulfuric acid.

Amyloidosis represents a group of diseases characterized by deposition of such insoluble proteins in several organs as a generalized or localized process. To date, there are more than 31 proteins, which are driven to the pathway of generating morphologically identical amyloid fibrils. The amyloidogenic tendency primarily occurs due to “misfolding” of the proteins, and therefore, amyloidosis is an example of “conformational” disease. Despite its systemic nature, in most instances, the fibril has one or more target organs. The organ affected usually establishes the prognosis and optimal patient management. AmCMP is one of the common examples of infiltrative CMP and forms about 10% of nonischemic CMPs. It is also often under-recognized and a cause of significant morbidity and mortality.

Though several amyloidogenic processes can involve the heart, 95% of the disease is produced by deposition of immunoglobulin light chain proteins and transthyretin protein in a setting of blood dyscrasias, inherited disorders, or mere ageing. Excess amounts of monoclonal light chains (lambda or kappa, the AL amyloidosis) are produced due to covert or overt plasma cell dyscrasias and it constitutes nearly 80% of AmCMP. This type of amyloidosis has a male preponderance (ratio of 3:2), manifesting in the fifth to sixth decades of life and almost 90% of these patients sooner or later develop heart disease. The transthyretin-derived amyloidosis (ATTR) accounts for nearly 18% of the cases of AmCMP and is seen as a nonhereditary wild type variant (ATTRwt) or as hereditary mutant variant (ATTRm). The nonhereditary form is commonly referred to as senile systemic amyloidosis because of its late age of onset (usually after the seventh decade of life) and has a very strong male predominance. The true prevalence is unknown, but it is likely to increase due to the increasing aged population and the use of sophisticated imaging tools. On the other hand, hereditary amyloidosis (ATTRm) is an autosomal dominant disease associated with more than 100 point mutations in the TTR gene. The mutant protein tends to affect the heart and nervous system. There is, however, variable penetrance and phenotype variability and therefore a wide age range. Clinical effects are usually apparent in mid-life, though late onset of the disease is known. Few mutations predispose to localized cardiac amyloidosis in the elderly. The remaining types like serum amyloid protein or β2-microglobulin produce a minimal degree of cardiac involvement with alterations in the left ventricular wall thickness and motion on echocardiography. There are also other inherent cardiac disorders characterized by amyloid restricted to the heart (localized disease) such as dystrophic amyloidosis in the atria or valves.

Pathological features[17],[18],[19]

All parts of the heart (pericardium, myocardium, endocardium, valves, coronary vessels, or conduction system) are involved to a variable extent leading to congestive heart failure, restrictive CMP, conduction defects and arrhythmias, including SCD. A pattern of involvement of the cardiac structures may not always point toward the underlying cause. Most of the morphologic alterations and clinical effects are produced by the infiltration of the myocardium. On gross examination, the heart is moderately enlarged in size [Figure 4]a, with weights ranging from 400 to 850 g; weights over 1000 g are exceptional. It is to be noted that the heart weights in cases of ATTRwt are much more as compared to those in the AL type amyloidosis. The walls of both ventricles, especially the LV, appear hypertrophied, firm, rubbery, and pale brown throughout; a waxy or lardaceous appearance is typical [Figure 4]b. The ventricular cavities are of normal size, but there is biatrial enlargement. In some patients, the interventricular septum appears thicker than the free wall, particularly with ATTRwt. Thickening of LV wall and absence of compensatory dilatation may be confused with HCM and hypertensive heart disease (HHD). The patients with hereditary ATTRm may also have concomitant HHD. The progressive disease may lead to biventricular dilatation. Some element of RV hypertrophy may develop due to concomitant pulmonary involvement and pulmonary hypertension. Surprisingly, in some, there are no visible changes in the heart. Endocardial involvement is seen as bead-like, tan-colored, translucent nodules, especially in the atria, where the amyloid imparts a “sand-paper” or granular texture. Valvular deposits lead to diffuse, waxy, glistening thickening or may be verrucous, resembling candle-droppings. Thrombi may be identified in the cardiac chambers due to myocardial dysfunction. Pericardial deposits can produce small effusions.
Figure 4: (a) An enlarged heart (530 g) in a 72-year-old male; (b) Moderate concentric left ventricular LV hypertrophy with a pale brown waxy appearance (A: Anterior wall, AA: Ascending aorta, IVS: Interventricular septum, L: Lateral wall, P: Posterior wall, PT: Pulmonary trunk, RV: Right ventricle); (c) Ribbons of glassy eosinophilic material deposited alongside the longitudinally oriented myofibers (H and E ×400)

Click here to view

In the myocardium, the amyloid is deposited in the interstitium throughout the heart, leading to the expansion of the extra-cellular matrix and consequent stiffening leading to usually a restrictive pathophysiology. The interstitial deposits may be pericellular [Figure 4]c or nodular. The pattern of distribution may help in differentiating AL amyloidosis from senile amyloidosis, as pericellular, endocardial and arterial and/or arteriolar deposits (leading to angina) are more pronounced in the former. Heavier deposits may be present in the conduction system and epicardial nerve bundles in cases of familial amyloidosis. Subsequent myofiber vacuolation, atrophy and interstitial fibrosis can be explained not only based on small-vessel disease but also on the direct toxic effects of the amyloid fibrils, light chains in particular, affecting the myocyte function and extracellular matrix homeostasis. Final characterization is made by immunohistochemical stains with antibodies directed against the specific fibril and sometimes immunoelectron microscopy may be performed.

   Iron-overload Cardiomyopathy (IOCM)[20–22] Top


Iron is an essential nutrient required for many body functions. A peculiar feature of iron metabolism is the need for the regulation of iron excretion rather than iron absorption. Although iron deficiency is a fairly common problem worldwide, iron overload also occurs when iron in the body exceeds the storage capacity. The catalytically active iron produces tissue damage that involves the liver, the pancreas, and the skin, and in time the heart as well, to produce IOCM. It occurs in genetic disorders of iron metabolism, i.e., primary hemochromatosis or as a consequence of hemolytic anemia, ineffective erythropoiesis, multiple blood transfusions, excessive iron intake, and liver diseases, i.e., secondary hemochromatosis or hemosiderosis. Primary hemochromatosis is caused by mutations of proteins involved in iron metabolism, inherited as autosomal recessive or dominant patterns, which lead to increased gastrointestinal iron absorption. IOCM is seen in around 35% of these affected individuals. The incidence of IOCM in thalassemia major ranges from 11.4% to 15.1%, while in other hemolytic anemias, it may be up to 5%. In both these systemic diseases of iron mishandling, the cardiovascular disease contributes significantly to their morbidity and mortality.

Iron-overload is associated with an increased cytoplasmic, labile iron pool, which represents a significant fraction of iron available for Fenton-type reactions. There is a conversion of reduced iron (Fe2+) into oxidized iron (Fe3+), generating free radicals that lead to depletion of antioxidants, increased peroxidation and damage to lipids, proteins, and nucleic acids, triggering apoptosis and mitochondrial dysfunction. Several key proteins involved in cardiac excitation-contraction coupling are highly sensitive to changes in cellular redox state, particularly the calcium channels that play a role in the passage of the unbound iron. Altered function of these proteins may reduce systolic Ca2+ levels and elevate diastolic Ca2+ levels, thereby causing impaired systolic and diastolic function.

Pathological features

The deposition of iron in the heart is independent of the severity of hepatic disease, and in some cases, the organ may even be spared. The heart is enlarged with mild-to-moderate concentric or asymmetric left ventricular hypertrophy with a rusty brown color. Light microscopy using Prussian blue staining [Figure 5]a and [Figure 5]b shows greatest iron deposition in the subepicardial regions of the basal aspects of the anterior and inferior walls, followed by the subendocardial regions, and least commonly in the mid-myocardium. Iron deposition appears to be more extensive in the ventricular myocardium compared with the atrial myocardium and tends to affect the conduction system. Transmission electron microscopy coupled with X-ray elemental analysis is useful for confirming the qualitative nature of electron-dense deposits, while quantitative assessment of iron levels by atomic absorption spectrometry allows for a more objective determination of iron content.
Figure 5: (a) Brown pigment-hemosiderin producing fusiform expansion of the myofibers (H and E ×250); (b) Positive Prussian blue staining (×400)

Click here to view

In siderotic hearts, there is a gradual development of mechanical/electrical instability and the degree of cardiac dysfunction is proportional to the degree of iron deposition. IOCM, regardless of its etiology, is characterized by restrictive changes, with a prominent early diastolic dysfunction, which invariably progresses to an end-stage DCM. The dysfunction is mainly as a result of toxic effects since the areas of fibrosis are small. Chronic iron-overload can lead to a variety of arrhythmias including AV nodal block, conduction defects, bradyarrhythmias, tachyarrhythmias, and sudden cardiac death, often with greater severity in male patients. AV nodal block is particularly a common occurrence, relative to SA nodal dysfunction, which is consistent with the greater accumulation of iron in the AV nodal versus SA nodal cells.

   Other Causes Top

Myocarditis can also be caused by other infective agents like Toxoplasma gondii or Mycobaterium tuberculosis, toxic agents or auto-immune processes, which can cause SCD. Among the nongenetic causes, post-myocarditis or post-inflammatory DCM (especially post-viral) is an important subset seen in one-third of the cases of patients with DCM. Certain drugs/toxins, nutritional deficiencies, autoimmune disorders, endocrinopathies, long-standing tachyarrhythmias, and pregnancy can also cause DCM as a result of overlapping environmental and genetic factors.

   Conclusion Top

NIMDs are perhaps the globally under-recognized type of structural heart diseases, which may contribute significantly to SCD. It is important to carry out a systematic evaluation of the clinical, anatomical, and genetic risk factors in patients who have succumbed to NIMDs. Autopsy provides the first and last chance to make a precise diagnosis in SCD. There is a need for a recommended method of investigation that includes not only a protocol for examination of the heart and histological sampling but also for toxicology, microbiology, biochemistry, and molecular investigations where necessary. This applies not only to academic medical centers and regional hospitals but also to all pathology and forensic medicine professionals. The recommendations introduced would lead to improvements in standards of practice and allow meaningful comparisons between different communities and regions. Most importantly, it will facilitate the identification of novel causes, and emerging patterns of diseases, contributing to NIMDs. We strongly endorse the establishment of regional multidisciplinary expert networks. These should include Forensic medicine experts, pathologists, cardiologists, and geneticists, working in collaboration with microbiologists, toxicologists, and radiologists. The main objectives of these networks are to improve the diagnosis of NIMDs and to recognize and organize preventive strategies for family members in the setting of genetic abnormalities. Identification of the genetic cause not only provides an answer to the family about the most probable cause of death of the family member who died suddenly but also helps to identify relatives who are carriers of the genetic alteration that may be at risk for NIMDs.


The authors thank Dr. Jagdish Butany, Professor Emeritus, University of Toronto and Director Division of Pathology, Department of Laboratory Medicine and Pathobiology, University Health Network/Laboratory Medicine Program, Toronto General Hospital, Toronto, Ontario, Canada for use of images in [Figure 3]c and [Figure 5].

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Trachtenberg BH, Hare JM. Inflammatory cardiomyopathic syndromes. Circ Res 2017;121:803-18.  Back to cited text no. 1
Rose NR. Viral myocarditis. Curr Opin Rheumatol 2016;28:383-9.  Back to cited text no. 2
Huber SA. Viral myocarditis and dilated cardiomyopathy: Etiology and pathogenesis. Curr Pharm Des 2016:22:408-26.  Back to cited text no. 3
Arava S, Ray R, Seth S, Ali F, Jain P. Myocarditis: Pathologist's perspective. J Pract Cardiovasc Sci 2015;1:161-7.  Back to cited text no. 4
  [Full text]  
Leone O, Pieroni M, Rapezzi C, Olivotto I. The spectrum of myocarditis: From pathology to the clinics. Virchows Arch 2019;475:279-301.  Back to cited text no. 5
Razzano D, Fallon JT. Myocarditis: Somethings old and something new. Cardiovasc Pathol 2020;44:107155.  Back to cited text no. 6
Vaideeswar P, Cooper LT. Giant cell myocarditis: Clinical and pathological features in an Indian population. Cardiovasc Pathol 2013;22:70-4.  Back to cited text no. 7
Xu J, Brooks EG. Giant cell myocarditis; A brief review. Arch Pathol Lab Med 2016;140:1429-34.  Back to cited text no. 8
Llanos O, Hamzeh N. Sarcoidosis. Med Clin North Am 2019;103:527-34.  Back to cited text no. 9
Moller DR, Rybicki BA, Hamzeh NY, Montgomery CG, Chen ES, Drake W, et al. Genetic, immunologic, and environmental basis of sarcoidosis. Ann Am Thorac Soc 2017;14:S429-36.  Back to cited text no. 10
Isobe M, Tezuka D. Isolated cardiac sarcoidosis: Clinical characteristics, diagnosis and treatment. Int J Cardiol 2015;182:132-40.  Back to cited text no. 11
Hulten E, Aslam S, Osborne M, Abbasi S, Bittencourt MS, Blankstein R. Cardiac sarcoidosis-State of the art review. Cardiovasc Diagn Ther 2016;6:50-63.  Back to cited text no. 12
Okada DR, Smith J, Derakhshan A, Gowani Z, Misra S, Berger RD, et al. Ventricular arrhythmias in cardiac sarcoidosis. Circulation 2018;138:1253-64.  Back to cited text no. 13
Ekström K, Räisänen-Sokolowski A, Lehtonen J, Nordenswan H, Mäyränpää MI, Kupari M. Idiopathic giant cell myocarditis or cardiac sarcoidosis? A retrospective audit of a nationwide case series. ESC Heart Fail 2020;7:1362-70.  Back to cited text no. 14
Kyle RA. Amyloidosis: A convoluted story. Br J Haematol 2001:114:529-38.  Back to cited text no. 15
Martinez-Naharro A, Hawkins PN, Fontana M. Cardiac amyloidosis. Clin Med 2018;18:s30-5.  Back to cited text no. 16
Siddiqi OK, Ruberg FL. Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment. Tr Cardiovasc Med 2018;28:10-21.  Back to cited text no. 17
Maleszewski JJ. Cardiac amyloidosis: Pathology, nomenclature, and typing. Cardiovasc Pathol 2015;24:343-50.  Back to cited text no. 18
Flodrova P, Flodr P, Pika T, Vymetal J, Holub D, Dzubak P, et al. Cardiac amyloidosis: From clinical suspicion to morphological diagnosis. Pathology 2018;50:261-8.  Back to cited text no. 19
Diez-Lopeza C, Comin-Coletb J, Gonzalez-Costelloa J. Iron overload cardiomyopathy: From diagnosis to management. Curr Opin Cardiol 2018;33:334-40.  Back to cited text no. 20
Siri-Angkul N, Xie LH, Chattipakorn SC, Chattipakorn N. Cellular electrophysiology of iron-overloaded cardiomyocytes. Front Physiol 2018;9:1615.  Back to cited text no. 21
Kirk P, Sheppard M, Carpenter JP, Anderson L, He T, St Pierre T, et al. Post-mortem study of the association between cardiac iron and fibrosis in transfusion dependent anaemia. J Cardiovasc Magn Reson 2017;19:36.  Back to cited text no. 22

Correspondence Address:
Pradeep Vaideeswar
Department of Pathology (Cardiovascular and Thoracic Division), Seth GS Medical College, Mumbai, Maharashtra
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_856_20

Rights and Permissions


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

    Inflammatory CMP...
    Cardiac Amyloido...
    Iron-overload Ca...
   Other Causes
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded22    
    Comments [Add]    

Recommend this journal