The Cardiovascular Pathologist in the Aortic Team.

Aortic diseases require a multidisciplinary management for diagnosis, treatment and follow-up with better outcomes in referral centers using a team-based approach. The setting up of a multi-disciplinary aortic team for the discussion of complex cases has been already proposed; it is also supported by the ACC/AHA. Surgeons and radiologists, more or less other physicians such as cardiologists, geneticists, rheumatologists/internal medicine specialists and pathologists are involved into such a team. The role of the cardiovascular pathologist is to examine the aortic specimens, to diagnose and classify the aortic lesions. Herein, the role of the pathologist in the aortic team is discussed and the pathobiology of aortic diseases is reviewed for reference by pathologists. The aortic specimens are mainly obtained from emergency or elective surgical procedures on the thoracic aorta, less frequently from organ/tissue (including cardiac or heart valve) donors, post-mortem procedures or abdominal aortic surgery. In the last decade, together with the progress of medical sciences, the histological definitions and classifications of the aortic pathology are undergoing thorough revisions that are addressed to an etiopathogenetic approach because of possible clinico-pathological correlations, therapeutic and prognostic impact. Pathologists may also have an important role in research and teaching. Therefore, histological analyses of the aortic specimens require adequate sample processing and pathologist expertise because histology contributes to definite diagnosis, correct management of patients and even (in genetic diseases) families, but also to research in the challenging field of aortopathies.

Sudden unexpected intrapartum death and left ventricular noncompaction involving the right ventricle.

Left ventricular noncompaction (LVNC), involving mainly the right ventricle, is a rare form of congenital heart disorder characterized by a developmental arrest in myocardial compaction, resulting in a spongy appearance of the myocardium, mainly of the right ventricle, rarely detected in fetuses. We report the case of a female fetus with a gestational age of 41+4 weeks who came to our attention for intrapartum sudden unexpected death, resulting in stillbirth. The ventricular walls, particularly the right ventricular wall, appeared thick, hypertrabeculated and spongy, leading to the diagnosis of LVNC involving mainly the right ventricle. The atrioventricular node and His bundle presented areas of fetal dispersion and resorptive degeneration; islands of conduction tissue were detected in the central fibrous body. Arcuate nucleus of the brainstem showed bilateral severe hypoplasia. The right bundle branch was hypoplastic. The final cause of death was an electrical conduction disfunction in an LVNC involving mainly the right ventricle. To the best of our knowledge, the herein described case is the first reported observation of sudden intrapartum death from LVNC involving mainly the right ventricle well documented post-mortem with cardiac conduction and brainstem studies. Our findings confirm the need of an accurate post-mortem examination including the study of the cardiac conduction system on serial section in every case of sudden unexpected fetal death, although there are no universally recognized guidelines.

A Rare Autopsy Case of Aggressive Combined Hepatocellular-Cholangiocarcinoma in 59-Year-Old Female.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a liver tumor with features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It consists of intermingled malignant biliary and hepatic tissue and thus a distinct entity, rather than two separate coexisting malignancies. A 59-year-old female with a history of hepatitis C and cirrhosis presented with abdominal pain and altered mental status. She developed hematemesis, and despite extensive interventions, she expired one day after her initial presentation. At autopsy, the liver was diffusely and markedly fibrotic with numerous nodules of varying size with invasion into adjacent vasculature. Microscopic examination of the nodules revealed cHCC-CC with stem cell features, lymphovascular invasion, and tumor emboli scattered throughout the right lung. The patient had end-stage liver disease due to the accumulation of damage and consequent fibrosis. This led to portal hypertension with subsequent massive gastrointestinal bleeding, hemorrhagic shock, and death. cHCC-CC is a rare, aggressive primary liver tumor with a poor prognosis. It can present with a cirrhotomemetic pattern with small nodules that can evade clinical and radiographic detection. Autopsy findings can provide valuable insights into the pathogenesis and clinical course of cHCC-CC, highlight the aggressive nature of the disease, and may inform future diagnostic and therapeutic strategies. Accurate diagnosis of this tumor is important for patient management and prognostication.

Insights From the Histopathologic Analysis of Acquired and Genetic Thoracic Aortic Aneurysms and Dissections.

OBJECTIVE: The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases. METHODS: A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74). RESULTS: The various types of lesions of medial degeneration and the overall severity of medial degeneration overlapped considerably between those patients with heritable disease and those with sporadic disease; however, patients with heritable thoracic aortic disease had significantly more overall medial degeneration (P = .004) and higher levels of elastic fiber fragmentation (P = .03) and mucoid extracellular matrix accumulation (P = .04) than patients with sporadic thoracic aortic disease. Heritable thoracic aortic disease with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .04), and women had more severe medial degeneration than men (P = .04). Medial degeneration scores were significantly lower for patients with bicuspid aortic valves than for patients with tricuspid aortic valves (P = .03). CONCLUSION: The study's findings indicate considerable overlap in the pattern, extent, and severity of medial degeneration between sporadic and hereditary types of thoracic aortic disease. This finding suggests that histopathologic medial degeneration represents the final common outcome of diverse pathogenetic factors and mechanisms.

Pericentrin deficiency in smooth muscle cells augments atherosclerosis through HSF1-driven cholesterol biosynthesis and PERK activation.

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell-specific (SMC-specific) Pcnt deficiency (PcntSMC-/-) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. The increased cholesterol biosynthesis in PcntSMC-/- SMCs augmented PERK signaling and phenotypic modulation compared with control SMCs. Treatment with the HMGCR inhibitor, pravastatin, blocked the augmented SMC modulation and reduced plaque burden in hyperlipidemic PcntSMC-/- mice to that of control mice. These data support the notion that Pcnt deficiency activates cellular stress to increase SMC modulation and plaque burden, and targeting this pathway with statins in patients with MOPDII has the potential to reduce CAD in these individuals. The molecular mechanism uncovered further emphasizes SMC cytosolic stress and HSF1 activation as a pathway driving atherosclerotic plaque formation independently of cholesterol levels.

Sudden cardiac death in the young: A consensus statement on recommended practices for cardiac examination by pathologists from the Society for Cardiovascular Pathology.

Sudden cardiac death is, by definition, an unexpected, untimely death caused by a cardiac condition in a person with known or unknown heart disease. This major international public health problem accounts for approximately 15-20% of all deaths. Typically more common in older adults with acquired heart disease, SCD also can occur in the young where the cause is more likely to be a genetically transmitted process. As these inherited disease processes can affect multiple family members, it is critical that these deaths are appropriately and thoroughly investigated. Across the United States, SCD cases in those less than 40 years of age will often fall under medical examiner/coroner jurisdiction resulting in scene investigation, review of available medical records and a complete autopsy including toxicological and histological studies. To date, there have not been consistent or uniform guidelines for cardiac examination in these cases. In addition, many medical examiner/coroner offices are understaffed and/or underfunded, both of which may hamper specialized examinations or studies (e.g., molecular testing). Use of such guidelines by pathologists in cases of SCD in decedents aged 1-39 years of age could result in life-saving medical intervention for other family members. These recommendations also may provide support for underfunded offices to argue for the significance of this specialized testing. As cardiac examinations in the setting of SCD in the young fall under ME/C jurisdiction, this consensus paper has been developed with members of the Society of Cardiovascular Pathology working with cardiovascular pathology-trained, practicing forensic pathologists.

Pathobiology of Myocardial Ischemia and Reperfusion Injury: Models, Modes, Molecular Mechanisms, Modulation, and Clinical Applications.

This review presents an integrated approach to the analysis of myocardial ischemia and reperfusion injury and the modulating influence of myocardial conditioning during the evolution of acute myocardial infarction (AMI) and other clinical settings. Experimental studies have involved a spectrum of in vitro, ex vivo, and in vivo models, and guidelines have been developed for the conduct of rigorous preclinical studies and for the identification of various forms of cell injury and death in evolving AMI. AMI in vivo is dominated by oncosis (cell injury with swelling) leading to necroptosis and final necrosis of ischemic cardiomyocytes (CMCs), without or with contraction band formation. Early after coronary occlusion, reperfusion salvages a significant amount of ischemic myocardium in the subepicardium while reperfusion injury contributes up to 50% of the final subendocardial infarct. AMI progression is mediated by damage (or danger)-associated molecular patterns, also known as alarmins, which activate pattern recognition receptors and initiate the inflammatory response. In preclinical studies, lethal reperfusion injury can largely be prevented with preconditioning or postconditioning by pharmacologic or physical means due to effects on both the CMC and microvasculature. Conditioning involves triggers, cytosolic mediators, and intracellular effectors. Mitochondria have a central role in the maintenance and loss of viability of CMCs. Reperfusion of severely ischemic myocardium leads to sustained opening of the mitochondrial permeability transition pore (MPTP). Once the MPTP is opened, the mitochondrial membrane potential (ΔΨm) is rapidly lost and energy production ceases. Conditioning blocks the sustained opening of the MPTP. Translation of conditioning strategies to the clinical management of patients has been challenging. The status of translation of experimental findings to approaches to modulate and ameliorate ischemic and reperfusion injury is discussed for the clinical settings of acute coronary syndromes treated with percutaneous interventions and cardiac preservation during open heart surgery and cardiac transplantation.

Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation.

Purpose: This study aimed to identify and correlate pathological findings with clinical outcomes in patients after orthotopic heart transplantation (OHT) who either died or underwent a re-transplantation. Methodology and study design: Single-center retrospective analysis of primary OHT patients who died or were re-transplanted between October 2012 and July 2021. Clinical data were matched with corresponding pathological findings from endomyocardial biopsies on antibody-mediated rejection, cellular rejection, and cardiac allograft vasculopathy. Re-assessment of available tissue samples was performed to investigate acute myocardial injury (AMI) as a distinct phenomenon. These were correlated with clinical outcomes, which included severe primary graft dysfunction. Patients were grouped according to the presence of AMI and compared. Results: We identified 47 patients with truncated outcomes after the first OHT. The median age was 59 years, 36 patients (76%) were male, 25 patients (53%) had a prior history of cardiac operation, and 21 patients (45%) were supported with a durable assist device before OHT. Of those, AMI was identified in 22 (47%) patients (AMI group), and 25 patients had no AMI (non-AMI group). Groups were comparable in baseline and perioperative data. Histopathological observations in AMI group included a non-significant higher incidence of antibody-mediated rejection Grade 1 or higher (pAMR ≥ 1) (32% vs. 12%, P = 0.154), and non-significant lower incidence of severe acute cellular rejection (ACR ≥ 2R) (32% vs. 40%, P = 0.762). Clinical observations in the AMI group found a significantly higher occurrence of severe primary graft dysfunction (68% vs. 20%, P = 0.001) and a highly significant shorter duration from transplantation to death or re-transplantation (42 days [IQR 26, 120] vs. 1,133 days [711-1,664], P < 0.0001). Those patients had a significantly higher occurrence of cardiac-related deaths (64% vs. 24%, P = 0.020). No difference was observed in other outcomes. Conclusion: In heart transplant recipients with a truncated postoperative course leading to either death or re-transplantation, AMI in endomyocardial biopsies was a common pathological phenomenon, which correlated with the clinical occurrence of severe primary graft dysfunction. Those patients had significantly shorter survival times and higher cardiac-related deaths. The presence of AMI suggests a truncated course after OHT.

Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19. METHODS: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation. FINDINGS: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization. INTERPRETATION: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19. FUNDING: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167-01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.

Aortic Root Dissection Due to an Automated Fastener Device.

Minimally invasive aortic valve replacement through a right thoracotomy is frequently performed in patients with aortic valve disease. The Cor-Knot Device (LSI Solutions) is an automated fastener that secures valve sutures. This case report is for a patient who developed postcardiotomy shock during a minimally invasive aortic valve surgery. The patient was found to have an aortic root dissection involving 90% of the aortic root circumference, including bilateral coronary ostia. The autopsy revealed that the aortic damage could be explained by a direct aortic intimal tear from the distal tip of the device shaft. The device was most likely not in perfect apposition to the sewing ring because of the restricted angle and space between the ribs.

Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab.

PURPOSE: Systemic chemotherapy including monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. METHODS: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. RESULTS: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. CONCLUSION: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

Career transitions: Reflections of former chairs and academic health center leaders.

The 2022 Association of Pathology Chairs Annual Meeting included a live discussion session and a pre-meeting recorded panel webinar sponsored by the Senior Fellows Group (former chairs of academic departments of pathology who have remained active in the Association of Pathology Chairs). The presentation was focused on transition planning for academic health center leaders. Each of the discussion group panelists had served as a pathology department chair as well as in more senior leadership positions, and they provided perspectives based upon their personal experiences. It was noted that such positions are often "at will" appointments of indeterminate length and that those above department chair generally carry greater risks and less stability. Becoming "addicted" to a leadership position was not considered beneficial to the individual or to the institution served and makes transitioning more difficult. Ongoing organizational succession planning was deemed helpful to mitigate such addiction and facilitate personal transition planning. Modes of transitioning discussed included those planned (e.g., voluntary retirement, resignation, administrative advancement) and unplanned (e.g., being "fired"; unexpected personal, health, or family issues). Unplanned transitions were felt to be more difficult, while anticipating when it is time to go and planning for it provided greater personal fulfillment after transition. Many career options were identified after serving in a leadership position, including a return to teaching, research, and/or clinical service; writing; mentoring; becoming more active in professional organizations and boards; philanthropic work; and "reinventing oneself" by moving to another career entirely.

Commentary on the enigma of small vessel disease in hypertrophic cardiomyopathy: is invasive assessment of microvascular resistance a novel independent predictor of prognosis?

The key pathophysiological features in hypertrophic cardiomyopathy are ventricular hypertrophy, diastolic dysfunction, and abnormalities in the mitral valve apparatus, but coronary microvascular dysfunction and ischemia have also been described. The small vessel disease changes could be reflected in the invasive measurement of the index of microvascular resistance, with prognostic potential.

Hypertrophic cardiomyopathy with a complex clinical course leading to heart transplantation.

The purpose of this report is to present clinicopathological features of two cases of hypertrophic cardiomyopathy (HCM) that underwent orthotopic heart transplantation (OHT) because of an unusually complex clinical course. One case is that of a 37-year-old man with HCM who underwent OHT because of a combination of recurrent severe ventricular arrhythmias and progressive heart failure that were refractory to medical treatment. The second case is that of a 43-year-old woman who underwent OHT because of progressive heart failure following 2 myectomy procedures. Both patients have had an uneventful post-OHT course. These cases highlight the variable spectrum of disease progression of HCM and the clinical challenges in the management of these patients.

Evaluation of contemporary echocardiographic and histomorphology parameters in predicting mortality in patients with endomyocardial biopsy-proven cardiac AL amyloidosis.

Introduction: This study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis. Methods: Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images and endomyocardial biopsy samples were processed for myocardial strain analysis and a detailed histomorphology characterization. Results: Of 43 patients; 44% were women and 63% white. Median age was 65 years; 51% underwent stem cell transplantation (SCT). Thirty patients (70%) died during follow up (median follow up: 4.1 years). Lower LA strain (<13.5%) and absence of SCT as a time-varying covariate were significantly associated with increased risk of death in the multivariate cox regression analysis. Higher LV mass and lower RV tricuspid annular plane systolic excursion were associated with increased odds of having ≥5% interstitial amyloid deposition on biopsy in the multivariate logistic regression analysis. Conclusion: Lower LA strain independently predicted mortality in our cohort, and its performance in the routine assessment of AL amyloidosis may be beneficial. Furthermore, SCT for cardiac AL amyloidosis was associated with improved OS. These findings need to be confirmed by larger studies in the era of contemporary systemic therapies.

Granulomatous fungal and non-tuberculous mycobacterial infestation complicating chronic lung disease: Outcomes in patients undergoing lung transplantation.

INTRODUCTION: Granulomatous infections are common in patients with chronic lung disease. We aim to study the incidence and clinicopathological features of granulomatous infections in a cohort of patients undergoing lung transplantation for end-stage chronic lung disease. METHODS: Pathology reports of 50 explanted native lungs of patients who underwent lung transplantation since 2015 at our institution were reviewed. Four cases with granulomatous lesions were identified. Correlation was made with clinical findings in the 4 cases. RESULTS: The granulomatous infections include non-necrotizing cryptococcal pneumonitis (case 1), necrotizing pneumonia due to Scedosporium sp. and Mycobacterium avium Complex (MAC) (Cases 2 and 3), and invasive Aspergillus pneumonia (Case 4). One patient received pre-transplant fungal prophylaxis (Case 4). Post-transplant infectious complications included invasive (Cases 2 and 4) and non-invasive (Case 1) fungal infections and bacterial pneumonia (Cases 1 and 2). Two patients (Cases 3 and 4) developed acute cellular rejection (ACR) in the first 30 days. The third patient (Case 1) was identified with ACR in the 9 months post-transplant and chronic lung allograft dysfunction at 29 months. In terms of mortality, 1 patient (Case 1) died at 30 months post-transplant from pseudomonal sepsis and chronic graft failure. Two patients with invasive fungal infections (Cases 2 and 4) are on secondary prophylaxis and doing well. One patient (Case 3) remains infection-free and on MAC prophylaxis. CONCLUSIONS: In our case series, patients with chronic lung diseases with superimposed granulomatous infestations frequently experienced post-transplant complications. These include invasive infections and repeat ACRs that predispose patients to chronic graft dysfunction. Pre- and post-transplant antifungal prophylaxis reduces fungal load and complication risk post-transplant.

Sudden Unexpected Death Associated with Arrhythmogenic Cardiomyopathy: Study of the Cardiac Conduction System.

A retrospective study was conducted on pathologically diagnosed arrhythmogenic cardiomyopathy (ACM) from consecutive cases over the past 34 years (n = 1109). The anatomo-pathological analyses were performed on 23 hearts diagnosed as ACM (2.07%) from a series of 1109 suspected cases, while histopathological data of cardiac conduction system (CCS) were available for 15 out of 23 cases. The CCS was removed in two blocks, containing the following structures: Sino-atrial node (SAN), atrio-ventricular junction (AVJ) including the atrio-ventricular node (AVN), the His bundle (HB), the bifurcation (BIF), the left bundle branch (LBB) and the right bundle branch (RBB). The ACM cases consisted of 20 (86.96%) sudden unexpected cardiac death (SUCD) and 3 (13.04%) native explanted hearts; 16 (69.56%) were males and 7 (30.44%) were females, ranging in age from 5 to 65 (mean age ± SD, 36.13 ± 16.06) years. The following anomalies of the CCS, displayed as percentages of the 15 ACM SUCD cases in which the CCS has been fully analyzed, have been detected: Hypoplasia of SAN (80%) and/or AVJ (86.67%) due to fatty-fibrous involvement, AVJ dispersion and/or septation (46.67%), central fibrous body (CFB) hypoplasia (33.33%), fibromuscular dysplasia of SAN (20%) and/or AVN (26.67%) arteries, hemorrhage and infarct-like lesions of CCS (13.33%), islands of conduction tissue in CFB (13.33%), Mahaim fibers (13.33%), LBB block by fibrosis (13.33%), AVN tongue (13.33%), HB duplicity (6.67%%), CFB cartilaginous meta-hyperplasia (6.67%), and right sided HB (6.67%). Arrhythmias are the hallmark of ACM, not only from the fatty-fibrous disruption of the ventricular myocardium that accounts for reentrant ventricular tachycardia, but also from the fatty-fibrous involvement of CCS itself. Future research should focus on application of these knowledge on CCS anomalies to be added to diagnostic criteria or at least to be useful to detect the patients with higher sudden death risks.