Maleszewski, Joseph J.

Prognostic stratification of pulmonary carcinoids into “typical” and “atypical” categories requires examination of large tissue volume. However, there is a need for tools that provide similar prognostic information on small biopsy samples. Ki-67 and OTP immunohistochemistry have shown promising prognostic value in studies of resected pulmonary carcinoids, but prognostic value when using biopsy/cytology specimens is unclear. Ki-67 immunohistochemistry was performed on small biopsy/cytology specimens from pulmonary carcinoid tumors (n=139), and labeling index was scored via automated image analysis of at least 500 cells. OTP immunohistochemistry was performed on 70 cases with sufficient tissue and scored as positive or negative (<20% tumor nuclei staining). Higher Ki-67 index was associated with worse disease-specific progression-free survival (ds-PFS), with 3% and 4% thresholds having similarly strong associations with ds-PFS ( P <0.001, hazard ratio ≥11). Three-year ds-PFS was 98% for patients with Ki-67 <3% and 89% for patients with Ki-67≥3% ( P =0.0006). The optimal Ki-67 threshold for prediction of typical versus atypical carcinoid histology on subsequent resection was 3.21 (AUC 0.68). Negative OTP staining approached significance with atypical carcinoid histology ( P =0.06) but not with ds-PFS ( P =0.24, hazard ratio=3.45), although sample size was limited. We propose that Ki-67 immunohistochemistry may contribute to risk stratification for carcinoid tumor patients based on small biopsy samples. Identification of a 3% hot-spot Ki-67 threshold as optimal for prediction of ds-PFS is notable as a 3% Ki-67 threshold is currently used for gastrointestinal neuroendocrine tumor stratification, allowing consideration of a unified classification system across organ systems.

Introduction: Recently, we demonstrated transcriptional down-regulation of hypertrophy pathways in myectomy tissue derived from patients with obstructive hypertrophic cardiomyopathy (HCM) despite translational activation of associated hypertrophy pathways. Previous studies of other forms of cardiac hypertrophy demonstrate hypertrophy pathways are activated via histone acetylation and histone deacetylase (HDAC) inhibitors prevented development of hypertrophy. Whether histone modifications regulate hypertrophy pathways in HCM remains unexplored. Methods: Chromatin immunoprecipitation sequencing (ChIP-seq) was performed on myectomy tissues from 40 patients with HCM and 23 controls to characterize differential histone marks for H3K4me3 (active promoter), H3K9ac (active promoter), H3K9me3 (heterochromatin), H3K27ac (active enhancer), H3K27me3 (repression) across the genome. The differential histone marks were integrated with RNA-sequencing (RNA-seq) data derived from the same patients. Results: Overall, we identified 2,912 (7%) differential H3K4me3 peaks impacting 5 pathways, 23,339 (21%) differential H3K9ac peaks impacting 87 pathways, 33 (0.05%) differential H3K9me3 peaks, and 58,837 (42%) differential H3K27ac peaks impacting 50 pathways. There was increased H3K27ac (q-value = 0.002) and H3K9ac (q-value = 0.009) at RAS-MAPK loci. Univariate analysis of concordance between H3K9ac with RNA-seq data showed activation of cardiac hypertrophy signaling (z-score=4.5; -log [BH p-value] = 3.1), while H3K27me showed down-regulation of cardiac hypertrophy signaling (z-score=-2.4; -log [BH p-value] = 2.4). Multivariate integration of the ChIP-seq data with RNA-seq data identified 3,189 transcripts concordant with all five histone marks impacting 254 pathways, 18 (7%) of which are involved in cardiac hypertrophy. Conclusions: Myectomy tissue from patients with obstructive HCM shows enrichment of histone modifications at cardiac hypertrophy loci with activation via H3K27 and H3K9 acetylation and repression via H3K27 methylation. Further studies are needed to understand the balance and temporal relationship between these competing regulators in HCM pathobiology and the potential for epigenetic therapies.

Background: The incidence and causes of sudden cardiac death (SCD) among young competitive athletes impact prevention strategies yet remain incompletely understood. Methods: National Collegiate Athletic Association (NCAA) athlete deaths from 7/1/2002-6/30/2022 were identified through 4 independent databases/search strategies. Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. Poisson regression was used to calculate incidence rate ratios (IRR) for 5-year intervals over the 20-year study. Results: A total of 143 SCD cases were identified among 1102 athlete deaths and 9,106,516 athlete-years (AYs). The incidence of SCD among NCAA athletes was 1:63,682 AYs [95% CI 1:54,065, 1:75,010]. Incidence was higher in males compared to females (1:43,348 vs. 1:164,504 AYs) and Black compared to White athletes (1:27,217 vs. 1:74,581 AYs). The highest incidence of SCD was among Division 1 male basketball players (1:8,188; White 1:5,848; Black 1:7,696 AYs). The incidence rate for SCD decreased over the study period (5-year IRR 0.71 [95% CI 0.61,0.82]), whereas the rate of non-cardiovascular deaths remained stable (5-year IRR 0.98 [95% CI 0.94,1.04]; Figure 1A ). Autopsy-negative sudden unexplained death (AN-SUD, 19.5%) was the most common post-mortem exam finding, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (CM, 16.9%) and hypertrophic CM (12.7%) in cases with enough information for adjudication (118/143, Figure 1B ). There were 8 cases of myocarditis, with none attributed to COVID-19 infection. SCD events occurred most commonly during exertion among athletes with coronary artery anomalies (100%) and arrhythmogenic CM (83%), whereas AN-SUD and hypertrophic CM had a higher proportion of non-exertional SCD (44% and 40%, respectively). Conclusions: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

Hepatocellular carcinoma (HCC), constituting the predominant manifestation of liver cancer, stands as a formidable medical challenge. The prognosis subsequent to surgical intervention, particularly for individuals presenting with a solitary tumor, relies heavily on the degree of invasiveness. The decision-making process surrounding therapeutic modalities in such cases assumes paramount importance. This case report illuminates a rather unusual clinical scenario. Here, we encounter a patient who, following a disease-free interval, manifested an atypical presentation of HCC, specifically, a solitary cardiac metastasis. The temporal interval of remission adds an additional layer of complexity to the case. Through a multidisciplinary planning process, the decision was made for surgical removal of the metastatic tumor.

This new volume on the heart and great vessels has been expanded to become a comprehensive atlas of all cardiovascular disease—both neoplastic and non-neoplastic. In the spirit of prior editions, correlation of expertly curated pathology photographs and photomicrographs with clinical presentation, imaging and molecular genetics remains the cornerstone. The spectrum of cardiovascular disease, both congenital and acquired, is vast; accounting for the relative size of this fascicle. Every attempt has been made to focus on the clinically-relevant features of the diseases helping not only pathologists, but also providing cardiologists, radiologists, and surgeons a reference to understand the pathologic basis of the conditions they diagnose and treat each day. The authors have meticulously provided gross photographs that mirror (where possible) planar imaging techniques that will enable pathologic-radiologic correlation and facilitate a multidisciplinary approach to patient care.

BACKGROUND: Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. METHODS: This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. RESULTS: A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63 682 athlete-years (95% CI, 1:54 065–1:75 010). Incidence was higher in male athletes than in female athletes (1:43 348 [95% CI, 1:36 228–1:51 867] versus 1:164 504 [95% CI, 1:110 552–1:244 787] athlete-years, respectively) and Black athletes compared with White athletes (1:26 704 [1:20 417–1:34 925] versus 1:74 581 [1:60 247–1:92 326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61–0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94–1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). CONCLUSIONS: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

AimsGiant cell arteritis (GCA) is a systemic vasculitis affecting medium and large arteries in patients aged over 50 years. Involvement of temporal arteries (TA) can lead to complications such as blindness and stroke. While the diagnostic gold standard is temporal artery biopsy (TAB), comorbidities and age‐related changes can make interpretation of such specimens difficult. This study aims to establish a baseline of TA changes in subjects without GCA to facilitate the interpretation of TAB.Methods and resultsBilateral TA specimens were collected from 100 consecutive eligible postmortem examinations. Subjects were divided into four age groups and specimens semiquantitatively evaluated for eccentric intimal fibroplasia, disruption and calcification of the internal elastic lamina (IEL), medial attenuation and degree of lymphocytic inflammation of the peri‐adventitia, adventitia, media and intima. The individual scores of intimal fibroplasia, IEL disruption and medial attenuation were added to yield a ‘combined score (CS)’. Seventy‐eight 78 decedents were included in the final analysis following exclusion of 22 individuals for either lack of clinical information or inability to collect TA tissue. A total of 128 temporal artery specimens (50 bilateral from individual decedents, 28 unilateral) were available for examination. Intimal proliferation, IEL loss, IEL calcification and CS increased with age in a statistically significant fashion. Comparison of the oldest age group with the others showed statistically significant differences, although this was not uniformly preserved in comparison between the three youngest groups.ConclusionSenescent arterial changes and healed GCA exhibit histological similarity and such changes increase proportionally with age. The CS demonstrates significant association with age overall and represents a potential avenue for development to ‘normalise’ TA biopsies from older individuals.

Abstract Background and Aims Bicuspid aortic valve (BAV) is the most common congenital heart anomaly. Lifetime morbidity and whether long-term survival varies according to BAV patient-sub-groups are unknown. This study aimed to assess lifetime morbidity and long-term survival in BAV patients in the community. Methods The authors retrospectively identified all Olmsted County (Minnesota) residents with an echocardiographic diagnosis of BAV from 1 January 1980 to 31 December 2009, including patients with typical valvulo-aortopathy (BAV without accelerated valvulo-aortopathy or associated disorders), and those with complex valvulo-aortopathy (BAV with accelerated valvulo-aortopathy or associated disorders). Results 652 consecutive diagnosed BAV patients [median (IQR) age 37 (22–53) years; 525 (81%) adult and 127 (19%) paediatric] were followed for a median (IQR) of 19.1 (12.9–25.8) years. The total cumulative lifetime morbidity burden (from birth to age 90) was 86% (95% CI 82.5–89.7); cumulative lifetime progression to ≥ moderate aortic stenosis or regurgitation, aortic valve surgery, aortic aneurysm ≥45 mm or z-score ≥3, aorta surgery, infective endocarditis and aortic dissection was 80.3%, 68.5%, 75.4%, 27%, 6% and 1.6%, respectively. Survival of patients with typical valvulo-aortopathy [562 (86%), age 40 (28–55) years, 86% adults] was similar to age-sex-matched Minnesota population (P = .12). Conversely, survival of patients with complex valvulo-aortopathy [90 (14%), age 14 (3–26) years, 57% paediatric] was lower than expected, with a relative excess mortality risk of 2.25 (95% CI 1.21–4.19) (P = .01). Conclusion The BAV condition exhibits a high lifetime morbidity burden where valvulo-aortopathy is close to unavoidable by age 90. The lifetime incidence of infective endocarditis is higher than that of aortic dissection. The most common BAV clinical presentation is the typical valvulo-aortopathy with preserved expected long-term survival, while the complex valvulo-aortopathy presentation incurs higher mortality.

Background: The bicuspid aortic valve (BAV) exhibits abnormal geometry and transvalvular flow and is susceptible to calcification with subsequent cardioembolic stroke from calcific embolic material. However, the description of embolic ischemic strokes in patients with BAV is limited to case reports. Methods: Consecutive patients from 1975-2015 with BAV (n=5401) at our institution were retrospectively identified. Patients with ischemic stroke before aortic valve replacement (AVR) were analyzed, and the stroke was characterized. Patients were grouped according to stroke etiology: calcific embolism from a BAV (BAV stroke); large artery atherosclerotic or lacunar stroke (LA stroke); and non-BAV, non-large artery embolic stroke (nLA stroke). Results: There were 83/5401 (1.5%) patients with ischemic stroke. Mean age was 54 ± 12 years and 28% were female. Stroke etiology was BAV stroke in 26/83 (31%), LA stroke in 23/83 (28%), nLA stroke in 30/83 (36%), and other in 4/83 (5%). Stroke was embolic in 72/83 (87%), as shown in Figure 1. CHA 2 DS 2 -VASc score was not different in patients with BAV stroke (1.4 ± 1.2) versus nLA stroke (1.8 ± 1.2, p=0.188) but was higher in LA stroke (2.3 ± 1.2, p=0.005 vs. BAV stroke). Recurrent stroke occurred in 41% overall (50% BAV stroke vs. 30% LA stroke vs. 47% nLA stroke, both p=NS vs. BAV stroke). BAV stroke was more commonly located in the retinal circulation (39% BAV stroke vs. 13% LA stroke [p=0.044] vs. 0% nLA stroke [p=0.002]). Patients with BAV and LA stroke were more likely to have moderate-to-severe aortic stenosis and undergo AVR sooner after stroke compared to patients with nLA stroke. Conclusions: Stroke is an important complication in patients with BAV. The most common type of stroke in BAV is embolic. Greater than one-third of embolic stroke resulted from embolism from a calcific aortic valve. Patients with BAV stroke commonly have a history of recurrent cerebral ischemic events, severe valvular disease, and proceed to AVR soon after stroke.

Introduction: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy. Approximately 40-50% of HCM is caused by pathogenic variants in genes encoding proteins of the cardiac sarcomere. Patients with sarcomeric HCM have earlier expression and more severe disease progression. Herein, we evaluated the proteomic differences between patients with sarcomeric HCM and genotype negative HCM. Methods: Mass-spectrometry was performed on cardiac tissue from genotyped patients with HCM obtained after surgical myectomy, followed by differential proteomics (log2fc ≥