Aortic aneurysms have traditionally been studied as a single pathological entity, with emphasis on valve morphology. While histopathological differences between bicuspid (BAV) and tricuspid (TAV) aortopathy are well documented, less is known about how these mechanisms interact with aneurysm location within the ascending aorta. This gap complicates risk assessment and surgical planning beyond diameter-based criteria. We aimed to evaluate histopathological features of ascending aortic aneurysms across three topographical subgroups-root, tubular, and combined involvement-and assess modification by valve cuspidity. Using systematic criteria from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology consensus statement, the analysis focused on medial degeneration, adventitial alterations and atherosclerosis in patients undergoing ascending aortic surgery at a Finnish tertiary care center. The cohort comprised 296 patients with aneurysms located in the sinus of Valsalva (n = 122), tubular part (n = 130), and both regions (n = 44). Medial degeneration was present in all samples and predominantly moderate, with comparable median severity score of 2 (range 1-3, P = 0.829) across groups. In the overall cohort, no statistically significant differences were observed between topographical groups. Among TAV patients, tubular aneurysms demonstrated significantly higher histopathological scores for medial degeneration, elastic fiber fragmentation and loss, elastic fiber disorganisation, smooth muscle cell disorganization and nuclei loss, laminar medial collapse, medial fibrosis, adventitial fibrosis and atherosclerosis (all P < 0.05). In BAV patients, no statistical differences were found. Tubular aneurysms are characterized by more extensive wall remodeling and adventitial changes compared to root aneurysms, particularly in TAV patients. Notably, female sex emerged as a strong independent predictor of advanced medial and adventitial pathology. These findings underscore the importance of considering anatomical location, valve morphology, and sex in risk stratification and may inform surgical decision-making beyond diameter-based criteria.
OBJECTIVE:Long-term patency of saphenous vein grafts (SVGs) remains a significant challenge in coronary artery bypass grafting (CABG). The biological factors underlying successful human grafts are poorly understood. We aimed to characterize the structural and molecular features associated with successful graft function. METHODS:Patent and occluded SVG and internal thoracic artery (ITA) grafts were obtained from explanted hearts of CABG patients undergoing heart transplantation for end-stage heart failure not attributable to graft failure, along with freshly harvested ITA and SVG controls. Samples underwent histomorphological analysis, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics. RESULTS:Patent ITA (ITA-P) showed minimal intimal hyperplasia with medial reinforcement, whereas patent SVGs (SVG-P) had organized, α-smooth muscle actin (αSMA)-positive myofibroblast-rich neointima. Endothelial nitric oxide synthase (eNOS) was markedly upregulated in patent grafts at two sites-the luminal endothelium and adventitial microvessels within perivascular adipose tissue (PVAT)-and lost at both sites in occluded SVG (SVG-O). Adventitial CD31-positive microvessels were significantly increased in patent grafts. Proteomically, ITA-P and SVG-P shared a largely common adaptive proteome enriched in translation, RNA processing, and extracellular matrix (ECM) organization, with shared upstream activation of NR4A3, EGFR, and STAT1, and conduit-specific signatures (IGF-1/RUNX2 in ITA-P; RETN/SRC/PTGES in SVG-P). PTGES was strongly expressed in the adventitia of SVG-P. CONCLUSIONS:Patent arterial and venous bypass grafts exhibited a shared adaptive phenotype characterized by dual-site upregulation of eNOS in both the luminal endothelium and the perivascular microvessels/PVAT. In SVG-P, PTGES was co-upregulated alongside eNOS, indicating a mechanistic link between the proteomic and IHC findings. These findings highlight the perivascular compartment as a site of adaptive, eNOS-associated changes in patent vein grafts.
Background Intensive low-density lipoprotein cholesterol (LDL-C) lowering is a cornerstone of secondary prevention after myocardial infarction, but theoretical concerns persist regarding potential adverse effects of very low LDL-C on cellular membrane integrity. Phase angle at 50 kHz (PhA50), derived from bioelectrical impedance analysis (BIA), is a non-invasive marker reflecting cell membrane bioelectrical properties. This study assessed whether LDL-C reduction after myocardial infarction is associated with deterioration in PhA50. Methods This longitudinal analysis included 45 patients undergoing outpatient cardiac rehabilitation after myocardial infarction. Lipid profile, body mass index (BMI), and PhA50 were assessed at rehabilitation entry and completion. Within-person changes were analyzed using paired tests. Associations between LDL-C reduction and change in PhA50 were examined using correlation and linear regression models adjusted for age, sex, BMI change, follow-up time, and baseline PhA50. Results Median assessment interval was 55 [37-91] days. LDL-C decreased significantly from 131.42±36.32 mg/dL to 51.90±22.40 mg/dL (p < 0.001), corresponding to an approximate 60.5% reduction at the group level. PhA50 remained stable over follow-up (5.57 [5.08, 6.05] vs. 5.55 [5.12, 6.07] degrees; p = 0.332). LDL-C reduction was not correlated with change in PhA50 (R=-0.004; p = 0.981) and was not associated with ΔPhA50 in regression analyses. Age emerged as an independent inverse predictor of ΔPhA50 (p = 0.02). Conclusions Substantial LDL-C reduction after myocardial infarction was not associated with deterioration in BIA-derived PhA50, providing physiological reassurance regarding cellular integrity during intensive lipid lowering.
BACKGROUND:Cardiac amyloidosis, primarily due to immunoglobulin light chain (AL) or transthyretin (ATTR) amyloid, is an increasingly recognized cause of heart failure. Modern diagnostic advances suggest that ATTR, particularly in older adults, may be more prevalent than historically reported. METHODS:All Olmsted County decedents aged ≥40 years from 1970 to 1976 were identified. Available ventricular myocardium from retained paraffin blocks was screened histologically for amyloid using sulfated Alcian blue staining; positive cases underwent grading and proteomic typing by laser microdissection coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Beyond prevalence estimation, this analysis characterizes amyloid type, deposition grade and distribution, associated comorbidities, and cause-of-death patterns, comparing amyloid-positive decedents with age- and sex-matched controls. RESULTS:Of 2,566 eligible deaths, 1,028 autopsy cases with evaluable myocardium formed the study cohort (mean age 70.5 years; 61.1% male; 97% White). Cardiac amyloid was present in 52 cases giving an overall prevalence of 5.1% (95% CI: 3.8-6.6, which rose from 0% under age 60 to 37.5% (95% CI: 21.1-56.3) in those ≥90 years (p < 0.001). While prevalence estimates were higher in men above age 80 compared to women, there was no evidence of an interaction of age and sex (p = 0.90). The quantity of amyloid was sufficient for typing in 38 cases: ATTR (84.2%), AL (7.9%), serum amyloid A (5.3%), and apolipoprotein A-IV (2.6%). Adjusted estimates assuming untyped mild cases were ATTR-type increased ATTR prevalence to 4.5% (95% CI: 3.3-5.9) overall. Comorbidity profiles were similar between amyloid-positive and negative groups, though syncope and leg weakness were more common in amyloid-positive decedents. CONCLUSIONS:In an unselected autopsy cohort, cardiac amyloid was common, particularly ATTR in older adults. Prevalence increased steeply after age 80. These findings suggest that ATTR amyloidosis is not rare and is likely underdiagnosed and has similar prevalence in women and men, despite the male predominance reported in the literature.
Data suggests that COVID-19 is less frequent in children, with a milder course. However, multisystem inflammatory syndrome in children has been reported to occur after COVID-19 and can cause severe cardiac manifestations, including coronary dilation and aneurysms. We report on the first histologically proven arteritis with coronary dilatation and thrombosis following Multisystem Inflammatory Syndrome induced by COVID-19 in a 21-month-old male infant.
We report the autopsy case of a female 10-month-old infant who presented with cardiocirculatory arrest due to hypoxia secondary to compressive asphyxia due parental co-sleeping on the sofa. Despite advanced life support, vasoactive therapy, and rescue administration of methylene blue for refractory vasoplegic shock, no hemodynamic improvement was achieved, and death occurred following recurrent cardiac arrest. Autopsy revealed a bluish-green discoloration of the myocardium with no structural cardiac abnormalities. To our knowledge, this is the first pediatric case describing the autoptic findings following the use of methylene blue.
Benign stromal proliferations of pigmented melanocytes or blue nevi have been documented in several extracutaneous sites, such as uterine cervix, prostate, and lymph nodes. We report a 54-year-old male with melanocytic pigmentation of the adventitia of the ascending aorta. This would appear to be the first documentation of stromal melanocytosis (or "blue nevus") of the aorta.
A 26-year-old woman was referred for the assessment of a symptomatic pulmonary valve lesion clinically thought to represent a papillary fibroelastoma. After surgery, a lipomatous hamartoma of pulmonary valve was diagnosed. Microarray analysis was compatible with a clonal neoplastic proliferation, similar to that seen in a classical lipoma. Benign primary adipocytic tumors of the heart, such as lipomatous hamartomas of a valve, lipomatous hypertrophy of the atrial septum and lipoma, are distinct and very rare entities, with incomplete understanding of their pathogenesis. The results of this case suggest that the so called lipomatous hamartoma of the valves may actually be better classified as a neoplasm.
Cardiac transthyretin amyloidosis (ATTR-CA) is caused by myocardial deposition of misfolded transthyretin, leading to progressive heart failure. Disease pathology, however, extends beyond passive amyloid deposition and also involves active processes such as extracellular matrix (ECM) remodeling and immune activation. Mass spectrometry (MS) is the gold standard for amyloid typing in diagnostics. Here, we applied quantitative MS-driven proteomics on formalin-fixed paraffin-embedded whole cardiac tissue sections from six ATTR-CA cases, ten unaffected controls and four AL-CA controls to investigate protein expression changes. In addition to transthyretin, over 500 proteins were upregulated in ATTR-CA biopsies, including complement and coagulation factors as well as extracellular matrix (ECM) remodeling proteins. Among these, members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family, metalloproteinases (MMPs), and Tissue Inhibitor of Metalloproteinase-3 (TIMP3) showed significant upregulation. These proteins are key regulators of ECM turnover and structural integrity. Immunohistochemistry confirmed ADAMTS4 enrichment in amyloid deposits, while TIMP3 showed strong expression in cardiomyocytes and weaker staining within amyloid deposits. Together, these findings indicate that ECM remodeling, alongside complement and coagulation activation, represents a reproducible feature of cardiac ATTR amyloidosis. Whole-tissue proteomics provides biological insights that extend beyond amyloid typing, with potential implications for biomarker discovery and therapeutic targeting in ATTR-CA.
OBJECTIVES:Coronary atherosclerosis (CA) can remain subclinical for decades before clinical onset, while the complex pathophysiological mechanisms underlying its progression remain poorly understood. Proteomics offers a novel perspective for elucidating its pathogenic mechanisms and improving risk prediction. METHODS:The plasma proteomic data were from 29,020 UK Biobank participants comprising 2,907 Olink-measured proteins. 1,000 iterations of resampling-based univariable Cox regression were performed to identify robust CA-associated proteins. Locally estimated scatterplot smoothing was used to model the temporal trajectories of CA-associated proteins. Cox proportional hazards models integrating CA-associated proteins with traditional risk factors were constructed to predict incident CA, with model performance evaluated using the area under the curve (AUC) of receiver operating characteristic (ROC). RESULTS:During the 15-year follow-up, 65 proteins were found to be significantly associated with CA risk across the long-term, short-term, and overall follow-up periods. These CA-associated proteins were predominantly involved in collagen-containing extracellular matrix, endoplasmic reticulum lumen, and defense response to bacterium. By integrating multi-stage significance rankings using the robust rank aggregation method, we identified 5 key candidate proteins. Among these proteins, MMP12 remained persistently elevated 15 years before CA diagnosis, whereas GDF15, WFDC2, EDA2R and CST3 exhibited progressive abnormalities approximately 8 to 13 years prior to diagnosis. The model constructed using only the 5 key candidate proteins combined with traditional risk factors achieved high accuracy for 10-year (AUC = 0.749) and 5-year (AUC = 0.722) CA risk prediction. CONCLUSIONS:This study provides a temporal proteomic landscape of CA progression and highlights a compact panel of five plasma proteins that effectively predict CA risk. These findings not only advance understanding of the molecular mechanisms driving CA but also offer translational potential for early detection and precision prevention in clinical practice.
BACKGROUND:Previous post-mortem studies in victims of intoxication have typically focused on toxicological and biochemical analyses. This study aimed to assess the prevalence and types of cardiovascular disease in fatal intoxication cases. METHODS:We included post-mortem autopsy examinations of 865 fatal intoxication cases performed on medico-legal basis at the Gade Laboratory for Pathology at Haukeland University Hospital, Bergen between 2000 and 2013. RESULTS:The mean age at death was 42.1 years (range 13-97) and 72% were males. The cause of death was attributed to intoxication with drugs in 35% cases, combination of drugs and narcotics in 17%, narcotics in 17%, ethanol and drugs in 15%, and ethanol alone in 8% cases. More than a third (36.0%) had concomitant causes of death. The mean heart weight was 387 ± 86 g. A total of 12.3% patients had mild, 8.4% moderate and 9.7% had severe atherosclerosis, while 69.6% had no atherosclerosis or only minor changes in the coronary arteries. A total of 14.9% patients had pathological changes in the brain: cerebral oedema in 23% (n = 29) cases, old ischemic strokes in 22% (n = 28), traumatic brain injury in 13.2% (n = 17) and intracranial hemorrhage in 8.5% (n = 11), while the incidence of acute ischemic stroke was 3.1% (n = 4). Myocardial infarction (old/healed) was evident in 10.3% (n = 89) of the victims. The incidence of left ventricular hypertrophy was nearly 3-fold higher than right ventricular hypertrophy (29.2% vs 10.6%). CONCLUSIONS:In victims of intoxication, cerebrovascular disease was found in 15% and heart diseases in up to 30% of cases. It is possible that the acute toxic effects of alcohol and substance abuse are aggravated in patients with underlying cardiac and cerebrovascular diseases. The findings from the current study highlight the importance of enhanced cardiovascular risk assessment in substance use disorders, with major forensic and public health implications.
Immune cells play key roles in cardiac homeostasis and disease. Although the function and significance of diverse immune cell populations in the heart in health, aging, and in disease is not fully understood, it is clear that these immune populations can be of diagnostic and therapeutic significance. The field of cardio-immunology is vast and evolving constantly. Herein, we aim to focus on a subset of the immune cells that are abundant and significant in healthy and diseased heart, providing relevant biological concept and clinical implications for practicing pathologists.
BACKGROUND:Epidemiological evidence has established a strong association between iron deficiency (ID) and the exacerbation of heart failure (HF) and increased mortality. However, the molecular mechanisms by which iron deficiency drives cardiac diastolic dysfunction remain incompletely understood. This study aimed to elucidate the mechanism by which iron deficiency causes cardiac dysfunction through disruption of myocardial energy homeostasis and consequent impairment of heart function. METHODS:An in vivo iron deficiency (ID) mouse model was established via phlebotomy combined with a low-iron diet, while an in vitro model was induced by treating H9C2 cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) with deferoxamine (DFO). Serum ferritin level was measured by enzyme-linked immunosorbent assay (ELISA). Cardiac function was assessed by echocardiography. Cardiomyocyte hypertrophy and myocardial fibrosis were evaluated using wheat germ agglutinin (WGA) and Masson's trichrome (MT) staining. Integrated transcriptomic sequencing (RNA-Seq) and targeted metabolomics analyses in DFO treated H9C2 cardiomyocytes were performed to identify key dysregulated pathways, which were further validated by Western blot and immunofluorescence. Mitochondrial function and energy production were quantified using the Seahorse XFe24 Extracellular Flux Analyzer. RESULTS:After 250 to 300 μL blood withdrawal and low-iron diet treatment for 4 weeks, serum ferritin level was significantly lower in ID model group compared with the sham group. ID model displayed a cardiac diastolic dysfunction phenotype, as indicated by an increased ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/E' ratio), while left ventricular ejection fraction remained preserved. Histological analyses of mouse hearts revealed significant cardiomyocyte hypertrophy and interstitial fibrosis in ID model hearts. In vitro, multi-omics profiling in DFO treated H9C2 cells uncovered profound metabolic reprogramming induced by iron deficiency, characterized by suppressed mitochondrial oxidative phosphorylation and ATP production, accompanied by a compensatory shift toward glycolysis, ultimately leading to cellular energy depletion, evidenced by a marked reduction in oxygen consumption rate (OCR) and intracellular adenosine triphosphate (ATP) levels. The energetic stress activated AMPK, as evidenced by increased AMPKα phosphorylation, which in turn inhibited mTORC1 signaling. Consistently, phosphorylation of downstream mTORC1 effectors, including P70S6K, S6, and 4EBP1, was significantly reduced in left ventricular tissue, DFO-treated H9C2 cells and hiPSCCMs. Pharmacological inhibition of AMPK with Compound C rescued the impaired mTORC1 signaling. CONCLUSIONS:Iron deficiency directly disrupts myocardial ATP production via the ATP-AMPK-mTORC1 axis, leading to pathological cardiac remodeling and diastolic dysfunction. These findings provide mechanistic insight into iron deficiency-related heart failure, highlighting metabolic signaling pathways as potential therapeutic targets.
Atrial fibrillation (AF) is the most common heart rhythm disorder with an estimated prevalence of 2-4% in adults. AF is a recognised risk factor for sudden cardiac death (SCD) and has been associated with most cardiac diseases. As the atria enlarge the risk of developing AF increases. We sought to establish the cardiac diseases associated with AF from a cohort of individuals who experienced SCD from a national referral centre for SCD. Cases were randomly age and sex matched to individuals without AF who experienced SCD. Characteristics and cardiac diseases were compared between cohorts. Sudden arrhythmic death syndrome (SADS), where no cardiac pathology was found was significantly underrepresented in AF compared to controls (46 vs 27, p = 0.01). Cardiomyopathy was more common in AF compared to controls (32 vs 15, p = 0.01). Ischemic Heart Disease and other cardiac pathologies were similar in prevalence across AF and controls (22 vs 20, p = 0.86; 27 vs 27, p = 0.99). AF is a concerning development in cardiomyopathy and increases the risk of SCD. Heart failure can lead to an enlargement of the atria which is in turn linked to an elevated risk of AF. Aggressive medical treatment of heart failure is important to prevent cavity dilation and the development of AF. AF is a concerning development in cardiomyopathy and may indicate an increase in the risk of SCD as we observed cardiomyopathy and AF more commonly in younger individuals.
Cardiac allograft rejection has traditionally been assessed by endomyocardial biopsy (EMB). Blood-based assays such as donor-derived cell-free DNA (dd-cfDNA) are increasingly used, yet emerging data highlight discordance between these approaches. This review evaluates recent data, examines causes of disagreement, and suggests strategies to better align EMB and dd-cfDNA.
Anorexia nervosa is associated with severe cardiovascular complications and an increased risk of sudden death. While cardiac atrophy is well recognized, unusual connective-tissue alterations of the heart are rarely described. A 28-year-old woman with a longstanding history of anorexia nervosa was found deceased at home. She was profoundly underweight, with extreme cachexia and a body mass index of 10.6. External examination revealed severe emaciation with near-complete loss of subcutaneous fat and marked muscular atrophy. Autopsy demonstrated near-total depletion of subcutaneous and visceral adipose tissue and a global cardiac atrophy. The epicardial surface appeared gelatinous and translucent, extending along the coronary arteries. Histological examination revealed extensive alcianophilic myxoid degeneration involving both the epicardium and myocardial interstitial tissue, confirmed by Alcian blue staining. This case represents an unprecedented example of combined epicardial and myocardial alcianophilic degeneration in severe anorexia nervosa, likely reflecting extreme connective-tissue remodeling due to profound malnutrition.
INTRODUCTION:Despite imaging advancements, proper management for cardiac amyloidosis hinges on accurate diagnosis and subtyping of amyloid in endomyocardial biopsies (EMBx). Nonetheless, the approach toward identifying amyloid in EMBx varies among pathologists. Various staining techniques can be used, each with its own advantages and limitations. There is a lack of evidence-based data to compare different methodologies to detect amyloid in EMBx. In this study, we compared the efficacy of H&E stains only, Congo red (bright field, polarized, and fluorescence), trichrome, and Thioflavin S for the diagnosis of amyloid in EMBx. We also validated a digital imaging workflow for Congo red (brightfield, polarized, and fluorescence microscopy) and Thioflavin S in EMBx. METHODS:We retrospectively identified 40 EMBx (21 positive and 19 negative) that were evaluated for amyloid deposition. Each biopsy was stained with H&E, Congo red, trichrome, and Thioflavin S. The slides were separated into three independently randomized and blinded cohorts: HE + Congo red, HE + trichrome, and HE + thioflavin S. Cases were evaluated for amyloid deposition by three cardiothoracic pathologists (CTP) and two pathologists-in-training (PIT) based on (1) H&E only (2) Congo red brightfield (3) Congo red polarized, (4) Congo red fluorescence, (5) trichrome, and (6) Thioflavin S. After a 3-month washout period, the Congo red and Thioflavin S slides were scanned using an Olympus VS200 slide scanner to capture brightfield, polarized, and fluorescent images, which were then reviewed by all reviewers. This validation was exempt from IRB review. RESULTS:Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each stain when reviewed by CTP alone as well as CTP+PIT. When glass slides were reviewed by CTP + PIT, sensitivity ranged from 86.7%-99.1%, specificity 93.6%-99.0%, PPV 94.4%-99.1%, and NPV 86.8%-99.0%. Statistical analysis revealed no significant differences in sensitivity, specificity, PPV, or NPV between Congo red polarized and any other studied stain. When digital images were reviewed by CTP + PIT, sensitivity ranged from 88.6%-97.1%, specificity 91.6%-100%, PPV 92.2%-100%, and NPV 88.6%-96.9%. Statistical analysis revealed no significant differences between stains interpreted by digital imaging and their corresponding glass slides. CONCLUSION:Congo red staining with polarized microscopy is often considered the gold standard for detecting amyloid deposits. We demonstrated that trichrome and Thioflavin S stains show comparable results and can be considered as appropriate methods for diagnosis. In addition, reviewing Congo red brightfield, polarized, and fluorescence as well as Thioflavin S with digital imaging shows a comparable diagnostic yield to glass slides for identification of cardiac amyloid deposition. These findings suggest that a digital workflow can be implemented for diagnosing cardiac amyloid deposition in routine practice.
