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Hypertrophic cardiomyopathy is the most common genetic cardiac disease and is characterized by left ventricular hypertrophy. Although this hypertrophy often associates with sarcomeric gene mutations, nongenetic factors also contribute to the disease, leading to diastolic dysfunction. Notably, this dysfunction manifests before hypertrophy and is linked to hypercontractility, as well as nonuniform contraction and relaxation (myofibril asynchrony) of the myocardium. Although the distribution of hypertrophy in hypertrophic cardiomyopathy can vary both between and within individuals, in most cases, it is primarily confined to the interventricular septum. The reasons for septal thickening remain largely unknown. In this article, we propose that alterations in muscle fiber geometry, present from birth, dictate the septal shape. When combined with hypercontractility and exacerbated by left ventricular outflow tract obstruction, these factors predispose the septum to an isometric type of contraction during systole, consequently constraining its mobility. This contraction, or more accurately, this focal increase in biomechanical stress, prompts the septum to adapt and undergo remodeling. Drawing a parallel, this is reminiscent of how earthquake-resistant buildings are retrofitted with vibration dampers to absorb the majority of the shock motion and load. Similarly, the heart adapts by synthesizing viscoelastic elements such as microtubules, titin, desmin, collagen, and intercalated disc components. This pronounced remodeling in the cytoskeletal structure leads to noticeable septal hypertrophy. This structural adaptation acts as a protective measure against damage by attenuating myofibril shortening while reducing cavity tension according to Laplace Law. By examining these events, we provide a coherent explanation for the septum's predisposition toward hypertrophy., Competing Interests: Disclosures Dr Maack serves on advisory boards to Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, Servier, Amgen, Novo Nordisk, Bayer, Novartis, Edwards, and Berlin Chemie. Dr Sequeira has received research funding support from Bristol Myers Squibb. The other authors report no conflicts.

As the population ages, the prevalence of heart failure and individuals wearing an implanted cardiac device is increasing. The combination of different underlying pathophysiologies and (the combination of) implanted cardiac devices can become a challenge with regard to the determination of cause and manner of death in such individuals. Additionally, heart disease is frequently associated with mental disease, ranging from anxiety and depression to suicidality and suicide (attempts). At the same time, the correct diagnosis of cause and manner of death is the basis for quality assurance, further therapeutic advances, legal safety, and suicide prevention. By that, an interdisciplinary field between legal medicine, clinicians, and law enforcement opens up. In this field, the different participants can simultaneously benefit from and need each other. For example, legal medicine experts need investigatory results and clinical expertise for the interpretation of readout data of implanted cardiac devices in order to correctly determine the cause of death. A correctly determined cause of death can assist law enforcement and help clinicians to further improve various therapeutic approaches based on correct mortality data collection. In addition, it is the basis for identification of suicides of device carriers, allowing psychological and psychiatric experts to better understand the burden of mental disease in this particular cohort. Against this interdisciplinary background, this manuscript summarizes information about psychiatric comorbidities and suicidality while being on a device. Thereby, basic information on complications and malfunctions of implanted cardiac devices, device-associated deaths with particular emphasis on device manipulation is displayed as basic information needed for correct determination of the cause of death. Also, legal and ethical issues in this field are outlined. The final result is a proposal of an interdisciplinary assessment workflow for a conjoint approach to improve the diagnosis of deaths associated with implanted cardiac devices. It will allow for a differentiation between an individual who died with or due to the device., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Federspiel, Potente, Abeln, Hennemann, Heinbuch, Burkhard, Richl, Kettner, Lux, Schmidt, Verhoff and Ramsthaler.)

In the frame of an experimental setting, the formation of round-shaped compounded glass fragments on the exit site after gunshots through a windshield was examined. For that purpose, a 9 × 19 mm pistol (HK P30) and two different cartridges containing (a) a full metal jacketed round-nosed projectile and (b) a deformation projectile were used. On the basis of 52 gunshots, the morphology, impact angles and terminal ballistics of occurring compounded glass fragments were examined. The results showed that the compounded glass fragments' morphology allowed for the differentiation of two used projectiles. Fragments were able to cause round-shaped defects in a single cotton layer (T-shirt) with subsequent penetration of up to 2.4 cm into ballistic gelatin (10%, 4 °C). As a function of the projectile type, the compounded glass fragments showed different reproducible impact angles that differed notably from the known conical pattern of expelled glass fragments after bullet penetration. These findings might help to explain the atypical morphology of gunshot wounds with laminated glass as an intermediate target and prevent possible misinterpretations when reconstructing the sequence of events., (© 2022. The Author(s).)

Three intermediate-range shots from a Browning, model 1955, 7.65 mm caliber, pistol were fired from the driver's seat of a car at a woman in the passenger seat. She sustained three wounds: An, ultimately fatal, penetrating head wound, a graze wound across her forehead, and a tangential, perforating, wound, with bullet entry over the medial sternum and exit through the right flank. Neither postmortem CT nor forensic autopsy discovered bony thoracic injuries or perforations of the thoracoabdominal cavities. There was pulmonary contusion in the medial lobe of the right lung and hemorrhage in the adipose tissue around the right kidney. The tangential bullet had left an almost 40-cm-long wound channel through a pronounced layer of subcutaneous fat. Based on 3D reconstructed CT-data determinations, a straight bullet trajectory between entry and exit wounds would have traversed the abdominothoracic cavities, right lung, and liver. The actual trajectory, however, described a prominent curve, without signs of deflection by bone. Postulated explanations for this unusual bullet track are that the woman was twisting her body in a dynamic scene when the bullet struck; further, due to its shallow angle of incidence on the skin, the bullet was deflected to an intracutaneous path. Additionally, soft tissue resistance may have caused the bullet to yaw. Caution should, thus, be exercised when reconstructing bullet trajectories solely from entry and exist wounds, also for bullet wounds through basically homogenous soft tissues., (© 2022. The Author(s).)

Both particular myocardial locations in the human heart and the canonical transient receptor potential 6 (TRPC6) cation channel have been linked with cardiac pathophysiologies. Thus, the present study mapped TRPC6-protein distribution in select anatomic locations associated with cardiac disease in the context of an orienting pathological assessment. Specimens were obtained from 5 body donors (4 formalin fixation, 1 nitrite pickling salt-ethanol-polyethylene glycol (NEP) fixation; median age 81 years; 2 females) and procured for basic histological stains and TRPC6-immunohistochemistry. The latter was analyzed descriptively regarding distribution and intensity of positive signals. The percentage of positively labelled myocardium was also determined (optical threshold method). Exclusively exploratory statistical analyses were performed. TRPC6-protein was distributed widespread and homogenously within each analyzed sample. TRPC6-immunoreactive myocardial area was comparable regarding the different anatomic regions and sex. A significantly larger area of TRPC6-immunoreactive myocardium was found in the NEP-fixed donor compared to the formalin fixed donors. Two donors with more severe heart disease showed smaller areas of myocardial TRPC6-immunoreactivity overall compared to the other 3 donors. In summary, in the elderly, TRPC6-protein is widely and homogenously distributed, and severe cardiac disease might be associated with less TRPC6-immunoreactive myocardial area. The tissue fixation method represents a potential confounder.

Background: The transient receptor potential canonical 6 (TRPC6) channel has been studied in pathologies of the hepatobiliary system. Information on the localization of TRPC6-protein in anatomical and histological structures of the human hepatobiliary system in elderly with and without liver disease is lacking., Methods: Samples were obtained from twelve nitrite pickling salt-ethanol-polyethylene glycol-fixed corpses of the four anatomical liver lobes, collum and the remaining gallbladder, the common bile duct (gender: 5 females, 41.67%; age [years]: median 84, range 20; postmortem interval before fixation [h]: median 60, range 74.15). Orienting histomorphologic assessment was done in a hematoxylin-eosin stain. Immunohistochemical labelling of TRPC6 was carried out following a cross-evaluation scheme. TRPC6-immunoreactivity was assessed regarding intensity (semi-quantification, three independent observers) and area (optical threshold method). Explorative statistical analyses were performed using R (inter-rater-reliability: Fleiss' kappa; comparisons: Wilcoxon-Rank-sum-test)., Results: Extensive autolysis was found in the liver of one and the biliary samples of three corpses. Extensive liver disease was found in 4 corpses, while 8 corpses only showed age-appropriate degeneration. Only the intrahepatic connective tissue showed no TRPC6-immunoreactivity. Individuals with extensively diseased livers exhibited statistically significantly less TRPC6-immunoreactive area in the bile duct and liver tissue while statistically significant more TRPC6-immunoreactive area in the gallbladder compared to individuals with age-appropriate degeneration of the liver only in the respective organ., Conclusion: Age-associated degeneration of the hepatobiliary system is likely to be associated with widespread, homogenous TRPC6-expression. Liver disease potentially influences the distribution of TRPC6-protein within the liver and within the biliary tract in elderly., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: During the recent pandemic with the severe acute respiratory syndrome-corona virus‑2 the first messenger ribonucleic acid (mRNA) vaccines were approved. To facilitate mass vaccination, confidence of the general population in these new vaccines is mandatory, which is in turn strongly dependent on the availability of reliable data on complications., Objective: Summary of the current knowledge on mRNA vaccination-associated myocarditis as a potentially fatal side effect., Methods: Systematic literature review., Results: Diagnostic algorithm for the postmortem diagnosis of mRNA vaccination-associated myocarditis., Conclusion: Autopsy series of fatalities following mRNA SARS-CoV‑2 vaccination up to 6 weeks with subsequent sophisticated and interdisciplinary work-up are necessary to complement clinical data on vaccination-associated myocarditis, especially regarding the incidence of fatal courses., Supplementary Information: The online version of this article (10.1007/s00194-022-00587-9) includes a PDF file with supplemental clinical features., Competing Interests: Conflict of interestJ. M. Federspiel, F. Ramsthaler, M. Kettner, and G. Mall declare that they have no competing interests., (© The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022.)

Introduction: Multiple cardiovascular conditions can lead to unexpected fatality, which is defined as sudden cardiac death. One of these potentially underlying conditions is aortic regurgitation, which can be caused by discrete changes of the geometry of the proximal aorta. To analyze aortic valve competency and furthermore to elucidate underlying pathological alterations of the coronary arteries and the vasa vasorum a perfusion method to simulate a diastolic state was designed., Material and Methods: A postmortem approach with retrograde perfusion of the ascending aorta with methylene blue was applied to three bodies. The procedure comprised cannulation of the brachiocephalic trunk, clamping of the aortic arch between brachiocephalic trunk and left carotid artery, infusion of 250 ml of methylene blue, and optical clearing of the superficial tissue layers after perfusion. Organs were examined directly following perfusion and after optical clearing., Results: Assessment and visualization of aortic valve competency and the vasa vasorum were possible in all three instances. Visualization of the coronary perfusion was impaired by postmortem thrombus formation. Optical clearing did not provide additional information., Discussion: The method presented here is a time- and cost-efficient way of visualizing aortic valve competency and the vasa vasorum. The visualization of the vasa vasorum highlights the potential of this method in basic research on diseases of the great arteries and coronaries. However, for a time-efficient functional analysis of the coronaries, other methods must be applied., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background: We have proposed an external stabilization technique to minimize autograft dilatation after the Ross operation. This study analyzed autograft function and root dimensions after root replacement with and without external root support., Methods: Between October 1995 and February 2021, 185 adult patients (73% male; age, 38 ± 9 years) underwent a Ross operation as full-root replacement, 136 with support and 49 without support. Autograft function and root dimensions were determined echocardiographically. Median follow-up was 3.4 years (interquartile range, 1.13-14.74 years) and was 95% complete. Survival and freedom from reoperation were calculated. Changes in autograft root dimensions were analyzed using mixed-effect models., Results: Survival (95%) and freedom from autograft reoperation (94%) at 15 years were higher with than without support (P = .003 or P = .004). In the first 5 years, patients with support showed an indexed root size progression of 0.712 mm/(y ∙ m) (P = .003) compared with 1.554 mm/(y ∙ m) (P = .001) without. Progression rates were higher for patients without stabilization (P = .045). After 5 years, progression rates were similar in both groups at 0.248 mm/(year ∙ m) (P < .001) but with persistent a difference between the groups., Conclusions: The Ross procedure as full-root replacement is associated with a relevant rate of autograft dilatation and reoperation. The use of external root stabilization may reduce autograft dilatation and is associated with improved survival and durability., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Certain aortic valve malformations predispose to ascending aortic aneurysm, although the mechanisms are incompletely understood. The aim of this study was to determine whether turbulence across the unicuspid aortic valve (UAV) contributes to regional differences in endothelial nitric oxide (eNOS) signaling in the ascending aortic wall., Methods: Samples were collected intraoperatively from the convex and concave ascending aortic wall from 64 patients with tricuspid aortic valves (TAVs; 25 nondilated, 17 dilated), or UAVs (9 nondilated, 13 dilated)., Results: In normal-sized aortas, eNOS protein was decreased in UAV compared with TAV ( P  = .02) whereas mRNA was similar ( P  = .62). eNOS protein was increased in UAV-dilated aortas compared with UAV-nondilated aortas ( P  = .04), whereas dilatation had no impact on eNOS protein levels in TAV aortas ( P  = .73). Comparing only aneurysmal aortas, we found no difference in eNOS mRNA or protein between dilated TAV and UAV aortas ( P  = .26, P  = .76). For eNOS mRNA and protein levels in normal and dilated UAV-associated aortas, no differences were found between concavity and convexity (all P  > .05). This differed from dilated TAV aortas, which showed decreased eNOS mRNA in the convexity ( P  = .004) whereas eNOS protein levels were similar ( P  = .75)., Conclusions: eNOS downregulation is observed in the UAV-associated ascending aorta and is apparently independent of dilatation. No regional differences were found, however, which would be expected if eNOS changes occur due to wall shear stress. This implies a congenital defect in eNOS signaling that may be stronger than turbulence-induced expression patterns. Further research should define the role of eNOS in aortopathy associated with aortic valve disease., (© 2021 The Author(s).)

We report a case in whom aortic wrapping had been performed for aortic dilatation. Ten years later, further progression of aortic root diameter was documented (root size of 66 mm). We performed complete replacement of the proximal aorta. Macroscopically and microscopically, there was extreme degeneration and thinning of the aorta under the graft., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The unicuspid aortic valve (UAV) is a rare cardiac malformation and is associated with the formation of ascending aortic aneurysms. To characterize its associated aortic wall changes, normal and aneurysmatic ascending aortic wall specimens were analysed, focusing on the potential mechanisms of aneurysm formation. Patients with tricuspid aortic valve (TAV) served as controls., Methods: In a retrospective observational study, 74 specimens (dilated and non-dilated aortas; individuals with UAV and TAV) obtained intraoperatively were studied. Standard stains and immunohistochemical labelling of cleaved caspase-3, cluster of differentiation 31 and endothelial nitric oxide synthase (eNOS) were performed to assess the degree of apoptosis, distribution of eNOS within the aortic wall, smooth muscle cell (SMC) nuclei loss and mucoid extracellular matrix accumulation (MEMA)., Results: Deeper ingrowth of vasa vasorum was found in dilated aortas. Interestingly, eNOS was expressed mostly in vasa vasorum. More apoptosis was seen in UAV aortas compared to TAV aortas (P < 0.001). Both UAV and TAV aortas were comparable regarding SMC nuclei loss (P = 0.419). In dilated compared to non-dilated aortas regardless valve morphology SMC nuclei loss was increased (P = 0.005) and more pronounced translamellar MEMA was present (P = 0.011). The highest grade of distribution (P = 0.043) and the highest severity (P = 0.005) regarding MEMA were seen in TAV dilated specimens compared to UAV dilated specimens., Conclusions: Aneurysms with UAV show increased apoptosis, the role of which is unclear. Strikingly, more severe MEMA was found in TAV aneurysms compared to UAV aneurysms. Thus, UAV-associated aortic wall changes and resulting aneurysm may be less aggressive than aneurysms with TAV., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose of Review: Preservation or repair of the aortic valve has evolved dynamically in the past 20 years. It leads to a high freedom from valve-related complications if an adequate valve durability can be achieved; it may possibly also improve survival. To date, little structured information is available about which valves can be repaired and which should better be replaced., Recent Findings: For surgical decision-making, the size of the aortic root is important and the anatomy of the aortic valve must be considered. In the presence of root aneurysm, most tricuspid and bicuspid aortic valves can be preserved. In aortic regurgitation and normal aortic dimensions, the majority of tricuspid and bicuspid aortic valves can be repaired with good long-term durability. In bicuspid aortic valves, the morphologic characteristics must be taken into consideration. Unicuspid and quadricuspid aortic valves can be repaired in selected cases. Generally, cusp calcification is a sign of a poor substrate for repair; the same is true for cusp retraction and cusp destruction due to active endocarditis. They are associated with limited valve durability. Using current concepts, many non-calcified aortic valves can be repaired. Modern imaging, in particular three-dimensional transesophageal echocardiography (TEE), should be able to define repairable aortic valves with a high probability.

Objective: The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and Results: Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas ( P =0.005) but not AS-aortas ( P =0.23). This pathological remodeling included mucoid extracellular matrix accumulation ( P =0.005), elastin loss ( P =0.003), elastin fragmentation ( P =0.008), and decreased expression of fibrillin ( P =0.003) and collagen ( P =0.008). Furthermore, eNOS (endothelial nitric oxide synthase) expression was decreased in the intima ( P =0.0008) and in vasa vasorum ( P =0.004) of AR-aortas but not AS-aortas (all P >0.05). Likewise, subendothelial apoptosis was increased in AR-aortas ( P =0.03) but not AS-aortas ( P =0.50)., Conclusions: AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR. Graphic Abstract: A graphic abstract is available for this article.

Background Bicuspid aortic valves (BAVs) predispose to ascending aortic aneurysm. Turbulent blood flow and genetic factors have been proposed as underlying mechanisms. Endothelial nitric oxide synthase (eNOS) has been implicated in BAV aortopathy, and its expression is regulated by wall shear stress. We hypothesized that if turbulent flow induces aneurysm formation in patients with a BAV, regional differences in eNOS expression would be observed in BAVs. Methods and Results Ascending aortic specimens were harvested intraoperatively from 48 patients with tricuspid aortic valve (19 dilated, 29 nondilated) and 38 with BAV (28 dilated, 10 nondilated) undergoing cardiac surgery. eNOS mRNA and protein concentration were analyzed at the convex and concave aortic wall. In nondilated aortas, eNOS mRNA and protein concentration were decreased in BAV compared with tricuspid aortic valve (all P <0.05). eNOS expression was increased in association with dilation in BAV aortas ( P =0.03), but not in tricuspid aortic valve aortas ( P =0.63). There were no regional differences in eNOS mRNA or protein concentration in BAV aortas (all P >0.05). However, eNOS expression was increased at the concave wall (versus convexity) in tricuspid aortic valve dilated aortas (all P <0.05). Conclusions Dysregulated eNOS occurs independent of dilation in BAV aortas, suggesting a potential role for aberrantly regulated eNOS expression in the development of BAV-associated aneurysms. The absence of regional variations of eNOS expression suggests that eNOS dysregulation in BAV aortas is the result of underlying genetic factors associated with BAV disease, rather than changes stimulated by hemodynamic alterations. These findings provide insight into the underlying mechanisms of aortic dilation in patients with a BAV.

Only limited data are available on the extent of the vasa vasorum of the human thoracic aorta, although this could be important with regard to certain pathophysiological states, i.e. aortic aneurysm or atherosclerosis. A preliminary investigation shows that the vascularization of the human thoracic aorta reaches deeper layers than generally believed., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Risk of superior vena cava (SVC) obstruction following repair of anomalous right upper pulmonary veins in children is unclear. The incidence and outcome of subclinical obstruction remained unknown. Retrospective single institutional study (07/1993-02/2017) in a pediatric population (N = 42, median age 3.9-year, range 0.1-15.3 years). 33 (79%) children had repair without SVC translocation ("non-Warden") and 9 (21%) had Warden-type surgery. Echocardiographic SVC obstruction was defined as (I) turbulent flow across SVC and (II) continuous flow pattern without return to baseline velocity (0 m/s); severe obstruction was defined as loss of distinct biphasic profile ± mean gradient ≥ 5 mmHg. 3 (7%) patients required intra-operative revision due to obstruction (non-Warden: 1, Warden: 2). After discharge, 2 (5%) patients required reintervention (3 and 6-month post-op) for severe symptomatic obstruction (non-Warden: 1, Warden-type: 1). Both patients responded to balloon angioplasty with symptomatic resolution (one required repeat catheter reintervention). 10 (24%) patients had subclinical echocardiographic obstruction (2, 22% Warden vs. 8, 24% non-Warden; p = 1.0; 8 of 10 patients had mild gradient), which resolved and remained well without reintervention. At follow-up (mean 7.2-year, range 0-23 years), all patients were alive. Freedom from SVC reintervention at 10 and 20-year is 95% (97% at 10, 20-year in non-Warden and 89% at 5, 8-year in Warden-type group; log-rank p = 0.34). Surgical repair for anomalous right upper pulmonary veins is associated with risk of SVC obstruction in children. The need for reintervention for severe obstruction is rare at late follow-up. Patients with subclinical obstruction remain asymptomatic and demonstrate echocardiographic improvement.