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Mitral annular disjunction (MAD), a separation between the left atrium/mitral valve annulus and the left ventricular myocardium, is frequently seen in patients with arrhythmic mitral valve prolapse. Although an association exists between MAD and ventricular arrhythmias, little is known regarding the identification of individuals at high risk. Multimodality imaging including echocardiography, computed tomography, cardiac magnetic resonance, and positron emission tomography can play an important role in both the diagnosis and risk stratification of MAD. Due to a paucity of data, clinical decision making in a patient with MAD is challenging and remains largely empirical. Although MAD itself can be corrected surgically, the prevention and treatment of associated arrhythmias may require medical therapy, catheter ablation, and an implantable cardioverter-defibrillator. Prospective data are required to define the role of implantable cardioverter-defibrillators, targeted catheter ablation, and surgical correction in selected, at-risk patients., Competing Interests: Funding Support and Author Disclosures The Department of Cardiology of Leiden University Medical Center has received research grants from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, and Medtronic. Dr Stassen has received grants from the European Society of Cardiology (Training Grant App000064741). Dr Haugaa has received grants from the Norwegian Research Council (ProCardio #309762, #288438, #298736). Dr Faletra has received speaker fees from Philips Healthcare. Dr Enriquez-Sarano has received consulting fees from Artivion, ChemImage, Edwards Lifesciences, and HighLife. Dr Marsan has received speaker fees from Abbott Vascular and GE Healthcare. Dr Bax has received speaker fees from Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George's Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. "Discrete" subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald-Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term "functional subaortic stenosis" was used in 1959 and "idiopathic hypertrophic subaortic stenosis" in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy's Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989-1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled "HCM without hypertrophy". Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death.

Over the last 20 years, the scientific progresses in molecular biology and genetics in combination with the increasing use in the clinical setting of contrast-enhanced cardiac magnetic resonance (CMR) for morpho-functional imaging and structural myocardial tissue characterization have provided important new insights into our understanding of the distinctive aspects of cardiomyopathy, regarding both the genetic and biologic background and the clinical phenotypic features. This has led to the need of an appropriate revision and upgrading of current nosographic framework and pathobiological categorization of heart muscle disorders. This article proposes a new definition and classification of cardiomyopathies that rely on the combination of the distinctive pathobiological basis (genetics, molecular biology and pathology) and the clinical phenotypic pattern (morpho-functional and structural features), leading to the proposal of three different disease categories, each of either genetic or non-genetic etiology and characterized by a combined designation based on both "anatomic" and "functional" features, i.e., hypertrophic/restrictive (H/RC), dilated/hypokinetic (D/HC) and scarring/arrhythmogenic cardiomyopathy (S/AC). The clinical application of the newly proposed classification approach in the real-world practice appears crucial to design a targeted clinical management and evaluation of outcomes of affected patients. Although current treatment of cardiomyopathies is largely palliative and based on drugs, catheter ablation, device or surgical interventions aimed to prevent and manage heart failure and malignant arrhythmias, better knowledge of basic mechanisms involved in the onset and progression of pathobiologically different heart muscle diseases may allow to the development of disease-specific curative therapy., Competing Interests: Declaration of competing interest No disclosures., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Arrhythmogenic cardiomyopathy (AC) is a hereditary cardiac disorder characterized by the gradual replacement of cardiomyocytes with fibrous and adipose tissue, leading to ventricular wall thinning, chamber dilation, arrhythmias, and sudden cardiac death. Despite advances in treatment, disease management remains challenging. Animal models, particularly mice and zebrafish, have become invaluable tools for understanding AC's pathophysiology and testing potential therapies. Mice models, although useful for scientific research, cannot fully replicate the complexity of the human AC. However, they have provided valuable insights into gene involvement, signalling pathways, and disease progression. Zebrafish offer a promising alternative to mammalian models, despite the phylogenetic distance, due to their economic and genetic advantages. By combining animal models with in vitro studies, researchers can comprehensively understand AC, paving the way for more effective treatments and interventions for patients and improving their quality of life and prognosis.

Aims: Transvenous lead extraction (TLE) is potentially complicated by significant tricuspid valve regurgitation increase (TRI). However, there are limited data on the effect of the bidirectional rotational mechanical sheaths on significant TRI. The aim of the present study was to investigate the rate of significant changes in tricuspid regurgitation (TR) severity following mechanical rotational TLE and their outcomes., Methods and Results: In 158 patients (mean age 66 ± 16.9 years) undergoing mechanical rotational TLE, acute changes in TR severity were assessed by echocardiography evaluation. A significant acute TRI was defined as an increase of at least one grade with a post-extraction severity at least moderate. A total of 290 leads were extracted (mean implant duration, 93 ± 65 months). Significant TRI was noted in 5.7% of patients, and it was linked to tricuspid valve damage, TLE infection indication, and longer lead implant duration. Univariate predictors of significant TRI included implant duration of all leads [odds ratio (OR) 1.01; 95% confidence interval (CI) 1.003-1.018; P = 0.001] and right ventricular leads (OR 1.01; 95% CI 1.004-1.017; P = 0.002). Severe increase of TR following TLE was an independent predictor of mortality [hazard ratio (HR) 5.20; 95% CI 1.44-18.73; P = 0.012 ] along with severe systolic dysfunction (HR 2.37; 95% CI 1.01-5.20; P = 0.032), and systemic infection (HR 2.28; 95% CI 1.06-4.89; P = 0.035)., Conclusion: Significant TRI was detected in 5.7% of patients following transvenous rotational mechanical lead extraction. The duration of lead implantation emerged as the sole predictor of significant TRI. Physicians engaged in TLE should exercise greater vigilance for this potential complication., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 ( TMEM43 ), desmin ( DES ), phospholamban ( PLN ), filamin c ( FLNC ), cadherin 2 ( CDH2 ), and tight junction protein 1 ( TJP1 ), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC , 9 DES , 2 TMEM43 , and 2 CDH2 . No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.

The role of the immune system in myocarditis onset and progression involves a range of complex cellular and molecular pathways. Both innate and adaptive immunity contribute to myocarditis pathogenesis, regardless of its infectious or non-infectious nature and across different histological and clinical subtypes. The heterogeneity of myocarditis etiologies and molecular effectors is one of the determinants of its clinical variability, manifesting as a spectrum of disease phenotype and progression. This spectrum ranges from a fulminant presentation with spontaneous recovery to a slowly progressing, refractory heart failure with ventricular dysfunction, to arrhythmic storm and sudden cardiac death. In this review, we first examine the updated definition and classification of myocarditis at clinical, biomolecular and histopathological levels. We then discuss recent insights on the role of specific immune cell populations in myocarditis pathogenesis, with particular emphasis on established or potential therapeutic applications. Besides the well-known immunosuppressive agents, whose efficacy has been already demonstrated in human clinical trials, we discuss the immunomodulatory effects of other drugs commonly used in clinical practice for myocarditis management. The immunological complexity of myocarditis, while presenting a challenge to simplistic understanding, also represents an opportunity for the development of different therapeutic approaches with promising results.

Sudden death by commotio cordis is rare. It is the consequence of a blunt trauma of the chest overlying the heart. The mechanism is a cardiac arrest by ventricular fibrillation in the absence of grossly or microscopically apparent myocardial injury. It has been reproduced in animals. The first historical case was reported by Giovanni Maria Lancisi in his book "De Subitaneis Mortibus'' published in 1707. Sudden death occurred in a man receiving a powerful blow under the xiphoid cartilage. Lancisi advanced the hypothesis of acute heart failure by a diastolic stand still ("death in diastole'')., 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 © 2024 Elsevier Inc. All rights reserved.)

For many years, cardiac pacing has been based on the stimulation of right ventricular common myocardium to correct diseases of the conduction system. The birth and the development of cardiac resynchronization have led to growing interest in the correction and prevention of pacing-induced dyssynchrony. Many observational studies and some randomized clinical trials have shown that conduction system pacing (CSP) can not only prevent pacing-induced dyssynchrony but can also correct proximal conduction system blocks, with reduction of QRS duration and with equal or greater effectiveness than biventricular pacing. Based on these results, many Italian electrophysiologists have changed the stimulation target from the right ventricular common myocardium to CSP. The two techniques with greater clinical impact are the His bundle stimulation and the left bundle branch pacing. The latter, in particular, because of its easier implantation technique and better electric parameters, is spreading like wildfire and is representing a real revolution in the cardiac pacing field. However, despite the growing amount of data, until now, the European Society of Cardiology guidelines give a very limited role to CSP.

Bicuspid aortic valve (BAV) is the most frequent congenital heart disease, with an incidence of approximately 1%. It can be silent and associated with normal valve function. However, a series of complications, even catastrophic, may occur with time: valve incompetence, valve stenosis by dystrophic calcification, infective endocarditis, progressive dilatation of the ascending aorta, aortic dissection, sudden death. The problem of BAV is not just about the number of semilunar cusps, but also the aortic wall. Severe noninflammatory degenerative changes (elastic fiber fragmentation, smooth muscle cells death, mucoid extracellular matrix accumulation=MEMA) are observed in the aortic wall of BAV patients, with intrinsic weakness accounting for progressive aneurysmal dilatation of the ascending aorta, valve incompetence, and wall dissection. The link between valve and aortic wall pathology finds most probably an explanation in the embryology of the arterial pole since neurocrestal cells play a role in the development of both the ascending aorta, aortic arch, and semilunar valves. The frequent association of adult aortic coarctation and BAV provides evidence for this hypothesis. BAV has a significant genetic component as to require screening of first-degree relatives, as outlined by AHA/ACC 2022 guidelines., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This review explores the historical development of cardiology knowledge, from ancient Egyptian psychostasis to the modern comprehension of cardiac neuromodulation. In ancient Egyptian religion, psychostasis was the ceremony in which the deceased was judged before gaining access to the afterlife. This ritual was also known as the "weighing of the heart" or "weighing of the soul". The Egyptians believed that the heart, not the brain, was the seat of human wisdom, emotions, and memory. They were the first to recognize the cardiocentric nature of the body, identifying the heart as the center of the circulatory system. Aristotle (fourth century BC) considered the importance of the heart in human physiology in his philosophical analyses. For Galen (third century AD), the heart muscle was the site of the vital spirit, which regulated body temperature. Cardiology knowledge advanced significantly in the 15th century, coinciding with Leonardo da Vinci and Vesalius's pioneering anatomical and physiological studies. It was William Harvey, in the 17th century, who introduced the concept of cardiac circulation. Servet's research and Marcello Malpighi's discovery of arterioles and capillaries provided a more detailed understanding of circulation. Richard Lower emerged as the foremost pioneer of experimental cardiology in the late 17th century. He demonstrated the heart's neural control by tying off the vagus nerve. In 1753, Albrecht von Haller, a professor at Göttingen, was the first to discover the heart's automaticity and the excitation of muscle fibers. Towards the end of the 18th century, Antonio Scarpa challenged the theories of Albrecht von Haller and Johann Bernhard Jacob Behrends, who maintained that the myocardium possessed its own "irritability", on which the heartbeat depended, and was independent of neuronal sensitivity. Instead, Scarpa argued that the heart required innervation to maintain life, refuting Galenic notions. In contemporary times, the study of cardiac innervation has regained prominence, particularly in understanding the post-acute sequelae of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection (PASC), which frequently involves cardiorespiratory symptoms and dysregulation of the intrinsic cardiac innervation. Recently, it has been recognized that post-acute sequelae of acute respiratory infections (ARIs) due to other pathogens can also be a cause of long-term vegetative and somatic symptoms. Understanding cardiac innervation and modulation can help to recognize and treat long COVID and long non-COVID-19 (coronavirus disease 2019) ARIs. This analysis explores the historical foundations of cardiac neuromodulation and its contemporary relevance. By focusing on this concept, we aim to bridge the gap between historical understanding and modern applications. This will illuminate the complex interplay between cardiac function, neural modulation, cardiovascular health, and disease management in the context of long-term cardiorespiratory symptoms and dysregulation of intrinsic cardiac innervations.

In 1900, Fiedler first reported autopsy cases with peculiar inflammation of the myocardium, which he named interstitial myocarditis. He postulated an isolated cardiac inflammation of the myocardium in the absence of multiorgan involvement and with a poor prognosis due to invisible microorganisms, which years later would have been identified as viruses. The revision of original histologic sections by Schmorl showed cases with lymphocytes and others with giant-cell inflammatory histotypes. The in vivo diagnosis of myocarditis became possible thanks to right cardiac catheterization with endomyocardial biopsy (EMB). The gold standard for diagnosis was achieved with the employment of immunohistochemistry and molecular investigation by Polymerase Chain Reaction (PCR), which allows for the detection of viruses as causal agents. Both RNA and DNA were revealed to be cardiotropic, with a common receptor (CAR). A protease, coded by coxsackie virus, disrupts the cytoskeleton and accounts for cell death. Unfortunately, vaccination, despite having been revealed to be effective in animal experiments, has not yet entered the clinical field for prevention. Cardiac Magnetic Resonance turned out to be a revolutionary tool for in vivo diagnosis through the detection of edema (inflammatory exudate). Myocarditis may be fulminant in terms of clinical presentation but not necessarily fatal. The application of ExtraCorporeal Membrane Oxygenation (ECMO) allows for relieving the overloaded native heart.

Objective: Evidence on the increased risk of sports-related sudden cardiac arrest and death (SCA/D) and the potential benefit of cardiovascular preparticipation screening (PPS) in children is limited. We assessed the burden and circumstances of SCA/D and the diagnostic yield of cardiovascular PPS in children aged 8-15 years., Methods: Data on the incidence and causes of SCA/D from 2011 to 2020 were obtained from the Veneto region (Italy) sudden death registry, hospital records and local press. During the same period, we assessed the results of annual PPS in 25 251 young competitive athletes aged 8-15 years who underwent 58 185 evaluations (mean 2.3/athlete) in Padua, Italy., Results: Over 10 years, 26 SCA/D occurred in children aged 8-15 years in the Veneto region: 6 in athletes (incidence 0.7/100 000/year, all ≥12 years) versus 20 in non-athletes (0.7/100 000/year, 17/20 ≥12 years). In total, 4/6 athletes versus 1/20 non-athletes survived. The cause of SCA/D remained unexplained in four athletes and in nine non-athletes. No athlete suffered SCA/D from structural diseases potentially identifiable by PPS. The incidence of SCA/D in athletes and non-athletes was 0.2/100 000/year in the 8-11 years group versus 1.3/100 000/year in the 12-15 years group. PPS identified 26 new diagnoses of cardiovascular diseases (CVDs) at risk of SCA/D, more often in children ≥12 years old (0.06%/evaluation) than <12 years old (0.02%/evaluation, p=0.02). Among athletes with a negative PPS, two suffered unexplained SCA/D during follow-up, one during exercise., Conclusions: In children aged 8-15 years, the incidence of SCA/D and the yield of PPS for identifying at-risk CVD were both substantially higher in those ≥12 years, suggesting that systematic PPS may be more useful beyond this age., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late‑gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosures None.

Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). We present here the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease, on which environmental factors and candidate drugs can be tested. Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, oedema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed "pale", disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Overall, our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade., (© 2023. The Author(s).)

Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease at risk of sudden cardiac death and heart failure, even requiring heart transplantation. A "muscular mitral-aortic discontinuity" has been reported during surgery in the obstructive form. We aimed to validate these findings through pathological analysis of HCM heart specimens from the cardiovascular pathology tissue registry. Hearts with septal asymmetric HCM from sudden cardiac death, other causes of death, or heart transplantation were included. Sex-matched and age-matched patients without HCM served as controls. Gross and histologic analysis of the mitral valve (MV) apparatus and the mitral-aortic continuity were performed. Thirty HCM hearts (median age, 29.5 years; 15 men) and 30 controls (median age, 30.5 years; 15 men) were studied. In HCM hearts, a septal bulging was present in 80%, an endocardial fibrous plaque in 63%, a thickening of the anterior MV leaflet in 56.7%, and an anomalous insertion of papillary muscle in 10%. All cases but 1 (97%) revealed a myocardial layer overlapping the mitral-aortic fibrous continuity on the posterior side, corresponding to the left atrial myocardium. A negative correlation between the length of this myocardial layer and the age and the anterior MV leaflet length was found. The length did not differ between HCM and controls. Pathologic study of obstructive HCM hearts does not confirm the existence of a "muscular mitral-aortic discontinuity". An extension of left atrial myocardium, overlapping posteriorly the intervalvular fibrosa, is rather visible, and its length decreases with age, possibly as a consequence of left atrial remodeling. Our study highlights the fundamental role of thorough gross examination and the value of organ retention for further analysis in order to validate new surgical and imaging findings., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

History of cardiology starts scientifically in 1628, when William Harvey (1578-1657) published his revolutionary book Extercitatio anatomica de motu cordis et sanguinis in animalibus , where he described "general" circulation, movements and functions of heart, heart valves, veins and arteries [1]. Consequently, all theories and practices of ancient medicines were reduced to superstitions. Historians relegated pre-Harveian cardiology to roughs notes, preventing a proper historical evaluation of many centuries of conceptions and practices. All the ancient civilizations shared the conviction that the heart was the biological and spiritual center of the body, the seat of emotions, mind, will, a vital energy produced by breathing and healing, and the soul. This cardiocentric view maintained a special role both in religion and in medicine across millennia from east to west, passing over cultural and scientific revolutions. Here, we will try to give a schematic account of medical beliefs on the heart from the most important pre-classic medicines. Some of them today show to have a kernel of truth. This demonstrates, at least, that history is a non-linear process and that intuitions or even truths, potentially useful for the present and scientific development, can re-emerge from the past., Competing Interests: 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., (© 2023 The Authors.)

Aims: Myocardial longitudinal strain (LS) by two-dimensional (2D) speckle-tracking echocardiography has a diagnostic and prognostic role in cardiac amyloidosis (CA). Typically, the apical segments of the left ventricle (LV) are less affected by LS abnormalities, a finding called relative apical sparing (RELAPS). Whether a variable burden of CA might explain the RELAPS remains unknown.We aimed to evaluate the extent, distribution, and deposition pattern of amyloid in autopsy hearts of CA patients and to correlate the histopathology findings with 2D echocardiography., Methods and Results: This is a retrospective study of whole heart specimens of CA patients who died and underwent autopsy and 2D echocardiography. Amyloid burden quantification was assessed by histomorphometry in each segment at different LV levels. The LS analysis results were compared with the amyloid burden and the base-to-apex distribution.Histopathology investigation of 27 hearts with CA [immunoglobulin light chains (AL) 17 cases and transthyretin (ATTR) 10 cases] demonstrated an amyloid base-to-apex gradient. In 11 CA patients with 2D echocardiography, analysis of LS and histological amyloid burden allowed to identify different patterns: RELAPS (8 cases, 73%), with (2) or without (6) amyloid gradient, normal or mildly reduced LS with diffuse low amyloid (2, 18%), and severely reduced LS with diffuse high amyloid (1, 9%)., Conclusion: The typical RELAPS pattern at echocardiography is not always explained by a base-to-apex gradient of amyloid burden at histopathology, suggesting that RELAPS might be an epiphenomenon of complex interactions among amyloid infiltration, myocardial structure, and adaptation., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation family, published in 1728. Contemporary history at the University of Padua started with Dalla Volta, who haemodynamically investigated patients with "auricularization" of the right ventricle, and with Nava, who confirmed familiarity. The contemporary knowledge advances consisted of (a) AC as a heart muscle disease with peculiar electrical instability of the right ventricle; (b) the finding of pathological substrates, in keeping with a myocardial dystrophy; (c) the inclusion of AC in the cardiomyopathies classification; (d) AC as the main cause of sudden death in athletes; (e) the discovery of the culprit genes coding proteins of the intercalated disc (desmosome); (f) progression in clinical diagnosis with specific ECG abnormalities, angiocardiography, endomyocardial biopsy, 2D echocardiography, electron anatomic mapping and cardiac magnetic resonance; (g) the discovery of left ventricular AC; (h) prevention of SCD with the invention and application of the lifesaving implantable cardioverter defibrillator and external defibrillator scattered in public places and playgrounds as well as the ineligibility for competitive sport activity for AC patients; (i) genetic screening of the proband family to unmask asymptomatic carriers. Nondesmosomal ACs, with a phenotype overlapping desmosomal AC, are also treated, including genetics: Transmembrane protein 43, SCN5A, Desmin, Phospholamban, Lamin A/C, Filamin C, Cadherin 2, Tight junction protein 1.

Competing Interests: Conflict of interest All authors declare no conflict of interest for this contribution.

The designation of 'arrhythmogenic cardiomyopathy' reflects the evolving concept of a heart muscle disease affecting not only the right ventricle (ARVC) but also the left ventricle (LV), with phenotypic variants characterized by a biventricular (BIV) or predominant LV involvement (ALVC). Herein, we use the term 'scarring/arrhythmogenic cardiomyopathy (S/ACM)' to emphasize that the disease phenotype is distinctively characterized by loss of ventricular myocardium due to myocyte death with subsequent fibrous or fibro-fatty scar tissue replacement. The myocardial scarring predisposes to potentially lethal ventricular arrhythmias and underlies the impairment of systolic ventricular function. S/ACM is an 'umbrella term' which includes a variety of conditions, either genetic or acquired (mostly post-inflammatory), sharing the typical 'scarring' phenotypic features of the disease. Differential diagnoses include 'non-scarring' heart diseases leading to either RV dilatation from left-to-right shunt or LV dilatation/dysfunction from a dilated cardiomyopathy. The development of 2020 upgraded criteria ('Padua criteria') for diagnosis of S/ACM reflected the evolving clinical experience with the expanding spectrum of S/ACM phenotypes and the advances in cardiac magnetic resonance (CMR) imaging. The Padua criteria aimed to improve the diagnosis of S/ACM by incorporation of CMR myocardial tissue characterization findings. Risk stratification of S/ACM patients is mostly based on arrhythmic burden and ventricular dysfunction severity, although other ECG or imaging parameters may have a role. Medical therapy is crucial for treatment of ventricular arrhythmias and heart failure. Implantable cardioverter defibrillator (ICD) is the only proven life-saving treatment, despite its significant morbidity because of device-related complications and inappropriate shocks. Selection of patients who can benefit the most from ICD therapy is one of the most challenging issues in clinical practice., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Our story dates back in the late 70s, when a series of juvenile sudden death (SD) occurred in the Veneto region, north east of Italy. A successful application for a prospective study on young people dying suddenly (<35-year-old, sudden infant death syndrome excluded) was submitted to the regional health authorities, thus implementing a network of collaboration with local anatomic and forensic pathologists, to collect all such events and to gather demographic data. The project is still in progress, and since then, we studied hundreds of consecutive juvenile SD cases, allowing to identify the culprit diseases in the various organs and cardiac structures (aorta, coronary arteries, myocardium, valves, and conduction system). The long-standing Veneto region experience clearly shows that autopsy still plays a pivotal role in the study and prevention of SD and should be carried out regularly. With time, the investigation of SD moved from the classic post-mortem study to molecular autopsy, especially in cases of SD with structurally normal heart. Sudden death prevention in the young has to be faced by an interdisciplinary team, including pathologists, cardiologists, sport physicians, and geneticists, the clinicopathologic correlation method still being the polar star. The game in the fight against SD is still played in the anatomical theatre, the place where 'death enjoys to save lives'., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Sudden cardiac death (SCD) pathophysiological point of view can be either mechanical or electrical. In case of mechanical SCD, the most frequent causes are pulmonary thromboembolism and cardiac tamponade due to intrapericardial rupture (aortic dissection, heart rupture). This distinction is important because cardiac arrest retains survival potential through cardiopulmonary resuscitation and defibrillators only if the rhythm is shockable. The heart diseases that can cause SCD vary according to the age of the individual. In young people, primary electrical diseases ('ion channel diseases') and cardiomyopathies (particularly hypertrophic and arrhythmogenic), both genetically determined and therefore potentially recurred in the proband's family, as well as myocarditis and coronary anomalies prevail; in adult-elderly populations, coronary atherosclerosis with its complications and degenerative valve diseases (aortic stenosis and mitral valve prolapse) predominate. In this short text, the main structural heart diseases characterized by electrical instability at risk of SCD will be recalled, with a focus on coronary, myocardial, and valvular diseases., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The University of Padua (Italy) preserves the skull of Santorio Santorio, father of the modern clinical experimental physiology. A recent study performed with modern anthropological methods and medical instruments (CT scan) revealed the presence of a lobular formation in the left temporal bone, with an irregular morphology, internal bone sequestrum, a well-defined non-continuous sclerosis and both internal and external thinning of the cranial plate. Three oval depressions observed in the cranial vault, edentulism and moderate osteoarthritis of the temporomandibular joint were also investigated. The lobular formation was an epidermoid cyst and the oval depressions were the result of other cysts. The edentulism was consistent with some metabolic deficiency or disease, whilst the osteoarthritis appeared to be the result of antemortem tooth loss. This study allowed to investigate a complex and peculiar palaeopathological picture, linked to a piece of the history of the University of Padua., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cardiomyopathies (CMP) comprise a heterogenous group of diseases affecting primarily the myocardium, either genetic and/or acquired in origin. While many classification systems have been proposed in the clinical setting, there is no internationally agreed pathological consensus concerning the diagnostic approach to inherited CMP at autopsy. A document on autopsy diagnosis of CMP is needed because the complexity of the pathologic backgrounds requires proper insight and expertise. In cases presenting with cardiac hypertrophy and/or dilatation/scarring with normal coronary arteries, a suspicion of inherited CMP must be considered, and a histological examination is essential. Establishing the actual cause of the disease may require a number of tissue-based and/or fluid-based investigations, be it histological, ultrastructural, or molecular. A history of illicit drug use must be looked for. Sudden death is frequently the first manifestation of disease in case of CMP, especially in the young. Also, during routine clinical or forensic autopsies, a suspicion of CMP may arise based on clinical data or pathological findings at autopsy. It is thus a challenge to make a diagnosis of a CMP at autopsy. The pathology report should provide the relevant data and a cardiac diagnosis which can help the family in furthering investigations, including genetic testing in case of genetic forms of CMP. With the explosion in molecular testing and the concept of the molecular autopsy, the pathologist should use strict criteria in the diagnosis of CMP, and helpful for clinical geneticists and cardiologists who advise the family as to the possibility of a genetic disease., (© 2023. The Author(s).)

Aims: Bioprosthetic heart valves (BHVs), made from glutaraldehyde-fixed heterograft materials, are subject to more rapid structural valve degeneration (SVD) in paediatric and young adult patients. Differences in blood biochemistries and propensity for disease accelerate SVD in these patients, which results in multiple re-operations with compounding risks. The goal of this study is to investigate the mechanisms of BHV biomaterial degeneration and present models for studying SVD in young patients and juvenile animal models., Methods and Results: We studied SVD in clinical BHV explants from paediatric and young adult patients, juvenile sheep implantation model, rat subcutaneous implants, and an ex vivo serum incubation model. BHV biomaterials were analysed for calcification, collagen microstructure (alignment and crimp), and crosslinking density. Serum markers of calcification and tissue crosslinking were compared between young and adult subjects. We demonstrated that immature subjects were more susceptible to calcification, microstructural changes, and advanced glycation end products formation. In vivo and ex vivo studies comparing immature and mature subjects mirrored SVD in clinical observations. The interaction between host serum and BHV biomaterials leads to significant structural and biochemical changes which impact their functions., Conclusions: There is an increased risk for accelerated SVD in younger subjects, both experimental animals and patients. Increased calcification, altered collagen microstructure with loss of alignment and increased crimp periods, and increased crosslinking are three main characteristics in BHV explants from young subjects leading to SVD. Together, our studies establish a basis for assessing the increased susceptibility of BHV biomaterials to accelerated SVD in young patients., Competing Interests: Conflict of interest: The Authors declare that there is no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Foetal Growth Restriction (FGR), previously known as Intrauterine Growth Restriction (IUGR), is an obstetrical condition due to placental insufficiency, affecting yearly about 30 million newborns worldwide. In this work, we aimed to identify and pharmacologically target signalling pathways specifically involved in the FGR condition, focusing on FGR-related cardiovascular phenotypes. The transcriptional profile of human umbilical cords from FGR and control cases was compared with the response to hypoxia of zebrafish ( Danio rerio ) transgenic lines reporting in vivo the activity of twelve signalling pathways involved in embryonic development. Wnt/β-catenin and Jak/Stat3 were found as key pathways significantly dysregulated in both human and zebrafish samples. This information was used in a chemical-genetic analysis to test drugs targeting Wnt/β-catenin and Jak/Stat3 pathways to rescue a set of FGR phenotypes, including growth restriction and cardiovascular modifications. Treatments with the Wnt/β-catenin agonist SB216763 successfully rescued body dimensions, cardiac shape, and vessel organization in zebrafish FGR models. Our data support the Wnt/β-catenin pathway as a key FGR marker and a promising target for pharmacological intervention in the FGR condition., 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 © 2022 Risato, Celeghin, Brañas Casas, Dinarello, Zuppardo, Vettori, Pilichou, Thiene, Basso, Argenton, Visentin, Cosmi, Tiso and Beffagna.)

Background: Desmoplakin (DSP) genetic variants have been reported in arrhythmogenic cardiomyopathy with particular regard to predominant left ventricular (LV) involvement., Objective: The purpose of this study was to improve our understanding of clinical phenotype and outcome of DSP variant carriers., Methods: The clinical picture and outcome of 73 patients (36% probands) harboring a pathogenic/likely pathogenic DSP variant were evaluated., Results: The phenotype during follow-up (mean 11 years; range 1-39 years) changed in 25 patients (35%), arrhythmogenic LV cardiomyopathy (ALVC) forms being the most frequent (n = 26 [36%]), followed by biventricular (BIV; n = 20 [27%]) and arrhythmogenic right ventricular cardiomyopathy (ARVC; n = 16 [22%]) forms. Major ventricular arrhythmias were detected in 21 patients (29%), and they were more common in ARVC (n = 6, 56%) and BIV forms (n = 8, 40%) than in ALVC forms (n = 4, 15%). In patients with ALVC, major ventricular arrhythmias occurred in the setting of a normal/mildly reduced systolic function. Heart failure (HF) occurred in 6 patients (8%); none affected with ALVC. Females showed more commonly LV involvement, while ARVC forms were more frequently detected in males (21 [61%] vs 15 [38%]; P = .147). Males showed a higher incidence of major ventricular arrhythmias (18 [52%] vs 9 [24%]; P = .036), HF (11 [31%] vs 1 [3%]; P = .004), and cardiac death (11 [31%] vs 0 [0%]; P < .001)., Conclusion: The clinical phenotype in pathogenic/likely pathogenic DSP variant carriers is wide. Although most patients show LV involvement, 16 (22%) has right ventricular abnormalities in keeping with a "classical" arrhythmogenic cardiomyopathy form. In ALVC, HF and major ventricular arrhythmias seem less common than in right ventricular and BIV variants. Females show more frequently LV involvement and a better outcome., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Outcome predictors in myocarditis are not well defined; we aimed at identifying predictors of death, heart transplantation (HTx) and relapse before the introduction of immunosuppression., Methods and Results: From 1992 to 2012, 466 consecutive patients (68% male, mean age 37 ± 17 years, single centre recruitment, median follow-up 50 months) were included, of whom 216 had clinically suspected and 250 biopsy-proven myocarditis. Serum anti-heart (AHA) and anti-intercalated disk (AIDA) autoantibodies were measured by indirect immunofluorescence. Univariable and multivariable analyses of clinical and diagnostic features at diagnosis were performed. Survival free from death or HTx at 10 years was 83% in the whole study population and was lower in biopsy-proven versus clinically suspected myocarditis (76% vs. 94%, p < 0.001). Female gender (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1-6.5), fulminant presentation (HR 13.77, 95% CI 9.7-261.73), high-titre organ-specific AHA (HR 4.2, 95% CI 1.2-14.7) and anti-nuclear antibodies (ANA) (HR 5.2, 95% CI 2.1-12.8) were independent predictors of death or HTx; higher echocardiographic left ventricular ejection fraction (LVEF) at diagnosis was protective, with a 0.93-fold risk reduction for each 1% LVEF increase (95% CI 0.89-0.96). History of myocarditis at diagnosis (HR 8.5, 95% CI 3.5-20.7) was an independent predictor of myocarditis relapse at follow-up; older age was protective (HR 0.95, 95% CI 0.91-0.99). Predictors of death, HTx and relapse did not differ in biopsy-proven versus clinically suspected myocarditis., Conclusions: Young age and a previous myocarditis were independent relapse predictors; female gender, fulminant onset, lower LVEF at presentation and high-titre organ-specific AHA and ANA were independent predictors of death and HTx, suggesting that autoimmune features predict worse prognosis., (© 2022 European Society of Cardiology.)

A unique specimen of argyria is preserved in the Morgagni Museum of Pathological Anatomy at the University of Padua (Italy). It is a stuffed head belonging to a man who decided to cure his syphilis by himself with the so-called infernal stone (silver nitrate) every day for years, thus developing argyria in the second half of the nineteenth century. Paleopathological and historical studies were performed on the specimen to confirm the diagnosis of argyria. Furthermore, a morphological investigation of the specimen was conducted with histological and ultrastructural investigations, including environmental scanning electron microscopy and electron dispersive x-ray spectroscopy, recording high presence of silver in the dermis and epidermis and also other chemical elements correlated to the "infernal stone." A comparison with actual cases may also lead to a common feature: a potential dependence on the perceived benefits brought by silver compound that may sustain a further prolonged intake., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Lesion Index (LSI) has been developed to predict lesion efficacy during radiofrequency (RF) catheter ablation. However, its value in predicting lesions size has still to be established. The aim of our study was to assess the lesions size reproducibility for prespecified values of LSI reached during RF delivery in an in vivo beating heart., Methods: Ablation lesions were created with different values of LSI in seven domestic pigs by means of a contact force-sensing catheter (TactiCath TM , Abbott). Lesions were identified during RF delivery by means of a three-dimensional mapping system (EnSite TM Precision, Abbott) and measured after heart explantation. Histology was carried out after gross examination on the first three lesions to confirm the accuracy of the macroscopic evaluation., Results: A total of 64 myocardial lesions were created. Thirty-nine lesions were excluded from the analysis for the following reasons: histological confirmation of macroscopic lesion measurement (n = 3), transmurality (n = 24), unfavorable anatomic position (n = 10), not macroscopically identifiable (n = 2). In a final set of 25 nontransmural lesions, injury width and depth were, respectively, 4.6 ± 0.6 and 2.6 ± 0.8 mm for LSI = 4, 7.3 ± 0.8 and 4.7 ± 0.6 mm for LSI = 5, and 8.6 ± 1.2 and 7.2 ± 1.1 mm for LSI = 6. A strong linear correlation was observed between LSI and lesion width (r = .87, p < .00001) and depth (r = .89, p < .00001). Multiple linear regression analysis identified LSI as the only ablation parameter that significantly predicted lesion width (p < .001) and depth (p < .001)., Conclusion: In our in vivo study, LSI proved highly predictive of lesion size and depth., (© 2022 Wiley Periodicals LLC.)

We report the case of a professional soccer athlete who died suddenly for arrhythmogenic cardiomyopathy that was not diagnosed at the time of preparticipation screening. Exercise testing had repeatedly shown effort-induced premature ventricular beats with normal echocardiography, which was considered reassuring. However, there is emerging evidence that cardiac diseases characterized by focal ventricular scarring may not cause wall motion abnormalities and can be revealed only by tissue characterization with cardiac magnetic resonance. Modern interpretation of premature ventricular beats features is essential to select athletes who should undergo advanced cardiac imaging investigations, to achieve a correct diagnosis and allow safe sport participation., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sixty years ago, 2 cardiac operations dramatically influenced the survival of patients with valvular heart disease. The replacement of an aortic valve by Dwight Harken and of a mitral valve by Albert Starr with mechanical caged-ball valves, both in 1960, was a true milestone in the history of cardiac surgery and the beginning of a long journey toward prosthetic valve replacement full of expectations, hopes, and dreams fulfilled. Caged-ball prostheses underwent numerous modifications in design and materials to improve reliability and prevent specific mechanical and thrombogenic complications. Clinical and pathologic experience gained during the past 6 decades has enabled the development of safe, durable, and minimally thrombogenic mechanical prostheses., (© 2022 by the Texas Heart® Institute, Houston.)

Background: Mutations in filamin-C (FLNC) are involved in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM), and have been associated with a left ventricular (LV) phenotype, characterized by nonischemic LV fibrosis, ventricular arrhythmias, and sudden cardiac death (SCD)., Objective: The purpose of this study was to investigate the prevalence of FLNC variants in a gene-negative ACM population and to evaluate the clinical phenotype and SCD risk factors in FLNC-associated cardiomyopathies., Methods: ACM probands who tested negative for mutations in ACM-related genes underwent FLNC genetic screening. Clinical and genetic data were collected and pooled together with those of previously published FLNC-ACM and FLNC-DCM patients., Results: In a cohort of 270 gene-elusive ACM probands, 12 (4.4%) had FLNC variants, and 13 additional family members carried the same mutation. Eighteen FLNC variant carriers (72%) had a diagnosis of ACM (72% male; mean age 45 years). On pooled analysis, 145 patients with FLNC-associated cardiomyopathies were included. Electrocardiographic (ECG) low QRS voltages were detected in 37%, and T-wave inversion (TWI) in inferolateral/lateral leads in 24%. Among 67 patients who had cardiac magnetic resonance (CMR), LV nonischemic late gadolinium enhancement (LGE) was found in 75%. SCD occurred in 28 patients (19%), 15 of whom showed LV nonischemic LGE/fibrosis. Compared with patients with no SCD, those who experienced SCD more frequently had inferolateral/lateral TWI (P = .013) and LV LGE/fibrosis (P = .033)., Conclusion: Clinical phenotype of FLNC cardiomyopathies is characterized by late-onset presentation and typical ECG and CMR features. SCD is associated with the presence of LV LGE/fibrosis but not with severe LV systolic dysfunction., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Arrhythmogenic Cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes. AC hearts show fibro-fatty myocardial replacement, which favors stress-related life-threatening arrhythmias, predominantly in the young and athletes. AC lacks effective therapies, as its pathogenesis is poorly understood. Recently, we showed that cardiac Mesenchymal Stromal Cells (cMSCs) contribute to adipose tissue in human AC hearts, although the underlying mechanisms are still unclear., Purpose: We hypothesize that the sympathetic neurotransmitter, Neuropeptide Y (NPY), participates to cMSC adipogenesis in human AC., Methods: For translation of our findings, we combined in vitro cytochemical, molecular and pharmacologic assays on human cMSCs, from myocardial biopsies of healthy controls and AC patients, with the use of existing drugs to interfere with the predicted AC mechanisms. Sympathetic innervation was inspected in human autoptic heart samples, and NPY plasma levels measured in healthy and AC subjects., Results: AC cMSCs expressed higher levels of pro-adipogenic isotypes of NPY-receptors (i.e. Y1-R, Y5-R). Consistently, NPY enhanced adipogenesis in AC cMSCs, which was blocked by FDA-approved Y1-R and Y5-R antagonists. AC-associated PKP2 reduction directly caused NPY-dependent adipogenesis in cMSCs. In support of the involvement of sympathetic neurons (SNs) and NPY in AC myocardial remodeling, patients had elevated NPY plasma levels and, in human AC hearts, SNs accumulated in fatty areas and were close to cMSCs., Conclusions: Independently from the disease origin, AC causes in cMSCs a targetable gain of responsiveness to NPY, which leads to increased adipogenesis, thus playing a role in AC myocardial remodeling., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Limited mid-term durability of 12A/LX Mitroflow bioprosthesis has been reported. Aim of the study was to ascertain the pathologic substrates and possible mechanisms of structural valve deterioration in explants from animals and humans., Methods: Nine aortic 12A/LX Mitroflow bioprostheses preserved in hypotonic solution and three aortic 12A/LX bioprostheses, preserved in isotonic solution, were explanted from juvenile sheep, mean time from implant 95.66 ± 36.04 days and 132.33 ± 28.88 days from implant respectively. One stented unimplanted 12A/LX Mitroflow preserved in isotonic colution before glutaraldeyde fixation served as control. Ten aortic 12A/LX Mitroflow bioprostheses were explanted from humans because of severe dysfunction: five children, (3 females and 2 males, mean age 14.19 ± 4.77 years, range 11-21), 26 ± 8.24 months from implant and 5 adults (4 females and 1 male, mean age 57.4 ± 19.85 years, range 31-72), 64.4 ± 26.94 months from implant. X-ray, histology, and transmission electron microscopy were carried out as well as spectroscopy for calcium (Ca++) and phosphorus (P) content in human explants., Results: Explants, from both animals and humans, showed cusp folding and stiffness, with coarse calcific deposits at gross examination and X-ray. Severe collagen denaturation, plasma insudation and massive calcification, involving both collagen and cell debris, were observed microscopically. Mean Ca++ content of 183.27 ± 62.48 and P content of 94.35 ±33.76 mg/g dry weight was found in children and Ca++ content of 205.49 ± 2.23 and P content of 99.75 ± 0.11 mg/g dry weight in adults. Obstructive fibrous tissue overgrowth was detected in 6 human cases., Conclusions: Collagen denaturation was observed in pericardial Mitroflow 12A/LX bioprosthesis with premature structural valve deterioration. Optimal collagen fixation and preservation as well as phospholipids reduction by removing cell debris, as employed in the novel CROWN PRT Mitroflow bioprosthesis, are expected to solve the flaw and achieve long-term durability., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Perceval S is a self-expandable, stent-mounted bioprosthetic valve (BPV), with glutaraldehyde treated bovine pericardium, processed with homocysteic acid as an anti-calcification treatment. The stent is crimpable but the valve insertion is done surgically via a shorter procedure which does not require sutures. OBJECTIVES: MATERIAL AND METHODS: RESULTS: CONCLUSIONS: Collapsing and ballooning do not alter cusp collagen periodicity. Structural valve deterioration with stenosis, due to dystrophic calcification and fibrous tissue overgrowth, seldom occurred in the mid-term. Glutaraldehyde fixed pericardium has the potential to undergo structural valve deterioration with time, similar to well-known BPV failure. This supports the recommendation to pursue improvement of tissue valve treatment with enhanced durability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The ongoing COVID-19 pandemic has a major precedent almost exactly a century ago: the world-famous H1N1 influenza virus pandemic, sometimes known to the general public as the Spanish flu. From a history of medicine perspective, it is possible to underline many potential common traits between the two. In this article, hygiene and prophylaxis strategies are analyzed in a review of the most popular Italian general medical journals at the time of Spanish flu, Il Policlinico being the most representative of them. The analysis included 40 original journal articles as well as important references to the most influential coeval national manuals and international journals. The main issues in the context of public hygiene are prophylaxis with quinine and quinine derivatives, vaccinations, face masks, disinfection, and social distancing. We draw a comparison between these and the most recent international World Health Organization and Italian national guidelines on the topic. Sadly, little has changed since those times in terms of most of the prevention techniques, even with technical improvements, showing how shortsighted doctors and physicians can be when dealing with medical history. ( Am J Public Health . 2021;111(10):1815-1823. https://doi.org/10.2105/AJPH.2021.306412).

Criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) were first proposed in 1994 and revised in 2010 by a Task Force. Although the Task Force criteria demonstrated a good accuracy for diagnosis of the original right ventricular phenotype (arrhythmogenic right ventricular cardiomyopathy), they lacked sensitivity for identification of the expanding phenotypic spectrum of ACM, which includes left-sided variants and did not incorporate late-gadolinium enhancement findings by cardiac magnetic resonance. The 2020 International criteria ("Padua criteria") have been developed by International experts with the aim to improve the diagnosis of ACM by providing new criteria for the diagnosis of left ventricular phenotypic features. The key upgrade was the incorporation of tissue characterization findings by cardiac magnetic resonance for noninvasive detection of late-gadolinium enhancement/myocardial fibrosis that are determinants for characterization of arrhythmogenic biventricular and left ventricular cardiomyopathy. The 2020 International criteria are heavily dependent on cardiac magnetic resonance, which has become mandatory to characterize the ACM phenotype and to exclude other diagnoses. New criteria regarding left ventricular depolarization and repolarization ECG abnormalities and ventricular arrhythmias of left ventricular origin were also provided. This article reviews the evolving approach to diagnosis of ACM, going back to the 1994 and 2010 International Task Force criteria and then grapple with the modern 2020 International criteria.

Background: Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations whose pathogenesis is incompletely understood., Objective: The purpose of this study was to identify molecular pathways underlying early AC by gene expression profiling in both humans and animal models., Methods: RNA sequencing for differentially expressed genes (DEGs) was performed on the myocardium of transgenic mice overexpressing the Desmoglein2-N271S mutation before phenotype onset. Zebrafish signaling reporters were used for in vivo validation. Whole exome sequencing was undertaken in 10 genotype-negative AC patients and subsequent direct sequencing in 140 AC index cases., Results: Among 29 DEGs identified at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) showed reduced cardiac expression in transgenic mice and in 3 AC patients who suffered sudden cardiac death without overt structural remodeling. Four rare missense variants of LGALS3 were identified in 5 human AC probands. Pharmacologic inhibition of Lgals3 in zebrafish reduced Wnt and transforming growth factor-β signaling, increased Hippo/YAP-TAZ signaling, and induced alterations in desmoplakin membrane localization, desmosome integrity and stability. Increased LGALS3 plasma expression in genotype-positive AC patients and CD98 activation supported the galectin-3 (GAL3) release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions., Conclusion: GAL3 plays a crucial role in early AC onset through regulation of Wnt/β-catenin signaling and intercellular adhesion., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: To define the prevalence, progression, and the relationship between carotid and subclavian artery atherosclerosis and to identify factors associated with disease progression in a population of asymptomatic patients., Methods: Among all consecutive patients without a history of cardiovascular disease admitted to our hospital for duplex ultrasound examinations of the supra-aortic arteries, from January to December 2012, we retrospectively identified 530 patients with two evaluations at least 3 years apart. Each artery was graded according to stenosis degree, as absent or less than 20%, 20-49%, 50-69%, 70-99% and total occlusion. Disease progression was defined for any class increase at any time interval. Patients were grouped according to the presence of a more than 20% stenosis of the supra-aortic district at baseline, as controls, without atherosclerosis: n = 111, 21%; isolated carotid artery disease: n = 390, 74%; concomitant subclavian artery-carotid artery disease: n = 29, 5%. There were no cases with isolated subclavian artery atherosclerosis., Results: The mean time-lapse between the two evaluations was 3.1 ± 0.3 years; we documented disease progression in 32 patients (6%), all limited to the carotid artery (P = 0.009 vs. controls, with no differences between isolated carotid artery disease and concomitant carotid and subclavian artery disease). Hypertension was significantly (P < 0.001) associated with disease progression, regardless of the single or double district involvement., Conclusion: The subclavian artery is far less prone to atherosclerosis than the carotid artery, and features lesser disease progression. Understanding factors for the different susceptibility to atherosclerosis in these two close arterial districts provides insight into local factors prompting vascular disease., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)