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In the ESC 2023 guidelines, cardiomyopathies are conservatively defined as ‘myocardial disorders in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormality’. They are morpho-functionally classified as hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathy with the addition of the left ventricular non-dilated cardiomyopathy that describes intermediate phenotypes not fulfilling standard disease definitions despite the presence of myocardial disease on cardiac imaging or tissue analysis. The new ESC guidelines provide ‘a guide to the diagnostic approach to cardiomyopathies, highlight general evaluation and management issues, and signpost the reader to the relevant evidence base for the recommendations’. The recommendations and suggestions included in the document provide the tools to build up pathways tailored to specific cardiomyopathy (phenotype and cause) and define therapeutic indications, including target therapies where possible. The impact is on clinical cardiology, where disease-specific care paths can be assisted by the guidelines, and on genetics, both clinics and testing, where deep phenotyping and participated multi-disciplinary evaluation provide a unique tool for validating the pathogenicity of variants. The role of endomyocardial biopsy remains underexploited and confined to particular forms of restrictive cardiomyopathy, myocarditis, and amyloidosis. New research and development will be needed to cover the gaps between science and clinics. Finally, the opening up to disciplines such as bioinformatics, bioengineering, mathematics, and physics will support clinical cardiologists in the best governance of the novel artificial intelligence–assisted resources.

Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.

The mechanisms underlying sudden cardiac death (SCD) in patients with ischaemic heart disease (IHD) caused by coronary atherosclerosis are not yet clarified. For decades, acute coronary causes have been sought as the main triggers of SCD in these patients. In fact, angiographic and pathological studies in cardiac arrest survivors and SCD victims, respectively, consistently show that acute plaque events occur in ∼50% of SCD of patients with IHD. Among the acute events, plaque rupture and erosion triggering acute coronary thrombosis remain the main substrates; however, a significant percentage of plaque haemorrhage (20%) is identified by pathological studies. Its role in acute coronary thrombosis is unknown and deserves future intravascular imaging developments. In the remaining 50% of SCD, the atherosclerotic coronary disease shows the characteristics of structural stability. More recent studies have focused attention not only on the coronary tree and on the search for acute complications of atherosclerotic plaques but also on myocardial tissue, identifying replacement and patchy fibrosis as the most frequent findings in the post-mortem hearts of these patients, a feature followed by cardiac hypertrophy, as assessed by the heart weight, usually associated with fibrosis. The possibility of characterizing myocardial fibrosis in vivo, besides confirming the pathological data, now offers new risk stratification perspectives to prevent SCD in IHD, alongside the consolidated secondary prevention criteria based on left ventricular dysfunction.

Spontaneous coronary artery dissection (SCAD) is an under-recognized cause of acute coronary syndrome that predominantly affects women in adulthood and is the leading cause of acute myocardial infarction in pregnancy. The most common clinical presentation is ST-segment elevation myocardial infarction (STEMI) or non-STEMI, followed by cardiogenic shock (∼2%), sudden cardiac death (0.8% in autopsy series), cardiac arrest, ventricular arrhythmias (∼5%), and Takotsubo syndrome. The prevalence of SCAD in the general population is largely uncertain due to underdiagnosis. Oral contraceptives, post-menopausal therapy, and infertility treatments are recognized associated factors. The pathological substrates (fibromuscular dysplasia) and triggers (especially emotional stress) are commonly present in affected women. The few cases with a precise genetic aetiology occur in the context of syndromic and non-syndromic connective tissue diseases. The only true certainty in SCAD is the overwhelming prevalence in women. The first event as well as the recurrence (up to 30%, which varies depending on the definition) is largely unpredictable. The treatment strategy is highly individualized and requires extensive additional study in order to optimize outcomes and prevent major adverse cardiovascular events in affected individuals. We have known about SCAD for nearly a century, but we still do not know how best to prevent, diagnose, and treat it, making SCAD a highly important and unmet clinical need.

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application.

Cardiomyopathies (CMPs) are primary disorders of myocardial structure and function in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease. Knowledge of the incidence and prevalence of CMPs may help clinicians to compare their observations in clinical practice with expected cases per person-year and to avoid under-reporting in clinical context. Currently, available estimates of prevalence and incidence of CMPs are based on clinical data, collected with a wide variability in population-source, and before the genetic testing evolved as a standard diagnostic tool. This review focuses on the epidemiology of CMPs in subjects aged between 18 and 55 years. A structured up-to-date diagnostic flow-chart for CMPs diagnosis and assessment is proposed to avoid misdiagnosis of CMPs in the young population and in subjects with unexplained cardiac disorders.

Introduction: DICER1 syndrome is characterized by increased susceptibility to malignancies, mostly occurring in childhood. The range of phenotypic effects of DICER1variants is under investigation, and the syndrome’s phenotypic spectrum is steadily widening. We report on three Italian families showing heterogeneous clinical presentation and reduced penetrance in family members.Case descriptions: Patient 1 is a 10-year-old girl with a Sertoli-Leydig cell tumor. Although family history was unremarkable, genetic testing identified a DICER1germline variant, inherited from her healthy father. Benign thyroid nodules were subsequently diagnosed in both the proband and her father. Patient 2 is an 8-month-old boy with type 1 pleuropulmonary blastoma. His sister developed a nephroblastoma at age 2 years. A DICER1novel variant was identified in both siblings and their healthy father. Patient 3 is a 22-year-old man who developed a spinal extramedullary intradural mass diagnosed as rhabdomyosarcoma with a peculiar tubular, gland-like component. Tumor testing revealed two pathogenic DICER1variants, one of which was confirmed to be germline and identified in his 17-year-old healthy brother and in his father, who showed multiple thyroid nodules.Conclusions: Among our patients, three developed tumors most frequently associated with DICER1 syndrome (i.e. pleuropulmonary blastoma, nephroblastoma, and Sertoli-Leydig cell tumor). One developed a peculiar sarcoma of the spinal cord not previously described in DICER1 syndrome. Genetic testing in relatives highlighted the paternal origin and reduced penetrance in all families, with thyroid benign lesions as the most common features in otherwise unaffected individuals.

ABSTRACTlncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNA structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their downstream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs, we demonstrate first the significant association of an SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.

The term Long COVID (or Post COVID) describes a condition characterized by persistence of symptoms for at least 12 weeks after the onset of COVID-19. It may last several months but the duration is still matter of observation. The symptoms and the clinical manifestations are clinically heterogeneous and suggesting involvement of multi-organs/systems, including the cardiovascular system. The general recurrent symptoms include fatigue, breathlessness, myalgia, headache, loss of memory, and impaired concentration. Patients report loss of their previous psychophysical performance. Cardiovascular involvement manifests with common symptoms such as palpitations and chest pain, and, less commonly, with events such as late arterial and venous thromboembolisms, heart failure episodes, strokes or transient ischaemic attack, ‘myo-pericarditis’. The diagnostic criteria are mainly based on the narrative of the patients. Measurable biomarkers or instrumental findings or clinical events are not yet framed in a shared diagnostic framework. The open question for clinicians and researchers is whether biomarkers, electrocardiogram, non-invasive imaging, and clinical monitoring should be included in a shared diagnostic protocol aimed at defining the diagnostic path and protecting patients at risk of unexpected events.

Niemann-Pick Disease type B (NPDB) is a rare autosomal recessive disease belonging to the family of lysosomal storage disorders. NPDB is caused by mutations of sphingomyelin phosphodiesterase 1 gene (SMPD1) and is characterized by hepatosplenomegaly, interstitial lung disease, recurrent pulmonary infections, and neurologic disorders. Bronchiectasis are atypical. Until now, only three cases of lung transplantation for severe respiratory impairment have been reported. We describe a case of NPDB that was diagnosed after lung transplantation for cystic bronchiectasis. In 2016, a 31-year-old woman who was experiencing hypoxemic respiratory failure and recurrent pulmonary infections due to cystic bronchiectasis received a double-lung-transplantation. Histopathologic study on removed lungs revealed clusters of CD68 foamy lipid-laden macrophages with concentric and palisade arrangement, compatible with the diagnosis of NPDB, which was confirmed after SMPD1genetic sequencing. Twenty-three months after transplantation, allograft function is stable (FEV1was 100% of best-FEV1). The singularity of this case lies in the presence of bronchiectasis, which is an unprecedently described phenotype of NPDB. This finding was accompanied by the detection of a novel SMPD1mutation (p.Ala46=) of uncertain meaning.

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Interaction between arterial stiffness and hypertension plays an important role in the development of cardiovascular disease. Accordingly, assessment of arterial stiffness may provide a tool for estimating cardiovascular risk and monitoring therapy in hypertensive patients. Radiofrequency-based vascular ultrasound allows accurate noninvasive assessment of local mechanical properties of large arteries, but for its use in clinical practice, reference values according to age and sex are mandatory for each vascular site. To provide reference values for common carotid artery stiffness as assessed by an echo-tracking imaging system Hitachi-Aloka, we pooled measurements collected in 1847 healthy subjects aged 3–74 years (1008 males and 839 females) recruited in 14 European centers in the E-tracking International Collaboration (ETIC). Statistical models were developed to describe relationships of different stiffness indices with age and to calculate median values and Z-scores corresponding to ± 1 and ± 2 standard deviations. In our apparently healthy population, age accounted for 53% of variability in the elastic modulus (epsilon), 39% in arterial compliance, 47% in stiffness index (β), and 56% in local pulse wave velocity; on average, blood pressure accounted for a further 7.5% of variability. Dependence on age was not linear; changes in mean values increased at older ages, especially for epsilon and β. There was an interaction between age and gender for arterial compliance, which was higher in males. We present nomograms and a software that can be used for the automated calculation of Z-scores for local carotid stiffness in individual patients. These tools can be used to establish prognostic indicators or surrogate targets for treatment monitoring.

ObjectivesN-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM.MethodsWe prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion.ResultsOf 357 patients enrolled, the median age was 52 (IQR: 36–65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p<10–4) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1–2 vs 3–4 (HR=0.35, 95% CI 0.16 to 0.77, p<0.01), LVEF (HR=0.96, 95% CI 0.94 to 0.98, p=0.0005) and MR-proANP (HR=3.77, 95% CI 2.01 to 7.08, p<0.0001).ConclusionsMR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

Marfan syndrome (MFS) is an inherited, autosomal dominant disorder that targets the connective tissue. As in other similar disorders, joint hypermobility can contribute to abnormal proprioceptive information from joint receptors, faulty reflex patterns and impairment in balance control. Aim of this study was to analyse static and dynamic balance and the effect of vision in patients with MFS. Twenty-seven patients with a proven genetic diagnosis of MFS were enrolled. Twenty-nine healthy subjects were the control group. Balance evaluations (eyes open and eyes closed) were performed by using a computerized force platform that recorded Sway Path (SP) and Sway Area (SA) of centre of feet pressure (CoP) displacement under static and dynamic conditions produced by mobilizing the support base. All control subjects performed the static and dynamic trials regardless of the visual conditions. Two thirds of the Marfan patients gave results superimposable to those of normal subjects’ eyes open. However, sway area measures were significantly larger under eyes closed conditions. One third of the patients did not complete the dynamic trials eyes closed (some of these even with eyes open). Vision is critical for patients with MFS because of abnormal proprioceptive information, possibly connected to confounding mechanical reflex effects from joints and muscle receptors. It would seem appropriate to plan a rehabilitative approach centred on proprioception in order to prevent the risk of fall.

Supplemental Digital Content is available in the text.

Lamins A and C are intermediate filament nuclear envelope proteins encoded by the LMNAgene. Mutations in LMNAcause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an LMNAmutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for LMNA, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude LMNAmutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our LMNAknowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

Genetic susceptibility to primary cutaneous melanoma (PCM) may account for up to 12% of PCMs, presenting as the familial atypical mole/multiple melanoma syndrome (FAMMM), an autosomal dominant condition with incomplete penetrance and variable expressivity, characterized by PCM in at least two relatives and/or more than one PCMs in the same patient. To identify individuals at high genetic risk of PCM, from 1 January 2012 to 31 December 2015, we offered genetic counselling and molecular analysis of the two high-penetrance FAMMM susceptibility genes, cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4), to 92 consecutive, unrelated patients with FAMMM. Age at diagnosis and number of PCMs were obtained from medical records; the number of PCMs and affected relatives were recorded for each family. The diagnostic work-up consisted of genetic counselling and cascade genetic testing in patients and further extension to relatives of those identified as mutation carriers. All exons and exon/intron boundaries of CDKN2Aand CDK4genes were screened by direct bidirectional sequencing. We identified CDKN2Amutations in 19 of the 92 unrelated patients (20.6%) and in 14 additional, clinically healthy relatives. Eleven of these latter subsequently underwent excision of dysplastic nevi, but none developed PCM during a median follow-up of 37.3 months. In three patients from unrelated families, the novel CDKN2Ap.D84V (c.251A>T) mutation was observed, associated with PCM in each pedigree. Genetic screening of FAMMM patients and their relatives can contribute towards specific primary and secondary prevention programmes for individuals at high genetic risk of PCM. The novel CDKN2Ap.D84V (c.251A>T) mutation adds to the known mutations associated with FAMMM.

Endovascular repair of inflammatory abdominal aortic aneurysms (IAAAs) has emerged as an alternative to open surgery, but direct comparisons are limited. The aim of the study was to compare clinical outcomes of endovascular and open repair for IAAA according with specific clinical characteristics.

Supplemental Digital Content is available in the text.

Optical coherence tomography (OCT) is the current state-of-the-art intracoronary imaging modality that allows visualization of detailed morphological characteristics of both atherosclerotic plaque and stent. So far, three expert review documents have been released for standardization of OCT image analysis. In the real world, a variety of definitions are being used by different groups and by different core laboratories to analyze OCT findings because of different clinicalprocedural contexts in which OCT research has been carried out. This comprehensive overview is aimed to summarize different applicable definitions used by different research groups in plaque and stent analysis using OCT. In addition, it presents readers with a panoramic view to select the best definition of OCT measurement for one’s own study purpose. We divided this review article into two parts: Part I – Plaque analysis, and Part II – Stent analysis. The plaque analysis section summarizes the definitions of plaque composition, rupture, erosion, protruding calcific nodules, macrophages, microvessels, and cholesterol crystal. The stent analysis section includes the classification of stent struts, features of neointimal hyperplasia, and other stent-related findings such as tissue protrusion, thrombus, intrastent, and stent edge dissections. In each case of controversy, an explanation for the specific context is provided.

Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy.