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Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

We evaluated the impact of weight loss (WL) using a Mediterranean diet and mild-to-moderate–intensity aerobic exercise program, on clinical status of obese, symptomatic patients with hypertrophic cardiomyopathy (HCM). Compared with nonresponders, responders showed a significant reduction of left atrial diameter, left atrial volume index (LAVI), E/Eʹaverage, pulmonary artery systolic pressure (PASP), and a significant increase in VO2max (%) and peak workload. Body mass index changes correlated with reduction in left atrial diameter, LAVI, E/Eʹaverage, PASP, and increase of VO2max (mL/Kg/min), VO2max (%), peak workload. Mediterranean diet and aerobic exercise is associated with clinical-hemodynamic improvement in obese symptomatic HCM patients.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a homozygous GAA triplet repeat expansion in the frataxin gene. Cardiac involvement, usually manifesting as hypertrophic cardiomyopathy, can range from asymptomatic cases to severe cardiomyopathy with progressive deterioration of the left ventricular ejection fraction and chronic heart failure. The management of cardiac involvement is directed to prevent disease progression and cardiovascular complications. However, direct-disease therapies are not currently available for FRDA. The present review aims to describe the current state of knowledge regarding cardiovascular involvement of FRDA, focusing on clinical-instrumental features and management of cardiac manifestation.

Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. Cardiac involvement is common in FD and is responsible for impaired quality of life and premature death. The classic cardiac involvement is a nonobstructive form of hypertrophic cardiomyopathy, usually manifesting as concentric left ventricular hypertrophy, with subsequent arrhythmogenic intramural fibrosis. Treatment of patients with FD should be directed to prevent the disease progression to irreversible organ damage and organ failure. The aim of this review is to describe the current state of knowledge regarding cardiovascular involvement in FD, focusing on clinical and instrumental features, cardiovascular management, and targeted therapy.

The inherited connective tissue disorders (Marfan syndrome, Loeys-Dietz syndrome [LDS], and Ehlers-Danlos syndrome [EDS]) involve connective tissue of various organ systems. These pathologies share many common features, nonetheless compared to Marfan syndrome, LDS' cardiovascular manifestations tend to be more severe. In contrast, no association is reported between LDS and the presence of ectopia lentis. The EDS are currently classified into thirteen subtypes. There is substantial symptoms overlap between the EDS subtypes, and they are associated with an increased incidence of cardiovascular abnormalities, such as mitral valve prolapse and aortic dissection.

BACKGROUND The radial artery is recommended by international guidelines as the default vascular access in patients with acute coronary syndromes (ACS) managed invasively. However, crossover from radial to femoral access is required in 4-10% of cases and has been associated with worse outcomes. No standardised algorithm exists to predict the risk of radial crossover. AIMS We sought to derive and externally validate a risk score to predict radial crossover in patients with ACS managed invasively. METHODS The derivation cohort consisted of 4,197 patients with ACS undergoing invasive management via the randomly allocated radial access from the MATRIX trial. Using logistic regression, we selected predictors of radial crossover and developed a numerical risk score. External validation was accomplished among 3,451 and 491 ACS patients managed invasively and randomised to radial access from the RIVAL and RIFLE-STEACS trials, respectively. RESULTS The MATRIX score (age, height, smoking, renal failure, prior coronary artery bypass grafting, ST-segment elevation myocardial infarction, Killip class, radial expertise) showed a c-index for radial crossover of 0.71 (95% CI: 0.67-0.75) in the derivation cohort. Discrimination ability was modest in the RIVAL (c-index: 0.64; 95% CI: 0.59-0.67) and RIFLE-STEACS (c-index: 0.66; 95% CI: 0.57-0.75) cohorts. A cut-off of ≥41 points was selected to identify patients at high risk of radial crossover. CONCLUSIONS The MATRIX score is a simple eight-item risk score which provides a standardised tool for the prediction of radial crossover among patients with ACS managed invasively. This tool can assist operators in anticipating and better addressing difficulties related to transradial procedures, potentially improving outcomes.

Heart failure (HF) is an important health care issue in children because of its considerable morbidity and mortality. Advanced HF encompasses patients who remained symptomatic despite optimal medical treatment and includes patients who require special management, such as continuous inotropic therapy, mechanical circulatory support, or heart transplantation (HT). HT is the gold standard for children with advanced HF; nonetheless, the number of suitable donors has not increased for decades, leading to prolonged waitlist times and increased mortality rates. Therefore, the role of pediatric mechanic circulatory support has been assessed as an alternative treatment in patients in whom heart transplant could not be performed. The authors discuss the epidemiology, causes, pathophysiology, clinical manifestation, medical treatment, device therapy, and HT in pediatric HF, and a particular emphasis was posed on patients with advanced HF.

OBJECTIVES The aim of this study was to assess the impact of access-site crossover in patients with acute coronary syndrome undergoing invasive management via radial or femoral access. BACKGROUND There are limited data on the clinical implications of access-site crossover. METHODS In the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox)-Access trial, 8,404 patients with acute coronary syndrome were randomized to radial or femoral access. Patients undergoing access-site crossover or successful access site were investigated. Thirty-day coprimary outcomes were a composite of death, myocardial infarction, or stroke (major adverse cardiovascular events [MACE]) and a composite of MACE or Bleeding Academic Research Consortium type 3 or 5 bleeding (net adverse clinical events [NACE]). RESULTS Access-site crossover occurred in 183 of 4,197 patients (4.4%) in the radial group (mainly to femoral access) and 108 of 4,207 patients (2.6%) in the femoral group (mainly to radial access). In multivariate analysis, the risk for coprimary outcomes was not significantly higher with radial crossover compared with successful radial (MACE: adjusted rate ratio [adjRR]: 1.25; 95% confidence interval [CI]: 0.81 to 1.93; p = 0.32; NACE: adjRR: 1.40; 95% CI: 0.94 to 2.06; p = 0.094) or successful femoral access (MACE: adjRR: 1.17; 95% CI: 0.76 to 1.81; p = 0.47; NACE: adjRR: 1.26; 95% CI: 0.86 to 1.86; p = 0.24). Access site-related Bleeding Academic Research Consortium type 3 or 5 bleeding was higher with radial crossover than successful radial access. Femoral crossover remained associated with higher risks for MACE (adjRR: 1.84; 95% CI: 1.18 to 2.87; p = 0.007) and NACE (adjRR: 1.69; 95% CI: 1.09 to 2.62; p = 0.019) compared with successful femoral access. Results remained consistent after excluding patients with randomized access not attempted. CONCLUSIONS Crossover from radial to femoral access abolishes the bleeding benefit offered by the radial over femoral artery but does not appear to increase the risk for MACE or NACE compared with successful radial or femoral access. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox [MATRIX]; NCT01433627) (C) 2021 by the American College of Cardiology Foundation. The MATRIX trial was sponsored by Societa Italiana di Cardiologia Invasiva (a nonprofit organization), which received grant support from The Medicines Company and Terumo. This substudy did not receive any direct or indirect funding. Dr. Leonardi has received grants and personal fees from AstraZeneca, Bristol Myers Squibb/ Pfizer, and Chiesi; and has received personal fees from Bayer outside the submitted work. Dr. Vranckx has received personal fees from AstraZeneca, Terumo, CSL Behring, Daiichi-Sankyo, and Bayer Health Care outside the submitted work. Dr. Frigoli is affiliated with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by not-forprofit and for- profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up- to-date list of CTU Bern's conflicts of interest, see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng. html. Dr. Windecker has received research and educational grants to the institution from Abbott, Amgen, Bristol Myers Squibb, Bayer, Boston Scientific, Biotronik, Cardinal Health, CardioValve, CSL Behring, Daiichi- Sankyo, Edwards Lifesciences, Johnson & Johnson, Medtronic, Querbet, Polares, Sanofi, Terumo, and Sinomed; serves as an unpaid member of the steering and/or executive groups of trials funded by Abbott, Abiomed, Amgen, Bristol Myers Squibb, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Polares, Sinomed, V-Wave, and Xeltis (but has not received personal payments from any pharmaceutical company or device manufacturer); and is a member of the steering and/or executive committee groups of several investigator- initiated trials that receive funding from industry without impact on his personal remuneration. Dr. Valgimigli has received grants and personal fees from Abbott, Terumo, and AstraZeneca; has received personal fees from Chiesi, Bayer, Daiichi-Sankyo, Amgen, Alvimedica, Biosensors, and Idorsia; and has received grants from Medicure outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Valgimigli, M (corresponding author), Ente Osped Cantonale, Cardioctr Ticino Inst, Via Tesserete 48, CH-6900 Lugano, Switzerland. marco.valgimigli@cardiocentro.org

Heart failure is a complex syndrome affecting several organs including kidney, lungs, liver, brain muscles and sympathetic system. Each of these organs might contribute to its severity and prognosis. The prognosis assessment is critical for a correct heart failure management. It has already been demonstrated that a single parameter is weaker for prognosis than different parameters combined. The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has been built and validated for heart failure with reduced ejection fraction (HFrEF) patients by considering cardiopulmonary exercise test data combined with clinical, laboratory and echocardiographic measurements. The betablockers treatment is a milestone in the HFrEF management. In the MECKI score database, the association of betablockers treatment with outcome has been investigated in different settings.

Introduction: We sought to determine prevalence and predictive accuracy of clinical markers (red flags, RF), known to be associated with specific systemic disease in a consecutive cohort of patients with hypertrophic cardiomyopathy (HCM). Methods: We studied 129 consecutive patients (23.7 ± 20.9 years, range 0–74 years; male/female 68%/32%). Pre-specified RF were categorized into five domains: family history; signs/symptoms; electrocardiography; imaging; and laboratory. Sensitivity (Se), specificity (Sp), negative predictive value (NPV), positive predictive value (PPV), and predictive accuracy of RF were analyzed in the genotyped population. Results: In the overall cohort of 129 patients, 169 RF were identified in 62 patients (48%). Prevalence of RF was higher in infants (78%) and in adults >55 years old (58%). Following targeted genetic and clinical evaluation, 94 patients (74%) had a definite diagnosis (sarcomeric HCM or specific causes of HCM). We observed 14 RF in 13 patients (21%) with sarcomeric gene disease, 129 RF in 34 patients (97%) with other specific causes of HCM, and 26 RF in 15 patients (45%) with idiopathic HCM (p < 0.0001). Non-sarcomeric causes of HCM were the most prevalent in ages 55yo. Se, Sp, PPV, NPV and PA of RF were 97%, 70%, 55%, 98% and 77%, respectively. Single and clinical combination of RF (clusters) had an high specificity, NPV and predictive accuracy for the specific etiologies (syndromes/metabolic/infiltrative disorders associated with HCM). Conclusions: An extensive diagnostic work up, focused on analysis of specific diagnostic RF in patients with unexplained LVH facilitates a clinical diagnosis in 74% of patients with HCM.

DiGeorge syndrome (DGS), also known as "22q11.2 deletion syndrome" (22q11DS) (MIM # 192430 # 188400), is a genetic disorder caused by hemizygous microdeletion of the long arm of chromosome 22. In the last decades, the introduction of fluorescence in situ hybridization assays, and in selected cases the use of multiplex ligation-dependent probe amplification, has allowed the detection of chromosomal microdeletions that could not be previously identified using standard karyotype analysis. The aim of this review is to address cardiovascular and systemic involvement in children with DGS, provide genotype-phenotype correlations, and discuss their medical management and therapeutic options.

Cardiac amyloidosis is an infiltrative disorder caused by transthyretin or immunoglobulin free light-chain deposition, which determines clinical disease with similar phenotype but different time course, prognosis and therapy. Multimodality imaging is the cornerstone for disease diagnosis and management. Multimodality imaging has revolutionized the approach to the disease favoring its awareness and simplifying its diagnosis, especially in ATTR cardiac amyloidosis. This describes the different imaging tools, from the traditional to the more novel ones, and highlights the different approach in each different setting (prognosis, subtyping, prognosis, monitoring disease progression, and response to therapy).

Transthyretin cardiac amyloidosis (ATTR-CA) is a systemic disorder resulting from the extracellular deposition of amyloid fibrils of misfolded transthyretin protein in the heart. ATTR-CA is a life-threatening disease, which can be caused by progressive deposition of wild type transthyretin (wtATTR) or by aggregation of an inherited mutated variant of transthyretin (mATTR). mATTR Is a rare condition transmitted in an autosomal dominant manner with incomplete penetrance, causing heterogenous phenotypes which can range from predominant neuropathic involvement, predominant cardiomyopathy, or mixed. Diagnosis of ATTR-CA is complex and requires integration of different imaging tools (echocardiography, bone scintigraphy, magnetic resonance) with genetics, clinical signs, laboratory tests, and histology. In recent years, new therapeutic agents have shown good efficacy and impact on survival and quality of life in this subset of patients, nevertheless patients affected by ATTR-CA may still carry an unfavorable prognosis, thus highlighting the need for new therapies. This review aims to assess cardiovascular involvement, diagnosis, and management of patients affected by ATTR-CA.

Introduction This study aimed to validate the increased wall thickness (IWT) score, a multiparametric echocardiographic score to facilitate diagnosis of cardiac amyloidosis (CA), in an independent population of patients with increased LV wall thickness suspicious for CA. Methods Between January 2019 and December 2020, 152 consecutive patients with increased LV wall thickness suspicious for CA were included. For all patient, the multiparametric echocardiographic score (IWT score) was calculated. To validate the diagnostic accuracy of an IWT score ≥ 8 to predict the diagnosis of CA, sensibility (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy (PA) were calculated. Results Among the 152 patients included in the study, 50 (33%) were diagnosed as CA, 25 (16%) had severe aortic stenosis, 25 (16%) had hypertensive remodeling, and 52 (34%) had hypertrophic cardiomyopathy. Among the 50 and 102 patients with and without CA, 19 (38%) and 1 (1%) showed an IWT score ≥ 8, respectively. Overall, the diagnostic accuracy of an IWT score ≥ 8 for the diagnosis of CA in our population was the following: Se 38% (95%CI 25–53%); Sp 99% (95%CI 95–100%); PPV 95% (95%CI 72–99%); NPV 77% (95%CI 73–80%); PA 79% (95%CI 72–85%). Conclusions This study reports the first external validation of the IWT score for the diagnosis of CA in patients with increased LV wall thickness. A score ≥ 8 showed a high Sp, PPV and PA, suggesting that the IWT score can be used to identify CA patients in those with increased LV wall thickness.

Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by left ventricular hypertrophy not solely explained by abnormal loading conditions. Despite its rare prevalence in pediatric age, HCM carries a relevant risk of mortality and morbidity in both infants and children. Pediatric HCM is a large heterogeneous group of disorders. Other than mutations in sarcomeric genes, which represent the most important cause of HCM in adults, childhood HCM includes a high prevalence of non-sarcomeric causes, including inherited errors of metabolism (i.e., glycogen storage diseases, lysosomal storage diseases, and fatty acid oxidation disorders), malformation syndromes, neuromuscular diseases, and mitochondrial disease, which globally represent up to 35% of children with HCM. The age of presentation and the underlying etiology significantly impact the prognosis of children with HCM. Moreover, in recent years, different targeted approaches for non-sarcomeric etiologies of HCM have emerged. Therefore, the etiological diagnosis is a fundamental step in designing specific management and therapy in these subjects. The present review aims to provide an overview of the non-sarcomeric causes of HCM in children, focusing on the pathophysiology, clinical features, diagnosis, and treatment of these rare disorders.

Laboratory medicine, along with genetic investigations in sports medicine, is taking on an increasingly important role in monitoring athletes’ health conditions. Acute or intense exercise can result in metabolic imbalances, muscle injuries or reveal cardiovascular disorders. This study aimed to monitor the health status of a basketball player with an integrated approach, including biochemical and genetic investigations and advanced imaging techniques, to shed light on the causes of recurrent syncope he experienced during exercise. Biochemical analyses showed that the athlete had abnormal iron, ferritin and bilirubin levels. Coronary Computed Tomographic Angiography highlighted the presence of an intramyocardial bridge, suggesting this may be the cause of the observed syncopes. The athlete was excluded from competitive activity. In order to understand if this cardiac malformation could be caused by an inherited genetic condition, both array-CGH and whole exome sequencing were performed. Array-CGH showed two intronic deletions involving MACROD2 and COMMD10 genes, which could be related to a congenital heart defect; whole exome sequencing highlighted the genotype compatible with Gilbert syndrome. However, no clear pathogenic mutations related to the patient’s cardiological phenotype were detected, even after applying machine learning methods. This case report highlights the importance and the need to provide exhaustive personalized diagnostic work up for the athletes in order to cover the cause of their malaise and for safeguarding their health. This multidisciplinary approach can be useful to create ad personam training and treatments, thus avoiding the appearance of diseases and injuries which, if underestimated, can become irreversible disorders and sometimes can result in the death of the athlete.

Patients with bicuspid aortic valve (BAV) have an increased risk of aortic dilation and aortic dissection or rupture. The impact of physical training on the natural course of aortopathy in BAV patients remains unclear. The aim of this study was to evaluate the impact of regular physical activity on aortic diameters in a consecutive cohort of paediatric patients with BAV. Consecutive paediatric BAV patients were evaluated and categorized into two groups: physically active and sedentary subjects. Only the subjects with a complete 2-year follow-up were included in the study. To evaluate the potential impact of physical activity on aortic size, aortic diameters were measured at the sinus of Valsalva and mid-ascending aorta using echocardiography. We defined aortic diameter progression the increase of aortic diameter ≥ 10% from baseline. Among 90 BAV patients (11.5 ± 3.4 years of age, 77% males), 53 (59%) were physically active subjects. Compared to sedentary, physically active subjects were not significantly more likely to have > 10% increase in sinus of Valsalva (13% vs. 8%, p-value = 0.45) or mid-ascending aorta diameter (9% vs. 13%, p-value = 0.55) at 2 years follow-up, both in subjects with sinus of Valsalva diameter progression (3.7 ± 1.0 mm vs. 3.5 ± 0.8 mm, p-value = 0.67) and in those with ascending aorta diameter progression (3.0 ± 0.8 mm vs. 3.2 ± 1.3 mm, p-value = 0.83). In our paediatric cohort of BAV patients, the prevalence and the degree of aortic diameter progression was not significantly different between physically active and sedentary subjects, suggesting that aortic dilation is unrelated to regular physical activity over a 2-year period.

BACKGROUND Contemporary definitions of bleeding endpoints are restricted mostly to clinically overt events. Whether hemoglobin drop per se, with or without overt bleeding, adversely affects the prognosis of patients with acute coronary syndrome (ACS) remains unclear. OBJECTIVES The aim of this study was to examine in the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial the incidence, predictors, and prognostic implications of in-hospital hemoglobin drop in patients with ACS managed invasively stratified by the presence of in-hospital bleeding. METHODS Patients were categorized by the presence and amount of in-hospital hemoglobin drop on the basis of baseline and nadir hemoglobin values and further stratified by the occurrence of adjudicated in-hospital bleeding. Hemoglobin drop was defined as minimal (

Cardiomyopathies (CMPs) represent a diverse group of heart muscle diseases, grouped into specific morphological and functional phenotypes. CMPs are associated with mutations in sarcomeric and non-sarcomeric genes, with several suspected epigenetic and environmental mechanisms involved in determining penetrance and expressivity. The understanding of the underlying molecular mechanisms of myocardial diseases is fundamental to achieving a proper management and treatment of these disorders. Among these, inflammation seems to play an important role in the pathogenesis of CMPs. The aim of the present study is to review the current knowledge on the role of inflammation and the immune system activation in the pathogenesis of CMPs and to identify potential molecular targets for a tailored anti-inflammatory treatment.

Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic background that predisposes a person to the risk of fatal arrhythmias is a trigger for SCD. Therefore, knowledge of the athlete’s genetic conditions underlying the onset of SCD must be extended, in order to develop new effective prevention and/or therapeutic strategies. Arrhythmic features occur across a broad spectrum of cardiac diseases, sometimes presenting with overlapping phenotypes. The genetic basis of arrhythmogenic disorders has been greatly highlighted in the last 30 years, and has shown marked heterogeneity. The advent of next-generation sequencing has constantly updated our understanding of the genetic basis of arrhythmogenic diseases and is laying the foundation for precision medicine. With the exception of a few clinical cases involving a single athlete showing a highly suspected phenotype for the presence of a heart disease, there are few studies to date that analysed the applicability of genetic testing on cohorts of athletes. This evidence shows that genetic testing can contribute to the diagnosis of up to 13% of athletes; however, the presence of clinical markers is essential. This review aims to provide a reference collection on current knowledge of the genetic basis of sudden cardiac death in athletes and to review updated evidence on the effectiveness of genetic testing in early identification of athletes at risk for SCD.

In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM.

Background Syndromic dilated cardiomyopathy (DCM) includes a group of complex disorders with a very heterogeneous genetic etiology, leading to delay in definitive diagnosis. Conversely, an early genetic diagnosis is very important in determining the disease course, the prognosis, and may guide personalized treatments and family counseling. Methods We analyzed two brothers with a multisystemic disorder, including dilated cardiomyopathy, diabetes, bilateral neurosensorial hearing loss, and optic atrophy, using different genetic approaches, namely mitochondrial DNA sequencing, comparative genomic hybridization‐array (a‐CGH) and whole exome sequencing (WES). Results Sequencing of the wide mitochondrial genome revealed, in both brothers, the known homoplasmic variant rs2853826 in the subunit 3 of the NADH dehydrogenase gene (MT‐ND3), whose pathogenicity was conflicting. Comparative genomic hybridization‐array analysis revealed in both patients and their father two heterozygous deletions in Phosphodiesterase 4d‐Interacting Protein (PDE4DIP) and Protocadherin‐related 15 (PCDH15) genes, respectively. The use of WES detected a pathogenetic mutation in ALMS1, enabling the definitive diagnosis of Alström syndrome. Conclusion We demonstrated how the diagnosis of a complex heterogeneous disease may be difficult, due to several overlapping manifestations and the possible interaction of more genetic variants that could lead to a more severe and complex phenotype. This paper strongly evidences how genomics is revolutionizing the diagnosis of rare complex disease, representing one of the most essential steps to enable a definitive diagnosis and to establish the etiology for diseases, such as syndromic DCM., The diagnosis of a complex heterogeneous disease may be difficult, due to several overlapping manifestations and the possible interaction of more genetic variants. By using different genetic approaches we obtained a definitive diagnosis of Alström syndrome in two brothers with a multisystemic disorder.

Prolonged dual antiplatelet therapy after 12 months in patients with previous myocardial infarction (MI) is attractive to reduce long-term ischemic complications. In the PEGASUS-TIMI 54, the use of low-dose ticagrelor (60 mg b.i.d.) plus aspirin after 12 months from MI reduced the risk of ischemic events, at the price of limited increase on bleeding complications. However, data on the use of low-dose ticagrelor in real-world practice lack. We aim at providing data on prescription/eligibility criteria and outcomes in patients receiving low-dose ticagrelor in the real-world setting. We enrolled consecutive patients eligible for ticagrelor 60 mg according to Italian national regulation in 3 high-volume centers and collected 1-year outcomes. The primary objective of the study is to generate real-world data about clinical characteristics, eligibility criteria, major adverse cardiovascular events, bleeding, and adverse event in patients receiving low-dose ticagrelor from our cohort. One hundred eighty-one patients were consecutively enrolled with a median follow-up of 18 months. The most used and the least used prescription criteria were multivessel coronary disease (72.4%) and chronic kidney disease (15.5%), respectively. At 1-year follow-up, the rate of major adverse cardiovascular events was 4.97%; of these, 3.86% of patients had a MI, and 1.1% had a stroke/transient ischemic attack, whereas no major bleeding occurred. In conclusion, in a real-world study, including patients with previous MI, low-dose ticagrelor for prolonged dual antiplatelet therapy showed to be effective and safe, with no major bleeding occurring at follow-up.

The purpose of this paper is to present a clinical and laboratory study of a family, in which a 12-year-old boy was examined to assess his health status before starting competitive sports. A variety of clinical and instrumental tests were used to evaluate the status of the heart and its functions. Using Sanger sequencing (SS), we sequenced six related genes to verify suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) hypothesized at the cardiac assessment and, subsequently, by a next-generation sequencing (NGS)-based multi-gene panel for more paramount genetic risk of sudden cardiac death (SCD) assessment. SS revealed two variants in the PKP2 gene, one was inherited from the father and the other from the mother. The analysis on a large panel of genes (n = 138), putatively associated with sudden cardiac death, revealed, in the proband, a third variant in a different gene (DES) that encodes the protein desmin. Our results indicate that: i) NGS revealed a mutational event in a gene not conventionally screened as a first-line test in the presence of clinical suspicion of the arrhythmic disease; ii) a plurality of variants in different genes in the same subject (the proband) may increase the risk of heart disease; iii) in silico analysis with various methodological software and bioinformatic prediction tools indicates that the cumulative effects of the three variants in the same subject constitute an additional risk factor. This case report indicates that more pathogenic variants or likely pathogenic variants can contribute to the clinical phenotype of an individual, thereby contributing to the diagnosis and prognosis of inherited heart diseases.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a crucial role in lipid metabolism, particularly due to its function in low-density lipoprotein receptor degradation. Gain-of-function genetic mutations of PCSK9 result in autosomal dominant familial hypercholesterolemia, characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and clinical signs of early atherosclerosis. In recent years, PCSK9 has become an important therapeutic target for cholesterol-lowering therapy. Particularly, its inhibition with monoclonal antibodies has shown excellent efficacy in decreasing LDL-C and reducing cardiovascular events. However, PCSK9, first identified in the brain, seems to be a ubiquitous protein with different tissue-specific functions also independent of cholesterol metabolism. Accordingly, it appears to be involved in the immune response, haemostasis, glucose metabolism, neuronal survival, and several other biological functions. This review provides a comprehensive overview of the genetics, biochemical structure, expression, and function of PCSK9 and discusses the potential implications of its long-term pharmacological inhibition.

Background:Marfan syndrome is an autosomal dominant disorder of the connective tissue, whose cardinal features affect eyes, musculoskeletal, and cardiovascular system. Despite prevalence and natural history of cardiovascular manifestation are well known in adults, little is known about children and young adult patients. The aim of this study was to describe a well-characterised cohort of consecutive children and young patients with marfan syndrome, looking at the impact of family history and presence of bicuspid aortic valve on disease severity.Methods:A total of 30 consecutive children and young patients with Marfan syndrome were evaluated. All patients underwent a comprehensive clinical–instrumental–genetic evaluation. Particular attention was posed to identify differences in prevalence of cardiovascular abnormalities between patients with and without family history of Marfan syndrome or bicuspid aortic valve.Results:Of these 30 patients, family history of Marfan syndrome and bicuspid aortic valve were present in 76 and 13%, respectively. Compared to patients with family history of Marfan syndrome, those without showed higher prevalence of aortic sinus dilation (87 versus 32%, p-value = 0.009), greater aortic sinus diameters (4.2 ± 2.1 versus 1.9 ± 1.1 z score, p-value = 0.002), and higher rate of aortic surgery during follow-up (37 versus 0%, p-value = 0.002). Compared to patients with tricuspid aortic valve, those with bicuspid aortic valve were younger (3.2 ± 4.3 versus 10.7 ± 6.8 years old, p-value = 0.043), showed greater aortic sinus diameters (4.2 ± 0.9 versus 2.2 ± 1.6 z score, p-value = 0.033), and underwent more frequently aortic root replacement (50 versus 4%, p-value = 0.004).Conclusions:In our cohort of patients with Marfan syndrome, the absence of family history and the presence of bicuspid aortic valve were associated to severe aortic phenotype and worse prognosis.

Multimodality imaging is a comprehensive strategy to investigate left ventricular hypertrophy (LVH), providing morphologic, functional, and often clinical information to clinicians. Hypertrophic cardiomyopathy (HCM) is defined by an increased LV wall thickness not only explainable by abnormal loading conditions. In the context of HCM, multimodality imaging, by different imaging techniques, such as echocardiography, cardiac magnetic resonance, cardiac computer tomography, and cardiac nuclear imaging, provides essential information for diagnosis, sudden cardiac death stratification, and management. Furthermore, it is essential to uncover the specific cause of HCM, such as Fabry disease and cardiac amyloidosis, which can benefit of specific treatments. This review aims to elucidate the current role of multimodality imaging in adult patients with HCM.

Kawasaki disease is an acute systemic vascular disease, generally self-limited and typically affecting children

Introduction Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB. Methods We measured the aortic diameters in 15 KO male mice, 5 for each LSD: 5 GLA-/- mice for FD, 5 NAGLU-/- mice for MPS IIIB, 5 GAA-/- mice for PD, and 15 wild type (WT) mice: 5 for each strain. In order to compare the aortic parameters between KO and WT mice deriving from the same colonies, different diameters were echocardiographically measured: aortic annulus, aortic sinus, sino-tubular junction, ascending aorta, aortic arch and descending aorta. Storage material content and aortic defects of the KO mice were also analyzed by histology, when available. Results Compared to their correspondent WT mice: GAA-/- mice showed greater diameters of ascending aorta (1.61mm vs. 1.11mm, p-value = 0.01) and descending aorta (1.17mm vs 1.02mm, p-value 0.04); GLA-/- mice showed greater diameters of aortic annulus (1.35mm vs. 1.22mm, p-value = 0.01), sinus of Valsalva (1.6mm vs. 1.38mm, p-value

Background The twelve‑lead electrocardiogram (ECG) has become an essential tool for the diagnosis, risk stratification, and management of patients with acute coronary syndromes (ACS). However, several areas of residual controversies or gaps in evidence exist. Among them, P-wave abnormalities identifying atrial ischemia/infarction are largely neglected in clinical practice, and their diagnostic and prognostic implications remain elusive; the value of ECG to identify the culprit lesion has been investigated, but validated criteria indicating the presence of coronary occlusion in patients without ST-elevation are lacking; finally, which criteria among the multiple proposed, better define pathological Q-waves or success of revascularisation deserve further investigations. Methods The Minimizing Adverse hemorrhagic events via TRansradial access site and systemic Implementation of AngioX (MATRIX) trial was designed to test the impact of bleeding avoidance strategies on ischemic and bleeding outcomes across the whole spectrum of patients with ACS receiving invasive management. The ECG-MATRIX is a pre-specified sub-study of the MATRIX programme which aims at analyzing the clinical value of ECG metrics in 4516 ACS patients (with and without ST-segment elevation in 2212 and 2304 cases, respectively) with matched pre and post-treatment ECGs. Conclusions This study represents a unique opportunity to further investigate the role of ECGs in the diagnosis and risk stratification of ACS patients with or without ST-segment deviation, as well as to assess whether the radial approach and bivalirudin may affect post-treatment ECG metrics and patterns in a large contemporary ACS population.

Coarctation of the aorta is a leading cause of morbidity and mortality among adults with congenital heart disease (ACHD). Lifelong surveillance is mandatory to screen for possible long-term cardiovascular events.Left ventricular systolic dysfunction has been reported in association with recoarctation, and association with dilated cardiomyopathy (DCMP) is very rare. Herein, we report the case of a 19-year-old boy with coarctation of the aorta who complained of mild exertional dyspnea. Cardiac magnetic resonance revealed a moderately dilated, hypokinetic left ventricle (LV), with mildly reduced EF (45%), and residual isthmic coarctation was excluded. Genetic tests revealed a heterozygous missense variant in TNNT2 (NM_001001430.2): c.518G>A (p. Arg173Gln). This case highlights the role of careful history taking: a family history of cardiomyopathy should not be overlooked even when the clinical setting seems to suggest a predisposition to hemodynamic factors for LVSD.

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