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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.

Coronaviruses (CoVs) represent a large family of RNA viruses that can infect different living species, posing a global threat to human health. CoVs can evade the immune response, replicate within the host, and cause a rapid immune compromise culminating in severe acute respiratory syndrome. In humans, the immune system functions are influenced by physical activity, nutrition, and the absence of respiratory or cardiovascular diseases. This review provides an in-depth study between the interactions of the immune system and coronaviruses in the host to defend against CoVs disease.

Coronaviruses (CoVs) are a large family of respiratory viruses that can cause mild to moderate illness. The new variant COVID-19 has started to spread rapidly since December 2019, posing a new threat to global health. To counter the spread of the virus, the Italian government forced the population to close all activities starting from 9 March 2020 to 4 May 2020. In this scenario, we conducted a cross-sectional study on a heterogeneous sample (average age of 28 ± 12 years, 62.6% females) of the University of Naples Federico II (Italy). The aim of the study was to describe the lifestyle change in the university population during quarantine for the COVID 19 pandemic. Participants compiled an online survey consisting of 3 sections: socio-demographic data, dietary behaviours, physical activity habits and psychological aspects. The different results by gender are: 90.8% of females continued to work from home (81.9% were students), 34.8% increased their physical activity, and, only 0.8% prefer ready meals. Whereas, the same percentage of men continued to work from home (90%), but only 72.1% were students (p &lt, 0.001 vs. females), only 23.9% increased physical activity (p &lt, 0.001) and 1.7% favous ready meals. Our data shows that the male population was more affected by isolation and quarantine reporting more unfavourable behavioural changes.

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.

To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing of 121 hospitalized patients. These 10 genes showed significant enrichment in predicted pathogenic point mutations in severe patients compared with the non-severe ones. Moreover, in the TNFRSF13C gene, the minor allele of the p.His159Tyr variant, which is known to increase NF-kB activation and B-cell production, was significantly more frequent in the 38 severe cases compared to both the 83 non-severe patients and the 375 asymptomatic subjects further genotyped. This finding identified a potential genetic risk factor of severe COVID-19 that not only may serve to unravel the mechanisms underlying the disease severity but, also, may contribute to build the rationale for individualized management based on B-cell therapy.

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.

Cystic Fibrosis (CF) is a genetic disease inherited by an autosomal recessive mechanism and characterized by a progressive and severe multi-organ failure. Mutations in Cystic Fibrosis Conductance Regulator (CFTR) protein cause duct obstructions from dense mucus secretions and chronic inflammation related to organ damage. The progression of the disease is characterized by a decline of lung function associated with metabolic disorders and malnutrition, musculoskeletal disorders and thoracic deformities, leading to a progressive decrement of the individual’s quality of life. The World Health Organization (WHO) qualifies Physical Activity (PA) as a structured activity produced by skeletal muscles’ movements that requires energy consumption. In the last decade, the number of studies on PA increased considerably, including those investigating the effects of exercise on cognitive and brain health and mental performance. PA is recommended in CF management guidelines, since it improves clinic outcomes, such as peripheral neuropathy, oxygen uptake peak, bone health, glycemic control and respiratory functions. Several studies regarding the positive effects of exercise in patients with Cystic Fibrosis were carried out, but the link between the effects of exercise and cognitive and brain health in CF remains unclear. Animal models showed that exercise might improve learning and memory through structural changes of brain architecture, and such a causal relationship can also be described in humans. Indeed, both morphological and environmental factors seem to be involved in exercise-induced neural plasticity. An increase of gray matter volume in specific areas is detectable as a consequence of regular training in humans. Neurobiological processes associated with brain function improvements include biochemical modifications, such as neuromodulator or neurohormone release, brain-derived neurotrophic factor (BDNF) production and synaptic activity changes. From a functional point of view, PA also seems to be an environmental factor enhancing cognitive abilities, such as executive functions, memory and processing speed. This review describes the current state of research regarding the impacts of physical activity and exercise on cognitive functions, introducing a possible novel field of research for optimizing the management of Cystic Fibrosis.

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.

Acute or strenuous exercise is sometimes related to upper respiratory tract infections in athletes. Practicing intense and regular exercise can lead to incorrect activation of the immune system, causing athletes to be excluded from training programs and competitions. Defensins are small antimicrobial peptides that are part of the innate immune system and dynamically involved in several biological activities. In this study, we highlight the role of human defensins in competitive basketball athletes. In particular, we consider the behavior of alpha- and beta-defensins together with white blood cells in a cohort of players. Moreover, we focus our attention on cortisol, a physiological indicator of stress, and testosterone, both of which are human hormones involved in muscle metabolism. The free-testosterone/cortisol ratio is considered to be an indicator of overtraining among athletes. This paper provides an up-to-date information of the role of human defensins as self-defense molecules during a continuous stressor such as long-term exercise, and it recognizes them as potential markers of infection.

The first studies on Staphylococcus aureus (SA) infections in athletes were conducted in the 1980s, and examined athletes that perform in close physical contact, with particular attention to damaged or infected skin. Recent studies have used molecular epidemiology to shed light on the transmission of SA in professional athletes. These studies have shown that contact between athletes is prolonged and constant, and that these factors influence the appearance of infections caused by SA. These results support the need to use sanitary measures designed to prevent the appearance of SA infections. The factors triggering the establishment of SA within professional sports groups are the nasal colonization of SA, contact between athletes and sweating. Hence, there is a need to use the most modern molecular typing methods to evaluate the appearance of cutaneous SA disease. This review aims to summarize both the current SA infections known in athletes and the diagnostic methods employed for recognition, pointing to possible preventive strategies and the factors that can act as a springboard for the appearance of SA and subsequent transmission between athletes.

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.

In the last few years, a significant increase of childhood obesity incidence unequally distributed within countries and population groups has been observed, thus representing an important public health problem associated with several health and social consequences. Obese children have more than a 50% probability of becoming obese adults, and to develop pathologies typical of obese adults, that include type 2-diabetes, dyslipidemia and hypertension. Also environmental factors, such as reduced physical activity and increased sedentary activities, may also result in increased caloric intake and/or decreased caloric expenditure. In the present review, we aimed to identify and describe a specific panel of parameters in order to evaluate and characterize the childhood obesity status useful in setting up a preventive diagnostic approach directed at improving health-related behaviors and identifying predisposing risk factors. An early identification of risk factors for childhood obesity could definitely help in setting up adequate and specific clinical treatments.

In the era of next generation sequencing (NGS), genetic testing for inherited disorders identifies an ever-increasing number of variants whose pathogenicity remains unclear. These variants of uncertain significance (VUS) limit the reach of genetic testing in clinical practice. The VUS for hypertrophic cardiomyopathy (HCM), the most common familial heart disease, constitute over 60% of entries for missense variants shown in ClinVar database. We have studied a novel VUS (c.1809T>G-p.I603M) in the most frequently mutated gene in HCM, MYBPC3, which codes for cardiac myosin-binding protein C (cMyBPC). Our determinations of pathogenicity integrate bioinformatics evaluation and functional studies of RNA splicing and protein thermodynamic stability. In silico prediction and mRNA analysis indicated no alteration of RNA splicing induced by the variant. At the protein level, the p.I603M mutation maps to the C4 domain of cMyBPC. Although the mutation does not perturb much the overall structure of the C4 domain, the stability of C4 I603M is severely compromised as detected by circular dichroism and differential scanning calorimetry experiments. Taking into account the highly destabilizing effect of the mutation in the structure of C4, we propose reclassification of variant p.I603M as likely pathogenic. Looking into the future, the workflow described here can be used to refine the assignment of pathogenicity of variants of uncertain significance in MYBPC3. J.A.C. was funded by the Ministerio de Ciencia, Innovación y Universidades (MCNU) through grants BIO2017-83640-P (AEI/FEDER, UE) and RYC-2014-16604, the European Research Area Network on Cardiovascular Diseases (ERA-CVD/ISCIII, MINOTAUR, AC16/00045), the Comunidad de Madrid (P2018/NMT-4443) and the CNIC-Severo Ochoa intramural grant program (03-2016 IGP). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). G.F. was funded by the Ministero dell’Istruzione, dell’Università e della Ricerca-Rome PS35-126/IND. Sí

Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is fundamental part of MDs management and allows achieving the definitive diagnosis. In this article, we review the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement. We searched for publications on mitochondrial and nuclear genes involved in MCM, mainly focusing on genetic screening based on targeted gene panels for the molecular diagnosis of the MCM, by using Next Generation Sequencing. Here we report twelve case reports, four case-control studies, eleven retrospective studies, and two prospective studies, for a total of twenty-nine papers concerning the evaluation of cardiac manifestations in mitochondrial diseases. From the analysis of published causal mutations, we identified 130 genes to be associated with mitochondrial heart diseases. A large proportion of these genes (34.3%) encode for key proteins involved in the oxidative phosphorylation system (OXPHOS), either as directly OXPHOS subunits (22.8%), and as OXPHOS assembly factors (11.5%). Mutations in several mitochondrial tRNA genes have been also reported in multi-organ or isolated MCM (15.3%). This review highlights the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies.

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.

Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.