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BACKGROUND AND AIM: Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) with significant effects on outcome. We aim to compare the left atrial (LA) diameter measurement with HCM-AF Score in predicting atrial fibrillation (AF) development in HCM. METHODS: From the regional cohort of the Campania Region, Italy, 519 HCM patients (38% women, age45 ± 17 years) without history of AF, were enrolled in the study. The primary clinical endpoint was the development of AF, defined as at least 1 episode documented by ECG. RESULTS: During the follow-up (mean 8 ± 6, IQ range 2.5-11.2 years), 99 patients (19%) developed AF. Patients who developed AF were more symptomatic, had higher prevalence of ICD implantation, had larger LA diameter, greater left ventricular (LV) maximal wall thickness and LV outflow tract obstruction (p < 0.01). Both LA diameter and HCM-AF score were higher in patients who developed AF versus those who did not (LA diameter 49 ± 7 versus 43 ± 6 mm; HCM-AF score 22 ± 4 versus 19 ± 4; p < 0.0001); however, ROC curve analysis demonstrated that LA diameter had a significant greater area under the curve than HCM-AF Score (p < 0.0001). At 5 years follow-up, a LA diameter > 46 mm, showed a similar accuracy in predicting AF development of HCM-AF score ≥ 22, which identifies patients at high risk to develop AF. CONCLUSION: Our analysis shows that LA diameter, a worldwide and simple echocardiographic measure, is capable alone to predict AF development in HCM patients.

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Double-outlet left ventricle (DOLV) is an abnormal ventriculo-arterial connection characterized by the origin of both great arteries from the morphological left ventricle. The aim of our paper is to describe the morphological and imaging features of DOLV and to assess the prevalence of the associated malformations and their surgical outcomes. METHODS From 2011 to 2022, we retrospectively reviewed the electronic case records of patients diagnosed with DOLV at the Bambino Gesu Children's Hospital. A systematic search was developed in MEDLINE, Web of Science, and EMBASE databases to identify reports assessing the morphology and outcomes of DOLV between 1975 and 2023. RESULTS: Over a median follow-up of 9.9 years (IQR 7.8-11.7 y), four cases of DOLV were identified at our institution. Two patients were diagnosed with (S,D,D) DOLV subaortic VSD and pulmonary stenosis (PS): one patient had (S,D,D) DOLV with doubly committed VSD and hypoplastic right ventricle, and another patient had (S,D,L) DOLV with subaortic VSD and PS (malposition type). Pulmonary stenosis was the most commonly associated lesion (75%). LITERATURE REVIEW: After systematic evaluation, a total of 12 reports fulfilled the eligibility criteria and were included in our analysis. PS or right ventricular outflow tract obstruction was the most commonly associated lesion (69%, 95% CI 62-76%). The most common locations of VSD were subaortic (pooled prevalence: 75%, 95% CI 68-81), subpulmonary (15%, 95% CI 10-21), and doubly committed (7%, 95% CI 4-12). The position of the great arteries showed that d-transposition of the aorta was present in 128 cases (59% 95% CI 42-74), and l-transposition was present in 77 cases (35%, 95% CI 29-43).

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Hypertrophic cardiomyopathy is a myocardial disease defined by an increased left ventricular wall thickness not solely explained by abnormal loading conditions. It is often genetically determined, with sarcomeric gene mutations accounting for around 50% of cases. Several conditions, including syndromic, metabolic, infiltrative, and neuromuscular diseases, may present with left ventricular hypertrophy, mimicking the hypertrophic cardiomyopathy phenotype but showing a different pathophysiology, clinical course, and outcome. Despite being rare, they are collectively responsible for a large proportion of patients presenting with hypertrophic heart disease, and their timely diagnosis can significantly impact patients' management. The understanding of disease pathophysiology has advanced over the last few years, and several therapeutic targets have been identified, leading to a new era of tailored treatments applying to different etiologies associated with left ventricular hypertrophy. This review aims to provide an overview of the existing and emerging therapies for the principal causes of hypertrophic heart disease, discussing the potential impact on patients' management and clinical outcome.

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BACKGROUND: This study aims to evaluate the prevalence and the clinical significance of the right ventricular pulmonary arterial (RV-PA) uncoupling in patients with cardiac amyloidosis (CA). METHODS: The study population consisted in 92 consecutive patients with CA (age 71.1 ± 12.2 years, 71% males; 47% with immunoglobulin light chain (AL), 53% with transthyretin [ATTR]). A pre-specified tricuspid anulus plane systolic excursion on pulmonary arterial systolic pressure (TAPSE/PASP) value <0.31 mm/mmHg was used to define RV-PA uncoupling and to dichotomize the study population. RESULTS: Thirty-two patients (35%) showed RV-PA uncoupling at baseline evaluation (15/44 [34%] AL and 17/48 [35%] ATTR). Patients with RV-PA uncoupling, in both AL and ATTR, showed worse NYHA functional class, lower systemic blood pressure, and more pronounced left ventricular and RV systolic dysfunction than those with RV-PA coupling. During a median follow-up of 8 months (IQR 4-13), 26 patients (28%) experienced cardiovascular death. Patients with RV-PA uncoupling showed lower survival at 12 months follow-up than those with RV-PA coupling (42.7% [95%CI 21.7-63.7%] vs. 87.3% [95%CI 78.3-96.3%], p-value<0.001). Multivariate analysis identified high-sensitivity troponin I values (HR 1.01 [95%CI 1.00-1.02] per 1 pg/mL increase; p-value 0.013) and TAPSE/PASP (HR 1.07 [95%CI 1.03-1.11] per 0.01 mm/mmHg decrease; p-value 0.002) as independent predictors of cardiovascular death. CONCLUSIONS: RV-PA uncoupling is common among patient with CA, and it is a marker of advanced disease and worse outcome. This study suggest that TAPSE/PASP ratio has the potential to improve risk stratification and guide management strategies in patients with CA of different etiology and advanced disease.

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BACKGROUND: We aimed to examine clinical features and outcomes of consecutive molecularly characterized patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy. METHODS: A retrospective, longitudinal multicenter cohort of consecutive children and adults with a genetic diagnosis of Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy between 2002 and 2019 was assembled. We defined a priori 3 different patterns of left ventricular remodeling during follow-up: (1) an increase in ≥15% of the maximal left ventricular wall thickness (MLVWT), both in mm and z-score (progression); (2) a reduction ≥15% of the MLVWT, both in mm and z-score (absolute regression); (3) a reduction ≥15% of the MLVWT z-score with a stable MLVWT in mm (relative regression). The primary study end point was a composite of cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator-shock. RESULTS: The cohort comprised 42 patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy, with a median age at diagnosis of 3.5 (interquartile range, 0.2-12.3) years. Freedom from primary end point was 92.7% (95% CI, 84.7%-100%) 1 year after presentation and 80.9% (95% CI, 70.1%-90.7%) at 5 years. Patients with MLVWT z-score >13.7 showed reduced survival compared with those with <13.7. During a median follow-up of 3.7 years (interquartile range, 2.6-7.9), absolute regression was the most common type of left ventricular remodeling (n=9, 31%), followed by progression (n=6, 21%), and relative regression (n=6, 21%). CONCLUSIONS: These findings provide insights into the natural history of left ventricular hypertrophy, and can help inform clinicians regarding risk stratification and clinical outcomes in patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy.

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Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe the clinical, molecular, and histological characteristics of a consecutive cohort of patients with cardiomyopathy associated with NMDs or MDs referred to a tertiary cardiomyopathy clinic. Consecutive patients with a definitive diagnosis of NMDs and MDs presenting with a cardiomyopathy phenotype were described. Seven patients were identified: two patients with ACAD9 deficiency (Patient 1 carried the c.1240C>T (p.Arg414Cys) homozygous variant in ACAD9; Patient 2 carried the c.1240C>T (p.Arg414Cys) and the c.1646G>A (p.Ar549Gln) variants in ACAD9); two patients with MYH7-related myopathy (Patient 3 carried the c.1325G>A (p.Arg442His) variant in MYH7; Patient 4 carried the c.1357C>T (p.Arg453Cys) variant in MYH7); one patient with desminopathy (Patient 5 carried the c.46C>T (p.Arg16Cys) variant in DES); two patients with mitochondrial myopathy (Patient 6 carried the m.3243A>G variant in MT-TL1; Patient 7 carried the c.253G>A (p.Gly85Arg) and the c.1055C>T (p.Thr352Met) variants in MTO1). All patients underwent a comprehensive cardiovascular and neuromuscular evaluation, including muscle biopsy and genetic testing. This study described the clinical phenotype of rare NMDs and MDs presenting as cardiomyopathies. A multidisciplinary evaluation, combined with genetic testing, plays a main role in the diagnosis of these rare diseases, and provides information about clinical expectations, and guides management.

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The term arrhythmogenic cardiomyopathy (ACM) describes a large spectrum of myocardial diseases characterized by progressive fibrotic or fibrofatty replacement, which gives the substrate for the occurrence of ventricular tachyarrhythmias and the development of ventricular dysfunction. This condition may exclusively affect the left ventricle, leading to the introduction of the term arrhythmogenic left ventricular cardiomyopathy (ALVC). The clinical features of ALVC are progressive fibrotic replacement with the absence or mild dilation of the LV and the occurrence of ventricular arrhythmias within the left ventricle. In 2019, the diagnostic criteria for the diagnosis of ALVC, based on family history and clinical, electrocardiographic, and imaging features, have been proposed. However, since the significant clinical and imaging overlap with other cardiac diseases, genetic testing with the demonstration of a pathogenic variant in an ACM-related gene is required for diagnostic confirmation. In ALVC, the multimodality imaging approach comprises different imaging techniques, such as echocardiography, cardiac magnetic resonance, and cardiac nuclear imaging. It provides essential information for the diagnosis, differential diagnosis, sudden cardiac death risk stratification, and management purposes. This review aims to elucidate the current role of the different multimodality imaging techniques in patients with ALVC.

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Heritable thoracic aortic disease (HTAD) is a term used to define a large group of disorders characterized by the occurrence of aortic events, mainly represented by aneurysm or dissection. These events generally involve the ascending aorta, although the involvement of other districts of the aorta or peripheral vessels may occur. HTAD can be classified as non-syndromic if the disorder is limited to the aorta, and syndromic when associated with extra-aortic features. About 20-25% of patients with non-syndromic HTAD exhibit a family history of aortic disease. Thus, a careful clinical evaluation of the proband and the first-degree family members is required to differentiate familial and sporadic cases. Genetic testing is essential since it allows confirmation of the etiological diagnosis of HTAD (particularly in patients with a significant family history) and may guide family screening. In addition, genetic diagnosis significantly impacts patients' management since the different conditions significantly differ with respect to natural history and treatment strategies. The prognosis in all HTADs is determined by the progressive dilation of the aorta, potentially leading to acute aortic events, such as dissection or rupture. Moreover, the prognosis varies according to the underlying genetic mutations. This review aims to describe the clinical characteristics and natural history of the most common HTADs, with particular emphasis on the role of genetic testing in risk stratification and management.

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BACKGROUND: Studies exploring the extent of aortic root dilation across the different types of sport are limited. We aimed to define the physiological limits of aortic remodelling in a large population of healthy elite athletes in comparison with nonathletic controls. METHODS: A total of 1995 consecutive athletes evaluated at the Institute of Sports Medicine (Rome, Italy) and 515 healthy controls underwent a comprehensive cardiovascular screening. The aortic diameter was measured at the level of the sinuses of Valsalva. The 99th percentile from the mean of the aortic diameter in the control population was used to define an abnormally enlarged aortic root dimension. RESULTS: Athletes showed a larger aortic root diameter (30.6 [± 3.3] vs 28.1 [± 3.1] mm, P value < 0.001) than controls. The difference was evident in male and female athletes, regardless of sport- predominant component and level of intensity. The 99th percentile value for aortic root diameter in control male and female subjects was 37 mm and 32 mm, respectively. Based on these values, 50 (4.2%) male and 21 (2.6%) female athletes would have been diagnosed with an enlarged aortic root. However, aortic root diameter of clinical relevance-ie, ≥ 40 mm-was observed in only 17 male athletes (0.85%) and did not exceed > 44 mm. CONCLUSIONS: Athletes show a mild, although significant, increased aortic dimension in comparison with healthy controls. The degree of aortic enlargement varies in relation to type of sports and sex. Eventually, only a small minority of athletes exhibited a markedly enlarged aortic diameter (ie, ≥ 40 mm) in a range of clinical relevance.

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Gastrointestinal involvement is a common clinical feature of patients with systemic amyloidosis. This condition is responsible for invalidating gastrointestinal symptoms, a significant macro and micronutrient deficit, and is a marker of disease severity. Gastrointestinal involvement should be actively sought in patients with systemic amyloidosis, while its diagnosis is challenging in patients with isolated gastrointestinal symptoms. The nutritional status in systemic amyloidosis plays an essential role in the clinical course and is considered a significant prognostic factor. However, the definition of nutritional status is still challenging due to the lack of internationally accepted thresholds for anthropometric and biochemical variables, especially in specific populations such as those with systemic amyloidosis. This review aims to elucidate the fundamental steps for nutritional assessment by using clinical and instrumental tools for better prognostic stratification and patient management regarding quality of life and outcomes.

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Several treatments have demonstrated safety and effectiveness in the treatment of patients with hypertrophic cardiomyopathy; however, no drug has been shown to modify the natural history of the disease or to decrease maximal wall thickness. Improvement in our knowledge of the physiopathology of the disease has permitted the development of new therapeutical approaches, including sarcomere modulators and gene therapy. A sarcomere modulator - mavacamten - has been shown to improve exercise capacity, left ventricular outflow tract obstruction, New York Heart Association functional class and health status in a phase 3 trial. Gene therapy - although still far from human experimentation - also has promising characteristics that may radically revolutionize the treatment of hypertrophic cardiomyopathy in the future. This therapy is currently approved for the treatment of select haematological malignancies, inherited retinal dystrophy and spinal muscular atrophy, and could potentially correct the genetic alterations of the most frequent sarcomeric forms of hypertrophic cardiomyopathy. This review provides an overview of current conventional therapies for the management of patients with hypertrophic cardiomyopathy, discusses emerging therapeutic approaches and presents future perspectives.

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Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib.

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Thoracic aortic dilatation is a progressive condition that results from aging and many pathological conditions (i.e., connective tissue, inflammatory, shear stress disorders, severe valvular heart disease) that induce degenerative changes in the elastic properties, leading to the loss of elasticity and compliance of the aortic wall. Mild aortic root enlargement may be also observed in athletes and is considered as a normal adaptation to regular exercise training. On the other hand, high-intensity physical activity in individuals with a particular genetic substrate, such as those carrying gene variants associated with Marfan syndrome or other inherited aortopathies, can favor an excessive aortic enlargement and trigger an acute aortic dissection. The evaluation of the aortic valve and aortic root diameters, as well as the detection of a disease-causing mutation for inherited aortic disease, should be followed by a tailored decision about sport eligibility. In addition, the risk of aortic complications associated with sport in patients with genetic aortic disease is poorly characterized and is often difficult to stratify for each individual athlete. This review aims to describe the relationship between regular physical activity and aortic dilation, focusing on patients with bicuspid aortic valve and inherited aortic disease, and discuss the implications in terms of aortic disease progression and sport participation.

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Cardiomyopathies (CMPs) are myocardial diseases 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. Thought for a long time to be rare diseases, it is now clear that most of the CMPs can be easily observed in clinical practice. However, there is a group of specific heart muscle diseases that are rare in nature whose clinical/echocardiographic phenotypes resemble those of the four classical morphological subgroups of hypertrophic, dilated, restrictive, arrhythmogenic CMPs. These rare CMPs, often but not solely diagnosed in infants and paediatric patients, should be more properly labelled as specific CMPs. Emerging consensus exists that these conditions require tailored investigation and management. Indeed, an appropriate understanding of these conditions is mandatory for early treatment and counselling. At present, however, the multisystemic and heterogeneous presentation of these entities is a challenge for clinicians, and time delay in diagnosis is a significant concern. The aim of this paper is to define practical recommendations for diagnosis and management of the rare CMPs in paediatric or adult age. A modified Delphi method was adopted to grade the recommendations proposed by each member of the writing committee.

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AIMS: To evaluate the role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In this retrospective study, patients with HCM with an LVOT gradient ≥50 mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient <30 mmHg or the maximum tolerated dose. The primary endpoint was the achievement of a LVOT gradient <30 mmHg and ≥ 1 NYHA class improvement. The secondary endpoints were proportion of patients with LVOT gradient <30 mmHg or < 50 mmHg, proportion of patients with ≥1 NYHA class improvement, and change from baseline in LVOT gradient. Between December 2001 and December 2020, 92 patients were enrolled into the study. Sixteen (17%) patients on bisoprolol met the primary endpoint. Bisoprolol reduced the LVOT gradient to less than 30 mmHg in 33 (36%) patients, to less than 50 mmHg in 57 (62%), and improved NYHA class in 30 (33%). The mean reduction of LVOT gradient on bisoprolol was 28 (±14) mmHg and the percentage reduction was 42 (±21) %. In 35 (38%) patients, bisoprolol did not reduce the gradient to less than 50 mmHg requiring disopyramide and/or myectomy to achieve this goal. CONCLUSION: Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM.

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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.

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BACKGROUND: This study sought to describe the characteristics and the natural course of left ventricular hypertrophy (LVH) in a well-characterized consecutive cohort of infants of diabetic mothers (IDMs). METHODS: Sixty consecutive IDMs with LVH have been retrospectively identified and enrolled in the study. All IDMs were evaluated at baseline and every 6 months until LV wall thickness regression, defined as the decrease of wall thickness measurement into the normal reference range for cardiac parameters (z-score > -2 and < 2). A comprehensive assessment was performed in those patients with diagnostic markers suggestive of a different cause and/or without significant reduction of the LVH during follow-up. RESULTS: At 1-year follow-up, all IDMs showed a significant reduction of maximal wall thickness MWT (6.00 mm [IQR 5.00-712] vs. 5.50 mm [IQR 5.00-6.00], p-value <0.001; MWT-z-score: 4.86 [IQR 3.93-7.61] vs. 1.72 [IQR 1.08-2.85], p-value <0.001) compared to baseline, and all patients showed LV wall thickness regression or residual mild or moderate LVH (57%, 28%, and 12%, respectively), except 2 patients with persistent severe LVH, that after a comprehensive clinical-genetic assessment were diagnosed as Noonan syndrome with multiple lentigines. At multivariate analysis, MWT was negatively associated with LV wall thickness regression at 1-year follow-up (MWT-mm: OR 0.48[0.29-0.79], p-value = 0.004; MWT-z-score: OR 0.71[0.56-0.90], p-value = 0.004). CONCLUSIONS: LVH in IDMs represents a benign condition with complete regression during the first years of life. In those patients without LV wall thickness regression, combined with clinical markers suggesting a specific disease, a complete work-up is required for a definite diagnosis.

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"Sudden unexplained death (SUD) is a tragic event for both the family and community, particularly when it occurs in young individuals. Sudden cardiac death (SCD) represents the leading form of SUD and is defined as an unexpected event without an obvious extracardiac cause, occurring within 1 hour after the onset of symptoms. In children, the main causes of SCD are inherited cardiac disorders, whereas coronary artery diseases (congenital or acquired), congenital heart diseases, and myocarditis are rare. The present review examines the current state of knowledge regarding SCD in children, discussing the epidemiology, clinical causes, and prevention strategies."

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