Clinical, Genetic, and Histological Characterization of Patients with Rare Neuromuscular and Mitochondrial Diseases Presenting with Different Cardiomyopathy Phenotypes.

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.

The Risk of Sudden Unexpected Cardiac Death in Children: Epidemiology, Clinical Causes, and Prevention.

"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."

Clinical Manifestations of 22q11.2 Deletion Syndrome.

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.

The Heart Muscle and Valve Involvement in Marfan Syndrome, Loeys-Dietz Syndromes, and Collagenopathies.

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.

Diagnosis and Management of Cardiovascular Involvement in Friedreich Ataxia.

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.

Diagnosis and Management of Cardiovascular Involvement in Fabry Disease.

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.

Cardiovascular Involvement in mtDNA Disease: Diagnosis, Management, and Therapeutic Options.

Mitochondrial diseases (MD) include an heterogenous group of systemic disorders caused by sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA), causing impairment of oxidative phosphorylation system. Hypertrophic cardiomyopathy is the dominant pattern of cardiomyopathy in all forms of mtDNA disease, being observed in almost 40% of the patients. Dilated cardiomyopathy, left ventricular noncompaction, and conduction system disturbances have been also reported. In this article, the authors discuss the current clinical knowledge on MD, focusing on diagnosis and management of mitochondrial diseases caused by mtDNA mutations.

Hypertrophic Cardiomyopathy in RASopathies: Diagnosis, Clinical Characteristics, Prognostic Implications, and Management.

RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be triggered by clinical clues ("red flags") which may direct the clinician toward a specific gene test. Compared with sarcomeric hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in RASopathies (R-HCM) is associated with higher prevalence of congestive heart failure and shows increased prevalence and severity of left ventricular outflow tract obstruction. Biventricular involvement and the association with congenital heart disease, mainly pulmonary stenosis, have been commonly described in R-HCM. The aim of this review is to assess the prevalence and unique features of R-HCM and to define the available therapeutic options.

Cardiovascular Involvement in Transthyretin Cardiac Amyloidosis.

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.

The Role of New Imaging Technologies in the Diagnosis of Cardiac Amyloidosis.

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).

A complex unit for a complex disease: the HCM-Family Unit.

Hypertrophic cardiomyopathy (HCM) is a group of heterogeneous disorders that are most commonly passed on in a heritable manner. It is a relatively rare disease around the globe, but due to increased rates of consanguinity within the Kingdom of Saudi Arabia, we speculate a high incidence of undiagnosed cases. The aim of this paper is to elucidate a systematic approach in dealing with HCM patients and since HCM has variable presentation, we have summarized differentials for diagnosis and how different subtypes and genes can have an impact on the clinical picture, management and prognosis. Moreover, we propose a referral multi-disciplinary team HCM-Family Unit in Saudi Arabia and an integrated role in a network between King Faisal Hospital and Inherited and Rare Cardiovascular Disease Unit-Monaldi Hospital, Italy (among the 24 excellence centers of the European Reference Network (ERN) GUARD-Heart).   Graphical Abstract.

Advanced Heart Failure in Special Population-Pediatric Age.

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.

Cognitive Function and Atrial Fibrillation: From the Strength of Relationship to the Dark Side of Prevention. Is There a Contribution from Sinus Rhythm Restoration and Maintenance?

Atrial fibrillation (AF) is the most common chronic cardiac arrhythmia with an increasing prevalence over time mainly because of population aging. It is well established that the presence of AF increases the risk of stroke, heart failure, sudden death, and cardiovascular morbidity. In the last two decades several reports have shown an association between AF and cognitive function, ranging from impairment to dementia. Ischemic stroke linked to AF is a well-known risk factor and predictor of cognitive decline. In this clinical scenario, the risk of stroke might be reduced by oral anticoagulation. However, recent data suggest that AF may be a predictor of cognitive impairment and dementia also in the absence of stroke. Cerebral hypoperfusion, reduced brain volume, microbleeds, white matter hyperintensity, neuroinflammation, and genetic factors have been considered as potential mechanisms involved in the pathogenesis of AF-related cognitive dysfunction. However, a cause-effect relationship remains still controversial. Consequently, no therapeutic strategies are available to prevent AF-related cognitive decline in stroke-free patients. This review will analyze the potential mechanisms leading to cognitive dysfunction in AF patients and examine the available data on the impact of a sinus rhythm restoration and maintenance strategy in reducing the risk of cognitive decline.

Prediction of incident atrial fibrillation in hypertrophic cardiomyopathy.

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.

Aortic Root Diameter in Highly-Trained Competitive Athletes: Reference Values According to Sport and Prevalence of Aortic Enlargement.

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.

Targeted Therapies in Pediatric and Adult Patients With Hypertrophic Heart Disease: From Molecular Pathophysiology to Personalized Medicine.

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.

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines.

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.

Double-Outlet Left Ventricle: Case Series and Systematic Review of the Literature.

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).