Effect of Migalastat on cArdiac InvOlvement in FabRry DiseAse: MAIORA study.

BACKGROUND: A small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET). METHODS: Sixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat. RESULTS: No change in LV mass was detected at 18 months compared to baseline (95.2 g/m2 (66.0-184.0) vs 99.0 g/m2 (69.0-121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848-882) vs 860.0 ms (833.0-875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO2) at anaerobic threshold (15.50 mL/kg/min (13.70-21.50) vs 14.50 mL/kg/min (11.70-18.95), p=0.02), and a trend towards an increase in percent predicted peak VO2 (72.0 (63.0-80.0) vs 69.0 (53.0-77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6-76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance. CONCLUSION: In treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others. TRIAL REGISTRATION NUMBER: NCT03838237.

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.

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

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 < 0.001 and 37 versus 349, P < 0.001, respectively) and 2018 (117 versus 389, P < 0.001 and 37 versus 282, P < 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak. 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.

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."

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 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 pilot clinical trial with losartan in Myhre syndrome.

INTRODUCTION: Myhre syndrome (MS) is an ultra-rare disorder due to pathogenic variants in the SMAD4 gene that encodes a protein regulating the TGF-ß pathway and extra-cellular matrix (ECM) homeostasis. Main clinical features of MS include thickening of skin and joint stiffness. Previous studies showed that losartan improved ECM deposition in MS fibroblasts. MATERIALS AND METHODS: Four molecularly confirmed MS subjects (mean age 23.8 ± 17 years) were evaluated for: (a) skin thickness by Rodnan score, (b) joint range of motion (ROM) by goniometry, and (c) speckle-tracking echocardiogram. Following baseline evaluations, three MS individuals received losartan for 12 months and pre-defined endpoints were monitored after 6 and 12 months of treatment. RESULTS: At baseline, Rodnan scores were increased, joint ROM was reduced, and speckle-tracking echocardiogram revealed reduced myocardial strain. In three MS subjects, improvements in skin thickness, joint ROM and to a lesser extent of myocardial strain, were observed after 6 and 12 months of losartan treatment. CONCLUSIONS: Although further long-term controlled clinical trials with a larger number of affected individuals are needed, the present study suggests that losartan might improve skin, joint and heart abnormalities of MS.

Impact of Regular Physical Activity on Aortic Diameter Progression in Paediatric Patients with Bicuspid Aortic Valve.

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.

Cardiac Resynchronization Therapy in Patients with Heart Failure: What is New?

Cardiac resynchronization therapy (CRT) is an established treatment of patients with medically refractory, mild-to-severe systolic heart failure (HF), impaired left ventricular function, and wide QRS complex. The pathologic activation sequence observed in patients with abnormal QRS duration and morphology results in a dyssynchronous ventricular activation and contraction leading to cardiac remodeling, worsening systolic and diastolic function, and progressive HF. In this article, the authors aim to explore the current CRT literature, focusing their attentions on the promising innovation in this field.

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.

Combined Effect of Mediterranean Diet and Aerobic Exercise on Weight Loss and Clinical Status in Obese Symptomatic Patients with Hypertrophic Cardiomyopathy.

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/E'average, 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/E'average, 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.

Clinical significance of family history and bicuspid aortic valve in children and young adult patients with Marfan syndrome.

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.

Molecular Basis of Inflammation in the Pathogenesis of Cardiomyopathies.

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.

The challenge of cardiomyopathies and heart failure in pregnancy.

PURPOSE OF REVIEW: To discuss the risk preexisting or new onset cardiomyopathy/heart failure (CMP/heart failure) in pregnant woman, and recent insights regarding their management and therapy. RECENT FINDINGS: Recent data from the European Registry on Pregnancy and Heart disease of the European Society of Cardiology (ROPAC) suggest that, after an adequate prepregnancy evaluation in specialized centres, the vast majority of pregnancies are safe for both mother and foetus. A tailored approach is required according to cardiac phenotype (i.e. type of cardiomyopathy), clinical and functional status, and new potential treatments (i.e. bromocriptine in patients with peripartum cardiomyopathy). SUMMARY: In clinical practice, prepregnancy cardiac evaluation is mandatory, including evaluation of the clinical status, standard ECG (and 24-48 h monitoring, whenever required), and imaging, to define the individual risk profile. In presence of severe symptoms (advanced New York Heart Association class), cardiac dysfunction (moderate-severe reduced ejection fraction), haemodynamic load (left ventricular outflow tract obstruction, pulmonary hypertension), pregnancy is contraindicated. A tailored monitoring is warranted in other cases (mild-moderate risk pregnancies). Likewise, in women who develop PPCM, a risk stratification and tailored monitoring and therapy should be achieved by an expert, multidisciplinary team, including cardiologists, gynaecologists, obstetricians, genetic counsellor, and psychologists.

Management of Bradyarrhythmias in Heart Failure: A Tailored Approach.

Patients with heart failure (HF) may develop a range of bradyarrhythmias including sinus node dysfunction, various degrees of atrioventricular block, and ventricular conduction delay. Device implantation has been recommended in these patients, but the specific etiology should be sought as it may influence the choice of the type of device required (pacemaker vs. implantable cardiac defibrillator). Also, pacing mode must be carefully set in patients with heart failure (HF) and left ventricular systolic dysfunction.In this chapter, we summarize the knowledge required for a tailored approach to bradyarrhythmias in patients with heart failure.

Genetics of Takotsubo Syndrome.

Takotsubo syndrome (TTS) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. A genetic predisposition has been suggested based on the few familial TTS cases. Conflicting results have been published regarding the role of functional polymorphisms in relevant candidate genes, such as α1-, ß1-, and ß2-adrenergic receptors; G protein-coupled receptor kinase 5; and estrogen receptors. Further research is required to help clarify the role of genetic susceptibility in TTS.

[Clinical and genetic manifestations of left ventricular non-compaction in children]. / Caratteristiche cliniche e genetiche del ventricolo sinistro non compatto in età pediatrica.

Left ventricular non-compaction (LVNC) is a myocardial disease characterized by a two-layered structure typically seen at the apical and lateral left portions of the ventricular myocardium, distal to the papillary muscles. While considered a rare disease, its prevalence in children is increasing due to the increased awareness of this condition and improved resolution of imaging techniques. The etiology is heterogeneous, ranging from inherited conditions to acquired diseases. Although many patients are asymptomatic, some patients may experience adverse events, including heart failure, arrhythmias, or thromboembolic events. Several echocardiographic or cardiac magnetic resonance imaging diagnostic criteria have been proposed for diagnosing LVNC. However, their application in children is significantly limited. This review aims to describe the clinical and genetic characteristics of children with LVNC and discuss the role of the proposed diagnostic criteria.

Prevalence and Clinical Significance of Intraventricular Conduction Disturbances in Hospitalized Children.

Introduction: Data on the prevalence and clinical significance of interventricular conduction disturbances (IVCDs) in children are scarce. While incomplete right bundle branch blocks (IRBBBs) seem to be the most frequent and benign findings, complete bundle blocks and fascicular blocks are often seen in children with congenital/acquired cardiac conditions. This study aims to delineate the prevalence and the diagnostic accuracy of IVCD in children admitted to a paediatric cardiology unit. Methods: Children admitted to the paediatric cardiology unit between January 2010 and December 2020 who had an ECG were included in the study. IVCDs were diagnosed according to standard criteria adjusted for age. Results: Three thousand nine hundred and ninety-three patients were enrolled. The median age was 3.1 years (IQR: 0.0-9.2 years), and 52.7% were males. IVCDs were present in 22.5% of the population: 17.4% of the population presented with IRBBBs, 4.8% with a complete right bundle branch block (CRBBB), 0.1% with a complete left bundle branch block (CLBBB), 0.2% with a left anterior fascicular block (LAFB) and 0.2% with a combination of CRBBB and LAFB. Also, 26% of children with congenital heart disease had an IVCD, and 18% of children with an IVCD had previous cardiac surgery. The overall sensitivity of IVCD in detecting a cardiac abnormality was 22.2%, with a specificity of 75.5%, a PPV of 83.1% and an NPV of 15.1%, but the values were higher for CLBBB and LAFB. Conclusions: IVCDs were present in one-fifth of children admitted to the cardiology unit. IRBBB was the most frequent disturbance, while CRBBB, CLBBB and fascicular blocks were much rarer, though they had a higher predictive value for cardiac abnormalities.