[ANMCO Position paper: Amyloidosis for the clinical cardiologist. A "clinical primer" from the ANMCO Rare Disease Working Group]. / Position paper ANMCO: L'amiloidosi per il cardiologo clinico. Un "clinical primer" dell'Area Malattie Rare ANMCO.

Cardiac amyloidosis, in the three forms of immunoglobulin light chain (AL), transthyretin (ATTR) wild type (ATTRwt) and mutated (ATTRv) amyloidosis, is an increasingly known and recognized disease in the cardiovascular setting. The first stage of the patient's journey is the clinical suspicion of the disease, which is placed, in presence of a hypertrophic phenotype, by the identification of red flags, both extracardiac and cardiac clues whose presence increase the probability of being faced with a patient with this disease. The second stage is represented by diagnosis, which occurs with certainty through the identification of amyloid substance in cardiac tissue. This stage is spotted in wo parts, i.e. disease confirmation and disease etiology definition (AL vs ATTRwt vs ATTRv). However, it is possible in some selected cases to make a diagnosis of ATTR without the need for tissue assessment, in presence of a positive grade 2-3 bisphosphonate scintigraphy and absence of monoclonal component. Once the diagnosis has been made, the third stage is the assessment of prognosis, the fourth is the patient therapy pathway and fifth is the follow-up plan. Prognosis evaluation is based on different staging systems at the onset of the disease, whose applicability in the era of new effective therapies is still to be defined. To date, the transthyretin tetramer stabilizer tafamidis is the only approved treatment for both wild-type and mutant ATTR cardiomyopathy without polyneuropathy, while ATTRv with associated neuropathy can benefit from treatment with patisiran, an inhibitor of hepatic protein synthesis. Therapies for complications and comorbidities, must be addressed individually, due to the lack of specific clinical trials on this category of patients. In fact, it is important to take into consideration the risks linked to the use of some drugs due to the infiltration of the conduction tissue by the amyloid substance, which increases the risk of bradycardia and heart blocks, the tendency towards hypotension and the increased thromboembolic risk. It is also essential to follow the course of the disease and the efficacy of the treatment in affected patients with a standardized follow-up, and to identify early the signs/symptoms of the disease in asymptomatic TTR mutation carriers.This ANMCO position paper on amyloidosis aims to provide the clinical cardiologist with a practical summary of the disease, to accompany the patient with amyloidosis in the various stages of his journey.

Filamin C missense variant associated with severe right atrial disease and skeletal myopathy.

INTRODUCTION: Filamin C (FLNC) gene variants associated with atrial cardiomyopathies have not been reported so far. The aim of this study was to assess the genetics of two siblings presenting with recurrent right atrial arrhythmias, severe right atrial dilatation, and skeletal myopathy. METHODS: A family with subjects affected by recurrent atrial arrhythmias and skeletal myopathy was extensively evaluated by the means of electrocardiographic recordings, magnetic resonance, intracardiac high-density mapping, and genetic testing. RESULTS: Two siblings with right atrial arrhythmias and severe right atrial disease were found to be heterozygous carriers of the variant FLNC-c.925G>A p.(Glu309Lys), previously reported as a variant of uncertain significance. Despite the presence of a severe dilatation of the right atrium in both patients, one presented with skeletal muscle myopathy and an atrial arrhythmia refractory to pharmacological and invasive treatment, while the other one did not have any myopathy, and rhythm control was easily achieved by drugs. CONCLUSION: Filamin C missense variant c.925G>A p.(Glu309Lys) is associated with the severe right atrial disease. Considering cosegregation with the disease (PP1 supporting), this variant should be classified as likely pathogenic.

[Sex and gender medicine: the foundation of gender medicine]. / "Sex and gender medicine": il principio della medicina di genere.

"Sex and gender medicine" is the original name of gender medicine. It is important to define medical concepts without ignoring key terminology. The purpose of "sex and gender medicine" is to focus on both sex and gender differences, to analyze how these two sides of the human being overlap and, finally, to improve their medical understanding. On the one hand sex, besides defining male and female, refers to the biological differences among humans, animals, tissues and cells. On the other, the concept of gender is applicable only to humans, and includes identity, roles and relations in the society. However, despite its 20 years of history, gender medicine is still little known. Biological differences among cardiovascular diseases are ignored. Symptoms and their expressions, which may be different in women, are often described as "atypical" because of the masculine vision of the heart attack and pain. Similarly, anxious syndrome is often conceived as the first reason to explain chest discomfort in women. In reality, prejudices and vagueness around women still dominate prevention and medical treatment. Our objective is to distinguish the concepts of sex and gender in order to understand the best way to face differences and medical knowledge in both.

Aortopathy in Marfan syndrome: an update.

Marfan syndrome (MFS) is an inherited autosomal dominant multisystem disease caused by mutations in the FBN1 gene encoding fibrillin-1, an extracellular matrix glycoprotein widely distributed in mesenchymal-derived tissues that provide a scaffold for elastin deposition. MFS is characterized by variable clinical manifestations, including skeletal, ocular, and cardiovascular abnormalities; ascending aortic aneurysm with ensuing dissection and rupture is the main life-threatening cardiovascular manifestation of MFS. Histological aspects of MFS aortopathy include a medial degeneration from disarray and fragmentation of elastic fibers and accumulation of basophilic ground substance areas depleted of smooth muscle cells (SMCs). Transmission electron microscopy well evidences the high number of interruptions and the thick appearance of the elastic lamellae and the accumulation of abundant extracellular glycosaminoglycan-rich material, sometimes SMCs showing a prevalent synthetic phenotype. The aberrant signaling of transforming growth factor-ß (TGF-ß) as the consequence of the altered structure of fibrillin-1 induces activation and the overexpression of Smad-dependent profibrotic signaling pathway and ERK1/2-mediated increased synthesis of matrix metalloproteinases. In addition, MFS is accompanied by an impaired aortic contractile function and aortic endothelial-dependent relaxation, which is caused by an enhancement of the oxidative stress and increased reactive oxygen species during the progression of the disease. Many studies are currently evaluating the contribution of TGF-ß-mediated biomolecular pathways to the progression of MFS aortopathy and aneurysm development, in order to discover new targets for pharmacological strategies aimed to counteract aortic dilation.

[ The new 2010 Ghent criteria for the indication to surgical treatment of patients affected by Marfan syndrome. Experience of a single cardiac surgery center]. / I nuovi criteri di Ghent del 2010 nell'indicazione all'intervento cardiochirurgico nei pazienti affetti da sindrome di Marfan. L'esperienza di un singolo Centro di Cardiochirurgia.

BACKGROUND: The diagnosis and surgical treatment of patients with Marfan syndrome remain controversial. It is of utmost importance to identify patients at risk for acute aortic events to establish the correct surgical timing and the appropriate surgical treatment. METHODS: From May 2008 to December 2012, 500 patients were screened at the Marfan Presidium of the Tor Vergata University Hospital of Rome (Italy). Patients were evaluated by a cardiac surgeon, including echocardiographic, orthopedic, ophthalmologic and dental examinations. All patients received genetic counseling, and genetic sampling was performed if appropriate. RESULTS: The diagnosis of Marfan syndrome was confirmed in 146 patients (29.2%). Fifty-four patients (37%) underwent cardiac surgery on the aortic root, 4 patients had surgery on the mitral valve, 13 patients had combined surgery; 11 cases were emergent surgery for acute aortic dissection. Twenty-eight patients (52%) were operated on at our Division: 13 underwent valve-sparing aortic root replacement (David procedure), 1 underwent Yacoub remodeling procedure and 14 underwent Bentall procedure. Following the establishment of the Marfan Center, the David aortic valve-sparing operation was the most frequently performed procedure compared to the previous period of surgical activity (63 vs 22%, p<0.0001). CONCLUSIONS: Regular follow-up twice a year may allow to identify patients at risk for acute aortic syndromes. Early surgical treatment is recommended in these patients to achieve optimal results of valve-sparing procedures and life-saving management, especially for patients who live far away from a cardiac surgery center.

Association between Oro-Facial Defects and Systemic Alterations in Children Affected by Marfan Syndrome.

BACKGROUND: It is important to establish an early diagnosis of the Marfan Syndrome (MFS) for providing an adequate pharmacological or surgical therapy. Nevertheless, this diagnosis may be complex, given the multi-organic involvement of this disease. AIMS: In this work, we evaluated the oral phenotype in a group of paediatric patients with a clinical diagnosis of MFS, to quantify the association of the oro-facial defects with other systemic alterations. SETTINGS AND DESIGN: Paediatric subjects who were aged, with a clinical diagnosis of MFS, were selected from our regional Marfan monitoring unit. METHODS AND MATERIAL: All the patients were subjected to Paediatric Dentistry examinations and a radiological screening with Panoramic and Cephalometric X-Rays. The aortic dilation (Aortic Z-score value), the hyperlaxity of the ligaments and scoliosis were evaluated by cardio-surgical and orthopaedics specialists. STATISTICAL ANALYSIS: The correlations between the oral and systemic alterations were analyzed by using the chi square test for the nominal variables. RESULTS AND CONCLUSIONS: We found a significant correlation of the Aortic Z - score with multiple oral defects which included retrognathia, malar hypoplasia, cross bite, oral respiration and an ogival palate. An association of the oral defects with hyperlaxity of the ligaments and scoliosis was also found. Thus, the data suggested that dentists should be more involved in a multidisciplinary approach, to provide an early MFS diagnosis in paediatric patients.

Surgical treatment of aortic valve regurgitation secondary to ascending aorta aneurysm: is adjunctive subcommissural annuloplasty necessary?

BACKGROUND: Subcommissural aortic annuloplasty (SCA) has been recommended for treatment of functional aortic regurgitation (AR), but its association with sinotubular junction adjustment is still controversial. METHODS: Sixty patients with moderate or severe functional AR secondary to proximal ascending aorta aneurysm operated on between May 2004 and December 2010 were reviewed. Forty patients underwent SCA and ascending aorta repair (SCA group; mean age, 65 ± 9 years) and 20 underwent ascending aorta repair alone (non-SCA group; mean age, 69 ± 8 years). Preoperative AR grades were comparable between groups (p = 0.9). Echocardiographic data at discharge and during follow-up (SCA group, 41 ± 13 months; non-SCA group, 46 ± 13 months) were analyzed. RESULTS: Improvement of mean AR grade was better in the SCA group than in the non-SCA group at discharge (0.78 ± 0.9 vs 1.8 ± 0.1/4+, p = 0.0001) and at follow-up (0.44 ± 0.8 vs 2.4 ± 0.7/4+, p = 0.0001). Cox-regression analysis (odds ratio [95% confidence interval]) identified a higher residual AR at discharge (0.14 [0.012-0.37], p = 0.02) and the surgical technique, SCA or not (0.5 [0.03-0.899], p = 0.04), as predictors of more than grade 2/4+ AR at follow-up. Five-year freedom from more than grade 2/4+ AR was 94.4% ± 5.4% vs 58% ± 16% in SCA vs non-SCA (p = 0.02), respectively, and the survival rate was 95% ± 5% vs 89% ± 7.5% (p = 0.7). No valve stenosis was observed in the SCA group. CONCLUSIONS: SCA is effective for treatment of functional AR, providing stable results even for significant AR. Our results suggest that it should be possibly associated to sinotubular junction adjustment. SCA seems to not impair normal aortic valve opening.

Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure.

The clinical history of patients with heart failure (HF) is complicated by arterial thromboembolism. Platelet activation is reported in this population, but the underlying mechanism has not been clarified. Forty-two patients with HF scored according to New York Heart Association (NYHA) classification had higher levels of collagen-induced platelet aggregation, platelet tumor necrosis factor-alpha (TNF-alpha) receptor expression, and serum thromboxane B2 and higher circulating levels of TNF-alpha than 20 healthy subjects. Coincubation of platelets from HF patients with an inhibitor of TNF-alpha receptors significantly reduced collagen-induced platelet aggregation. In vitro study demonstrated that TNF-alpha amplified the platelet response to collagen; this effect was inhibited by TNF-alpha receptor antagonist and inhibitors of arachidonic acid metabolism. This study showed that TNF-alpha behaves as a trigger of platelet activation through stimulation of the arachidonic acid pathway.