Search

Background Anderson-Fabry disease (AFD) is a rare genetic lysosomal storage disorder which often goes unnoticed until symptom onset requires aggressive treatment. Prompt diagnosis remains crucial. Dedicated multidisciplinary centres are a remarkable opportunity to develop early detection strategies and appropriate management. Purpose To describe the long-term outcomes of patients diagnosed with AFD followed at a Cardiomyopathy Referral Centre according to baseline phenotype (clinical involvement vs sub-clinical involvement). Methods All consecutive patients with AFD visited at our Cardiomyopathy Unit from 1989 to 2020 with >1-year follow-up were retrospectively reviewed. Clinical involvement was defined by one among left ventricular hypertrophy (LVH)>15mm, presence of conduction blocks or cardiac implantable electronic devices (CIED), atrial fibrillation, kidney disease (CKD), stroke or transient ischemic attack (TIA). The primary outcome was disease progression, defined as de novo CIED implantation, increased or de novo LVH, de novo Stroke/TIA, or progression of CKD. Of 110 patients diagnosed with AFD, 86 (78%) with >1-year follow-up were selected. Results Clinical involvement was present in 60 (70%) patients. Age at diagnosis was similar between patients with clinical and subclinical phenotype (42+17 vs 39+15, p=0.277). Patients with clinical involvement were more frequently men (N=25 [42%] vs 4 [15%], p=0.025) and probands (p=0.01). Overall, 1-organ involvement was present in 31 (52%) patients, 2-organ involvement in 24 (40%) patients and 3-organ in 5 (8%). A total of 46 (77%) patients were referred to enzyme replacement therapy (ERT): 52% received agalsidase α, 26% agalsidase β, and 22% migalastat. Among those with a clinical involvement not on ERT, 9 (15%) were scheduled for ERT initiation, 3 (5%) were considered old for ERT, 1 (1.5%) refused ERT and 1 (1.5%) had an allergic reaction to ERT. At 7 [3–12] years follow up, both study cohorts manifested signs and symptoms of disease progression: N=28 (47%) vs N=4 (15%), p=0.01, in patients with vs. without baseline clinical involvement, respectively. The main causes for diseases progression were increase (28%) or de novo LVH (13%), CKD (7%) and CIED implantation (5%). At Cox multivariable analysis, however, after adjustment for age at diagnosis, late onset phenotype and gender, the impact of clinical vs subliclinical involvement on disease progression was lost (Hazard Ratio 0.92, 95% C.I. 0.30–2.81). Conclusion Clinical involvement in AFD is frequent, irrespective of age at diagnosis, being present in more than 1-in-2 patients at baseline. Prompt referral to dedicated centres is warranted for appropriate care as the disease may progress in both patients with and without initial overt clinical phenotype despite optimal medical management. Funding Acknowledgement Type of funding sources: None.

Background Only one score for prediction of new-onset atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) has been developed in North America (HCM-AF North America score). Purpose To develop a new score (HCM-AF South Italy score) in an Italian derivation cohort and to test the new score with that from North America, in an Italian validation cohort. Methods A cohort of 228 patients with HCM and without history of AF, followed at referral center 1 for HCM, was used for model development. A cohort of 226 patients without history of AF, followed at referral center 2, was used for external validation. During follow-up (IQR 3–13 years, median 8 years), 59 (26%) patients developed new-onset AF. Data in the development cohort generated the HCM-AF South Italy score, a point score to predict AF probability: left atrial dimension >49 mm (+5 points), age at clinical evaluation 25 mmHg (+2 points), NYHA class >1 (+1 point). Results Patients from the validation cohort were older, had lower prevalence of HCM family history, lower systolic and diastolic blood pressure, taken fewer drugs like beta-blockers, ACE or ARB, calcium-channel blockers, and antiarrhythmic drugs and had lower LVOTO than patients from the derivation cohort, (overall p4 identified patients at risk of AF with a sensitivity of 48%, specificity of 76%, PPV of 20% and NPV of 92%. Conclusion Although derived and tested in little and quite different populations, the performance of the HCM-AF South Italy score was superior to that of the score developed in North America. Funding Acknowledgement Type of funding sources: None.

Background This study aims to evaluate the prevalence and 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]). All patients underwent a comprehensive evaluation. A pre–specified tricuspid annulus plane systolic excursion on pulmonary arterial systolic pressure (TAPSE/PASP) value 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 and right ventricular 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 Conclusions RV–PA uncoupling is common among patients with CA, and it is a marker of advanced disease and worse outcomes. This study suggest that TAPSE/PASP ratio has the potential to improve risk stratification and guide management strategies in patients with CA.

Background Clinicians need to identify patients with amyloid cardiomyopathy (AC) at an early stage, due to the availability of disease–modifying therapies. Some echocardiographic findings may rise the suspicion of AC, also in patients with mild or no symptoms, addressing second level diagnostic tests. Aim To investigate the prevalence of AC in consecutive patients ≥55 years undergoing clinically indicated, routine transthoracic echocardiogram in Italy and presenting echocardiographic signs suggestive of AC. Methods This is a prospective multicentric study conducted in Italy. It comprises two phases: 1) a recording phase consisting in a national survey on prevalence of possible echocardiographic red flags of AC in consecutive unselected patients ≥55 years undergoing routine echocardiogram (previously published) and 2) an AC diagnostic phase involving a diagnostic work–up for AC to investigate AC prevalence among patients with at least one echocardiographic red flag (herein presented). Patients that in Phase 1 presented an “AC suggestive” echocardiogram (i.e., at least one red flag of AC in hypertrophic, non–dilated left ventricles with preserved ejection fraction) underwent clinical evaluation, blood and urine tests and scintigraphy with bone tracer. Diagnosis of transthyretin related–AC (ATTR–AC) was made in presence of grade 2–3 Perugini uptake at scintigraphy and absence of monoclonal protein. The study was registered at ClinicalTrials.gov (#NCT04738266). Results Of the 5315 screened echocardiograms, 381 exams (7.2%) were classified as “AC suggestive” and proceeded to Phase 2. 217 patients completed Phase 2 investigations. Main reasons for the 164 non–entering patients into Phase 2 were death (n = 49) and refusal to participate (n = 66). A final diagnosis of AC was made in 62 patients with an estimated prevalence of 28,6% (95% CI: 22,5%–34,7%). ATTR–AC was diagnosed in 51 and AL–AC in 11 patients, ascertaining a prevalence of 23,5% (95% CI: 17,8%–29,2%) and 5,1% (95% CI: 2,2%–8,0%), respectively. Conclusion Among a cohort of consecutive unselected patients ≥55 years with echocardiographic findings suggestive of AC, the prevalence of AC ranged from 23% up to 35%. Although ATTR–AC was predominant, AL–AC was diagnosed in a significant number of cases. Echocardiography has a fundamental role in screening patients, raising the suspicion of disease and orienting diagnostic work–up for AC.

Funding Acknowledgements Type of funding sources: None. BACKGROUND & PURPOSE. Cardiac amyloidosis (CA) is an infiltrative disorder characterized by left ventricular (LV) thickening with early systolic and diastolic dysfunction. Due to it poor prognosis, and the beneficial impact of novel treatments when started in early stages of disease, its forward detection is crucial. Aim of this study is comparing the diagnostic accuracy of classical and novel echocardiographic parameters in detecting CA among other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. METHODS. We enrolled 50 pts with CA (26 AL and 24 wtATTR) and 75 phenocopies (LVH group) [25 hypertrophic cardiomyopathy (HCM) pts, 25 hypertensive (HypCM) pts, and 25 pts with non-severe aortic stenosis (AS)]. Standard and novel LV morpho-functional echo parameters [LV ejection fraction (LVEF), myocardial contraction fraction (MCF), global longitudinal strain (GLS), relative regional strain ratio (RRSR), ejection fraction on strain ratio (EFSR)], and novel Myocardial Work (MW) parameters [Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE)] were analyzed. RESULTS. LV standard, novel and MW-derived systolic parameters were more impaired in CA compared to LVH group. At ROC curve analysis, GCW showed the best performance in discriminating CA from other forms of LVH (AUC 0.886; 95% CI: 0.819-0.954; P CONCLUSIONS. Despite CA and LVH patients shows a similar phenotype, the systolic function differs greatly. In the present study, the GCW showed the best ability in detecting CA among other forms of LVH. Its reduction in CA seems reflect the infiltrative burden and its consequences on myocardial deformation properties, while its reduction in LVH group has been attributed elsewhere to fibrotic derangement. GCW showed to be a promising novel diagnostic and prognostic factor in this setting. Abstract Figure 1 Abstract Table 1

Funding Acknowledgements Type of funding sources: None. BACKGROUND & PURPOSE. Left atrial function (LAF) is a determinant of clinical status and outcome in many cardiac disorders, including cardiac amyloidosis (CA). Aim of this study is to explores the LAF in CA and other cardiomyopathies with hypertrophic phenotype, and its consequences on cardiovascular haemodynamics, right ventricular function and survival. METHODS. We enrolled 50 patients with CA (26 AL and 24 wtATTR) and 75 with hypertrophic phenotype (LVH group) [25 hypertrophic cardiomyopathy (HCM) pts, 25 hypertensive pts (HypCM), and 25 pts with aortic stenosis (AS)]. LAF was analysed using the phasic method [LAEI as reservoir, LAPEF as conduit, LAAEF as active pump and TLAEF as total emptying function; see figure 1] by LA volumes determination. RESULTS. ATTR patients showed higher LA dimensions and impaired reservoir and total LA emptying function (TLAEF) compared to AL without differences LAF. Compared to the LVH group, CA patients showed higher LA dimension with impaired LAF in all phasic parameters, higher LV filling pressures and reduced biventricular function. We further divided CA and LVH patients into four subgroups based on the presence or absence of LA dysfunction (LADys+ for TLAEF values below the median: CONCLUSIONS. LAF is significantly more impaired in CA than LVH group and is associated with worst clinical status, RV dysfunction and higher LV filling and pulmonary pressure. Moreover, LADys is a frequent feature of CA and significantly associated with higher CV mortality. We suggests that LADys in LVH group could results from chronic pressure overload due to LA"s exposure to high LV diastolic pressure (impaired LV compliance). In CA, LADys could also be determined by direct LA infiltration. The pathophysiological result is a progressive LA remodelling with increased LA pressure, consequent backward transmission to the pulmonary venous system and, ultimately, RV dysfunction. TLAEF is parameter of LAF that correlates with increased pulmonary vascular resistance (measured elsewhere with cardiac catheterisation) and RV dysfunction. In CA, it seems promising as marker of the haemodynamic consequences of LADys and CV mortality. Abstract Figure 1 Abstract Figure 2

Funding Acknowledgements Type of funding sources: None. BACKGROUND & PURPOSE. Right ventricular (RV) dysfunction in cardiomyopathies is a consequence of chronic overload (i.e. aortic stenosis, AS) or direct involvement of systemic disorders (i.e. cardiac amyloidosis, CA). The Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure (TAPSE/sPAP) ratio has been recently proposed as a surrogate of RV-arterial coupling (RVAC). This study aims to compare RVAC between CA subgroups and between CA and other forms of genetic and non-genetic cardiomyopathies with hypertrophic phenotype. METHODS. We enrolled 50 patients with CA (26 AL and 24 wtATTR) and 75 cardiomyopathies with hypertrophy phenotype (LVH group) [25 pts with hypertrophic cardiomyopathy (HCM), 25 hypertensive pts(HypCM), and 25 pts with AS]. Besides routine echocardiographic measurements, we analysed right chambers dimensions and classical and novel parameters of RV function [TAPSE, TAPSE/sPAP, St wave, global (RVGLS) and free-wall (RVFWS) strain]. RESULTS. Compared to AL, the ATTR group showed higher right chambers dimensions, without differences in all RV systolic parameters. Compared to the LVH group, CA patients showed no differences in RV dimensions while RV systolic parameters, including the TAPSE/sPAP ratio, were significantly reduced in the presence of significantly higher LV filling pressures. At ROC curve analysis, TAPSE (AUC 0.877; 95% CI: 0.811-0.943; p CONCLUSIONS. The RVAC is significantly impaired in CA compared to the LVH group but not between CA subgroups. Its reduction seems attributable to both increase LV filling pressure, due to the restrictive nature of the infiltrative cardiomyopathy, and reduced RV systolic function, due to either indirect RV chronic overload and direct myocardial infiltration. The TAPSE/sPAP ratio is a surrogate of RVAC and proved to be a novel echocardiographic parameter useful in both discriminating CA among genetic and non-genetic forms of LVH, and stratifying the prognosis. Abstract Table 1 Abstract Figure 1

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies. © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology

Background: Mitochondrial diseases (MDs) (1:5000-10000) represents a wide group of human disorders associated with mitochondrial DNA (mtDNA) variations causing defect of oxidative phosphorylation system, whereas nuclear genome mutations are somewhat rare. The extremely heterogeneous clinical phenotype, extending from oligosymptomatic condition to complex syndromes involving neurological, ophtalmological, gastroenterological and endocrine features, depends to the involved tissue well as to the specific mtDNA mutations and their heteroplasmic level. Diabetes and deafness are common features of mitochondrial diseases, while renal alterations are rarely reported, especially in adults, probably because of lack of association to mitochondrial conventional phenotypes. Case Presentation: We investigated a 62 years old male affected by hypertrophic cardiomyopathy (HCM) and renal failure that caused already a bilateral transplantation. Pathological anamnesis revealed also diabetes, deafness and Crohn disease. Family history of cardiomyopathy showed a strong mitochondrial involvement. The proband's mother, three brothers (one of which died of renal failure at 26 years), the sister and her child were affected. Materials and Methods: Genomic DNA from peripheral blood and buccal cells was extracted with the Kit-Nucleon-BACC2 (Illustra DNA-Extraction Kit-BACC2-GE Healthcare, UK) and the whole mitochondrial genome was amplified by two pair of primers designed in our laboratory to generate two overlapping fragments. The PCR products were then sequenced and compared to mitochondrial reference sequence (rCRS NC_012920). Results and Discussion: In both biological samples the mtDNA analysis showed the heteroplasmic A3243G mutation in the tRNALeu (UUR), frequently associated with MDs. A cardiological involvement leading to hypertrophic remodelling, caused to mitochondria intermyofibrillar proliferation, occurs up to 40% of patients with mtDNA disease. Molecular backgrounds of mitochondrial cardiomyopathy of adult age are still quite poorly known and the A3243G mutation in tRNA Leu(UUR) of mtDNA has been reported in 40-60% of patients with HCM. The interesting finding presented here support the knowledge that mitochondrial gene altertation represents a possible etiology in cardiological patients with unexplained renal failure. This is particularly true, as in this case, when other associated symtoms linked with dysfunctional oxidative phosphorylation are present. The case presented in this report further suggests that a differential diagnosis in presence of HCM should be solved by a multidisciplinary approach together with mutation analysis of mitochondrial DNA.

Sudden cardiac death (SCD) of athletes is a topical issue. “Borderline cardiac abnormalities”, which occur in ~2% of elite male athletes, may result in SCD, which may have a genetic base. Genetic analysis may help identify pathological cardiac abnormalities. We performed phenotype-guided genetic analysis in athletes who, pre-participation, showed ECG and/or echo “borderline” abnormalities, to discriminate subjects at a greater risk of SCD. Methods: We studied 24 elite athletes referred by the National Federation of Olympic sports; and 25 subjects seeking eligibility to practice agonistic sport referred by the Osservatorio Epidemiologico della Medicina dello Sport della Regione Campania. Inclusion criteria: a) ECG repolarization borderline abnormalities; b) benign ventricular arrhythmias; c) left ventricular wall thickness in the grey zone of physiology versus pathology (max wall thickness 12-15 mm in females; 13-16 mm in males). Based on the suspected phenotype, we screened subjects for the LMNA gene, for 8 sarcomeric genes, 5 desmosomal genes, and cardiac calcium, sodium and potassium channel disease genes. Results: Genetic analysis was completed in 37/49 athletes, 22 competitive and 27 non-competitive athletes, showing “borderline” clinical markers suggestive of hypertrophic cardiomyopathy (HCM,n. 24), dilated cardiomyopathy (n. 4), arrhythmogenic right ventricular dysplasia/cathecholaminergic polymorphic ventricular tachycardia (ARVD/CPVT, n. 11), long QT syndrome (LQTS, n. 4), sick sinus syndrome (SSS, n. 5), Brugada syndrome (BrS, n. 1). We identifyed 11 mutations in 9 athletes (an ARVD athlete was compound heterozygote for the PKP2 gene and an HCM athlete was double heterozygote for the MYBPC3 and TNNT2 genes): 3 known mutations related to LQTS, HCM and ARVD, respectively, and 8 novel mutations, located in the SCN5A, RyR2, PKP2, MYBPC3 and ACTC1 genes. The new mutations were absent in ~800 normal chromosomes and were predicted “probably damaging” by in silico analysis. Patch clamp analysis in channelopathies indicated for some mutation abnormal biophysical behavior of the corresponding mutant protein. Conclusion: Genetic analysis may help distinguish between physiology and pathology in athletes with clinically suspected heart disease.

Background: Sudden cardiac death (SCD) of athletes is a topical issue. Borderline cardiac abnormalities may result in SCD, which in turn may be genetically based; thus, genetic analysis may help to identify potentially pathological cardiac abnormalities. Aim: We performed phenotype-guided genetic analysis in athletes who, pre-participation, showed ECG and/or Echo borderline abnormalities, to discriminate subjects at a greater risk of SCD. Subjects and Methods: We studied 24 elite athletes referred by the National Federation of Olympic Sports; and 25 subjects seeking eligibility to practice agonistic sport referred by the Osservatorio Epidemiologico della Medicina dello Sport, Regione Campania. Inclusion criteria were: a) borderline ECG repolarization abnormalities; b) benign ventricular arrhythmias; c) LVWT in the grey zone of physiology versus pathology (MWT 12-15 mm in females; 13-16 mm in males). Based on the suspected phenotype, we screened subjects for LMNA gene, 8 sarcomeric genes, 5 desmosomal genes, and cardiac calcium, sodium and potassium channel disease genes. Results: Genetic analysis was completed in 37 out of 49 athletes, 22 competitive and 27 non-competitive athletes, showing borderline clinical markers suggestive of hypertrophic cardiomyopathy (HCM n 24), dilated cardiomyopathy (n 4), arrhythmogenic right ventricular dysplasia/catecholaminergic polymorphic ventricular tachycardia (ARVD/CPVT n 11), long QT syndrome (LQTS n 4), sick sinus syndrome (SSS n 5), or Brugada syndrome (BrS n 1). We identified 11 mutations in 9 athletes (an ARVD athlete was a compound heterozygote for the PKP2 gene and an HCM athlete was a double heterozygote for the MYBPC3 and TNNT2 genes): 3 known mutations related to LQTS, HCM and ARVD, respectively, and 8 novel mutations, located in the SCN5A, RyR2, PKP2, MYBPC3 and ACTC1 genes. The new mutations were absent from ~800 normal chromosomes and were predicted probably damaging by in silico analysis. Patch clamp analysis in channelopathies indicated that some mutations were associated with abnormal biophysical behavior of the corresponding mutant protein. Conclusion: Genetic analysis may help distinguish between physiology and pathology in athletes with suspected familial or sporadic heart disease.

Dilated cardiomyopathy (DCM) is characterized by ventricular dilatation and impaired systolic function, which may proceed into congestive heart failure. Although DCM is a final common pathway of various acquired diseases, up to 50% of cases are reported to be idiopathic (i.e., without any obvious aetiological trigger) and approximately 20% of DCM cases display familial prevalence. More than 20 genes are associated with DCM in humans, although DCM genetic tests present low diagnostic sensibility (< 20%). DCM associated genes encode structural proteins of cardiomyocytes and ion channels. These last include SCN5A, which encodes the alpha subunit of the major Na+ channel in the heart, Nav1.5. Dilated cardiomyopathy with SCN5A mutations has been generally associated with reduced expression of the cardiac sodium channel Nav1.5. We hypothesized that the p.H558R polymorphism could be a genetic risk factor in dilated cardiomyopathy, as the R minor allele of this polymorphism has been shown to alter SCN5A function, by reducing depolarizing sodium current and modulating the biological effects of concomitant SCN5A mutations. We recruited 134 DCM patients (50 with familial DCM -FDCM-, 58 with idiopatic DCM and 26 patients affected by post-ischemic DCM) and 168 age, ethnicity, and gender matched controls. The mean age at diagnosis was 45+12 y., with a mean follow-up of 8.2+5.5 y. SCN5A was subject to comprehensive mutation scanning in all cases and to targeted genotyping of a common loss-of-function p.H558R polymorphism in controls. The Hardy-Weinberg law was applied to analyze distribution of SCN5A p.H558R genotypes. Association between the three genotypes and categorical variables were tested using the χ2 test or Fisher’s exact test. Mutation scanning of all SCN5A translated exons in 134 DCM patients reveals one novel mutation (c.A1383T, p.M463L) in a patient with idiopatic DCM. This mutation was absent in 350 unrelated chromosomes from matched healthy control and it produced a change in a highly conserved residue among species and isoforms. The major finding of this study was a significant difference in frequencies of the three p.H558R genotypes in familial DCM compared to normal controls: HH 40 vs 49%, HR 36 vs 44%, RR 24 vs 7%; p = 0.004). 60% of familial DCM subjects had at least one R allele compared with 51% of controls. The minor R allele frequency was 42% in familial DCM compared with 29% in the normal controls. Notably, compared with the HH and HR genotype, the RR genotype confers an OR for developing DCM in familial cases of 4.1 (95% CI 1.7-9.9; p = 0.001). Six FDCM patients carrying RR genotype (50%) experienced serious arrhythmic events; unlike in the remaining FDCM the percentage of patients who developed arrhythmic events was 29%. In conclusion, our data demonstrate that: (1) mutations in coding regions of SCN5A are not a common cause for DCM; (2) the SCN5A p.558RR genotype is associated with dilated cardiomyopathy in patients with familial DCM. This result may help to early identify candidates to develop DCM among asymptomatic relatives of FDCM patients in families without an identified mutation.

Hypertrophic cardiomyopathy (HCM) is the most frequent genetic cardiovascular disease worldwide and is an important cause of heart failure-related disability in young people. To date, more than 20 different genes have been identified and the number is increasing. We evaluted a novel approach to identify causative mutations in a large number of HCM-related and candidate genes. Four HCM patients previously analysed by DHPLC/Sanger sequencing for causative mutations in 8 sarcomeric genes were enrolled in this study. Overall, 234 genes were selected for array on the chip, and a custom sequence capture array was designed for target enrichment of all coding regions. The size of our target was 3,908,196 bp. Each DNA sample was enriched using one custom array, and then sequenced in two runs by the GS FLX System. We obtained an average of 164 Mb/sample, which is equivalent to 503,775 sequencing reads/sample with an average read length of 325.6 bp. Sequence and data analysis were performed using the Roche/454 gsMapper software. High confidence variants were blasted against the SNP database to distinguish between known and unknown variants. We found 7864 different variants, of which 6725 were intronic, 424 intergenic and 715 exonic. About 31% of these variants were novel and 56 novel variants were in 35 HCM related genes. In all patients, we confirmed the mutations and polymorphisms previously identified in them with the DHPLC/Sanger approach. The simultaneous analysis of a vocabulary of genes so to increase sensitivity for the molecular diagnosis may in turn increase the information for those patients in whom traditional screening was not adequate. With this new technology it may be possible to identify mutations in genes that, also acting as phenotype modifiers, could be responsible for clinical variability thereby explaining the pathogenetic mechanism underlying HCM development. Consequently, by reducing time and costs and increasing the sensitivity of molecular testing, routine HCM molecular diagnostics could be implemented also to obtain a model readily applicable to other genetic diseases.

According to the World Health Organization, obesity is one of the most common nutritional problem among children. The major determinant of this enormous increase in obesity prevalence is modern lifestyle and the consumption of very caloric foods such as fast-food products. Actually, there is a strong relationship between obesity and hypertension, type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea, and orthopedic problems. The aim of this review is to discuss the main mechanisms that link obesity to cardiovascular disease.

Takotsubo cardiomyopathy (TTC) is a distinct clinical entity characterized by the presence of transient left ventricular wall dysfunction without significant culprit obstructive coronary artery disease. Invasive coronary angiography and ventriculography are the 'gold standard' for definitive diagnosis, with an integrated multi-modality imaging approach offering advantages in various clinical scenarios. Echocardiography is a widely available, first-line, non-invasive imaging technique appropriate both in emergency setting to confirm diagnosis, assess for various potential acute complications, and in serial follow-up to track myocardial recovery. Cardiac magnetic resonance (CMR) may be helpful to discriminate TTC from other acute cardiac syndromes with troponin elevation and ventricular dysfunction. Echocardiography, CMR, and nuclear imaging may also provide new insights into possible underlying pathophysiological mechanisms, and myocardial (123)I-metaiodobenzyl-guanidine imaging may have a role for retrospective diagnosis in the subacute phase of late-presenting cases. The potential diagnostic role of coronary computed tomography angiography in the emergency room requires a further study.