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Increase of left atrial (LA) diameter in trained athletes has been regarded as another component of the “athlete's heart”. To evaluate the possible impact of competitive training on LA volume and to define reference values of LA volume index in athletes. Six hundred fifteen consecutive elite athletes (370 endurance- [ATE] vs 245 strength-trained athletes [ATS]; 385 men; 28.4 ± 10.2 years, range 18-40 years) underwent a comprehensive transthoracic echocardiography exam. LA maximal volume was measured at the point of mitral valve opening using the biplane area-length method, and corrected for body surface area. LA mild dilatation was defined as a LA volume index between 29 and 33 mL/m 2, while a moderate dilatation was identified by a LA volume index ≥34 mL/m 2. Left ventricular (LV) mass index and ejection fraction did not significantly differ between the 2 groups. Conversely, ATS showed increased body surface area, sum of wall thickness (septum + LV posterior wall), LV circumferential end-systolic stress (ESSc) and relative wall thickness, whereas LA volume index, LV stroke volume and LV end-diastolic volume were greater in ATE. The range of LA volume index was 26 to 36 mL/m 2 (mean 28.2 ± 9.2) in men and 22 to 33 mL/m 2 (mean 26.5 ± 7.2) in women ( P < .01). LA volume index was mildly enlarged in 150 athletes (24.3%) and moderately enlarged only in 20, all males (3.2%). Mild mitral regurgitation was observed in 64 athletes (10.3%). LA volume index was significantly greater in ATE ( P < .01). By multivariate analysis, the overall population type ( P < .01) and duration ( P < .01) of training and LV end-diastolic volume ( P < .001) were the only independent predictors of LA volume index. In a large population of highly trained athletes, a mild enlargement of LA volume index was relatively common and may be regarded as a physiologic adaptation to exercise conditioning.

Background The closed-loop stimulation (CLS) pacemaker algorithm is a system that permanently monitors the contractile state of the myocardium and converts the intrinsic information into rate regulation. The role that the CLS algorithm plays in the prevention of syncope recurrences still remains unclear. The aim of our prospective, randomised, single-blind, crossover study was to evaluate the effect of dual-chamber CLS in the prevention of syncope recurrence in patients with refractory vasovagal syncope (VVS) and a cardioinhibitory response to head-up tilt test (HUT) during a 36 months follow-up. Method sand results We studied 50 patients (mean age 53±5.1; 33 male) with the indication for permanent dual-chamber cardiac pacing for HUT-induced vasovagal cardioinhibitory syncope. They were randomised after 1 month of stabilisation period to CLS algorithm features programmed OFF or ON for 18 months each, using a crossover design. The number of syncopal and presyncopal episodes during active treatment was lower than those registered during no treatment (n syncopal episodes: 2 vs 15; p=0.007; n presincopal episodes: 5 vs 30; p = 0.004). Lead parameters remained stable over time, and there were no lead-related complications. Conclusions Based on these 36 months follow-up data, it is concluded that dual-chamber CLS is an effective algorithm for preventing syncope recurrences in healthy patients with tilt-induced vasovagal cardioinhibitory syncope.

Background: Anabolic androgenic steroids (AAS) are sometimes used by power athletes to improve performance by increasing muscle mass and strength. Recent bioptical data have shown that in athletes under the pharmacological effects of AAS, a focal increase in myocardial collagen content might occur as a repair mechanism against myocardial damage. Objective: To investigate the potential underlying left ventricular myocardial dysfunction after chronic misuse of AAS in athletes by use of Doppler myocardial imaging (DMI) and strain rate imaging (SRI). Methods: Standard Doppler echocardiography, DMI, SRI and ECG treadmill test were undertaken by 45 bodybuilders, including 20 athletes misusing AAS for at least 5 years (users), by 25 anabolic-free bodybuilders (non-users) and by 25 age-matched healthy sedentary controls, all men. The mean (SD) number of weeks of AAS use per year was 31.3 (6.4) in users, compared with 8.9 (3.8) years in non-users, and the mean weekly dosage of AAS was 525.4 (90.7) mg. Results: The groups were matched for age. Systolic blood pressure was higher in athletes (145 (9) vs 130 (5) mm Hg) than in controls. Left ventricular mass index did not significantly differ between the two groups of athletes. In particular, both users and non-users showed increased wall thickness and relative wall thickness compared with controls, whereas left ventricular ejection fraction, left ventricular end-diastolic diameter and transmitral Doppler indexes were comparable for the three groups. Colour DMI analysis showed significantly lower myocardial early: myocardial atrial diastolic wave ratios in users at the level of the basal interventricular septum (IVS) and left ventricular lateral wall (p<0.01), in comparison with both non-users and controls. In addition, in users, peak systolic left ventricular strain rate and strain were both reduced in the middle IVS (both p<0.001) and in the left ventricular lateral free wall (both p<0.01). By stepwise forward multivariate analyses, the sum of the left ventricular wall thickness (β coefficient = −0.32, p<0.01), the number of weeks of AAS use per year (β = −0.42, p<0.001) and the weekly dosage of AAS (β = −0.48, p<0.001) were the only independent determinants of middle IVS strain rate. In addition, impaired left ventricular strain in users was associated with a reduced performance during physical effort (p<0.001). Conclusions: Several years after chronic misuse of AAS, power athletes show a subclinical impairment of both systolic and diastolic myocardial function, strongly associated with mean dosage and duration of AAS use. The combined use of DMI and SRI may therefore be useful for the early identification of patients with more diffused cardiac involvement, and eventually for investigation of the reversibility of such myocardial effects after discontinuation of the drug.

Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families.

Although often referred to as “the forgotten chamber”, compared with left ventricle (LV), especially in the past years, the left atrium (LA) plays a critical role in the clinical expression and prognosis of patients with heart and cerebrovascular disease, as demonstrated by several studies. Echocardiographers initially focused on early detection of atrial geometrical abnormalities through monodimensional atrial diameter quantification and then bidimensional (2D) areas and volume estimation. Now, together with conventional echocardiographic parameters, new echocardiographic techniques, such as strain Doppler, 2D speckle tracking and three-dimensional (3D) echocardiography, allow assessing early LA dysfunction and they all play a fundamental role to detect early functional remodelling before anatomical alterations occur. LA dysfunction and its important prognostic implications may be detected sooner by LA strain than by volumetric measurements.

Hybridization- and tag-based technologies have been successfully used in Down syndrome to identify genes involved in various aspects of the pathogenesis. However, these technologies suffer from several limits and drawbacks and, to date, information about rare, even though relevant, RNA species such as long and small non-coding RNAs, is completely missing. Indeed, none of published works has still described the whole transcriptional landscape of Down syndrome. Although the recent advances in high-throughput RNA sequencing have revealed the complexity of transcriptomes, most of them rely on polyA enrichment protocols, able to detect only a small fraction of total RNA content. On the opposite end, massive-scale RNA sequencing on rRNA-depleted samples allows the survey of the complete set of coding and non-coding RNA species, now emerging as novel contributors to pathogenic mechanisms. Hence, in this work we analysed for the first time the complete transcriptome of human trisomic endothelial progenitor cells to an unprecedented level of resolution and sensitivity by RNA-sequencing. Our analysis allowed us to detect differential expression of even low expressed genes crucial for the pathogenesis, to disclose novel regions of active transcription outside yet annotated loci, and to investigate a plethora of non-polyadenylated long as well as short non coding RNAs. Novel splice isoforms for a large subset of crucial genes, and novel extended untranslated regions for known genes--possibly novel miRNA targets or regulatory sites for gene transcription--were also identified in this study. Coupling the rRNA depletion of samples, followed by high-throughput RNA-sequencing, to the easy availability of these cells renders this approach very feasible for transcriptome studies, offering the possibility of investigating in-depth blood-related pathological features of Down syndrome, as well as other genetic disorders.

BackgroundRecent data show that there is an unexpectedly high prevalence of ‘inappropriate’ pulmonary responses to exercise among patients with systemic sclerosis (SS). However, no consensus exists as to which threshold of pulmonary artery systolic pressure (PASP) can be considered diagnostically relevant.AimTo evaluate pulmonary vascular reserve and right ventricular function changes induced by exercise in SS patients without overt pulmonary arterial hypertension.Methods and resultsThe study enrolled 172 consecutive SS patients in NYHA class I–II, with a peak tricuspid regurgitant jet velocity at echocardiography not greater than 3 m/s, and 88 control subjects. Echocardiography was performed at rest and at the end of a maximal exercise test. SS patients showed a higher exercise-induced PASP than control subjects (36.9±8.7 vs 25.9±3.3 mm Hg, p=0.00008). The response to effort was higher in the presence of moderate interstitial lung disease (39.7±9.3 vs 36.0±8.4 mm Hg, p=0.016) or subclinical left ventricular diastolic dysfunction (42.3±5.8 vs 37.0±8.6 mm Hg, p=0.015). In control subjects, PASP values were normally distributed at rest and after exercise. In SS patients, the distribution was normal at rest but bimodal after exercise, with a second peak at 52.2 mm Hg including 13% of the total SS population. Patients in this subgroup showed subtle abnormalities of right ventricular function at rest and, most importantly, a blunted increase in right ventricular systolic function with exercise.ConclusionExercise echocardiography may identify a subset of SS patients with an inappropriate exercise-induced increase in PASP and early signs of right ventricular dysfunction.

Enlargement and dysfunction of the right atrium might be an early sign for pulmonary hypertension in systemic sclerosis (SSc). This is the first study to analyse right atrial morphology and function in SSc patients compared to healthy controls by speckle-tracking two-dimensional strain echocardiography (2DSE) at rest and during exercise. Furthermore, right atrial function was correlated with further clinical findings. Adult patients with SSc for >3 years ( n  = 90) and 55 age- and gender-matched healthy controls underwent a panel of non-invasive assessments including transthoracic echocardiography, pulsed Doppler myocardial imaging and 2DSE at rest and during exercise. Furthermore, serological tests and high-resolution chest computed tomography were performed. SSc patients showed significant impairment of right atrial function and the right atrial enlargement, measured by 2DSE at rest and during exercise compared to controls (both p  < 0.001). These findings were more evident in SSc patients with pulmonary fibrosis ( p  < 0.001) and in patients with high pulmonary artery systolic pressures (PAPs) during exercise. In the SSC patients, right atrial lateral strain was significantly associated with PAPs during effort, right atrial area, left ventricle stroke volume and inferior vena cava diameter using multivariable analysis. The findings of this study suggest that a high proportion of SSc patients reveal right atrial dysfunction even without manifest pulmonary hypertension. Impaired right atrial function occurred mostly in patients with pulmonary fibrosis and/or elevated PAPs during exercise, was independently associated with prognostic factors and may therefore be useful for risk stratification. Further studies are needed to analyse if right atrial dysfunction assessed by 2DSE may help to improve early diagnosis of pulmonary hypertension.

Aortic regurgitation (AR) has increased in the pediatric population because of the expanded use of new surgical and hemodynamic procedures. Unfortunately, the exact timing for operation in patients with AR is still debated. Conventional echocardiographic parameters, left ventricular (LV) dimensions and the LV ejection fraction, have limitations in predicting early LV dysfunction. Two-dimensional strain imaging, an emerging ultrasound technology, has the potential to better study those patients. The aim of this study was to assess the prognostic value of 2-dimensional longitudinal strain in young patients with congenital isolated moderate to severe AR. Twenty-six young patients with asymptomatic AR (aged 3 to 16 years) were studied. The mean follow-up duration was 2.9 ± 1.2 years (range 0.5 to 6). Baseline LV function by speckle-tracking and conventional echocardiography in patients with stable disease was compared with that in patients with progressive AR (defined as development of symptoms, increase in LV volume ≥15%, or decrease in the LV ejection fraction ≤10% during follow-up). LV ejection fractions were similar between groups. The jet area/LV outflow tract area ratio was significantly increased in patients with AR with progressive disease (31.2 ± 5.6% vs 39.2 ± 3.8%, p <0.001). The peak transmitral early velocity/early diastolic mitral annular velocity ratio was significantly increased in patients with progressive AR (p = 0.001). LV average longitudinal strain was significantly reduced in patients with progressive AR compared to those with stable AR (−17.8 ± 3.9% vs −22.7 ± 2.7%, p = 0.001). On multivariate analysis, the only significant risk factor for progressive AR was average LV longitudinal strain (p = 0.04, cut-off value >−19.5%, sensitivity 77.8%, specificity 94.1%, area under the curve 0.889). In conclusion, 2-dimensional strain imaging can discriminate young asymptomatic patients with progressive AR. This could allow young patients with AR to have a better definition of surgical timing before the occurrence of irreversible myocardial damage.

Congenital long QT syndrome (LQTS) is associated with high genetic and allelic heterogeneity. In some cases, more than one genetic variant is identified in the same (compound heterozygosity) or different (digenic heterozygosity) genes, and subjects with multiple pathogenic mutations may have a more severe disease. Standard-of-care clinical genetic testing for this and other arrhythmia susceptibility syndromes improves the identification of complex genotypes. Therefore, it is important to distinguish between pathogenic mutations and benign rare variants. We identified four genetic variants (KCNQ1-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S could be LQTS modifiers.