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Background The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown. Purpose To ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV. Methods In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV(+)), 25 with AM and negative gene testing (DGV(−)), and 36 AM patients without genetics (w/o genetics). All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance imaging (CMRI). In 86 patients CMRI changes in function and structure were re-assessed at follow-up. Results In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular (LV) ejection fraction was 56% on CMRI (p=NS vs. the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared to DGV(−) and w/o genetics patients (62.3% vs. 17.5% vs. 5.3% at 5 years respectively; p Conclusions Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with AM patients without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health

Background B-lines detected by lung ultrasound (LUS) during exercise stress echocardiography (ESE), indicating pulmonary congestion, are present in 1 out of 3 patients with hypertrophic cardiomyopathy (HCM). Aim To assess the functional and anatomical correlates of exercise B-lines in HCM. Methods We enrolled 191 HCM patients (age 53±15 years, 123 males) consecutively referred for ESE (treadmill in 74, bicycle in 117 patients) in 11 quality-controlled centers from 8 countries. ESE assessment at rest and peak stress included: left ventricular (LV) outflow tract gradient, left atrial (LAVi) and LV end-diastolic volume index (EDVi), mitral regurgitation (MR, score from 0 to 3); E/e'; systolic pulmonary arterial pressure (SPAP) and LV force (LV outflow tract gradient+systolic blood pressure/LV end-systolic volume). B-lines at rest and at peak exercise were assessed by LUS with the 4-site simplified scan. B-lines positivity was considered if the sum of detected B-lines was ≥2. Results LUS was feasible in all subjects. B-lines were present in 55 (29%) patients during stress. When compared to patients without stress B-lines (n=136), patients with B-lines (n=55) at peak exercise had lower peak EDVi (43±17 vs 52±18 ml/m2, p=0.003) higher peak E/e' (16±6 vs 12±5, p Conclusion HCM patients with pulmonary congestion on exercise show different, and not mutually exclusive mechanisms of diastolic dysfunction and worsening mitral regurgitation. These different hemodynamic mechanisms may require personalized therapeutic actions beyond a pulmonary decongestion therapy with diuretics. Funding Acknowledgement Type of funding sources: None.

Background B-lines detected by lung ultrasound (LUS) indicate pulmonary congestion during exercise stress echo (ESE). Aim To assess B-lines during ESE in hypertrophic cardiomyopathy (HCM). Methods We enrolled 110 HCM patients (age 52±16 years, 74 males) referred for ESE (treadmill in 39, semi-supine bicycle in 71 patients) in 10 quality-controlled centers from 8 countries (Belgium, Brazil, Bulgaria, Hungary, Italy, Portugal, Serbia, Spain). ESE assessment included: left ventricular outflow tract gradient (LVOTG); mitral regurgitation (MR, score from 0 to 3); E/e'; systolic pulmonary arterial pressure (SPAP, from tricuspid regurgitant jet velocity); end-diastolic volume (EDV); left atrial volume (LAV). B-lines were assessed by LUS with the 4-site simplified scan, each site scored from 0 (normal A-lines) to 10 (coalescing B-lines). The positivity criterion was a B-line score stress ≥2 points. Results LUS was feasible in all subjects, with additional scanning and analysis time Conclusion B-lines are found in about 1 of 10 HCM patients at rest and in 1 of 3 during ESE. Acute backward heart failure during exercise can recognize multiple mechanisms in HCM, and ESE can help to capture this heterogeneity. Funding Acknowledgement Type of funding sources: None. Functional correlates of stress B-lines

Objective: The present study aims to identify the long-term effects of atrial fibrillation (AF) on atrial remodelling and on the progression of mitral/tricuspid valve regurgitation (MR/TR). Methods: The severity of MR/TR was assessed by the colour jet area and by multi-integrative approach at baseline and after a period of 65 +/- 10 months in 37 patients with permanent AF, in 80 patients with non-permanent AF (of whom 43 were treated with ablation) and in 53 control patients with sinus rhythm. Results: At baseline, AF patients had larger MR jet areas than control patients. At follow up, progression of MR, expressed as delta MR jet area, was 0.05 +/- 1.3 cm(2) in the control group, 0.73 +/- 2.1 cm(2) in the non-permanent AF group and 1.95 +/- 3.6 cm(2) in the permanent AF group (p = .001). Severe MR at follow up was observed in 0%, 2.5%, 8%, respectively. There was a significant positive correlation between progression of MR and increase of left atrium volume (r = 0.31, p < .001). After adjustment for baseline clinical and echocardiographic parameters, permanent AF remained independently associated with the progression of MR. Although rhythm control was better with AF ablation than with medical treatment only, the MR evolution was similar. Comparable findings, albeit less pronounced, were observed for the association between of AF and TR progression. Conclusions: The presence of longstanding AF is associated with a significant progression of MR/TR mainly due to atrial remodelling. Our data showed a beneficial effect of sustained rhythm control, either medically or by ablation, on MR/TR progression.

Funding Acknowledgements Type of funding sources: None. Background/Introduction: Atrial fibrillation (AF) carries a thrombotic risk related to left atrial blood stasis. Many risk scores, such as the CHA2DS2-VASc score, have been developed to guide physicians in initiating anticoagulant therapy. However, the risk prediction with these models is modest at best (C-statistic = 0.6). The presence of mitral regurgitation (MR) has been shown to reduce thrombotic risk in patients with rheumatic AF. In nonrheumatic AF, direct evidence of a lower thrombotic risk in patients with MR is still controversial. Purpose The current study assessed the effect of MR on thrombotic risk in nonrheumatic AF patients. Methods The prevalence of atrial thrombosis, defined as the presence of left atrial appendage thrombus (LAAT) and/or left atrial spontaneous echo contrast (LASEC) grade >2, was determined in 686 consecutive nonrheumatic AF patients without (adequate) anticoagulation scheduled for transoesophageal echocardiography before electrical cardioversion and was related to the severity of MR adjusted for the CHA2DS2-VASc score. The independent predictors of atrial thrombosis were assessed by stepwise multiple logistic regression analysis. Results A total of 103 (15%) patients had severe MR, 210 (31%) had moderate MR, and 373 (54%) had no-mild MR; the median CHA2DS2-VASc score was 3.0 (IQR 2.0-4.0). Atrial thrombosis (LAAT and/or LASEC grade >2) was observed in 118 patients (17%). The prevalence of atrial thrombosis decreased with increasing MR severity: 19.9% versus 15.2% versus 11.6% for no-mild, moderate, and severe MR, respectively (p for trend = 0.03) (Figure 1). Patients with moderate and severe MR had a lower risk of atrial thrombosis than patients with no-mild MR, with adjusted odds ratios (ORs) of 0.51 (95% CI 0.31-0.84) and 0.24 (95% CI 0.11-0.49), respectively. The other independent predictors of atrial thrombosis were: the CHA2DS2-VASc score with an adjusted OR of 1.25 (95% CI 1.10-1.42), poor left ventricular ejection fraction (LVEF, 37 ml/m²) with an adjusted OR of 1.90 (95% CI 1.19-3.03) (Figure 1, upper right corner). The C-statistic of the regression model increased significantly (p = 0.0003) from 0.62 to 0.75 by adding MR grade, LVEF, and LAVI to the univariate CHA2DS2-VASc score model. The protective effect of MR was present across all levels of the CHA2DS2-VASc score and the presence of moderate-severe MR in patients with an intermediate CHA2DS2-VASc score (2-3) lowered the atrial thrombotic risk to the level of patients with a low CHA2DS2-VASc score (0-1). Conclusion Our data show that the presence of MR attenuated the atrial thrombotic risk by more than 50% in patients with nonrheumatic AF, independent of the CHA2DS2-VASc risk score. Moderate to severe MR can therefore be considered a new risk modifier of the CHA2DS2-VASc score, which might help refine the indication of anticoagulants in AF patients. Abstract Figure 1. Thrombotic risk per MR grade.

AimsPatients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality.Method and resultsWe used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existent heart disease and in-hospital mortality. 16,511 patients with COVID-19 were included (21.1% aged 66 – 75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male and often had other comorbid conditions when compared to those without. Mortality was higher in patients with cardiac disease (29.7%; n=1545 versus 15.9%; n=1797). However, following multivariable adjustment this difference was not significant (adjusted risk ratio (aRR) 1.08 [95% CI 1.02 – 1.15; p-value 0.12 (corrected for multiple testing)]). Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure aRR (1.19 [1.10 – 1.30]; p-value ConclusionConsiderable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. Of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare.

Background Atrial functional mitral regurgitation (A-FMR) is a novel entity characterized by a MR due to atrial remodeling but with preserved left ventricular (LV) systolic function. Purpose To assess the clinical and haemodynamic impact of percutaneous edge-to-edge mitral valve repair with MitraClip in patients with A-FMR as compared to ventricular (V)-FMR. Methods MR grade, functional status (NYHA class), and major adverse cardiac events (MACE= all-cause mortality or hospitalization for heart failure (HF)) were evaluated in 52 A-FMR patients (pts.) and in 307 V-FMR pts. who underwent MitraClip implantation in 7 Belgian centers. In a subgroup of 56 pts (10 A-FMR and 46 V-FMR) haemodynamic assessment during a symptom-limited exercise echocardiography was performed before and 6-month after intervention. Results MitraClip implantation resulted in similar MR reductions in A-FMR and V-FMR (MR grade ≤2 at 6-month in 94% versus 82%, respectively (p=0.08)) and was associated with improvement of functional status in both groups (NYHA class ≤2 at 6 months in 90% versus 80%, respectively (p=0.2)). Serial haemodynamic assessment revealed that the cardiac output at 6-month was significantly higher in A-FMR pts. both at rest (5.1±1.5 L/min versus 3.8±1.5 L/min, p=0.002) and during peak exercise (7.9±2.4 L/min versus 6.1±2.1 L/min, p=0.02). Also the reduction in systolic pulmonary artery pressure (sPAP) was more pronounced in A-FMR: Δ sPAP at rest – 13.1±15.1 mmHg versus – 2.2±13.3 mmHg (p=0.03). During a follow-up period of 1.3±1.2 years MACE rate was significantly lower in A-FMR versus V-FMR with an adjusted OR of 0.46 (95% CI 0.24–0.88, see figure), which was mainly driven by a reduction in HF hospitalization. Conclusion Percutaneous edge-to-edge mitral valve repair with MitraClip is at least as effective in A-FMR as in V-FMR in reducing MR. But, the haemodynamic and clinical impact is stronger in A-FMR pts. Funding Acknowledgement Type of funding sources: None. MACE in A-FMR versus V-FMR pts

Background The health benefits of extensive endurance training have been debated due to the report of myocardial fibrosis (MF), arrhythmias and temporary post-race cardiac impairment in middle-aged and veteran athletes. The extent of these changes is unknown in elite young athletes. Purpose To assess the prevalence of MF and its structural, functional and electrical impact in highly trained young endurance athletes (YA, 15–23 years) as compared to middle-aged athletes (MA, 30–50 years). We hypothesised that MF would be more frequent in MA and associated with more structural, functional and electrical abnormalities. Methods We prospectively assessed 197 YA and 34 MA. All had ECG, maximal oxygen consumption (VO2max) testing, cardiac magnetic resonance imaging (CMR), echocardiography and 24h-holter. Indexed left ventricular and right ventricular end diastolic volume (LVEDVi, RVEDVi), ejection fraction (LVEF, RVEF), left ventricular mass (LVMi), and MF defined as delayed gadolinium enhancement were assessed by CMR. LV and RV free wall strain (LVSL, RVfwSL) were assessed by 2D speckle tracking echocardiography. Ventricular premature beats (VPB) and non-sustained ventricular tachycardia (nsVT) were assessed by 24h-holter. Results YA and MA (18±2 vs 38±5 years [p MF+ MA(A) and YA(B) as well as MF− MA(C) and YA(D) had similar structural remodelling (LVEDVi 110±14 vs 118±14 vs 113±19 vs 110±16 mL/m2; RVEDVi 120±14 vs 128±17 vs 117±19 vs 125±23mL/m2; LVMi 77±11 vs 83±14 vs 81±14 vs 77±15g/m2, p>0.05). LVEF, LVSL and RVSL were similar (59±3 vs 58±5 vs 61±6 vs 58±6%; −18.8±2 vs −18.8±2 vs −19.8±2 vs −19.3±2%; −26.3±2.4 vs −24.4±2.4; −26.3±3 vs −25.8±3.5% respectively, p>0.05). LVEF 100VPB/24h (12.5 vs 5 vs 11.1 vs 5.1%, p=0.42). 2 athletes had nsVT, both in D. All had similar exercise capacity (% predicted VO2max 157±26 vs 152±15 vs 147±24 vs 158±32%; p=0.11). Conclusion Hinge-point fibrosis was more prevalent in MA, possibly due to repeated hemodynamic stress during exercise, but is not associated with structural, functional or electrical consequences. Figure 1. Cardiac remodelling in elite athletes Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fonds voor Wetenschappelijk Onderzoek (FWO)

Background Percutaneous mitral valve repair using MitraClip offers symptomatic benefit and improves rest and exercise hemodynamics in patients with severe functional mitral regurgitation (MR). Recent randomized trials have shown contradictory results regarding the impact of MitraClip on mid-term survival in functional MR. It is unknown whether improved hemodynamics are related to patients" outcome. Purpose To assess whether residual MR and altered resting and exercise hemodynamics are predictors of outcome in patients with functional MR treated with MitraClip. Methods Consecutive patients (n = 45, 72 ± 10years, left ventricular ejection fraction (LVEF) 34 ± 9%) with symptomatic severe functional MR were prospectively evaluated by Doppler echocardiography at rest and during symptom-limited exercise on a semi-supine bicycle pre- and 6 months post-MitraClip procedure. LVEF, MR severity, cardiac output (CO), systolic pulmonary artery pressure (SPAP) and a flow-corrected SPAP/CO ratio were assessed at rest and peak exercise. 2-year follow-up clinical data were collected from patient records. Results During 2-year follow-up post-MitraClip, 15 patients (33%) experienced major cardiac events (hospitalization for heart failure (n = 14) and/or cardiac death (n = 5)). Age, gender, a history of coronary artery disease, diabetes, baseline MR severity and baseline SPAP/CO ratio at rest and during exercise were not related to a worse event-free survival. In contrast, patients with events at 2-year follow up had more often a history of hospitalization for heart failure (73 vs. 37%, p = 0.029), lower baseline LVEF (30 ± 8 vs. 36 ± 10%, p = 0.041), more residual MR at 6 months post-MitraClip (MR jet area/left atrial area 27 ± 14 vs. 15 ± 10%, p = 0.004) and higher SPAP/CO ratios at rest and during exercise 6 months post-MitraClip (13.9 ± 5.3 vs. 9.9 ± 3.4mmHg/L/min, p = 0.007 and 13.6 ± 4.9 vs. 9.4 ± 4.6mmHg/L/min, p = 0.009, respectively). When corrected for baseline LVEF, residual MR 6 months post-MitraClip remained an independent predictor for worse 2-year outcome. Residual MR was moderately correlated to a worse SPAP/CO ratio 6 months post-MitraClip (Pearson Rho 0.518, p Conclusions In patients with functional MR treated with MitraClip, residual MR at 6-month follow-up is associated with impaired hemodynamics, and is an independent predictor of cardiac events at 2-year follow-up.

Background Recent randomised trials have shown conflicting results regarding the usefulness of percutaneous mitral valve repair using MitraClip in patients with severe functional mitral regurgitation (FMR). At present, it remains unclear whether patients with FMR and advanced heart failure might benefit from MitraClip therapy. Moreover, it has been shown that left ventricular reverse remodelling (LVRR) post-MitraClip is associated with a favourable outcome. Purpose We sought to assess whether baseline contractile reserve (CR) can predict LVRR and improvement of LV ejection fraction (EF) in FMR patients undergoing MitraClip therapy. Methods Consecutive patients with symptomatic severe FMR referred for MitraClip were recruited in two tertiary centres. All patients were scheduled for a semi-supine bicycle exercise echocardiography before and 6 months after the intervention. Patients who were not able to perform an exercise test and who did not complete 6 month follow up were excluded from further analysis. Baseline CR was obtained by subtracting peak exercise LVEF from LVEF at rest. LVRR was defined as a 10% decrease in LV end systolic volume (ESV) at follow-up. Results 34 patients completed 6 month follow up (61% male, age 71 ± 10 years, LVEF 32 ± 8%). LVRR was observed in 15 patients (44%). We found a trend towards a moderate correlation between baseline CR and relative decrease in LVESV at 6 months (Pearson Rho -0.321, p = 0.064). This correlation became significant in a sub-analysis considering only patients with post-procedural FMR grade ≤2 (n = 27; Pearson Rho -0.444, p = 0.020). In contrast, LVRR was not related to baseline LVEF, LV dimensions or volumes. Furthermore, baseline CR was strongly correlated with an increase of LVEF at 6 months post-MitraClip in these patients (Pearson Rho 0.653, p Conclusion CR predicts LVRR and improvement of LVEF in patients with FMR after successful MitraClip therapy (reduction of FMR towards grade ≤2), in contrast to resting indices of LV dysfunction and dilatation. More studies with outcome data are needed to determine whether CR is a useful parameter to identify patients with FMR who might benefit from MitraClip therapy.

Background Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular (LV) dysfunction requiring inotropes and/or mechanical circulatory support. Based on a retrospective single-center study published in 2000, patients with FM were considered to have better outcomes than those affected by acute non-fulminant myocarditis (NFM) presenting with LV systolic dysfunction (LVSD). Recently, this tenet was challenged, though substantial disagreement still exists. Purpose Aim of the present study is to provide additional evidence on the outcome of FM and to ascertain if patient stratification based on the main histologic subtypes can provide additional prognostic information. Methods Two hundred and twenty patients (median age 42 years, 46.3% female) with histologically proven acute myocarditis (onset of symptoms Results Patients with FM (N=165) had significantly higher rates of cardiac death and HTx compared with those with NFM (N=55), both at 60 days (28.0% vs. 1.8%, p=0.0001) and at 7-year follow up (47.7% vs. 10.4%, p Outcome of FM vs NFM Conclusions The results of this international registry confirm that patients with FM have higher rates of cardiac death and HTx both in the short and long-term compared with patients with NFM. Furthermore, we provide evidence that the histologic subtype of FM carries independent prognostic value, highlighting the need for timely endomyocardial biopsy in this condition. Acknowledgement/Funding None

Background While severe mitral regurgitation is a well-established risk factor for atrial fibrillation (AF), it is less known whether atrial fibrillation induces mitral/tricuspid valve regurgitation (MR/TR). The present study aims to identify the long-term effects of permanent or non-permanent AF on atrial remodelling and on the progression of MR/TR. Methods The severity of MR/TR was assessed at baseline and after a period of 65±10 months in 37 patients with permanent AF, in 80 patients with non-permanent AF (of whom 43 were treated with ablation) and in 53 control patients with persistent sinus rhythm. MR/TR was qualitatively assessed by the multi-integrative approach, and quantitatively by measurement of the colour jet area. Results At baseline, AF patients had larger MR jet areas than control patients. At follow up, progression of MR, expressed as delta MR jet area, was 0.05±1.3 cm2 in the control group, 0.73±2.1 cm2 in the non-permanent AF group and 1.95±3.6 cm2 in the permanent AF group (p=0.001). Severe MR at follow up was observed in 0%, 2.5%, 8%, respectively. After adjustment for baseline clinical and echocardiographic parameters, permanent AF remained independently associated with the progression of MR. There was a significant positive correlation between a progression of MR and an increase in left atrial volume index (r=0.31, p MR jet area Conclusions The presence of longstanding AF is associated with a significant progression of MR/TR mainly due to atrial remodelling. Our data showed a beneficial effect of sustained rhythm control, either medically or by ablation, on MR/TR progression.

PURPOSE: There are conflicting data related to the use of implantable cardioverter-defibrillators (ICDs) in patients supported with continuous-flow ventricular assist devices (LVADs). Several US studies have shown a neutral effect on mortality, whereas a recent European study suggested better outcomes in LVAD patients who have an ICD. We aimed to investigate the benefit of ICDs in patients bridged to transplant with a LVAD in the TRans-Atlantic registry on VAd and TrAnsplant (TRAViATA). METHODS: Data from consecutive patients that received a LVAD as a bridge to transplantation between January 2008 and April 2017 were collected in 7 EU (n=299) and 3 US centers (n=225). Survival analysis was performed using Kaplan-Meier and Cox proportion hazard regression analysis. Patients were censored at time of transplantation. RESULTS: Patients with an ICD at the time of LVAD (n=350) implantation were older (56 vs. 53 years, p

Contains fulltext : 57277.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. OBJECTIVE: To assess a possible genotype-phenotype correlation for GJB2. DESIGN: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. SUBJECTS: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. RESULTS: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. CONCLUSIONS: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.

Introduction: In degenerative mitral regurgitation (MR), brain natriuretic peptide (BNP) is a surrogate biomarker of the consequences of MR on the left ventricle (LV) and left atrium (LA). LV global longitudinal strain (GLS), quantified by 2-D speckle-tracking imaging (2DSt) improved the detection of subclinical LV dysfunction. We aimed at evaluating the impact of BNP on outcome and its relationship with GLS, in asymptomatic patients with degenerative MR. Methods and results: Comprehensive transthoracic echocardiography including 2DSt quantification was performed in 135 consecutive asymptomatic patients (60+14 years, 55% of male) with moderate to severe degenerative MR (61% with severe MR) and preserved LV function. Simultaneously, blood sample was drawn and plasma BNP level was measured. BNP widely varied over patients (mean=61+70, range: 5-439, median= 41pg/ml) and was correlated with age (r=0.28, p=0.009), indexed LV endsystolic diameter (r=0.30, p=0.0006), indexed LA volume (r=0.51, p,0.0001), E/Ea ratio (r=0.33, p,0.0001), systolic pulmonary pressure (r=0.24, p=0.006) and GLS (r=-0.54, p,0.0001). On multiple regression analysis, only indexed LA volume and GLS were independently associated with BNP (b=1.1+0.4, p=0.002 and b=6.6+1.4, p,0.001, respectively). During follow-up (mean=23+19 months), 54 events occurred resulting in a 4-year cardiac event-free survival=50+6%. According to the median of BNP, patients with high BNP level had significant reduced eventfree survival (21+8% vs. 75+6%, p,0.0001). A GLS,23% was also associated with a lower event-free survival (85+6% vs. 33+7%, p,0.0001). In Cox multivariate analysis, after adjustment for age, sex, E/Ea ratio and indexed end-systolic diameter, only indexed LA volume (hazard ratio [HR]=1.01, 95% confidence interval [CI]: 1.01.3, p=0.036), GLS,23% (HR=3.3, 95%CI: 1.1-9.9, p=0.03) and BNP,41pg/ml (HR=3.5, 95%CI: 1.7-7.2, p=0.001) were independent determinants of cardiac eventfree survival. In addition, compared to the first quartile of BNP (,19pg/ml), second (19-41pg/ml), third (42-70pg/ml) and fourth (71-439pg/ml) quartiles of BNP were associated with a 3.5-, 10and 11-fold increase in risk of cardiac events (p=0.06, p,0.0001 and p,0.0001, respectively). Conclusion: In asymptomatic degenerative MR, LV longitudinal function and LA volume are the main determinants of BNP release. BNP is a powerful independent predictor of cardiac events. Assessment of plasma BNP level, LA volume, and LV longitudinal function may help to improve risk stratification and the management of these patients.

Background Exercise training improves peak oxygen uptake (VO2) in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are unknown. In other cardiovascular diseases, exercise training improves vascular function and increases levels of circulating endothelium-repairing cells. We aimed to investigate the effects of moderate continuous training (MCT) and high intensity interval training (HIIT) on vascular function and cellular endothelial repair in HFpEF. Methods This was a prespecified subanalysis of the Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure randomized trial. HFpEF patients (n=180) were randomized to HIIT, MCT or attention control. At baseline and after 12 weeks, we measured peak VO2, fingertip arterial tonometry (n=109), brachial artery flow-mediated dilation (n=59), aortic pulse wave velocity (n=94), and flow cytometry (n=136) for endothelial progenitor cells (CD45dimCD34+VEGFR2+) and angiogenic T cells (CD3+CD31+CD184+). Changes in these parameters were compared between groups using linear mixed models. Parameters were correlated using Spearman's rho. Results At 3 months, we did not observe significant differences between HIIT, MCT and control group regarding changes in vascular function throughout the vascular tree (fingertip arterial tonometry, brachial artery flow-mediated dilation and central arterial stiffness, Table 1) or levels of circulating endothelium-repairing cells (endothelial progenitor cells and angiogenic T cells, Table 1). Results were similar at 12 months and when restricting analysis to patients with at least 70% adherence to training sessions. Patients with higher peak VO2 at baseline had lower numbers of circulating endothelial progenitor cells (rho=−0.22, p=0.011). Conclusions In patients with HFpEF, exercise training did not change vascular function or levels of endothelium-repairing cells. Thus, improved vascular function likely does not contribute to the change in peak VO2 after training. These findings are in contrast with the benefits of exercise on vascular function in heart failure with reduced ejection fraction and coronary artery disease. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Framework Programme 7 Table 1

Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein connexin 26. One mutation of this gene, the 35delG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder effect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for different single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJB2, while two were positioned up to 76 kb from it. Significant differences between the genotypes of patients and controls for the five SNPs closest to GJB2 were found, with nearly complete association of one SNP allele with the 35delG mutation. For the most remote SNP, we could not detect any association. We conclude that the 35delG mutation is derived from a common, albeit ancient founder. Keywords: connexin 26; GJB2; 35delG; founder effect