Aims The present study aims to characterise the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results We carried out a genome-wide association study (GWAS) including 2,236 BAV patients and 11,604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism (SNP) rs2550262 was genome-wide significant BAV-associated (P = 3.49 × 10−08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10−16), GATA4 (P = 1.61 × 10−09), and TEX41 (P = 7.68 × 10−04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and approximately 20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single-marker and polygenic level.

Purpose In echocardiography the severity of aortic stenosis (AS) is defined by effective orifice area (EOA), mean pressure gradient (mPGAV) and transvalvular flow velocity (maxVAV). The hypothesis of the present study was to confirm the pathophysiological presence of combined left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and pulmonary artery hypertension (PAH) in patients with “pure” severe AS. Methods and Results Patients (n = 306) with asymptomatic (n = 133) and symptomatic (n = 173) “pure” severe AS (mean age 78 ± 9.5 years) defined by indexed EOA < 0.6 cm2 were enrolled between 2014 and 2016. AS patients were divided into 4 subgroups according to mPGAV and indexed left ventricular stroke volume: low flow (LF) low gradient (LG)-AS (n = 133), normal flow (NF) LG-AS (n = 91), LF high gradient (HG)-AS (n = 21) and NFHG-AS (n = 61). Patients with “pure” severe AS showed mean mPGAV of 31.7 ± 9.1 mmHg and mean maxVAV of 3.8 ± 0.6 m/s. Only 131 of 306 patients (43%) exhibited mPGAV > 40 mmHg and maxVAV > 4 m/s documenting incongruencies of the AS severity assessment by Doppler echocardiography. LVH was documented in 81%, DD in 76% and PAH in 80% of AS patients. 54% of “pure” AS patients exhibited all three alterations. Ranges of mPGAV and maxVAV were higher in patients with all three alterations compared to patients with less than three. 224 (73%) patients presented LG-conditions and 82 (27%) HG-conditions. LVH was predominant in NF-AS (p = 0.014) and PAH in LFHG-AS (p = 0.014). Patients’ treatment was retrospectively assessed (surgery: n = 100, TAVI: n = 48, optimal medical treatment: n = 156). Conclusion In patients with “pure” AS according to current guidelines the presence of combined LVH, DD and PAH as accepted pathophysiological sequelae of severe AS cannot be confirmed. Probably, the detection of these secondary cardiac alterations might improve the diagnostic algorithm to avoid overestimation of AS severity.

AimsPredictors of progression of moderate aortic valve stenosis (AS) are incompletely understood. The objective of this study was to evaluate the prognostic value of left ventricular hypertrophy (LVH), diastolic dysfunction, and right ventricular (RV) load in moderate AS.Methods and resultsModerate AS was defined by aortic valve area (AVA), peak transvalvular velocity (Vmax) or mean pressure gradient (PGmean). A total of 131 Patients were divided into two groups according to the number of pathophysiological changes (LVH, diastolic dysfunction with increased LV filling pressures and/or RV load): &lt;2 (group 1); ≥2 (group 2). The primary outcome was survival without aortic valve replacement (AVR). After follow-up of 30 months, the reduction of AVA (–0.06 ± 0.16 vs. –0.24 ± 0.19 cm2, P &lt; 0.001), the increase of PGmean (2.89 ± 6.35 vs 6.29 ± 7.13 mmHg, P &lt; 0.001) and the decrease of the global longitudinal strain (0.8 ± 2.56 vs. 1.57 ± 3.42%, P &lt; 0.001) from baseline to follow-up were significantly more pronounced in group 2. Survival without AVR was 82% (group 1) and 56% (group 2) [HR 3.94 (1.74–8.94), P &lt; 0.001]. Survival without AVR or progression of AS was 77% (group 1) and 46% (group 2) [HR 3.80 (1.84–7.86), P &lt; 0.001]. The presence of ≥2 pathophysiological changes predicted outcome whereas age, comorbidities, LDL-cholesterol did not.ConclusionThe presence of ≥2 pathophysiological changes is a strong predictor of outcome in moderate AS and may be useful for risk stratification, particularly for scheduling follow-up time intervals and deciding the timing of AVR.

Patients with severe aortic stenosis are classified according to flow-gradient patterns. We investigated whether left ventricular (LV) mechanical dispersion, a marker of dyssynchrony and predictor of mortality, is associated with low-flow status in aortic stenosis. 316 consecutive patients with aortic stenosis and QRS duration < 120 ms were included in the retrospective analysis. Patients with severe aortic stenosis (aortic valve area ≤ 1.0 cm 2) were classified as normal-flow (NF; stroke volume index > 35 ml/m 2) high-gradient (HG; mean transvalvular gradient ≥ 40 mmHg) (n = 79), NF low-gradient (LG) (n = 62), low-flow (LF) LG ejection fraction (EF) ≥ 50% (n = 57), and LF LG EF < 50% (n = 23). Patients with moderate aortic stenosis (aortic valve area 1.5-1.0 cm 2 ; n = 95) served as comparison group. Mechanical dispersion (calculated as standard deviation of time from Q/S onset on electrocardiogram to peak longitudinal strain in 17 left ventricular segments) was similar in patients with NF HG (49.4 ± 14.7 ms), NF LG (43.5 ± 12.9 ms), LF LG EF ≥ 50% (47.2 ± 16.3 ms) and moderate aortic stenosis (44.2 ± 15.7 ms). In patients with LF LG EF < 50%, mechanical dispersion was increased (60.8 ± 20.7 ms, p < 0.05 vs. NF HG, NF LG, LF LG EF ≥ 50% and moderate AS). Mechanical dispersion correlated with global longitudinal strain (r = 0.1354, p = 0.0160) and heart rate (r = 0.1587, p = 0.0047), but not with parameters of aortic stenosis. Mechanical dispersion was similar among flow-gradient subgroups of severe aortic stenosis with preserved LVEF, but increased in patients with low-flow low-gradient and reduced LVEF. These findings indicate that mechanical dispersion is rather a marker of systolic myocardial dysfunction than of aortic stenosis.