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BackgroundThe effect of FBN1 mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results.ObjectivesThis study aims to determine the impact of the FBN1 mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality).MethodsMFS patients with a pathogenic FBN1 mutation followed at two specialised units were included. FBN1 mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients.ResultsTwo hundred and ninety patients with MFS were included: 113 (39%) with an HI-FBN1 mutation and 177 (61%) with a DN-FBN1. At baseline, patients with HI-FBN1 had a larger aortic root diameter than patients with DN-FBN1 (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI-FBN1 (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI-FBN1 tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-FBN1 (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060).ConclusionsPatients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.

Introduction and purpose: Bicuspid aortic valve (BAV) disease is associated with faster aortic valve degeneration and a high incidence of aortic stenosis (AS). In this study, we aimed to identify differences in the pathophysiology of AS between BAV and tricuspid aortic valve (TAV) patients in a multiomics study integrating metabolomics and transcriptomics as well as clinical data. Methods: Eighteen patients underwent aortic valve replacement due to severe aortic stenosis: 8 of them had a TAV, while 10 of them had a BAV. RNA sequencing (RNA-seq) and proton nuclear magnetic resonance spectroscopy (1H-NMR) were performed on these tissue samples to obtain the RNA profile and lipid and low-molecular-weight metabolites. These results combined with clinical data were posteriorly compared, and a multiomic profile specific to AS in BAV disease was obtained. Results: H-NMR results showed that BAV patients with AS had different metabolic profiles than TAV patients. RNA-seq also showed differential RNA expression between the groups. Functional analysis helped connect this RNA pattern to mitochondrial dysfunction. Integration of RNA-seq, 1H-NMR and clinical data helped create a multiomic profile that suggested that mitochondrial dysfunction and oxidative stress are key players in the pathophysiology of AS in BAV disease. Conclusions: The pathophysiology of AS in BAV disease differs from patients with a TAV and has a specific RNA and metabolic profile. This profile was associated with mitochondrial dysfunction and increased oxidative stress.

End-systolic diameter (ESD) is an important parameter in the prognosis and indication for surgery in chronic aortic regurgitation (AR). It has been suggested that ESD values noncorrected for body surface area (BSA) could be inappropriate in the management of patients with extreme BSA. The aim of the study was to assess the usefulness of indexed ESD (IESD) of the left ventricle in the management of patients with severe isolated chronic AR. One hundred forty-seven patients underwent surgery for chronic AR and were followed up for a mean of 8 ± 6 years (1-22 years). A post hoc assessment was made of the prognostic value of preoperative ESD and IESD in different BSA percentiles: group 1, ≤ 25th percentile (BSA 1.43-1.68 m 2, n = 40); group 2, >25th percentile and ≤75th percentile (BSA 1.69-1.91 m 2, n = 68); and group 3, >75th percentile (BSA 1.92-2.24 m 2, n = 39). Age-adjusted preoperative ESD and IESD were independent predictors of mortality or heart failure in the entire population. Magnitude of the relative risk was slightly greater using preoperative IESD than ESD (HR 1.07, 95% CI 1.01-1.29, P = .017; HR 1.04, 95% CI 1.01-1.08, P = .016). In group 1, the age-adjusted expected mortality rate would drop if IESD of 25 mm/m 2 was used as a surgical criterion instead of ESD 50 mm, from 37.94% to 24.27% at 10 years ( P = .002). The use of IESD improves the prediction of unfavorable outcomes after surgery in patients with low BSA but not in those with high BSA. In patients with low BSA, IESD ≥25 mm/m 2 should be used as a cutoff point for surgery rather than ESD >50 mm.

Introduction Ascending aorta aneurysm and dissection are the most common cardiovascular complications affecting Marfan syndrome patients (MFS). Recent large increase in life expectancy of MFS driven the growing prevalence of descending aorta (DAo) dilation and dissection. Despite local abnormal vortices in the proximal Dao were related to local dilation, their origins have never been explored. We investigated the link between aortic geometrical characteristics and abnormal flow pattern in the thoracic aorta of MFS. Methods Fifty-tree MFS without significant aortic valve disease and forty age-matched healthy volunteers (HV) were prospectively included in 4D flow-MRI study, obtaining flow field and angiography. Spatial distribution of flow (in-plane rotational flow (IRF) and systolic flow reversal ratio (SFRR)) and geometric (diameter, ellipticity and curvature) parameters were investigated. Results Compared to HV, MFS presented larger aortic diameters only in the proximal AAo (p < 0.001) and DAo (p = 0.028). Increased ellipticity and a more distal location for the peak of aortic curvature were evident, even in the absence of dilation. Through most of the thoracic aorta, IRF was substantially lower in MFS, while SFRR was larger. Interestingly, non-dilated MFS had decreased IRF in the thoracic aorta compared to HV, although SFRR was not increased. Statistically-significant bivariate relations were found between arch IRF and arch ellipticity (R = −0.34) and proximal DAo peak curvature (R = −0.35). Local diameter was negatively correlated with local IRF (R = −0.3) and positively correlated to local SFRR (R = 0.605). Conclusions MFS presented altered ellipticity and curvature distribution, which are related to abnormal flow patterns even in the absence of dilation.

Background Left atrial deformation (LAD) parameters are new markers of atrial structural remodelling that seem to be affected in atrial fibrillation (AF) and atrial flutter (AFL). This study aimed to determine whether LAD can identify patients with a higher risk of thrombosis and unsuccessful electrical cardioversion (ECV). Methods Retrospective study including 56 patients with AF or AFL undergoing ECV, with previous transthoracic (TTE) and transoesophageal echocardiography (TEE) studies. Echocardiographic parameters analysed were as follows: left ventricle function, left atrium (LA) dimensions, LAD parameters (positive and negative strain peaks), left atrial appendage (LAA) filling and emptying velocities and the presence of thrombi. Strain values were analysed according to thrombotic risk and success of ECV. Results Lower mean values of peak-positive strain (PPS) in patients with prothrombotic velocities (<25 cm/s) and a higher incidence of thrombi in LAA were observed compared with those with normal velocities. Multivariate analysis revealed PPS normalised by LA maximum volume indexed by body surface area (BSA) to be associated with prothrombotic risk (odds ratio 0.000 (95% CI: 0.000–0.243), P 0.017), regardless of CHADs2VASC score. Peak-negative strain normalised by LA volumes indexed by BSA were associated with unsuccessful ECV. Conclusions Atrial deformation parameters identify AF and AFL patients with a high risk of thrombosis and unsuccessful ECV. Therefore, these new parameters should be included in anticoagulation management and rhythm vs rate control strategies.

Background Aortic root dilation and type A aortic dissection are the most common cardiovascular complications of Marfan syndrome (MFS). Current clinical management of MFS patients relies on a close follow-up of aortic root diameter and preventive aortic root surgery in case of severe or fast-progressing dilation. However, as the capacity of aortic diameter to predict type A aortic dissection is limited, new non-invasive biomarkers to improve risk stratification are needed. We investigated the capacity of proximal aorta circumferential and longitudinal strain and ascending aorta distensibility to predict aortic root diameter dilation and occurrence of major cardiovascular events in Marfan patients. Methods Eighty-seven Marfan patients without previous cardiac/aortic surgery or dissection were prospectively included in a multicenter follow-up. Proximal aorta longitudinal and circumferential strain and distensibility were computed from baseline CMR. Results During a follow-up of 81.6 ± 17 months, 11 patients underwent elective aortic root replacement, and 2 experienced type A aortic dissections. Mean dilation rate was 0.65 ± 0.67 mm/year and z-score growth rate 0.07 ± 0.131/year. In multivariable analysis, proximal aorta longitudinal strain but not circumferential strain and distensibility were independent predictors of diameter growth-rate (p = 0.001, p = 0.385 and p = 0.381, respectively), z-score growth-rate (p = 0.018, p = 0.515 and p = 0.484, respectively) and major cardiovascular events (p = 0.018, p = 0.064 and p = 0.205, respectively) corrected for demographic and clinical characteristics and baseline aortic root diameter. Conclusions In Marfan syndrome, proximal aorta longitudinal strain is an independent predictor of aortic root dilation and major cardiovascular events beyond aortic root diameter and established risk factors.

Purpose Different altered flow dynamics may influence ascending aorta (AAo) dilation morphotypes in bicuspid aortic valve (BAV) (1). Using 4D-flow CMR, we aimed to identify flow variables related to root or ascending dilation in BAV. Methods One-hundred and one BAV patients (no severe valvular disease, aortic diameters <45 mm) underwent 4D-flow on GE 1.5T Signa scanner (GE Healthcare, Waukesha, USA). Peak velocity, jet angle, normalized flow displacement, in-plane rotational flow (IRF), systolic flow reversal ratio (SFRR) and wall shear stress (WSS) were evaluated at proximal, mid and distal AAo. Dilation morpho-types were classified as non-dilated, ascending and root (2), using z-score > 2. Univariate and multivariate linear regression were used to identify factors related to dilation. ROC curves were performed to assess the relationship between variables obtained in the multivariate analysis and dilation morphotypes. Results Fusion phenotype was right-left (RL) in 78 patients, and right-non coronary (RN) in 23. Dilation morphotype was non-dilated in 24 patients, root in 11 and ascending in 66. On univariate analysis, BAV phenotype (RN), displacement and circumferential WSS presented the highest odds ratios (Table). On multivariate analysis, sex (male), proximal velocity and axial WSS were related to root morphotype (AUC 0.91, P < 0.001), while RN-BAV, distal IRF, and mid-AAo SFRR and circumferential WSS were related to ascending morphotype (AUC 0.81, P < 0.001) (Table and Figure). Table Univariate and multivariate factors related to of aortic dilation and dilation morphotypes. Univariate analysis of aortic dilation Multivariate analysis of aortic dilation Root morphotype Ascending morphotype Odds Ratio P-value Odds Ratio P-value Odds Ratio P-value BAV phenotype (RL/RN) 3.23 0.02 1.33 0.008 Sex (Male) 1.10 0.02 4.67 0.005 Prox Peak velocity 1.02 0.028 1.10 0.043 Jet angle 1.05 0.037 Displacement 3.56 0.001 1.11 0.021 IRF 1.01 0.002 WSS axial 1.20 0.003 7.64 0.008 WSS Cireumf 1.65 0.05 Mid Jet angle 1.07 0.006 Displacement 2.46 0.002 IRF 1.01 0.007 SFRR (%) 1.20 0.001 1.2 <0.001 WSS axial 1.21 0.05 WSS Cireumf 2.43 0.02 2.23 0.037 Dist IRF 1.01 0.026 1.10 0.026 WSS Cireumf 1.49 0.05 SFRR (%) 1.10 0.005 Figure ROC curves showing flow variables related to aortic dilation morphotypes. Conclusions Different altered flow parameters are related to root and ascending morphotypes in BAV. Further longitudinal studies are warranted to evaluate the impact of these flow parameters in determining the risk for aortopathy.

Purpose Bicuspid aortic valve (BAV) is a cardiac congenital disease associated with ascending aorta (AAo) dilation. The study of the impact of aortic biomechanics in this population has been limited by technical difficulties. Contrasting results have been reported for distensibility while studies including regional pulse wave velocity (PWV) are still lacking. Using 4D-flow MRI, we assessed AAo and descending aortic (DAo) biomechanical properties and determined their association in BAV aortopathy. Methods One-hundred thirty-six BAV patients with no severe valvular disease and 40 healthy volunteers were recruited. The protocol included a 4D-flow acquisition and a set of 2D CINE PC-MRI at 1.5 T. Aortic 3D geometry was reconstructed from 4D-flow-derived angiography and at least 100 analysis planes were identified in the thoracic aorta. Transit time was calculated on the velocity upslope through wavelet analysis[1].CINE PC-MRI were used to compute distensibility. Statistical significance is reported corrected for confounding factors. Results Non-dilated BAV and controls have similar AAo and DAo PWV and distensibility. Dilated patients presented lower AAo PWV and higher DAo PWV compared to non-dilated (p < 0.001 and p = 0.017, respectively). Distensibility did not differentiate dilated from non-dilated patients and presented lower association with dilation severity (see Figure). Conclusions Confirming for the first time previous findings in abdominal aorta aneurysm and fluid-mechanics theory, AAo PWV is reduced in aneurysmatic BAV patients. BAV aortopathy is related to a stiffer DAo. Regional PWV outperforms distensibility as a marker of local aortic biomechanics. These data exclude congenital aortic wall pathology related to BAV

Electrocardiography is an excellent tool for decision making in patients with ST elevation myocardial infarction (STEMI). However, little is known on the correlation between its dynamic changes during primary percutaneous coronary intervention (PCI) and the anatomic information provided by cardiovascular magnetic resonance. The study aimed to assess the predictive value of dynamic ST-segment changes before and after PCI on myocardial area at risk (AAR), infarct size, and left ventricular function in patients with STEMI. Eighty-five consecutive patients with a first STEMI were included. An electrocardiogram was recorded before and after PCI at 1, 24, 48, 72, and 120 hours. Sum of ST elevation (sumSTE), the number of STE, and STE resolution (resSTE) were determined. Complete resSTE was defined as ≥70% resolution, and patients were classified into 3 groups: group 1 (resSTE 1 hour after PCI) n = 39; group 2 (resSTE 120 hour after PCI) n = 27; and group 3, without resSTE (n = 19). Cardiovascular magnetic resonance was performed during hospitalization and at 6 months. Left ventricular volumes, ejection fraction, AAR, infarct size, myocardial salvage index, and microvascular obstruction were determined. Before PCI, the number of STE and sumSTE were best associated with AAR (p <0.001). After PCI, lack of resSTE (group 3) was associated with larger infarct size, MVO, and lower myocardial salvage index. However, sumSTE at 120 hours after PCI best discriminated patients with larger infarct size, ventricular volumes, and lower ejection fraction during hospitalization and at follow-up. In conclusion, admission sumSTE best correlates with AAR, whereas sumSTE at 120 hours rather than early resSTE best correlates with infarct size and left ventricular volumes during hospitalization and at 6 months.

BackgroundPathogenic variants in TGFB3 may lead to a syndromic genetic aortopathy. Heritable thoracic aortic disease (HTAD) and arterial events may occur in TGFB3-related disease but there are limited outcomes data on vascular events in this condition.MethodsClinical data, phenotypical features and aortic outcomes in individuals with pathogenic/likely pathogenic (P/LP) TGFB3 variants enrolled in the Montalcino Aortic Consortium registry were reviewed.Results34 individuals (56% male, median age 42 years, IQR 17–49, range 3–74 years) with P/LP TGFB3 variants were studied. Craniofacial, cutaneous and musculoskeletal features seen in Loeys-Dietz syndrome were variably present. Extra-aortic cardiovascular features included arterial tortuosity (25%), extra-aortic arterial aneurysms (6%) and mitral valve prolapse (21%).Aortic dilation (Z-Score>2) was present in 10 individuals (29%) and aortic dissection occurred in 2 (6%). Type A aortic dissection occurred in two patients (aged between 55 years and 60 years), and one of these patients experienced a type B aortic dissection 6 years later. Seven adults (median age 62 years, range 32–69 years) with aortic root dilation (41–49 mm) are being followed. No patients have undergone prophylactic aortic surgery. Twenty-five per cent of children have aortic dilation. Sixty-eight per cent of the entire cohort remains free of aortic disease. No deaths have occurred.ConclusionsTGFB3-related HTAD is characterised by late-onset and less penetrant thoracic aortic and arterial disease compared with other transforming growth factor β HTAD. Based on our data, a larger aortic size threshold for prophylactic aortic surgery is appropriate in patients with TGFB3-related HTAD compared with HTAD due to TGFBR1 or TGFBR2 variants.