Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Replacement Myocardial Fibrosis in Patients With Mitral Valve Prolapse: Relation to Mitral Regurgitation, Ventricular Remodeling, and Arrhythmia.

BACKGROUND: Mitral valve prolapse (MVP) is a frequent disease that can be complicated by mitral regurgitation (MR), heart failure, arterial embolism, rhythm disorders, and death. Left ventricular (LV) replacement myocardial fibrosis, a marker of maladaptive remodeling, has been described in patients with MVP, but the implications of this finding remain scarcely explored. We aimed at assessing the prevalence, pathophysiological and prognostic significance of LV replacement myocardial fibrosis through late gadolinium enhancement (LGE) by cardiac magnetic resonance in patients with MVP. METHODS: Four hundred patients (53±15 years of age, 55% male) with MVP (trace to severe MR by echocardiography) from 2 centers, who underwent a comprehensive echocardiography and LGE cardiac magnetic resonance, were included. Correlates of replacement myocardial fibrosis (LGE+), influence of MR degree, and ventricular arrhythmia were assessed. The primary outcome was a composite of cardiovascular events (cardiac death, heart failure, new-onset atrial fibrillation, arterial embolism, and life-threatening ventricular arrhythmia). RESULTS: Replacement myocardial fibrosis (LGE+) was observed in 110 patients (28%; 91 with myocardial wall including 71 with basal inferolateral wall, 29 with papillary muscle). LGE+ prevalence was 13% in trace-mild MR, 28% in moderate MR, and 37% in severe MR, and was associated with specific features of mitral valve apparatus, more dilated LV and more frequent ventricular arrhythmias (45% versus 26%, P<0.0001). In trace-mild MR, despite the absence of significant volume overload, abnormal LV dilatation was observed in 16% of patients and ventricular arrhythmia in 25%. Correlates of LGE+ in multivariable analysis were LV mass (odds ratio, 1.01 [95% CI, 1.002-1.017], P=0.009) and moderate-severe MR (odds ratio, 2.28 [95% CI, 1.21-4.31], P=0.011). LGE+ was associated with worse 4-year cardiovascular event-free survival (49.6±11.7 in LGE+ versus 73.3±6.5% in LGE-, P<0.0001). In a stepwise multivariable Cox model, MR volume and LGE+ (hazard ratio, 2.6 [1.4-4.9], P=0.002) were associated with poor outcome. CONCLUSIONS: LV replacement myocardial fibrosis is frequent in patients with MVP; is associated with mitral valve apparatus alteration, more dilated LV, MR grade, and ventricular arrhythmia; and is independently associated with cardiovascular events. These findings suggest an MVP-related myocardial disease. Last, cardiac magnetic resonance provides additional information to echocardiography in MVP.

Critical Structural Defects Explain Filamin A Mutations Causing Mitral Valve Dysplasia.

Mitral valve diseases affect ∼3% of the population and are the most common reasons for valvular surgery because no drug-based treatments exist. Inheritable genetic mutations have now been established as the cause of mitral valve insufficiency, and four different missense mutations in the filamin A gene (FLNA) have been found in patients suffering from nonsyndromic mitral valve dysplasia (MVD). The filamin A (FLNA) protein is expressed, in particular, in endocardial endothelia during fetal valve morphogenesis and is key in cardiac development. The FLNA-MVD-causing mutations are clustered in the N-terminal region of FLNA. How the mutations in FLNA modify its structure and function has mostly remained elusive. In this study, using NMR spectroscopy and interaction assays, we investigated FLNA-MVD-causing V711D and H743P mutations. Our results clearly indicated that both mutations almost completely destroyed the folding of the FLNA5 domain, where the mutation is located, and also affect the folding of the neighboring FLNA4 domain. The structure of the neighboring FLNA6 domain was not affected by the mutations. These mutations also completely abolish FLNA's interactions with protein tyrosine phosphatase nonreceptor type 12, which has been suggested to contribute to the pathogenesis of FLNA-MVD. Taken together, our results provide an essential structural and molecular framework for understanding the molecular bases of FLNA-MVD, which is crucial for the development of new therapies to replace surgery.

The effects of cardiac resynchronization therapy on left ventricular and mitral valve geometry and secondary mitral regurgitation in patients with left bundle branch block.

BACKGROUND: Secondary mitral regurgitation (MR) is common in patients with left bundle branch block (LBBB) undergoing cardiac resynchronization therapy (CRT). We aimed to define CRT effects on left ventricular (LV) and mitral valve (MV) geometry, and their correlation with MR severity. METHODS: Forty-one patients with LBBB and ≥mild secondary MR underwent CRT between 2009 and 2012, and had baseline and follow-up echocardiograms available. Repeated measure and linear regression analyses were performed to assess for changes in MV and LV geometry and MR severity, and associations with follow-up MR grade. RESULTS: The mean age and baseline QRS duration were 65.5 ± 14.9 years and 160 ± 24 ms. At a mean follow-up of 2.6 ± 1.8 years, there was an increase in LV ejection fraction and reductions in LV end-systolic volume index, MR grade, and end-systolic interpapillary muscle distance (P < .05 for all). Linear correlations were observed between follow-up MR grade and baseline MV tenting height (r = .44), left atrial volume index (r = .41), LV end-systolic volume index (r = .4), MV tenting area (r = .38), LV ejection fraction (r = -.34), and end-systolic interpapillary muscle distance (r = .34) (P < .05 for all). Multiple regression analysis revealed associations between follow-up MR grade and baseline MV tenting height (ß/mm = 0.42, P = .006) and left atrial volume index (ß/mL/m2  = 0.4, P = .008), independent of QRS duration (ß/ms=-0.07; P = 0.6) and nonischemic cardiomyopathy (ß = -0.34, P = .02). CONCLUSIONS: Cardiac resynchronization therapy in patients with LBBB and secondary MR results in LV and MV geometric reverse remodeling and decreases MR severity. Extent of baseline MV tethering is independently associated with persistent MR at follow-up.

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study.

Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis. Methods and results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001). Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.

Effects of cardiac resynchronization therapy after inferior myocardial infarction on secondary mitral regurgitation and mitral valve geometry.

BACKGROUND: The effects of cardiac resynchronization therapy (CRT) on secondary mitral regurgitation (MR), and mitral valve (MV) and left ventricular (LV) geometry, in patients with prior inferior myocardial infarction is not clearly defined. We assessed these outcomes utilizing two-dimensional echocardiography, and analyzed echocardiographic geometric variables that may correlate with follow-up MR severity. METHODS: Between 2009 and 2012, 229 CRT were implanted. Twenty-two had prior inferior myocardial infarction, ≥mild MR at baseline, and serial echocardiography. A left bundle branch block was present in 12 (54.5%) patients. The pre-CRT and follow-up echocardiograms were analyzed for: (1) MR severity; (2) MV and LV geometry; and (3) LV remodeling. RESULTS: The median follow-up time was 2.2 years (interquartile range, 0.7-4). In 16 patients without an inferior myocardial scar, there was a reduction in MR jet area/left atrial area ratio (33.2% vs 25.8%; P = 0.06) and MR grade (2.3 vs 1.8; P = 0.05), and an increased LV ejection fraction (26.1% vs 30.9%; P = 0.04) and end-systolic posterior ventricular sulcus-anterolateral papillary muscle angle (133.9 vs 143.9 degrees; P = 0.01). In six patients with scar, there was no change in LV or MR parameters. Regression analysis revealed linear associations between baseline MV tenting height (r = 0.57; P = 0.006), LV end-diastolic diameter index (r = 0.5; P = 0.02), mitral septolateral annular diameter (r = 0.48; P = 0.03), and MV tenting area (r = 0.46; P = 0.03), with follow-up MR jet area/left atrial area ratio. CONCLUSIONS: In patients with prior inferior myocardial infarction and no scar, CRT is associated with decreased MR severity, and improved papillary muscle alignment and LV systolic function at follow-up.

Impact of Left Ventricular to Mitral Valve Ring Mismatch on Recurrent Ischemic Mitral Regurgitation After Ring Annuloplasty.

BACKGROUND: In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty. METHODS: Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV end-diastolic dimension/ring size and LVESd/ring size). RESULTS: At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd (P=0.02) and LVESd/ring size (P=0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05-4.62; P=0.038) remained significantly associated with 1-year MR recurrence. CONCLUSIONS: LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone. CLINICAL TRIAL REGISTRATION: URL:http://clinicaltrials.gov. Unique identifiers: NCT00806988 and NCT00807040.

Impact of cardiac resynchronization therapy on mitral valve apparatus geometry and clinical outcomes in patients with secondary mitral regurgitation.

BACKGROUND: Cardiac resynchronization therapy (CRT) may improve secondary mitral regurgitation (MR) in patients with cardiomyopathy. The effects on mitral valve (MV) and left ventricular (LV) geometry, however, have not been clearly defined. METHODS: Between 2009 and 2012, 229 CRT implants were performed at a single academic center. Seventy-one had ≥mild MR at baseline and serial echocardiography, without subsequent MV intervention. The pre-CRT and follow-up echocardiograms were retrospectively reviewed for (1) MV and LV geometry measurements; (2) MR grade; and (3) LV remodeling indices. RESULTS: The mean age was 67 ± 15 years, and the cardiomyopathy was ischemic in 37 (52%). At a mean follow-up of 4.0 ± 1.9 years, there were significant improvements in LV ejection fraction and size, MR grade, MV tenting area and anterior leaflet tethering angle, and end-systolic interpapillary muscle distance (IPMD), and reductions in moderate-to-severe or severe MR (27% vs 15%; P = .04) and New York Heart Association functional class III/IV symptoms (83% vs 41%; P < .001). Multivariable analysis revealed the pre-CRT MV tenting height (OR 1.25, 95% CI 1.01-1.56; P = .04) and end-systolic IPMD (OR 1.14, 95% CI 0.99-1.32; P = .08) as independently associated with moderate or greater MR at follow-up. Finally, at 5 years post-CRT implantation, the estimated survival and freedom from LV assist device or cardiac transplantation was 61%. CONCLUSIONS: CRT results in favorable effects on MV and LV geometry and decreases the prevalence of moderate-to-severe or severe MR and heart failure symptoms. The pre-CRT MV tenting height and IPMD are independently associated with persistent MR at follow-up.

Combined papillary muscle sling and ring annuloplasty for moderate-to-severe secondary mitral regurgitation.

BACKGROUND: There is a 30-60% incidence of recurrent mitral regurgitation (MR) after mitral valve annuloplasty (Ring) for secondary MR. A concomitant papillary muscle sling (Ring+Sling) may improve valve repair by providing a more physiologic geometry of the mitral apparatus. METHODS: We retrospectively identified 58 consecutive patients with moderate-to-severe secondary MR who underwent a Ring+Sling repair, between March 2008 and May 2015. A Ring+Sling consisted of combined annuloplasty and papillary muscle approximation, utilizing a 4-mm polytetrafluoroethylene graft placed around the base of each muscle. Comparison of echocardiographic variables with patients who underwent a Ring only was performed utilizing 2:1 propensity-score matching (Ring+Sling = 34; Ring = 17). RESULTS: The baseline demographics were similar between the groups. The mean time to follow-up echocardiogram was 10.1 months (range 0.25-42 months). At follow-up, a Ring+Sling repair was associated with a lower mitral valve tenting height (p = 0.005), mitral valve tenting area (p = 0.009), and interpapillary muscle distance (p = 0.001); a smaller posterior leaflet tethering angle (p = 0.003); and a greater leaflet coaptation length (p = 0.002), when compared with Ring only. Recurrence of moderate or greater MR occurred significantly less in the Ring+Sling group (14.7%), as compared with Ring only (35.3%) (p < 0.001). Finally, actuarial survival at three years was 87% for Ring+Sling, and 82% for Ring only (p = 0.49). CONCLUSIONS: A Ring+Sling for secondary MR results in favorable changes in the mitral valve apparatus geometry, and is associated with less MR recurrence in the early postoperative period. Longer-term follow-up is needed to assess its durability and effects on left ventricular remodeling and survival.

Sex-Specific Functional Status Decline and Outcomes in Mild-to-Moderate Aortic Stenosis: Results From the PROGRESSA Study.

Background: Little is known about the effect of sex on functional status decline in aortic valve stenosis (AS) patients. Objectives: The purpose of this study was to examine the changes in functional status according to sex in patients with mild-to-moderate AS and its association with the composite of death or aortic valve replacement (AVR). Methods: We included patients with mild-to-moderate AS prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study (NCT01679431). Functional status was assessed using the New York Heart Association classification and the Duke Activity Status Index (DASI). Results: A total of 244 patients (mean age 64 ± 14 years, 29% women) were included. The mean follow-up was 4.3 ± 2.4 years. Women with intermediate-to-fast AS progression rate (median change in peak aortic jet velocity ≥0.11 m/s/year) had significantly faster decline in DASI score compared to men with similar progression rate (P < 0.05). In linear mixed analysis adjusted for several clinical and echocardiographic factors, female sex and change in peak aortic jet velocity remained strongly associated with the worsening of New York Heart Association class and the decline of DASI score (all, P < 0.001). The composite of death or AVR occurred in 115 patients (16 deaths and 99 AVRs). In multivariable Cox regression analyses, functional status decline during follow-up remained significantly associated with the composite of death or AVR (HR: 2.13; 95% CI: 1.22-3.73; P = 0.008). Conclusions: In patients with mild-to-moderate AS at baseline, intermediate-to-fast progression rate of AS was associated with a more rapid decline of functional status during follow-up, particularly in women. Functional status decline during follow-up was strongly associated with the incidence of death or AVR, with comparable effect in both women and men.

Combined Value of Dimensionless Index and Transvalvular Flow Rate in Risk Stratification of Aortic Stenosis.

Aortic stenosis (AS) is difficult to phenotype. The metrics of severity are frequently discordant, making prognostication challenging. Flow state is central to accurately determining severity. We sought to evaluate the prognostic value of dimensionless index (DI) and transvalvular flow rate (Q) in AS. We evaluated 2 independent, longitudinal registries of ≥ moderate severity AS (aortic valve area ≤1.5 cm2 or mean gradient ≥20 mm Hg) with complete data follow-up. In the primary cohort (n = 1,104, 77 ± 11 years, 40% female), the DI and Q category significantly predicted mortality (p <0.001) (Figure 1), with the highest risk being low DI and low Q (DI <0.25, Q ≤210 mL/s). In the validation cohort (n = 939, 70 ± 13 years, 42% female), similar results were seen in Kaplan-Meier (p <0.001) and multivariable Cox model analyses (p <0.01). We advocate for wider combined use of DI and Q in AS assessment to augment current diagnostic and prognostic approaches.

Unmet needs and knowledge gaps in aortic stenosis: A position paper from the Heart Valve Council of the French Society of Cardiology.

Nowadays, valvular heart disease remains a significant challenge among cardiovascular diseases, affecting millions of people worldwide and exerting substantial pressure on healthcare systems. Within the spectrum of valvular heart disease, aortic stenosis is the most common valvular lesion in developed countries. Despite notable advances in understanding its pathophysiological processes, improved cardiovascular imaging techniques and expanding therapeutic options in recent years, there are still unmet needs and knowledge gaps regarding aortic stenosis pathophysiology, severity assessment, management and decision-making strategy. This review, prepared on behalf of the Heart Valve Council of the French Society of Cardiology, describes these gaps and future research perspectives to improve the outcome of patients with aortic stenosis.

Severe Mitral Regurgitation in Paradoxical Low-Flow Low-Gradient Severe Aortic Stenosis.

Background: Patients with paradoxical low-flow, low-gradient severe aortic stenosis (LFLGAS) exhibit low transvalvular flow rate (Q), while maintaining preserved left ventricular ejection fraction (LVEF). Concomitant severe mitral regurgitation (MR) contributes to the low flow state, adding complexity to diagnosis and management. This study aimed to examine the impact of severe MR on outcomes in paradoxical LFLGAS. Methods: Data from an institutional echo database identified 1,189 patients with adjudicated severe aortic stenosis (AVA≤1.0 cm 2 ), low transaortic gradients (mean gradient<40 mmHg), preserved LVEF (≥50%), and low flow rate (Q≤210 ml/sec), to confirm paradoxical LFLGAS. Subgroups were based on MR severity (severe and non-severe). Clinical outcomes included all-cause mortality, aortic valve replacement (AVR), heart failure hospitalizations, and a composite outcome. Results: In the severe MR group (n=80), patients had lower flow rates, increased LV dimensions and a more eccentric hypertrophy pattern compared to non-severe MR (n=1,109). Over a median 5-year follow-up, severe MR correlated with higher all-cause mortality (p=0.02) and AVR rates (p=0.012). After adjustment, severe MR was independently associated with increased all-cause mortality risk (HR=1.43, p=0.011) and composite outcome (HR=1.64, p<0.001). AVR significantly reduced mortality at every MR degree, with the most substantial impact in severe MR (HR=0.18, p<0.001). Propensity-adjusted models demonstrated a stronger AVR impact with increasing MR degree (p-for-interaction=0.044). Conclusions: Severe MR in paradoxical LFLGAS is associated with adverse outcomes and distinctive LV remodeling. Aortic valve replacement improves survival across all MR grades, with greater impact in severe MR.

Effect of aortic valve phenotype and sex on aorta dilation in patients with aortic stenosis.

BACKGROUND: Bicuspid aortic valve (BAV) is often associated with a concomitant aortopathy. However, few studies have evaluated the effect of the aortic valve (AV) phenotype on the rate of dilation of the aorta. This study aimed to compare the progression rate of aorta dimensions according to AV phenotype (BAV vs tricuspid AV (TAV)), fusion type and sex in patients with aortic stenosis (AS). METHODS: 310 patients with AS (224 TAV and 86 BAV) recruited in the Metabolic Determinants of the Progression of Aortic Stenosis study (PROGRESSA, NCT01679431) were included in this analysis. Doppler echocardiography was performed annually to assess AS severity and measure ascending aorta (AA) dimensions. Baseline and last follow-up visit measurements were used to assess the annualised change. RESULTS: Median AA annualised change was larger in BAV versus TAV (0.33±0.65 mm/year vs 0.21±0.56 mm/year, p=0.04). In the whole cohort, BAV phenotype and higher low-density lipoprotein (LDL) levels were significantly associated with fast progression of AA dilation in univariate analysis (OR 1.80, 95% CI 1.08 to 2.98, p=0.02; 1.37, 95% CI 1.04 to 1.80, p=0.03, respectively). AA dilation rate did not vary according to the BAV subtype (p=0.142). Predictors of AA progression rate were different between valve phenotypes, with higher apolipoprotein B/apolipoprotein A-I ratio, higher baseline peak aortic jet velocity (Vpeak) and smaller baseline AA diameter in the TAV cohort (all p<0.05) versus absence of hypertension, higher LDL levels and smaller baseline AA diameter in the BAV cohort (all p<0.02). In men, higher baseline Vpeak and smaller baseline AA (p<0.001) were independently associated with increased annualised AA dilation, while in women, higher LDL levels (p=0.026) were independently associated with faster AA dilation. CONCLUSION: This study suggests that BAV is associated with faster dilation of the AA. Predictors of AA dilation are different between valve phenotype and sex, with higher LDL levels being associated with faster AA dilation in BAV.

Grading of Aortic Valve Calcification Severity and Risk Stratification in Aortic Stenosis.

BACKGROUND: Thresholds of aortic valve calcification (AVC) to define hemodynamically moderate aortic stenosis (AS) from mild are lacking. We aimed to establish a novel grading classification of AVC as quantified by computed tomography and determine its prognostic value. METHODS AND RESULTS: This study included 915 patients with at least mild AS (mean age 70±12 years, 30% women) from a multicenter prospective registry. All patients underwent Doppler-echocardiography and noncontrast computed tomography within 3 months. Primary end point was the occurrence of all-cause death. Receiver operating characteristic curves analyses were used to determine the sensitivity and specificity of sex-specific thresholds of AVC to identify hemodynamically moderate AS. Optimal thresholds (ie, with best sensitivity/specificity) of AVC to distinguish moderate (aortic valve area 1.0-1.5 cm2 and mean gradient 20-39 mm Hg) from mild AS (aortic valve area >1.5 cm2 and mean gradient <20 mm Hg) were AVC ≥360 arbitrary units in women and ≥1037 arbitrary units in men. Based on the guidelines' thresholds for severe AS and the new thresholds in our study for moderate AS, 312 (34%) patients had mild, 253 (28%) moderate, and 350 (38%) severe AVC. During a mean follow-up of 5.6±3.9 years, 183 (27%) deaths occurred. In Cox multivariable models, AVC remained associated with an increased risk of death (adjusted hazard ratio per grade increase, 1.94 [95% CI, 1.53-2.56]; P<0.001). CONCLUSIONS: A novel grading classification of anatomic AS severity based on sex-specific thresholds of AVC provides significant prognostic value for predicting mortality. These findings support the complementarity of computed tomography-calcium scoring to Doppler-echocardiography to corroborate AS severity and enhance risk stratification in patients with AS.

Filamin A heart valve disease as a genetic cause of inherited bicuspid and tricuspid aortic valve disease.

OBJECTIVE: Variants in the FLNA gene have been associated with mitral valve dystrophy (MVD), and even polyvalvular disease has been reported. This study aimed to analyse the aortic valve and root involvement in FLNA-MVD families and its impact on outcomes. METHODS: 262 subjects (37 (18-53) years, 140 male, 79 carriers: FLNA+) from 4 FLNA-MVD families were included. Echocardiography was performed in 185 patients and histological analysis in 3 explanted aortic valves. The outcomes were defined as aortic valve surgery or all-cause mortality. RESULTS: Aortic valve alterations were found in 58% of FLNA+ compared with 6% of FLNA- (p<0.001). 9 (13.4%) FLNA+ had bicuspid aortic valve compared with 4 (3.4%) FLNA- (p=0.03). Overall, the transvalvular mean gradient was slightly increased in FLNA+ (4.8 (4.1-6.1) vs 4.0 (2.9-4.9) mm Hg, p=0.02). The sinuses of Valsalva and sinotubular junction diameters were enlarged in FLNA+ subjects (all p<0.05). 8 FLNA+ patients underwent aortic valve surgery (0 in relatives; p<0.001). Myxomatous remodelling with an infiltration of immune cells was observed. Overall survival was similar between FLNA+ versus FLNA- subjects (86±5% vs 85±6%, p=0.36). There was no statistical evidence for an interaction between genetic status and sex (p=0.15), but the survival tended to be impaired in FLNA+ men (p=0.06) whereas not in women (p=0.71). CONCLUSION: The patients with FLNA variants present frequent aortic valve disease and worse outcomes. Bicuspid aortic valve is more frequent in patients carrying the FLNA-MVD variants. These unique features should be factored into the management of patients with dystrophic and/or bicuspid aortic valve.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression: A Systematic Review and Meta-Analysis.

Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles. Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Calcification of surgical aortic bioprostheses and its impact on clinical outcome.

AIMS: Aortic valve calcification (AVC) of surgical valve bioprostheses (BPs) has been poorly explored. We aimed to evaluate in vivo and ex vivo BP AVCs and its prognosis value. METHODS AND RESULTS: Between 2011 and 2019, AVC was assessed using in vivo computed tomography (CT) in 361 patients who had undergone surgical valve replacement 6.4 ± 4.3 years earlier. Ex vivo CT scans were performed for 37 explanted BPs. The in vivo CT scans were interpretable for 342 patients (19 patients [5.2%] were excluded). These patients were 77.2 ± 9.1 years old, and 64.3% were male. Mean in vivo AVC was 307 ± 500 Agatston units (AU). The AVC was 562 ± 570 AU for the 183 (53.5%) patients with structural valve degeneration (SVD) and 13 ± 43 AU for those without SVD (P < 0.0001). In vivo and ex vivo AVCs were strongly correlated (r = 0.88, P < 0.0001). An in vivo AVC > 100 AU (n = 147, 43%) had a specificity of 96% for diagnosing Stage 2-3 SVD (area under the curve = 0.92). Patients with AVC > 100 AU had a worse outcome compared with those with AVC ≤ 100 AU (n = 195). In multivariable analysis, AVC was a predictor of overall mortality (hazard ratio [HR] and 95% confidence interval = 1.16 [1.04-1.29]; P = 0.006), cardiovascular mortality (HR = 1.22 [1.04-1.43]; P = 0.013), cardiovascular events (HR = 1.28 [1.16-1.41]; P < 0.0001), and re-intervention (HR = 1.15 [1.06-1.25]; P < 0.0001). After adjustment for Stage 2-3 SVD diagnosis, AVC remained a predictor of overall mortality (HR = 1.20 [1.04-1.39]; P = 0.015) and cardiovascular events (HR = 1.25 [1.09-1.43]; P = 0.001). CONCLUSION: CT scan is a reliable tool to assess BP leaflet calcification. An AVC > 100 AU is tightly associated with SVD and it is a strong predictor of overall mortality and cardiovascular events.

Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology.

BACKGROUND: Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved. METHODS: We prospectively enrolled 284 unrelated MVP probands, of whom 178 (63%) had bi-leaflet MVP and 106 had PostMVP (37%). Familial screening within PostMVP patients allowed the identification of 20 families with inherited forms of PostMVP for whom whole genome sequencing was carried out in probands. Functional in vivo and in vitro investigations were performed in zebrafishand in Hek293T cells. RESULTS: In the 20 families with inherited form of PostMVP, 38.8% of relatives had a MVP/prodromal form, mainly of the posterior leaflet, with transmission consistent with an autosomal dominant mode of inheritance. Compared with control relatives, PostMVP family patients have clear posterior leaflet dystrophy on echocardiography. Patients with PostMVP present a burden of rare genetic variants in ARHGAP24. ARHGAP24 encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation. In vitro functional studies showed that variants of FilGAP, found in PostMVP families, are loss-of-function variants impairing cellular adhesion and mechano-transduction capacities. CONCLUSIONS: PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of loss-of-function variants in ARHGAP24 further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP. CLINICAL PERSPECTIVE: Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic traitPostMVP has both genetic and functional pathophysiological origins Genetic variants in the ARHGAP24 gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities.