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European and U.S. clinical guidelines diverge regarding pulmonary hypertension (PHTN) in degenerative mitral regurgitation (DMR). Gaps in knowledge underpinning these divergences affect risk assessment and management recommendations attached to systolic pulmonary pressure (SPAP) in DMR. This study sought to define PHTN links to DMR severity, prognostic thresholds, and independent outcome impact in a large quantitative DMR registry. This study gathered a large multicentric registry of consecutive patients with isolated moderate-to-severe DMR, with DMR and SPAP quantified prospectively at diagnosis. In 3,712 patients (age 67 ± 15 years, 36% women) with ≥ moderate-to-severe DMR, effective regurgitant orifice (ERO) was 0.42 ± 0.19 cm2, regurgitant volume 66 ± 327 mL/beat and SPAP 41 ± 16 mm Hg. Spline-curve analysis showed excess mortality under medical management emerging around SPAP 35 mm Hg and doubling around SPAP 50 mm Hg. Accordingly, severe pulmonary hypertension (sPHTN) (SPAP ≥50 mm Hg) was detected in 916 patients, moderate pulmonary hypertension (mPHTN) (SPAP 35-49 mm Hg) in 1,128, and no-PHTN (SPAP <35 mm Hg) in 1,668. Whereas SPAP was strongly associated with DMR-ERO, nevertheless excess mortality with sPHTN (adjusted HR: 1.65; 95% CI: 1.24-2.20) and mPHTN (adjusted HR: 1.44; 95% CI: 1.11-1.85; both P ≤ 0.005) was observed independently of ERO and all baseline characteristics and in all patient subsets. Nested models demonstrated incremental prognostic value of mPHTN and sPHTN (all P < 0.0001). Despite higher operative risk with mPHTN and sPHTN, DMR surgical correction was followed by higher survival in all PHTN ranges with strong survival benefit of early surgery (<3 months). Postoperatively, excess mortality was abolished (P ≥ 0.30) in mPHTN, but only abated in sPHTN. This large international registry, with prospectively quantified DMR and SPAP, demonstrates a Doppler-defined PHTN impact on mortality, independent of DMR severity. Crucially, it defines objectively the new and frequent mPHTN range, independently linked to excess mortality under medical management, which is abolished by DMR correction. Thus, at DMR diagnosis, Doppler-SPAP measurement defining these new PHTN ranges, is crucial to guiding DMR management. [Display omitted] [ABSTRACT FROM AUTHOR]

Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) results in better sensitivity for prosthetic valve endocarditis (PVE) diagnosis, but visual image analysis results in relatively weak specificity and significant interobserver variability. The primary objective of this study was to evaluate the performance of a radiomics and machine learning–based analysis of 18F-FDG PET/CT (PET-ML) as a major criterion for the European Society of Cardiology score using machine learning as a major imaging criterion (ESC-ML) in PVE diagnosis. The secondary objective was to assess performance of PET-ML as a standalone examination. All 18F-FDG-PET/CT scans performed for suspected aortic PVE at a single center from 2015 to 2021 were retrospectively included. The gold standard was expert consensus after at least 3 months' follow-up. The machine learning (ML) method consisted of manually segmenting each prosthetic valve, extracting 31 radiomics features from the segmented region, and training a ridge logistic regressor to predict PVE. Training and hyperparameter tuning were done with a cross-validation approach, followed by an evaluation on an independent test database. A total of 108 patients were included, regardless of myocardial uptake, and were divided into training (n = 68) and test (n = 40) cohorts. Considering the latter, PET-ML findings were positive for 13 of 22 definite PVE cases and 3 of 18 rejected PVE cases (59% sensitivity, 83% specificity), thus leading to an ESC-ML sensitivity of 72% and a specificity of 83%. The use of ML for analyzing 18F-FDG-PET/CT images in PVE diagnosis was feasible and beneficial, particularly when ML was included in the ESC 2015 criteria. Despite some limitations and the need for future developments, this approach seems promising to optimize the role of 18F-FDG PET/CT in PVE diagnosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Mitral valve prolapse is a common disease affecting 2 to 3% of the population, characterized by a myxomatous mitral valve disease (MVD). In 2007, the first causal mutation in the FLNA gene (FLNA-P637Q), was associated with MVD. The FlnA-P637Q KI rat model was recently generated. As early as 3 weeks (D21), the presence of MVD was confirmed and was associated with transcriptomic signature of chemotaxis and immune cells migration. This study aims at delineating the role of the recruitment and activation of macrophages in the pathophysiology of MVD. KI and WT animals were phenotyped at birth (D0), day 2 (D2), and day 7 (D7). Morphological alterations of the MV were evaluated by anatomopathological score (D7). Cell proportions were analyzed by flow cytometry (D7 and D21), and molecular phenotyping was done by bulk RNAseq (D7). WT and KI MVs were also dissociated for valvular interstitial cells (VICs) primary culture and subsequent in vitro studies. Flow cytometry at D21 revealed a 2-fold increase proportion of myeloid cells in KI MV compared to WT (13 vs. 7%). Interestingly, although no morphological differences were seen at D0 an D2, we observed a remodeling of the MV characteristic of the presence of MVD at D7. Accordingly, histological score was significantly higher in KI rats (7 vs. 4, P < 0.001). This was consistent with the transcriptomic analysis of D7 MV that revealed enrichment of GO-Terms (P < 0.05) related to ECM-receptor interaction, cell adhesion, proteoglycans and extracellular space. Of note, pathways related to chemotaxis were also enriched (P < 0.05), but flow cytometry at D7 revealed no difference in myeloid cell proportions (7% in WT and KI). The in vitro modulation of mechanical stresses imposed to VICs (i.e. stiffness or laminar flow) induced an increased expression of monocytes adhesion molecules ICAM1 and GITRL in KI compared to WT VICs (all P < 0.05). MVD is observed from day 7 in FLNA-KI rats and is associated to pro-inflammatory signature enrichment but no increase in macropahges proportions. The response of VICs to in vitro mechanical stresses suggest that FlnA-KI VICs are more susceptible to express monocytes adhesion molecules which could explain the increased proportion of macrophages seen at D21 in FlnA-KI rats. [ABSTRACT FROM AUTHOR]

For older patients undergoing cardiac surgery, geriatric factors are known to increase postoperative complications and prolong length of stay (LOS). Comprehensive geriatric assessment (CGA) is an evidence-based method for geriatric evaluation to develop an individualized-care plan to optimize physical, functional, and social issues. This study analyzed the association between preoperative CGA and hospital LOS after combined cardiac surgery. This retrospective monocentric study included all patients aged 75 years and greater who underwent combined cardiac surgery between 2014 and 2017. Hospital LOS, intensive care unit LOS, and postoperative complications were compared between patients with or without preoperative CGA before and after propensity-score matching. Mean age of the 407 patients was 79.6 years; 114 underwent a preoperative CGA (28%). For 305 patients (74.9%), coronary artery bypass was associated with aortic valve replacement. After propensity-score matching, a significant difference was found between the 2 groups (preoperative CGA versus none) for in-hospital LOS (12 versus 13 days; P =.04) and intensive care unit LOS (3 versus 4 days; P =.01). In multivariable analysis, a significant association remained between hospital LOS and CGA (P =.02), renal function (P =.02), mitral replacement (P =.001), and complications (P =.001). Our results favor the use of systematic preoperative CGA. These encouraging results need to be validated by prospective studies that assess the impact of individualized-care plan established after CGA on postoperative outcomes. With an aging population, efforts are required to determine how to implement preoperative individualized-care plans to improve postoperative outcomes for vulnerable patients undergoing cardiac surgery. [Display omitted] [ABSTRACT FROM AUTHOR]

Calcific aortic valve stenosis (CAVS) affects more than 10% of the population over 75 years old and aortic valve replacement is the only option. Biological prostheses are largely used in this context but have a limited durability with the development of structural bioprosthetic degeneration (SVD) post implantation. Lipid factors such as proprotein convertase subtilisin/kexin type 9 (PCSK9), Lipoprotein (a) and LDL-cholesterol have been recently associated with SVD, even if the underlying mechanisms remain unknown. We aim at evaluating the impact of hypercholesterolemia and/or PCSK9 on the early processes leading to SVD. To study bioprosthetic tissue degradation, subcutaneous implantation of this tissue was performed in wild type (WT), PCSK9 knock-out (KO) and PCSK9 overexpressing mice for 28 days. A qualitative anatomopathological score based on cell density, infiltration, and matrix degradation was developed. Immunochemistry was performed to characterize immune cells infiltration, with a focus on anti- (i.e. CD163+) and pro-inflammatory (i.e. F4/80+) macrophages, lymphocytes (CD3+) and polynuclear eosinophils (i.e. EPX+). Histological analysis of explanted punches revealed an infiltration of mononuclear cells into the biological matrix among the 3 groups, with a significant increase in mice overexpressing PCSK9 compared to WT and KO. The anatomopathological score was significantly higher in overexpressing mice compared to the WT and KO mice (median value 7.0 [4.1–8.4] versus 4.0 [3.0–4.5] and 2.8 [2.0–3.9], respectively; P = 0.008). The macrophages (both CD163+ and F4/80+) and polynuclear eosinophils were the most abundant cell types, even if few lymphocytes were also observed. Interestingly, polynuclear eosinophils were more abundant in mice overexpressing PCSK9 compared to WT and KO (P = 0.01 and P = 0.002, respectively). Hypercholesterolemia and/or high circulating PCSK9 level enhance the response against the bioprosthetic tissue. Macrophages are the most abundant cell types invading the tissue. Hypercholesterolemia/high PCSK9 potentiate the infiltration of polynuclear eosinophils, which point out for a direct impact on the inflammatory response post implantation. Deeper molecular analyses will provide mechanistic evidence linking hypercholesterolemia and PCSK9 to the early inflammation processes leading to SVD. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Myxomatous valve dystrophy (MVD) is characterized by an elongated, and thickened mitral valve (MV) with extracellular matrix (ECM) accumulation. Using the FilaminA P637Q Knock-In (FLNA-KI) rat model of MVD, we previously demonstrated that it recapitulates the human pathology. RNA-Seq analysis revealed important contribution of immune cells. Cytometry experiments showed increase proportion of macrophages at D21 in KI valves. The objective is to decipher how macrophages contribute to the development of MVD. Seven days, two days and newborn FLNA-KI rats (D7, D2 and D0) were phenotyped through a quantitative histological analysis. Cytometry, to assess valvular macrophages population, as well as qPCR for expression of the key molecular targets was performed. At D7, FLNA-KI rats exhibit thickened and elongated mitral valve leaflets, and presented a higher histological score as compared to WT rats (P = 0.0007). qPCR experiments revealed dysregulation of genes involved in ECM regulation (HAS1 FC = 8 and HYAL1 FC = 0.63 vs. WT, both P < 0.01) and endothelial dysfunction (ESM1 FC = 2.2 vs. WT, P = 0.005) concordant with the results at D21. Preliminary results at D0 and D2 showed upregulation of genes related to ECM remodeling (HAS1 FC = 2.6 and 3.2 vs. WT, respectively, P < 0.01). Morphological analysis at D0 and D2 is still ongoing. Although a pro-inflammatory environment was present at D7 (CCL7 FC = 2.6 and S100A8 FC = 4.2 vs. WT, P < 0.5), no changes in the proportion of macrophages was detected by cytometry (6% in both WT and KI MV, P > 0.5). The expression of inflammatory cytokines was not different at D0 and D2 in KI rats' mitral valves (all P > 0.5). Our study indicates that MVD is present in KI as soon as birth. The ECM remodeling is probably a basis for the pro-inflammatory environment that promotes macrophages recruitment in the valvular leaflets. This suggests that macrophages infiltration is not causal of MVD but rather participates to the evolution of the disease. Further investigations are ongoing to understand how macrophages contribute to the pathophysiology of MVD. [ABSTRACT FROM AUTHOR]

Calcific aortic valve stenosis (CAVS) is one of the most frequent cardiovascular diseases affecting more than 10% of the population over 70 years old. There is currently no pharmacological treatment to stop this process, and the only solution remains to replace the diseased valve with a prosthesis. A shift toward the use of biological prosthesis occurred in the last 10 years, as these protheses presented better hemodynamic profile without lifelong anticoagulation treatment. However, the main disadvantage of the bioprostheses is their limited durability overtime, with the development of a gradual structural bioprosthetic degeneration (SVD) in the following years post intervention. Our objective is to test the role of hypercholesterolemia and/or PCSK9, a well-know modulator of the cholesterol metabolism, on the early process leading to SVD. As the currently gold standard technic to test calcification potential of biological tissue from bioprosthetic valve, we implanted subcutaneously 5 mm punches of biological matrix from bovine pericardium, in 3 groups of mice: PCSK9 KO, WT and overexpressing hepatic PCSK9 (with AAV injection). After 28 days, punches werehandled and analyzed. Histology and molecular screening were performed. As compared to WT, KO PCSK9 mice presented a 25% to 50% reduction in cholesterol, and mice overexpressing hepatic PCSK9 a 2-time higher circulating cholesterol over the course of the protocol (all P < 0.003). PCSK9 circulating level was not detectable in KO and was significantly increased in mice overexpressing hepatic PCSK9 (fold change > 10 vs. WT; all P < 0.001). Preliminary histological analysis of explanted punches after 28 days revealed an important infiltration of mononuclear cells into the pericardial matrix, consistent over the 3 groups of mice. However, the quantity and degree of infiltration of these cells appeared to be exacerbated in mice overexpressing hepatic PCSK9. Further molecular screening is ongoing. We successfully developed an animal model allowing us the investigation of PCSK9 and hypercholesterolemia roles in SVD. Preliminary analyses suggest that high PCSK9 and/or cholesterol can potentiate cell infiltration post-implantation of bovine pericardial matrix. Further molecular analyses will provide key elements to decipher the mechanisms related to PCSK9 and cholesterol in the development of SVD. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Mitral Valve Dystrophy (MVD) is an outgrowing disease, however little is known regarding the involved pathophysiological mechanisms. We have generated a unique knock-in (KI) animal model for the P637Q mutation on the FLNA gene, the first causal gene associated with MVD identified by our team. We established the relevance of this model to study MVD by confirming the presence of the disease in 3-week-old (D21) KI rats. The molecular phenotyping at this time highlighted specific biological processes such as immune cell recruitment, extracellular matrix remodeling or response to molecular stress, as central players in the development of MVD. The aim of the present study was to analyze earlier time point (7-day post-natal; D7) and the specific role of endothelial, interstitial and immune cells in the onset and the progression of MVD. D7 and D21 WT and KI rats were studied. Classical histology was performed at D7 to evaluate the valve remodeling. Cytometry was performed to determine the nature and the proportion of cell subpopulation at each time-points. Following cell sorting, qPCR experiments allowed the characterization of the molecular signature for each subpopulation. The MV phenotyping at D7 confirmed the presence of MVD, but no difference was observed in myeloid cell proportion at this age (6% vs 6% for WT and KI animals, respectively; P = 0.63). However, concordant with the RNA-seq data at D21, cytometry experiments revealed a 2-fold increase in the proportion of myeloid cells in MV from KI animals compared to WT (13% vs 7% respectively; P < 0.05). CD45+ leukocytes and CD206+ developmental macrophages were located in the medial third and atrial border of the MV leaflet in WT rats, and more diffusely observed in KI animals at D21. Transcript levels of typical inflammatory markers (Esm1 + 4.3x in KI VECs vs WT, n = 4; P = 0.05), ECM markers (Cspg4 + 1.90x in KI VICs vs WT, n = 5; P = 0.008), and cellular activation confirmed the pro-inflammatory environment and the activation of interstitial cells in KI animals. Our results revealed a specific role of myeloid cells in the progression of MVD rather than the onset of the disease. Furthermore, preliminary results on the cell-specific activity shows an activation of myeloid cells, endothelial and interstitial cells in MVD. Cellular cross-talk needs to be further studied to decipher the molecular mechanisms leading to MVD. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the value of stress-echocardiography in patients with paradoxical low-flow, low-gradient (PLFLG) aortic stenosis (AS). The projected aortic valve area (AVAProj) at a normal flow rate was calculated in 55 patients with PLFLG AS. In the subset of patients (n = 13) who underwent an aortic valve replacement within 3 months after stress echocardiography, AVAProj correlated better with the valve weight compared to traditional resting and stress echocardiographic parameters of AS severity (AVAProj: r = −0.78 vs. other parameters: r = 0.46 to 0.56). In the whole group (N = 55), 18 (33%) patients had an AVAProj >1.0 cm2, being consistent with the presence of pseudo severe AS. The AVAProj was also superior to traditional parameters of stenosis severity for predicting outcomes (hazard ratio: 1.32/0.1 cm2 decrease in AVAProj). In patients with PLFLG AS, the measurement of AVAproj derived from stress echocardiography is helpful to determine the actual severity of the stenosis and predict risk of adverse events. [ABSTRACT FROM AUTHOR]

Objective: To define the objective and subjective measures of aortic stenosis (AS) severity linked to survival after diagnosis in community practice. Methods: All 360 Olmsted County, Minnesota residents (74 ± 14 years; 44% men) with AS diagnosed from 1988 to 1997 by echocardiography and without life-threatening comorbid conditions were enrolled. The presentation at first diagnosis, outcomes (mortality, heart failure, cardiac surgery), and coherence of guideline-based criteria for severe AS were analyzed. Results: The presentation was challenging. Cardiac symptoms were frequent (59%) and unassociated with the AS severity (all P > .13). Of the patients with severe AS, as determined by a valve area less than 1.0 cm2, 67% had low gradient AS (≤40 mm Hg). An aortic valve area less than 1.0 cm2 was the only objective measure independently determining survival (adjusted risk ratio, 1.81; 95% confidence interval [CI], 1.19–2.70; P < .01) and heart failure (adjusted risk ratio, 2.3; 95% CI, 1.3–4.0; P < .01), even in patients with low-gradient AS and/or an ejection fraction of 50% or greater. Excess mortality (vs expected mortality) occurred with an aortic valve area of less than 1.0 cm2 (risk ratio, 1.78; 95% CI, 1.33–2.35; P < .001) even without symptoms (risk ratio, 1.65; 95% CI, 1.05–2.47; P = .02). Aortic valve replacement, ultimately performed in only 45% of those with an aortic valve area less than 1.0 cm2, reduced mortality (risk ratio, 0.61; 95% CI, 0.39–0.94; P = .02) and heart failure (risk ratio, 0.29; 95% CI, 0.13–0.64; P < .01). Conclusions: In community practice, AS affects elderly patients, and its presentation is challenging owing to the high frequency of low-gradient severe AS despite a normal ejection fraction and because symptoms are frequently not specific to AS. Consequently, aortic valve replacement is seldom performed despite its considerable benefit. Physicians should be aware that an aortic valve area of less than 1.0 cm2 predicts for unfavorable outcomes, irrespective of symptoms or gradient. Thus, such patients should undergo a thorough evaluation to detect those who could benefit from aortic valve replacement, despite their challenging presentation. [Copyright &y& Elsevier]

Background: The Society of Thoracic Surgeons (STS) score aims at predicting operative mortality in cardiac surgery. The value of this score in predicting short- and long-term survival with medical or surgical management in patients with asymptomatic severe aortic stenosis (AS) is unknown. Methods: In a cohort of 694 patients (aged 71 ± 11 years) with isolated, asymptomatic severe AS (velocity ≥4 m/s), STS score was calculated at baseline and its link to survival analyzed. Patients were stratified by STS score less than 4%, 4% to 6.5%, and 6.5% or greater. Results: The STS score showed no association with operative mortality within 1 year of diagnosis or any time (1%, 2.9%, and 6.1%, respectively, by strata; p = 0.08) and a weak association with 1-year survival (p = 0.04). Conversely, long-term survival (10-year) was strongly predicted by STS score strata (78%, 47%, and 16%, respectively; p < 0.0001). In multivariate analysis, STS score independently predicted mortality (hazard ratio/1%, 1.15 [1.12 to 1.18], p < 0.0001) or cardiac death (1.21 [1.17 to 1.25], p < 0.0001). Aortic valve replacement within 1 year of diagnosis markedly improved survival (adjusted hazard ratio, 0.58, p < 0.001). However, benefit of early surgery varied according to strata, with no overt benefit with low score (p = 0.83), whereas early surgery considerably improved survival in the intermediate strata (p < 0.001). Conclusions: For patients with asymptomatic severe AS, STS score is a powerful tool for predicting long-term outcome and for selecting patients (particularly those at intermediate risk) who benefit markedly from early surgery. Hence, risk-scoring using STS score should be routinely performed in patients with AS to support the clinical decision-making process. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: The purpose of this paper was to assess the link between left atrial (LA) volume at diagnosis and outcome of patients with mitral regurgitation (MR). Background: Left atrial enlargement is a consequence of organic MR, but its association with clinical outcome independently of MR severity is uncertain. Methods: We prospectively enrolled 492 patients (age 63 ± 15 years, 60% men) in sinus rhythm with organic MR (regurgitant volume 68 ± 42 ml/beat) and performed at baseline triple echocardiographic quantitation (MR severity, LA volume, and left ventricular characteristics). Outcome with medical and surgical management was analyzed. Results: Left atrial volume indexed to body surface area (LA index) was 55 ± 26 ml/m2 (<40 ml/m2 in 158 patients, 40 to 59 ml/m2 in 160 patients, and ≥60 ml/m2 in 174 patients). Under medical management, 5-year survival was 80 ± 2.9% and cardiac events 28 ± 3%. Adjusting for established predictors of outcome, LA index was independently associated with survival after diagnosis (hazard ratio [HR]: 1.3 [95% confidence interval (CI): 1.1 to 1.5] per 10 ml/m2 increment, p = 0.001). Patients with LA index ≥60 ml/m2 had lower 5-year survival than those with no or mild LA enlargement (p < 0.0001) and than the rates of survival expected in the U.S. population (53 ± 8.6% vs. 76%, p = 0.017). Compared with patients with LA index <40 ml/m2, those with LA index ≥60 ml/m2 had increased mortality (HR: 2.8 [95% CI: 1.2 to 6.5], p = 0.016) and cardiac events (HR: 5.2 [95% CI: 2.6 to 10.9], p < 0.0001) with medical management. Mitral surgery was associated with decreased mortality (HR: 0.46 [95% CI: 0.26 to 0.84], p = 0.01) and cardiac events (HR: 0.38 [95% CI: 0.23 to 0.62], p = 0.0001) and after surgery patients with LA index ≥60 ml/m2 versus <60 ml/m2 did not incur excess mortality or cardiac events (both p > 0.30). Conclusions: In organic MR, LA index at diagnosis predicts long-term outcome, incrementally to known predictors of outcome. This marker of risk is particularly important because mitral surgery in these patients markedly improves outcome and restores life expectancy. LA index should be measured in routine clinical practice for risk-stratification and for clinical decision making in patients with organic MR. [Copyright &y& Elsevier]

Abstract: Background: Fibrates are peroxisome proliferator-activated receptor α (PPARα) agonists which modulate many aspects of lipoprotein metabolism and inflammation. They have been recently demonstrated to inhibit in vitro expression of tissue factor (TF), the main initiator of blood coagulation, which probably plays a pivotal role in thrombotic complications after plaque rupture. We investigated whether a 4-week fenofibrate treatment might affect the TF expression and cellular modifications in angioplasty-induced rabbit plaque rupture. Methods: After plaque rupture by balloon angioplasty in atheromatous rabbits, animals were randomized in an untreated group or a group receiving fenofibrate. The TF content of arterial wall and the histological modifications were analyzed after 4 weeks. Results: Fenofibrate decreased in vivo TF expression (−42%, P<.05) and plaque cholesterol content (P<.01) in iliac arteries. Fenofibrate significantly improved the reendothelialization process by 51% (P<.05) and modified cellular distribution in the plaque toward increased stabilization. Conclusions: These data indicate that the PPARα-activator fenofibrate reduces plaque thrombogenicity and accelerates endothelial regrowth which, altogether, might improve plaque stability. These effects may underlie the preventive effects of fibrate therapy in atherosclerosis complications. [Copyright &y& Elsevier]

Background: During cardiopulmonary bypass, aspirated blood exhibits strong activation features, but the triggering event remains unclear. Contact of blood with the pericardial cavity and surgical wound has been advocated as the main trigger, but suction forces are also considered as a possible contributor. We thus designed a study to identify the possible causes involved in this activation. Methods: In 10 patients, we analyzed hemostasis activation markers and inflammatory mediators in blood collected in the pericardial cavity and in blood actively aspirated from the left ventricle without any contact with the pericardial cavity. In addition, the same variables were determined in blood sampled in the cardiopulmonary bypass circuit. Results: Markers of tissue factor pathway activation and of thrombin generation, microparticles, free hemoglobin, interleukin 6, and tumor necrosis factor-α were significantly increased in pericardial samples as compared with the left ventricle and cardiopulmonary bypass circuit samples. All measured variables were similar between left ventricle and cardiopulmonary bypass samples, except free hemoglobin, interleukin 6, and microparticle levels, which were significantly higher in the left ventricle. Conclusions: Blood contact with the pericardial cavity induces strong hemolysis, inflammatory mediator release, and coagulation activation, driven by tissue factor pathway activation. By contrast, suction forces applied to left ventricular blood poorly contribute to blood trauma and activation. Comparison of pericardial and left ventricular blood shows that contact with the pericardial cavity, and not suction forces, is the leading cause of blood activation. The specific trigger for blood trauma and activation present in the pericardial cavity remains to be identified. [Copyright &y& Elsevier]

Background: Although mitral regurgitation (MR) has been associated with an increased risk of death and heart failure after myocardial infarction (MI), the relationship between post-MI MR and left ventricular (LV) remodeling has not been entirely clarified. In addition, the optimal timing for assessing MR after MI remains unknown. Methods: Post-MI MR was assessed by Doppler echocardiography at hospital discharge (baseline) and after 3 months in 261 patients with an inaugural anterior MI. We studied LV remodeling during a 1-year period and clinical follow-up after 3 years, according to MR severity at baseline and at 3 months. Results: Left ventricular remodeling was demonstrated as an increase in LV end-diastolic volume from 56 +/- 15 mL/m(2) at baseline to 63 +/- 19 mL/m(2) at 1 year (P < .0001). MR severity at baseline was not significantly associated with LV remodeling. By contrast, MR severity at 3 months was a strong indicator of LV remodeling. There was a graded increase in the proportion of patients with a >20% increase in LV end-diastolic volume between baseline and 1 year according to MR severity at 3 months (no MR: 21%, mild MR: 32%, moderate/severe MR: 60%) (P = .008). Both MR at baseline and at 3 months were associated with death or rehospitalization for heart failure by univariate analysis (P = .014 and P < .0001, respectively). By multivariable analysis, MR at baseline was not an independent predictor of adverse outcome (P = .66). By contrast, MR at 3 months was independently associated with adverse outcome with a hazard ratio of 2.23 (1.02-4.91 [P = .04]). Conclusions: After an inaugural anterior MI, MR is associated with LV remodeling and adverse clinical outcome. For prognostic purpose, the optimal timing for assessing MR is the chronic post-MI stage rather than the early post-MI period. [ABSTRACT FROM AUTHOR]

Background: Previous studies, with limited number of patients, have tried to determine the predictors of left ventricular ejection fraction (LVEF) improvement after beta-blockade. No study has demonstrated that LVEF improvement was an independent predictor of cardiac survival. Methods: The aims of the study were to determine in a large group of patients with stable chronic heart failure associated with reduced LVEF the predictors of LVEF improvement (difference in LVEF [δLVEF], ie, the value after β-blockade minus the value before β-blockade) after beta-blockade and to analyze prognostic impact of δLVEF. Three hundred fourteen consecutive patients underwent an echocardiogram, a radionuclide angiogram, and a maximum cardiopulmonary exercise test before and 3 months after maximal tolerated doses of β-blockers have been reached. Results: After beta-blockade, LVEF improved from 30% ± 11% to 40% ± 13%. In the whole population, independent predictors of δLVEF were nonischemic etiology, baseline LVEF (negative correlation), and baseline heart rate (positive correlation). In ischemic patients, independent predictors of δLVEF were absence of history of myocardial infarction, baseline heart rate, and baseline LVEF; whereas in nonischemic patients, independent predictors were baseline LVEF and baseline QRS width (negative correlation). After 1082 days of follow-up, there were 53 cardiovascular deaths and 2 urgent transplantations. Left ventricular ejection fraction improvement (defined as an absolute increase in LVEF >5%) was an independent predictor of cardiac survival. Patients who had an LVEF ≤45% after beta-blockade with a δLVEF ≤5% represented a high-risk subgroup. Conclusions: In patients with chronic heart failure, predictors of LVEF improvement after beta-blockade were different according to etiology. Left ventricular ejection fraction improvement was an independent predictor of cardiac survival. [Copyright &y& Elsevier]

Objective: Bone marrow stem cells, especially the mesenchymal stem cell subpopulation, have been used to create in vitro tissue-engineered heart valves. We hypothesized that autologous bone marrow cells, injected in a decellularized porcine scaffold before surgical implantation, could promote in vivo recolonization and limit valve deterioration. We thus analyzed the effects of in situ injection of autologous bone marrow mononuclear cells and of mesenchymal stem cells on the outcome of xenogenic decellularized scaffolds in a lamb model. Methods: Decellularized porcine pulmonary valves were implanted in the pulmonary artery under cardiopulmonary bypass in 14 lambs after injection in the scaffold of autologous bone marrow mononuclear cells (BMMC) group (n = 7) or of mesenchymal stem cells (MSC) group (n = 7). At 4 months, valve function was evaluated by echocardiography, and valves were explanted for macroscopic and histologic analysis. Results: Mean transvalvular and distal gradients (millimeters of mercury) were lower in the MSC than those in the BMMC group (1.3 ± 0.39 vs 4.24 ± 0.91 and 4.05 ± 1.89 vs 12.02 ± 6.95, respectively; P < .02). Histologic examination showed significant recolonization and re-endothelialization in both groups. However, significant valve thickening and inflammatory cell infiltration were observed in the BMMC group. By contrast, valves from the MSC group displayed extracellular matrix and cell disposition close to those of native pulmonary valves. Conclusions: Tissue-engineered heart valves created from mesenchymal stem cells, injected directly in a decellularized xenograft scaffold, exhibited satisfactory hemodynamic and histologic aspects after 4 months. Further long-term studies are needed to demonstrate the potential of mesenchymal stem cells for clinical application in heart valve surgery. [Copyright &y& Elsevier]

Background: Restoration of sinus rhythm is thought to lead to a reduction in left atrial size and to recovery of atrial contraction. We aimed to investigate changes in atrial size and function in patients undergoing radiofrequency ablation for atrial fibrillation during mitral valve surgery. Methods: In a prospective study, 70 patients (64 ± 10 years) with mitral valve disease and atrial fibrillation underwent mitral surgery and left atrial endocardial radiofrequency ablation. Evaluation was achieved before surgery, at 7 days, 5 months, and 22 months after surgery. Maximal right and left atrial areas, left atrial diameter, and volume were measured. Atrial filling fraction (ventricular filling related to atrial contraction to total ventricular filling ratio) was used as an index of atrial contraction. Results: At the end of follow-up (22 ± 10 months) most patients (91%) were in sinus rhythm. Actuarial freedom from atrial fibrillation recurrence was 62.5% after 2 years. Atrial size decreased, with a significant improvement in right (36 ± 15 vs 10 ± 20% preoperatively, p < 0.0001) and left (25 ± 12 vs 7 ± 14%, p < 0.0001) atrial filling fraction. Despite similar preoperative atrial size, at the end of follow-up atrial fibrillation recurrence was associated with a higher left atrial volume than in patients free of recurrence (41 ± 14 vs 32 ± 9 mL/m2, p = 0.004). Independent predictors of atrial fibrillation recurrence were previous mitral procedure (p = 0.029), left ventricular ejection fraction (p = 0.033), and mitral rheumatic lesion (p = 0.034). Conclusions: Left atrial radiofrequency ablation for atrial fibrillation during mitral surgery is an effective procedure restoring sinus rhythm. Right and left atrial size was significantly reduced, with a recovery in atrial contraction. [Copyright &y& Elsevier]

: BackgroundThere are little comparative data on Carpentier-Edwards supraannular and pericardial second-generation bioprostheses. The aim of this work was to compare their hemodynamic and clinical outcomes in patients with aortic stenosis.: MethodsWe conducted a retrospective study including 150 patients operated on for aortic stenosis between 1989 and 1993. Patients undergoing aortic valve replacement with either a Carpentier-Edwards supraannular or pericardial prosthesis were matched for sex (49% male), age (72 ± 8 years), body surface area, valve size, associated procedures, and left ventricular ejection fraction.: ResultsMean follow-up was 6.5 ± 3.3 years, giving a total follow-up of 983 patient-years. Thirty-day mortality and 10-year actuarial survival were, respectively, 8% and 51% in the supraannular group and 6.7% and 43.4% in the pericardial group. At 10 years, freedom from thromboembolism, structural failure, and all valve-related events were, respectively, 88.7%, 88.9%, and 68.7% in the supraannular group and 85%, 100%, and 82.2% in the pericardial group. There were four (5.3%) structural failures, and four (5.3%) reoperations for degeneration (n = 3) and endocarditis (n = 1) in the supraannular group. Freedom from structural dysfunction or reoperation was 87.3% in the supraannular group and 100% (p < 0.05) in the pericardial group. Echocardiographic review of 62 of 76 survivors (81.5%) demonstrated a trend toward a better hemodynamic profile of pericardial valves at the end of follow-up.: ConclusionsTen years after aortic valve replacement for aortic stenosis, Carpentier-Edwards pericardial prostheses give comparable and probably better results than Carpentier-Edwards supraannular prostheses. [Copyright &y& Elsevier]

We report a case of circumflex artery stenosis after intraoperative radiofrequency ablation for permanent atrial fibrillation in a patient who had a previous mitral valve replacement. The patient presented with acute pulmonary edema and severe angina 1 year after an uneventful recovery. The patient underwent a diagnostic angiography that showed the presence of stenosis of a long segment of the circumflex artery, adjacent to the radiofrequency ablation site, which was reopened successfully by angioplasty. Intraoperative radiofrequency ablation caused circumflex artery stenosis. We believe that this complication could have been avoided by applying the radiofrequency ablation more distally between the left pulmonary veins and the mitral valve. [Copyright &y& Elsevier]

Abstract Objectives Structural valve deterioration (SVD) remains a major bioprosthesis-related complication, as recently described for the Mitroflow valve (models LX and 12A) (LivaNova, London, United Kingdom). The real incidence of the SVD risk remains unclear, often due to methodologic pitfalls by systematically using the Kaplan-Meier estimator and/or the Cox model. In this report, we propose for the first time a precise statistical modeling of this issue. Methods Five hundred sixty-one patients who underwent aortic valve replacement with the aortic Mitroflow valve between 2002 and 2007 were included. We used an illness–death model for interval-censored data. Median follow-up was 6.6 years; 103 cases of SVD were diagnosed. Results The 4-year and 7-year SVD cumulative incidences after the first anniversary of surgery were 15.2% (95% confidence interval, 11.9-19.1) and 31.0% (95% confidence interval, 25.8-37.2), respectively. Female gender, dyslipidemia, chronic obstructive pulmonary disease, and severe patient-prosthesis mismatch were significant risk factors of SVD. The occurrence of SVD was associated with a 2-fold increase in the risk of death. Conclusions Appropriate statistical models should be used to avoid underestimating the SVD complication associated with worse long-term survival. [ABSTRACT FROM AUTHOR]

Abstract: Multiple cardiac papillary fibroelastomas (PFEs) are thought to account for less than 10% of patients with PFE. We aimed at evaluating the frequency and location of multiple PFEs and the reliability of transthoracic (TTE) and transoesophageal (TEE) echocardiography in diagnosing multiple PFEs. Twenty-six consecutive patients (52±14years, 65% males) with pathologically confirmed PFE had 21 PFEs diagnosed by TTE, 33 by TEE, and 62 at surgery. Eight patients (31%) had multiple PFEs found either by TEE or at surgery. Aortic valve was involved in 75% of patients with multiple PFEs and left ventricle in 38% of patients. The sensitivity of TTE in diagnosing any PFEs was 51.3% and 76.9% for TEE. Our study emphasizes the high frequency of multiple PFEs, the need of TEE for all presumed PFE and the need for careful assessment of left-sided endocardial surfaces, especially of the aortic valve, during PFE excision. [ABSTRACT FROM AUTHOR]

Background: Latent obstruction in hypertrophic cardiomyopathy (HCM) have clinical and prognostic consequences. Baseline obstruction impairs hemostatic properties of von Willebrand factor (VWF) in HCM. Objectives: We sought to assess the acute effect of exercise-induced obstruction on VWF in patients with latent obstruction, and the determinants of obstruction and VWF impairment. Methods: A comprehensive echocardiography was performed at rest and during exercise in 32 patients with HCM. Sixteen patients (44±16 years) with latent obstruction (baseline peak gradient < 30 mmHg and exercise peak gradient≥30 mmHg) were matched with 16 patients without obstruction. Maximal peak gradient was recorded; the type and duration of obstruction during exercise were characterized by an obstruction score. Blood was sampled before and after exercise. Results: Baseline median [25-75th percentiles] peak gradient was 8[6-11] mmHg, and rose up to 32[17-104] mmHg with exercise. Baseline predictors of exercise-induced obstruction (R_ of the model 0.66) were incomplete SAM (r=0.76, p<0.0001) and mitral S velocity (r=0.34, p=0.004). At rest, VWF function was modestly impaired in patients with latent obstruction. VWF-collagen binding activity to antigen ratio (VWF:CB/Ag) and the percentage of high molecular weight multimers of VWF (%HMWM) did not change after exercise in the non obstructive group but were lowered in patients with latent obstruction (both p=0.003). Incomplete SAM at rest was the strongest independent predictor of%HMWM drop (r=-0.70, p<0.0001). %HMWM after exercise tightly correlated with exercise peak gradient (r=-0.78, p<0.0001) and the persistence of obstruction during recovery (r=-0.67, p=0.005). Conclusion: Incomplete SAM and mitral S velocity at rest are the main predictors of latent obstruction in HCM. Latent obstruction elicits a rapid cleavage of the largest multimers of VWF which is related to the peak gradient but also to the persistence of obstruction during recovery. [Copyright &y& Elsevier]

Our objectives were to identify MVP causative genes using familial approach, to assess MVP phenotype and to determine the molecular and cellular mechanisms involved in the pathology. The family was identified after one member underwent valve surgery for Barlow-type MVP. Exome sequencing in 3 affected coupled to IBD analysis identified a rare variant (MAF<0,001) (chr1(GRCh37): g.44044896C>G (p.Ile328Met) in PTPRF gene. Out of 16 mutated patients, 12 (75%) had a MVP (7 bileaflet and 5 posterior leaflet MVP) and 3 (19%) abnormal anterior coaptation. Phenotype assessed by echocardiography showed elongated and significantly thickened mitral leaflets. PTPRF alternative splicing gives rise to several isoforms in humans. The longest isoform encodes the LAR receptor involved in neuronal development and axon guidance. LAR is a repressor of cell migration and proliferation, participates in adherens junctions, modulates small GTPases activity by interacting with the Rho/Rac regulator Trio and inhibits EGF/FGF signaling. It also interacts with Heparan Sulfates Proteoglycans (HSPGs) involved in cell-cell and cell-matrix adhesion. PTPRF thus appeared as a good MVP causing candidate gene. However, the identified mutation (I328M) only targets the short isoform (sPTPRF) whose structure, expression profile and functions remain unknown. We showed here by RT-PCR in mitral valve tissue that sPTPRF is expressed in human mitral valve together with the longest PTPRF isoform encoding LAR. Re-expression study in Hek293 cells revealed the sPTPRF isoform interacts with HSPGs. PTPRF protein stability experiments evaluated by western blotting after cycloheximide treatment showed that the I328M mutation decreases the protein stability.Our results suggest a potential loss of function mutation in PTPRF-short isoform in autosomal dominant Barlow's disease. The precise role of the mutation on cell proliferation, cytokine (EGF-TGFβ) signaling and cell matrix interaction remains to be elucidated. The author hereby declares no conflict of interest [ABSTRACT FROM AUTHOR]

Background Heart failure (HF) symptoms, related to pulmonary capillary hypertension, are frequent in hypertrophic cardiomyopathy (HCM). Pulmonary hypertension (PH) is the consequence of left ventricular (LV) diastolic pressure elevation and/or functional mitral regurgitation. We aimed to evaluate determinants and prognostic significance of rest and exercise PH in HCM. Methods and Results We included 235 patients referred for clinical work-up of HCM. Rest pulmonary artery systolic pressure (PASP) was measurable in 214 (91%) patients (48±16 years, 161 males). A symptom-limited semi-supine bicycle exercise was carried out in 188 patients. PASP was measurable during exercise in 108 patients (57%). Resting PH (≥36mm Hg) was present in 56 patients (26.2%) and exercise PH (≥60mm Hg) in 38 patients (35.2%). Mutivariate correlates of rest PASP were sinus rhythm (β= –0.15, P=0.021), LV obstruction tract (LVOT) peak gradient (β= 0.22, P=0.001) and left atrial volume (β= 0.39, P<0.0001). Multivariate resting correlates of exercise PASP were PASP (β=0.28, p=0.001) and mitral regurgitation (MR) grade (β=0.48, P<0.0001). LVOT peak gradient emerged as an independent correlate of exercise PASP when MR was excluded. Patients with rest PH had a worse event-free survival at 4 years (24.8 ± 8.8 vs 66.2 ± 5.2%, P < 0.0001), survival without HF (55.6 ± 10.5 vs 81.8 ± 4.3%, P = 0.005), and overall survival (84.2 ± 7.1 vs 97.1 ± 1.7%, P = 0.001). Patients with exercise PH had also a worse event-free survival (47.7 ± 9.5 vs 65.7 ± 7.5%, P = 0.007) and a worse survival without HF (64.1 ± 9.4 vs 83.4 ± 5.5%, P = 0.016). By contrast, there was no difference regarding overall survival (p = 0.49). Conclusion In patients with HCM, the main determinants of rest PH are sinus rhythm, LVOT peak gradient and left atrium volume. Determinants of exercise PH are rest PASP, grade of MR and rest LVOT gradient. Rest and exercise PH predict a poor outcome in HCM. [ABSTRACT FROM AUTHOR]

Mitral valve prolapse (MVP) affects 2-4% of the general population and remains one of the most frequent indications for valvular surgery. So far, the only gene described in MVP, with an X-linked form of inheritance, is FLNA but only represents a small part of MVP. To this respect, we investigated a french MVP pedigree to uncover new molecular insights associated to the disease. We focus on a family of 5 affected patients characterized by a dysmorphic myxomatous phenotype with 2 operated patients. From 4 MVP patients, we performed a Whole Exome Sequencing screening. From bioinformatics analysis, we focused on rare (MAF<0.1%) functional variants shared by the 4 affected patients. Among 25 variants of interest, 11 were novel. One of them, found in a highly conserved residue (GERP=4.88), in DOCK1 (c.4646G>A; p. R1549Q) co-segregates in all affected members in the family. DOCK1 is highly expressed in the mitral valve as evidenced by RNA sequencing experiments using human mitral valve tissue. DOCK1 , encodes an atypical Rac exchange factor, Dock180, which acts as a guanine exchange factors (GEF) for small Rho family G proteins. Interestingly, Sanematsu et al. (2010) described a major role of Dock180 during cardiovascular development. Mitral valves of Dock1 depleted mice are thickened and lead to blood retention in left atrium. We currently investigate repercussions of p. R1549Q (located in GEF activity domain of Dock180) on Dock180 activity in the cellular adhesion phenotype (XCELLigence; IF assays) and GEF activity (Pull-Down assays) using a heterologous transfection system. Finally, a cohort of 285 MVP affected patients is screened to evaluate the prevalence of DOCK1 in the disease. This study reports a familial approach, coupled to an exome sequencing strategy which identifies a novel DOCK1 missense mutation associated with MVP phenotype. In vivo previous studies and cellular mechanisms learning will allow us to better understand mechanisms involved in the MVP pathogenesis. [ABSTRACT FROM AUTHOR]

Heart valves diseases affect 3% of world population, and surgery is often the only therapeutic mean. A genetic study performed on a family in which several members exhibited a MVP identified a R94G mutation on LRRFip1 gene. LRRFip1 alternative transcription splicing gives rise to five isoforms in humans, three of which are targeted by the mutation (Iso1, 3 and 4). Previous studies only focused on LRRFip1-iso5 that was first described as a transcription factor interacting with positive (Dishevelled) and negative (Flightless-1) regulators of the canonical Wnt β-catenin dependant pathway. As it may participate and regulate crucial events of cardiac valve development and homeostasis involving Wnt pathway, we hypothesised that LRRFip1 could be involved in MVP pathology. We first analysed the expression of LRRFip1 in valves by RNA sequencing and quantitative PCR and showed that LRRFip1- iso1 is expressed in human valves. In mouse, it prevails during embryonic development and then levels down to that other isoforms expression. We thus focused on LRRFip-iso1. Using cell fractionation, we showed a nuclear localization of LRRFip1-iso1 while other isoforms are strictly cytoplasmic. Using luciferase-based Wnt reporter assays and co-IP, we further demonstrated that out of the five isoforms, LRRFip1-iso1 is the strongest interactor of Dvl-1 and Fli-1, and the strongest activator of the canonical Wnt pathway. Although activation requires beta-catenin, it does not involve beta-catenin stabilization nor activation. Using site directed mutagenesis, we mapped the domain responsible for Wnt pathway activation to the 25 amino-acids region surrounding arginine 94 and showed that R94G mutation also decreases Wnt activation. This work demonstrates the involvement of LRRFip1-iso1 in canonical Wnt pathway activation. Taken together, our results suggest a potential role for LRRFip1 in valvulogenesis and/or valve homeostasis regulation that may be impeded by the R94G mutation. [ABSTRACT FROM AUTHOR]

The mitral valve prolapse (MVP) is a common cardiac disorder which affects 2-4% of the population and remains one of the most frequent indications for valvular surgery. The familial nature of MVP has been proposed for many years and so far, FLNA remains the only identified gene. Recently, it has been shown that FLNA mutations deregulate the RhoA/ Rac1 GTPases balance and provided evidences for a role of the Rac1 specific GTPase activating protein, FilGAP, in this network. FilGAP is a recognized FlnA-binding RhoGTPase-activating protein. Giving the tight interactions of FlnA and FilGAP, we first tested, using a candidate gene approach, the hypothesis that FilGAP, encoded by ARHGAP24 , could be involved in MVP. We have sequenced ARHGAP24 in 95 MVP operated patients and identified 3 rare missense mutations in highly conserve residues (FilGAP p.R95Q; p.P417H and p.T481M). One mutation was novel and the 2 others present a minor allele frequency lower than 0.1% in EVS. Moreover, p.T481M co-segregates with the pathology in a family with 3 affected patients. We then investigated the impact of these mutations in HEK293 cells. The role of FilGAP is to decrease Rac1 activity and thus to regulate cell processes involved in actin cytoskeleton properties as adhesion, protrusion and intracellular dynamics. From pull-down assays, we have shown that FilGAP mutations alter Rac1 GTPase activity and significantly decrease the FilGAP interaction with the active form of Rac1 (p<0.01). We have also shown, using the XCELLigence system, that cell adhesion and spreading was significantly increased with mutated FilGAP (p<0.01). Our results indicate that ARHGAP24 variants are loss-function mutations. Moreover, we demonstrate that FilGAP mutations alter the downstream signaling pathway by two different mechanisms. FilGAP p.P417H and p.T481M decrease the interaction with FlnA while p.R95Q impacts the plasma membrane anchorage. This work reinforces the involvement of GTPases pathway in MVP pathogenesis. [ABSTRACT FROM AUTHOR]

Objectives Pevalence, determinants and prognosis value of right ventricular (RV) ejection fraction (EF) in organic mitral regurgitation (MR). Methods Two-hundred eight pts (62±13 years, 138 males, AF 57 pts) with organic MR referred to surgery underwent an echocardiography and left ventricular (LV) and RV radionuclide angiography. LV and RV regional function was assessed. Results Mean RV EF was 40.7±10.1%, ranging from 10 to 65%. Sixty pts (29%) had a RV EF ≤35%. In multivariate analysis, LV septal function (LV EF 8: β=0.56, P<0.0001; LV EF 9: β=0.22, P=0.046), LV EDD index (β=-0.27, P<0.0001) and PASP (r=-0.19, P=0.008) were predictors of RVEF. In the subgroup with MR quantitation (n=85) predictor of RV EF was mitral ERO (β=-0.30, P=0.007). After surgery, RV EF increased strongly (27.5±4.3 to 37.9±7.3, P<0.0001) in pts with preoperative RV EF ≤35% while it did not change in pts with RV EF>35% (46.0±6.9 to 46.1±8.2, P=0.91). Independent predictors of postoperative RV EF were preoperative RV EF (β=0.32, P=0.013) and TR ≥grade 2 (β=–0.22, P=0.036) while LV septal function (LV EF 8, β=0.24, P=0.069) was marginally predictive. Fifty-seven pts died during post-operative follow-up of 7.1±4.3 years. Pts with RV EF ≤35% compared with RVEF>35% had a similar survival rate at 10 years (63.6±8.7% versus 68.8±5.3%, P=0.68), but cardiovascular mortality was higher (25.3±8.0% versus 8.1±3.5%, P=0.03; HR=2.67, 95% CI 1.06-6.76, P=0.037). RV EF was not a predictive factor of operative mortality. In a Cox model, NYHA class, CABG, and left atrial diameter, but not RV EF, were independent predictors of overall mortality. Conclusion In organic MR RV function depends not only on PASP but mainly on LV remodeling and septal function, and improves strongly after surgery. RV EF is a predictor of cardiovascular mortality in univariate but not in multivariate analysis. Hence, impaired RV EF before surgery is not a sufficient argument to deny surgery in patients with organic MR. [ABSTRACT FROM AUTHOR]

Background: Left atrial (LA) enlargement is a consequence of organic mitral regurgitation (MR) but its association with clinical outcome independently of MR severity is uncertain. Objectives: To assess the link between LA volume at diagnosis and outcome of patients with MR. Methods: We prospectively enrolled 492 patients (63±15 years, 60% males) in sinus rhythm with organic MR (RVol. 68±42mL/beat) and performed triple echocardiographic quantitation (MR severity, LA volume and left ventricular characteristics). Outcome with medical and surgical management were analyzed. Results: LA volume indexed to body surface area (LA-index) was 55±26mL/m2 (<40ml/m2 in 158, 40–59ml/m2 in 160 and 60ml/m2 in 174 patients). Under medical management, 5-year survival was 80±2.9% and cardiac events 28±3%. Adjusting for established predictors of outcome, LA-index was independently associated with survival after diagnosis (HR1.3[1.1–1.5] per 10ml/m2 increment, P=0.001). Patients with LA-index 60mL/m2 had lower 5-year survival than those with no or mild LA enlargement (P<0.0001) and than survival expected in US population (53±8.6% versus 76%, P=0.017). Compared to patients with LA-index <40ml/m2, those with LA-index 60mL/m2 had increased mortality (HR2.8[1.2–6.5], P=0.016) and cardiac events (HR5.2[2.6–10.9], P<0.0001) with medical management. Mitral surgery was associated with decreased mortality (HR 0.46[0.26–0.84], P=0.01) and cardiac events (HR 0.38[0.23–0.62] P=0.0001). After surgery patients with LA-index 60mL/m2 did not incur excess mortality or cardiac events (P>0.30). Conclusion: In organic MR, LA-index at diagnosis predicts long-term outcome, incrementally to known predictors of outcome. This marker of risk is particularly important because mitral surgery in these patients markedly improves outcome and restores life-expectancy. LA-index should be measured in routine clinical practice for risk-stratification and for clinical decision making in patients with organic MR. [Copyright &y& Elsevier]

Purpose: There is a paucity of data regarding consequences of mitral stenosis (MS) on respiratory function and exercise capacity. In view of frequent discrepancies between symptoms and anatomy in MS, identification of determinants of aerobic capacity could be useful in the clinical-decision making process. Our objective was to evaluate the role of cardiac and pulmonary alterations on aerobic capacity in MS. Methods: Twenty-eight patients (53±7 y) with history of MS were prospectively included. A comprehensive echocardiography was performed at rest and during exercise. Right ventricular (RV) systolic function was assessed with tricuspid lateral annulus S wave velocity (STric). Respiratory function was assessed at rest with measure of transfer of carbon monoxide (DLCO). We analyzed the two components of DLCO: membrane diffusion (DM) and capillary volume (VCAP). Maximal oxygen uptake (VO2max) was determined during cardio-pulmonary exercise test. Results: Ten patients were examined before (native MS group) and 18 after corrective treatment (treated MS group). The mitral valve functional area (MVA) was 1.3±0.3 cm2 in native MS group and 1.6±0.1 cm2 in treated MS group. Overall, NYHA class was 1.8±0.3, VO2max 18±3 ml/kg/min, maximal workload 85±13 Watts. There were no differences between groups in NYHA class, maximal workload, VO2max, trans-mitral and trans-tricuspid gradients and DLCO. DM and VCAP were impaired in patients with a history of MS. In univariate analysis determinants of VO2max were gender (r=0.6, p=0.001), DM (r=0.65, p=0.04), VCAP (r=0.69, p=0.001), exercise cardiac output (r=0.55, p=0.003), and exercise STric (r=0.56, p=0.008). In multivariate analysis, independent determinants of VO2max were exercice STric (r=0.55, p=0.005) and VCAP (r=0.46, p=0.01). Conclusion: DM and VCAP are impaired in MS. RV contractile reserve and VCAP are the main determinants of aerobic capacity in MS. Theses parameters could be used in the clinical-decision making process in MS. [Copyright &y& Elsevier]

Background: Thrombo-embolic events (TE) are frequent after mechanical mitral valve replacement (MVR) but their association to anticoagulation quality is unclear and was never studied in a population-based setting with complete anticoagulation record. Methods: We compiled complete record of all residents of Olmsted County, MN, who underwent mechanical MVR between 1981 and 2004, for all TE, bleedings and international normalized ratios (INR) measured from prosthesis implantation. Results: In the 112 residents (57±16 years, female 60%) who underwent mechanical MVR, 19,647 INR samples were obtained. While INR averaged 3.02±0.57, almost 40% of INR were below 2 or above 4.5. Thirty-four TE and 28 bleedings occurred during 8.2±6.1 years follow-up. There was no trend of association of INR (average, standard deviation-SD, growth variance rate or intensity specific incidence of events) with TE. Previous cardiac surgery (P=0.014), and ball prosthesis (2.92[1.43–5.94], P=0.003) independently determined TE. With MVR-ball, despite higher anticoagulation intensity (p=0.002), 8-year freedom from TE was considerably lower (50±9 vs. 81±5%, p<0.0001). Compared to expected stroke rates in the population, stroke-risk was elevated with non-ball MVR (2.6[1.3-5.2], P=0.007) but considerable with MVR-ball (11.7[7.5-18.4], P<0.0001). INR-variability (SD) was higher with higher INR-average (p<0.0001). INR-variability (2.48[1.11-5.55], P=0.027) and cancer history (P<0.0001) independently determined bleeding rates. Conclusion: This population-based comprehensive study of anticoagulation and TE post-MVR shows that in these closely anticoagulated patients, anticoagulation intensity is highly variable and not associated with TE incidence post-MVR. Higher anticoagulation intensity is linked to higher variability and thus to bleeding. The MVR-ball design is associated with higher TE rates notwithstanding higher anticoagulation intensity and should be retired worldwide. [Copyright &y& Elsevier]