Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but--even in adult life--remains dynamic and ...accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.
In light of the adverse prognosis related to severe mitral regurgitation, heart failure, or sudden cardiac death in a subset of patients with mitral valve prolapse (MVP), identifying those at higher ...risk is key. For the first time in decades, researchers have the means to rapidly advance discovery in the field of MVP thanks to state-of-the-art imaging techniques, novel omics methodologies, and the potential for large-scale collaborations using web-based platforms. The National Heart, Lung, and Blood Institute recently initiated a webinar-based workshop to identify contemporary research opportunities in the treatment of MVP. This report summarizes 3 specific areas in the treatment of MVP that were the focus of the workshop: 1) improving management of degenerative mitral regurgitation and associated left ventricular systolic dysfunction; 2) preventing sudden cardiac death in MVP; and 3) understanding the mechanisms and progression of MVP through genetic studies and small and large animal models, with the potential of developing medical therapies.
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•Severe DMR, SCD, and postoperative LV dysfunction develop in a subset of patients with MVP.•Better risk stratification is essential to improve management and prevent adverse events in patients with MVP.•Retrospective and observational cardiac imaging, genetic, and molecular studies have suggested mechanisms that may underlie adverse events, but prospective multicenter collaborations are needed to identify patients at highest risk.
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.
•ASP/cefazolin are the most effective treatment to reduce the duration of bacteraemia.•Aminoglycosides use was not associated with shorter duration of bacteraemia.•Third generation cephalosporins are ...associated with longest duration of bacteraemia.•The duration of bacteraemia was similar between patients treated by cefazolin or ASP.•Empirical treatment for MSSA IE should include cefazolin or ASP.
The empirical treatment of infective endocarditis is still debated. The aim of this study was to compare the impact of empirical treatment with antistaphylococcal penicillin (ASP) or cefazolin vs. other treatments in methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis.
A post hoc analysis of a prospective cohort study of patients hospitalized in a French reference centre with MSSA endocarditis was conducted between 2013 and 2022. The primary outcome was the duration of bacteraemia under treatment.
Of the 208 patients included, 101 patients (48.6%) were classified in the reference group (ASP or cefazolin) and 107 (52.4%) in the non-reference group. Empirical treatment with ASP/cefazolin was associated with a shorter duration of bacteraemia compared to other treatments (3.6 d vs. 4.6 d, P = 0.01). This difference was not corrected by the addition of an aminoglycoside (3.6 d vs. 4.7 d, P < 0.01). In multivariate analysis, empirical treatment with ASP/cefazolin was associated with a duration of bacteraemia ≤72 h (P = 0.02), whereas endocarditis on native valves (P = 0.01), and intracardiac abscess were associated with longer duration of bacteraemia (P = 0.01).
Empirical treatment of endocarditis with ASP or Cefazolin is more effective than other treatments in MSSA endocarditis, even when the other treatments are combined with aminoglycosides.
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Abstract
Background and aims
Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter ...intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE.
Methods
A total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years.
Results
The TRI-SCORE was low (≤3) in 32%, intermediate (4–5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P < .0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87%, and 79%, respectively, P = .0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71%, and 71%, respectively, P = .13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81%, and 71%, respectively, P = .009). In the high TRI-SCORE category, survival was not different to conservative management in the surgical and successful repair group (61% and 68% vs 58%, P = .26 and P = .18 respectively).
Conclusions
Survival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.
Structured Graphical Abstract
Structured Graphical Abstract
Comparison of the survival rates at 2 years between the different treatment modalities according to the TRI-SCORE category in patients with severe isolated functional tricuspid regurgitation.
Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the ...causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene,
A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.
Abstract
Aims
Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The ...limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique knock-in (KI) rat model for the FilaminA-P637Q (FlnA-P637Q) mutation associated-MVD.
Methods and results
Wild-type (WT) and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signalling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1 mm vs. 1.8 ± 0.1, P = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% vs. WT, P = 0.02). Histological analyses revealed a myxomatous remodelling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signalling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of transforming growth factor-β and inflammation in the disease.
Conclusion
The KI FlnA-P637Q rat model mimics human myxomatous MVD, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, response to mechanical stress, and a central contribution of immune cells are highlighted as the main signalling pathways leading to myxomatous MVD. Our findings pave the road to decipher underlying molecular mechanisms and the specific role of distinct cell populations in this context.
Graphical Abstract
Graphical Abstract
Transcatheter aortic-valve replacement (TAVR) reduces mortality and improves quality of life in patients with severe aortic valve stenosis. One third of patients have no benefit one year after TAVR. ...Sarcopenia, an age-related loss of skeletal muscle mass, is associated with increased physical disability and mortality. The main purpose was to evaluate the impact of severe sarcopenia on rehospitalization one year after TAVR in older patients.
All patients aged ≥75 referred for a TAVR in 2018 were included. Severe sarcopenia was defined by a loss of skeletal muscle mass defined on CT-scan measurement associated with a gait speed ≤0.8m/s. The main outcome was rehospitalization one year after TAVR.
Median age of the 182 included patients was 84, and 35% had an unplanned hospitalization at one year. Severe sarcopenia was diagnosed in 9 patients (4.9%). Univariable analysis showed that gait speed was a factor associated with readmission HR=0.32, 95% CI (0.10-0.97), p=0.04 but not severe sarcopenia. In multivariable analysis, only diabetes was significantly associated with rehospitalization HR=2.06, 95% CI (1.11-3.84), p=0.02. Prevalence of severe sarcopenia varied according to different thresholds of skeletal muscle mass on CT-scan.
Even though severe sarcopenia was not correlated with rehospitalization and mortality at one year after TAVR, our results emphasize the changes in the prevalence according to cutoff used. It highlights the need to define standardized methods and international threshold for sarcopenia diagnosis by CT-scan measurements, in general population and for patients with valvular heart disease.
Left atrial enlargement is frequent in degenerative mitral regurgitation (DMR), but its link to outcomes remains unproven in routine clinical practice.
The purpose of this study was to assess whether ...left atrial volume index (LAVI) measured in routine clinical practice of multiple sonographers/cardiologists is associated independently with DMR survival.
A cohort of 5,769 (63 ± 16 years, 47% women) consecutive patients with degenerative mitral valve disease, in whom LAVI was prospectively measured, was enrolled and the long-term survival was analyzed.
LAVI (43 ± 24 ml/m2) was widely distributed (<40 ml/m2 in 3,154 patients, 40 to 59 ml/m2 in 1,606, and ≥60 ml/m2 in 1,009). Overall survival throughout follow-up (10-year 66 ± 1%) was strongly associated with LAVI (79 ± 1% vs. 65 ± 2% and 54 ± 2% for LAVI <40, 40 to 59, and ≥60 ml/m2, respectively; p < 0.0001) even after comprehensive adjustment, including for DMR severity (adjusted hazard ratio HR: 1.05 95% confidence interval (CI): 1.03 to 1.08 per 10 ml/m2; p < 0.0001). Mortality under medical management was profoundly affected by LAVI (adjusted HR: 1.07 95% CI: 1.04 to 1.10 per 10 ml/mm2 and 1.55 95% CI: 1.31 to 1.84 for LAVI ≥60 ml/m2 vs. <40 ml/m2; both p < 0.0001) incrementally to adjusting variables (p < 0.0001) and in all subgroups, particularly sinus rhythm (adjusted HR: 1.25 95% CI: 1.21 to 1.28) or atrial fibrillation (adjusted HR: 1.10 95% CI: 1.06 to 1.13 per 10 ml/m2; both p < 0.0001). Thresholds of excess mortality in spline curve analysis were approximated at 40 ml/m2 in all subgroups. Survival markedly improved after mitral surgery (time-dependent adjusted HR: 0.43 95% CI: 0.36 to 0.53; p < 0.0001) but remained modestly linked to LAVI (10-year survival 85 ± 3% vs. 86 ± 2% and 75 ± 3% for LAVI <40, 40 to 59, and ≥60 ml/m2, respectively; p < 0.0001).
The frequent left atrial enlargement of DMR as measured by LAVI in routine practice displays, overall and in all subsets, a powerful, incremental, and independent link to excess mortality, which is partially alleviated by mitral surgery. Hence, LAVI measurement should be part of routine DMR evaluation and the clinical decision-making process.
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