NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.

BACKGROUND: Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. METHODS: C57BL/6 mice lacking ApoE , NOS3, and/or MMP13 were fed with a high-fat diet for 6 weeks. Entire aortas were extracted and frozen to analyze protein and nucleic acid expression. Atherosclerotic plaques were detected by ultrasound imaging, Oil Red O (ORO) staining, and Western Blot. RNA-seq and RT-qPCR were performed to evaluate EMMPRIN, MMP-9, and EMMPRIN-targeting miRNAs. Mouse aortic endothelial cells (MAEC) were incubated to assess the role of active MMP-13 over MMP-9. One-way ANOVA or Kruskal-Wallis tests were performed to determine statistical differences. RESULTS: Lack of NOS3 in ApoE null mice fed with a high-fat diet increased severe plaque accumulation, vessel wall widening, and high mortality, along with EMMPRIN-induced expression by upregulation of miRNAs 46a-5p and 486-5p. However, knocking out MMP-13 in ApoE/NOS3 -deficient mice was sufficient to prevent mortality (66.6 vs. 26.6%), plaque progression (23.1 vs. 8.8%), and MMP-9 expression, as confirmed in murine aortic endothelial cell (MAEC) cultures, in which MMP-9 was upregulated by incubation with active recombinant MMP-13, suggesting MMP-9 as a new target of MMP-13 in atherosclerosis. CONCLUSION: We describe a novel mechanism by which the absence of NOS3 may worsen atherosclerosis through EMMPRIN-induced ECM proteolytic degradation by targeting the expression of miRNAs 146a-5p and 485-5p. Focusing on NOS3 regulation of ECM degradation could be a promising approach in the management of atherosclerosis.

Transcatheter Tricuspid Annuloplasty in a Patient With Very Long Segment of Right Coronary Artery Proximity.

A 78-year-old woman with severe symptomatic secondary atrial tricuspid regurgitation and a long segment of right coronary artery proximity in the posterior tricuspid annulus was treated with transcatheter annuloplasty. Six consecutive anchors were implanted at the level of the atrial wall, crossing the right coronary artery, achieving residual mild regurgitation. (Level of Difficulty: Advanced.).

Contemporary Outcomes Following Transcatheter Edge-to-Edge Repair: 1-Year Results From the EXPAND Study.

BACKGROUND: The third-generation MitraClip NTR/XTR transcatheter edge-to-edge repair system was introduced to assist in leaflet grasping with the longer clip arms of MitraClip XTR and to improve ease of use with the modified delivery catheter. OBJECTIVES: The EXPAND study evaluated contemporary real-world outcomes in subjects with mitral regurgitation (MR) treated with the third-generation MitraClip NTR/XTR transcatheter edge-to-edge repair system. METHODS: EXPAND is a prospective, multicenter, international, single-arm study that enrolled patients with primary MR and secondary MR at 57 centers. Follow-up was conducted through 12 months. Echocardiograms were analyzed by an echocardiographic core laboratories. Study outcomes included: MR severity, functional capacity measured by New York Heart Association functional class, quality of life measured by Kansas City Cardiomyopathy Questionnaire, heart failure hospitalizations, all-cause mortality. RESULTS: 1,041 patients were enrolled from April 2018 through March 2019, of which 50.5% had primary or mixed etiology. Implant success was 98.9%; 1.5 ± 0.6 clips were implanted per subject. Significant MR reduction from baseline (≥MR 3+: 56.0%) to 30 days (≤MR 1+:88.8%) was maintained through 1 year (MR ≤1+: 89.2%). A total of 84.5% and 93.0% of subjects in primary MR and secondary MR, respectively, had ≤1+ MR at 1 year. Significant improvements were observed in clinical outcomes (New York Heart Association functional class I/II in 80.3%, +21.6 improvement in Kansas City Cardiomyopathy Questionnaire score) at 1 year. All-cause mortality and heart failure hospitalizations at 1 year were 14.9% and 18.9%, respectively, which was significantly lower than previous studies. CONCLUSIONS: The study demonstrates treatment with the third-generation system resulted in substantial reduction of MR in a contemporary real-world practice, compared with the results of earlier EVEREST and COAPT trials.(The MitraClip® EXPAND Study of the Next Generation of MitraClip® Devices [EXPAND]; NCT03502811).

Transcatheter edge-to-edge repair for secondary mitral regurgitation with third-generation devices in heart failure patients - results from the Global EXPAND Post-Market study.

AIMS: Mitral valve transcatheter edge-to-edge repair is a guideline-recommended treatment option for patients with secondary mitral regurgitation (SMR). The purpose of this analysis was to report contemporary real-world outcomes in SMR patients treated with third-generation MitraClip systems. METHODS AND RESULTS: EXPAND is a prospective, multicentre, international, single-arm study with 1041 patients treated for mitral regurgitation (MR) with MitraClip NTR/XTR, with 30-day and 1-year follow-up. All echocardiograms were analysed by an independent echocardiographic core lab. Study outcomes included procedural outcomes, durability of MR reduction, and major adverse events including all-cause mortality and heart failure hospitalizations (HFH). A subgroup of 413 symptomatic patients (age 74.7 ± 10.1 years, 58% male) with severe SMR were included. MR reduction to MR ≤ 1+ and MR ≤ 2+ was achieved in 93.0% and 98.5% of patients, respectively, which was sustained at 1-year follow-up. All-cause mortality was 17.7% at 1-year- follow-up, and the combined endpoint of all-cause mortality or first HFH occurred in 34% of patients. This combined endpoint was significantly less frequently observed in MR ≤ 1+ patients (Kaplan-Maier estimates: 29.7% vs. 69.6% for MR ≤ 1+ vs. MR ≥ 2 +; p < 0.0001). New York Heart Association (NYHA) functional class improved significantly from baseline (NYHA ≤ II: 17%) to 1-year follow-up (NYHA ≤ II: 78%) (p < 0.0001). While MR reduction was comparable between NTR-only vs. XTR-only treated patients, less XTR clips were required for achieving MR reduction. CONCLUSIONS: Under real-world conditions, optimal sustained MR reduction to MR ≤ 1+ was achieved in a high percentage of patients with third-generation MitraClip, which translated into symptomatic improvement and low event rates. These results appear to be comparable with recent randomized clinical trials.

Safety and efficacy of MitraClip in acutely ill (NYHA Class IV) patients with mitral regurgitation: Results from the global EXPAND study.

AIM: Patients with severe mitral regurgitation (MR) and acute heart failure (HF) have refractory symptoms without adequate response to medical therapy. The objective of this analysis was to assess the impact of the MitraClip device in acutely ill HF patients, characterized by NYHA Class IV at baseline, in a real-world, contemporary setting. METHODS AND RESULTS: EXPAND was a prospective, multicenter, international study enrolling patients with MR who consented to receive the MitraClip System at 57 sites globally. The study outcomes included acute procedural success (APS), quality of life, heart failure hospitalizations (HFH), and all-cause mortality. The study population comprised 1,041 patients, with 118 patients having baseline NYHA Class IV, and 922 having baseline NYHA Class I/II/III. NYHA Class IV patients had a significantly higher rate of baseline co-morbidities and secondary MR aetiology compared with NYHA Class I/II/III patients. APS was achieved in 92.4% of NYHA Class IV patients and significant improvement in MR grade to ≤Mild (1+) in 90.7% of subjects at 30 days and 92.9% at 1 year was observed. 1-year-mortality was higher in the NYHA Class IV subjects compared with the NYHA Class I/II/III subjects (29.2% vs. 17.7%, P < 0.01). Significant improvement in functional capacity assessed by NYHA Functional Class and Quality of Life assessed through KCCQ score was observed. At 1 year, 72.6% of NYHA Class IV subjects improved to NYHA Class I/II and ΔKCCQ was 31.2 (24.1, 38.3) compared with baseline. CONCLUSION: In the prospective, real-world EXPAND study, MitraClip in patients with severe MR and NYHA Class IV was found to be safe and effective in treating MR, and significantly improving QoL and long-term clinical outcomes.

Prevalence and Prognostic Implications of Moderate or Severe Mitral Regurgitation in Patients with Bicuspid Aortic Valve.

BACKGROUND: Significant (moderate or greater) mitral regurgitation (MR) could augment the hemodynamic effects of aortic valvular disease in patients with bicuspid aortic valve (BAV), imposing a greater hemodynamic burden on the left ventricle and atrium, possibly culminating in a faster onset of left ventricular dilation and/or symptoms. The aim of this study was to determine the prevalence and prognostic implications of significant MR in patients with BAV. METHODS: In this large, multicenter, international registry, a total of 2,932 patients (mean age, 48 ± 18 years; 71% men) with BAV were identified. All patients were evaluated for the presence of significant primary or secondary MR by transthoracic echocardiography and were followed up for the end points of all-cause mortality and event-free survival. RESULTS: Overall, 147 patients (5.0%) had significant primary (1.5%) or secondary (3.5%) MR. Significant MR was associated with all-cause mortality (hazard ratio [HR], 2.80; 95% CI, 1.91-4.11; P < .001) and reduced event-free survival (HR, 1.97; 95% CI, 1.58-2.46; P < .001) on univariable analysis. MR was not associated with all-cause mortality (adjusted HR, 1.33; 95% CI, 0.85-2.07; P = .21) or event-free survival (adjusted HR, 1.10; 95% CI, 0.85-1.42; P = .49) after multivariable adjustment. However, sensitivity analyses demonstrated that significant MR not due to aortic valve disease retained an independent association with mortality (adjusted HR, 1.81; 95% CI, 1.04-3.15; P = .037). Subgroup analyses demonstrated an independent association between significant MR and all-cause mortality for individuals with significant aortic regurgitation (HR, 2.037; 95% CI, 1.025-4.049; P = .042), although this association was not observed for subgroups with significant aortic stenosis or without significant aortic valve dysfunction. CONCLUSIONS: Significant MR is uncommon in patients with BAV. Following adjustment for important confounding variables, significant MR was not associated with adverse prognosis in this large study of patients with BAV, except for the patient subgroup with moderate to severe aortic regurgitation. In addition, significant MR not due to aortic valve disease demonstrated an independent association with all-cause mortality.

European survey on valvular heart disease clinical experience from the European Society of Cardiology council on valvular heart disease.

Aims: The aim of this survey is to analyze how current recommendations on valvular heart disease (VHD) management have been adopted. Identifying potential discrepancies between recommendations and everyday clinical practice would enable us to better understand and address the remaining challenges in this controversial and complex field. Methods and results: A total of 33 questions, distributed via email to all European Society of Cardiology (ESC) affiliated countries through the newsletter of the ESC council on VHD, were answered by 689 respondents, mainly from tertiary care settings. The results of this survey showed that VHD patients are mostly managed by tertiary care centres, where multi-disciplinary heart teams are frequently a reality. Cardiac computed tomography (CT) is often used in the preprocedural planning of transcatheter interventions, particularly for sizing and deliverability assessment. Echocardiography represents the most widely used imaging modality in the diagnostic, intra-operative and follow-up phase of VHD patients. Cardiac magnetic resonance (CMR) is still largely underused, also for conditions such as mitral annular disjunction, or for the assessment of left ventricle volumes where it is considered as the gold standard, despite 3D volumes by echocardiography having proved good comparability with CMR. As for endocarditis, despite still underused, transesophageal echocardiography (TEE) represents the approach of choice for the diagnosis of native and prosthesis valve endocarditis (up to 46% of the respondents use it). In this context, positron emission tomography-CT is largely underused. Conclusion: There is widespread adoption of current recommendation on the evaluation of VHD and these are frequently used to guide patient management. Nonetheless, there are still many discrepancies across centres and countries which need to be addressed with the aim of improving patients' management and outcomes and ultimately positively impacting on healthcare resources.

Impact of Left Ventricular Ejection Fraction on Clinical Outcomes in Bicuspid Aortic Valve Disease.

BACKGROUND: The prognostic impact of left ventricular ejection fraction (LVEF) in patients with bicuspid aortic valve (BAV) disease has not been previously studied. OBJECTIVES: The purpose of this study was to determine the prognostic impact of LVEF in BAV patients according to the type of aortic valve dysfunction. METHODS: We retrospectively analyzed the data collected in 2,672 patients included in an international registry of patients with BAV. Patients were classified according to the type of aortic valve dysfunction: isolated aortic stenosis (AS) (n = 749), isolated aortic regurgitation (AR) (n = 554), mixed aortic valve disease (MAVD) (n = 190), or no significant aortic valve dysfunction (n = 1,179; excluded from this analysis). The study population was divided according to LVEF strata to investigate its impact on clinical outcomes. RESULTS: The risk of all-cause mortality and the composite endpoint of aortic valve replacement or repair (AVR) and all-cause mortality increased when LVEF was <60% in the whole cohort as well as in the AS and AR groups, and when LVEF was <55% in MAVD group. In multivariable analysis, LVEF strata were significantly associated with increased rate of mortality (LVEF 50%-59%: HR: 1.83 [95% CI: 1.09-3.07]; P = 0.022; LVEF 30%-49%: HR: 1.97 [95% CI: 1.13-3.41]; P = 0.016; LVEF <30%: HR: 4.20 [95% CI: 2.01-8.75]; P < 0.001; vs LVEF 60%-70%, reference group). CONCLUSIONS: In BAV patients, the risk of adverse clinical outcomes increases significantly when the LVEF is <60%. These findings suggest that LVEF cutoff values proposed in the guidelines to indicate intervention should be raised from 50% to 60% in AS or AR and 55% in MAVD.

Serum microRNAs are key predictors of long-term heart failure and cardiovascular death after myocardial infarction.

BACKGROUND: Patients with acute myocardial infarction (MI) are at high risk of upcoming events, in particular heart failure (HF), but reliable stratification methods are lacking. Our goal was to evaluate the potential role of circulating miRNAs as prognostic biomarkers in patients presenting with MI. METHODS AND RESULTS: We conducted a prospective study among 311 consecutive patients hospitalized with MI (65% ST-segment elevation MI & median age of 55 years) with long-term follow-up. An initial screening was conducted to select candidate miRNAs, with subsequent study of 14 candidate miRNAs. The primary outcome was the composite of hospital admission for HF or cardiovascular death. During a mean follow-up of 2.1 years miR-21-5p, miR-23a-3p, miR27b-3p, miR-122-5p, miR210-3p, and miR-221-3p reliably predicted the primary outcome. Multivariate Cox regression analyses highlighted that miR-210-3p [hazard ratio (HR) 2.65 per 1 SD increase, P < 0.001], miR-23a-3p (HR 2.11 per 1 SD increase, P < 0.001), and miR-221-3p (HR 2.03 per 1 SD increase, P < 0.001) were able to accurately predict the primary outcome, as well as cardiovascular death, HF hospitalizations, and long-term New York Heart Association (NYHA) functional class. These three miRNAs clearly improved the performance of multivariate clinical models: ΔC-statistic = 0.10 [95% confidence interval (CI), 0.03-0.17], continuous net reclassification index = 34.8% (95%CI, 5.8-57.4%), and integrated discrimination improvement (P < 0.001). CONCLUSIONS: This is the largest study evaluating the prognostic value of circulating miRNAs for HF-related events among patients with MI. We show that several miRNAs predict HF hospitalizations, cardiovascular mortality, and poor long-term NYHA status and improve current risk prediction methods.

Cardiac troponin T and NT-proBNP for detecting myocardial ischemia in suspected chronic coronary syndrome.

BACKGROUND: Elevated N-terminal pro-B-type natriuretic peptides (NT-proBNP) and cardiac troponin T (cTnT) are associated with poor outcome in patients with chronic coronary syndrome (CCS). The performance of these biomarkers in diagnosing ischemia, and their association with myocardial hypoperfusion and hypokinesis is unclear. METHODS: Patients with suspected CCS (history of angina, estimated cardiovascular risk >15% or a positive stress test) were included in the prospective, multi-center DOPPLER-CIP study. Patients underwent Single Positron Emission Computed Tomography for assessment of ischemia and NT-proBNP and cTnT were measured in venous blood samples. RESULTS: We included 430 patients (25% female) aged 64 ± 8 years. Reversible hypoperfusion and hypokinesis were present in 139 (32%) and 89 (21%), respectively. Concentrations of NT-proBNP and cTnT correlated moderately (rho = 0.50, p < 0.001). NT-proBNP and cTnT concentrations (median [IQR]) were higher in patients with versus without reversible ischemia: 150 (73-294) versus 87 (44-192) ng/L and 10 (6-13) versus 7 (4-11) ng/L, respectively (p < 0.001 for both), and the associations persisted after adjusting for possible confounders. The C-statistics to discriminate ischemia ranged from 63%-73%, were comparable for cTnT and NT-proBNP, and higher for hypokinesis than hypoperfusion, and both were superior to exercise electrocardiography and stress echocardiography. Very low concentrations (≤5 ng/L cTnT and ≤ 60 ng/L NT-proBNP) ruled out reversible hypokinesis with negative predictive value >90%. CONCLUSION: cTnT and NT-proBNP are associated with irreversible and reversible ischemia in patients with suspected CCS, particularly hypokinesis. The diagnostic performance was comparable between the biomarkers, and very low concentrations may reliably rule out ischemia.

Reducing residual cardiovascular risk in Europe: Therapeutic implications of European medicines agency approval of icosapent ethyl/eicosapentaenoic acid.

Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Hypertriglyceridemia, a major risk factor for premature ASCVD, is present in more than 20% of the European population, and is a key feature of atherogenic dyslipidemia. Recent findings from the Progression of Early Subclinical Atherosclerosis (PESA) cohort in Spain showed that even in apparently healthy, middle-aged individuals without a history of cardiovascular (CV) risk, elevated triglyceride levels are associated with subclinical atherosclerosis and arterial inflammation. Emerging evidence from epidemiologic and genetic studies supports an independent causative role of triglycerides, triglyceride-rich lipoproteins, and their remnants in this pathology. Icosapent ethyl (IPE) is a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) that was initially approved by the United States Food and Drug Administration to treat severe hypertriglyceridemia, and subsequently received an expanded indication to reduce the risk of CV events in adult statin-treated patients. Approval was based on the pivotal, randomized, placebo-controlled, double-blind Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), which showed that high-dose IPE (4 g/day) significantly reduced the risk of primary and secondary composite endpoints comprising major CV events and CV death relative to placebo. In 2021, the European Medicines Agency (EMA) approved IPE to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated triglyceride levels (≥1.7 mmol/L [≥150 mg/dL]) and established CV disease, or diabetes and at least one other CV risk factor. Clinical studies in Europe, which included patients with acute myocardial infarction, coronary artery disease, and those undergoing cardiac rehabilitation, established that 12.5% to 23.3% of these high-risk populations may benefit from treatment with IPE. Such clinical benefit may in part result from the moderate triglyceride-lowering properties of IPE/EPA; equally however, concentrations of atherogenic remnant particle-cholesterol are markedly reduced. Furthermore, IPE/EPA exerts pleiotropic actions beyond its lipid-lowering properties, which include modulation of endothelial function, attenuation of intra-plaque inflammation and oxidative stress, and reduction in macrophage accumulation. Plasma phospholipids, into which EPA is primarily incorporated and transported, appear to serve as precursors for a series of anti-inflammatory metabolites involving the resolvins RvE1 to RvE3, a pathway which may confer cardioprotective benefits. In addition, plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials show that plaque stabilization may be favorably affected. These factors may act synergistically to stabilize atherosclerotic plaques and reduce CV risk. In addition to robust efficacy data, multiple cost-utility studies across several countries indicate that IPE/EPA is a cost-effective treatment option that is favorably situated relative to some common willingness-to-pay thresholds. This review will evaluate the relevance of hypertriglyceridemia to residual ASCVD burden in statin-treated dyslipidemic patients, the potential of IPE/EPA to reduce the risk of ASCVD and cardiovascular mortality in high-risk patient populations, and the mechanisms which may underlie these effects. Finally, the clinical implications of the EMA label for IPE will be critically appraised in light of the updated 2019 European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidemia and the recent European Atherosclerosis Society consensus statement on triglyceride-rich lipoproteins and their remnants, together with considerations of its cost-effectiveness across several countries.

Tricuspid regurgitation: recent advances in understanding pathophysiology, severity grading and outcome.

Heightened interest in tricuspid regurgitation (TR) stems from the consistent association of mortality with greater severity of TR, and a low use of surgical solutions in the setting of high in-hospital mortality attributed to the late presentation of the disease. The delay in intervention is likely related to a limited understanding of the valvular/ventricular anatomy and disease pathophysiology, along with an underestimation of TR severity by standard imaging modalities. With the rapid development of transcatheter solutions which have shown early safety and efficacy, there is a growing need to understand and accurately diagnose the valvular disease process in order to determine appropriate management solutions. The current review will describe both normal and pathologic tricuspid valvular anatomy, the classification of these anatomic substrates of TR, the strengths and limitations of the current guidelines-recommended multi-parametric echocardiographic approach and the role of multi-modality imaging, as well as the role of transcatheter device therapy in the management of the disease.

Left ventricular remodelling in bicuspid aortic valve disease.

AIMS: Characterization of left ventricular (LV) geometric pattern and LV mass could provide an important insight into the pathophysiological adaptations of the LV to pressure and/or volume overload in patients with bicuspid aortic valve (BAV) and significant (≥moderate) aortic valve (AV) disease. This study aimed to characterize LV remodelling and its prognostic impact in patients with BAV according to the predominant type of valvular dysfunction. METHODS AND RESULTS: In this international, multicentre BAV registry, 1345 patients [51.0 (37.0-63.0) years, 71% male] with significant AV disease were identified. Patients were classified as having isolated aortic stenosis (AS) (n = 669), isolated aortic regurgitation (AR) (n = 499) or mixed aortic valve disease (MAVD) (n = 177). LV hypertrophy was defined as a LV mass index >115 g/m2 in males and >95 g/m2 in females. LV geometric pattern was classified as (i) normal geometry: no LV hypertrophy, relative wall thickness (RWT) ≤0.42, (ii) concentric remodelling: no LV hypertrophy, RWT >0.42, (iii) concentric hypertrophy: LV hypertrophy, RWT >0.42, and (iv) eccentric hypertrophy: LV hypertrophy, RWT ≤0.42. Patients were followed-up for the endpoints of event-free survival (defined as a composite of AV repair/replacement and all-cause mortality) and all-cause mortality. Type of AV dysfunction was related to significant variations in LV remodelling. Higher LV mass index, i.e. LV hypertrophy, was independently associated with the composite endpoint for patients with isolated AS [hazard ratio (HR) 1.08 per 25 g/m2, 95% confidence interval (CI) 1.00-1.17, P = 0.046] and AR (HR 1.19 per 25 g/m2, 95% CI 1.11-1.29, P < 0.001), but not for those with MAVD. The presence of concentric remodelling, concentric hypertrophy and eccentric hypertrophy were independently related to the composite endpoint in patients with isolated AS (HR 1.54, 95% CI 1.06-2.23, P = 0.024; HR 1.68, 95% CI 1.17-2.42, P = 0.005; HR 1.59, 95% CI 1.03-2.45, P = 0.038, respectively), while concentric hypertrophy and eccentric hypertrophy were independently associated with the combined endpoint for those with isolated AR (HR 2.49, 95% CI 1.35-4.60, P = 0.004 and HR 3.05, 95% CI 1.71-5.45, P < 0.001, respectively). There was no independent association observed between LV remodelling and the combined endpoint for patients with MAVD. CONCLUSIONS: LV hypertrophy or remodelling were independently associated with the composite endpoint of AV repair/replacement and all-cause mortality for patients with isolated AS and isolated AR, although not for patients with MAVD.

Transcatheter treatment for tricuspid valve disease.

Approximately 4% of subjects aged 75 years or more have clinically relevant tricuspid regurgitation (TR). Primary TR results from anatomical abnormality of the tricuspid valve apparatus and is observed in only 8-10% of the patients with tricuspid valve disease. Secondary TR is more common and arises as a result of annular dilation caused by right ventricular enlargement and dysfunction as a consequence of pulmonary hypertension, often caused by left-sided heart disease or atrial fibrillation. Irrespective of its aetiology, TR leads to volume overload and increased wall stress, both of which negatively contribute to detrimental remodelling and worsening TR. This vicious circle translates into impaired survival and increased heart failure symptoms in patients with and without reduced left ventricular ejection fraction. Interventions to correct TR are underutilised in daily clinical practice owing to increased surgical risk and late patient presentation. The recently introduced transcatheter tricuspid valve interventions aim to address this unmet need. Dedicated expertise and an interdisciplinary Heart Team evaluation are essential to integrate these new techniques successfully and select patients. The present article proposes a standardised approach to evaluate patients with TR who may be candidates for transcatheter interventions. In addition, a state-of-the-art review of the available transcatheter therapies, the main criteria for patient and device selection, and information concerning the remaining uncertainties are provided.

Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR.

BACKGROUND: The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS: We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS: A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS: In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).